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Full text of "Organic Chemistry vol 2"

ORGANIC 
CHEMISTRY 

VOLUME TWO 

STEREOCHEMISTRY 

AND THE CHEMISTRY 

OF NATURAL PRODUCTS 

by 

I. L. FINAR 
B.Sc, Ph.D.(LoncL), A.R.I.C. 

Senior Lecturer in Organic Chemistry, 
Northern Polytechnic, Holloway, London 







LONGMANS 



LONGMANS, GREEN AND CO LTD 
48 Grosvenor Street, London W.l 

Associated companies, branches and representatives 
throughout the world 

Second and Third 'Editions © /. L. Finar, 1959 and 1964 

First Published 19S6 
Second Impression 1958 

Second Edition 1959 
Second Impression 1960 

Third Edition 1964 



CITY OF LEEDS 

TRAINING COLLEGE 

LIBRARY. 

Acc 31 JUM 1865 

'Class...... f4l 



Printed in Great Britain by Butler & Tanner Ltd, Frome and London 



PREFACE TO THIRD EDITION 

This third edition has been revised to bring it up to date. This has been 
made possible by the information I have obtained from articles written by 
experts on important developments in their field of research. Since the 
volume of research published on topics dealt with (and not dealt with) in 
this book make it impossible to include all new work, I have therefore had 
to choose, but any deficiencies in my choice are, I hope, partly compensated 
by the reading references given at the end of each chapter. 

Chapter III has been rewritten (and renamed), but the section on transi- 
tion state theory of reactions has been omitted; it has now been included 
in Volume I (4th ed., 1963). Expanded topics include nuclear magnetic 
resonance, correlation of- configurations, conformational analysis, molecular 
overcrowding, the Beckmann rearrangement, nucleophilic substitution at a 
saturated carbon atom, elimination and addition reactions, carotenoids, 
penicillins, amino-acids, biosynthesis, etc. Some additions are rotatory 
dispersion, electron spin resonance, specification of absolute configurations, 
Newman projection formulae, neighbouring group participation, the Wagner- 
Meerwein rearrangement, sesquiterpenes, etc. 

I. L. FINAR 

1964 



PREFACE TO SECOND EDITION 

This volume has now been revised to bring it up to date; this has involved 
the expansion of some sections and the addition of new material. It may 
be useful if I indicate briefly the more important changes I have made in 
this new edition. Two major additions are conformational analysis and 
biosynthesis : in each case I have given an introduction to the problem, and 
have also discussed various applications. Some other additions are nuclear 
magnetic resonance, correlation of configurations, woflavones, and vitamin 
B 12 . Expanded topics include dipole moments, molecular rotation, optical 
isomerism, steric effects (including steric factors and the transition state, 
molecular overcrowding), ascorbic acid, structure and synthesis of chol- 
esterol, vitamin A 1( polypeptides, mechanism of enzyme action, fiavones, 
streptomycin and patulin. 

I wish to thank those reviewers and correspondents who have pointed 
out errors and have made suggestions for improving the book. 

I. L. FINAR 

1958 



VI 



PREFACE TO FIRST EDITION 

In the Preface of my earlier book, Organic Chemistry, Longmans, Green 
(1954, 2nd ed.), I expressed the opinion that the chemistry of natural pro- 
ducts is the application of the principles of Organic Chemistry. The present 
work is, in this sense, a continuation of my earlier one. It is my belief that 
a student who has mastered the principles will be well on the road to master- 
ing the applications when he begins to study them. At the same time, a 
study of the applications will bring home to the student the dictum of 
Faraday: " Ce n'est pas assez de savoir les principes, il faut savoir Mani- 
puler " (quoted by Faraday from the Dictionnaire de Trevoux). 

In the sections on Stereochemistry, I have assumed no previous know- 
ledge of this subject. This has meant a certain amount of repetition of 
some of the material in my earlier book, but I thought that this way of 
dealing with the subject would be preferable, since the alternative would 
have led to discontinuity. I have omitted an account of the stereochemistry 
of co-ordinated compounds since this subject is dealt with in textbooks 
on Inorganic Chemistry. 

The section of this book dealing with natural products has presented 
many difficulties. I have tried to give a general indication of the problems 
involved, and in doing so I have chosen, to a large extent, the most typical 
compounds for fairly detailed discussion. At the same time, I believe that 
the subject matter covered should serve as a good introduction to the 
organic chemistry required by students reading for Part II of the Special 
Honours degree in chemistry of the London University. I have given a 
selected number of reading references at the end of each chapter to enable 
students to extend their knowledge and also to make up for any omissions 
I may have made. It is impossible to express my indebtedness to those 
authors of monographs, articles, etc., from which I have gained so much 
information, and I can only hope that some measure of my gratitude is 
expressed by the references I have given to their works. 

Since physical measurements are now very much used in elucidating 
structures of organic compounds, I have included a short chapter on these 
measurements (Chapter I). I have introduced only a minimum amount 
of theory in this chapter to enable the student to understand the terms used; 
the main object is to indicate the applications of physical measurements. 

In this book, cross-references are indicated by section and chapter. If 
a cross-reference occurs to another section in that chapter, then only the 
section number is given. It should also be noted that the numbers assigned 
to formulae, etc., are confined to each section, and not carried on to sub- 
sequent sections in that chapter. When references have been given to my 
earlier volume, the latter has been referred to as Volume I. In such cases 
the pages have not been quoted since the pagination of the various editions 
changes. The student, however, should have no difficulty in locating the 
reference from the index of Volume I. 

I. L. FINAR 

1955 



Vll 



PAGE 



CONTENTS 
LIST OF JOURNAL ABBREVIATIONS .... *xii 

CHAPTER 

I. PHYSICAL PROPERTIES AND CHEMICAL 

CONSTITUTION .... 1 

Introduction, 1. Van der Waals forces, 1. The hydrogen bond, 2. 
Melting point, 3. Boiling point, 4. Solubility, 4. Viscosity, 5. 
Molecular volumes, 5. Parachor, 6. Refrachor, 7. Refractive 
index, 7. Molecular rotation, 8. Rotatory dispersion, 10. Dipole 
moments, 11. Magnetic susceptibility, 12. Absorption spectra, 13. 
X-ray analysis, 16. Electron diffraction, 17. Neutron crystallo- 
graphy, 17. Electron spin resonance, 17. Nuclear magnetic reson- 
ance, 17. 

II. OPTICAL ISOMERISM 20 

Stereoisomerism: definitions, 20. Optical isomerism, 20. The 
tetrahedral carbon atom, 21. Conformational analysis, 28. Con- 
ventions used in stereochemistry, 30. Correlation of configurations, 
34. Specification of asymmetric configurations, 35. Elements of 
symmetry, 37. Number of isomers in optically active compounds, 
40. The racemic modification, 45. Properties of the racemic modi- 
fication, 48. Methods for determining the nature of the racemic 
modification, 49. Quasi-racemate method, 50. Resolution of 
racemic modifications, 51. The cause of optical activity, 56. 

III. NUCLEOPHILIC SUBSTITUTION AT A 

SATURATED CARBON ATOM .... 60 

S N 1 and S N 2 mechanisms, 60. Factors affecting mechanism: 
Polar effects, 61. Steric effects, 63. Nature of the halogen atom, 
65. Nature of reagent, 66. Nature of solvent, 67. Walden 
Inversion, 69. Mechanism of Walden inversion, 71. S N i mechan- 
ism, 73. Participation of neighbouring groups, 74. Asymmetric 
Synthesis: Partial asymmetric synthesis, 79. Conformational 
analysis, 82. Absolute asymmetric synthesis, 85. 

IV. GEOMETRICAL ISOMERISM .... 87 

Nature of geometrical isomerism, 87. Rotation about a double 
bond, 88. Modern theory of the nature of double bonds, 88. 
Nomenclature of geometrical isomers, 89. Determination of con- 
figuration of geometrical isomers, 91. Stereochemistry of addition 
reactions, 98. Stereochemistry of elimination reactions, 100. 
Stereochemistry of Cyclic Compounds: eycZoPropane types, 105. 
cycZoButane types, 107. cye/oPentane types, 108. cj/c/oHexane 
types; conformational analysis, 109. Fused ring systems; con- 
formational analysis, 116. 

V. STEREOCHEMISTRY OF DIPHENYL 

COMPOUNDS 126 

Configuration of the diphenyl molecule, 126. Optical activity of 
the diphenyl compounds, 127. Absolute configurations of di- 
phenyls, 130. Other examples of restricted rotation, 130. Mole- 
cular overcrowding, 133. Racemisation of diphenyl compounds, 
135. Evidence for the obstacle theory, 138. Stereochemistry 

OF THE AlXENES, 139. STEREOCHEMISTRY OF THE SPIRANS, 140. 

ix 



CONTENTS 

CHAPTER PAGB 

VI. STEREOCHEMISTRY OF SOME ELEMENTS 

OTHER THAN CARBON . . 143 

Shapes of molecules, 143. Nitrogen compounds, 143. Phosphorus 
compounds, 161. Arsenic compounds, 163. Antimony compounds, 
169. Sulphur compounds, 169. Silicon compounds, 174. Tin 
compounds, 174. Germanium compounds, 174. Selenium com- 
pounds, 174. Tellurium compounds, 175. 

VII. CARBOHYDRATES 176 

Determination of the configuration of the monosaccharides, 176. 
Ring structure of the monosaccharides, 181. Methods for deter- 
mining the size of sugar rings, 187. Conformational analysis, 201. 
isoPropylidene derivatives of the monosaccharides, 203. Vitamin C, 
208. Disaccharides, 214. Trisaccharides, 223. Polysaccharides, 
224. Photosynthesis, 232. Glycosides, 234. 

VIII. TERPENES . . . 242 

Isoprene rule, 242. Isolation of terpenes, 244. General methods 
for determining structure, 244. Monoterpenes: Acyclic mono- 
terpenes, 245. Monocyclic monoterpenes, 255. Bicyclic mono- 
terpenes, 271. Correlation of configuration, 292. Sesquiterpenes: 
Acyclic sesquiterpenes, 295. Monocyclic sesquiterpenes, 297. Bi- 
cyclic sesquiterpenes, 299. Diterpenes, 308. Triterpenes, 313. 
Biosynthesis of terpenes, 314. Polyterpenes : Rubber, 317. 

IX. CAROTENOIDS 321 

Introduction, 321. Carotenes, 321. Vitamin A, 330. Xantho- 
phylls, 335. Carotenoid acids, 336. 

X. POLYCYCLIC AROMATIC HYDROCARBONS . 339 

Introduction, 339. General methods of preparation, 339. Benz- 
anthracenes, 347. Phenanthrene derivatives, 351. 

XL STEROIDS 358 

Introduction, 358. Sterols: Cholesterol, 359. Stereochemistry of 
the steroids, 376. Conformational analysis, 380. Ergosterol, 382. 
Vitamin D group, 384. Stigmasterol, 387. Biosynthesis of sterols, 
389. Bile Acids, 390. Sex Hormones : Androgens, 395. (Estro- 
gens, 398. Gestagens, 409. Adrenal Cortical Hormones, 415. 
Auxins, 418. 

XII. HETEROCYCLIC COMPOUNDS CONTAINING 

TWO OR MORE HETERO-ATOMS . . .421 

Nomenclature, 421. Azoles: Pyrazoles, 421. Imidazoles, 428. 
Oxazoles, 430. Thiazoles, 431. Triazoles, 433. Sydnones, 434. 
Tetrazoles, 436. Azines: Pyridazines, 437. Pyrimidines, 438. 
Pyrazines, 444. Benzodiazines, 445. Oxazines, 446. Phenox- 
azines, 446. Thiazines, 447. Triazines and Tetrazines, 447. 

XIII. AMINO-ACIDS AND PROTEINS . . . .449 

Classification of amino-acids, 449. General methods of preparation, 
449. Isolation of amino-acids, 457. General properties of amino- 
acids, 458. Thyroxine, 462. Proteins: General nature of 
proteins, 465. Structure of proteins, 468. Polypeptides, 471. 
Enzymes: Nomenclature, 477. Classification, 477. Conditions for 
enzyme action, 478. Biosynthesis of amino-acids and proteins, 480. 

XIV. ALKALOIDS 484 

Introduction, 484. Extraction of alkaloids, 484. General methods 
for determining structure, 485. Classification, 488. Phenylethyl- 
amine group, 489. Pyrrolidine group, 495. Pyridine group, 497. 
Pyrrolidine-Pyridine group, 504. Quinoline group, 520. isoQuino- 
line group, 533. Phenanthrene group, 537. Biosynthesis of alka- 
loids, 541. 



CONTENTS 



XI 



XV. ANTHOCYANINS 545 

Introduction, 645. General nature of anthocyanins, 545. Struc- 
ture of the anthocyanidins, 546. Flavones, 557. moFlavones, 
565. Biosynthesis of flavonoids, 566. Depsides, 566. 

XVI. PURINES AND NUCLEIC ACIDS . . .569 

Introduction, 569. Uric acid, 569. Purine derivatives, 576. 
Xanthine bases, 580. Biosynthesis of purines, 586. Nucleic 
Acids, 587. 

XVII. VITAMINS 598 

Introduction, 598. Vitamin B complex, 598. Vitamin E group 
619. Vitamin K group, 623. 



XVIII. CHEMOTHERAPY 

Introduction, 627. Sulphonamides, 627. Antimalarials, 630. 
Arsenical drugs, 631. Antibiotics: The Penicillins, 632. Strepto- 
mycin, 637. Aureomycin and Terramycin, 638. Patulin, 639. 
Chloramphenicol, 640. 

XIX. HEMOGLOBIN, CHLOROPHYLL AND 

PHTHALOCYANINES 

Introduction, 643. Haemoglobin, 643. Biosynthesis of porphyrin 
654. Chlorophyll, 656. Phthalocyanines, 662. 



AUTHOR INDEX 
SUBJECT INDEX 



627 



643 

667 
674 



LIST OF JOURNAL ABBREVIATIONS 



Abbreviations 
Ann. Reports (Chem. Soc.) 

Ber. 

Bull. Soc. chim. 

Chem. Reviews 

Chem. and Ind. 

Experientia 

Ind. chim. belg. 

Ind. Eng. Chem. 

J. Amer. Chem. Soc. 

J. Chem. Educ. 

J.C.S. 

J. Pharm. Pharmacol. 

J. Roy. Inst. Chem. 

Nature 

Proc. Chem. Soc. 

Quart. Reviews (Chem. Soc.) 

Science 

Tetrahedron 



Journals 

Annual Reports of the Progress of Chemistry (The 
Chemical Society, London). 

Berichte der deutschen chemischen Gesellschaft (name 
now changed to Chemische Berichte). 

Bulletin de la Soci£t£ chimique de France. 

Chemical Reviews. 

Chemistry and Industry. 

Experientia. 

Industrie chimique beige. 

Industrial and Engineering Chemistry. 

Journal of the American Chemical Society. 

Journal of Chemical Education. 

Journal of the Chemical Society. 

Journal of Pharmacy and Pharmacology. 

Journal of the Royal Institute of Chemistry. 

Nature. 

Proceedings of the Chemical Society. 

Quarterly Reviews of the Chemical Society (London) 

Science. 

Tetrahedron. 



Xll 



CHAPTER I 

PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 

§1. Introduction. A tremendous amount of work has been and is being 
done to elucidate the relationships between physical properties and chemical 
structure. An ideal state to be achieved is one where the chemist can pre- 
dict with great accuracy the physical properties of an organic compound 
whose structure is known, or formulate the correct structure of an organic 
compound from a detailed knowledge of its physical properties. A great 
deal of progress has been made in this direction as is readily perceived by 
examining the methods of elucidating structures of organic compounds over 
the last few decades. In the early work, the structure of an organic com- 
pound was solved by purely chemical means. These are, briefly: 

(i) Qualitative analysis. 

(ii) Quantitative analysis, which leads to the empirical formula. 

(iii) Determination of the molecular weight, which leads to the molecular 
formula. 

(iv) If the molecule is relatively simple, the various possible structures 
are written down (based on the valency of carbon being four, that 
of hydrogen one, oxygen two, etc.). Then the reactions of the 
compound are studied, and the structure which best fits the facts 
is chosen. In those cases where the molecules are not relatively 
simple, the compounds are examined by specific tests to ascertain 
the nature of the various groups present (see, e.g., alkaloids, §4. 
XIV). The compounds are also degraded and the smaller frag- 
ments examined. By this means it is possible to suggest a tenta- 
tive structure. 

(v) The final stage for elucidation of structure is synthesis, and in general, 
the larger the number of syntheses of a compound by different 
routes, the more reliable will be the structure assigned to that 
compound. 

In recent years, chemists are making increasing use of physical properties, 
in addition to purely chemical methods, to ascertain the structures of new 
compounds. Furthermore, information on structure has been obtained 
from physical measurements where such information could not have been 
obtained by chemical methods. The early chemists identified pure com- 
pounds by physical characteristics such as boiling point, melting point, 
refractive index; nowadays many other physical properties are also used 
to characterise pure compounds. 

The following account describes a number of relationships between 
physical properties and chemical constitution, and their application to the 
problem of elucidating chemical structure. 

§2. Van der Waals forces. Ostwald (1910) classified physical properties 
as additive (these properties depend only on the nature and number of 
atoms in a molecule), constitutive (these properties depend on the nature, 
number and arrangement of the atoms in the molecule), and colligative 
(these properties depend only on the number of molecules present, and are 
independent of their chemical constitution). It is extremely doubtful 
whether any one of these three classes of properties is absolutely independent 
of either or both of the others, except for the case of molecular weights, 
which may be regarded as truly additive and independent of the other two. 



2 ORGANIC CHEMISTRY [CH. I 

In constitutive and colligative properties, forces between molecules have a 
very great effect on these properties. Attractive forces between molecules 
of a substance must be assumed in order to explain cohesion in liquids and 
solids. Ideal gases obey the equation PV = RT, but real gases do not, 
partly because of the attractive forces between molecules. Van der Waals 
(1873) was the first to attempt to modify the ideal gas law for the behaviour 
of real gases by allowing for these attractive forces (he introduced the term 
a/v % to correct for them). These intermolecular forces are now usually 
referred to as van der Waals forces, but they are also known as residual 
or secondary valencies. These forces may be forces of attraction or forces 
of repulsion; the former explain cohesion, and the latter must be assumed 
to exist at short distances, otherwise molecules would collapse into one 
another when intermolecular distances become very small. The distances 
to which atoms held together by van der Waals forces can approach each 
other, i.e., the distances at which the repulsion becomes very large, are 
known as van der Waals radii. Some values (in Angstroms) are: 

H, 1-20; O, 140; N, 1-50; CI, 1-80; S, 1-85. 
These values are very useful in connection with molecules that exhibit the 
steric effect, e.g., substituted diphenyl compounds (§2. V). 

Van der Waals forces are electrostatic in nature. They are relatively 
weak forces {i.e., in comparison with bond forces), but they are greater for 
compounds than for atoms and molecules of elements. In fact, the more 
asymmetrical the molecule, the greater are the van der Waals forces. These 
forces originate from three different causes: 

(i) Forces due to the interaction between the permanent dipole moments 
of the molecules (Keesom, 1916, 1921). These forces are known as Keesom 
forces or the dipole-dipole effect, and are dependent on temperature. 

(ii) Forces which result from the interaction of a permanent dipole and 
induced dipoles. Although a molecule may not possess a permanent dipole, 
nevertheless a dipole may be induced under the influence of neighbouring 
molecules which do possess a permanent dipole (Debye, 1920, 1921). These 
forces are known as Debye forces, the dipole-induced dipole effect or 
induction effect, and are almost independent of temperature. 

(iii) London (1930) showed from wave mechanics that a third form of 
van der Waals forces is also acting. A nucleus and its " electron cloud " 
are in a state of vibration, and when two atoms are sufficiently close to each 
other, the two nuclei and the two electron clouds tend to vibrate together, 
thereby leading to attraction between different molecules. These forces are 
known as London forces, dispersion forces, or the wave-mechanical 
effect, and are independent of temperature. 

It should be noted that the induced forces are smaller than the other two, 
and that the dispersion forces are usually the greatest. 

It can now be seen that all those physical properties which depend on 
intermolecular forces, e.g., melting point, boiling point, viscosity, etc., will 
thus be largely determined by the van der Waals forces. Van der Waals 
forces may also be responsible for the formation of molecular complexes 
(see Vol. I). 

§3. The hydrogen bond. A particularly important case of electrostatic 
attraction is that which occurs in hydrogen bonding (Vol. I, Ch. II) ; it occurs 
mainly in compounds containing hydroxyl or imino groups. There are two 
types of hydrogen bonding, intermolecular and intramolecular. Intermole- 
cular bonding gives rise to association, thereby raising the boiling point ; it 
also raises the surface tension and the viscosity, but lowers the dielectric 
constant. Intermolecular hydrogen bonding may exist in compounds in the 
liquid or solid state, and its formation is Very much affected by the shape of 



§4] PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 3 

the molecules, i.e., by the spatial or steric factor; e.g., w-pentanol is com- 
pletely associated, whereas totf.-pentanol is only partially associated. Inter- 
molecular hydrogen bonding is also responsible for the formation of various 
molecular compounds, and also affects solubility if the compound can form 
hydrogen bonds with the solvent. 

Intramolecular hydrogen bonding gives rise to chelation, i.e., ring forma- 
tion, and this normally occurs only with the formation of 5-, 6-, or 7-mem- 
bered rings. Chelation has been used to explain the volatility of ortho- 
compounds such as o-halogenophenols and o-nitrophenols (as compared with 
the corresponding m- and ^-derivatives). Chelation has also been used to 
account for various or^o-substituted benzoic acids being stronger acids than 
the corresponding m- and ^-derivatives (see Vol. I, Ch. XXVIII). 

When chelation occurs, the ring formed must be planar or almost planar. 
Should another group be present which prevents the formation of a planar 
chelate structure, then chelation will be diminished or even completely in- 
hibited (Hunter et al., 1938; cf. steric inhibition of resonance, Vol. I, Ch. 
XXVIII). Compound I is chelated, but II is associated and not chelated. 
In I the o-nitro-group can enter into the formation of a planar six-membered 



CHjCO ^ , CH 3 Ca ,H 





I 

ring. In II, owing to the strong repulsion between the negatively charged 
oxygen atoms of the two nitro-groups, the plane of each nitro-group will 
tend to be perpendicular to the plane of the benzene ring, and consequently 
a chelated planar six-membered ring cannot be formed. 

The presence of hydrogen bonding may be detected by various means, 
e.g., infra-red absorption spectra, X-ray analysis, electron diffraction, exam- 
ination of boiling points, melting points, solubility, etc. The best method 
appears to be that of infra-red absorption spectra (see §15b). 

§4. Melting point. In most solids the atoms or molecules are in a state 
of vibration about their fixed mean positions. These vibrations are due 
to the thermal energy and their amplitudes are small compared with inter- 
atomic distances. As the temperature of the solid is raised, the amplitude 
of vibration increases and a point is reached when the crystalline structure 
suddenly becomes unstable; this is the melting point. 

In many homologous series the melting points of the M-members rise 
continuously, tending towards a maximum value. On the other hand, some 

homologous series show an alternation or oscillation of melting points 

" the saw-tooth rule ", e.g., in the fatty acid series the melting point of an 
"even " acid is higher than that of the " odd " acid immediately below and 
above it. It has been shown by X-ray analysis that this alternation of 
melting points depends on the packing of the crystals. The shape of the 
molecule is closely related to the melting point; the more symmetrical the 
molecule, the higher is the melting point. Thus with isomers, branching of 
the chain (which increases symmetry) usually raises the melting point; also 
*ra«s-isomers usually have a higher melting point than the cis-, the former 
haying greater symmetry than the latter (see §5. IV). In the benzene 
series, of the three disubstituted derivatives, the ^-compound usually has 
the highest melting point. 

Apart from the usual van der Waals forces which affect melting points 



4 ORGANIC CHEMISTRY [CH. I 

hydrogen bonding may also play a part, e.g., the melting point of an alcohol 
is higher than that of its corresponding alkane. This may be attributed to 
hydrogen bonding, which is possible in the former but not in the latter. 

Various empirical formulae have been developed from which it is possible 
to calculate melting points; these formulae, however, only relate members 
of an homologous series. 

The method of mixed melting points has long been used to identify a 
compound, and is based on the principle that two different compounds 
mutually lower the melting point of each component in the mixture. This 
method, however, is unreliable when the two compounds form a solid 
solution. 

§5. Boiling point. The boiling point of a liquid is that temperature at 
which the vapour pressure is equal to that of the external pressure. Thus 
the boiling point varies with the pressure, being raised as the pressure is 
increased. 

In an homologous series, the boiling point usually increases regularly for 
the w-members, e.g., Kopp (1842) found that with the aliphatic alcohols, 
acids, esters, etc., the boiling point is raised by 19° for each increase of CH 2 
in the composition. In the case of isomers the greater the branching of 
the carbon chain, the lower is the boiling point. Calculation has shown 
that the boiling point of the w-alkanes should be proportional to the number 
of carbon atoms in the molecule. This relationship, however, is not observed 
in practice, and the cause of this deviation still remains to be elucidated. 
One strongly favoured theory attributes the cause to the fact that the 
carbon chains of w-alkanes in the liquid phase exist largely in a coiled con- 
figuration. As the branching increases, the coil becomes denser, and this 
lowers the boiling point. 

In aromatic disubstituted compounds the boiling point of the ortho-isomer 
is greater than that of the meta-isomer which, in turn, may have a higher 
boiling point than the ^am-isomer, but in many cases the boiling points 
are about the same. 

Since the boiling point depends on the van der Waals forces, any structural 
change which affects these forces will consequently change the boiling 
point. One such structural change is the branching of the carbon chain 
(see above). Another type of change is that of substituting hydrogen by 
a negative group. This introduces a dipole moment (or increases the value 
of an existing dipole moment), thereby increasing the attractive forces 
between the molecules and consequently raising the boiling point, e.g., the 
boiling points of the nitro-alkanes are very much higher than those of the 
corresponding alkanes. The possibility of intermolecular hydrogen bonding 
also raises the boiling point, e.g., alcohols boil at higher temperatures than 
the corresponding alkanes. 

§6. Solubility. It is believed that solubility depends on the following 
intermolecular forces: solvent/solute; solute/solute; solvent/solvent. The 
solubility of a non-electrolyte in water depends, to a very large extent, on 
whether the compound can form hydrogen bonds with the water, e.g., the 
alkanes are insoluble, or almost insoluble, in water. Methane, however, is 
more soluble than any of its homologues. The reason for this is uncertain ; 
hydrogen bonding with water is unlikely, and so other factors must play 
a part, e.g., molecular size. A useful guide in organic chemistry is that 
" like dissolves like ", e.g., if a compound contains a hydroxyl group, then 
the best solvents for that compound also usually contain hydroxyl groups 
(hydrogen bonding between solvent and solute is possible). This " rule " 
is accepted by many who use the word " like " to mean that the cohesion 
forces in both solvent and solute arise from the same source, e.g., alkanes 



§8] PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 5 

and alkyl halides are miscible; the cohesion forces of both of these groups 
of compounds are largely due to dispersion forces. 

In some cases solubility may be due, at least partly, to the formation of 
a compound between the solute and the solvent, e.g., ether dissolves in 
concentrated sulphuric acid with the formation of an oxonium salt, 
(CHJ,OH}+HS0 4 - 

§7. Viscosity. Viscosity (the resistance to flow due to the internal 
friction in a liquid) depends, among other factors, on the van der Waals 
forces acting between the molecules. Since these forces depend on the 
shape and size of the molecules, the viscosity will also depend on these 
properties. At the same time, since the Keesom forces (§2) depend on 
temperature, viscosity will also depend on temperature; other factors, how- 
ever, also play a part. 

A number of relationships have been found between the viscosity of pure 
liquids and their chemical structure, e.g., 

(i) In an homologous series, viscosity increases with the molecular weight. 

(ii) With isomers the viscosity of the »-compound is greater than that 
of isomers with branched carbon chains. 

(iii) Abnormal viscosities are shown by associated liquids. Viscosity 
measurements have thus been used to determine the degree of association 
in liquids. 

(iv) The viscosity of a fo-aws-compound is greater than that of the corre- 
sponding as-isomer. 

Equations have been developed relating viscosity to the shape and size 
of large molecules (macromolecules) in solution, and so viscosity measure- 
ments have offered a means of determining the shape of, e.g., proteins, and 
the molecular weight of, e.g., polysaccharides. 

§8. Molecular volumes. The molecular volume of a liquid in milli- 
litres (V m ) is given by the equation 

v _ gram molecular weight 
m ~ density 

The relation between molecular volume and chemical composition was 
studied by Kopp (1839-1855). Since the density of a liquid varies with the 
temperature, it was necessary to choose a standard temperature for com- 
parison. Kopp chose the boiling point of the liquid as the standard tempera- 
ture. This choice was accidental, but proved to be a fortunate one since 
the absolute boiling point of a liquid at atmospheric pressure is approxi- 
mately two-thirds of the critical temperature, i.e., Kopp unknowingly com- 
pared liquids in their corresponding states, the theory of which did not 
appear until 1879. As a result of his work, Kopp was able to compile a 
table of atomic volumes based on the assumption that the molecular volume 
was an additive property, e.g., 

C 11-0 CI 22-8 

H 5-5 Br 27-8 

O (0=0) 12-2 I 37-5 

0(0H) 7-8 

It should be noted that Kopp found that the atomic volume of oxygen 

(and sulphur) depended on its state of combination. Kopp also showed 

that the molecular volume of a compound can be calculated from the sum 

of the atomic volumes, e.g., acetone, CH 3 'COCH 3 . 

3C = 33-0 Molecular weight of acetone = 58 

6H = 33-0 Density at b.p. = 0-749 

O(CO) = 12-2 , . , . , , 58 

. . molecular volume (obs.) — tt-^tk = 77-4 

78-2 [cole.) V ; 0-749 



6 ORGANIC CHEMISTRY [CH. I 

Further work has shown that the molecular volume is not strictly addi- 
tive, but also partly constitutive (as recognised by Kopp who, however, 
tended to overlook this feature). If purely additive, then isomers with 
similar structures will have the same molecular volume. This has been 
found to be the case for, e.g., isomeric esters, but when the isomers belong 
to different homologous series, the agreement may be poor. 

Later tables have been compiled for atomic volumes with structural cor- 
rections. Even so, the relation breaks down in the case of highly polar 
liquids where the attractive forces between the molecules are so great that 
the additive (and structural) properties of the atomic volumes are com- 
pletely masked. 

§9. Parachor. Macleod (1923) introduced the following equation: 

y = C(* - d a y 

where y is the surface tension, d t and d g the densities of the liquid and 
vapour respectively, and C is a constant which is independent of the 
temperature. • 

Macleod's equation can be rewritten as: 

r* c * 

dl dg 

Sugden (1924) multiplied both sides of this equation by the molecular 
weight, M, and pointed out that the expression 

should also be valid. Sugden called the constant P for a given compound 
the parachor of that compound. Provided the temperature is not too high, 
d g will be negligible compared with di, and so we have 

Hence the parachor represents the molecular volume of a liquid at the 
temperature when its surface tension is unity. Thus a comparison of 
parachors of different liquids gives a comparison of molecular volumes at 
temperatures at which liquids have the same surface tension. By this 
means allowance is made for the van der Waals forces, and consequently 
the comparison of molecular volumes is carried out under comparable 
conditions. 

The parachor is largely an additive property, but it is also partly consti- 
tutive. The following table of atomic and structural parachors is that 
given by Mumford and Phillips (1929). 



c 


9-2 


Single bond 


H 


15-4 


Co-ordinate bond 





20 


Double bond 19 


N 


17-5 


Triple bond 38 


CI 


55 


3-Membered ring 12-5 


Br 


69 


4- „ „ 6 


I 


90 


5- „ „ 3 


S 


50 


6- „ „ 0-8 

7- „ „ -4 



The parachor has been used to enable a choice to be made between 
alternative structures, e.g., structures I and II had been suggested for 
^-benzoquinone. Most of the chemical evidence favoured I, but Graebe 



§11] PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 7 

(1867) proposed II to explain some of the properties of this compound (see 
Vol. I). The parachor has been used to decide between these two: 

[P] calculated for I is 233-6; 

[6 X 9-2 + 4 x 15-4 + 2 x 20 + 4 X 19 + 0-8] 
[P] calculated for II is 215-4; 

[6 X 9-2 + 4 X 15-4 + 2X20 + 3X19 + 2X 0-8] 

[P] observed is 236-8. This indicates structure I. 



II 

According to Sutton (1952), the parachor is not a satisfactory property 
for the analysis of molecular structure. It is, however, still useful as a 
physical characteristic of the liquid-vapour system. 

§10. Refrachor. Joshi and Tuli (1951) have introduced a new physical 
constant which they have named the refrachor, [F]. This has been obtained 
by associating the parachor, [P], with the refractive index, (wg>), according 
to the following equation: 

[F] = -[P] log « - 1) 

The authors have found that the observed refrachor of any compound is 
composed of two constants, one dependent on the nature of the atoms, 
and the other on structural factors, e.g., type of bond, size of ring, etc., 
i.e., the refrachor is partly additive and partly constitutive. Joshi and 
Tuli have used the refrachor to determine the percentage of tautomers in 
equilibrium mixtures, e.g., they found that ethyl acetoacetate contains 
7-7 per cent, enol, and penta-2 : 4-dione 72-4 per cent. enol. 

§11. Refractive index. Lorentz and Lorenz (1880) simultaneously 
showed that 

w a - 1 M 

where R is the molecular refradivity, n the refractive index, M the mole- 
cular weight, and d the density. The value of n depends on the wave- 
length and on temperature; d depends on temperature. 

Molecular refractivity has been shown to have both additive and con- 
stitutive properties. The following table of atomic and structural refrac- 
tivities has been calculated for the H„ line. 



c 


2-413 


CI 


5-933 


H 


1092 


Br 


8-803 


O(OH) 


1-522 


I 


13-757 


O(CO) 


2-189 


Double bond (C=C) 


1-686 


O(ethers) 


1-639 


Triple bond (C=C) 


2-328 



Molecular refractivities have been used to determine the structure of com- 
pounds, e.g., terpenes (see §25. VIII). They have also been used to detect the 
presence of tautomers and to calculate the amount of each form present. Let 
us consider ethyl acetoacetate as an example; this behaves as the keto form 
CH 3 «COCH 2 -C0 2 C 2 H B , and as the enol form CH s «C(OH)=CH'C0 2 C 2 H 5 . 



8 ORGANIC CHEMISTRY [CH. I 

The calculated molecular refractivities of these forms are: 



CH 3 CO-CH 2 -C0 2 C 2 H 6 


CH 3 -C(OH)=:CH-C0 2 C 2 H 5 


6 C = 14-478 


6 C = 14-478 


10 H = 10-92 


10 H = 10-92 


2 (CO) = 4-378 
(ether) = 1-639 

31-415 


(OH) = 1-522 

(CO) = 2-189 

(ether) = 1-639 

Double bond = 1-686 




32-434 



The observed molecular refractivity of ethyl acetoacetate is 31-89; hence 
both forms are present. 

When a compound contains two or more double bonds, the value of the 
molecular refractivity depends not only on their number but also on their 
relative positions. When the double bonds are conjugated, then anomalous 
results are obtained, the observed molecular refractivity being higher than 
that calculated, e.g., the observed value for hexa-1 : 3 : 5-triene is 2-06 units 
greater than the value calculated. This anomaly is known as optical exalta- 
tion, and it usually increases with increase in length of conjugation (in un- 
substituted chains). Although optical exaltation is characteristic of acyclic 
compounds, it is also exhibited by cyclic compounds. In single-ring systems, 
e.g., benzene, pyridine, pyrrole, etc., the optical exaltation is negligible; 
this has been attributed to resonance. In polycyclic aromatic compounds, 
however, the exaltation may have a large value. In general, large exalta- 
tions are shown by those compounds which exhibit large electronic effects. 

Another application of the refractive index is its relation to hydrogen 
bonding. Arshid et al. (1955, 1956) have used the square of the refractive 
index to detect hydrogen-bond complexes. 

§12. Molecular rotation. When a substance possesses the property of 
rotating the plane of polarisation of a beam of plane-polarised light passing 
through it, that substance is said to be optically active. The measurement 
of the rotatory power of a substance is carried out by means of a polari- 
meter. If the substance rotates the plane of polarisation to the right, i.e., 
the analyser has to be turned to the right (clockwise) to restore the original 
field, the substance is said to be dextrorotatory; if to the left (anti-clockwise), 
Ixvorotatory. 

It has been found that the amount of the rotation depends, for a given 
substance, on a number of factors: 

(i) The thickness of the layer traversed. The amount of the rotation is 
directly proportional to the length of the active substance traversed (Biot, 
1835). 

(ii) The wavelength of the light. The rotatory power is approximately 
inversely proportional to the square of the wavelength (Biot, 1835). There 
are some exceptions, and in certain cases it has been found that the rotation 
changes sign. This change in rotatory power with change in wavelength 
is known as rotatory dispersion. Hence it is necessary (for comparison of 
rotatory power) to use monochromatic light; the sodium d line (yellow: 
5893 A) is one wavelength that is commonly used (see also §12a). 

(iii) The temperature. The rotatory power usually increases with rise in 
temperature, but many cases are known where the rotatory power decreases. 
Hence, for comparison, it is necessary to state the temperature ; in practice, 
measurements are usually carried out at 20 or 25°. 

(iv) The solvent. The nature of the solvent affects the rotation, and so 
it is necessary to state the solvent used in the measurement of the rotatory 



§12] PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 9 

power. There appears to be some relation between the effect of a solvent 
on rotatory power and its dipole moment. 

(v) The concentration. The rotation appears to be independent of the 
concentration provided that the solution is dilute. In concentrated solu- 
tions, however, the rotation varies with the concentration; the causes for 
this have been attributed to association, dissociation, or solvation (see 
also vi). 

(vi) The amount of rotation exhibited by a given substance when all the 
preceding factors (i-v) have been fixed may be varied by the presence of 
other compounds which are not, in themselves, optically active, e.g., in- 
organic salts. It is important to note in this connection that optically 
active acids or bases, in the form of their salts, give rotations which are 
independent of the nature of the non-optically active ion provided that the 
solutions are very dilute. In very dilute solutions, salts are completely dis- 
sociated, and it is only the optically active ion which then contributes to 
the rotation. The rotation of a salt formed from an optically active acid 
and an optically active base reaches a constant value in dilute solutions, 
and the rotation is the sum of the rotations of the anion and cation. This 
property has been used to detect optical activity (see §5a. VI). 

When recording the rotations of substances, the value commonly given is 
the specific rotation, fVl . This is obtained from the equation: 



[«I = nrs or H! = ; 



ccx 



I X c 

where I is the thickness of the layer in decimetres, d the density of the liquid 
(if it is a pure compound), c the number of grams of substance per millilitre 
of solution (if a solution is being examined), a the observed rotation, t the 
temperature and X the wavelength of the light used. The solvent should 
also be stated (see iv). 

The molecular rotation, TmT, is obtained by multiplying the specific 
rotation by the molecular weight, M. Since large numbers are usually 
obtained, a common practice is to divide the result by one hundred; thus: 



r _ fal X M 
L Ja 100 



The relation between structure and optical activity is discussed later 
(see §§2, 3. II). The property of optical activity has been used in the study 
of the configuration of molecules and. mechanisms of various reactions, and 
also to decide between alternative structures for a given compound. The 
use of optical rotations in the determination of structure depends largely 
on the application of two rules. 

(i) Rule of Optical Superposition (van't Hoff, 1894) : When a compound 
contains two or more asymmetric centres, the total rotatory power of the 
molecules is the algebraic sum of the contributions of each asymmetric 
centre. This rule is based on the assumption that the contribution of each 
asymmetric centre is independent of the other asymmetric centres present. 
It has been found, however, that the contribution of a given asymmetric 
centre is affected by neighbouring centres and also by the presence of chain- 
branching and unsaturation. Hence the rule, although useful, must be 
treated with reserve (see also §6. VII). 

A more satisfactory rule is the Rule of Shift (Freudenberg, 1933): If two 
asymmetric molecules A and B are changed in the same way to give A' 
and B', then the differences in molecular rotation (A' — A) and (B' — B) 
are of the same sign (see, e.g., §4b. XI). 



10 



ORGANIC CHEMISTRY 



[CH. I 



(ii) Distance Rule (Tschugaev, 1898) : The effect of a given structural 
change on the contribution of an asymmetric centre decreases the further 
the centre of change is from the asymmetric centre. 

Only asymmetric molecules have the power, under normal conditions, to 
rotate the plane of polarisation (of plane-polarised light). Faraday (1845), 
however, found that any transparent substance can rotate the plane of polarisa- 
tion when placed in a strong magnetic field. This property of magnetic 
optical rotation (Faraday effect) is mainly an additive one, but is also partly 
constitutive. 

§12a. Rotatory dispersion. In §12wehavediscussedthemethodof optical 
rotations using monochromatic rotations. There is also, however, the method 
of rotatory dispersion. Optical rotatory dispersion is the change in rotatory 
power with change in wavelength, and rotatory dispersion measurements 
are valuable only for asymmetric compounds. In order to study the essen- 
tial parts of dispersion curves, it is necessary to measure the optical rotation 
of a substance right through an absorption band of that substance. This 
is experimentally possible only if this absorption band is in an accessible 
part of the spectrum. Up to the present, the carbonyl group (Amax. at 
280-300 mp) is the only convenient absorbing group that fulfils the neces- 
sary requirements. Thus, at the moment, measurements are taken in the 
range 700 to 270 mp. 

There are three types of rotatory dispersion curves: (a) Plain curves; 
(6) single Cotton Effect curves; (c) multiple Cotton Effect curves. We shall 
describe (a) and (6); (c) shows two or more peaks and a corresponding 
number of troughs. 

Plain curves. These show no maximum or minimum, i.e., they are smooth 
curves, and may be positive or negative according as the rotation becomes 
more positive or negative as the wavelength changes from longer to shorter 
values (Fig. la). 

Single Cotton Effect curves. These are also known as anomalous curves 
and show a maximum and a minimum, both of these occurring in the region 



$ 





300 ny< 700mft 

(a) 



300 m/< 



(*) 



700 m// 



Fig. 1.1. 



of maximum absorption (Fig. 1 6). The curves are said to be positive or 
negative according as the peak or trough occurs in the longer wavelength. 
Thus the curve shown in Fig. 1 (&) is positive. 

As pointed out above, to obtain single Cotton Effect curves (see also §8. 
Ill) the molecule must contain a carbonyl group. The wavelength of maxi- 
mum ultraviolet absorption is referred to as " the optically active absorp- 
tion band ", and since rotatory dispersion measurements are of value only 
for asymmetric compounds, to obtain suitable curves compounds containing 
a carbonyl group in an asymmetric environment must be used. Enantio- 
morphs have curves which are mirror images of each other; compounds 



§13] PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 11 

which are enantiomorphic in the neighbourhood of the carbonyl group have 
dispersion curves which are approximately mirror images of each other; 
and compounds which have the same relative configurations in the neigh- 
bourhood of the carbonyl group have dispersion curves of the same sign. 
There are many applications of rotatory dispersion: (i) quantitative 
analytical uses; (ii) identification of the carbonyl group; (iii) location of 
carbonyl groups; (iv) the determination of relative configurations; (v) the 
determination of absolute configurations; (vi) the determination of con- 
formation. Some examples of these applications are described in the text 
(see Index). 

§13. Dipole moments. When the centres of gravity of the electrons 
and nuclei in a molecule do not coincide, the molecule will possess a perma- 
nent dipole moment, ft, the value of which is given by fi = e X d, where e 
is the electronic charge, and d the distance between the charges (positive 
and negative centres). Since e is of the order of 10 -10 e.s.u., and d 10~ 8 cm., 
p is therefore of the order 10~ 18 e.s.u. This unit is known as the Debye 
(D), in honour of Debye, who did a great deal of work on dipole moments. 

The dipole moment is a vector quantity, and its direction in a molecule 
is often indicated by an arrow parallel to the line joining the points of 

charge, and pointing towards the negative end, e.g., H — CI (Sidgwick, 1930). 
The greater the value of the dipole moment, the greater is the polarity of 
the bond. It should be noted that the terms polar and non-polar are used 
to describe bonds, molecules and groups. Bond dipoles are produced be- 
cause of the different electron-attracting powers of atoms (or groups) joined 
by that bond. This unequal electronegativity producing a dipole moment 
seems to be a satisfactory explanation for many simple molecules, but is 
unsatisfactory in other cases. Thus a number of factors must operate in 
determining the value of the dipole moment. It is now believed that four 
factors contribute to the bond moment: 

(i) The unequal sharing of the bonding electrons arising from the different 
electronegativities of the two atoms produces a dipole moment. 

(ii) In covalent bonds a dipole is produced because of the difference in 
size of the two atoms. The centres of gravity (of the charges) are at the 
nucleus of each contributing atom. Thus, if the atoms are different in size, 
the resultant centre of gravity is not at the mid-point of the bond, and so a 
bond moment results. 

(iii) Hybridisation of orbitals produces asymmetric atomic orbitals; conse- 
quently the centres of gravity of the hybridised orbitals are no longer at 
the parent nuclei. Only if the orbitals are pure s, p or d, are the centres of 
gravity at the parent nuclei. Thus hybridised orbitals produce a bond 
moment. 

(iv) Lone-pair electrons (e.g., on the oxygen atom in water) are not 
" pure " s electrons; they are " impure " because of hybridisation with p 
electrons. If lone-pair electrons were not hybridised, their centre of gravity 
would be at the nucleus; hybridisation, however, displaces the centre of 
gravity from the nucleus and so the asymmetric orbital produced gives rise 
to a bond moment which may be so large as to outweigh the contributions 
of the other factors to the dipole moment. 

The following points are useful in organic chemistry: 

(i) In the bond H— Z, where Z is any atom other than hydrogen or carbon, 

the hydrogen atom is the positive end of the dipole, i.e., H — Z. 

(ii) In the bond C — Z, where Z is any atom other than carbon, the carbon 



atom is the positive end of the dipole, i.e., C — Z (Coulson, 1942). 



12 ORGANIC CHEMISTRY [CH. I 

(iii) When a molecule contains two or more polar bonds, the resultant 
dipole moment of the molecule is obtained by the vectorial addition of the 
constituent bond dipole moments. A symmetrical molecule will thus be 
non-polar, although it may contain polar bonds, e.g., CC1 4 has a zero dipole 
moment although each C — CI bond is strongly polar. 

Since dipole moments are vector quantities, the sum of two equal and 
opposite group moments will be zero only if the two vectors are collinear or 
parallel. When the group moment is directed along the axis of the bond 
formed by the " key " atom of the group and the carbon atom to which it 
is joined, then that group is said to have a linear moment. Such groups 
are H, halogen, Me, CN, N0 2 , etc. On the other hand, groups which have 
non-linear moments are OH, OR, C0 2 H, NH a , etc. This problem of linear 
or non-linear group moments has a very important bearing on the use of 
dipole data in, e.g., elucidating configurations of geometrical isomers (see 
§5. IV), orientation in benzene derivatives (see Vol. I). 

When any molecule (polar or non-polar) is placed in an electric field, the 
electrons are displaced from their normal positions (towards the positive 
pole of the external field). The positive nuclei are also displaced (towards 
the negative pole of the external field), but their displacement is much less 
than that of the electrons because of their relatively large masses. These 
displacements give rise to an induced dipole, and this exists only while the 
external electric field is present. The value of the induced dipole depends 
on the strength of the external field and on the polarisability of the molecule, 
i.e., the ease with which the charged centres are displaced by the external 
field. If P is the total dipole moment, P^ the permanent dipole moment, 
and P a the induced dipole moment, then 

P = P„ + Pa 

"Pf, decreases as the temperature rises, but P a is independent of the tempera- 
ture. The value of P in solution depends on the nature of the solvent and 
on the concentration. 

By means of dipole moment measurements, it has been possible to get a 
great deal of information about molecules, e.g., 

(i) Configurations of molecules have been ascertained, e.g., water has a 
dipole moment and hence the molecule cannot be linear. In a similar way 
it has been shown that ammonia and phosphorus trichloride are not flat 
molecules. 

(ii) Orientations in benzene derivatives have been examined by dipole 
moments (see Vol. I). At the same time, this method has shown that the 
benzene molecule is flat. 

(iii) Dipole moment measurements have been used to distinguish between 
geometrical isomers (see §5. IV). 

(iv) Dipole moments have been used to demonstrate the existence of reso- 
nance and to elucidate electronic structures. 

(v) Energy differences between different conformations (see §4a. II) have 
been calculated from dipole moment data. 

(vi) The existence of dipole moments gives rise to association, the forma- 
tion of molecular complexes, etc. 

§14. Magnetic susceptibility. When a substance is placed in a mag- 
netic field, the substance may or may not become magnetised. If I is the 
intensity of magnetisation induced, and H the strength of the magnetic field 
inducing it, then the magnetic susceptibility, k, is given by 

I 
K = H 



§15] PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 13 

The magnetic induction, B, is given by 

B = H + 4ttI 
Since I = *H, B = H(l + 4n K ) 
The quantity 1 -f- 4jik is called the magnetic permeability, /i. 

Elements other than iron, nickel and cobalt (which are ferromagnetic) 
may be divided into two groups: 

(i) Paramagnetic: in this group [i is greater than unity and k is there- 
fore positive. 

(ii) Diamagnetic: in this group fi is less than unity and k is therefore 
negative. 

All compounds are either paramagnetic or diamagnetic. Paramagnetic 
substances possess a permanent magnetic moment and consequently orient 
themselves along the external magnetic field. Diamagnetic substances do 
not possess a permanent magnetic moment, and tend to orient themselves 
at right angles to the external magnetic field. 

Electrons, because of their spin, possess magnetic dipoles. When electrons 
are paired {i.e., their spins are anti-parallel), then the magnetic field is 
cancelled out. Most organic compounds are diamagnetic, since their elec- 
trons are paired. " Odd electron molecules ", however, are paramagnetic 
(see also §19). & 

Magnetic susceptibility has been used to obtain information on the nature 
of bonds and the configuration of co-ordination compounds. Organic com- 
pounds which are paramagnetic are generally free radicals (odd electron 
molecules), and the degree of dissociation of, e.g., hexaphenylethane into 
triphenylmethyl has been measured by means of its magnetic susceptibility. 

§15. Absorption spectra. When light (this term will be used for electro- 
magnetic waves; of any wavelength) is absorbed by a molecule, the molecule 
undergoes transition from a state of lower to a state of higher energy. If 
the molecule is monatomic, the energy absorbed can only be used to raise 
the energy levels of electrons. If, however, the molecule consists of more 
than one atom, the light absorbed may bring about changes in electronic, 
rotational or vibrational energy. Electronic transitions give absorption (or 
emission) in the visible and ultraviolet parts of the spectrum, whereas 
rotational and vibrational changes give absorption (or emission) respectively 
in the far and near infra-red. Electronic transitions may be accompanied 
by the other two. A study of these energy changes gives information on 
the structure of molecules. 

Spectrum Wavelength (A) 

Ultraviolet . . . 2000-4000 

Visible .... 4000-7500 

Near infra-red . . . 7500-15 x 10 4 

Far infra-red . . . 15 x 10 4 -100 x 10 4 

The position of the absorption band can be given as the wavelength A (cm., 
/i, A, m/j.) or as the wave number, v (cm. -1 ). 

1 fi (micron) = in- 3 mm. 1 m/i (millimicron) = 10~ 6 mm. 
1 A (Angstrom) = 10~ 8 cm. = 10-' mm. 1 m f i = 10 A. 

10* 



v (cm. -1 ) = 



v (cm.- 1 ) 

1 10 4 10 8 



A (cm.) A (/i) A (A) 
If I is the intensity of an incident beam of monochromatic light, and I 
that of the emergent beam which has passed through an absorbing medium 
of thickness I, then T 

I = I 10-" or log 10 ^ = el 



14 ORGANIC CHEMISTRY [CH. I 

where e is the extinction coefficient of the medium. The ratio I /I is called 
the transmittance of the medium, and the reciprocal the opacity; the function 
log 10 I /I is called the density (d). 

If the absorbing substance is in solution (the solvent being colourless), 
and if c is the concentration (number of grams per litre), then 

I = i io-« rf 

This equation is Beer's law (1852), and is obeyed by most solutions pro- 
vided they are dilute. In more concentrated solutions there may be diver- 
gencies from Beer's law, and these may be caused by association, changes 
in solvation, etc. 

If the extinction coefficient is plotted against the wavelength of the light 
used, the absorption curve of the compound is obtained, and this is char- 
acteristic for a pure compound (under identical conditions). 

§15a. Ultraviolet and visible absorption spectra. When a molecule 
absorbs light, it will be raised from the ground state to an excited state. 
The position of the absorption band depends on the difference between the 
energy levels of the ground and excited states. Any change in the structure 
of the molecule which alters the energy difference between the ground and 
excited states will thus affect the position of the absorption band. This 
shifting of bands (in the ultraviolet and visible regions) is concerned with the 
problem of colour (see Vol. I, Ch. XXXI). 

With few exceptions, only molecules containing multiple bonds give rise 
to absorption in the near ultraviolet. In compounds containing only one 
multiple-bond group, the intensity of the absorption maxima may be very 
low, but when several of these groups are present in conjugation, the absorp- 
tion is strong, e.g., an isolated oxo (carbonyl) group has an absorption at 
Amax. 2750 A; an isolated ethylene bond has an absorption at ^max. 1950 A. 
When a compound contains an oxo group conjugated with an ethylenic bond, 
i.e., the compound is an ocjS-unsaturated oxo compound, the two bands no 
longer occur in their original positions, but are shifted to 3100-3300 A and 
2200-2600 A, respectively. Thus, in a compound in which the presence of 
an ethylenic bond and an oxo group has been demonstrated (by chemical 
methods), it is also possible to tell, by examination of the ultraviolet absorp- 
tion spectrum, whether the two groups are conjugated or not. (see, e.g., 
cholestenone, §3(ii). XI). 

Ultraviolet and visible absorption spectra have also been used to differen- 
tiate between geometrical isomers and to detect the presence or absence of 
restricted rotation in diphenyl compounds (§2. V). 

§15b. Infra-red spectra. In a molecule which has some definite con- 
figuration, the constituent atoms vibrate with frequencies which depend on 
the masses of the atoms and on the restoring forces brought into play when 
the molecule is distorted from its equilibrium configuration. The energy 
for these vibrations is absorbed from the incident light, and thereby gives 
rise to a vibrational spectrum. A given bond has a characteristic absorption 
band, but the frequency depends, to some extent, on the nature of the 
other atoms joined to the two atoms under consideration. It is thus possible 
to ascertain the nature of bonds (and therefore groups) in unknown com- 
pounds by comparing their infra-red spectra with tables of infra-red ab- 
sorption spectra. At the same time it is also possible to verify tentative 
structures (obtained from chemical evidence) by comparison with spectra 
of similar compounds of known structure. 

The study of infra-red spectra leads to information on many types of 
problems, e.g., 

(i) Infra-red spectroscopy has been used to distinguish between geo- 



§15c] PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 15 

metrical isomers, and recently Kuhn (1950) has shown that the spectra of 
the stereoisomers methyl a- and ^-glycosides are different. It also appears 
that enantiomorphs in the solid phase often exhibit different absorption 
spectra. Infra-red spectroscopy has also been a very valuable method in 
conformational studies (see §11. IV). 

(ii) The three isomeric disubstituted benzenes have characteristic absorp- 
tion bands, and this offers a means of determining their orientation. 

(hi) Infra-red spectroscopy has given a great deal of information about 
the problem of free rotation about a single bond; e.g., since the intensity of 
absorption is proportional to the concentration, it has been possible to 
ascertain the presence and amounts of different conformations in a mixture 
(the intensities vary with the temperature when two or more conformations 
are present). 

(iv) Tautomeric mixtures have been examined and the amounts of the 
tautomers obtained. In many cases the existence of tautomerism can be 
ascertained by infra-red spectroscopy (cf. iii). 

(v) Infra-red spectroscopy appears to be the best means of ascertaining 
the presence of hydrogen bonding (both in association and chelation). In 
" ordinary " experiments it is not possible to distinguish between intra- 
and intermolecuiar hydrogen bonding. These two modes of bonding can, 
however, be differentiated by obtaining a series of spectra at different 
dilutions. As the dilution increases, the absorption due to intermolecuiar 
hydrogen bonding decreases, whereas the intramolecular hydrogen-bonding 
absorption is unaffected. 

(vi) It is possible to evaluate dipole moments from infra-red spectra. 

(vii) When a bond between two atoms is stretched, a restoring force im- 
mediately operates. If the distortion is small, the restoring force may be 
assumed to be directly proportional to the distortion, i.e., 

f oc d or f —M 
where k is the stretching force constant of the bond. It is possible to calculate 
the values of these force constants from infra-red (vibrational) spectra. 

(viii) The far infra-red or micro-wave region contains the pure rotational 
spectrum. Micro-wave spectroscopy (a recent development) offers a very 
good method for measuring bond lengths. It is possible to calculate atomic 
radii from bond lengths, but the value depends on whether the bond is 
single, double or triple, and also on the charges (if any) on the atoms con- 
cerned. Thus the character of a bond can be ascertained from its length, 
e.g., if a bond length (determined experimentally) differs significantly from 
the sum of the atomic radii, then the bond is not " normal ". Resonance 
may be the cause of this. 

Some atomic covalent radii (in Angstroms) are: 

H 0-30 

C (single) 0-77 

C (double) 0-67 

C (triple) 0-60 

Micro-wave spectroscopy is particularly useful for information on the 
molecular structure of polar gases, and is also used for showing the presence 
of free radicals. 

§15c. Raman spectra. When a beam of monochromatic light passes 
through a transparent medium, most of the light is transmitted or scattered 
without change in wavelength. Some of the light, however, is converted 
into longer wavelengths, i.e., lower frequency (a smaller amount of the light 
may be changed into shorter wavelengths, i.e., higher frequency). The 



N (single) 0-70 


CI 0-99 


N (double) 0-61 


Br 1-14 


N (triple) 0-55 


I 1-33 


O (single) 0-66 


S 104 


O (double) 0-57 





16 ORGANIC CHEMISTRY [CH. I 

change from higher to lower f requency is known as the Raman effect (Raman 
shift) . It is independent of the frequency of the light used, but is character- 
istic for a given bond. 

Raman spectra have been used to obtain information on structure, e.g., 
the Raman spectrum of formaldehyde in aqueous solution shows the absence 
of the oxo group, and so it is inferred that formaldehyde is hydrated: 
CH 2 (OH) 2 . Raman spectra have also been used to ascertain the existence 
of keto-enol tautomerisrft and different conformations, to provide evidence 
for resonance, to differentiate between geometrical isomers, to show the 
presence of association, and to give information on force constants of bonds. 

§16. X-ray analysis. X-rays may be used with gases, liquids or solids, 
but in organic chemistry they are usually confined to solids, which may be 
single crystals, or substances consisting of a mass of minute crystals (powder 
method), or fibres. When X-rays (wavelength 0-7-1-5 A) fall on solids, they 
are diffracted to produce patterns (formed on a photographic film). Since 
X-rays are diffracted mainly by the orbital electrons of the atoms, the 
diffraction will be a function of the atomic number. Because of this, it is 
difficult to differentiate between atoms whose atomic numbers are very 
close together, e.g., carbon and nitrogen. Furthermore, since the scattering 
power of hydrogen atoms (for X-rays) is very low, it is normally impossible 
to locate these atoms except in very favourable conditions, and then only 
with fairly simple compounds. 

Two problems are involved in the interpretation of X-ray diffraction 
patterns, viz., the dimensions of the unit cell and the positions of the indi- 
vidual atoms in the molecule. The positions of the diffracted beams depend 
on the dimensions of the unit cell. A knowledge of these dimensions leads 
to the following applications: 

(i) Identification of stibstances; this is done by looking up tables of unit 

cells. 

(ii) Determination of molecular weights. If V is the volume of the Unit 
cell, d the density of the compound, and n the number of molecules in a 
unit cell, then the molecular weight, M, is given by 

M = — 

n 

(iii) Determination of the shapes of molecules. Many long-chain polymers 
exist as fibres, e.g., cellulose, keratin. These fibres are composed of bundles 
of tiny crystals with one axis parallel, or nearly parallel, to the fibre axis. 
When X-rays fall on the fibre in a direction perpendicular to its length, 
then the pattern obtained is similar to that from a single crystal rotated 
about a principal axis. It is thus possible to obtain the unit cell dimensions 
of such fibres (see, e.g., rubber, §33. VIII). 

The intensities of the diffracted beams depend on the positions of the 
atoms in the unit cell. A knowledge of these relative intensities leads to 
the following applications: 

(i) Determination of bond lengths, valency angles, and the general elec- 
tron distribution in molecules. 

(ii) Determination of molecular symmetry. This offers a means of dis- 
tinguishing between geometrical isomers, and also of ascertaining the shape 
of a molecule, e.g., the diphenyl molecule has a centre of symmetry, and 
therefore the two benzene rings must be coplanar (see §2. V). 

(iii) Determination of structure. This application was originally used for 
compounds of known structure. Trial models based on the structure of the 
molecule were compared with the X-ray patterns, and if they " fitted ", 
confirmed the structure already accepted. If the patterns did not fit, then 
it was necessary to look for another structural formula. More recently, 



§19a] PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 17 

however. X-ray analysis has been applied to compounds of unknown or 
partially known structures, e.g., penicillin (§6a. XVIII). 

(iv) X-ray analysis has been used to elucidate the conformations of 
rotational isomers (§4a. II), and also to determine the absolute configura- 
tions of enantiomorphs (§5. II). 

§17. Electron diffraction. Electron diffraction is another direct method 
for determining the spatial arrangement of atoms in a molecule, and is 
usually confined to gases or compounds in the vapour state, but may be 
used for solids and liquids. Electrons exhibit a dual behaviour, particle or 
wave, according to the nature of the experiment. The wavelength of 
electrons is inversely proportional to their momentum: the wavelength is 
about 0-06 A for the voltages generally used. Because of their small diffract- 
ing power, hydrogen atoms are difficult, if not impossible, to locate. 

By means of electron diffraction it is possible to obtain values of bond 
lengths and the size and shape of molecules, particularly macromolecules. 
Electron diffraction studies have been particularly useful in the investigation 
of conformations in cyc/ohexane compounds (see §11. IV). 

§18. Neutron crystallography. A beam of slow neutrons is diffracted 
by crystalline substances. The equivalent wavelength of a slow beam of 
neutrons is 1 A, and since this is of the order of interatomic distances in 
crystals, the neutrons will be diffracted. This method of analysis is par- 
ticularly useful for determining the positions of light atoms, a problem which 
is very difficult, and often impossible, with X-ray analysis. Thus neutron 
diffraction is extremely useful for locating hydrogen atoms. 

In addition to studying solids, neutron diffraction has also been applied 
to gases, pure liquids and solutions. 

§19. Electron spin resonance. Electrons possess spin (and consequently 
a magnetic moment) and are therefore capable of interacting with an external 
magnetic field. The spin of one electron of a covalent pair and its resulting 
interaction with a magnetic field is cancelled by the equal and opposite 
spin of its partner (see also §14). An unpaired electron, however, will have 
an interaction that is not cancelled out and the energy of its interaction 
may change if its spin changes to the opposite direction (an electron has a 
spin quantum number s; this can have values of +J and — \), For an un- 
paired electron to change the sign of its spin in a magnetic field in the 
direction of greater energy, it must absorb energy, and it will do this if electro- 
magnetic energy of the appropriate wavelength is supplied. By choosing a 
suitable strength for the magnetic field, the unpaired electron can be made 
to absorb in the micro-wave region; a field of about 3000 gauss is usually 
uged in conjunction with radiation of a frequency in the region of 9 kMc./sec. 
This method of producing a spectrum is known as electron spin resonance 
(ESR) or electron paramagnetic resonance (EPR). ESR is used as a method 
for the study of free radicals; it affords a means of detecting and measuring 
the concentration of free radicals, and also supplies specific information 
about their structure. The application of ESR has shown that free radicals 
take part in photosynthesis. 

§19a. Nuclear magnetic resonance. Just as electrons have spin, so 
have the protons and neutrons in atomic nuclei. In most nuclei the spins 
are not cancelled out and hence such nuclei possess a resultant nuclear 
magnetic moment. When the nucleus possesses a magnetic moment, the 
ground state consists of two or more energy levels which are indistinguish- 
able from each other. Transition from one level to another, however, can 
be induced by absorption or emission of a quantum of radiation of the 
proper frequency which is determined by the energy difference between the 



18 ORGANIC CHEMISTRY [CH. I 

two nuclear levels. This frequency occurs in the radiofrequency region, 
and can be varied by changing the strength of the applied field. In this 
way is obtained the spectrum by the method of nuclear magnetic resonance 
(NMR). The resonance frequencies of most magnetic nuclei lie between 
0-1 and 40 Mc. for fields varying from 1000 to 10,000 gauss. 

Of particular importance are the nuclear properties of the proton; here 
we have the special case of NMR, proton magnetic resonance. A large pro- 
portion of the work in this field has been done with protons; protons give 
the strongest signals. Analysis of structure by NMR depends mainly on 
the fact that although the same nucleus is being examined, the NMR spectrum 
depends on the environment of that nucleus. This difference in resonance 
frequency has been called chemical shift; chemical shifts are small. Thus 
it is possible to identify C— H in saturated hydrocarbons and in olefins; a 
methyl group attached to a saturated carbon atom can be differentiated 
from one attached to an unsaturated one; etc. 

NMR has been used to provide information on molecular structure, to 
identify molecules, and to examine the crystal structure of solids. It has 
also been used to measure keto-enol equilibria and for the detection of 
association, etc. NMR is also useful in conformational analysis (§4a. II) 
and for distinguishing between various cis- and trans-isomvcs (§5. IV). 

READING REFERENCES 

Partington, An Advanced Treatise on Physical Chemistry, Longmans, Green. Vol. I-V 
(1949—1964). 

Ferguson, Electronic Structures of Organic Molecules, Prentice-Hall (1952). 

Ketelaar, Chemical Constitution, Elsevier (1953). 

Gilman, Advanced Organic Chemistry, Wiley (1943, 2nd ed.). (i) Vol. II. Ch. 23. Con- 
stitution and Physical Properties of Organic Compounds, (n) Vol. Ill (19£a) 
Ch. 2. Applications of Infra-red and Ultra-violet Spectra to Organic Chemistry. 

Wells, Structural Inorganic Chemistry, Oxford Press (1950, 2nd ed.). 

Syrkin and Dyatkina, Structure of Molecules and the Chemical Bond, Butterworth (1950 
translated and revised by Partridge and Jordan). 

Weissberger (Ed.), Technique of Organic Chemistry, Interscience Publishers. Vol. 1 
(1949, 2nd ed.). Physical Methods of Organic Chemistry. 

Berl (Ed.), Physical Methods in Chemical Analysis, Academic Press. Vol. I (1950); 

Waters, Physical Aspects of Organic Chemistry, Routledge and Kegan Paul (1950, 
4th ed.). 

Reilly and Rae, Physico-Chemical Methods, Methuen (Vol. I and II; 1954, 5th ed.). 

Stuart, Die Struklur des Freien Molekiils, Springer-Verlag (1952). 

Mizushima, Structure of Molecules and Internal Rotation, Academic Press (1954). 

Ingold, Structure and Mechanism in Organic Chemistry, Bell and Sons (1953). Ch. III. 
Physical Properties of Molecules. . 

Braude and Nachod (Ed.), Determination of Organic Structures by Physical Methods, 
Academic Press (1955). Nachod and Phillips, Vol. 2 (1962). 

Pimental and McClellan, The Hydrogen Bond, Freeman and Co. (1960). 

Quayle, The Parachors of Organic Compounds, Chem. Reviews, 1953, 53, 439. 

Dierassi, Optical Rotatory Dispersion, McGraw-Hill (1960). 

Advances in Organic Chemistry, Interscience (1960). Klyne, Optical Rotatory Disper- 
sion and the Study of Organic Structures, Vol. I, p. 239. 

Smith, Electric Dipole Moments, Butterworth (1955). 

Herzberg, Infrared and Raman Spectra, Van Nostrand (1945). 

Whiffen, Rotation Spectra, Quart. Reviews (Chem. Soc), 1950, 4, 131. 

Bellamy, The Infrared Spectra of Complex Molecules, Methuen (1958, 2nd ed.). 

Cross, Introduction to Practical Infrared Spectroscopy, Butterworth (1959). 

Mason, Molecular Electronic Absorption Spectra, Quart. Reviews (Chem. Soc), 19bl, 
15, 287. 

Rose, Raman Spectra, /. Roy. Inst. Chem., 1961, 83. 

Walker and Straw, Spectroscopy, Vol. I (1961), Chapman and Hall. 

Robertson, Organic Crystals and Molecules, Cornell (1953). 

Jeffrey and Cruikshank, Molecular Structure Determination by X-Ray Crystal Analysis: 
Modern Methods and their Accuracy, Quart. Reviews (Chem. Soc), 1953, 7, 335. 

Richards, The Location of Hydrogen Atoms in Crystals, Quart. Reviews (Chem. Soc), 
1956, 10, 480. 



PHYSICAL PROPERTIES AND CHEMICAL CONSTITUTION 19 

Ann. Review of Phys. Chem. (Vol. I, 1950; — ). 

Newman (Ed.), Steric Effects in Organic Chemistry, Wiley (1956). Ch. 11. Steric 

Effects on Certain Physical Properties. 
McMillan, Electron Paramagnetic Resonance of Free Radicals, /. Chem. Educ, 1961, 

38, 438. 
Advances in Organic Chemistry, Interscience (1960). Conroy, Nuclear Magnetic 

Resonance in Organic Structural Elucidation, Vol. 2, p. 265. 
Corio, The Analysis of Nuclear Magnetic Resonance Spectra, Chem. Reviews, 1960, 

OUj ouo. 

Roberts, Nuclear Magnetic Resonance Spectroscopy, /. Chem. Educ, 1961, 37, 581 
Durrant and Durrant, Introduction to Advanced Inorganic Chemistry, Longmans Green 
(1962). Ch. 1-12 (Quantum Theory, Valency, Spectra, etc.). 



CHAPTER II 

OPTICAL ISOMERISM 

§1. Stereoisomerism. Stereochemistry is the " chemistry of space ", 
i.e., stereochemistry deals with the spatial arrangements of atoms and groups 
in a molecule. Stereoisomerism is exhibited by isomers having the same 
structure but differing in their spatial arrangement, i.e., having different 
configurations. Different configurations are possible because carbon forms 
mainly covalent bonds and these have direction in space. The covalent 
bond is formed by the overlapping of atomic orbitals, the bond energy 
being greater the greater the overlap of the component orbitals. To get 
the maximum overlap of orbitals, the orbitals should be in the same plane. 
Thus non-spherical orbitals tend to form bonds in the direction of the greatest 
concentration of the orbital, and this consequently produces a directional 
bond (see also Vol. I, Ch. II). 

There are two types of stereoisomerism, optical isomerism and geo- 
metrical isomerism (ofs-trans isomerism). It is not easy to define 
them, but their meanings will become clear as the study of stereochemistry 
progresses. Even so, it is highly desirable to have some idea about their 
meanings at this stage, and so the following summaries are given. 

Optical isomerism is characterised by compounds having the same 
structure but different configurations, and because of their molecular asym- 
metry these compounds rotate the plane of polarisation of plane-polarised 
light. Optical isomers have similar physical and chemical properties ; the 
most marked difference between them is their action on plane-polarised 
light (see §12. I). Optical isomers may rotate the plane of polarisation by 
equal and opposite amounts ; these optical isomers are enantiomorphs (see 
§|). On the other hand, some optical isomers may rotate the plane of 
polarisation by different amounts; these are diastereoisomers (see §7b). 
Finally, some optical isomers may possess no rotation at all; these are 
diastereoisomers of the meso-type (see §7d). 

Geometrical isomerism is characterised by compounds having the same 
structure but different configurations, and because of their molecular sym- 
metry these compounds do not rotate the plane of polarisation of plane- 
polarised light. Geometrical isomers differ in all their physical and in many 
of their chemical properties. They can also exhibit optical isomerism if 
the structure of the molecule, apart from giving rise to geometrical isomer- 
ism, is also asymmetric. In general, geometrical isomerism involves mole- 
cules which can assume different stable configurations, the ability to do 
so being due, e.g., to the presence of a double bond, a ring structure, or 
the steric effect (see Ch. IV and V). 

§2. Optical isomerism. It has been found that only those structures, 
crystalline or molecular, which are not superimposable on their mirror images, 
are optically active. Such structures may be dissymmetric, or asymmetric. 
Asymmetric structures have no elements of symmetry at all, but dis- 
symmetric structures, although possessing some elements of symmetry, are 
nevertheless still capable of existing in two forms (one the mirror image of 
the other) which are not superimposable. To avoid unnecessary complica- 
tions, we shall use the term asymmetric to cover both cases (of asymmetry 
and dissymmetry). 

A given molecule which has at least one element of symmetry (§6) when 
its "classical" configuration (i.e., the Fischer projection formula; §5) is 

20 



§3] OPTICAL ISOMERISM 21 

inspected may, however, have a conformation (§4a) which is devoid of any 
element of symmetry. At first sight, such a molecule might be supposed 
to be optically active. In practice, however, it is not; individual molecules 
are optically active, but statistically, the whole collection of molecules is 
not. It therefore follows that when a molecule can exist in one or more 
conformations, then provided that at least one of the conformations (whether 
preferred or not) is superimposable on its mirror image, the compound will 
not be optically active (see §11 for a discussion of this problem). 

Optical activity due to crystalline structure. There are many sub- 
stances which are optically active in the solid state only, e.g., quartz, sodium 
chlorate, benzil, etc. Let us consider quartz, the first substance shown to 
be optically active (Arago, 1811). Quartz exists in two crystalline forms, 
one of which is dextrorotatory and the other laevorotatory. These two 
forms are mirror images and are not superimposable. Such pairs of crystals 
are said to be enantiomorphous (quartz crystals are actually hemihedral and 
are mirror images) . X-ray analysis has shown that the quartz crystal lattice 
is built up of silicon and oxygen atoms arranged in left- and right-handed 
spirals. One is the mirror image of the other, and the two are not super- 
imposable. When quartz crystals are fused, the optical activity is lost. 
Therefore the optical activity is entirely due to the asymmetry of the crystal- 
line structure, since fusion brings about only a physical change. Thus we 
have a group of substances which are optically active only so long as they 
remain solid; fusion, vaporisation or solution in a solvent causes loss of 
optical activity. 

Optical activity due to molecular structure. There are many com- 
pounds which are optically active in the solid, fused, gaseous or dissolved 
state, e.g., glucose, tartaric acid, etc. In this case the optical activity is 
entirely due to the asymmetry of the molecular structure (see, however, §11). 
The original molecule and its non-superimposable mirror image are known 
as enantiomorphs (this name is taken from crystallography) or optical anti- 
podes. They are also often referred to as optical isomers, but there is a 
tendency to reserve this term to denote all isomers which have the same 
structural formula but different configurations (see §1). 

Properties of enantiomorphs. It appears that enantiomorphs are 
identical physically except in two respects: 

(i) their manner of rotating polarised light; the rotations are equal but 
opposite. 

(ii) the absorption coefficients for dextro- and lavocircularly polarised 
light are different; this difference is known as circular dichroism or the 
Cotton effect (see also §8. III). 

The crystal forms of enantiomorphs may be mirror images of each other, 
i.e., the crystals themselves may be enantiomorphous, but this is unusual 
[see also §10(i)]. Enantiomorphs are similar chemically, but their rates of 
reaction with other optically active compounds are usually different [see 
§10(vii)]. They may also be different physiologically, e.g., (-f-)-histidine is 
sweet, (— )-tasteless; (— )-nicotine is more poisbnous than (+)-. 

§3. The tetrahedral carbon atom. In 1874, van't Hoff and Le Bel, 
independently, gave the solution to the problem of optical isomerism in 
organic compounds, van't Hoff proposed the theory that if the four valencies 
of the carbon atom are arranged tetrahedrally (not necessarily regular) with 
the carbon atom at the centre, then all the cases of isomerism known are 
accounted for. Le Bel's theory is substantially the same as van't Hoff 's, but 
differs in that whereas van't Hoff believed that the valency distribution was 
definitely tetrahedral and fixed as such, Le Bel believed that the valency direc- 
tions were not rigidly fixed, and did not specify the tetrahedral arrangement. 



22 



ORGANIC CHEMISTRY 



[CH. II 



but thought that whatever the spatial arrangement, the molecule Cdbde 
would be asymmetric. Later work has shown that van't Hoff's theory is 
more in keeping with the facts (see below). Both van't Hoff's and Le Bel's 
theories were based on the assumption that the four hydrogen atoms in 
methane are equivalent; this assumption has been shown to be correct by 
means of chemical and physico-chemical methods. Before the tetrahedral 
was proposed, it was believed that the four carbon valencies were planar, 
with the carbon atom at the centre of a square (Kekule, 1858). 

Pasteur (1848) stated that all substances fell into two groups, those which 
were superimposable on their mirror images, and those which were not. 
In substances such as quartz, Optical activity is due to the dissymmetry 
of the crystal structure, but in compounds like sucrose the optical activity 
is due to molecular dissymmetry. Since it is impossible to have molecular 
dissymmetry if the molecule is fiat, Pasteur's work is based on the idea 
that molecules are three-dimensional and arranged dissymmetrically. A 
further interesting point in this connection is that Pasteur quoted an 
irregular tetrahedron as one example of a dissymmetric structure. Also, 
Patemo (1869) had proposed tetrahedral models for the structure of the iso- 
meric compounds C S H 4 C1 2 (at that time it was thought that there were 
three isomers with this formula; one ethylidene chloride and two ethylene 
chlorides). 

§3a. Evidence for the tetrahedral carbon atom. The molecule CX 4 
constitutes a five-point system, and since the four valencies of carbon are 
equivalent, their disposition in space may be assumed to be symmetrical. 
Thus there are three symmetrical arrangements possible for the molecule 
CX 4 , one planar and two solid — pyramidal and tetrahedral. By comparing 
the number of isomers that have been prepared for a given compound with 
the number predicted by the above three spatial arrangements, it is possible 
to decide which one is correct. 

Compounds of the types Ca 2 6 2 and Ca^bd. Both of these are similar, and 
so we shall only discuss molecule C« 2 6 2 . 



k- 




Fig. 2.1. 



(i) If the molecule is planar, then two forms are possible (Fig. 1). This 
planar configuration can be either square or rectangular; in each case there 
are two forms only. 





Fig. 2.2. 



(ii) If the molecule is pyramidal, then two forms are possible (Fig. 2). 
There are only two forms, whether the base is square or rectangular. 

(iii) If the molecule is tetrahedral, then only one form is possible (Fig. 3 ; 
the carbon atom is at the centre of the tetrahedron). 



§3a] 



OPTICAL ISOMERISM 



23 



In practice, only one form is known for each of the compounds of 
the types Cfl 2 6 g and Ca 2 bd; this agrees with the tetrahedral con- 
figuration. 




Fig. 2.3. 



Compounds of the type Cabie. 
forms are possible (Fig. 4). 



(i) If the molecule is planar, then three 



a*- 



T'A 



Fig. 2.4. 



! r * 



(ii) If the molecule is pyramidal, then six forms are possible; there are 
three pairs of enantiomorphs. Each of the forms in Fig. 4, drawn as a 
pyramid, is not superimposable on its mirror image, e.g., Fig. 5 shows one 
pair of enantiomorphs. 




ei~ 




i 
Fig. 2.5. 

(iii) If the molecule is tetrahedral, there are two forms possible, one related 
to the other as object and mirror image, which are not superimposable, 
i.e., the tetrahedral configuration gives rise to one pair of enantiomorphs 
(Fig. 6). y 





Fig. 2.6. 

In practice, compounds of the type Cabde give rise to only one pair 
of enantiomorphs; this agrees with the tetrahedral configuration. 

When a compound contains four different groups attached to a carbon 
atom, that carbon atom is said to be asymmetric (actually, of course, it 
is the group which is asymmetric; a carbon atom cannot be asymmetric). 
The majority of optically active compounds (organic) contain one or more 
asymmetric carbon atoms. It should be remembered, however, that the 
essential requirement for optical activity is the asymmetry of the molecule. 



24 ORGANIC CHEMISTRY [CH. II 

A molecule may contain two or more asymmetric carbon atoms and still 
not be optically active (see, e.g., §7d). 

A most interesting case of an optically active compound containing one 
asymmetric carbon atom is the resolution of s-butylmercuric bromide, 
EtMeCH'HgBr (Hughes, Ingold et al., 1958). This appears to be the first 
example of the resolution of a simple organometaUic compound where the 
asymmetry depends only on the carbon atom attached to the metal. 

Isotopic asymmetry. In the optically active compound Cabde, the 
groups a, b, d and e (which may or may not contain carbon) are all different, 
but two or more may be structural isomers, e.g., propylz'sopropylmethanol 
is optically active. The substitution of hydrogen by deuterium has also 
been investigated in recent years to ascertain whether these two atoms are 
sufficiently different to give rise to optical isomerism. The earlier work 
gave conflicting results, e.g., Clemo et al. (1936) claimed to have obtained a 
small rotation for a-pentadeuterophenylbenzylamine, C 6 D 5 *CH(C 6 H5)'NH 2 , 
but this was disproved by Adams et al. (1938). Erlenmeyer et al. (1936) 
failed to resolve C 6 H 5 -CH(C 6 D 5 )-C0 2 H, and Ives et al. (1948) also failed 
to resolve a number of deutero-compounds, one of which was 

C 6 H 5 -CH 2 -CHD-C0 2 H. 

More recent work, however, is definitely conclusive in favour of optical 
activity, e.g., Eliel (1949) prepared optically active phenylmethyldeutero- 
methane, CH 3 *CHD-C 6 H 5 , by reducing optically active phenylmethylmethyl 
chloride, CHg-CHCl-CgHg, with lithium aluminium deuteride; Ross et al. 
(1956) have prepared (— )-2-deuterobutane by reduction of (— )-2-chloro- 
butane with lithium aluminium deuteride; and Alexander et al. (1949) 
reduced trans-2-p-menthene with deuterium (Raney nickel catalyst) and 
obtained a 2 : 3-dideutero-tfra«s-^>-menthane (I) that was slightly lsevo- 
rotatory. Alexander (1950) also reduced (— )-menthyl toluene-/>-sulphonate 
and obtained an optically active 3-deutero-^a«s-j^-menthane (II). 

CH 3 ,0H 8 CH 3 CH 3 

CH ^CH 



Y : 



H 2 CHD CH 2 CHD 



CH 2 CHD CH 2 CH 2 

\)H CH 

I I 

CH 3 CH 3 

I II 

Some other optically active compounds with deuterium asymmetry are, 
e.g., (Ill; Streitwieser, 1955) and (IV; Levy et al, 1957): 

CH 3 -CH 2 -CH 2 -CHDOH CH 3 -CHDOH 

III IV 

A point of interest here is that almost all optically active deuterium com- 
pounds have been prepared from optically active precursors. Exceptions 
are (V) and (VI), which have been resolved by Pocker (1961). 

C 6 H 5 -CHOH-C 6 D s C 6 H 6 -CDOH-C 6 D 5 

V VI 

Further evidence for the tetrahedral carbon atom 

(i) Conversion of the two forms (enantiomorphs) of the molecule Cabde 



§3a] 



OPTICAL ISOMERISM 



25 



into Ca 2 bd results in the formation of one compound only (and disappearance 
of optical activity), e.g., both dextro- and laevorotatory lactic acid may be 
reduced to the same propionic acid, which is not optically active. These 
results are possible only with a tetrahedral arrangement (Fig. 7; see §5 for 
the convention for drawing tetrahedra). 



C0 2 H 




OH 



CH-, 



D-lactic acid 




HO 




propionic acid 
Fig. 2.7. 



CH 3 
L-lactic acid 



(u) If the configuration is tetrahedral, then interchanging any two groups 
in the molecule Cabde will produce the enantiomorph, e.g. b and e (see 
Fig. 8). Fischer and Brauns (1914), starting with (+)-wopropylmalonamic 





CONH 2 
I 
H— C— GH(CH 3 ) 2 

C0 2 H 
(+)-acid 



Fig. 2.8. 
CONH 2 
£MVH-C-CH(CH 3 ) 2 S^ 



C0 2 CH 3 



C0 2 H 
H— C — CH(CH 3 )!j 
C0 2 CH 3 




C0 2 H C0 2 H 



CONHNH 2 



CON, 



CONH 2 
(-)-acid 



acid earned out a series of reactions whereby the carboxyl and the carbon- 
amide groups were interchanged; the product was (-)-wopropylmalonamic 
acid. It is most important to note that in this series of reactions no bond 
connected to the asymmetric carbon atom was ever broken (for an explana- 
tion, see Walden Inversion, Ch. III). F 

i u T x iS x Cl i an J ge , fr ? m one enant iomorph into the other is in agreement with 
the tetrahedral theory. At the same time, this series of reactions shows 
that optical isomers have identical structures, and so the difference must 
be due to the spatial arrangement. 

(iii) X-ray crystallography, dipole moment measurements, absorption 
spectra and electron diffraction studies show that the four valencies of carbon 
are arranged tetrahedraUy with the carbon atom inside the tetrahedron 

It should be noted in passing that the tetrahedra are not regular unless 
four identical groups are attached to the central carbon atom; only in this 



26 



ORGANIC CHEMISTRY 



[CH. II 

case are the four bond lengths equal. In all other cases the bond lengths 
will be different, the actual values depending on the nature of the atoms 
joined to the carbon atom (see §15b. I). 

§4. Two postulates underlie the tetrahedral theory. 

(i) The principle of constancy of the valency angle. Mathematical 
calculation of the angle subtended by each side of a regular tetrahedron 
at the central carbon atom (Fig. 9) gives a value of 109° 28'. Originally, 
it was postulated (van't Hoff) that the valency angle was fixed at this value. 
It is now known, however, that the valency angle may deviate from this 
value. The four valencies of carbon are formed by hybridisation of the 



4^ 


// 


\ 


/ / 


\ 


/ i 


\ 




\ 


/ L 


«c \ 






f i 


*»\\ 


L/-C43J 


«/~^--''' 


Fig. 


2.9. 



2s a and 2p 2 orbitals, i.e., there are four sp 3 bonds (see Vol. I, Ch. II). 
Quantum mechanical calculations show that the four carbon valencies in 
the molecule Ca 4 are equivalent and directed towards the four corners of 
a regular tetrahedron. Furthermore, quantum-mechanical calculations re- 
quire the carbon bond angles to be close to the tetrahedral value, since 
change from this value is associated with loss in bond strength and con- 
sequently decrease in stability. According to Coulson et al. (1949), calcula- 
tion has shown that the smallest valency angle that one can reasonably 
expect to find is 104°. It is this value which is found in the cyc/opropane 
and cyc/obutane rings, these molecules being relatively unstable because of 
the " bent " bonds (Coulson; see Baeyer Strain Theory, Vol. I, Ch. XIX). 
(ii) The principle of free rotation about a single bond. Originally, 
it was believed that internal rotation about a single bond was completely 
free. When the thermodynamic properties were first calculated for ethane 
on the assumption that there was complete free rotation about the carbon- 
carbon single bond, the results obtained were in poor agreement with those 
obtained experimentally. This led Pitzer et al. (1936) to suggest that there 

H H 



c c c c 

b b b 



*x 


^v/H 




f 


R 


H-^O^H 


¥ 


H 


I 

stags 
(tra 

( 
Fig. 2.10. 


I 

ered 
ns) 




eel 
( 


ipsed 
is) 

c) 



0° 60° 120° 180° 240° 300° 360° 
Angle of Rotation 

(a) 



was restricted rotation about the single bond, and calculations on this basis 
gave thermodynamic properties in good agreement with the experimental 
ones. The potential energy curve obtained for ethane, in which one methyl 
group is imagined to rotate about the C — C bond as axis with the other 
group at rest, is shown in Fig. 10 (a). Had there been complete free rota- 
tion, the graph would have been a horizontal straight line. Fig. 10 (b) is 
the Newman (1952) projection formula, the carbon atom nearer to the eye 



§4] 



OPTICAI, ISOMERISM 



27 



being designated by equally spaced radii and the carbon atom further from 
the eye by a circle with three equally spaced radial extensions. Fig. 10 (b) 
represents the trans- or staggered form in which the hydrogen atoms (on 
the two carbon atoms) are as far apart as possible. Fig. 10 (c) represents 
the cis- or eclipsed form in which the hydrogen atoms are as close together 
as possible. It can be seen from the graph that the eclipsed form has a 
higher potential energy than the staggered, and the actual difference has 
been found to be (by calculation) about 2-85 kg.cal./mole. The value of 




0° 60° 120° 180° 240° 300° 360° 
Angle of Rotation 



CI 



CI 

staggered 
(trattsoid) 



CI 



CI 



Cl^-J^/H H \^-4-v/Cl 



^O^H H^O^H h-^O^h 



H 



H 



gauche or skew 




fully eclipsed 
(cisoid) 




eclipsed 
Fig. 2.11 (i). 



this potential energy barrier is too low to permit the isolation of each form 
by chemical methods. 

Now let us consider the case of ethylene chloride. According to Bern- 
stem (1949), the potential energy of ethylene chloride undergoes the changes 
shown m Fig. 2.11 (i) when one CH 2 C1 group is rotated about the C— C bond 
with the other CH 2 C1 at rest. There are two positions of minimum energy 
one corresponding to the staggered (transoid) form and the other to the 
gauche (skew) form, the latter possessing approximately 1-1 kg.cal. more 
than the former. The fully eclipsed (cisoid) form possesses about 4-5 kg cal 
more energy than the staggered form and thus the latter is the preferred 
form, i.e., the molecule is largely in this form. Dipole moment studies 
show that this is so in practice, and also show (as do Raman spectra studies) 
that the ratio of the two forms varies with the temperature. Furthermore 



28 



ORGANIC CHEMISTRY 



[CH. II 



infra-red, Raman spectra and electron diffraction studies have shown that 
the gauche form is also present. According to Mizushima et al. (1938), only 
the staggered form is present at low temperatures. 

The problem of internal rotation about the central C — C bond in w-butane 
is interesting, since the values of the potential energies of the various forms 
have been used in the study of cyclic compounds (see cyc/ohexane, §11. IV). 
The various forms are shown in Fig. 2.11 (ii), and if the energy content of 
the staggered form is taken as zero, then the other forms have the energy 
contents shown (Pitzer, 1951). 

From the foregoing account it can be seen that, in theory, there is no free 





1 1 




V 3 3 / 


t 

E 


w 

1 1 ¥ 1 r— 



3-6kg.cal. 
2-9kg.cal. 



--V/ 0-8kg.cal. 




0° 60° 120° 180° 240° 300° 360° 
Angle of Rotation 
Fig. 2.11 (ii). 

Me 



Me 



tt^^/Me Me^-^H 



H 
2 



H 
2' 





rotation about a single bond. In practice, however, it may occur if the 
potential barriers of the various forms do not differ by more than about 
10 kg.cal./mole. Free rotation about a single bond is generally accepted 
in simple molecules. Restricted rotation, however, may occur when the 
molecule contains groups large enough to impede free rotation, e.g., in ortho- 
substituted diphenyls (see Ch. V). In some cases resonance can give rise 
to restricted rotation about a " single " bond. 

§4a. Conformational analysis. Molecules which can form isomers by 
rotation about single bonds are called flexible molecules, and the different 
forms taken up are known as different conformations. The terms rota- 
tional isomers and constellations have also been used in the same sense as 
conformations. 

Various definitions have been given to the term conformation (which was 



§4a] OPTICAL ISOMERISM 29 

originally introduced by W. N. Haworth, 1929). In its widest sense, con- 
formation has been used to describe different spatial arrangements of a 
molecule which are not superimposable. This means, in effect, that the 
terms conformation and configuration are equivalent. There is, however, an 
important difference in meaning between these terms. The definition of 
configuration, in the classical sense (§1), does not include the problem of 
the internal forces acting on the molecule. The term conformation, how- 
ever, is the spatial arrangement of the molecule when all the internal' forces 
acting on the molecule are taken into account. In this more restricted 
sense, the term conformation is used to designate different spatial arrange- 
ments arising by twisting or rotation of bonds of a given configuration 
(used in the classical sense). 

The existence of potential energy barriers between the various conforma- 
tions shows that there are internal forces acting on the molecule The 
nature of these interactions that prevent free rotation about single bonds 
however, is not completely clear. According to one theory, the hindering 
of internal rotation is due to dipole-dipole forces. Calculation of the dipole 
moment of ethylene chloride on the assumption of free rotation gave a 
value not in agreement with the experimental value. Thus free rotation 
cannot be assumed, but on the assumption that there is interaction between 
the two groups through dipole-dipole attractive or repulsive forces there 
will be preferred conformations, i.e., the internal rotation is not completely 
free. This restricted rotation is shown by the fact that the dipole moment 
of ethylene chloride increases with temperature; in the staggered form the 
dipole moment is zero, but as energy is absorbed by the molecule rotation 
occurs to produce finally the eclipsed form in which the dipole moment is 
a maximum. Further work, however, has shown that factors other than 
djpole-dipole interactions must also be operating in opposing the rotation 
One of these factors is steric repulsion, i.e., repulsion between the non- 
bonded atoms (of the rotating groups) when they are brought into close 
proximity (cf. the van der Waals forces, §2. I). The existence of steric 
repulsion may be illustrated by the fact that although the bond moment 
of C— CI is greater than that of C— Br, the energy difference between the 
eclipsed and staggered conformations of ethylene chloride is less than that 
of ethylene bromide. Furthermore, if steric repulsion does affect internal 
rotation, then in the ethylene halides, steric repulsion between the hydrogen 
and halogen atoms, if sufficiently large, will give rise to two other potential 
energy minima (these correspond to the two gauche forms, and these have 
been shown to be present; see Fig. 2.11 (i), §4). 

Other factors also affect stability of the various conformations. Staggered 
and gauche forms always exist in molecules of the type CH.Y-CH.Z (where 
Y and'Z are CI, Br I, CH 3 , etc.), and usually the staggered forrn is more 
stable than the gauche. In a molecule such as ethylene chlorohydrin how- 
ever, it is the gauche form which is more stable than the staggered and this 
is due to the fact that intramolecular hydrogen bonding is possible in the 
former but not in the latter. 

In addition to the factors already mentioned, there appear to be other 
factors that cause the absence of complete free rotation about a single 
bond, e.g., the energy barrier in ethane is too great to be accounted for 
by steric repulsion only. Several explanations have been offered" es 
Pauling (1958) has proposed that the energy barrier in ethane (and in" 
similar molecules) results from repulsions between adjacent bonding pairs 
of electrons, i.e. the bonding pairs of the C— H bonds on one carbon atom 
repel those on the other carbon atom. Thus the preferred conformation 
will be the staggered one {cf. §1. VI). It is still possible, however that 
steric repulsion is also present, and this raises the barrier height 



30 ORGANIC CHEMISTRY [CH. II 

When the stability of a molecule is decreased by internal forces produced 
by interaction between constituent parts, that molecule is said to be under 
steric strain. There are three sources of steric strain, i.e., the internal 
forces may arise from three different causes, viz., (i) repulsion between non- 
bonded atoms, (ii) dipole interactions and (iii) distortion of bond-angles. 
Which of these plays the predominant part depends on the nature of the 
molecule in question. This study of the existence of preferred conforma- 
tions in molecules, and the relating of physical and chemical properties of 
a molecule to its preferred conformation, is known as conformational 
analysis. The energy differences between the various conformations deter- 
mine which one is the most stable, and the ease of transformation depends 
on the potential energy barriers that exist between these conformations. 
It should be noted that the molecule, in its unexcited state, will exist largely 
in the conformation of lowest energy content. If, however, the energy 
differences between the various conformations are small, then when excited, 
the molecule can take up a less favoured conformation, e.g., during the course 
of reaction with other molecules (see §11. IV). 

Because of the different environments a reactive centre may have in 
different conformations, conformation will therefore affect the course and 
rate of reactions involving this centre (see §11. IV). 

Many methods are now used to investigate the conformation of mole- 
cules, e.g., thermodynamic calculations, dipole moments, electron and X-ray 
diffraction, infra-red and Raman spectra, rotatory dispersion, NMR and 
chemical methods. 

§5. Conventions used in stereochemistry. The original method of 
indicating enantiomorphs was to prefix each one by d or I according as it 
was dextrorotatory or lsevorotatory. van't Hoff (1874) introduced a + 
and — notation for designating the configuration of an asymmetric carbon 
atom. He used mechanical models (built of tetrahedra), and the + and 
— signs were given by observing the tetrahedra of the mechanical model 
from the centre of the model. Thus a molecule of the type Cabd-Cabd may 

be designated + +, , and H . E. Fischer (1891) pointed out that 

this + and — notation can lead to wrong interpretations when applied to 
molecules containing more than two asymmetric carbon atoms (the signs 
given to each asymmetric carbon atom depend on the point of observation 
in the molecule). Fischer therefore proposed the use of plane projection 
diagrams of the mechanical models instead of the + and — system. 

Fischer, working on the configurations of the sugars (see §1. VII), obtained 
the plane formulae I and II for the enantiomorphs of saccharic acid, and 



C0 2 H 

1 
H— C— OH 

1 


C0 2 H 
HO— C— H 


CHO 
H— C— OH 
HO— C— H 
H— C— OH 
H— C— OH 

CH 2 OH 


HO— C— H 
H— C— OH 
H— C— OH 


H— C— OH 
HO— C— H 
HO— C— H 
C0 2 H 


C0 2 H 


I 


II 


III 



arbitrarily chose I for dextrorotatory saccharic acid, and called it d- 
saccharic acid. He then, from this, deduced formula III for rf-glucose. 
Furthermore, Fischer thought it was more important to indicate stereo- 



§°] OPTICAL ISOMERISM 31 

chemical relationships than merely to indicate the actual direction of rota- 
tion. He therefore proposed that the prefixes d and / should refer to 
stereochemical relationships and not to the direction of rotation of 
the compound. For this scheme to be self-consistent (among the sugars) 
it is necessary to choose one sugar as standard and then refer all the others 
to it. Fischer apparently intended to use the scheme whereby the com- 
pounds derived from a given aldehyde sugar should be designated according 
to the direction of rotation of the parent aldose. 

Natural mannose is dextrorotatory. Hence natural mannose will be 
rf-mannose, and all derivatives of rf-mannose, e.g., mannonic acid, mannitol 
mannose phenylhydrazone, etc., will thus belong to the ^-series. Natural 
glucose is dextrorotatory. Hence natural glucose will be rf-glucose and all 
its derivatives will belong to the rf-series. Furthermore, Fischer (1890) 
converted natural mannose into natural glucose as follows: 

i-mannose — > rf-mannonic acid — >. i-mannolactone — > rf-glucose 
Since natural glucose is rf-glucose (according to Fischer's scheme) the pre- 
fix d for natural glucose happens to agree with its dextrorotation (with 
rf-mannose as standard) . Natural fructose can also be prepared from natural 
mannose (or natural glucose), and so will be i-fructose. Natural fructose 
however, is laevorotatory, and so is written as d{~) -fructose, the symbol d 
indicating its stereochemical relationship to the parent aldose glucose and 
the symbol - placed in parentheses before the name indicating the actual 
direction of rotation. 

More recently the symbols d and / have been replaced by d and l for 
configurational relationships, e.g., L(+)-lactic acid. Also, when dealing 
with compounds that cannot be referred to an arbitrarily chosen standard 
(+)- and (— )- are used to indicate the sign of the rotation. The prefixes 
dextro and laevo (without hyphens) are also used. 

Fischer's proposal to use each aldose as the arbitrary standard for its 
derivatives leads to some difficulties, e.g., natural arabinose is dextrorotatory 
and so is to be designated D-arabinose. Now natural arabinose (D-arabinosej 
can be converted into mannonic acid which, if D-arabinose is taken as the 
parent aldose, will therefore be D-mannonic acid. This same acid however 
can also be obtained from L-mannose, and so should be designated as 
L-mannonic acid. Thus in cases such as this the use of the symbol d or l 
will depend on the historical order in which the stereochemical relationships 
were established. This, obviously, is an unsatisfactory position, which was 
realised by Rosanoff (1906), who showed that if the enantiomorphs of 
glyceraldehyde (a molecule which contains only one asymmetric carbon 
atom) are chosen as the (arbitrary) standard, then a satisfactory system 
for correlating stereochemical relationships can be developed. He also pro- 
posed that the formula of dextrorotatory glyceraldehyde should be written 
as in Fig. 12 (c), in order that the arrangement of its asymmetric carbon 
atom should agree with the arrangement of C s in Fischer's projection 
formula for natural glucose (see formula III above). 

It is of great interest to note in this connection that in 1906 the active 
forms of glyceraldehyde had not been isolated, but in 1914 Wohl and Momber 
separated DL-glyceraldehyde into its enantiomorphs, and in 1917 they showed 
that dextrorotatory glyceraldehyde was stereochemically related to natural 
glucose, i.e., with d(+) -glyceraldehyde as arbitrary standard, natural glucose 
is d(+ )-glucose (see §1. VII). 6 

The accepted convention for drawing D(+)-glyceraldehyde— the agreed 
{arbitrary) standard— is shown in Fig. 12 («). The tetrahedron is drawn so 
that three corners are imagined to be above the plane of the paper, and the 
fourth below the plane of the paper. Furthermore, the spatial arrangement 



32 



ORGANIC CHEMISTRY 



[CH. II 

of the four groups joined to the central carbon atom must be placed as 
shown in Fig. 12 (a), i.e., the accepted convention for drawing d(+)- 
glyceraldehyde places the hydrogen atom at the left and the hydroxyl 
group at the right, with the aldehyde group at the top corner. Now 

imagine the tetrahedron to rotate about the horizontal line joining H and 
OH until it takes up the position shown in Fig. 12 (b). This is the con- 
ventional position for a tetrahedron, groups joined to full horizontal lines 



CHO 



CHO 



CHO 



CHO 




OH HO- 



CH 2 OH 
(d) 



being above the plane of the paper, and those joined to broken vertical lines 
being below the plane of the paper. The conventional plane-diagram is 
obtained by drawing the full horizontal and broken vertical lines of Fig. 12 (b) 
as full lines, placing the groups as they appear in Fig. 12 (b), and taking the 
asymmetric carbon atom to be at the point where the lines cross. Although 
Fig. 12 (c) is a plane-diagram, it is most important to remember that hori- 
zontal lines represent groups above the plane, and vertical lines groups 
below the plane of the paper. Many authors prefer to draw Fig. 12 (c) 
[and Fig. 12 (d)] with a broken vertical line. Fig. 12 {d) represents the 
plane-diagram formula of l(— )-glyceraldehyde ; here the hydrogen atom is 
to the right and the hydroxyl group to the left. Thus any compound that can 
be prepared from, or converted into, D(+)-glyceraldehyde will belong to 
the D-series. Similarly, any compound that can be prepared from, or con- 
verted into, l(— )-glyceraldehyde will belong to the L-series. When repre- 
senting relative configurational relationship of molecules containing more 
than one asymmetric carbon atom, the asymmetric carbon atom of glycer- 
aldehyde is always drawn at the bottom, the rest of the molecule being built 
up from this unit. 





D-senes 



L-senes 



Thus we have a scheme of classification of relative configurations based 
on D(+)-glyceraldehyde as arbitrary standard. Even on this basis con- 
fusion is still possible in relating configurations to the standard (see later). 

Until recently there was no way of determining, with certainty, the 
absolute configuration of molecules. Arbitrary choice makes the configura- 
tion of D(+)-glyceraldehyde have the hydrogen to the left and the hydroxyl 
to the right. Bijvoet et al. (1951), however, have shown by X-ray analysis 
of sodium rubidium tartrate that it is possible to differentiate between the 
two optically active forms, i.e., it is possible to determine the absolute con- 
figuration of these two enantiomorphs. These authors showed that natural 
dextrorotatory tartaric acid has the configuration assigned to it by Fischer 
(who correlated its configuration with that of the saccharic acids). The 
configurations of the tartaric acids are a troublesome problem. Fischer 



§5] OPTICAL ISOMERISM 33 

wrote the configuration of natural dextrorotatory tartaric acid as IV. If 
we use the convention of writing the glyceraldehyde unit at the bottom, 

COjjH C0 2 H 

H—C— OH HO — O— H 

I I 

HO— C— H H—C— OH 

I I 

C0 2 H C0 2 H 

IV V 

then IV is L(+)-tartaric acid and V D(-)-tartaric acid. This relationship 
(to glyceraldehyde) is confirmed by the conversion of d(+) -glyceraldehyde 



CHO CN 



CN 

H-O-OH HcN H-C*- OH HO-C 2 -H 

I >- | + I 

CH 2 OH H -_ C _ 0H H _ c 0H 

I I 

D(+) -glyceraldehyde CH 2 OH CH 2 OH 



C0 2 H C0 2 H 

I I 

(0 hydrolysis H— Cr-OH HO— C 2 — H 

(ii) oxidation • "*" f 

H—C!— OH H — C.— OH 

I I 1 

C0 2 H G0 2 H 

mesotartaric (-)-tartaric 

acid acid 

into tevorotatory tartaric acid via the Kiliani reaction (see Vol. I) Thus 
(-)-tartanc acid is D(-)-tartaric acid (V). On the other hand, (+)-tartaric 
^ .^te.conyjrtei into D(-)-glyceric acid, and so (+)-tartaric acid is 
D(+)-tartaric acid (IV). In this reduction of (+)-tartaric acid to (+)-malic 

C0 2 H O0 2 H COiH. 

H— C 2 — OH H— C 2 — OH H— C 2 — OH 

I ►- I >- | 

HO-C-H CH 2 CH 2 

e 2 H C0 2 H CONH 2 

IV (+)-maIic (+)-p-malamic 

acid acid 



COaH C0 2 H CHO 

I I I 

■ H-C 2 — OH 5- H -C„-OH -* H-G— OH 

I I I 

CH 2 -NH 2 CH 2 OH CH 2 OH 

(+)-KO'serine D(-) -glyceric D(+) -glyceraldehyde 

acid 



-C x -I 

C0 2 H Co 2 H C0 2 H 

IV (-f)-malic d(— )-glyceric 



34 ORGANIC CHEMISTRY [CH. II 

acid (by hydriodic acid), it has been assumed that it is C x which has been 
reduced, i.e., in this case the configuration of C 2 has been correlated with 
glyceraldehyde and not that of Cj as in the previous set of reactions. Had, 
however, C 2 been reduced, then the final result would have been (+)-tartaric 
acid still through the intermediate, {-\-)-malic acid (two exchanges of groups 
give the same malic acid as before). Since (+)-malic acid has been correlated 

COJE C0 2 H 

I I 

H— C 2 — OH CH 2 CH 2 OH 

I ~> I "> I 

HO— ty— H HO— C— H HO— C!— H 

CC 

-me 
acid acid 

with (-f)-glyceraldehyde (see §9a), (+)-tartaric acid should be designated 
D(+)-tartaric acid. The designation L(+)-tartaric acid is used by those 
chemists who regard this acid as a carbohydrate derivative (see also §5a). 

§5a. Correlation of configurations. As we have seen (§5), since the 
relative configurations of (+)-tartaric acid and (-f)-glycer aldehyde have 
been established, it is now possible to assign absolute configurations to many 
compounds whose relative configurations to (+)-glyceraldehyde are known, 
since the configurations assigned to them are actually the absolute con- 
figurations. The methods used for correlating configurations are: 

(i) Chemical reactions without displacement at the asymmetric centre 
concerned (see §5b). 

(ii) Chemical reactions with displacement at the asymmetric centre con- 
cerned (see the Walden inversion, §§3, 4. III). 

(iii) X-ray analysis (see §5). 

(iv) Asymmetric inductive correlation (see asymmetric synthesis, §7. III). 

(v) Optical rotations: (a) Monochromatic rotations (see, e.g., carbo- 
hydrates, §6. VII; steroids, §4b. XI). (6) Rotatory dispersion (see steroids, 
§4b. XI). 

(vi) The study of quasi-racemic compounds (see §9a). 

(vii) Enzyme studies. 

§5b. Correlation of configurations without displacement at the 
asymmetric centre concerned. Since no bond joined to the asymmetric 
centre is ever broken, this method is an extremely valuable method of 
correlation. Before discussing examples, the following point is worth noting. 
For amino-acids, natural (— )-serine, CH 2 OH'CH(NH 2 )-C0 2 H, was chosen 
as the arbitrary standard. Thus correlation with glyceraldehyde was indi- 
cated by D, or l„, and with serine by d, or l,. These two standards have 
now been correlated, and it has been shown that l„ = l s , i.e., natural 
(— )-serine belongs to the L-series (with glyceraldehyde as absolute standard; 
see also §4. XIII). 

The following examples illustrate this method of correlation. 

(i) 

CHO C0 2 H C0 2 H C0 2 H 



HO- 



-h ae*. ho- 



_ H J™°! ho- 



_ H ™^ H0 - 



-H 



CH 2 OH CH 2 OH CH 2 NH 2 CH 2 Br 

l(— ) -glyceraldehyde l(+) -glyceric acid l(— )-»soserine L- 



§6c] 



OPTICAL ISOMERISM 



35 



Na/Hg I 

' > HO — f- 



00 2 H 



-H 



CH 3 

L(+)-lactic acid 

It can be seen from this example that change in the sign of rotation does 
not necessarily indicate a change in configuration. 
(») 

Me Me Me 

(i) EtOH/HCl | „ HBr 



HO- 



co 2 "h (u)Na / EtOH 

r>(—) -lactic acid 



(i) KCN 



HO- 



-j H 

CH 2 OH 

D- 



HO- 



-J — H 
CH 2 Br 



Me 



HO- 



-H 



(iii) 



(ii) hydrolysis 

OH 2 -00 2 H 

r>{— )-£-hydroxybatyric acid 



Me 



H- 



-OH 



(i) EtOH/HCl 
(ii) Na/EtOH *" 

CH 2 C0 2 H 

*-(+)-£-hydroxybutyric acid 



Me 



H 



Me 



OH 



HT 



H- 



CH 2 CH 2 OH 

Me 
H OH 



-OH 
CH 2 CH2l 



CH 2 *CH3 

L(+)-butan-2-ol 

(iv) Another example is that in the terpene series (see §23e. VIII). 

u § ? C ' mE!^ 51 * 1011 °, f as ymmetric configurations. Cahn, Ingold and 
Frelog (1956) have produced a scheme for the specification of absolute con- 
figurations. Let us consider the procedure for a molecule containing one 
asymmetric carbon atom. 

(i) The four groups are first ordered according to the sequence rule. 
According to this rule, the groups are arranged in decreasing atomic number 
pt the atoms by which they are bound to the asymmetric carbon atom 
11 two or more of these atoms have the same atomic number, then the 
relative priority of the groups is determined by a similar comparison of 
the atomic numbers of the next atoms in the groups (i.e., the atoms joined 
to the atom joined to the asymmetric carbon atom). If this fails then the 
next atoms of the groups are considered. Thus one works outwards from 
the asymmetric carbon atom until a selection can be made for the sequence 
of the groups. ^ 

(ii) Next is determined whether the sequence describes a right- or left- 
handed pattern on the molecular model as viewed according to the con- 
version rule. When the four groups in the molecule Cubed have been 
ordered in the priority a, b, c, d, the conversion rule states that their spatial 
pattern shall be described as right- or left-handed according as the sequence 
a—>b-±c is clockwise or anticlockwise when viewed from an external 
point on the side remote from d (the group with the lowest priority) e g 
(I) m Fig. 13 shows a right-handed (i.e., clockwise) arrangement 



36 



ORGANIC CHEMISTRY 



[CH. II 

(iii) Absolute configuration labels are then assigned. The asymmetry 
leading under the sequence and conversion rules to a right- and left-handed 

b 



/ 
-Cr-~ 

c 

(I) 



■> 




Fig. 2.13. 



pattern is indicated by R and S respectively (R; rectus, right: S; sinister, 
left). 

Let us first consider bromochloroacetic acid (II). The priority of the 
groups according to the sequence rule is Br (a), CI (b), C0 2 H (c) and H {d). 

b CI 



Br- 



H 
(II) 



-C0 2 H 



Hence by the conversion rule, (II) is the (R)-form {a — > b — »■ c is clockwise). 

Now let us consider D(+)-glycer aldehyde. By convention it is drawn as 

III (this is also the absolute configuration). Oxygen has the highest priority 

CHO CHO CHO b 



H- 



-OH 



CH 2 OH- 



-OH HO ■ 



-CH 2 OH a- 



CH 2 OH 

III 



H 

IV 



H 

V 



d 

VI 



and H the lowest. Thus OH is a and H is d. Since both the CHO and 
CH 2 OH groups are attached to the asymmetric carbon by carbon, it is 
necessary to determine the priorities of these two groups by working out- 
wards. The C of the CHO is bound to (H, 0=) and that of the CH 2 OH 
to (H, H, OH). When a double or triple bond is present in the group, 
the atom at the remote end of the multiple bond is regarded as duplicated 
or triplicated, respectively. Thus the double-bonded oxygen atom gives 
higher priority to the CHO group (=H, O, O). Hence CHO is- b and 
CH 2 OH is c. Since the interchanging of two groups inverts the configura- 
tion, the sequence (III) — > (IV) — > (V) gives the original configuration. 
Since (V) corresponds to (VI), it thus follows that D(+)-glyceraldehyde is 
(2?) -glyceraldehyde. 



C0 2 H 



H- 



r- OH 
CHOH-C0 2 H 



H- 
HO- 



C0 2 H 
-OH 
H 



= HO- 



CH0H-C0 2 H 



-H 



C0 2 H 



C0 2 H 



(2 interchanges) 



I (2 interchanges) 



HO- 



C0 2 H 

-y-CHOHC0 2 H 
H 



HO- 



CO-H 



-CHOHCO.H 



H 



§6] 



OPTICAL ISOMERISM 



37 



When a molecule contains two or more asymmetric carbon atoms, each 
asymmetric carbon atom is assigned a configuration according to the sequence 
and conversion rules and is then specified with R or 5, e.g., (+) -tartaric 
acid. Thus the absolute configuration of (+) -tartaric acid is (RR) -tartaric 
acid [this clearly indicates the relationship between (+) -tartaric acid and 
D(+)-glyceraldehyde]. 

In a similar way it can be demonstrated that D(+)-glucose has the 
absolute configuration shown. 



H- 

HO- 

H- 

H- 



CHO 

-OH (R) 
-H (S) 
-OH (R) 
-OH (.R) 
CH 2 OH 
D(+)-glucose 

The system has also been extended to include asymmetric molecules 
which have no asymmetric carbon atoms, e.g., spirans, diphenyls, etc. 

§6. Elements of symmetry. The test of superimposing a formula (tetra- 
hedral) on its mirror image definitely indicates whether the molecule is 
symmetrical or not ; it is asymmetric if the two forms are not superimposable. 
The most satisfactory way in which superimposability may be ascertained 
is to build up models of the molecule and its mirror image. Usually this is 
not convenient, and so, in practice, one determines whether the molecule 
possesses (i) a plane of symmetry, (ii) a centre of symmetry or (iii) an alter- 
nating axis of symmetry. If the molecule contains at least one of these 
elements of symmetry, the molecule is symmetrical; if none of these elements 
of symmetry is present, the molecule is asymmetric. 

It should be remembered that it is the Fischer projection formula that 
is normally used for inspection. As pointed out in §2, it is necessary, when 
dealing with conformations, to ascertain whether at least one of them has 
one or more elements of symmetry. If such a conformation can be drawn, 
then the compound is not optically active. 

(i) A plane of symmetry divides a molecule in such a way that points 
(atoms or groups of atoms) on the one side of the plane form mirror images 
of those on the other side. This test may be applied to both solid (tetra- 
hedral) and plane-diagram formulae, e.g., the plane-formula of the meso- 
form of Cabd'Cabd possesses a plane of symmetry; the other two, (+) and 
(— ), do not 



a- 
d- 



-d d- 
-a a~ 



b 
(+)-form 



-a 
-d 



b 

(-)-form 



a- 
a- 



b 
meso form 



- plane of 
symmetry 



(u) A centre of symmetry is a point from which lines, when drawn on 
one side and produced an equal distance on the other side, will meet exactly 
similar points in the molecule. This test can be satisfactorily applied only 



38 



ORGANIC CHEMISTRY 



[CH. II 

to three-dimensional formulae, particularly those of ring systems, e.g., 2 : 4- 
dimethylcycfobutane-1 : 3-dicarboxylic acid (Fig. 14). The form shown pos- 
sesses a centre of symmetry which is the centre of the ring. This form is 
therefore optically inactive. 

Another example we shall consider here is that of dimethyldiketopiper- 
azine; this molecule can exist in two geometrical isomeric forms, cis and 



« 


- H 3 

\ 




-0 2 H 


/ H 

H_Z 

/ 




\~7 


H 


:o 2 h 


\ 
\ 

\ 
CH 3 

Fig. 2.14. 



trans (see also §11. IV). The cw-isomer has no elements of symmetry and 
can therefore exist in two enantiomorphous forms; both are known. The 
fraws-isomer has a centre of symmetry and is therefore optically inactive. 



CH 3 CH 3 

I CO NH| 

| N NH — ccy | 



<?H 3 B 

I XX> NHI 



H 



H 



cts 



?H 3 
,CO NHl 

< • > 

| N NH — CO | 

H CH 3 

trans 



It is important to note that only even-membered rings can possibly possess 
a centre of symmetry. 

(iii) Alternating axis of symmetry. A molecule possesses an «-fold 
alternating axis of symmetry if, when rotated through an angle of 360°/« 
about this axis and then followed by reflection in a plane perpendicular 
to the axis, the molecule is the same as it was in the starting position. Let 
us consider the molecule shown in Fig. 15 (a) [1 : 2 : 3 : 4-tetramethylcyc/o- 
butane]. This contains a four-fold alternating axis of symmetry. Rota- 



H S C A 




H 



CH 3 / CH 3 H3C 



(a) 




2 


;+ 






I 


1 




1 


i 






z 


/ 


i 




y 


1 




*/ 


h/i 


1 


Z + / 


/z- 2 


r+ / 


/ z - 


H / 


/ H 


A 




4 




(0 


A 




3 


















id) 


z~ 




I 


1 




I 


1 






2 


r 





Fig. 2.15. 



§6] 



OPTICAL ISOMERISM 



39 



turn of (a) through 90° about axis AB which passes through the centre of 
the ring perpendicular to its plane gives {b), and reflection of (6) in the 
plane of the ring gives (a). It also happens that this molecule possesses 
two vertical planes of symmetry (through each diagonal of the ring), but 
if the methyl groups are replaced alternately by the asymmetric groups 
(+)— CH(CH 3 )-C a H 8 and (_)_CH(CH 3 )-C 2 H B) represented by Z+ and ir- 
respectively, the resulting molecule (Fig. 15c) now has no planes of sym- 
metry. Nevertheless, this molecule is not optically active since it does 
possess a four-fold alternating axis of symmetry [reflection of Id) (which 
is produced by rotation of (c) through 90° about the vertical axis) in the 
plane of the ring gives (c); it should be remembered that the reflection of 
a (+)-form is the (— )-form]. 

The cyc/obutane derivative (c) given above to illustrate the meaning of 
an alternating axis of symmetry is an imaginary molecule. No compound 
was known in which the optical inactivity was due to the existence of only 

H 



<JH,"1 




^CH 3 


*S 




\ + hT 


CH^ 


W 


-vH 


^CH 3 


v\ 


CH 3 ^ 




^H 


CHf 





I 



II 



an alternating axis until McCasland and Proskow (1956) prepared such a 
molecule for the first time. This is a spiro-type of molecule (§7. V), viz. 
3:4:3': 4'-tetramethylspiro-(l : l')-dipyrrolidinium ^-toluenesulphonate, I 
(the ^-toluenesulphonate ion has been omitted). This molecule is discussed 
in some detail in §2a. VI, but here we shall examine it for its alternating 
axis of symmetry. Molecule I is superimposable on its mirror image and 
hence is not optically active. It does not contain a plane or centre of 
symmetry, but it does contain a four-fold alternating axis of symmetry 
To show the presence of this axis, if I rotated through 90° about the co- 
axis of both rings, II is obtained. Reflection of II through the central 
plane (i.e., through the N atom) perpendicular to this axis gives a mole- 
cule identical and coincident with I. 

McCasland et al. (1959) have now prepared a second compound, a pentaery- 
thritol ester, whose optical inactivity can be attributed only to the presence 

?L a Tr?^" fold alternatin g axi s of symmetry (R = menthyl radical; see 
§16. VIII): 

(-)-ROCH 2 COOCH, ^CHa-OCOCHijOR (-) 

(+)-RO- CH 2 COO- Cft/ ^CRVO- CO • City OR (+) 

In practice one decides whether a molecule is symmetrical or not by 
looking only for a plane or centre of symmetry, since no natural compound 
has yet been found to have an alternating axis of symmetry. The presence 
of two or more asymmetric carbon atoms will definitely give rise to optical 
isomerism, but nevertheless some isomers may not be optically active because 
these molecules as a whole are not asymmetric (see §7d). 



40 



ORGANIC CHEMISTRY 



[CH. II 



§7. The number of isomers in optically active compounds. The 

number of optical isomers that can theoretically be derived from a mole- 
cule containing one or more asymmetric carbon atoms is of fundamental 
importance in stereochemistry. 

§7a. Compounds containing one asymmetric carbon atom. With 
the molecule Cabde only two optical isomers are possible, and these are 
related as object and mirror image, i.e., there is one pair of enantiomorphs, 
e.g., d- and L-lactic acid. If we examine an equimolecular mixture of dextro- 
rotatory and laevorotatory lactic acids, we shall find that the mixture is 
optically inactive. This is to be expected, since enantiomorphs have equal 
but opposite rotatory power. Such a mixture (of equimolecular amounts) 
is said to be optically inactive by external compensation, and is known 
as a racemic modification (see also §9). A compound which is optically 
inactive by external compensation is known as the racemic compound 
and is designated as r-, (±)- or dl-, e.g., r-tartaric acid, (ij-limonene, 
DL-lactic acid. 

Thus a compound containing one asymmetric carbon atom can exist in 
three forms: (+)-. (— ) and (±). 

Conversion of molecule Ca 2 bd into Cabde. Let us consider as an example 
the bromination of propionic acid to give oc-bromopropionic acid. 

CH 3 -CH 2 -C0 2 H ^*> CH 3 -CHBr-C0 2 H 

II and III (Fig. 16) are enantiomorphs, and since molecule I is symmetrical 
about its vertical axis, it can be anticipated from the theory of probability 



CO z H 




C0 2 H 




CQ 2 H 




that either hydrogen atom should be replaced equally well to give (±)-a- 
bromopropionic acid. This actually does occur in practice. 

§7b. Compounds containing two different asymmetric carbon 
atoms. When we examine the molecule Cabd'Cabe, e.g., a : /?-dibromo- 
butyric acid, CH 3 *CHBrCHBr*C0 2 H, we find that there are four possible 
spatial arrangements for this type of molecule (Fig. 17). I and II are 
enantiomorphs (the configurations of both asymmetric carbon are reversed), 







b 


b 


b 


b 


I 


II 


III 

Fig. 2.17. 


IV 



and an equimolecular mixture of them forms a racemic modification; simi- 
larly for III and IV. Thus there are six forms in all for a compound of 
the type Cabd-Cabe: two pairs of enantiomorphs and two racemic modifica- 
tions. 

I and III are not identical in configuration and are not mirror images 



OPTICAL ISOMERISM 



41 



§7b] 

(the configuration of one of the two asymmetric carbon atoms is reversed) ; 
they are known as diastereoisomers, i.e., they are optical isomers but 
not enantiomorphs (mirror images). Diastereoisomers differ in physical 
properties such as melting point, density, solubility, dielectric constant and 
specific rotation. Chemically they are similar, but their rates of reaction 
with other optically active compounds are different Icf. the properties of 
enantiomorphs, §2). 

The plane-diagrams of molecules I-IV (Fig. 17) will be V-VIII, respec- 
tively, as shown. It should be remembered that groups joined to hori- 
zontal lines lie above the plane of the paper, and those joined to vertical 
lines lie below the plane of the paper (§5). 



a- 
a- 



-d 

-e 



d- 
e- 



b 
V 



-a 

-a 



a- 
e- 



b 
VI 



b 



-d 

-a 



d- 
a- 



b 
VII 



-a 
-e 



b 
VIII 




or 




Instead of writing down all the possible configurations, the number of 
optical isomers for a compound of the type Cabd-Cabe may be obtained by 
indicating the configuration of each asymmetric carbon atom by the symbol 
+ or — , or by d or l; thus: 

+ - ». Li 

DL 

Conversion of molecule Ca z b-Cabe into Cabd-Cabe. Let us consider the 
brommation of /?-methylvaleric acid to give a-bromo-0-methylvaleric acid. 

CH 3 .CH 2 -CH(CH3)-CH a .C0 2 H ^ CH 3 -CH 2 -CH(CH 3 ).CHBr-C0 2 H 
/?-Methylvaleric acid contains one asymmetric carbon atom, but the bromine 
derivative contains two. Let us first consider the case where the configura- 
tion of the asymmetric carbon atom in the starting material is d, (IX) 
Brommation of this will produce molecules X and XI; these are diastereo- 
isomers and are produced in unequal amounts. This is to be anticipated- 
the two a-hydrogen atoms are not symmetrically placed with respect to 
the lower half of the molecule, and consequently different rates of sub- 
stitution can be expected. In the same way, brommation of the starting 
material in which the configuration of the asymmetric carbon atom is L, 
(XII) leads to the formation of a mixture of diastereoisomers (XIII and 
XIV) in unequal amounts. One can expect, however, that the amount of 
XIII produced from XII would be the same as that of X from IX since 



C0 2 H 



H- 
H- 



COjjH 



D» 



-Br 



C 2 H 5 
X 



CH, 



3- 
H- 



C0 2 H 



D 4 

C2H5 
IX 



-H 
-CHj 



Br- 



C 2 H 5 
XI 



-CH, 



42 ORGANIC CHEMISTRY [CH. II 

in both cases, the positions of the bromine atoms with respect to the methyl 
group are the same. Similarly, the amount of XIV from XII will be the 
same as that of XI from IX. Thus bromination of (±)-/?-methylvaleric 



C0 2 H 



Br- 



CHr 



C0 2 H 



-H 



L, 



-H 



H- 
CHo- 



COj-H 



-H 



Lx 



-H 



H- 
CH,- 



Lx 



-Br 
-H 



C 2 H S C 2 H 5 C 2 H 5 

XIII XII XIV 

acid will result in a mixture of four bromo derivatives which will consist 
of two racemic modifications in unequal amounts, and the mixture will be 
optically inactive. 

§7c. Compounds containing three different asymmetric carbon 
atoms. A molecule of this type is Cabd'Cab-Cabe, e.g., the pentoses, and 
the number of optical isomers possible is eight (four pairs of enantiomorphs) : 



r> 3 1.3 





DL 



DL 



DL 



All the cases discussed so far are examples of a series of compounds which 
contain n structurally distinct carbon atoms, i.e., they belong to the series 
Cabd'(Cab) n -2'Cabe. In general, if there are n asymmetric carbon atoms in 
the molecule (of this series), then there will be 2*» optically active forms and 
2** -1 resolvable forms (i.e., 2 n_1 pairs of enantiomorphs). These formulae 
also apply to monocyclic compounds containing n different asymmetric 
carbon atoms; they may or may not apply to fused ring systems since 
spatial factors may play a part in the possible existence of various con- 
figurations (see, e.g., camphor, §23a. VIII). 

§7d. Compounds of the type Cabd^CaVj^Cabd. In compounds of 
this type the two terminal asymmetric carbon atoms are similar, and the 
number of optically active forms possible depends on whether x is odd or 
even. 



(i) EVEN SERIES 

(a) Cabd'Cabd, e.g., tartaric acid. In a compound of this type the rota- 
tory power of each asymmetric carbon atom is the same. Now let us con- 
sider the number of optical isomers possible. 



D 


L 


D 


L 


D 


L 


L 


D 


I 


II 


III 


IV 



In molecules I and II, the upper and lower halves reinforce each other; 
hence I, as a whole, has the dextro- and II, the lsevo-configuration, i.e., I and 
II are optically active, and enantiomorphous. On the other hand, in III 
the two halves are in opposition, and so the molecule, as a whole, will not 
show optical activity. It is also obvious that III and IV are identical, 
i.e., there is only one optically inactive form of Cabd'Cabd. Molecule III 
is said to be optically inactive by internal compensation. Molecule III 



OPTICAL ISOMERISM 



43 



§7d] 

is known as the meso-form, and is a diastereoisomer of the pair of enantio- 
morphs I and II. The meso-iorm is also known as the inactive form and is 
represented as the t'-form; the meso-torm cannot be resolved (see also 
§10). Thus there are four forms possible for the molecule Cabd'Cabd: one 
pair of enantiomorphs, one racemic modification and one tneso- (*-) form. 
These forms for tartaric acid are: 



COjH 



HO- 
H- 



C0 2 H 



-H H- 

-OH HO- 



CQjH 

L- 



C0 2 H 



-OH 
-H 



H- 
H- 



CO s H 



-OH , 
plane of 

_ jj symmetry 



COgH 
meso~(i-) 



DL- 



Inspection of these formula; shows that the d- and l- forms do not possess 
any elements of symmetry; the meso-form, however, possesses a plane of 
symmetry. 

(6) Cabd'Cab'Cab-Cabd, e.g., saccharic acid, 

C0 2 H-CHOH-CHOH-CHOH-CHOH-CO a H. 

The rotatory powers of the two terminal asymmetric carbon atoms are 
the same, and so are those of the middle two (the rotatory powers of the 
latter are almost certainly different from those of the former; equality 
would be fortuitous). The possible optical isomers are as follows (V-XIV) : 




Li 
*>a 
d 2 



VII VIII IX 



L a 
»l 

X 



D, 



Li 
La 



DL 



DL 



XI XII 

DL 



»1 

La 

Li 

XIII 



"1 
La 
D 2 

Li 

XIV 



meso-iorms 



Molecules V and VI are optically active (enantiomorphous) and are not 
"internally compensated"; VII and VIII are optically active (enantio- 
morphous) and are not " internally compensated "; IX and X are optically 
active (enantiomorphous) but are " internally compensated at the ends "; 
XI and XII are optically active (enantiomorphous) but are " internally 
compensated in the middle "; XIII and XIV are meso-iorms and are optic- 
ally inactive by (complete) internal compensation. Thus there are eight 
optically active forms (four pairs of enantiomorphs), and two meso-forms. 
In general, in the series of the type Cabd'{Cab) n - 2 -Cabd, if n is the number 
of asymmetric carbon atoms and « is even, then there will be 2 n ~ 1 optically 

active forms, and 2~ weso-forms. 



(H) ODD SERIES 

(a) Cabd-Cab-Cabd, e.g., trihydroxyglutaric acid. If the two terminal 
asymmetric carbon atoms have the same configuration, then the central 
carbon atom has two identical groups joined to it and hence cannot be 
asymmetric. If the two terminal configurations are opposite, then the 
central carbon atom has apparently four different groups attached to it 



44 



ORGANIC CHEMISTRY 



[CH. II 

(the two ends are mirror images and not superimposable). Thus the central 
carbon atom becomes asymmetric, but at the same time the two terminal 
atoms "compensate internally" to make the molecule as a whole sym- 
metrical (there is now a plane of symmetry), and consequently the com- 
pound is not optically active. In this molecule the central carbon atom 

Cabd d l d d 



1 

Cab 
1 




-^•t>"- 


..I'.jj.'— 


plane of 
symmetry 


Cabd 


D L 


L 


L 






XV XVI 


XVII 
meso 


XVIII 

meso 





DL 

is said to be pseudo-asymmetric, and is designated " d " and " L " (or © 
and if the + and — convention is used; §7b). There will, however, be 
two meso-ioims since the pseudo-asymmetric carbon atom can have two 
different configurations (see XV-XVIII). Thus there are five forms in all: 
two optically active forms (enantiomorphs), one racemic modification, and 
two meso-ioxms. The following are the corresponding trihydroxyglutaric 
acids, all of which are known. 



C0 2 H 



HO 



H- 



H- 



CO ? H 



C0 2 H 



CO,H 



-H H- 

-OH HO- 
-OH HO- 



-OH H- 
-H H- 

-H H- 



-OH H- 
-OH HO- 
-OH H- 



-OH 

-H 

-OH 



C0 2 H 
D 



C0 2 H 
L 



C0 2 H 
meso 



C0 2 H 
meso 



(b) Cabd-Cab'Cab-Cab-Cabd. In this molecule the central carbon atom is 
pseudo-asymmetric when the left-hand side of the molecule has the opposite 
configuration to that of the right-hand side; the central carbon atom is sym- 
metrical when both sides have the same configuration. In all other cases the 
central carbon atom is asymmetric, the molecule now containing five asymmetric 
carbon atoms. The following table shows that there are sixteen optical isomers 
possible, of which twelve are optically active (six pairs of enantiomorphs), and 
four are meso-forms. 

Ends with opposite configurations 






"d' 



D, 



meso 



meso 



Ends with the same configurations 



DL 



DL 



§ 8 3 OPTICAL ISOMERISM 46 

Molecule with five asymmetric carbon atoms 







In general, in the series of the type Cabd'(Cab) n - s -Cabd, if n is the number 
of asymmetric " carbon atoms and n is odd, then there will be 2"- 1 optical 

isomers, of which 2"T~ are meso-iorms and the remainder optically active 
forms. 

§8. The racemic modification. The racemic modification is an equi- 
molecular mixture of a pair of enantiomorphs, and it may be prepared in 
several ways. 

(i) Mixing of equimolecular proportions of enantiomorphs produces the 
racemic modification. 

(ii) Synthesis of asymmetric compounds from symmetrical compounds 
always results in the formation of the racemic modification. This state- 
ment is true only if the reaction is carried out in the absence of other 
optically active compounds or circularly polarised light (see asymmetric 
synthesis, §7. III). J 

(iii) Racemisation. The process of converting an optically active com- 
pound into the racemic modification is known as racemisation. The {+)- 
and (— )-forms of most compounds are capable of racemisation under the 
influence of heat, light, or chemical reagents. Which agent is used depends 
on the nature of the compound, and at the same time the ease of racemisa- 
tion also depends on the nature of the compound, e.g., 

{a) Some compounds racemise so easily that they cannot be isolated in 
the optically active forms. 

(b) A number of compounds racemise spontaneously when isolated in 
optically active forms. 

(c) The majority of compounds racemise with various degrees of ease 
under the influence of different reagents. 

(d)A relatively small number of compounds cannot be racemised at all 

When a molecule contains two or more asymmetric carbon atoms and 
the configuration of only one of these is inverted by some reaction the 
process is then called epimerisation. 

Many theories have been proposed to explain racemisation, but owing 
to the diverse nature of the structures of the various optically active com- 
pounds, one cannot expect to find one theory which would explain the 
racemisation of all types of optically active compounds. Thus we find that 
a number of mechanisms have been suggested, each one explaining the 
racemisation of a particular type of compound. 

A number of compounds which are easily racemisable are those in which 
the asymmetric carbon atom is joined to a hydrogen atom and a negative 
group. Since this type of compound can undergo tautomeric change the 
mechanism proposed for this racemisation is one via enolisation. When 
the intermediate enol-form, which is symmetrical, reverts to the keto-form 
it can do so equally well to produce the (+)- or (-)-forms, i.e., the com- 
pound will racemise. Let us consider the case of keto-enol tautomerisnv 
In the keto-form, I, the carbon joined to the hydrogen atom and the oxo 
group is asymmetric; in the enol-form, II, this carbon atom has lost its 
asymmetry. When the enol-form reverts to the keto-form, it can do so 
to produce the original keto molecule I, but owing to its symmetry the 



46 ORGANIC CHEMISTRY [CH. II 

enol-form can produce equally well the keto-form III in which the configura- 
tion of the asymmetric carbon atom is opposite to that in I. Thus racemisa- 
tion, according to this scheme, occurs via the enol-form, e.g., (— )-lactic acid 

H 

I I 

— 0—0=0 ^=£= — C=C— OH ==^r — C— 0=0 

, , ,i ,11 

I II III 

is racemised in aqueous sodium hydroxide, and this change may be formu- 
lated: 

0H O ° H .0 HO, o- 



,— C— Of *J£»» CH 3 — C— of < > 



CH 3 — C— C^ ^=* CH 3 — C— C' < > / C=C \ 

s 0- X 0- CH 3 X X 0- 



H 

(-) 



H .0 



H+ - i-c/ 



CH. 



AhV 



(+) 

There is a great deal of evidence to support this tautomeric mechanism. 
When the hydrogen atom joined to the asymmetric carbon atom is replaced 
by some group that prevents tautomerism (enolisation) then racemisation 
is also prevented (at least under the same conditions as the original com- 
pound), e.g., mandelic acid, C 6 H 5 -CHOH-C0 2 H, is readily racemised by 
wanning with aqueous sodium hydroxide. On the other hand, atrolactic 
acid, C 6 H 6 'C(CH 3 )(OH)'C0 2 H, is not racemised under the same conditions; 
in this case keto-enol tautomerism is no longer possible. 

Racemisation of compounds capable of exhibiting keto-enol tautomer- 
ism is catalysed by acids and bases. Since keto-enol tautomerism is also 
catalysed by acids and bases, then if racemisation proceeds via enolisation, 
the rates of racemisation and enolisation should be the same. This relation- 
ship has been established by means of kinetic studies, e.g., Bartlett et al. 
(1935) found that the rate of acid-catalysed iodination of 2-butyl phenyl 
ketone was the same as that of racemisation in acid solution. This is in 
keeping with both reactions involving the rate-controlling formation of the 
enol (see Vol. I, Ch. X) : 

OH 

slow I fast 

Ph-CO-CHMeEt *— =* Ph-C=CMeEt ^ * Ph-CO-CHMeEt 

(+) fast I, I fast 9low (-) 

Ph-CO-CIMeEt 

On the other hand, on the basis that the rate-determining step in base- 
catalysed enolisation and racemisation is the formation of the enolate ion, 
then the two processes will also occur at the same rate. 

O- OH 

B + R-CO-CHR 2 t^- BH+ + R-C=CR 2 JSL* B + R-C=CR 2 
fast slow 



§8] OPTICAL ISOMERISM 47 

Hsii et al. (1936) found that the rates of bromination and racemisation (in 
the presence of acetate ions) of 2-o-carboxybenzyl-l-indanone were identical. 



CO,H 




Further support for this mechanism is the work of Ingold et al. (1938) 
who showed that the rate of racemisation of (+)-2-butyl phenyl ketone in 
dioxan-deuterium oxide solution in the presence of NaOD is the same as 
the rate of deuterium exchange. This is in keeping with the formation 
of the enolate ion (or carbanion), which is common to both reactions. 



o 

PhC=CMeEt 



(+)-Pll-CO'CHMeEt + OIT^sHOD + PhCOCMeEt 



Ph-CO-CDMeEt (-)-Ph-CO-CHMeEt 

+ 
OD~ 

There are many compounds containing an asymmetric carbon atom which 
can be racemised under suitable conditions although there is no possibility 
of tautomerism. A number of different types of compounds fall into this 
group, and the mechanism proposed for racemisation depends on the type 
of compound under consideration. In the case of compounds of the type 
of (— )-lhnonene (§13. VIII), which is racemised by strong heating, the 
mechanisms proposed are highly speculative (see, for example, Werner's 
theory, §4. V). A number of optically active secondary alcohols can be 
racemised by heating with a sodium alkoxide. This has been explained 
by a reversible dehydrogenation (Huckel, 1931) and there is some evidence 
to support this mechanism (Doering et al., 1947, 1949). 

? »' H 



■2H ^ I +o H | 



R-G-OH ^=± R-6=0 ^±: R-C-OH 
H 



(+)- 



i 



B- 



Another different type of compound which can be readily racemised is that 
represented by a-chloroethylbenzene. When the (+)- or (— )-form is dis- 
solved in liquid sulphur dioxide, spontaneous racemisation occurs. This 
has been explained by assuming ionisation into a carbonium ion (Polanvi 
et al., 1933). v 

C 6 H B -CHC1-CH S ^ C 6 H 5 -CH-CH 3 + Cl~ ^ C 6 H 5 -CHC1-CH 3 
(+)" (-)- 

The carbonium ion is planar (the positively charged carbon atom is prob- 
ably in a state of trigonal hybridisation) and consequently symmetrical; 
recombination with the chlorine ion can occur equally well to form the 
(+)- and (— )-forms, i.e., racemisation occurs. The basis of this mechanism 
is that alkyl halides in liquid sulphur dioxide exhibit an electrical con- 
ductivity, which has been taken as indicating ionisation. Hughes, Ingold 



48 ORGANIC CHEMISTRY [CH. II 

et al. (1936), however, found that pure oc-chloroethylbenzene in pure liquid 
sulphur dioxide does not conduct, but when there is conduction, then 
styrene and hydrogen chloride are present. These authors showed that 
under the conditions of purity, the addition of bromine leads to a quanti- 
tative yield of styrene dibromide. 

Polanyi showed that the rate of racemisation of oc-chloroethylbenzene 
in liquid sulphur dioxide is unaffected by added chloride ions. Hughes 
and Ingold suggest that the rate of racemisation is accounted for by the 
rate of formation of hydrogen chloride; thus: 

C 6 H 5 -CHC1-CH 3 -^> C 6 H 5 -CH-CH 3 + Cl~ 

C 6 H 5 -CH-CH 3 -^ C 6 H 5 -CH = CH 2 + H+ 

It is the recombination of the styrene with the hydrogen chloride that 
produces the racemised product; this may be written as follows 

C 6 H 5 -CHC1-CH 3 ^ C 6 H 5 -CH = CH 2 + HC1 ^ C 6 H 6 -CHC1-CH 3 
(+)- (-)- 

The racemisation of optically active hydrocarbons containing a tertiary 
hydrogen atom is very interesting. It has been shown that such hydro- 
carbons undergo hydrogen exchange when dissolved in concentrated sul- 
phuric acid (Ingold et al., 1936), and the mechanism is believed to occur 
via a carbonium ion (Burwell et al., 1948). 

R 3 CH + 2H 2 S0 4 — ► R 3 C+ + HSO,- + SO a + 2H 2 
R 3 C+ + R 3 CH — >■ R 3 CH + R 3 C+, etc. 

This reaction is very useful for racemising optically active hydrocarbons, 
e.g., Burwell et al. (1948) racemised optically active 3-methylheptane in 
concentrated sulphuric acid (the carbonium ion is flat): 

CH 3 CH S 



C 2 H 6 - — CH — C 4 H, + C 2 H 5 — C+ — C 4 H 9 

(+)- 



CH a 



C 2 H 6 — C+ — C 4 H 9 + C 2 H 5 — CH — C 4 H 9 

(±)- 
The racemisation of other types of optically active compounds is described 
later (see diphenyl compounds, §4. V; nitrogen compounds, §2a. VI; phos- 
phorus compounds, §3b. VI; arsenic compounds, §4a. VI). 

§9. Properties of the racemic modification. The racemic modifica- 
tion may exist in three different forms in the solid state. 

(i) Racemic mixture. This is also known as a (±) -conglomerate, 
and is a mechanical mixture of two types of crystals, the (+)- and (— )- 
forms; there are two phases present. The physical properties of the racemic 
mixture are mainly the same as those of its constituent enantiomorphs. 
The most important difference is the m.p. (see §9a). 

(ii) Racemic compound. This consists of a pair of enantiomorphs in 
combination as a molecular compound; only one solid phase is present. 
The physical properties of a racemic compound are different from those 
of the constituent enantiomorphs, but in solution racemic compounds dis- 
sociate into the (+)- and (— )-forms. 

(iii) Racemic solid solution. This is also known as a. pseu do -racemic 
compound, and is a solid solution (one phase system) formed by a pair of 
enantiomorphs crystallising together due to their being isomorphous. The 



§9a] 



OPTICAL ISOMERISM 



49 



properties of the racemic solid solution are mainly the same as those of its 
constituent enantiomorphs ; the m.p.s may differ (see §9a). 

§9a. Methods for determining the nature of a racemic modifica- 
tion. One simple method of examination is to estimate the amounts of 
water of crystallisation in the enantiomorphs (only one need be examined) 
and in the racemic modification; if these are different, then the racemic 
modification is a racemic compound. Another simple method is to measure 
the densities of the enantiomorphs and the racemic modification; again, 
if these are different, the racemic modification is a racemic compound; 
e.g., tartaric acids. 



Melting point 

Water of crystallisation . 

Density 

Solubility in H,0 (at 20°) 



D-Tartaric acid 



L-Tartaric acid 



170° 

None 

1-7598 

139 g./lOO ml. 



170° 

None 

1-7598 

139 g./lOO ml. 



Racemic 
Tartaric acid 



206° 

lH s O 

1-697 

20-6 g./lOO ml. 



There are, however, two main methods for determining the nature of a 
racemic modification: a study of the freezing-point curves and a study of 
the solubility curves (Roozeboom, 1899; Andriani, 1900). 

Freezing-point curves. These are obtained by measuring the melting 
points of mixtures containing different amounts of the racemic modification 
and its corresponding enantiomorphs. Various types of curves are possible 
according to the nature of the racemic modification. In Fig. 18 (a) the 



ioo7o(+) sol ioo%<-) 
(«) 



100%(+) 50% 100%(-) 

(*) 
Fig. 2.18. 



100%(+) 50% 100%(-) 
(0 



melting points of all mixtures are higher than that of the racemic modifica- 
tion alone. In this case the racemic modification is a racemic mixture (a 
eutectic mixture is formed at the point of 50 per cent, composition of each 
enantiomorph), and so addition of either enantiomorph to a racemic mixture 
raises the melting point of the latter; (±)-pinene is an example of this type. 
In Fig. 18 (6) and (c) the melting points of the mixtures are lower than the 
melting point of the racemic modification which, therefore, is a racemic 
compound. The melting point of the racemic compound may be above 
that of each enantiomorph (Fig. 18 b) or below (Fig. 18 c) ; in either case 
the melting point is lowered when the racemic compound is mixed with an 
enantiomorph; an example of Fig. 18 (b) is methyl tartrate, and one of 
Fig. 18 (c) is mandelic acid. 

When the racemic modification is a racemic solid solution, three types 
of curves are possible (Fig. 19). In Fig. 19 (a) the freezing-point curve is 
a horizontal straight line, all possible compositions having the same melting 
point, e.g., (+)- and (— )-camphor. In Fig. 19 (b) the freezing-point curve 
shows a maximum, e.g., (+)- and (— )-carvoxime; and in Fig. 19 (c) the 
freezing-point curve shows a minimum, e.g., (+)- and (— )-w>opentyl (iso- 
amyl) carbamate. 



50 



ORGANIC CHEMISTRY 



[CH. II 



In a number of cases there is a transition temperature at which one form 
of the racemic modification changes into another form, e.g., (±)-camphor- 
oxime crystallises as the racemic solid solution above 103°, whereas below 
this temperature it is the racemic compound that is obtained [see also §10(i)]. 



ioo%(+) 



ioo%(-> 



(«) 



100%(+) 100%B 

(b) 
Fig. 2.19. 



100%(+) 



100%(-) 



(c) 



Fredga (1944) has introduced the study of quasi-racemic compounds as a 
means of correlating configurations (§5). Quasi-racemic compounds are 
equimolecular compounds that are formed from two optically active com- 
pounds which have closely similar structures but opposite configurations, e.g., 



a 

I 

I 
d 

I 



a 
e— C— j 



-f 



d 
II 



I and II. The formation of a quasi-racemic compound is detected by study- 
ing the melting-point curves of the two components. The curves obtained 
are similar to those of the racemic modification shown in Fig. 18 [a), 18 (6) 
and 19 (a), but with the quasi-racemic compounds these curves are un- 
symmetrical (since the m.p.s of the components will be different). An 
unsymmetrical curve 18 (a) indicates a eutectic mixture, an unsymmetrical 
19 (a) a solid solution and an unsymmetrical 18 (b) a quasi-racemic com- 
pound. Curves for quasi-racemic compounds are given only by compounds 
(containing one asymmetric carbon atom) which have closely similar struc- 
tures but opposite configurations. On the other hand, curves of the other 
two types are given by compounds of like configuration (but some cases 
are known where the configurations have been opposite). Various examples 
of this method of correlating configurations have now been described, e.g., 
Fredga (1941) showed (partly by chemical methods and partly by using the 
quasi-racemate method) that (-j-)-malic acid (III) and (— )-mercaptosuccinic 



H- 



C0 2 H 

oh; 



HS- 



C0 2 H 

-J — H 



C0 2 H 

H — I— Me 



CH 2 -C0 2 H 
III 



IV 



CH 2 C0 2 H 

V 



acid (IV) had opposite configurations. He then showed (1942) that (— )- 
mercaptosuccinic acid formed a quasi-racemic compound with (+)-methyl- 
succinic acid (V). Therefore (IV) and (V) have opposite configurations and 
consequently (-f-)-malic acid and (+)-methylsuccinic acid have the same 
configuration (see also §§10(vi) and 23e. VIII). 

Mislow et al. (1956) have applied the m.p. curves in a somewhat different 
manner. They worked with 3-mercapto-octanedioic acid (VI) and 3-methyl- 
octanedioic acid (VII). These authors found that compounds (— )-VI and 
(+)-VII gave solid solutions for all mixtures (unsymmetrical 19 a), whereas 
(-f-)-VI and (+)-VII gave a diagram with a single eutectic (unsymmetrical 



§10] OPTICAL ISOMERISM 01 

18 a). These results indicate that (— )-VI and (+)-VII are of the same 
CH 2 -C0 2 H CH 2 -C0 2 H 

H— C— SH H— C— Me 

(CH 2 ) 4 -C0 2 H (CH 2 ) 4 -C0 2 H 

(— )-form (+)-form 

VI VII 

absolute configuration, whereas (+)-VI and (+)-VII are of opposite con- 
figurations. 

Solubility curves. The interpretation of solubility curves is difficult, 
but in practice the following simple scheme based on solubility may be used. 
A small amount of one of the enantiomorphs is added to a saturated solution 
of the racemic modification, and the resulting solution is then examined in 
a polarimeter. If the solution exhibits a rotation, then the racemic modifica- 
tion is a compound, but if the solution has a zero rotation, then the racemic 
modification is a mixture or a solid solution. The reasons for this behaviour 
are as follows. If the racemic modification is a mixture or a solid solution, 
then the solution (in some solvent) is saturated with respect to each enantio- 
morph and consequently cannot dissolve any of the added enantiomorph. 
If, however, the racemic modification is a compound, then the solution (in 
a solvent) is saturated with respect to the compound form but not with 
respect to either enantiomorph ; hence the latter will dissolve when added 
and thereby produce a rotation. It should be noted that this simple method 
does not permit a differentiation to be made between a racemic mixture 
and a racemic solid solution. 

Infra-red spectroscopy is also being used to distinguish a racemic com- 
pound from a racemic mixture or a racemic solid solution. In the latter 
the spectra are identical, but are different in the former. These observa- 
tions are also true for X-ray powder diagrams, and so X-ray analysis in 
the solid state may also be used. 

§10. Resolution of racemic modifications. Resolution is the process 
whereby a racemic modification is separated into its two enantiomorphs. 
In practice the separation may be far from quantitative, and in some cases 
only one form may be obtained. A large variety of methods for resolution 
have now been developed, and the method used in a particular case depends 
largely on the chemical nature of the compound under consideration. 

(i) Mechanical separation. This method is also known as spontaneous 
resolution, and was introduced by Pasteur (1848). It depends on the 
crystallisation of the two forms separately, which are then separated by 
hand. The method is applicable only to a few cases, and then only for 
racemic mixtures where the crystal forms of the enantiomorphs are them- 
selves enantiomorphous (§2). Pasteur separated sodium ammonium race- 
mate in this way. The transition temperature of sodium ammonium 
racemate is 28°; above this temperature the racemic compound crystallises 
out, and below this temperature the racemic mixture. Now Pasteur crystal- 
lised his sodium ammonium racemate from a concentrated solution at room 
temperature, which must have been below 28° since had the temperature 
been above this he would have obtained the racemic compound, which can- 
not be separated mechanically. Actually, Staedel (1878) failed to repeat 
Pasteur's separation since he worked at a temperature above 28°. 

(ii) Preferential crystallisation by inoculation. A super-saturated 
solution of the racemic modification is treated with a crystal of one enantio- 
morph (or an isomorphous substance), whereupon this form is precipitated. 



52 ORGANIC CHEMISTRY [CH. II 

The resolution of glutamic acid by inoculation has been perfected for in- 
dustrial use (Ogawa et al., 1957; Oeda, 1961). Harada et al. (1962) have 
also resolved the copper complex of DL-aspartic acid by inoculation. 

(iii) Biochemical separation (Pasteur, 1858). Certain bacteria and 
moulds, when they grow in a dilute solution of a racemic modification, 
destroy one enantiomorph more rapidly than the other, e.g., Penicillium 
glaucum (a mould), when grown in a solution of ammonium racemate, 
attacks the D-form and leaves the L-. 

This biochemical method of separation has some disadvantages: 

(a) Dilute solutions must be used, and so the amounts obtained will be 
small. 

(b) One form is always destroyed and the other form is not always 
obtained in 50 per cent, yield since some of this may also be destroyed. 

(c) It is necessary to find a micro-organism which will attack only one of 
the enantiomorphs. 

(iv) Conversion into diastereoisomers (Pasteur, 1858). This method, 
which is the best of all the methods of resolution, consists in converting 
the enantiomorphs of a racemic modification into diastereoisomers (§7b); 
the racemic modification is treated with an optically active substance and 
the diastereoisomers thereby produced are separated by fractional crystal- 
lisation. Thus racemic acids may be separated by optically active bases, 
and vice versa, e.g., 

(Dacid + Lacid) + 2Db a se — > (D a ciflDbase) + (L ac idDbase) 

These two diastereoisomers may then be separated by fractional crystallisa- 
tion and the acids (enantiomorphs) regenerated by hydrolysis with inorganic 
acids or with alkalis. In practice it is usually easy to obtain the less- 
soluble isomer in a pure state, but it may be very difficult to obtain the 
more-soluble isomer. In a number of cases this second (more-soluble) 
isomer may be obtained by preparing it in the form of another diastereo- 
isomer which is less soluble than that of its enantiomorph. 

Resolution by means- of diastereoisomer formation may be used for a 
variety of compounds, e.g., 

(a) Acids. The optically active bases used are mainly alkaloids: brucine, 
quinine, strychnine, cinchonine, cinchonidine and morphine. Recently, 
optically active benzimidazoles (§3a. XII) have been used (Hudson et al., 
1939). 

(6) Bases. Many optically active acids have been used, e.g., tartaric acid, 
camphor-/3-sulphonic acid and particularly a-bromocamphor-Tr-sulphonic 
acid (see §23a. VIII). 

(c) Alcohols. These are converted into the acid ester derivative using 
either succinic or phthalic anhydride (Pickard and Kenyon, 1912). The 
acid ester, consisting of equimolecular amounts of the (+)- and (— )-forms, 





may now be resolved as for acids. Racemic alcohols may also be resolved 
by diastereoisomer formation with optically active acyl chlorides (to form 
esters) or with optically active wocyanates (to form urethans): 

ROCH 2 -COC1 + R'OH -► ROCH 2 -C0 2 R' + HC1 

R-NCO + R'OH -> R-NH-COsjR' 

In these equations R is the (— )-menthyl radical (§16. VIII); recently 



§10] OPTICAL ISOMERISM 53 

N-(— )-menthyl-^-sulphamylbenzoyl chloride, I, has been used (Mills et al., 
1950). 



C 10 H 19 NHSO 2 -^^^~COCl 



I 

(d) Aldehydes and Ketones. These have been resolved by means of opti- 
cally active hydrazines, e.g., (— )-menthylhydrazine. Sugars have been re- 
solved with (+)-Mopentanethiol (cf. §1. VII). Nerdel et al. (1952) have 
resolved oxo compounds with D-tartramide acid hydrazide, 

NH a -CO-CHOH-CHOH-CO-NH-NH a ; 

this forms diastereoisomeric tartramazones. 

(e) Amino-compounds. These may be resolved by conversion into dia- 
stereoisomeric anils by means of optically active aldehydes. a-Amino-acids 
have been resolved by preparing the acyl derivative with an optically active 
acyl chloride, e.g., (— )-menthoxyacetyl chloride {cf. alcohols). Another 
method of resolving DL-amino-acids is asymmetric enzymic synthesis (§7. 
III). The racemic amino-acid is converted into the acyl derivative which 
is then allowed to react with aniline in the presence of the enzyme papain 
at the proper pH. (Albertson, 1951). Under these conditions only the 
L-amino-acid derivative reacts to form an insoluble anilide; the D-acid does 
not react but remains in the solution. 

'' NHCOR' papain NH-COR' NHCOR' 

R-CH-C0 2 H+ C 6 H 5 -NH* *"r-CH-CO-NH-C 6 H 5 + R-CHC0 2 H 

DL-acid L-acid D-acid * 

Amino-acids have also been resolved by other means (see §4. XIII). 

Asymmetric transformation. Resolution of racemic modifications by 
means of salt formation (the diastereoisomers are salts; cf. acids and bases) 
may be complicated by the phenomenon of asymmetric transformation. This 
phenomenon is exhibited by compounds that are optically unstable, i.e., the 
enantiomorphs are readily interconvertible 

(+)-c^(-)-c 

There are two types of asymmetric transformation, first order and second 
order. These were originally defined by Kuhn (1932), but were later re- 
defined by Jamison and Turner (1942). 

Suppose we have an optically stable (+)-base (one equivalent) dissolved 
in some solvent, and this is then treated with one equivalent of an optically 
unstable (±)-acid. At the moment of mixing, the solution will contain 
equal amounts of [(+)-Base'(+)-Acid] and [(-f-)-Base'(- )-Acid] ; but since 
the acid is optically unstable, the two diastereoisomers will be present in 
unequal amounts when equilibrium is attained. 

[(+)-Base-(+)-Acid] ^ [(+)-Base-(-)-Acid] 

According to Jamison and Turner, first-order asymmetric transformation 
is the establishment of equilibrium in solution between the two diastereo- 
isomers which must have a real existence. In second-order asymmetric 
transformation it is necessary that one salt should crystallise from solution; 
the two diastereoisomers need not have a real existence in solution. In 
second-order asymmetric transformation it is possible to get a complete 
conversion of the acid into the form that crystallises ; the form may be the 
(+)- or (— )-, and which one it is depends on the nature of the base and 
the solvent. 



54 



ORGANIC CHEMISTRY 



[CH. II 

Many examples of first- and second-order asymmetric transformation are 
known, and a large number of these compounds are those which owe their 
asymmetry to restricted rotation about a single bond (see Ch. V), e.g., Mills 
and Elliott (1928) tried to resolve iV-benzenesulphonyl-8-nitro-l-naphthyl- 
glycine, II, by means of the brucine salt. These authors found that either 

C 6 H 5 -SOa CHjj-COsjH 

N 

NO, 




diastereoisomer could be obtained in approximately 100 per cent, yield by 
crystallisation from methanol and acetone, respectively. Another example 
of second-order asymmetric transformation is hydrocarbostyril-3-carboxylic 
acid. This compound contains an asymmetric carbon atom, and Leuchs 




0H-CO 2 H 




O00 2 H 

II 

COH 



(1921), attempting to resolve it with quinidine, isolated approximately 90 per 
cent, of the (+)-form. Optical instability in this case is due to keto-enol 
tautomerism (cf. §8). 

A very interesting example of second-order asymmetric transformation 
is 2-acetomethylamido-4' : 5-dimethylphenylsulphone, III. When this com- 

CH 3 CO-CH 3 




s ° r "^3 >cH3 



m 

pound was crystallised from a supersaturated solution in ethyl (+)-tartrate, 
the crystals obtained had a rotation of +0-2°; evaporation of the mother 
liquor gave crystals with a rotation of —0-15° (Buchanan et al., 1950). 

(v) Another method of resolution that has been tried is the conversion 
of the enantiomorphs into volatile diastereoisomers, which are then separated 
by fractional distillation. So far, the method does not appear to be very 
successful, only a partial resolution being the result, e.g., Bailey and Hass 
(1941) converted ( = j = )-pentan-2-ol into its diastereoisomers with L(+)-lactic 
acid, and then partially separated them by fractional distillation. 

(vi) Selective adsorption. Optically active substances may be selec- 
tively adsorbed by some optically active adsorbent, e.g., Henderson and 
Rule (1939) partially resolved ^-phenylenebisiminocamphor on lactose as 
adsorbent; Bradley and Easty (1951) have found that wool and casein 
selectively adsorb (+)-mandelic acid from an aqueous solution of (±)-man- 



§10] OPTICAL ISOMERISM 55 

delic acid. A particularly important case of resolution by chromatography 
is that of Troger's base (see §2c. VI). 

Jamison and Turner (1942) have carried out a chromatographic separa- 
tion without using an optically active adsorbent; they partially resolved 
the diastereoisomers of (— )-menthyl (±)-mandelate by preferential ad- 
sorption on alumina. It is also interesting to note that the resolution of 
a racemic acid by salt formation with an optically active base is made 
more effective by the application of chromatography. 

Resolution has also been carried out by vapour-phase chromatography, 
e.g., s-butanol and s-butyl bromide have been separated into two over- 
lapping fractions using a column of starch or ethyl tartrate as the stationary 
phase (Karagounis et al., 1959). Casanova et al. (1961) have resolved 
(±)-camphor by gas chromatography. 

Beckett et al. (1957) have introduced a novel method for correlating and 
determining configurations (cf. §9). These authors have prepared " stereo- 
selective adsorbents ". These are adsorbents prepared in the presence of 
a suitable reference compound of known configuration, e.g., silica gel in the 
presence of quinine. Such an adsorbent exhibits higher adsorptive power 
for isomers related to the reference compound than for their stereoisomers, 
provided that their structures are not too dissimilar from that of the refer- 
ence compound. Thus silica gel prepared in the presence of quinine adsorbs 
quinine more readily than its stereoisomer quinidine; cinchonidine (con- 
figurationally related to quinine) is adsorbed more readily than its stereo- 
isomer cinchonine (configurationally related to quinidine). 

(vii) Kinetic method of resolution. Marckwald and McKenzie (1899) 
found that (— )-menthol reacts more slowly with (— )-mandelic acid than 
with the (+)-acid. Hence, if insufficient (— )-menthol is used to completely 
esterify (±)-mandelic acid, the resulting mixture of diastereoisomers will 
contain more (— )-menthyl (-f-)-mandelate than (— )-menthyl (— )-man- 
delate. Consequently there will be more (— )-mandelic acid than (-f-)-man- 
delic acid in the unchanged acid, i.e., a partial resolution of (±)-mandelic 
acid has been effected (see also §5b. VI). 

(viii) Ferreira (1953) has partially resolved (±)-narcotine and (±)-lau- 
danosine (1-2-5 per cent, resolution) without the use of optically active 
reagents. He dissolved the racemic alkaloid in hydrochloric acid and then 
slowly added pyridine; the alkaloid was precipitated, and it was found to 
be optically active. The explanation offered for this partial resolution is 
as follows (Ferreira). When a crystalline racemic substance is precipitated 
from solution, a crystallisation nucleus is first developed. Since this nucleus 
contains a relatively small number of molecules, there is more than an even 
chance that it will contain an excess of one enantiomorph or other. If it 
be assumed that the forces acting on the growth of crystals are the same 
kind as those responsible for adsorption [cf. (vi)], the nucleus will grow 
preferentially, collecting one enantiomorph rather than the other. Crystal- 
lisation, when carried out in the usual manner, results in the formation of 
crystals containing more or less equivalent numbers of both enantiomorphs. 

Channel complex formation has also been used to resolve racemic modifica- 
tions (see Vol. I). This also offers a means of carrying out a resolution 
without asymmetric reagents, e.g., Schlenk (1952) added (±)-2-chloro-octane 
to a solution of urea and obtained, on fractional crystallisation, the two urea 
inclusion complexes urea/(+)-2-chloro-octane and urea/(— )-2-chloro-octane. 

Baker et al. (1952) have prepared tri-o-thymotide, and found that it formed 
clathrates with ethanol, »-hexane, etc. Powell et al. (1952) have shown that 
tri-o-thymotide crystallises as a racemate, but that resolution takes place 
when it forms clathrates with w-hexane, benzene or chloroform. By means 
of seeding and slow growth of a single crystal, it is possible to obtain the 



56 



ORGANIC CHEMISTRY 



[CH. II 

(+)- or (— )-form depending on the nature of the seed. Furthermore, 
crystallisation of tri-o-thymotide (dl) from a solvent which is itself a racemic 
modification (d'l') and which forms a clathrate, produces crystals of the 



Me,CH 




CHMe 2 



CHMe 



tri-o-thymotide 

types dd' and IV . Thus such (solvent) racemic modifications can be resolved, 
e.g., sec-butyl bromide has been resolved in this way. 

§11. The cause of optical activity. Two important points that arise 
from the property of optical activity are: What types of structure give 
rise to optical activity, and why? Fresnel (1822) suggested the following 
explanation for optical activity in crystalline substances such as quartz, 
basing it on the principle that any simple harmonic motion along a straight 
line may be considered as the resultant of two opposite circular motions. 
Fresnel assumed that plane-polarised light, on entering a substance in a 
direction parallel to its optic axis, is resolved into two beams of circularly 
polarised light, one right-handed (dextro-) and the other left-handed (laevo-), 
and both having the same frequency. If these two component beams travel 
through the medium with the same velocity, then the issuing resultant 
beam suffers no rotation of its plane of polarisation (Fig. 20 a). If the 
velocity of the laevocircularly polarised component is, for some reason, re- 
tarded, then the resultant beam is rotated through some angle to the right 
(in the direction of the faster circular component; Fig. 20 b). Similarly, 
the resultant beam is rotated to the left if the dextrocircularly polarised 
component is retarded (Fig. 20 c). Fresnel tested this theory by passing 





(a) 



(b) 
Fig. 2.20. 



(c) 



a beam of plane-polarised light through a series of prisms composed alter- 
nately of dextro- and lsevorotatory quartz (Fig. 21). Two separate beams 
emerged, each circularly polarised in opposite senses; this is an agreement 
with Fresnel's explanation. Fresnel suggested that when plane-polarised 
light passed through an optically active crystalline substance, the plane of 
polarisation was rotated because of the retardation of one of the circular 
components. Stated in another way, Fresnel's theory requires that the 
refractive indices for dextro- and laevocircularly polarised light should be 
different for optically active substances. It has been shown mathematically 
that only a very small difference between these refractive indices gives rise 



§11] 



OPTICAL ISOMERISM 



57 



to fairly large rotations, and that if the refractive index for the laevocircularly 
polarised light is greater than that for the dextro component, the substance 
will be dextrorotatory. The difficulty of Fresnel's theory is that it does 
not explain why the two circular components should travel with different 
velocities. It is interesting to note, however, that Fresnel (1824) suggested 
that the optical activity of quartz is due to the structure being built up 
in right- and left-handed spirals (cf. §2). 




Fig. 2.21. 

Now let us consider the problem of optical activity of substances in 
solution. In this case the optical activity is due to the molecules themselves, 
and not to crystalline structure (see also §2). Any crystal which has a plane 
of symmetry but not a centre of symmetry (§6) rotates the plane of polarisa- 
tion, the rotation varying with the direction in which the light travels 
through the crystal. No rotation occurs if the direction of the light is 
perpendicular or parallel to the plane of symmetry. If we assume that 
molecules in a solution (or in a pure liquid) behave as individual crystals, 
then any molecule having a plane but not a centre of symmetry will also 
rotate the plane of polarisation, provided that the light travels through 
the molecule in any direction other than perpendicular (or parallel) to the 
plane of symmetry. Let us consider the molecule Ca 2 bd (Fig. 22). This 
has a plane of symmetry, and so molecule I and its mirror image II are 
superimposable. Now let us suppose that the direction of plane-polarised 





Fig. 2.22. 

light passing through molecule I makes an angle 8° with the plane of sym- 
metry, and that the resultant rotation is +a°. Then if the direction of 
the light through molecule II also makes an angle 8° with the plane of 
symmetry, the resultant rotation will be — a°. Thus the total rotation pro- 
duced by molecules I and II is zero. In a solution of compound Ca 2 bd, 
there will be an infinite number of molecules in random orientation. Statisti- 
cally one can expect to find that whatever the angle 8 is for molecule I, 
there will always be molecule II also being traversed by light entering at 
angle 8. Thus, although each individual molecule rotates the plane 
of polarisation by an amount depending on the value of 8, the statisti- 
cal sum of the contributions of the individual molecules will be zero. 
When a molecule is not superimposable on its mirror image, then if only 
one enantiomorph is present in the solution, the rotation produced by each 
individual molecule will (presumably) depend on the angle of incidence (with 
respect to any face), but there will be no compensating molecules (i.e., 
mirror image molecules) present. Hence, in this case, there will be a net 



58 



ORGANIC CHEMISTRY 



[CH. II 

rotation that is not zero, the actual value being the statistical sum of the 
individual contributions (which are all in the same direction). Thus, if we 
consider the behaviour of a compound in a solution (or as a pure liquid) 
as a whole, then the observed experimental results are always in accord 
with the statement that if the molecular structure of the compound 
is asymmetric, that compound will be optically active (§2). Any 
compound composed of molecules possessing a plane but not a centre of 
symmetry is, considered as a whole, optically inactive, the net zero rotation 
being the result of " external compensation " (cf. §7a). This point is of 
great interest in connection with flexible molecules (§4). Let us consider 
wesotartaric acid, a compound that is optically inactive by internal com- 
pensation (§7b). X-ray studies (Stern et al., 1950) have shown that the 
staggered form of the molecule is the favoured one (Fig. 23 a). This has 
a centre of symmetry, and so molecules in this configuration are individually 



C0 2 H 



CQ 2 H 



HO 




OH 



-OH 



-OH HO 




C0 2 H 



CO z H 


C0 2 H 


CO z H 


W 


Fig. 2.23. 


w 



optically inactive. On the other hand, wesotartaric acid is usually repre- 
sented by the plane-diagram formula in Fig. 23 (b). This corresponds to 
the eclipsed form, and has a plane of symmetry. In this conformation the 
individual molecules are optically active except when the direction of the 
light is perpendicular (or parallel) to the plane of symmetry; the net rotation 
is zero by " external compensation ". It is possible, however, for the mole- 
cule to assume, at least theoretically, many conformations which have no 
elements of symmetry, e.g., Fig. 23 (c). All molecules in this conformation 
will contribute in the same direction to the net rotation. If the total number 
of molecules present were in this conformation, then mesotartaric acid would 
have some definite rotation. On the theory of probability, however, for 
every molecule taking up the conformation in Fig. 23 (c), there will also be 
present its mirror image molecule, thereby giving a net zero rotation due 
to " external compensation ". As we have seen, raesotartaric acid is opti- 
cally inactive (as shown experimentally), and by common usage the in- 
activity is said to be due to internal compensation (§7b). 



READING REFERENCES 

Gilman, Advanced Organic Chemistry, Wiley (1943, 2nd ed.). Vol. I. Ch. 4. Stereo- 
isomerism. 

Wheland, Advanced Organic Chemistry, Wiley (1960, 3rd ed.). 

Partington, An Advanced Treatise on Physical Chemistry, Longmans, Green. Vol. IV 
(1953), p. 290 et seq. Optical Activity. 

Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill (1962). 

Frankland, Pasteur Memorial Lecture, J.C.S., 1897, 71, 683. 

Walker, van't Hofi Memorial Lecture, J.C.S., 1913, 103, 1127. 

Pope, Obituary Notice of Le Bel, J.C.S., 1930, 2789. 

Pasteur, Researches on the Molecular Asymmetry of Natural Organic Products, Alembic 
Club Reprints — No. 14. 



OPTICAL ISOMERISM 59 

Mann and Pope, Dissymmetry and Asymmetry of Molecular Configuration, Chem. and 

Ind., 1925, 833. 
Barker and Marsh, Optical Activity and Enantiomorphism of Molecular and Crystal 

Structure, J.C.S., 1913, 103, 837. 
van't Hoff, Chemistry in Space, Oxford Press (1891; translated by Marsh). 
Bijvoet, Structure of Optically Active Compounds in the Solid State, Nature, 1954, 

173, 888. 
Rosanoff, On Fischer's Classification of Stereoisomers, /. Amer. Chem. Soc, 1906, 28, 

114. 
Cahn, Ingold and Prelog, The Specification of Asymmetric Configuration in Organic 

Chemistry, Experientia, 1956, 12, 81. 
Turner and Harris, Asymmetric Transformation and Asymmetric Induction, Quart. 

Reviews (Chem. Soc.), 1948, 1, 299. 
Fredga, Steric Correlations by Quasi-Racemate Method, Tetrahedron, 1960, 8, 126. 
Bent, Aspects of Isomerism and Mesomerism, /. Chem. Educ, 1953, 30, 220, 284, 328. 
Kauzmann, Walter and Eyring, Theories of Optical Rotatory Power, Chem. Reviews, 

1940, 26, 339. 
Jones and Eyring, A Model for Optical Rotation, /. Chem. Educ., 1961, 38, 601. 
Hargreaves, Optical Rotatory Dispersion: Its Nature and Origin, Nature, 1962, 195, 

560. 
Hudson, Emil Fischer's Stereo-Formulas, Advances in Carbohydrate Chemistry, Academic 

Press. Vol. 3 (1948). Ch. 1. 
Barton and Cookson, The Principles of Conformational Analysis, Quart. Reviews (Chem. 

Soc), 1956, 10, 44. 
Newman (Ed.), Steric Effects in Organic Chemistry, Wiley (1956). Ch. I. Conforma- 
tional Analysis. 
Newman, A Notation for the Study of Certain Stereochemical Problems, /. Chem. Educ, 

1955, 32, 344. 
Eliel, Conformational Analysis in Mobile Systems, /. Chem. Educ, 1960, 37, 126. 
Mizushima, Structure of Molecules and Internal Rotation, Academic Press (1954). 
Klyne (Ed.), Progress in Stereochemistry, Butterworth. Vol. I (1954) ; Vol. II (1958). 
Cram, Recent Advances in Stereochemistry, /. Chem. Educ, 1960, 37, 317. 
Brewster, A Useful Model of Optical Activity, /. Amer. Chem. Soc, 1959, 81, 5475. 



CHAPTER III 

NUCLEOPHILIC SUBSTITUTION AT A SATURATED 
CARBON ATOM 

§1. The most extensively studied type of heterolytic substitution in 
saturated compounds is the nucleophilic type, i.e., the S N 1 and S N 2 mechan- 
isms. 

One-stage process. When two molecules simultaneously undergo covalency 
change in the rate-determining step, the mechanism is called bimolecular and 
is labelled Sn2 (substitution, nucleophilic, bimolecular). 

Two-stage process. In this case the first step is the slow heterolysis of the 
compound to form a carbonium ion, and this is then followed by the second step 
of rapid combination of the carbonium ion with the nucleophilic reagent. The 
rate-determining step is the first, and since in this step only one molecule is 
undergoing covalency change, the mechanism is called unimolecular and is 
labelled SnI (substitution, nucleophilic, unimolecular). 

The symbols SnI and Sn2 were introduced by Ingold (1928), the number in 
the symbol referring to the molecularity of the reaction and not to the kinetic 
order. Any complex reaction may be designated by the molecularity of its 
rate-determining stage, the molecularity of the rate-determining stage being 
defined as the number of molecules necessarily undergoing covalency change 
(Ingold, 1933). 

The main difference between the two mechanisms is the kinetic order of the 
reaction. Sn2 reactions would be expected to be second order (first order with 
respect to each reactant), whereas SnI reactions would be expected to be first 
order. These orders are only true under certain circumstances. In a bi- 
molecular reaction, if both reactants are present in small and controllable con- 
centrations, the reaction will be of the second order. If, however, one of the 
reactants is in constant excess (e.g., one reactant is the solvent), then the mech- 
anism is still bimolecular but the reaction is now of the first order. Unimolecular 
mechanisms often lead to first-order kinetics but may, under certain circum- 
stances, follow a complicated kinetic expression. Since, however, it is possible 
to derive such an equation theoretically, it may be still decided whether the 
mechanism is SnI by ascertaining whether the data fit this kinetic expression. 

Another important difference between the Sn2 and the Sn 1 mechanism is that 
in the former the configuration of the molecule is always inverted, whereas in 
the latter there may be inversion and/or retention, the amount of each depending 
on various factors (see later). 

The nucleophilic reagent may be negatively charged or neutral; the 
primary requirement is that it must possess an unshared pair of electrons 
which it can donate to a nucleus capable of sharing this pair. One widely 
studied example of nucleophilic aliphatic substitution is that of the hydrolysis 
of alkyl halides (T.S. = transition state ; see also Vol. I) : 

S N 2 Y- + R-X-^Y-"R-«X-^Y-R + X- 
T.S. 

slow <* + ^~ fast 

S N 1 R— X-^>R---X-^!>R+ + X- 

T.S. 

R+ + Y--^>RY 

Of particular interest is the evidence for the SnI mechanism. A fundamental 
part of this mechanism is the postulate of carbonium ions as transient inter- 
mediates; but there appears to be no direct physical evidence for the presence 
of aliphatic carbonium ions. Symons et al. (1959) have shown that monoaryl- 

6o 



§2a] 



NUCLEOPHILIC SUBSTITUTION 



61 



carbonium ions axe stable in dilute solutions of sulphuric acid. They have also 
found that the spectroscopic examination of solutions of 2-butanol and tsobutene 
in sulphuric acid shows a single measurable ultraviolet band in both solutions. 
This band appears slowly according to the first-order rate law for *-butanol, but 
very rapidly for the olefin; the solutions are stable (and reproducible). The 
authors conclude that there are trimethylcarbonium ions, CMe 3 +, in solution, 
and that it is probable that this ion is planar. Symons et al. (1961) have also 
obtained evidence, from ultraviolet studies, for the existence of the allyl car- 
bonium ion in sulphuric acid; they examined solutions of allyl alcohol, chloride, 
bromide, etc., in sulphuric acid. 

On the other hand, triarylcarbonium ions have been obtained as salts, e.g., 
triphenylmethyl perchlorate, Ph s C+C10 4 - , and fluoroborate, Ph s C+BF 1 _ 
(Dauben jun. et al., 1960). 

§2. Any factor that affects the energy of activation (E) of a given type 
of reaction will affect the rate and/or the mechanism. Attempts have been 
made to calculate E in terms of bond strengths, the steric factor, heats of 
solutions of ions, etc., but apparently the results are conflicting. The 
following discussion is therefore largely qualitative, and because of this, one 
cannot be sure which are the predominant factors in deciding the energy of 
activation. We shall discuss, for the hydrolysis of alkyl halides, the influ- 
ence of the following factors : The nature of R (polar and steric effects) ; 
the nature of X and Y; and the nature of the solvent. 

§2a. The nature of R. {a) Polar effects. Let us consider the series 
EtX, s'-PrX, and tf-BuX. Since the methyl group as a +1 effect, the larger 
the number of methyl groups on the carbon atom of the C — X group, the 
greater will be the electron density on this carbon atom. This may be 
represented qualitatively as follows: 

Me^ 

8- >V OS- 

Me-^CH 2 -^-X ^;cH-*>-: 






Me' 



Me 



This increasing negative charge on the central carbon atom increasingly 
opposes attack at this carbon by a negatively charged nucleophilic reagent ; 
it also opposes, to a lesser extent, attack by a neutral nucleophilic reagent 
since this still donates an electron pair. Thus the formation of the transition 
state for the Sn2 mechanism is opposed more and more as the charge on the 
central carbon atom increases. (There is also an increasing steric effect 
operating; this is dealt with in §2b.) The anticipated result, therefore, is 
that as the number of methyl groups increases on the central carbon atom, 
the Su2 mechanism is made more difficult in passing from EtX to 2-BuX. 
On the other hand, since the S^l mechanism involves ionisation of RX 
(in the rate-determining step), any factor that makes easier the ionisation 
of the molecule wiE therefore facilitate the S N 1 mechanism. The anticipated 
result, therefore, is that the greater the negative charge on the central 
carbon atom, the easier will be the ionisation of RX since X is displaced 
with its covalent electron pair; thus the tendency for the Sifl mechanism 
should increase from EtX to tf-BuX. 

These predicted results have been verified experimentally. Hughes, 
Ingold et al. (1935-1940) examined the rates of hydrolysis of alkyl bromides 
in alkaline aqueous ethanol at 55°: 





MeBr 


EtBr 


t-PrBr 


f-BuBr 


2nd-order rate const, x 10 5 
lst-order rate const, x 10 5 


2140 


170 


4-7 
0-24 


1010 



62 ORGANIC CHEMISTRY [CH. Ill 

It can be seen from these results that MeBr and EtBr undergo hydrolysis 
by the S N 2 mechanism, *'-PrBr by both S N 2 and S N 1, and tf-BuBr by S N 1 only. 
Thus, as the polar effects in the alkyl group produce an increasing electron 
density on the central carbon atom, the rate of the Su2 mechanism decreases 
and a point is reached where the mechanism changes over to Sjjl. With 
j'-PrBr both Sn2 and S^l mechanisms operate, and the rate of the Sn2 
mechanism is much less than that of the Su2 mechanism for EtBr. With 
i-BuBr the electron density on the central carbon atom is so great that the 
Sn2 mechanism is completely inhibited; a very rapid hydrolysis occurs by 
the S»il mechanism only. Since the mechanism is S^l, it therefore means 
that the hydroxide ion does not enter into the rate-determining step of 
the hydrolysis (§1). This has been proved as follows. The hydrolysis of 
<-BuBr was carried out in an alkaline solution containing less than the 
equivalent amount of hydroxide ion (compared with the alkyl bromide). 
Thus, although the solution was originally alkaline, as the hydrolysis pro- 
ceeds, the solution becomes neutral and finally acid; nevertheless, the rate 
constant of the hydrolysis remained unchanged. 

As pointed out above, there are reactions which occur under intermediate 
conditions, i.e., at the border-line between the extreme S^l and Sn2 
mechanisms. Some authors believe that in this border-line region there 
is only one mechanism operating, e.g., Prevost (1958) has postulated, on 
theoretical grounds, the existence of a more universal " mesomechanism ". 
There is, however, much experimental work in favour of concurrent Si*l 
and S N 2 mechanisms operating. Gold (1956) has described evidence for 
this view, and more recently Swart et al. (1961) have shown that the ex- 
change reaction between diphenylmethyl chloride and radiochlorine (as 
LiCl*) in dimethylformamide occurs by a simultaneous Sn1-Sn2 mechanism. 

The actual position where the mechanism changes over from Sn2 to SnI 
in a graded series, e.g., in the one already described, is not fixed but depends 
on other factors such as the concentration and nature of the nucleophilic 
reagent, and on the nature of the solvent (see below). 

Experimental work has shown that higher «-alkyl groups behave similarly 
to ethyl. For a given set of conditions, the kinetic order is the same, but 
the rates tend to decrease as the number of carbon atoms increases, e.g., 
Hughes, Ingold et al. (1946, 1948) showed that the reactions between primary 
alkyl bromides and ethoxide ion in dry ethanol are all S N 2, and their relative 
rates (at 55°) are Me, 17-6; Et, 1-00; «-Pr, 0-31; »-Bu, 0-23; w-pentyl, 0-21. 
Similar results were obtained for secondary alkyl groups. In these cases 
the mechanisms were both S N 2 and S N 1, but the rates for one or other 
order were reasonably close, e.g., for the second-order reactions of secondary 
bromides with ethoxide ion in dry ethanol at 25°, Hughes, Ingold et al. 
(1936- ) found that the relative rates were: *-Pr, 1-00; 2-«-Bu, 1-29; 
2-w-pentyl, 1-16; 3-»-pentyl, 0-93. These authors also showed that higher 
tertiary alkyl groups behaved similarly to t-Bu, all showing a strong tendency 
to react by the S^l mechanism. 

When hydrogen atoms in methyl chloride are replaced by phenyl groups, 
the mechanism of the hydrolysis may be changed (from S N 2). The presence 
of a phenyl group produces a carbonium ion which can be stabilised by 
resonance; this acts as the driving force to produce ionisation; e.g., 



: CH 2 *-^ 



<3-cH 2C ,^cr + ^3-6h 2 ~ <^3= ( 

Thus one can anticipate that as the number of phenyl groups increases, the 
stability of the carbonium ion produced will increase, i.e., the carbonium 
ion will be formed more readily and consequently the Sjjl mechanism will 



§2b] NUCLEOPHILIC SUBSTITUTION 63 

be increasingly favoured. Thus in the series MeCl, PhCH 2 Cl, Ph 2 CHCl, 
Ph 3 CCl, it has been found that in alkaline solution the hydrolysis of methyl 
chloride proceeds by the S N 2 mechanism, that of phenylmethyl chloride 
by both S N 2 and S N 1, and that of diphenylmethyl chloride by S^l; the 
hydrolysis of triphenylmethyl chloride is too fast to be measured, but this 
high rate is very strong evidence for an S N 1 mechanism. 

Various groups in the ^ara-position of the phenyl nucleus either assist 
or oppose ionisation. It has been found that alkyl groups enhance ionisation 
in the order Me > Et > t'-Pr > t-Bu. Since this order is the reverse of 
that expected from the general inductive effects of these groups, it has been 
explained by the hyperconjugative effects of these groups (which are in this 
order; see Vol. I). On the other hand, a nitro-group retards the ionisation, 
and this attributed to the electron-withdrawing effect of this group. 



fa a^>£WJ 




Me^ y-GH^Cl /N*< V-CH 2 -K>1 



Another group of interest is the carbonyl group; this is electron-attracting 
(through resonance): 



I I a+l I 

-c 1 —t=o «-> — Ci-*— c+— o- 



Thus the covalent electron-pair of a halogen atom attached to C t is drawn 
closer to Cj and consequently it is more difficult for this halogen atom to 
ionise. Thus the S^l mechanism is opposed, and at the same time, the 
small positive charge on C x encourages the Sn2 mechanism. It can there- 
fore be anticipated that any electron-attracting (or withdrawing) group will 
tend to inhibit the S^l mechanism for a compound with an a-halogen atom. 
Such groups are C0 2 R, N0 2 , CN, etc.; e.g., both ethyl a-bromopropionate 
and diethyl bromomalonate undergo hydrolysis by the Sn2 mechanism. 

On the other hand, the car boxy late ion has a +1 effect due to its negative 
charge and hence its presence should enhance the ionisation of an a-halogen 
atom. At the same time, the a-carbon atom tends to acquire a small 
negative charge, and this will tend to oppose the approach of a hydroxide 
ion. Thus there are two influences acting, one increasing the tendency for 
the Sjjl mechanism and the other decreasing the tendency for the Sn2; 
both therefore oppose the Sn2 mechanism. Some experimental results that 
illustrate these arguments are the alkaline hydrolyses of the following 
compounds: 

COi C0£ 

s - ^° t26- t 35 - 

Br-t-CH 2 --«-a Br-w-CH Br- **»-C -t-Me 

co 2 col 

Sn2 SnI SnI 

§2b. The nature of R. (b) Steric effects. In the transition state for 
the Sjf2 mechanism, there are five atoms or groups bonded or partly bonded 
to the reaction carbon atom (see §4). Thus the larger the bulk of these 
groups, the greater will be the compression energy (i.e., greater steric strain) 
in the transition state and consequently the reaction will be stericaUy 
hindered. The problem is different for the S N 1 mechanism. Here, the 
transition state does not contain more than four groups attached to the 
reaction carbon atom and hence one would expect that steric hindrance 
should be less important. On the other hand, if the molecule undergoing 



64 ORGANIC CHEMISTRY [CH. Ill 

the S N 1 mechanism contains particularly large groups, then the first step 
of ionisation may relieve the steric strain (§4a. II) and so assist the formation 
of the carbonium ion, i.e., the reaction may be sterically accelerated. 

Let us now examine some examples involving steric effects. 

(i) The following series of alkyl halides, MeX, EtX, «'-PrX and tf-BuX, 
may be made to undergo the S N 2 mechanism under suitable conditions 
(cf. §2a) ; the transition state contains three o-bonds (sp 2 hybridisation) in 
one plane and two partial bonds which are collinear and perpendicular to 
this plane. Thus we have: 

.» ? -i -i r - } _ t f* ., . t f - t 

T--C--X Y--C--X Y--C--X Y--C--X 

A «1 -1 "4. 

Inspection of these transition states shows that steric hindrance increases 
as the hydrogen atoms are progressively replaced by methyl groups. This 
increasing steric effect has been demonstrated by Hughes et al. (1946), 
who showed that the relative reactivities of the alkyl bromides towards 
iodide ions in acetone (by the S K 2 mechanism) are: Me, 10,000; Et, 65; 
j-Pr, 0-50; t-Bu, 0-039. 

Now let us consider w-propyl, /sobutyl and weopentyl halides ; their transi- 
tion states will be (for the S N 2 mechanism): 



Me 

i 


Me 


Me 


H\l/H 


Kj/H 


Me\ I^Me 


Y— C— -X 1 

4 


-i 1 -x 
Y— C— X 1 

»4 


-i 1 -i 
Y— C— X s 

H 



At first sight one would not expect w-PrX to show an added steric effect 
when compared with EtX since the added methyl group can occupy a 
position close to the plane of the transition state (i.e., the plane containing 
the three <r-bonds), and so would not offer any appreciable steric hindrance. 
In practice, however, w-propyl halides are less reactive than the correspond- 
ing ethyl halides (cf. §2a). The reason for this relatively large decreased 
reactivity is not certain. Magat et al. (1950) have offered the following 
explanation. The smaller the number of conformations available in the 
activated as compared with the initial state produces a decrease in the 
frequency factor (A in the Arrhenius equation k = A<?- E / BT ). In w-propyl 
halides (2 H and 1 Me) there is only one conformation for the transition 
state whereas for ethyl halides (3 H) there are three equivalent conforma- 
tions. Thus the frequency factor for w-propyl halides is 1/3 that for the 
ethyl halides, and so the reaction rate (k) of the former will be 1/3 that of 
the latter (on the assumption that E of both reactions is the same). 

In wobutyl halides the methyl groups will produce a large steric effect 
since at least one methyl group will be fairly close to X or Y. It has been 
shown experimentally that wobutyl halides are less reactive than «-propyl 
halides. Finally, in weopentyl halides, the presence of three methyl groups 
produces a very large steric effect. In the " normal " transition state, 
the entering and displaced groups are collinear. This is readily possible 
with all the halides except possibly wobutyl halides ; but it is not possible 
with weopentyl halides because of the presence of the three methyl groups 
(in the 2-butyl group). Thus in the transition state involving the weopentyl 
radical, the Y— C— X bonds are believed not to be collinear but " bent 
away " from the J-butyl group. Such a " bent " transition state has a large 
compression energy and so is far more difficult to form than a " normal " 



§2c] NUCLEOPHILIC SUBSTITUTION 65 

transition state. Experimental data are in agreement with these ideas, 
e.g., Hughes et al. (1946) showed the following relative (S N 2) reaction rates 
towards the ethoxide ion at 95°: 

Et : i-Bu : Me 3 OCH 2 :: 1 : 0-04 : 10~ s 
These very slow S N 2 reactions of «eopentyl halides occur with the neopentyl 
radical remaining intact. By changing the solvent conditions so that the 
mechanism becomes S N 1, the products are no longer weopentyl derivatives 
but rearranged products formed by a 1,2-shift (see §23d. VIII). 

(ii) A very interesting example of steric hindrance is the case of 1-chloro- 
apocamphane (I). Bartlett et al. (1938) found that this compound does 
not react with reagents that normally react with alkyl halides, e.g., it is 
unaffected when refluxed with aqueous ethanolic potassium hydroxide or 

ci 






III IV 

with ethanolic silver nitrate. As we have seen, the hydrolysis of 2-butyl 
chloride takes place by the S N 1 mechanism. 1-Chloroapocamphane is a 
tertiary chloride, but since it does not ionise, the S N 1 mechanism is not 
possible. This failure to ionise is believed to be due to the fact that the 
carbonium ion is flat (sp 2 hybridisation). Removal of the chloride ion from 
(I) would produce a positive carbon atom which cannot become planar 
because of the steric requirements of the bridged-ring structure. Further- 
more, since the rear of the carbon atom of the C— CI group is " protected " 
by the bridge, the S N 2 mechanism is not possible (since the nucleophilic 
reagent must attack from the rear; see §4). The failure to replace bromine 
in 1-bromotriptycene (II) is explained similarly (Bartlett et al., 1939). On 
the other hand, Doering et al. (1953) showed that (III) gave the corresponding 
alcohol when heated with aqueous silver nitrate at 150° for two days, and 
(IV) gave the corresponding alcohol after four hours at room temperature. 
The reason for this behaviour (as compared with the other bridged com- 
pounds) is not certain, but it has been suggested that the extra bonds in 
the larger bridge in (IV) help to relieve the strain in the formation of the 
carbonium ion which tries to assume a planar configuration. 

(iji) Brown et al. (1949) showed that the solvolysis of tertiary halides is 
subject to steric acceleration. {Solvolysis is the nucleophilic reaction in 
which the solvent is the nucleophilic reagent.) 

R 3 C-^X -^- R 3 C + + X" 

tetrahedral planar; trigonal 

(large strain) (small strain) 

It was shown that as R increases in size, the rate of solvolysis increases. 
However, the larger R is, the more slowly will the carbonium ion be expected 
to react with the solvent molecules, and so a factor is introduced which 
opposes steric acceleration. Carbonium ions can undergo elimination re- 
actions to form olefins (see also Vol. I), and Brown et al. (1950) have shown 
that this elimination reaction increases as the R groups become larger. 

§2c. The nature of the halogen atom. Experimental work has shown 
that the nature of the halogen atom has very little effect, if any, on mech- 
anism, but it does affect the rate of reaction for a given mechanism; e.g., 
it has been found that in S N 1 reactions, the rate follows the order 



66 ORGANIC CHEMISTRY [CH. Ill 

RI > RBr > RC1. It has been suggested that a contributing factor to 
this order is steric strain, since the volume order of these halogen atoms is 
I > Br > CI. Another contributing factor is the increase in energy of 
activation in the order RC1 > RBr > RI, since the bond to be broken 
increases in strength in this order; the bond energies are: C — CI, 77 kg.cal. ; 
C — Br, 65 kg.cal.; C — I, 57 kg.cal. These energy differences also explain 
the order of reactivity RI > RBr > RC1 in S N 2 reactions. 

§2d. The nature of the nucleophilic reagent. The more pronounced 
the nucleophilic activity of the reagent, i.e., the greater its electron avail- 
ability, the more the Sn2 mechanism will be favoured as compared with 
the SnI mechanism, since in the latter the nucleophilic reagent does not 
enter into the rate-determining step. 

It can be anticipated that as nucleophilic activity decreases, the rate of 
an Sn2 reaction will decrease for a given series of substitutions (under 
similar conditions), and when the nucleophilic activity is sufficiently low, 
the mechanism may change from Sn2 to S^l. Hughes, Ingold et al. (1935) 
examined the rates of decomposition of various trimethylsulphonium salts 
in ethanol (Me 3 S + X~ — ► Me a S + MeX) and obtained the following results 
(see also §4): 



Anion 


OH- 


OPh- 


HCO,- 


Br- 


ci- 


2nd-order rate const, x 10 5 
lst-order rate const, x 10 6 


74,300 


1340 


7-38 


7-85 


7-32 



It can be seen from these results that the strong nucleophiles OH- and 
OPh~ react rapidly by the Sn2 mechanism and the other, and weaker, 
nucleophiles react at about the same slow speed by the S N 1 mechanism. 
Although many kinetic investigations of displacement reactions with 
alkyl halides have been carried out, relatively little information is avail- 
able for determining nucleophilicity. One set of data that may be cited 
is that obtained from the reaction between methyl iodide and various bases 
in benzene at 25° (Hinshelwood el al., 1935): 





Pyridine 


Me,N 


Et s N 


Quinoline 


Relative rate 


1 


1730 


144 


0-26 



A point of interest in connection with the nature of the nucleophile is 
that when it affects the rate of substitution, the reaction is usually proceed- 
ing by the Su2 mechanism. When the nature of the nucleophile has very 
little effect on the rate, then the reaction is probably S^l. Another point 
to note is that steric effects in the nucleophile will also affect the rate of 
reaction, and this is probably a contributing factor to the different rates 
observed with reagents with similar nucleophilicity. 

In general, it has been found that within a given periodic group, the 
nucleophilic activity increases with the atomic number of the atom, e.g., 

I- > Br- > CI- > F-; RS~ > RO~. 

This order is opposite to that anticipated on the basis of basicities (and 
steric effects) of the different nucleophiles. This lack of some sort of 
parallelism between nucleophilic reactivity and basicity is unexpected, since 
both of these properties depend on the donating power of the donor atom. 
However, as a result of experimental work, it is now well established that 



§2e] NUCLEOPHILIC SUBSTITUTION 67 

nucleophilic reactivity does not follow the order of increasing basicity 
towards protons, but varies with the nature of the reaction and with the 
reaction conditions. 

§2e. The effect of the solvent on mechanisms and reaction rates. 

Experimentally, it has been found that the ionising power of a solvent 
depends on at least two factors, dielectric constant and solvation. 

Dielectric constant. A very rough generalisation is that ionisation of the 
solute increases both in amount and speed the higher the dielectric constant 
of the solvent. 

Solvation. This factor appears to be more important than the dielectric 
constant. Solvation is the interaction between solvent molecules and solute 
molecules, and is partly accounted for by the attraction of a charge for a 
dipole. If the solute has polarity, then solvent molecules will be attracted 
to the solute molecules. The greater the polarity of the solvent, the greater 
the attraction and consequently the more closely the solvent molecules will 
be drawn to the solute molecules. Thus more electrostatic work is done 
and so more energy is lost by the system, which therefore becomes more 
stable. Thus increasing the dielectric constant of the solvent increases 
the ionising potentiality of the solute molecules, and the higher the polarity 
of the solvent the more stable becomes the system due to increased solvation. 
Solvation, however, may also be partly due to certain chemical properties, 
e.g., sulphur dioxide has an electrophilic centre (the sulphur atom carries 
a positive charge); hydroxylic solvents can form hydrogen bonds. 

There is also another problem that may arise. This is that although 
the solute molecules have ionised, the oppositely charged pair are enclosed 
in a " cage " of surrounding solvent molecules and may therefore recombine 
before they can escape from the cage. Such a complex is known as an 
ion-pair, and their recombination is known as internal return. It has now 
been shown that many organic reactions proceed via ion-pairs rather than 
dissociated ions. According to some authors there are two types of ion- 
pairs: 

(i) Intimate or internal ion-pairs. These are enclosed in a solvent cage 
and the ions of the pair are not separated by solvent molecules. 

(ii) Loose or external ion-pairs. The ions of these pairs are separated by 
solvent molecules but still behave as a pair. External ion-pairs may also 
give rise to ion-pair return {external return), but they are more susceptible 
to attack by other reagents than are intimate ion-pairs. Many workers 
believe it unnecessary to postulate the existence of this type of ion-pair. 

Thus, when ionisation takes place, the following steps are possible: 





Ionisation 


Dissociation 


RX 


-*=^R+X- 

-l 


^R+||X- 

-2 " 


•*-i* R+ + x- 

-3 




intimate 


external 


dissociated 




ion-pair 


lon-pair 


ions 



N.B. (i) —1 is internal return, and it appears uncertain whether this type 
of ion-pair is a transition state or an intermediate; (ii) —2 is external return; 
(iii) only equilibrium 3 is sensitive to a common ion effect; this is because 
an ion-pair behaves as a single particle, as has been shown by the effect 
on the depression of the freezing point (i = 1). 

A number of equations have been proposed correlating rates and the 
nature of the solvent, but none is completely general. Hughes and Ingold 
(1935, 1948) proposed the following qualitative theory of solvent effects: 
(i) Ions and polar molecules, when dissolved in polar solvents, tend to 
become solvated. (ii) For a given solvent, solvation tends to increase with 



68 ORGANIC CHEMISTRY [CH. Ill 

increasing magnitude of charge on the solute molecules or ions, (iii) For 
a given solute, solvation tends to increase with the increasing dipole moment 
of the solvent, (iv) For a given magnitude of charge, solvation decreases 
as the charge is spread over a larger volume, (v) The decrease in solvation 
due to the dispersal of charge will be less than that due to its destruction. 
Since the rate-determining step in the S^l mechanism is ionisation, any 
factor assisting this ionisation will therefore facilitate S^l reactions. Sol- 
vents with high dipole moments are usually good ionising media and, in 
general, it has been found that the more polar the solvent the greater is 
the rate of S^l reactions. We have, however, also to consider the problem 
of solvation. 

R_X -^ it-X -^> R+ + X- ^> ROH 

fast 

Increasing the polarity of the solvent will greatly increase the reaction rate, 
and since the transition state has a larger charge than the initial reactant 
molecule, the former is more solvated than the latter (rule ii). Thus the 
transition state is more stabilised than the reactant molecule. Thus solva- 
tion lowers the energy of activation and so the reaction is assisted. 
The rates of S N 2 reactions are also affected by the polarity of the solvent. 

HO^R-41 ^V HO— R— X -^HO-R + X~ 

A solvent with high dipole moment will solvate both the reactant ion and 
the transition state, but more so the former than the latter, since in the 
latter the charge, although unchanged in magnitude (d— = —1/2), is more 
dispersed than in the former (rule iv). Thus solvation tends to stabilise 
the reactants more than the transition state, i.e., the activation energy is 
increased and so the reaction is retarded. 

Now let us consider the Menschutkin reaction: 

A A s+ s- _ 

R 3 N+ R-Lx >■ R 3 N— R— X — >- R 4 N + X 

The charge on the transition state is greater than that on the reactant mole- 
cules ; hence the former is more solvated than the latter. Thus the energy 
of activation is lowered and the rate of reaction thereby increased. Also, 
the greater the polarity of the solvent, the greater should be the solvation. 
The foregoing predictions have been observed experimentally. 

In the following S N 2 reaction, charges decrease in the transition state, 

HO"'RNR 3 ** HO-~R — NR 3 — »~HOR + R 3 N 

and hence increasing the polarity of the solvent will retard the reaction; 
and retardation will be greater than that in the S N 2 hydrolysis of alkyl 
halides (see above; only the hydroxide ion is charged in this case). 

The polarity of the solvent not only affects rates of reactions, but may 
also change the mechanism of a reaction, e.g., Olivier (1934) showed that 
the alkaline hydrolysis of benzyl chloride in 50 per cent, aqueous acetone 
proceeds by both the Su2 and S^l mechanisms. In water as solvent, the 
mechanism was changed to mainly S N 1. The dipole moment of water is 
greater than that of aqueous acetone, and consequently the ionisation of 
benzyl chloride is facilitated. 

Another example we shall consider is the hydrolysis of the alkyl bromides, 
MeBr, EtBr, *-PrBr and <-BuBr. As we have seen (§2a), Hughes, Ingold 
et al. showed that in aqueous alkaline ethanol the mechanism changed 
from S N 2 for MeBr and EtBr to both S N 2 and S N 1 for i-PrBr, and to S N 1 



§3] NUCLEOPHILIC SUBSTITUTION 69 

for i-BuBr. These results were explained by the +1 effects of the R groups, 
but it also follows that the greater the ionising power of the solvent, the less 
will be the +1 effect of an R group necessary to change the mechanism 
from Sjj2 to S^l. Formic acid has been found to be an extremely powerful 
ionising solvent for alkyl halides, and the relative rates of hydrolysis, at 
100°, for the above series of bromides with the very weak nucleophilic 
reagent water, dissolved in formic acid, was found to be (Hughes et al., 1937, 
1940): MeBr, 1-00; EtBr, 1-71; *-PrBr, 44-7; t-BuBr, ca. 10 8 . This con- 
tinuous increase in reaction rate shows that the mechanism is mainly S N 1 
(the rate increasing with the increasing +1 effect of the R group). Thus 
both MeBr and EtBr are also hydrolysed by the S^l mechanism under these 
favourable conditions of high solvent-ionising power. 

Solvents may also affect the proportions of the products in competitive 
reactions, i.e., the attack on the same substrate by two substituting reagents 
in the same solution: 

RY «-^— RX —%- RZ 

In the Sn2 mechanism there is only one reaction step, and so the overall rate 
and product ratio will be determined by that stage. In the S^l mechanism, 
however, the rate is determined by the rate of ionisation of RX, and the 
product ratio is thus determined by the competition of the fast second steps. 
It therefore follows that for solvent changes, in the Sn2 mechanism the 
rate and product ratio will proceed in a parallel fashion, whereas in the 
S N 1 mechanism the rate and product ratio will be independent of each 
other. A simple example that illustrates this problem is the solvolysis of 
benzhydryl chloride (diphenylmethyl chloride). Hammett et al. (1937, 
1938) showed that the solvolysis of benzhydryl chloride in initially neutral 
aqueous ethanol gave benzhydryl ethyl ether and benzhydrol. Hughes, 
Ingold et al. (1938) showed that if ethanol is first used as solvent and then 
water is progressively added, the overall rate increases, but there is very 
little increase in benzhydrol formation ; the main effect is an increased rate 
of formation of benzhydryl ethyl ether. Thus the rate of the reaction and 
the ratio of the products are determined independently; this is consistent 
with the S N 1 mechanism but not with the Sjj2. 

It can be seen from this example that kinetic solvent effects may be used 
to differentiate between Su2 and S^l mechanisms. 

§3. The Walden inversion (Optical inversion). By a series of replace- 
ment reactions, Walden (1893, 1895) transformed an optically active com- 
pound into its enantiomorph. In some cases the product is 100 per cent, 
optically pure, i.e., the inversion is quantitative; in other cases the product 
is a mixture of the (+)- and (— )-forms in unequal amounts, i.e., inversion 
and retention (racemisation) have taken place. 

The phenomenon was first discovered by Walden with the following 
reactions : 

CHOH-CO.H pci. CHCl-CO a H CHOH-C0 2 H 

I > I "AgOH" j 

CH 2 -C0 2 H c koh CH a -C0 2 H ^CHg-CCyi 

(— )-malic (+)-chlorosuccinic (+)-malic acid 

acid acid 

I II III 

This conversion of the (— )-form into the (+)-form constitutes a Walden 
inversion. The Walden inversion was " defined " by Fischer (1906) as the 
conversion of the (+)-form into the (— )-form, or vice versa, without recourse 
to resolution. In one, and only one, of the two reactions, must there be an 



70 ORGANIC CHEMISTRY [CH. Ill 

interchange of position between the two groups, e.g., if the configuration of 
(I) corresponds with that of (II), the inversion of configuration must have 
taken place between (II) and (III). Now that the mechanism of substitu- 
tion at a saturated carbon has been well worked out, the term Walden 
inversion is applied to any single reaction in which inversion of configuration 
occurs. 

As the above experiment stands, there is no way of telling which stage is 
accompanied by inversion. As we have seen (§5b. II), change in sign of 
rotation does not necessarily mean that inversion configuration has occurred. 
Various methods of correlating configuration have already been described 
(§5a. II), but here we shall describe the method where bonds attached to 
the asymmetric carbon atom are broken during the course of the reactions. 
This method was established by Kenyon et al. (1925), who carried out a 
series of reactions on optically active hydroxy compounds. Now it has 
been established that in the esterification of a monocarboxylic acid by an 
alcohol under ordinary conditions, the reaction proceeds by the acyl-oxygen 
fission mechanism (see also Vol. I); thus: 



)-L(M* H-^5 



R-CO J -OH ,( H-^OR' >- RCOOR' + H 2 

Kenyon assumed that in all reactions of this type the R' — O bond remained 
intact and consequently no inversion of the alcohol is possible. The follow- 
ing chart shows a series of reactions carried out on ethyl (+)-lactate; 
Ts — tosyl group = />-toluenesulphonyl group, /-Me'CgH^SOj-; the symbol 
— o— >- is used to represent inversion of configuration in that step. (IV) and 



Me 


C0 2 Et Me C0 8 Et 

f/ TsC1 > \r 


x OH 


W N OTs 


(+)•; iv 


(+)-; v 
l 


^ 


Ac.O 


J AcO"K+ 


Me C0 8 Et 
c 

/\ 

W OAc 


T 

Me OAc 

C 
K x CO a Et 


(-) 


-; vi 


(+)-; vii 



(VI) have the same relative configurations even though the sign of rotation 
has changed. Similarly, (IV) and (V) have the same relative configurations. 
Reaction of (V) with potassium acetate, however, produces (VII), the 
enantiomorph of (VI). Therefore inversion must have occurred in the 
formation of (VII); (V) and (VI) are produced without inversion since in 
these cases the C — O bond in (IV) is never broken. It should be noted 
here that if inversion is going to take place at all, the complete group attached 
to the asymmetric carbon atom must be removed (in a displacement re- 
action) (cf. Fischer's work on (+)-*sopropylmalonamic acid, §3a. II). The 
converse, however, is not true, i.e., removal of a complete group does not 
invariably result in inversion (see later, particularly §4). 

The above series of reactions has been used as a standard, and all closely 
analogous reactions are assumed to behave in a similar way, e.g., the action 
of lithium chloride on the tosylate (V) is assumed to be analogous to that 



§4] NUCLEOPHILIC SUBSTITUTION 7l 

of potassium acetate, and the chloride produced thus has an inverted 
configuration: 

Me C0 2 Et Me CI 

W OTs W N C0 2 Et 



By similar procedures, Kenyon etal. (1929, 1930) showed that (+)-octan-2-ol 
and (+)-2-chloro-, 2-bromo- and 2-iodo-octane have the same relative con- 
figurations; and also that (+)-a-hydroxyethylbenzene (Ph'CHOH-Me), 
(+)-a-chloro- and (+)-«-bromoethylbenzene have the same relative con- 
figurations (see also the S N 2 mechanism, §4). 

§4. Mechanism of the Walden Inversion. As the result of a large 
amount of work on the Walden inversion, it has been found that at least 
three factors play a part in deciding whether inversion or retention (race- 
misation) will occur: (i) the nature of the reagent; (ii) the nature of the 
substrate; (iii) the nature of the solvent. Hence it is necessary to explain 
these factors when dealing with the mechanism of the Walden inversion. 

Many theories have been proposed, but we shall discuss only the Hughes- 
Ingold theory, since this is the one now accepted. According to this theory, 
aliphatic nucleophilic substitution reactions may take place by either the 
S N 2 or S N 1 mechanism (see also §5). 

HO * R-^X >■ HO— R— X *- HO— R + X (1) 

Hughes et al. (1935) studied (a) the interchange reaction of (+)-2-iodo- 
octane with radioactive iodine (as Nal*) in acetone solution, and (b) the 
racemisation of (+) -2-iodo-octane by ordinary sodium iodide under the same 
conditions. These reactions were shown to take place by the Su2 mech- 
anism, and the rate of racemisation was shown to be twice the rate of 
radioactive exchange, i.e., every iodide—iodide* displacement is always 
accompanied by inversion. (Suppose there are n molecules of optically 
active iodo-octane. When w/2 molecules have exchange with I* and in 
doing so have been inverted, racemisation is now complete although the 
exchange has taken place with only half of the total number of molecules.) 
Thus this experiment leads to the assumption that inversion always occurs 
in the Sjf2 mechanism. This is fully supported by other experimental 
work, e.g., Hughes et al. (1936, 1938) studied the reaction of optically active 
oc-bromoethylbenzene and a-bromopropionic acid with radioactive bromide 
ions, and again found that the rates of exchange (of bromide ions) and 
inversion were the same. 

Thus the Walden inversion affords a means of studying the mechanism 
of substitution reactions. If complete inversion occurs, the mechanism is 
S N 2, or conversely, if the mechanism is known to be S N 2 (by, e.g., kinetic 
data), complete inversion will result. This is the stereokinetic rule for Sjj2 
reactions, and its use thus offers a means of correlating configurations. 

The essential problem that now arises is the consideration of the forces 
that determine the direction of attack, since the S N 2 mechanism might 
conceivably have taken place with retention as follows: 

,x 8 - 

RX + OH" *- RC' ** ROH + X" (2) 

\>H- 



72 ORGANIC CHEMISTRY [CH. HI 

Polanyi et al. (1932) suggested that the polarity of the C— X bond causes 
the negative ion (such as OH~) to approach the molecule RX from the 
side remote from X; this is end-on attack: 

R \ ,. . ^ ,. R 

HO~ + C— X — >■ HO— C— X — *- HO— C^ + X" 

R K R R 

Hughes and Ingold (1937), however, suggested from quantum-mechanical 
arguments that, independently of the above electrostatic repulsions, the 
minimum energy of activation results when the attacking ion approaches 
from a direction that would lead to inversion. Furthermore, these authors 
believe that the quantum-mechanical forces are more powerful than the 
electrostatic forces. There is much evidence to support this, e.g., if electro- 
static forces were the only or the predominating factor, then attack by a 
negatively charged nucleophilic reagent on a compound in which the dis- 
placed group has a positive charge would be expected to occur with retention 
(equation 2). In practice, however, inversion is still obtained, e.g., the 
acetoxyl ion attacks the (-f-)-trimethyl-a-phenylethylammonium ion to give 
inversion (Snyder et al., 1949): 

- *\ ♦ ^ 

AcO + >C— NMe 3 » AcO— O. + Me.N 

Hy ^H 3 

Me Me 

A point of interest about the S N 2 reaction is that there are four electro- 
statically distinct types: 

Reagent Substrate 

1. Y- + RX ->YR +X- negative neutral 

2. Y- + RX+ — ► YR + X negative positive 

3. Y + RX -> YR+ + X- neutral neutral 

4. Y + RX+ ->• YR+ + X neutral positive 

The stereokinetic rule for Sn2 reactions is well established for only reactions 
of type 1. Hughes, Ingold et al. (1960) have also shown that the rule 
applies to type 2, e.g., the reaction between a sulphonium iodide and sodium 
azide (cf. Snyder's work): 

CHMePh-SMe 2 + + N,- -► CHMePh-N 3 + Me 2 S 

These authors have also demonstrated that type 4 proceeds by the Sn2 
mechanism, e.g., with a sulphonium nitrate: 

Me 3 N + MeSMe 8 + — ► Me 3 NMe+ + Me^S 

Now let us consider the S N 1 mechanism. 

R-^X >- R-- -X >■ R + +X" -^V ROH + X" 

When the reaction proceeds by this mechanism, then jnversion and reten- 
tion (racemisation) will occur, the amount of each depending on various 
factors. The carbonium ion is flat (trigonal hybridisation), and hence 
attack by the nucleophilic reagent can take place equally well on either side, 
i.e., equal amounts of the (+)- and (— )-forms will be produced; this is 
racemisation. One can expect complete racemisation only if the carbonium 
ion has a sufficiently long life; this is favoured by low reactivity of the 
carbonium ion and low concentration of the nucleophilic reagent. However, 
during the actual ionisation step, the retiring group will " protect " the 
carbonium ion from attack on that side, i.e., there is a shielding effect, and 
this encourages an end-on attack on the other side, thereby leading to 



§5] NUCLEOPHILIC SUBSTITUTION 73 

inversion. An example of this type is the following. Bunton et al. (1955) 
studied the reaction of 18 0-enriched water on optically active s-butanol in 
aqueous perchloric acid, and found that the overall rate of racemisation is 
twice that of the oxygen exchange. Thus every oxygen exchange causes 
complete inversion of configuration {cf. the iodide-iodide* exchange described 
above) . Bunton proposed the following mechanism to explain these results : 

HCIO 

EtMeCHOH + H+ . EtMeCHOH 2 + (3) 

fast v ' 

slow ^+ 0+ 

EtMeCHOH 2 + =^ i= EtMeCH— OH a (4) 

H 2 0* + EtMeCH— OH 2 =< — =*H 2 0*— EtMeCH— OH 2 

. fast » H 2 0*— CHMeEt + H 2 (5) 

+ fast 

H 2 0*— CHMeEt .. HO*— CHMeEt + H+ (6) 

(5) occurs before the OH 2 + has completely separated in (4), and so this 
side is shielded and the H 2 0* is forced to attack on the other side as shown ; 
the result is thus inversion. The above reaction proceeds by the S N 1 
mechanism since (4) is the rate-determining step (only one molecule is under- 
going covalency change in this step). Had the reaction been S N 2, complete 
inversion would still have been obtained. It was shown, however, that the 
reaction rate was independent of the concentration of H 2 0*. The mech- 
anism is therefore S N 1, since had it been S N 2, the kinetic expression would 
require the concentration of the H 2 0*: 

, „ slow 8+ 6+ f nai 

H 2 0* + EtMeCHOH 2 + , H 2 Q*— EtMeCH— OH 2 >, 

H 2 0*— CHMeEt + H 2 

The stereochemical course of S^l reactions may also be affected by 
neighbouring group participation (see, e.g., §6a). 

§5. The S n j mechanism. Another important S N reaction is the S N i 
type (substitution, nucleophilic, internal). The reaction between thionyl 
chloride and alcohols has been studied extensively. A well-examined 
example is the alcohol a-phenylethanol, PhCHOHMe; this is an arylmethanol, 
and according to Hughes, Ingold et al. (1937), the first step is the formation 
of a chlorosulphinate. No inversion occurs at this stage (which is a four- 
centre reaction) ; in the following equations, R = PhMeCH- : 

R— O * S=0 — >~ R— O— S=0 + HC1 

CI CI 

This chlorosulphinate could then form a-chloroethylbenzene by one or more 
of the following mechanisms: 

(i) S N 2. This occurs with inversion. 

<rCl 
R-O- S=0 -***-+• Cf + R-0-S=0 - J ^ 

CI— -R-— OSO - «•**> . CI— R + S0 2 
(ii) S N 1. This occurs with inversion and retention (racemisation). 
CI CI 

R-^— S=0 -i!°*^R + + o"— S=0 -^^ RC1 + S0 2 



74 ORGANIC CHEMISTRY [CH. III 

The second stage may possibly be: 

0— 8=0 - &|L >- S0 2 + Cf f *, * - RC1 

(iii) S N t. This occurs with retention (the reaction is effectively a four- 
centre type). 




S=0 



R-^-0^ 



s=o 



->■ RCl + S0 2 



In practice, the a-chloroethylbenzene obtained has almost complete reten- 
tion of configuration, and consequently the mechanism must be Sn*. A 
point of interest here is that it is apparently difficult to postulate the nature 
of the transition state in this mechanism. 

When a-phenylethanol and thionyl chloride react in the presence of 
pyridine, the a-chloroethylbenzene obtained now has the inverted configura- 
tion (Hughes, Ingold et al., 1937). The explanation offered is that the S N 2 
mechanism is operating, the substrate now being a pyridine complex: 

R0S0C1 + C 5 H 6 N -* CI- + ROSONC 5 H 8 -► 

Cl— R— OSONC 6 H 6 -> CI— R + S0 2 + C 5 H 5 N 
Optically active a-phenylethanol reacts with phosphorus trichloride, phos- 
phorus pentachloride, and phosphoryl chloride, in the presence or absence 
of pyridine, and with hydrochloric acid, to give the inverted chloride. Thus 
all these proceed by the Sn2 mechanism. It is reasonable to assume that 
the chloride ion attacks some intermediate other than a pyridinium ion, 
since inversion occurs whether pyridine is present or absent. 

§6. Participation of neighbouring groups in nucleophilic substitu- 
tions. So far, we have discussed polar effects (inductive and resonance) 
and steric effects on the rates and mechanisms of reactions. In recent 
years it has been found that another factor may also operate in various 
reactions. This factor is known as neighbouring group participation. Here 
we have a group attached to the carbon atom adjacent to the carbon atom 
where nucleophilic substitution occurs and, during the course of the reaction, 
becomes bonded or partially bonded to the reaction centre. Thus the rate 
and/or the stereochemistry of a reaction may be affected by this factor. 
When a reaction is accelerated by neighbouring group participation, that 
reaction is said to be anchimerically assisted (Winstein et al., 1953). For 
anchimeric assistance to occur, the neighbouring group, which behaves as a 
nucleophilic reagent, must be suitably placed stereochemically with respect 
to the group that is ejected. This is the ^raws-configuration, and in this 
configuration the conditions for intramolecular displacement are best. 
Neighbouring group participation is also of great importance in the 1,2-shifts 
(see Vol. I; see also §2h. VI). 

§6a. Neighbouring carboxylate anion. Hughes, Ingold et al. (1937) 
studied the following reaction of methyl D-a-bromopropionate : 

Me-CHBr-C0 2 Me ->- Me-CH(OMe)-C0 2 Me 
With concentrated methanolic sodium methoxide, the reaction was shown 
to be S N 2, and the product was L-methoxy ester (100 per cent, inversion). 
Under these conditions, the nucleophilic reagent is the methoxide ion, and 
the reaction is first order with respect to both methoxide ion and ester. 



§6a] NUCLEOPHILIC SUBSTITUTION 75 

When the ester was subjected to methanolysis, i.e., methanol was the 
solvent (no methoxide ion now present), the product was again L-methoxy 
ester (100 per cent, inversion). The reaction was now first order [i.e., pseudo 
first order), but still Sn2, the nucleophilic reagent being the solvent mole- 
cules of methanol. When the sodium salt of D-a-bromopropionic acid was 
hydrolysed in dilute sodium hydroxide solution, the mechanism was shown 
to be SnI, and the product was now D-a-hydroxypropionate anion (100 per 
cent, retention). In concentrated sodium hydroxide solution, however, the 
mechanism was S^2 (due to the high concentration of the hydroxide ion), 
and the product was L-oc-hydroxypropionate anion (100 per cent, inversion). 
Hughes and Ingold have proposed the following explanation for the 
retention experiment. The first step is ionisation to a carbonium ion in 
which the negatively charged oxygen atom forms a " weak electrostatic 
bond " with the positively charged carbon atom on the side remote from 
that where the bromide ion is expelled. Thus this remote side is " pro- 
tected " from attack by the hydroxide ion, which is consequently forced 
to attack from the same side as that of the expelled bromide ion, thereby 
leading to retention of configuration. 

/Me /Me 
7> r/ t, stow - +/ oh- 
O x X— Br > Br- + O C ► 

^^ \h Nx>/ \h 



protection 



O x X— OH 

XXX \ 



Me 
OI 
H 



retention 

Hughes, Ingold et al. (1950) showed that the deamination of optically 
active alanine by nitrous acid gave an optically active lactic acid with 
retention of configuration. This is also explained by neighbouring group 
participation of the a-carboxylate anion: 

COi J C0 2 H 

H N h 2 -™^6^I + -^ H OH 

Me Y * 2 Me 

Me 
d(-) -alanine d(-) -lactic acid 

This effect of neighbouring group participation is supported by the fact 
that in the absence of the a-carboxylate ion, Hughes, Ingold et al. observed 
that there was an overall inversion of configuration (with much racemisation) 
in the deamination of simple optically active amines, and explained this as 
being due to asymmetrical shielding of the carbonium ion by the expelled 
nitrogen. 

As we have seen above, neighbouring group participation involves a group 
on the adjacent carbon atom. Austin et al. (1961) have offered an example 
where the " neighbouring group " is on the y-carbon atom. These authors 
have shown that there is 80 per cent, retention of configuration in the 
deamination of y-aminovaleric acid; the product is a lactone. Thus a 
" free " carbonium jon is not involved in tbe formation of the lactone, 



76 ORGANIC CHEMISTRY [CH. Ill 

The authors suggest the following mechanism, neighbouring group participa- 
tion occurring as shown: 



Me Me (^ 



I . 
.CH— Nj CH + 



■N 2 



/ /\} / 



CH 2 O *-CH 2 f N 

CH 2 — C— O— H. N CH— C^O-^H cHa 



I 
CH 

CH 2 ? 



/CO 



Thus the oxygen atom of the y-carboxyl group enters the site, originally 
occupied by the amino-group, by an Su» mechanism. 

§6b. Neighbouring halogen atoms. Brominium (bromonium) ions 
were first proposed by Roberts and Kimball (1937) as intermediates in the 
addition of bromine to olefins (see §5. IV). The existence of this cyclic 
brominium ion has been demonstrated by Winstein and Lucas (1939), who 
found that the action of fuming hydrobromic acid on (— )-^ra>-3-bromo- 
butan-2-ol gave (±)-2,3-dibromobutane. 



TT ( 



OH 



H-Y 
Br 

(— )-form 



/Me 




H 0H 2 


..Me 


H. 




,-Me 




H + , 






-H 2 y 
inversion 
at Ci 


Y 

,.c 2 . 


>Br + 


a 




ii-- 1 - 

Br 


-Me 


H' 




~-Me 


-^> 


H-. B, YMe 

f 


+ 


H-. B VMe 

Y 








H'' 


Br " Me 




.c 2 

H X Br^ Me 








(- 


-)-form 




(+)-form 







If no neighbouring group participation of bromine occurred in the above 
reactions, then if the reaction were S N 2, complete inversion would have 

Br 
S N 2 — C 2 — Ci— — ^-» — C 2 — (V- + H 2 
Br +OH 2 Br 



Br 
SnI — C 2 — Cj — >■ — C 2 — ^i\ ^ ^2 *^i I ^2 ^1 



-H s I + Br- 



Br+OH, Br Br Br Br 



*2 



occurred only at C v If the reaction were the ordinary S N 1, the C x would 
have been a classical carbonium ion (flat), and so inversion and retention 
(racemisation) would have occurred only at C v Since either retention of 
inversion occurs at both C x and C 2 , the results are explained by neighbouring 
group participation of the bromine atom. 

The above mechanism also explains the formation of weso-2,3-dibromo- 
butane by the action of fuming hydrobromic acid on optically active erythro- 



§6c] NUCLEOPHILIC SUBSTITUTION 77 

3-bromobutan-2-ol (I) ; (II) and (III) are identical and correspond to the 
meso-form. 



OH 


.Me 
H 


OH 2 

Me 1 
Br 


Me 
H 


-H 2 o ^ 


H-. .-Me 


1 

-'C2-. 

Vie' P 
Br 


inversion 
at Ci 


1 ^>Br 

."< 
Me H 


I 














Br^ 


Br 
H\T/-Me 

I 1 

Me' | "H 


+ 




Br 
H-.. I ..-Me 

Me"; ^H 








Br 






Br 








II 






III 





There is evidence that all the halogen atoms can form cyclic ions and 
offer anchimeric assistance, e.g., Winstein et al. (1948, 1951) studied the 
acetolysis of cis- and ft-««s-2-halogeno-cycZohexyl brosylates (i.e., />-bromo- 
benzenesulphonates; this group is often written as OBs): 

-X X 




-OBs" 



^ 



AcOH 




OAc 



trans 



X 



BsO. 




:OBs~ 




as 

In the absence of neighbouring group participation, the rates would be 
expected to be about the same. If participation occurs, then this is readfly 
possible in the trans-isomer (la : 2a) by attack of X at the rear of the ejected 
OBs- ion, but this is not so for the cw-isomer (le : 2a; see §11. IV). The 
rate ratios observed were: 

trans /cis: X = I, 2-7 x 10 6 /1; X = Br, 800/1; X = CI, 3-8/1. 

Thus iodine affords the greatest anchimeric assistance and chlorine the 
least (see also §6c). 

§6c. Neighbouring hydroxyl group. Bartlett (1935) showed that 
alkali converts <raMs-2-chlorocycZohexanol into cycMiexene oxide, and pro- 
posed a mechanism in which an alkoxide ion is formed first and this then 
ring-closes with ejection of the chloride ion: 




oh: 



H 2 + 




-cr 




78 



ORGANIC CHEMISTRY 



[CH. Ill 



Bergvist (1948) showed that this reaction proceeds more than 100 times as 
fast as that when the cts-compound is used. Here again, the trans-iorm 
permits ready attack at the rear of the chloride ion whereas the cw-isomer 
does not (cf. §6b). The fact that the cw-form does react may be explained 
by assuming that the reaction proceeds via the trans-torm, i.e., the former 
is first converted into the latter. This requires energy of activation and 
consequently the reaction for the a's-form is slowed down (cf. §6d). 

Another example of neighbouring hydroxyl participation is the conversion 
of sugars into epoxy-sugars (see §9. VII). 

§6d. Neighbouring acetoxyl group. Winstein et al. (1942, 1943) 
showed that a neighbouring acetoxyl group leads to the formation of an 
acetoxonium ion. foms-2-Acetoxycyc/ohexyl brosylate (I) forms trans-1,2- 
diacetoxycyc/ohexane (II) when treated with silver acetate, and the same 
product (II) is obtained when the starting material is trans-2-acetoxycyclo- 
hexyl bromide (III). The authors believe that the course of the reaction, 
based on the stereochemical evidence, proceeds through the same acetox- 
onium ion (IV). This mechanism is supported by the fact that in each 
case, when the reaction was carried out in the presence of a small amount 
of water, the product was now the monoacetate of c*'s-cycMiexane-l,2-diol(V) ; 
some diacetate of this a's-diol was also obtained. 



Me 



,0 




<$ 



-BsO" 



-OBs 



(I) 




A.c 



AcO" 




OAc 



(II) 




Me 
HO^JU-0 
/° 

o 



OAc 




HO. 




>Br 

(in) (v«) (V) 

Further support for the formation of (IV) is afforded by the fact that 
the M's-isomers of (I) and (III) undergo the same reactions but at much 
slower rates; anchimeric assistance can readily operate in the trans-iorm. 
It is possible that for the ws-forms, the reactions proceed via the trans- 
forms, i.e., the cw-form is first converted into the trans. This requires 
energy of activation and consequently the reactions with the as-forms are 
slowed down. The formation of the intermediate (Va) is supported by the 



EtO 




§7] NUCLEOPHILIC SUBSTITUTION 79 

fact that when the solvolysis of (I) is carried out in ethanol, (VI) is obtained 
(Winstein et al., 1943). 

ASYMMETRIC SYNTHESIS 

§7. Partial asymmetric synthesis. Partial asymmetric synthesis may 
be defined as a method for preparing optically active compounds from 
symmetrical compounds by the intermediate use of optically active com- 
pounds, but without the necessity of resolution (Marckwald, 1904). In 
ordinary laboratory syntheses, a symmetrical compound always produces 
the racemic modification (§7a. II). 

The first asymmetric synthesis was carried out by Marckwald (1904), 
who prepared an active (— )-valeric acid (laevorotatory to the extent of 
about 10 per cent, of the pure compound) by heating the half-brucine salt 
of ethylmethylmalonic acid at 170°. 

I and II are diastereoisomers; so are III and IV. V and VI are enantio- 
morphs, and since the mixture is optically active, they must be present in 
unequal amounts. Marckwald believed this was due to the different rates 
of decomposition of diastereoisomers I and II, but according to Eisenlohr 
and Meier (1938), the half-brucine salts I and II are not present in equal 
amounts in the solid form (as thought by Marckwald). These authors sug- 
gested that as the less soluble diastereoisomer crystallised out (during 

CH 3\ /C0 2 H w . brudne 
CgH^ ^C0 2 H 

CH, C0 2 H[B-brucine] CH 3 G0 2 H 

<\Kf ^C0 2 H G 2 Bf NX> 2 H [(-)-brucine] 

I II 

„, y OIK /C0 2 H[(-)-brucine] CH 3 ^ ^H 

CjsHf' ^H C 2 H.f ^C0 2 H[(-)-brucine] 

III IV 

hc. CI K /C0 2 H CH. H 

2 Hf ^H C 2 Hf^ ^0O 2 H 

V VI 

evaporation of the solution), some of the more soluble diastereoisomer spon- 
taneously changed into the less soluble diastereoisomer to restore the 
equilibrium between the two; thus the final result was a mixture of the 
half-brucine salt containing a larger proportion of the less soluble diastereo- 
isomer. If this be the explanation, then we are dealing with an example 
of asymmetric transformation and not of asymmetric synthesis (see §10. II). 
Further work, however, has shown that Marckwald had indeed carried out 
an asymmetric synthesis. Kenyon and Ross (1951) decarboxylated optically 
active ethyl hydrogen ethylmethylmalonate, VII, and obtained an optically 
inactive product, ethyl (^J-a-methylbutyrate, VIII. 

co 2 + X 

C 2 Hr ^C0 2 C 2 H 5 
VIII 

inactive 



CH S \ /C0 2 H 




C 2 H 5 -^ ^C0 2 C 2 H 5 

VII 

active 





80 ORGANIC CHEMISTRY [CH. Ill 

These authors (1952) then decarboxylated the cinchonidine salt of VII, and 
still obtained the optically inactive product VIII. 

CH^ ^C0 2 H(cinchonidine) CH^ ^H 

^C . >- .0 ^ + COo + cinchonidine 

C 2 Hf \C0 2 C 2 H 5 C 2 H,< \C0 2 C 2 H 5 

VIII 

inactive 

Kenyon and Ross suggest the following explanation to account for their 
own experiments and for those of Marckwald. Decarboxylation of dia- 
stereoisomers I and II takes place via the formation of the same carbanion 
la, and decarboxylation of VII and its cinchonidine salt via Vila. 

CHj. C0 2 H[(-)-brucine] 

C 2 Hf^ ^C0 2 H \ 

T \ CH 3. e 

1 /"*" ^0-C0 2 HT(-)-brucine] 

CH 3 C0 2 H / ° 2H5 la 

C ' 

C 2 Hf^ ^C0 2 H[(-)-brucine] 

II 



CH 3 / C0 2 H 

C 2 H 5 ^ \C0 2 C 2 H 5 \ ch 

VH >— >■ 3 ^C-C0 2 C 2 H 5 

/ C H 

CH 3 C0 2 H(cinchonidine)/ 2 5 Vila 

C 2 Hf ^C0 2 C 2 H 5 

Combination of carbanion \a with a proton will produce diastereoisomers 
III and IV in different amounts, since, in general, diastereoisomers are 
formed at different rates (§76. II). On the other hand, carbanion Vila will 
give equimolecular amounts of the enantiomorphs of VIII. If the formation 
of optically active a-methylbutyric acid (V and VI) were due to different 
rates of decarboxylation of III and IV (Marckwald's explanation) or to 
partial asymmetric transformation during crystallisation (Eisenlohr and 
Meier's explanation), then these effects are nullified if Kenyon 's explanation 
is correct, since the intermediate carbanion is the same for both diastereo- 
isomers. Thus, if the asymmetric transformation theory were correct, then 
decarboxylation of the dibrucine salt of ethy methylmalonic acid to a-methyl- 
butyric acid should give an optically inactive product, since only one type 
of crystal is now possible (asymmetric transformation is now impossible). 

CH,. ^CQjHCB-brucine] CHj^G 

*\QT *~ ^C — 0O 2 H [(-)-brucine] 

C 2 Hs ^COaHCH-brucine] C 2 Hf 

la 

On the other hand, if the carbanion la is an intermediate in this decomposi- 
tion, it is still possible to obtain an optically active product. Kenyon and 
Ross did, in fact, obtain a Isevorotatory product. 



§7] NUCLEOPHILIC SUBSTITUTION 81 

McKenzie (1904) carried out a number of partial asymmetric syntheses 
by reduction of the keto group in various keto-esters in which the ester 
group contained an asymmetric group, e.g., benzoylformic acid was esterified 
with (— )-menthol, the ester reduced with aluminium amalgam, and the 
resulting product saponified; the mandelic acid so obtained was slightly 
laevorotatory. 

C 6 H 5 -COC0 2 H + (-)-C 10 H 19 OH -+ C 6 H 6 -COC0 2 C 10 H 19 + H 2 ^% 

CeHs-CHOH-COjAoHi, -^ C 6 H 5 -CHOH-C0 2 H + (-)-C 10 H 19 OH 

(—) -rotation 

Similarly, the pyruvates of (— )-menthol, (— )-pentyl alcohol and (— )-borneol 
gave an optically active lactic acid (slightly laevorotatory) on reduction. 

CH 3 -CO-C0 2 R(-) J5i> CH 3 -CHOH-C0 2 R(-) -^> 

CH 3 -CHOH-C0 2 H + (-)-ROH 

(—) -rotation 

McKenzie (1904) also obtained similar results with Grignard reagents, e.g., 
the (— )-menthyl ester of benzoylformic acid and methylmagnesium iodide 
gave a slightly laevorotatory atrolactic acid. 

/OMgl 
C 6 H s -CO-CO 2 C 10 H M + CH 3 -MgI >- CeHs-C^-COjAoHjg 



OH 

^*- C 6 H 5 C^C0 2 H + (-)-C 10 H 19 OIi 
^CH 3 
(-)-rotation 



CH 3 



Turner et al. (1949) carried out a Reformatsky reaction (see Vol. I) using 
acetophenone, (— )-menthyl bromoacetate and zinc, and obtained a dextro- 
rotatory /Miydroxy-/3-phenylbutyric acid. 



OH/ 



0=0 + Zn+ CHaBr-COadoHj, 



CsH^ ^.OZnBr C 6 H 5 \ ^,OH 

c > c 

OHs^ ^CHa-COgCioHjg CHj^ \CH 2 -C0 2 H 

(+) -rotation 

Reid et al. (1962) have also used aldehydes in the Reformatsky reaction, 
e.g., benzaldehyde gave a laevorotatory /3-hydroxy-/3-phenylpropionic acid. 
Jackman et al. (1950) reduced tert. -butyl w-hexyl ketone with aluminium 
(+)-l : 2 : 2-trimethylpropoxide at 200°, and obtained a slightly laavorota- 
tory alcohol. 

(CH 3 ) 3 OCO.C 6 H 13 WWTOM > (CH 3 ) 3 C.CHOH.C 6 H 13 

(— )-rotation 

Another example of asymmetric synthesis involving the use of a Grignard 

reagent is the reduction of 3 : 3-dimethylbutan-2-one into a dextrorotatory 

(CH 3 ) 3 OCOCH 3 '^-ch.^.ch^.ch.m.c^ (CH3)sC . CHOH , CH3 

(-(-)-rotation 



82 ORGANIC CHEMISTRY [CH. Ill 

3 : 3-dimethylbutan-2-ol by means of (+)-2-methylbutylmagnesium chloride 
(Mosher et al., 1950; see also Vol. I for abnormal Grignard reactions). 

Bothner-By (1951) reduced butanone with lithium aluminium hydride in 
the presence of (+)-camphor, and thereby obtained (-f )-z'soborneol (from 
the camphor) and a small amount of a dextrorotatory butan-2-ol. The 
reducing agent in this case is a complex aluminohydride ion formed from 
lithium aluminium hydride and camphor, e.g., Al(OR)H 3 - . 

CH 3 -COC 2 H s ^^ — > CH 3 -CHOH-C 2 H 5 

3 a s (+)-camphor B z s 

(+)-rotation 

It has already been pointed out that a molecule containing one asym- 
metric carbon atom gives rise to a pair of diastereoisomers in unequal 
amounts when a second asymmetric carbon atom is introduced into the 
molecule (§7b. II). In general, if a new asymmetric centre is introduced 
into a molecule which is already asymmetric, the asymmetric part of the 
molecule influences the configuration formed from the symmetrical part of 
the molecule, the two diastereoisomers being formed in unequal amounts, 
e.g., the Kiliani reaction (see also Vol. I). 

CN CN 

I I 

CHO hcn H— C— OH HO— C— H 

I *- I + I 

CHOH CHOH CHOH 

I i ' 

■ J ■ 

Prelog et al. (1953) have studied, by means of conformational analysis, the 
steric course of the addition of Grignard reagents to benzoylformic (phenyl- 
glyoxylic) esters of asymmetric alcohols. If the letters S, M and L refer re- 
spectively to small, medium and large groups attached to the carbinol carbon 
atom of the asymmetric alcohol, then the general reaction may be written : 

C 6 H B -CO-CO a CSML ^5- C,H B -CR(OH)-C0 2 CSML ^% C 6 H 6 -CR(OH)CO a H 

Prelog et al. found that the configuration of the asymmetric carbon atom 
in the stereoisomer that predominated in this reaction could be correlated 
with that of the carbinol carbon of the alcohol. The basis of this correlation 
was the assumption that the Grignard reagent attacks the carbon atom (of 
the ketone group) preferentially from the less hindered side. This necessi- 
tates a consideration of the possible conformations of the ester molecule. 
The authors considered that the most stable conformation of the ester was 
the one in which the two carbonyl groups are planar and trans to each 
other, with the smallest group lying in this plane and the other two groups 
skew. Furthermore, with the groups on the carbinol atom of the alcohol 
arranged in the staggered conformation with respect to the rest of the 
molecule, then IX and X will be the conformations of the esters with the 
enantiomorphous alcohol residues IX a and X a respectively (thick lines 
represent groups in front of the plane, broken lines groups behind, and 
ordinary lines groups in the plane). Thus, with L behind, methylmag- 
nesium halide attacks preferentially from the front (IX); and with L in 
front, the attack is from behind (X). The a-hydroxyacid obtained from 
IX is IX b, and that from X is X b. IX b and X b are enantiomorphs and 
hence the configuration of the new asymmetric centre is related to that of 
the adjacent asymmetric centre in the original molecule. Thus for the 
same keto-acid and the same Grignard reagent, and using different optically 
active alcohols belonging to the same configurational series, the product 
should contain excess of a-hydroxyacids with the same sign of rotation. 
This has been shown to be so in practice, e.g., (— )-menthol and (— )-borneol 



§7] 



NUCLEOPHILIC SUBSTITUTION 



83 



are both configurationally related to l(— )-glyceraldehyde, and both lead to 
a predominance of the (— )-hydroxyacid. On the other hand, if the keto- 
acid is pyruvic acid and the Grignard reagent phenylmagnesium bromide, the 
(+)-hydroxyacid should predominate in the product (this method of pre- 
paration produces an interchange of the positions of the phenyl and methyl 
groups, thereby leading to the formation of the enantiomorph). This can 

M M 



HO C S 

i 
i 
i 
L 

IX a 

I 

Q 



Ph 



Ph. 



N^N)' 



II \ 



.,0^— M 



Ph. 



I 

Me 



MeMgX 
IX 

I 

o 

.OH || A, 

a /0^-m 



-c— 

I 

I 

I 
L 

Xa 

I 

O 

II 



-OH 



x O' 



,Cb 



-M 
-L 



O 



Plu 



.Me 



MeMgX 
X 

J 

O 



I 

OH 



^O' 



M 



Me- 



C0 2 H 



i 
-C- 



-OH 



C0 2 H 



HO C Me 



Ph 
IX b 



i 
Ph 

Xb 



be seen from the following equation : starting with the pyruvic ester XI in 
which the configuration of the alcohol is IX a, the product would be X b. 



Me. 



O 

II 
XL 



-XT NK 

ll\ 
°PhMgBr 

XI 
C0 9 H 



O 
,L Me^ .OH || Au 

-M >- ^CT- CL JOg-M 

Ph 



-HO- 



i 
-0- 



-Me 



Ph 
Xb 



84 



ORGANIC CHEMISTRY 



[CH. Ill 



These results have been obtained in practice. Thus, when the configuration 
of the active alcohol is known, it is possible to deduce the configuration of the 
a-hydroxyacid obtained in excess. This method has been used to determine 
the configuration of hydroxyl groups in steroids. 

Cram et al. (1952) have also dealt with asymmetric syntheses in which the 
molecule contains an asymmetric centre that belongs to the molecule, i.e., 
remains in the molecule (cf. the Kiliani reaction mentioned above). As a 
result of their work, these authors have formulated the rule of " steric 
control of asymmetric induction ". This is: "In non-catalytic reactions 
of the type shown, that diastereoisomer will predominate which would be 
formed by the approach of the entering group from the least hindered side 
of the double bond when the rotational conformation of the C — C bond is 
such that the double bond is flanked by the two least bulky groups attached 
to the adjacent asymmetric centre." Thus : 



R'MgX 



H- 



..R' 



M— ^C— C^-OH 
IT ^R 



or, using the Newman projection formulae: 
M 



:A 



R'MgX^ 



HO 



R 
L 




An example of this type of reaction is the reaction between phenylpropion- 
aldehyde (M = Me, L = Ph) and methylmagnesium bromide (R' = Me) ; 
two products can be formed, viz., XII the [erythro-compound) and XIII 
(the ^ra>-compound) : 



Me 



Me 



Me 



X 



y^„ 


HOv. 

MeMgBr 

H^ 


£ 


? 


^H 
NPh 


+ 


Mes 
IK 


i 


? 


/H 
^Ph 






Me 








OH 








X 


II 








X] 


[II 





According to the above rule, XII should predominate; this has been found 
to be so in practice. 

Cram's rule does not give the correct stereochemical prediction when one 
of the groups (e.g., hydroxyl) attached to the carbon atom alpha to the 
carbonyl group is capable of chelating with a metal atom in the reagent, 
unless this chelating group is " medium " in effective bulk. 

The influence of enzymes on the steric course of reactions has also been 
investigated, e.g., Rosenthaler (1908) found that emulsin converted benzalde- 
hyde and hydrogen cyanide into dextrorotatory mandelonitrile which was 
almost optically pure. It has been found that in most enzymic reactions 
the product is almost 100 per cent, of one or other enantiomorph. Enzymes 
are proteins and optically active (see also §12. XIII), but since they are so 
" one-sided " in their action, it appears likely that the mechanism of the 
reactions in which they are involved differs from that of partial asymmetric 



§8] NUCLEOPHILIC SUBSTITUTION 85 

syntheses where enzymes are not vised. It has been suggested that enzymes 
are the cause of the formation of optically active compounds in plants. 
Although this is largely true, the real problem is: How were the optically 
active enzymes themselves produced? Ferreira's work [§10(viii). II], how- 
ever, shows that optically active compounds may possibly be produced in 
living matter by activation of a racemic modification. This theory appears 
to be superior to that of the formation of optically active compounds by 
the action of naturally polarised light (see following section). 

§8. Absolute asymmetric synthesis. Cotton (1896) found that dextro- 
and laevocircularly polarised light was unequally absorbed by enantiomorphs, 
provided the light has a wavelength in the neighbourhood of the character- 
istic absorption bands of the compound. This phenomenon is known as 
the Cotton effect or circular dichroism (cf. §2. II). 

It has been suggested that circularly polarised light produced the first 
natural active compounds, and to support this theory, racemic modifications 
have been irradiated with circularly polarised light and attempts made to 
isolate one enantiomorph. There was very little success in this direction 
until W. Kuhn and Braun (1929) claimed to have obtained a small rotation 
in the case of ethyl a-bromopropionate. The racemic modification of this 
compound was irradiated with right- and left-circularly polarised light (of 
wavelength 2800 A), and the product was found to have a rotation of -f or 
— 0-05°, respectively. Thus we have the possibility of preparing optically 
active products from inactive substances without the intermediate use of 
optically active reagents (cf. Ferreira's work). This type of synthesis is 
known as an absolute asymmetric synthesis; it is also known as an 
absolute asymmetric decomposition. The term asymmetric decom- 
position is also applied to reactions such as the formation of the (-(-)- and 
(— )-forms of ay-di-1-naphthyl-ay-diphenylallene (see §6. V) by the action 
of (+J- and (— )-camphorsulphonic acid on the symmetrical alcohol. 

Front -1930 onward, more conclusive evidence for absolute asymmetric 
syntheses has been obtained, e.g., W. Kuhn and Knopf (1930) irradiated 
(±)-<x-azidopropionic dimethylamide, CH 3 'CHN 3 *CON(CH 3 ) 8 , with right- 
circularly polarised light and obtained an undecomposed product with a 
rotation of +0'78°; with left-circularly polarised light, the undecomposed 
product had a rotation of — 1-04°. Thus the (— )- or (-f-)-form is decom- 
posed (photochemically) by right- or left-circularly polarised light, respec- 
tively. Similarly, Mitchell (1930) irradiated humulene nitrosite with right- 
and left-circularly polarised red light, and obtained slightly optically active 
products. 

Davis and Heggie (1935) found that the addition of bromine to 2 : 4 : 6- 
trinitrostilbene in a beam of right-circularly polarised light gave a dextro- 
rotatory product. 

N0 2 N0 2 

N0^2V-CH=CH-h€^> ^ NOy^^-CHBr-CHBr-^^ 

N0 2 N0 2 

(+) -rotation 

Small (-f-)-rotations were also observed when a mixture of ethyl fumarate 
and anhydrous hydrogen peroxide in ethereal solution was irradiated with 
right-circalarly polarised light (Davis et al., 1945). 



86 ORGANIC CHEMISTRY [CH. Ill 

READING REFERENCES 

Hinshelwood, The Kinetics of Chemical Change, Oxford Press (1940, 4th ed.). 
Moelwyn-Hughes, The Kinetics of Reactions in Solutions, Oxford Press (1947, 2nd ed.). 
Glasstone, Laidler and Eyring, The Theory of Rate Processes, McGraw-Hill (1941). 
Frost and Pearson, Kinetics and Mechanism, Wiley (1961, 2nd ed.). 
Friess and Weissberger (Ed.), Technique of Organic Chemistry, Interscience Publishers. 

Vol. 8 (1953). Investigation of Rates and Mechanisms of Reactions. 
Ingold, Structure and Mechanism in Organic Chemistry, Bell and Sons (1953). 
Hine, Physical Organic Chemistry, McGraw-Hill (1962, 2nd ed.). 
Gould, Mechanism and Structure in Organic Chemistry, Holt and Co. (1959). 
Streitwieser, Solvolytic Displacement Reactions at Saturated Carbon Atoms, Chem. 

Reviews, 1956, 56, 571. 
Bethell and Gold, The Structure of Carbonium Ions, Quart. Reviews (Chem. Soc), 1958, 

12, 173. 
Casapieri and Swart, Concomitant First- and Second-order Nucleophilic Substitution, 

J.C.S., 1961, 4342. 
Hudson et al., Nucleophilic Reactivity, J.C.S., 1962, 1055, 1062, 1068. 
Ritchie, Asymmetric Synthesis and Asymmetric Induction, St. Andrews University Press 

(1933). 
Ritchie, Recent Views on Asymmetric Synthesis and Related Processes, Advances in 

Enzymology, Interscience Publishers, 1947, 7, 65. 
Cram and Kopecky, Models for Steric Control of Asymmetric Induction, /. Amer. 

Chem. Soc, 1959, 81, 2748. 
Klyne (Ed.), Progress in Stereochemistry, Butterworth (1954). Ch. 3. Stereochemical 

Factors in Reaction Mechanisms and Kinetics. Vol. II (1958). Chh. 2, 3. 



CHAPTER IV 

GEOMETRICAL ISOMERISM 

§1. Nature of geometrical isomerism. Maleic and fumaric acids both 
have the same molecular formula C 4 H 4 4 , but differ in most of their physical 
and in many of their chemical properties, and neither is optically active. 
It was originally thought that these two acids were structural isomers; 
this is the reason for different names being assigned to each form (and to 
many other geometrical isomers). It was subsequently shown, however, 
that maleic and fumaric acids were not structural isomers, e.g., both (i) are 
catalytically reduced to succinic acid; (ii) add one molecule of hydrogen 
bromide to form bromosuccinic acid; (iii) add one molecule of water to form 
malic acid; (iv) are oxidised by alkaline potassium permanganate to tartaric 
acid (the stereochemical relationships in reactions (ii), (iii) and (iv) have been 
ignored; they are discussed later in §5a). Thus both acids have the same 
structure, viz., COjH-CHtCH-COaH. van't Hoff (1874) suggested that if 
we assume there is no free rotation about a double bond, two spatial arrange- 
ments are possible for the formula COgH-CHtCH'COgH, and these would 
account for the isomerism exhibited by maleic and fumaric acids. Using 
tetrahedral diagrams, van't Hoff represented a double bond by placing the 
tetrahedra edge to edge (Fig. 1). From a mechanical point of view, such 



C0 2 H H *- ^CQ 2 H 




C0 2 H H0 2 C 




Fig. 4.1. 

an arrangement would be rigid, i.e., free rotation about the double bond is 
not to be expected. Furthermore, according to the above arrangement, the 
two hydrogen atoms and the two carboxyl groups are all in one plane, i.e., 
the molecule is flat. Since a flat molecule is superimposable on its mirror 
image, maleic and fumaric acids are therefore not optically active (§2. II). 
As we shall see later, modern theory also postulates a planar structure for 
these two acids, but the reasons are very much different from those proposed 
by van't Hoff as described above (see also §3a. V). 

The type of isomerism exhibited by maleic and fumaric acids is known as 
geometrical isomerism or cis-trans isomerism. One isomer is known 
as the cts-compound, and the other as the trans, the as-compound being 
the one which (usually) has identical or similar atoms or groups, on the 
same side (see also §4). Thus molecule I is c*s-butenedioic acid, and II is 

87 



88 



ORGANIC CHEMISTRY 



[CH. IV 



frans-butenedioic acid. As will be shown later (§5), I is maleic acid and II 
fumaric acid. 

Geometrical isomerism is exhibited by a wide variety of compounds, and 
they may be classified into three groups: 

(i) Compounds containing a double bond: C=C, C=N, N=N. 
(ii) Compounds containing a cyclic structure — homocyclic, heterocyclic 

and fused ring systems, 
(iii) Compounds which may exhibit geometrical isomerism due to restricted 

rotation about a single bond (see §3. V for examples of this type). 

§2. Rotation about a double bond. We have already seen that, 
theoretically, there is always some opposition to rotation about a single 
bond and that, in many cases, the opposition may be great enough to cause 
the molecule to assume some preferred conformation (§4a. II). When we 
consider the problem of rotation about a double bond, we find that there is 
always considerable opposition to the rotation. Let us first consider the 
simple case of ethylene; Fig. 2 (a) shows the energy changes in the molecule 
when one methylene group is rotated about the carbon-carbon double bond 
with the other methylene group at rest. Thus there are two identical 
favoured positions (one at 0° and the other at 180°), and the potential 
energy barrier is 40 kg.cal./mole. The examination of many olefinic com- 
pounds has shown that the potential energy barrier for the C==C bond varies 
with the nature of the groups attached to each carbon, e.g., 

CH 2 =CH 2 , 40 kg.cal./mole; 
C 6 H 5 -CH=CH-C 6 H 5 , 42-8 kg.cal./mole; 
CH 3 -CH=CH-CH 3 , 18 kg.cal./mole; 
C0 2 H-CH=CH-C0 2 H, 15-8 kg.cal./mole. 

Let us consider the case of maleic and fumaric acids in more detail. It 
can be seen from the diagram (Fig. 2 b) that there are two favoured positions, 
with the trans-iorm more stable than the cis, the energy difference between 
the two being 6-7 kg.cal./mole. The conversion of the trans to the cis 
requires 15-8 kg.cal. energy, but the reverse change requires about 10 kg.cal. 
(see also §6 for a further discussion of cis-trans isomerisation). 




90° 180° 270' 
Angle of Rotation 

(a) 



360' 



90" 180° 270° 
Angle of Rotation 

(6) 



360° 



Fig. 4.2. 



§3. Modern theory of the nature of double bonds. In the foregoing 
account of geometrical isomerism, the distribution of the carbon valencies 
was assumed to be tetrahedral (as postulated by van't Hoff). According 
to modern theory, the four valency bonds of a carbon atom are distributed 
tetrahedrally only in saturated compounds. In such compounds the carbon 
is in a state of tetrahedral hybridisation, the four sp 3 bonds being referred 
to as ff-bonds (see Vol. I, Ch. II). In olefinic compounds, however, the two 
carbon atoms exhibit the trigonal mode of hybridisation. In this condition 
there are three coplanar valencies (three c-bonds produced from sp 2 hybrid- 



§4] GEOMETRICAL ISOMERISM 89 

isation), and the fourth bond (?r-bond) at right angles to the trigonal hybrids 
(Fig. 3). 7r-Bonds, which appear to be weaker than cr-bonds, tend to overlap 
as much as possible in order to make the bond as strong as possible. Maxi- 
mum overlap is achieved when the molecule is planar, since in this con- 
figuration the two p„ orbitals are parallel. Distortion of the molecule from 
the planar configuration decreases the overlap of the ^-electrons, thereby 
weakening the zr-bond; and this distortion can only be effected by supplying 
energy to the molecule. It is therefore this tendency to produce maximum 
overlap of the ^-electrons in the 7r-bond that gives rise to resistance 




Fig. 4.3. 

of rotation about a " double " bond. For simplicity we shall still represent 
a " double " bond by the conventional method, e.g., C=C, but it should 
always be borne in mind that one of these bonds is a a-bond (sp 2 bond), 
and the other is a rc-bond perpendicular to the <r-bond. It is these ^-electrons 
{mobile electrons) which undergo the electromeric and resonance effects. 
They are held less firmly than the a-electrons and are more exposed to 
external influences; it is these 7t-electrons which are responsible for the high 
reactivity of unsaturated compounds. 

In compounds containing a triple bond, e.g., acetylene, the two carbon 
atoms are in a state of digonal hybridisation ; there are two c-bonds (sp bonds) 
and two w-bonds (one p y and one p z orbital), both perpendicular to the 
a-bonds which are collinear (see Vol. I, Ch. II). 

The above treatment of the double (and triple) bond is in terms of sp 2 
(and sp) hybridisation and jr-bonds. It is still possible, however, to use sp 3 
hybridisation to describe carbon-carbon multiple bonds ; this treatment gives 
rise to " banana-shaped " orbitals, i.e., " bent " bonds (Fig. 4 ; see also 
Vol. I): 

H \ y\ / H H \ ^^ / H 

) c \ ) C C ) c c ( 

Fig. 4.4 

This method of approach still produces a " rigid " molecule, and so again 
there is no free rotation about the double bond. 

§4. Nomenclature of geometrical isomers. When geometrical iso- 
merism is due to the presence of one double bond in a molecule, it is easy to 
name the geometrical isomers if two groups are identical, e.g., in molecules 
I and II, I is the a's-isomer, and II the trans; similarly III is cis, and IV is 
trans. When, however, all four groups are different, nomenclature is more 
difficult. In this case it has been suggested that the prefixes cis and trans 
should indicate the disposition of the first two groups named, e.g., the two 
stereoisomers of l-bromo-l-chloro-2-iodoethylene, V and VI; V is cis-1- 
bromo-2-iodo-l-chloroethylene or fraws-l-chloro-2-iodo-l-bromo-ethylene ; 



90 ORGANIC CHEMISTRY [CH. IV 

VI is cis-l-chloro-2-iodo-l-bromoethylene or tfr«»s-l-bromo-2-iodo-l-chloro- 
ethylene. On the other hand, since this method of nomenclature usually 
deviates from the rule of naming groups in alphabetical order, it has been 

a b a b a. J> a b 

NK NK Nj^ ^C" 

II II II II 

* /( N b^^a ^N ^% 

I II III IV 

cis trans cis trans 

suggested that the groups corresponding to the prefix cis or trans should be 
italicised, thus V may be named cw-l-6rowo-l-chloro-2-i'o^oethylene and VI 
2ra»s-l-&rowo-l-chloro-2-M>rfoethylene. This method, it must be admitted, 
would offer difficulties when the names are spoken. 

Br^ ^Cl CI JBv 



V VI 

Some pairs of geometrical isomers have trivial names, e.g., maleic and 
fumaric acids, angelic and tiglic acids, etc. (c/. §1). Sometimes the prefix 
tso has been used to designate the less stable isomer, e.g., crotonic acid 
(foms-isomer) and isocrotonic acid (cis-isomer; the cis-isomer is usually the 
less stable of the two ; see §2) . The use of iso in this connection is undesirable 
since it already has a specific meaning in the nomenclature of alkanes. The 
prefix alio has also been used to designate the less stable isomer (cis), e.g., 
aWocinnamic acid. 

When geometrical isomers contain two or more double bonds, nomen- 
clature may be difficult, e.g., VII. In this case the compound is considered 

X C=C CH 3 

H X X CH(CH3) 2 

vn 

as a derivative of the longest chain which contains the maximum number 
of double bonds, the prefixes cis and trans being placed before the numbers 
indicating the positions of the double bonds to describe the relative positions 
of the carbon atoms in the main chain; thus VII is 3-isopropylhexa-cis- 
2 : cis-4-diene. 

If a compound has two double bonds, e.g., CHa=CH — CH=CH6, four geo- 
metrical isomers are possible: 

II II 

II II II 

B< ^b b' ^H H 

The number of geometrical isomers is 2", where n is the number of double bonds; 
this formula applies only to molecules in which the ends are different. If the 
ends are identical, e.g., CHa=CH : — CH=CHa, then the number of stereo- 



^a 
II 


C^ 

II 


■b 


b' V H 



§6] GEOMETRICAL ISOMERISM 91 

isomers is 2"- 1 + 2P~ l , where p = n/2 when n is even, and p = — ^ — when n 
is odd (Kuhn et al., 1928). 

§5. Determination of the configuration of geometrical isomers. 

There is no general method for determining the configuration of geometrical 
isomers. In practice one uses a number of different methods, the method 
used depending on the nature of the compound in question. The following 
are methods which may be used mainly for compounds that owe their 
geometrical isomerism to the presence of a double bond, but several of the 
methods are special to geometrical isomers possessing a cyclic structure 
(see also §7). 

(i) Method of cyclisation. Wislicenus was the first to suggest the 
principle that intramolecular reactions are more likely to occur the closer 
together the reacting groups are in the molecule. This principle appears 
always to be true for reactions in which rings are formed, but does not hold 
for elimination reactions in which a double (or triple) bond is produced 
[see, e.g., (xi)]. 

(a) Of the two acids maleic and fumaric, only the former readily forms a 
cyclic anhydride when heated; the latter does not form an anhydride of its 
own, but when strongly heated, gives maleic anhydride. Thus I is maleic 
acid, and II is fumaric acid. 

H x ^COisH H^ ^C0 2 H 

c c 

II <+ — II 

H^ ^C0 2 H H0 2 C^ ^H 

maleic acid fumaric acid 



H \'/ C <? 



H/^ 



II /> + H,0 

CO 



Cyclisation reactions must be performed carefully, since one isomer may 
be converted into the other during the cyclising process, and so lead to un- 
reliable results. In the above reaction, somewhat vigorous conditions have 
been used; hence there is the possibility that intercon version of the stereo- 
isomers has occurred. Since maleic acid cyclises readily, and fumaric acid 
only after prolonged heating, the former is most probably the cw-isomer, 
and the latter the trans which forms maleic anhydride via the formation of 
maleic acid (see also §6). The correctness of the conclusion for the con- 
figurations of the two acids may be tested by hydrolysing maleic anhydride 
in the cold; only maleic acid is obtained. Under these mild conditions it 
is most unlikely that interconversion occurs, and so we may accept I as the 
configuration of maleic acid. 

(6) Citraconic acid forms a cyclic anhydride readily, whereas the geo- 
metrical isomer, mesaconic acid, gives the same anhydride but much less 
readily. Thus these two acids are: 



CHj.. ^C0 2 H 



C 


II 


II 


H^ ^CO g H 


H0 2 C^ ^H 


citraconic acid 


mesaconic acid 



92 



ORGANIC CHEMISTRY 



[CH. IV 



(c) There are two o-hydroxycinnamic acids, one of which spontaneously 
forms the lactone, coumarin, whereas the other does not. Thus the former 
is the cM-isomer, coumarinic acid, and the latter the trans-isomer, coumaric 
acid. 




*■ c 
°* II 

H0 2 CT ^H 
coumarinic acid 




°* II 
H- TJO,H 

coumaric acid 




coumarin 



(d) Two forms of hexahydroterephthalic acid are known, one of which 
forms a cyclic anhydride, and the other does not. Thus the former is the 
ct's-isomer, and the latter the trans (see also §§9, 11). 



HOgC 




H0 2 C 



H H 
as -acid 




C0 2 H 



H H 
trans -a,cid 



(ii) Method of conversion into compounds of known configuration. 

In a number of cases it is possible to determine the configurations of pairs of 
geometrical isomers by converting them into compounds the configurations 
of which are already known. As an example of this type let us consider 
the two forms of crotonic acid, one of which is known as crotonic acid 
(m.p. 72°), and the other as wocrotonic acid (m.p. 15-5°). Now there are 
two trichlorocrotonic acids, III and IV, one of which can be hydrolysed to 
fumaric acid. Therefore this trichlorocrotonic acid must be the trans- 
isomer, III; consequently the other is the cis-isomer IV. Both these tri- 



H v 



,C0 2 H 






.0. 



H0 2 C ^H 

fumaric acid 



HO 2 0^ ^H 
III 

|[H] 



H^ /CC1 3 

II 
H^ ^C0 2 H 
IV 

|[H] 



H 



\^/ 



CH 3 



H^ 



,CH 3 



H0 2 CT ^H 
V 
crotonic acid 



W ^C0 2 H 
VI 

zsocrotonic acid 



§5] 



GEOMETRICAL ISOMERISM 



93 



chlorocrotonic acids may be reduced by sodium amalgam and water, or by 
zinc and acetic acid, to the crotonic acids, III giving crotonic acid, V, and 
IV giving wocrotonic acid, VI. Thus crotonic acid is the trans-isomer, and 
isocrotonic the cis (von Auwers el al., 1923). 

(iii) Method of conversion into less symmetrical compounds. 
Certain pairs of geometrical isomers may be converted into less symmetrical 
compounds in which the number of geometrical isomers is increased, and 
by considering the number of products obtained from each original stereo- 
isomer, it is possible to deduce the configurations of the latter. E.g., there 
are two 2 : 5-dimethylcyc/opentane-l : 1-dicarboxylic acids, and these, on 
heating, are decarboxylated to 2 : 5-dimethylcyc/opentane-l-carboxylic acid. 
Consideration of the following chart shows that the cis-iorm of the original 
dicarboxylic acid can give rise to two stereoisomeric monocarboxylic acids, 
whereas the trans-iorm can produce only one product. Thus the configura- 
tions of the dicarboxylic acids are determined (see also §10). 



H,C 




CH S 



H„C 



C0 2 H 
CK-form 




C0 2 H 
trans- form 



-co 2 



H H 



H,C 





H,C 



CH, 



(iv) Method of optical activity. In many pairs of geometrical isomers 
one form may possess the requirements for optical activity (§2. II), whereas 
the other form may not. In such cases a successful resolution of one form 
will determine the configuration, e.g., there are two hexahydrophthalic 
acids; the «s-form possesses a plane of symmetry and consequently is 
optically inactive. The trans-form, however, possesses no elements of 
symmetry, and so should be resolvable; this has actually been resolved 
(see also §11). 

COaH C0 2 H C0 2 H H 



H H 

cii- form 

optically inactive 




H H 

trans-form. 
resolvable 



(v) Method of dipole moments. The use of dipole moments to assign 
configurations to geometrical isomers must be used with caution. The 
method is satisfactory so long as the groups attached to the olefinic carbon 
atoms have linear moments (see §13. I), e.g., cts-l,2-dichloroethylene has a 
dipole moment of 1-85 D; the value of the dipole moment of the trans 
isomer is zero. When, however, the groups have non-linear moments, then 
the vector sum in the trans-isomer will no longer be zero and the difference 



94 ORGANIC CHEMISTRY [CH. IV 

between the dipole moments of the cis- and trans-isomers may be too small 
to assign configuration with any confidence, e.g., the dipole moment of 
diethyl maleate is 2-54 D and that of diethyl fumarate is 2-38 D. 

(vi) X-ray analysis method. This method of determining the con- 
figuration of geometrical isomers is probably the best where it is readily 
applicable (see also §16. I). 

(vii) Ultraviolet, visible, infra-red, Raman, and NMR spectra 
methods. Geometrical isomers may show different spectra, e.g., the in- 
tensity of the band in the ultraviolet absorption spectrum depends on the 
dipole moment (see Vol. I, Ch. XXXI), and this, in turn, depends on the 
distance between the charges. In the trans-iorm of a conjugated molecule, 
the distance between the ends is greater than that in the ds-form. Conse- 
quently the intensity of absorption of the trans-iorm. is greater than that of 
the cis (see also §15. 1). Thus, in cases such as these, it is possible to assign 
configurations to pairs of geometrical isomers. 

NMR spectra (§19a. I) have recently been used to determine configura- 
tions of geometrical isomers, e.g., Curtin et al. (1958) have used this method 
to distinguish between the cis- and trans-isomers of stilbene and azobenzene ; 
Musher et al. (1958) have assigned configurations to cis- and trans-decaMn 
[§ll(vii)]. 

(viii) Method of surface films. Long-chain geometrical isomers which 
contain a terminal group capable of dissolving in a solvent will form surface 
films, but only the trans-iorm can form a close-packed film, e.g., the long- 
chain unsaturated fatty acids. 

II II 

c c 

H0 2 C^ ^H H^ \C0 2 H 

«'s-form trans-form 

(ix) Method of formation of solid solutions. In compounds which 
owe their property of geometrical isomerism to the presence of an olefinic 
bond, the shape of the trans-iorm. is similar to that of the corresponding 
saturated compound, whereas that of the cis-iorm is different, e.g., the shapes 
of fumaric and succinic acids are similar, but the shape of maleic acid is 
different from that of succinic acid. Now molecules which are approximately 

H. X!0 2 H .C0 2 H w X0 2 H 

TT CH 2 Nr 

II I II 

H0 2 Cr ^H H0 2 C / S< ^C0 2 H 

fumaric acid succinic acid maleic acid 

of the same size and shape tend to form solid solutions. Thus fumaric acid 
forms a solid solution with succinic acid, whereas maleic acid does not; 
hence the configurations of maleic and fumaric acids may be determined. 

(x) Methods based on generalisations of physical properties. Com- 
parison of the physical properties of geometrical isomers of known con- 
figurations has led to the following generalisations: 

(a) The meltirg point and intensity of absorption of the cis-isomer are 
lower than those of the trans. 

(6) The boiling point, solubility, heat of combustion, heat of hydrogena- 
tion, density, refractive index, dipole moment and dissociation constant (if 
the compound is an acid) of the cts-isomer are greater than those of the trans. 

Based on certain of these generalisations is the Auwers-Skita rule (1915, 
1920), viz., in a pair of cis-trans isomers (of alicyclic compounds), the cis 



§5] 



GEOMETRICAL ISOMERISM 



95 



has the higher density and refractive index. This rule has been used to 
elucidate configurations, particularly in terpene chemistry, e.g., the men- 
thones (see §16. VIII), but recently it has been shown that the use of this 
rule may give misleading results (see §11). 

It can be seen from the above physical properties that the trans-form is 
usually the stabler of the two isomers, i.e., the trans-isomer is the form with 
the lower internal energy (c/. §2). 

Thus, in general, the above physical properties may be used to determine 
the configurations of unknown geometrical isomers, but the results should 
always be accepted with reserve, since exceptions are known. Even so, 
determination of as many as possible of the above physical properties will 
lead to reliable results, since deviations from the generalisations appear to 
be manifested in only one or two properties. It should also be noted that 
where the method of dipole moments can be applied, the results are reliable 

[of- (v)]. 

Another method based on generalisations of physical properties is that 
suggested by Werner. Werner (1904) pointed out that ethylenic cis-trans 
isomers may be compared with the ortho- and para-isoraers in the benzene 
series, the assumption being made that the melting points of the cis- and 
ortffto-isomers are lower than those of the corresponding trans- and para- 



somers, e.g., 



EU 



\r 



'CH» 



r^Kr 



H" ^C0 2 H 

•cis-crotaflic acid 

m.p. 15 - 5° 




H' ^c X!0 2 H 

0-toluic acid 

m.p. 105° 



CH; 




II 

rrons-crotonic acid ^-tohric acid 

m.p. 72° m.p. 180 9 

Thus comparison of melting points offers a means of assigning configurations 
to geometrical isomers. Examination of the above structures shows that, 
as far as the shape of the molecule is concerned, the benzene ring may be 
regarded as usurping the function of C=C in the olefinic compound. By 
making use of this idea, it has been possible to assign configurations to 
difficult cases of geometrical isomerism, e.g., there are two ethyl oc-chloro- 
crotonates, and by comparing their physical properties with ethyl 5-chloro-o- 
and 3-chloro^>-toluates, configurations may be assigned to the chlorocro- 
tonates. 



b.p. 56°/l0mm 

\ 

Cl^ ^C0 2 C 2 H 5 
b.p. 61°/I0mm. 



CI 




0020^115 



b.p. 122° 






CK ^-^ "C0 2 C 2 H 6 
b.p. 130° 



96 ORGANIC CHEMISTRY [CH. IV 

(xi) Method of stereospecific addition and elimination reactions. 

This method for determining the configurations of geometrical isomers is 
based on the assumption that addition reactions to a double or triple bond 
always occur in a definite manner — either cis or trans — for a given addendum 
under given conditions. Similarly, elimination reactions are also assumed 
to take place in a definite manner. 

(a) Conversion of acetylenic compounds into ethylenic compounds, 
and vice versa. This problem was first studied by Wislicenus (1887), who 
suggested that when one of the acetylenic bonds is broken, the two groups 
of the addendum should add on in the cis-position, e.g., the addition of 
bromine to acetylenedicarboxylic acid should produce dibromomaleic acid. 

^a 11 Br^ C0 2 H 

C ^G 

«WI ^ C0 ° H 

In practice, however, a mixture of dibromofumaric and dibromomaleic acids 
is obtained, with the former predominating. Similarly, halogen acids add 
on to give mainly halogenofumaric acid. Thus, in these two examples, the 
suggestion of Wislicenus is incorrect. On the other hand, the reduction 
of tolan with zinc dust and acetic acid (Rabinovitch et al., 1953) produces 
Mostilbene (the cw-compound) : 



in +2H 

C 6 H„ H ^ ^ C « H « 






This is a «'s-addition, but the problem of reduction of a triple bond is com- 
plicated by the fact that the results depend on the nature of the compound 
and the conditions used, e.g., Fischer (1912) found that phenylpropiolic 
acid on catalytic reduction gave cw-cinnamic acid, whereas on reduction 
with zinc dust and acetic acid, trans-cmnamic acid was obtained. 



V 



H 2 -Pd C Zn/CIWCOM. 

-< HI »- 



TS< NX) 2 H ^, 0H H^ NX) 2 H 

Benkeser et al. (1955), on the other hand, have shown that the reduction 
of acetylenes with lithium in aliphatic amines of low molecular weight pro- 
duces trans-oleftns. It appears that, in general, chemical reduction produces 
the tfraws-olefin, whereas catalytic hydrogenation produces the cw-olefin. 
As a result of a large amount of experimental work, it has been found that 
addition reactions to a triple bond where the addenda are halogens or halogen 
acids produce predominantly the trans-ethy\enic compound, and so, using 
this generalisation, one can determine the configurations of geometrical 
isomers when prepared from acetylenic compounds (provided, of course, 
the addenda are halogen or halogen acid). 

Wislicenus also supposed that removal of halogen, halogen acid, etc., from 
olefinic compounds to produce acetylenic compounds was easier in the ex- 
position than in the trans. This again was shown to be incorrect experi- 
mentally, and thus the elimination reaction may be used to determine 



GEOMETRICAL ISOMERISM 



97 



§5] 

configuration if the assumption is made that trans-elimination occurs more 
readily than cis (see also oximes, §2f. VI). 

(6) Conversion of ethylenic compounds into ethane derivatives, and 
vice versa. Just as it was assumed that the addition of halogens and 
halogen acids to a triple bond takes place in the a's-position, so the same 
assumption was made with respect to the double bond. Thus the addition 
of bromine to maleic acid should give meso-x : a'-dibromosuccinic acid. 
Configurations VII (formed by attack from behind the molecule) and VIII 



Br 



Br 



H^ 



.C0 2 H 



H_ 



Br 4 



JO. 

Br 
VII 



^0O 2 H 



H 



> 



,C0 2 H 



v C0 2 H 



H. 



,C0 2 H 



H' I ND0 2 H 
Br 
VIII 



(formed by attack in front) are identical, both being the same weso-dibromo- 
succinic acid. Similarly fumaric acid would be expected to give (±)-oc : a'- 
dibromosuccinic acid. IX and X are mirror images, and since they will be 



Br 
H. S /C0 2 H 



HOsC^V^-H 



Br 2 



H^ /C0 2 H 
XT 



HO»C 



"H 



Br 



Br 
H,, I ,-C0 2 H 

.£- 
HOgC | % -H 

Br 



IX X 

formed in equal amounts (see §7a. II), the racemic modification is produced. 
Experimental work, however, has shown that the reverse is true, i.e., maleic 
acid gives mainly (±)-dibromosuccinic acid (IX and X), and fumaric acid 
gives mainly wesodibromosuccinic acid (VII). Thus the addition of bromine 
must be trans. In the same way it has been shown that the addition of 
halogen acid is also trans. Hence, assuming foam-addition always occurs 
with these addenda, the nature of the products indicates the configuration 
of the ethylenic compound. 

The configuration of the product formed by hydroxylation of a double 
bond depends on the nature of the hydroxylating agent used and on the 
conditions under which the reaction is carried out. Permanganate and 
osmium tetroxide apparently always give cw-addition, whereas permono- 
sulphuric acid (Caro's acid) and perbenzoic acid give foms-addition. On 



Reagent 


Type of 
addition 


Maleic acid 


Fumaric acid 


KMn0 4 

Os0 4 

H a S0 6 

C,H 6 -CO-O s H . . . 
H a O a — Os0 4 . . . 
H 2 2 — SeO a . . . 


cis 

cis 
trans 
trans 

cis 
trans 


mesotaxtaxic acid 
wesotartaric acid 
DL-tartaric acid 
DL-tartaric acid 
mesotartaric acid 
DL-tartaric acid 


DL-tartaric acid 
DL-tartaric acid 
mesotartaric acid 
wesotartaric acid 
DL-tartaric acid 
mesotartaric acid 



the other hand, hydroxylation with hydrogen peroxide catalysed by osmium 
tetroxide in tertiary-bu.ta.nol gives «'s-addition ; if the reaction is catalysed 
by selenium dioxide in tertiary-butanol or in acetone, then the addition is 
trans (see also below). The table above shows the products formed by 
hydroxylation of maleic and fumaric acids. 



98 ORGANIC CHEMISTRY [CH. IV 

§5a. Stereochemistry of addition reactions. The mechanisms of the 
addition of halogen and halogen acids to olefinic double bonds and the 
hydroxylation of olefinic double bonds have been discussed in Vol. I (Ch. IV). 
Here we shall discuss the stereochemical aspects of these additions. As we 
have seen, the polar addition of halogen and halogen acid is two-stage and 
electrophilic; e.g., 

CH 2 =±=CH 2 ^ Br-^-Br *- CH 2 -CH 2 Br + Br~ — »► CH 2 Br- CH 2 Br 

CH 2 =tCH 2 ^ H-Ql *- CH 2 -CH 3 + CI" — »■ CH 2 C1-CH 3 

It has already been demonstrated above (xii) that experimental results 
have proved that these additions are almost entirely trans. The two-stage 
mechanism is consistent with foms-addition. 

In order to account for tfraws-addition, Roberts and Kimball (1937) 
suggested that the first step is the formation of a cyclic halogenium ion, 
e.g., with bromine the brominium (bromonium) ion is formed first. If a 
classical carbonium ion were formed first, then one could expect free rota- 
tion about the newly-formed single bond and in this case the stereochemical 
addition would not be the one observed in practice. Thus for maleic acid 
the reaction may be formulated as follows: 

Br Br 

tt^ £0 2 H tt. „-C0 2 H H-. | ,C0 2 H HL j .C0 2 H 

o '•or ^ D - ^c" Nr 

|| +Br 2 -^ |>r* -^ I +1 

H C0 2 H H' ^C0 2 H W \ C0 2 H H'' | "C0 2 H 

Br Br 

(XI) (XII) 

Since the bromide ion can attack " conveniently " only along the C — Br+ 
bonding line and on the side remote from the bromine, a Walden inversion 
occurs at the carbon atom attacked. Since the brominium ion is sym- 
metrical, it can be anticipated that either carbon atom will be attacked 
equally well, thereby resulting in the formation of (XI) and (XII) in equal 
amounts, i.e., maleic acid will produce (±)-dibromosuccinic acid. Winstein 
and Lucas (1939) have demonstrated the existence of this cyclic ion (see 
§6b. III). 

The above mechanism explains fraws-addition, but, as we have seen, 
although this predominates, it is not exclusive. The reason for this is not 
certain, but it is possible that the cyclic ion is not firmly held, i.e., the ring 
opens to give the classical carbonium ion, and this is followed by rotation 
about the single C — C bond due to electrostatic repulsion between the car- 
boxyl groups. This would explain the experiments of Michael (1892) that 
both the maleate ion and fumarate ion add chlorine or bromine to give 
mainly wteso-dihalogenosuccinic acid. The configurations of the products 
indicate that tfraws-addition has occurred with the fumarate ion but cis- 
addition with the maleate ion. Roberts and Kimball, however, have 
explained these results by assuming that the intermediate maleate bro- 
minium ion (cis) changes to the fumarate brominium ion (trans) due to the 
powerful repulsions of the negatively charged carboxylase ion groups. 

Additions to a triple bond may be assumed to take place by the mechanism 
proposed for a double bond. 

Now let us consider the mechanism of hydroxylation, i.e., the addition 
of two hydroxyl groups to a double bond. With potassium permanganate 



§5a] GEOMETRICAL ISOMERISM 99 

and osmium tetroxide the «°s-addition is readily explained by assuming the 
formation of a cyclic organo-metallic intermediate. 

OH ' 

OH 
This cyclic intermediate is definitely known in the case of osmium tetroxide 
(see Vol. I) ; for potassium permanganate it may be assumed that the per- 
manganate ion, Mn0 4 - (or the manganate ion, MnO^, behaves in a similar 
manner. This is supported by the work of Wiberg et al. (1957), who used 
potassium permanganate labelled with 18 and showed that both glycol 
oxygen atoms come from the permanganate ion. This also indicates that 
fission of the cyclic compound occurs between the O and Mn atoms. 

With per-acids the hydroxylation results in iraws-addition. The first 
product of oxidation is an epoxide (Prileschaiev reaction; see Vol. I). 
Evidence from kinetic studies on solutions of epoxides under high pressure 
strongly suggests that acid-catalysed hydrolysis is a bimolecular substitu- 
tion of the conjugate acid (Whalley et al., 1959). This will result in trans- 
hydroxylation. Thus: 



/ C \ /< /< 

OH 2 OH 

NK _ H+ N^ 

J. ~^ ' 

OH OH 

The addition of hydrogen peroxide may result in cis or trans compounds. 
Which occurs depends on the conditions of the experiment, e.g., the catalyst 
(see above). Where ^raws-addition occurs, the mechanism may possibly 
be through the epoxide, but a free hydroxyl radical mechanism could also 
result in the tfnros-glycol. Ct's-addition in the presence of certain oxides 
probably occurs via a cyclic intermediate. 

The addition of a dienophile to a diene in the Diels-Alder reaction is 
stereospecific; cw-addition always occurs (see Vol. I). Since it is usually 
possible to determine the configuration of the cyclic adduct, this offers a 
means of ascertaining the configuration of the dienophile. E.g., butadiene 
forms adducts with cis- and tfrans-cinnamic acids, and hence determination 
of the configurations of the stereoisomeric adducts will determine the con- 
figurations of the cinnamic acids (see §11); thus: 



H X. 



^~X +^0=0^ — <H~H 

Plf' ^C0 2 H N |— 

cis cis ph C0 2 H 

trans trans H C0 2 H 



100 ORGANIC CHEMISTRY [CH. IV 

§5b. Stereochemistry of elimination reactions. The mechanisms of 
elimination in alkyl halides and 'onium salts have been discussed in Vol. I 
(Ch. V, XIII, XIV). Here we shall deal mainly with the stereochemical 
aspects of elimination reactions. In olefin-forming eliminations, two mech- 
anisms are possible, El and E2, e.g., 

ijy z ^^ z- + h^cr>cr. -^* 



El H-CR 2 — CR^-Z ^^ Z~ + H^CR^-CR 2 

H + + CR 2 =CR 2 

E2 Y^H-^CR^CRy^Z — *- YH + CR 2 =CR 2 + Z~ 

Many examples in the literature show that trans elimination occurs more 
readily than cis, e.g. (also see later): 

(a) Michael (1895) showed that reaction 1 was about 50 times as fast 
as 2. 

C0 2 H 
H0 2 C v /CI | Ck /C0 2 H 

XX NaQH ^ C NaOH X/ 

|| (-HC1) HI (-HC1) || 

h/ x:o 2 H | h/N;o 2 h 

CO a H 

(6) Chavanne (1912) showed that reaction 1 was about 20 times as fast 
as 2. 

CI 
H x .CI | H x /CI 

XX NaOH C NaOH X/ 

|| (-HC1) HI \-HCl) || 

is/ \C1 | CK^H 

H 

(c) Cristol (1947) showed that the /3-isomer of hexachlorocyc/ohexane 
underwent base-catalysed elimination with great difficulty, whereas under 
the same conditions all the other known isomers (four at that time; see 
also §11) readily underwent second-order elimination to form trichloro- 
benzenes; the /}-isomer is the only one in which all the 1,2-HCl pairs are 
cis. Thus in the E2 reaction, the trans requirement is necessary (see also 
below). 

According to Hughes and Ingold, bimolecular elimination reactions (E2) 
take place when the two groups (to be eliminated) are trans and the groups 



H 


Cl 

1 


H 


/i 


k ci 


y 


' H 


C1\J 


Cl 


\« 


»/i 




1 
H 


Cl 




/3-isomer 



and the two carbon atoms (to which the groups are attached) all lie in one 
plane. In this way the planar transition state will be readily formed. As 
the proton is being removed from the |3-carbon atom by the base, the 



GEOMETRICAL ISOMERISM 



101 



§5b] 

" liberated " covalent pair of electrons attacks the a-carbon atom from 
the rear, thereby forming the double bond with displacement of the halogen 
atom. This type of sequence is not possible when the /3-hydrogen atom is 
cis to the halogen atom. 

Before discussing olefin-forming eliminations, let us consider acetylenic- 
forming eliminations. As already pointed out above, the elimination has 
been found to occur more readily in the tfraws-isomer than in the cis. This 
may be explained by assuming that the elimination occurs by the E2 
mechanism : 



XT 

II 



Al 



+ OH" 



Br' 



Br' 



I 



.H' 



s- 





III 

c 



+ H 2 0+Br" 



Now let us consider eliminations in ethane derivatives to form ethylene 
derivatives, e.g., the debromination of 2 : 3-dibromobutane by means of 
potassium iodide in acetone solution. Winstein et al. (1939) showed that 
this reaction is bimolecular (first order in dibromide and first order in iodide 
ion). Thus, in the transition state, the two carbons (of the CBr groups) 
and the two bromine atoms will all lie in the same plane and at the same 
time the two bromine atoms will be in the staggered position. Now 2 : 3- 
dibromobutane exists in (+)-, (— )- and meso-iorras, and it has been shown 
that the (:t)-form gives w's-butene, whereas the meso-iorm gives trans- 
butene. These eliminations may therefore be written as follows (following 
Winstein et al., 1939; the iodine atom is probably in the same plane as the 
other four groups involved in the planar transition state): 




H 

Me 

H 

Me 




H 
£. + IBr+Br" 
Me 



CIS 




Me 

+ IBr+Br" 

H 



trans 



In the (±)-form, as the transition state changes into the ethylene com- 
pound, the two methyl groups become eclipsed; in the meso-form a methyl 
group becomes eclipsed with a hydrogen. Thus the energy of activation 
of the transition state of the (±)-form will be greater than that of the 
meso-iorm. and consequently the latter should be formed more readily, i.e., 
the meso-iorm should undergo debromination more readily than the (re- 
form. Winstein et al. (1939) have shown that this is so in practice, the 
rate of debromination being about twice as fast. These authors also showed 
that the rate of debromination of weso-stilbene dibromide 

(Ph-CHBr-CHBr-Ph) 

is about 100 times as fast as that of the (±)-form. 



102 



ORGANIC CHEMISTRY 



[CH. IV 



Cram et al. (1952) have shown that the base-catalysed dehydrobrornina- 
tion of the diastereoisomeric 1-bromo-l : 2-diphenylpropanes (I and II) 
gives olefins that can only arise by trans elimination. 




"Ph-^0^ H 



as 







Ph-^~"\^-Me 



Phv 



W 





II 



Me 



Th 



trans 



Cram et al. (1956) examined the elimination reaction of the following 
'onium ion with base: 



PhCHMe-CHPh-NMe 3 + }I~ 



OEt- 



> PhMeC=CHPh 



This 'onium ion exists in two forms, threo and erythro, and the results were 
that the 2&ra>-compound gave the fr-ans-olefin and the ery/wo-compound 

H^OEt 



Ek 


r 


-N/ Ph 




H^ 


Or 


^-Ph 


Ph'' 


^O^Me 




Ph- 


<> 


~~Me 




+ NMe 3 






trans 






threo 
H*0Et 










Ph v 


r 


■\^ H 




Ph-~ 
Ph— 


e 


--H 


Ph^- 


^O^Me 




--Me 




+ NMe 3 






CIS 






ery 


ithro 











the c»s-olefm ; this is in keeping with trans elimination. The rates of elimina- 
tion, however, were very different, the threo-iorm reacting over 50 times as 
fast as the erythro. In the cw-product, the two phenyl groups become 
eclipsed and hence the energy of activation for this product is greater than 
that for the tows-product, and consequently the latter is formed more 
readily (see also §12). 
An interesting point that now arises is: What is the mechanism when 



§6] 



GEOMETRICAL ISOMERISM 



103 



the two eliminated groups cannot assume the tfro«s-position? An example 
of this type is the ^-isomer of hexachlorocyc/ohexane. Cristol (1951, 1953) 
and Hughes, Ingold et al. (1953) have proposed that the first step, which 
is the rate-determining one, is the formation of a carbanion: 




CI" N^ci 
y-isomer 

It should be noted that even if the chair form of the /3-isomer given above 
could change to its other chair form, the " ideal " /raws-position of 1,2-HCl 
would still not be achieved; the conformations of all hydrogens and chlorines 
would be reversed. It is possible, however, when both groups to be elimi- 
nated are equatorial, that both become axial if the ring is sufficiently flexible. 
Thus the favourable conformation would be produced, but the elimination 
would be slowed down since energy must be supplied for this conversion. 
When the two groups cannot assume the favourable ^rows-position, the 
normal E2 mechanism will not operate. It appears most likely that the 
elimination then proceeds via the formation of carbanions. It is possible, 
however, that the elimination might proceed by the El mechanism (see 
trans-4-t-bvLtylcyclohexyl tosylate, §12). 

§6. Interconversion (stereomutation) of geometrical isomers. The 

a's-isomer, being usually the more labile form, is readily converted into 
the trans-iona under suitable physical or chemical conditions. The usual 
chemical reagents used for stereomutation are halogens and nitrous acid, 
e.g., 



maleic acid- 
oleic acid- 



Br,; I, 



>fumaric acid 



HNO, 



>elaidic acid 



Other methods such as distillation or prolonged heating above the melting 
point also usually convert the cw-isomer into the trans, but, in general, the 
result is a mixture of the two forms. 

The conversion of the tfrons-isomer into the cis may be effected by means 
of sunlight, but the best method is to use ultraviolet light in the presence 
of a trace of bromine. 

Many theories have been proposed for the interconversion of geometrical 
isomers, but none is certain. To effect conversion, the. double bond must 
be " dissociated " so as to allow rotation about the single bond (i.e., the 
ff-bond; see §3). Let us consider the conversion of maleic acid into fumaric 
acid under the influence of light and in the presence of a trace of bromine. 
One mechanism that has been suggested for this change is a free-radical 



104 ORGANIC CHEMISTRY [CH. IV 

chain reaction, since the conversion does not appear to be effected by bromine 
in the dark. Thus: 

Br 2 hv v Br« + Br» 

Br Br' 

H\ ^C0 2 H H\ ! ^C0 2 H H\ I /C0 2 H 

1 +Br. >■ I *=± ? 

/C. ^CL JJ^ 

H^ ^C0 2 H H^'^OOgH H0 2 (T '^H 

I II 

Br Br 

H. i X0 2 H Hv^ ^C0 2 H H. ^C0 2 H H\ ! /C0 2 H 

I + II — >■ II + I ^* 

II 

In free radicals I and II, the upper carbon atom is in a state of tetrahedral 
hybridisation, and the lower one (the free radical part) in a trigonal state 
(and therefore flat). Owing to the repulsion between the carboxyl groups, 
configuration I tends to change into configuration II by rotation about the 
single bond (cf. §4. II). If II now reacts with a molecule of maleic acid, 
the latter is converted into a free radical containing the bromine atom, 
and II is converted into fumaric acid if " inversion " occurs on the lower 
carbon atom; if no " inversion " occurs, II would form maleic acid again. 

Similarly, various other reagents are also believed to act by a free-radical 
mechanism, e.g., the conversion of cw-stilbene into toms-stilbene by means 
of light in the presence of hydrogen bromide. In the absence of light, the 
conversion takes place very slowly, but in the presence of oxygen or benzoyl 
peroxide, the conversion is rapid. These reagents are known to generate 
free radicals; this supports the free-radical mechanism, the reaction being 
initiated by the formation of free radicals from the hydrogen bromide. 
Furthermore, if the reaction is carried out in the presence of benzoyl per- 
oxide and quinol, the conversion of cis- into toms-stilbene is extremely 
slow. This is in keeping with the free-radical mechanism, since it is known 
that quinol removes free radicals. 

Boron trifluoride also catalyses the conversion of cis- into tows-stilbene. 
In this case the mechanism is less certain, but a reasonable one is: 

BF 3 BF, 

H./CeHs H^i/C 6 H 5 H^:/C 6 H 5 H^ /C 6 H 5 

f j*v G \ -— | '-^v | 

H /C ^C 6 H 6 iK+NyH, CeH^+^H Crff ^H 

Now let us consider thermal interconversion. Kistiakowsky (1935) has 
shown experimentally that there are at least two mechanisms for thermal 
cis-trans isomerisation of ethylene compounds, and that both are first-order 
reactions. Experimental results have also shown that one mechanism re- 
quires a high and the other a low energy of activation. In the transition 
state (in both thermal and chemical isomerisations), the two parts of the 
molecule are perpendicular to each other. To reach this state the double 
bond, as we have seen, must undergo " dissociation "; this occurs by the 
decoupling of the jr-electrons. The spins of these electrons may remain 
anti-parallel in the perpendicular (i.e., transition) state. This type of " dis- 



§8] GEOMETRICAL ISOMERISM 105 

sociation " of a double bond requires energy of about 40 kg.cal., and the 
transition is said to be from a singlet ground state to an upper singlet state. 
On the other hand, it is also possible for the spins of the jr-electrons to be 
parallel (this state is said to be the triplet state), and the energy required 
for this " dissociation " is about 25 kg.cal. It has been observed that 
alkylated ethylenes favour the triplet-state pathway, whereas arylated 
ethylenes favour the singlet-state pathway (see table in §2). 



§7. STEREOCHEMISTRY OF CYCLIC COMPOUNDS 

Geometrical and optical isomerism may exist in any sized ring. In the 
following account, the saturated rings are treated as rigid flat structures, 
and the groups attached to the ring-carbon atoms are regarded as being 
above or below the plane of the ring (see also, in particular, cyc/ohexane 
compounds, §11). Furthermore, the examples described deal only with 
those cases in which the asymmetric carbon atoms are part of the saturated 
ring system. In general, the pattern of optical isomerism followed by cyclic 
compounds is similar to that of the acyclic compounds. The main differ- 
ence between the two is that, since there is no free rotation about ring- 
carbon atoms, geometrical isomerism may therefore be manifested as well 
as optical isomerism. On the other hand, geometrical isomerism may exist 
without optical isomerism (see §5 for methods of determination of the con- 
figuration of geometrical isomers; see also §§9, 10, 11). 

§8. cyctoPropane types. Molecule I contains one asymmetric carbon 
atom (*), and is not superimposable on its mirror image molecule II. Thus 
I and II are enantiomorphs, i.e., a ryc/opropane derivative containing one 





asymmetric carbon atom can exist in two optically active forms (and one 
racemic modification; cf. §7a. II). Molecule III contains two different 
asymmetric carbon atoms, and since it has no elements of symmetry (§6. II), 
it is not superimposable on its mirror image molecule. Thus III can exist 
in two optically active forms (and one racemic modification). Structure III, 





H 2 




aH ^2£ *X Hi 

V 

however, is capable of exhibiting geometrical isomerism, the two geometrical 
isomers being III and IV. Now IV also contains two different asymmetric 
carbon atoms, and these are not disposed towards each other as in III. 
Since IV possesses no elements of symmetry, it can also exist in two optically 
active forms which are different from those of III. Thus V, which may be 
regarded as the non-committal way of writing the configurations III and 
IV, is similar, as far as optical isomerism is concerned, to the acyclic mole- 
cule Cabd-Cabe, i.e., there are four optically active forms in all (two pairs 
of enantiomorphs). In general, any monocyclic system can exist in 2" 



106 



ORGANIC CHEMISTRY 



[CH. IV 



optically active forms, where n is the number of different asymmetric ring- 
carbon atoms (c/. §7c. II). Molecule VI contains two similar asymmetric 



(110 



aH 



H, 




H« 



VI 





VII 



VIII 



carbon atoms, and can exist as geometrical isomers VII and VIII. VII 
has a (vertical) plane of symmetry and therefore represents a meso-ioim. 
VIII, however, possesses no elements of symmetry and can therefore exist 
in two optically active forms (and one racemic modification). IX contains 




XII 



XIII 



three different asymmetric carbon atoms and can therefore exist in 2 3 = 8 
optically active forms (four pairs of enantiomorphs). Each pair of enantio- 
morphs is derived from the four geometrical isomers X-XIII. Inspection 
of these configurations shows that all of them possess no elements of sym- 
metry. XIV contains two similar asymmetric carbon atoms, and the third 



(v) 



aH 



Ha 




m 




XIV 



xv 



XVI 



H H 

XVII 



carbon atom is pseudo-asymmetric (c/. §7d. II). Three geometrical iso- 
mers, XV-XVII, are possible; XV and XVI each possess a (vertical) plane 
of symmetry, and therefore each represents a meso-iorm. XVII, however, 
possesses no elements of symmetry and so can exist in two optically active 

a H 

(vi) Ha 



aH 




XVIII 



Ha 





forms (and one racemic modification). XVIII contains three similar asym- 
metric carbon atoms which are all pseudo-asymmetric. Two geometrical 
isomers are possible, XIX and XX, both of which possess at least one 
(vertical) plane of symmetry, and therefore represent wieso-forms. 



§9] GEOMETRICAL ISOMERISM 107 

In the above account, the stereochemistry of the eyc/opropane ring has 
been dealt with from the theoretical point of view, and thus most of the 
ideas connected with the stereochemistry of monocyclic systems have been 
described. In the following sections more emphasis is laid on specific 
examples, and any further points that arise are dealt with in the appro- 
priate section. 

§9. cyc/oButane types. Two important examples of the cycMmtane 
type are truxillic and truxinic acids; truxillic acid is 2 : 4-diphenylcycfo- 
butane-1 : 3-dicarboxylic acid, and truxinic acid is 3 : 4-diphenylcyc/obutane- 
1 : 2-dicarboxylic acid. a's-Cinnamic acid (allocinnamic acid), on irradiation 
with light, forms mainly /?-truxinic acid and 2ra»s-cinnamic acid, together 
with some of the dimer of the latter, a-truxillic acid (de Jong, 1929). Bern- 
stein et al. (1943) found that irradiation of commercial iraws-cinnamic acid 
gave only /S-truxinic acid. When toms-cinnamic acid was slowly recrystal- 
lised from aqueous ethanol, dried, and then irradiated, only a-truxillic acid 
was obtained. Truxillic and truxinic acids have been isolated from natural 
sources. 

Truxillic acid. This acid can exist theoretically in five stereoisomeric 
forms, all of which are known (the acid is of the type I). All five are meso- 
forms, II-V having planes of symmetry, and VI a centre of symmetry. 
The configurations of these stereoisomers have been assigned as follows. 
When one of the carboxyl groups is converted into the anilido-group, 
•CONH'C 6 H 6 , two of the five forms give optically active compounds, each 
giving a pair of enantiomorphs. Now only the stereoisomers with the two 



aH 
Ml 



Hb 
Ha 



3 6 H 5 C0 2 H C 6 H 6 



ho 2 c/ H H 5 q/ H HA H 5 c/ C0 ° H 




C0 2 H H 
III 

£- 




C0 2 H 



H0 2 C/" HZ" HO,c/ H W C °° H 



phenyl groups in the 2ra«s-position can produce asymmetric molecules 
under these conditions; the remaining forms will each have a (vertical) 
plane of symmetry. Thus only IV and VI satisfy the necessary conditions. 
One of these is known as the a-acid (m.p. 274°) and the other the y-acid 
(m.p. 288°) . This then raises the problem : Which is which? This is readily 
answered by the fact that of the anilido-derivatives of these two acids, only 
one can be dehydrated to a cyclic iV-phenyl imide, -— CO— N(C g H 5 )— CO— . 
This reaction can be expected to take place only when the two carboxyl 
groups are in the cts-position (see §5. i). Therefore IV is y-truxillic acid, 
and VI is a-truxillic acid (since the acid with the melting point 288° has 
been called the y-acid). By considering the ease of formation of the cyclic 
anhydride, the configurations of the remaining three stereoisomers may be 
determined. Two form anhydrides readily, and therefore one of these acids 



108 ORGANIC CHEMISTRY [CH. IV 

must be II and the other III. The third acid does not form its own an- 
hydride, but gives a mixture of the anhydrides produced by II and III. 
Thus the third acid, e^'-truxillic acid, is V. The final problem is to decide 
which of the two, II and III, is ^>m'-truxillic acid, and which is e-truxillic 
acid. ^>m-Truxillic acid, under the influence of aluminium chloride, under- 
goes an internal Friedel-Crafts reaction to form a truxonic acid, VII, and 
a truxone, VIII. This is only possible when the phenyl and carboxyl groups 
are in the cj's-position. Thus II is ^m-truxillic acid, and therefore III is 
e-truxillic acid. 



ftH* 





H H 


H H 


truxonic acid 


truxone 


VII 


VIII 



Truxinic acid. This acid can exist theoretically in six geometrical iso- 
meric forms, four of which are resolvable ; thus ten forms in all are possible 
theoretically. Truxinic acid is of the type IX, and the six geometrical 
isomers possible are X-XV. X and XI are meso-iorms (each has a plane 
of symmetry); XII-XV are resolvable (theoretically), since all possess no 
elements of symmetry. The configurations of these stereoisomers have been 
determined by methods similar to those used for the truxillic acids; it 
appears, however, that only four of these six forms are known with certainty, 
viz., /?, d, £ and neo. 

C 6 H 6 C0 2 H 9 6 H 6 H C 6 H 5 C0 2 H 

Kb ^-f \- 

H H H C0 2 H H 

IX X XI XII 

to- p. neo- 

C 6 H 5 C0 2 H C 6 H 5 




aH 





HO 




t!0 2 H 



2S 



C0 2 H 



§10. eyc/oPentane types. A number of examples involving the stereo- 
chemistry of the five-membered ring occur in natural products, e.g., cam- 
phoric acid (§23a. VIII), furanose sugars (§7b. VII). In this section we 
shall discuss the case of 2 : 5-dimethylcyc/opentane-l : 1-dicarboxylic acid. 
This acid can exist in two geometrical isomeric forms, which may be differ- 
entiated by decarboxylation, the cis-isomer giving two monocarboxylic 
acids, I and II, and the toms-isomer one monocarboxylic acid, III (see 
§5. iii). All three acids contain two similar asymmetric carbon atoms and 
one pseudo-asymmetric carbon atom. Both I and II possess a (vertical) 



GEOMETRICAL ISOMERISM 



109 



§11] 

plane of symmetry, and are therefore meso-iorms ; III possesses no elements 
of symmetry, and can therefore exist in two optically active forms (and 
one racemic modification). All the possible forms are known, and I and II 



H,C 



CH S 




II 



II 



II 



SfcJT^F 




* 


H^<U^H 


H ^Jp^ 


CH 3 


C0 2 H 


H 




II 


III 





have been differentiated as follows. The diethyl ester of the m-dicarboxylic 
acid, IV, can be partially hydrolysed to the monoethyl ester, which most 
probably has the configuration V. This is based on the assumption that 
the carbethoxyl group on the same side as the two methyl groups is far 
more resistant to attack than the other carbethoxyl group because of the 
steric effect (see Vol. I). Decarboxylation of V gives VI, and this, on 
hydrolysis, gives I. Thus the configuration of I (and therefore also of II) 
is determined. 



H 3 C 



H,C 




The above treatment of the cyrfopentane derivatives has been based on 
the assumption that the ring is planar. This classical treatment leads to 
agreement between prediction and the number of stereoisomers actually 
obtained (see cyc/ohexane, §11, for a further discussion of this problem). 
It is now known that the cyc/opentane ring is not planar; the puckering, 
however, is very small. The non-planarity of this ring has been shown 
from entropy determinations (Aston et al., 1941), spectroscopic studies 
(Miller et al., 1950) and from a study of the polarisabilities of C— C a iip ha tic 
and C — H bonds (Le Fevre et al., 1956). 

§11. cycfoHexane types. The stereochemistry of cyc/ohexane and its 
derivatives presents a detailed example of the principles of conformational 
analysis (§4a. II). On the basis of the tetrahedral theory, two forms are 
possible for cyc/ohexane, neither of which is planar. These two forms, 
known as boat and chair conformations (Fig. 5), were first proposed by 
Sachse (1890; see Vol. I, Ch. XIX), who also pointed out that both are 
strainless. Hassel et al. (1943) showed by means of electron diffraction 
studies that at room temperature most of the molecules existed mainly 
in the chair conformation. Pitzer (1945) then showed by calculation that 
the energy difference between the two forms is about 5-6 kg.cal./mole (the 



110 



ORGANIC CHEMISTRY 



[CH. IV 



boat form having the higher energy content; see also below). This value, 
however, is too small for stability, and consequently neither conformation 
retains its identity, each being readily converted into the other. 



III .» 14 ■ . . »* _ ._ • 



"boat" or 
C form 



"chair or 
Z form 



Fig. 4.5. 



Although these two forms are free from " angle strain ", forces due to 
steric repulsion (i.e., repulsive forces between non-bonded atoms) are acting, 
and it is because of their different total effects that the two conformations 
differ in energy content. A simple method of calculating this energy differ- 
ence has been introduced by Turner (1952). Fig. 6 (a) and 6 (6) represent 
the chair and boat conformations and the directions of the C— H bonds. 
In the chair conformation, all the C — H bonds on adjacent carbons are 





(a) chair form (b) boat form 

Fig. 4.6. 

in the skew position (i.e., the arrangement is skew as in the skew form of 
M-butane, §4. II). On the other hand, in the boat conformation there are 
four skew interactions (1:2, 3:4, 4:5 and 6 : 1) and two eclipsed inter- 
actions (2 : 3 and 5:6). According to Pitzer (1940), skew interaction of 
the hydrogens in w-butane is 0-8 kg.cal., and an eclipsed interaction is 
3-6 kg.cal. Thus the steric strain in the chair form is 6 x 0-8 = 4-8 
kg.cal., and in the boat form 4x0-8 + 2x3-6 = 10-4 kg.cal. Thus 
the boat form has the greater energy content, and the amount (according 
to the above method of calculation) is 5-6 kg.cal. There is, however, a 
further interaction in the boat form, viz. the interaction of the two flagpole 
UP) hydrogens (at positions 1 and 4). These are closer together than any 
other two hydrogens (see table below) and so produce an additional steric 
repulsion. The actual value of this interaction is not certain, but it is 
believed to be about the same as that of two eclipsed hydrogens. Thus 
the energy content of the boat form is 10-4 + 3-6 = 14 kg.cal., and hence 
the boat form contains 14 — 4-8 = 9-2 kg.cal. more than the chair form. 

Johnson et al. (I960), from measurements of heat of combustion and 
other measured quantities, have found that the energy difference between 
the boat and chair forms of cycfohexane is 5-3 ± 0-3 kg.cal./mole (at 25°; 
vapour phase). This value has been confirmed by the work of Allinger 
et al. (1960) ; their value is 5-9 ± 0-6 kg.cal./mole. 

Inspection of Fig. 6 (a) shows that the twelve hydrogen atoms in the chair 
conformation are not equivalent ; there are two sets of six. In one of these 
sets the six C — H bonds are parallel to the threefold axis of symmetry of 
the molecule; these are the axial (a) bonds (they have also been named 
s- or polar bonds). In the other set the six C — H bonds make an angle of 
109° 28' with the axis of the ring (or ±19° 28' with the horizontal plane of 
the ring) ; these are the equatorial (e) bonds (they have also been named 



§11] GEOMETRICAL ISOMERISM 111 

*<-bonds). On the other hand, in Fig. 6 (b) it can be seen that the " end " 
of the boat is different stereochemically from the chair conformation; the 
various C — H bonds have been named: flag-pole (fp), bowsprit( bs), boat- 
equatorial (be), and boat-axial (ba). 

Angyal and Mills (1952) have calculated the distances between the various 
hydrogen atoms (and carbon atoms) in both the chair and boat conforma- 
tions. 



Conformation 


Position 


H— H (A) 


Chair 
(Fig. 6a) 


le:Ze 
le:2a 
la : 2a 
la: 3a 


2-49 
2-49 
306 
2-51 


Boat 
(Fig. 66) 


2a: 3a 
2e: 3e 


2-27 
2-27 
1-83 



It appears that the boat conformation occurs in relatively few cases, and 
so in the following account we shall only study the problem of the chair 
conformation. Inspection of the above table shows that a 1 : 2-interaction 
for two adjacent equatorial hydrogens or for an equatorial and adjacent 
axial hydrogen is about the same as for a 1 : 3-interaction for two meta 
axial hydrogens. Furthermore, a study of accurate scale models has shown 
that with any axial substituent (which is necessarily larger than hydrogen), 
the 1 : 3-interactions are larger than the 1 : 2-interactions when the same 
substituent is equatorial. Using these principles, we can now proceed to 
study the conformations of cyc/ohexane derivatives. 

Because of the flexibility of the chair conformation, one chair form is 
readily converted into the other chair form, and in doing so all a- and 
e-bonds in the first now become e- and a-bonds, respectively, in the second. 




Both forms are identical and so cannot be distinguished. If, however, one 
hydrogen is replaced by some other atom or group, the two forms are no 
longer identical, e.g., methylcyc/ohexane. In the a-methyl conformation 

Me jj 




H- . . , H 




Me- 7/ ^- H 

H H 

a-methy] e- methyl 

there are 1 : 3-interactions acting, whereas in the c-methyl conformation 
these interactions are absent; instead, the weaker 1 : 2-interactions are act- 
ing. Thus the energy content of axial conformation is greater than that 
of the equatorial, and consequently the latter will be the preferred form. 
Hassel (1947) has shown experimentally from electron-diffraction studies 
that the e-methyl conformation predominates in methylcycfohexane. Hassel 
et al. (1950) have also shown that in chlorocyclohexane the e-form also pre- 
dominates and that very little of the a-form is present. 



112 ORGANIC CHEMISTRY [CH. IV 

The nature of the intermediate in the transformation of one chair form into 
the other is not certain. According to Johnson et al. (1961), the boat form of 
cycfohexane is twisted, and Jensen et al. (1962) believe that the transition state 
(of the intermediate) is the structure approximately halfway between the chair 
and twisted boat forms. 

Now let us discuss the conformations of disubstituted cycfohexanes. Here 
we have a number of factors to consider : position isomerism, stereoisomerism 
(geometrical and optical), the relative sizes of the two substituents, and 
the nature of the substituents. 

(i) 1 : 2-Compounds 

Classical formula Conformations 



¥ 




cis-V.2 le:2a la:2e 

It should be noted that in these «'s-compounds one substituent must be 
axial and the other equatorial. If the substituents differ in size, the 1 : 3- 
interactions will be most powerful when the larger group is axial. Thus 
the conformation with the lower energy will be the one in which the larger 
group is equatorial, i.e., this is the preferred form. An example of this 
type is m-2-methylcyc/ohexanol; the methyl group is larger than the 
hydroxyl, and so the preferred form can be expected to be la-hydroxyl : 2e- 
methyl. This has been shown to be so in practice. In general, the greater 
the difference in size between the two substituents, the greater will be the 
predominance of the form with the larger group in the equatorial conforma- 
tion. 

The classical formula of the as-compound when the two substituents are 
identical has a plane of symmetry and is therefore not resolvable. On the 
other hand, the two conformations are mirror images but not superimposable 
and hence, in theory, are resolvable. Such compounds, however, have never 
yet been resolved. The reason for this is that the two forms are separated 
by such a low energy barrier that they are readily interconvertible. 

Classical formula Conformations 





le:2e 

Whether Y 1 and Y 2 are identical or not, the two conformations are dif- 
ferent, and because of the 1 : 3-interactions the e : e-form will be the preferred 
form. Furthermore, this form will be more stable than the «'s-isomer 
(a : e-form). An example that illustrates this is 2-methylcycMiexanol. The 
trans-form has been shown to be more stable than the cis; the latter is 
readily converted into the former when heated with sodium, and also the 
reduction of 2-methylcycMiexanone (with sodium and ethanol) produces the 
trans-Alcohol. 

Both the classical formula and the e : e- (and a : a) conformation of the 



§11] 



GEOMETRICAL ISOMERISM 



113 



trans-1 : 2-compound (whether Y x and Y g are identical or not) are not super- 
imposable on their mirror images and hence should be optically active. 
This has been found to be so in practice. 

(ii) 1 : 3-Compounds 

Classical formula Conformations 



cis- 1:3 




trans -1:3 



e:a 



The two tows-conformations are identical when the two Y groups are 
identical. The cis-e : e-form will be more stable than the cis-a : a, and will 
also be more stable than the trans-e : a-conformation, e.g., the most stable 
conformation of 1 : 3-dimethylcycfohexane has been shown to be the cis- 
1 : 3-e : e-form. It should be noted that this situation is the reverse of that 
of the 1 : 2-dimethylcycMiexanes. 

The Auwers-Skita rule (§5(x)6) has been shown to break down when 
applied to 1 : 3-disubstituted cyc/ohexanes : the reverse holds good. Allinger 
(1954) modified the rule for cycfohexanes as follows: The isomer which has 
the higher boiling point, refractive index and density is the one with the 
less stable configuration. Thus, according to this rule, the trans-1 : 3- 
disubstituted cyc/ohexanes have the higher physical constants (the trans- 
form has more axial substituents than the more stable a's-form); e.g., 
Macbeth et al. (1954) have shown that the physical constants of (±)-trans- 
3-methylcyc/ohexylamine are higher than those of its cis-isomer. 

(iii) 1 : 4-Compounds 

Classical formula Conformations 



o 



cis-1.4 




trans - 1 : 4 



a:a 



The two c/s-conformations are identical when the Y groups are identical. 
Also, the trans-e : e-iorm will be more stable than the cis-a : e-form. 



114 ORGANIC CHEMISTRY [CH. IV 

The arguments used for the disubstituted cyc/ohexanes can also be applied 
to the higher substituted cyc/ohexanes. As the result of a large amount 
of work, the following generalisations may be made: 

(i) In cycfohexane systems, mono-, di-, tri- and poly-substituted derivatives 
always tend to take up the chair conformation whenever possible. 

(ii) The chair conformation with the maximum number of equatorial 
substituents will be the preferred conformation. This generalisation, how- 
ever, is only satisfactory when the internal forces due to dipole interactions 
or hydrogen bonding are absent. When these are present, it is necessary 
to determine which forces predominate before a conformation can be assigned 
to the molecule. As an illustration of this problem, we shall consider 
2-bromocyc/ohexanone; the two possible chair forms are: 





-Br 

H 
a-Br e-Br 

On the basis that a substituent preferably takes up an equatorial conforma- 
tion, it would therefore be expected that the conformation 2e-bromocyc/o- 
hexanone would be favoured. Infra-red studies, however, have shown that 
the fl-bromo conformation predominates. This has been explained as 
follows. The C — Br and C==0 bonds are both strongly polar, and when 
the bromine is equatorial the dipolar repulsion is a maximum, and a mini- 
mum when the bromine is axial. Since the axial form predominates, this 
equatorial dipolar repulsion must therefore be larger than the 1 : 3-inter- 
actions. When, however, other substituents are present, the 1 : 3-inter- 
actions may become so large as to outweigh the dipolar effect and the 
bromine would now be equatorial. Such is the case with 2-bromo-4 : 4- 
dimethylcycfohexanone (see also §12). 

*0 




Me H 

(iii) The energy barriers between the various conformations are too small 
to prevent interconversion (but see §12). Up to the present time, the 
number of geometrical (and optical) isomers obtained from a given cyclo- 
hexane derivative is in agreement with the number that can be expected 
from a planar ring with the substituents lying above and below the plane 
of the ring. We shall now, therefore, discuss the stereochemistry of some 
cyc/ohexane derivatives from the classical point of view. 

(i) Hexahydrophthalic acids (cyc/ohexane-1 : 2-dicarboxylic acids). Two 
geometrical isomers are theoretically possible, the cis, I, and the trans, II. 

CO,H 





§11] 



GEOMETRICAL ISOMERISM 



115 



Molecule I has a plane of symmetry, and therefore represents the meso- 
form; II has no elements of symmetry, and can therefore exist in two 
optically active forms (and one racemic modification). All of these possible 
forms are known, and it has been found that the m-compound, I, forms a 
cyclic anhydride readily, whereas the ^raws-compound, II, forms a cyclic 
anhydride with difficulty (cf. §5. i). 

(ii) Hexahydroisophthalic acids (eycMiexane-1 : 3-dicarboxylic acids). Two 
geometrical isomers are possible; the c*s-form, III, has a plane of symmetry, 
and therefore represents the meso-iorm; IV has no elements of symmetry, 
and can therefore exist in two optically active forms (and one racemic 

C0 2 H H H 



Ha 





ii0 *9/h H0 2 

H H 
IV 

modification). All of these forms are known; the as-isomer forms a cyclic 
anhydride, whereas the trans-isomer does not. 

(iii) Hexahydroterephthalic acids (cycJohexane-1 : 4-dicarboxylic acids). 
Two geometrical isomers are possible; the cts-form, V, has a plane of sym- 
metry, and the trans-iorm, VI, a centre of symmetry. Hence neither is 

H H H H 



HOjjC 



C0 2 H H0 2 C 




C0 2 H 



V VI 

optically active. They may be distinguished by the fact that the cis- 
isomer forms a cyclic anhydride, whereas the trans-isomer does not. 

(iv) Inositol (hexahydroxycycMiexane). There are eight geometrical iso- 
mers possible theoretically, and only one of these is not superimposable on 
its mirror image molecule; thus there are nine forms in all (and also one 
racemic modification). If we imagine that we are looking down at the 
molecule, and insert the groups which appear above the plane of the ring, 
then the eight geometrical isomers may be represented as follows: 

H OH OH OH 




H 



H 




H 




OH H 




HL /'H HLJH HL JH HI JOH 

H H H H 

■tneso- inositol 




OH 




OH 



OH 



HO 




OH 



OH H 

resolvable scyllitol 

Examination of these configurations shows that all except one — the one 
labelled resolvable — have at least one plane of symmetry, and so are all 



116 



ORGANIC CHEMISTRY 



[CH. IV 



meso-ionas. All the meso-iorms and both of the optically active forms are 
known; of these meso-inositol, scyllitol and (+)- and (— )-inositol occur 

naturally. „ . , . 

(v) Benzene, hexachloride (hexachlorocycfohexane) . Here again eight geo- 
metrical isomers are possible theoretically; seven are known, a, p, y, o, 
e v 0* the y-isomer is a powerful insecticide (see Vol. I). All have been 
shown to exist in the chair form, and the conformations that have been 
assigned are: 

a-, aaeeee; ji-, eeeeee; y-, aaaeee; d-, aeeeee; s-, aeeaee. 
Of these forms, it is the (3- which loses hydrogen chloride with the greatest 
difficulty (see §5b). All of the other stereoisomers possess at least one 



H 



CI 
H 



CI 



H 



CI 





P- 



pair of chlorine atoms cis to each other (thus having H and CI trans). 
Cristol (1949) has also identified the a-isomer as the (±)-form. 

(vi) So far we have discussed the stereochemistry of the cycfohexane 
ring The same types of stereoisomerism are also exhibited by various 
sized heterocyclic systems, e.g., dimethyldiketopiperazine (§6. II), furanose 
(§7b. VII) and pyranose (§7a. VII) sugars. 

(vii) Decalins and decalols. As we have seen, the boat and chair forms 
of cycfohexane are readily interconvertible, and the result is that cyclo- 
hexane behaves as if it were planar. Mohr (1918), however, elaborated 
Sachse's theory, and predicted that the fusion of two cycloserine rings, 
e s>. as in decalin, should produce the cis- and *ra«s-forms which would be 
sufficiently stable to retain their identities. This prediction has now been 
confirmed experimentally. . . , ,. „,- 

A non-committal way of writing the two geometrical isomers of decalin 
is given by formula: VII and VIII . On the other hand, several conventions 





cis -decalin 



H 2 H 2 

VIII 

rrarcs-decalin 



have been introduced to represent these isomers. One convention uses full 
lines to represent groups above the plane of the molecule, arid broken lines 
to represent those below the plane (cf. §5. xi); thus «s-decalm will be IX 





GEOMETRICAL ISOMERISM 



117 



§11] 

and trans-decaixn X. This convention appears to be the one most widely 
used (see, e.g., Steroids, Ch. XI), but there is another, introduced by Linstead 
(1937), which is favoured by many. According to this convention, a hydro- 
gen atom is represented as being above the plane of the ring when drawn 
as in XI, and below the plane when drawn as in XII; thus cw-decalin will 
be XIII, and trans-decahn XIV. 



T T 



XI 



XII 





Fig. 7 shows the original diagrammatical method of representing cis- 
decalin by the fusion of two boat forms of cyclohexa.ne, and foms-decalin 
by the fusion of two chair forms; these are the forms suggested by Mohr. 



m-decalin 



trans -decalin 



Fig. 4.7. 



The configurations of the decalins, however, are now known to be more 
complicated than this, the complication arising from the fact that a number 
of strainless modifications are possible, which differ in the type of " locking ", 
i.e., whether axial or equatorial bonds are used to fuse the rings. According 
to Hassel et al. (1946), cis- and trans-decalins are as shown in Fig. 8; the 





as- decalin 



trans -decalin 



Fig. 4.8. 



a's-form is produced by joining one axial and one equatorial bond of each 
ring, whereas the trans-form is produced by joining the two rings by equa- 
torial bonds only; in both cases the cycJohexane rings are all chair forms 
(see also below). 

Johnson (1953) has calculated the difference in energy content between 
these two forms in the following simple manner. The trans-form is arbi- 
trarily assigned a value of zero energy, and when this form is compared 
with the cis, it will be found that the latter has three extra skew interactions 
involving the two axial bonds (this is shown in the following diagram; the 
cis-iorm has 3 staggered and 15 skew arrangements, and the trans-form 
6 staggered and 12 skew).. Since each of these skew interactions is associated 
with an energy increase of 0-8 kg.cal., the total energy difference between 
the cis- and trans-forms is 3 X 0-8 = 2-4 kg.cal. This value agrees well 
with that of Rossini et al. (1960) from measurements of heat of combustion. 



118 



ORGANIC CHEMISTRY 



[CH. IV 



It might be noted, in passing, that if these two decalins are regarded as 
1 : 2-disubstituted eyc/ohexanes, then the trans-iorm (e : e) would be expected 
to be more stable than the cis- (e : a). 





tram 

We shall now deal with the determination of configuration in the decalin 
series. The configurations may be ascertained by using the Auwers-Skita 
rule (see §5. (x)6). Hiickel (1923, 1925), however, isolated two forms of 
2-decalol and determined their configurations by the following chemical 
methods. 2-Naphthol, on hydrogenation in the presence of nickel as catalyst, 
gave two 2-decalols, XV and XVI, each of which, on oxidation with chromic 
acid, gave a decal-2-one (XVII and XVIII). These two decalones each 
gave, on oxidation with permanganate, a cycfohexane-1 : 2-diacetic acid. 
These diacetic acids were geometrical isomers ; one was resolvable and there- 
fore must be the trans-isomer, XX ; and the other, which was not resolvable, 
must therefore be the cw-isomer, XIX (this is the meso-iovm). Thus the 
configurations of the two decalols and the two decalones are established: 




OH 



-CD 

H 
XV cis- 



OH 



nW 


^° ^ 


-^N. 


,.CH 2 -C0 2 H 


JJ 


r-c 




Sh 

,'-CH 2 -C0 2 H 


^y^y 




V^H 


H 






XVII 




XIX 




OH 



H 
XVI trans - 




,.CH 2 -C0 2 H 

H 
,--H 
CH 2 -C0 2 H 



In addition to the two cycfohexane-1 : 2-diacetic acids (which are formed 
by scission of the 2 : 3-bond of the decalone), two other geometrical isomers 
were also obtained, viz. cis- and <rans-cyciohexane-l-carboxyl-2-propionic 
acids, XXI and XXII (these are formed by scission of the 1 : 2-bond of 
the decalone). 

-C0 2 H ^\ ,-C0 2 H 

»H \ ><H 

L'CH 2 -CH 2 -C0 2 H I L'H 

*H ^v/^CHz-CHg-CQaH 

XXI XXII 

The conversion of 2-naphthol into two decalols does not prove that the 
two decalols are the cis- and tfraws-isomers described above. It is possible 
that both compounds could have been the cis- and trans-ioxvns of a given 
decalol; since the carbon atom of the CHOH group in the 2-decalol is asym- 




§11] 



GEOMETRICAL ISOMERISM 



119 



metric, it can exist in two configurations, i.e., each decalol, XV and XVI, 
can exist in two forms; XVa and XVIa. Had the two decalols been the 




XV a 




XVI a 

two forms of either XV or XVI, then on their oxidation, only one decalone 
would have been produced. Since, however, two decalones were obtained, 
the two decalols must be of the types XV and XVI — one of each, or even 
a mixture of the pairs; further proof of the existence of the types XV and 

XVI lies in the fact that the two decalones gave geometrical isomers of 
cycJohexane-1 : 2-diacetic acid. 

Consideration of formulae XVa and XVIa shows the presence of three 
asymmetric carbon atoms in each of the four possible forms, and since all 
four possess no elements of symmetry, four pairs of enantiomorphs should 
be possible theoretically. Actually all eight forms have been isolated, but 
their configurations have not yet been established with certainty. 

There are only two geometrical isomers possible for the decalins, and their 
configurations have been established by the reduction of the two decalones, 

XVII and XVIII, by means of the Wolff-Kishner method (Eisenlohr et al., 
1924; see also Vol. I) ; each decalone gives the corresponding decalin. It 
is interesting to note in this connection that Willstatter et al. (1924) found 
that hydrogenation of naphthalene in the presence of platinum black as 
catalyst gives mainly cw-decalin, whereas in the presence of nickel as catalyst 
the main product is tfnms-decalin. The configurations of the decalins have 
also been determined by means of their NMR spectra (see also end of this 
section). 

Various other fused ring systems have also been shown to exhibit the 

H 




Ct> oH 

H 

CK-hydrindanoI. 
Two forms; both meso- 

H 




HOH 



trans- hydrindanol . 
Resolvable 





NH 



Decahydroquinolines 



DecahydroJSdquinohnes 



120 ORGANIC CHEMISTRY [CH. IV 

same type of geometrical isomerism as the decalins, e.g., the hydrindanols 
exist in cis- and trans-forms (Huckel et al., 1926), and also the decahydro- 
quinolines and decahydrowoquinolines (Heifer et al., 1923, 1926). 

It has already been pointed out that in monosubstituted cye/ohexanes, 
the preferred conformation is the one with the substituent equatorial, but 
owing to the low energy barrier between this and the axial form, the two 
are readily interconvertible. In the case of the monosubstituted decalins, 
the problem is more complicated. In cw-decalin, since ring fusion involves 
equatorial and axial bonds, the molecule is flexible and can interchange 
with the other a's-form, i.e., there are two cw-forms possible (XXIII and 
XXIV), and these are identical and in equilibrium (cf. cyc/ohexane). This 
has been shown to be so by Hassel (1950); thus: 




e XXIII 



XXIV 



As pointed out above, Musher et al. (1958) distinguished between cis- 
and tfnms-decalin by means of their NMR spectra. The former gives a 
sharp band whereas the latter gives a broad spectrum. These differences 
are due to the former molecule undergoing relatively rapid interconversion 
between the two conformations, whilst the latter molecule has a more rigid 
structure and hence the axial and equatorial hydrogen atoms are distinguish- 
able (and so give a broad spectrum). 

Now let us consider cw-2-decalol. Here there are four possible conforma- 
tions which, in pairs, are in equilibrium. Two arise from XXIII (XXIIIa 
and XXIIB), and two from XXIV (XXIVa and XXIV6). 

In XXIIIa and XXIV6 the hydroxyl group is equatorial, and so these 
two conformations contain about the same energy. In XXIVa and XXIII6 
the hydroxyl group is axial, and on the basis that an equatorial conforma- 
tion is more stable than an axial, then XXIIIa and XXIV6 will contribute 




XXIV* 



§12] GEOMETRICAL ISOMERISM 121 

more to the actual state of the molecule than will XXIVa and XXIII6, 
i.e., the hydroxyl group in cw-2-decalol should possess more equatorial 
character than axial. It is also interesting to note that the two axial 
forms do not contain the same energy. In XXIIIZi the a-hydroxyl group 
is involved in the normal 1 : 3-hydrogen interactions (at 4 and 9), but in 
XXIVa the interaction is the normal 1 : 3- with the hydrogen at 4 and the 
larger 1 : 3-interaction with the CH a group at 8. Thus XXIVa should be 
less stable than XXIII6. 

In fowts-decalin there is only one stable conformation, since the ring 
fusions use equatorial bonds. If the molecular conformation were " in- 
verted ", the two ring fusions would now have to be axial, and this type 
of fusion is impossible (the axial bonds on adjacent carbon atoms are point- 
ing in opposite directions). Thus, in inms-2-decalol, there are only two 
conformations possible, XXV and XXVI. Furthermore, the latter, with 




XXV XXVI 

the equatorial-hydroxyl conformation, would be expected to be more stable 
than the former (with the axial hydroxyl). 

§12. Effect of conformation on the course and rate of reactions. 

Since the environments of axial and equatorial groups are different, it may 
be expected that the reactivity of a given group will depend on whether 
it is axial or equatorial. Now S N 2 reactions always occur with inversion 
(§4. III). Hence if the geometry of the molecule is such as to hinder the 
approach of the attacking group (Z) along the bonding line remote from 
the group to be expelled (Y), then the S N 2 reaction will be slowed down. 
Examination of formulae I and II shows that the transition state for an 
S N 2 reaction is more readily formed when Y is axial (I) than when it is 
equatorial (II). In I, the approach of Z is unhindered and the expulsion 





I II 

of Y assisted by the normal 1 : 3-interactions. In II, the approach of Z 
is hindered by the rest of the ring. Thus S N 2 reactions take place more 
readily with an axial substituent than with an equatorial. 

The study of S N 1 reactions in cyc/ohexane derivatives is made difficult 
because of the ease with which elimination reactions usually occur at the 
same time. It can be expected, however, that an S N 1 reaction will be 
sterically accelerated for an axial substituent, since the formation of a 
carbonium ion will relieve the steric strain due to 1 : 3-interactions. On 
the other hand, since these 1 : 3-interactions are absent for an equatorial 
substituent, no steric acceleration will operate in this conformation. 

A particularly important substituent group in cyclic compounds is 
hydroxyl, and two very important reactions in which this group is involved 
are esterification and hydrolysis (of the ester). Owing to the hindered 
character of an axial group due to 1 : 3-interactions, esterification and 
hydrolysis will occur more readily with the equatorial conformation. In 



122 ORGANIC CHEMISTRY [CH. IV 

the same way, esterification and hydrolysis of esters in which a carboxyl 
group is the substituent will also occur more readily when this group is 
equatorial. On the other hand, the relative rates of oxidation of secondary 
a- and e-alcohols to ketones by chromic acid (or hypobromous acid) is the 
reverse of the relative rates of hydrolysis of their carboxylic esters, i.e., an 
a-hydroxyl is more readily oxidised than an e-. The reason for this is 
that the rate-determining step in this oxidation is a direct attack on the 
hydrogen atom of the C — H bond. If the hydroxyl is axial, the hydrogen 
is equatorial, and vice versa; thus: 

>Xa >- >3=o -e — yxZ 

Elimination reactions are also of great importance in cyclic compounds. 
As we have seen (§5b), in ionic E2 reactions the four centres involved lie in 
a plane. In cyc/ohexane systems this geometrical requirement is only found 
in trans-1 : 2-diaxial compounds, and these compounds thus undergo ready 
elimination reactions. In rigid systems, e.g., the trans-decalin type, elimina- 
tion in trans-1 : 2-diequatorial compounds is slower than in the correspond- 
ing diaxial compounds, cis-l : 2-Compounds (in which one substituent must 
be axial and the other equatorial) undergo elimination reactions slowly. 

The steric course of El reactions is more difficult to study than that of 
E2 reactions because of the two-stage mechanism. This makes it difficult 
to ascertain the geometry of the intermediates involved. The formation 
of the carbonium ion will be sterically accelerated if the ionising group is 
axial and, if a second group is eliminated to form a double bond, this second 
stage will also be sterically accelerated if the second group is axial. Barton 
et al. (1951) have pointed out various examples in which El reactions are 
favoured by the diaxial conformation. 

The arguments used above are satisfactory so long as we know whether 
the group under discussion is axial or equatorial. Since, however, the two 
chair forms are readily interconvertible and in equilibrium, to study these 
predictions experimentally it is necessary to deal with " rigid " conforma- 
tions. The tf-butyl group, because of its large size, is far more stable in 
the e- than in the a-position (the energy difference between the two forms 
is about 5-6 kg.cal./mole ; Winstein et al., 1955). Thus almost only the 
e-form is present and consequently this position is " locked ". Therefore 
4-substituents must be axial when cis to the *-butyl group and equatorial 
when trans to this group (§11). Working with different substituents in the 
4-position with respect to the i-butyl group, various workers have confirmed 
the above predictions experimentally, e.g., it has been shown that cis-4-t- 
butylcydohexanol forms esters more slowly than the trans-isomer, and simi- 
larly c»s-4-2-butylcycfohexane-l-carboxylic acid is more slowly esterified and 
the ester more slowly hydrolysed than the toms-isomer. 

Another interesting example is the case of 4-<-butylcyc/ohexyl tosylate 
(Eliel et al., 1956). Two forms are possible, cis and trans, but because of 
the large bulk of the £-butyl group, this group is always equatorial. Under 





cis- H trans 



the same conditions (sodium ethoxide in ethanol at 70°), the cis-iona readily 
undergoes bimolecular elimination (E2), but the trans- does not. The latter, 
however, does undergo unimolecular (El) elimination. 



§12] GEOMETRICAL ISOMERISM 123 

Some examples of neighbouring group participation in cycloh.exa.ne systems 
have been described in Ch. Ill (§§6b, 6c, 6d). These examples clearly show 
the effect of conformation on rates of reaction when anchimeric assistance 
is possible. 

Not only does conformation control the rate of reactions, but it also may 
affect the course of a reaction. An example of the latter effect is the elimina- 
tion reaction undergone by 2-phenylcyc/ohexanol in the presence of phos- 
phoric acid to form phenylcyc/ohexene. Price et ril. (1940) have shown that 
both the cis and trans alcohols are dehydrated, the former more readily 
than the latter. The product was shown to be a mixture of phenylcyc/o- 
hex-1- and 2-ene, the former predominating when the w's-alcohol was used, 
and both olefins being present in about equal amounts when the trans- 
alcohol was used. The reaction has been shown to proceed by the El 
mechanism, but the reason for the different proportions of olefins is un- 
certain. 



Ph. 



I H | 1-ene 2-ene 

H H (88%) (12%) 



as 




-£*■ (50%) + (50%) 



trans 

Another example of the effect of conformation on the course of a reaction 
in cyefohexane systems is the action of nitrous acid on amines. Mills (1953) 
has proposed the following generalisation: When the amino-group is equa- 
torial, the product is an alcohol with an equatorial conformation ; but when 
the amino-group is axial, the main product is an olefin together with some 
equatorial alcohol. 

Just as trans elimination is favoured with the two groups axial and trans, 
so it has been found that addition of electrophilic reagents to a double 
bond in cyc/ohexenes is predominantly diaxial. 

As we have seen, although there is a preferred form in cycZohexane de- 
rivatives, the energy of interconversion between the preferred and less stable 
form is too low to permit their being distinguished by the classical methods 
of stereochemistry. This predominance of the preferred form holds good 
at room temperature (or below). At higher temperatures, or during the 
course of a chemical reaction, the preponderance of the preferred form may 
be reduced. In chemical reactions, it may be possible for the reaction to 
proceed more readily through the less stable conformation because it is this 
one which more closely approaches the geometry of the transition state. 
An example of this type if chlorocycfohexane. As we have seen, the pre- 
ferred form is the equatorial conformation. This compound, on treatment 
with ethanolic potassium hydroxide, undergoes dehydrohalogenation to form 
cycJohexene. Since trans elimination is preferred, the reaction probably 
proceeds via the axial form. 

CI 




124 ORGANIC CHEMISTRY [CH. IV 

Allinger et al. (1961) have examined the conformations of the 2-halocyc/o- 
hexanones by polarographic methods. It was suggested that since these 
compounds are polarographically reduced (Elving et al., 1956), it seems likely 
that the reduction potential of such a system will depend on the conforma- 
tion of the halogen atom. This prediction was shown to be the case in 
practice. The authors showed that for systems with relatively fixed con- 
formation, such as the 2-halo-4-£-butylcycZohexanones, the epimer with the 
axial halogen is reduced more easily. Furthermore, it was found that a 
flexible molecule such as 2-chlorocyc2ohexanone, which contains comparable 
amounts of the two conformations, showed the potential characteristic of 
the more easily reduced (axial) form. This is understandable on the basis 
that the e-iorm. is very readily converted into the a-form, the rate of the 
conversion being rapid compared with the rate of the reduction. 

Now let us consider reactions involving the hydroxyl group. It has 
already been pointed out that equatorial hydroxyl groups are more readily 
esterified, and equatorial esters more readily hydrolysed, than when these 
groups are axial. If an axial ester group has to stay in this position during 
hydrolysis, then because of the steric hindrance (1 : 3-interactions), the rate 
will be relatively slow (reaction path A). It is possible, however, that prior 
to reaction, the molecule is forced into the equatorial conformation (c/. 
chlorocyc/ohexane above). If this were to happen, then the slower rate 
of hydrolysis would be due to the additional energy required to bring about 
the change in conformation (reaction path B). 




R-COO 



Experimental data has enabled one path to be distinguished from the other 
(see also §16. VIII). 

In fused, systems, owing to the rigidity of the structure, such intercon- 
versions (as described above) are far less likely to occur. 

In this chapter, the discussion of conformational analysis has been applied 
to cyc/ohexane and its derivatives, and this has been done in order to intro- 
duce some of the ideas connected with this problem. The generalisations 
applicable to cyclohexsme compounds, however, are also applicable to hetero- 
cyclic compounds containing nitrogen, oxygen or sulphur (see, e.g., tropines, 
§22. XIV; carbohydrates, §7h. VII). They are also applicable to the poly- 
nuclear compounds, e.g., the Steroids; in fact, much of the work leading to 
these generalisations has been carried out on these compounds (see §4c. XI). 

READING REFERENCES 

Wheland, Advanced Organic Chemistry, Wiley (1960, 3rd ed.). Ch. 7. The Stereo- 
chemistry of Additions to Carbon-Carbon Double Bonds. 

Ingold, Structure and Mechanism in Organic Chemistry, Bell and Sons (1953). Ch. 12. 
Additions and Their Retrogressions. 

Gilman (Ed.), Advanced Organic Chemistry, Wiley. Vol. IV (1953). Ch. 12. Oxida- 
tion Processes. 

Crombie, Geometrical Isomerism about Carbon-Carbon Double Bqnds, Quart. Reviews 

(Chem. Soc), 1952, 6, 101. 



GEOMETRICAL ISOMERISM 125 

Reid, The Triplet State, Quart. Reviews (Chem. Soc), 1958, 12, 205 (see especially 
pp. 216-219). 

Porter, The Triplet State in Chemistry, Proc. Chem. Soc, 1959, 291. 

DePuy and King, Pyrolytic Cis Eliminations, Chem. Reviews, 1960, 60, 431. 

Hassel, Stereochemistry of cye/oHexane, Quart. Reviews {Chem. Soc.), 1953, 7, 221. 

Bent, Aspects of Isomerism and Mesomerism, /. Chem. Educ., 1953, 30, 220, 284, 328. 

Figueras, Stereochemistry of Simple Ring Systems, /. Chem. Educ, 1951, 28, 134. 

Klyne (Ed.), Progress in Stereochemistry, Butterworth (1954). Ch. 2. The Conforma- 
tion of Six-membered Ring Systems. 

Barton and Cookson, The Principles of Conformational Analysis, Quart. Reviews {Chem. 
Soc), 1956, 10, 44. 

Orloff, The Stereoisomerism of cyctoHexane Derivatives, Chem. Reviews, 1954, 54, 347. 

Newman (Ed.), Steric Effects in Organic Chemistry, Wiley (1956). Ch. 1. Conforma- 
tional Analysis. 

Angyal, The Inositols, Quart. Reviews {Chem. Soc), 1957, 11, 212. 

Brewster, The Optical Activity of Saturated Cyclic Compounds, /. Amer. Chem. Soc, 
1959, 81, 5483. 

Eliel, Conformational Analysis in Mobile Systems, /. Chem. Educ, 1960, 37, 126. 



CHAPTER V 

STEREOCHEMISTRY OF DIPHENYL COMPOUNDS 

§1. Configuration of the diphenyl molecule. If we assume that the 
benzene ring is planar, then the diphenyl molecule will consist of two planar 
rings; but without any further information we cannot say how these two 
rings are arranged spatially. Kaufler (1907) proposed the " butterfly " 
formula, I, in order to account for the chemical behaviour of various di- 
phenyl derivatives, e.g., Michler and Zimmermann (1881) had condensed 



NH- 



O 






ii 




N0 2 

o 

C0 2 H 
0O 2 H 

O 

NO, 
IV 



benzidine with carbonyl chloride and obtained a product to which Kaufler 
assigned structure II. According to Kaufler, the co-axial structure III 
was impossible, since the two amino-groups are too far apart to react simul- 
taneously with carbonyl chloride; it should be noted that this simultaneous 
reaction at both ends was assumed by Kaufler. Simultaneous reaction, 
however, is reasonable (according to Kaufler) on the folded structure, II. 

Now Schultz (1880) had prepared a dinitrodiphenic acid by the nitration 
of diphenic acid, and Schmidt et al. (1903), from their work on this acid, 
believed it to be 6 : 6'-dinitrodiphenic acid, IV; these workers, it should be 
noted, did not synthesise the acid. In 1921, however, Kenner et al. syn- 
thesised 6 : 6'-dinitrodiphenic acid by means of the UUmarin reaction (see 
Vol. I) on the ethyl ester of 2-chloro-3-nitrobenzoic acid, and hydrolysing 
the product. This acid, V (written with the two benzene rings co-axial), 
did not have the same melting point as Schultz's acid, and so Kenner, 
believing that his and Schultz's acid were both 6 : 6'-dinitrodiphenic acid, 
suggested that the two were stereoisomers. Then Christie and Kenner 



CO.AH 6 COAH; NO, 

N0 2 N0 2 CO 2 2 H 5 



C0 2 H NO 




N0 2 C0 2 H 
V 



(1922) showed that Kenner's acid was resolvable, and pointed out that this 
could be explained on the Kaufler formula, IV, since this structure has no 
elements of symmetry. These authors, however, also pointed out that the 
optical activity could also be accounted for by the co-axial structure, V, 
provided that the two benzene rings do not lie on one plane (see also §2). 
Kaufler's formula, as we have seen, was based on the assumption that the 
two amino-groups in benzidine react simultaneously with various reagents. 
Re-investigation of these reactions showed that this was not the case, e.g., 
Turner and Le Fevre (1926) found that the compound produced from 

126 



§2] STEREOCHEMISTRY OF DIPHENYL COMPOUNDS 127 

benzidine and carbonyl chloride was not as originally formulated (see II 
or III), but had a free amino-group, i.e., the compound was 
[NH 2 -C 6 H 4 -C 6 H 4 .NH] 2 CO. 

Hence Kaufier's reason for his butterfly formula is incorrect, and although 
it does not necessarily follow that the formula is incorrect, nevertheless 
Turner's work weakened Kaufier's claim. One of the strongest bits of 
chemical evidence for rejecting Kaufier's formula is that of Barber and 
Smiles (1928). These workers prepared the three dimercaptodiphenyls, 
VI, VII and VIII, and oxidised each one. Only one of them, the 2 : 2'- 

SH 8H SH SH 

VI VII VIII 



J3-S. 




IX 

derivative, VI, gave the intramolecular disulphide (diphenylene disulphide, 
IX). On the Kaufler formula, all three dithiols would be expected to give 
the intramolecular disulphides, since the two thiol groups are equally distant 
in all three compounds. 

Physico-chemical methods have also been used to determine the con- 
figuration of the diphenyl molecule, e.g., the crystal structure of 4 : 4'- 
diphenyl derivatives shows a centre of symmetry; this is only possible for 
the co-axial formula. Dipole moment measurements also confirm this con- 
figuration, e.g., the dipole moment of 4 : 4'-dichlorodiphenyl is zero; this 
again is only possible if the two benzene rings are co-axial. 

§2. Optical activity of diphenyl compounds. Christie and Kenner's 
work (see above) has been extended by other workers, who showed that 
compounds in which at least three of the four ortfAo-positions in diphenyl are 
occupied by certain groups could be resolved. It was then soon found that 
two conditions were necessary for diphenyl compounds to exhibit optical 
activity: 

(i) Neither ring must have a vertical plane of symmetry. Thus I is not 
resolvable, but II is. 

A B A A B B 

-o-o- <^^ 

A B A B 

I II 

(ii) The substituents in the oriAo-positions must have a large size, e.g., 
the following compounds were resolved: 6-nitrodiphenic acid, 6 : 6'-dinitro- 
diphenic acid, 6 : 6'-dichlorodiphenic acid, 2 : 2'-diamino-6 : 6'-dimethyl- 
diphenyl (see also §4). 

The earlier work showed that three groups had to be present in the ortho- 
positions. This gave rise to the theory that the groups in these positions 
impinged on one another when free rotation was attempted, i.e., the steric 
effect prevented free rotation. This theory of restricted rotation about the 
single bond joining the two benzene rings (in the co-axial formula) was 
suggested simultaneously in 1926 by Turner and Le Fevre, Bell and Kenyon, 



128 ORGANIC CHEMISTRY [CH. V 

and Mills. Consider molecule III and its mirror image IV. Provided that 
the groups A, B and C are large enough to " interfere mechanically ", i.e., 
to behave as " obstacles ", then free rotation about the single bond is 



A C 

B 
III 



C A 



^~0 



B 
IV 



restricted. Thus the two benzene rings cannot be coplanar and consequently 
IV is not superimposable on III, i.e., Ill and IV are enantiomorphs. In 
molecule III there is no asymmetric carbon atom; it is the molecule as a 
whole which is asymmetric, due to the restricted rotation. 

In diphenyl the two benzene rings are co-axial, and in optically active 
diphenyl derivatives the rings are inclined to each other due to the steric 
and repulsive effects of the groups in the orf/k>-positions. The actual angle 
of inclination of the two rings depends on the nature of the substituent 
groups, but it appears to be usually in the vicinity of 90°, i.e., the rings 
tend to be approximately perpendicular to each other. Thus, in order to 
exhibit optical activity, the substituent groups in the o^Ao-positions must 

C0 2 H C0 2 H COgH 

V VI 2 

be large enough to prevent the two rings from becoming coplanar, in which 
case the molecule would possess a plane or a centre of symmetry, e.g., 
diphenic acid is not optically active. In configuration V the molecule has 
a plane of symmetry, and in configuration VI a centre of symmetry; of 
these two, VI is the more likely because of the repulsion between the two 
carboxyl groups (cf. §4. II). 

If restricted rotation in diphenyl compounds is due entirely to the spatial 
effect, then theoretically we have only to calculate the size of the group in 
order to ascertain whether the groups will impinge and thereby give rise 
to optical activity. In practice, however, it is found that groups (and 
atoms) behave as if they were larger than the volumes obtained from group 
(and atomic) radii (cf. §15b. I). This behaviour is largely due to the fact 
that groups also repel (or attract) one another because of the electric charges 
that are usually present on these groups. Thus the actual distance that 
the atoms or groups (in the o^o-positions) can approach one another is 
greater than that obtained from the atomic and group radii. Better agree- 
ment with experiment is obtained when the van der Waals radii (§2. I) 
are used for calculating the " size " of a group. 

Later work has shown that if the substituent groups are large enough, 
then only two in the o- and o'-positions will produce restricted rotation, 
e.g., Lesslie and Turner (1932) resolved diphenyl-2 : 2'-disulphonic acid, VII. 
In this molecule the sulphonic acid group is large enough to be impeded 
by the or<Ao-hydrogen atoms. Lesslie and Turner (1933) have also resolved 

S0 3 H Br 

S0 3 H j + A8(CHs)3 

vii viii 1 



§2] STEREOCHEMISTRY OF DIPHENYL COMPOUNDS 129 

the arsonium compound VIII; here also the trimethylarsonium group is 
large enough to be impeded by the ortho-hydvogen atoms (the bromine atom 
in the meta--position gives asymmetry to this ring). This example is unique 
up to the present in that only one substituent in the o^Ao-position produces 
optical activity in diphenyl compounds. 

It has already been pointed out that diphenic acid is not optically active, 
and that its configuration is most probably VI. Now calculation shows 
that the effective diameter of the carboxyl group is large enough to prevent 
configuration V from being planar, and consequently, if the two rings could 
be held more or less in this configuration, the molecule would not be co- 
planar and hence would be resolvable. Such a compound, IX, was pre- 
pared and resolved by Adams and Kornblum (1941). The two benzene 






_C0 2 II CQ 2 H 

« = 8or"l0 (C0 2 C 2 H s ) 2 (0O 2 C 2 H 5 ) 2 

IX X XI 

rings are not coplanar and are held fairly rigid by the large methylene ring. 
Iffland et al. (1956) have also prepared the optically active diphenyl X which 
has a 2 : 2'-bridge and two amino-groups in the 6 : 6'-positions. On the 
other hand, these authors have also prepared XI in optically active forms ; 
this compound has the 2 : 2'-bridge but no substituents in the 6 : 6'-positions. 
Mislow (1957) has also obtained the dibenzocyc/o-octadiene acids, XII, in 
optically active forms; both forms were highly optically labile. Similar to 





N 
H0 2 C N C0 2 H Ph^ Th 

XII XIII 

_C0 2 H OH OH 
HO 

HO OH 

XV 

XII is XIII which has been resolved by Bell (1952). Mislow et al. (1961) 
have also resolved the diphenyl derivative XIV. 

Cxl2 C/H2 





130 



ORGANIC CHEMISTRY 



[CH. V 



A point of interest in connection with optically active diphenyls is that 
Schmidt et al. (1957) have shown that XV occurs naturally in an optically 
active form. 

§2a. Absolute configurations of diphenyls. Mislow et al. (1958) have 
determined the absolute configuration of 6 : 6'-dinitro-2 : 2'-diphenic acid. 
Their method was chemical; assignment of absolute configuration has been 
obtained from a consideration of the transition states in the Meerwein- 
Ponndorf-Verley reduction of a dissymmetric diphenylic ketone by asym- 
metric alcohols of known absolute configuration (c/. §7. III). Using this 
diphenyl as absolute standard, Mislow et al. (1958) then correlated con- 
figurations in the diphenyl series by the quasi-racemate method (§9a. II). 
In this way these authors determined the configurations of 6 : 6'-dichloro- 
and 6 : 6'-dimethyl-2 : 2'-diphenic acid. Mislow et al. (1960) have also con- 
firmed absolute configurations in the diphenyl series by the rotatory dis- 
persion method (§12a. I). 

§3. Other examples of restricted rotation. In addition to the di- 
phenyl compounds, there are many other examples where optical activity 
in the molecule is produced by restricted rotation about a single bond 
which may or may not be one that joins two rings. The following examples 
are only a few out of a very large number of compounds that have been 
resolved. 

(i) Adams et al. (1931) have resolved the following iV-phenylpyrrole and 
N : iV'-dipyrryl. 



H0 2 C CII 3 C0 2 H H0 2 C CH 3 CH 3 



=N, 



=/ 
0H3 



CH3 'CH3 C02H 

Adams et al. (1932) have also resolved the 3 : 3'-dipyridyl 

C0 2 H C0 2 H 

00 2 H CCfeH 

(ii) 1 : l'-Dinaphthyl-8 : 8'-dicarboxylic acid has been obtained in opti- 
cally active forms by Stanley (1931). 




COjjH 



This compound gives rise to asymmetric transformation (§10 iv. II) ; resolu- 
tion with brucine gave 100 per cent, of either the (+)- or (— )-compound. 

Other compounds similar to the dinaphthyl which have been obtained 
in optically active forms are 1 : l'-dinaphthyl-5 : 5'-dicarboxylic acid, I 
(Bell et al., 1951), the dianthryl derivatives, II and III (Bell et al., 1949), 
and the 4 : 4'- and 5 : 5'-diquinolyls, IV and V (Crawford et al., 1952). 

(hi) Mills and Elliott (1928) obtained iV-benzenesulphonyl-8-nitro-l- 
naphthylglycine, VI, in optically active forms; these were optically unstable, 



§3] STEREOCHEMISTRY OF DIPHENYL COMPOUNDS 

H0 2 C 



131 





C0 2 H 



H0 2 C 



II 





III 

undergoing asymmetric transformation with brucine. Mills and Kelham 
(1937) also resolved iV-acetyl-iV-methyl-/>-toluidine-3-sulphonic acid, VII, 
with brucine, and found that it racemised slowly on standing. In both 



9^ /CH^COaH 

N 
N0 2 




CH 3 CO-CH 3 

^S0 3 H 



VI 

VI and VII the optical activity arises from the restricted rotation about 
the C — N bond (the C being the ring carbon to which the N is attached). 
Asymmetry arising from the same cause is also shown by 2-acetomethyl- 
amido-4' : 5-dimethyldiphenylsulphone, VIII; this was partially resolved 
by Buchanan et al. (1950; see also §10 iv. II). It is also interesting to note 
in this connection that Adams et al. (1950) have isolated pairs of geometrical 
isomers of compounds of the types IX and X; here geometrical isomerism 
is possible because of the restricted rotation about the C— N bonds. 



R .SCVCgHs 





VIII 



R SOj'CjHs 

IX 



132 



ORGANIC CHEMISTRY 

R R 

I CH 3 I 

C 6 H 5 - S0 2 -N XN^N-SO^CeHs 
CH 



R S0 2 "C 6 H 5 



[ch. v 




(iv) Liittringhaus et al. (1940, 1947) isolated two optically active forms 
of 4-bromogentisic acid decamethylene ether. In this compound the methy- 
lene ring is perpendicular to the plane of the benzene ring; the two sub- 
stituents, Br and C0 2 H, prevent the rotation of the benzene nucleus inside 



HO,C 




(CH 2 ) 1( 



CH 



CH 



CH, 



CH, 



^=\ 



COoH 



the large ring. Cram et al. (1955) have obtained a paracyclophane in opti- 
cally active forms; there is insufficient space to allow the benzene ring 
carrying the carboxyl group to rotate to give the enantiomorph. In this 
compound the two benzene rings are parallel and perpendicular to the plane 



HO„C 




(CH 2 ) 



10 



of the ring. On the other hand, Blomquist et al. (1961) have resolved the 
simple paracyclophane shown. 

(v) Terphenyl compounds can exhibit both geometrical and optical iso- 
merism when suitable substituents are present to prevent free rotation about 
single bonds, e.g., Shildneck and Adams (1931) obtained the following com- 
pound in both the cis- and trans-forms. 

Br CH 3 0H 0H CH 3 Br 

^=fa 3 OH OH C h 3 
cis 

Br CH 3 0H 0H CH 3 

CH 3 OH 0H CH 3 Br 
trans 

Interference of the methyl and hydroxyl groups in the or^o-positions pre- 
vents free rotation and tends to hold the two outside rings perpendicular 
to the centre ring. Inspection of these formulae shows that if the centre 
ring does not possess a vertical plane of symmetry, then optical activity is 



§3a] 



STEREOCHEMISTRY OF DIPHENYL COMPOUNDS 
CI *3 Br O H ^ 3 3 

ch 3 <^3~c>-^€=> uH3 

^=^ OH Br 



133 



CH Br OH __. 
CH s ^>-^^-^^CH 3 
OH Br CH 3 
trans 
possible. Thus Browning and Adams (1930) prepared the dibromo cis- and 
trans-forms, and resolved the «'s-isomer; the foms-isomer is not resolvable 
since it has a centre of symmetry. 

(vi) A very interesting case of restricted rotation about a single bond is 
afforded by the compound 10-m-aminobenzylideneanthrone. This was pre- 
pared by Ingram (1950), but he failed to resolve it. He did show, however, 

O 




NH 2 



that it was optically active by the mutarotation of its camphorsulphonate 
salt, and by the preparation of an active hydriodide. Thus the molecule 
is asymmetric, and this asymmetry can only be due to the restricted rota- 
tion of the phenyl group about the C — phenyl bond, the restriction being 
brought about by hydrogen atoms in the wtf/w-positions. The two hydrogen 
atoms labelled H x overlap in space, and consequently the benzene ring 
cannot lie in the same plane as the 10-methyleneanthrone skeleton. 

§3a. Molecular overcrowding. All the cases discussed so far owe their 
asymmetry to restricted rotation about a single bond. There is, however, 
another way in which steric factors may produce molecular asymmetry. 
It has been found that, in general, non-bonded carbon atoms cannot approach 




CO,H 



closer to each other than about 3-0 A. Thus, if the geometry of the mole- 
cule is such as to produce " intramolecular overcrowding ", the molecule 
becomes distorted. An example of this type is 4:5: 8-trimethyl-l-phen- 
anthrylacetic acid, I. The phenanthrene nucleus is planar and substituents 



134 ORGANIC CHEMISTRY [CH. V 

lie in this plane. If, however, there are fairly large groups in positions 4 
and 5, then there will not be enough room to accommodate both groups in 
the plane of the nucleus. This leads to strain being produced by intra- 
molecular overcrowding, and the strain may be relieved by the bending 
of the substituents out of the plane of the nucleus, or by the bending (buck- 
ling) of the aromatic rings, or by both. Thus the molecule will not be 
planar and consequently will be asymmetric and therefore (theoretically) 
resolvable. Newman et al. (1940, 1947) have actually partially resolved it, 
and have also partially resolved II and III (both of which also exhibit 
out-of-plane distortions). All of these compounds were found to have low 
optical stability, but Turner et al. (1955) have prepared the optically active 
forms of 9 : 10-dihydro-3 : 4-5 : 6-dibenzophenanthrene (IV), which is more 



Me Me 






IV 



VI 



optically stable than I, II and III. Newman et al. (1955, 1956) have pre- 
pared V and VI which, so far, are the most optically stable compounds of 
the intramolecular overcrowding type. 

It will be noticed that in IV and VI the only way in which out-of-plane 
distortion can occur is through buckling of the molecule. The simplest 





VII 



VIII 




molecule exhibiting overcrowding and consequent out-of-plane buckling of 
the molecule is 3 : 4-benzophenanthrene (VII); this has been shown to be 
non-planar by X-ray analysis (Schmidt et al., 1954). Similarly, Robertson 
et al. (1954) have shown that VIII exhibits out-of-plane buckling. 

Another point to note in connection with out-of-plane buckling is that 
the buckling is distributed over all the rings in such a manner as to cause 
the minimum distortion in any one ring. This distortion, which enables 
non-bonded carbon atoms to avoid being closer together than 3-0 A (marked 
with dots in VII and VIII), forces some of the other carbon atoms to adopt 
an almost tetrahedral valency arrangement (the original hybridisation is 
trigonal), and this affects the physical and chemical properties of the mole- 
cule, e.g., Coulson et al. (1955) have calculated that the deformation in 
VIII produces a loss of resonance energy of about 18 kg.cal./mole. 

Just as benzene rings may suffer distortion, so can a molecule which owes 
its planarity to the presence of a double bond. Such an example is di- 
anthronylidene (IX). The carbon atoms marked with dots are overcrowded 
(the distance between each pair is 2-9 A), and the strain is relieved by a 



§4] STEREOCHEMISTRY OF DIPHENYL COMPOUNDS 135 

rotation of about 40° around the olefinic double bond (Schmidt et al., 1954). 
Even in such simple molecules as tiglic acid (X) the two methyl groups 
give rise to molecular overcrowding with the result that the /S-methyl group 

Me \c/ H Me \c/ H 

II II 

Ms/ Nx>,H HO a c/ N 



■Me 



X XI 



appears to be displaced from the molecular plane, thereby relieving over- 
crowding which is also partly relieved by small distortions in bond angles. 
These results were obtained by Robertson et al. (1959) from X-ray studies, 
and these authors also showed similar distortions in angelic acid (XI). 

In polynuclear aromatic hydrocarbons in which the strain tends to be 
overcome by out-of-plane displacements of substituents and out-of-plane 
ring buckling, these effects cause changes in the ultraviolet spectra, but it is 
not yet possible to formulate any correlating rules. NMR studies by Ried 

(1957) have shown a shift for the hydrogen atoms in positions 4 and 5 in 
phenanthrene itself. A similar phenomenon has been detected by Brownstein 

(1958) in 2-halogenodiphenyls, and the explanation offered is that the shift 
is due to the steric effect between the 2-halogen and the 2'-hydrogen atom. 

Although molecular overcrowding is normally confined in the polynuclear 
type to systems containing three or more rings, nevertheless various sub- 
stituted benzenes may also exhibit out-of-plane displacements of the sub- 
stituents. Electron-diffraction studies of polyhalogenobenzenes suggest 
that such molecules are non-planar (Hassel et al., 1947), whereas X-ray 
studies indicate that in the solid state such molecules are very closely or 
even exactly planar (Tulinsky et al., 1958; Gafner et al., 1960). Ferguson 
et al. (1959, 1961) have examined, by X-ray analysis, polysubstituted ben- 
zenes containing not more than one halogen atom, e.g., o-chloro- and bromo- 
benzoic acid, and 2-chloro-5-nitrobenzoic acid. In all three molecules the 
steric strain is relieved by small out-of-plane displacements of the exocyclic 
valency bonds in addition to the larger in-plane displacements of these 
bonds away from one another. Ferguson et al. (1962) have also shown 
that in 2-chloro-5-nitrobenzoic acid the carboxyl group is twisted further 
out of the benzene plane than in o-chlorobenzoic acid. 

§4. Racemisation of diphenyl compounds. Since the optical activity 
of diphenyl compounds arises from restricted rotation, it might be expected 
that racemisation of these compounds would not be possible. In practice, 
it has been found that many optically active diphenyl compounds can be 
racemised under suitable conditions, e.g., boiling in solution. The general 
theory of these racemisations is that heating increases the amplitude of 
the vibrations of the substituent groups in the 2 : 2' : 6 : 6'-positions, and 
also the amplitude of vibration of the two benzene rings with respect to 
each other, thereby permitting the substituent groups to slip by one another. 
Thus the nuclei pass through a common plane and hence the probability 

A B 




B A 



136 ORGANIC CHEMISTRY [CH. V 

is that the final product will contain an equimolecular amount of the (+)- 
and (— )-forms. Westheimer (1946-1950) has assumed, in addition to the 
above bond-stretchings, that the angles a, /? and y are deformed, and also 
the benzene rings themselves are deformed during racemisation. 

The foregoing theory of racemisation is analogous to Werner's theory 
for the racemisation of compounds which contain an asymmetric carbon 
atom. According to Werner (1904), the groups in the compound Cabde 
are set vibrating under the influence of heat, and if the amplitude of vibra- 
tion becomes large enough, all four groups will become coplanar at some 
instant (Fig. 1). This planar structure is symmetrical, and when the mole- 
cule emerges from this condition, there is an equal chance of its doing so 



Plane when 
coplanar 




Fig. 5.1. 

in the (+)- or (—) -configuration, i.e., the molecule racemises. There is, 
however, a great deal of evidence against this mechanism in compounds of 
the type Cabde, e.g., from spectroscopic data it appears that the bonds would 
break before the vibrations were large enough to permit a planar configura- 
tion to be reached. Furthermore, Kincaid and Henriques (1940), on the 
basis of calculations of the energy required for the inversion of molecules, 
were led to suggest that the molecule Cabde can only be racemised by the 
bonds actually breaking. Evete>lso, this theory of racemisation appears to 
be the most reasonable one for the racemisation of diphenyl compounds. 
In this case, the amplitude of vibration does not have to be large in order 
to permit the ortfto-groups to slip by one another. This is supported by 
the fact that it has been found that diphenyl compounds with small sub- 
stituent groups racemise easily, whereas when the groups are large, racemisa- 
tion is difficult or even impossible. 

2 : 2' : 6 : 6'-Tetrasubstituted diphenyl compounds may be classified under 
three headings according to the nature of the substituent groups. 

(i) Non-resolvable. These contain any of the following groups: hydrogen, 
methoxyl or fluorine. The volumes (effective volumes) of these groups are 

OCH 3 F C0 2 H 

H0 2 G F OCH s 

I 

too small to prevent rotation about the single bond. Thus 2 : 2'-difluoro- 
6 : 6'-dimethoxydiphenyl-3 : 3'-dicarboxylic acid, I, is non-resolvable. 

(ii) Resolvable, but easily racemised. These must contain at least two 
amino-groups, or two carboxyl groups, or one amino- and one carboxyl 

F C0 2 H 

C0 2 H F 
II 



§4] 



STEREOCHEMISTRY OF DIPHENYL COMPOUNDS 



137 



group; the remaining groups may be any of those given in (i) [but not 
hydrogen]. Thus 6 : 6'-difluorodiphenic acid, II, is resolvable, and is readily 
racemised. 

(iii) Not racemisable at all. Diphenyl compounds which fall in this group 
are those which contain at least two nitro-groups ; the other groups can 
be any of those given in (i) — but not hydrogen — and (ii). Thus 2 : 2'- 
difluoro-6 : 6'-dinitrodiphenyl, III, is resolvable, and cannot be racemised. 

N0 2 F 

o-o 

F NO, 

III 

In addition to the size of the groups in the ortho-positions, the nature and 
position of other substituent groups also play a part in the rate of racemisa- 
tion, e.g., the rate of racemisation of IV is much slower than that of V 
(Adams et al., 1932, 1934). Thus the nitro-group in position 3' has a much 

N0 2 H 3 CO NOj; N0 2 H3CO 

C0 2 H C0 2 H N0 2 

IV V 

greater stabilising influence than in position 5'. The reason for this is un- 
certain, but one possible explanation is as follows. In VI, the methyl 
group of the methoxyl group is probably in the configuration shown. In 
VII, the nitro-group in the 3'-position would tend to force the methyl 
group away, the resulting configuration being somewhat as shown in VII; 



CH, 



NO, 



G 



/ 





C0 2 H 

VI 

in this condition there would be greater interference between the methoxyl 
group and the two groups in the other benzene ring. 

Adams et al. (1954, 1957) have examined the rate of racemisation of 
(VIII). The rate is increased when R is an electron-attracting group such 



PhS0 2 CH 2 C0 2 H 

\ N / 



PhS0 2 + / CH 2 C0 2 H 



PhS0 2v ^CH 2 C0 2 H 






+ N0 2 " 

IX 

as N0 2 or CN, and is decreased when R is an electron-releasing group such 
as Me or OMe. These results were explained as follows. With, e.g., 
R == N0 2 , (IX) contributes to the resonance hybrid as well as (VIII). 
The resonance hybrid therefore has increased C=N double bond character 



138 



ORGANIC CHEMISTRY 



[CH. V 

and consequently it is now easier for the molecule to pass through a planar 
transition state. With, e.g., R = Me, the C — N bond acquires far less 
double bond character than in its absence, and so it is more difficult for 
the molecule to pass through a planar transition state. 

Adams et al. (1957, 1961) also examined the optical stability of compounds 
of type X; they found that the half -life was in the following order for R: 
Me < Et < *'-Pr > M3u. If the effect of R were due merely to the in- 
ductive effect, then the unexpected value for 2-Bu cannot be explained on 
this basis. The authors have proposed the following explanation. The 
2-Bu group, because of its large bulk, displaces the adjacent Me groups out 
of the plane of the benzene ring, thereby causing molecular overcrowding; 
this decreases the interference to rotation about the N — C (ring) bond (§3a). 
A molecular model of this compound showed such an interference. Accord- 
ing to Bryan et al. (1960), it is possible that steric repulsion also operates 
to cause considerable angle distortion. 

§5. Evidence for the obstacle theory. Evidence for the obstacle theory, 
i.e., interference of groups, amounts to proving that the two benzene rings 
in optically active diphenyl compounds are not coplanar. A direct chemical 
proof for the non-coplanar configuration was given by Meisenheimer et al. 
(1927). The method was to unite the " obstacle groups " in optically active 
diphenyl compounds, thereby forming five- or six-membered rings. Now 
such systems are known to be planar, and hence optical activity should 
disappear; this was found to be so in practice. Meisenheimer started with 
2 : 2'-diamino-6 : 6'-dimethyldiphenyl, resolved it and then carried out the 
following reactions on one of the enantiomorphs : 



CH,IJ JNH-COCH, 




CH,-CO-NH 




CH, 



optically active 
form 



optically active 
I CO] 




. H s S0 4 



H0 2 Cl 



CH,CONH(i 



4nh-coch 3 



bC0 2 H 



optically inactive 



optically active 



In all the optically active compounds, the rings cannot be coplanar, since 
if they were, the molecules would possess a centre or plane of symmetry. 
If the dilactam, however, is not planar, then it would possess no elements 
of symmetry, and consequently would be optically active. If the dilactam 
is planar, then it has a centre of symmetry, and consequently cannot be 



§6] STEREOCHEMISTRY OF DIPHENYL COMPOUNDS 139 

optically active. This compound was, in fact, not optically active, and so 
must be planar. 

According to Dhar (1932), X-ray analysis studies have shown that in 
the solid state the diphenyl molecule is planar. On the other hand, accord- 
ing to Robertson (1961), who also examined crystalline diphenyl by X-ray 
analysis, the molecule is not strictly planar. This non-planarity has been 
attributed to steric repulsion between the o-hydrogen atoms. Gas phase 
electron-diffraction studies indicate that the two rings are inclined at about 
45° to one another (Brockway et ak, 1944; Bastiansen, 1949). In the solid 
state, crystal forces presumably tend to keep the diphenyl molecule almost 
planar. 

§6. STEREOCHEMISTRY OF THE ALLENES 

Allenes are compounds which have the general structure I. 

abC==C=Cde «6C=C=Ca6 

I II 

Examination of the space formula of compounds of this type shows that 
the molecule and its mirror image are not superimposable. The modern 
way of writing I is shown in Fig. 2. The two end carbon atoms are in a 
state of trigonal hybridisation, and the centre carbon atom is in the digonal 
state. Thus the centre carbon atom forms two jr-bonds which are per- 
pendicular to each other; in Fig. 2 the rc^-bond is perpendicular to the 

a — a 

Fig. 5.2. 

plane of the paper, and the 71,,-bond is in the plane of the paper. In the 
trigonal state, the si-bond is perpendicular to the plane containing the three 
(r-bonds (see Vol. I, Ch. II); consequently the groups a and b lie in the 
plane of the paper, and the groups d and e in the plane perpendicular to 
the plane of the paper. This molecule does not possess a plane or centre 
of symmetry; this is also true for molecule II. Thus I and II will be 
resolvable (see also §3. IV). 

The resolvability of allenes was predicted by van't Hoff in 1875, but 
experimental verification was not obtained until 1935, when Mills and 
Maitland carried out a catalytic asymmetric dehydration on <x : y-di-1- 
naphthyl-a : y-diphenylallyl alcohol, III, to give the dinaphthyldiphenyl- 




-HsO^ 




III IV 

allene, IV. When the dehydration was carried out with an optically in- 
active dehydrating catalyst, e.g., ^-toluenesulphonic acid, the racemic modi- 
fication of the allene derivative was obtained. When, however, the alcohol 



140 ORGANIC CHEMISTRY [CH. V 

III was boiled with a one per cent, benzene solution of (-(-)-camphorsulphonic 
acid, a dextrorotatory allene was obtained. Similarly, (— )-camphor- 
sulphonic acid gave a lsevorotatory allene. 

The first successful resolution of an allene derivative was carried out by 
Kohler et al., also in 1935. Lapworth and Wechsler (1910) prepared y-1- 

C 6 H 5 C 6 H 5 C 6 H 5 C 6 H 5 

G=C=C C=C=C 

1-C 10 H 7 / \C0 2 H 1-C 10 H 7 ^ ^CO-0-CH 2 -C0 2 H 

V VI 

naphthyl-a : y-diphenylallene-a-carboxylic acid, V, but failed to resolve it; 
they were unable to crystallise the salts with active bases. Kohler con- 
verted this acid into the glycollic acid ester, VI, and was then able to resolve 
VI by means of brucine. 

Landor et al. (1959) have prepared an optically active allene by a method 
which correlates it stereochemically with a tetrahedrally asymmetric alcohol. 
An optically active acetylenic alcohol, on treatment with thionyl chloride, 
gave an optically active allene; the mechanism is possibly S N i'. 



OH 

' son* 

(+)-CMe 3 -CMe-C=CH -^^ 



^-*- (+)-CMe 3 -CMe=C=CHCl 



CMe 3 - CMe^C^CH 



Landor et al. (1962) have also deduced the absolute configuration of the 
(+)-chloride by first determining the absolute configuration of the (+)- 
alcohol; the (R) -(— ) -alcohol gave the (S)-(— )-allene. 

Although allenes were not successfully resolved until 1935, compounds 
with a similar configuration were resolved as early as 1909. In this year, 

CH3 -.CH 2 'CH 2 JH 

ST ^CHs-CH^ ^COssH 

VII 

Pope et al. resolved l-methylcyc/ohexylidene-4-acetic acid, VII ; in this com- 
pound one of the double bonds of allene has been replaced by a six-membered 
ring, and the general shape of the allene molecule is retained. 

It is interesting to note, in connection with allenes, that the antibiotic 
mycomycin has been shown to contain the allene grouping. Mycomycin is 
optically active, and is the only known natural compound which owes its 
optical activity to the presence of this grouping. Celmer and Solomons 
(1953) have shown that the structure of mycomycin is: 

CH^C-(^-CH=C=CH-CH=CH-CH=CH-CH 2 -CO a H 



§7. STEREOCHEMISTRY OF THE SPIRANS 

If both double bonds in allene are replaced by ring systems, the resulting 
molecules are spirans. One method of naming spirans obtains the root 
name from the number of carbon atoms in the nucleus; this is then prefixed 
by the term " spiro ", and followed by numbers placed in square brackets 



§7] STEREOCHEMISTRY OF DIPHENYL COMPOUNDS 141 

which indicate the number of carbon atoms Joined to the " junction " 
carbon atom. The positions of substituents are indicated by numbers, the 

3 4 5 

CH 2 . ^-CH 2 ^ CH Z \- ^CH 2 — CH 2 6 

/C^i *c\ pc ":ch 2 

GKf N^H 2 x CHCr ^CH 2 -CHr 

1 8 7 

I II 

numbering beginning with the smaller ring and ending on the junction 
carbon atom; e.g., I is spiro-[2 : 2]-pentane, II is l-chlorospiro-[5 : 3]-nonane. 
Examination of these formulae shows that the two rings are perpendicular 
to each other, and hence suitable substitution will produce molecules with 
no elements of symmetry, thereby giving rise to optically active forms, 
e.g., Mills and Nodder (1920, 1921) resolved the dilactone of benzophenone- 
2 : 2' : 4 : 4'-tetracarboxylic acid, III. In this molecule the two shaded 



C0 2 H C0 2 Na 




Ott^C— ~b 

ii'li 1 ti 



J-''!'' 





portions are perpendicular to each other, and consequently there are no 
elements of symmetry. When this compound is treated with sodium 
hydroxide, the lactone rings are opened to form IV, and the optical rotation 
disappears. 

Boeseken et al. (1928) condensed penta-erythritol with pyruvic acid and 
obtained the spiro-compound V, which they resolved. Some other spiro- 

2CH 3 -CO-C0 2 H+C(CH 2 OH) 4 — >■ 

CH 3 ^ ^O-CH^ ^CH 2 -0^ C0 2 H 

H0 2 C' ^0-CH 2 -^ ^CH 2 -0^ C ^CH 3 

V 

compounds that have been resolved are the spiro-heptane, VI (Backer et al., 
1928, 1929), the spiro-hydantoin, VII (Pope and Whitworth, 1931), and the 
spiroheptane, VIII (Jansen and Pope, 1932). 

H0 2 C 

>; 



CH^ - 




Vv C0 2 H 


NH- 
| 


-CCk. .,NH- 
-NIT ^CO- 


-CO 

1 


CH^ 


CO- 


1 

-NH 


VI 








VII 




NH 2 


/ CH 2 


CH 
^ C ^CH 


'N 


,/ H 




^CH 2 


S ^NH 2 








VIII 









142 



ORGANIC CHEMISTRY 



[CH. V 



In all the cases so far discussed, the optical activity of the spiran is due 
to the asymmetry of the molecule as a whole; thus there is only one pair 
of enantiomorphs. If a spiro-compound also contains asymmetric carbon 
atoms, then the number of optically active forms is increased (above two), 
the actual number depending on the compound in question, e.g., Sutter 
and Wijkman (1935) prepared the spiro-compound IX, which contains two 
similar asymmetric carbon atoms (*). If we imagine the left-hand ring of 
IX to be horizontal, then the right-hand ring will be vertical; and if we 
represent them by bold horizontal and vertical lines, respectively, then 



H 

I* 
CH 3 -C— CH^ 



CO— O^ ^"0 



IX 



H 

U 

CHa-C-CHs 
CO 



H CH 3 CH 3 

|— |ch 3 |— |h rTH 

CH, CH, H 



X 



XI 



XII 



there are three different geometrical isomers possible, X, XI and XII (this 
can be readily demonstrated by means of models). Each of these geo- 
metrical isomers has no elements of symmetry, and so each can exist as a 
pair of enantiomorphs. Three racemic modifications were actually isolated 
by Sutter and Wiikman, but were not resolved. 

Cram et al. (1954) have also prepared the following three spiro [4 : 4] 
nonanediols (as racemates): 



OH 



OH^Xf/OH 




as-cts 



HO 
cis-trans 




HO 
trans-trans 



Various spiro-compounds have been prepared in which the spiro-atom is 
nitrogen (§2a. VI), phosphorus (§3b. VI), or arsenic (§4a. VI). 
A spiran compound, acorone, has now been found in nature (§28c. VIII). 



READING REFERENCES 

Stewart and Graham, Recent Advances in Organic Chemistry, Longmans, Green. Vol. Ill 

(1948, 7th ed.). Ch. 11. The Diphenyl Problem. 
Adams and Yuan, The Stereochemistry of Diphenyls and Analogous Compounds, 

Chem. Reviews, 1933, 12, 261. 
Gilman (Ed.), Advanced Organic Chemistry, Wiley (1943, 2nd ed.). Vol. I. Ch. 4, 

pp. 337-382. 
Crawford and Smyth, The Effect of Groups in Non-Blocking Positions on the Rate 

of Racemisation of Optically Active Diphenyls, Chem. and Ind., 1954, 346. 
Ann. Reports (Chem. Soc), Stereochemistry of Diphenyl Compounds, 1926, 23, 119; 

1931, 28, 394; 1932, 29, 69; 1935, 32, 246; 1939, 36, 2S5; 19S3, 50, 154; 1955, 52, 131. 
Klyne and de la Mare (Ed.), Progress in Stereochemistry, Butterworth. Vol. II (1958). 

Ch. I, p. 22. Molecular Overcrowding. 
Mislow et al., The Absolute Configuration of 6,6'-Dinitro-2,2'-diphenic Acid, /. Amer. 

Chem. Soc, 1958, 80, 465, 473, 476, 480. 



CHAPTER VI 

STEREOCHEMISTRY OF SOME ELEMENTS OTHER 
THAN CARBON 

§1. Shapes of molecules. Many elements other than carbon form com- 
pounds which exhibit optical isomerism. Since the criterion for optical 
activity must be satisfied, viz. the molecule must not be superimposable 
on its mirror image, it therefore follows that the configurations of the various 
molecules can never be planar. 

In Vol. I, Ch. II, the theory of shapes of molecules has been explained 
on the basis that all electrons (shared and unshared) in the valency shell 
of the central atom arrange themselves in pairs of opposite spin which 
keep as far apart as possible. Furthermore, it was assumed that deviations 
from regular shapes arise from electrostatic repulsions between electron 
pairs in the valency shell as follows: 

lone-pair — lone-pair > lone-pair — bond-pair > bond-pair — bond-pair. 

It was also assumed that a double (and triple) bond repels other bond-pairs 
more than does a single bond. The following two tables illustrate these 
ideas. 

Shapes of molecules containing single bonds 



Number of 

electrons 

in valency 

shell 


Number of 

bonding 

pairs 


Number 
of lone- 
pairs 


Hybrid 

orbitals 

used 


Shape of 
molecule 


Examples 


2 
3 

4 

5 
6 


2 
3 

4 
3 

2 
5 

6 






1 

2 





sp 
sp* 

sp* 
sp* 

sp 3 
sp*d 

spH* 


Linear 
Triangular 

plane 
Tetrahedron 
Trigonal 

pyramid 
V-shape 
Trigonal 

bipyramid 
Octahedron 


HgCl, 
BCl a 

CH 4 
NH, 

H a O 
PC1 6 

SF, 



When dealing with molecules containing multiple bonds (treated in terms 
of a- and ir-bonds), the shapes may also be predicted in a similar fashion 
if it is assumed that the electron-pairs (2 in a double and 3 in a triple bond) 
occupy only one of the positions in the various arrangements described in 
the above table, i.e., a multiple bond is treated as a " single " bond. This 
means that the shape of the molecule is determined by the number of a- 
bonds and lone-pairs only; the jr-bonds are " fitted in " afterwards (p. 144). 



§2. STEREOCHEMISTRY OF NITROGEN COMPOUNDS 

According to the electronic theory of valency, nitrogen can be tercovalent 
or quadricovalent unielectrovalent; in both of these states nitrogen, as the 
" central " atom, can exhibit optical activity. 

§2a. Quaternary ammonium salts. Originally, the valency of nitro- 
gen in quaternary ammonium salts was believed to be quinquevalent; later, 

143 



144 



ORGANIC CHEMISTRY [CH. VI 

Shapes of molecules containing multiple bonds 



Total number 

of o-bonds and 

lone-pairs 


Number 
of a- 
bonds 


Number 
of lone- 
pairs 


Shape of _ 
molecule : Examples 


2 
3 

4 


2 
3 

2 

4 
3 





1 


1 


Linear 

Triangular 
plane 

Triangular 
plane 

Tetrahedron 

Trigonal 
pyramid 


0=C=0; H— C=N 

°\s^° C1 \c/ C1 

II II 
o o 

oA<o ci/^Vo 

O OH CI 

X °=v 

or x OH X C1 

o^|\;i 

Cl 



however, it was shown that one valency was different from the other four. 
Thus, using the formula, [Uabcdj+X-, for quaternary ammonium salts, and 
assuming that the charge on the nitrogen atom has no effect on the con- 
figuration of the cation, the cation may be considered as a five-point system 
similar to that of carbon in compounds of the type Cabde. This similarity 
is based on the assumption that the four valencies in the ammonium ion 
are equivalent, and this assumption is well substantiated experimentally 
and also theoretically. Hence there are three possible configurations for 
the cation [Nabcd]+, I, II and III (cf. §3a. II). If the cation is planar (I), 



a 

I 
d— N— b 

I 
I— c 




II 




then it would not be resolvable; it would be resolvable, however, if the 
configuration is pyramidal (II) or tetrahedral (III). Le Bel (1891) claimed 
to have partially resolved wobutylethylmethylpropylammonium chloride, 
IV, by means of Penicillium glaucum (cf. §10 iii. II), but later work apparently 



CH 3 
I 



-i + 



CH 3 CH 2 CH 2 -N— CH 2 CH(CH 3 ) 2 Cf 

I 
C 2 H 5 

IV 

showed this was wrong. The first definite resolution of a quaternary am- 
monium salt was that of Pope and Peachey (1899), who resolved allyl- 
benzylmethylphenylammonium iodide, V, by means of (+)-bromocamphor- 
sulphonic acid. This was the first case of optical activity due to a " central " 



§2a] 



STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 

-1 + 



145 



CH 3 

CH 2 =CH- CH-r- N— CH 2 C 6 H 6 

I 
C 6 H 5 

V 

atom other than carbon. This resolution was then followed by the work 
of Jones (1905), who resolved benzylethylmethylphenylammonium iodide. 
Thus the ammonium ion cannot be planar, but must be either pyramidal or 
tetrahedral. Bischoff (1890) had proposed a pyramidal structure, and this 
configuration was supported by Jones (1905) and Jones and Dunlop (1912). 
On the other hand, Werner (1911) had suggested the tetrahedral configura- 
tion, and this was supported by Neagi (1919) and Mills and Warren (1925). 
It was, however, Mills and Warren who gave the most conclusive evidence 
that the configuration is tetrahedral. Their evidence is based on the follow- 
ing argument. Compounds of the type abC=C=Cab are resolvable since 
carbon is " tetrahedral " (see allenes, §6. V), and if nitrogen is also " tetra- 
hedral", then the compound a&C=:N=C«& should be resolvable, but will 
not be resolvable if the nitrogen is pyramidal. Mills and Warren prepared 
4-carbethoxy-4'-phenylbispiperidinium-l : l'-spiran bromide, and resolved 
it. If the configuration of this molecule is VI, i.e., a spiran, then it possesses 
no elements of symmetry, and hence will be resolvable; if the configuration 
is VII {i.e., pyramidal), then it will possess a vertical plane of symmetry, 



H CH 2 — CH 2 CH-CH 2 H 

/ C C ^ N \ ^ c C 

C 6 Hf CH 2 — CKf ^CH 2 — CHf ^C0 2 C 2 H 6 

VI 



Br 




C 6H 6 



CO2C2H5 



VII 



and hence will be optically inactive. Since the compound was resolved, 
the configuration must be tetrahedral, i.e., VI. This tetrahedral configura- 
tion has been confirmed by physico-chemical studies (see §2b). More 
recently, Hanby and Rydon (1945) have shown that the diquaternary salts 
of dimethylpiperazine exhibit geometrical isomerism, and this is readily 
explained on the tetrahedral configuration of the four nitrogen valencies 
(cf. cyclohexaxie, §11. IV). 



R 

CH 3 



CIL-CH, 



K. 



CH 2 -CH 2 



CIS 






ch 3 



++ 



R 



2 Br 



,CHr-CH 2 ^ ( j ,H 3"l ++ 



\, 



N 'N 

^° H - CH2 R 
trans 



2 Br 



146 



ORGANIC CHEMISTRY 



[CH. VI 

It has already been mentioned (§6. II) that McCasland and Proskow 
(1956) prepared a spiro-nitrogen compound which contained no plane or 
centre of symmetry, but was nevertheless optically inactive because it con- 
tained an alternating axis of symmetry. We shall now examine this com- 
pound (VIII; Y~ is the ^>-toluenesulphonate ion) in more detail. This 
molecule can exist in four diastereoisomeric forms, three active and one 




CH- 



■E* "EH "JP ,1= b 



VIII 



(+) (-) 

cis-cis 
IX 



(+) (-) 

cis-trans 

X 



jpa< a-q^ 3 ,py s ujp, 



(+) (-) 


meso 


trans-trans 


trans-trans 


XI 


XII 



meso. All four have been prepared, and are depicted as shown in IX, X, 
XI and XII. The co-axis of each spiran is assumed to be perpendicular 
to the plane of the paper, and the intersecting lines represent the two rings. 
The short appendages show whether the two substituents (methyl) are cis 
or trans. The ring nearer the observer's eye is indicated by the heavy line, 
and a uniform orientation has been adopted : the front ring is always vertical, 
and the back horizontal ring with at least one substituent directed upwards 
and the cis ring placed at the back in the case of the cis /trans ring com- 
bination. 

Racemisation of optically active quaternary ammonium salts is far more 
readily effected than that of carbon compounds containing an asymmetric 
carbon atom, i.e., compounds of the type Cabde. The mechanism of the 
racemisation of the ammonium salts is believed to take place by dissociation 
into the amine, which then rapidly racemises (§2c): 

Nabcd} +X- ^ N«Z>c + dX 

Recombination of the racemised amine with dX results in the racemisation 
of the quaternary compound (see §4a). 

§2b. Tertiary amine oxides. In tertiary amine oxides, aftcNO, the 
nitrogen atom is joined to four different groups, and on the basis that the 
configuration is tetrahedral, such compounds should be resolvable. In 



CH 3 
C 2 Hs-N->0 

C 6 H S 
I 




C.H.— N-K> 



CH 3 
II 




§2c] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 147 

1908, Meisenheimer resolved ethylmethylphenylamine oxide, I, and this 
was then followed by the resolution of other amine oxides, e.g., ethylmethyl- 
1-naphthylamine oxide, II, and kairoline oxide, III. 

The evidence in favour of the structure IV as opposed to that of V is 
based on dipole moment measurements and on the fact that such compounds 
can be resolved. It should be noted that the pyramidal structure would 

R 3 N— »-0 or R 3 N— 5 R 3 N=0 

IV V 

also account for the optical activity of these compounds as well as the 
tetrahedral. Consequently these compounds cannot be used as a criterion 
for the pyramidal or tetrahedral configuration of the nitrogen atom. How- 
ever, by analogy with the quaternary ammonium salts, the configuration 
of amine oxides may be accepted as tetrahedral. Further evidence for 
this is as follows. The electronic configuration of nitrogen is (ls 2 )(2s 2 )(2^> 3 ). 
For nitrogen to be quinquevalent, the " valence state " will be derived 
from the arrangement (ls 2 )(2s)(2^> 3 )(3s). Now the amount of energy re- 
quired to promote an electron from a 2s to a 3s orbital appears to be too 
large for it to occur, and consequently nitrogen is (apparently) never quinque- 
valent. The valence state of nitrogen is thus achieved by the loss of one 
2s electron and then hybridisation of the 2s and 2p 3 orbitals, i.e., nitrogen 
becomes quadricovalent unielectrovalent, and the four bonds (sp 3 bonds) 
are arranged tetrahedrally. The charged nitrogen atom is isoelectronic 
with carbon, and so one can expect the formation of similar bonds. Further- 
more, evidence obtained by an examination of the vibration frequencies of 
the ammonium ion indicates that the configuration of this ion is tetrahedral. 
Recently, Bennett and Glynn (1950) have obtained two geometrical iso- 
mers of 1 : 4-diphenylpiperazine dioxide; this is readily explained on the 
tetrahedral configuration of nitrogen (c/. §2a). 

*^CH 2 -CHf i i^-CHjs-CHf I 

C 6 H 6 

cis trans 

§2c. Amines. If the tertiary amine molecule, Nabc, is planar, it will 
be superimposable on its mirror image, and therefore cannot be optically 
active. All attempts to obtain tertiary amines in optically active forms 
have failed up to the present time, e.g., Kipping and Salway (1904) treated 
secondary amines, R-NH-R', with (±)-benzylmethylacetyl chloride; if the 
three valencies of the nitrogen atom are not planar, then the base will be 
a racemic modification, and on reaction with the acid chloride, the following 
four substituted amides should be formed: B + A + , B_A_, B + A_, B_A+, 
i.e., a mixture of two pairs of enantiomorphs. Experiments carried out 
with, e.g., methylaniline and benzylaniline gave homogeneous products. 
Meisenheimer et al. (1924) attempted to resolve iV-phenyl-2V-^-tolylanthranilic 
acid, I, and also failed. In view of these failures, it would thus appear that 

yCgHs 




148 ORGANIC CHEMISTRY [CH. VI 

the tertiary amine molecule is planar. Physico-chemical methods, e.g., 
dipole moment measurements, infra-red absorption spectra studies, etc., 
have, however, shown conclusively that the configuration of ammonia and 
of tertiary amines is tetrahedral. Thus ammonia has been shown to have 
a dipole moment of 1-5 D; had the molecule been planar, the dipole moment 
would have been zero. Furthermore, the nitrogen valency angles in, e.g., 
trimethylamine have been found to be 108°, thus again showing that the 
amine molecule is not planar. Why, then, cannot tertiary amines be re- 
solved? Is it a question of experimental technique, or is there something 
inherent in the tertiary amine molecule that makes it impossible to be 
resolved? Meisenheimer (1924) explained the failure to resolve as follows. 
In the tertiary amine molecule, the nitrogen atom oscillates rapidly at 
right angles above and below the plane containing the groups a, b and c 
(see Fig. 1) ; II and III are the two extreme forms, and they are mirror 



flk- 



images and not superimposable (IV is III " turned over", and it can be 
seen that IV is the mirror image of II). Thus this oscillation brings about 
very rapid optical inversion. This oscillation theory is supported by evi- 
dence obtained from the absorption spectrum of ammonia (Barker, 1929; 
Badger, 1930), and the frequency of the oscillation (and therefore the inver- 
sion) has been calculated to be 2-3 X 10 10 per second (Cleeton et al., 1934). 

In the foregoing explanation for the racemisation of amines, it has been 
assumed that the nitrogen valency angles and the bond lengths change. 
This inversion of amines, however, is better represented as an " umbrella " 
switch of bonds, i.e., the bond lengths remain unaltered and only the nitro- 
gen valency angles change. This interpretation is more in keeping with 
the facts, e.g., as the groups a, b and c increase in weight, the frequency of 
the inversion of the molecule decreases. 

Theoretical calculations have shown that an optically active compound 
will not racemise spontaneously provided that the energy of activation for 
the change of one enantiomorph into the other is greater than 12-15 kg.cal./ 
mole. The two forms, II and III, have been shown to be separated by an 
energy barrier of about 6 kg.cal./mole, and consequently the two forms are 
readily interconvertible. 

It has already been mentioned (§2b) that the electronic configuration of 
the nitrogen atom is (ls*)(2s 2 ){2p 3 ). According to Hund's rule, electrons 
tend to avoid being in the same orbital as far as possible (see Vol. I, Ch. II). 
Thus, in ammonia and its derivatives, bonds are formed by pairing with 
the three single orbitals 2p x , 2p v and 2p z . Since these are mutually at 
right angles, the configuration of the ammonia molecule will be a trigonal 
pyramid, i.e., a pyramid with a triangular base, with the nitrogen atom 
situated at one corner. Oscillation of the nitrogen atom brings about in- 
version in the tertiary amines, ~Nabc. This picture of the configuration of 
the ammonia molecule, however, requires modification. The valency angles 
in ammonia have been shown to be approximately 107°. The deviation 
from the value of 90° (on the assumption that the bonds are pure 2p orbitals) 
is too great to be accounted for by repulsion between the hydrogen atoms. 
As we have seen (§1), according to modern theory the orbitals in ammonia 




§2d] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 149 

are sp 3 , one orbital being occupied by the lone-pair. The deviation of the 
valency angle of 107° from the tetrahedral value of 109° 28' has been ex- 
plained by the greater repulsion between a lone-pair and a bond-pair than 
between a bond-pair and a bond-pair. 

In view of what has been said above, it appears that tertiary amines of 
the type Na&c will never be resolved. Now, Kincaid and Henriques (1940), 
on the basis of calculations of the energy of activation required for the 
inversion of the amine molecule, arrived at the conclusion that tertiary 
amines are incapable of resolution because of the ease of racemisation, but 
if the nitrogen atom formed a part of a ring system, then the compound 
would be sufficiently optically stable to be isolated. This prediction was 
confirmed by Prelog and Wieland (1944), who resolved Troger's base, V, 



CH, 



by chromatographic adsorption on D-lactose (cf. §10 vi. II). In this com- 
pound, the nitrogen is tervalent, but the frequency of osculation has been 
brought to zero by having the three valencies of nitrogen as part of the 
ring system. 

Roberts et at. (1958) have examined- iV-substituted ethyleneimines (see 
Vol. I) by NMR spectroscopy. Their results support the " umbrella " 
switch of bonds, and these authors believe that optical resolution of this 
type of compound may be possible below —50°. 

§2d. Oximes. In 1883, Goldschmidt found that benzil dioxime, 

C 6 H 6 -C(=NOH)-C(=NOH)-C 6 H 5 , 

could be converted into an isomeric form by boiling it in ethanolic solution; 
and then, in 1889, Meyer et al. isolated a third isomer of this compound. 
Beckmann, also in 1889, found that benzaldoxime existed in two isomeric 
forms, and from that time many aromatic oximes were shown to exist in 
two isomeric forms. The existence of isomerism in aromatic oximes was 
first explained by structural isomerism, two of the following four structures 
corresponding to the two isomers (where R is an alkyl or an aryl group) ; 
II is the modern way of writing the nitrone structure (originally, it was 



II 


Ar^ ^R 

II 


Ar 


— ,^R 

N=0 


Arv. .R 

l> 


oxime 


nitrone 








I 


II 




III 


IV 



written with quinquevalent nitrogen, the nitrogen being linked to the oxygen 
by a double bond). Hantzsch and Werner (1890), however, suggested that 
the isomerism of the oximes was geometrical and not structural. Accord- 
ing to these authors, nitrogen is tervalent (in oximes), and is situated at 
one corner of a tetrahedron with its three valencies directed towards the 
other three corners; consequently the three valencies are not coplanar (cf. 
tertiary amines). These authors also assumed that there is no free rotation 
about the C=N double bond (cf. §2. IV), and therefore proposed configura- 
tions V and VI for the two isomers: 



150 ORGANIC CHEMISTRY [CH. VI 

Ar^ ^R Arv. /R 

» ii 

V VI 

Many facts are in favour of geometrical isomerism, e.g., 

(i) If Ar = R, then isomerism disappears. 

(ii) III and IV would be optically active; this is not found to be so in 
practice. 

(iii) Absorption spectra measurements show that the two isomers have 
identical structures. 

As pointed out above, Hantzsch and Werner chose structure I as the 
formula for the oximes, but examination of II shows that this would also 
satisfy the requirements for geometrical isomerism; structure I was chosen 
because oximes were known to contain the group >C=NOH. Later work, 
however, has shown that the problem is not so simple as this; methylation 
of an oxime (with methyl sulphate) usually produces a mixture of two 
compounds, one of which is the O-methyl ether, VII, and the other the 
iV-methyl ether, VIII. These two are readily distinguished by the fact 

Ar.. Ar. CH 3 

^C=NOCH 3 ^C=1T 

BT R^ "^O 

VII VIII 

that on heating with hydriodic acid, VII gives methyl iodide, whereas VIII 
gives methylamine. Thus, Semper and Lichtenstadt (1918) obtained four 
methyl derivatives of phenyl ^>-tolyl ketoxime, IX-XIL On treatment 



'C e H 5 



*>-CH 3 -C 6 H 4 . .C 6 H 6 />-CH 3 -C 6 H 4 \ 



^OCH 3 CH 3 Cr 

IX X 



/.-CHsCeH^ ^C 6 H 5 p-CHj-C.H^ ^C^ 



3 kj w <jxa 3 



XI XII 



with concentrated hydriodic acid, two of these compounds gave methyl 
iodide, and therefore correspond to the O-methyl derivatives, IX and X; 
the other two compounds gave methylamine, and therefore correspond to 
the iV-methyl derivatives, XI and XII. Thus it appears that oximes can 
exist in forms I and II. Brady (1916) considered that oximes in solution 
are a tautomeric mixture of I and II {oximino-nitrone diad system). Ultra- 
violet absorption spectra studies show that the spectra of the oximes are 
the same as those of the O-methyl ethers, whereas those of the iV-methyl 
ethers are entirely different. Hence, if oximes are tautomeric mixtures of 
I and II, the equilibrium must lie almost completely on the oxime side, 
i.e., 



§2e] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 151 

Ar \ G /' 11 Ar \ G / R ^c^* Ar \ c /R 

II =^~ II and II ^~ II 

^OH H^ ^O HO^ O^ ^H 

It is possible, however, that none of the nitrone form is present, but its 
methyl derivative is formed during the process of methylation . If we assume 
that methyl sulphate provides methyl carbonium ions, then it is possible 
that these ions attack the nitrogen atom (with its lone-pair) or the oxygen 
atom (with its two lone-pairs). This would result in the formation of the 
N- and O-methyl ethers, without having to postulate the existence of the 
oximino-nitrone tautomeric system. 

CRgQ)- SOjj-OCHg — *-CH£ + -0-S0 2 -OCH 3 

Ar \ c / R Ar \ c / R + Al \ c ^ U 



| + CHS 



J. 



Nj— H CH<" ^(P-H CH^ "N) 



Ar \ c / R Ar \ c / R Ar \ c / R 



+ CH 3 + - 



-H + 



>(}— H ^CP-H ^OCH 3 

CH, 

In the foregoing account, the geometrical isomerism of the oximes is based 
on the assumption that the nitrogen atom, in the oximino-form, exhibits the 
trigonal pyramidal configuration. Further proof for this configuration is 
obtained from the examination of the oxime of cycfohexanone-4-carboxylic 
acid (XHIa or b). If the three nitrogen valencies are non-planar (i.e., the 

H CH^-CH, OH H GHrCH^ 

H0 2 CT ^CHg-CHg H0 2 Cr ^CHg-CH^ 

XHIa XIII6 

N — O bond is not collinear with the C=N double bond), the configuration 
is XHIa, and it will therefore be optically active. If, however, the three 
nitrogen valencies are coplanar and symmetrically placed, then the con- 
figuration will be XIII&, and this will not be optically active, since it possesses 
a plane of symmetry. Mills and Bain (1910) prepared this oxime and re- 
solved it; hence its configuration must be Xllla. This is readily explained 
on the modern theory of valency (§2c). 

§2e. Nomenclature of the oximes. In oxime chemistry the terms syn 
and anti are used instead of the terms cis and trans. When dealing with 
aldoximes, the syw-form is the one in which both the hydrogen atom and 
the hydroxyl group are on the same side; when these groups are on opposite 
sides, the configuration is anti. Thus I is syn- and II is awfo-benzaldoxime. 
With ketoximes, the prefix indicates the spatial relationship between the 



152 



Co Hi 



*\rt/ 



H 



ORGANIC CHEMISTRY 

C 6 H 5 \ JR /»-CH 3 -C 6 H 4X 

o c 



[CH. VI 



'Q»Hi 



'6*1-5 



N 

I 

syn 



^OH 



HO^" 



N 
II 



anti 



HO 



III 



first group named and the hydroxyl group (cf. §4. IV). Thus III may be 
named as syn-p-tolyl phenyl ketoxime or awfo'-phenyl ^>-tolyl ketoxime. 

§2f. Determination of the configuration of aldoximes. As we have 
seen, aromatic aldoximes can be obtained in two geometrical isomeric forms, 
the syn and the anti. Aliphatic aldoximes, however, appear to occur in 
one form only, and this is, apparently, the anti-iorm. The problem, then, 
with aromatic aldoximes, is to assign configurations to the stereoisomeric 
forms. The two forms (of a given aldoxime) resemble each other in many 
ways, but differ very much in the behaviour of their acetyl derivatives 
towards aqueous sodium carbonate. The acetyl derivative of one isomer 
regenerates the aldoxime; this form is known as the a-isomer. The other 
isomer, however, eliminates a molecule of acetic acid to form an aryl cyanide ; 
this form is known as the /5-isomer. Hantzsch and Werner (1890) suggested 
that the /3-form readily eliminates acetic acid because the hydrogen atom 
and the acetoxy-group are close together, i.e., the /9-isomer is the syn-form. 
Such a view, however, is contrary to many experimental results (cf. §5 xi. IV), 
i.e., the experimental results are: 



*v* 



Ar, 



N-OCOCH 3 

syn- 

H 



Ar x M 

k 



Na ' co ». II +CH 3 -C0 2 H 



^-OH 



Ar 



Na a CO, 

>- 



CH 3 -COON 

anti- 



C + CH 3 -C0 2 H 

n 



Brady and Bishop (1925) found that only one of the two isomers of 
2-chloro-5-nitrobenzaldoxime readily gave ring closure on treatment with 



2 N 




NaOll 



O.N 




2 N 




0,N 



0,N 



Na 2 C0 3 




STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 



153 



§2g] 

sodium hydroxide. It therefore follows that this form is the anti-isomer 
(cf. method of cyclisation, §5 i. IV). It was also found that it was this 
isomer that gave the cyanide on treatment with acetic anhydride followed 
by aqueous sodium carbonate. Thus awfe'-elimination must have occurred, 
i.e., the /?-isomer is the anti-form. These reactions may be formulated as 
shown at foot of previous page. 

Actually, the ring compound produced, the 5-nitrobenzwo-oxazole, is 
unstable, and rearranges to nitrosalicylonitrile. 

In a similar manner, Meisenheimer (1932) found that of the two isomeric 
2 : 6-dichloro-3-nitrobenzaldoximes, it was the awfo'-isomer that gave ring 
closure, and was also the one that gave the cyanide. Hence, if anti- 
elimination is used as the criterion for these reactions, the configurations 



cr — >- 






Nu 2 COj 




of the syn- and anti-ioxms can be determined. It might be noted here, 
in passing, that since the sy«-form was originally believed to form the 
cyanide, the configurations of the isomers in the literature up to 1925 
(i.e., before Brady's work) are the reverse of those accepted now. 

§2g. Determination of the configuration of ketoximes. The con- 
figurations of ketoximes have been mainly determined by means of the 
Beckmann rearrangement (1886). Aromatic ketoximes, i.e., ketoximes 
containing at least one aromatic group, occur in two forms; aliphatic 
ketoximes appear to occur in one form only. When treated with certain 
acidic reagents such as sulphuric acid, acid chlorides, acid anhydrides, 
phosphorus pentachloride, etc., ketoximes undergo a molecular rearrange- 
ment, resulting in the formation of an acid amide: 



Ar x 



Ar' 



0=NOH -> Ar-CONHAr 



This rearrangement is known as the Beckmann rearrangement or Beckmann 
transformation. The best method is to treat an ethereal solution of the 
oxime with phosphorus pentachloride at a temperature below —20°. On 
the other hand, Horning et al. (1952) have found that a very good method 
for effecting the Beckmann rearrangement is to heat the oxime in poly- 
phosphoric acid at 95° to 130°. 

Hantzsch (1891) suggested that the course of the rearrangement indicated 



154 



ORGANIC CHEMISTRY 



[CH. VI 



the configuration of the oxime, and assumed that the sy«-exchange of groups 
occurred since they were closer together in this isomer. This, again, was 
shown experimentally to be the reverse, i.e., it is the «»&'-rearrangement 
that occurs, and not the syn; thus: 



Ar V/ R 



N N 



MDH 






•N 



AC 



°V* 



NHAr 



Ar ^/ E 



/N 



HCK 



Ar v -OH 



*L 



^R 



A N/-° 
i 

NHR 



Meisenheimer (1921) subjected triphenyh'so-oxazole, I, to ozonolysis, and 
thereby obtained the benzoyl-derivative of anfc'-phenyl benzil monoxime, II. 
This configuration is based on the reasonable assumption that the ozonolysis 
proceeds without any change in configuration. Furthermore, the monoxime 
designated the /S-isomer gave II on benzoylation, and so the configuration 



C 6 H 5 -C 

■N. 



X 0^ 



C'GeHj; ozonolysis C 6 H B -C- 
II - I 

c-c 6 h 6 K 



■ C-C 6 H 5 CpH 5 coci C 6H 5 "C- 



O 
"0-COC 6 H 5 

II 



ijiii 



N 



-OC 6 H 5 
II 
O 



III 



of the /?-isomer, III, is determined. Meisenheimer then subjected this 
/}-oxime (i.e., the anti-phenyl oxime) to the Beckmann rearrangement, and 
obtained the anilide of benzoylformic acid, IV; thus the exchange of groups 



C 6 H 5 -C-CO-C 6 H 5 pc. 



III 



^OH 



O=C-CO0 6 H 6 
NHC 6 H 5 

IV 



must occur in the awfo'-position. The configuration of the /?-monoxime, III, 
is confirmed by the fact that it may be obtained directly by the ozonolysis 
of 3 : 4-diphenyhso-oxazole-5-carboxylic acid, V (Kohler, 1924). Meisen- 
heimer et al. (1925) also demonstrated the awfo'-rearrangement as follows. 

C 6 H 5 -C CC 9 H S ozonolysis C 6 H 5 -C-COC„H 5 

II II —+■ 

N ^CC0 2 H & 

V III 

The a-oxime of 2-bromo-5-nitroacetophenone is unaffected by sodium 
hydroxide, whereas the /f-isomer undergoes ring closure to form 3-methyl-5- 
nitrobenzt'so-oxazole; thus the a-oxime is the sytt-methyl isomer VI, and 
the /?-oxime the antf-methyl isomer VII. When treated with sulphuric 
acid or phosphorus pentachloride, the oc-oxime underwent the Beckmann 



§2g] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 156 

rearrangement to give the iST-substituted acetamide; thus the exchange 
occurs in the tfn*i-positions. 



Q 2 Ni 




2 N 




HO-^ 



VII 




NaOH 



OoN 




Further evidence for the ««fo'-exchange of groups in the Beckmann re- 
arrangement has been obtained by studying the behaviour of compounds 
exhibiting restricted rotation about a single bond, e.g., Meisenheimer et al, 
(1932) prepared the two isomeric oximes of l-acetyl-2-hydroxynaphthalene- 
3-carboxylic acid, VIII and IX, and of these two forms only one was re- 
solvable. This resolvable isomer must therefore be IX, since asymmetry 

^ H » /OH 



C6 



OH 
iCOsH 




VIII 



IX 



due to restricted rotation is possible only with this form (c/. §3. V). Meisen- 
heimer found that the ethyl ester of IX, on undergoing the Beckmann 
rearrangement, gave the amide Ar'CONH>CH a (where Ar is the naphthalene 
part of the molecule), whereas the ethyl ester of VIII gave the amide 
CH 3 *CO'NH'Ar. These results are in agreement with the awfo-exchange 
of groups in each case. 

Thus the evidence is all in favour of the awfo'-exchange of groups in the 
Beckmann rearrangement, and hence by using this principle, the Beckmann 
rearrangement may be used to determine the configuration of ketoximes. 

An interesting application of the Beckmann rearrangement is in the 
formation of heterocyclic rings, e.g., when cyc/opentanonoxime is subjected 
to the Beckmann rearrangement, the nitrogen atom enters the ring (thus 
producing ring expansion) to form 2-piperidone (see also §2h). 



CH,- 



CH* 



-CH 2 
,CH 2 



H,so 4 



CH 2 CH 2 

i I 

N CH 2 



CHo CHo 

II 

NH _CH 2 
^•CO 



NOH 



OH 



156 ORGANIC CHEMISTRY [CH. VI 

On the other hand, Hill et al. (1956) have shown that the oximes of some 
spiro-ketones undergo abnormal Beckmann rearrangements in the presence 
of polyphosphoric acid, e.g., spiro-[4 : 4]-nonanone-l-oxime gives hydrind- 
8 : 9-en-4-one: 




NOH 




Although aliphatic ketoximes are not known in two isomeric forms, some 
may produce two products when subjected to the Beckmann rearrangement, 
e.g., the oxime of pentan-2-one gives iV-propylacetamide and iV-methyl- 
butyramide. The reason for this is uncertain; possibly oximes of this type 
are actually a mixture of the two forms ; or alternatively, they exist in one 

CH«\ pcu 

^C=NOH -^^*- 

CH3* CH2" CI12 

CH 3 -CONH-CH 2 -CH 2 -CH 3 + CH 3 -CH 2 -CH 2 -CO-NH-CH 3 

stable form which, during the Beckmann rearrangement, is partially con- 
verted into the labile form which then undergoes the rearrangement (cf. 
benzaldoxime, below). 

Whereas the majority of ketoximes undergo the Beckmann rearrangement, 
it appears that few aldoximes do so. In an attempt to prepare quinoline 
by the dehydration of cinnamaldoxime with phosphorus pentoxide, Bam- 
berger and Goldsehmidt (1894) actually obtained woquinoline; the formation 
of the latter compound and not the former can only be reasonably explained 
on the assumption that the oxime first undergoes the Beckmann rearrange- 
ment, and the rearranged product then undergoes ring closure to form iso- 
quinoline. Recently, Horning et al. (1952) have shown that aldoximes can 



-h 2 o 



be made to undergo the Beckmann rearrangement under the influence of 
polyphosphoric acid, e.g., sy«-benzaldoxime gives a mixture of formanilide 
and benzamide, the latter being produced by the conversion of the syn- 

C 6 H— C-H ^C 6 H 5 -NH-CHO+ C 6 H 5 CONH 2 

syn -isomer 






C fi H 5 -C— H 



N 



HO' 



anti- isomer 



-*-C 6 H 5 -CO-NH 2 



form into the anti; a«ft'-benzaldoxime gives benzamide only. These results 
are in agreement with the configurations obtained by other methods (see 
§2f). 



§2h] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 157 

§2h. Mechanism of the Beckmann rearrangement. This rearrange- 
ment is an example of the 1,2-shift in which the migration origin is carbon 
and the migration terminus is nitrogen (see also 1,2-shifts, Vol. I, Ch. V). 
As we have seen above (§2g), an integral part of the rearrangement is the 
anti migration of the group. Since the oxime itself does not rearrange, it 
is reasonable to suppose that some intermediate is formed between the 
oxime and the reagent used to effect the rearrangement, and it is this inter- 
mediate which then rearranges. Kuhara et M. (1914, 1916) prepared the 
benzenesulphonate of benzophenone oxime and showed that this readily 
underwent rearrangement in neutral solvents in the absence of any acid 
catalyst to give an isomeric compound which, on hydrolysis, gave benzanilide 
and benzenesulphonic acid; thus: 

Ph Ph Ph-CONHPh 

Ph-C=N -> Ph-C=N *2*$. + 



OSO.-Ph OSO.-Ph Ph-SO,H 



Kuhara assigned structure I to this intermediate on the fact that its absorp- 
tion spectrum was almost identical with that of the compound prepared 
by reaction between iV-phenylbenzimidoyl chloride and silver benzene- 
sulphonate: 

Ph-CCl=NPh + AgOSCyPh -► I + AgCl 

Kuhara (1926) also showed that the rate of rearrangement of the benzo- 
phenone oxime ester is faster the stronger the acid used to form the ester; 
the order obtained was: 

Ph-S0 3 H > CH 2 C1-C0 2 H > Ph-C0 2 H > Me-C0 2 H 

Chapman (1934) showed that the rate of rearrangement of benzophenone 
oxime picryl ester is faster in polar than in non-polar solvents. Thus the 
work of Kuhara and Chapman is strong evidence that the rate-determining 
step in the rearrangement is the ionisation of the intermediate. 

Now let us consider the migration of the R or Ar group. This could be 
either intermolecular or intramolecular, but Kenyon et al. have shown it 
to be the latter; e.g., in 1946, Kenyon et al. showed that when (+)-a-phenyl- 
ethyl methyl ketoxime is treated with sulphuric acid the product, 2V-<x- 
phenylethylacetamide, is almost 100 per cent, optically pure. Thus the 
migrating group never separates during the rearrangement, since if it did 
a racemised product would have been obtained. Furthermore, this retention 
of optical activity might be cited as evidence for the formation of a bridged- 
ion during the migration, since in such an ion the migrating group is not 
free and the " new partial " bond is formed on the same side as the bond 
which is breaking (see below). 

PhMeCH-C-Me w ao 0=C-Me 

II -^> I 

NOH HN-CHMePh 

Another problem that arises here is: Does the anion separate completely 
during the ionisation or does it also migrate intramolecularly? The work 
of Kuhara and Chapman strongly suggests corhplete separation, and this 
is supported by the work of Brodskii et al. (1941), who found that when 
benzophenone oxime was treated with phosphorus pentachloride and then 
with water enriched with the isotope 18 0, the benzanilide obtained con- 
tained some of this isotope. Thus the oxygen atom of the oxime group 



158 ORGANIC CHEMISTRY [CH. VI 

must have been completely removed in the ionisation stage (see below). 
The following mechanism is in agreement with all of the above facts (Y is 
PC1 4 , MeCO, etc.); the lower set of equations is the alternative route via 



Ml 






y 



R' 



R 



/* 



YO 

\ 



+ OY" 



/*' 



H.O 



R 



/ 



V R ' 

- I 

NHR 



R> 



R' 

I 
-C 

III 
--N 



+ OY" 



V 0Y 



R 



/ 



N 



a bridged-ion. It might also be noted that when acid is used as the re- 
arranging reagent, OY is probably OH 2 +. Support for this mechanism is 
the evidence obtained for the intermediate formation of the imidoyl ester 
(RN = CR-OY) ; compound II was obtained by Heard el al. (1959), who 
examined the rearrangement of a 17-keto-16-oxime (a steroid; Ch. XI): 




yys 



OAc 






OAo 



It has been shown that when the migrating group is aryl, the rate of the 
rearrangement is accelerated when there is an electron-releasing group, 
e.g., Me, in the ^-position. This may be cited as evidence to support the 
formation of a bridged-ion (at least for migrating aryl groups). 

On the basis of the above mechanism, we can now explain Brodskii's 
results as follows: 



Ph .Ph 

V 



OPCh 




+ 0PC1 4 " 



Ph V ora < 



JH.O 



Ph x OH 2 
Pli 


Ph\ .OH 

C^ 


PhOONHPh 


1 

PhCONHPh 



Stephen et al. (1956) have shown that one molecule of phosphorus penta- 
chloride, phosphoryl chloride, thionyl chloride, or benzenesulphonyl chloride 
rearranges two molecules of the ketoxime to yield the corresponding amide 
and imidoyl chloride in approximately equimolecular amounts, e.g., 

2R a C=NOH + PCI. -> R-CO-NH-R + R-CC1=N-R + POCl 8 + HC1 

It has also been shown that hydrogen chloride is essential during the re- 
arrangement, but that it does not itself cause the rearrangement of the 



§2i] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 159 

oxime. On the basis of these results, Stephen et al. have proposed the 
following mechanism for the Beckmann rearrangement of ketoximes. The 
reagent first produces some acid amide and imidoyl chloride, and the latter 
then dehydrates unchanged ketoxime to the anhydride which then reacts 
as shown: 



2R 2 C=NOH 



-HjO 



(R 2 C=N— ) 2 

anhydride 



HC1. 



R\ 



CR 2 
N 



cr 



-HCl 



RC 

► II 
RN 



£p* 



.0. 



RC 

II 
RN 



CR 

II 
NR 



HCl 



anhydride salt 



RCC1 0=CR 

- II + I 
RN NHR 



-R 



ketoxime imidate 



It is also suggested that other reagents which effect the Beckmann rearrange- 
ment may function as dehydrating agents for the formation of the ketoxime 
anhydride. 

When a trace of the reagent is used, a large yield of amide is obtained. 
The mechanism is believed to be the same as that given above, provided 
that in the initial stage there is sufficient to form a trace of the ketoxime 
anhydride in the presence of hydrogen chloride. Rearrangement of the 
anhydride will now take place as above with the formation of the imidoyl 
chloride which can then dehydrate ketoxime to anhydride, itself being 
converted into the amide: 

2R a C=NOH + R-CC1=N-R— > (R a C=N— ) a O + R-CONH-R + HCl 

Thus the yield of amide increases at the expense of the imidoyl chloride. 
It can be seen from the foregoing account that two mechanisms appear 
possible for the Beckmann rearrangement. Both are intramolecular, but 
now an intermolecular mechanism has also been proposed by Hill et al. 
(1962) who have reported an example in which the migrating group had the 
inverted configuration in the amide. These authors examined the rearrange- 
ment of 9-acetyl-m-decalin oxime and have suggested the following mechan- 
ism: 

^OH Me X( J^0H; Me-03 mO 0V» 







-H,0 



The authors identified methyl cyanide as a product of the reaction of III 
with phosphorus pentachloride, and also showed that methyl cyanide and 
m-/S-decalol in sulphuric acid gave IV. 

§2i. Stereoisomerism of some other tervalent nitrogen compounds 
containing a double bond. There are several other types of compounds 
besides the oximes in which the nitrogen atom is linked by a double bond. 
The other atom joined by this double bond may be a carbon atom (as in 
the oximes), or another nitrogen atom, and in both cases stereoisomerism is 
possible; e.g., Krause (1890) obtained two isomeric forms of the phenyl- 
hydrazone of o-nitrophenylglyoxylic acid, I, and Hopper (1925) isolated two 



160 ORGANIC CHEMISTRY [CH. VI 

N0 2 



II 
N-NH-C 6 H 5 


C 6 H 5 -C-CO-C 6 H 5 
N-NH-CO-NH 


I 


II 


H0 2 C^ ^CHaCHa^ 


^COC 6 H 5 



III 

isomers of the monosemicarbazone of benzil, II. Mills and Bain (1914) 
resolved III; this is resolvable because of the non-planar configuration of 
the three nitrogen valencies (cf. the oximes, §2d). Karabatsos et al. (1962) 
have examined the NMR spectra of a number of ketone dinitrophenyl- 
hydrazones and semicarbazones, and have distinguished between the syn- 
and anti-forms, and have also calculated the amounts of each in solution. 
Phillips (1958) had already examined aldoximes by means of their NMR 
spectra. 

Many cases of geometrical isomerism are known in which the two forms 
are due to the presence of a nitrogen-nitrogen double bond. Examples of 
this type which have been most extensively studied are the diazoates, IV, 
the diazosulphonates, V, and the diazocyanides, VI (see Vol. I, Ch. XXIV, 
for an account of these compounds). 

II II II 

.N' N N 

NaCT ^S0 3 K ^CN 

IV V VI 

syn-form own -form and- form 

Azobenzene is also an example of this type, and according to Hartley (1938), 
" ordinary " azobenzene is the anti-iorm. 

II II 

CeH 5 C 6 H 5 

syn-azobenzene <z«tt'-azobenzene 

m.p. 71 -4" m.p. 68° 

Azoxybenzene (in which one nitrogen atom is tercovalent and the other 
quadricovalent) also exists in two geometrical isomeric forms, the anti- 
isomer being " ordinary " azoxybenzene. 

C 6 H b ^ n C « H «^ N 

II II 

C 6 Hf ^O O^ ^C 6 H 6 

syn -azoxybenzene owtt'-azoxybenzene 

m.p. 86° m.p. 36° 



§3a] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 161 

Recently, Le Fevre et al. (1951) have measured the dipole moments and the 
ultraviolet absorption spectra of a number of triazens, and have concluded 
that these compounds exist in the ara&'-configuration about the nitrogen- 
nitrogen double bond, i.e., the configuration is: 



E, 



II 

^NH-R 

These authors also believe that this anti-form is converted into an equili- 
brium mixture of the anti- and sy w-forms when exposed to sunlight. 

Harley-Mason et al. (1961) have offered evidence to show that they have 
isolated the three theoretically possible geometrical isomers of o-nitroaceto- 
phenone azine (Ar = o-N0 2 C 6 H 4 -) : 

Me. /Ar Ai\ Ms A\ /Me 

Y Y 



*r 



N N .N 



A X 

Ar/ N Me Ar^^Me Me/\A.r 

Their evidence was based on infra-red, ultraviolet and NMR spectra. This 
compound appears to be the first example of the isolation and characterisa- 
tion of all three possible geometrical isomers of an azine. 



§3. STEREOCHEMISTRY OF PHOSPHORUS COMPOUNDS 

Nitrogen, as we have seen, can exhibit covalencies of 3 and 4; phosphorus 
(and arsenic), however, can exhibit covalencies of 3, 4, 5 and 6, and con- 
sequently gives rise to more possible configurations than nitrogen. In 
tercovalent compounds the valency disposition is tetrahedral (sp 3 ), one 
orbital being occupied by a lone-pair; and in quinquevalent compounds 
the valency disposition is trigonal bipyramidal (sp 3 d). In quadricovalent 
unielectrovalent compounds one electron is transferred from the phosphorus 
or arsenic atom to the anion and the valency disposition is tetrahedral 
(sp 3 ) (see also §4b). When there are double bonds present, one is a a- and 
the other is a jr-bond; thus, in POCl 3 , the shape is tetrahedral (see also §1). 

§3a. Tercovalent phosphorus compounds. Since the electronic con- 
figuration of phosphorus is (ls 8 )(2s 2 )(2^«)(3s !! )(3^ 8 ), it might be expected 
that suitable tercovalent compounds, R 3 P, could be resolved, since the 
configuration would be a trigonal pyramid (cf. §2c). No tertiary phosphines, 
however, have yet been resolved, and the reason for this appears to be the 
same as for tertiary amines, viz., that the phosphorus atom is in a state of 
oscillation. Calculation has shown that the frequency of this oscillation in 
phosphine is 5 x 10* ; this is slower than that of nitrogen (2-3 X 10 10 ), 
and if it could be brought to zero, then tertiary phosphines would be re- 
solvable. Increasing the weight of the groups slows down the oscillation 
in phosphorus compounds, e.g., replacement of the three hydrogen atoms 
by deuterium atoms changes the frequency to 6 x 10 s . It seems possible, 
therefore, that very large groups might produce phosphines which would be 
resolvable; and if not zero in these compounds, the oscillation certainly 
can be expected to be zero in ring compounds (cf. nitrogen, §2c). Thus, if 
chemical difficulties can be overcome, tercovalent phosphorus compounds 
would be resolvable (see also §4c.) 



162 ORGANIC CHEMISTRY [CH. VI 

§3b. Quadricovalent and quinquevalent phosphorus compounds. 

The earliest phosphorus compounds to be resolved were the phosphine 
oxides, e.g., Meisenheimer et al. (1911) resolved ethylmethylphenylphosphine 

CH 3 QH 3 

I I 

C 6 H 5 — P=0 C 6 H 5 — P = 

C 2 H 6 OH 2 -C 6 H 5 

I II 

oxide, I, and benzylmethylphenylphosphine oxide, II. Recent measure- 
ments of the P — (and As — O) bond length indicate that this bond is a 
double bond. 

Some phosphine oxides that have been resolved recently are: 

Me OEt 

I 
0=P— C 6 H 4 -NMe 3 (p) }I- Et— P=0 



I. 



OMe SH 

(McEwen et al., 1956) (Aaron et al., 1958) 

Kipping (1911) obtained two optically active forms of the 2V-(— )-menthyl 
derivative of 2-naphthylphenylphosphoramidic acid, III, and Davies and 
Mann (1944) resolved M-butylphenyl-/)-carboxymethoxyphenylphosphine 
sulphide, IV. 

NH-C 10 H 19 (-) C 6 H 6 



C 6 H 5 0— P=0 

O'C 10 H 7 (2) 


^-COijH-CHjOCjH— P=S 

I 


1 
CH 2*CH2*CH 2 " CH 


III 


IV 



Michalski et al. (1959) have prepared the phosphorus sulphenyl chloride, 
(EtO)EtP(=0)-SCl, in its (+)- and (— )-forms, and Green et al. (1961) have 
partially resolved phenylethylphosphinothiolic acid, PhEtP(=0)*SH. 

Another interesting phosphorus compound from the point of view of 
optical isomerism is ethyl triphenylmethylpyrophosphonate, V. If the two 
phosphorus atoms are asymmetric, then V contains two similar asymmetric 
carbon atoms, and so its structure corresponds to the molecule Cabd-Cabd. 

OC 2 H 5 OC 2 H 5 

(C 6 H 5 ) S Q— P— O— P— C(C 6 H 5 ) 3 

II " II 

o o 

V 

Thus there will be one racemic modification (composed of the pair of enantio- 
morphs) and one meso-iorm (cf. §7d. II). Hatt (1933) obtained two forms 
of compound V; both were inactive and so correspond to the racemic modi- 
fication and the meso-iorm., but it was not possible to tell which was which. 
Many attempts have been made to resolve quaternary phosphonium 
compounds, but until recently, all these attempts failed. This failure is 
attributed to the occurrence in solution of a " dissociation-equilibrium ", 
which causes very rapid racemisation (see §4a). 

labcdF]+X- ^ abcV + dX 

The earlier attempts to resolve phosphonium compounds were always carried 



§4] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 163 

out on compounds containing at least one alkyl group; consequently dis- 
sociation in solution could occur, thereby resulting in racemisation. Holli- 
man and Mann (1947) overcame this difficulty by preparing a much more 
stable type of phosphonium compound; these workers prepared a salt in 
which the phosphorus atom was in a ring, viz., 2-phenyl-2-^-hydroxyphenyl- 
1:2:3: 4-tetrahydro-wophosphinoliniurn bromide, VI, and resolved it. 

^ + 

CH i /P Nj g HiOH( /> ). 

VI 

The resolution of 3-covalent compounds of phosphorus does not prove that 
the phosphorus atom has a tetrahedral configuration; it only proves that 
the phosphorus atom cannot be in the same plane as the other four groups 



Br" 




VII 

attached to it. Mann et al. (1955), however, have now synthesised P-spiro- 
bis-1 : 2 : 3 : 4-tetrahydrophosphinoliniUm iodide (VII) and resolved it into 
(+)- and (— )-forms which have high optical stability. The phosphorus 
atom is not asymmetric in this compound; it is the tetrahedral disposition 
of the four valencies which produces the dissymmetric cation (c/. nitrogen, 
§2a; see also §4b). 

Campbell et al. (1960) have prepared a series of azaphosphaphenanthrene 
(IX; e.g., R = H, R' = NMe 2 ), but could not resolve them. When the 




HN— P 




HN— P=0 




phosphine IX was oxidised with hydrogen peroxide, the phosphine oxide 
obtained, X, was resolved. Reduction of the (+)-oxide with lithium alu- 
minium hydride gave the (— )-phosphine IX, and in the same way the 
reduction of the (—) -oxide gave the (+)-phosphine IX. It is not certain 
whether the optical activity in IX is due to an asymmetric tervalent phos- 
phorus atom or to a rigid puckering of the molecular framework. 



§4. STEREOCHEMISTRY OF ARSENIC COMPOUNDS 

Arsenic, like phosphorus, can exhibit covalencies of 3, 4, 5 and 6; con- 
sequently these two elements show a great similarity to each other, and 
differ from nitrogen which has a maximum covalency of 4. 



164 ORGANIC CHEMISTRY [CH. VI 

§4a. Quadricovalent and quinquevalent arsenic compounds. The 

first resolution of an arsonium compound was carried out by Burrows and 
Turner (1921). These workers obtained a solution of benzylmethyl-1- 



CH, 



CzHg 



1-C 



1 1 + 

H 7 — As— CeH I 



I-C10H7 



f 



CH2 - C 6 H 5 
I 



-As— CH 2 -CH 2 -CH 3 f I 

I 
CH^'CgHs 

II 



naphthylphenylarsonium iodide, I, that had a rotation of +12°, but race- 
mised rapidly (in solution). Similarly, Kamai (1933) isolated the (-f)-form 
of benzylethyl-1-naphthyl-w-propylarsonium iodide, II, which also racemised 
rapidly in solution. This rapid racemisation is believed to be due to a 
" dissociation-equilibrium " in solution. This explanation was suggested 
by Pope and Harvey (1901) to account for the racemisation of certain 
ammonium salts, but definite evidence for this theory was provided by 
Burrows and Turner (1921) in their work on arsonium salts. If this dis- 
sociation-equilibrium occurs, then in solution there will be: 

[abcdAs] + I~ ^ abcAs + dl 
Burrows and Turner showed that when dimethylphenylarsine is treated 
with ethyl iodide, the expected ethyldimethylphenylarsonium iodide is 



CH 3 

I 
CHj— As + C 2 H S I 

CeH 5 



CH 3 
CHr-As-C 2 H 5 
C 6 H 6 



CH 3 

As— C 2 H 5 + CH3I 

C «H 6 



CH 3 

CHj-As + CH3I 

I 
C6H5 



CH 3 

CH 3 -As— CH 3 
I 



obtained, but at the same time a considerable amount of trimethylphenyl- 
arsonium iodide is also formed. These results are readily explained by the 
dissociation-equilibrium theory. 

Since all the arsonium compounds investigated contained at least one 
alkyl group, Holliman and Mann (1943) prepared an arsonium compound 
with the arsenic atom in a ring, in the hope of stabilising the compound 
(cf. phosphorus, §3b). These authors prepared 2-^>-chlorophenacyl-2-phenyl- 
1:2:3: 4-tetrahydro-woarsinolinium bromide, III, resolved it, and found 
that it did not racemise in solution at room temperature. 




CH. 



VH* 



.CJI S 



Cir^ 8 ^CH 2 -C0-C 6 H 4 -C1(^) 



III 



Br" 



Although phosphine oxides of the type abcVO have been resolved (§3b), 
similar arsine oxides have not ; the reason for this is obscure. On the other 
hand, arsine sulphides have been resolved, e.g., Mills and Raper (1925) 
resolved ^-carboxyphenylmethylethylarsine sulphide, IV. 



§4b] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 165 



CH 3 



C 2 H S — As=S 




CH. CH 2 -CH 2 -CH 2 -CH 3 

Clfc-As^CgHs r -i- 

| * 0-C 6 H 2 (N0 2 ) 3 

CIV-A^-C 6 H 5 u -'t 

CB.{ ^C^-CHaCHij-CHa 

V 



C 6 H5 /CHj-CHg-CHg-CH, 
CH^A8=S 

CH 2 -As=S 
CjHj^ ^CH 2 OH 2 -CH 2 -CH 3 

VI 



C e H s /CHg-CHa-CHisCHs 

| ^PdCl 2 

CH 2 — Aa ^ 

C 6 H^ X CH 2 CH 2 CH 2 -CH 3 
VII 



Chatt and Mann (1939) prepared ethylene-1 : 2-bis(M-butylmethylphenyl- 
arsonium) picrate, V, ethylene-1 : 2-bis(»-butylphenylarsine sulphide), VI, 
and ethylene-1 : 2-bis(»-butylphenylarsine)-dichloropalladium, VII, and 
obtained each compound in two forms. Each of these compounds is of 
the type Cabd'Cabd, and hence each should exist in one racemic modification 
and one weso-form (cf. §7d. II). As has already been stated, two forms of 
each were isolated; both were inactive, but the authors had no evidence 
for deciding which was which. 

It has already been pointed out above that Holliman and Mann prepared 



► Br" 





VIII 



the optically stable arsonium compound III. These authors, in 1945, also 
resolved an arsonium compound of the spiran type, viz., As-spiro-bis- 
1:2:3: 4-tetrahydro-isoarsinolinium bromide, VIII. This does not con- 
tain an asymmetric arsenic atom; the optical activity is due to the asym- 
metry of the molecule (the two rings are perpendicular to each other), and 
this is evidence that the four valencies of arsenic are arranged tetrahedrally 
(see also §4b). Mann et al. (1960) have also resolved compound IX. 

§4b. Tercovalent arsenic compounds. The electronic configuration 
of arsenic is (ls 2 )(2s 2 )(2p< i )(3s 2 )(3p< i )(3d 10 )(4s i )(4p 3 ). Thus the configuration 
of tercovalent arsenic compounds will be a trigonal pyramid (cf. phosphorus, 



166 



ORGANIC CHEMISTRY 



[CH. VI 



§3a). Physico-chemical evidence (X-ray analysis, spectroscopy and electron 
diffraction) has shown that in tercovalent compounds the arsenic atom is 
at the apex of a tetrahedron, and that the intervalency angle is 100 ± 4°. 
It has also been shown that the arsenic is in a state of oscillation, the fre- 
quency of this oscillation through the plane of the three hydrogen atoms 
in arsine being 16 x 10 4 . This is slower than that of phosphorus (5 x 10*), 
and very much slower than that of nitrogen (2-3 X 10 10 ). Thus, preventing 
the oscillation of the arsenic atom, possibly by attachment to very large 
groups, should lead to the isolation of optically active tercovalent com- 
pounds. So far, however, all attempts to resolve compounds of the type 
Asdbc have failed (cf. nitrogen and phosphorus). On the other hand, terco- 
valent arsenic compounds in which arsenic has two of its valencies occupied 
in a ring compound have been resolved; the ring structure prevents oscilla- 
tion of the arsenic atom (cf. Troger's base, §2c). Thus Lesslie and Turner 
(1934) resolved 10-methylphenoxarsine-2-carboxylic acid, I. These authors 
suggested that the assymetry of the molecule is due to the presence of a 
folded structure about the — As axis, as well as the asymmetry due to the 
presence of an asymmetric arsenic atom (see structure II). This molecule 




C0 2 H CH 




CO,H 




CH 3 C 2 H 5 



II 



I" 



III 



and its mirror image are not superimposable. It might be noted, however, 
that the position of the methyl group with respect to the O — As axis is 
uncertain (cf. the arsanthrens, below). This folded structure is reasonable 
in view of the fact that the valency angle of oxygen is also approximately 
104°; if the molecule were planar, then the valency angles of both arsenic 
and oxygen would be in the region of 120°, which is a very large increase 
from the normal valency angle. When each enantiomorph of II is treated 
with ethyl iodide, the same racemised product is obtained. This is due to 
the fact that when the arsonium compound, III, is formed, the asymmetric 
quaternary arsenic atom is racemised owing to the dissociation-equilibrium. 

X) v . . .0. 




C0 2 H 




CO,H 



as 
<f X C 6 H 5 



Lesslie and Turner (1936) also resolved 10-phenylphenoxarsine-2-car- 
boxylic acid, IV. This compound was very stable, and oxidation to the 
arsine oxide, V, gave a completely racemised product. 

Campbell et at. (1956) have resolved some substituted 9-arsafiuorenes, 
e.g., 9-/>-carboxyphenyl-2-methoxy-9-arsafluorene (V«). Campbell (1956) 
has also resolved 2^>-carboxyphenyl-5-methyl-l : 3-dithia-2-arsaindane (Vb). 
This compound is optically stable in chloroform solution, but is racemised 
in aqueous sodium hydroxide. Campbell believes that this racemisation is 
due to the fission of the As— S bonds by aqueous alkali, and subsequent 
reversal of the reaction by acid, a type of behaviour observed in triaryl 



§4b] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 167 




OCH, 



CH, 




Sv 



O 



CO2H 



Vb 



COjH 



thioarsenites (Klement et al., 1938). Furthermore, Cohen et al. (1931) have 
shown that in sodium hydroxide solution, alkyl thioarsenites exist in equi- 
librium with thiol and arsenoxide: 



R-As 



/ 



SR' 



OH 



OH" / 

+ 2H a O »5==^ R-As 

\ H+ \ 

SR' OH 



+ 2R'SH 



Chatt and Mann (1940) prepared 5 : 10-di-/>-tolyl-5 : 10-dihydroarsanthren, 
and pointed out that if the valency angle of arsenic remains constant at its 
normal angle (of approximately 100°), then the structure will be folded, 
and consequently the three geometrical isomers, VI, VII and VIII, are 
apparently possible (T represents the ^-tolyl group). Chatt and Mann also 






VII 



VIII 



pointed out that evidence obtained from models constructed to scale showed 
that the two ^>-tolyl radicals (T) in VIII would almost be coincident, and 
hence this isomer cannot exist. These authors isolated two optically in- 
active forms, but were unable to say which was which. When each com- 
pound was treated with bromine, both gave the same tetrabromide which, 
on hydrolysis, gave only one tetrahydroxide. The loss of isomerism in the 
tetrabromide (and in the tetrahydroxide) may be explained as follows. 
Bromination of VI and VII converts tercovalent arsenic into quinque- 
covalent arsenic, and in the latter state the ring valency angles of the arsenic 
become 120°, and so the arsanthren nucleus is now planar. Thus both the 




forms VI and VII would give the same tetrabromide, IX (the same is true 
for the tetrahydroxide) ; the tetrabromide should thus be planar, the con- 
figuration of each arsenic atom being trigonal bipyramidal in the 5-covalent 
state (Fig. 2). 



168 ORGANIC CHEMISTRY [CH. VI 

Quinquevalent phosphorus and arsenic can make use of the 3d or Ad 
orbitals, respectively (cf. nitrogen, §2b). Thus nitrogen has a maximum 
covalency of 4, whereas that of phosphorus and arsenic is 5 or 6, e.g., the 
covalency of 6 is exhibited by phosphorus in solid phosphorus pentachloride ; 
X-ray diffraction shows this " molecule " (in the solid state) is PC1 4 + PC1 6 ~. 



Phosphorus, which is (Is 2 ) (2s 2 ) (2p*) (3s 2 ) (3p s ) in the ground state, may 
become (ls 2 )(2s i )(2p s ){3s)(3p 3 )(3d) in its '* valence state ", since the 3s and 
3d orbitals have energy levels which are close together. Kimball (1940) 
showed, by calculation, that this arrangement, i.e., sp s d, could give rise to 
the stable trigonal bipyramidal configuration. This consists of three equi- 
valent coplanar orbitals pointing towards the corners of an equilateral 
triangle, and two orbitals perpendicular to this plane (see Fig. 2) . Electron 
diffraction studies of the vapours of phosphorus pentachloride and penta- 
fluoride indicate the trigonal bipyramidal configuration in these molecules. 
The phosphonium ion might possibly be formed from this trigonal bipyramid 
by the transference of one of the electrons, or by the transference of a 3s 
electron and hybridisation of the (3s)(3p 3 ) orbitals; in either case the tetra- 
hedral configuration of the phosphonium ion can be asymmetric, but only 
in the case of the hybridisation of the (3s)(3p s ) orbitals will the four bonds 
be equivalent. Since the properties of phosphonium compounds are in 
agreement with the equivalence of the four bonds, it therefore appears, 
on theoretical grounds, that the tetrahedral configuration with the phos- 
phorus atom at the centre is the probable one. 

From the experimental side, the preparation of optically active spiro- 
compounds of phosphorus (§3b) and of arsenic (§4a) proves the tetrahedral 
configuration of these atoms. Earlier work by Mann et al. (1936, 1937) 
has also definitely established this configuration. These authors prepared 
compounds of the type [R 3 As — Cul] 4 by combination of tertiary arsines or 
phosphines with cuprous iodide (or silver iodide) ; in these compounds the 
phosphorus or arsenic is 4-covalent, and X-ray analysis studies of the arsenic 
compound showed that the arsenic atom is at the centre of a tetrahedron. 
Since the corresponding phosphorus compounds are isomorphous, the con- 
figuration of the phosphorus is also tetrahedral. 

In the solid state, phosphorus and arsenic compounds may contain a 
negatively charged phosphorus or arsenic atom, e.g., PC1 4 + PC1 6 ~ (see above). 
In this condition, the phosphorus acquires an electron to become 

— (3s)(3^)(3i 2 ), 

and the arsenic also acquires an electron to become — -(As)(Ap s )(Ad z ). In 
both cases the configuration is octahedral (six sp s d 2 bonds), e.g., the follow- 
ing compound has been resolved (Rosenheim et al., 1925). 




§5a] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 169 

Harris et al. (1956) have shown that a negatively charged phosphorus 
atom can also exist in solution ; these authors showed that triphenyl phosphite 
dibromide ionises in methyl cyanide solution as follows: 

2P(OPh) 3 Br 2 ^[P(OPh) 3 Br] + + [P(OFh) t BrJ- 

§4c. Stereochemistry of antimony compounds. Some optically active 
tervalent antimony compounds have been prepared, the phenoxstibine (I) 
and the stibiafiuorene (II; Campbell, 1947, 1950). The asymmetry in I is 
probably due to the folding about the — Sb axis (cf. phenoxarsines, §4b). 
Campbell et al. (1958) have also resolved the stibine (III). 



CO.H 




H0 2 C 



It is of interest to note, in this connection, that calculations by Weston 
(1954) have led him to the conclusion that tervalent antimony, arsenic and 
sulphur compounds should be stable to inversion at room temperature. On 
the other hand, similar compounds of phosphorus would be optically stable 
only at low temperatures, and those of nitrogen not at all. 

§5. STEREOCHEMISTRY OF SULPHUR COMPOUNDS 

Various types of sulphur compounds have been obtained in optically 
active forms, and although the general picture of the configurations of these 
molecules is quite clear, the details of the nature of the bonds of the central 
sulphur atom are in a state of flux (see §5e). 

§5a. Sulphonium salts. Pope and Peachey (1900) prepared carboxy- 
methylethylmethylsulphonium bromide by the reaction between ethyl 
methyl sulphide and bromoacetic acid, and formulated the reaction as 
follows: 

At this time (before the electronic theory of valency, 1916), sulphur was 
believed to be quadricovalent, and so Pope and Peachey accounted for the 
optical activity of this compound (see below) by assuming that the sulphur 
atom was at the centre of a tetrahedron, i.e., the configuration was similar 
to carbon. According to the electronic theory of valency, however, sulphur 



170 



ORGANIC CHEMISTRY 



[CH. VI 



is tercovalent unielectrovalent in sulphonium salts, and the valency dis- 
position is (s£ 8 ), one orbital being occupied by a lone-pair of electrons 
(Fig. 3). This molecule is not superimposable on its mirror image, and 
hence can, at least theoretically, exist in two optically active forms. This 
bromide was treated with silver (+)-camphorsulphonate and the salt 



A 

/ ' \ 

/ ' v 

/ ' s 

' ' J \ 

CH 3 ^V-- -^CH 2 C0 2 H 

C 2 H 5 

Fig. 6.3. 

obtained was fractionally crystallised from a mixture of ethanol and ether. 
Pope and Peachey found that the (+)-sulphonium camphorsulphonate was 
the less soluble fraction, and had an M D of +68°. Since the rotation of 
the (+)-camphorsulphonate ion is about +52°, this leaves +16 as the 
contribution of the sulphonium ion to the total rotation (see §12. I). Al- 
though this does not prove conclusively that the sulphur compound is 
optically active, it is certainly strong evidence in its favour. Final proof 
was obtained by replacement of the camphorsulphonate ion by the platini- 
chloride ion to give [CH 3 (C 2 H 6 )-S-CH 4 -CO a H] s +PtCl,= ; this compound had 
an [a] D of +4-5° in water. In a similar way, Smiles (1900) prepared ethyl- 
methylphenacylsulphonium picrate, I, in two optically active forms, one 



CH$v 
AHf 



S— CH,j-CO-C 6 H 5 



I 



2 N| 




with an [<x] D of +8-1° and the other -9-2°. A more recent example of 
an optically active sulphonium salt is one with the sulphur atom in a ring; 
this compound, II, was obtained as the optically active ion with the picrate 
Mann and Holliman, 1946). 




CH, 



CH5 



/8-CH2-CO-CeH 4 Cl(/)) 



/' 



Br 



II 



§5b. Sulphlnic esters. Phillips (1925) partially resolved sulphimc esters, 
R-S0 8 R', by means of the kinetic method of resolution (§10 vii. II). Two 
molecules of ethyl ^-toluenesulphinate were heated with one molecule of 
(— )-menthyl alcohol or (— )-sec.-octyl alcohol, i.e., the sulphinate was sub- 
jected to alcoholysis. Now, if the sulphinate is a racemic modification, 
then the (+)- and (— )- forms will react at different rates with the optically 
active alcohol (see §§2, 7b. II). Phillips actually found that the (+)-ester 
reacted faster than the (— )-ester. If we represent the ester by E, the 
alcohol by A, and unchanged ester by E r , then the following equation 
symbolises the alcoholysis: 
(+)E + (-)E + (-)A-* [(+)E( _ )A] + [( _ )E( _ )A] + (+)Er + (_ )Er 



§5c] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 171 

Since [(+)E(— )A] is greater than [(— )E(— )A], it therefore follows that 
(+)E r is less than (— )E r ; thus a partial resolution has occurred. The un- 
changed ester, having a lower boiling point than the new ester, distilled off 
first ; this contained more of the (— )-form. The residual ester (the higher 
boiling fraction) was then heated with a large excess of ethanol; ajcoholysis 
again occurred, this time the (— )-alcohol (menthol or octyl) being displaced 
to regenerate the original ethyl *-toluenesulphinate. This resulted in a 
fraction containing more of the (+)-form. 

To account for the optical activity of these sulphinates, the older formula I, 
with quadricovalent sulphur linked to the oxygen atom by a double bond, 
was replaced by formula II, in which the sulphur atom is at the centre of 
the tetrahedron, but one corner is occupied by a lone-pair of electrons 



C 6 H 4 -CH,(/>) 



,S 



C.H5O- 



S 



o 



CjHsO^^Ce^-CH,^) 
O 

II 



(cf. Fig. 3). In I, the sulphur atom was considered to be at the centre of 
a tetrahedron, and the molecule is flat, and consequently is superimposable 
on its mirror image. Molecule II, however, is asymmetric, and so is optically 
active. Recent evidence, however, is now in favour of structure I, and the 
molecule is not flat (see §5e). The formulae of sulphoxides, etc., will there- 
fore be written with double bonds. 

§5c. Sulphoxides. Sulphoxides of the type R-SOR' have also been 
resolved; sulphoxides I and II were resolved by Phillips et al. (1926), and 
Karrer et al. (1951) obtained III in the (— )-form and the racemic modifica- 
tion. 



C0 2 H 




H 2 N 



S=0 



CH 




s=o 



CHf=CH-CH^ 



CH 3 

S = 



III 



Bell and Bennett (1927) investigated disulphoxides of the type 
CHs-SOCHa-CHjj-SOCHs. 
This molecule contains two similar asymmetric carbon atoms and so is of 
the type Cabd'Cabd. Thus it should exist in one racemic modification and 
one meso-iona. Bell and Bennett failed to resolve this compound, but 
succeeded in resolving the following disulphoxide. 

C0 2 H 



CH 3 — S 




S — CH, 



O O 

If the former disulphoxide (the dioxide of a 1 : 4-dithian) is converted 



172 ORGANIC CHEMISTRY [CH. VI 

into the corresponding ring compound (i.e., into a cyclic 1 : 4-dithian), then 
two geometrical isomers are possible, neither of which is resolvable; these 
two forms have been isolated by Bell and Bennett (1927, 1929). Shearer 
(1959) has examined the trans-ioim by X-ray analysis and showed that the 
ring is in the chair form with the S=0 in trans and axial positions. 



O 



// 



,CH 2 — CIL 

S 
CH— CH 2 > 



O 



O 



^CH 2 CH 2 ^ ^ 
^ ^CH 2 — CHf' 



O 



as 



X 2 <^X1 2 

trans 



Thianthren dioxide, IV, also exists in two geometrical isomeric forms, 
a, m.p. 284°, fi = 1-7 D; and p\ m.p. 249°, fi = 4-2 D (Bergmann et al., 
1932). On the basis of these dipole moments, Bergmann assigned the 
^raws-configuration to the a-form and the cw-connguration to the /?-form. 
Hosoya et al. (1957) have examined the a-form by X-ray analysis and showed 
it was boat-shaped (only this part of the molecule is shown in the diagrams), 
with the molecule folded along the S — S axis [cf. the dithian dioxides above). 
These authors also showed that this a-form has the awft'-«'s-configuration 




^ 



O 



°"\^ 



cc-form 



^ 



O 



S" 



p-form 



of the two S=0 bonds. The j9-form is therefore assumed to be a trans- 
form. Thus the configurations are the reverse of those given by Bergmann. 
When either of these disulphoxides is oxidised to the disulphone, both give 
the same compound (Hosoya, 1958). 

It is of interest to note, in connection with optically active sulphoxides, 
that Schmid and Karrer (1948) have isolated sulphoraphen from its glycoside 
which occurs in radish seed. These authors showed that sulphoraphen is 
a lsevorotatory oil which owes its optical activity to the presence of a 
sulphoxide group. 

CH 3 -SO-CH=CH-CH 2 -CH 2 -NCS 
sulphoraphen 



§5d. Sulphilimines. 

sulphilimines, e.g., 



Chloramine T reacts with alkyl sulphides to form 



C0 2 H 



CH 3 <^^-S(Vn' + :S 



CH 



o~ 



■SOg-N- 




+ NaCl 



§6] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 173 

The electronic structure of this molecule appears to be uncertain; one 
possibility has been given above, and in this one the sulphur atom is asym- 
metric (it is of the type that occurs in the sulphonium salts). An alter- 
native electronic structure is: 



C0 2 H 



CH 3 ^_\— S0 2 -N=S 




In this structure, the sulphur atom can still be asymmetric (see §5e). This 
sulphilimine has been resolved by Kenyon et al. (1927). 

It seems likely that sulphilimines are resonance hybrids of the above 
two contributing structures. 

§5e. The valency disposition of the sulphur atom. The electronic 
configuration of sulphur is (ls 2 )(2s 2 )(2/> 6 )(3s 2 )(3/> 4 ). As we have seen, the 
older formulae (Ha) and (Ilia) for sulphoxides and sulphinic esters were 
replaced by Phillips by (II) and (III) respectively. However, in the light 
of more recent work, these compounds are now believed to contain double 
bonds, e.g., the length of the S — O bond in sulphoxides and sulphones is 
shorter than the single S— O bond. 

R 3 SJX~ R 2 S— **0 Jl — S— OR' 

Y 
I II O 

III 

R 2 S=0 R— S— OR' 

II 
11a O 

Ilia 

It has already been pointed out that these multiple bond formulae were 
rejected on the grounds that such molecules, on the assumption that the 
sulphur atom was quadrivalent and at the centre of a tetrahedron, would 
be flat and hence not optically active. If we consider the shapes of opti- 
cally active sulphur compounds from the point of view of the ideas dis- 
cussed in §1, then in the formulas (I), (Ila) and (Ilia), the sulphur atom 
has one lone-pair of electrons (these are not shown in the formulae), three a- 
and one jr-bond. Thus the bond spatial arrangement will be tetrahedral, 
the lone-pair occupying one of these orbitals. Consequently each molecule 
will be a trigonal pyramid and is not superimposable on its mirror image 
when all three groups are different. It might be noted here that the double 
bonds are composed of one a- and one d„-fi„ bond. In these compounds the 
d orbitals are produced by promotion of one 3s and one 3p electron to 3d; 
this is possible because of the small energy differences between the orbitals 
concerned. In sulphonium salts, since only three single bonds and one 
lone-pair are present, the hybridisation is sp 3 (tetrahedral); one electron 
has been transferred to the halogen atom, thereby producing the positively 
charged sulphonium ion. 

§6. Stereochemistry of silicon compounds. Kipping (1907) prepared 
benzylethylpropylsilicyl oxide, I, and isolated one form of it. If the silicon 
atom has a tetrahedral configuration, this molecule is of the type Cabd'Cabd, 



174 



ORGANIC CHEMISTRY 

•^""^CHj-Si— O— Si — CH, 

«-C 3 H 7 ^C 3 H 7 -k 

I 



[CH. VI 



_ C 2 Hr c 2 h 5 ^ 

HOaS^^CHg-^Si— O— Si^-CHa^^SOaH 



»-C 3 H 7 C 3 H 7 -« 

II 



C 2 H 5 CH, 

Si 
/ \ 
«-C 3 H 7 CH 

III 



o 

i<f^Vo 3 H 



*'.«., it should exist in (+)-, (— )- and meso-forms. When I was sulphonated 
to give II, the latter compound was resolved. Challenger and Kipping 
(1910) also resolved the silane III, and Eaborn et al. (1958) have resolved 
the silane IV. 

C,H K 

H0 2 C 




§7. Stereochemistry of tin compounds. Pope and Peachey (1900) 
obtained ethylmethyl-»-propylstannonium iodide in the dextrorotatory 
form; concentration of the mother liquor also gave this (+)-form. Thus 
we have an example of asymmetric transformation (§10 iv. II). 

CKL ,C 2 H 6 



w-C 3 H 7 



1 



§8. Stereochemistry of germanium compounds. Schwarz and 
Lewinsohn (1931) obtained the (+)-form of ethylphenyltso-propylgermanium 
bromide, but failed to get the (— )-form; this latter form appears to racemise 
in the mother liquor. 

(CH 3 ) a CH yC s H 5 

X 

C 2 H/ x Br 

§9. Stereochemistry of selenium compounds. Pope et al. (1902) re- 
solved carboxymethylmethylphenylselenonium bromide in the same way 
as the corresponding sulphonium salts (§5a); they obtained the active 
platinichloride. 

r ~~l + 

^Se-CHjj-COjjH PtCl„ 
C 6 H 6 



175 



§10] STEREOCHEMISTRY OF SOME ELEMENTS OTHER THAN CARBON 

Mann et al. (1945) also resolved the following selenonium salt: 

CH Z 
X CH 2 ^^ 

^e— OHjj-CO— < ^y > 

So far, attempts to resolve selenoxides have failed. 

§10. Stereochemistry of tellurium compounds. Lowry et al. (1929) 
obtained the optically active forms of methylphenyl-^-tolyltelluronium 
iodide, I, and Mann et al. (1945) have resolved II. 





CH,<C^ 



CH 3 

Te: 
I 




,Te-CH 2 CO-C 6 H 4 Cl (/>) } Br" 



II 



READING REFERENCES 

Gilman (Ed.), Advanced Organic Chemistry, Wiley (1943, 2nd ed.). Ch. 4, pp. 400-443. 

Optical Isomerism of Elements other than Carbon. 
Dickens and Linnett, Electron Correlation and Chemical Consequences, Quart. Reviews 

{Chem. Soc), 1957, 11, 291. 
Gillespie and Nyholm, Inorganic Stereochemistry, Quart. Reviews {Chem. Soc), 1957, 

11, 339. 
Organic Reactions, Wiley. Vol. 11 (1960). Ch. 1. The Beckmann Rearrangement. 
Mann, The Heterocyclic Derivatives of P, As, Sb, Bi, and Si, Interscience Publishers 

(1950). 
Campbell and Way, Synthesis and Stereochemistry of Heterocyclic Phosphorus Com- 
pounds, J.C.S., I960, 5034. 
Abrahams, The Stereochemistry of Sub-group VIB of the Periodic Table, Quart. Reviews 

(Chem. Soc), 1956, 10, 407. 
McCasland and Proskow, Synthesis of an Image-Superposable Molecule which Contains 

no Plane or Centre of Symmetry, /. Amer. Chem. Soc, 1956, 78, 5646. 
Klyne and de la Mare (Ed.), Progress in Stereochemistry, Butterworth. Vol. II (1958). 

Ch. 6. The Stereochemistry of the Group V Elements. 



CHAPTER VII 

CARBOHYDRATES 

This chapter is mainly concerned with the stereochemistry of the carbo- 
hydrates and the structures of the disaccharides and polysaccharides. It 
is assumed that the reader is familiar with the open-chain structures and 
general reactions of the monosaccharides (for an elementary account of 
these compounds, see Vol. I, Ch. XVIII). 

§1. DETERMINATION OF THE CONFIGURATION OF 
THE MONOSACCHARIDES 

Aldotrioses. There is only one aldotriose, and that is glyceraldehyde. 
As we have seen (§5. II), the enantiomorphs of this compound have been 
chosen as the arbitrary standards for the d- and l- series in sugar chemistry : 



CHO 



H- 



CHO 



-OH 



HO- 



-H 



0H 2 OH 
D (+) -glyceraldehyde 



CH 2 OH 
L(— ) -glycera] dehy de 



The conventional planar diagrams of the sugars are always drawn with 
the CHO (or CH a OH-CO) group at the top and the CH 2 OH group at the 
bottom; the following short-hand notation is also used: 

CHO O CHO 





D-series L-series 

Aldotetroses. The structural formula of the aldotetroses is 
CH 2 OH-CHOH-CHOH-CHO. 
Since this contains two unlike asymmetric carbon atoms, there are four 

CHO 



0O 2 H 



-H- 
CHO 



-OH-, 



CH 2 OH 



CHO 



H- 
H- 



-OH H- 

, ,[0] 

-OH H- 



-OH 
-OH 



HO- 
H- 



-H HO- 

[QI 
-OH H- 



COjH CH 2 OH 

meso-tartaric D(— )-erythroae 
aoid I 



CH 2 OH 
D(-)-threose 
II 



176 



C0 2 H 
-H 
-OH 



C0 2 H 

L(— ) -tartaric 
acid 



§1] 



CARBOHYDRATES 



177 



optically active forms (two pairs of enantiomorphs) possible theoretically. 
All four are known, and correspond to D- and L-threose and D- and L-eryth- 
rose. D(+)-Glyceraldehyde may be stepped up by the Kiliani reaction to 
give d(— )-erythrose and d(— )-threose. The question now is: Which is 
which? On oxidation, D-erythrose gives mesota.rta.ric, and on reduction 
gives mesoerythritol. Therefore D-erythrose is I, and consequently II must 
be D-threose. The configuration of the latter is confirmed by the fact that 
on oxidation, D-threose gives l(— )-tartaric acid. 

Aldopentoses. These have the structural formula 

CHO-CHOH-CHOH-CHOH-CH 2 OH, 

and since it contains three unlike asymmetric carbon atoms, there are eight 
optically active forms (four pairs of enantiomorphs). All are known, *and 
correspond to the d- and L-forms of ribose, arabinose, xylose and lyxose. 
Their configurations may be ascertained by either of the following two 
methods. 



r 



D-erythrose 



1 



CHO 



CHO 



H- 
H- 
H- 



-OH HO- 
-OH H- 
-OH H- 



CH 2 OH 
D(— )-ribose 
III 



r D-threose — n 
II I 

CHO CHO 



-H H- 

-OH HO- 
-OH H- 



DH 



CH 2 OH 
arabinose 
IV 



-OH HO- 
-H HO- 
-OH H- 



-H 
-H 
-OH 



CH 2 OH 

D(+)-xylose 
V 



CH 2 OH 

D(— )-]yxose 
VI 



One method starts by stepping up the aldotetroses by the Kiliani reaction. 
Thus D-erythrose gives d(— )-ribose and d(-) -arabinose; similarly, D-threose 
gives D(+)-xylose and d(— )-lyxose. Ill and IV must be ribose and arabin- 
ose, but which is which? On oxidation with nitric acid, arabinose gives an 
optically active dicarboxylic acid (a trihydroxyglutaric acid), whereas ribose 
gives an optically inactive dicarboxylic acid. When the terminal groups, 
i.e., CHO and CH 2 OH, of III are oxidised to carboxyl groups, the molecule 
produced (Ilia) possesses a plane of symmetry, and so is inactive. Oxidation 
of IV gives IVa, and since this molecule has no plane (or any other elerftent) 
of symmetry, it is optically active. Thus III is D-ribose and IV is d- 
arabinose. 



H- 
H- 
H- 



I] 

1 


[I 

,[o] 

)0 2 H 


r 

\ 
c 


V 

r [0] 

^0 2 H 


\ 
C 


T 
,[0] 

:o 2 H 


V 

\ 


I 

,[o] 

;0 2 H 








IT 




HTT 


1TO 


TT 




— OH 


H — 


—OH 


HO — 


— H 


HO — 


— H 




— OH 


H — 


—OH 


H — 


— OH 


H — 





( 

ina 
II 


)O a H 
ctive 
la 


ac 

r 


:o 2 h 

;ive 
Va 


( 

int 


X> 2 H 

ictive 
Va 


C 

act 
V 


)0 2 H 

ive 

la 



V and VI must be xylose and lyxose, but which is which? The former 
sugar, on oxidation, gives an optically inactive dicarboxylic acid, whereas 



178 



ORGANIC CHEMISTRY 



[CH 

Therefore V 



VII 

is 



the latter gives an optically active dicarboxylic acid, 
D-xylose and VI is D-lyxose. 

The following is the alternative method of elucidating the configurations 
of the aldopentoses; it is more in keeping with Fischer's solution to the 
problem. The structural formula of the aldopentoses can give rise to four 
pairs of enantiomorphs, the D-forms of which are as follows: 



CHO 



OHO 



CHO 



CHO 



H- 
H- 
H- 



-OH HO- 
-OH H- 
-OH H- 



CH 2 OH 
III 



-H H- 

-OH HO- 
-OH H- 



-OH HO- 
-H HO- 
-OH H- 



-H 
-H 
-OH 



CH 2 OH 
IV 



CH 2 OH 
V 



CH«OH 
VI 



It should be noted that these four configurations have been obtained from 
first principles (see §7c. II) ; no recourse has been made to the configurations 
of the aldotetroses. Arabinose and lyxose, on oxidation with nitric acid, 
produce optically active dicarboxylic acids (trihydroxyglutaric acids). 
Therefore these two pentoses must be IV and VI, but we cannot say which 
is which. Xylose and ribose, on oxidation, produce optically inactive di- 
carboxylic acids (trihydroxyglutaric acids). Therefore these two pentoses 
must be III and V, and again we cannot say which is which. When each 



S m \ 



IV 

/ \ 



COjjH 



H- 
H- 
H- 
H- 



-OH HO- 

-OH H- 

-OH H- 

-OH H- 



C0 2 H 



-H 



C0 2 H 

inactive 



CO2H 



CO.H 



-OH 
-OH 
-OH 



H- 

HO- 

H- 

H- 



*0H HO- 

-H HO- 

-OH H- 

-OH H- 



-H 
-H 
-OH 
-OH 



C0 2 H 

active 



C0 2 H 

active 



C0 2 H 
active 



/X 



/ V \ 



C0 2 H 



H- 

H- 

HO- 

H- 



-OH HO- 
-OH H- 



C0 2 H 
-H 
-OH 



-H 
-OH 



HO- 
H- 



C0 2 H 



-H 
-OH 



H- 
HO- 
HO- 

H- 



C0 2 H 



-OH HO- 
-H HO- 



-H 
-OH 



HO- 
H- 



-H 
-H 
-H 
-OH 



C0 2 H 

active 



C0 2 H 

active 



C0 2 H 
inactive 



C0 2 H 

active 



§1] 



CARBOHYDRATES 



179 



aldopentose is stepped up by one carbon atom (by means of the Kiliani 
reaction) and then oxidised to the dicarboxylic acid (the terminal groups 
are oxidised), it is found that arabinose and xylose each give two active 
dicarboxylic acids, whereas ribose and lyxose each give one active and one 
inactive (meso) dicarboxylic acid. The chart at foot of previous page 
shows the dicarboxylic acids obtained from the configurations III-VI. 

It therefore follows that D-ribose is III, D-arabinose is IV, D-xylose is V 
and D'lyxose is VI. These configurations are confirmed by the facts that 
ribose and arabinose give the same osazone, and xylose and lyxose give the 
same osazone; the only difference between sugars giving the same osazone 
is the configuration of the second carbon atom, i.e., Ill and IV are epimers, 
as are V and VI. It should also be noted that arabinose and lyxose produce 
the same trihydroxyglutaric acid on oxidation. 

Aldohexoses. The structural formula of these compounds is 

CHO-CHOH-CHOH-CHOH-CHOH-CHjOH, 
and since it contains four unlike asymmetric carbon atoms, there are sixteen 
optically active forms (eight pairs of enantiomorphs). All are known, and 
may be prepared by stepping up the aldopentoses: D-ribose gives D(+)-allose 
and D(+)-altrose; D-arabinose gives D(+)-glucose and D(-f)-mannose; 
D-xylosegivesD(— )-guloseandD(— )-idose;andD-lyxosegivesD(+)-galactose 
and D(+)-talose. 



rD -ribose > 
III | 



CHO 



H— 
H — 



H- 
H- 



CHO 



-OH HO- 

-OH H- 

-OH H- 

-OH H- 



CH 2 OH 
D(+)-allose 
VII 



-H 
OH 
-OH 
-OH 



CH 2 OH 

D(+)-altrose 
VIII 



f 



D -arabinose 
IV 



1 



CHO 



H- 

HO- 

H- 

H- 



CHO 



-OH HO- 
-H HO- 



-OH 
-OH 



H- 
H- 



-H 
-H 
-OH 
-OH 



CH 2 OH 
D(+)- glucose 
IX 



CH 2 OH 
D(+)- mannose 
X 



H- 

H- 

HO- 

H- 



rD -xylose — . 
V | 



CHO 



-H 
-OH 



CH 2 OH 

D(— )-gulose 
XI 



CHO 



-OH HO- 
-OH H- 



HO- 
H- 



-H 
-OH 
-H 
-OH 



CH 2 OH 
D(— )-idose 
XII 



H- 
HO- 
HO- 

H- 



. D-lyxose — . 

I VI | 



CHO 

-OH HO 

-H 

-H 

-OH 



CH 2 OH 

D(+)-galactose 
XIII 



CHO 



HO- 
HO- 



H- 



-H 
-H 
-H 
-OH 



CH 2 OH 

D(+)-talose 
XIV 



VII and VIII must be allose and altrose, but which is which? On oxida- 
tion with nitric acid, the former gives an optically inactive (allomucic) and 



180 



ORGANIC CHEMISTRY 



[CH. VII 



the latter an optically active (talomucic) dicarboxylic acid. Therefore allose 
is VII and altrose is VIII. 

XIII and XIV must be galactose and talose, but which is which? On 
oxidation with nitric acid, the former gives an optically inactive (mucic) 
and the latter an optically active (talomucic) dicarboxylic acid. Therefore 
XIII is galactose and XIV is talose. 

The elucidation of the configurations of the remaining four aldohexoses 
is not quite so simple, since, on oxidation with nitric acid, glucose and 
mannose both give optically active dicarboxylic acids, as also do gulose and 
idose; in all four configurations (IX, X, XI, XII), replacement of the two 
terminal groups (CHO and CH 2 OH) by carboxyl groups leads to dicarboxylic 
acids whose structures have no plane (or any other element) of symmetry. 
It has been found, however, that the dicarboxylic acid from glucose (saccharic 
acid) is the same as that obtained from gulose (actually the two saccharic 
acids obtained are enantiomorphous, D-glucose giving D-saccharic acid and 
D-gulose L-saccharic acid). Since saccharic acid, C0 2 H , (CHOH) 4 -C0 8 H, is 
produced by the oxidation of the terminal groups with the rest of the mole- 
cule unaffected, it therefore follows that the " rest of molecule " must be 
the same for both glucose and gulose. Inspection of formulae IX, X, XI 
and XII shows that only IX and XI have the " rest of the molecule " the 
same; by interchanging the CHO and CH 2 OH groups of IX, the enantio- 
morph of XI, i.e., L-gulose, is obtained. Therefore IX must be glucose (since 
we know that glucose is obtained from arabinose), and XI must be gulose. 
Consequently X is mannose and XII is idose. 

Ketohexoses. All the ketohexoses that occur naturally have the ketonic 
group adjacent to a terminal CH 2 OH group, i.e., the structural formula of 
all the natural ketohexoses is 

CH 2 OH-CO-CHOH-CHOH-CHOH-CH 2 OH. 
Since this structure contains three dissimilar asymmetric carbon atoms, 



CH 2 OH 
I 
CO 



HO- 
H- 
H- 



-H CH.NHNH; HQ- 



-OH 
-OH 



H- 
H- 



CH=N-NH-C 6 H 5 

C =N-NH-C 6 H 6 H- 

— H CgH.-NH-NHa HO 

-OH H- 



CHO 



-OH 



H- 



-OH 



-H 

-OH 

-OH 



CH 2 OH 

Df— l-fructose 
XV 



CH 2 OH 

osazone 



CH 2 OH 
D(+) -glucose 




[hydrolysis 



CHO 

I 
CO 



HO- 
H- 
H- 



-H 

-OH 

-OH 



CH 2 OH 
osone 



§2] 



CARBOHYDRATES 



181 



there are eight optically active forms (four pairs of enantiomorphs) possible 
theoretically; of these the following six are known: d(— )- and L(+)-fructose, 
»(+)- and l(— )-sorbose, D(+)-tagatose and l(— )-psicose. Only d(— )- 
fructose, l(— )-sorbose and D(+)-tagatose occur naturally. 

Fructose. Natural fructose is laevorotatory, and since D-glucose gives 
the same osazone as natural fructose, the latter must be d(— )-fructose. 
Furthermore, since osazone formation involves only the first two carbon 
atoms in a sugar, it therefore follows that the configuration of the rest of 
the molecule in glucose and fructose must be the same. Hence the con- 
figuration of d(— )-fructose is XV, and is confirmed by the fact that d(+)- 
glucose may be converted into d(— ) -fructose via the osazone (see chart at 
foot of previous page). 

The configurations of the other ketohexoses are: 



CHjjOH 



CH.OH 



CH 2 OH 



GO 



CO 



CO 



H- 



HO- 



H- 



-OH 
-H 



HO- 



HO- 



-OH 



H- 



-H 
-H 



HO- 



-OH 



HO- 
HO- 



-H 
-H 
-H 



CH 2 OH 
D(+)-sorbose 



CH 2 OH 

D(+)-tagatose 



CH 2 OH 

L(-)-psicose 



§2. Ring structure of the monosaccharides. When a monosaccharide 
is dissolved in water, the optical rotatory power of the solution gradually 
changes until it reaches a constant value (Dubrunfaut, 1846); e.g., a freshly 
prepared solution of glucose has a specific rotation of +111°, and when 
this solution is allowed to stand, the rotation falls to +52-5°, and remains 
constant at this value. The final stage can be reached more rapidly either 
by heating the solution or by adding some catalyst which may be an acid 
or a base. This change in specific rotation is known as mutarotation; all 
reducing sugars (except a few ketoses) undergo mutarotation. 

To account for mutarotation, Tollens (1883) suggested an oxide ring 
structure for d(+) -glucose, whereby two forms would be produced, since, in 
the formation of the ring, another asymmetric carbon atom (which can exist 
in two configurations) is produced (cf. the Kiliani reaction). Tollens assumed 
that a five-membered ring (the y-form) was produced: 




OHO 



H- 

HO- 

H- 

H- 



-OH 
-H 
-OH 
-OH 




CH 2 OH 
D(+)- glucose 

The difficulty of this suggestion was that there was no experimental evidence 
for the existence of these two forms. Tanret (1895), however, isolated two 

Q 



182 ORGANIC CHEMISTRY [CH. VII 

isomeric forms of D(+)-glucose, thus apparently verifying Tollens' supposi- 
tion (but see §§7a, 7f ). The two forms, I and II, are known respectively as 
a- and /J-d(+ )-y-glucose (see also §7b for the nomenclature of these forms). 

Ring formation of a sugar is really hemiacetal formation, one alcoholic 
group of the sugar forming a hemiacetal with the aldehyde group of the 
same molecule, thus producing a ring structure which is known as the lactol 
form of the sugar. 

Mechanism of mutarotation. According to Lowry (1925), mutarota- 
tion is not possible without the presence of an amphiprotic solvent, i.e., a 
solvent which can function both as an acid and a base, e.g., water. Thus 
Lowry and Faulkner (1925) showed that mutarotation is arrested in pyridine 
solution (basic solvent) and in cresol solution (acidic solvent), but that it 
takes place in a mixture of pyridine and cresol. It has been assumed that 
when mutarotation takes place, the ring opens and then recloses in the 
inverted position or in the original position. There is some evidence for 
the existence of this open-chain form. The absorption spectra of fructose 
and sorbose in aqueous solution indicate the presence of open-chain forms; 
aldoses gave negative results (Bednarczyk et al., 1938). Solutions of glucose 
and arabinose in 50 per cent, sulphuric acid gave an ultraviolet absorption 
spectrum containing the band characteristic of the oxo (carbonyl) group 
(Pascu et al., 1948). Aldoses in solution contain a form which is reducible 
at the dropping mercury electrode (Cantor et al., 1940). Although the 
nature of this reducible form has not been established, it is probably the 
open-chain form, either free or hydrated. Furthermore, a relationship was 
shown to exist between the amount of this reducible form and the rate of 
mutarotation. One interpretation of this observation is that the reducible 
form is an intermediate in mutarotation. Rate constants for the conversion 
of the ring forms of aldoses to the open-chain form have been calculated from 
polarographic measurements, and it has also been shown that the energy of 
activation required to open the pyranose ring is the same for glucose, 
mannose, galactose, arabinose and xylose (Delahay et al., 1952). The forma- 
tion of this acyclic intermediate during mutarotation has been confirmed 
by isotopic evidence (Goto et al., 1941) and by further polarographic evidence 

CH(SCH 3 ) 2 CH(SCH 3 )ij 

H— 0— OH H— C— 0-CO-CH 3 

HO-C— H (CHiCO^o^CHs-CO-O-C-H 

H-o-OH Pyridine H-C-OCOCH s 

I I 

H— C — OH H— C— 0-CO-CH S 

I I 

CH 2 OH CHjjO-CO-CHs 

glucose dimethyl 



mercaptal 



HjO/CdCO, tt r, 



CHO 
I 
H— G— 0-C0-CH g 

CH 3 -CO-0— C— H 
I 
H— C— 0-CO-CH 3 

H— C— O-CO-CHs 

CHijO-CO-CHs 




§2] CARBOHYDRATES 183 

(Overend et al., 1957). It is interesting to note in connection with this 
problem of the existence of the open-chain structure, that aldehydo-sugars, 
i.e., aldoses in which the aldehyde group is present, can only be isolated 
if all the hydroxy! groups in the open-chain form are " protected "; e.g., 
Wolfrom (1929) prepared 2:3:4:5: 6-penta-acetylaldehydoglucose as 
shown at foot of previous page. 

The problem now is: What is the mechanism of the formation of the open- 
chain form from the ring-form? Lowry (1925) suggested that it occurred 
by the simultaneous addition and elimination of a proton, since both an 
acid and a base must be present (see above). This concerted mechanism 
would conform to a third-order reaction: 

H-^-A ^=±: | + HB + + A - 

6hoh 

i 
! ' 

Swain et al. (1952) have shown that the mutarotation of tetramethylglucose, 
catalysed by phenol and pyridine in benzene solution, is a third-order 
reaction; this supports the above mechanism. On the other hand, some 
authors believe that the reaction proceeds in two independent ways, one 
being an acid-catalysed reaction, and the other a base-catalysed reaction. 
In this case the mechanism would conform to a second-order reaction. Hill 
et al. (1952) have shown that the mutarotation of glucose in aqueous methanol 
containing acetate buffers is in better agreement with a second-order reaction 
than with a third-order. 

It can thus be seen that the mechanism of mutarotation cannot be regarded 
as settled, and it appears likely that the sugar investigated (free or as a 
derivative) and the experimental conditions may play a part in deciding 
which mechanism will operate (see §7h). 

Preparation of the a- and (3-forms of a sugar. Experimentally, it 
is very difficult to isolate the a- and /S-forms of a sugar. The ordinary form 
of D(+)-glucose is the oc-isomer, m.p. 146° and [oc] D = +111°; this form 
may be prepared by crystallising glucose from cold ethanol. The /3-isomer, 
m.p. 148-150°, [ac] D = +19*2°, can be obtained by crystallising glucose from 
hot pyridine. Thus the a-form may be converted into the /?-, and vice versa, 
during the process of crystallisation; this is an example of asymmetric 
transformation (§10 iv. II). Both forms show mutarotation, the final value 
of the specific rotation being +52-5°; this corresponds to a mixture contain- 
ing about 38 per cent, of the oc-isomer, and 62 per cent, of the /?-. The two 
stereoisomeric ring-forms of a sugar are often referred to as anomers. 

Summary of the evidence for the ring structures of sugars. The 
cyclic structure of the sugars accounts for the following facts: 

(i) The existence of two isomeric forms (anomers) of a given sugar, e.g., 
a- and /J-glucose. 

(ii) Mutarotation. 

(iii) Glucose and other aldoses do not give certain characteristic reactions 
of aldehydes, e.g., Schiff 's reaction, do not form a bisulphite or an aldehyde- 
ammonia compound. Recently, however, it has been shown that by pre- 
paring Schiff's reagent in a special way, it becomes very sensitive, simple 
aldoses restoring the pink colour to this solution; the monosaccharide aldoses 
react strongly, but the disaccharide aldoses react weakly (Tobie, 1942). 
This reaction with a sensitive Schiff's reagent appears to indicate that some, 
although a very small amount, of the open-chain form of a sugar is present 
in solution in equilibrium with the two ring-forms. 

(iv) Glucose penta-acetate does not react with hydroxylamine ; this 



184 



ORGANIC CHEMISTRY 



[CH. VII 



indicates that the aldehyde group is absent in this derivative (glucose itself 
does form an oxime). 

(v) Aldehydes normally form acetals by combination with two molecules 
of a monohydric alcohol ; aldoses (and ketoses) combine with only one mole- 
cule of an alcohol. It should be noted, however, that aldoses will combine 
with two molecules of a thiol to form a mercaptal (thioacetal). 

(vi) X-ray analysis definitely proves the existence of the ring structure, 
and at the same time indicates the size of the ring (see §7f). 

§3. Glycosides. Just as simple hemi-acetals react with another mole- 
cule of an alcohol to form acetals, so can the sugars, in their ring-forms 
(lactols), react with a molecule of an alcohol to form the acetal derivative, 
which is known under the generic name of glycoside; those of glucose are 
known as glucosides; of fructose, fructosides, etc. The hydroxyl group pro- 
duced at the oxo group by ring formation is known as the glycosidic hydroxyl 
group. This group can be acetylated and methylated, as can all the other 
hydroxyl groups in the sugar, but the glycoside derivatives are far more 
readily decomposed by various reagents. 

E. Fischer (1893) remixed glucose in methanol solution in the presence of 
one-half per cent, hydrochloric acid, and thereby obtained a white crystalline 
product which contained one methyl group (as shown by analysis), and which 
did not reduce Fehling's solution or mutarotate, and did not form an osazone. 
Thus the hemiacetal structure is no longer present in this compound; in fact, 
this compound appears to be an acetal since it is stable in alkaline solution 
(Fehling's solution). Furthermore, on boiling with dilute inorganic acids, 
the compound regenerated the original sugar, a reaction again typical of 
acetals. Ekenstein (1894) isolated a second isomer from the reaction mixture 
when he repeated Fischer's work, and Fischer explained the existence of 
these two isomers by suggesting ring structures for the two methyl glucosides, 
viz., 



H— C— OCH 3 

H— C— OH 
I 
HO— C — H 



H— C- 







CH,0— C— H 
I 
H— C— OH 
I 
HO— C— H 



O 



H— C- 



H— C— OH 



T 

CH 2 OH 

methyl a-D-glucos,ide 



H— C — OH 

I 
CH 2 OH 

methyl (3-D-glucoside 



Fischer assumed that these methyl glucosides were five-membered ring 
systems, basing his assumption on Tollens' suggestion (§2). As we shall 
see later (§7a), Fischer's assumption is incorrect. 

The non-sugar part of a glycoside is known as the aglycon (or aglycone), 
and in many glycosides that occur naturally, the aglycon is often a phenolic 
compound (see §24). 

Fischer (1894) found that methyl oc-D-glucoside was hydrolysed by the 
enzyme maltase, and the yS-D-glucoside by the enzyme emulsin. Further- 
more, Fischer also found that maltase would not hydrolyse the /5-glucoside, 
and that emulsion would not hydrolyse the a-glucoside. Thus the two 
isomers can be distinguished by the specificity of action of certain enzymes 
(see also §16, XIII). Armstrong (1903) followed these enyzmic hydrolyses 
polarimetrically, and showed that methyl a-D-glucoside liberates a-D-glucose, 



§4] CARBOHYDRATES 185 

and that the yS-glucoside liberates /?-D-glucose ; Armstrong found that 
hydrolysis of the a-glucoside produced a " downward " mutarotation, 
whereas that of the /?-glucoside produced an " upward " mutarotation. It 
therefore follows that a-D-glucose is stereochemically related to methyl 
a-D-glucoside, and /3-D-glucose to methyl /J-D-glucoside. 

§4. Configuration of C x in glucose. The configurations of C x in a- 
and /9-D-glucose have been written, in the foregoing account, as: 

H— Cr-OH HO— C— H 

II ! I 

ct-isomer p-isomer 

I II 

The question that now confronts us is : What justification is there for this 
choice, i.e., what is the evidence that enables us to say that the a-isomer 
(characterised by certain physical constants) actually has the hydrogen atom 
to the left and the hydroxyl group to the right? Hudson (1909) proposed 
the empirical rule that of an a, /? pair of sugars in the D-series, the a-isomer, 
which has the higher dextrorotation (i.e., this physical constant decides 
which of the two is to be designated a-), has the hydrogen to the left (i.e., I) ; 
the /S-isomer consequently has the hydrogen atom to the right (II). Thus 
a-D(+)-glucose is the isomer with the specific rotation +111°, and /?-d(+)- 
glucose is the isomer with the specific rotation +19-2°. If the D-sugar has 
a negative rotation, then, according to the empirical rule, the /J-isomer has 
the higher negative rotation (i.e., the less positive rotation), e.g., a-D(— )- 
fructose is the isomer with the specific rotation —20°, and the /S-isomer 
— 133°. In the L-sugars, the a-isomer is the one with the higher laevorota- 
tion, and the other is the /9-isomer; thus the a-forms (and the /5-forms) of 
the D- and L-series are enantiomorphous. 

Boeseken (1913) found that when boric acid is added to a solution of a 
cyclic 1 : 2-glycol, the electrical conductivity of the solution is greater than 
that of boric acid itself, and that the increase is greater for the m-isomer 
than for the trans- (see Vol. I). This phenomenon has been used to dis- 
tinguish between the two anomers of D-glucose ; the results obtained showed 
that the conductivity of the isomer called the a (from the above empirical 
rule), in the presence of boric acid, decreased during mutarotation, whereas 
the conductivity of the /J-isomer increased. This suggests that the a-isomer 
has configuration III, and the /f-isomer IV. Thus we now have physico- 
chemical evidence that the 1 : 2-hydroxyl groups are in the m-position in 



H— C— OH 

I 
H— C— OH 



HO— C— H 
I 
H— C— OH o 



O 

J I II 

III IV 

the a-isomer, i.e., there is now some experimental evidence in support of 
Hudson's empirical rule. These configurations have been confirmed by 
further work, e.g., Ruber (1931) found that, in general, fraws-compounds 
have a higher molecular refraction than the corresponding cis- ; the molecular 
refraction of /?-D-glucose is greater than that of the a-isomer, and so agrees 
with the results obtained by the conductivity experiments. The strongest 
bit of evidence for the configurations of the a- and /9-isomers has been 
obtained from X-ray studies of a-D-glucose (see §7f). 



186 



ORGANIC CHEMISTRY 



[CH. VII 



§5. Hudson's lactone rule. Hudson (1910) studied the rotation of the 
lactones derived from the aldonic acids. Using the usual projection formulae, 
the lactone ring will be on the right or left according as the hydroxyl group 
on C 4 (i.e., the y-hydroxyl group) is on the right or left, i.e., according as C 4 
has a dextro or Isevo configuration: 



■93— 



o 



o 



H— C 4 - 



-f 

— a— 



-9 3 — 



-C„— H 



dextrorotatory 



lsevorotatory 



From an examination of 24 lactones derived from aldonic acids, and assum- 
ing that they were y-lactones, Hudson concluded that if the lactone ring was 
on the right, the compound was dextrorotatory ; if the ring was on the left, 
then lsevorotatory. 

§6. Hudson's Isorotation rules. Hudson (1909, 1930) applied the rule 
of optical superposition (§12. I) to carbohydrate chemistry, and his first 
application was to the problem of the configuration of C x in the anomers of 
aldoses. Hudson pointed out that the only structural difference between 
the a- and /J-anomers (of sugars and glycosides) is the configuration of C v 
Thus, representing the rotation of this terminal group as A and that of the 
rest of the molecule as B, and then taking the a-anomer as the one with the 
higher positive rotation (in the D-series) we have: 



C 



-OR 



O 



+ A 
+ B 



BO — 0— H 

-—4 

C 



-A 



O 



+B 



a 



P 



Molecular rotation of the a-anomer = + A + B 

„ „ /?- „ = - A + B 

Thus in every pair of a- and /S-anomers the following rules will hold : 

Rule 1. The sum of the molecular rotations (2B) will be a constant value 
characteristic of a particular sugar and independent of the nature of R. 
Rule 2. The difference of the molecular rotations (2A) will be a constant 
value characteristic of R. 

As we have seen, the rule of optical superposition does not hold exactly 
(due to neighbouring action, etc.; see §12. I). In the sugars, however, the 
rotation of C x is affected only to a small extent by changes in the rest of the 
molecule, and vice versa. This is illustrated in the following table, from 
which it can be seen that the sum of the molecular rotations (2B) for various 
pairs of glucopyranoside anomers is fairly constant. 



Cj substituent 


M„ 


M/3 


Ma + M^ = 2B 


OH .... 
OCH, .... 
OC t H s . . . 


+ 202 
+ 309 
+ 314 


+ 34 
-66 
-69-5 


+ 236 
+243 
+ 245-5 



§7] CARBOHYDRATES 187 

These isorotation rules have been used to ascertain which of an anomeric 
pair of glycosides is a and which is /J, and to determine the type of glycosidic 
link in disaccharides and polysaccharides. 

Lemieux et al. (1958), by means of proton magnetic resonance studies, 
have shown that the configurations assigned to the a- and /5-anomers of sugar 
acetates on the basis of Hudson's rules are correct. 

§7. Methods for determining the size of sugar rings. As pointed 
out previously, Fischer followed Tollens in proposing the y-oxide ring. 
There was, however, no experimental evidence for this ; ihe y-hydroxyl group 
was chosen as being involved in ring formation by analogy with the ready 
formation of y-lactones from y-hydroxyacids. The problem was further 
complicated by the fact that Hudson et al. (1915) isolated four galactose 
penta-acetates, none of which had a free aldehyde group. Furthermore, 
these four compounds were related to each other as pairs, i.e., there were two 
a- and two /J-isomers. The only reasonable explanation for this was that 
there are two ring systems present, but once again there is no evidence to 
decide the actual sizes of the rings. 

The original experimental approach to the problem of determining the 
size of the ring present in sugars consisted essentially in studying the methyl- 
ated sugars. A more recent method uses the methyl glycosides (for this 
method, see §7g). Since methylation is so important in the original method, 
the following account describes briefly the methods used. 

(i) Purdie's method (1903). The sugar is first converted into the corres- 
ponding methyl glycoside (methanol and hydrochloric acid), and this is then 
heated with methyl iodide in the presence of dry silver oxide; thus: 



i 1 i 1 I 

CHOH CHOCH. CHOCH, 

1 + nvr rm^L. I ' CH »' . I 

CHOH ? + CH » OH — c^HOH ? W>+ CHOCH, ?+AgI 



a 3 



Purdie's method is only applicable to glycosides and other derivatives in 
which the reducing group is missing or has been protected by substitution. 
Methylation of a free reducing sugar by this method would result in the 
oxidation of that sugar by the silver oxide. 

In certain cases, thallous hydroxide may be used instead of silver oxide 
(Fear et al., 1926). 

(ii) Haworth's method (1915). In this method methyl sulphate and aqueous 
sodium hydroxide are added to a well-stirred sugar solution at such a rate 
that the liquid remains practically neutral: 

CHOH + (CH 3 ) a S0 4 + NaOH -> CHOCH 3 + CH 3 NaS0 4 + H 2 

This method is directly applicable to all reducing sugars. 

(iii) More recent methods of methylation use sodium and methyl iodide 
in liquid ammonia, or diazomethane in the presence of moisture. 

Having obtained the fully methylated methyl glycoside, the latter is then 
hydrolysed with dilute hydrochloric acid, whereby the glycosidic methyl 
group is eliminated. A study of the oxidation products of the methylated 
sugar then leads to the size of the ring. It should be noted that throughout 
the whole method, the assumption is made that no methyl groups migrate 
or that any change in the position of the oxide ring occurs (see, however, 
later). The number of methyl groups present in the methylated sugar and 



188 



ORGANIC CHEMISTRY 



[CH. VII 



the various oxidation products are determined by the Zeisel method (see 
Vol. I). Also, these methyl derivatives are often purified by distillation 
in vacuo. Bishop et al. (1960) have now separated methylated methyl 
glycosides by gas chromatography. 

§7a. Pyranose structure. This structure is also sometimes referred to 
as the S-oxide or amylene oxide ring. As an example of the method used, 
we shall consider the case of d(+) -glucose (Haworth and Hirst, 1927). 
D(+)-Glucose, I, was refluxed in methanol solution in the presence of a small 
amount of hydrochloric acid, and the methyl D-glucoside, II, so produced 
was methylated with methyl sulphate in the presence of sodium hydroxide 
to give methyl tetramethyl-D-glucoside, III, and this, on hydrolysis with 
dilute hydrochloric acid, gave tetramethyl-D-glucose, IV. When this was 
dissolved in water and then oxidised by heating with excess of bromine at 
90°, a lactone, V, was isolated, and this, on further oxidation with nitric 
acid, gave xylotrimethoxyglutaric acid, VI. The structure of this com- 
pound is known, since it can be obtained directly by the oxidation of methyl- 
ated xylose; thus its structure is VI (see also §7d). The structure of this 



C0 2 H 



H- 

CH 3 0- 

H- 



-OCH 3 
-H 



-OCH 3 



C0 2 H 

VI 

compound is the key to the determination of the size of the ring in the sugar. 
One of the carboxyl groups in VI must be that which is combined in the 
formation of the lactone ring in the tetramethylgluconolactone, V. The 
other carboxyl group is almost certainly the one that has been derived from 
the non-methylated carbon atom, i.e., from the CHOH group that is involved 
in the ring formation in the sugar. Therefore there must be three methoxyl 
groups in the lactone ring. Thus the lactone cannot be a y-lactone, and 
consequently C 5 must be involved in the ring formation. It therefore 
follows that the lactone, V, must be 2 : 3 : 4 : 6-tetra-O-methyl-D-glucono- 
lactone. Working backwards from this compound, then IV must be 
2:3:4: 6-tetra-O-methyl-D-glucose, III methyl 2:3:4: 6-tetra-O-methyl- 
D-glucoside, II methyl D-glucopyranoside, and I D-glucopyranose (see §7f 
for the significance of the term pyranose). It should be noted that the 
question as to whether the sugar is a or /S has been ignored; starting with 
either leads to the same final results. The foregoing experimental results 
can now be represented by the following equations: 



H- 

110- 

II- 

H- 



CHOH 



-OH 



H- 

chsQh/hci 

-H O reflux HO- 



OHOCH3 



-OH 



-OH 



H- 
H- 



H- 

(CH,) 2 SQ4 
-H O NaOH * CH S 0- 



-OH 



H- 



OHOCH3 
-OCH3 
-H ° 
-OCH 



H- 



CH 2 OH 
I 



CH 2 OH 
II 



CHjjOCHs 
III 



§Va] 



CARBOHYDRATES 



189 



HC! 



H- 
■*- CH s O - 

H- 
H- 



CHOH 



-OCH, 



H 



-H O *- CH3O 



-OCH, 



CHjOCHj 
IV 



H 
H 




CH 2 OCH 3 
V 



HNOj 



H- 

CH3O- 

H- 

H- 



C0 2 H 



-OCH3 
-H 

-6ch 3 

-OH 



CH 2 OCH, 



H- 



HNO» 



CH3O- 

H- 



C0 2 H 



-OCH 3 

-H 

-OCH, 



COjjH 
VI 



There is a slight possibility that the ring might have been an £-ring, i.e. 
the oxide ring involves C x and C 6 , and that C 5 is converted to the carboxy 
group with loss of C„. Haworth, however, made certain that this was not 
the case by the following method. Had the ring been 1 : 6-, then 2:3:4:5- 
tetramethylgluconic acid, VII, would have been obtained (instead of V). 
VII was obtained by Haworth et al. (1927) from melibiose and gentiobiose 
(see §§18, 19) and, on oxidation, gave tetramethylsaccharic acid, VIII, and 
not the dicarboxylic acid, VI. 



CO,H 



H- 

CH s O- 

H- 

H- 



C0 2 H 



-OCH, 
-H 

-OCH, 
-OCH, 



H- 

-+- CH3O- 

H- 



H 



CH 2 OH 
VII 



-OCH3 

-H 

-OCH3 



-OCH3 

C0 2 H 
VIII 



Thus there is a 1 : 5-ring in the tetramethylgluconolactone, tetra-O- 
methylglucose, methyl tetra-O-methylglucoside, methyl glucoside, and there- 
fore in glucose itself. This conclusion is based on the assumption that no 
change in the ring position occurs during the methylation of glucose. Thus 
glucose is a d- or pyranose sugar. 

By similar methods it has been shown that hexoses and pentoses all 
possess a pyranose structure. There is also a large amount of evidence to 



190 ORGANIC CHEMISTRY [CH. Vlt 

show that the oximes, phenylhydrazones and osazones of hexoses and 
pentoses may be cyclic or open-chain, e.g., the oxime of glucose: 

^NHOH 
CH=NOH CH , 



(CHOH) 4 n _ (CHOH) 3 O 

I 



CH 2 OH CH ' 

CHjOH 

Mester et al. (1951-1955) showed that aldose phenylhydrazones react in 
pyridine solution with solutions of diazonium salts to give brilliant-red sugar 
diphenylf ormazans : 

CH=NNHPh phN + / N=NPh 

i PhN * > ■ c; /H 

CHOH |^ N _ N .^ 

! CHOH X Ph 

Formazan formation proves the acyclic structure of the sugar phenylhydra- 
zones. The cyclic structures do not react, e.g., there are three modifications 
of D-glucose phenylhydrazone («, m.p. 159-160°; p\ m.p. 140-141°; y, m.p. 
115-116°) ; two of these do not form formazans, but the third does. Hence 
the former two are cyclic and the third is- acyclic. 

§7b. Furanose structure. This structure is also sometimes referred to 
as the y-oxide or butylene oxide ring. Fischer (1914) prepared methyl 
D(+)-glucoside by a slightly modified method, viz., by dissolving d(+)- 
glucose in methanol, adding one per cent, hydrochloric acid, and then allow- 
ing the mixture to stand at 0° (instead of refluxing, as in his first procedure). 
On working up the product, he obtained a syrup (a crystalline compound 
was obtained by the first procedure). Fischer called this compound methyl 
y-glucoside, and believed it was another isomer of the «- and /3-forms; this 
is the significance of the symbol y as used by Fischer. This syrup, however, 
was subsequently shown to be a mixture of methyl a- and /3-glucofuranosides, 
i.e., this glucoside contained a y- or 1 : 4-ring (Haworth et al., 1927). This 
syrup, I, when completely methylated (methyl sulphate method), gave a 
methyl tetra-O-methyl-D-glucoside, II, and this, on hydrolysis with dilute 
hydrochloric acid, gave tetra-O-methyl-D-glucose, III. On oxidation with 
bromine water at 90°, III gave a crystalline lactone, IV, and this, when 
oxidised with nitric acid, gave dimethyl-D-tartaric (dimethoxysuccinic) acid, 
V. This compound (V) is the only compound of known structure, and is 
therefore the key to the determination of the size of the ring in the sugar. 
Working backwards from V, then IV is 2 : 3 : 5 : 6-tetra-O-methyl-D-glucono- 
lactone, III is 2 : 3 : 5 : 6-tetra-O-methyl-D-glucose, II is methyl 2:3:5:6- 
tetra-O-methyl-D-glucoside, and I is methyl D-glucofuranoside. If we write 
D-glucose as D-glucofuranose, then the foregoing reactions may be formu- 
lated as shown on next page (see §7f for the meaning of furanose). 

These reactions prove that I, II, III and IV all contain a y-oxide ring, i.e., 
the methyl glucoside, I, prepared at 0°, has a 1 : 4-ring. This then raises 
the question: What is the size of the ring in glucose itself? Is it 1 : 4 or 
1 : 5? Preparation of the methyl glucoside at reflux temperature gives th6 
1 : 5-compounds (see §7a) ; preparation at 0° gives the 1 : 4-compounds. It 
is therefore not possible to say from these experiments whether glucose 
itself exists in the pyranose (1 : 5-) or furanose (1 : 4-) forms originally, or 
whether these two forms are in equilibrium. Further information is neces- 



§7c] 



CARBOHYDRATES 



191 



H- 
HO- 



CHOH 
-OH 
-H 



H- 
H- 



CHOCH3 



O 



CH«OH/HCI^ 

s ** 



H- 
HO- 



-OH 



H- 
H- 



-OH 
-H 



CHOCH. 



O 



(CHjfcSO. 



H- 



NaOH 



-OH 



CHsO- 
H- 
H- 



-OCHj 
-H 



O 



GH 2 OH 
D-glucofuranose 



CH 2 OH 
I 



-OCH 3 

CH 2 OCH $ 
II 



GHOH 



H- 

HCl 

CH s O- 
H- 
H- 



-OCH3 , H 



-H 



-OCH. 



900 CH3O 
H 
H- 



GH2OCH3 
III 




COgH 



H- 
CH3O- 



-OCH 3 
-H 



C0 2 H 
V 



CHaOOHj 
IV 



sary to supply an answer to these questions. As we shall see later, the 
normal form of a sugar is the pyranose structure (see §7f ) ; pyranosides are 
often referred to as the " normal " glycosides. 

By similar methods it has been shown that hexoses and pentoses give 
methyl glycosides possessing a furanose structure when prepared at 0° (or 
at room temperature). 

§7c. Determination of ring size by means of lactone formation. 

As we have seen, glycoside formation at reflux temperature leads ultimately 
to a methylated ^-lactone, whereas at 0° a methylated y-lactone is obtained. 
Haworth (1927) examined the rates of hydration of these two types of 
lactones to the open-chain acids; the rates were measured by changes in the 
rotation or conductivity. Haworth found that the rate of hydration was 
much faster in one series than in the other; the d-lactones were converted 
almost completely to the acids, whereas the y-lactones were converted at a 
much slower rate (see Fig. 1). Thus, by comparing the stabilities (to 
hydration) of the various methylated lactones, it is possible to say whether 
the lactone under investigation is y- or 6-. It is very important to note 



I j/-mannolactone 

II y-galactonolactone 

III y-gluconolactone 

IV <5-mannonolactone 

V <5-gluconolactone 

VI rf-galactonolactone 




12 3 4 5 6 7 3 
Time in days 



9 iO 



FIG. 7.1. 



192 



ORGANIC CHEMISTRY 



[CH. VII 



that this method easily distinguishes a y- from a ^-lactone, but it does not 
prove one to be y- and the other 8-. The actual nature of the lactone was 
proved chemically ; the fast-changing lactone was shown to be the d-lactone, 
and the slow-changing one the y- (the chemical evidence was obtained by 
the degradative oxidation already described). However, having once estab- 
lished the relationship between the rate of hydration and the nature of the 
lactone, e.g., in the case of glucose, mannose, galactose and arabinose, the 
property can then be used to determine the size of the ring in an unknown 
lactone of a sugar acid. 

OHO CO 1 i CO 



H- 
HO- 
IIO- 

H- 



-OH 



-H 
-H 



-OH 



CH 2 OH 





CHijOCHj 



D -galactose (+)-lactone; (-)-lactone; 

(open-chain) 8-lactone Y-lactone 

Correlation between the above scheme and Hudson's lactone rule has been 
demonstrated in certain cases, e.g., galactose. Preparation of the methyl 
galactoside at reflux temperature, then methylation, hydrolysis, and finally 
oxidation with bromine water, leads to the formation of a methylated lactone 
which is dextrorotatory, and since it is a rapidly hydrated lactone, it must 
be 8-. Preparation of the methyl galactoside at 0°, etc., leads to the forma- 
tion of a methylated lactone which is laevorotatory and is very stable to 
hydration. Thus, this lactone will have the ring to the left (Hudson's 
lactone rule), and hence must be a y-lactone; at the same time, since it is a 
slowly hydrated lactone, it must be y- (see the above formulae). 

§7d* Pyranose and furanose structures of pentoses. The methods 
used for determining the size of sugar rings have been described with glucose 
(an aldohexose) as the example. It is also instructive to apply these methods 
to the aldopentoses. L(+)-Arabinose has been chosen as the example, and 
the following equations and footnotes should now be readily followed: 

(i) Glycoside formation at reflux temperature (Haworth et al., 1927). 

I is L(+)-arabinopyranose, and since it is dextrorotatory, the ring has been 
drawn to the right. This way of drawing the projection formula is based 
on the observation of Haworth and Drew (1926), who pointed out that if a 
ring in a sugar is 1 : 5- (i.e., d-), then Hudson's lactone rule holds good for 
sugars as for y-lactones. 

II is 2 : 3 : 4-tri-O-methyl-L-arabinose. 



OHOH 



H- 
HO- 



HO- 



-OH 

-H 

-H 



(!) CHjOH/HCl; reflux 
O (ii) (CHjJsSOj/NaOH 
(iii) HCI 



CH 2 - 
I 



H- 
CH 3 0- 



CH 3 0- 



CHOH 
-OCH3 
-H 
-H 



O 



CH 2 - 
II 



§7e] 



CARBOHYDRATES 



193 



GO 



Br,/H,Q 
90° * 



H- 
CH 3 C- 
CH s O- 



-OCH3 

-H 

-H 



C0 2 H 



O 



HNO s 



CH 2 - 
III 



H- 
CH3O- 
CH 3 0- 



-OCH3 

-H 

-H 



C0 2 H 
IV 



III is 2 : 3 : 4-tri-O-methyl-L-arabinolactone ; it is a 6-lactone as shown by 
oxidation to IV, and also by the fact that it is of the type that is readily 
hydrated. 

IV is 2 : 3 : 4-L-arabinotrimethoxyglutaric acid (this is the key compound). 

(ii) Glycoside formation at room temperature (Haworth et al., 1925, 1927). 

V is L-arabinofuranose. 

VI is 2 : 3 : 5-tri-O-methyl-L-arabinose. 

VII is 2 : 3 : 5-tri-O-methyl-L-arabinolactone (Hudson's lactone rule, and 
is slow-changing type). 

VIII is dimethyl-D-tartaric acid (this is the key compound). 



CHOH 







H- 
HO- 



CHOH 



-OH "FT— 

(QCH.QH/HC1; 18°^ q 

-H <H)(CH,),S0 1 /NaOH CH.O 

(iii) HC1 S 

-H 



CH 2 OH 
V 



-OCH, 
-H 



CH2OCH3 
VI 



Br a /H,Q^ 




C0 2 H 



HNOs 



H- 



CH3O- 



-OCH3 

-H 



CH 2 OCH, 
VII 



C0 2 H 
VIII 



§7e. Ketose ring structures. Only D-fructose will be considered; the 
method is essentially the same as that for the aldoses, but there is one im- 
portant variation, and that is in the oxidation of the tetramethylfructose. 
This cannot be oxidised by bromine water as can the tetramethylaldose ; the 
fructose derivative is first oxidised with dilute nitric acid and then with 
acid permanganate, and by this means the lactone is obtained. The lactone 
is then further oxidised by moderately concentrated nitric acid. The fol- 
lowing equations and footnotes explain the method, but before giving these, 
let us first consider the way of writing the projection formula of the ring 
structure of fructose. The usual open-chain formula is I, and to form the 
ring the ketone group is involved with C 6 in the pyranose form, and with C 5 
in the furanose form ; each of these can exist as the a- and /^-isomers. When 



194 



HO- 
H- 
H- 



ORGANIC CHEMISTRY 



CHgOH 

c=o 



[CH. VII 



-H 

-OH 

-OH 



CH 2 OH 
I 



CHgOH— C— OH 



O 



HO- 



H- 
H- 



-H 

-OH 

-OH 



-CH 



2 



II 

a-form 



1 



HO— C — CH 2 OH HO— C — OHijOH 



O 



HO- 
H- 
H- 



-H 

-OH 

-OH 



HO- 
H- 
H- 



CH 2 

III 

p-form 



-H 
-OH 



O 



CHjjOH 

IV 
p-form 



the ring is closed, then if the hydroxyl group is drawn on the right, this will 
be the oc-isomer (the CH 2 OH group now replaces a hydrogen atom in the 
aldoses). Furthermore, since D-fructopyranose is laevorotatory, the oxide 
ring is drawn to the left (see the comments on L(+)-arabinopyranose, §7d). 
Thus a-D(— )-fructopyranose is II, and /3-d(— )-fructopyranose is III. The 
furanose forms are obtained in a similar manner, but in this case the ring 
must be written to the right since the hydroxyl group on C s is on the right ; 
thus /S-D-fructofuranose is IV (see also sucrose, §13). 

(i) Glycoside formation at reflux temperature (Haworth et al., 1926, 1927). 

V is j8-d(— )-fructopyranose. 

VI is methyl /J-D-fructopyranoside. 

VII is methyl 1:3:4: 5-tetra-<9-methyl-/?-D-fructoside. 

VIII is 1:3:4: 5-tetra-0-methyl-/?-D-fructose. 

IX is 3 : 4 : 5-tri-0-methyl-j8-D-fructuronic acid (as lactol). 

X is 2 : 3 : 4-tri-O-methyl-D-arabinolactone; this is a quick-changing lac- 
tone, and is therefore a ^-lactone. 

XI is D-arabinotrimethoxyglutaric acid. 



HO— C— CHgOH 



HO- 
O H- 
H- 



CHaOH/HC^ 
-OH reflu * 



1 

CH 3 0— C— CH 2 OH 



HO- 



O H- 



-OH 



•GHi! 
V 



H- 



-H 

-OH 

-OH 



(CH,),SO« 
NaOH 



-CH|j 

VI 



§7e] 



CHjO— C— CHjOCHg 



CARBOHYDRATES 



195 



O 



CH3O- 

H- 
H- 



-H 

-OCH3 
-OCH 3 



HCl 



-CH. 



VII 



HO— C— CH«OGH 3 



O 



CH3O- 



H- 
H- 



-H 

-OCH s 

-OCH s 



HNO, 



-CH 2 



VIII 



HO— C — C0 2 H 
0H 3 O- 







H- 
H- 



H CH s O 

OCH, h»so 4 



-OCH 3 



H- 
H- 



-CH 2 
IX 



CO- 



-H 

-OCH, 
-OCHj 



q HNO t> 



CH 3 0- 



CH 2 - 
X 



H- 



H- 



CO.H 



-H 

-OCH3 

-OCH, 



C0 8 H 
XI 



(ii) Glycoside formation at room temperature (Haworth et al., 1927). 

XII is j8-D-fructofuranose. 

XIII is 1:3:4: 6-tetra-0-methyl-j8-D-fructose. 

XIV is 3:4: 6-tri-0-methyl-j3-D-fructuronic acid (as lactol). 



HO— C— CHjjOH 



HO- 



H- 
H- 



-H 
-OH 



HO— C-CHgOCHs 

(i)CH,OH/HCl; 18° 
(ii)(CH,) il SO,/NaOH > CHjO- 
V (iii) HCI 



CH 2 OH 
XII 



H- 



H- 



-H 
-OCH, 



CH 2 OCH, 
XIII 



O 



HNO. 



HO— C— COjH 



CH,0- 
H- 
H- 



-H O 
-OCH. 



KMnCv 
HjSO« 



CH,0- 
H- 
H- 



CH 2 OCH, 
XIV 



CO- 



-H 
-OCH, 



O 



CH,0- 



HNOa 



H- 



CO.H 



-H 
-OCH, 



CH 2 OCH, 
XV 



C0 2 H 
XVI 



XV is 2 : 3 : 5-tri-O-methyl-D-arabinolactone ; this is a slow-changing lac- 
tone, and so is y-. 

XVI is dimethyl-L-tartaric acid. 



196 



ORGANIC CHEMISTRY 



[CH. VII 



§7f. Conclusion. From the foregoing account it can be seen that the 
sugars exist as ring structures and not as open chains. Haworth (1926) 
therefore proposed a hexagonal formula for ^-sugars based on the pyran 
ring, I. The problem now is to convert the conventional plane-diagrams 
that we have been using into the pyranose formula. Let us take a-D- 
glucopyranose, II, as our example. The conventional tetrahedral diagram 
of II is III (see §5. II). Examination of III shows that the point of attach- 
ment of the oxide ring at C x is below the plane of the paper, and that at C 5 
it is above the plane of the paper. If the tetrahedron with C 5 at its centre is 
rotated so that the point of attachment of the oxide ring is placed below 
the plane of the paper, III will now become IV, and the oxide ring will now 
be perpendicular to the plane of the paper, i.e., perpendicular to the plane 
containing all the other groups (these all lie in a plane above the plane of 
the paper). The conventional plane-diagram of IV is V, but in order to 
emphasise the fact that the oxide ring is actually perpendicular to the plane 
of the paper, the part of the ring lying below the plane of the paper is shown 
by a broken line (the true plane-diagram should have a normal line drawn 



.CH=CH ^ 
CH 2 
N CH=CH 

I 



/° 



H— C — OH 



H- 

HO- 

H- 

H- 



H— C— OH 



H 

HO 

H 

HOCH 



-OH 



-H 



O 



-OH ■ 
i 

-h y 



-OH 



-H 
-OH 



O 



CH.jOH 
II 




HOCH 2 





IV 



0. 



VI 



VII 



as in II). Comparison of V with II shows that where the CH 2 OH was 
originally is now the point of attachment of the oxide ring, the CH 4 OH 
occupying the position where the H atom was, and the latter now where the 
oxide ring was. Thus, if we consider the conversion of II into V without 
first drawing III and IV, then in effect two Walden inversions have been 
effected, and consequently the original configuration is retained. V is now 
transformed into the perspective formula VI by twisting V so that the oxide 
ring is perpendicular to the plane of the paper and all the other groups are 
joined to bonds which are parallel to the plane of the paper. By convention, 
Cj is placed to the right and the oxygen atom at the right-hand side of the 
part of the ring furthest from the observer. Sometimes the lower part of 
the ring, which represents the part nearest to the observer, is drawn in thick 
lines. Thus, to change V into VI, first draw the hexagon as shown in VI, 
and then place all the groups on the left-hand side in V above the plane of 
the ring in VI ; all those on the right-hand side in V are placed below the 



m 



CARBOHYDRATES 



197 



plane of the ring in VI. VII represents a " short-hand representation " of 
D-glucose. 

In a similar manner, Haworth proposed a five-membered ring for y-sugars 
based on the furan ring, VIII. Using the above scheme of transformation, 
the plane-diagram of methyl /?-D(+)-glucofuranoside, IX, is first changed 
into X (two changes are carried out), and then X is twisted so as to be 
represented by XI, in which the oxygen atom is furthest from the observer. 



CH 3 0— C— H 



^ // 
CH-CH 

VIII 



H- 

HO- 

H- 

H- 



-OH 



-H 



O 



-OH 




CH 2 OH 
IX 



CH 3 0— C— H 1 
H- 



HO- 
CH 2 OH-CHOH- 



1 

-oh! 
o 
-h ! 

1 

-h ; 



Two other examples which illustrate the conversion into the perspective 
formula are: 



(i) <x-d(— )-fructopyranose. 



fcH 2 OH 
-C— OH 



HO- 



O H- 
H- 



^-H 

±- OH 



-OH 



-CH, 



HOCH— C— OH HOCH 2 — C— OH ! 



O 



HO- 
H- 



H- 



-H 

-OH 

-OH 



CH 2 




HO- 
H- 
H- 
H- 



-H 



1 

O 
1 

-OH ' 



-OH 



-H 



198 ORGANIC CHEMISTRY 

(ii) Methyl p-D(+)-fructofuranoside. 



[CH. VII 



CH 2 OH 



CH s O-r C 




CH 3 0— C— CH 2 OH 



HO- 
H- 
H- 



-H 
-OH 



1 
CH3O- C— CHjOH! 
1 

O 



O 



HO 

H 

HOCH, 



-H 



-OH 
-H 



CH»OH 



CH,OH 




OCH s 



^HgOH 



Actual size of sugar rings. Since glycoside formation under different 
conditions gives compounds containing different sized rings, the important 
question then is: What is the size of the ring in the original sugar? Oxida- 
tion of an aldose with hypobromite produces an unstable ^-lactone; this is 
the first product, but slowly changes into the stable y-lactone (Hudson, 1932). 
It therefore follows that the size of the ring in normal sugars is pyranose. 
By analogy, ketoses are also believed to exist normally as pyranose com- 
pounds. This pyranose structure has been confirmed by X-ray analysis 
of various crystalline monosaccharides (Cox, 1935). McDonald et al. (1950) 
examined oc-D-glucose by X-ray analysis, and confirmed the presence of the 
six-membered ring, the configuration as found chemically, and also the cis 
arrangement of the 1 : 2-hydroxyl groups in the a-form. Eiland et al. 
(1950) subjected difructose strontium chloride dihydrate to X-ray analysis, 
and showed the presence of a six-membered ring, and confirmed the con- 
figuration found chemically. It might be noted here that furanose sugars 
have not yet been isolated, but some furanosides have. It is also interesting 
to note that apparently fructose and ribose always occur in compounds as the 
furanose structure. Barker et al. (1959), however, have obtained evidence 
to show that D-ribose exists as the pyranose form at the moment of dissolu- 
tion and its mutarotation involves change in size of the ring {cf. the fructose 
residue in sucrose, §13). 

§7g. More recent methods for determining the size of the ring in 
sugars. These methods make use of the fact that periodic acid splits 
1 : 2-glycols (Malaprade, 1928) ; thus periodic acid splits the following types 
of compounds (see also Vol. I): 



R-CHOH-CHOH-R' 

R-CHOH-COR' 

R-COCOR' 



lHIO, 



> R-CHO + R'-CHO 



1H10. 



> R-CHO + R'-COgH 



1H10. 



> R-CO.H + R'-C0 2 H 



Thus a free sugar is broken down completely, e.g., 
CH 2 OH-CHOH-CHOH-CHOH-CHO -^^ 



> H-CHO + 4H-CO a H 



§7g] CARBOHYDRATES 199 

In all of these reactions, one molecule of periodic acid is used for each pair 
of adjacent alcoholic groups (or oxo groups). Thus, by estimating the 
periodic acid used, and the formic acid and formaldehyde formed, the number 
of free adjacent hydroxy 1 groups in a sugar can be ascertained. Hudson 
(1937, 1939) oxidised " normal " methyl a-D-glucoside, I, with periodic acid, 
and found that two molecules of periodic acid were consumed, and that one 
molecule of formic acid was produced. It should be noted that although 
periodic acid can completely degrade a. free sugar, the oxide ring in glycosides 
is sufficiently stable to resist opening by this reagent. The first product 



I 

H— C— OCH 3 

H— C — OH 

HO— C— H 

H— C— OH 



O 2H10« 



H— C- 

I 



H- 



*- HC0 2 H + 



•C— OCH3 

I 
CHO 



B^/HnO^ 



CHO 



CHgOH 
I 



H— C< 

I 



SrCO, 



CHgOH 
II 



H— C— OCH 3 

I 
O— CO 



V 



-co 



H— C- 



O (0 H,SO« > 
(ii) Bn/H,0 



I 

CHgOH 
III 



H- 



C0 2 H 

C0 2 H 

IV 

+ 
C0 2 H 
I 
C— OH 

I 
CH 2 OH 

V 



of oxidation of methyl a-D-glucoside was D'-methoxy-D-hydroxyrnethyldi- 
glycolaldehyde, II, and this, on oxidation with bromine water in the presence 
of strontium carbonate, gave the crystalline salt, III. Ill, on acidification 
with sulphuric acid (for hydrolysis), followed by further oxidation with 
bromine water, gave oxalic acid, IV, and d(— )-glyceric acid, V. Isolation 
of II, III, IV and V indicates that the ring in I is d-; this is also supported 
by the fact that only one carbon atom was eliminated as formic acid, and 
that two molecules of periodic acid were consumed. By similar experiments, 
it has been shown that all methyl a-D-hexosides of the " normal " type con- 
sume two molecules of periodic acid and produce one molecule of formic acid, 
and all also give products II, III, IV and V. Thus all these hexosides must 
be six-membered rings, and also it follows that all " normal " methyl 
a-pyranosides have the same configuration for C x ; this has already been 
shown to be VI. 



H— C— OCH 3 




VI 



200 



ORGANIC CHEMISTRY 



[CH. VII 



Similarly, all ^-compounds, on oxidation with periodic acid, give the 
stereoisomer of II, i.e., L'-methoxy-D-hydroxymethyldiglycolaldehyde. 

Aldopentopyranosides also give similar products as those obtained from 
the aldohexopyranosides, e.g., methyl a-D-arabinopyranoside, VII, gives 
D'-methoxydiglycolaldehyde, VIII. Since all methyl oc-D-aldopentopyrano- 



H— C— OCH 3 
HO— C— II 

H— C— OH 

+ 

H— C— OH 



II — C— OCH 3 



2H1Q 4 



>■ HCOoH + 



VII 



CHO 

CIIO 
I 
CH 2 - 



O 



VIII 



sides give the same diglycolaldehyde, they too have the same configuration 
for C ± , viz., VI. 

When hexofuranosides, i.e., the " abnormal " glycosides, are oxidised with 
periodic acid, two molecules of acid are consumed and one molecule of 
formaldehyde is formed. These results are in keeping with the presence of a 
five-membered ring, e.g., methyl ot-D-glucofuranoside. 



H— C— OCH3 
H— C— OH 

— H 

HO— C— H 
I 
H— C- 



O 



2HIQ 4 . 



H- 



H- 



r 
-o- 



-OCH, 



CHO 

CHO 

I 

-c — 



o 



H— C— OH 

1 

CH 2 OH 



CHO 

+ 
H-CHO 



Oxidation of methyl oc-D-arabinofuranoside, IX, consumes one molecule 
of periodic acid, and no carbon atom is eliminated (either as formaldehyde 
or formic acid); thus the ring is five-membered. Furthermore, since the 
dialdehyde II obtained is the same as that from methyl a-D-glucopyranoside, 
I, the configuration of C t is the same in both I and IX. 



H— C— OCH3 
HO— C— H 

H— C— OH 

I 
H— C 



O 



CH 2 OH 
IX 



1H1O4 



H— C— OCH3 
CHO 



O 



CHO 



H— C- 



CH< 



II 



OH 



There appears to be some doubt about the structure of II. Various 
formulae have been proposed (Hurd et al., 1953; Smith et al., 1955), and 



§7h] CARBOHYDRATES 201 

Mester et al. (1957) have obtained evidence that of these structures the cyclic 
hemiacetal (Ila) is the most likely. 



OH 
H-4- 



CH 3 — C— H 



A 



CH 9 - 



6 



OCH — C— H 

I 

OHo 



or 



I 

II 

o 



H 



-OL H 



O 



L; 



II a 



I 

OH 



OCH, 



Hough et al. (1956) have carried out periodate oxidations on phenylosa- 
zones of reducing monosaccharides (X) and obtained formaldehyde, formic 
acid and mesoxalaldehyde 1 : 2-bisphenylhydrazone (XI). These authors 
found that XI is obtained from all monosaccharides in which C 3 and C 4 are 



CH=N-NH-Ph 

1 


CH=N-NH-Ph 


C=N-NH-Ph 


C=N-NH-Ph 


1 
CHOH 

— 1 

CHOH 


3H10, | 

>CHO 

XI 


— 1 

CHOH 


4- 
2H-C0 2 H 


— I" 

CH 8 OH 


+ 
CH 2 


X 





free, and 1 molecule of formaldehyde from the terminal CH 2 OH group when 
this is free. They also showed that the osazones of the disaccharides maltose 
(§15), cellobiose (§16), and lactose (§17) did not give XI but did give formalde- 
hyde. Thus C 3 or C 4 are linked in these disaccharides. On the other hand, 
the oxidation of the osazone of melibiose (§18) gave XI but no formaldehyde; 
thus C 6 is linked in this molecule. These oxidations therefore offer a means 
of differentiating between the two types of disaccharides. 

§7h. Conformation of pyranoside rings. Cyclic 1 : 2-glycols form 
complexes in cuprammonium solutions, a five-membered ring being produced 
in which the copper atom is linked to two oxygen atoms. Furthermore, 
the extent of complex formation depends on the spatial arrangement of the 
two adjacent hydroxyls, the most favoured position being that in which the 
two groups and the two carbon atoms to which they are attached lie in one 
plane. Since complex formation changes the molecular rotation, the mole- 
cular rotational shift will indicate the extent of complex formation (cf. boric 
acid complexes, §4). Reeves (1950), using this cuprammonium complex 
formation, has shown that the pyranose sugars assume a chair form in 
preference to any boat form wherever both are structually possible. Substi- 
tution of an oxygen atom for a carbon atom in cycfohexane causes only minor 
distortions in the ring (Hassel et al., 1947), and consequently the general 
conformational features are retained in the pyranose sugars. Reeves (1951) 
proposed the two regular conformations shown, and named them Cl (the 
normal chair) and 1C (the reverse chair). Reeves (1958) pointed out that 
there is an infinite number of skew conformations in which angle strain is 



202 



ORGANIC CHEMISTRY 



[CH. VII 



absent. It is still usual, however, to use the regular conformations of Reeves 
since these are readily related to the Haworth formulae. Reeves has shown 
that the CI conformation is the more stable, and this is supported by Barker 
et al. (1959) who studied the ring structures by periodate oxidations in 
buffered solutions. Also, according to these authors, the chief exceptions 
are /9-D-altrose, /S-D-mannose and /S-D-talose, which are considered to be 



O v 



0- 




CI 



IC 



appreciably less stable in the IC conformation. a-D-Lyxose appears to 
favour the CI conformation, and the authors consider that oc-D-allose, 
/3-D-ribose, and a-D-xylose favour the IC rather than CI conformation. 

As we have seen (§2), D-glucopyranose is an equilibrium mixture (in 
solution) of the a- and /3-anomers: the conformations of these are: 



,CH 2 OH 



HO 




We have also seen that the more stable isomer is the one with the larger 
number of equatorial substituents, and so the /S-form can be expected to 
be more stable than the a-. Whiffen et al. (1954) have used infra-red spectro- 
scopy to distinguish between a- and jS-anomers; the absorption maxima 
depend on the axial or equatorial conformation of hydroxyl groups. 

In general, /5-anomers are more reactive than a-, e.g., Bunton et al. (1954) 
have shown that acid-catalysed hydrolysis proceeds more rapidly for 
/3-methyl pyranosides than for the corresponding a-compounds. According 
to these authors (1955), the hydrolysis proceeds by a unimolecular decom- 
position of the conjugate acids of the pyranosides. The rate-determining 
step, however, may be formulated in two ways, both of which are con- 
sistent with the evidence available at present. 



(i) CHOMe 



H 
CH-^b+Me 



O 



+ H s O+: 



fast 



o 



CH- 



CH 



J 



slow 



-*-MeOH 



+ 
CH 



CH- 



fast 



CHOH 



'I J 

CH— ' 



+ H+ 



§8] CARBOHYDBATES 203 

(ii) CHOMe CHOMe CHOMe 

+ H.O+ =?=* j Q H > I 



CH — 



»*« ■* j | >- i 

.HOH 



A*. 



i i 

i i 



H 8 0— CH— OMe CHOH 

H,0 | 1^. 

~K^ ! Jff^j +M eOH + H+ 

I < 

CHOH CH — I 



On the other hand, axial hydroxyl groups are less reactive (to esterification 
and hydrolysis reactions) than equatorial groups (§12. IV). In /?-pyrano- 
sides, the methoxyl group is equatorial and so mechanism (i) would be more 
in keeping with the fact that /S-anomers are more readily hydrolysed than 
a- (in which the methoxyl group is axial). However, Bunton et al. (1955) 
also showed that the rate of hydrolysis depends on the nature of the aglycon. 
In the above example the aglycon is methyl, but when it is phenyl then it is 
the a-anomer which is hydrolysed faster. 

Since the hemiacetal linkage in the ring-form of reducing sugars is very 
labile, reactions involving the carbonyl group may possibly proceed through 
the acyclic or the cyclic form (see also mutarotation, §2). Isbell et al. 
(1932) have obtained evidence that the oxidation of an aldose with bromine- 
water proceeds to the 1,5-lactone by direct oxidation of the pyranose form. 
Isbell et al. (1932-1946) also showed that /S-D-anomers (equatorial OH at C x ) 
are oxidised much faster than the corresponding oc-D-anomers (axial OH at 
Cj). Further experiments on the oxidation of D-glucose by bromine-water 
appear to show that the a-anomer is first converted into the j8-anomer which 
is then rapidly oxidised directly to o-gluconolactone (Perlmutter-Hayman 
et al., 1960). Pentoses (except D-lyxose) are also oxidised in the /3-form 
(Overend et al., 1960). Isbell (1961), however, disagrees with Overend's 
claim that the rate-determining step is the transformation of oc-D-aldopyran- 
oses into the /3-anomers. 

§8. fcoPropylidene derivatives of the monosaccharides. Sugars con- 
dense with anhydrous acetone in the presence of hydrogen chloride, sulphuric 
acid, etc., at room temperature to form mono- and di-wopropylidene (or 
acetone) derivatives. These are stable towards alkalis, but are readily 
hydrolysed by acids. In the di-wopropylidene derivatives, one wopropyli- 
dene group is generally removed by hydrolysis more readily than the other, 
and thus by controlled hydrolysis it is possible to isolate the mono-j'so- 
propylidene derivative, e.g., di-isopropylideneglucose may be hydrolysed 
by acetic acid to the mono-derivative. 

The structures of these isopropylidene derivatives have been determined 
by the methods used for the sugars themselves, i.e., the compound is first 
methylated, then hydrolysed to remove the acetone groups, and the product 
finally oxidised in order to ascertain the positions of the methyl groups. 
Let us consider D-glucose as an example. This forms a di-tsopropylidene 
derivative, I, which is non-reducing; therefore C x is involved in the formation 
of I. On methylation, I forms a monomethyldi-Mopropylideneglucose, II, 
and this, on hydrolysis with hydrochloric acid, gives a monomethylglucose, 
III. Hydrolysis of I with acetic acid produces a mono-tsopropylidene- 
glucose, IV, which is also non-reducing. Thus C t in IV must be combined 
with the wopropylidene radical. Methylation of IV, followed by hydrolysis, 



204 ORGANIC CHEMISTRY [CH. VII 

gives a trimethylglucose, V. Methylation of V gives a methyl tetramethyl- 
glucoside, and this, on hydrolysis, gives 2:3:5: 6-tetra-O-methyl-D-glucose, 
VI, a known compound (see §7b). Thus V must be 2 : 3 : 5-, 2 : 3 : 6-, or 
3:5: 6-tri-O-methyl-D-glucose. Now V forms an osazone without loss of 
any methyl group; therefore C 2 cannot have a methoxyl group attached 
to it, and so V must be 3 : 5 : 6-tri-O-methyl-D-glucose. Thus one wopro- 
pylidene radical in di-wopropylideneglucose, I, must be 3 : 5-, 3 : 6- or 5 : 6-. 
Monomethylglucose, III, on methylation followed by hydrolysis, gives 
2:3:4: 6-tetra-O-methyl-D-glucose, VII, a known compound (see §7a). 
Hence III must be 2-, 3-, 4- or 6-O-methyl-D-glucose. Since III gives 
sodium cyanate when subjected to the Weerman test (see §11), it therefore 
follows that C 2 has a free hydroxyl group. Oxidation of III with nitric acid 
produces a monomethylsaccharic acid ; therefore C 6 cannot have a methoxyl 
group attached to it. This monomethylsaccharic acid forms a lactone which 
behaves as a y-lactone ; therefore a methoxyl group cannot be at C 4 . Thus, 
by the process of elimination, this monomethylglucose, III, must be 3-0- 
methyl-D-glucose. It therefore follows that the two isopropylidene groups 
in the di-wopropylidene derivative must be 1 : 2- and 5 : 6-, the ring being 
furanose, and the mono-z'sopropylidene derivative being 1 : 2-. The fore- 
going reactions can be written as on opposite page: 



§8] 



CARBOHYDRATES 



205 



H— C-OH 

I 
H-C-OH 

HO-C-H 

H-C-OH 

I 
H— C 



H— C— (\ 

<CH,) a CO_ jj_ ( l_ ^ C(CH3)2 



O 



HC1 



CH 2 OH 
«-D(+)-glueose 



HO 



O-H 
I 
H-C 



H-C-Q^ 
O n»oh * H-<|--0 
CH 3 0-C-H 



O 



H-C— 
I 
CH 2 

I 



)C(CH 3 ) 2 



CH,-COjH 



H— O 

I 

H-C-Q, 
I J 

ch 2 o 
ii 

I HCl 



:c(ch s ) 2 



H— C— O 

I )C(CH 3 )2 
H-C— O 

I 
HO— C— H 

H-C 

I 
H— C— OH 
I 
CHjjOH 

IV 



O 



f 



)(CHJ,S0 4 
i) MCI 



CHOH 
I 
H-C— OH 
I 
CH 3 0-C— H 

H-C-OH 



O 



H— C- 

I 



CH 2 OH 
III 



1(0 
f 



i)(CHJ,SO« 
HCI 



CHOH 

H-C -OCH3 

CH3O-C-H 
I 
H— C 

H-C— OCH3 

CH 2 OCH 3 
VI 



CHOH 

I 
(i)(CHj,so 4 H— C— OH 



O (») hci I O 

CH3O-C-H 

H— C 



H-C— OCH 3 
I 
CH 2 OCH 3 

V 



CHOH 

I 
H-C-OCH3 

I 
CH3O-C-H 

I 
H— C— OCHj 

H— C 



O 



CH 2 OCH, 
VII 



As a result of much experimental work (of the foregoing type), it has 
been found that acetone usually condenses with cj's-hydroxyl groups on 
adjacent carbon atoms, the condensation occurring in such a way as to 
favour the formation of the di-t'sopropylidene derivative. For this to occur, 
the ring often changes size, e.g., in a-D-galactopyranose, VIII, the hydroxyl 
groups on C x and C 2 are in the cis position, as are also the hydroxyl groups 
on C 3 and C 4 . Thus galactose forms the 1 : 2-3 : 4-di-O-t'sopropylidene-D- 
galactopyranose, IX. On the other hand, in a-D-glucopyranose, only the 
two hydroxyl groups on C t and C 2 are in the cis position, and thus, in order 
to form the dt-isopropylidene derivative, the ring changes from pyranose 
to furanose, the latter producing 1 : 2-5 : 6-di-O-wopropylidene-D-gluco- 
furanose (I). The mono-derivative is 1 : 2-0-wopropylidene-D-gluc6furanose 



206 



ORGANIC CHEMISTRY 



[CH. VII 



H— C— OH 

I 

H— C— OH 



HO— C- 
I 

HO— C- 
I 
H— C- 



-H 
-H 



O 



(CH 3 ) 2 C 



H — C— 

I 
H— C— O' 

I 
,0— C— H 



/C(CH 3 ) 2 



O 



I 

-c- 



o- 

I 

H— C- 



-H 



CH 2 OH 
VIII 



CH 2 OH 
IX 



(IV). Fructose can form two di-wopropylidene derivatives which both con- 
tain the pyranose ring. 



CH 2 
I )C(CH3) 2 

-c— o 



HO— C— H 



(CH 3 ) 2 C N 



CH 2 OH 
I 

o-c 



O— C — H 



O 



H— C— O. 

I 
H— C— O 

I 



>(CH 3 ) 2 



I 
H— C— Q, 



O 



H- 



— 0H 2 
1:2-4:5- 



-C— O 
CH. 



y C(CH 3 ) 2 



2:3-4:5- 



§9. Other condensation products of the sugars. Not only does 
acetone condense with sugars, but so do other oxo compounds such as 
formaldehyde, acetaldehyde and benzaldehyde. Benzaldehyde condenses 
with two cis hydroxyl groups on alternate carbon atoms, e.g., glucose forms 
4 : 6-0-benzylidene-D-glucopyranose, I. 

Triphenylmethyl chloride reacts with sugars to form triphenylmethyl 
ethers; these are usually known as trttyl derivatives. Trityl ethers are 



CHOH 
I 
H-G— OH 
I 



O 



HO-C— H 
I 
H— C— u./ 



H— C- 



rv 



CH'CgHg 



CHOCHj 
I 
H-0— OH 

I 
HO— 0— H 

I 
H— C— OH 

I 
H— C 



CH 2 
I 



CH 2 0-C(CH 6 ) s 
II 



formed much faster with primary alcoholic groups than with secondary, 
e.g., methyl glucopyranoside reacts with triphenylmethyl chloride in pyridine 
solution to form methyl 6-tritylglucopyrano,side, II. 

^-Joluenesiilphonyl chloride (represented as TsCl in the following equa- 
tions) reacts with sugars in the presence of pyridine to form tosyl esters. 
These esters usually produce epoxy-sugars (anhydro sugars) when hydro- 
lysed with sodium methoxide in the cold, provided that there is a free 



§9] 



CARBOHYDRATES 



207 



hydroxyl group on an adjacent carbon atom and that this hydroxyl and the 
tosyl group are trans to each other. This is an example of neighbouring 
hydroxyl group participation (§6c. Ill), and the mechanism is: 



H— C— OH 
I 
HO-C— H 



TsCl 



C,H 6 N 



H— C— OTs 
I 
HO— C— H 



OMe 



>A 



H-=C 
O— C— H 



Ts 



-° Ts ~> o X 



C— H 

I 
V C— H 



On hydrolysis with alkali, these anhydro sugars form a mixture of two 
sugars, inversion occurring at either carbon when the epoxide ring opens 
(see §5. IV). 

H— C— OH Na0H /C— H Na0H HO— C— H 
HO— C— H \C— H H— C— OH 



III 



IV 



In III the configurations of the two carbon atoms are the same as in the 
original sugar, but in IV both configurations are inverted (to form a new 
sugar). 

When the tosyl group is trans to two hydroxyl groups (on adjacent carbon 
atoms), two anhydro sugars are formed. At the same time, however, larger 
epoxide rings may be produced without inversion, e.g., Peat et al. (1938) 
treated 3-tosyl methyl /?-glucoside (V) with sodium methoxide and obtained 
a mixture of 2 : 3-anhydroalloside (VI; with inversion), 3 : 4-anhydroalloside 
(VII; with inversion), and 3 : 6-anhydroglucoside (VIII; no inversion). 



CH 2 OH 



H 



HO 



0. OMe 



'H 
OTs H 



H 



H OH 

V 



MeONa . 



CH 2 OH 



O. OMe 



HO 




CH 2 OH 
H J— Ot OMe 




OH 
VII (25%) 



VI (60%) 



O v OMe 




H OH 

VIII (15%) 



It is possible, however, by using suitable derivatives of a tosyl ester to 
obtain only one anhydro sugar, e.g., 2-benzoyl-3-tosyl 4: 6-benzylidene 



208 



ORGANIC CHEMISTRY 



[CH. VII 

methyl ac-glucoside (IX), on treatment with sodium methoxide, forms 
2 : 3-anhydro 4 : 6-benzylidene methyl a-alloside (X). 



OCH 



O v H 



PhCH 




OCH, 



MeONa 



PhCH 



OMe 
OCOPh 



IX 




OMe 



For the formation of the epoxide to proceed easily, it is necessary that 
the trans OH and Ts groups should be diaxial. In the majority of tosyl 
derivatives, however, both the tosyl group and the vicinal fraws-hydroxyl 
group are equatorial (cf. §7h). Nevertheless, these tosyl derivatives are still 
easily converted into epoxides. This may be explained on the basis that 
the' normal chair form (CI) readily changes into the reverse chair form (1C) ; 
consequently both groups are now axial and so epoxide formation proceeds 
readily (cf. §5b. IV). 

§10. Glycate and glycosamines and anhydro sugars. Glycals are 

sugar derivatives which have a pyranose ring structure and a double bond 
between Q and C 2 , e.g., D-glucal is I. Glycals may be prepared by reducing 
acetobromo compounds (see §24) with zinc dust and acetic acid, e.g.> D-glucal 
from tetra-O-acetyl-D-glucopyranosyl bromide, II, followed by hydrolysis 
of the acetyl groups. 

Glycosamines are amino-sugars in which a hydroxyl group has been 
replaced by an amino-group. All naturally occurring amino-sugars are 



CH 2 OH 
H /I— — O, 




CH 
II 

, CH 

CHOH 

H I 

or CHOH 

I 
CH 

I 
CH 2 OH 



CHBr 
I 
CHO-CO-CH 3 

CHO-CO-CH 3 

I 
CHO-CO-CH 3 



O 



CH 

I 
CH 2 0-CO-CH 3 

II 



CHOH 
I 
CH-NH 2 

CHOH 

CHOH 

I 
CH 



O 



I 
CH 2 OH 

III 



hexoses, and the amino-group always occurs on C 2 , e.g., glucosamine, which 
occurs in chitin, is 2-aminoglucose, III (see also §23). 

Anhydro sugars. These may be regarded as being derived from mono- 
saccharides by the elimination of a molecule of water to form an epoxide. 
The size of the oxiran ring varies from 1 : 2- to 1 : 6-. The 1 : 2-anhydro 
sugars are commonly known as ae-glycosans, and may be prepared in various 
ways, e.g., by heating a sugar under reduced pressure (Pictet et al., 1920). A 
general method of producing the ethylene oxide series is by the hydrolysis 
of suitable tosyl esters (see §9). 

§11. Vitamin C or L-ascorbic acid. Ascorbic acid is very closely re- 
lated to the monosaccharides, and so is conveniently dealt with here. 
Hawkins (1593) found that oranges and lemons were effective for treating 



§11] 



CARBOHYDRATES 



209 



scurvy, a disease particularly prevalent among seamen. The first significant 
step in elucidating the nature of the compound, the absence of which frorh 
the diet caused scurvy, was that of Hoist and Frolich (1907), who produced 
experimental scurvy in guinea-pigs. Then Szent-Gyorgi (1928) isolated a 
crystalline substance from various sources, e.g., cabbages, paprika, etc,, and 
found that it had antiscorbutic properties. This compound was originally 
called hexuronic acid, and later was shown to be identical with vitamin C, 
m.p. 192°, [a] D of +24°. 

The structure of vitamin C was elucidated by Haworth, Hirst and their 
co-workers (1932, 1933). The molecular formula was shown to be C 6 H 8 6 , 
and since the compound formed a monosodium and monopotassium salt, ■ 
it was thought that there was a carboxyl group present. Vitamin C behaves 
as an unsaturated compound and as a strong reducing agent; it also forms a 
phenylhydrazone and gives a violet colour with ferric chloride. All this 
suggests that a keto-enol system is present, i.e., 



-CO— CH- 



-C(OH)=C- 



The presence of an aldehyde group was excluded by the fact that vitamin C 
does not give the Schiff reaction. Now, when boiled with hydrochloric acid, 
ascorbic acid gives a quantitative yield of furfuraldehyde: 



~ hci CH CH 

C 6 H,0 6 -^ || || 



+ C0 2 + 2H 2 



This reaction suggests that ascorbic acid contains at least five carbon atoms 
in a straight chain, and also that there are a number of hydroxyl groups 
present (cf. the pentoses). Aqueous iodine solution oxidises ascorbic acid 
to dehydroascorbic acid, two atoms of iodine being used in the process arid 
two molecules of hydrogen iodide are produced; the net result is the removal 
of two hydrogen atoms from ascorbic acid. Dehydroascorbic acid is neutral 
and behaves as the lactone of a monobasic hydroxy-acid; and on reduction 
with hydrogen sulphide, dehydroascorbic acid is reconverted into ascorbic 
acid. Since this oxidation-reduction process may be carried out with 
" mild " reagents, it leads to the suggestion that since the oxidation product, 
dehydroascorbic acid, is a lactone, then ascorbic acid itself is a lactone and 
not an acid as suggested previously. Since, however, ascorbic acid can form 
salts, this property must still be accounted for. One reasonable possibility 
is that the salt-forming property is due to the presence of an enol group, thfc 
presence of which has already been indicated. Thus all the preceding re- 
actions can be explained by the presence of an oc-hydroxyketone grouping 
in ascorbic acid: 



HCOH 

I =F 

C=0 
I 

Reducing; 

forms a 

phenylhydrazone 



C— OH 

II 

C— OH 



h + 2H 8 Q 



Unsaturated ; 

colour with 
ferric chloride; 
sodium enolate 



-2H a Q^ 



C=0 

I 

c=o 



C(OH) 2 

C(OH)js 
I 



+ 2HI 



210 



ORGANIC CHEMISTRY 



[CH. VII 



The final result is the removal of two hydrogen atoms to form dehydro- 
ascorbic acid. 

C„H 8 8 + I* -> C 6 H 6 6 + 2HI 

Although all these reactions may appear to be speculative, they are known 
to occur with dihydroxymaleic acid; hence by analogy with this compound, 
the explanation offered for the reactions of ascorbic acid is very strongly 
supported. 

HO>. ^C0 2 H 
C 
II 

; HO^ ^C0 2 H 

Dihydroxymaleic 
acid 



When dehydroascorbic acid is oxidised with sodium hypoiodite, oxalic 
and L-threonic acids are produced in quantitative yields (Hirst, 1933). 
L-Threonic acid, IV, was identified by methylation and then conversion into 
the crystalline amide; this compound was shown to be identical with tri-O- 
methyl-L-threonamide (obtained from L-threose). Further evidence for the 
nature of product IV is given by the fact that on oxidation with nitric acid 
it gives D(+)-tartaric acid. The formation of oxalic and L-threonic acids 
suggests that dehydroascorbic acid is III, the lactone of 2 : 3-diketo-L- 
gulonic acid. Hence, if we assume that I is the structure of ascorbic acid, 
the foregoing reactions may be formulated as follows, dehydroascorbic acid 
being formed via II. 




H 2 OH 



CO 

I 
C(OH) 2 

I O 

C(OH) 2 | 



H— C ' 

I 
HO-C— H 
I 
CH 2 OH 

II 




I 



HO— C-H 
I 
CHjOH 

III 



C0 2 H 

COjsH 

+ 
C0 2 H 

H— C-OH 
I 
HO— G— H 
I 
CHaOH 

IV 



The ring in ascorbic acid has been assumed to be five- and not six- 
membered, because the lactone (i.e., ascorbic acid) is stable towards alkali 
(cf. §7c). In actual fact, however, the same final products would also have 
been obtained had the ring been six-membered. It must therefore be ad- 
mitted that the weakness of the above proof of structure lies in the evidence 
used for ascertaining the size of the ring. Structure I, however, has been 
amply confirmed by other analytical evidence. Diazomethane converts 
ascorbic acid into dimethylascorbic acid (V) ; these two methoxyl groups are 
most likely on C g and C s , since diazomethane readily methylates acidic (in 
this case, enolic) hydroxyl groups. This dimethyl derivative is neutral, and 
dissolves in aqueous sodium hydroxide to form a sodium salt without the 
elimination of a methyl group; thus there cannot be a carbomethoxyl group 
present, and so it is most likely that two enolic hydroxyl groups are present 
(Hirst, 1933). Furthermore, the formation of the sodium salt from the 
neutral compound suggests the opening of a lactone ring (the two enolic 



§11] CARBOHYDRATES 211 

groups are now methylated and so cannot form a sodium salt). The similar- 
ity in structure between ascorbic acid and its dimethyl derivative is shown 
by the fact that the absorption spectra of both are similar. When this 
dimethyl derivative is methylated with methyl iodide in the presence of 
dry silver oxide (Purdie method; see §7), two further methyl groups are 
introduced (VI), and since all four methyl groups behave as methyl ethers, 
it therefore follows that two alcoholic groups are present in dimethylascorbic 
acid. Ozonolysis of this tetramethyl compound produces one neutral sub- 
stance containing the same number of carbon atoms as its precursor. Since 
ozonolysis of a carbon-carbon double bond results in scission of that bond, 
there must be a ring system present in the tetramethyl compound to hold 
together the two fragments (VII). This ozonised product, on hydrolysis 
with barium hydroxide, gives oxalic acid and dimethyl-L-threonic acid 
(VIII). These products contain three carboxyl groups in all, and since 
ozonolysis of a double bond produces only two, the third carboxyl group 
must have already been present as a lactone in order that ascorbic acid 
should behave as a neutral compound. 

The key to the size of the ring in ascorbic acid is the structure of this 
dimethyl-L-threonic acid, the nature of which has been ascertained as follows. 
On methylation, followed by conversion to the amide, dimethyl-L-threonic 
acid gives trimethyl-L-threonamide. Thus this dimethyl compound, which 
was unknown when isolated, is a dimethyl-L-threonic acid; but where are 
the two methoxyl groups? Their positions were ascertained by means of 
the Weerman test. This test is used for showing the presence of a free 
hydroxyl group in the a-position to an amide group, i.e., in an a-hydroxy- 
amide. Treatment of a methylated hydroxy-amide with alkaline sodium 



CO-NH 2 

CHOH NaOCI > 
I 
R 



CNO 

I 
CHOH 

I 
R 



NaOH > CHO + NaNCO 
I 
R 



hypochlorite gives an aldehyde and sodium cyanate if there is a. free hydroxyl 
group on the oc-carbon atom. If there is no free hydroxyl group on tijwe 
a-carbon atom, i.e., this atom is attached to a methoxyl group, then treat- 
ment with alkaline sodium hypochlorite produces an aldehyde, methanol, 
ammonia and carbon dioxide. 

CO-KH 2 

I NaOCl 

CHOCH3 „ „„ > CHO + CH 3 OH + NH 3 + 00^ 

■ NaOH I 

R R 

The dimethylthreonic acid obtained from the ozonised product was converted 
into the amide (IX), and this, when subjected to the Weerman test, gave 
sodium cyanate as one of the products. Thus this dimethylthreonic acid 
contains a free a-hydroxyl group, and consequently must be 3 : 4-di-0- 
methyl-L-threonic acid, Vlll. Therefore the lactone ring in ascorbic acid 
must be y-, since a <5-lactone could not have given VIII (actually, 2 : 4-di-O- 
methyl-L-threonic acid would have been obtained). The amide IX was also 
obtained, together with oxamide, by the action of ammonia in methanol on 
the ozonised product, VII. All the foregoing facts can be represented by 
the following equations: 



212 



HO- 



CO 

I 
-C 



1 



ORGANIC CHEMISTRY 
CO-r 



[CH. VII 



HO ~ < j ! I CH,N, 

H— C 1 

I 

HO— C— H 

I 
CH 2 OH 

I 



O 



CII3O— c 

CH3O— c 

H 
I 
HO-C— H 



CO— 1 
I 
CHjO— C 



CH3O— C 



O 



I |£!M^"" 3 ~ J I 
— C — > Ag! ° H— C ' 



o 3 



CH3O- 



I 
-C- 



co- 
CH3O— c=o 
CH3O— c=o 

I 

H— C- 



O 



-H 



CH 2 OH 
V 



CH 2 OCH 3 
VI 



CH3O — C— H 

CH 2 OCH 3 
VII 

Ba(OH) 2 




CONH 2 

CONH 2 
+ 

CONH 2 
I 2 

H— C— OH 
I 
CH3O - C— H 

CH 2 OCH 3 
IX 



C0 2 H 

C0 2 H 

+ 
C0 2 H 

H— C— OH 
I 
CH3O — C— H 

CH 2 0CH 3 
VIII 



An interesting point about ascorbic acid is that it is not reduced by lithium 
aluminium hydride (Petuely et al., 1952). Thus ascorbic acid does not con- 
tain a " normal " carbonyl group. It has now been shown that all reduc- 

CO COH 



CH 2 



COH 



CH 2 
reductic acid 
tones are not reduced by lithium aluminium hydride. Reductones are 
compounds which contain the ene-a-diol-a-carbonyl grouping, 
— CO— C(OH)=C(OH)— 

and examples of reductones are ascorbic and reductic acids. 

Synthesis of ascorbic acid. Many methods of synthesising ascorbic 
acid are now available, e.g., that of Haworth and Hirst (1933), L-Lyxose, 
X, was converted into l(— )-xylosone, XI (treatment with phenylhydrazine 
and then hydrolysis of the osazone with hydrochloric acid), and XI, on treat 



CHO 

HO— C— H ■ 

I 

H-C— OH 

I 
HO— C— H 

I 
CH 2 OH 



CHO 
I 
CO 

I 

H— C— OH 
I 
HO— C— H 

I 
CH 2 OH 

XI 



KCN 
CaCla 



CN 
I 
CHOH 

I 
CO 

I 

H— C— OH 
I 
HO-C— H 
I 
CH 2 OH 

XII 



§11] 



HoO 



COsjH 
1 

CHOH 
I 
CO 



H-C— OH 
I 
HO— C— H 
I 
CH 2 OH 

XIII 



CARBOHYDRATES 



C0 2 H 

r oH 

C— OH 
I 
H— 0— OH 

HO— C— H 
I 
CH 2 OH 



213 



CO -i 

HO " 

-^£+- HO— C I 

-J J 

I 
HO— C— H 

CH 2 OH 
XIV 



HO 



H- 



ment in an atmosphere of nitrogen with aqueous potassium cyanide contain- 
ing calcium chloride, gave the 0-keto-cyanide XII, which hydroLyses spon- 
taneously into ^sewio-L-ascorbic acid, XIII. This, on heating for 26 hours 
with 8 per cent, hydrochloric acid at 45-50°, gave a quantitative yield of 
L(-j-)-ascorbic acid, XIV. 

CH,OH CH a OH CH 2 OH 



HOCH 
HOCH 
HCOH 

HOCH 

I 
CHO 

D-glucose 



H, 



Cu-Cr 




HOCH 

HOCH 

I 
HCOH 
I 
HOCH 



( + )-sorbitol 



2 MeXO 



Acetobacter 



CO 
HOCH 



suboxydans HCO"H 

HOCH 

I 
CH 2 OH 



H 2 S0 1 



CH 2 OH 




(-)- sorbose 



KMn0 4 




diacetone - (- )-sorbose 
C0 2 H 

CO 



H 2 SQ 4 , 



C0 2 Na 



HOCH 

I 
HCOH 

I 
HOCH 



CH 2 OH 



2-ketogulonic-acid 



CH 9 0H 



h -ascorbic acid 



214 ORGANIC CHEMISTRY [CH. VII 

Ascorbic acid is now synthesised commercially by several methods, e.g., 
D-glucose is catalytically hydrogenated to (+)-sorbitol which is then con- 
verted into (— )-sorbose by microbiological oxidation (using Acetobacter 
suboxydans or Acetobacter xylinum). (—) -Sorbose can be oxidised directly 
to 2-keto-(— )-gulonic acid with nitric acid, but the yield is less than when 
the oxidation is carried out as shown above. Nitric acid oxidises other 
alcohol groups besides the first, but by protecting these by means of 2 : 3- 
4 : 6-di-isopropylidene formation (§8), the yield of the gulonic acid is higher. 
The gulonic acid is then dissolved in mixed solvents (of which chloroform is 
the main constituent) and hydrogen chloride passed in. The product, 
L-ascorbic acid, is then finally purified by charcoaling (see previous page). 

Biosynthesis of ascorbic acid (see also §32a. VIII). Horowitz et al. (1952) 
and Burns et al. (1956) have shown that rat and plant tissues can convert d- 
glucose into ascorbic acid. A very interesting observation is that glucose 
labelled at C x (with 14 C) produces the vitamin labelled at C„. In this way, the 
glucose molecule is " turned upside down " to form the glucose derivative (cf. 
the stereochemistry of glucose and gulose, §1). 

DISACCHARIDES 

§12. Introduction. The common disaccharides are the dihexoses, and 
these have the molecular formula C u H 22 O u . Just as methanol forms methyl 
glycosides with the monosaccharides, so can other hydroxy compounds also 
form glycosides. The monosaccharides are themselves hydroxy compounds, 
and so can unite with other monosaccharide molecules to form glycosidic 
links. Study of the disaccharides (of the dihexose type) has shown that three 
types of combination occur in the natural compounds: 

(i) The two monosaccharide molecules are linked through their reducing 
groups, e.g., sucrose. 

(ii) C t of one molecule is linked to C 4 of the other, e.g., maltose, 
(iii) C t of one molecule is linked to C 8 of the other, e.g., melibiose. 

Since the glycosidic link may be a or /?, then different stereoisomeric 
forms become possible for a given pair of hexoses. In group (i), there are 
four forms possible theoretically: OL l ~ ac -i> a i - &> ft -a a an( i Px~fiz- I n groups 
(ii) and (iii), the reducing group of the second molecule is free, and so in 
these two cases there are only two possibilities: aj- and ;8j-. In group (i), 
since both reducing groups are involved in glycoside formation, the resultant 
disaccharide will be non-reducing. In groups (ii) and (iii), since one reducing 
group is free, the resultant disaccharide will be reducing, and can exist in 
two forms, the <x- and /J-. 

General procedure. The disaccharide is first hydrolysed with dilute 
acids, and the two monosaccharide molecules then identified. One of the 
earlier methods of separating sugars in a sugar mixture was by fractional 
crystallisation ; the separation and identification is now carried out by means 
of partition chromatography. When the constituents have been identified, 
the next problem is to ascertain which hydroxyl group of the molecule 
acting as the alcohol {i.e., the aglycon; §3) is involved in forming the glyco- 
sidic link. This is done by completely methylating the disaccharide; the 
methyl glycoside (of a reducing sugar) cannot be prepared by means of 
methanol and hydrochloric acid, since this will lead to hydrolysis of the 
disaccharide. Purdie's method cannot be used for reducing disaccharides 
since these will be oxidised (see §7). The only satisfactory way is Haworth's 
method, and to ensure complete methylation, this may be followed by the 
Purdie method. The methylated disaccharides are then hydrolysed, and the 
methylated monosaccharides so obtained are investigated by the oxidation 



CARBOHYDRATES 



215 



§13] 

methods described previously (see §§7a, 7b, 7e). Reducing disaccharides 
are also oxidised to the corresponding bionic acid, this is then fully methyl- 
ated, hydrolysed, and the methylated monosaccharide molecules examined. 
By this means the hydroxyl group involved in the glycosidic link and the 
size of the oxide ring are ascertained. 

The final problem is to decide whether the glycosidic link is a or /?. This 
is done by means of enzymes, maltase hydrolysing oc-glycosides and emulsin 
/^-glycosides (cf. §3). In non-reducing sugars, the problem is far more 
difficult since the links o^-aa. «x-/?2, /?i-«2 would all be hydrolysed by maltase. 
Consideration of the optical rotations has given information on the nature 
of the link (cf. §6) . Finally, a number of disaccharides have been synthesised, 
the acetobromo-sugars being the best starting materials (see §24). 

§13. Sucrose. Sucrose has been shown to be a-D-glucopyranosyl-/5-D- 
fructofuranoside. Sucrose is hydrolysed by dilute acids or by the enzyme 
invertase to an equimolecular mixture of D(+)-glucose and d(-) -fructose. 
Methylation of sucrose (Haworth method) gives octa-O-methylsucrose and 
this, on hydrolysis with dilute hydrochloric acid, gives 2:3:4: 6-tetra-O- 
methyl-D-glucose and 1:3:4: 6-tetra-O-methyl-D-fructose. The structures 
of these compounds were determined by the oxidation methods previously 
described (see §§7a, 7e). Thus glucose is present in the pyranose form, and 
fructose as the furanose. 

Since sucrose is a non-reducing sugar, both glucose and fructose must be 
linked via their respective reducing groups. The stereochemical nature of 
the glycosidic link may be any one of the four possibilities discussed (see §12), 
but the evidence indicates that it is a-glucose linked to /3-fructose. Maltase 
hydrolyses sucrose; therefore an ac-link is present. Furthermore, since the 
mutarotation of the glucose produced is in a downward direction, it there- 
fore follows that a-glucose is liberated at first. The mutarotation of fructose 
is too rapid to be followed experimentally, and hence the nature of the link 
in this component remains to be determined. There is, however, an enzyme 
which hydrolyses methyl /3-fructofuranosides, and it has been found that it 
also hydrolyses sucrose. This suggests that fructose is present in sucrose 
in the /3-form, and is supported by calculations of the optical rotation of the 
fructose component. The following structure for sucrose accounts for all 
of the above facts: 



H— C 




CH 2 OH 



CH 2 OH 



or 



CH 2 OH 




„ H CH 2 OH ,. 



i_0-i 




CH 2 OH 



OH H 



216 



ORGANIC CHEMISTRY 



[CH. VII 




Oxidation of sucrose with periodic acid confirms this structure (but not 
the nature of the glycosidic link). Three molecules of periodic acid are 
consumed, and one molecule of formic acid is produced. Subsequent oxida- 
tion with bromine water, followed by hydrolysis, gives glyoxylic, glyceric 
and hydroxypyruvic acids (Fleury et al., 1942). 



HC= 

I 
HCOH 

HOCH O 

2-H— 
HCOH 

I 
HC — 

I 
CH 2 OH 



-O-j CH 2 OI 

1— f! , 



CH 2 OH HC=r-0- 

C 1 CHO 

^^HC0 2 H + 



HOCH 
3— -I- o 
HCOH 

I 
HC — 

CH 2 OH 



CHO 
I 

HC 

I 
CH,OH 



CH 2 OH 

-C — 
I 
CHO 







CHO 



H r 



CH 2 OH 



(i) Brg/HaO 
(ii) hydrolysis 



CHO 
I 
C0 2 H 

+ 
C0 2 H 

HCOH 

I 
CH 2 OH 



+ 



CH 2 OH 

I 
CO 

I 

C0 2 H 

+ 

C0 2 H 
I 
HCOH 

I 
CH 2 OH 



Beevers et al. (1947) examined sucrose sodium bromide dihydrate by X-ray 
analysis, and confirmed the stereochemical configuration found chemically, 
and also showed that the fructose ring is five-membered. 

Sucrose has now been synthesised by Lemieux et al. (1953, 1956). Brigl 
(1921) prepared the sugar epoxide, 3:4: 6-tri-O-acetyl-l : 2-anhydro-a-D- 
glucose, II, from tetra-0-acetyl-/?-D-glucose, I (cf. §9; see also §24). 



CH 2 OAc 

° x OAc 

'H \i pci 6 

OAc H A 

AcO \ | |/ H 

H OAc 
I 



CH 2 OAc 

U/^-~ °\ CI 

OAc H. 



(i) NH 3 in ether 



AcO 



(ii) NH3 in benzene 



H OCOCCI3 



§13] 



CARBOHYDRATES 



217 



CH 2 OAc 
H A— — O x H 



AcO 




CH 2 OAc 

H X~ — -O v OMe 



MeOH. 



AcO 




II 

Brigl also showed that II reacted with methanol to give methyl /9-d- 
glucopyranoside triacetate, III, whereas with phenol, the a-glucopyranoside 
was the main product. Other workers showed that secondary alcohols 
gave <x,/S-mixtures. Lemieux was therefore led to believe that fructo- 
furanose, a hindered secondary alcohol, would react with anhydrogluco- 
pyranose to form an a-glucose linkage. 1 : 2-Anhydro-a-D-glucopyranose 
triacetate and 1:3:4: 6-tetra-O-acetyl-D-fructofuranose were heated in a 
sealed tube at 100° for 104 hours. The product, sucrose octa-acetate, on 
deacetylation, gave sucrose (yield about 5 per cent.) . According to Lemieux, 
the reaction proceeds as follows: 

CH 2 OAc 



AcO 




CH-jOAc 



CH 2 OAc 



The CH 2 OAc group at position 6 in the glucopyranose molecule enters into 
neighbouring group participation in the opening of the oxide ring, and 
consequently shields this side from attack. Thus the fructofuranose mole- 
cule is forced to attack from the other side and this produces the desired 
a-glucopyranose linkage. 

One other point that is of interest is the " inversion " of sucrose on 
hydrolysis. Hydrolysis of sucrose gives first of all a-D(+)-glucopyranose 
and /S-D(+)-fructofuranose (this is believed to be dextrorotatory), but the 
latter is unstable and immediately changes into the stable form, d(— )-fructo- 
pyranose (the rotation of (— )-fructose is much greater than that of (+)- 
glucose). 

CH 2 OH CH 2 OH 



HO- 

HO- 

H- 

H- 



OH 



-H 
-OH 



CHjjOH 

(+)- 




218 



ORGANIC CHEMISTRY 



[CH. VII 

§14. Trehalose. This is believed to be a-D-glucopyranosyl-a-D-gluco- 
pyranoside. It is a non-reducing sugar which occurs in yeasts and fungi. 
It is hydrolysed by hydrochloric acid to two molecules of D-glucose; methyla- 
tion of trehalose gives octa-O-methyltrehalose which, on hydrolysis, produces 
two molecules of 2 : 3 : 4 : 6-tetra-O-methyl-D-glucose (see §7a). The nature 
of the glycosidic link is uncertain, but there is some evidence to show that 
it is a : a, e.g., the high positive rotation. Thus trehalose may be written. 



H— C 



O J H— C=J- 




CH 2 OH H OH 

II OH H 



CH 2 OH 



5 CHjjOH -Q 



HO 




§15. Maltose. This is 4-O-a-D-glucopyranosyl-D-glucopyranose. Mal- 
tose is hydrolysed by dilute acids to two molecules of D-glucose; it is a 
reducing sugar, undergoes mutarotation, and forms an osazone. Thus there 
is one free reducing group present, and since maltose is hydrolysed by maltase, 
the glycosidic link of the non-reducing half of the molecule is therefore a-. 
Complete methylation of maltose gives an octamethyl derivative which is 
non-reducing, and this, on hydrolysis with very dilute cold hydrochloric acid, 
is converted into heptamethylmaltose, which has reducing properties. Thus 
the original octamethyl derivative must be methyl hepta-O-methyl-D- 
maltoside; this is further evidence that only one free reducing group is 
present in maltose. Hydrolysis of hepta-O-methylmaltose with moderately 
concentrated hydrochloric acid produces 2:3: 6-tri-O-methyl-D-glucose and 
2:3:4: 6-tetra-O-methyl-D-glucose. The structure of the latter is known 
(see §7a), but that of the former was elucidated as follows. Analysis of the 
compound showed that it was a trimethyl derivative, and since it formed a 
phenylhydrazone but not an osazone, C 2 must therefore be attached to a 
methoxyl group. On further methylation, this trimethylglucose gave 
2:3:4: 6-tetra-O-methyl-D-glucose, and so the trimethyl compound must 
be one of the following: 2 : 3 : 4-, 2 : 3 : 6- or 2 : 4 : 6-tri-O-methyl-D-glucose. 
Now, on careful oxidation with nitric acid, the trimethylglucose forms a 
dimethylsaccharic acid. This acid contains two terminal carboxyl groups ; 
one has been derived from the free " aldehyde " group, and the other by oxid- 
ation at C 6 , and since in its formation one methyl group is lost, this dimethyl- 
saccharic acid must have been derived from a trimethylglucose having a 
methoxyl group at C„. Thus the trimethylglucose must be either 2:3:6- 
or 2 : 4 : 6-tri-O-methyl-D-glucose. On further oxidation, the dimethyl- 
saccharic acid forms dimethyl-D-tartaric acid; this can only arise from a 
precursor with two methoxyl groups on adjacent carbon atoms, and so it 



§15] 



CARBOHYDRATES 



219 



follows that the trimethylglucose must be 2:3: 6-tri-O-methyl-D-glucose. 
This is confirmed by the fact that the other two possible compounds, viz., 
2:3:4- and 2:4: 6-tri-C-methyl-D-glucose, have been synthesised, and 
were shown to be different from the trimethylglucose obtained from maltose. 
The foregoing reactions may thus be written: 



CHOH 



H- 

CH 3 0- 

H- 

H- 



-OCH 3 
-H 



C0 2 H 



O 



-OH 



[o] 



H- 
CH,0- 



H- 



H- 



CH2OCH3 
2:3:6-trimethyl- 
glucose 



-OCH3 
-OH 



C0 2 H 



H- 
CH s O- 



-OH 



-OCH3 
-H 



C0 2 H 
2:3-dimethyl- 
saccharic acid 



C0 2 H 
dimethyl- D- 
(+)-tartaric acid 



From this it can be seen that structure I for maltose satisfies all the above 
facts. This structure, however,. is not the only one that satisfies all the 
facts. The structure of the non-reducing half is certain, but that of the 
reducing half need not necessarily be pyranose as shown in I, since a furanose 
structure, II, would also give 2:3: 6-tri-O-methyl-D-glucose. To decide 
whether C 4 (as in I) or C 6 (as in II) was involved in the glycosidic link, 



GHOH 



H- 
HO- 



H- 
H- 



-OH 



O 



-H 



O 



H-C= 
H- 
HO- 
H- 
H- 



CH 2 OH 

reducing 
half 

CH 2 OH 
H J— Q H 



-OH 
-H o 
-OH 



or 



CH 2 OH 

non-reducing 
half 



CH,OH 




"-0 



OH 



non-reducing 
half 




H-OH 



reducing 
half 



HO 




HO 



H (a-anomer) 



220 



ORGANIC CHEMISTRY 



[CH. VII 



H- 
HO- 

H- 
H- 



CHOH 
OH 



O 



H— C 
H- 



-H 







HO- 



H- 
H- 



-OH 

-H 

-OH 



O 



CH 2 OH 



CH 2 OH 



II 



Haworth et al. (1926) oxidised maltose with bromine water to maltobionic 
acid, III, and this, on methylation, gave the methyl ester of octamethyl- 
maltobionic acid, IV, which, on vigorous hydrolysis, gave 2:3:5: 6-tetra- 
O-methyl-D-gluconic acid, V (as lactone), and 2:3:4: 6-tetra-O-methyl-D- 




CH 2 OH 



CHgOH 



CH 2 OH 



III 



CHoOH 




CH 2 OCH 3 



CH 2 OCH 3 



IV 



HCl 



C0 2 H 



H- 
0H,O- 



H- 
H- 



CHOH 



-OCH 3 

-H 

-OH 

-OCH 3 
GH 2 OCH 3 
V 



H- 



OH 3 0- 
H- 
H- 



-OCH 3 

-H 

-OCH 3 



CH 2 OOH 3 
VI 



O 



§16] 



CARBOHYDRATES 



221 



glucose, VI. V can be obtained only if maltose has structure I ; structure II 
would have given 2:3:4: 6-tetra-O-methyl-D-gluconic acid. Thus maltose 
is I andnot II. Confirmation of the oc-glycosidic linkage is afforded by the 
agreement of the specific rotation of maltose with that calculated for struc- 
ture I, and further evidence for the linkage at C 4 is as follows. Since maltose 
is a reducing sugar, C x (of the reducing half) is free, and since maltose forms 
an osazone, C 2 is also free, i.e., not combined with an alkoxyl group. Zem- 
plen (1927) degraded maltose by one carbon atom (see Vol. I), and obtained 
a compound which still formed an osazone; therefore C 3 is free. On further 
degrading by one carbon atom, a compound was obtained which did not 
form an osazone; therefore C 4 in maltose is not free (see also §7g). 

Maltose has been synthesised by the action of yeast on D-glucose (Prings- 
heim el al., 1924), and maltose octa-acetate has been synthesised by heating 
a mixture of equimolecular amounts of a- and p'-D-glucose at 160°, and then 
acetylating the product (Pictet et al., 1927). 

§16. Cellobiose (4-0-j8-D-glucopyranosyl-D-glucopyranose). Cellobioseis 
hydrolysed by dilute acids to two molecules of d(+) -glucose; since this 
hydrolysis is also effected by emulsin, the glycosidic link must be /?. Cello- 
biose is a reducing sugar, and so one reducing group is free. Methylation, 
followed by hydrolysis, gives 2:3: 6-trimethyl-D-glucose and 2:3:4:6- 
tetramethyl-D-glucose (these are the same products obtained from maltose, 
§15). Oxidation with bromine water converts cellobiose into cellobionic acid, 
and this, on methylation followed by hydrolysis, gives 2:3:5: 6-tetra- 
methylgluconic acid and 2:3:4: 6-tetramethylglucose (again the same pro- 
ducts as for maltose). Thus cellobiose and maltose differ only in that the 
former has a /5-glycosidic link, whereas the latter has an a-. Thus cellobiose 
is (a-form): 



H— C— OH 



H- 

HO- 

H- 

H- 



-OH 
-H 



O O 



H- 

HO- 

H- 

H- 



— H 
-OH 



CH 2 OH 



-H 
-OH 



O 



CH 2 OH 
H J— -O 



or 




OH 



O H 



CH 2 OH 



CH 2 OH 




^ JjCH 2 OH^O 

Degradation experiments confirm the C 4 linkage (see also §7g), and the 
structure has also been confirmed by synthesis {e.g., Stacey, 1946). 

§17. Lactose (4-0-/?-D-galactopyranosyl-D-glucopyranose). Lactose is a 
reducing sugar, and is hydrolysed by dilute acids to one molecule of d(+)- 
glucose and one molecule of D(+)-galactose. Since lactose is hydrolysed 
by lactase (which has been shown to be identical with the /S-glycosidase in 
emulsin), the two monosaccharide molecules are linked by a j3-glycosidic 
link. The evidence, given so far, does not indicate which molecule is the 
reducing half. On methylation, lactose forms methyl heptamethyl-lacto- 
side, and this, on vigorous hydrolysis, gives 2:3: 6-tri-O-methyl-D-glucose 



222 



ORGANIC CHEMISTRY 



[CH. VII 



(see §15) and 2:3:4: 6-tetra-O-methyl-D-galactose ; thus glucose is the 
reducing half. Oxidation with bromine water converts lactose into lacto- 
bionic acid, and this, on methylation followed by hydrolysis, gives 2:3:5:6- 
tetra-O-methyl-D-gluconic acid and 2:3:4: 6-tetra-O-methyl-D-galactose. 
Lactose is therefore (/9-form) [see also §7g]: 



CH 2 OH 
OH J o. 




H 



OH 



CH 2 OH 



CH,OH 






O OH 



CH 2 OH 




§18. Melibiose (6-0-a-D-galactopyranosyl-D-glucopyranose). This di- 
saccharide is obtained from the trisaccharide, raffinose (§20) ; it is a reducing 



H- 

HO- 

H- 

H- 



CHO0H 3 
-OH 



-H O 
-Oil 



CH 2 OH 
III 



H- 
HO- 



H- 
H- 



I 

CHOOH3 



-OH 



-H O 
-OH 



CH 2 0-C(C 8 H 5 ) 3 
IV 




sugar, forms an osazone, and undergoes mutarotation. When hydrolysed 
by dilute acids, melibiose gives D-glucose and D-galactose. Methylation 
converts melibiose into methyl heptamethylmelibioside, and this, on hydro- 
lysis, forms 2:3: 4-trimethyl-D-glucose and 2:3:4: 6-tetramethyl-D-galac- 



§19] 



CARBOHYDRATES 



223 



tose. The structure of the former has been established as follows. The 
trimethylglucose, I, readily forms a crystalline methyl trimethylglucoside, II. 
Now methyl glucopyranoside, III, can be converted into the 6-trityl deriva- 
tive, IV (see §9), and this, on methylation followed by removal of the trityl 
group, gives II. Thus II must be methyl 2:3: 4-tri-O-methyl-D-glucopy- 
ranoside, and consequently I is 2 : 3 : 4-tri-O-methyl-D-glucose. From the 
foregoing facts, it can be seen that galactose is the non-reducing half of 
melibiose, and that its reducing group is linked to C 6 of glucose, the reducing 
half. This has been confirmed by gxidation of melibiose with bromine water 
to melibionic acid, and this, on methylation followed by hydrolysis, gives 
2:3:4: 5-tetra-O-methyl-D-gluconic acid and 2:3:4: 6-tetra-O-methyl-D- 
galactose; the structure of the former is shown by the fact that, on oxidation 
with nitric acid, it forms tetramethylsaccharic acid. There has been some 
doubt about the nature of the glycosidic link, but the evidence appears to be 
strongly in favour of a-. Thus the structure of melibiose is (jff-form) [see 
also §7g]: 



CH 8 OH 
OH 1— — (x H 

or 






0— OH;; 



Melibiose has been synthesised chemically. 

§19. Gentiobiose (6-0-/S-D-glucopyranosyl-D-glucopyranose). This was 
originally obtained from the trisaccharide, gentianose (§20), but it also occurs 
in some glycosides, e.g., amygdalin (§27). Gentiobiose is a reducing sugar, 
forms an osazone and undergoes mutarotation; hydrolysis with dilute acids 
produces two molecules of D-glucose. Since this hydrolysis is also effected 
by emulsin, the glycosidic link must be {}-. Methylation, followed by 
hydrolysis, gives 2:3: 4-trimethyl-D-glucose and 2:3:4: 6-tetramethyl-D- 
glucose. Oxidation to gentiobionic acid, this then methylated and followed 
by hydrolysis, gives 2:3:4: 5-tetramethyl-D-gluconic acid and 2:3:4:6- 
tetramethyl-D-glucose. Thus gentiobiose is 0-iorm): 



I 
HO— V— H 



H- 

HO- 

H- 

H- 



-OH 



-H 



O 



-OH 



CHr 



H- 

HO- 

H- 

H- 



C— H 
-OH 



H ° 
-•"• or 



-OH 



CH 2 OH 



-o. 



Ur 



O— GH 2 



OH 



OH H 



\ 



OH 



H H 



H 



OH 




OH II 



CHjjOH 



Gentiobiose has been synthesised chemically. 

Another disaccharide containing the 1 : 6-glycosidic link is primeverose 
(§26). 

§20. Trisaccharides. The trihexose trisaccharides have the molecular 
formula C 18 H 32 O ie . They are of two types, reducing and non-reducing. 



224 



ORGANIC CHEMISTRY 



[CH. VII 



Manninotriose is the only reducing trisaccharide that has been isolated 
from natural sources. All the others of this group have been obtained by 
degrading polysaccharides or by synthesis, e.g., cellotriose from cellulose. 
Two important non-reducing trisaccharides are rafnnose and gentianose. 

Rafflnose occurs in many plants, particularly beet. Controlled hydro- 
lysis with dilute acids gives D-fructose and melibiose; vigorous hydrolysis 
gives D-fructose, D-glucose and D-galactose. It is also hydrolysed by the 
enzyme invertase to fructose and melibiose, and by an a-glycosidase to 
galactose and sucrose. These facts show that the three monosaccharide 
molecules are linked in the following order: 

galactose — glucose — fructose 

This arrangement is confirmed by the products obtained by methylation of 
rafnnose, followed by hydrolysis, viz., 2:3:4: 6-tetramethylgalactose, 
2:3: 4-trimethylglucose and 1:3:4: 6-tetramethylfructose. Furthermore, 
since the structures of sucrose (§13) and melibiose (§18) are known, the 
structure of rafnnose must therefore be: 



sucrose part 



H 2 OH 
OHJ n H 



H 



OH H 



H OH ^-CH 8 




CH 2 OH 



melibiose part 

Gentianose occurs in gentian roots. Controlled hydrolysis with dilute 
acids gives D-fructose and gentiobiose ; this hydrolysis is also effected by the 
enzyme invertase. Emulsin also hydrolyses gentianose to D-glucose and 
sucrose. Thus the arrangement of the three monosaccharide molecules is: 

glucose — glucose — fructose 

Hence the structure of gentianose is: 

sucrose part 




CH 2 OH 



gentiobiose part 



CH 2 OH 



POLYSACCHARIDES 

Polysaccharides are high polymers of the monosaccharides, and may be 
roughly divided into two groups: those which serve as "structures" in 
plants and animals, e.g., cellulose, and those which act as a metabolic 
reserve in plants and animals, e.g., starch. 

§21. Cellulose. The molecular formula of cellulose is (C 6 H J0 O 5 )». When 
hydrolysed with fuming hydrochloric acid, cellulose gives D-glucose in 96-96 



§21] 



CARBOHYDRATES 



225 



per cent, yield (Irvine el al., 1922) ; therefore the structure of cellulose is 
based on the D-glucose unit. Methylation, acetylation, or " nitration " of 
cellulose produces a trisubstitution product as a maximum substitution 
product, and it therefore follows from this that each glucose unit present 
has three hydroxyl groups in an uncombined state. When fully methylated 
cellulose is hydrolysed, the main product is 2 : 3 : 6-tri-O-methyl-D-glucose 
(90 per cent.). Thus the three free hydroxyl groups in each glucose unit 
must be in the 2, 3 and 6 positions, and positions 4 and 5 are therefore 
occupied. Now, if we assume that the ring structure is present in each 
unit, then this would account for position 5 (or alternatively, 4) being 
occupied. Furthermore, if we also assume that the glucose units are linked 
by C z of one unit to C 4 of the next (or alternatively, C 5 ), then the following 
tentative structure for cellulose would account for the facts: 




HCl 



H- 



CHOH 
-OCH, 



CHjO- 
H- 
H- 



OH a OH 

glucose unit 



CH 2 OCH 3 



-H 
-OH 



CH 2 OCH„ 

2:3:6-trimethyl- 
glucose 



It should be noted, however, that if the linkages at 4 and 5 were inter- 
changed, the same trimethylglucose would still be obtained on hydrolysis 
(cf. maltose, etc.). 

When subjected to acetolysis, i.e., simultaneous acetylation and hydrolysis 
(this is carried out with a mixture of acetic anhydride and concentrated 
sulphuric acid), cellulose forms cellobiose octa-acetate. Thus the cellobiose 
unit is present in cellulose, and since the structure of cellobiose is known 
(see §16), it therefore follows that the glucose units are present in the pyranose 
form, i.e., C 5 is involved in ring formation, and so the glucose units are linked 
C t — Q. The isolation of cellobiose indicates also that pairs of glucose units 
are joined by /Minks, but it does indicate whether the links between the 



H- 

HO- 

H- 

H- 



I 

CHOH 

-OH 

-H 



I 

•C— H 



O 



O 



H- 

HO- 

H- 

H- 



CH.OH 



-OH 



-H 
-OH 



O 



cellobiose 



CH 2 OH 



glucose units are the same (all /?-) or alternate (a and /?), since all the links 
could be /S-, or each pair of cellobiose units could be joined by a-links; the 
latter possibility is not likely, but it is not definitely excluded. Very careful 
acetolysis of cellulose, however, has produced a cellotriose, cellotetraose and 



226 



ORGANIC CHEMISTRY 



[CH. VII 



a cellopentaose, and in all of these the C t — C 4 links have been shown to be 
/?- (from calculations of the optical rotations), and so we may conclude that 
all the links in cellulose are /?-. This conclusion is supported by other 
evidence, e.g., the kinetics of hydrolysis of cellulose. 

Cellulose forms colloidal solutions in solvents in which glucose is soluble, 
and so it is inferred that cellulose is a very large molecule. Moreover, since 
cellulose forms fibres, e.g., rayon, it appears likely that the molecule is linear; 
X-ray analysis also indicates the linear nature of the molecule, and that the 
cellulose molecule has a long length. Hence a possible structure for cellu- 
lose is: 



I 

CHOH 



H- 
HO- 



H- 
H- 



-OH 
-H 



O 



CH 2 OH 



-O-C— H 



H- 

HO- 

H- 

H- 



-OH 
-II 



r— O— C— H 



O 



H- 
IIO- 



H- 
H- 



-OH 
-II 



O 



CH,OH 



CH 2 OII 



-0-0— H 



H- 

HO- 

II- 

H- 



-OH 

-II 

-OH 



O 



CH 2 OH 




It should be noted that in the structure given for cellulose, the first glucose 
unit in la (i.e., the one on the left-hand side; this unit is on the right-hand 
side in 16) has a free reducing group, but since this group is at the end of a 
very long chain, its properties tend to be masked; thus cellulose does not 
exhibit the strong reducing properties of the sugars. 

The cellulose molecule is not planar, but has a screw-axis, each glucose 
unit being at right angles to the previous one. Although free rotation about 
the C— O— C link might appear possible at first sight, it apparently does 
not occur owing to the steric effect. This and the close packing of the atoms 
give rise to a rigid chain molecule. The long chains are held together by 
hydrogen bonding, and thus cellulose has a three-dimensional brickwork. 
This would produce strong fibres with great rigidity but no flexibility, and 
consequently, although the fibres would have great tensile strength, they 
could not be knotted without snapping. Since the fibres can be knotted 
without snapping, they must possess flexibility, and the presence of the 
latter appears to be due to the partly amorphous character of cellulose. 

The chemical structure of cellulose appears to be more complicated than 
the one given above. Schmidt et al. (1932) showed that carboxyl groups are 
present in carefully purified cotton fibres. Kleinert et al, (1944) have sug- 
gested that various other groups, which are not necessarily carbohydrate in 



§21] CARBOHYDRATES 227 

nature, may bind the glucose chains together. It should be remembered, 
in this connection, that 100 per cent, glucose is never obtained from the 
hydrolysis of cellulose. 

The molecular weight of cellulose. Owing to its insolubility, simple 
methods of molecular weight determination (depression of freezing point 
and elevation of boiling point) cannot be applied to cellulose. 

Chemical methods. Examination of the formula of cellulose shows 
that on methylation, followed by hydrolysis, the end unit (the non-reducing 
end) would contain four methoxyl groups, and all the other units three. 
Hence, by the determination of the percentage of the tetramethyl derivative 
(2:3:4:6-) it is therefore possible to estimate the length of the chain. 
Haworth (1932) separated the methylated glucoses by vacuum distillation; 
Hibbert (1942) used fractional distillation ; Bell (1944), using silica, and Jones 
(1944), using alumina, effected separation by means of chromatography. 
The value for the molecular weight of cellulose was found to be between 
20,000 and 40,000 (Haworth, 1932) ; this corresponds approximately to 100 
to 200 glucose units. This " end-group assay ", however, gives rise to the 
following difficulty. When cellulose is very carefully prepared from cotton, 
and then methylated in an atmosphere of nitrogen, i.e., in the absence of 
oxygen, no 2:3:4: 6-tetramethylglucose was obtained after hydrolysis 
(Haworth et al., 1939). One explanation that has been offered is that during 
methylation under ordinary conditions, i.e., in air, cellulose is partially 
degraded, e.g., osmotic pressure measurements carried out on methylated 
cellulose, produced by two methylations in air, gave a value of 190 glucose 
units; sixteen successive methylations in air gave a methylated cellulose of 
45 glucose units, as estimated by osmotic pressure measurements (Haworth 
et al., 1939). Haworth explained these results by suggesting that the cellu- 
lose molecule consists of a very large loop, which undergoes progressive 
shortening on methylation. When the methylation is carried out in an 
atmosphere of nitrogen, the exposed ends of the shortened loop recombine, 
but cannot do so when methylated in the presence of air. Haworth also 
suggested that in order that the two chains should be held parallel to form a 
loop, it is necessary to have cross-linkages holding the two sides together. 
The nature of these suggested cross-links is unknown. If primary valencies 
were involved, then some dimethylglucose should be obtained from the 
hydrolysate. Some of this compound has in fact been isolated, but it is not 
certain that it is actually present in the methylated cellulose, since it may 
arise by demethylation during the degradation of the methylated cellulose. 
The following is a pictorial representation of Haworth's suggestion. 

In nitrogen In air 



\ 

\ ■ . 1 ,«__: . J 



CXXDOZO 
I 

o::d 
i 

CD CD 



rr 


• ; i i ) 


I 


C : 


i V. i : ) 


1 

1 ; r-*> 1 1 r->- 




1 

1— r->-|— }-»" 
■*-i— 1 -e-i— | 



228 ORGANIC CHEMISTRY [CH. VII 

By means of chromatography, McGilvray (1953) has detected 2:3:4:6- 
tetra-O-methyl-D-glucose in the hydrolysate after the methylation of cellu- 
lose in an atmosphere of nitrogen. Thus degradation of the chain has occurred 
under these conditions, and so there is no evidence for the linking of the end 
groups in the absence of oxygen. Furthermore, McGilvray determined the 
degree of polymerisation from viscosity and osmotic pressure measurements, 
and also from the end-group assay. The values obtained from the first 
two methods were greater than that obtained from the third method, and 
McGilvray suggests these results may be accounted for by assuming a 
slightly branched structure for the soluble methylcelluloses. 

A number of other chemical methods have been used for estimating the 
molecular weight of cellulose, e.g., that of Hirst et al. (1945) ; this is based on 
the periodate oxidation (§7g). Examination of the formula of cellulose 
shows that the terminal reducing unit would give two molecules of formic 
acid and one of formaldehyde (this reducing unit, which is left in la, behaves 
as the open-chain molecule, since it is not a glycoside), whereas the other 
terminal unit (right in la) would give one molecule of formic acid; i.e., one 
cellulose molecule gives three molecules of formic acid and one of formalde- 
hyde. Estimation of the formic acid produced gives the value of the chain- 
length as approximately 1000 glucose units. There appears, however, to be 
some uncertainty with these results, since " over-oxidation " as well as 
normal oxidation with periodic acid results, the former possibly being due 
to the progressive attack on the chain-molecules from their reducing ends 
(Head, 1953). 

Physical methods. Ultracentrifuge measurements have given a value 
of 3600 glucose units for native cellulose; lower values were obtained for 
purified cellulose and its derivatives (Kraemer, 1935). These differences 
are probably due to the degradation of the chains during the process of 
purification and preparation of the derivatives. Viscosity measurements on 
cellulose in Schweitzer's solution give a value of 2000-3000 glucose units; 
lower values were obtained for viscosity measurements on derivatives of 
cellulose in organic solvents (Staudinger et al., 1935-1937). Osmotic pres- 
sure measurements on derivatives of cellulose have given values of approxi- 
mately 1000 glucose units (Meyer, 1939). Schulz et al. (1954, 1958) have 
determined the molecular weight of cellulose nitrate by measurements of 
viscosity, etc., and obtained results varying from 1400 to 7800 glucose units, 
the value depending on the source of the cellulose. 

From the foregoing account, it can be seen that the values obtained 
chemically and physically are not in agreement. This indicates the uncer- 
tainty of the value of n, and also that the value of n depends on the source 
and treatment of cellulose. However, the more recent work of Schulz (see 
above) is reliable in that evidence was obtained that no degradation occurred 
in the course of purification and conversion into the nitrates. 

§22. Starch. The molecular formula of starch is (C 6 H 10 O B )„. Hydrolysis 
of starch with acids produces a quantitative yield of D-glucose (cf. cellulose) ; 
thus the structure of starch is based on the glucose unit. Methylation of 
starch gives the trimethylated compound (maximum substitution), and this, 
on hydrolysis, produces 2:3: 6-tri-O-methyl-D-glucose as the main product, 
and a small amount (about 4-5 per cent.) of 2 : 3 : 4 : 6-tetra-O-methyl-D- 
glucose. Oxidation studies (periodic acid) have also shown the presence of 
1 : 4-linked D-glucopyranose residues. Starch is hydrolysed by the enzyme 
diastase (/5-amylase) to maltose (see also below). Thus the maltose unit is 
present in starch, and so we may conclude that all the glucose units are 
joined by a-links (cf. cellulose). The following structure for starch fits these 
facts : 



§22] 



CARBOHYDRATES 



229 



CH 2 OH 




CH 2 OH CH 2 OH 

maltose unite 



CH 2 OH 



or 



pH 2 OH 
H J—— O v H 




H OH 




CH 2 OH 



A— O H H J— O. H 
H NJ L/H \ 

h/L JV>h iy\ 



H OH J 



CH 2 OH 
H J— — Q H 




OH 



H OH 



The Haworth end-group assay (1932) showed that starch is composed of 
approximately 24-30 glucose units. Thus starch is a linear molecule, at least 
as far as 24-30 units. Haworth, however, pointed out that this was a 
minimum chain-length, and that starches may differ by having different 
numbers of this repeating unit (see also below). Viscosity measurements, 
however, showed the presence of a highly branched structure. Now, it has 
long been known that starch can be separated into two fractions, but it is 
only fairly recently that this separation has been satisfactorily carried out ; 
the two fractions are a-amylose (the A-fraction; 17-34 per cent.) and 
/?-amyIose (amylopectin, or the B-fraction). The fractionation has been 
carried out in several ways, e.g., w-butanol is added to a hot colloidal solution 
(aqueous) of starch, and the mixture allowed to cool to room temperature. 
The A-fraction is precipitated, and the B-fraction is obtained from the 
mother liquors by the addition of methanol (Schoch, 1942). Haworth et al. 
(1946) have used thymol to bring about selective precipitation. 

a-Amylose is soluble in water, and the solution gives a blue colour with 
iodine. /J-Amylbse is insoluble in water, and gives a violet colour with 
iodine. Both amyloses are mixtures of polymers, and the average mole- 
cular weight depends on the method of preparation of the starch used. 

a-Amylose (A-fraction). Meyer et al. (1940) measured the osmotic 
pressure of solutions of a-amylose acetate, and obtained values of 10,000- 
60,000 for the molecular weight; values up to 1,000,000 have been reported. 
When a-amylose with a chain-length of about 300 glucose units (as shown 
by osmotic pressure measurements) was methylated and then hydrolysed, 
about 0-3 per cent, of 2:3:4: 6-tetra-O-methyl-D-glucose was obtained. 
This value is to be expected from a straight chain composed of approximately 
300 glucose units. From this evidence it would therefore appear that 
a-amylose is a linear polymer, and this is supported by the early work with 
soya-bean jS-amylase (diastase). This enzyme converts a-amylose into 
maltose in about 100 per cent, yield; this indicates that a large number of 
maltose units are joined by a-links, i.e., a-amylose is a linear molecule. Peat 
et al. (1952), however, showed that highly purified soya-bean /J-amylase 



230 ORGANIC CHEMISTRY [CH. VII 

gives only about 70 per cent, of maltose, and this has been confirmed by 
other workers. Since /J-amylase only attacks a-1 : 4-glucosidic linkages, it 
thus appears that a-amylose contains a small number of other linkages. 
Careful purification of " crude " soya-bean /5-amylase showed the presence 
of two enzymes, |?-amylase and another which was named Z-enzyme; it is 
the latter which was shown to hydrolyse the non a-1 : 4-linkages. Thus 
unpurified /3-amylase (which contains both enzymes) degrades a-amylose 
completely to maltose. It has also been shown that Z-enzyme has /S-gluco- 
sidase activity and that emulsin can hydrolyse these " anomalous " linkages. 
These observations suggest that a-amylose contains a small number of 
/3-glucosidic linkages. 

Another difficulty arises from the fact that the structure of potato amylose 
depends on its method of preparation, e.g., one sample is completely degraded 
by purified /3-amylase, whereas other samples are not. The first sample 
represents about 40 per cent, (by weight) of the total amylose in potato 
starch, and thus it follows that potato amylose is heterogeneous both in 
structure and in size. A large proportion is completely linear (and contains 
about 2000 glucose units), and the remainder (which contains about 6000 
units) contains a small number of these anomalous linkages. The nature of 
these anomalous linkages is still uncertain. 

Amylopectin (B-fraction). Molecular weight determinations of amylo- 
pectin by means of osmotic pressure measurements indicate values of 50,000 
to 1,000,000 (Meyer et al., 1940). Larger values have also, been reported, 
e.g., Witnauer et al. (1952) have determined the molecular weight of potato 
amylopectin by the method of light scattering, and report an average value 
of 10,000,000 or more. Let us consider an amylopectin having an average 
molecular weight of 550,000; this corresponds to about 3000 glucose units. 
The end-group assay by methylation shows the presence of one unit with 
four free hydroxyl groups per 24-30 glucose units; the same results are also 
obtained by the periodate method. Thus the 3000 units are joined in such 
a manner as to give about 100 end units ; it therefore follows that the chain 
must be branched,. The problem is further complicated by the fact that 
Hirst (1940), after methylating amylopectin and hydrolysing the product, 
obtained, in addition to tri- and tetra-O-methyl-D-ghicose, about 3 per cent, 
of 2 : 3-di-O-methyl-D-glucose. This has been taken to mean that some 
glucose units are also joined by C t and C g atoms. Furthermore, in certain 
experiments, enzymic hydrolysis has given a small amount of 1 : 6 a-linked 
diglucose, i.e., womaltose is also present in amylopectin (Montgomery et al., 
1947, 1949). Wolfrom et al. (1955, 1956) have obtained evidence that there 
is also an a-D-1 : 3-bond in amylopectin ; the principal bond is a-D-1 : 4, and 
branching occurs through a-D-1 : 6-bonds. 

The branching of the chains in amylopectin is supported by the following 
evidence: 

(i) Amylopectin acetate does not form fibres; fibre formation is character- 
istic of linear molecules. 

(ii) /?- Amylase hydrolyses amylopectin to give only about 50 per cent, of 
maltose. Thus there are " blocked " points, and these will occur at the 
branch points. 

(iii) Amylopectin solutions do not show an orientation of the molecules 
in the direction of flow in the concentric cylinder technique; the molecules 
are therefore not linear. 

The detailed structure of amylopectin is still not settled. Haworth and 
Hirst (1937) suggested a laminated formula for amylopectin; each line 
represents a basal chain of 24r-30 glucose units joined by a C x — C 4 links, 
and each arrow head represents the joining of the terminal reducing group 
(C x ) of each chain to the central glucose member (at C 6 ) of the next chain. 



§23] CARBOHYDRATES 231 

If it is branched in the fashion shown, then methylated amylopectin should 
give some dimethylglucose on hydrolysis. Since 2 : 3-di-O-methyl-D-glucose 
is actually obtained, the link must be C x of one chain to C 6 of the next. If 



1. 



the unions are as regular as this, then there will be one Cj — C 6 link for 
every one end group. Hirst et al. (1946), however, showed by the end- 
group assay by the periodic acid method that amylopectin contains only 
traces of glucose residues joined solely by Cj— C 6 links. 

Prolonged methylation of amylopectin produces a diminution of the 
molecular size (as determined by physical methods); e.g., methylation of 
starch seventeen times changed the particle size from 3000 glucose units 
to 190 units (Averill, 1939). This diminution in particle size cannot be 
due to the break-down of the basal chains, since the end-group assay always 
gives the same basal chain-length, whether the methylation is carried out in 
air or in an atmosphere of nitrogen. Haworth therefore suggested that this 
diminution in particle size is due to the " disaggregation " of the basal 
chains. 

As pointed out previously, /^-amylase gives only 50 per cent, of maltose 
with amylopectin. The high molecular weight residue is known as dextrin, 
and this is not degraded because of the presence of the C x — C 9 link (/9-amylase 
breaks only a Q^—C^ links). According to Haworth (1946), ^-amylase 
attacks the chain, breaking them into units of two, the attack stopping at 
the cross-links. Thus: 



u 



n * » x —^maltose + L» 

18 f II \ 18 

12 4 12 4- 12 

* , . ^^ 

dextrin 

In support of this explanation, it has been found that dextrin has a unit 
chain-length of 11-12 glucose units. 

Further work has shown that the Haworth laminated formula does not 
satisfy the behaviour of amylases on amylopectin; the formula is far too 
regular (c/. Hirst's work, above). Meyer (1940) proposed a highly branched 
structure; this fits the behaviour of the amylases better. Furthermore, 




mathematical calculations have shown that the regular form is unlikely. 
A difficulty of the Meyer structure, however, is that amylopectin would be 
globular; this is not in keeping with all the evidence. 

§23. Some other polysaccharides. A number of other polysaccharides 
besides cellulose and starch also occur naturally, and some of these are 
described briefly below. 

Glycogen. This is the principal reserve carbohydrate in animals. It is 



232 



ORGANIC CHEMISTRY 



[CH. VII 

hydrolysed by |3-amylase to maltose, and molecular weight determinations 
by physical methods give values between 1 and 2,000,000. The molecular 
structure of glycogen appears to be similar to that of amylopectin; both 
polysaccharides have many features in common. One main difference is 
their degree of branching, the average chain-length in amylopectin being 
about 24 glucose units and in glycogen about 12. 

Inulin. This is a fructosan, and occurs in dahlia tubers, dandelion roots, 
etc. Acid hydrolysis gives D-fructose, but if inulin is first methylated and 
then hydrolysed, 3:4: 6-tri-O-methyl-D-fructose is the main product, thus 
indicating that inulin is composed of fructofuranose units. 

Mannans are polysaccharides which yield only jnannose on hydrolysis ; 
they are found in ivory nut, seaweeds, bakers' yeast, etc. Similarly, galac- 
tans yield only galactose on hydrolysis; they occur in seeds, wood, etc. 
There are also polysaccharides which contain pentose residues only, viz. 
pentosans, e.g., xylans give D-xylose; arabans give L-arabinose. Some 
pentosans are composed of both xylose and arabinose, and other poly- 
saccharides are composed of pentose and hexose units, e.g., xylo-glucans 
(xylose and glucose), arabo-galactans, etc. In addition to these neutral poly- 
saccharides, there are also the acid polysaccharides. These are gums and 
mucilages, and owe their acidity to the presence of uronic acids. Gums 
are substances which swell in water to form gels (or viscous solutions), 
e.g., gum arabic and gum tragacanth; on hydrolysis, the former gives ara- 
binose, galactose, rhamnose and glucuronic acid, and the latter xylose, 
L-fructose and galacturonic acid. Mucilages are polysaccharides which swell 
in water to form viscous solutions; on hydrolysis, they give galacturonic 
acid, arabinose, xylose, etc. The hemi-celluloses (which are widely dis- 
tributed in the cell-wall of plants) also contain both uronic acids (glucuronic 
or galacturonic) and pentoses (xylose, arabinose). 

Pectin. This occurs in plants, particularly fruit juices. It is composed 
of D-galacturonic acid residues and the methyl ester. 

Alginic acid. This occurs in the free state and as the calcium salt in 
various seaweeds. Hydrolysis of alginic acid produces D-mannuronic acid. 

Chitin. This is the polysaccharide that is found in the shells of crus- 
taceans. Hydrolysis of chitin by acids produces acetic acid and D-glucos- 
amine (chitosamine ; 2-aminoglucose) . Chitin is also hydrolysed by an 
enzyme (which occurs in the intestine of snails) to iV-acetylglucosamine. 
X-ray analysis has shown that the structure of chitin is similar to that of 
cellulose (N-acetylglucosamine replaces glucose). 



H- 



HO- 
H- 
H- 



CHOH 
-NH 2 
-H 
-OH 



CH 2 OH 








H NH-CO-CH 3 

CH 2 OH A r -acety]glucosamine 

D -glucosamine 

iV-Methyl-L-glucosamine is a component of streptomycin (see §7. XVIII). 

§23a. Photosynthesis of carbohydrates. The scheme outlined below 
is largely that proposed by Calvin et al. (1954). These authors exposed 
certain algae to carbon dioxide (labelled with 14 C) and light, then killed the 



§23a] CARBOHYDRATES 233 

CH 2 OH CH 2 OH 

I 



CO CO 



H— 
H— 



—OH HO— !— H 

—OH H— — OH 



ribulose 



H— j— OH 

H— :— OH 

CH 2 OH 
sedoheptulose 

algae and extracted with ethanol and chromatographed (on paper) the 
extract. Two monosaccharides, ribulose and sedoheptulose, play an essen- 
tial part in the photosynthesis of carbohydrates, and the steps involved 
are as follows : 

(i) Ribulose diphosphate accepts one molecule of carbon dioxide and one 
of water. 

(ii) The product now splits into two molecules of phosphogryceric acid 
(CH20-P0 3 H 2 -CHOH-C0 2 H) . 

(iii) Phosphoglyceric acid undergoes reduction to phosphoglycer aldehyde. 

(iv) Two molecules of phosphoglyceraldehyde combine to form hexose 
phosphate. 

(va) Hexose phosphate forms disaccharides and polysaccharides. 

(v6) A molecule of hexose phosphate reacts with a molecule of phospho- 
glyceraldehyde to form ribulose phosphate and a tetrose phosphate. The 
latter reacts with a molecule of phosphoglyceraldehyde to produce sedo- 
heptulose phosphate which, in turn, also reacts with a molecule of phospho- 
glyceraldehyde to produce one molecule of ribose phosphate and one mole- 
cule of ribulose phosphate. The ribose phosphate is then converted into 
ribulose phosphate, thus completing the cycle. 

All the aldohexoses and all the aldopentoses are interconvertible by inver- 
sion of one asymmetric carbon atom, but how this occurs in the plant is not 
certain. Furthermore, aldohexoses may be stepped down to aldopentoses, 
and again how this occurs is not certain; one suggestion is (see also S32a. 
VIII): 

CHO-(CHOH) s -CHOH-CH 2 OH oxidat " >n > CHO-(CHOH) 3 -CHOH-C0 2 H 

decarboxylation 

> CHO-(CHOH) 3 -CH 2 OH 

The foregoing account of photosynthesis describes the various inter- 
mediates produced. In green plants the presence of chlorophyll (§6. XIX) 
is necessary for photosynthesis, but its exact function is not certain. It 
appears that all the light energy is used in the " light phase " to raise chloro- 
phyll a from its ground state to an excited state, and then this energy of 
the excited state is used in the " dark phase " to convert carbon dioxide 
into carbohydrates (Trebst el al., 1958-1960). Furthermore, the same series 
of dark-phase reactions has also been shown to occur in non-chlorophyllous 
cells (inter alia, McFadden el al., 1957, 1959). What is peculiar to photo- 
synthesis is its light phase. 



234 



ORGANIC CHEMISTRY 



[CH. VII 



GLYCOSIDES 

§24. Introduction. A great variety of glycosides occur in plants. The 
simple glycosides are colourless, soluble in water and are optically active ; 
they do not reduce Fehling's solution. On hydrolysis with inorganic acids, 
glycosides give a sugar and a hydroxylic compound, the aglycon (§3), which 
may be an alcohol or a phenol. Most glycosides are hydrolysed by emulsin ; 
therefore they are ^-glycosides. Actually, in the natural state, each glyco- 
side is usually associated with an enzyme which occurs in different cells of 
the plant. Maceration of the plant thus produces hydrolysis of the glyco- 
side by bringing the enzyme in contact with the glycoside. Glucose has 
been found to be the most common sugar component; when methylated 
and then hydrolysed, most glycosides give 2:3:4: 6-tetra-O-methyl-D- 
glucose. Thus most glycosides are /?-D-glucopyranosides. 

Synthesis of glycosides. The synthesis of a glycoside uses an aceto- 
bromohexose as the starting material; this compound is now named 
systematically as a tetra-O-acetyl-D-hexopyranosyl 1-bromide, e.g., if the 
hexose is glucose, then the a-form will be tetra-0-acetyl-a-D-glucopyranosyl 
1-bromide. 

When glucose is treated with acetic anhydride at 0° in the presence of 
zinc chloride, the product is 1 : 2 : 3 : 4 : 6-penta-O-acetyl-oc-D-ghicose (a-D- 
glucose penta-acetate). If, however, glucose is heated with acetic anhydride 
in the presence of sodium acetate, the product is 1:2:3:4: 6-penta-0- 
acetyl-/3-D-glucose. Furthermore, the /9-isomer may be converted into the 
a- by heating with acetic anhydride at 110° in the presence of zinc chloride. 



I 

CHOH 

I 
(GHOH) 3 

I 
CH 



O 



(CH 3 -CO) 2 0;ZnCl2 



H-C— OCO-CH 3 

(CHOCOCH 3 ) 3 
I 
CH 







CH 2 OH 
glucose 



(CH 3 CO) 2 0; 
CH,C0 2 Na; 
heat 



CH 2 C-COCH 3 
a-glucose penta-acetate 



(CH 3 CO),0; 

2nCl 2 /U0° 




CH 3 -COO- C-H 

1 O 

(CHO-COCH 3 ) 3 

I 

CH 

I 
CH 2 0-COCH 3 

p-glucose penta-acetate 

These penta-acetates are readily hydrolysed to glucose by means of dilute 
aqueous sodium hydroxide, ethanolic ammonia at 0°, or by methanol con- 
taining a small amount of sodium methoxide. When dissolved in glacial 
acetic acid saturated with hydrogen bromide, the glycosidic acetoxyl group 
of a hexose penta-acetate is replaced by bromine to give an oc-acetobromo- 
hexose; the a-isomer is obtained whether the penta-acetate used is the a- 
or ^-compound (Fischer, 1911). Thus a Walden inversion occurs with the 
^-compound (§1. III). 



§25] 



CARBOHYDRATES 



235 



Scheurer et al. (1954) have synthesised acetobromo sugars in good yield 
as follows. Bromine is added to a suspension of red phosphorus in glacial 
acetic acid, and to this solution (which now contains acetyl bromide) is 
added the sugar or acetylated sugar, the latter giving the better yields. 

The bromine atom in these acetobromohexoses is very active. Thus it 
may be replaced by a hydroxyl group when the acetobromohexose is treated 
with silver carbonate in moist ether (Fischer et al., 1909), or by an alkoxyl 
group when treated with an alcohol in the presence of silver carbonate 
(Kfinigs and Knorr, 1901). In the latter reaction the yields are improved 
if anhydrous calcium sulphate and a small amount of iodine are used instead 
of silver carbonate (Evans et al., 1938). In either case, the a-acetobromo- 
hexose gives the /ff-glycoside. On the other hand, if mercuric acetate is 
used instead of silver carbonate, then the a-glycoside is obtained. The 
foregoing reactions may thus be written (using the symbol — a-> to represent 
a Walden inversion; see §3. III). 



H-C-C-CO~CH 3 | 

(GHO-CO-CH 3 ) 3 ° 
I 
CH 



CH2OCOCH3 
a-penta-acetate 



CH,0-C-H 




<%. H-C-Br 

I O 

(CHO-COCH 3 ) 3 



CH- 



CH 2 OCOCH 3 
o-acetobromohexose 



CH 3 -COO-C-H I 

l O 

(CHOCC~CH 3 ) 3 




(CHO-CO-CH 3 ) 3 

L 

I 
CH 2 0-CO-CH 3 

(3-glycoside 



CH- 



CH 2 G~CC-CH 3 
(3-penta -acetate 



OH 2 OCC~CH 3 
a -glycoside 



O 



H— C-GCH, I 

I 

(CHO-CO-CH 3 ) 3 

I 
CH 



§25. Indican. This glycoside occurs in the leaves of the indigo plant 
and in the woad plant. When the leaves are macerated with water, the 
enzyme present hydrolyses indican to glucose and indoxyl, and the latter, 
on exposure to air, is converted into indigotin (see Vol. I). 

The molecular formula of indican is C 14 H 17 0„N, and since it gives D-glucose 
and indoxyl on hydrolysis, it is therefore indoxyl D-glucoside. When indican 
is methylated (with methyl iodide in the presence of dry silver oxide), tetra- 
methylindican is obtained, and this, on hydrolysis with methanol containing 
1 per cent, hydrogen chloride, gives indoxyl and methyl 2:3:4: 6-tetra-O- 
methyl-D-glucoside. Thus the glucose molecule is present in the pyranose 
form, and since indican is hydrolysed by emulsin, the glycosidic link must 
be p. Thus the structure of indican is III, and this has been confirmed by 
synthesis from indoxyl, I, and tetra-O-acetyl-a-D-glucopyranosyl 1-bromide, 
II, as follows: 



236 



ORGANIC CHEMISTRY 



[CH. VII 




CH 2 OCOCH 3 

II 



Ag s C0 3 

— u~ 




CH 2 OCOCH 3 



CH 2 OH 



III 



§26. Ruberythrlc acid. This occurs in the madder root, and on hydro- 
lysis, it was originally believed to give one molecule of alizarin and two 
molecules of D-glucose. Jones and Robertson (1933), however, showed that 
two molecules of D-glucose were not present in the hydrolysate ; a mixture 
of two sugars was actually present, D-glucose and D-xylose. Thus the mole- 
cular formula of ruberythric acid is C 25 H 26 13 , and not, as was originally 
believed, C 26 H 28 14 . Thus the hydrolysis is: 

O 

OH 



CaHasOu+aHgO— ^CgHjiA, + C s H 10 O 5 + 




OH 



Jones and Robertson also showed that the two monosaccharide molecules 
were present in the form of the disaccharide primeverose. Now, this 
disaccharide is 6-0-^-D-xylopyranosyl-D-glucopyranose (Helferich, 1927), and 



H- 
HO- 



CHOH 



-OH 



H- 
H- 



-H O O 
-OH 



CH, 



H- 

HO- 

H- 



1 

C-H 

■OH 

H 

OH 



O 



CH<r 



primeveros§ 



§27] 



CARBOHYDRATES 



237 



it therefore follows that alizarin is linked to the glucose half of the prime- 
verose molecule. Further work has shown that the glucosidic link is /S, 
and that it is the 2-hydroxyl group of alizarin that is involved. Thus the 
structure of ruberythric acid is: 




§27. Amygdalin. This occurs in bitter almonds. The molecular formula 
is C 20 H 27 O 1:l N, and it is hydrolysed by acids to one molecule of benzaldehyde, 
two molecules of D-glucose, and one of hydrogen cyanide. 

C 20 H 27 O u N + 2H 2 0-* C 6 H 5 -CHO + 2C 6 H 12 6 + HCN 

Since emulsin also brings about this hydrolysis, amygdalin must contain a 
/J-glycosidic link. On the other hand, the enzyme zymase hydrolyses amyg- 
dalin into one molecule of glucose and a glucoside of (+)-mandelonitrile 
(this compound is 



C2oH a7 O u N + H 2 0- 



C 6 H 12 6 



C 6 H 5 -CH(CN)-OC 6 H u O s 



identical with prunasin, a naturally occurring glucoside). Thus the agly- 
con of amygdalin is (H-)-mandelonitrile, and the sugar is a disaccharide. 
Haworth et al. (1922, 1923) have shown that this disaccharide is gentiobiose 
(§19), and have synthesised. amygdalin (in 1924) as follows. Gentiobiose, I, 
was converted into hepta-acetyl-bromogentiobiose, II, by means of acetic 
anhydride saturated with hydrogen bromide, and then II was condensed 
with racemic ethyl mandelate in the presence of silver oxide, whereby the 
^-glycoside, III, was obtained. Treatment of this with ethanolic ammonia 
hydrolysed the acetyl groups, and at the same time converted the ester 
group into the corresponding amide; thus the (±)-amido-glycoside, IV, was 
obtained. IV was then treated with acetic anhydride in pyridine solution, 
and the (ij-hepta-acetyl derivative of the amide, V, was then separated 
into its diastereoisomers by fractional crystallisation (the mandelic acid 
portion is + and — , the gentiobiose portion is +; hence the two forms 
present are ++ and — [-, i.e., they are diastereoisomers). The (-f-)-form 
was then dehydrated with phosphorus pentoxide to give the (+)-nitrile, VI, 
and this, on de-acetylation with ethanolic ammonia, gave (+) -amygdalin, 
VII, which was shown to be identical with the natural compound. (See 
overleaf.) 



238 



ORGANIC CHEMISTRY 



[CH. VII 



H- 

HO- 



GHOH 
-OH 



-OH 



-H 



OO 



H-I-OH 
H- 



CH, 



H- 
HO- 



-OH 



-H 
H-I-OH 

H 



0- 



CH,000 



H-C-Br 
II-l-OCOCHj 

H 
H-(-OCOCH 3 

H 



-C-H 



H 



OO 



CH 2 OH 



CH, 



CH.COO 



OCOCH, 

II 
H-j-OCOCH 3 
H 







CH 2 OCOCH 3 



I 

C 6H 5 

CH — 0- 

C0 2 C 2 H 5 » 
"O-*- CH3COO- 



II 



-C-H 

OCOCH3 

H 
H-|-OCOCH, 
H 



-C-H 



OO 



H — OCOCH3 



CH 2 



CH3COO 



H 

H-I-OCOCH3 
H 



CH.0C0CH, 



III 



C 6 H 5 | 

CH — O— C-H 



1 

C0NH 2 H- 

HO- 
H- 
H- 



-0H 

-H 

-OH 



00 



I 

■C-H 

H-}-OH 



CH, 



HO- 



-H 



O 



H-I-OH 
H- 



( CH 3 CO) a O 
pyridine 



(±)-hepta- 

acetyl 
derivative 

V 



(+)-form p 3 o 6 
of V ' 



CH,OH 



IV 



CeH 5 



r 



CH-O-C-H 

I 
CN H-+-OCOCH3 

CH3COO-I-H 



H- 
H- 



C-H 



H- 



00 



-OCOCH3 



GH 2 



CH,000 — H 



H- 
H- 



■OCOCH, 



O 



CcHc 

r 5 1 

CH-O-C-H 
CN H — OH 



-OCOCH, 



HO--H 00 H0 — H 



CH 2 OCOCH 3 



C-H 
-OH 



H+OH 
H 



CH,- 



O 



H+OH 
H- 



CH,OH 



VI 



VII 



§28. Arbutin and Methylarbutin. Arbutln is hydrolysed by cmulsin 
to give one molecule of D-glucose and one of quinol; thus arbutin is a /?- 
glucoside. When methylated (with methyl sulphate in the presence of 
sodium hydroxide), arbutin forms pentamethylarbutin, and this on hydro- 
lysis with methanolic hydrogen chloride, gives methyl 2:3:4: 6-tetra-O- 
methyl-D-glucoside and monomethylquinol (Macbeth et al., 1923) ; structure I 
for arbutin accounts for all these facts. 



§29] 



CARBOHYDRATES 



239 



rio<f~~j> O-C-H 



HO- 
H- 
H- 



-011 

-H 

-OH 



(CH,) a so t CH 3 0<<> — O-C-H 

XT.rtll ■ * ■ ' 



NaOH 



O 



II- 

CH 3 0- 

H- 
H- 



-OCH3 
-H 

-OCH3 



O 



CH 2 OH 
I 

OCH, 



CH 2 OCH 3 



HCI 



CHjOH 



H- 

CH3O- 

H- 

H- 



CHOCH3 
-OCH, 



-H O 
-OCH3 



CH 2 OCH 3 

Pentamethylarbutin has been synthesised by converting 2:3:4: 6-tetra- 
O-methyl-D-glucose into tetra-0-methyl-ix-D-glucopyranosyl 1-bromide, and 
condensing this with monomethylquinol; the product is identical with the 
methylated natural compound. 

Methylarbutin. This is hydrolysed by emulsin to one molecule of d- 
glucose and one molecule of monomethylquinol; thus methylarbutin is a 
/?-glucoside, and its structure is: 



cHs0 0" ~~ ®~~** 



H- 

HO- 

H- 

H- 



-OH 
-H O 
-OH 



CH 2 OH 

Methylarbutin has been synthesised by condensing tetra-O-acetyl-a-D-gluco- 
pyranosyl 1-bromide with monomethylquinol in the presence of silver 
carbonate, followed by de-acetylation. 

§29. Salicin. This is hydrolysed by emulsin to one molecule of D-glucose 
and one of salicyl alcohol (saligenin). Thus salicin is a j8-glucoside, but it 
is not possible to tell from the hydrolytic products whether it is the phenolic 
or alcoholic group of the salicyl alcohol which forms the glycosidic link. 
Which group is involved is readily shown as follows (Irvine et al., 1906). 
Oxidation of salicin with nitric acid forms helicin, and this, on hydrolysis, 
gives glucose and salicylaldehyde. Thus the phenolic group in salicyl alcohol 
must form the glucoside. Methylation of salicin produces pentamethyl- 
salicin, and this, on hydrolysis, gives 2:3:4: 6-tetra-O-methyl-D-glucose. 
Hence the glucose residue is in the pyranose form; the structure given for 
salicin fits the foregoing facts. This structure has been confirmed by con- 
densing tetra-0-methyl-a-D-glucopyranosyl 1-bromide with salicyl alcohol. 



240 



ORGANIC CHEMISTRY 



[CH. VII 



CH 2 OH 
H- 



HO- 



H- 
H- 



-OH 

-H 

-OH 



O 



CH 2 OH 

and then methylating the product. The pentamethylsalicin so obtained 
was identical with the methylated natural product (Irvine et al., 1906). 

§30. Sinigrin. This glycoside occurs in black mustard seed, and on 
hydrolysis with the enzyme myrosin, D-glucose, allyl wothiocyanate and 
potassium hydrogen sulphate are obtained. 

C 10 H 16 O 9 NS 2 K + H 2 — ► C 6 H X2 6 + CH 2 =CH-CH 2 -NCS + KHS0 4 

Sodium methoxide degrades sinigrin, and one of the products obtained is 
thioglucose, C e H u 5 *SH. From this it is inferred that the glucose residue 
is linked to a sulphur atom in sinigrin. Gadamer (1897) proposed I for the 



K+0 3 S-0-C-S-C 6 H u O a 

II 
N-CH 2 -CH=CH 2 

I 



CH, 



=CH-CH 2 -OS-C 6 H U 5 



N-OSO.-K+ 



II 



structure of sinigrin, but Ettlinger et al. (1956) have proposed II, since 
these authors have shown that allyl wothiocyanate is produced by re- 
arrangement when the glycoside is hydrolysed by myrosin (cf. the Lossen 
rearrangement; see Vol. I). 



READING REFERENCES 

Handbook for Chemical Society Authors, Chemical Society (1960). Ch. 5. Nomenclature 

of Carbohydrates. 
Rosanoff, On Fischer's Classification of Stereoisomers, /. Amer. Chem. Soc, 1906, 28, 

114. 
Haworth, The Constitution of Sugars, Arnold (1929). 
Honeyman, Chemistry of the Carbohydrates, Oxford Press (1948). 
Percival, Structural Carbohydrate Chemistry, Muller (2nd ed., 1962). 
Pigman and Goepp, Chemistry of the Carbohydrates, Academic Press (1948). 
Gilman (Ed.), Advanced Organic Chemistry, Wiley, (i) Vol. II (1943, 2nd ed.). Ch. 20, 

21. Carbohydrates. Ch. 22. Cellulose, (ii) Vol. IV (1953). Ch. 9. Starch. 
Percival, Carbohydrate Sulphates, Quart. Reviews (Chem. Soc), 1949, 3, 369. 
Barker and Bourne, Enzymic Synthesis of Polysaccharides, Quart. Reviews (Chem. Soc), 

1953, 7, 56. 
Hudson, Emil Fischer's Discovery of the Configuration of Glucose, /. Chem. Educ, 

1941, 18, 353. 
Advances in Carbohydrate Chemistry, Academic Press (1945-). 
Manners, The Enzymic Degradation of Polysaccharides, Quart. Reviews (Chem. Soc), 

1955, 9, 73. 
Sir Robert Robinson, The Structural Relationships of Natural Products, Oxford Press 

(1955). 
Downes, The Chemistry of Living Cells, Longmans, Green (2nd ed., 1963). 
Newth, Sugar Epoxides, Quart. Reviews (Chem. Soc), 1959, 13, 30. 
Ferrier and Overend, Newer Aspects of the Stereochemistry of Carbohydrates, Quart. 

Reviews (Chem. Soc), 1959, 13, 265. 
Sunderwirth and Olson, Conformational Analysis of the Pyranoside Ring, /. Chem. 

Educ, 1962, 39, 410. 



CARBOHYDRATES 241 

Manners, Structural Analysis of Polysaccharides, Roy. Inst. Chew,., Lectures, Mono- 
graphs and Reports, 1959, No. 2. 

Wiggins, Sugar and its Industrial Applications, Roy. Inst. Chem., Lectures, Monographs 
and Reports, 1960, No. 5. 

Bassham, Photosynthesis, /. Chem. Educ, 1959, 36, 548. 

Park, Advances in Photosynthesis, /. Chem. Educ, 1962, 39, 424. 

Arnon et at., Photoproduction of Hydrogen, Photofixation of Nitrogen and a Unified 
Concept of Photosynthesis, Nature, 1961, 192, 601. 

Roderick, Structural Variety of Natural Products, /. Chem. Educ, 1962, 39, 2. 



CHAPTER VIII 

TERPENES 

§1. Introduction. The terpenes form a group of compounds the majority 
of which occur in the plant kingdom; a few terpenes have been obtained 
from other sources. The simpler mono- and sesquiterpenes are the chief 
constituents of the essential oils; these are the volatile oils obtained from 
the sap and tissues of certain plants and trees. The essential oils have 
been used in perfumery from the earliest times. The di- and tri-terpenes, 
which are not steam volatile, are obtained from plant and tree gums and 
resins. The tetraterpenes form a group of compounds known as the caro- 
tenoids, and it is usual to treat these as a separate group (see Ch. IX). 
Rubber is the most important polyterpene. 

Most natural terpene hydrocarbons have the molecular formula (C 5 H 8 )„, 
and the value of n is used as a basis of classification. Thus we have the 
following classes (these have already been mentioned above): 

(i) Monoterpenes, CxoH^. (ii) Sesquiterpenes, C^H^. 

(hi) Diterpenes, C 20 H 3a . (iv) Triterpenes, C 30 H 48 . 

(v) Tetraterpenes, C 40 H 64 (these are the carotenoids). 
(vi) Polyterpenes, (C 5 H g )„. 

In addition to the terpene hydrocarbons, there are the oxygenated derivatives 
of each class which also occur naturally, and these are mainly alcohols, 
aldehydes or ketones. 

The term terpene was originally reserved for those hydrocarbons of mole- 
cular formula C 10 H 16 , but by common usage, the term now includes all com- 
pounds of the formula (C 5 H g )„. There is, however, a tendency to call the 
whole group terpenoids instead of terpenes, and to restrict the name terpene 
to the compounds C ]0 H 16 . 

The thermal decomposition of almost all terpenes gives isoprene as one 
of the products, and this led to the suggestion that the skeleton structures 
of all naturally occurring terpenes can be built up of isoprene units; this is 
known as the isoprene rule, and was first pointed out by Wallach (1887). 
Thus the divisibility into isoprene units may be regarded as a necessary 
condition to be satisfied by the structure of any plant-synthesised terpene. 
Furthermore, Ingold (1925) pointed out that the isoprene units in natural 
terpenes were Joined " head to tail " (the head being the branched end of 
isoprene). This divisibility into isoprene units, and their head to tail union, 
may conveniently be referred to as the special isoprene rule. It should be 
noted, however, that this rule, which has proved very useful, can only be 
used as a guiding principle and not as a fixed rule. Several exceptions to 
it occur among the simpler terpenes, e.g., lavandulol is composed of two 
isoprene units which are not joined head to tail; also, the carotenoids are 
joined tail to tail at their centre (see Ch. IX). 

>c=CH-GH 2 -cn-c^ cii3 CII? J_ CK=CIl2 

' 3 ClI 2 OH 

lavandulol isoprene 

242 



§1] TERPENES 243 

The carbon skeletons of open-chain monoterpenes and sesquiterpenes are : 



C 
I 
C— C- 

head 




I. 



■C— C- 
tail 



C-C— C— C+C 



C 
I 
•C— C — 0— C 

head tail 



C C 

i : » 

■ c— c— c4-c— c— c— c 



Monocyclic terpenes contain a six-membered ring, and in this connection 
Ingold (1921) pointed out that a gem-dialkyl group tends to render the 
cyc/ohexane ring unstable. Hence, in closing the open chain to a cyclo- 
hexane ring, use of this " gem-dialkyl rule " limits the number of possible 
structures (but see, e.g., abietic acid, §31). Thus the monoterpene open 
chain can give rise to only one possibility for a monocyclic monoterpene, 
viz., the />-cymene structure. This is shown in the following structures, 
the acyclic structure being written in the conventional " ring shape ". 



? 


C 
1 


c c 

-h- 1 

o c 

1 


C C 
-K 1 


cA 


</\ 


acyclic 
structure 


/>-cymene 
structure 



All natural monocyclic monoterpenes are derivatives of ^-cymene. 

Bicyclic monoterpenes contain a six-membered ring and a three-, four- 
or five-membered ring. Ingold (1921) also pointed out that cyc/opropane 
and cyc/obutane rings require the introduction of a gem-dimethyl group to 
render them sufficiently stable to be capable of occurrence in nature. Thus 
closure of the C 10 open chain gives three possible bicyclic structures; all 
three types are known. 



c4 X c 

/ 1 C-ChC'. | 



c 
i 

<£■> 

i i 

C ;0 



c 

A 

o — . c 
,'j'c-c-ci | 

\\y° 



If we use these ideas with the sesquiterpene acyclic structure, then we find 
that only three monocyclic and three bicyclic structures are possible (not 
all are known; see the sesquiterpenes). 



244 



\ C C 

/°N V / 

c c-hc-c-c 



ORGANIC CHEMISTRY 

C 
I 
C 

/\ 

I ,1- ^ 

c ;C-c-c 

K"V^ c 

' c \ 

J> '•■■ 

/ v 

c c-c\ 



[ch. VIII 

C 
I 

/\ 

^ c c 

-Rx i . 

C N \C^C-C-C-C 

c c 



c 



c 

A A 

c c 



,c. 9 a 



c 



Wc. 



■ : k. 



V< x \l/\ V\ ;T\ 

c c > X c c C-C C ,',' c-c 



^^-A ; ! c-c o-C' --c c c.-.'-c'; c 
I \ < ! .c'v. 



(/ x c 



/ V 

c c 



Recently some furano-terpenes have been isolated, e.g., dendrolasin, which 
is believed to have the following structure (Quilico et al., 1957) ; it contains 
three isoprene units Joined head to tail. 

-CH 2 • CH 2 • CH= C • CH 2 - CH 2 - CH=CMe 2 



O 



Me 



§2. Isolation of monoterpenes and sesquiterpenes. Plants contain- 
ing essential oils usually have the greatest concentration at some particular 
time, e.g., Jasmine at sunset. In general, there are four methods of extrac- 
tion of the terpenes: (i) expression; (ii) steam distillation; (iii) extraction 
by means of volatile solvents; (iv) adsorption in purified fats (enfleurage). 
Method (ii) is the one most widely used; the plant is macerated and then 
steam distilled. If the compound decomposes under these conditions, it 
may be extracted with light petrol at 50°, and the solvent then removed 
by distillation under reduced pressure. Alternatively, the method of ad- 
sorption in fats is used. The fat is wanned to about 50°, and then the 
flower petals are spread on the surface of the fat until the latter is saturated. 
The fat is now digested with ethanol, any fat that dissolves being removed 
by cooling to 20°. The essential oils so obtained usually contain a number 
of terpenes, and these are separated by fractional distillation. The terpene 
hydrocarbons distil first, and these are followed by the oxygenated de- 
rivatives. Distillation of the residue under reduced pressure gives the 
sesquiterpenes, and these are separated by fractional distillation. 

§3. General methods of determining structure. The following brief 
account gives an indication of the various methods used in elucidating the 
structures of the terpenes (see the text for details). 

(i) A pure specimen is obtained, and the molecular formula is ascertained 
by the usual methods. If the terpene is optically active, its specific rotation 



§4] TERPENES 245 

is measured. Optical activity may be used as a means of distinguishing 
structures (see, e.g., §12). 

(ii) If oxygen is present in the molecule, its functional nature is ascertained, 
i.e., whether it is present as hydroxyl, aldehyde, ketone, etc. (cf. alkaloids, 
§4. XIV). 

(iii) The presence of olefinic bonds is ascertained by means of bromine, 
and the number of double bonds is determined by analysis of the bromide, 
or by quantitative hydrogenation, or by titration with monoperphthalic 
acid. These facts lead to the molecular formula of the parent hydrocarbon, 
from which the number of rings present in the structure may be deduced. 

(iv) The preparation of nitrosochlorides and a study of their behaviour 
(see also the nitroso compounds, Vol. I). 

(v) Dehydrogenation of terpenes with sulphur or selenium, and an exami- 
nation of the products thereby obtained (see also §2 vii. X). 

(vi) Measurement of the refractive index leads to a value for the molecular 
refractivity. From this may be deduced the nature of the carbon skeleton 
(see, in particular, sesquiterpenes). Also, optical exaltation indicates the 
presence of double bonds in conjugation (cf. §11. I). 

(vii) Measurement of the ultraviolet, infra-red and Raman spectra. More 
recently X-ray analysis of crystals has also been used. 

(viii) Degradative oxidation. The usual reagents used for this purpose 
are ozone, acid or alkaline permanganate, chromic acid and sodium hypo- 
bromite. In general, degradative oxidation is the most powerful tool for 
elucidating the structures of the terpenes. 

(ix) After the analytical evidence has led to a tentative structure (or 
structures), the final proof of structure depends on synthesis. In terpene 
chemistry, many of the syntheses are ambiguous, and in such cases analytical 
evidence is used in conjunction with the synthesis. Many terpenes have not 
yet been synthesised. 



MONOTERPENES 

The monoterpenes may be subdivided into three groups: acyclic, mono- 
cyclic and bicyclic. This classification affords a convenient means of study 
of the monoterpenes. 

ACYCLIC MONOTERPENES 

§4. Myrcene, C 10 H 16 , is an acyclic monoterpene hydrocarbon which occurs 
in verbena and bay oils. It is a liquid, b.p. 166-168°. Catalytic hydro- 
genation (platinum) converts myrcene into a decane, C^H^; thus myrcene 
contains three double bonds, and is an open-chain compound. Furthermore, 
since myrcene forms an adduct with maleic anhydride, two of the double 
bonds are conjugated (Diels et al., 1929; see the Diels-Alder reaction, Vol. I). 
This conjugation is supported by evidence obtained from the ultraviolet 
spectrum of myrcene (Booker et al., 1940). These facts, i.e., that myrcene 
contains three double bonds, two of which are in conjugation, had been 
established by earlier investigators (e.g., Semmler, 1901). Ozonolysis of 
myrcene produces acetone, formaldehyde and a ketodialdehyde, C 5 H 6 3 , 
and the latter, on oxidation with chromic acid, gives succinic acid and 
carbon dioxide (Ruzicka et al., 1924). These results can be explained by 
assigning structure I to myrcene. In terpene chemistry it has become 
customary to use conventional formulae rather than those of the type I. 
In these conventional formulae only lines are used; carbon atoms are at 
the junctions of pairs of lines or at the end of a line, and unsaturation is 
indicated by double bonds. Furthermore, the carbon skeleton is usually 
i 



246 



ORGANIC CHEMISTRY 



[CH. VIII 



drawn in a ring fashion (the cyc/ohexane ring). Thus myrcene may be 
represented as II, and this type of structural formula will, in general, be 



CH 3 



OH, 



;c=CH— GH 2 — CH 2 — C— CH=CH 2 




CH 



used in this book. Thus the process of ozonolysis and oxidation of the 
ketodialdehyde may be written: 



Y + 



o 

acetone 



2CII 2 + 

formaldehyde 



XiHO 

V H0 

O 

ketodialdehyde 



CHO 



.CHO 



/CO-jH 
CH 2 
CH 2 

\o 2 H 



CO- 



This structure for myrcene is supported by the fact that on hydration 
(under the influence of sulphuric acid), myrcene forms an alcohol which, 
on oxidation, gives citral. The structure of this compound is known (see 
§5), and its formation is in accord with the structure given to myrcene. 

§4a. Ocimene, Ci H 16 , b.p. 81°/30 mm. When catalytically hydro- 
genated, ocimene adds on three molecules of hydrogen to form a decane. 
Thus ocimene is an acyclic compound which contains three double bonds. 
Furthermore, since ocimene forms an adduct with maleic anhydride, two 
of the double bonds are conjugated. On ozonolysis, ocimene produces 
formaldehyde, methylglyoxal, lsevulaldehyde, acetic and malonic acids, and 
some acetone. All of these products, except acetone, are accounted for by 
structure I for ocimene (this has an wopropenyl end-group). In order to 
account for the appearance of acetone in the oxidation products, ocimene 



CHO 



+ 0. /CHO + CH 2 

I 

CH., 



CH3CO 



,H + C^f, 



C0 2 H 



COjjH 



§5] TERPENES 247 

is also believed to exist in the j'sopropylidene form, II, i.e., ocimene is a 
mixture of I and II, with I predominating (but see citral, §5). 




yGO^l 




CH 3 - COCHO + CH 2 



§5. Citral, C 10 H 16 O. This is the most important member of the acyclic 
monoterpenes, since the structures of most of the other compounds in this 
group are based on that of citral. Citral is widely distributed and occurs 
to an extent of 60-80 per cent, in lemon grass oil. Citral is a liquid which 
has the smell of lemons. 

Citral was shown to contain an oxo group, e.g., it forms an oxime, etc. 
On heating with potassium hydrogen sulphate, citral forms ^-cymene, II 
(Semmler, 1891). This reaction was used by Semmler to determine the posi- 
tions of the methyl and tsopropyl groups in citral; Semmler realised that 
the citral molecule was acyclic, and gave it the skeleton structure, I (two 



/> CH, / 

N C CH 

I I 

/ /\ 

C C CH 



CH, 



r 



C C CH CH 

I I 

C CH 3 

I II 

isoprene units joined head to tail). Citral can be reduced by sodium amal- 
gam to an alcohol, geraniol, C 10 H 18 O, and is oxidised by silver oxide to 
geranic acid, C^H^Oa; since there is no loss of carbon on oxidation to the 
acid, the oxo group in citral is therefore an aldehyde group (Semmler, 1890). 
Oxidation of citral with alkaline permanganate, followed by chromic acid, 
gives acetone, oxalic and laevulic acids (Tiemann and Semmler, 1895). Thus, 
if citral has structure III, the formation of these oxidation products may be 



CHO 



CH 3 

accounted for. This structure is supported by the work of Verley (1897), 
who found that aqueous potassium carbonate converted citral into 6-methyl- 
hept-5-en-2-one, IV, and acetaldehyde. The formation of these products 



CH 3 CH 3 
C 


C0 2 H 
CH 2 


CO a H 


II + 


1 + 


1 





CH 2 
CO 


C0 2 H 



248 ORGANIC CHEMISTRY [CH. VIII 

is readily explained by assuming III undergoes cleavage at the a : /S-double 
bond; this cleavage by alkaline reagents is a general reaction of a : ^-un- 
saturated oxo compounds (see Vol. I). Furthermore, methylheptenone it- 
self is also oxidised to acetone and laevulic acid; this is again in accord with 




CHO + H 2 



k 2 co 3 




CHO 
I 
CH 3 



structure III. The structure of methylheptenone was already known from 
its synthesis by Barbier and Bouveault (1896). These workers condensed 
2 : 4-dibromo-2-methylbutane with sodio-acetylacetone, and heated the re- 
sulting compound with concentrated sodium hydroxide solution. Barbier 



CH 3 /CHs 



CBr 
I 
.CH 2 

CH 2 Br 



+ NaCH(COCH 3 )r 



CH 3/ CH 3 
CBr 



.CH 2 
CH 2 

CH(COCH 3 ) 2 



NaOH 



CH, CH 3 
C 



CH, 



CH 



CH. 



CO 

I 

CH 3 



and Bouveault (1896) then converted methylheptenone into geranic ester, V, 
by means of the Reformatsky reaction, using zinc and ethyl iodoacetate. 
The synthesis of citral was completed by Tiemann (1898) by distilling a 



+ Zn+ CH 2 I-C0 2 Et- 




,CH 2 -C0 2 Et 
iZnl 



/CHjj-COjjEt 
'OH 



(CH 3 CO) a O 
-H»0 



,CH-CO»Et 



mixture of the calcium salts of geranic and formic acids (ca represents 
" half an atom of calcium ") : 



§5] 



TERPENES 



249 



CH-COjjca 



+ H-COiCa 




CHO + CaCO, 



A more recent synthesis of citral is that of Arens and van Dorp (1948). 
Methylheptenone was first prepared as follows: 



CH» ,CH 3 



QH, ,CH, 



O 



CH 3 £tt 3 



V/ " . p tt (ONa-liquidNHs "VV" " Zn-Cu ~\^./~ 
O T l^ila rrrrr^ *- C^ ^ 



(ii) H,0 



-OH 



"h^*~ ^OH 



CH 



^CH 
CH 2 



PBrj 



CH 3 CH 3 

V 

II 

CH 
/ 
CH 2 Br 



E.A.A. 



synthesis 



CH, CH, 

C 

II 

/ill 

CH 2 

I 
CH 2 

CO 

I 

CH 3 



Then the methylheptenone was treated with ethoxyacetylene-magnesium 
bromide, the product reduced and then de-alkylated. It should be noted 



Y 



CO 



CMgBr 

+ 111 ^ 

COC 2 H 5 




COC 2 H 5 



Pd-BaSOi 



CHOC 2 H 5 



^OH 



HCl. 



CHO 



that an aUylic rearrangement occurs in both parts of this synthesis (see also 
§8). Ethoxyacetylenemagnesium bromide may conveniently be prepared 
from chloroacetaldehyde diethyl acetal as follows (Jones et al., 1954): 

CH 2 Cl-CH(OC 2 H 5 ) 2 i^ CH=C-OC 2 H 6 ^X BrMgC=C-OC 2 H 5 



250 ORGANIC CHEMISTRY [CH. VIII 

Examination of the formula of citral shows that two geometrical isomers 
are possible: 





mzHS- form; as -form; 

citral-a; citral-6; 

geranial neral 

Both isomers occur in natural citral, e.g., two semicarbazones are formed by 
citral; both forms of citral itself have also been obtained: citral-a (also 
known as geranial) has a b.p. 118-119°/20 mm., and citral-b (also known 
as neral) has a b.p. 117-118°/20 mm. The configurations of these two 
forms have been determined from a consideration of the ring closures of 
the corresponding alcohols (see geraniol, §7). 

The problem of the structure of citral is further complicated for the 
following reasons. Ozonolysis of citral gives acetone, lsevulaldehyde and 
glyoxal (Harries, 1903, 1907); these products are to be expected from 
structure III. On the other hand, Grignard et al. (1924) also isolated a 
small amount of formaldehyde from the products of ozonolysis; this points 
towards structure VI, which has an wopropenyl end-group. Thus citral 



CHO / CHO 




has been regarded as a mixture of four substances, two geranials and two 
nerals. Assuming, then, that both the wopropylidene and wopropenyl forms 
are present, it is possible that these two structures form a three-carbon 
tautomeric system: 

CH 3 CH, 

CH-C=CH~ =F^= CH 2 =C-CH2— 

Recent work, however, has cast doubt on the existence of these two forms 
in citral. According to infra-red spectroscopic studies, it appears that 
naturally occurring acyclic monoterpenes as a class possess only the iso- 
propylidene end-group structure (Barnard, Bateman et al., 1950). Accord- 
ing to these authors, during oxidative degradation, partial rearrangement 
from the t'sopropylidene to the wopropenyl structure occurs, and so this 
method of determining fine structure is unreliable (see also geraniol, §7). 
Oliver (1961) has developed a chemical together with a chromatographic 



§6] TERPENES 251 

method for separating a mixture of tsopropylidene and t'sopropenyl isomers. 
This should be of value in the studies of natural terpenes. 

§6. Ionones. When citral is condensed with acetone in the presence of 
barium hydroxide, v^ionone is formed and this, on heating with dilute 
sulphuric acid in the presence of glycerol, forms a mixture of a- and /S-ionones 
(Tiemann and Kriiger, 1893). The proportion of a to /S varies with the 
nature of the cyclising agent used, e.g., with sulphuric acid, /taonone is 
the main product; with phosphoric acid, a-ionone is the main product. 
Both ionones have been obtained from natural sources; the /S-isomer is 
optically inactive, whereas the a-isomer can exist in optically active forms 



CH 3 CH 3 

X 

eft CHCHO 



CH 2 C-CH 3 
N CH a 



CH 3 CH 3 



+ CH 3 COCH 3 



Ba(OH)j 



;£ X ° H 



CH 2 -CH=CHCOCH, 



:^>« 



CH, /CH, 

CH CH-CH=CHCOCH 3 h s so 1 
I 




CHjt C-CH 3 
N CH 2 
«f/-ionone 



,CH=OHC6CH 3 

+ 



(+2H s O) 




CH=CHCOCH, 



p-ionone 



a-ionone 



since it contains one asymmetric carbon atom. Actually, the (+)-, (— )- 
and (±)-forms of oc-ionone occur naturally. Very dilute ethanolic solutions 
of /?-ionone have the odour of violets. 

The structures of the ionones were established by a study of the oxidation 
products produced by potassium permanganate (Tiemann, 1898, 1900); 




.CH=CHCOCH 3 




p-ionone 



C0 2 H 
CO-CH 3 




C0 2 H 



C0 2 H 
III 



/5-ionone gave geronic acid, I, a : a-dimethyladipic acid, II, and a : a-di- 
methylsuccinic acid, III. On the other hand, a-ionone gave a mixture of 
wogeronic acid, IV, /? : 5-dimethyladipic acid, V, and a : a-dimethylglutaric 
acid, VI. 




CH=CHCO-CH 3 



CO-CH 3 
s CO„H 



C0 2 H 
^COjjH 



C0 2 H 



252 ORGANIC CHEMISTRY [CH. VIII 

Theimer et al. (1962) have isolated y-ionone (by vapour-phase chromato- 

,CH=CHCOCH, 




graphy) from the mixture of ionones obtained above (this ionone corresponds 
to the y-irone; see below). 

The ionones are related to irone, C 14 H 2a O; this occurs in the oil obtained 
from the orris root. The structure of irone was established by Ruzicka 
et al. (1947), who showed that on ozonolysis, irone gives formaldehyde and 
/3 : /? : y-trimethylpimelic acid, VIII ; also, reduction of irone with hydriodic 
acid and red phosphorus, followed by dehydrogenation with selenium, gives 
1:2: 6-trimethylnaphthalene, IX. Ruzicka therefore proposed structure 



fr 



CH-CO-CH 3 



VII 





VII for irone. Ruzicka (1947) further showed that irone was a mixture 
of three isomers (VII is y-irone): 




CH=CH-COCH, 



a-irone 




PH=CH-COCH 3 




,OH=CHCOCH 3 



(J-irone , 



•y-irone 



§7. Geraniol, Ci H 18 O, b.p. 229-230°/757 mm. This is found in many 
essential oils, particularly rose oil. Geraniol was shown to be a primary 
alcohol, e.g., on oxidation it gives an aldehyde (citral-a); and since it forms 
a tetrabromide, geraniol therefore contains two double bonds. Reduction 
of citral produces geraniol, but at the same time some nerol is formed. 
The structural identity of geraniol and nerol is shown by the following facts. 
Both add on two molecules of hydrogen when hydrogenated catalytically; 
thus both contain two double bonds. Both give the same saturated alcohol, 
C 10 H 22 O. Also, on oxidation, geraniol and nerol give the same oxidation 
products which, at the same time, show the positions of the double bonds 
to be 2 and 7 (cf. citral, §5). Thus geraniol and nerol are geometrical iso- 
mers. Geraniol has been assigned the trans configuration and nerol the cis 
on the fact that cyclisation to a-terpineol (§11) by means of dilute sulphuric 
acid takes place about 9 times as fast with nerol as it does with geraniol; 



§8] TERPENES 253 

this faster rate with nerol is due to the proximity of the alcoholic group 
to the carbon (*) which is involved in the ring formation. Thus: 



OH 





a-terpineol geraniol 

(trans-) 

Nerol also occurs naturally in various essential oils, e.g., oil of neroli, berga- 
mot, etc.; its b.p. is 225-226°. 

Knights et al. (1955) have found that, on ozonolysis, geranyl acetate gives 
less than 3 per cent, of formaldehyde, and have concluded that the acetate 
and geraniol itself have predominantly the isopropylidene structure (cf. 
citral, §5). 

§8. Linalool, C 10 H 18 O, b.p. 198-199°. This is an optically active com- 
pound; the (— )-form occurs in rose oil and the (+)-form in orange oil. 
It was shown to be a tertiary alcohol, and since it adds on two molecules of 
hydrogen on catalytic hydrogenation, it must contain two double bonds. 
When heated with acetic anhydride, linalool is converted into geranyl 
acetate ; and the latter is converted into the former by heating with steam 
at 200° under pressure. Also, heating linalool with hydrogen chloride in 
toluene solution at 100° produces geranyl chloride, and this, when treated 
with moist silver oxide in benzene solution, is reconverted into linalool. 
These reactions are parallel to those which occur when crotyl alcohol is 
treated with hydrogen bromide; a mixture of crotyl bromide and methyl- 
vinylcarbinyl bromide is obtained. When either of these products is treated 
with moist silver oxide, a mixture of crotyl alcohol and methylvinylcarbinol 
is obtained. 

€H3-CH:CH-CH 2 OH-i^CH3-CH:CH-OH 2 Br + CH 3 CHBr-CH:CH 2 




CH 3 -CH:CHCH 2 OH+CH 3 CHOHCH:CH 2 

Thus the elucidation of the structure of linalool is complicated by the ease 
with which the aUylic rearrangement occurs (see also Vol. I). Since the 
structure of geraniol is known, a possible structure for linalool is obtained 
on the basis of this allylic rearrangement. 



CH 2 OH 



geraniol linalool 



254 ORGANIC CHEMISTRY [CH. VIII 

This structure has been confirmed by synthesis of linalool (Ruzicka et al., 
1919); 6-methylhept-5-en-2-one was treated as follows: 



NaNH 2 f C 2 H a 

; »- 



C-ONa 




Na 



moist ether 



(+)-linalool 

Normant (1955) has synthesised linalool in one step by the action of vinyl- 
magnesium bromide on methylheptenone. 

§9. Citronellal, Ci H 18 O. This is an optically active compound which 
occurs in citronella oil. Citronellal is an aldehyde; reduction with sodium 
amalgam converts it into the alcohol citronellol, C X0 H 80 O, and oxidation 
gives citronellic acid, C 10 H 18 O a . Now there is another aldehyde, rhodinal, 
which is isomeric with citronellal, and on reduction, rhodinal gives the 
alcohol, rhodinol, which is isomeric with citronellol. Furthermore, reduc- 
tion of ethyl geranate with sodium and ethanol gives rhodinol (Bouveault 
et al., 1900). 

Oxidation of citronellal with chromic acid gives /?-methyladipic acid and 
acetone (Tiemann et al. , 1896, 1897) . Rhodinal also gives the same products 

O + C0 2 H 
OHO crf\ ( 0O 2 H 



I 
on oxidation. Thus structure I would fit the facts for both citronellal and 
rhodinal. On the other hand, ozonolysis of citronellal gives /?-methyladipic 
acid, acetone and some formaldehyde (Harries et al., 1908). These results 
point towards structure II for citronellal, as well as I. Thus citronellal 
appears to be a mixture of I (wopropylidene end-group) and II (wopropenyl 
end-group). Furthermore, a detailed study of rhodinal has shown that this 



,C0 2 H 
( j IHO -2^CH 2 0+CH 3 -C0 2 H + [ C0 2 H 



§10] 



TERPENES 



255 



compound is identical with citronellal, but consists of a mixture of the two 
forms in different proportions (but cf. citral, §5). 

§9a. Citronellol and Rhodinol, C 10 H M O. (— )-Citronellol occurs in rose 
and geranium oils, and is a mixture of the two forms: 




CH,OH 




CH 2 OH 



The (+)-form of citronellol is made commercially by reduction of citronellal 
with sodium or aluminium amalgam; it also occurs in Java citronella oil. 
Rhodinol is identical with citronellol, but the proportions of the two forms 
are different from those which occur in citronellol; the identity of citronellol 
and rhodinol is shown by the products of ozonolysis. 

MONOCYCLIC MONOTERPENES 

§10. Nomenclature. For the purposes of nomenclature of the mono- 
cyclic monoterpenes, the fully saturated compound ^-methyHsopropylcyc/o- 
hexane, hexahydro-_£-cymene or ^-menthane, C 10 H 20 , is used as the parent 
substance ; it is a synthetic compound, b.p. 170°. ^-Menthane is I, and II 
is a conventional method of drawing formula I. The positions of sub- 
stituents and double bonds are indicated by numbers, the method of number- 
ing being shown in I (and II). When a compound derived from ^>-menthane 

9 10 

CH 3 CH 3 
CH 



CH 
CH 2 



af* 



CH 

7 l 

CH 3 
I 

contains one or more double bonds, ambiguity may arise as to the position 
of a double bond when this is indicated in the usual way by a number which 
locates the first carbon atom joined by the double bond. To prevent am- 
biguity, the second carbon atom joined to the double bond is also shown, 




A 2 -^-menthene ; 
2-^-menthene; 
£-<menth-2-ene; 
p-menthene-2. 



/Kmenth- 
i(7)-ene 



p-mentha- 
l:4(8)-diene 



256 ORGANIC CHEMISTRY [CH. VIII 

but is placed in parentheses. The previous examples illustrate the method 
of nomenclature; in the first example, all the types of methods of nomen- 
clature have been given ; in the second and third examples, only the nomen- 
clature that will be used in this book is given. 

§lla. a-Terplneol. This is an optically active monoterpene that occurs 
naturally in the (+)-, (— )- and (±)-forms; it is a solid, m.p. (of the racemic 
modification) 35°. The molecular formula of a-terpineol is C 10 H 18 O, and 
the oxygen atom is present as a tertiary alcoholic group (as shown by the 
reactions of a-terpineol). Since a-terpineol adds on two bromine atoms, it 
therefore contains one double bond. Thus the parent (saturated) hydro- 
carbon of a-terpineol has the molecular formula C 10 H 20 . This corresponds 
to C„H 2 „, the general formula of the (monocyclic) cyc/oalkanes, and so it 
follows that a-terpineol is a monocyclic compound. 

When heated with sulphuric acid, a-terpineol forms some f-cymene. 
Taking this in conjunction with the tentative proposal that a-terpineol is 
monocyclic, it is reasonable to infer that a-terpineol contains the ^-cymene 
skeleton. Thus we may conclude that a-terpineol is probably ^-menthane 
with one double bond and a tertiary alcoholic group. The positions of 
these functional groups were ascertained by Wallach (1893, 1895) by means 
of graded oxidation. The following chart gives the results of Wallach's 
work; only the carbon content is indicated to show the fate of these carbon 
atoms (the formulae are given in the text). 

a-Terpineol — - — '->■ Trihydroxy compound V [Ketohydroxyacid] 

I II III 

— >- Keto-lactone 

IV 

warm 

alk. 

KMnO, 

Terpenylic acid ^->Terebic acid 

V VI 

+ 
CH 3 -C0 2 H 

Oxidation of a-terpineol, I, with 1 per cent, alkaline potassium permanganate 
hydroxylates the double bond to produce the trihydroxy compound II, 
C 10 H 20 O 3 . This, on oxidation with chromic acid (chromium trioxide in 
acetic acid), produces a compound with the molecular formula C 10 H 16 O 3 
(IV). This compound was shown to contain a ketonic group, and that it 
was neutral, e.g., it gave no reaction with sodium carbonate solution. When, 
however, IV was refluxed with excess of standard sodium hydroxide solu- 
tion, and then back titrated, it was found that alkali had been consumed, the 
amount corresponding to the presence of one carboxyl group. Thus com- 
pound IV appears to be the lactone of a monocarboxylic acid. Furthermore, 
since it is the lactone that is isolated and not the hydroxy acid, this spon- 
taneous lactonisation may be interpreted as being produced from a y-hydroxy- 
acid, i.e., IV is a y-lactone, and therefore III is a y-hydroxyacid. It is 
possible, however, for (5-hydroxyacids to spontaneously lactonise, and so 
whether IV is a y- or (5-lactone is uncertain at this stage of the evidence. 
Now, since IV is formed from II by scission of the glycol bond, and since 



§lla] 



TERPENES 



257 



-OH 




OH 



OH 



OH 




-CH 3 C0 2 H + /\ O 
> — I 





HO,C CO- 



there is no loss of carbon atoms in the process, the double bond must there- 
fore be in the ring in I. On warming with alkaline permanganate, IV gave 
acetic acid and a compound C 8 H, 2 4 (V). The formation of acetic acid 
suggests that IV is a methyl ketone, i.e., a CH 3 'CO group is present. Thus 
IV is a methyl ketone and a lactone ; it is known as homoterpenyl methyl 
ketone, and the structure assigned to it has been confirmed by synthesis 
(Simonsen et al., 1932). A study of the properties of terpenylic acid, V, 
showed that it was the lactone of a monohydroxydicarboxylic acid. Further 
oxidation of terpenylic acid gives terebic acid C 7 H 10 O 4 (VI), which is also 
the lactone of a monohydroxydicarboxylic acid. 

The above reactions can be formulated as shown, assuming I (p-meaih.- 
l-en-8-ol) as the structure of a-terpineol. These reactions were formulated 
by Wallach, who adopted formula I which had been proposed by Wagner 
(1894). The structures of terpenylic (V) and terebic (VI) acids were estab- 
lished by synthesis, e.g., those of Simonsen (1907). 

Terebic acid, m.p. 175°. 



CH 3 
I 

CO c s H,ONa 



CH, 
C0 2 C 2 H 6 



CH 3 

CO 
I 

OHNa 
I 
CO2C2H5 



CH 8 a-CQ 8 C a H5 



ICHsMgl 



CH 3 

I 

CO 

I 

CH 

/ \ 
COsCijHs CH 2 



C0 2 C 2 H 5 



CH3 CH3 

1 ° hydrolysis 

C0 2 C 2 Hs CH 2 

C0 2 C 2 H 5 




C0 2 H 



OH 



C0 2 H 




258 ORGANIC CHEMISTRY 

Terpenylic acid, m.p. 90°. 

OH, CHs 

CO CO 

I + 2CH 2 C1-C0 2 C 2 H 5 z ^"'^% I 



CH 2 



CO 2 2 H 6 



(2 steps) 



,c- 



[CH. VIII 



ketonic 

->. 

hydrolysis 



CH 2 C0 2 C 2 H 6 CH 2 
CO 2 2 H 6 C0 2 C 2 H 5 



CH, 

CO 

I 

CH 
CH 2 CH 2 



HC1 



CII 3 CH 3 CH 3 

?° 1CH.M*! C-OMgl 



CH CH 

/ \ / \ 

CH 2 CH 2 CH 2 CH 2 

I I II 

C0 2 H C0 2 H COjCzHg C0 2 C 2 H 5 COAH5 C0 2 C 2 H 6 



hydrolysis 



\z 



OH 




C0 2 H C0 2 H 



lactonises 




o 



0O 2 H CO— 1 
terpenylic acid 



It is of interest to note here that Sandberg (1957) has prepared the 
/?-acetotricarballylate in one step from acetoacetic ester and ethyl bromo- 
acetate in the presence of sodium hydride (in benzene solution). 

These syntheses strengthen the evidence for the structure assigned to 
a-terpineol, but final proof rests with a synthesis of a-terpineol itself. This 
has been carried out by Perkin, junior (1904), and by Perkin, junior, with 
Meldrum and Fisher (1908). Only the second synthesis is given here; this 
starts with ^-toluic acid. 



C0 2 H 



CO,H 



CO,H 



C0 2 H 



C0 2 H 



H 2 SO, 



KOH 



feOjH 



CH, 



heat in 

pyridine 

f^HBr) 



CH, 



C0 2 H 



C,H B OH 
HC1 




OH 



VII 



(±) -a-terpineol 



§12] TERPENES 259 

Compound VII was also resolved with strychnine, each enantiomorph treated 
as shown above (esterified, etc.), and thereby resulted in the formation of 
(+)- and (— )-terpineol. It should be noted that in the above synthesis 

C0 2 H C0 2 H 

pyridine 




CH, 




VIII 



the removal of a molecule of hydrogen bromide from 3-bromo-4-methyl- 
cycfohexane-1-carboxylic acid to give VII is an ambiguous step; instead of 
VII, compound VIII could have been formed. That VII and not VIII is 
formed rests on the analytical evidence for the position of this double bond; 
VIII cannot give the products of oxidation that are actually obtained from 
a-terpineol. 

A much simpler synthesis of a-terpineol has been carried out by Alder 
and Vogt (1949) ; this makes use of the Diels-AIder reaction, using isoprene 
and methyl vinyl ketone as the starting materials (see also Vol. I). 



CH 3 CH 3 

CO CO 

Hi 



£CH >■ CH - — ^->. 

w g w / \ (i,)acid 



»^ 



+ 



w yPH CH 2 ^pH 

c c 

I I 

CH3 CHj 



(i) CH.MgBr V-OH 

H 

I 



Two other terpineols are also known, viz., p-terpineol and y-terpineol; 
both occur naturally. 



OH I \)H 

p-terpineol -y-terpineol 

m.p. 32-33° m.p. (38-70° 

§12. Carvone, Ci„H 14 0, b.p. 230°/755 mm. This occurs in various essen- 
tial oils, e.g., spearmint and caraway oils, in optically active forms and also 
as the racemic modification. 

Carvone behaves as a ketone and, since it adds on four bromine atoms, it 
therefore contains two double bonds. Thus the parent hydrocarbon is 
CioHgo, and since this corresponds to the general formula CnHgn, carvone is 
monocyclic. When heated with phosphoric acid, carvone forms carvacrol; 
this suggests that carvone probably contains the ^>-cymene structure, and 
that the keto group is in the ring in the o^Ao-position with respect to the 
methyl group. 



260 



ORGANIC CHEMISTRY 



[CH. VIII 



A 

i i 

c c=o 

V 

I 
c 

carvone 
skeleton 



QH 3 .CH 3 




OH 



The structure of carvone is largely based on the fact that carvone may be 
prepared from a-terpineol as follows: 




H a so 4 . 




NOH 



The addition of nitrosyl chloride to a-terpineol, I, produces a-terpineol 
nitrosochloride, II, the addition occurring according to Markownikoff's rule 
(the chlorine is the negative part of the addendum; see Vol. I). This 
nitrosochloride rearranges spontaneously to the oximino compound, III 
(see nitroso-compounds, Vol. I ; it might be noted that this rearrangement 
proves the orientation of the addition of the nitrosyl chloride to the double 
bond; addition the other way could not give an oxime, since there is no 
hydrogen atom at position 1 in a-terpineol). Removal of a molecule of 
hydrogen chloride from III by means of sodium ethoxide produces IV, and 
this, on warming with dilute sulphuric acid, loses a molecule of water with 
simultaneous hydrolysis of the oxime to form carvone, V. Thus, according 
to this interpretation of the reactions, carvone is ^>-menth-6 : 8-dien-2-one. 
Actually, these reactions show that carvone has the same carbon skeleton 
as a-terpineol, and also confirm the position of the keto group. They do 
not prove conclusively the positions of the two double bonds; instead of 
position 6 (in IV), the double bond could have been 1(7), and instead of 
position 8 (as in V), the double bond could have been 4(8). Thus the above 
reactions constitute an ambiguous synthesis of carvone (a-terpineol has 
already been synthesised). The exact positions of these two double bonds 
have been determined analytically as follows. 

The double bond in the disposition. The following reactions were carried 
out by Tiemann and Semmler (1895). 



arvone — *■ ui 

vc 10 (+iH > 


Vi c„ KMn ° 4 


VII 


Cio 






COjjH 


CrO s _ Ketonic 
cH,cOaH* alcohol 


NaOBr Hydroxy 
* acid 


Bra/HjO 1 
190° * | 


. JoH 


VIII c 9 


IX c„ 


CH 3 








X 



§12] 



TERPENES 



261 



Reduction of carvone, V, with sodium and ethanol gives dihydrocarveol, 
C Z0 H 18 O (VI); this is a secondary alcohol and contains one double bond, 
i.e., the keto group and one of the two double bonds in carvone have been 
reduced. Hydroxylation of the double bond in dihydrocarveol by means 
of 1 per cent, alkaline permanganate produces the trihydroxy compound 
C 10 H 2o O 3 (VII). Oxidation of VII with chromic acid causes scission of the 
glycol bond to produce a compound C 9 H 16 2 (VIII); this was shown to 
contain a keto group and a hydroxyl (alcoholic) group. The action of 
sodium hypobromite on VIII caused the loss of one carbon atom to produce 
the compound C 8 H u 3 (IX) ; this was shown to be a hydroxymonocarboxylic 
acid, and since one carbon is lost in its formation, its precursor VIII must 
therefore be a methyl ketone. Finally, dehydrogenation of IX by heating 
with bromine-water at 190° under pressure produced m-bydroxy-£-toIuic 
acid, X (a known compound). Tiemann and Semmler explained these 
reactions on the assumption that one double bond in carvone is in the 
8-position. Thus: 

CH 3 CH 2 OH CH 3 
N ^-OH X C=0 




JOH 



VIII 



OH 



Had the double bond been in the 4(8)-position (structure V<z), then com- 
pound VIII, and consequently X, could not have been obtained, since 
three carbon atoms would have been lost during the oxidation. 




CH 3 -COCH 3 + 



>GR 



It might be noted in passing that V contains an asymmetric carbon atom, 
whereas Va is a symmetrical molecule and so cannot exhibit optical activity. 
Since carvone is known in optically active forms, structure Va must be 
rejected on these grounds. 

The double bond in the ^-position. Carvone adds on one molecule of 
hydrogen bromide to form carvone hydrobromide, C 10 H 15 OBr (XI), and 
this, on treatment with zinc dust and methanol, is converted into carvo- 
tanacetone, C l0 Hi 6 O (XII), by replacement of the bromine atom by hydro- 
gen. Thus the final result of these reactions is to saturate one of the two 
double bonds in carvone. Carvotanacetone, on oxidation with perman- 
ganate, gives t'sopropylsuccinic acid, XIII, and pyruvic acid, XIV (Semmler, 



262 



ORGANIC CHEMISTRY 



[CH. VIII 



1900). These products are obtainable only if the ring contains the double 
bond in the 6-position. Had the double bond been in the l(7)-position, 




C0 2 H CO 
*■ I + I 

C0 2 H CH 3 



.CO,H 



XIII 



XIV 



C0 2 H 



COjjH C0 2 H CH 3 



XII 



formic acid and not pyruvic acid would have been obtained. Further 
support for the 6-position is provided by the work of Simonsen et al. (1922), 
who obtained /9-wopropylglutaric acid and acetic acid on oxidation of carvo- 
tanacetone with permanganate. 

§13. Limonene, C 10 H 16 , b.p. 175-5-1 76-5°. This is optically active; the 
(+)-form occurs in lemon and orange oils, the (— )-form in peppermint oil, 
and the (ij-form in turpentine oil. The racemic modification is also pro- 
duced by racemisation of the optically active forms at about 250°. The 
racemic modification is also known as dipentene; this name was given to 
the inactive form before its relation to the active form (limonene) was 
known. 

Since limonene adds on four bromine atoms, it therefore contains two 
double bonds. (+) -Limonene may be prepared by dehydrating (+)-a- 
terpineol with potassium hydrogen sulphate, and limonene (or dipentene) 
may be converted into a-terpineol on shaking with dilute sulphuric acid. 



OH 




-HaO^ 



or 



Thus the carbon skeleton and the position of one double bond in limonene 
are known. The position of the other double bond, however, remains un- 
certain from this preparation; I or II is possible. 

Proof for position 8. Structure I contains an asymmetric carbon atom 
(C 4 ), and hence can exhibit optical activity. II is a symmetrical molecule 
and so cannot be optically active. Therefore I must be limonene. 

Chemical proof for position 8 is afforded by the following reactions: 



Limonene 
I 



NOCl 



> Limonene nitrosochloride ■ 



KOH 



III 



C.H.OH 



■f*- carvoxrme 
IV 



§13] 



TEEPENES 



263 



Since the structure of carvoxime is known, it therefore follows that I must 
have one double bond in position 8; thus the above reactions may be 
written: 



noci 





OH 




OH 



The connection between limonene and dipentene is shown by the fact 
that (+)- or (— )-limonene adds on two molecules of hydrogen chloride in 
the presence of moisture to form limonene dihydrochloride, and this is 
identical with dipentene dihydrochloride. 




+ 2HC1 ■ 



(+)- or (-)- 
limonene 

Limonene dihydrochloride no longer contains an asymmetric carbon atom, 
and so is optically inactive. It can, however, exhibit geometrical isomer- 
ism; the cw-form is produced from limonene, and the trans-form from 
cineole (§14). 



H 



CH, 



o 



(CH 3 ) 2 CC1 



H 



CI 



(CHskCCl 



CI 



CH, 



as 



trans 



Dipentene can be regenerated by heating the dihydrochloride with sodium 
acetate in acetic acid, or boiling with aniline. On the other hand, when 
limonene dihydrochloride is heated with silver acetate in acetic acid, and 
then hydrolysing the ester with sodium hydroxide, 1 : 8-terpin is formed; 
the direct action of sodium hydroxide on the dihydrochloride regenerates 
dipentene. 



-OCO-CH 



CHs-COjAg 




^OCO-CHa 




264 



ORGANIC CHEMISTRY 



[CH. VIII 



1 : 8-Terpin exists in two geometrical isomeric forms, corresponding to the 
cis and trans dipentene dihydrochlorides. cis-1 : 8-Terpin is the common 
form, m.p. 105°, and readily combines with one molecule of water to form 
terpin hydrate. The trans-iorm, m.p. 158-159°, does not form a hydrate 
(see also §14). 

There is also a 1 : 4- terpin; this was originally prepared by the action 
of dilute alkali on terpinene dihydrochloride. 



•OH 



NaOH 




^OH 



Terpinenes, C 10 H 16 . There are three isomeric terpinenes, and all give 
the same terpinene dihydrochloride with hydrogen chloride. 



o-terpinene 
b.p. 180-182° 



p-terpinene 
b.p. 173-174° 



y-terpinene 
b.p. 69-73°/20mm. 



All three occur naturally. 

Terpinolene, C 10 H] e , b.p. 67-68°/10 mm. This occurs naturally. It is 
not optically active, and since it may be prepared by dehydrating a-terpineol 
with oxalic acid, its structure is known (it is II, the alternative formula 
offered for limonene). Terpinolene adds on two molecules of hydrogen 
chloride to form dipentene dihydrochloride. 

-OH 



-H s O 



Phellandrenes, C^H^. There are two phellandrenes, both of which 
are optically active, and all the enantiomorphs occur naturally. 



o-phellandrene 
b.p. 58-59°/ 16 mm. 



p-phellaudrene 
b.p. 171-172° 



§14] 



TERPENES 



265 



§14* 1 : 8-Cineole, C 10 H 18 O, b.p. 174-4°. This occurs in eucalyptus oils. 
It is isomeric with a-terpineol, but contains neither a hydroxyl group nor 
a double bond. The oxygen atom in cineole is inert, e.g., it is not attacked 
by sodium or by the usual reducing agents. This inertness suggests that 
the oxygen atom is of the ether type. Support for this is obtained from 
the fact that dehydration of cis-1 : 8-terpin gives 1 : 8-cineole; at the same 
time, this reaction suggests that the structure of cineole is I. 



-OH 



-H,Q 




-OH 



Further support for this structure is afforded by a study of the products 
obtained by oxidation (Wallach et al., 1888, 1890, 1892). When oxidised 
with potassium permanganate, cineole forms cineolic acid, II, and this, on 
distillation with acetic anhydride, forms cineolic anhydride, III. When 
distilled at atmospheric pressure, cineolic anhydride forms 6-methylhept- 
5-en-2-one, IV, a known compound (§5). These reactions were interpreted 
by Wallach as follows: 




Co], 




C0 2 H- Hi ,o O 
jC0 2 H 




I II 

Further work on the structure of cineolic acid has confirmed the above 
sequence of reactions (Rupe, 1901, — ). 

It seems most probable that the 1 : 8-terpins have chair conformations, 
but when they form 1 : 8-cineole, the latter possesses the boat conforma- 
tion; thus: 





cis-terpin 1 : 8-cineole 

There is also a 1 : 4-cineole; this occurs naturally. 




l:4-cineole 
b.p. 172° 



266 



ORGANIC CHEMISTRY 



[CH. VIII 



Ascaridole, C 10 H 16 O s , b.p. 96-97°/8 mm. The cineoles are oxides ; ascari- 
dole, however, is a peroxide, the only known terpene peroxide, and it occurs 
naturally in, e.g., chenopodium oil. When heated to 130-150°, ascaridole 
decomposes with explosive violence. When reduced catalytically, ascari- 
dole forms 1 : 4-terpin (Wallach, 1912), and this led to the suggestion that 



ascaridole is V. This structure has been confirmed by further analytical 
work. Ascaridole has been synthesised by Ziegler et al. (1944) by the irradia- 
tion of oc-terpinene in dilute solution in the presence of chlorophyll. 

§15. Sylvestrene, C 10 H 16 , b.p. 176-178°. This compound exists in (+ )-, 
(— )- and (±)-forms; the racemic modification is also known as carvestrene 
(cf. limonene and dipentene, §13). The (+)-form of sylvestrene was first 
obtained from Swedish pine needle oil (Attenberg, 1877), and was shown 
to contain the w-cymene carbon skeleton (Baeyer et al., 1898). Thus syl- 
vestrene appeared to be the only monocyclic monoterpene which did not 
have the />-cymene structure and was obtainable from natural sources. 
Although the w-cymene structure can be divided into two isoprene units 
(Wallach's isoprene rule), these two units are not Joined head to tail. 

\ C r 

c \ c-c 



W-cymene skeleton 

Subsequent work, however, showed that sylvestrene does not occur in pine 
oil. In the extraction of sylvestrene, the pine oil is heated with hydrogen 
chloride to give sylvestrene dihydrochloride. This compound was shown 



car-3-ene 




sylvestrene 



car-4-ene 



§16] TERPENES 267 

by Simonsen et al. (1923, 1925) to be produced by the action of hydrogen 
chloride on car-3-ene, i.e., these workers showed conclusively that the terpene 
originally present in Swedish pine oil is car-3-ene. Sylvestrene may be 
obtained from its dihydrochloride by heating the latter with aniline; removal 
of hydrogen chloride from the ring can give rise to two possible positions 
for the ring double bond. Analytical work has shown that the side-chain 
is wopropenyl (and not tsopropylidene), and that sylvestrene is a mixture 
of the two forms, w-mentha-1 : 8-diene and m-mentha-6 : 8-diene. Further- 
more, it has been shown that car-4-ene is also present in pine oil; both of 
these carenes are readily converted into sylvestrene, and so it appears that 
the precursor of sylvestrene (itself a mixture) is a mixture of the two carenes 
(see §21). 

The enantiomorphs of sylvestrene have been synthesised (Perkin, junior, 
et al., 1913), and it has also been shown that an equimolecular mixture of 
the dihydrochlorides of (+)- and (—) -sylvestrene is identical with car- 
vestrene dihydrochloride. 

§16. Menthol and menthone. Menthol, C 10 H ao O, is an optically active 
compound, but only the (— )-form occurs naturally, e.g., in peppermint oils. 
(— )-Menthol, m.p. 34°, is a saturated compound, and the functional nature 
of the oxygen atom is alcoholic, as shown by its reactions, e.g., menthol 
forms esters. Furthermore, since oxidation converts menthol into men- 
thone, a ketone, the alcoholic group in menthol is therefore secondary. Also, 
since reduction with hydrogen iodide gives />-menthane, menthol most prob- 
ably contains this carbon skeleton. Finally, since (+)-pulegone gives men- 
thol on reduction, and since the structure of pulegone is known to be I 
(see §17), it therefore follows that menthol must be II. This structure, 





OH 



^>-menth-3-ol, for menthol has been confirmed by consideration of the oxida- 
tion products of menthone (see below), and also by the synthesis of menthol. 
Examination of the menthol structure shows that three dissimilar asym- 
metric carbon atoms (1, 3 and 4) are present; thus eight optically active 
forms (four racemic modifications) are possible theoretically. All eight 
enantiomorphs are known and their configurations are as follows (the hori- 
zontal lines represent the plane of the cycloh.exa.ne ring): 



CH, 



OH 

3 



H h c: 

Menthol 



CH, H H 



H(CH 3 ) Z H OH CH(CH S ) 2 
neo Menthol 



CH, 
l 



H O] 
OH H 



H(CH 3 ) 2 



H 

/so Menthol 



CH 3 

li 



OH CH(CH 3 ) 2 



I 



H H H 
neoiso Menthol 



268 



ORGANIC CHEMISTRY 



[CH. VIII 



These configurations have been assigned from a study of chemical and 
optical relationships and the Auwers-Skita rule. More recently the applica- 
tion of conformational analysis has confirmed these results. Eliel (1953) 
applied the principle that the esterification of an axial hydroxyl group 
occurs less readily than with an equatorial one. Furthermore, Eliel postu- 
lated that the reaction proceeds via the conformation of the molecule in 
which the reactive hydroxyl group is equatorial, and that the rate differences 
should be attributed to that energy necessary to place the other substituents, 
if necessary, into the axial conformation (see also §12. IV). On this basis, 
the rates of esterification of the isomeric menthols will be: 

menthol > iso- > neoiso- > neo-. 
These are the orders of rates actually obtained by Read et al. (1934). The 
following conformations have been assigned by Eliel from chemical studies, 
and are supported by Cole et al. (1956) from their infra-red spectra and 
conformation studies. 



«'-Pr 




H H 

Menthol 



H OH 

weoMenthol 



H 



H 




z-Pr 



OH 



Me H 

woMenthol 




Me OH 

weoMoMenthol 



In menthol, all of the substituents are equatorial, and in the rest one is 
axial. It should also be noted that the larger of the two alkyl groups {iso- 
propyl) is always equatorial (cf. §11. IV). 

Menthone, C 10 H 18 O, b.p. 204°/750 mm. (— )-Menthone occurs in pepper- 
mint oil, and it may readily be prepared by the oxidation of (— )-menthol 
with chromic acid. Menthone is a saturated compound which has the 
characteristic properties of a ketone. When heated with hydriodic acid 
and red phosphorus, menthone is reduced to ^-menthane; thus this skeleton 
is present in menthone. Oxidation of menthone with potassium perman- 
ganate produces a compound C 10 H 18 O 3 ; this compound was shown to con- 
tain a keto-group and one carboxyl group, and is known as ketomenthylic 
acid (IV). Ketomenthylic acid itself is very readily oxidised by perman- 
ganate to /?-methyladipic acid (V) and some other acids (Arth, 1886; Manasse 
et al., 1894). The foregoing oxidative reactions may be formulated as 
follows, on the assumption that III is the structure of menthone. This 



C0 2 H _[£]_ 





§17] TERPENES 269 

structure for menthone has been confirmed by synthesis, e.g., Kotz and 
Schwarz (1907) obtained menthone by the distillation of the calcium salt of 
/J'-methyl-a-/sopropylpinielic acid, which was prepared as follows. 3-Metbyl- 
c^c/ohexanone, VI, was condensed with ethyl oxalate in the presence of 
sodium, and the product VII then heated under reduced pressure; this gave 
the ethyl ester of 4-methylcyc/ohexan-2-one-l-carboxylic acid, VIII. VIII, 
on treatment with sodium ethoxide followed by wopropyl iodide, gave IX, 
and this when boiled with ethanolic sodium ethoxide and the product then 
acidified, gave j8'-methyl-a-/sopropylpimelic acid, X (note the acetoacetic 
ester fragment in VIII). 

Structure III contains two dissimilar asymmetric carbon atoms (1 and 
4), and so four optically active forms (and two racemic modifications) are 
possible. All are known, and correspond to the menthones and women- 
thones; these are geometrical isomers, each one existing as a pair of enantio- 
morphs. The configurations have been assigned on physical evidence; the 
«'s-isomer has the higher refractive index and density (Auwers-Skita rule; 
see §5 x. IV). 




+ (0O 2 C 2 H 5 ) 2 J^ 



!0 2 C 2 H 5 \ 




(i)C a H„ONa 
(ii)(CH 5 )jCHI 



VII 



VIII 



C0 2 C 2 H 5 

(i) CjH„ONa 




(ii) HC1 



30 2 H 
CH 2 -C0 2 H 



Ca 




o 
(ch 3 ) 2 ch1L 



"xf* 5 



(CH 3 ) 2 CHl 



H 



H 



CH, 



as-isomer 
z'soMenthone 



trans- isomer 
Menthone 



§17. (±)-Pulegone, C 10 H 16 O, b.p. 221-222°. This occurs in pennyroyal 
oils. Pulegone contains one double bond, and behaves as a ketone. On 
reduction, pulegone first gives menthone and this, on further reduction, 
gives menthol. When oxidised with permanganate, pulegone forms acetone 
and /S-methyladipic acid (Semmler, 1892) ; when boiled with aqueous ethan- 
olic potassium hydroxide, acetone and 3-methylcyc/ohexanone are obtained 
(Wallach, 1896). These reactions show that pulegone is ^>-menth-4(8)-en- 
3-one. 



270 ORGANIC CHEMISTRY [CH. VIII 





pulegone 



This structure has been confirmed by synthesis, starting from 3-methyl- 
cyc/ohexanone (Black et al., 1956: cf. menthone, §16). 




(p-MeC„H 4 'S0 3 H 
catalyst) 



cyclic ketal pulegone iwpulegone 

t'soPulegone can be isomerised to pulegone by alkaline reagents (Kon et al., 
1927), and Black et al. found that, on treating their mixture with sodium 
ethoxide, the resulting compound was pure pulegone. 

§18. (-)-Piperitone, C 10 H 16 O, b.p. 232-233°/768 mm. This occurs in 
eucalyptus oils, and is a valuable source of menthone and thymol. Piperi- 
tone contains one double bond, and behaves as a ketone. Piperitone, on 
catalytic hydrogenation (nickel), gives menthone in almost quantitative 
yield; on oxidation with ferric chloride, thymol is obtained (Smith et al., 
1920). These reactions show that piperitone is j!>-menthene-3-one, but do 



C0 2 H 





not show the position of the double bond. This had been shown by Schim- 
mel (1910), who found that on oxidation with alkaline permanganate, piperi- 
tone gave a-hydroxy-a-methyl-aWsopropyladipic acid, II, y-acetyl-a-t'so- 
propylbutyric acid, III, and oc-t'sopropylglutaric acid, IV. These results 
can be explained only if piperitone is £-menth-l-en-3-one, I. This struc- 
ture for piperitone has been confirmed by various syntheses (e.g., Henecka, 



§19] 



TERPENES 



271 



1948; Birch et al., 1949). Bergmann et al. (1959) have shown that piperitone 
is formed directly by the condensation of mesityl oxide with methyl vinyl 
ketone. 

BICYCLIC MONOTERPENES 

§19. Introduction. The bicyclic monoterpenes may be divided into 
three classes according to the size of the second ring, the first being a six- 
membered ring in each class. 

Class I (6- + 3-membered ring). 



CH 3 

CH ^CH 2 
l\ 1 




CH 3 

> 

ClC ^CH, 

1 1 


l\ 1 
CHA .CH 2 

1 

CH3 CH3 




1 1 
CH 2 CH 

^j^CH 
CH 3 


thujane 




carane 


Class II (6- + 4-membered ring). 






CH 3 






CH 





CH 2 



-CH 



CHj-C^HsJ 



CH, 



CH 2 





CH 






pinane 




Class III (6- + 5-membered 


ring). 




CH 3 






CH 2 | CH 2 
| CHs-C-CHjl 




CH 2 J C .. 

| CH 2 | CH 3 


CH 2 CH 2 
^CH 




CHg 1 ^CH"Cji3 
^CH 


camphane 




ixocamphane 


CH 3 






1 
CH 2 1 CH 2 




CH 2 | CH 2 


1 ™> I/CH3 
CH 2 .C 

^CH^ ^ 




CH 3 — C-CH 3 | 
CH 2 1 CH-CH 3 

^CH 


fenchane 




zsobornylane 



272 



ORGANIC CHEMISTRY 



[CH. VIII 



It is important to note that the two rings do not lie in one plane, but are 
almost perpendicular to each other (see, e.g., §23b). 

§20. Thujone and its derivatives. The members of this group which 
occur naturally are the following: 



OH 



a-thujene thujyl alcohol 






thujone 



§21. Carane and its derivatives. 

derivatives occur naturally: 



umbellulone sabinene sabinol 

It appears that only three carane 






car-3-eno 



car-4-ene car-3-ene-5:6-epoxide 



Car-3-ene occurs in Swedish pine needle oil. It is a liquid, b.p. 170°; 
when treated with hydrogen chloride it forms a mixture of sylvestrene 
dihydrochloride (see §15) and dipentene dihydrochloride (§13). 





(+)-Car-4-ene, b.p. 165-5-167°/707 mm., occurs in various essential oils. 
It forms sylvestrene dihydrochloride on treatment with hydrogen chloride 
(§15)- 

Car-3-ene-5 : 6-epoxide, b.p. 83-85°/14 mm., occurs in certain essen- 
tial oils. 

Carone, b.p. 99-100°/15 mm., is a synthetic compound, and is of some 
importance because of its relationship to carane. It was first prepared by 




dihydrocarvone carone 

Baeyer et al. (1894) by the action of hydrogen bromide on dihydrocarvone, 
which was then treated with ethanolic potassium hydroxide, whereupon 
carone was obtained. 



§22] TERPENES 273 




C0 2 H 
HO 2 



[Q] > V U « 




The structure of carone was established by Baeyer et al. (1896), who 
obtained caronic acid on oxidation of carone with permanganate. Baeyer 
suggested that caronic acid was a cyclopropane derivative, and this was 
confirmed by synthesis (Perkin, junior, and Thorpe, 1899), starting with 
ethyl /? : /J-dimethylacrylate and ethyl cyanoacetate. 

CIJ3 CH 3 CH 3 .CH 3 

Jl ^ CN C a H B ONa I ^H hydrolysis 

CH + CH 2 -COAH 5 (Michae , » CH 2 ^cOhCtH. ' * > 

I condensation) ' 

C0 2 C 2 H 5 C0 2 C 2 H 5 



OHTf ^NxtfT^ CH 3 / < f~ CH2 ' C ° 2H " 

CH 2 -C0 2 H CH 2 -C0 2 H 

p:p-dimethylglutaric acid 

,m, , ^ CHErC0B r c a H 8 OH /CHBr-C0 2 C 2 H 5 ..... 

(CH 3 ) 2 C X "( CH^Ctf 

CHg-COBr CH 2 C0 2 C 2 H 6 



KOH 



CH-C0 2 H 

(CH&CT I 

^CHC0 2 H 



An interesting point about carone is that its ultraviolet absorption spec- 
trum shows similarities to that of a : /9-unsaturated ketones (Klotz, 1941). 

§22. Pinane and its derivatives. Pinane, the parent compound of 
this group, is a synthetic substance which may be prepared by the catalytic 
hydrogenation (nickel or platinum) of either a- or /?-pinene. Pinane exists 



o-pinene pinane p-pinene 

in two geometrical isomeric forms, cis and tran$, and each of these exists 
as a pair of enantiomorphs. 




cis trans 



274 



ORGANIC CHEMISTRY 



[CH. VIII 



§22a. a-Pinene. This is the most important member of the pinane class. 
It occurs in both the (+)- and (— )-forms in all turpentine oils; it is a 
liquid, b.p. 156°. 

The analytical evidence for the structure of a-pinene may conveniently 
be divided into two sections, each section leading independently to the 
structure, and the two taken together giving very powerful evidence for 
the structure assigned. 

Method 1. The molecular formula of a-pinene is C^Km, and since a-pinene 
adds on two bromine atoms, one double bond is present in the molecule. 
Thus the parent hydrocarbon is C 10 H 18 , and since this corresponds to the 
general formula C„H 2 »_2 the general formula of compounds containing 
two rings, it therefore follows that a-pinene is bicyclic (Wallach, 1887- 
1891). In the preparation of a-pinene nitrosochloride (by the action of 
nitrosyl chloride on a-pinene) the by-products which were formed were 
steam distilled, and the compound pinol, C 10 H 16 O, was thereby obtained. 
Pinol adds on one molecule of bromine to form pinol dibromide, and so 
pinol contains one double bond. Furthermore, the action of lead hydroxide 
on pinol dibromide converts the latter into pinol glycol, C 10 H 16 O(OH) a , and 
this, on oxidation, gives terpenylic acid (Wallach et al., 1889). Pinol (III) 
is also obtained by the action of sodium ethoxide on a-terpineol dibromide, 
II (Wallach, 1893). Wagner (1894) showed that the oxidation of pinol with 
permanganate gives pinol glycol (IV), which is further oxidised to terpenylic 
acid (V). All these facts can be explained as follows, based on I being the 
structure of a-terpineol (see also §11). 




IV v 

Support for the structure given for pinol (III) is obtained from the fact 
that oxidation of sobrerol (pinol hydrate) produces a tetrahydnc alcohol, 
sobrerythritol. Sobrerol itself is readily prepared by the action of hydrogen 
bromide on pinol, followed by sodium hydroxide. These reactions may thus 
be formulated: 





pinol 



pinol 
hydrobromide 



sobrerol 



sobrerythritol 



§22a] terpenes 275 

Thus, if the formula for oc-pinene is VI, then the formation of the above 
substances can be explained. This structure also accounts for other re- 
actions of a-pinene, e.g., its ready hydration to oc-terpineol (see later). 



Although the Wagner formula (VI) for a-pinene readily explains all the 
facts, there is no direct evidence for the existence of the cyc/obutane ring. 
Such evidence was supplied by Baeyer (1896) . This is described in method 2. 

Method 2. As in method 1, a-pinene was shown to be bicyclic. When 
treated with ethanolic sulphuric acid, a-pinene is converted into a-terpineol 
(Flavitzky, 1879). Therefore a-pinene contains a six-membered ring and 
another ring (since it is bicyclic), the carbon skeleton of pinene being such 
as to give a-terpineoi when this second ring opens. Since, in the formation 
of a-terpineol, one molecule of water is taken up and the hydroxyl group 
becomes attached to C 8 , this suggests that the C 8 of a-terpineol is involved 
in forming the second ring in a-pinene. There are three possible points of 
union for this C 8 , resulting in two three-membered and one four-membered 
ring (see VII) ; at the same time the position of the double bond in a-pinene 
is also shown by the conversion into a-terpineol (I). 




VII A-OH 

Vila 

A point of interest here is that there are actually four possible points of 
union for C 8 , the three shown in VII and the fourth being at the double 
bond to form a four-membered ring (Vila) . This one, however, was rejected 
on the grounds of Bredt's rule (1924) which states that a double bond cannot 
be formed by a carbon atom occupying the bridge-head (of a bicyclic system). 
The explanation for this rule is that structures such as Vila have a large 
amount of strain. 

This second ring was shown to be four-membered by Baeyer (1896), who 
carried out the following series of reactions. 

_. 1% alt. . ■ warm alk. „. 

a-Pinene ———*• Pmene glycol >-Pmomc acid 

KMnOj ° J KMn0 4 

Pio Vio C 10 

VI VIII IX 

Xa0B r t>- • • j , r-TT-o (i) Br, (ii) Ba(OH), . „ 

► Pimc acid + CHBr 3 ^ > as-Norprnic acid 

c 9 C 8 

X XI 

Pinene glycol, C 10 H 18 (OH) a , is produced by hydroxylation of the double 
bond in a-pinene, and pinonic acid, C^H^Og, is produced by scission of the 
glycol bond. Pinonic acid was shown to be a saturated keto-monocarboxylic 



276 



ORGANIC CHEMISTRY 



[CH. VIII 



acid. The formation of pinic acid, C 8 H 14 4 , and bromoform, indicates the 
presence of an acetyl group in pinonic acid. Pinic acid, which was shown 
to be a saturated dicarboxylic acid, on treatment with bromine, then barium 
hydroxide, and finally the product oxidised with chromic acid, gives cis- 
norpinic acid, C 8 H 12 4 . This was shown to be a saturated dicarboxylic 
acid, and so its formula may be written C 6 H 10 (CO 2 H) 2 . Furthermore, since 
oc-pinene contains two methyl groups attached to a carbon atom in the 
second ring (see VII), and it is the other ring (the six-membered one con- 
taining the double bond) that has been opened by the above oxidation, then 
norpinic acid (with this second ring intact) contains these two methyl groups. 
Thus the formula for norpinic acid may be written (CH 3 ) 2 C 4 H 4 (C0 2 H) 2 . 
Hence, regarding the methyl and carboxyl groups as substituents, the parent 
(saturated) hydrocarbon (from which norpinic acid is derived) is C 4 H 8 . This 
corresponds to cyc/obutane, and so norpinic acid is (probably) a dimethyl- 
cycZobutanedicarboxylic acid. On this basis, pinic acid could therefore be 
a cycfobutane derivative with one side-chain of — CH 2 -C0 2 H. 

Baeyer therefore assumed that pinic and norpinic acids contained a cyclo- 
butane ring, and so suggested the following structures to account for the 
above reactions, accepting structure VI for a-pinene, the structure already 
proposed by Wagner (1894). 

CH 3 
HOj I 

HO A C< 1 

[Q3 > Y>| J?I^ C0 2 H> 






VIII 



-*-CHBr 3 + 




C0 2 H 




Ba(OH)2 



bromopinic 
acid 



CQ 2 H 
COIpj 

hcAK 

hydroxypinic 
acid 



COjjH 



[o] 



H0 2 Cn 



The synthesis of norpinic acid (to confirm the above reactions) proved 
to be a very difficult problem, and it was not carried out until 1929, when 
Kerr succeeded with the following ingenious method (apparently the presence 
of the gem dimethyl group prevents closure to form the cyc/obutane ring). 

The norpinic acid obtained was the trans-isomer ; this is readily converted 
into the «'s-isomer (the isomer obtained from the oxidation of a-pinene) 
by heating the trans acid with acetic anhydride, whereupon the cis anhydride 
is formed and this, on hydrolysis, gives the cis acid (Simonsen et ak, 1929). 

CN 
CN 



CH 2 'C0 2 C 2 H5 - TTT e thanol ln „ , -' 

(CH s ) 2 CO + „ _ +NH 3 solution ' (CH 3 ) 2 C 



CHCCk 



CH 2 C0 2 C 2 H 6 



C,H,ONa 



CN 
lWcC> 



Hch 3 ) 2 c v 



;nh 



CH 2 I a 



■"CNa-CO 
I 

CN 



(CH 3 ) 2 C^ 



^CH-CO- 
I 

CN 

CN 
,C— COv. 

pH 2 
"CWX)' 

CN 



NH 



:nh 



§22a] TEEPENES 277 

/C0 2 H 

(i)NaOH C^OjjH ntf ^CI^COgH 

(15)Hci "(CH&C. /CH 2 »- (CH 3 ) 2 C^ /CH 2 

C;C0 2 H CH-C0 2 H 

C0 2 H 

The total synthesis of oc-pinene has now been carried out in the following 
way. Guha et al. (1937) synthesised pinic acid from norpinic acid, and 
Rao (1943) synthesised pinonic acid from synthetic pinic acid. 

Ruzicka et al. (1920-1924) had already synthesised oc-pinene starting from 
pinonk. acid (obtained by the oxidation of oc-pinene). Thus we now have 

,C0 2 H 

(i)HBr 




.CH 2 OH (ii,KCN 
rraMS-norpinic acid as-anhydride 
^C0 2 H C0 2 H C0 2 CaH5 

hydrolysis [C C0 2 H C 3 H 5 OH S^ C0 2 C 2 H 5 partial 

.CH 2 -C^ " l^CH 2 "~ 1Rr *" ^pCH 2 1 ^ S ^ 

pinic acid 

/!0 2 C 2 H 5 /C0 2 C 2 H s /COaH 

CO, H (i)soa. |C QQ-NfCJi, v, H a so 4 K 0O-N(C«S.l 

*' (ii)(c,H B ) a NH {nr) [nr) 

CH 3 CH 3 

CO CO 

(i)SOCl a (\ CO-N(C 6 H 6 ) 2 (i)KOH^K 9°2 H 




(ii)CH 3 CdCI LT~J (ii)HCl 

rraws-pinonic acid ■ 

a total synthesis of oc-pinene. Ruzicka's synthesis makes use of the Darzens 
glycidic ester synthesis (see Vol. I); the steps are: 

CH 3 CH S 

,0° / C^ : ^1CH-C0 2 C 2 H 5 

C0 2 C 2 H s + CHgClCOAHs ^ j^COAHj ac ,- d > 




ethyl pinonate glycidic ester 




jas^j^pg^g^K^S. 



278 ORGANIC CHEMISTRY [CH. VIII 




(Dieckmann I "T — ! I I J (") M 

reaction) \|/\x3 2 C,H B 




■ , i )NH 8 OH^/\-^ 




/n/ 1 



,N(CH 3 ) 3 } + OH 

(i)CH 3 I > [\ | distil 

(ii) A S OH l"T~ J U j nder , 



reduced 
pressure 



a-pinene 8-pinene 



The final step gives a mixture of two compounds, a- and <5-pinene. The 
former was identified by the preparation of the nitrosochloride; this proves 
that one of the products is a-pinene, but does not prove which is a and which 
is d. These are differentiated by consideration of the analytical evidence ; 
the following evidence also supports the structure given for a-pinene. This 
evidence is based on the fact that diazoacetic ester combines with compounds 
containing a double bond to form pyrazoline derivatives, and these, on 
heating alone or with copper powder, decompose to produce cyclopropane 
derivatives (see also §2a. XII) . When the two pinenes were subjected to this 

CHC0 2 C 2 H 6 CH 3 /G0 2 H 

[o] 




H0 2 C 



C0 2 H 




COgH 
CH-CQAHfr' ^ 

H0 2 C 



8-pinene 



treatment, and the resulting compounds oxidised, a-pinene gave 1-methyl- 
cyc/opropane-1 : 2 : 3-tricarboxylic acid, and <5-pinene cycfopropane-1 : 2 : 3- 
tricarboxylic acid. These products are in accord with the structures assigned 
to a- and <5-pinene. 

Examination of the a-pinene structure shows that two dissimilar asym- 
metric carbon atoms are present; thus two pairs of enantiomorphs are 
possible. In practice, however, only one pair is known. This is due to 
the fact that the f our-membered ring can only be fused to the six-membered 
one in the m-position; trans fusion is impossible. Thus only the enantio- 
morphs of the cw-isomer are known. 

Isomeric with a-pinene are |3- and <3-pinene; the former occurs naturally, 
the latter is synthetic (see Ruzicka's synthesis) . Crowley (1962) has obtained 
a small amount of /J-pinene by irradiating a one per cent, ethereal solution 
of myrcene (§4) with ultraviolet light. This is of some interest in connection 
with the biosynthesis of terpenes (see §32a). 



§23a] 



TERPENES 



279 



p-pinene 



8-pinene 



is a 



syn- 



§23. Camphane and its derivatives. Camphane, C^Hjg, 
thetic compound, and may be prepared from camphor, e.g., 

(i) By reduction of camphor to a mixture of bomeols (§23t>), these then 
converted to the bornyl iodides which are finally reduced to camphane 
(Aschan, 1900). 




Zn 



CH,-CO a H 



camphor 



camphane 



(ii) Camphor may also be converted into camphane by means of the 
Wolff-Kishner reduction (see also Vol. I). 




N-NH 2 



C,H,ONh 
heat * 



"- +N 2 



Camphane is a solid, m.p. 156°; it is optically inactive. 

§23a. Camphor. This occurs in nature in the camphor tree of Formosa 
and Japan. It is a solid, m.p. 179°, and is optically active; the (+)- and 
(— )-forms occur naturally, and so does racemic camphor, which is the 
usual form of synthetic camphor (from <x-pinene; see later). 

A tremendous amount of work was done before the structure of camphor 
was successfully elucidated; in the following account only a small part of 
the work is described, but it is sufficient to justify the structure assigned 
to camphor. 

The molecular formula of camphor is C 10 H 16 O, and the general reactions 
and molecular refractivity of camphor show that it is saturated. The 
functional nature of the oxygen atom was shown to be oxo by the fact that 
camphor formed an oxime, etc., and that it was a keto group was deduced 
from the fact that oxidation of camphor gives a dicarboxylic acid containing 
10 carbon atoms; a monocarboxylic acid containing 10 carbon atoms cannot 
be obtained (this type of acid would be expected if camphor contained an 
aldehyde group). From the foregoing facts it can be seen that the parent 
hydrocarbon of camphor has the molecular formula C 10 Hi 8 ; this corresponds 
to C„H 2 n_2, and so camphor is therefore bicyclic. Camphor contains a 
— CH 2 *CO — group, since it forms an oxime with nitrous acid (tsoamyl nitrite 
and hydrogen chloride). Finally, distillation of camphor with zinc chloride 
or phosphorus pentoxide produces ^-cymene. 

Bredt (1893) was the first to assign the correct formula to camphor (over 
30 have been proposed). Bredt based his formula on the above facts and 
also on the facts that (a) oxidation of camphor with nitric acid gives cam- 
phoric acid, CjoHxeOj (Malaguti, 1837) ; (6) oxidation of camphoric acid 



280 



ORGANIC CHEMISTRY 



[CH. VIII 



(or camphor) with nitric acid gives camphoronic acid, C 9 H 14 O e (Bredt, 
1893). 

Since camphoric acid contains the same number of carbon atoms as 
camphor, the keto group must be in one of the rings in camphor. Camphoric 
acid is a dicarboxylic acid, and its molecular refractivity showed that it is 
saturated. Thus, in the formation of camphoric acid from camphor, the 
ring containing the keto group is opened, and consequently camphoric acid 
must be a monocyclic compound. 

Camphoronic acid was shown to be a saturated tricarboxylic acid, and 
on distillation at atmospheric pressure, it gave wobutyric acid, II, trimethyl- 
succinic acid, III, carbon dioxide and carbon (and a small amount of some 
other products). Bredt (1893) therefore suggested that camphoronic acid 
is a : a : j3-trimethyltricarballylic acid, I, since this structure would give the 
required decomposition products. In the following equations, the left-hand- 
side molecule is imagined to break up as shown; one molecule of carbon 
dioxide and two molecules of wobutyric acid are produced (but there is a 
shortage of two hydrogen atoms). The right-hand-side molecule breaks up 
to form one molecule of trimethylsuccinic acid, one molecule of carbon 
dioxide, one atom of carbon and two atoms of hydrogen which now make 
up the shortage of the left-hand-side molecule. Thus: 



CH 3 

CHs— C— C0 2 H 

\ H-- 
\ 9(CH 3 ) 2 

it!0 2 iH C0 2 H 



CH 3 
CHjj— C— C0 2 H 



7'A 



I 

Iheat 

QH 3 



C0 2 + 2CH 3 — CH-C0 2 H 
II \ 



,(CH 3 ) 2 

,co£h co 2 h 



CH3 

C0 2 + H— C — C0 2 H 
C(CH 3 ) 2 

C0 2 H , 
III 



2H +C 



Hence, if camphoronic acid has structure I, then camphoric acid (and cam- 
phor) must contain three methyl groups. On this basis, the formula of 
camphoric acid, C 10 H l6 O 4 , can be written as (CH 3 ) 3 C 5 H 5 (C0 2 H) 2 . The 
parent (saturated) hydrocarbon of this is C 5 H 1? , which corresponds to 
C„H 2 „, i.e., camphoric acid is a ryctopentane derivative (this agrees with 
the previous evidence that camphoric acid is monocyclic). Thus the oxida- 
tion of camphoric acid to camphoronic acid may be written: 



2C 



CH 3 



C(CH 3 



^X 



CH 3 
CHjf— C — ,0O 2 H 
-^U- I C(CH 3 ) 2 + 2 C0 2 

C0 2 H C0 2 H 



§23a] TERPENES 281 

This skeleton, plus one carbon atom, arranged with two carboxyl groups, 
will therefore be the structure of camphoric acid. Now camphoric an- 
hydride forms only one monobromo derivative (bromine and phosphorus) ; 
therefore there is only one a-hydrogen atom in camphoric acid. Thus the 
carbon atom of one carboxyl group must be X C (this is the only carbon atom 
joined to a tertiary carbon atom). Furthermore, X C must be the carbon of 
the keto or methylene group in camphor, since it is these two groups which 
produce the two carboxyl groups in camphoric acid. The problem is now 
to find the position of the other carboxyl group in camphoric acid. Its 
position must be such that when the cyc/opentane ring is opened to give 
camphoronic acid, one carbon atom is readily lost. Using this as a working 
hypothesis, then there are only two reasonable structures for camphoric 



H0 2 C' / N 



H 





IV 



IVa 



acid, IV and V. IV may be rewritten as IVa, and since the two carboxyl 
groups are produced from the — CH a «CO — group in camphor, the precursor 
of IVa [i.e., camphor) will contain a six-membered ring with a gem-dimethyl 
group. This structure cannot account for the conversion of camphor into 
^>-cymene. On the other hand, V accounts for all the facts given in the 
foregoing discussion. Bredt therefore assumed that V was the structure 
of camphoric acid, and that VI was the structure of camphor, and proposed 
the following reactions to show the relationships between camphor, cam- 
phoric acid and camphoronic acid. 




/V) 2 H 
•\s, v C0 2 H 

OH _ 



-CO. 



'V) 2 H^/\30 2 H 
H0 2 C C0 2 H 



I 



Bredt, however, realised that if camphor had structure VII, then all the 
foregoing facts would be equally satisfied, but he rejected VII in favour of 
VI for a number of reasons. One simple fact that may be used here for 





OH 



VII 



CH(CH 3 ) 2 
VIII 



rejection of VII is that camphor gives carvacrol, VIII, when distilled with 
iodine. The formation of this compound can be expected from VI but 
not from VII. 

Formula VI for camphor was accepted with reserve at the time when Bredt 
proposed it (in 1893), but by 1903 all the deductions of Bredt were confirmed 
by the syntheses of camphoronic acid, camphoric acid and camphor. 



282 ORGANIC CHEMISTRY [CH. VIII 

Synthesis of (±)-camphoronic acid (Perkin, Junior, and Thorpe, 1897). 

CH 3 CH 3 



CH, 



00 (i)C a H,ONa 9° (i)C 3 H,ONa C0 



Zn + CH a BfCOjCjH| 



CH. 

I 

coah 5 



(ii) CH 3 I 



CHCH 3 
C02C2H B 



(ii) GH S 



A/ntr \ (Reformatsky 
Xj(\/ki$)2 reaction) 

I 
CO2C2H5 



*- 



CH 3 CH 3 

/C\ ^c^ 

s' I ^OZnBr /^ | ^OH 

Cm C(CH 3 ) 2 acid, CH 2 C(CH 3 )2 (i)PCi. 

I I * I I (ii)KCN 

COAHg C0 2 C 2 H 5 COAH5 C02C 2 H 6 



CO,H 





C0 2 C 2 H 5 C0 2 C 2 H 5 C0 2 H C0 2 H 

Synthesis of (±)-camphoric acid (Komppa, 1903). Komppa (1899) 
first synthesised /3 : /S-dimethylglutaric ester as follows, starting with mesityl 

CO2C2H5 



(CH 3 ) 2 C=CHCOCH 3 + CH 2 (C0 2 C 2 H 5 )2 C '" 5 ° Na > 



(OH 3 ) 2 C ^C0 2 C 2 H 5 
CH 2 ^CH, 



CjH 5 ONa 



C0 2 C 2 H 6 

^CH^ 

(CH 3 ) 2 C CO (i ) Ba(OH) a 

CH 2 ,CH 2 OOHci *" 
T!0 



^CH 2 
(CH 3 ) 2 C ^CO 

CH 2 CH 2 
^CO 



NaOEr 



/CH 2 -C0 2 H CiH , OH .CH 2 -C0 2 C 2 H 6 

-CHBr 3+ (CH,) 2 C^ T5-«° H *S 3Hl .00AH, 



J 2 2 rl5 

oxide and ethyl malonate. The product obtained was 6 : 6-dimethyleycfo- 
hexane-2 : 4-dione-l-carboxylic ester (this is produced first by a Michael 
condensation, followed by a Dieckmann reaction). On hydrolysis, followed 
by oxidation with sodium hypobromite, /? : /S-dimethylglutaric acid was 
obtained (c/. carone, §21). 

Komppa (1903) then prepared camphoric acid as follows: 



CO2C2H5 
C0 2 C 2 H 6 



CH 2 C0 2 C 2 H 6 

C(CH S ) 2 

CH 2 -C0 2 C 2 H 5 



diketoapocamphoric 
ester 



§23a] 



TERPENES 



283 



(i)Na 



V'VjO-A 



(ii)CHjI 



— 



H 5 



0^\ /C0 2 C 2 H 5 

diketocamphoric 
ester 



Na-Hg 
NaOH 



HO. 



HO 




/NjObH 



— 



HBr 



^ C0 2 H 



/\x) 2 H 
/ J^ / C0 2 H 



/^COgH 

CH,C0 S H^ | TpQM 



Zn 



\ / C< 



The structure given for camphoric acid can exist in two geometrical 
isomeric forms, cis and trans, neither of which has any elements of sym- 
metry. Thus four optically active forms are possible; all are known, and 
correspond to the (+)- and (— )-forms of camphoric acid and wocamphoric 
acid. Since camphoric acid forms an anhydride, and wocamphoric acid 
does not, the former is the as-isomer, and the latter the trans- (§5 i. IV). 




CH 3 



C0 2 H 




C0 2 H 



CO2H 



CH 3 



CH 3 



camphoric acid, 
m.p.l87° 



MO-camphoric acid, 
m.p. 171-172° 



Synthesis of camphor (Haller, 1896). Haller started with camphoric 
acid prepared by the oxidation of camphor, but since the acid was syn- 
thesised later by Komppa, we now have a total synthesis of camphor. 




C0 2 H 



CH,COCl 



2 H 



camphoric 
acid 



CO 



camphoric o-campholide 

anhydride 



/N> 



KCN 



hydrolysis f ^ 



J 2 1 



X!H 2 -CN 



Ca salt 

— : »- 



^ CH 2 C0 2 H 

homocamphoric 
acid 



<lr 



This is not an unambiguous synthesis, since the campholide obtained might 
have had the structure IX (this is actually /3-campholide). 






p- campholide 
IX 



|/\iH 2 -C0 2 H 
*\/C0 2 H 
X 



284 ORGANIC CHEMISTRY [CH. VIII 

In this case, homocamphoric acid would have had structure X, and this 
would have given camphor with structure VII which, as we have seen, 
was rejected. Sauers (1959) has now oxidised camphor directly to oc-cam- 
pholide by means of peracetic acid. It is also of interest to note that 
Otvos et al. (1960) have shown, using labelled — CH a -C*O a H ( 14 C), that in 
the pyrolysis of the calcium salt of homocamphoric acid to camphor, it 
is the labelled carboxyl group that is lost. 

Stereochemistry of camphor. Camphor has two dissimilar asymmetric 
carbon atoms (the same two as in camphoric acid), but only one pair of 
enantiomorphs is known. This is due to the fact that only the cw-form 
is possible ; trans fusion of the gew-dimethylmethylene bridge to the cyclo- 
hexane ring is impossible. Thus only the enantiomorphs of the a's-isomer 
are known (c/. a-pinene, §22a). 

Camphor and its derivatives exist in the boat conformation. Since the 
gem-dimethyl bridge must be cis, the cye/ohexane ring must have the boat 
form (see also §23b for the usual way of drawing these conformations; the 
viewing point is different): 






camphor borneol isoborneol 

Some derivatives of camphor. The positions of substituent groups in 
camphor are indicated by numbers or by the Greek letters a (=3), /? or 
co (= 10) and n (= 8 or 9). When (+) -camphor is heated with bromine 
at 100°, a-bromo-(+)-camphor is produced. This, on warming with sul- 
phuric acid, is converted into a-bromo-(+)-camphor-7r-sulphonic acid which, 



10P(u) 




on reduction, forms (+)-camphor-ji;-sulphonic acid. (±)-Camphor-ji-sul- 
phonic acid is obtained by the sulphonation of (-f)-camphor with fuming 
sulphuric acid; under these conditions, (+)-camphor is racemised. Oh the 
other hand, sulphonation of (+)-camphor with sulphuric acid in acetic 
anhydride solution produces (+)-camphor-j8-sulphonic acid. These various 
(+)-camphorsulphonic acids are very valuable reagents for resolving racemic 
bases (§10 iv. II). 

Commercial preparation of camphor. Synthetic camphor is usually 
obtained as the racemic modification. The starting material is a-pinene, 
and the formation of camphor involves the Wagner-Meerwein rearrange- 
ments (see §23d). Scheme (i) is the earlier method, and (ii) is the one that 
is mainly used now. 

... iv HCl gas CH„-C0 2 Na CH,-CO a H 

(1) a-Pinene — >- Bornyl chloride > Camphene >■ 

w 10° J -HCl r H„SO» 

MoBornyl acetate > woBorneol — — — '■> Camphor 

.... -r,. HCl gas CH,-CO,Na H-CO.H 

(n) oc-Pmene > Bornyl chloride > Camphene >• 

v ' 10° J -HCl r 

■ t. r NaOH . O, 

tsoBornyl formate >■ woBorneol > Camphor 

J Ni; 200° r 



§23c] TERPENES 285 

§23b. Borneols, C X0 H 18 O. There are two stereoisomeric compounds of 
the formula C 10 H 18 O; these correspond to borneol and isoborneol, and 
both are known in the (+)- and (— )-forms. The borneols occur widely 
distributed in essential oils, but it appears that the woborneols have been 
isolated from only one essential oil. Borneol and woborneol are secondary 
alcohols, and the evidence now appears to be conclusive that borneol has 
the eWo-configuration in which the gem-dimethyl bridge is above the plane 








borneol woborneol 

m.p. 208-5° m.p. 217° 

of the cyc/ohexane ring and the hydroxyl group is below the plane, iso- 
Borneol has the e#o-configuration in which the bridge and the hydroxyl 
group are both above the plane of the cycfohexane ring (see also §23a). 
Kwart et al. (1956) have now obtained direct evidence on the configura- 
tion of bornyl chloride. Bornyl dichloride (I), the structure of which has 
been established by Kwart (1953), is converted into bornyl chloride (II) 
by sodium amalgam and ethanol, and into camphane (III) by sodium and 
ethanol. 



Na-Hg / I / Na 

EtOH 1^7*^^ I EtOH 



III 

Both borneol and woborneol are produced when camphor is reduced, but 
the relative amounts of each are influenced by the nature of the reducing 
agent used, e.g., electrolytic reduction gives mainly borneol, whereas catalytic 
hydrogenation (platinum) gives mainly woborneol; woborneol is also the 
main product when aluminium wopropoxide is used as the reducing agent 
(the Meerwein-Ponndorf-Verley reduction; see Vol. I). Borneol is con- 
verted into a mixture of bornyl and wobornyl chlorides by the action of 
phosphorus pentachloride. Borneol and wobomeol are both dehydrated to 
camphene (§23c), but the dehydration occurs more readily with woborneols 
than with borneol. Both alcohols are oxidised to camphor, but whereas 
borneol can be dehydrogenated to camphor by means of a copper catalyst, 
woborneol cannot. 

§23c. Camphene and Bornylene. Camphene, C 10 H 16 , m.p. 51-52°, 
occurs naturally in the (+)-, (— )- and (±)-forms. It may be prepared by 
the removal of a molecule of hydrogen chloride from bornyl and isobornyl 
chlorides by means of sodium acetate, or by the dehydration of the borneols 
with potassium hydrogen sulphate. These methods of preparation suggest 
that camphene contains a double bond, and this is supported by the fact 
that camphene adds on one molecule of bromine or one molecule of hydrogen 
chloride. Oxidation of camphene with dilute nitric acid produces carboxy- 
apocamphoric acid, C 10 H M O 6 , and apocamphoric acid, C„H 14 4 (Marsh et al., 
1891). The formation of the former acid, which contains the same number 
of carbon atoms as camphene, implies that the double bond in camphene 
is in a ring; and the fact that carboxyapocamphoric acid is converted into 



286 ORGANIC CHEMISTRY [CH. VIII 

apocamphoric acid when heated above its melting point implies that the 
former contains two carboxyl groups attached to the same carbon atom 

C0 2 H 

1 l^ C0 2 H *" iT^COaH 




CH,CO»Na 
-HC1 *" 



bornyl camphene carboxyapocamphoric apocamphoric 

chloride I acid acid 

(c/. malonic ester syntheses). These facts were explained by giving cam- 
phene the formula shown (I). The structure of apocamphoric acid was 
later proved by synthesis (Komppa, 1901; cf. camphoric acid, §23a). 

This structure for camphene, however, was opposed by Wagner. The 
oxidation of camphene with dilute permanganate gives camphene glycol, 
C 10 H 16 (OH) 2 [Wagner, 1890]. This glycol is saturated, and so camphene is 
a tricyclic compound (so, of course, is structure I). On further oxidation 
of camphene glycol, Wagner (1896, 1897) obtained camphenic acid, C 10 H 16 O 4 
(a dibasic acid), and camphenylic acid, C 10 H 16 O 3 (a hydroxy-monobasic 
acid), which, on oxidation with lead dioxide, gave camphenilone, C 9 H 14 
(a ketone). According to Wagner, it was difficult to explain the formation 
of these compounds if camphene had structure I. Wagner (1899) therefore 
suggested that camphene is formed by a molecular rearrangement when the 
borneols or bornyl chlorides are converted into camphene, and proposed 
structure II for camphene (see also §23d). 





CH. 



C=CH 2 
? H a l/OH 3 



\I/ N CH 3 
N CH 



With this formula, the formation of camphene glycol, camphenylic acid 
and camphenilone could be explained as follows: 

,OH A\y 0Ji A\yO 

vCH,OH (7 r-G0 2 H 






camphene 

glycol 

III 



camphenylic camphenilone 



V 





carbocamphenilone 
VI 



Camphenic 
acid 
VII 



Although it was easy to explain the formation of III, IV and V, it was 
difficult to explain the formation of VII. The formation of VII was ex- 



§23c] TERPENES 287 

plained by later workers, who suggested it was produced via carbocamphenil- 
one, VI. Another difficulty of the camphene formula, II, is that it does 
not explain the formation of apocamphoric acid when camphene is oxidised 
with nitric acid (see above). The course of its formation has been suggested 
by Komppa (1908, 1911), who proposed a mechanism involving a Wagner 
rearrangement. 

Structure II for camphene is supported by the fact that treatment of 
bornyl iodide with ethanolic potassium hydroxide at 170° gives bornylene, 
C 10 H 16 (m.p. 98°), as well as camphene (Wagner et al., 1899). Bornylene 
is readily oxidised by permanganate to camphoric acid; it therefore follows 
that bornylene has the structure I, the structure originally assigned to 
camphene; no rearrangement occurs in the formation of bornylene. 




KOH 



C,H e OH 




to] 




bornyl 
iodide 



bornylene 



camphoric 
acid 



Ozonolysis of camphene gives camphenilone and formaldehyde (Harries 
et al., 1910); these products are in keeping with the Wagner formula for 
camphene. 



+ CH 2 



II V 

Further support for this structure for camphene is afforded by the work of 
Buchner et al. (1913). These workers showed that camphene reacts with 
diazoacetic ester, and when the product is hydrolysed and then oxidised, 






+ CHN 2 C0 2 C 2 H 6 



(Df 



CO2C2H5 



(i) hydrolysis 
Cxi) oxidation 






><L 



VIII 



COjjH 



cycZopropane-1 : 1 : 2-tricarboxylic acid, VIII, is produced. VIII is to be 
expected from structure II, but not from I; I (bornylene) would give cyclo- 
propane-1 : 2 : 3-tricarboxylic acid, IX. 



--I + CHN 2 -C0 2 C 2 H 5 




C0 2 C,H 5 



(i) hydrolysis 
(ii) oxidation 



COjJI 

0O 2 H 
IX 



CO,H 



288 ORGANIC CHEMISTRY [CH. VIII 

Lipp (1914) has synthesised camphenic acid (VII), and showed that it 
has the structure assigned to it by Wagner. Finally, camphene has been 
synthesised as follows (Diels and Alder, 1928-1931). 




CHCHO 

+ 11 >- 

CH 2 




CHO 



H 2 -Pd 




CHO. 



(CH 3 CO),0 




CHO-COCH, 




(i)NaNHa 
(ii) CH S I 




CH 3 M g I 




acid 



(-H s O) 




§23d. Wagner-Meerwein rearrangements. Wagner, as we have seen, 
proposed a molecular rearrangement to explain the formation of camphene 
from the borneols and bornyl chlorides. Wagner also recognised that a 
molecular rearrangement occurred when oc-pinene was converted into bornyl 
chloride. Many other investigations concerning rearrangements in the ter- 
pene field were carried out by Meerwein and his co-workers, e.g., when 
oc-pinene is treated in ethereal solution at —20° with hydrogen chloride, 
the product is pinene hydrochloride. This is unstable, and if the tempera- 
ture is allowed to rise to about 10°, the pinene hydrochloride rearranges to 
bornyl chloride (Meerwein et al., 1922). Rearrangements such as these 
which occur with bicyclic monoterpenes are known as Wagner-Meerwein 
rearrangements. Furthermore, Meerwein extended the range of these re- 
arrangements to compounds outside bicyclic terpenes; these compounds 
were monocyclic. Finally, the range was extended to acyclic compounds, 
the classical example being that of weopentyl into i-pentyl compounds 
(Whitmore et al., 1932- ). 

All of these rearrangements conform to a common pattern, ionisation to 
a carbonium ion followed by rearrangement. Most rearrangements in the 
terpene field involve a change in ring structure, and in a few cases the 
migration of a methyl group. All of these rearrangements are examples 
of the 1,2-shifts (Vol. I, Ch. V). 

The following are examples, and the details of the mechanisms are dis- 
cussed later; (but see Vol. I for a discussion of example v). 

(i) The conversion of cc-pinene hydrochloride into bornyl chloride. 



(ii) The conversion of camphene hydrochloride into isobornyl chloride. 





£ci 






k 










HCI [~ 


: i 


-a*_ 




5 


*r=^ 


(' 


"J 


*(- 


-,, ^ 























y a 



§23d] TERPENES 289 

(i) and (ii) are of particular interest since both appear to proceed through the 
same carbonium ion. Why the epimers should be obtained is not certain (but 
see later). 

(iii) The dehydration of borneol to camphene (with acids). 




$?* 



(iv) The racemisation of camphene hydrochloride. 





^=H^ 



0?' 





cr 




(v) Rearrangements in the neopentyl system; e.g., the action of hydrobromic 
acid on neopentyl alcohol to give 2-pentyl bromide. 

Me 
Me 3 C — CH 2 OH ^- Me 3 C — CHr^Hg ""'"- Mef-C — CH 2 



-*■ Me 2 C— CH 2 Me Br "» - Me 2 0Br— CH 2 Me 



Evidence for the intermediate formation of a carbonium ion in the 
Wagner-Meerwein rearrangement. Meerwein et al. (1922), in their detailed 
investigation of the reversible conversion of camphene hydrochloride into iso- 
bornyl chloride (example ii), concluded that the first step was ionisation, and 
this was then followed by rearrangement of the carbonium ion: 



uct 



CI 



Their evidence for this mechanism was that the rate of the rearrangement was 
first order, and that the rate depended on the nature of the solvent, the rate 
being faster the greater the ionising power of the solvent. The order observed 
for some solvents was: 

SO a > MeN0 8 > MeCN > PhOMe > PhBr > PhH > Et a O 

This dependence of rate on solvent was more clearly shown by also studying 
the solvolysis rates of triphenylmethyl chloride in the same solvents. It was 
found that the rate of the rearrangement of camphene hydrochloride was faster 
in those solvents in which triphenylmethyl chloride undergoes solvolysis more 
readily. Meerwein also found that the rearrangement was strongly catalysed 
by Lewis acids such as stannic chloride, ferric chloride, etc. All of these form 
complexes with triphenylmethyl chloride. Furthermore, halides such as phos- 
phorus trichloride and silicon tetrachloride, which do not form complexes with 
triphenylmethyl chloride, did not catalyse the rearrangement. Further evidence 



290 ORGANIC CHEMISTRY [CH. VIII 

by Meerwein et al. (1927) and by Ingold (1928) also supports the mechanism 
given above. 

Meerwein, however, recognised a difficulty in his proposed mechanism. The 
carbonium ion formed in the rearrangement of camphene hydrochloride would 
presumably be the same as that formed in the rearrangement of pinene hydro- 
chloride to bornyl chloride (example i). The reason why the epimers are ob- 
tained is not certain; one possibility is that the ions are not the same, and as 
we shall see later, the ions are not identical if we assume there is neighbouring 
group participation producing a non-classical carbonium ion. 

Bartlett et al. (1937, 1938) showed that the rearrangement of camphene hydro- 
chloride in non-hydroxylic solvents is strongly catalysed by hydrogen chloride, 
and pointed out that the formation of Mobornyl chloride requires a Walden 
inversion at the new asymmetric carbon atom. According to these authors, the 
function of the hydrochloric acid is to help the ionisation of the chloride ion 
(from the camphene hydrochloride). Evidence for this is that phenols have a 
catalytic effect on the rearrangement rate of camphene hydrochloride, and that 
the order of this catalytic activity of substituted phenols is the same as the 
order of the increase in acid strength of hydrogen chloride which phenols promote 
in dioxan as solvent. These catalytic effects were explained by Bartlett et al. 
(1941) as being due to hydrogen bonding between the phenolic hydroxyl group 
and the receding chloride ion. 

Nevell et al. (1939) suggested that the type of resonance hybrid Z is involved 
in the rearrangement. Thus the hydrogen chloride-catalysed reaction in the 
inert solvents used would produce an ion-pair [Z+][HC1 2 _ ] (§2e. III). Z+ can 



now react with HCl a ~ at position 1 to regenerate camphene hydrochloride, or 
at position 2 to give wobornyl chloride. This interpretation is supported by 
experimental work. 

(i) Nevell et al. found that the rate of radioactive chlorine ( 86 C1) exchange 
between HC1* and camphene hydrochloride is 15 times faster than the rate of 
rearrangement to isobornyl chloride. It therefore follows that the rate-deter- 
mining step of the rearrangement is not the ionisation step, but is the reaction 
of the bridged-ion with HCl a - at position 2. It also follows, from the principle 
of microscopic reversibility (Vol. I), that the rate-determining step of the re- 
arrangement of wobornyl chloride back to camphene hydrochloride is the reac- 
tion with hydrogen chloride to produce the ion-pair directly. 

(ii) On the basis of the bridged-ion being an intermediate in the rearrangement 
in inert solvents and also for solvolytic reactions of both camphene hydrochloride 
and wobornyl chloride, then both isomers should give the same products Meer- 
wein et al. (1922) found that methanolysis, in the cold, of camphene hydrochloride 
gave at first the J-methyl ether (attack at position 1) and this, on long standing, 
gave Mobornyl methyl ether. woBornyl chloride also gave Mobornyl methyl 
ether, but in this case the reaction was slower. These results can be explained 
by the presence of the liberated hydrogen chloride which would make the methan- 
olysis reversible. 

(iii) Neighbouring group participation in solvolytic reactions of camphene 
hydrochloride would be expected to accelerate these reactions (anchimeric 
assistance) as compared with the formation of a classical carbonium ion inter- 
mediate. This will be so because the formation of the bridge will assist the 
expulsion of the chloride ion. Hughes, Ingold et al. (1951) have found that the 
ethanolysis of camphene hydrochloride is 6000 times faster (at 0°) than the cor- 
responding reaction with <-butyl chloride. Also, from the reaction rates of the 
solvolysis of 1-chloro-l-methylcyctopentane, it followed that camphene hydro- 
chloride is 370 times more reactive than this cyc/opentyl derivative. Purely on 
the basis of ring strain, the camphene compound should have been less reactive. 
Thus the high reactivity of the camphene compound is very strong evidence for 
neighbouring group participation. 



§23d] 



TERPENES 



291 



The relative rates of solvolysis of cyefopentyl chloride, bornyl chloride, and 
jsobornyl chloride (in 80 per cent, ethanol at 85°) are respectively 9-4, 1-0 and 
36,000 (Roberts et al., 1949; Winstein et al., 1952). This very large difference 
between the behaviour of bornyl and isobornyl chlorides is readily explained 
by neighbouring group participation. In isobornyl chloride the methylene group 
that forms the bridged ion is trans to the chloride ion ejected and so can readily 





isobornyl 
chloride 



CI 
bornyl 
chloride 




attack the C+ (of the C — CI) at the rear, thereby assisting ionisation; this neigh- 
bouring group participation cannot occur with bornyl chloride. Various repre- 
sentations of this bridged-ion are possible; I has been proposed by Winstein 
et al. (1952). 

Very strong evidence for the participation of a neighbouring saturated hydro- 
carbon radical has been obtained by Winstein et al. (1952) in their detailed 
examination of some reactions of the parent norbornyl systems. 





e#o-norbornyl 
alcohol 



endo-norbornyl 
alcohol 



These authors showed that the relative rates of acetolysis of the brosylates 
(^-bromobenzenesulphonates) of exo/endo norbornyl alcohols in acetic acid at 
25° are 350/1. The explanation offered for the large relative rate of the exo- 
isomer acetolysis was neighbouring group participation to form the non-classical 
carbonium ion (la). As the OBs~ ion is leaving from the front, the neighbouring 
group (group C„) can attack from the rear to form the bridged-ion. This 






OBs 



sequence is not possible as such for the «»<2o-compound, and so the latter reacts 
far more slowly. Further support for the formation of (la) is as follows. This 
ion has a plane of symmetry (see 16) and hence is optically inactive. It has 
been shown that solvolysis of e#o-norbornyl brosylate in aqueous acetone, 
ethanol or acetic acid gives only &*o-products, but in these products the carbon 
atoms have become " shuffled " (see below). Winstein et al. (1952) also showed 
that acetolysis of optically active e#o-norbornyl brosylate gave racemic exo- 
norbornyl acetate. Attack must be from the back of the CH 2 bridge and so 
this results in the e#o-product; also, since positions 1 and 2 are equivalent, equal 
amounts of the enantiomorphs (i.e., racemate) will be produced. 

When ewao-norbornyl brosylate undergoes acetolysis, ionisation of the OBs- 
group leaves the ewao-norbornyl carbonium ion. This is probably originally the 






292 



ORGANIC CHEMISTRY 



[CH. VIII 



classical carbonium ion, but it then rearranges to the more stable e#o-bridged- 
ion. The formation of the latter is shown by the fact that acetolysis of the opti- 
cally active endo-brosylafce produces racemic ew-acetate. 

The structure of the bridged carbonium ion, however, appears to be more 
complicated than that shown by formula (la). Examination of (lb) shows the 
equivalence of positions 1 and 2, and of positions 3 and 7. Thus labelling the 
brosylate with 14 C at positions 2 and 3 should give products equally labelled 
at positions 1, 2, 3 and 7. Roberts et al. (1954) carried out the acetolysis of this 
labelled e#o-brosylate, and the tracer atom was found at 1, 2, 3 and 7, but posi- 
tions 5 and 6 also contained labelled carbon (15 per cent, of the total radio- 
activity). These results can be explained on the basis that there is also a 1,3- 
hydride shift from position 2 to position 6. Thus positions 1, 2 and 6 become 
shuffled to a certain extent, and there is also the same amount of interchange 
among positions 3, 5 and 7. This raises the question as to whether some ions 





© 
C-bridging 






H-bridging 

have both carbon and hydrogen bridging. Winstein (1955) has pointed out that 
the '' extra " carbon shuffling (to positions 5 and 6) depends on the nucleophilic 
activity of the solvent, and is zero for very reactive solvents in which the life 
of the carbonium ion is short. This suggests that the hydrogen shift competes 
with the solvent attack and so occurs after the formation of the purely carbon 
bridgedrion. 

§23e. Correlation of configurations of terpenes. This has been made 
possible by the work of Fredga on quasi-racemic compounds (see §9a. II). 
This author has established the following configurations: 



CHO 



HO— C— H 



L-glyceraldehyde 



CH 2 -C0 2 H 

l(— )-methyl- 
succinic acid 



CO a H 
(CH S ) 2 CH-C— H 



l( — )-isopropyl- 
succinic acid 



By means of these configurations, combined with various interrelations 
obtained by oxidative degradations and by molecular rearrangements, it 
has been possible to correlate the configurations of many mono- and bicyclic 
terpenes with L-glyceraldehyde, e.g., 



§24] 



TERPENES 



293 






(+)-camphor (+)-a-pinene (+)-a- (+)-limonene (-)-carvone 

terpineol I 

H. Me H. Me H v Me H Me 

(X 



OHC 



CMe 2 
(+)-citronellal 





O 
Me 2 CH N H 

(-)-menthone 

t 




trans-(+)- 

tetrahydro- 

carvone 




Me 2 CH 'H 



d-(+)- methyl- (+)-piperitone 
succinic acid 



Me 2 CH V H 



phellandrene 




HO,0 



D-(+)-isopropyl- 
succinic acid 

§24. Fenchane and its derivatives. The most important natural ter- 
pene of this group is fenchone; this occurs in oil of fennel. It is a liquid, 
b.p. 192-193°, and is optically active, both enantiomorphs occurring 
naturally. 

The molecular formula of fenchone is C 10 H 16 O, and the compound behaves 
as a ketone. When fenchone (I) is reduced with sodium and ethanol, 
fenchyl alcohol, C, H 18 O (II), is produced, and this, on dehydration under 
the influence of acids, gives oc-fenchene, C 10 H 16 (III). On ozonolysis, a- 
fenchene is converted into a-fenchocamphorone, C 9 H 14 (IV), which, on 
oxidation with nitric acid, forms apocamphoric acid, V, a compound of 
known structure. This work was carried out by Wallach et al. (1890- 
1898), but it was Semmler (1905) who was the first to assign the correct 
structure to fenchone; the foregoing reactions may be formulated: 



294 



ORGANIC CHEMISTRY 



[CH. VIII 




or 



III 




o» 



II 

o /Nx> 2 h 

^/X> 2 H 

IV V 

It should be noted that the dehydration of fenchyl alcohol, II, to oc-fenchene, 
III, occurs via a Wagner-Meerwein rearrangement ; the mechanism for this 
reaction may thus be written (cf. §23d): 







-H 1 




or 




The structure of fenchone has been confirmed by synthesis (Ruzicka, 1917). 
,C0 2 C 2 H 6 UCOAH 5 




(i) Zn+CH 3 Br CO a C3H 8 
(ii) acid 




(■) PBr 3 



(ii) heat 



(i) HrPt y 
(ii) hydrolysis 



CH 2 co 2 c 2 H j 




HO CHg-COgCgHs 
I0 2 H ^ 

!0 2 H 




CH 2 C0 2 H 



2 vv/ 2 v 2 ri5 



CH 2 C0 2 H 



Pb salt 
heat 




(i) Na 
(ii) CH,I 




§26] 



TERPENES 



295 



SESQUITERPENES 



§25. Introduction. The sesquiterpenes, in general, form the higher boil- 
ing fraction of the essential oils; this provides their chief source. Wallach 
(1887) was the first to suggest that the sesquiterpene structure is built up 
of three isoprene units; this has been shown to be the case for the majority 
of the known sesquiterpenes, but there are some exceptions. 

The sesquiterpenes are classified into four groups according to the number 
of rings present in the structure. If we use the isoprene rule, then when three 
isoprene units are linked (head to tail) to form an acyclic sesquiterpene 
hydrocarbon, the latter will contain four double bonds. Each isoprene unit 
contains two double bonds, but one disappears for each pair that is con- 
nected: 

C C C 

I I I 

C=C— C=C+ C=C— C=C+ C=C— C=C 

c ^ ? 

o=c— c-c=c-c— c— c =c— c— c=c 

When this open-chain compound is converted into a monocyclic structure, 
another double bond is utilised in the process, and so monocyclic sesqui- 
terpene hydrocarbons contain three double bonds. In a similar manner, 
it will be found that a bicyclic structure contains two double bonds, and a 
tricyclic one. Thus the nature of the sesquiterpene skeleton is also charac- 
terised by the number of double bonds present in the molecule. The sesqui- 
terpene hydrocarbon structures may also be distinguished by the calculation 
of the molecular refractivities for the various types of structures, and then 
using these values to help elucidate the structures of new sesquiterpenes; 
e.g., zingiberene (§27a). 



Class of j Number of 
sesquiterpene double bonds 


Molecular 
refractivity 


l | 
Acyclic . . . . i 4 | 69-5 
Monocyclic . . . ! 3 - 67-8 
Bicyclic .... 2 66-1 
Tricyclic .... 1 1 J 64-4 



This type of information can also be used with the monoterpenes, but in 
this case it has not been so useful as in the sesquiterpenes. It might be 
noted here that the non-acyclic members of the sesquiterpenoid group may 
have rings of various sizes: 4, 5, 6, 7, 9, 10 and 11 ; and in many of these the 
rings are fused. 

ACYCLIC SESQUITERPENES 

§26. Farnesene, C^H^, b.p. 128-130°/12 mm., is obtained by the de- 
hydration of farnesol with potassium hydrogen sulphate (Harries et al., 





;-farnesene 



/3-farnesene 



296 



ORGANIC CHEMISTRY 



[CH. VIII 



1913). This compound is the oc-isomer, and it has now been shown that 
the /S-isomer occurs naturally (in oil of hops), and Sorm et al. (1949, 1950) 
have assigned it the structure shown. /S-Farnesene is also obtained by the 
dehydration of nerolidol. 

§26a. Farnesol, C 15 H 26 0, b.p. 120°/0-3 mm., occurs in the oil of ambrette 
seeds, etc. Its structure was elucidated by Kerschbaum (1913) as follows. 
When oxidised with chromic acid, farnesol is converted into farnesal, 
C 15 H 24 0, a compound which behaves as an aldehyde. Thus farnesol is a 
primary alcohol. Conversion of farnesal into its oxime, followed by de- 
hydration with acetic anhydride, produces a cyanide which, on hydrolysis 
with alkali, forms farnesenic acid, C 15 H 24 2 , and a ketone, C 13 H 22 0. This 
ketone was then found to be dihydro-^sewrfo-iondne (geranylacetone). In 
the formation of this ketone, two carbon atoms are removed from its pre- 
cursor. This reaction is characteristic of a : /3-unsaturated carbonyl com- 
pounds, and so it is inferred that the precursor, farnesenic acid (or its 
nitrile), is an a : /^-unsaturated compound. Thus the foregoing facts may 
be formulated as follows, on the basis of the known structure of geranyl- 
acetone. 



(i) NH,OH 




(ii) (CHs-CO)sO 



farnesol 



farnesal 




KOH 








farnesenonitrile 



farnesenic acid 



geranylacetone 



Kerschbaum's formula has been confirmed by Harries et al. (1913), who 
obtained acetone, laevulaldehyde and glycolaldehyde on the ozonolysis of 
farnesol. 




o 




CH 2 OH 
CHO 



CHO 



Ozonolysis, however, also gave some formaldehyde, thus indicating the 
presence of the isopropenyl end-group as well as the isopropylidene end- 
group (but c/. citral, §5). Ruzicka (1923) synthesised farnesol (with the 
j'sopropylidene end-group) by the action of acetic anhydride on synthetic 
nerolidol (cf. linalool, §8). 



§27] 



TERPENES 



297 




nerolidol farnesol 

§26b. Nerolidol, C 15 H 26 0, b.p. 125-127°/4-5 mm., occurs in the oil of 
neroli, etc., in the (+)-form. Nerolidol is isomeric with farnesol, and 
Ruzicka (1923) showed that the relationship between the two is the same 
as that between linalool and geraniol (see §8). Ruzicka (1923) confirmed 
the structure of nerolidol by synthesis. 




,CH 2 C1 



+ CHjCOCHa-COaCaHs 




CH-COAHs 
COCH 3 



geranyl chloride 



(i) Ba(OH) a 
(ii) HC1 




(i) NaNH ; 




co-cH 3 ;i:' c "; CH 

•* (in) HjO 



geranylacetone 




(±) -nerolidol 

MONOCYCLIC SESQUITERPENES 

§27. Bisabolene, C^H^, b.p. 133-134°/12 mm., occurs in the oil of 
myrrh and in other essential oils. The structure of bisabolene was deter- 
mined by Ruzicka et al. (1925). Bisabolene adds on three molecules of 
hydrogen chloride to form bisabolene trihydrochloride, and this regenerates 
bisabolene when heated with sodium acetate in acetic acid solution. Thus 
bisabolene contains three double bonds and is therefore monocyclic (see §25). 
Nerolidol may be dehydrated to a mixture of a- and /?-farnesenes (cf. §26). 
This mixture, on treatment with formic acid, forms a monocyclic sesqui- 
terpene (or possibly a mixture) which combines with hydrogen chloride to 
form bisabolene trihydrochloride. Removal of these three molecules of 



298 



ORGANIC CHEMISTRY 



[CH. VIII 



hydrogen chloride (by means of sodium acetate in acetic acid) produces 
bisabolene; thus bisabolene could be I, II or III, since all three would give 
the same bisabolene trihydrochloride. 



OH - H »°> 






nerolidol 



(i) H-COgH 
(ii) + 3HC1 



a-farnesene 


p-farnesene 


l/Cl 




T Lei 


-3HC1 



/CI 



biaabolene trihydrochloride 






-bisabolene 



II 

p-bisabolene 



III 

y-bisabolene 



Ruzicka et al. (1929) showed that synthetic and natural bisabolene con- 
sisted mainly of the y-isomer (III), since on ozonolysis of bisabolene, the 
products were acetone, laevulic acid and a small amount of succinic acid. 
These products are readily accounted for by III; and this structure has 
been confirmed by synthesis (Ruzicka et al., 1932). 

§27a. Zingiberene, C 15 H 24 , b.p. 134°/14 mm., occurs in the (— )-form 
in ginger oil. It forms a dihydrochloride with hydrogen chloride, and thus 
apparently contains two double bonds. The molecular refractivity, how- 
ever, indicates the presence of three double bonds and, if this be the case, 
zingiberene is monocyclic (see §25). The presence of these three double 
bonds is conclusively shown by the fact that catalytic hydrogenation (plati- 
num) converts zingiberene into hexahydrozingiberene, GuHg,,. Zingiberene 
can be reduced by means of sodium and ethanol to dihydrozingiberene, 
C 15 H 28 ; this indicates that two of the double bonds are probably conjugated 
(Semmler et al., 1913). Further evidence for this conjugation is afforded 
by the fact that zingiberene shows optical exaltation* whereas dihydro- 
zingiberene does not. The absorption spectrum of zingiberene also shows 
the presence of conjugated double bonds (Gillam et al., 1940). 

Ozonolysis of zingiberene gives acetone, laevulic acid and succinic acid 
(Ruzicka et al., 1929). Since these products are also obtained from bis- 
abolene (§27), it appears probable that zingiberene and bisabolene have the 
same carbon skeleton. Oxidation of dihydrozingiberene, I, with perman- 
ganate gives a keto-dicarboxylic acid, C 12 H 20 O 5 (II), which, on oxidation 



§28] 



TERPENES 



299 



with sodium hypobromite, forms a tricarboxylic acid, C u H 18 O e (III). Thus 
II must contain a methyl ketone group (CH 3 «CO— ), and so, if I be assumed 
as the structure of dihydrozingiberene, the foregoing oxidation reactions 
may be formulated: 




CO-CH 3 
CO,H XC ° 2H 




III 



C0 2 H 
C0 2 H 



Thus I, with another double bond in conjugation with one already present, 
will be (probably) the structure of zingiberene. The position of this third 
double bond was shown as follows (Eschenmoser et ah, 1950). Zingiberene 
forms an adduct with methyl acetylenedicarboxylate, and this adduct (which 
was not isolated), on pyrolysis, gives 2 : 6-dimethylocta-2 : 7-diene and 
methyl 4-methylphthalate. These reactions can be explained on the assump- 
tion that zingiberene has the structure shown below. 




G0 2 CH 3 

C 

III — 

? 
C0 2 CH s 




C-C0 2 CH 3 
C-C0 2 CH3 




COuCHs 
C0 2 CH 3 



§27b. Humulene (o-caryophyllene), C 15 H 24 , b.p. 264°, is an eleven- 
membered ring compound which contains three double bonds. Its structure is 
very closely related to that of caryophyllene (§28c). 





humulene 



OAc 
pyrethrosin 



Pyrethrosin is also a monocyclic sesquiterpene; it is a y-lactone which con- 
tains a ten-membered ring. 



BICYCXIC SESQUITERPENES 

§28. Cadinene, d^, b.p. 134-136 /11 mm., occurs in the (-)-form 
in oil of cubebs, etc. Catalytic hydrogenation converts cadinene into tetra- 
hydrocadinene, C 15 H ag . Thus cadinene contains two double bonds and is 



300 



ORGANIC CHEMISTRY 



[CH. VIII 



bicyclic. On dehydrogenation with sulphur, cadinene forms cadalene, 
C 15 H 18 (Ruzicka et ah, 1921). Cadalene does not add on bromine, and 
forms a picrate. This led to the belief that cadalene was an aromatic 
compound, and its structure was deduced as follows. Ruzicka assumed 
that the relationship of farnesol (§26a) to cadinene was analogous to that 
of geraniol (§7) to dipentene (§13). Furthermore, since dipentene gives 
^>-cymene when dehydrogenated with sulphur, then cadalene should be, if 
the analogy is correct, 1 : 6-dimethyl-4-wopropylnaphthalene; thus: 



CH 2 OH 



geraniol 



dipentene 



p-cymene 



farnesol 




cadinene 
skeleton 



cadalene 



1 : 6-Dimethyl-4-wopropylnaphthalene was synthesised by Ruzicka 
(1922), and was found to be identical with cadalene. 



et al. 




Zn 



CH 2 BrC0 2 C 2 H 6 




CH 2 -C0 2 C 2 H 5 



acid 



(-H 2 0) 




CH 2 
C0 2 H 




!H 2 OH 



(i) HBr 

(ii) CHyCNafCOaCaHaJa 




C(C0 2 C 2 H s ) 2 
0H 3 




CHCH 3 
C0 2 H 




TERPENES 



301 



yCH*CH3 

COGl 




(i) Na-C t H u OH 
(ii) S distillation 

CH 3 




Thus cadinene has the carbon skeleton assumed. The only remaining 
problem is to ascertain the positions of the two double bonds in cadinene. 
Since the molecular refractivity shows no optical exaltation, the two double 
bonds are not conjugated (§11. 1) ; this is supported by the fact that cadinene 
is not reduced by sodium and amyl alcohol. Ozonolysis of cadinene pro- 
duces a compound containing the same number of carbon atoms as cadinene. 
The two double bonds are therefore in ring systems, but they cannot be in 
the same ring, since in this case carbon would have been lost on ozonolysis. 
Ruzicka et al. (1924) were thus led to suggest I (a or /?) for the structure of 
cadinene, basing it on the relationship of cadinene to copaene, which had 
been given structure II by Semmler (1914). I was proposed mainly on the 




I 





II 



fact that copaene adds two molecules of hydrogen chloride to form copaene 
dihydrochloride, which is identical with cadinene dihydrochloride (both the 
a and /S structures of I would give the same dihydrochloride as II). Struc- 
ture I (a or /?) was accepted for cadinene until 1942, when Campbell and 
Soffer re-investigated the problem. These authors converted cadinene into 
its monoxide and dioxide by means of perbenzoic acid, treated these oxides 
with excess of methylmagnesium chloride, and then dehydrogenated the 
product with selenium. By this means, Campbell and Soffer obtained a 
monomethylcadalene from cadinene monoxide, and a dimethylcadalene from 
cadinene dioxide. Now the introduction of a methyl group via the oxide 
takes place according to the following scheme: 



C C c C 

H-C=C-C c ' H ' COOaH > H-C-C 



V 



c-c 



CH 3 -MgCI 



c c 
I I 

H-C— C-C 
I I 
CH, OH 



-H a O 



r f 

c=c-c 

I 

CH, 



Thus the positions of the additional methyl groups show the positions of 
the double bonds in cadinene. The Ruzicka formula for cadinene would 
give dimethylcadalene III (from the a isomer) or IV (from the /?), and the 
monomethylcadalenes would be V (from a or /9), VI (from a) and VII (from 
fi). Campbell and Soffer oxidised their dimethylcadalene, first with chromic 
acid and then with nitric acid, and thereby obtained pyromellitic acid 



302 



ORGANIC CHEMISTRY 



[CH. VIII 

(benzene-1 : 2 : 4 : 5-tetracarboxylic acid), VIII. The formation of VIII 
therefore rules out III as the structure of dimethylcadalene, but IV, with 







VIII 



VII 



the two methyl groups at positions 6 and 7 in ring B, could give VIII. 
Therefore the double bond in cadinene in ring B is 6 : 7. From this it 
follows that VI is also eliminated. If the double bond in ring A is as in 
structure I, then dimethylcadalene is IV, and monomethylcadalene is V 
or VII. Campbell and Softer synthesised IV and VII, and found that each 
was different from the methylcadalenes they had obtained from cadinene. 
Thus IV and VII are incorrect; consequently the double bond in ring A 
cannot be 3 : 4. The only other dimethylcadalene which could give VIII 
on oxidation is IX. This was synthesised, and was found to be identical 
with the dimethylcadalene from cadinene. Cadinene must therefore be X, 
and the introduction of one or two methyl groups may thus be formulated 
as follows: 




X could give two monoxides (oxidation of ring A or B), and one of these 
(ring B oxidised) would give VII. This, as pointed out above, was different 
from the monomethylcadalene actually obtained. Therefore, if X is the 
structure of cadinene, the monomethylcadalene obtained from cadinene 
must be XI. XI was synthesised, and was found to be identical with the 
compound obtained from cadinene. Thus X is the structure of cadinene. 



§28a] 



TERPENES 



303 



It should be noted, in passing, that this new structure for cadinene has 
necessitated revision of the structure of copaene. Briggs and Taylor (1947), 
using a technique similar to that of Campbell and Soffer, have assigned 
the following structure to copaene. 




copaene 

The absolute configurations of the cadinenes (and cadinols) have now 
been established (Motl et al., 1958; Soffer et al., 1958). 

§28a. Selinenes, C 1B H M . Selinene occurs in celery oil; when treated 
with hydrogen chloride, it forms a dihydrochloride which, when warmed 
with aniline, is converted into the compound C^H^. This is isomeric with 
selinene, and the natural compound was called /3-selinene, and the synthetic 
isomer a-selinene (Semmler et al., 1912). Semmler showed that the catalytic 
hydrogenation of the two selinenes gives the same tetrahydroselinene, C 1S H 28 . 
Thus they each contain two double bonds, and are tricyclic. Ozonolysis 
of /3-selinene produces a diketone (I) with the loss of two carbon atoms, 
and oxidation of I with sodium hypobromite gives a tricarboxylic acid (II), 
with the loss of one carbon atom. From this it follows that I contains a 
CHg'CO — group. Ozonolysis of a-selinene gives a diketo-monocarboxylic 
acid (III) with loss of one carbon atom, and III, on oxidation with sodium 
hypobromite, loses two carbon atoms to form II. Thus III contains two 
CHj'CO— groups (Semmler et al, 1912). Ruzicka et al. (1922) distilled 
/S-selinene with sulphur, and thereby obtained eudalene (see §28b for the 
evidence for the structure of this compound). If we use the isoprene rule, 
all the foregoing facts are explained by giving the selinenes the following 
structures (Ruzicka et al., 1922). The relationship of the selinenes to 
eudesmol (§28b) confirms the nature of the carbon skeleton given to the 
selinenes. 



CHg-CO 





eudalene 



NaOBr 



H0 2 C 




NaOBr 



C0 2 H 
C0 2 H CH 3 -CO' 



II 




304 ORGANIC CHEMISTRY [CH. VIII 

§28b. Eudesmol, C 15 H 26 0, occurs in eucalyptus oil. Catalytic hydro- 
genation converts eudesmol into dihydroeudesmol, C 15 H 28 0. Thus one 
double bond is present in the molecule, and since eudesmol behaves as a 
tertiary alcohol, the parent hydrocarbon is Ci 6 H 28 =C„H2,i-2; eudesmol is 
therefore bicyclic. When dehydrogenated with sulphur, eudesmol forms 
eudalene, C 14 H 16 , and methanethiol (Ruzicka et al., 1922). Eudalene be- 
haved as an aromatic compound (cf. cadalene, §28), and its structure was 
deduced as follows. Since eudalene was a naphthalene derivative, and 
since it contained one carbon atom less than cadalene, it was thought to 
be an apocadalene, i.e., cadalene minus one methyl group. Thus eudalene 
is either l-methyl-4-wopropylnaphthalene (II«) or 7-methyl-Wsopropyl- 
naphthalene (la). To test this hypothesis, Ruzicka oxidised cadalene with 
chromic acid, and thereby obtained a naphthoic acid, C 15 H 16 2 , which must 



C0 2 H 




J°U 




C0 2 H 



cadalene 



soda lime 





be I or II. Distillation of this acid with soda-lime gives a methyh'sopropyl- 
naphthalene which must be la or Ha. Ha was synthesised from carvone 
(the synthesis is the same as for cadalene except that ethyl malonate is 
used instead of ethyl methylmalonate ; see §28). The synthetic compound 
(Ha) was found to be different from the hydrocarbon obtained by the 
distillation of the naphthoic acid from cadalene. Thus the apocadalene 
obtained must be la, i.e., 7-methyl-l-wopropylnaphthalene. 

Ruzicka now found that eudalene was not identical with either la or lla. 
On oxidation, however, eudalene gives the same naphthalenedicarboxylic 
acid as that which is obtained by the oxidation of la. This is only possible 
if in eudalene the two side-chains in la are interchanged, i.e., eudalene is 
l-methyl-7-Mopropylnaphthalene ; thus : 




[o]. 




CO„H 




CO,H 



la 2 eudalene 

This structure for eudalene was proved by synthesis (Ruzicka et al., 1922). 



§28b] 



TERPENES 



305 



v_|T J HO + BrCH 2 -COAH 5+ Zn^^^ 




cuminal 



-HjjO V J CH Na-C 2 H 6 OH 

y-\J C0 2 C 2 H, * 



CHOH 
N CH 8 

COjCjHs 



(i)HBr 





CH 2 CN 



eudalene 



To develop the sesquiterpene carbon skeleton from that of eudalene, it 
is necessary to introduce one carbon atom in such a position that it is 
eliminated as methanethiol during the sulphur dehydrogenation (see above). 
If we use the isoprene rule with the units joined head to tail, then there is 
only one possible structure that fits the requirements, viz., Ill (cf. §1). 

^C Q A 

III c 

Now /S-selinene combines with hydrogen chloride to form selinene dihydro- 
chloride, which is also obtained by the action of hydrogen chloride on 
eudesmol (Ruzicka et al., 1927, 1931). Since eudesmol contains one double 
bond and a tertiary alcoholic group, it follows that the double bond must 
be in the side-chain, and the hydroxyl group in the ring, or vice versa, i.e., 
IV, V or VI is^the structure of eudesmol. 



, HCl 




p-selinene 



CI 
selinene 
dihydrochloride 




or 





OH 



306 



ORGANIC CHEMISTRY 



[CH. VIII 



Hydrogenation of eudesmol forms dihydroeudesmol, VII, and this, on treat- 
ment with hydrogen chloride followed by boiling with aniline (to remove 
a molecule of hydrogen chloride), gives dihydroeudesmene, VIII. VIII, on 
ozonolysis, forms 3-acetyl-5 : 9-dimethyldecalin, IX, with the elimination of 
one carbon atom. These results are explained if IV or V is the structure 
of eudesmol, but not by VI. Thus the hydroxyl group is in the tsopropyl 
side-chain. 




VII 



VIII 



The final problem is to ascertain the position of the double bond in eudesmol, 
i.e., Is the structure IV or V? Ozonolysis of eudesmol showed that eudesmol 
is a mixture of IV (a-eudesmol) and V (/3-eudesmol), since two products are 
obtained: a hydroxyketo-acid X, with no loss of carbon, and a hydroxy- 
ketone XI, with the loss of one carbon atom (but cf. citral, §5). 




OH 
IV 

o-eudesmol 




O a H 



X CH, 




O, 




+ CHjjO 



OH 

V 

p-eudeamol 

The proportions of these two isomers vary with the source, and McQuillin 
et al. (1956) have succeeded in separating them {via their 3 : 5-dinitrobenzo- 
ates), and at the same time have characterised a third, synthetic y-isomer. 




OH 

y -eudesmol 

§28c. Caryophyllene, C 15 H 24 , b.p. 123-125°/10 mm., is a bicyclic sesqui- 
terpene containing a fused system of a four- and a nine-membered ring. The 
main source of this compound is the sesquiterpene fraction of oil of cloves, and 
three isomeric hydrocarbons have been isolated. These were originally called 




caryophyllene 



§29] 



TERPENES 



307 






isocaryophyllene 



santonin 



a-, ft-, and y-caryophyllene, but it has now been shown that the a-isomer is 
identical with humulene (§27b) ; the /S-isomer (the main hydrocarbon) is called 
caryophyllene; and the y-isomer (which is believed to be produced by thermal 
isomerisation) is known as isocaryophyllene. 

Santonin is a lactone sesquiterpene of the decalin type (cf. pyrethrosin, 

Acorone is a most interesting bicyclic sesquiterpene in that it is a carbo- 
cyclic spiran, the first example of such a compound to be found in nature. 

§29. Azulenes. Many essential oils contain blue or violet compounds, 
or may form such compounds after distillation at atmospheric pressure or 
dehydrogenation with sulphur, selenium or palladium-charcoal (Ruzicka 
et al., 1923). These coloured compounds may be extracted by shaking an 
ethereal solution of the essential oil with phosphoric acid (Sherndal, 1915). 
These coloured substances are known as azulenes. Their molecular formula 
is C 15 H 18 , and they are sesquiterpenes, the parent substance being azulene, 
Ci H 8 , which contains a seven-membered ring fused to a five-membered one. 
Azulene has been synthesised as follows (Plattner et ah, 1936). 



OH 




O 



Na a CQ 3 



solution 



ryc/odecane-1 : 6 -dione 



C,H B OH 




azulene 



Azulene is a deep blue solid, m.p. 99°; its systematic name is bicyclo[5 : 3 : 0]- 
decane. Two sesquiterpenes containing this bicyclodecane skeleton are 





OH guaiol vetivone 

Azulene is a non-benzenoid aromatic compound in which n 

0@> 



2 (aromatics 





dipolar structure 

contain (4m + 2) ji-electrons in a " circular " system; see Vol. I, Ch. XX). 
undergoes many typical aromatic substitution reactions. 



It 



308 ORGANIC CHEMISTRY [CH. VIII 

DITERPENES 

§30. Phytol, C 20 H 40 O, b.p. 145°/0-03 mm., is an acyclic diterpene; it is 
produced from the hydrolysis of chlorophyll (§6. XIX), and it also forms 
part of the molecules of vitamins E and K (see Ch. XVII). The reactions 
of phytol showed that it is a primary alcohol (Willstatter et al., 1907), and 
since on catalytic reduction phytol forms dihydrophytol, C 20 H 42 O, it there- 
fore follows that phytol contains one double bond. Thus the parent hydro- 
carbon is C 20 H 42 (=C B H 2m+2 ), and so phytol is acyclic. Ozonolysis of phytol 
gives glycolaldehyde and a saturated ketone, C 18 H 36 (F. Fischer et al., 
1928). Thus this reaction may be written: 

Ci 8 H 36 =CH-CH 2 OH - 22 *- 0^380+ CHO-CH 2 OH 

The formula of phytol led to the suggestion that it was composed of four 
reduced isoprene units. If this were so, and assuming that the units are 
joined head to tail, the structure of the saturated ketone would be: 

r „ CH 3 CH 3 CH 3 

^CH-CH 2 -CH 2 -!CH 2 CH-CH 2 -CH 2 -;CH 2 -CH-CH 2 -CH 2 -;CH 2 -C=0 

This structure was proved to be correct by the synthesis of the ketone 
from farnesol (F. Fischer et al., 1928). The catalytic hydrogenation of 
farnesol, I, produces hexahydrofarnesol, II, which, on treatment with phos- 

CH 3 CH 3 CH 3 

CH 3 -C=CH-CH 2 -CH 2 • C=CH-CH 2 -CH 2 - C=CH-CH 2 OH 

JHj-Pd 

CrLi CILi (-*H 3 

1 3 I I 

CH 3 -CH-(CH 2 ) 3 -CH-(CH 2 ) 3 -CH-CH 2 -CH 2 OH 

II 

|PBr 3 

CHq Cxi5 OHo 

I 3 I I 

CHa-CH-CCH^-CH-CCHj^-CH-CHa-CHaBr 
III I 

CH s CO-CHNhCOjCjH 6 

CH 3 CH 3 CH 3 ^CO-CHj 

CH 3 -CH-(CH 2 ) 3 -CH-(CH 2 ) 3 -CH-CH 2 -CH 2 -CH 

Iconic C0 2 C 2 H 5 

I hydrol\-sis 

CHq ch 3 ch 3 

CH 3 -CH-(CH 2 ) 3 -CH-(CH 2 )3-CH-CH 2 -CH 2 -CH 2 -CO-CH 3 
IV 

phorus tribromide, gives hexahydrofarnesyl bromide, III. Ill, on treat- 
ment with sodio-acetoacetic ester, followed by ketonic hydrolysis, forms 
the saturated ketone, IV. This ketone (IV) was then converted into phytol 
as follows (F. Fischer et al., 1929) ; it should be noted that the last step 
involves an allylic rearrangement (cf. linalool, §8). 



§31] 



TERPENES 

CH 3 CH 3 CH 3 CH 3 

I I I I 

CH 3 - CH-(CH 2 ) 3 - CH-(CH 2 ) 3 -CH-(CH 2 ) 3 -C=0 



309 



IV 



|0> 



) NaNHj 
)CH=CH 



CH 3 



CH, 



CH, 



CH, 



CH 3 -CH-(CH 2 ) 3 • CH-(CH 2 ) 3 - CH-(CH 2 ) 3 - C ■ C=CH 

OH 



CH-* Oxio Crln vri* 

i 3 i 3 i 3 i 

CH 3 -CH-(CH 2 ) 3 -CH-(CH 2 ) 3 -CH-(CH 2 ) 3 -C-CH=CH 2 

OH 

(CH 3 CO) 2 



CH 3 



CH3 CH3 CH3 

CH3-CH-(CH 2 ) 3 -CH-(CH 2 ) 3 -CH-(CH 2 ) 3 -C=CH-CH 2 OH 
phytol 



It appears that natural phytol has a very small optical rotation; Karrer 
et al. (1943) have isolated a (-f)-form from nettles. 

§31. Abietic acid, C 20 H 30 O 2 , m.p. 170-174°, is a tricyclic diterpene. 
The non-steam volatile residue from turpentine is known as rosin (or colo- 
phony), and consists of a mixture of resin acids which are derived from the 
diterpenes. Abietic acid is one of the most useful of these acids. 



•C0 2 H 




abietic acid 




Me' v C0 2 H 



A great amount of work was done before the structure of abietic acid 
was elucidated. For our purpose it is useful to have the structure of abietic 
acid as a reference, and then describe the evidence that led to this structure. 
I is the structure of abietic acid; the system of numbering is shown, and 
also the four isoprene units comprising it. This way of numbering abietic 
acid follows the phenanthrene numbering. There has been recently, how- 
ever, a tendency to bring the numbering of all diterpenes in line with the 
steroids (§3. XI); this is shown in la. In the following discussion I has 
been used (the reader should work out the change-over for himself). 

The general reactions of abietic acid showed that it was a monocarboxylic 
acid. On dehydrogenation with sulphur, abietic acid gives retene (Vester- 
berg, 1903) ; better yields of retene are obtained by dehydrogenating with 
selenium (Diels et al., 1927), or with palladised charcoal (Ruzicka et al., 
1933). Retene, CigHjg, m.p. 99°, was shown by oxidative degradation to 



310 



ORGANIC CHEMISTRY 



[CH. VIII 

be l-methyl-7-i'sopropylphenanthrene (Bucher, 1910), and this structure 
was later confirmed by synthesis, e.g., that of Haworth et al. (1932). 




+ (CH 3 ) 2 CHBr^U CH3)2CH 



CIVCO^ 



~Y fl 1 CH,-CC~ 



A1C1 3 



(CH 3 ) 2 CH 




ch 3 oh (CH 3 ) 2 CH 



(i)CH 3 M g I 



H0 2 C CH 2 
CH, 




CH 3 2 C N /XR^ 
CH a 



(CH 3 ) 2 CH- 




(OH 3 ) 2 CH 



HI _ P (CH 3 ) 2 CH 



C-CH, 



H0 2 C GH 
CH, 




Zn-Hg (CH 3 ) 2 CH 



HjSO« 




(CH 3 ) 2 CH-XV\ 

XXX 



retene 



CH. 



Hence we may assume that this carbon skeleton is present in abietic 
acid. Thus: 




CH(CH 3 ) 2 



V 



\ 



N cr N c 

Now it is known that in sulphur dehydrogenations, carboxyl groups and 



§31] 



TERPENES 



311 



angular methyl groups can be eliminated (see §2 vii. X). It is therefore 
possible that the two carbon atoms lost may have been originally the carb- 
oxyl group (in abietic acid) and an angular methyl group. 

Abietic acid is very difficult to esterify, and since this is characteristic of 
a carboxyl group attached to a tertiary carbon atom, it suggests that abietic 
acid contains a carboxyl group in this state. This is supported by the fact 
that abietic acid evolves carbon monoxide when warmed with concentrated 
sulphuric acid; this reaction is also characteristic of a carboxyl group 
attached to a tertiary carbon atom. 

Catalytic hydrogenation of abietic acid gives tetrahydroabietic acid, 
C2oH 34 2 . Thus abietic acid contains two double bonds; also, since the 
parent hydrocarbon is C^H^ (regarding the carboxyl group as a substituent 
group), abietic acid is tricyclic (parent corresponds to C„H2„-4), which agrees 
with the evidence already given. 

Oxidation of abietic acid with potassium permanganate gives a mixture 
of products, among which are two tricarboxylic acids, C u H 16 6 (II), and 
C 12 Hi 8 6 (III) [Ruzicka et al., 1925, 1931]. II, on dehydrogenation with 
selenium, forms ra-xylene, and III forms hemimellitene (1:2: 3-trimethyl- 
benzene) [Ruzicka et al., 1931]. In both cases there is a loss of three carbon 
atoms, and if we assume that these were the three carboxyl groups, then 
two methyl groups in II and III must be in the mete-position. Further- 
more, since II and III each contain the methyl group originally present in 
abietic acid (position 1), acids II and III must contain ring A of abietic 
acid. This suggests, therefore, that there is an angular methyl group at 
position 12, since it can be expected to be eliminated from this position in 
sulphur dehydrogenations of abietic acid (this 12-methyl group is meta to 
the 1-methyl group). Vocke (1932) showed that acid II evolves two mole- 
cules of carbon monoxide when warmed with concentrated sulphuric acid; 
this indicates that II contains two carboxyl groups attached to tertiary 
carbon atoms. These results can be explained by assuming that one carboxyl 
group in II is that in abietic acid, and since in both cases this carboxyl 
group is attached to a tertiary carbon atom, the most likely position of 
this group is 1 (in abietic acid). Accepting these assumptions, the oxidation 
of abietic acid may be formulated as follows, also assuming IV as the carbon 



.C0 2 H 




J2L 




II 



C0 2 H 





III 




skeleton of abietic acid. Vocke subjected II to oxidative degradation, and 
obtained a dicarboxylic acid (V) which, on further oxidation, gave oc-methyl- 
glutaric acid (VI). Vocke assumed that II had the structure shown, and 
formulated the reactions as below, assuming structure V as the best way 
of explaining the results. 



312 



ORGANIC CHEMISTRY 



[CH. VIII 



v XJOaH 



aCHs 
C0 2 H j^ /\0O 2 H 
C0 2 H *" I x-COgH 

II V 



[o] 



COoH 



VI 



H 
C-C0 2 H 

CH, 



Structure V (assumed by Vocke) has been confirmed by synthesis (Rydon, 
1937). 

The position of the carboxyl group at position 1 in abietic acid (assumed 
above) has been confirmed by Ruzicka et al. (1922). Methyl abietate, 
C 19 H 29 -C0 2 CH 3 , on reduction with sodium and ethanol, forms abietinol, 
C 19 H 29 -CH 2 OH, which, on treatment with phosphorus pentachloride, loses 
a molecule of water to form " methylabietin ", C ao H 30 . This, on distillation 
with sulphur, forms homoretene, C 19 H 20 . Homoretene contains one CH 2 
group more than retene, and on oxidation with alkaline potassium ferri- 
cyanide, gives phenanthrene-1 : 7-dicarboxylic acid, the identical product 
obtained from the oxidation of retene under similar conditions (Ruzicka 
et al., 1932). These results can only be explained by assuming that homo- 
retene has an ethyl group at position 1 (instead of the methyl group in 
retene), i.e., homoretene is l-ethyl-7-wopropylphenanthrene. This has been 
confirmed by synthesis (Haworth et al., 1932; ethylmagnesium iodide was 
used instead of methylmagnesium iodide in the synthesis of retene). The 
formation of an ethyl group in homoretene can be explained by assuming 
that abietinol undergoes a Wagner-Meerwein rearrangement on dehydra- 
tion (see §23d). Thus: 



/X^CHg 



,CH,OH 



_EL 



PC1 5 




CoH 



methyl abietate abietinol "methyiabietin" 




DCH(CH 3 ) 2 
homoretene 



It has already been pointed out that abietic acid has two double bonds. 
Since abietic acid forms an adduct with maleic anhydride at above 100°, it 
was assumed that the two double bonds are conjugated (Ruzicka et al., 
1932). It was later shown, however, that levopimaric acid also forms the 
same adduct at room temperature. It thus appears that abietic acid iso- 
merises to levopimaric acid at above 100°, and then forms the adduct. 
Thus this reaction cannot be accepted as evidence for conjugation in abietic 
acid. Nevertheless, the conjugation of the double bonds in abietic acid 
has been shown by means of the ultraviolet spectrum, which has not only 
shown the conjugation, but also indicates that the two double bonds are 
not in the same ring (Kraft, 1935; Sandermann, 1941). 

Oxidation of abietic acid with potassium permanganate gives, among 
other products, wobutyric acid (Ruzicka et al., 1925). This suggests that 
one double bond is in ring C and the 6 : 7- or 7 : 8-position. If the double 
bond is in the 6 : 7-position, then the other double bond, which is con- 
jugated with it, must also be in the same ring (5 : 13 or 8 : 14) ; if 7 : 8, 
then the other double bond could be in the same ring C, but it could also 



§32] 



TERPENES 



313 



,CO(,H 




,C0 2 H 



CH(CH 3 ) 2 




CH(CH 3 ) 2 



:7- 



7:8- 



be in ring B. Since, as we have seen, the two double bonds are in different 
rings, their positions are probably 7 : 8 and 14 : 9. Further evidence for 
these positions is afforded by the fact that in the oxidation of abietic acid 
to give acids II and III (see above), in which ring A is intact, rings B and C 
are opened, and this can be readily explained only if rings B and C each 
have a double bond. Oxidative studies on abietic acid by Ruzicka et al. 
(1938-1941) have conclusively confirmed the positions 7 : 8 and 14 : 9. 

The only other point that will be mentioned here is the conversion of 
abietic acid into levopimaric acid. Since the latter was originally believed 
to be the enantiomorph of (+)-pimaric acid, it was called (— )-pimaric acid 
or laevopimaric acid. It is now known to be a structural isomer of dextro- 
pimaric acid, and so it has been suggested that levopimaric acid be called 
sapietic acid to avoid any confusion. The following equations show the 
formation of the adduct of abietic acid with maleic anhydride. 



£0 2 H 



COjjH 




CH-CO 
\ 



abietic acid 



sapietic acid 
(levopimaric acid) 



adduct 



TRITERPENES 

§32. Squalene, C 30 H 50 , b.p. 240-242°/4 mm., has been isolated from the 
liver oils of sharks. Other sources are olive oil and several other vegetable 
oils. Squalene has also been detected in leaves. Catalytic hydrogenation 
(nickel) converts squalene into perhydrosqualene, C 30 H 62 ; therefore squalene 
has six double bonds, and is acyclic. Ozonolysis of squalene gives, among 
other products, laevulic acid; this suggests that the following group is present 
in squalene: 

CH 3 
=CH-CH 2 -CH 2 -C= 

Since squalene cannot be reduced by sodium and amyl alcohol, there are 
no conjugated double bonds present in the molecule. Perhydrosqualene 
was found to be identical with the product obtained by subjecting hexa- 
hydrofarnesyl bromide to the Wurtz reaction. This led Karrer et al. (1931) 
to synthesise squalene itself from farnesyl bromide by a Wurtz reaction. 



314 ORGANIC CHEMISTRY [CH. VIII 

CH 3 CH 3 

2(CH 3 ) 2 C=CH-CH 2 -CH 2 -C=CH-CH 2 CH 2 -C=CH-CH 2 Br + Mg >- 



CH 3 CH 3 CH 3 CH 3 

((^ 3 ) 2 C=CH-(C^) 2 -C=CH-(C^) 2 -C=OTtCH 2 V(H=C-((H 2 ) 2 -CH=C-(C!H 2 ) 2 -CH=C(CEt) 2 

+ 
MgBr 2 

It should be noted that the centre portion of the squalene molecule has the 
two isoprene units joined tail to tail (cf. the carotenoids, Ch. IX). Squalene 
forms a thiourea inclusion complex, and hence it has been inferred that it 
is the a.U.-trans stereoisomer (Schiessler et al., 1952). This is supported by 
X-ray crystallographic studies of the thiourea inclusion complex (Nicolaides 
et al., 1954). 

§32a. Biosynthesis of terpenes. As more and more natural products 
were synthesised in the laboratory, so grew the interest in how these com- 
pounds are synthesised in the living organism (both animal and plant). 
The general approach to biosynthesis has been to break up the structure 
into units from which the compound could plausibly be derived. These 
units must, however, be known, or can be expected, to be available in the 
organism. Furthermore, this does not mean that the units chosen must 
necessarily be involved in the building-up of the compound. The general 
principle is that although a particular unit may itself be involved, it is also 
possible that its " equivalent " may act as a substitute, i.e., any compound 
that can readily give rise to this unit (by means of various reactions such 
as reduction, oxidation, etc.) may be the actual compound involved in the 
biosynthesis. E.g., the equivalent of formaldehyde could be formic acid, 
and that of acetone acetoacetic acid. One other point about the choice 
of units or their equivalents is to attempt to find some relationships between 
the various groups of natural products so that the units chosen are common 
precursors. 

When the units have been chosen, the next problem is to consider the 
types of reactions whereby the natural products are synthesised in the 
organism. The general principle is to use reactions which have been de- 
veloped in the laboratory. The difficulty here is that some types of labora- 
tory reactions require conditions that cannot operate in the organism, e.g., 
carboxylation and decarboxylation are known biological processes, but when 
carried out in the laboratory, these reactions normally require elevated 
temperatures. Deamination is also a known biological process, but in the 
laboratory this reaction is usually carried out under conditions of (pB) 
which would be lethal to the living organism. These differences between 
laboratory syntheses and biosyntheses are due to the action of enzymes in 
the latter. According to Schopf (1932), syntheses in plants may take place 
through the agency of specific or non-specific enzymes (see §§12-17. XIII), 
or without enzymes at all. Chemical syntheses (these do not involve the 
use of enzymes) must therefore, from the point of biosynthetic studies, be 
carried out under conditions of pH and temperatures comparable with those 
operating in plants. Chemical syntheses performed in this way (with the 
suitable units) are said to be carried out under physiological conditions (which 
involve a pH of about 7 in aqueous media and ordinary temperatures). 

Reactions which are commonly postulated in biosynthesis are oxidation, 
hydrogenation, dehydrogenation, dehydration, esterification, hydrolysis, 
carboxylation, decarboxylation, amination, deamination, isomerisation, con- 
densation and polymerisation. It might be noted here that the choice of 



§32a] TERPENES 315 

units and type of reaction are usually dependent on each other. Further- 
more, other reactions which are known to occur in biological syntheses are 
O- and iV-methylation or acylation. These may be described as extra-skeletal 
processes, and can occur at any suitable stage in the postulated biosynthesis. 
Another extra-skeletal process is C-methylation, but this is much rarer than 
those mentioned above. 

Now let us apply these principles to the biosynthesis of terpenes. As 
we have seen, according to the special isoprene rule, terpenes are built up 
of isoprene units joined head to tail (§1). Assuming then that the isoprene 
unit is the basic unit, the problem is : How is it formed, and how do these 
units join to form the various types of terpenes? At present it is believed 
that the fundamental units used in the cell in syntheses are water, carbon 
dioxide, formic acid (as " active formate "), and acetic acid (as " active 
acetate "). These " active " compounds are acyl derivatives of coenzyme A 
(written as CoA — H in the following equation); e.g., acetoacetic acid is 
believed to be formed as follows: 

2CH 3 -COCoA + H a O — ► CH,-COCH 2 -C0 2 H + 2CoA— H 
Now the biosynthesis of cholesterol (§7a. XI) from acetic acid labelled with 14 C 
in the methyl group (C m ) and in the carboxyl group (C c ) has led to the sugges- 
tion that the carbon atoms in the isoprene unit are distributed as follows: 

Cm. 

-Cc — Cm — Cc 
Cm/ 

This distribution is in agreement with a scheme in which senecioic acid 
(3-methylbut-2-enoic acid) is formed first, and this pathway was supported 
by the isolation of this acid from natural sources. Further support for the 
formation of this carbon skeleton is given by the fact that labelled isovaleric 
acid gives rise to cholesterol in which the wopropyl group and the carboxyl 
group have been incorporated. 

)CH-CH 2 -"C0 2 H 
"CHj/ 

Tavormina et al. (1956), however, have shown that the lactone of mevalonic 
acid (/3-hydroxy-/3-methyl-<5-valerolactone) is converted almost completely 
into cholesterol by rat liver, and is a much better precursor than senecioic 
acid. The following scheme has therefore been proposed for the early stages 
in the biosynthesis of terpenes; it is in agreement with the distribution of 
the carbon atoms in cholesterol (see above): 

Me Me 

| | HO^ Me HO -Me 

2 CO >- CO Mc - COCoA > \ / — \ c ^ 

CoA CH 2 CH„ CH, CH, ^CH, 

I I - | | ! 

COCoA COCoA C0 2 H CHO CO.H 



HMG 



leucine 



Me Me HO. .Me 



CH Me =^^= CH CH 2 CH 2 ^CH 2 

I I I I I 

COCoA COCoA C0 2 H CH 2 OH C0 2 H 



MVA 



senecioic acid 



Three molecules of active acetate form hydroxymethylglutaric acid, HMG 
(Lynen et al., 1958; Rudney, 1959), and this is then converted into mevalonic 



316 ORGANIC CHEMISTRY [CH. VIII 

acid (MVA), possibly through the intermediate mevaldic acid (Rudney et al., 
1958; Lynen, 1959). Support for this sequence is afforded by the following 
facts. MVA has been isolated from natural sources (Wolf et al., 1957), and 
it is also known that HMG may be formed from leucine by the route shown 
(Lynen et al., 1958, 1959). 

The biosynthesis of terpenes can be subdivided into three definite steps: 
(i) the formation of a biological wopentane unit from acetate ; (ii) the con- 
densation of this unit to form acyclic terpenes ; (iii) the conversion of acyclic 
into cyclic terpenes. 

The stages leading to MVA have been discussed above. What happens 
after this is uncertain. One suggestion is that MVA forms a pyrophosphate 
(at the primary alcoholic group), and then the carboxyl and the tertiary 
hydroxyl group are eliminated simultaneously to form wopentenyl pyro- 
phosphate (I). This isomerises to the wopropylidene compound, /? : /3-di- 
methylallyl pyrophosphate, which combines with (I) to form the pyro- 
phosphate of the acyclic terpene geraniol (in the following equations P 
represents the pyrophosphate residue, P 2 6 H 3 ): 

CH„— O— P CH a — O— P 

I I 

/OH CH, 




CH/ NMe J\ 

| CH 2 ^ Nvie 

CO a H 

I 

Hv XH 2 — O— P -t> P— O— CH 

il 
Me/ Nvie 

This is supported by the following work: Stanley (1958) has shown that 
labelled MVA (2- 14 C-MVA) is incorporated into a-pinene. Park et al. (1958) 
have observed the incorporation of labelled MVA into rubber (§33) by an 
enzyme system from latex, and Lynen et al. (1961) have also demonstrated 
the conversion of isopentenyl pyrophosphate into rubber (see also §7a. XI). 
Geranyl pyrophosphate has also been shown to be a precursor for farnesyl 
pyrophosphate, which then gives squalene. 

A point of interest here is that Harley-Mason et al. (1961) have prepared 
phenylpropiolic acid by the action of brosyl chloride on the sodium derivative 
of diethyl benzoylmalonate and treating the product with sodium hydroxide 
in aqueous dioxan at room temperature. The reaction has been formulated 
as follows: 

PhCOCH(C0 2 Et) 2 SS^U- PhC=C(C0 2 Et) 2 -^^*- 



OBs 

p> 

\±C r X »- PhCsCCOi+ co 2 + ob s - 

CoBs C0"" 2 

This provides one of the mildest known methods for making an acetylenic bond, 
and this reaction may be regarded as support for the mechanism proposed by 
Jones (1961) as a possible route for the biosynthesis of acetylenic bonds: 



§33] TERPENES 317 

C0 2 H 

MeCO-CoA + C0 2 H-CH 2 -CO-CoA »■ MeCOCH 

XiOCoA 

ft 

enzyme Me ^ /"V ^ 

— ** J^° ° ~ " *~ Me0 — C COCoA + OP 

^j> bOCoA 
P 



POLYTEKPENES 

§33. Rubber. Rubber {caoutchouc) is obtained from latex, which is an 
emulsion of rubber particles in water that is obtained from the inner bark 
of many types of trees which grow in the tropics and sub-tropics. When 
the bark of the rubber tree is cut, latex slowly exudes from the cut. Addi- 
tion of acetic acid coagulates the rubber, which is then separated from the 
liquor and either pressed into blocks or rolled into sheets, and finally dried 
in a current of warm air, or smoked. 

Crude latex rubber contains, in addition to the actual rubber hydro- 
carbons (90-95 per cent.), proteins, sugars, fatty acids and resins, the amounts 
of these substances depending on the source. Crude rubber is soft and 
sticky, becoming more so as the temperature rises. It has a low tensile 
strength and its elasticity is exhibited only over a narrow range of tempera- 
ture. When treated with solvents such as benzene, ether, light petrol, a 
large part of the crude rubber dissolves ; the rest swells but does not dis- 
solve. This insoluble fraction apparently contains almost all of the protein 
impurity. On the other hand, rubber is insoluble in acetone, methanol, etc. 
When unstretched, rubber is amorphous; stretching or prolonged cooling 
causes rubber to crystallise. 

Structure of rubber. The destructive distillation of rubber gives iso- 
prene as one of the main products; this led to the suggestion that rubber is 
a polymer of isoprene, and therefore to the molecular formula (C 6 H 8 ) n . This 
molecular formula has been confirmed by the analysis of pure rubber. Crude 
rubber may be purified by fractional precipitation from benzene solution by 
the addition of acetone. This fractional precipitation, however, produces 
molecules of different sizes, as shown by the determination of the molecular 
weights of the various fractions by osmotic pressure, viscosity and ultra- 
centrifuge measurements; molecular weights of the order of 300,000 have 
been obtained. 

The halogens and the halogen acids readily add on to rubber, e.g., bromine 
gives an addition product of formula (C 5 H g Br 2 )„, and hydrogen chloride 
the addition product (C 5 H 9 C1)„. Pure rubber has been hydrogenated to the 
fully saturated hydrocarbon (C 5 H 10 )„— this is known as hydrorubber— by 
heating with hydrogen in the presence of platinum as catalyst (Pummerer et 
al., 1922). Rubber also forms an ozonide of formula (C 5 H 8 3 )„. All these 
addition reactions clearly indicate that rubber is an unsaturated compound, 
and the formulae of the addition products show that there is one double 
bond for each isoprene unit present. 

Ozonolysis of rubber produces laevulaldehyde and its peroxide, lsevulic 
acid and small amounts of carbon dioxide, formic acid and succinic acid 
(Harries, 1905-1912). Pummerer (1931) showed that the hevulic derivatives 
comprised about 90 per cent, of the products formed by the ozonolysis. 
This observation led to the suggestion that rubber is composed of isoprene 
units joined head to tail. Thus, if rubber has the following structure, the 
formation of the products of ozonolysis can be explained: 



318 



ORGANIC CHEMISTRY 



[CH. VIII 



CH 3 



CH, 



CH, 



CHo'C — Cri'CHg'CxTo' C — CH'CHo'CIio *C — CH'CJL 



2' 



CH, 



pzonolysis 

CH, 



13 ^Xl 3 CH3 

-CH 2 -C=0 + 0CH-CH 2 -CH 2 -C=O + 0CHCH 2 -CH 2 -C=O + OCHCH 2 — 

Some of the laevulaldehyde is further oxidised to laevulic and succinic 
acids. 



CH,-CC-CH 2 -CH,-CHO 



-CH 3 -CC-CH 2 -CH 2 -C0 2 H 



"C0 2 + C0 2 H-CH 2 -CH 2 -C0 2 H 



Gutta-percha (which is also obtained from the bark of various trees) is 
isomeric with rubber; their structures are the same, as shown by the methods 
of analysis that were used for rubber. X-ray diffraction studies (Bunn, 



\ 
*~ CH 3 .CH 2 

C 

II 
G 

8-10 A fobs.) H / CH2 
9-13A (theor.) CH 2 ,CH 3 



CH^ H 

CH3 yCH 2 

c 



\ / 



4-72 A (obs.) 
5:04 A (theor.) 



L 



CH 2 H 
\ / 



H 



H CH 2 



rubber 
cis-form 



C 
/\ 
CH, 

II 

CH 2 H 

\ 2 



gutta-percha 
trans-iorm 



1942) have shown that rubber is composed of long chains built up of isoprene 
units arranged in the cw-form, whereas gutta-percha is the trans-iorm. 
Gutta-percha is hard and has a very low elasticity. 

In rubber, the chain repeat unit is 8-10 A, whereas in gutta-percha it is 
4-72 A. Both of these values are shorter than the theoretical values of the 
repeat distances (9-13 A and 5-04 A respectively) calculated from models. 
The reasons for these discrepancies are not clear, but for gutta-percha it 
has been explained by assuming that the isoprene units are not coplanar. 
The infra-red absorption spectrum of rubber has bands which are in keeping 
with the structure that has been proposed. Also, the linear shape of the 
molecule is indicated by viscosity measurements of rubber solutions. Schulz 
et al. have examined cycfohexane solutions of rubber by light-scattering 
methods, and obtained a value of 1,300,000 for the molecular weight. Their 
other work also supports the linear nature of the chain. 

§33a. Vulcanisation of rubber. When crude rubber is heated with a 
few per cent, of sulphur, the rubber becomes vulcanised. Vulcanised rubber 



§33b] TERPENES 319 

is less sticky than crude rubber, and is not so soluble and does not swell so 
much in organic solvents. Furthermore, vulcanised rubber has greater 
tensile strength and elasticity than crude rubber. 

The mechanism of vulcanisation is still not clear. Vulcanised rubber is 
not so unsaturated as rubber itself, the loss of one double bond corresponding 
approximately to each sulphur atom introduced. It therefore appears that 
some sulphur atoms enter the chain, vulcanisation thus occurring through 
intramolecular and intermolecular cross-links; it is the latter type of reaction 
that is desirable in vulcanisation. It should be noted that not all the 
sulphur is in a combined state ; some is free, and this can be readily extracted. 

Vulcanisation may be accelerated and carried out at lower temperatures 
in the presence of certain organic compounds. These compounds are con- 
sequently known as accelerators, and all of them contain nitrogen or sulphur, 
or both, e.g., 

.NH-C 8 H 5 § ff 

NH=CT (CH 3 ) 2 N-C-S-S-C-N(CH 3 ) 2 



NHC 6 H, 



•e*H 



tetramethylthiuram 



diphenylguanidine disuJphide 



S S 

II II 

(CH 3 ) 2 N- C-S-Zn-S-C-N(CH 3 ) 2 

zinc dimethyldithiocarbamate 



( 



C-SH 



mercaptobenzothiazole 



Mercaptobenzothiazole is the most widely used accelerator. Many inorganic 
compounds can also act as accelerators, e.g., zinc oxide. Organic accelerators 
are promoted by these inorganic compounds, and current practice is to 
vulcanise rubber with, e.g., mercaptobenzothiazole in the presence of zinc 
oxide. 

The actual properties of vulcanised rubber depend on the amount of 
sulphur used, the best physical properties apparently being achieved by 
using about 3 per cent, sulphur, 5 per cent, zinc oxide and about 1 per cent, 
of the accelerator. When 30-50 per cent, sulphur is used, the product is 
ebonite. 

The elasticity of rubber is believed to be due to the existence of rubber 
as long-chain molecules which are highly " kinked " in the normal state. 
When subjected to a stretching force, these chains " unkink ", and return 
to their normal condition when the force is removed. 

§33b. Synthetic rubbers. There are many synthetic rubbers in use, 
each type possessing certain desirable properties. A great deal of work has 
been done on the synthesis of natural rubber, but the difficulty has been to 
obtain the isoprene units in the all-«'s configuration. Wilson et al. (1956) 
have achieved this by using stereospecific catalysts. 

Buna rubbers. Under the influence of sodium, butadiene polymerises 
to a substance which has been used as a rubber substitute under the name 
of Buna (see Vol. I). Buna N is a synthetic rubber which is produced by 
the copolymerisation of butadiene and vinyl cyanide. Buna S or Perbunan 
is a copolymer of butadiene and styrene. 

Butyl rubber. Copolymerisation of tsobutylene with a small amount 
of isoprene produces a polyjsobutylene known as Butyl rubber. 

Neoprene. When passed into a solution of cuprous chloride in am- 
monium chloride, acetylene dimerises to vinylacetylene. This dimer can 



320 ORGANIC CHEMISTRY [CH. VIII 

add on one molecule of hydrogen chloride to form Chloroprene (2-chlorobuta- 
1 : 3-diene), the addition taking place in accordance with Markownikoff's 
rule (see also Vol. I). 

HC1 

2CHEEECH > CH 2 =CH— C=CH >- CH a =CH— CC1=CH 2 

Chloroprene readily polymerises to a rubber-like substance known as Neo- 
prene. Actually, the nature of the polychloroprene depends on the con- 
ditions of the polymerisation. 

Silicone rubbers. These are chemically similar to the silicone resins. 
The chief silicone rubber is prepared by treating the hydrolysis product of 
dimethyldichlorosilane, (CH 3 ) 2 SiCl 2 , with various compounds capable of in- 
creasing the molecular weight without the formation of cross-links, i.e., 
they produce long-chain molecules. 

— Si(CH 3 ) 2 — O— Si(CH 3 ) j-0-Si(CB,) 2 — O— 
Silicone rubbers have very high electrical insulating properties, and do not 
deteriorate on exposure to light and air, and are resistant to the action of 
acids and alkalis. 



READING REFERENCES 

The Terpenes, Cambridge University Press (2nd ed.). Sir John Simonsen and Owen. 

Vol. I (1947); Vol. II (1949). Sir John Simonsen and Barton. Vol. Ill (1952). 

Sir John Simonsen and Ross. Vol. IV. (1957); Vol. V. (1957). 
Gilman (Ed.), Advanced Organic Chemistry, Wiley (1953). Vol. IV, Ch. 7. The Terpenes. 
Rodd (Ed.), Chemistry of the Carbon Compounds, Elsevier, (i) Vol. IIA (1953). Ch. 11. 

Rubber and Rubber-like Compounds (p. 407). (ii) Vol. IIB (1953). Chh. 12-16. 

Terpenoids. 
Mayo, Vol. I. Mono- and Sesquiterpenoids. Vol. II. The Higher Terpenoids. Inter- 
science (1959). 
Pinder, The Chemistry of the Terpenes, Chapman and Hall (1960). 
Ruzicka, History of the Isoprene Rule, Proc. Chem. Soc, 1959, 341. 
Ginsburg (Ed.), Non-Benzenoid Aromatic Compounds, Interscience (1959). Chh. V, VI. 

Azulenes. 
Streitwieser, Solvolytic Displacement Reactions at Saturated Carbon Atoms, Chem. 

Reviews, 1956, 56, p. 698 (Wagner-Meerwein Rearrangements). 
Barton, The Chemistry of the Diterpenoids, Quart. Reviews (Chem. Soc), 1949, 3, 36. 
Gascoigne and Simes, The Tetracyclic Terpenes, Quart. Reviews (Chem. Soc.), 1955, 

9, 328. 
Barton and Mayo, Recent Advances in Sesquiterpenoid Chemistry, Quart. Reviews 

(Chem. Soc), 1957, 11, 189. 
Halsall and Theobald, Recent Aspects of Sesquiterpenoid Chemistry, Quart. Reviews 

(Chem. Soc), 1962, 16, 101. 
Progress in Organic Chemistry, Butterworths. Vol. 5 (1961). Ch. 4. The Chemistry 

of the Higher Terpenoids. 
Ciba Foundation Symposium on the Biosynthesis of Terpenes and Sterols, Churchill 

(1959). 
Sir Robert Robinson, The Structural Relations of Natural Products, Oxford Press (1955). 
Downes, The Chemistry of Living Cells, Longmans, Green (2nd ed., 1963). 
Birch, Some Pathways in Biosynthesis, Proc. Chem. Soc, 1962, 3. 
Gee, Some Thermodynamic Properties of High Polymers and their Molecular Inter- 
pretation, Quart. Reviews (Chem. Soc), 1947, 1, 265. 
Hardy and Megson, The Chemistry of Silicon Polymers, Quart. Reviews (Chem. Soc), 

1948, 2, 25. 
Flory, Principles of Polymer Chemistry, Cornell University Press (1953). 



CHAPTER IX 

CAROTENOIDS 

§1. Introduction. The carotenoids are yellow or orange pigments which 
are widely distributed in plants and animals. Chlorophyll is always associ- 
ated with the carotenoids carotene and lutein ; the carotenoids act as photo- 
sensitisers in conjunction with chlorophyll. When chlorophyll is absent, 
e.g., in fungi, then the carotenoids are mainly responsible for colour. Caro- 
tenoids are also known as lipochromes or chromolipids because they are 
fat-soluble pigments. They give a deep blue colour with concentrated sul- 
phuric acid and with a chloroform solution of antimony trichloride (the 
Carr-Price reaction) ; this Carr-Price reaction is the basis of one method of 
the quantitative estimation of carotenoids. Some carotenoids are hydro- 
carbons; these are known as the carotenes. Other carotenoids are oxygen- 
ated derivatives of the carotenes; these are the xanthophylls. There are 
also acids, the carotenoid acids, and esters, the xanthophyll esters. 

Chemically, the carotenoids are polyenes, and almost all the carotenoid 
hydrocarbons have the molecular formula C 40 H 66 . Also, since the carbon 
skeleton of these compounds has a polyisoprene structure, they may be 
regarded as tetraterpenes (cf. §1. VIII). 

In most of the carotenoids, the central portion of the molecule is composed 
of a long conjugated chain comprised of four isoprene units, the centre two 
of which are joined tail to tail. The ends of the chain may be two open- 
chain structures, or one open-chain structure and one ring, or two rings. 
The colour of the carotenoids is attributed to the extended conjugation of 
the central chain (see Vol. I). X-ray analysis has shown that in the majority 
of natural carotenoids, the double bonds are in the tfra«s-position ; a few 
natural carotenoids are cis-. Thus, if we represent the ends of the chain by 
R (where R may be an open-chain structure or a ring system), tfraws-caroteHes 
may be written: 

H CH 3 H CH 3 H H H H H 

AVvSVvvvy* 

i T i T i i i I i 

H H H H H CH 3 H CH 3 H 

If we use the conventional formulae of terpenes (§4. VIII), the above formula 
will be the following (the reader should write out in this way the various 
formulae given in the text; see §6 for an example): 




§2. Carotenes. Carotene was first isolated by Wackenroder (1831) from 
carrots (this was the origin of the name carotin, which was later changed to 
carotene). The molecular formula of carotene, however, was not determined 
until 1907, when Willstatter showed it was C 40 H 56 . Carotene was shown to 
be unsaturated, and when treated with a small amount of iodine, it forms 
a crystalline di-iodide, C 40 H 56 I 2 . Kuhn (1929) separated this di-iodide into 
two fractions by means of fractional crystallisation. Treatment of each 
fraction with thiosulphate regenerated the corresponding carotenes, which 
were designated a- and jS-carotene. Kuhn et al. (1933) then found that 

321 



322 



ORGANIC CHEMISTRY 



[CH. IX 



chromatography gives a much better separation of the carotenes themselves, 
and in this way isolated a third isomer, which he designated y-carotene. 

oc-Carotene, m.p. 187-187-5°; optically active (dextrorotatory). 

/J-Carotene, m.p. 184-5°; optically inactive. 

y-Carotene, m.p. 176-5°; optically inactive. 
It appears that all three carotenes occur together in nature, but their relative 
proportions vary with the source, e.g., carrots contain 15 per cent, a, 85 per 
cent. j3 and 0-1 per cent. y. Carotenes are obtained commercially by 
chromatography, two of the best sources being carrots and alfalfa. 

Biosynthetic studies of the carotenes have been carried out, and the pathways 
are those for the terpenes (§32a. VIII). Thus Braithwaite et al. (1957) and 
Grob (1957) have shown that labelled mevalonic acid is incorporated into /S- 
carotene. Scheuer et al. (1959) have also shown that this acid is incorporated 
into lycopene. Furthermore, Modi et al. (1961) have isolated mevalonic acid 
from carrots. 

§3. p-Carotene, C 40 H 66 . When catalytically hydrogenated (platinum), /3- 
carotene forms perhydro-/S-carotene, C 40 H 78 . Thus /J-carotene contains eleven 
double bonds, and since the formula of perhydro-/?-carotene corresponds to 
the general formula C„H 2 «-2, it follows that the compound contains two rings. 

When exposed to air, /?-carotene develops the odour of violets. Since 
this odour is characteristic of jS-ionone, it was thought that this residue is 
present in /J-carotene (see §6. VIII). This was confirmed by the fact that 
the oxidation of a benzene solution of /3-carotene with cold aqueous potas- 
sium permanganate gives /3-ionone. Now /3-ionone, I, on ozonolysis, gives, 
among other things, geronic acid, II (Karrer et al., 1929). 




!H=CH-CO-CH 3 



o». 



v CO-C0 2 H 
COCH 3 




I II 

/S-Carotene, on ozonolysis, gives geronic acid in an amount that corresponds 
to the presence of two /?-ionone residues (Karrer et al, 1930). T " 1 " 1C a +»"+=>- 
tive structure for /3-carotene is: 



Thus a tenta- 



CH, 




.CH=CH-C= 



C l: 



3 
f— C M j 



CH 3 
=OCH=CH 




Since the colour of /3-carotene is due to extended conjugation (§1), the C 14 
portion of the molecule will be conjugated. The presence of conjugation in 
this central portion is confirmed by the fact that jg-carotene forms an adduct 
with five molecules of maleic anhydride (Nakamiya, 1936). 

Geronic acid, on oxidation with cold aqueous potassium permanganate, 
forms a mixture of acetic acid, a : a-dimethylglutaric, III, a : a-dimethyl- 
succinic, IV, and dimethylmalonic acids, V. 



TOjjH 



JSL 



CO-CH, 



II 



*-CH 3 -C0 2 H + 



C0 2 H 




[O] 



>■— i 



\» 2 H [o] H0 2 C 



^XJOjH 



C0 2 H 
IV 



§3] CAROTENOIDS 323 

Oxidation of /5-carotene in benzene solution with cold aqueous permanganate 
gives a mixture of /S-ionone, III, IV, V, and acetic acid, the amount of acetic 
acid being more than can be accounted for by the presence of two /S-ionone 
residues. Thus there must be some methyl side-chains in the central C 14 
portion of the molecule. Since it is essential to know the exact number of 
these methyl side-chains, this led to the development of the Kuhn-Roth 
methyl side-chain determination (1931). The first method used was to 
oxidise the carotenoid with alkaline permanganate, but later chromic acid 
(chromium trioxide in sulphuric acid) was found to be more reliable, the 
methyl group in the fragment — C(CH 3 )= being always oxidised to acetic 
acid. It was found that alkaline permanganate only oxidises the fragment 
=C(CH 3 ) — CH= to acetic acid, and fragments such as =C(CH 3 ) — CH 2 — 
are incompletely oxidised to acetic acid, or not attacked at all (Karrer et al., 
1930). Since a molecule ending in an isopropylidene group also gives acetic 
acid on oxidation with chromic acid, this end group is determined by ozon- 
olysis, the acetone so formed being estimated volumetricahy. Application 
of the Kuhn-Roth methyl side-chain determination to /f-carotene gave four 
molecules of acetic acid, thus indicating that there are four — C(CH 3 )= 
groups in the chain. The positions of two of these have already been tenta- 
tively placed in the two end /S-ionone residues (see tentative structure above), 
and so the problem is now to find the positions of the remaining two. This 
was done as follows. Distillation of carotenoids under normal conditions 
brings about decomposition with the formation of aromatic compounds . Thus 
the distillation of /S-carotene produces toluene, wt-xylene and 2 : 6-dimethyl- 
naphthalene (Kuhn et al., 1933). The formation of these compounds may 
be explained by the cyclisation of fragments of the polyene chain, without 
the /8-ionone rings being involved. The following types of chain fragments 
would give the desired aromatic products: 



(a) I 

V ; CH 

CH 3 — C CH 




CH CH 

CH toluene 






CH N CH CH 3 C / \>CH S GB. 3 f\ 

1 1 II or I II — " L 

CH 3 -cL C-CH 3 CH CH \/ 
^CH ^CH 



CH 



3 



1:3 1:5 



(c) I I 

CH y CH CH /C ^ 

CH CH C-CHj CH 3 -C CH CH 



7K-xylene 




ch 3 -c /CH xm CH CH /-CHj 

xm N CH X CH 'CH 

2:6- dimethylnaphthalene 



1:6 1:8 



324 



ORGANIC CHEMISTRY 



[CH. IX 



The following symmetrical structure for /S-carotene would satisfy the require- 
ments of (a), (b) and (c) ; the tail to tail union of the two isoprene units at 
the centre should be noted. 




<?H 3 



CH 3 



=CH-C=CH-CH=CH-C=CHCH=CH-CH : 

234 5 6 7 I 9 10 11 



CH 3 

= C-CH= 

12 13 



-1:5- 
(*) 



-1:6- 

(c) 



<jJHs 
=CH-CH=C-CH=CH- 

14 15 16 17 18 



-1:5- 

(*) 




This symmetrical formula for /S-carotene has been confirmed by the follow- 
ing oxidation experiments (Kuhn et al., 1932-1935). When /S-carotene is 
oxidised rapidly with potassium dichromate, dihydroxy-/5-carotene, VI, is 
obtained and this, on oxidation with lead tetra-acetate, gives semi-/3- 
carotenone, VII, a diketone. Since both VI and VII contain the same number 
of carbon atoms as /S-carotene, it follows that the double bond in one of the 
fi-ionone rings has been oxidised; otherwise there would have been chain 
scission had the chain been oxidised. Oxidation of semi-/S-carotenone with 
chromium trioxide produces /S-carotenone, VIII, a tetraketone which also has 
the same number of carbon atoms as /S-carotene. Thus, in this compound, 
the other /S-ionone ring is opened. Now only one dihydroxy-/S-carotene 
and one semi-|S-carotenone are obtained, and this can be explained only by 
assuming a symmetrical structure for /S-carotene. Thus the oxidations may 
be formulated: 




,CH— CH- 



p-carotene 

\X)-CH— CH- 
CO-CH 3 
VII 




O-CH— CH-CO 
,COCH 3 CH 3 -CO N 
VIII 



This structure for /S-carotene has been confirmed by synthesis, e.g., that of 
Karrer et al. (1950). The acetylenic carbinol IX is treated with ethyl- 
magnesium bromide and the product is treated as shown on opposite page. 



§3] 




CAROTENOIDS 

CH 3 

H=CH-C-CH 2 -C=CH 
OH 



IX 



CjHjMgBr 




CH 3 
!H=CH-C-CH 2 -C=C-MgBr 
OMgBr 



CH, 




CO-CH 2 -CH=CH- CHj-CO 

CH 3 CH 3 

.CH=CH-C-Ce 2 -C=C- C-CH 2 -CH= 

OH OH 



Hj-Pd 



CH, 




CH 3 



CH=CH-C-CH 2 -CH=CH-C-CH 2 -CH= 



OH 




CH 3 



I 
OH 



p-CH 3 -C 6 H 4 'SO s H 
(-H a O> 



CH, 



J 2 



CH=CH- C=CH • CH=CH- C=CH-CH = 



325 



p -carotene jg 

IX has been prepared by Isler (1949) by treating pMonone with propargyl 
bromide in the presence of zinc (cf. the Reformatsky reaction): 

CH, 




CH=CHCO + CH 2 BrCHCH 



Zn 



A/ 



CH 3 

CH=CHC-CH 2 -C=CH 

OH 



IX 



326 



ORGANIC CHEMISTRY 



[CH. IX 



The most convenient way of preparing the diketone (oct-4-ene-2 : 7-dione) 
starts with but-l-yn-3-ol (Inhoffen et al., 1951): 

O. UAIBt 

2CH 3 -CHOH-C=CH -■ . - ,, .'__> CH 3 -CHOH-CeeC-Ce^C-CHOH-CH 3 > 



CuCl-NH.Cl 

CH 3 -CHOH-CH=CH-CH=CH-CHOH-CH 3 

Zn 



MnO, 
>• 



CH 3 -CO-CH==CH-CH==CH-CO-CH 3 



CH.COjH 



CH 3 -CO-CH 2 -CH=CH-CH 2 -CO-CH 3 
An important point to note in this synthesis is that lithium aluminium 
hydride will reduce a triple bond to a double bond when the former is ad- 
jacent to a propargylic hydroxyl group, i.e., 

— C(OH)-CeeeC ^V — C(OH)-CH=CH— 

It is worth while at this point to consider the general aspects of carotene 
syntheses. All syntheses have used the union of a bifunctional unit, which 
forms the central part of the carotene molecule, with two molecules (identical 
as for, e.g., /3-carotene, or not identical as for, e.g., oc-carotene). The various 
methods have been divided into four groups according to the carbon content 
of the three units used in the synthesis: C 19 + C 2 + C 19 ; C 16 + C 8 + C 16 ; 
C u + C12 + Ci 4 ; c io + C 2o + Cio- The second group has been used in the 
above synthesis of /3-carotene. 

An example of the synthesis of ^-carotene by the third is that of Isler et al. 
(1957) [% = jS-ionine ring]: 



+ BrMgC s=CMgBr 



OH 



OHO 



OH 



HC(OEt), 
P5SJ 



OEt 



OEt 



(EtO) 4 CHv/\/Rp 
B/ \f N CH(OEt) a + X + J 

jzhCl, 
| EtO I OEt OEt 



I' 0Et 



OEt OEt 



OEt 
lAcOB 




Im-1 



■P-Y reduction 
H 




(i) allylio rearr. and dehydration 
(ii) partial hydrogenation" 
(MY stereomutatioit 



jS-carotene 



§5] 



CAROTENOIDS 



327 



An example of the fourth group makes use of the Wittig reaction (see crocetin, 
§9 for an illustration of this method). 

§4. ot-Carotene, C^Hgg. This is isomeric with /?-carotene, and oxidation 
experiments on oc-carotene have led to results similar to those obtained for 
/J-carotene, except that isogeronic acid is obtained as well as geronic acid. 
Since isogeronic acid is an oxidation product of a-ionone, the conclusion is 
that a-carotene contains one /?-ionone ring and one a-ionone ring (§6. VIII) 
[Karrer et al., 1933]. 




,CH=CH-CO-CH, 



[O], 



CH-C0 2 H 
CO-CH 3 



a-ionone 
Thus the structure of a-carotene is: 



COCH 3 
'COjjH 
isogeronic acid 




CH 3 CH 3 CH 3 CH 3 

!H=CH-C=CH-CH=CHC=CHCH=CHCH=CCH=CH-CH=CCH=CH N 




As we have seen, a-carotene is optically active (§1), and this is due to the 
presence of the asymmetric carbon atom (*) in the a-ionone ring. The 
structure given for a-carotene has been confirmed by synthesis (Karrer 
et al., 1950). The method is the same as that described for ^-carotene, except 
that one molecule of the acetylenic alcohol (structure IX, §3) is used together 
with one molecule of the corresponding a-ionone derivative: 

CH, 

=CH-OCH 2 -C=CH 
I 2 
OH 



It is interesting to note that a-carotene has been converted into the /S-isomer 
by heating the a-compound with ethanolic sodium ethoxide and benzene at 
100-110° for some time (Karrer et al., 1947); this is an example of three 
carbon prototropy. 

§5. Lycopene, C 40 H B6 , m.p. 175°, is a carotenoid that is the tomato pig- 
ment. Since the structure of y-carotene depends on that of lycopene, the 
latter will be discussed here, and the former in the next section. 

On catalytic hydrogenation (platinum), lycopene is converted into per- 
hydrolycopene, C 40 H 82 . Therefore lycopene has thirteen double bonds, and 
is an acyclic compound (Karrer et al., 1928). Ozonolysis of lycopene gives, 
among other products, acetone and lsevulic acid; this suggests that lycopene 
contains the terminal residue: 



CH,^ 

CH 3 - 
acetone 



H.C . 

i I ! 

C=i=CH-CH 2 C!H 2 -C 4=0 — 

I 
I 

laevulic acid J 



- methylheptenone 



328 ORGANIC CHEMISTRY [CH. IX 

This is supported by the fact that controlled oxidation of lycopene with 
chromic acid produces 6-methylhept-5-en-2-one {cf. §5. VIII). Quantitative 
oxidation experiments (ozonolysis) indicate that this grouping occurs at each 
end of the molecule (Karrer et al., 1929, 1931). Also, the quantitative oxida- 
tion of lycopene with chromic acid gives six molecules of acetic acid per 
molecule of lycopene, thereby suggesting that there are six — C(CH 3 )= 
groups present in the chain (cf. §3). Controlled oxidation of lycopene with 
chromic acid gives one molecule of methylheptenone and one molecule of 
lycopenal, C 32 H 12 0, and the latter may be further oxidised with chromic acid 
to another molecule of methylheptenone and one molecule of a dialdehyde, 
c ai H 28 a (Kuhn et al., 1932). Thus this dialdehyde constitutes the central 
part of the chain, and the two molecules of methylheptenone must have 
been produced by the oxidation of each end of the chain in lycopene. The 
dialdehyde may be converted into the corresponding dioxime, and this, on 
dehydration to the dicyanide, followed by hydrolysis, forms the dicarboxylic 
acid C M H 28 4 , which is identical with norbixin (§9). Thus the dialdehyde 
must be bixindialdehyde, and so it may be inferred that the structure of 
lycopene is the following symmetrical one, since it accounts for all the above 
facts. 

CH 3 CH 3 CH 3 

(CH 3 ) 2 C=CH-CH 2 -CH z -C=CH-CH=CH-i = CH-CH=CH-C=CH-CH 

(CH 3 ) 2 C=CH-CH 2 -CH 2 -C=CH-CH=CH-C=CH-CH=CHC=CHCH 

CH 3 CH 3 CH 3 

lycopene 

J Cr 03 

CH 3 CH 3 CH 3 

(CH 3 ) 2 C=CH-CH 2 -CH 2 -C=0 + CHO-CH=CH-C=CH-CH=CH-C=CH-CH 
methylheptenone |l 

(CH 3 ) 2 C=CH • CH 2 - 0% C = CH- CH=CH-C =CH- CH=CHC =CH- CH 

CH 3 CH 3 CH 3 

lycopenal 

Cr0 3 

i CH 3 CH 3 

CH 3 CHO-CH=CH-C=CH-CH=CH-C=CH-CH 

(CH^C^HCHs-CTVcUo + CHO-CH=CH- C=CH-CH=CH-C=CH-CH 

methylheptenone CH 3 CH 3 

bixindialdehyde 

(i) NH 2 0H 

(HXCHa-COJaOG-HjO] 
) hydrolysis 

CH 3 CH 3 

C0 2 H-CH=CH-C=CH-CH=CH- C =CHCH 

0O 2 H- CH=CH-C=CH-CH=CH- C=CH-CH 

CH 3 CH 3 

norbixin 



§6] 



CAROTENOIDS 



329 



The structure assigned to lycopene has been confirmed by synthesis (Karrer 
et al., 1950). Instead of the acetylenic carbinol IX in §3, two molecules of the 
following compound were used. 

^C(CH S ) 2 CH 3 

OH CH-CH=CH-C-CH 2 CsCH 

CH 2 C-CH, OH 

M 

§6. y-Carotene, C 40 H 66 . Catalytic hydrogenation converts y-carotene 
into perhydro-y-carotene, C 40 H 80 . Thus there are twelve double bonds pre- 
sent, and the compound contains one ring. Ozonolysis of y-carotene gives, 
among other products, acetone, laevulic acid and geronic acid. The forma- 
tion of acetone and lsevulic acid indicates the structural relationship of 
y-carotene to lycopene, and the formation of geronic acid indicates the pre- 
sence of a /?-ionone ring (Kuhn et al., 1933). On this evidence, and also on 
the fact that the growth-promoting response in rats was found to be half 
that of /S-carotene, Kuhn suggested that y-carotene consists of half a molecule 
of /J-carotene joined to half a molecule of lycopene; thus: 




CH S <j!H 3 CH, CH 3 (CH^q 

H=CH-C=CH-CH=CHC=CH-CH=CH-CH=CCH=CH-CH=C-CH=CH-CH 



y-carotene 



CH 3 C CH S 
CH, 



This structure for y-carotene is supported by the fact that the absorption 
maximum of y-carotene in the visible region lies between that of /5-carotene 
and that of lycopene. Final proof for this structure has been obtained by 
the synthesis of y-carotene (Karrer et al., 1953) ; the following reactions are 
written with the conventional formulae (see §1): 



,CsCMgBr 
OMgBr + 



BrMgO 
.0 + BrMgC=C 





y-carotene 



330 



ORGANIC CHEMISTRY 



[CH. IX 



A <5-carotene has also been isolated, and this has been shown to be the 
a-ionone analogue of y-carotene (Kargel et al., 1960). 

§7. Vitamin A, C 20 H 30 O. Vitamin A is also known as Axerophthol, and 

is also usually referred to as vitamin Aj since a second compound, known as 
vitamin A a , has been isolated. 

Vitamin A x influences growth in animals, and also apparently increases 
resistance to disease. Night blindness is due to vitamin A x deficiency in the 
human diet, and a prolonged deficiency leads to xerophthalmia (hardening 
of the cornea, etc.). Vitamin A 1 occurs free and as esters in fats, in fish livers 
and in blood. It was originally isolated as a viscous yellow oil, but later 
it was obtained as a crystalline solid, m.p. 63-64° (Baxter et al., 1940). 
Vitamin A 1 is estimated by the blue colour reaction it gives with a solution 
of antimony trichloride in chloroform (the Carr-Price reaction; cf. §1); it is 
also estimated by light absorption (vitamin A x has a maximum at 328 m/j). 

Carotenoids are converted into vitamin A 1 in the intestinal mucosa, and 
feeding experiments showed that the potency of a- and y-carotenes is half 
that of /3-carotene. This provitamin nature of /3-carotene led to the sugges- 
tion that vitamin A t is half the molecule of /3-carotene. 

On catalytic hydrogenation, vitamin A x is converted into perhydro- 
vitamin A t , C 20 H 40 O; thus vitamin A t contains five double bonds. Since 
vitamin A x forms an ester with ^-nitrobenzoic acid (this ester is not crystal- 
lisable), it follows that vitamin A x contains a hydroxyl group. Thus the 
parent hydrocarbon of vitamin A t is C 20 H4 , and consequently the molecule 
contains one ring. Ozonolysis of vitamin A ± produces one molecule of 
geronic acid (§3) per molecule of vitamin A lt and so there must be one /S- 
ionone nucleus present (Karrer, 1931, 1932). Oxidation of vitamin A x with 
permanganate produces acetic acid; this suggests that there are some 
— C(CH 3 )=?= groups in the chain. All of the foregoing facts are in keeping 
with the suggestion that vitamin A x is half the /3-carotene structure. When 
heated with an ethanolic solution of hydrogen chloride, vitamin A x is con- 
verted into some compound (II) which, on dehydrogenation with selenium 
forms 1 : 6-dimethylnaphthalene, III (Heilbron et al., 1932). Heilbron 
assumed I as the structure of vitamin A lt and explained the course of the 
reaction as follows: 




Se 



HCl-CjH 5 OH 



CH CH 3 

CH=CH-C=CH-CH 2 OH 





CH 3 

CH3T CHs 

OH=CH-C=CHCH 2 OH 

II 



Perhydrovitamin A t has been synthesised from /3-ionone (Karrer, 1933), 
and was shown to be identical with the compound obtained by reducing 
vitamin A t ; thus there is evidence to support the structure assigned to 
vitamin A r Final proof of structure must rest with a synthesis of vitamin A t 
itself, and this has now been accomplished by several groups of workers. 



§7] 



CAROTENOIDS 



331 



The following synthesis is that of Isler et al. (1947). This starts with methyl 
vinyl ketone to produce compound IV, one stage of the reactions involving 



Preparation of IV. 

CH 3 



CH 3 



CH^CH-C^O ;;?, N c T^H NHj CH 2 =CH-C-C^CH ^+ 



ONa 



OH 3 CH 3 

CHi=CH-C-C=CH H,S °* > CH 2 OH-CH=C-CsCH 



OH 



C a H B M s Br 



CH 3 

^BrMgOCH 2 CH=C-C=CMgBr 
IV 



Preparation of V. 




<pH 3 
CH=CH-O0 



hydrolysis 




+ CHj,C] •C0 2 C 2 H r C ' H ,' ,ON > 

z z *^ » in hquid 

NH, 

CH 3 
.CH=CH-CH-CO-COs|H 

heat with Cu 



powder under 
red. press. 



isomerises 




CH 3 
CH 2 -CH=C-CHO 




CH 3 

■CH=CH-C— ■. 

V 



CH-C0 2 C 2 H 6 



CH 3 - 
!H=CH'CH-CHO 



an allylic rearrangement (cf. §8. VIII). Compound V is prepared from 
/S-ionone by means of the Darzens glycidic ester reaction (see also Vol. I). 
The following chart shows the steps of the synthesis, and it should be noted 
that another allylic rearrangement is involved in one of the later steps. 



332 ORGANIC CHEMISTRY 

Combination of IV and V, etc. 

CH 3 



[CH. IX 




CH 3 



+ BrMeCsOO=( 



■CH 2 -CH=OCHO + BrMgCsC-0=CH-CH 2 OMgBr 



IV 



CH 3 CH 3 

CH 9 -CH=C-CH-C=C-C=CH-CH 2 OH 





OH 




VI 






iH a 


-Pd- 


BaSO a 


CH 3 






CH 3 
1 



/ CH 2 -OH=C- CH- CH=CH-C=CH-CH 2 OH 
OH vil 

l(CH,-CO) a O 

CH 3 CH 3 

/ CH 2 -CH=C- CH-CH=CH- C=CH- GH 2 OCO- CH 3 
OH vm 

\ trace of Ig in benzene solution 



CH 3 

I 3 



?H 3 



,-CHC=CHCH=CH- C=CH -CH 2 0- CO • CH 3 
' I 
OH 



j_H a O 




CH 3 ' CH 3 

H=CH-C=CH-CH=CH-C=CH-CH 2 0-CO-CH 3 



IX 

hydrolysis 




CH ; 



CH 3 



CH=CH-C=CH-CH=CH- C=CH-CH 2 OH 



In the hydrogenation of VI to VII, barium sulphate is used to act as a 
poison to the catalyst to prevent hydrogenation of the double bonds. Partial 
acetylation of VII ((primary alcoholic groups are more readily acetylated than 
secondary) protects the terminal group from an allylic rearrangement in the 
conversion of VIII to IX. 

The crude vitamin A 1 obtained in the above synthesis was purified via 
its ester with anthraquinone-2-carboxylic acid, and was thereby obtained 
in a crystalline form which was shown to be identical with natural vitamin A t . 

Lindlar (1952) has shown that triple bonds may be partially hydrogenated 
in the presence of a Pd — CaC0 3 catalyst that has been partially inactivated 
by treatment with lead acetate; better results are obtained by the addition 
of quinoline. Thus the hydrogenation of VI gives VII in 86 per cent, yield 
when the Lindlar catalyst is used. 



§7] 



CAROTENOIDS 



333 



Another method of synthesising vitamin A x is due to van Dorp et al. (1946) 
who prepared vitamin A x acid (X), which was then reduced by means of 
lithium aluminium hydride to vitamin A t by Tishler (1949) ; /9-ionone and 
methyl y-bromocrotonate are the starting materials. 




CH 3 
CH=CHCO + CH 2 BrCH=CHC0 2 CH 3 



Zn (Reformatsky) 




CH 3 
CH= CH- C • CH 2 CH= CH- C0 2 CH 3 




OH 



CH 3 



(i) (C0 2 H) 2 11-HjO] 
(li) KOH 



CH=CH-C = CH-CH = CH-C0 2 H 



(i) SOCl 2 
(ii) CH 3 Li 




CH 3 CH 3 

,CH=CHC = CHCH = CHCO 



CH 2 Br-CO s C 2 H 5 /Zn 
( Reformatsky) 



CH, 



CH, 




CH=CH-C = CHCH=CHC-CH CO. ) C > H, 



OH 




(i) -H 3 
(ii) KOH 



CH 3 CH 3 

,CH=CHC = CHCH=CHC = CHCOoH 



LiAlH 4 




CH 3 CH 3 

CH=CHC = CHCH=CHC = CHCH 2 OH 



334 



ORGANIC CHEMISTRY 



[CH. IX 



Attenburrow et al. (1952) have also synthesised vitamin A x starting from 
2-methylcyc/ohexanone. 




NaNH 2 
CH S I 3 




CHSCH, 

Na/NH 3 ' 



ft r 



(i) EtMgBr 



(ii) CH a CH 3 

CO-CH=CH-CH=CCH=CH 3 




CH, 



CEU 



= C-C-CH=CHCH = CH-C-CH=CH, 
i - 

OH 

XI 



acid 



(rearr.) 



CH 3 



CH, 



,C = C-C=CH-CH=CH-C=CH'CH 2 OH 



\)H 



XII 



(i) LiAiH 4 



(il) (CH 3 CO) 2 



CH, 



CH, 



V' CH = CH-C=CHCH = CHC = CHCH 2 OCOCH 3 

Ca h xnl 



pMeC 6 H 4 S0 3 H 
(-H 2 0) ' 




CH, 



CH, 



CH=CHC = CHCH=CH-C = 



CH-CH 2 OH 



Acid causes rearrangement of XI to XII in which all multiple bonds are 
in complete conjugation, and the reduction of XII to XIII by lithium 
aluminium hydride is possible because of the presence of the propargylic 
hydroxyl grouping (§3). 

Synthetic vitamin A x is now a commercial product. 

Two biologically active geometrical isomers of Vitamin A x (all-trans) have 
also been isolated: neovitamin a from rat liver (Robeson et al., 1947) and neo- 
vitamin b from the eye (Oroshnik et al., 1956). Vitamin A t is the most active 
form in curing " vitamin A " deficiency. 




CH 2 OH 




vitamin A x 



CH 2 OH 



neovitamin a 




CftjOH 



neovitamin t> 



§8] 



CAROTENOIBS 



335 



Vitamin A a . A second vitamin A, vitamin A a , has been isolated from 
natural sources, and has been synthesised by Jones et al. {1951, 1952); it is 
dehydrovitamin A x . 



CH, 



CH 3 




CH=CH-C=CH- CH=CH- C=CH-CH 2 OH 



vitamin Ag 



Jones et al. (1955) have also introduced a method for converting vitamin A x 
into vitamin A 2 . Vitamin Aj may be oxidised to vitamin A x aldehyde (retin- 
enej) by means of manganese dioxide in acetone solution (Morton et al., 1948), 
and then treated as follows: 



/ [CH = CH-CMe = CH] 2 -CHO 
retinenej 



,[CH = CH-CMe= CH] 2 -CHO 



.N- phenyl - 

morpholine 

(-HBr) 



, [CH = CH- CMe = CHja-CHO 
retinene 2 



, [CH = CH' CMe = CH] 2 - CH 2 0H 
vitamin A 9 



§8. Xanthophylls. The xanthophylls occur naturally, and all have the same 
carbon skeletons as the carotenes or lycopene (except flavoxanthin). 

Cryptoxantbin, C^I^O, m.p. 169°, is monohydroxy-/S-carotene; it has 
provitamin-A activity. 



£r 




Rubixanthin, C^H^O, m.p. 160°, is monohydroxy-y-carotene, and lyco- 
xanthin, C 40 H 5 jO, m.p. 168°, appears to be monohydroxylycopene. 




CH; 

rubixanthin 



(CH„) 2 C. 
— CH 
II 
P 



HO 



fXPBtk (CH S ) 2 C 
CH CH 

CH 3 CH; 
lycoxanthin 




Rhodoxanthin, C M H 52 2 , m.p. 219°, is believed to be the following diketone. 



o^\«A y\A> 



336 

Lutein, C 40 H 56 O 2 , 
hydroxy-a-carotene. 



ORGANIC CHEMISTRY 



m.p. 



[CH. IX 
193°, was formerly known as xanthophyll; it is di- 




Zeaxanthin, m.p. 205°, and lycophyll, m.p. 179°, are the corresponding di- 
hydroxy derivatives of )3-carotene and lycopene, respectively. 




,C(CH S ) 2 
CH— 



OH 



HO 




zeaxanthin 



CH 3 CH, 
lycophyll 



(CHa^C. 




■OH 



These are compounds which do not contain 



§9. Carotenoid acids. 

40 carbon atoms. 

Blxin, C 25 H 30 O 4 . Natural bixin is a brown solid, m.p. 198°, and is the 
cw-form; it is readily converted into the more stable trans-iorm, m.p. 216- 
217°. 

When boiled with potassium hydroxide solution, bixin produces one mole- 
cule of methanol and a dipotassium salt which, on acidification, gives the 
dibasic acid norbixin, C 24 H 28 4 . Thus bixin is a monomethyl ester, and 
can be esterified to give methylbixin. 

On catalytic hydrogenation, bixin is converted into perhydrobixin, 
C 25 H 48 4 ; thus there are 9 double bonds present in the molecule (Lieber- 
mann el al., 1915). Perhydrobixin, on hydrolysis, forms perhydronorbixin. 
Oxidation of bixin with permanganate produces four molecules of acetic 
acid (Kuhn et al., 1929) ; thus there are four — C(CH 3 )— groups in the chain. 
Furthermore, since the parent hydrocarbon of perhydronorbixin, C 24 H 46 4 , 
is C 22 H 46 (the two carboxyl groups are regarded as substituents), the mole- 
cule is acyclic. 

The thermal decomposition of bixin produces toluene, w-xylene, w-toluic 
acid and the methyl ester of this acid (Kuhn et al., 1932). Hence the follow- 
ing assumptions may be made regarding the nature of the chain (cf. j3- 
carotene, §3). 

JCH 3 

CH 3 
=CH-CH=CH-C=CH-CH= 



^H 3 CH 3 

=CH-C=CH-CH=CH-C= 



CH 3 
H0 2 C-CH=CH-C=CH-CH=CH- 



CH, 



CH 



,O 2 C-CH=CH-C=0H-CH=CH- 




C0 2 H 



C0 2 CH 3 



§9] CAROTENOIDS 337 

The foregoing facts may be explained by assuming the following structure 
for bixin (Kuhn et al., 1932): 

CSHs CH 3 <j)Hj <pH 3 

H0 2 C-CH=CHG=CH-CH=CH-C=CH-CH=CH-CH=CCH=CH-CH=C-C!H=CH-C0 2 CH, 

This structure is supported by the fact that perhydronorbixin has been 
synthesised, and shown to be identical with the compound obtained from 
the reduction of bixin (Karrer et al., 1933). Further proof is the synthesis 
of norbixin (Isler et al., 1957). 

Jackman et al. (1960) have shown, from an examination of the NMR 
spectra (§19a. I) of many carotenoids, that the positions of the absorption 
bands resulting from the methyl groups give some indication of the molecular 
environment of these groups. " Natural " methylbixin is the cw-isomer of 
the following trans-isomer: 



Me0 2 C 




C0 2 Me 



The methyl ester of crocetin (see below) also probably has the a's-configura- 
tion at the corresponding 2,3-position. 

Crocetin, C 20 H 24 O 4 . Crocetin occurs in saffron as the digentiobioside, 
crocin. The structure of crocetin was elucidated by Karrer et al. (1928) and 
Kuhn et al. (1931). Crocetin behaves as a dicarboxylic acid and has seven 
double bonds (as shown by catalytic hydrogenation to perhydrocrocetin, 
C 20 H 38 O 4 ). On oxidation with chromic acid, crocetin gives 3-4 molecules 
of acetic acid per molecule of crocetin; thus there are 3-4 methyl side- 
chains. The structure of crocetin was finally shown by the degradation of 
perhydronorbixin, C 24 H 46 4 , by means of the following method: 

R-CIVC0 2 H ^U-R-CHBrC0 2 H hytlrolysis > RCHOHCOjjH 

CHaNa > RCHOH-CO 2 0H 3 CHaMgI > R-CHOH-C(OH)(CH 3 ) 2 

(CH 3 -co, )4 Pb > ;R . CHO _m_^ R . C02H 

This set of reactions was performed twice on perhydronorbixin, thereby 
resulting in the loss of four carbon atoms (two from each end) ; the product 
so obtained was perhydrocrocetin, C 20 H 3g O 4 . On these results, crocetin is 
therefore : 

CH 3 CH 3 CH 3 CH 3 

H0 2 CC=CH-CH=CH-C=CHCH=CH-CH=C-CH=CHCH=C-C0 2 H 

This structure is supported by the fact that the removal of two carbon atoms 
from perhydrocrocetin by the above technique (one carbon atom is lost 
from each end) resulted in the formation of a diketone. The formation of 
this compound shows the presence of an oc-methyl group at each end of the 
molecule. The structure of crocetin is further supported by the synthesis 
of perhydrocrocetin, and by the synthesis of crocetin diesters by Isler et al. 
(1957). These diesters probably have the c*s-configuration at the 2,3- 
position (see bixin, above). The tfraws-crocetin dimethyl ester has been 
synthesised by the Wittig reaction (a carbonyl group is exchanged for a 
methylene group; Vol. I) between the dialdehyde and two molecules of the 
phosphorane (Buchta et al, 1959, 1960). 



338 



ORGANIC CHEMISTRY 



[CH. IX 



Me0 2 C 



PPh 3 OHC 




CHO Ph 3 P< v ^X/G0 2 Me 



MeO,C 




CO, Me 



READING REFERENCES 

Karrer and Jucker, Carotenoids, Elsevier (translated and revised by Bfaude, 1950). 
Rodd (Ed), Chemistry of the Carbon Compounds, Elsevier. Vol. 11A (1953). Ch. 10. 

The Carotenoid Group. 
Gilman (Ed.), Advanced Organic Chemistry, Wiley. Vol. IV (1953). Ch. 7. The 

Terpenes (see the section on Tetraterpenes) . 
Bentley, The Natural Pigments, Interscience (I960). 



CHAPTER X 

POLYCYCLIC AROMATIC HYDROCARBONS 

§1. Introduction. Naphthalene, anthracene, phenanthrene, fluorene, 
etc., have been described in Volume I. All these compounds occur in coal- 
tar, but also present are many polycyclic hydrocarbons containing four or 
more rings, and others of this type have been synthesised. 

§2. General methods of preparation of polycyclic hydrocarbons. 

Before dealing with a number of individual hydrocarbons, it is instructive 
to review some of the general methods whereby these polycyclic hydro- 
carbons may be prepared (see also Vol. I). 

(i) Fittig reaction, e.g., anthracene and phenanthrene may be prepared 
by the action of sodium on o-bromobenzyl bromide. 




CH 2 Br Br 

+ 4Na + 
Br BrCH 2 / 




-fY H " 




CO] 




anthracene 




sifr BrUH 2 

!r+ 4Na + Br<^ ^> 



H,c— c; 







[o] 




phenanthrene 

(ii) Ullmann diaryl synthesis. This method results in the formation 
of isolated polynuclear compounds, e.g., heating iodobenzene with copper 
powder in a sealed tube produces diphenyl. 



2C 6 II 5 I + 2Cu 



+ 2CuI 



Compounds of the isolated system type can, under suitable conditions, be 
converted into condensed polycyclic compounds (see method iii). In certain 
cases, the Ullmann synthesis leads to condensed systems (see §4c). 

(iii) Many compounds of the isolated system type can be converted into 
condensed systems by strong heating, e.g., o-methyldiphenyl forms fluorene. 
2 : 2'-Dimethyldiphenyl forms phenanthrene when passed through a red-hot 

339 



340 



ORGANIC CHEMISTRY 



[CH. X 



CH, 









+ H 2 



tube, but a much better yield is obtained when the dimethyldiphenyl is 
heated with sulphur. The latter is an example of cyclodehydrogenation 
(see also method vii). 



CH 3 CH 3 

oo 




+ 21L 



CH 3 CH 3 




+ 2H 2 S 



(iv) Friedel-Crafts reaction. Condensed polycyclic compounds may 
be prepared via an external or an internal Friedel-Crafts reaction. An 
example of the former is the preparation of anthracene from benzyl chloride; 
an example of the latter is the preparation of phenanthraquinone from benzil. 



/y CH2C1 



C1CHJ 




MCI. 






co-co, 



o o 



^^_^^y_^>^ 



A very important case of the internal Friedel-Crafts reaction is that in which 
ring closure is effected on acid chlorides, e.g., the conversion of y-phenyl- 
butyryl chloride to a-tetralone. 




Aicu 



O 

This type of ring closure may be effected by the action of concentrated 
sulphuric acid on the carboxylic acid itself, e.g., 



H a SQ 4 





§2] POLYCYCLIC AROMATIC HYDROCARBONS 341 

(v) Elbs reaction. In this method, polynuclear hydrocarbons are pro- 
duced from a diaryl ketone containing a methyl group in the o-position to 
the keto group. The reaction is usually carried out by heating the ketone 
under reflux or at 400-450° until water is no longer evolved, e.g., o-methyl- 
benzophenone forms anthracene. 



-H a O 





(vi) Phenanthrene syntheses. The phenanthrene nucleus is parti- 
cularly important in steroid chemistry, and so a number of methods for 
synthesising phenanthrene are dealt with in some detail. 

(a) Pschorr synthesis (1896). This method offers a means of preparing 
phenanthrene and substituted phenanthrenes with the substituents in known 
positions. Phenanthrene may be prepared as follows, starting with o-nitro- 
benzaldehyde and sodium /?-phenylacetate. 




CHO 

N0 2 + 




(CJVCOJjO . 




CFt=C^CQ 2 H 
■N0 2 <Q» 



(i) M 
(ii)NaNO,/H,S0 4 






heat 



-CO* 



* A"^>A 






(b) Haworth synthesis (1932). Naphthalene is condensed with succinic 
anhydride in the presence of aluminium chloride in nitrobenzene solution. 
Two naphthoylpropionic acids are obtained, and these may be separated 
(see next page). 



342 



ORGANIC CHEMISTRY 



[CH. X 





CO CH 2 



CO,H 



+ I >0 

CH 2 CO 



A1CI, 



H0 2 C CH, 




Zn-Hg: 
HCI 



Zn-Hg; 
1 HCI 




H,SO t 





H 2 SO» 




(i) Zn-Hg/HCI 
f(«) Se' 
3 




The Haworth synthesis is very useful for preparing alkylphenanthrenes with 
the alkyl group in position 1 (from I) or position 4 (from II) ; e.g., 




OH 
CH. 



3 Pd-C 




§2] 



POLYCYCLIC AROMATIC HYDROCARBONS 



343 



By using methylsuccinic anhydride instead of succinic anhydride, a methyl 
group can be introduced into the 2- or 3-position ; in this case the condensa- 
tion occurs at the less hindered keto group, i.e., at the one which is farther 
removed from the methyl substituent. 

CH^CH 
H0 2 C N CH 2 




CH 3 -CH-C(X 
+ I >0 

CHjj-CO 



Aids 




CO 



a-Bromoketone derivatives of naphthalene may be used in the malonic 
ester synthesis to prepare alkylphenanthrenes, e.g., 




A1C1. 



■OH 3 -CH 2 -COCl inC6H ; NO > 




CO-CH 2 -CH 3 



Br 8 



main product 




'CHBr CHNa(COjCjH 6 )a 




CH-CH 3 

I 

CH(COAH 6 ) 2 



(i) KOH 



(ii) HC1 
(iii)heat 




CH 2 
CO 



y \ 2 

H0 2 C CH-CH 3 




(c) Stobbe condensation (1893). This method has been improved by 
Johnson (1944), and has been used to prepare phenanthrene derivatives (see 
Vol. I); e.g., 



CO-CH 3 CHjj-COaCuHs (ch,) s cok f)fV-C==C-CH 2 -C0 2 H 




+ I 
CHa-CO, 



° A \XJ 



I 
CH 3 C0 2 C2H 6 



HBr-CH,-C0 2 H 
reflux 




C-CHa-CI^C O ( i)NaOH 
CH, M H »* 




CH 3 
CH-CHa-CHa-OQiH 



344 



ORGANIC CHEMISTRY 



[CH. X 




(d) Bardhan-Sengupta synthesis (1932). In this synthesis the start- 
ing materials are 2-phenylethyl bromide and ethyl cyc/ohexane-2-carboxyl- 
ate; these may be prepared as follows: 



/K 



(i) C 6 H 6 Br-^C 6 H 6 MgBr 



HBr 



"*^/i „„_„_ ^i^Vc 6 H 5 -CH 2 -CH 2 OH^^C 6 H 5 -CH 2 -CH 2 Br 







(ii) I | + (OOAH& C ' H ' ONa > 



o 



o 




,COC0 2 C 2 H 5 



iCOAHs 



These two compounds are then treated as shown: 
/)H 2 Br 



CH2 — CH.2 




moist 
ether 



(e) Bogert-Cook synthesis (1933). The following chart shows the pre- 
paration of phenanthrene. 

^CHjCHjMgBr *f 2 HO I I 

+ 



H;,S04 




It might be noted here that the Bardhan-Sengupta and Bogert-Cook methods 



§2] POLYCYCLIC AROMATIC HYDROCARBONS 345 

both proceed via the formation of olefin III, which then gives a mixture of 
octahydrophenanthrene IV and the spiran V. 




OH 



, HO 





III 





(vii) Dehydrogenation of hydroaromatic compounds with sulphur, 
selenium or palladised charcoal. This method is mainly confined to 
the dehydrogenation of six-membered rings, but five-membered rings may 
sometimes be dehydrogenated when they are fused to a six-membered ring. 
The general methods are as follows: 

(a) Heating the compound with the calculated amount of sulphur at 200- 
220°; hydrogen is eliminated as hydrogen sulphide (Vesterberg, 1903). 

(6) Heating the compound with the calculated amount of selenium at 
250-280°; hydrogen is eliminated as hydrogen selenide (Diels, 1927). 

(c) Heating the compound with palladium-charcoal up to about 300°, or 
passing the vapour of the compound over the catalyst heated at 180- 
350°; hydrogen is eliminated catalytically. Simple examples of catalytic 
dehydrogenation are: 



Pd-C 



+ 3H, 



cyc/ohexane 




H 

hydrindane 



+ 5H, 



+ 4H 2 



indene 



Perhydro-compounds, i.e., fully hydrogenated compounds, are readily de- 
hydrogenated catalytically, but are very little affected, if at all, by the 
chemical reagents sulphur and selenium. Partially unsaturated compounds, 
however, are readily dehydrogenated by sulphur and selenium. 



346 ORGANIC CHEMISTRY [CH. X 

The method of dehydrogenation has been very useful in the elucidation of 
structure in terpene and steroid chemistry; specific examples are described 
in these two chapters. The following is an account of some of the general 
problems involved in dehydrogenation. 

Originally, dehydrogenation was applied almost entirely to hydrocarbons, 
but subsequently it was found that many compounds containing certain 
functional groups could also be dehydrogenated, the nature of the products 
depending on the nature of the functional group. 

(i) Alcoholic groups may be eliminated with the formation of unsaturated 
hydrocarbons, e.g., eudesmol gives eudalene (§28b. VIII) ; cholesterol gives 
Diels' hydrocarbon (§1. XI). 

(ii) Phenolic hydroxyl groups and methylated phenolic groups are usually 
unaffected by dehydrogenation with sulphur. With selenium, these groups 
may or may not be eliminated, but the higher the temperature at which the 
dehydrogenation is carried out (particularly above 300°), the greater the 
likelihood of these groups being eliminated. 

(iii) The products obtained from ketones depend on whether the keto 
group is in a ring or in an open chain. Thus cyclic ketones are dehydro- 
genated to phenols, e.g., 

OH 

S or Se 



When the keto group is in a side-chain, then it is often unaffected. 

(iv) Carboxyl (or carboalkoxyl) groups are eliminated when attached to 
a tertiary carbon atom, e.g. , abietic acid gives retene (§31 . VIII) . If, however, 
the carboxyl group is attached to a primary or secondary carbon atom, it 
is usually unaffected when the dehydrogenation is carried out with sulphur 
or palladium-charcoal. On the other hand, the carboxyl group is usually 
eliminated (decarboxylation) when selenium is used, but in some cases it is 
converted into a methyl group (see, e.g., vitamin D, §6. XI). 

(v) In a number of cases, dehydrogenation is accompanied by a rearrange- 
ment of the carbon skeleton, this tending to occur at higher temperatures 
and when the heating is prolonged. 

(a) Ring contraction may occur, e.g., 

CH, 




Se 



eyc/oheptane 

(b) Ring expansion may occur, e.g., cholesterol gives chrysene (see §1. XI). 

(c) Compounds containing an angular methyl group tend to eliminate this 
methyl group as CH 3 SH or CH 3 SeH, e.g., eudesmol gives eudalene (§28b. 
VIII), cholesterol gives Diels' hydrocarbon (§1. XI). In some cases, the 
angular methyl group enters a ring, 

CH 3 . 





CH, 



§3] 



POLYCYCLIC AROMATIC HYDROCARBONS 



347 



thereby bringing about ring expansion [c/. (6) above]. On the other hand, 
a normal substituent methyl group may migrate to another position, e.g., 
5:6:7: 8-tetrahydro-l : 5-dimethylphenanthrene gives 1 : 8-dimethylphen- 
anthrene on dehydrogenation with selenium. 

(d) Side-chains larger than methyl may remain intact, or be eliminated 
or be degraded, e.g., 

s r V ^]CH 2 -CH 2 -G g H 5 



CH 2 -CH 2 CH 2 -C0 2 H 




OGEL 



Se 



Se 




HO 

cholesterol Diels' hydrocarbon 

(e) Dehydrogenation may produce new rings (c/. method iii); e.g., 






Pd-C 




cm ch. 




BENZANTHRACENES 
§3. Naphthacene (2 : 3-Benzanthracene), C 18 H 12 , is an orange solid, 
m.p. 357°. It occurs in coal-tar, and has been synthesised as follows (Fieser. 
1931). 




H 2 S0 4 



348 ORGANIC CHEMISTRY [CH. X 

When oxidised with fuming nitric acid, naphthacene forms naphthacene- 
quinone. 

O 




§3a. Rubrene (5:6:11: 12-tetraphenylnaphthacene) may be prepared 
by heating 3-chloro-l : 3 : 3-triphenylprop-l-yne alone, or better, with 
quinoline at 120° in vacuo (Dufraisse et al., 1926). 




CsHs C 6 H 5 



CeH 5 CeHj 





It is interesting to note that Dufraisse originally gave rubrene structure II, 
but changed it to I in 1935. The mechanism of the reaction is uncertain. 
Rubrene is an orange-red solid, m.p. 334°. Its solution in benzene has a 
yellow fluorescence, but when this solution is shaken with air in sunlight, 
the fluorescence slowly disappears, and a white solid can now be isolated. 
This is rubrene peroxide, and when heated to 100-140° in a high vacuum, it 
emits yellow-green light and evolves oxygen, reforming rubrene. 




CeHij C 8 H 5 



air— sunlight 



heat in a vacuum 




Rubrene peroxide is actually a derivative of 5 : 12-dihydronaphthacene, and 
so the molecule is not flat but folded about the O-O axis (the carbon atoms 
at 5 and 12 are tetrahedrally hybridised). 

§3b. Two linear benzene derivatives of naphthacene have been prepared, 
viz., pentacene (a deep violet-blue solid) and hexacene (a deep-green solid) 
[Clar, 1930, 1939]. 



§3d] POLYCYCLIC AROMATIC HYDROCARBONS 349 

IS 14 1 12 13 14 15 

2 UC 

3 10$ 
7 6 5 4 

pentacene 

Clar (1942) thought he had prepared heptacene, but in 1950 he showed that 
the compound he had isolated was 1 : 2-benzohexacene. Bailey et al. (1955) 
have synthesised heptacene. 






heptacene 

§3c. 1 : 2-Benzanthracene, m.p. 160°, occurs in coal-tar, and has been 
synthesised as follows (Bachmann, 1937). 



iMgBr 







xxco 



1-naphthalene- 
magnesium 
bromide 



§3d. 1:2:5: 6-Dibenzanthracene, m.p. 266°, has been synthesised by 
Cook et al. (1931), who showed that it had strong carcinogenic activity. 




COOl 



2-naphthoic 
acid 




2-methyl- 
naphthalene 



350 



ORGANIC CHEMISTRY 



[CH. X 



Buu-Hoi et al. (1960) have shown that picene (§4a) is converted into 
1:2:5: 6-dibenzanthracene by aluminium chloride in benzene. 

§3e. 3 : 4-Benzpyrene is a pale yellow solid, m.p. 179°, which is very 
strongly carcinogenic. It occurs in coal-tar, and has been synthesised as 
follows from pyrene (see §4b). 



pyrene 





\\i ch 2 -cq 
+ 1 >o 

h CH 2 -CO 


MCI3 ( 




] Zn-10%NaOH 




C 6 HjNOj 1 






j 200° 


J3 




XX) 












CH» 



H0 2 C 



M 



'Ho 




Zrt dust 
distil 




HO 2 0. CR. 
XIH, 

§3f. 20-Methylcholanthrene is a pale yellow solid, m.p. 180°. It is a 
steroid derivative, and has been prepared by the degradation of, e.g., chol- 
esterol (see §3 iii. XI). Cook (1934) showed that methylcholanthrene has 
powerful carcinogenic properties, and Fieser et al. (1935) synthesised it in 
the following way: 



§4] 



POLYCYCLIC AROMATIC HYDROCARBONS 



351 



CH 




CI AIC1, 

+ COCl-CH 2 -CH 2 Cl -^ J - 




COCH 2 -CH 2 Cl CH 3 ' 




CO-CHaCI^Cl 




CH 3 



The alternative way of writing the formula shows more clearly the relation- 
ship of methylcholanthrene to the steroids (see §3. XI for the method of 
numbering in cholesterol). The steroids are phenanthrene derivatives, and 
so methylcholanthrene may also be regarded as a phenanthrene derivative 
(instead of an anthracene derivative). 



PHENANTHRENE DERIVATIVES 



§4. Chrysene (1 : 2-benzphenanthrene) is a colourless solid, m.p. 251°. 
It occurs in coal-tar, and has been synthesised in several ways: 
(i) By strongly heating 2-[l-naphthyl]-l-phenylethane. 




352 ORGANIC CHEMISTRY 

(ii) By a Bogert-Cook synthesis (cf. §2. (vi) e). 




/CHjjMgBr 
CH, 




[CH. X 




HjS0 4 





(iii) By a Pschorr synthesis [cf. §2 (vi) a]. 




(H) NaN0 2 -HCl 
(iii) Cu powder 



(iv) Phillips (1956) has prepared chrysene from naphthalene and the 
lactone of trans 2-hydroxycycMiexaneacetic acid: 




(i) pci 6 



(II) A1C1 3 




Chrysene is produced by the pyrolysis of indene, and also by the dehydro- 
genation of steroids with selenium. 

§4a. Picene (1:2:7: 8-dibenzphenanthrene), m.p. 365°, is obtained when 
cholesterol or cholic acid is dehydrogenated with selenium. It has been 



§4c] 



POLYCYCLIC AROMATIC HYDROCARBONS 



353 



synthesised by heating 1-methylnaphthalene with sulphur at 300° (see also 
§3d). 



IT i 






2 f 




T l 13 




CH 3 CH 3 U 


\ 1 s 




3 N 


4 


1 J 12 


J. 






1 l 11 




1 l) 








5^v 






L II 








6 T 




^/ 










7k 



§4b. Pyrene is a colourless solid, m.p. 150°. It occurs in coal-tar, and 
has been synthesised from diphenyl-2 : 2'-diacetyl chloride as follows : 




CH 2 
COC1 1 I Alcia x 

„ n x^ C0CI c 6 h b no 2 




Buchta et al. (1958) have synthesised pyrene using an internal Stobbe 
reaction [§2 (vi) c]: 



C0 2 Et ^2 




C0 2 Et 



CH 

+ J30 _MfONa^ 

QH 2 




Zn 



heaT 



C0 2 Et 




OH 



§4c. Perylene is a very pale yellow solid, m.p. 273°. It occurs in coal- 
tar, and has been synthesised in several ways. 

(i) 2-NaphthoI, on treatment with ferric chloride solution, forms I : I'-di- 
naphthol, and this, on heating with a mixture of phosphorus pentachloride 
and phosphorous acid, gives perylene. 



354 



ORGANIC CHEMISTRY 



[CH. X 




9 10 



(ii) Perylene may also be prepared by heating 1 : 8-di-iodonaphthalene 
with copper powder (i.e., by an Ullmann synthesis; cf. §2. ii). 




I I 
I I 



120-260° 





(iii) Perylene is formed when 1 : l'-dinaphthyl is heated with hydrogen 
fluoride under pressure. 




HF 




Robertson et al. (1953), by X-ray analysis of perylene, have shown that the 
two bonds connecting the two naphthalene units are longer (1-50 A) than the 
usual aromatic C — C bond (1-38-1-44 A). The existence of these long bonds is 
supported by some magnetic susceptibility measurements (Hazato, 1949). 

§4d. Coronene, m.p. 430°, is a yellow solid with a blue fluorescence in 
benzene solution; it has been found in coal-gas (Lindsay et al., 1956). It 
was synthesised by Scholl et al. (1932), starting from w-xylene and anthra- 
quinone-1 : 5-dicarbonyl chloride, the latter behaving in the tautomeric 
form shown in the following chart. 



§4d] 



POLYCYCLIC AROMATIC HYDROCARBONS 

CH 3 



355 



CI p-co 




CH 3 



+ 2 



1GR c « H » NO » 



CO-O CI 




alkaline 
KMn0 4 



C0 2 H 



C0 2 H 



C0 2 H 



COoH 




C0 2 H 



C0 2 H 



356 



ORGANIC CHEMISTRY 
C0 2 H 



|CH. X 




C0 2 H 



C0 2 H C0 2 H 




Newman (1940) has also synthesised coronene, starting from 7-methyl- 
tetralone, and proceeding as follows: 





OH heat 



OH (-2HaO) 




§4d] 



POLYCYCLIC AROMATIC HYDROCARBONS 



357 





The simplest and most efficient synthesis of coronene appears to be that 
of Clar et al. (1957). The starting material is perylene (§4c), and this is 
treated with (i) maleic anhydride and chloranil, and followed by (ii) heating 
with soda-lime; these processes are then repeated: 




(i) 



(ii) 




(i) 



(ii) 




READING REFERENCES 

Newer Methods of Preparative Organic Chemistry, Interscience Publishers (1948). De- 
hydrogenation with Sulphur, Selenium and Platinum Metals (pp. 21-59). 

Gilman (Ed.), Advanced Organic Chemistry, Wiley. Vol. IV (1953), pp. 1232- . 
Dehydrogenating Agents. 

Genie, La Cyclodeshydrogenation Aromatique, Ind. chim. belg., 1953, 18, 670. 

Cook, Polycyclic Aromatic Hydrocarbons, J.C.S., 1950, 1210. 

Traiti de Chimie Organique, Masson et Cie., Vol. XVII. Part II (1949). 

Encyclopaedia of Organic Chemistry, Elsevier. Vol. 14 (1940). Tetracyclic and Higher- 
Cyclic Compounds. See also Vol. 14 Supplement (1951). 

Cocker, Cross et al., The Elimination of Non-angular Alkyl Groups in Aromatisation 
Reactions. Part II. J.C.S., 1953, 2355. 

Cook (Ed.), Progress in Organic Chemistry, Butterworth. Vol. 2 (1953). Ch. 5. The 
Relationship of Natural Steroids to Carcinogenic Aromatic Compounds. 

Badger, The Structures and Reactions of Aromatic Compounds, Cambridge Press (1954). 



CHAPTER XI 

STEROIDS 

§1. Introduction. The steroids form a group of structurally related 
compounds which are widely distributed in animals and plants. Included 
in the steroids are the sterols (from which the name steroid is derived), vita- 
min D, the bile acids, a number of sex hormones, the adrenal cortex hormones, 
some carcinogenic hydrocarbons, certain sapogenins, etc. The structures 
of the steroids are based on the 1 : 2-cjyc/opentenophenanthrene skeleton 
(Rosenheim and King, 1932; Wieland and Dane, 1932). All the steroids 




1: 2-cyc/opentenophenanthrene 

give, among other products, Diels' hydrocarbon on dehydrogenation with 
selenium at 360° (Diels, 1927). In fact, a steroid could be defined as any 
compound which gives Diels' hydrocarbon when distilled with selenium. 
When the distillation with selenium is carried out at 420°, the steroids give 
mainly chrysene (§4. X) and a small amount of picene (§4a. X). 

Diels' hydrocarbon is a solid, m.p. 126-127°. Its molecular formula 
is C lg H 16 , and the results of oxidation experiments, X-ray crystal analysis 
and absorption spectrum measurements showed that the hydrocarbon is 
probably 3'-methyl-l : 2-cyc/opentenophenanthrene. This structure for the 
compound was definitely established by synthesis, e.g., that of Harper, Kon 
and Ruzicka (1934) who used the Bogert-Cook method [§2 (vi) e. X], starting 
from 2-(l-naphthyl)-ethylmagnesium bromide and 2 : 5-dimethylcyctopenta- 
none. 




358 



Diels' hydrocarbon 



§3] STEROIDS 359 

STEROLS 

§2. Sterols occur in animal and plant oils and fats. They are crystalline 
compounds, and contain an alcoholic group; they occur free or as esters of 
the higher fatty acids, and are isolated from the unsaponifiable portion of 
oils and fats. Cholesterol, cholestanol and coprostanol (coprosterol) are the 
animal sterols; ergosterol and stigmasterol are the principal plant sterols. 
The sterols that are obtained from animal sources are often referred to as 
the zoosterols, and those obtained from plant sources as the phytosterols. A 
third group of sterols, which are obtained from yeast and fungi, are referred 
to as the mycosterols. This classification, however, is not rigid, since some 
sterols are obtained from more than one of these groups. 

§3. Cholesterol, C 2 ,H 46 0, m.p. 149°. This is the sterol of the higher 
animals, occurring free or as fatty esters in all animal cells, particularly in 
the brain and spinal cord. Cholesterol was first isolated from human gall- 
stones (these consist almost entirely of cholesterol). The main sources of 
cholesterol are the fish-liver oils, and the brain and spinal cord of cattle. 
Lanoline, the fat from wool, is a mixture of cholesteryl palmitate, stearate 
and oleate. 

Cholesterol is a white crystalline solid which is optically active (larvo- 
rotatory). Cholesterol (and other sterols) gives many colour reactions, e.g., 

(i) The Salkowski reaction (1908). When concentrated sulphuric acid is 
added to a solution of cholesterol in chloroform, a red colour is produced in 
the chloroform layer. 

(ii) The Liebermann-Burchard reaction (1885, 1890). A greenish colour 
is developed when a solution of cholesterol in chloroform is treated with 
concentrated sulphuric acid and acetic anhydride. 

When an ethanolic solution of cholesterol is treated with an ethanolic 
solution of digitonin (a saponin; see §19. iii), a large white precipitate of 
cholesterol digitonide is formed. This is a molecular complex containing 
one molecule of cholesterol and one of digitonin, from which the components 
may be recovered by dissolving the complex in pyridine (which brings about 
complete dissociation) and then adding ether (the cholesterol remains in 
solution and the digitonin is precipitated). Digitonide formation is used for 
the estimation of cholesterol. 

The structure of cholesterol was elucidated only after a tremendous 
amount of work was done, particularly by Wieland, Windaus and their co- 
workers (1903-1932). Only a very bare outline is given here, and in order 
to appreciate the evidence that is going to be described, it is necessary to 



HO 




have the established structure of cholesterol at the beginning of our discus- 
sion. I is the structure of cholesterol, and shows the method of numbering. 
The molecule consists of a side-chain and a nucleus which is composed of 
four rings; these rings are usually designated A, B, C and D or I, II, III and 



360 ORGANIC CHEMISTRY [CH. XI 

IV, beginning from the six-membered ring on the left (see also (iii) below). 
It should be noted that the nucleus contains two angular methyl groups, one 
at C 10 and the other at C 13 . 

(i) Structure of the ring system. Under this heading we shall deal 
with the nature of the ring system present in cholesterol; the problem of 
the angular methyl groups is dealt with later [see (iv)]. 

The usual tests for functional groups showed that cholesterol contains one 
double bond and one hydroxyl group. Now let us consider the following 
set of reactions. 

Cholesterol — — > Cholestanol '-> Cholestanone > Cholestane 

^27"4«*~' ^27^48^' ^-'27"46^-' ^27X143 

I II III IV 

The conversion of cholesterol into cholestanol, II, shows the presence of 
one double bond in I, and the oxidation of II to the ketone cholestanone, III, 
shows that cholesterol is a secondary alcohol. Cholestane, IV, is a saturated 
hydrocarbon, and corresponds to the general formula C„H 2n _ 6 , and con- 
sequently is tetracyclic; thus cholesterol is tetracyclic. 

When cholesterol is distilled with selenium at 360°, Diels' hydrocarbon 
is obtained (see §1). The formation of this compound could be explained 
by assuming that this nucleus is present in cholesterol. The yield of this 
hydrocarbon, however, is always poor, and other products are always formed 
at the same time, particularly chrysene (see §1). Thus, on the basis of this 
dehydrogenation, the presence of the cyc/opentenophenanthrene nucleus 
must be accepted with reserve. Rosenheim, and King (1932) thought that 
chrysene was the normal product of the selenium dehydrogenation, and so 
proposed (on this basis and also on some information obtained from X-ray 
analysis work of Bernal, 1932; see §4a) that the steroids contained the chrys- 
ene skeleton. Within a few months, however, Rosenheim and King (1932) 
modified this suggestion, as did also Wieland and Dane (1932). These two 
groups of workers proposed that the cyc/opentenophenanthrene nucleus is 
the one present in cholesterol (i.e., in steroids in general). This structure 
fits far better all the evidence that has been obtained from a detailed investi- 
gation of the oxidation products of the sterols and bile acids. This structure 
has now been confirmed by the synthesis of cholesterol (see later in this 
section). 

Although an account of the oxidative degradation of the steroids cannot 
be discussed here, the following points in this connection are of some interest. 

(i) The nature of the nucleus in sterols and bile acids was shown to be the 
same, since cholanic acid or a//ocholanic acid is one of the oxidation pro- 
ducts (see §4a for the significance of the prefix alio). 

(ii) The oxidation of the bile acids led to the formation of products in 
which various rings were opened. The examination of these products 
showed that the positions of the hydroxyl groups were limited mainly to 
three positions, and further work showed that the hydroxyl groups behaved 
differently towards a given reagent, e.g., 

(a) The ease of oxidation of hydroxyl groups to keto groups by means of 
chromic acid is C 7 > C 12 > C 3 . More recently, Fonken et al. (1955) have 
shown that tert.-hutyl hypochlorite apparently oxidises the 3-OH group 
selectively to the keto group ; this reaction, however, failed with cholesterol. 
Sneedon et al. (1955) have also shown that the 3-OH group in steroids is 
oxidised by oxygen-platinum, but not those at 6, 7 or 12. 

(6) The three keto groups are not equally readily reduced to a methylene 
group (by the Clemmensen reduction) or to an alcoholic group (by H 2 — 
platinum). The ease of reduction is C 3 > C 7 > C 12 . This is also the order 



§3] STEROIDS 361 

for the ease of hydrolysis or acetylation when these positions are occupied 
by hydroxyl groups (see also testosterone, §13). More recently, it has been 
shown that the modified Wolff-Kishner reduction of Huang-Minion (see 
Vol. I) on steroid ketones reduces keto groups at 3, 7, 12, 17 and 20, but not 
at 11. Another interesting point in this connection is that lithium alu- 
minium hydride, in the presence of aluminium chloride, does not reduce 
unsaturated ketones to alcohols, e.g., cholest-4-en-3-one, under these condi- 
tions, is reduced to cholest-3-ene (Broome et al., 1956). 

Thus a knowledge of (a) and (6) enabled workers to open the molecule at 
different points by oxidation under the appropriate conditions. This led 
to a large variety of degradation products, the examination of which enabled 
the nature of the nucleus to be ascertained. 

(c) Blanc's rule was also used to determine the sizes of the various rings, 
but the failure of the rule in certain cases led to an erroneous formula; e.g., 
ring C was originally believed to be five-membered. Thus Windaus and 
Wieland (1928) proposed the following formula for cholesterol, and the un- 
certain point (at that time) was the nature of the two extra carbon atoms. 
These were assumed to be present as an ethyl group at position 10, but 
Wieland et al. (1930) finally proved that there was no ethyl group at this 



Me 

I 
CH(CH 2 ) 3 CHMe 2 




position. These two " homeless " carbon atoms were not placed until Rosen- 
heim and King first proposed that steroids contained the chrysene nucleus 
and then proposed the cycfopentenophenanthrene nucleus (see above). 
Bernal (1932) also showed, from the X-ray analysis of cholesterol, ergosterol, 
etc., that the molecule was thin, whereas the above structure for the steroid 
nucleus would be rather thick. 

(ii) Positions of the hydroxyl group and double bond. Let us con- 
sider the following reactions: 

Cholestanone > Dicarboxylic acid y Ketone 

C27H46O C 27 H 4g 04 C 2g H 44 

III V VI 

Since the dicarboxylic acid V contains the same number of carbon atoms as 
the ketone (III) from which it is derived, the keto group in III must therefore 
be in a ring. Also, since pyrolysis of the dicarboxylic acid V produces a 
ketone with the loss of one carbon atom, it therefore follows from Blanc's 
rule that V is either a 1 : 6- or 1 : 7-dicarboxylic acid. Now we have seen 
that the nucleus contains three six-membered rings and one five-membered 
ring. Thus the dicarboxylic acid V must be obtained by the opening of 
ring A, B or C, and consequently it follows that the hydroxyl group in 
cholesterol (which was converted into the keto group in cholestanone; see 
(i) above) is in ring A, B or C. 

Actually two isomeric dicarboxylic acids are obtained when cholestanone 
is oxidised. The formation of these two acids indicates that the keto group 



362 



ORGANIC CHEMISTRY 



[CH. XI 



in cholestanone is flanked on either side by a methylene group, i.e., the group- 
ing — CH 2 -COCH 2 — is present in cholestanone. Examination of the refer- 
ence structure I of cholesterol shows that such an arrangement is possible 
only if the hydroxyl group is in ring A. 

Now let us consider the further set of reactions: 



H O CrO 

Cholesterol > Cholestanetriol '-> Hydroxycholestanedione 

C27xi 46 (J * ' C^H^C^ L 27 xi 44 U3 



VII 



VIII 



(i) -H,0 



CrO, 



(ii) Zn— OH.-COjH 



> Cholestanedione > Tetracarboxylic acid 



IX 



*-'27"44^8 



In the conversion of I into VII, the double bond in I is hydroxylated. Since 
only two of the three hydroxyl groups in VII are oxidised to produce VIII, 
these two groups are secondary alcoholic groups (one of these being the 
secondary alcoholic group in cholesterol), and the third, being resistant to 
oxidation, is probably a tertiary alcoholic group. Dehydration of VIII (by 
heating in vacuo) and subsequent reduction of the double bond forms IX, 
and this, on oxidation, gives a tetracarboxylic acid without loss of carbon 
atoms. Thus the two keto groups in IX must be in different rings ; had they 
been in the same ring, then carbon would have been lost and X not obtained. 
It therefore follows that the hydroxyl group and double bond in cholesterol 
must be in different rings. Furthermore, since IX forms a pyridazine 
derivative with hydrazine, IX is a y-diketone. Since we have already 
tentatively placed the hydroxyl group in ring A, the above reactions can 
be readily explained if we place the hydroxyl group at position 3, and the 
double bond between 5 and 6. In the following equations only rings A and 
B are drawn; this is an accepted convention of focusing attention on any 
part of the steroid molecule that is under consideration (also note that full 
lines represent groups lying above the plane, and broken lines groups lying 
below the plane; see also §§4, 4a, 4b). Noller (1939) has shown that the 
pyridazine derivative is a polymer, and so the interpretation that IX is a 
y-diketone is rendered uncertain. Supporting evidence, however, for the 
above interpretation is afforded by the fact that when cholesterol is heated 
with copper oxide at 290°, cholestenone, XI, is produced, and this on oxida- 
tion with permanganate forms a keto-acid, XII, with the loss of one carbon 
atom. The formation of XII indicates that the keto group and the double 
bond in cholestenone are in the same ring. The ultraviolet absorption 
spectrum of cholestenone shows that the keto group and the double bond 
are conjugated (Menschick et al., 1932). These results can be explained if 
we assume that the double bond in cholesterol migrates in the formation 
of cholestenone, the simplest explanation being that the hydroxyl group 





VIII 



§3] 



STEROIDS 



363 




HOjC 
HQjC, 




X 



J 4T 
pyridazine 
derivative 

is in position 3 and the double bond between 5 and 6, position 5 being common 
to both rings A and B. Thus: 



+ CO, 




I 



XI 



XII 



The position of the hydroxyl group at position 3 is definitely proved by 
the experiments of Kon et al. (1937, 1939). These authors reduced chol- 
esterol, I, to cholestanol, II, oxidised this to cholestanone, III, treated this 
with methylmagnesium iodide and dehydrogenated the product, a tertiary 
alcohol, XIII, to 3' : 7-dimethylcyc/opentenophenanthrene, XIV, by means 
of selenium. The structure of XIV was proved by synthesis, and so the 
reactions may be formulated as follows, with the hydroxyl at position 3. 




It might be noted here that the orientation of the two hydroxyl groups 
(introduced across the double bond in cholesterol) depends on the nature 
of the reagent used. With hydrogen peroxide, or via the oxide, the choles- 
tanetriol is trans-5 : 6 (VII) ; with potassium permanganate or osmium 



364 ORGANIC CHEMISTRY [CH. XI 

tetroxide, the product is cis-5 : 6 (Vila; cf. §5a. IV). These orientations 
may be explained as follows. When the addition of the two hydroxyl groups 
occurs via the oxide (the 5 : 6-oxide), the oxide ring will be formed behind 
the plane of the molecule due to the steric effect of the methyl group. Since 
opening of the epoxide ring occurs by attack on the conjugate acid (§5a. IV), 
the water molecule will attack from the back of the ring {i.e., from the front 
of the molecule), and also preferably at position 6 due to the steric effect 
of the methyl group. Thus the orientation of the two hydroxyl groups 
(trans) will be as shown in VII. With permanganate (and osmium tetroxide), 





HO-^/?\/ HO 



Vila VII A 

the plane of the cyclic compound will lie at the back of the molecule, again 
due to the steric effect of the methyl group. Moreover, since in the forma- 
tion of the dihydroxy compound, both glycol oxygen atoms come from the 
permanganate ion (§5a. IV), it follows that both hydroxyl groups will be at 
the back of the molecule (Vila). 

The addition of bromine, occurring via a brominium ion (§5a. IV), will 
produce the dibromide Vllb, the reasons for the orientation being the same 
as those for the formation of VII (via the epoxide). 

Since secondary alcoholic groups in steroids are readily oxidised to keto 
groups, and the latter may be located by mass spectra measurements (see 
§4b), this offers a very good way of locating secondary hydroxyl groups in 
the steroid molecule. 

(iii) Nature and position of the side-chain. Acetylation of cholesterol 
produces cholesteryl acetate and this, on oxidation with chromium trioxide, 
forms a steam-volatile ketone and the acetate of a hydroxyketone (which is 
not steam volatile). The ketone was shown to be wohexyl methyl ketone, 
CH 3 'CO(CH 2 )3-CH(CH 3 ) 2 . Thus this ketone is the side-chain of cholesterol, 
the point of attachment of the side-chain being at the carbon of the keto 
group. These results do not show where the side-chain is attached to the 
nucleus of cholesterol, but if we accept that the position is at 17, then we 
may formulate the reactions as follows: 



§3] 



STEROIDS 



365 



HO' 




CH 3 -COO 



CrOj 



CHsCOO' 




CrO, 



CH 3 COO' 




CH. 



3 \ 



CHirCHaCHgCH 

X CH 3 



The nature of the side-chain has also been shown by the application of 
the Barbier-Wieland degradation. Since this method also leads to evidence 
that shows which ring of the nucleus is attached to the side-chain, we shall 
consider the problem. of the nature of the side-chain again. 

The Barbier-Wieland degradation offers a means of " stepping down " 
an acid one carbon atom at a time as follows: 



K*CH 2 'C0 2 H — > R-CH 2 'C0 2 CH 3 >• 



HCl 



H 2 



R-CH 2 -C(OH)(C 6 H 5 ) 2 — *-> R-CH=C(C 6 H 5 ) 



CrO, 



R-C0 2 H + (C 6 H 5 ) 2 CO 

Methylmagnesium bromide may be used instead of phenylmagnesium 
bromide, and the alcohol so obtained may be directly oxidised: 

R-CH 2 -C(OH)(CH 3 ) 2 '+ R-C0 2 H + (CH 3 ) 2 CO 

In the following account, only phenylmagnesium bromide will be used to 
demonstrate the application of the method to the steroids. 

Cholesterol was first converted into coprostane (a stereoisomer of choles- 
tane; see §§4, 4a). If we represent the nucleus of coprostane as Ar, and 



366 ORGANIC CHEMISTRY [CH. XI 

the side-chain as C M , then we may formulate the degradation of coprostane 
as follows (B-W represents a Barbier-Wieland degradation): 

Coprostane '-> CH s *COCH 3 + Cholanic acid > 

Ar— C„ Ar— C M _ 3 

B-W 

(C 6 H s ) a CO + Norcholanic acid > 

Ar — C n _ 4 

B-W 

(C 6 H 5 ) 2 CO -f- Bisnorcholanic acid > 

Ar — C n _5 

CtO 

(C 6 H 5 ) 2 CO + ^tiocholyl methyl ketone '-> Etianic acid 

Ar— C„_ 6 Ar— C„_7 

The formation of acetone from coprostane indicates that the side-chain 
terminates in an wopropyl group. The conversion of bisnorcholanic acid 
into a ketone shows that there is an alkyl group on the a-carbon atom in 
the former compound. Furthermore, since the ketone is oxidised to etianic 
acid (formerly known as setiocholanic acid) with the loss of one carbon 
atom, the ketone must be a methyl ketone, and so the alkyl group on the 
a-carbon atom in bisnorcholanic acid is a methyl group. 

Now the carboxyl group in etianic acid is directly attached to the nucleus ; 
this is shown by the following fact. When etianic acid is subjected to one 
more Barbier-Wieland degradation, a ketone, aetiocholanone, is obtained 
and this, on oxidation with nitric acid, gives a dicarboxylic acid, aetiobilianic 
acid, without loss of any carbon atoms. Thus aetiocholanone must be a cyclic 
ketone, and so it follows that there are eight carbon atoms in the side-chain, 
which must have the following structure in order to account for the foregoing 
degradations (see also the end of this section iii): 

Ar -j- CH-J-CH2-J-CH2 -f CHj-j-CHfCHa),, 

In addition to the Barbier-Wieland degradation, there are also more recent 
methods for degrading the side-chain: 

(i) Gallagher et al. (1946) have introduced a method to eliminate two carbon 
atoms at a time: 

(i) S0C1 TTC1 

Ar-CHMe-CH 2 -CH 2 -C0 2 H — '-*■ Ar-CHMe-CH 2 -CH 2 -COCHN, > 

(ii) CHjN, 

Ar-CHMe-CH 2 -CH 2 -CO-CH»Cl Z " > Ar-CHMe-CH 2 -CH 2 -CO-CH, ( ' )Br * > 

2 2 2 AcOH 2 2 3 (ii) -HBr 

CrO 

Ar-CHMe-CH=CH-CO-CH 3 V Ar-CHMe-C0 2 H 

(ii) Miescher et al. (1944) have introduced a method to eliminate three carbon 
atoms at a time: 

Ar-CHMe-CH 2 -CH 2 -C0 2 Me 2PhMgBr > Ar-CHMe-CH a -CH 2 -C(OH)Ph 2 — ^ 

Ar-CHMe-CH 2 -CH=CPh 2 ^""""""V Ar-CHMe-CHBr-CH=CPh 2 ^% 
succinimide 

CrO 

Ar-CMe=CH-CH=CPh 2 V Ar-COMe 

(iii) Jones et al. (1958) have carried out the fission of a steroid side-chain with 
an acid catalyst and have then subjected the volatile products to chromato- 
graphy. This method has been used with as little as 30 mg. of material. 



§3] 



STEROIDS 



367 



The problem now is: Where is the position of this side-chain? This is 
partly answered by the following observation. The dicarboxylic acid, setio- 
bilianic acid, forms an anhydride when heated with acetic anhydride. Thus 
the ketone (aetiocholanone) is probably a five-membered ring ketone (in 
accordance with Blanc's rule), and therefore the side-chain is attached to 
the five-membered ring D. The actual point of attachment to this ring, 
however, is not shown by this work. The formation of Diels' hydrocarbon 
(§1) from cholesterol suggests that the side-chain is at position 17, since 
selenium dehydrogenations may degrade a side-chain to a methyl group 
(see §2 vii. X). Position 17 is also supported by evidence obtained from 
X-ray photographs and surface film measurements. Finally, the following 
chemical evidence may be cited to show that the position of the side-chain 
is 17. As we have seen above, cholanic acid may be obtained by the oxida- 
tion of coprostane. Cholanic acid may also be obtained by the oxidation 
of deoxycholic acid (a bile acid; see §8) followed by a Clemmensen reduction. 
Thus the side-chains in cholesterol and deoxycholic acid are in the same 
position. Now deoxycholic acid can also be converted into 12-ketocholanic 
acid which, on heating to 320°, loses water and carbon dioxide to form de- 
hydronorcholene (Wieland et ah, 1930). This, when distilled with selenium, 
forms 20-methylcholanthrene, the structure of which is indicated by its 
oxidation to 5 : 6-dimethyl-l : 2-benzanthraquinone which, in turn, gives on 
further oxidation, anthraquinone-1 : 2 : 5 : 6-tetracarboxylic acid (Cook, 
1933). Finally, the structure of 20-methylcholanthrene has been confirmed 
by synthesis (Fieser et al., 1935; see §3f. X). The foregoing facts can be 
explained only if the side-chain in cholesterol is in position 17; thus: 




12-ketocholanic acid 



CrO, 




dehydronorcholene 20-methylcholanthrene 

C0 8 H 



CrO. 




C0 2 H 



5:6-dimethyl-l:2- 
benzanthraquinone- 



HOjC 

HOijC 

anthraquinone -1:2:5:6- 
tetracarboxylic acid 



It should be noted that the isolation of methylcholanthrene affords addi- 
tional evidence for the presence of the cycfopentenophenanthrene nucleus 
in cholesterol. 

Thus, now that we know the nature and position of the side-chain, we 
can formulate the conversion of coprostane into setiobilianic acid as follows: 



368 



ORGANIC CHEMISTRY 



[CH. XI 




OH 3 -COCH 3 + f 




00 2 H B _. 



w 



coprostane 



cholanic acid 




CO-H 



B--W 




C0 2 H 



B-W^ 




norcholanic acid 



C0 2 H 



bisnorcholanic 
acid 



CrO, , 



aetiocholyl methyl 
ketone 




B-w 




hno 3 



M/ 



.CO a H 



?OaH 



etianic acid 



setiocholanone 



setiobilianic acid 



A point of interest in this connection is that when the anhydride of setio- 
bilianic acid is distilled with selenium, 1 : 2-dimethylphenanthrene is ob- 
tained (Butenandt et al., 1933). This also provides proof for the presence 
of the phenanthrene nucleus in cholesterol, and also evidence for the position 
of the C 13 angular methyl group (see iv). 




ffitiobilianic 
acid 
XV 



anhydride 



1: 2-dimethyl- 
phenanthrene 
XVI 



(iv) Positions of the two angular methyl groups. The cyc/openteno- 
phenanthrene nucleus of cholesterol accounts for seventeen carbon atoms, 
and the side-chain for eight. Thus twenty-five carbon atoms in all have been 
accounted for, but since the molecular formula of cholesterol is C 27 H 46 0, two 
more carbon atoms must be fitted into the structure. These two carbon 
atoms have been shown to be angular methyl groups. 

In elucidating the positions of the hydroxyl group and double bond, one 
of the compounds obtained was the keto-acid XII. This compound, when 
subjected to the Clemmensen reduction and followed by two Barbier- 
Wieland degradations, gives an acid which is very difficult to esterify, and 
evolves carbon monoxide when warmed with concentrated sulphuric acid 
(Tschesche, 1932). Since these reactions are characteristic of an acid con- 
taining a carboxyl group attached to a tertiary carbon atom (cf. abietic 
acid, §31. VIII), the side-chain in XII must be of the type 



§3] 



STEROIDS 



369 



C 
L 



P 



C-C-C— C-C0 2 H 



2B-\V 



C 



Thus there must be an alkyl group at position 10 in XII. This could be 
an ethyl group (as originally believed by Windaus and Wieland) or a methyl 
group, provided that in the latter case the second " missing " carbon atom 
can be accounted for. As we shall see later, there is also a methyl group 
at position 13, and so the alkyl group at position 10 must be a methyl 
group. On this basis, the degradation of XII may be formulated: 




Zn-Hg 
HCl * 




H0 2 <I 



CO.H 




The position of the other angular methyl group is indicated by the follow- 
ing evidence. When cholesterol is distilled with selenium, chrysene is 
obtained as well as Diels' hydrocarbon (see §1). How, then, is the former 
produced if the latter is the ring skeleton of cholesterol? One possible 
explanation is that there is an angular methyl group at position 13, and on 
selenium dehydrogenation, this methyl group enters the five-membered 
ring D to form a six-membered ring; thus: 



HO 





cholesterol 



Diels' hydrocarbon 



chrysene 



This evidence, however, is not conclusive, since ring expansion could have 
taken place had the angular methyl group been at position 14. Further 
support for the positions of the two angular methyl groups is given by the 
following degradative experiments (Wieland et al., 1924, 1928, 1933) (see 
overleaf). 



370 



ORGANIC CHEMISTRY 



[CH. XI 




C0 2 H 



HNO3 



deoxycholic acid 



dehydrodeoxycholic 
acid 




CO,H 



H0 2 C 

deoxybilianic acid 



pyrodeoxybilianic acid 



KMn0 4 




CO,H 



C0 2 H C0 2 H 
XVII 



diketo-dicarboxylic 
acid 



heat 




C0 2 H 



HO, 



HNO a 




C0 2 H 



HO.C 



XVII was shown to be butane-2 : 2 : 4-tricarboxylic acid; thus there is a 
methyl group at position 10. XVIII was shown to be a tetracarboxylic 
acid containing a cyc/opentane ring with a side-chain 

— CH(CH 3 )-CH 2 -CH 2 -C0 2 H. 

Thus this compound is derived from ring D. XX was also shown to be a 
tricarboxylic acid containing a cyctopentane ring. Furthermore, one carb- 



§3] 



STEROIDS 



371 



oxyl group in XX was shown to be attached to a tertiary carbon atom, and 
so it follows that there is a methyl group at 13 or 14. XX was then shown 
to have the trans configuration, i.e., the two carboxyl groups are trans. 
Thus its precursor XIX must have its two rings in the trans configuration 
(the methyl group and hydrogen atom at the junction of the rings are thus 
trans). Theoretical considerations of the strain involved in the cis- and 
trans-iowas of XIX suggest that the m-form of XIX would have been 
obtained had the methyl group been at position 14. Thus the position of 
this angular methyl group appears (from this evidence) to be at 13, and this 
is supported by the fact that aetiobilianic acid (XV, section iii) gives 1 : 2- 
dimethylphenanthrene (XVI) on dehydrogenation with selenium. Had the 
angular methyl group been at position 14, 1-methylphenanthrene would 
most likely have been obtained. 

(v) Synthesis of cholesterol. Two groups of workers, viz., Sir R. 
Robinson et al. (1951) and Woodward et al. (1951), have synthesised choles- 
terol. One of the outstanding difficulties in the synthesis of steroids is the 
stereochemical problem. The cholesterol nucleus contains eight asymmetric 
carbon atoms and so 256 optical isomers are possible (see also §4 for further 
details) . Thus every step in the synthesis which produced a new asymmetric 
carbon atom had to result in the formation of some (the more the better) of 
the desired stereoisomer, and at the same time resolution of racemic modifica- 
tions also had to be practicable. Another difficulty was attacking a parti- 
cular point in the molecule without affecting other parts. This problem 
led to the development of specific reagents. The following is an outline of 
the Woodward synthesis. 4-Methoxy-2 : 5-toluquinone, XXI, was prepared 
from 2-methoxy-^>-cresol as follows: 



if\( 



C Ho(J CH3+ ^ S °— ° H3 






CH 3 

'NO, 



Sn-HCl CH 3 Of 

CH 3 Ol 



^H 3 FeC i 8 T nCH 3 



^ m '°\Ao 



XXI 

XXI was condensed with butadiene (Diels-Alder reaction) to give XXII. 
This had the cis configuration and was isomerised (quantitatively) to the 
trans-isomer XXIII by dissolving in aqueous alkali, adding a seed crystal of 
the trans-form, and then acidifying. XXIII, on reduction with lithium 
aluminium hydride, gave the glycol XXIV, and this, on treatment with 
aqueous acid, gave XXV. Conversion of XXV to XXVI by removal of 
the hydroxyl group was carried out by a new technique : XXV was acetylated 
and the product, the ketol acetate, was heated with zinc in acetic anhydride 
to give XXVI (reduction with metal and acid usually reduces <x : ^-un- 
saturated bonds in ketones). XXVI, on treatment with ethyl formate in 
the presence of sodium methoxide, gave the hydroxymethylene ketone 
XXVlI (Claisen condensation). When this was treated with ethyl vinyl 
ketone in the presence of potassium fert.-butoxide, XXVIII was formed 
(Michael condensation). The object of the double bond in the ketone ring 
in XXVI is to prevent formylation occurring on that side of the keto group, 
and the purpose of the formyl group is to produce an active methylene 



372 ORGANIC CHEMISTRY [CH. XI 

group (this is now flanked on both sides by carbonyl groups). The necessity 
for this " activation " lies in the fact that ethyl vinyl ketone tends to self- 
condense, and consequently decrease the yield of XXVIII. XXVIII was 
now cyclised (quantitatively) by means of potassium hydroxide in aqueous 
dioxan to the single product XXIX. This is the desired compound; the 
other possible isomer (XXIX with the two hydrogens cis instead of trans 
as shown) is not formed since the cw-isomer is less stable than the trans-. 
XXIX was then treated with osmium tetroxide to give two cw-glycols of 
structure XXX. These were separated, and the desired isomer (the one 
insoluble in benzene) was treated with acetone in the presence of anhydrous 
copper sulphate to give the wopropylidene derivative XXXI. This, on 
catalytic reduction (H 2 — Pd/SrC0 3 ) gave XXXII which was condensed with 
ethyl formate in the presence of sodium methoxide to give XXXIII, and 
this was then converted into XXXIV by means of methylaniline. The 
purpose of this treatment was to block undesired condensation reactions 
on this side of the keto group (at this position 3). When XXXIV was con- 
densed with vinyl cyanide (cyanoethylation) and the product hydrolysed 
with alkali, the product was a mixture of two keto acids. These were 
separated and the stereoisomer XXXV (methyl group in front and propionic 
acid group behind the plane of the rings) was converted into the enol 
lactone XXXVI which, on treatment with methylmagnesium bromide, gave 
XXXVII, and this, on ring closure by means of alkali, gave XXXVIII. 
When this was oxidised with periodic acid in aqueous dioxan, the dialdehyde 
XXXIX was obtained, and this, when heated in benzene solution in the 
presence of a small amount of piperidine acetate, gave XL (and a small 
amount of an isomer) . This ketoaldehyde was oxidised to the corresponding 
acid which was then converted into the methyl ester XLI with diazo- 
methane. XLI, a racemate, was resolved by reduction of the keto group 
with sodium borohydride to the hydroxy esters [(±)-3a- and (±)-3/S-]. 
The (+)-form of the 3/3-alcohol was preferentially precipitated by digi- 
tonin, and this stereoisomer was now oxidised (Oppenauer oxidation) to 
give the desired stereoisomer (+)-XLI. This was catalytically reduced 
(H 2 — Pt) to XLII, which was then oxidised to XLIII which was a mixture 
of stereoisomers (from the mixture of XLII; H at 17 behind and in front). 
These were separated, reduced (sodium borohydride), and hydrolysed. The 
jS-isomer, XLIV, was converted into the methyl ketone by first acetylating, 
then treating with thionyl chloride and finally with dimethylcadmium. This 
acetylated hydroxyketone, XLV, on treatment with wohexylmagnesium 
bromide, gave XLVI. This was a mixture of isomers (a new asymmetric 
carbon has been introduced at position 20). XLVI, on dehydration, gave 
one product, XLVII, and this, on catalytic hydrogenation (H 2 — Pt), gave a 
mixture of cholestanyl acetates (the asymmetric C 20 has been re-introduced). 
These acetates were separated and the desired isomer, on hydrolysis, gave 
cholestanol, XL VIII, which was identical with natural cholestanol. The 
conversion of cholestanol into cholesterol, LIII, is then carried out by a 
series of reactions introduced by various workers: XLVIII to XLIX (Bruce, 
1943) ; XLIX to L (Butenandt et al., 1935) ; L to LI (Ruzicka, 1938) ; LI to 
LII (Westphal, 1937); LII to LIII (Dauben et al., 1950). 



§3] 



373 



CH; 




/>H 2 
CH, CH 

+ CH 



LiAlH, 



CH3O 





C a H 8 -CO 
(CH 




H o s o 4 



XXIX 



/CH3 

^Q-CH=CH 3 CH 2 
s)aCOK pQ 

CH^oHd H 
!HO 

XXVIII 



XXX 



KOH 



(CHs)aCO 




C(CH,) 2 




XXXI 



:C(CH 3 ) 2 



XXXII 



374 



ORGANIC CHEMISTRY 
C> 




(ii) hydrolysis HOoC 



XXXV 




0^\} 



XXXVI 



(CH 3 )2 



XXXVII 




XXXVIII 



CHO 



XL 



XXXIX 




C0 2 CH 3 



XLI 



§3] 



STEROIDS 



375 



HO 



C0 2 CH 3 
L--H 



C0 2 CH 3 




CH 3 -COO 



XLVI 



XLVII 




XLVIH 

cholestanol 



XLIX 



376 



ORGANIC CHEMISTRY 



[CH. XI 




(CH 3 CO)jO 

CH3COO' 



LII 



LIII 

cholesterol 



§4. Stereochemistry of the steroids. If we examine the fully saturated 
sterol, we find that there are eight dissimilar asymmetric carbon atoms in 
the nucleus (3, 5, 8, 9, 10, 13, 14 and 17). Thus there are 2 8 = 256 optical 
isomers possible. If we also include the asymmetric carbon atom in the 
side-chain (20), then there are 512 optical isomers possible. 




The stereoisomerism of the steroids is conveniently classified into two 
types, one dealing with the way in which the rings are fused together, and 
the other with the configurations of substituent groups, particularly those 
at C 3 and C 17 . 

§4a. Configuration of the nucleus. There are six asymmetric carbon 
atoms in the nucleus (5, 8, 9, 10, 13 and 14), and therefore there are 2 6 = 64 
optically active forms possible. X-ray analysis has shown that the steroid 
molecule is long and thin, i.e., the molecule is essentially flat (Bernal, 1932). 
This is only possible if rings B and C are fused together in a trans manner 
(cf. trans-decakn, §11 vii. IV); rings A/B and C/D could be cis or trans. 
It has been found that all naturally occurring saturated steroids, except 
those of the heart poisons, belong either to the cholestane series or to the 
coprostane series; in the former the rings A/B are trans, and in the latter 
cis, the rings B/C and C/D being trans in both series. By convention a 
full line represents groups above the plane of the molecule, and a dotted 
(or broken) line represents groups below the plane (see also §11 vii. IV for 



§4a] 



STEROIDS 



377 



conventions). Furthermore, by convention, the methyl group at C 10 in 
cholestane has been placed above the plane of the molecule, and therefore 
this leads to four possible stereoisomers for cholestane (I-IV). X-ray 






analysis has shown that the hydrogen atom at C 9 is trans to the methyl 
group at C 10 (Bernal et al., 1940), and this conclusion is supported by chemical 
evidence. Thus cholestane must be I or III. Further chemical work has 
shown that the methyl groups at C 10 and C 13 are cis, and so cholestane is I, 
and consequently coprostane is also I, except that in this case the hydrogen 
atom at C 5 is above the plane (rings A/B are cis in coprostane). The final 
point to be settled in connection with this problem of the configuration of 
cholestane is the orientation of the side-chain R at C 17 . Chemical evidence 
and X-ray analysis studies have shown that this side-chain is above the plane 
of the molecule (i.e., cis with respect to the two angular methyl groups). 
Thus cholestane and coprostane are: 





Cholestane 

A/B trans 
B/C trans 
C/D trans 
alio series 



Coprostane 

A/B cis 
B/C trans 
C/D trans 
normal series 



Compounds derived from cholestane are known as the a/to-compounds, 
the prefix alio being reserved to indicate this configuration at C 6 . Com- 
pounds derived from coprostane are known as the normaZ-compounds, 
but it should be noted that it is not customary to prefix compounds of this 
series by the word normal, e.g., aWocholanic acid can be derived from choles- 
tane, whereas cholanic acid can be derived from coprostane. 



378 ORGANIC CHEMISTRY [CH. XI 

§4b. Configurations of substituent groups. The configuration of the 
side-chain at C 17 has already been mentioned above. The only other con- 
figuration that we shall discuss here is that of the hydroxyl group at C 3 . 
By convention, the hydroxyl at C 3 in cholestanol (and cholesterol) is taken 
as being above the plane of the ring, i.e., the hydroxyl group is taken as 
being in the cis position with respect to the methyl group at C 10 . This 
configuration occurs in all natural sterols, and gives rise to the (J-series, 
the prefix /? always indicating that the substituent group lies above the plane 
of the molecule. When the hydroxyl group lies below the plane, the com- 
pounds are said to belong to the a- or epi series ; the prefix epi indicates 
the epimer due to the inversion of the configuration of C 3 . 

X-ray analysis studies have shown that the hydroxyl group in cholesterol 
is above the plane of the molecule, i.e., it is cis to the methyl group at C 10 . 
This has been confirmed by chemical evidence (Shoppee, 1947). 

The assignment of the configurations of C 7 and C 17 in steroid alcohols 
has been determined by Prelog et al. (1953) by arguments based on asym- 
metric syntheses (see §7. III). It has been shown that the configuration 
of the hydroxyl group in, e.g., cholestan-7a-ol and androsten-17/S-ol is in 
agreement with the accepted conventional steroid formula. 

Mills (1952) has also correlated the configurations of steroids with glycer- 
aldehyde. This author collected the molecular optical rotations of a number 
of pairs of epimeric cyrfohex-2-enols and their esters, and on the assumption 
that the configurations given (in the literature) were correct, Mills showed 
that the alcohol represented as I is more laevorotatory than its epimer II, 
irrespective of the positions of alkyl groups in these allylic terpene alcohols 
(these compounds had already been correlated with glyceraldehyde by the 
work of Fredga; §23e. VIII). The differences in rotation are large, and 
are increased on esterification. Mills then applied this rule to seven known 





OH 
I 

pairs of epimeric, allylic steroid alcohols, and found that the differences 
were those which may be predicted on the basis that the conventional steroid 
formulae represent the absolute configurations. Thus the configuration of 
the 3/S-hydroxyl group in cholesterol corresponds to that of d(+) -glycer- 
aldehyde. 

These stereochemical relationships of steroids to d(+) -glyceraldehyde 
have now been proved by the degradation of cholesterol to derivatives of 
(+)-citronellal (§23e. VIII), in which the only asymmetric carbon atom is 
the C 20 of the steroid (Cornforth et al, 1954; Riniker et al, 1954). Thus 
the arbitrary choice of placing the angular methyl groups above the plane 
in the cholesterol nucleus [i.e., the /^-configuration) has proved to be the 
absolute configuration. Furthermore, since the configuration of the 3- 
hydroxyl group in cholesterol is /5, this configuration is also the absolute 
one. 

Barton (1944r- ) has also applied the method of optical rotations to steroid 
chemistry, and has called his treatment the Method of Molecular Rotation 
Differences (this is a modification of the Rule of Shift, §12. I). The basis 
of this method is that the molecular rotation of any steroid is considered 
as the sum of the rotation of the fundamental structure (which is the parent 
hydrocarbon cholestane, androstane, or pregnane) and the rotations con- 
tributed by the functional groups (these are called the A values). The A 



§4c] 



STEROIDS 



379 



value of a given group is a characteristic of its position and orientation, 
and the A values of different groups are independent of one another pro- 
vided that unsaturated groups are not present, i.e., conjugation is absent, 
or that the groups are not too close together, i.e., are separated by 3 or 4 
saturated carbon atoms. In this way it has been possible to assign con- 
figurations and also the positions of double bonds. 

Correlation of configurations in steroids has also been carried out by the 
method of rotatory dispersion (§12a. I). Saturated steroids have been 
examined (Djerassi et al., 1956) and the results show that as the position 
of the carbonyl group changes in A/B foms-steroids, the curves change in 
sign, shape and/or amplitude. Thus this method may be used to locate 
the unknown position of a carbonyl group in a steroid. The authors also 
showed that for a given position of the carbonyl group, the shape of the 
curve depends on the conformation of the molecule. Thus, by comparing 
the curve of the compound under investigation with that of a compound 
of known absolute configuration and containing the carbonyl group in the 
same position, it is then possible to deduce the absolute configuration of a 
group in the unknown compound. 

On the other hand, Djerassi et al. (1962) have shown that mass spectra 
measurements of keto steroids offer a means of locating the carbonyl group 
in a steroid molecule. However, when mass spectrometry is combined with 
optical rotatory dispersion measurements, it is then possible to locate in 
an unambiguous manner the carbonyl group. 

§4c. The preparation of the " stanols ". The catalytic hydrogenation 
(platinum) of cholesterol (cholest-5-en-3/?-ol) produces only cholestanol 
(cholestan-3/S-ol). On the other hand, oxidation of cholestanol with 
chromium trioxide in acetic acid gives cholestanone and this, on catalytic 
reduction in neutral solution, gives mainly cholestanol, whereas catalytic 
reduction in acid solution gives mainly epicholestanol (cholestan-3a-ol). 




H.-Pt 




cholesterol 



cholestanol 



H 

cholestanone 



Hj-Pt 



solution 



HO 




H 
cholestanol 

(main product) 




H 

epicholestanol 

(main product) 



380 



ORGANIC CHEMISTRY 



[CH. XI 

The corresponding C 5 epimers, coprostanol (coprostan-3/?-ol) and epico- 
prostanol (coprostan-3«-ol), may be prepared from cholesterol as follows, 
the first step being the conversion of cholesterol into cholest-4-en-3-one by 
means of the Oppenauer oxidation (aluminium tert.- butoxide in acetone; 
see also Vol. I). 



HO 




Oppenauer 
oxidation 




cholesterol 



cholest-4-en-3-one 



H 

coprostanone 




H s -Pt 



H 

coprostanol 




neutral 



H 
epicoprostanol 

A detailed study of the catalytic reduction of the decalones has shown that 
in an acid medium the product is usually the cts-compound, whereas in a 
neutral or alkaline medium the product is usually the trans-compound (von 
Auwers, 1920; Skita, 1920). This principle, which is known as the Auwers- 
Skita rule of catalytic hydrogenation, was used by Ruzicka (1934) to determine 
the configurations of the above " stanols ". The configurations assigned 
have been supported by measurement of the rates of hydrolysis of the 
acetates of the various " stanols " (Ruzicka et al., 1938). The acetates of 
cholestanol and epicoprostanol are hydrolysed much faster than those of 
epicholestanol and coprostanol (see §4d). 

A point of interest in connection with the Auwers-Skita rule is that this 
generalisation does not allow for the possibility of isomerisation. Schuetz 
et al. (1962) have shown that in the hydrogenation of the three xylenes, the 
yield of the trans-isomei increased with temperature. 

Now let us consider the configuration at C 5 . The results of experiments 
on the catalytic hydrogenation of substituted cyefohexanones and substi- 
tuted phenols have led to the generalisation that the initial addition is cis, 
and occurs on the more accessible side of the double bond (Peppiatt et al., 
1955; Wicker, 1956). In accordance with this generalisation, it has been 
found that when saturated steroids of the AfB-cis- and the A/B-trans- series 
are produced by catalytic hydrogenation of 3a-substituted A 5 -steroids, then 
the larger the size of the 3a-substituent, the larger is the proportion of the 
A/B-«'s-steroid; in some cases, this cw-steroid is apparently formed ex- 
clusively (Shoppee et al., 1955). 

§4d. Conformational analysis of steroids. The Auwers-Skita rule of 
catalytic hydrogenation (§4c) cannot be used with certainty since, as pointed 



§4d] STEROIDS 381 

out, the product is usually mainly cis or trans according to the conditions, 
and hence the exceptions can only be ascertained as such by other evidence. 
Barton (1953) has restated this Auwers-Skita rule of catalytic hydrogena- 
tion as follows: Catalytic hydrogenation of ketones in strongly acid media 
(rapid hydrogenation) produces the axial hydroxyl compound, whereas 
hydrogenation in neutral media (slow hydrogenation) produces the equa- 
torial alcohol if the ketone is unhindered or the axial alcohol if the ketone 
is very much hindered. 

All the evidence obtained has shown that all the cycJohexane rings in 
the steroid nucleus are chair forms; thus I is cholestane, and II is coprostane. 




Cholestane 
(A/B trans) 



Coprostane 
(A/B as) 

II 



The effect of conformation on the course and rate of reactions has been 
discussed in §12. IV. The following is a summary of the generalisations 
that have been formulated: 

(i) Equatorial groups are normally more stable than axial. Thus, when 
a (polycyclic) secondary alcohol is equilibrated with alkali, it is the equatorial 
isomer that predominates in the product. Similarly, when a (polycyclic) 
ketone is reduced with sodium and ethanol, the predominant isomer in the 
product is the equatorial alcohol (the more stable form). Furthermore, 
because of the rigidity of the system (which prevents interconversion of 
chair forms), the stable configurations of hydroxyl groups at different posi- 
tions in the cholestane series will be as shown in III (compare this with I). 




a a 



III 

The following are examples of equilibration (using sodium ethoxide at 
180°) (see also §8. II): 



Cholestanol [30(e)] 



io%i 

* 80% 

Epicholestanol [3<x(a)] 



Coprostanol [30(a)] 

I 90% 
T 

Epicoprostanol [3oc(e)] 



(ii) Equatorial hydroxyl and carboxyl groups are esterified more rapidly 



382 



ORGANIC CHEMISTRY 



[CH. XI 



than the corresponding axial groups. Similarly, hydrolysis of equatorial 
esters and acyloxy groups is more rapid than for the corresponding axial 
isomers. These principles explain Ruzicka's results on the " stanols " 
(§4c) ; in the acetates of cholestanol and epicoprostanol, the acetoxy groups 
are equatorial, whereas in the acetates of epicholestanol and coprostanol 
these groups are axial and therefore subject to 1 : 3-interactions. Hence 
the former pair are hydrolysed more rapidly than the latter pair. 

Empirical methods, using infra-red spectra, have been developed by Jones 
et al. (1951, 1952) for determining the conformation of 3-hydroxy (and 
3-acetoxy) steroids; characteristic bands are given by the axial and equa- 
torial groups. 

(iii) Secondary axial alcohols are more rapidly oxidised by chromic acid 
(or hypobromous acid) than secondary equatorial alcohols. Schreiber et al. 
(1955) have shown that the more hindered the alcohol, the faster is the 
oxidation (with chromic acid). 

(iv) Bimolecular ionic elimination reactions occur readily when the two 
groups (which are eliminated) are trans-di&xial, and less readily when trans- 
diequatorial or cw-axial : equatorial. 

(v) Epoxides are attacked by, e.g., hydrogen bromide, to give the trans- 
diaxial compound. Reduction with lithium aluminium hydride or catalytic 
hydrogenation converts epoxides into the axial hydroxy compound. 

§5. Ergosterol, C 28 H 44 0, m.p. 163°, occurs in yeast. Ergosterol forms 
esters, e.g., an acetate with acetic anhydride; thus there is a hydroxyl group 
present in ergosterol. Catalytic hydrogenation (platinum) of ergosterol pro- 
duces ergostanol, C 28 H 50 O ; thus there are three double bonds in ergosterol. 
When ergostanol is acetylated and the product then oxidised, the acetate 
of 3/S-hydroxynoraZ/ocholanic acid, I, is obtained (Fernholz et al., 1934). 
The identity of I is established by the fact that cholestanyl acetate, II (a 
compound of known structure), gives, on oxidation, the acetate of 3/3- 
hydroxyaZZocholanic acid, III, and this, after one Barbier-Wieland degrada- 
tion (§3 iii), gives I; thus: 



!0 2 H 



„ , , (CH 3 co) 2 o^ Ergostanyl op, 
Ergostanol >- * fe > 



CH,-COO 




COJI 



§5] 



STEROIDS 



383 



Thus ergostanol and cholestanol have identical nuclei, the same position 
of the hydroxyl group and the same position of the side-chain. The only 
difference must be the nature of the side-chain, and hence it follows that 
ergosterol contains one more carbon atom in its side-chain than cholesterol 
(the former compound is CjgH^O and the latter C 27 H 46 0). Ozonolysis of 
ergosterol gives, among other products, methyh'sopropylacetaldehyde, IV. 
This can be accounted for if the side-chain of ergosterol is as shown in V 
(Windaus et al, 1932). 




C0 2 H 



CHO 
I 
CH-CH(CH 3 ) 2 

CH S 
IV 



On this basis, the oxidation of ergostanyl acetate to the acetate of 3/3- 
hydroxynora/Zocholanic acid, I, is readily explained. 



CHvCOO' 




'C0 2 H 



ergostanyl acetate 



+ CH 3 

CO-CHfCHak 



We have now accounted for all the structural features of ergosterol except 
the positions of the three double bonds. The position of one of these is 
actually shown in the above account ; it is C 22 — C^. The side-chain must 
contain only one double bond, since if more than one were present, more 
than one fragment (IV) would have been removed on ozonolysis. Thus 
the other two double bonds must be in the nucleus. When heated with 
maleic anhydride at 135°, ergosterol forms an adduct, and so it follows that 
the two double bonds (in the nucleus) are conjugated (Windaus et al., 1931). 
Now ergosterol has an absorption maximum at 2810 A. Conjugated acyclic 
dienes absorb in the region of 2200-2500 A, but if the diene is in a ring 
system, then the absorption is shifted to the region 2600-2900 A. Thus 
the two double bonds in the nucleus of ergosterol are in one of the rings 
(Dimroth et al., 1936). When ergosterol is subjected to the Oppenauer 
oxidation (aluminium totf.-butoxide and acetone), the product is an a : /?- 
unsaturated ketone (as shown from its absorption spectrum). This can 
only be explained by assuming that one of the double bonds is in the 5 : 6- 
position, and moves to the 4 : 5-position during the oxidation (c/. cholesterol, 
§3 ii). The other double bond is therefore 7 : 8 in order to be conjugated 
with the one that is 5 : 6. Thus the conjugated system is in ring B and 
the oxidation is explained as follows: 



384 



ORGANIC CHEMISTRY 



[CH. XI 



HO 




ergosterol 



§6. Vitamin D. This vitamin is the antirachitic vitamin; it is essential 
for bone formation, its function being the control of calcium and phosphorus 
metabolism. 

Steenbock et al. (1924) showed that when various foods were irradiated 
with ultraviolet light, they acquired antirachitic properties. This was then 
followed by the discovery that the active compound was in the unsaponifiable 
fraction (the sterol fraction). At first, it was believed that the precursor of 
the active compound was cholesterol, but subsequently the precursor was 
shown to be some " impurity " that was in the cholesterol fraction {e.g., by 
Heilbron et al., 1926). The ultraviolet absorption spectrum of this " impure 
cholesterol " indicated the presence of a small amount of some substance 
that was more unsaturated than cholesterol. This led to the suggestion 
that ergosterol was the provitamin D in the " impure cholesterol ", and 
the investigation of the effect of ultraviolet light on ergosterol resulted in 
the isolation from the irradiated product of a compound which had very 
strong antirachitic properties. This compound was named calciferol by 
the Medical Research Council (1931), and vitamin D t by Windaus (1931). 
This potent crystalline compound, however, was subsequently shown to be 
a molecular compound of calciferol and lumisterol (one molecule of each). 
Windaus (1932) therefore renamed the pure potent compound as vitamin D 2 , 
but the M.R.C. retained the original name calciferol. The Chemical Society 
(1951) has proposed the name ergocalciferol for this pure compound. 

A detailed study of the irradiation of ergosterol with ultraviolet light 
has led to the proposal that the series of changes is as follows (R = C 9 H 17 ) : 



HO 





ergosterol 



pre-ergocalciferol 






OH 
tachysterol 



HO- 
ergocalciferol 



HO 




lumisterol 



§6a] steroids 385 

Velluz et al. (1949) isolated the pre-ergocalciferol (P) by irradiation of ergo- 
sterol at 20°, and showed that it formed ergocalciferol (E) on heating (see 
also below). Velluz et al. (1955) and Havinga et al. (1955) showed that 
pre-ergocalciferol is the 6 : 7-cw-isomer of tachysterol (T), and the inter- 
conversion of these two compounds has been studied by Inhoffen et al. 
(1959) and Havinga et al. (1959). Lumisterol (L) is converted directly 
into pre-ergocalciferol (Rappoldt, 1960). It should be noted that tachy- 
sterol and lumisterol are formed in a side reaction from pre-ergocalciferol 
and are not directly involved in the formation of ergocalciferol as postulated 
in the original scheme of Windaus et al., who carried out the irradiation 
in solution and allowed the temperature to rise to 50°: 

hv hv hv 

Ergosterol — >■ L — > T — >■ E 

§6a. Ergocalciferol (calciferol, vitamin D 2 ) is an optically active crystal- 
line solid, m.p. 115-117°. Its molecular formula is C 28 H 44 0, and since it 
forms esters, the oxygen is present as a hydroxyl group. Furthermore, 
since ergocalciferol gives a ketone on oxidation, this hydroxyl group is a 
secondary alcoholic group. Ozonolysis of ergocalciferol produces, among 
other products, methybsopropylacetaldehyde. Thus the side-chain in ergo- 
calciferol is the same as that in ergosterol. Catalytic hydrogenation converts 
ergocalciferol into the fully saturated compound octahydroergocalciferol, 
C 2g H 52 0. This shows that there are four double bonds present, and since 
one is in the side-chain, three are therefore in the nucleus. The parent 
hydrocarbon of ergocalciferol is C 28 H B2 , and since this corresponds to the 
general formula C„H 2re _4, the molecule therefore is tricyclic. Furthermore, 
ergocalciferol does not give Diels' hydrocarbon when distilled with selenium. 
These facts indicate that ergocalciferol does not contain the four-ring system 
of ergosterol. The problem is thus to ascertain which of the rings in ergo- 
sterol has been opened in the formation of ergocalciferol. The following 
reactions of ergocalciferol are readily explained on the assumption that its 
structure is I. The absorption spectrum of the semicarbazone of II (C 21 H 34 0) 
was shown to be characteristic of <x : ^-unsaturated aldehydes. The absents 
of -the hydroxyl group and the carbon content of II indicate the absence of 
ring A. These facts suggest that in ergocalciferol " ring B " is open between 
C 9 and C 10 , and that II arises by scission of the molecule at a double bond 
in position 5 : 6, and can be an a : /3-unsaturated aldehyde only if there is 
a double bond at 7 : 8 (these double bonds are also present in ergosterol). 
The isolation of the ketone III (C 19 H 32 0) confirms the presence of the double 
bond at 7 : 8 (Heilbron et al, 1935). 

The isolation of formaldehyde (IV) shows the presence of an exocyclic 
methylene group, and the presence of this group at C 10 is in keeping with 
the opening of ring B at 9 : 10. The formation of V (C 13 H 20 O 3 ), a keto- 
acid, suggests that ring B is open at 9 : 10, and that there are two double 
bonds at 7 : 8 and 22 : 23. The position of the latter double bond is con- 
firmed by the isolation of methyh'sopropylacetaldehyde, VI (Heilbron et al., 
1936). 

Structure I for ergocalciferol is also supported by the formation of VII, 
the structure of which is shown by the products VIII, IX, X and XI (Win- 
daus et al., 1936). The production of 2 : 3-dimethylnaphthalene (VIII) is 
in keeping with the fact that carboxyl groups sometimes give rise to methyl 
groups on selenium dehydrogenation (cf. §2 vii. X). Similarly, the forma- 
tion of naphthalene, IX, and naphthalene-2-carboxylic acid, X, shows the 
presence of rings A and " B " in VII. Catalytic reduction of VII (to reduce 
the double bond in the side-chain only), followed by ozonolysis, gives XI. 
Thus the formation of these compounds VIII-XI establishes the structure 
of VII, and shows that the double bonds are at 5 : 6, 10 : 19 and 7 : 8. 



386 



ORGANIC CHEMISTRY 



[CH. XI 



FH 




.^COjH 



X-ray analysis studies of the 4-iodo-3-nitrobenzoate of ergocalciferol con- 
firm structure I for ergocalciferol (Crowfoot et al., 1948). 

The presence of the two double bonds 5 : 6 and 7 : 8 gives rise to the 
possibility of various geometrical isomeric forms for ergocalciferol. Ultra- 
violet spectroscopic studies (Braude et al., 1955) and other work (§6) have 
led to the conclusion that ergocalciferol has the configuration shown in the 
chart in §6. This is further supported by the work of Crowfoot et al. (1957) 
who, from calculations of electron densities in the ester crystal (the 4-iodo- 
3-nitrobenzoate), have shown that their results agree with the configuration 
given in the chart. 

Lythgoe et al. (1957) have carried out a partial synthesis of ergocalciferol 
from the aldehyde II. 

§6b. Vitamins D 3 and D 4 . A detailed biological investigation has shown 
that the vitamin D in cod-liver oil is not identical with ergocalciferol, and 
that vitamin D activity could be conferred on cholesterol, or on some 



§7] 



STEROIDS 



387 



impurity in cholesterol other than ergosterol. Windaus (1935) therefore 
suggested that natural vitamin D (in cod-liver oil) is derived from 7-dehydro- 
cholesterol. The following chart shows the method of preparing 7-dehydro- 
cholesterol (originated by Windaus, 1935; and improved by Buser, 1947, 
and by Fieser et al., 1950). 



CHs-COO' 




Cr0 3 , 



cholesteryl 
acetate 



CH,CO 




uaih 4 



HO' 




C 8 H 6 COO 




OCOC 6 H 6 



C t H.N(CH»)a 
reflux 



6 Hfi-COO 




7-dehydrocholesterol 



7-Dehydrocholesterol, on irradiation with ultraviolet light, gives a product 
that is about as active as ergocalciferol (vitamin D 2 ). This product was 
shown to be impure, and the pure active constituent was isolated as the 
3 : 5-dinitrobenzoate (Windaus et al., 1936). This vitamin D with a choles- 
terol side-chain is named vitamin D 3 , and has been shown to be identical 
with the natural vitamin that is isolated from tunny-liver oil (Brockman, 
1937). Vitamin D 3 has also been isolated from other fish-liver oils, e.g., 
halibut. The Chemical Society (1951) has proposed the name cholecalci- 
ferol for vitamin D 3 . It has now been shown that the irradiation of 7-de- 
hydrocholesterol (at low temperature) first produces the previtamin D 3 , and 
this, on gentle heating, is converted into the vitamin itself (cf. ergocalciferol, 
§6). 

Irradiation of 22 : 23-dihydroergosterol gives a compound with antirachitic 
properties (Windaus et al., 1937); this is known as vitamin D 4 . 



HO 




HO 




vitamin D 3 



vitamin D t 



§7. Stigmasterol, C 29 H 48 0, m.p. 170°, is best obtained from soya bean 
oil. Since stigmasterol forms an acetate, etc., a hydroxyl group is therefore 



388 



ORGANIC CHEMISTRY 



[CH. XI 



present. Stigmasterol also forms a tetrabromide ; thus it contains two 
double bonds. Hydrogenation of stigmasterol produces stigmastanol, 
C 29 H 5a O, and since the acetate of this gives the acetate of 3/S-hydroxynor- 
aWocholanic acid on oxidation with chromium trioxide, it follows that stigma- 
stanol differs from cholestanol only in the nature of the side-chain (Fernholz 



C0 2 H 




CH 3 -000 

stigmastanyl acetate 



CH 3 -00O / 



acetate of 3p-hydroxynor- 
a//ocholanic acid 



et al., 1934 ; cf. ergosterol, §5) . Ozonolysis of stigmasterol gives, among other 
products, ethyh'sopropylacetaldehyde (Guiteras, 1933). This suggests that 
the side-chain is as shown in I, with a double bond at 22 : 23. 



CHO 
I 
CH-CH(CH3)2 

C 2 H 6 




ethyhsopropylacetaldehyde 

Thus the final problem is to ascertain the position of the second double 
bond in stigmasterol. This has been shown to be 5 : 6 by the method used 
for cholesterol (Fernholz, 1934) . Stigmasterol, on hydroxylation with hydro- 
gen peroxide in acetic acid, gives a triol which, on oxidation with chromium 
trioxide, forms a hydroxydiketone. This, on dehydration followed by re- 
duction, forms a dione which combines with hydrazine to form a pyridazine 
derivative. These reactions can be explained as follows (cf. cholesterol, 
§3 ii): 





hydroxydiketone 
X. 




dione 



pyridazine 



This position for the nuclear double bond is supported by other evidence; 
thus stigmasterol is: 



§7a] 



STEROIDS 



389 




stigmasterol 

§7a. Biosynthesis of sterols. It has long been known that animals 
can synthesise cholesterol, but the possible pathways were unknown until 
biosynthetic cholesterol was prepared from acetic acid labelled isotopically 
(with "C) in either the methyl (m) or the carboxyl (c) group, or labelled in 
both groups ( 13 CH 3 a4 C0 2 H). These tracer studies were carried out mainly 
by B\och etal. (1942- ) and by Cornforth et al. (1953- ), and the results estab- 
lished that the distribution of the carbon atoms is as shown in I. Thus 

c c 



m I | /m 



V 



m 



I I I 

m^ / m \ / m 

C 



-tn 



acetic acid can be regarded as the fundamental unit. Evidence was also 
obtained that isovaleric acid can serve as a precursor for cholesterol, and 
then Tavormina et al. (1956), using labelled mevalonic acid (MVA), showed 
that this is converted almost completely into cholesterol by rat liver; the 
route from acetic acid to MVA has been described in §32a. VIII. The prob- 
lem now is to discover the route whereby MVA is converted into cholesterol. 
As far back as 1926 Heilbron et al. suggested that squalene (§32. VIII) is a 
precursor of cholesterol, and Robinson (1934) proposed a scheme for the 
cyclisation of the squalene molecule with the loss of three methyl groups. 
Woodward et al. (1953), however, suggested that squalene is first cyclised 
to lanosterol, and then this loses three methyl groups to give cholesterol. 
Bloch et al. (1952) showed that squalene is a precursor of cholesterol in the 
intact animal. Furthermore, Bloch et al. (1955) showed that lanosterol is 
converted into cholesterol in rats, and in 1956 carried out the biosynthesis 
of lanosterol from labelled acetate. Thus we have evidence for the suggested 
route from squalene to cholesterol. As mentioned above, Woodward et al. 
(1953) suggested that squalene ring-closes to form lanosterol, and proposed 
a 1,3-shift of the methyl group at C 8 to C 13 (the squalene molecule is num- 
bered to give the numbering in the closed-ring system in the steroid) . On the 
other hand, Ruzicka etal. (1955) and Bloch et al. (1957) proposed a 1,2-shift 
of the methyl group from C M to C 13 and another 1,2-shift from C 8 to C 14 . 
Further work by Bloch et al. (1958) showed that the 1,2-shifts were correct; 
this is also supported by the work of Cornforth et al. (1958). 



390 



ORGANIC CHEMISTRY 



[CH. XI 




squalene 



lanosterol 



HO' 




cholesterol 



Bloch et al. (1957) also found that the three methyl groups of lanosterol 
are eliminated as carbon dioxide (via oxidation to carboxyl groups). Several 
intermediates and new precursors which function between lanosterol and 
cholesterol have now been identified (Cornforth, 1959; Crabbe, 1959). 
Finally, studies with yeast extracts have shown the mevalonic acid 5-pyro- 
phosphate, isopentenyl pyrophosphate, geranyl pyrophosphate and farnesyl 
pyrophosphate are successive intermediates in the biosynthesis of squalene 
(see §32a. VIII). 

The biosynthesis of ergosterol from acetate has been carried out by Bloch 
et al. (1951), and the distribution pattern corresponds to that of cholesterol. 
Bloch et al. (1957) also showed that formate is an efficient source for the 
methyl group at C 28 . 

BILE ACIDS 

§8. Introduction. The bile acids occur in bile (a secretion of the liver 
which is stored in the gall-bladder) of most animals combined as amides with 
either glycine (NH 2 *CH 2 'C0 2 H) or taurine (NH 2 *CH 2 "CH 2 -S0 3 H), e.g., glyco- 
cholic acid (= glycine + cholic acid), taurocholic acid (= taurine + cholic 




C0 2 H 



cholanic acid 



a/Zocholanic acid 



§9] STEROIDS 391 

acid). The bile acids are present as sodium salts, and they function as 
emulsifying agents in the intestinal tract, e.g., fats, which are insoluble in 
water, are rendered " soluble ", and so may be absorbed in the intestine. 

The bile acids are hydroxy derivatives of either cholanic acid or allo- 
cholanic acid (but see §10). Dehydration of a bile acid by heating in a 
vacuum, followed by catalytic reduction, gives either cholanic or a//ocholanic 
acid. 

About twelve natural bile acids have been characterised, and a number 
of others are synthetic. The positions of the hydroxyl groups are any of 
the following: 3, 6, 7, 11, 12 and 23, and in almost all of the natural bile 
acids the configurations of the hydroxyl groups are a (see §4b). Some of 
the more important natural bile acids are: 



Name 


M.p. 


Hydroxyl 
groups 


Source 






195° 
172° 
186° 
140° 
197° 


3a : 7a : 12a 

3a : 12a 

3a 

3a : 7a 

3a : 6a 


Man, ox 
Man, ox 
Man, ox 
Man, ox, hen 
Pig 


Deoxycholic acid . 
Lithocholic acid 
Chenodeoxycholic acid 
Hyodeoxycholic acid . 







§9. The structures of cholanic acid and Af/ocholanic acid. These 
acids may be derived from coprostane and cholestane, respectively, as 
follows (cf. §4c). At the same time, these reactions show the relationship 
between the bile acids and the sterols (Windaus, 1919). 

AZ/ocholanic acid. 



HO' 




cholesterol 



H 

cholestanol 



H 

cholestanone 



C0 2 H 




cholestane 



a/focholanic acid 



392 

Cholanic acid. 



ORGANIC CHEMISTRY 



[CH. XI 




cholesterol 



cholest-4-en-3-one 



(!) CrOa 



(ii) Zn-Hg/HCl 





coprostanol 



C0 2 H 



coprostane 



cholanic acid 



§10. Structure of the bile acids. Since all the bile acids can be con- 
verted into either of the cholanic acids, the former are therefore hydroxy 
derivatives of the latter, e.g., lithocholic acid can be converted into cholanic 
acid as follows: 



HO 




H 

lithocholic acid 



H 2 -Pt 




H H 

cholenic acid 



C0 2 H 



cholanic acid 

According to Fieser et al. (1955), cholenic acid is a mixture of the two com- 
pounds shown, the chol-3-enic acid being the main constituent. 

The positions of the hydroxyl groups in the bile acids have been deter- 
mined by means of oxidative degradation, e.g., the position of the hydroxyl 
group in lithocholic acid is shown to be at 3 as follows. Cholesterol can be 



§10] 



STEROIDS 



393 



converted into coprostanol I (see, e.g., §9) which, on oxidation with chromium 
trioxide, forms a ketone and this, when oxidised with nitric acid, gives a 
dicarboxylic acid, II. II, on further oxidation with nitric acid, produces 
the tricarboxylic acid, lithobilianic acid, III. Lithocholic acid, IV, on 
oxidation with chromium trioxide, forms dehydrolithocholic acid, V, and 
this, when oxidised with nitric acid, forms III. It therefore follows that the 
hydroxyl group in lithocholic acid is probably in the same position as in 
coprostanol, viz., position 3. Thus: 



C0 2 H 




C0 2 H 



The above evidence is not conclusive, since had the hydroxyl group in litho- 
cholic acid been at position 4, III could still have been obtained. In practice, 
however, the oxidation of I produces two isomeric acids for II, one being II 
as shown, and the other Ila, in which the ring A is opened between C 2 and 
C 3 ; this acid, on further oxidation, gives wolithobilianic acid, Ilia. Since 
the oxidation of lithocholic acid, IV, also produces a mixture of the same 
two acids, III and Ilia, there can be no doubt that the hydroxyl group is 
at position 3. 

The configuration of the hydroxyl group in lithocholic acid has been shown 
to be a by, e.g., the oxidative degradation of the acetates of lithocholic 
acid and epicoprostanol to 5-Moandrosterone (formerly known as 3a-hydroxy- 
setiocholan-17-one). Since all of the natural bile acids except one (" /? " 



394 



ORGANIC CHEMISTRY 



[CH. XI 



HO 




H0 2 C 
H0 2 C 





C0 2 H 



Ilia 



hyodeoxycholic acid) can be converted into lithocholic acid, all have there- 
fore the a-configuration for the hydroxyl group at C 3 . 




H 

lithocholic acid 



5 - jsoandrosterone 



H 

epicoprostanol 



The bile acids form molecular compounds with various substances. Cholic 
acid, in particular, forms these molecular compounds with such compounds 
as fatty acids, esters, alcohols, etc. ; these are known as the choleic acids. 
These choleic acids are of the channel complex type (like urea complexes; 
see Vol. I). 

The bile acids discussed in the foregoing account are all derivatives of 
cholanic or aWocholanic acid. There are, however, some bile acids which 
are not derivatives of the cholanic acids, e.g., in the bile of crocodiles there 
is the bile acid 3a : 7a : 12a-trihydroxycoprostanic acid, C 27 H 48 5 . 



SEX HORMONES 

§11. Introduction. Hormones are substances which are secreted by the 
ductless glands, and only minute amounts are necessary to produce the 
various physiological reactions in the body. As a group, hormones do not 
resemble one another chemically, and their classification is based on their 
physiological activity. There appear to be about 60 different hormones 
recognised so far, and more than half of these are steroids. The sex hormones 



§12] 



STEROIDS 



395 



belong to the steroid class of compounds, and are produced in the gonads 
(testes in the male, and ovaries in the female). Their activity appears to 
be controlled by the hormones that are produced in the anterior lobe of the 
pituitary gland. Because of this, the sex hormones are sometimes called 
the secondary sex hormones, and the hormones of the anterior lobe of the 
pituitary (which are protein in nature) are called the primary sex hormones. 
The sex hormones are of three types: the androgens (male hormones), 
the cestrogens (female or follicular homones) and progesterone (the corpus 
luteum hormone). The sex hormones are responsible for the sexual pro- 
cesses, and for the secondary characteristics which differentiate males from 
females. 



ANDROGENS 

§12. Androsterone, C 19 H 30 O 2 , m.p. 184-185°, is dextrorotatory. It was 
first isolated by Butenandt et al. (1931) from male urine (about 15 mg. from 
15,000 litres of urine). Androsterone behaves as a saturated compound, 
and since it forms mono-esters, one oxygen atom is present as a hydroxyl 
group. The functional nature of the other oxygen atom was shown to be 
oxo, since androsterone forms an oxime, etc. The parent hydrocarbon of 
androsterone, C^rl^Oa, is therefore C 19 H 32 , and since this corresponds to 
the general formula C„H 2 „_6, the molecule is tetracyclic. This led to the 
suggestion that androsterone probably contains the steroid nucleus, and 
since it is a hydroxyketone, it was thought that it is possibly related to 



CH s -COO 




cholestanyl acetate 



epiandrosterone 



CH,-COO' 




HO' 




epicholestanyl acetate 



H 
androsterone 



cestrone (§14). Butenandt (1932) therefore proposed a structure which was 
proved correct by Ruzicka (1934) as follows. Ruzicka oxidised cholestanyl 
acetate with chromium trioxide in acetic acid to epiandrosterone, a 
hydroxyketone with the structure proposed for androsterone by Butenandt. 
When, however, epicholestanyl acetate was oxidised, the product was andro- 
sterone. Thus the configuration of the hydroxyl group at C 3 is a and not p 
as Butenandt suggested. Epiandrosterone (formerly known as woandro- 
sterone) has about one-eighth of the activity of androsterone. 



396 



ORGANIC CHEMISTRY 



[CH. XI 

Sondheimer et al. (1955) have converted epiandrosterone into androsterone, 
starting with epiandrosterone ^-toluenesulphonate (c/. tosyl esters of sugars, 
§9. VII). 



TsO' 




Soon after the discovery of androsterone, Butenandt et al. (1934) isolated 
two other hormones from male urine, 5-woandrosterone and dehydroepi- 
androsterone. Then Laqueur (1935) isolated the hormone testosterone from 
steer testes (10 mg. from 100 kg. of testes). 



HO-' 





5-z.s0androsterone dehydroepiandrosterone 



testosterone 



§13. Testosterone, C ]9 H 28 2 , m.p. 155°, is dextrorotatory. Testosterone 
has been produced commercially by the following method of Butenandt 



§13] 



STEROIDS 



397 



(1935) and Ruzicka (1935) ; the Oppenauer oxidation step in this method 
was introduced by Oppenauer (1937). This preparation of testosterone 
establishes the structure of this hormone. This method has been improved 




CrOa-CKs-COsH 



cholesterol 



cholesteryl acetate dibromide 



CH,COO 




HO 
dehydroepiandrosterone 



OH 



CH 3 -COO' 




(i) CeHfCOCl 
(ii) mild hydrolysis 
(CH 3 OH-NaOH) 



HO 




OCO-C«H 5 




0-CO-C 6 H 5 




testosterone 



by Mamoli (1938), who converted dehydroepiandrosterone into testosterone 
by means of micro-organisms; the first stage uses an oxidising yeast in the 
presence of oxygen, and the second stage a fermenting yeast. 



398 



ORGANIC CHEMISTRY 



[CH. XI 



Elisberg et al. (1952) have shown that sodium borohydride selectively 
reduces the 3-keto group in the presence of others at 11, 12, 17 or 20. On 




HO' V V O" V \y O* 

dehydroepiandrosterone androst-4-ene-3:17-dione 



testosterone 



the other hand, Norymberski et al. (1954) have shown that if there is a double 
bond in position 4 : 5, then the keto group at 17 or 20 is preferentially reduced 
to that at 3. Thus androst-4-ene-3 : 17-dione is reduced to testosterone by 
sodium borohydride {cf. §3 i). Johnson et al. (1960) have adapted Johnson's 
synthesis of equilenin (§17) to provide an improved synthesis of testosterone. 
It appears that testosterone is the real male sex hormone in the body; 
the others are metabolic products of testosterone. The ketonic steroids are 
separated from the non-ketonic steroids (all from urine) by means of Girard's 
reagents (P and T); the ketonic compounds form soluble derivatives, and 
may be regenerated by hydrolysis (see also Vol. I). Many other hormones 
have also been isolated from urine. 



(ESTROGENS 

§14. (Estrone. It has been known for a long time that there are hor- 
mones which control the uterine cycle, but it was not until 1929 that 
Butenandt and Doisy independently isolated the active substance cestrone 
from the urine of pregnant women. (Estrone is the first known member of 
the sex hormones, and soon after its discovery two other hormones were 
isolated, cestriol and cestradiol. 

(-f-)-(Estrone, m.p. 259°, has the molecular formula C 18 H 22 O a . It behaves 
as a ketone (forms an oxime, etc.), and contains one hydroxyl group (it 
forms a monoacetate and a monomethyl ether) . Furthermore, this hydroxyl 
group is phenolic, since cestrone couples with diazonium salts in alkaline 
solution (this reaction is typical of phenols). When distilled with zinc dust, 
cestrone forms chrysene; this led to the suggestion that cestrone is related 
to the steroids {cf §1). The X-ray analysis of cestrone also indicates the 
presence of the steroid nucleus, and at the same time showed that the keto 
group and the hydroxyl group are at the opposite ends of the molecule 
(Bernal, 1932). On catalytic hydrogenation, cestrone forms octahydro- 
cestrone, C 18 H 30 O 2 . This compound contains two hydroxyl groups (two 
hydrogen atoms are used for converting the keto group to an alcoholic 
group), and so six hydrogen atoms are used to saturate three double bonds. 
If these three double bonds are in one ring, i.e., there is a benzenoid ring 
present, then the phenolic hydroxyl group can be accounted for. The 
presence of one benzene ring in the structure of cestrone is supported by 
measurements of the molecular refractivity and the ultraviolet absorption 
spectrum. 

When the methyl ether of cestrone is subjected to the Wolff-Kishner 
reduction, and the product distilled with selenium, 7-methoxy-l : 2-cyclo- 
pentenophenanthrene is formed. The structure of this compound was 
established by the following synthesis (Cook et al., 1934): 



%U] 



STEROIDS 



399 



,CH 2 MgBr 



/CH 2 , OH. 



CH 3 




CH3O' 

7-methoxy-l:2-cyc/opentenophenanthxene 

Thus the benzene ring in oestrone is ring A, and the (phenolic) hydroxyl 
group is at position 3; hence the skeleton of oestrone is: ' 




Into this skeleton we must fit the keto group, and since this skeleton con- 
tains only 17 carbon atoms, another carbon atom must also be placed. The 
position of the keto group was shown to be at 17, and the extra carbon atom 
was shown to be an angular methyl group at position 13, as follows (Cook 
et al., 1935). When the methyl ether of oestrone, I, is treated with methyl- 
magnesium iodide, compound II is obtained. When II is dehydrated with 
potassium hydrogen sulphate to III, this catalytically reduced to IV, and 
then IV distilled with selenium, the product is 7-methoxy-3' : 3'-dimethyl- 
1 : 2-cyc/opentenophenanthrene, V. The formation of V can be explained 
only if there is a keto group at position 17 and an angular methyl group at 
position 13. It should be noted that in the given equations, the dehydration 
is accompanied by the migration of the angular methyl group; this assump- 
tion is based on the analogy with known examples in which this occurs 
(see overleaf). 



400 



CH,0 




ORGANIC CHEMISTRY [CH. XI 

O HO, y CH, 



GH 3 




(-H a O) 



II 



CH 3 , /CH 3 



CH 3 \ yCH 3 



CH3O 



CH,0 




The structure of V has been confirmed by synthesis (Cook et al., 1935). 
Thus the structure of cestrone is: 




cestrone 



This has been confirmed by the synthesis of Anner and Miescher (1948). 
These authors started with the phenanthrene derivative VI, which had been 
prepared previously by Robinson et al. (1938), and by Bachmann et al. (1942). 
The first step of the Anner-Miescher synthesis involves the Reformatsky 
reaction, and a later one the Arndt-Eistert synthesis. 

The stereochemical problems involved in the synthesis of cestrone are not 
so complicated as in cholesterol, since only four asymmetric carbon atoms 
are present in the hormone (c/. §3). VI contains 3 asymmetric carbon atoms, 
and so four racemates are possible. Three have been isolated by Anner and 
Miescher, and one of these was converted into (±) -cestrone (C/D trans) and 
the stereoisomer (C/D cis) as shown above. These were separated and the 



§15] 



STEROIDS 



401 



CH 3 



POClj 



,C0 2 CH 3 ^^COjCHs 

+ CUJBr-COJJH.n+Zrt-*- I C 

- /\ZV/rCH,<XV3H, 




CH.N / ^W 



CH 3 0* 



C0 2 CH 3 aq. /\l/C0 2 CH 3 

methanolic I ^ 

^CHC0 2 CH 3 AyAcH^COjCHs^" <\Vm3H 2 -C0 2 H 



(COCI)j 



(\>AcH 2 -COCl 




C0 2 CH 3 



AgOH ^ 
CH s OH 



CH 2 -CO-CHN 2 
diazoketone 



^ N i / C0 2 CH 3 

I C 160 

<\/ V CH 2 -CH 2 -C0 2 CH 3 



X 




C0 2 H 



Pb(CO„), 



CH 2 -CH 2 C0 2 H 



CH 3 




HBr 



CH 3 -COjH 



HO 




(±)-oestroDe 

(±)-cestrone resolved with (— )-menthoxyacetic acid. The (+)-enantio- 
morph that was obtained was shown to be identical with the natural com- 
pound. 

Johnson et al. (1958, 1962) have carried out a total synthesis of cestrone; 
each step in their synthesis was stereoselective. Hughes et al. (1960) have 
reported total syntheses of cestrone which appear to be simpler than any 
previous method and just as efficient. 

§15. CEstriol, C 18 H M 3 , m.p. 281°, was isolated from human pregnancy 
urine by Marrian (1930). Since cestriol forms a triacetate, three hydroxyl 
groups must be present in the molecule. One was shown to be phenolic 
(cf. cestrone), and the other two secondary alcoholic, since, on oxidation, a 
diketone is produced. Furthermore, X-ray analysis indicates that the two 
alcoholic groups are in the vicinal position (i.e., 1 : 2-). When cestriol is 
heated with potassium hydrogen sulphate, one molecule of water is removed 



402 



ORGANIC CHEMISTRY 



[CH. XI 



and cestrone is produced. It therefore follows that cestriol has the same 
carbon skeleton as cestrone, and that the two alcoholic groups in cestriol 
are at positions 16 and 17. Structure I for cestriol fits the above facts, 
and is supported by the following evidence. When fused with potassium 
hydroxide, cestriol forms marrianolic acid, II, and this, on dehydrogenation 
with selenium, is converted into a hydroxydimethylphenanthrene, III, which, 
on distillation with zinc dust, gives a dimethylphenanthrene, IV. The struc- 
ture of IV was shown to be 1 : 2-dimethylphenanthrene by synthesis, and 
since marrianolic acid forms an anhydride when heated with acetic anhydride, 
it therefore follows that cestriol contains a phenanthrene nucleus and a five- 
membered ring, the position of the latter being 1 : 2 (where the two methyl 
groups are in IV). Finally, the structure of III was shown to be 7-hydroxy- 
1 : 2-dimethylphenanthrene by synthesis (Haworth et al., 1934), and so if I 
is the structure of cestriol, the degradation to the phenanthrene derivatives 
may be explained as follows: 



HO 




..OH 



HO 




C0 2 H 



Hg-COgH Se 



II 



HO 




III 




The chemical relationship between cestrone, cestriol and cestradiol (§16) 
is shown by the following reactions. 

(i) (Estrone may be reduced to cestradiol by catalytic hydrogenation, by 
aluminium t'sopropoxide (the Meerwein-Ponndorf-Verley reduction), or by 
lithium aluminium hydride. 



HO 




cestrone 



cestradiol 



'(ii) (Estriol may' be converted into cestrone by the action of potassium 
hydrogen sulphate (see above), and cestrone may be converted into cestriol 
as follows (Huffman et at., 1947, 1948). 



§15] 



STEROIDS 



403 




CH 3 

methyl ether of cestrone 



CH3O 




Na 



(CH,) s CHOH 

CH3O 



OH 



NOH 



Zn dust 
CH 3 -COjH 




/OH 



HBr 



CUs-COjH 



Leeds et al. (1954) have converted cestrone into cestriol by a simpler 
method: 



OAc 



HO 




CEstriol is more soluble than cestrone in water, and is more potent than 
either cestrone or cestradiol when taken orally. 



404 



ORGANIC CHEMISTRY 



[CH. XI 

There are two stereoisomeric (Estradiols, a 
and j8; the a-isomer is much more potent than the (1-. 



§16. (Estradiol, C 18 H 24 2 . 



HO. ,H 



HO 




HO 




OH 



ot-cestradiol 
(oestradiol-17(3) 



p-oestradiol 
(cestradiol-17et) 



a-(Estradiol was first obtained by the reduction of cestrone (see §15), but 
later it was isolated from the ovaries of sows (Doisy et al., 1935). When 
the phenolic methyl ether of cestradiol is heated with zinc chloride, a mole- 
cular rearrangement occurs, the angular methyl group migrating to the 
cycZopentane ring D (c/. §2 viii. X). This compound, when dehydrogenated 
with selenium, produces 7-methoxy-3'-methyl-l : 2-cyc/opentenophenan- 
threne, the structure of which has been ascertained by synthesis (Cook et al., 
1934). Thus the structure of cestradiol is established. 



OH 



CHjN a 



HO 




CH 3 




-oestradiol 



CH3O 




7-methoxy-3 -methyl-1: 2- 
cyc/opentenophenanthrene 



Velluz et al. (1960) have synthesised cestradiol starting from 6-methoxy- 
1-tetralone; this is therefore a total synthesis of the hormone. 

/?-(Estradiol has been isolated from the pregnancy urine of mares (Winter- 
steiner et al., 1938) . a-QEstradiol is much more active than cestrone, whereas 
/5-cestradiol is much less active. It appears that cestradiol is the real 
hormone, and that cestrone and cestriol are metabolic products. It might 
be noted here that when the second cestradiol was discovered, the earlier 
one was arbitrarily designated as the "a "-isomer. Subsequently, this 



§17] 



STEROIDS 



405 



isomer was shown to have the 17/? configuration, and the " fi "-isomer the 
17a configuration. 

A very active synthetic oestrogen is 17ce-ethinyloestradiol, and has the 
advantage that it is very active when taken orally. This synthetic com- 
pound has been prepared by the action of acetylene on cestrone in a solution 
of liquid ammonia containing potassium. 



HO 




cestrone 



K-NH. 
C 2 H 2 



HO 




OH 
/C=CH 



1 7a-ethinylcestradiol 



§17. (+)-Equilenin, C 18 H 18 2 , m.p. 258-259°, has been isolated from 
the urine of pregnant mares by Girard et al. (1932) ; it is not a very potent 
oestrogen. The reactions of equilenin show that a phenolic hydroxyl group 
and a ketonic group are present, and also that the molecule contains five 
double bonds (cf. cestrone, §14). When the methyl ether of equilenin is 
treated with methylmagnesium iodide, then the alcohol dehydrated, cata- 
lytically reduced and then dehydrogenated with selenium, the product is 
7-methoxy-3' : 3'-dimethyl-l : 2-cycZopentenophenanthrene, II (cf. cestrone, 
§14). Thus the structure of equilenin is the same as that of cestrone, except 
that the former has two more double bonds than the latter (Cook et al., 
1935). Now the absorption spectrum of equilenin shows that it is a naph- 
thalene derivative. Thus, since ring A in cestrone is benzenoid, it appears 
probable that ring B in equilenin is also benzenoid, i.e., rings A and B form 
the naphthalene nucleus in equilenin. All the foregoing reactions of equi- 
lenin may be readily explained by assuming that I is its structure, and 
further evidence that has been given to support this is the claim by Marker 
et al. (1938) that equilenin may be reduced to cestrone, III, by sodium and 
ethanol. This reduction, however, has apparently never been substantiated 
(cf. Dauben et al., 1956). 



Cxi» v CxLj 



CHoO 




HO 




equilenin 



This structure of equilenin has been confirmed by synthesis. The first 
synthesis was by Bachmann et al. (1940), but was somewhat improved by 
Johnson et al. (1947). In the following chart, compound IV is synthesised 
by the method of Bachmann, and the rest of the synthesis is that of Johnson, 



406 



ORGANIC CHEMISTRY 



[CH. XI 



who started with compound IV (Johnson's synthesis involves fewer steps 
than Bachmann's). 



H0 3 S 




NH, 



NH-CO-OHs 



HO 




(CH 3 -CO) s O 



Cleve's acid 



NH, 



(i)(CH 3 )aS0 4 -NaOH 

(ii) hydrolysis CH..0 n 




CH 3 




CH.OH 



(i) N aN02-H 2 S0 4 

(ii > KI CH3O 



/ CH 2 Br 
CH 2 




PBr 3 



CH 3 



CH3O 




.CH^ 
OH. QH 2 



C0 2 H 



(i)SOCla^ 
(ii)SnCU CH 




IV 



§17a] STEROIDS 

Johnson's synthesis starting from IV. 



407 



CH,0 




) HCOjCjH. 

CH.ONa * r A 

CH 3 o 




OHO 



n ^ NHaOHHCl 

' CHj'COjH 




— vN. 


CH "1 


[ c 


r > 




l OH 


vy 


OH 


X 1 





CH 3 I 



. CH 3 




Pd-C 



Reduction of V gives a mixture of (±)-equilenin methyl ether, VI (rings 
C/D trans), and woequilenin methyl ether (rings C/D cis) ; these are separated 
by fractional crystallisation from acetone-methanol, the equilenin derivative 
being the less soluble isomer. Product VII is (±)-equilenin, and is resolved 
via the menthoxyacetic ester. The (+)-equilenin so obtained is identical 
with the natural product. It should be noted here that equilenin contains 
only two asymmetric carbon atoms, and so the stereochemical problems 
involved are far simpler than those for cholesterol and cestrone. 

§17a. (+)-Equilin, C 18 H 20 O ?) m.p. 238-240°, has also been isolated from 
the urine of pregnant mares (Girard et al., 1932), and its structure has been 
shown to be: 



408 



ORGANIC CHEMISTRY 

o 



[CH. XI 



HO 




equilin 

§18. Artificial hormones. Many compounds with cestrogenic activity 
but not of steroid structure have been prepared synthetically. 

Stilboestrol (4 : 4'-dihydroxydiethylstilbene) was prepared by Dodds et al. 
(1939) as follows: 

2CH,0<^j>CHO ^CH 3 ^~%-GHOH-CO -^"^OCH, 

de anisoin 

CH 3 <r~^CH 2 CO^T~^OCH 3 

deoxyanisoin 



anisaldehyde 



C 2 H 6 ONh 



c 2 h b i 



QHsMgl 



*■ CH 3 



*- CH,0 




PBr 3 



(-H2O) 



->- CH3O 



ethanolic 
KOH 



HO 



C2H5 



CH-CO 



Q2HS C2H5 

CH— C 
I 
OH 

C2H5 C 2 H 5 
C==C 



O2H5 CjHs 
C=C 





OOH 3 



OCH 3 



OCH, 



OH 



stilboestrol 
The above structure of stilboestrol can exist in two geometrical isomeric 
forms ; it is the trans-iorm which is the active substance, and this con- 
figuration has been confirmed by X-ray analysis (Crowfoot et al., 1941). 



HO 




rrans-stilboestrol 



§19] STEROIDS 409 

Kharasch et al. (1943) have introduced a simpler synthesis of stilboestrol. 
Anethole is treated with hydrobromic acid and the product, anethole hydro- 
bromide, is then treated with sodamide in liquid ammonia. The resulting 
compound, I, gives stilboestrol on demethylation and isomerisation in the 
presence of alkali. The structure of I is uncertain, but it is believed to be 
the one given. 

CH 3 0<^ J>CH=CH-CH 3 -^ CH 3 0<^ J)>CHBrCH 2 -CH 3 
anethole 

NaNH 3 



liq. NH 3 



c H30Yy-CH-CH-<^y>0CH3 



CH CH 2 

II I 

1 



Stilbcestrol is more active than cestrone when administered subcutane- 
ously, and it can also be given orally. 

Hexoestrol (dihydrostilbcestrol) may be prepared from anethole hydro- 
bromide as follows: 

2CH 3 o/~ = ~\cHBrC 2 H 5 -^+ CHaO^^^CH-CH-^^^OCHs 
HO^-CH-C^^^OH 



m^t c 2 h 6 



KOH 

C 2 H 6 C2H5 
hexoestrol 

The active form is the meso-isomer (as shown by X-ray crystallography by 
Crowfoot et al., 1941), and this compound appears to be the most potent 
of the oestrogens. 

GESTOGENS 

§19. Progesterone, C 21 H 30 O 2 , m.p. 128°, was first isolated in a pure 
form by Butenandt et al. (1934) from the corpora lutea of pregnant sows. 

The chemical reactions of progesterone show that there are two keto 
groups present, and since on catalytic reduction three molecules of hydrogen 
are added to form the dialcohol C 21 H 36 O s , it therefore follows that pro- 
gesterone contains one double bond (four hydrogen atoms are used to convert 
the two keto groups to alcoholic groups) . Thus the parent hydrocarbon of 
progesterone is C 21 H 36 , and since this corresponds to the general formula 
C„H 2 „_ 6 , progesterone is therefore tetracyclic. Furthermore, X-ray studies 
have shown that progesterone contains the steroid nucleus, and this is 
further supported by the fact that progesterone may be prepared from, 
e.g., stigmasterol and cholesterol. These preparations also show the struc- 
ture of progesterone, but do not provide conclusive evidence for the position 
of the double bond in progesterone, since the results can be interpreted 
equally well on the assumption that the double bond is 4 : 5 or 5 : 6. The 



410 



ORGANIC CHEMISTRY 



[CH. XI 



absorption spectrum of progesterone, however, shows that it is an a : /S- 
unsaturated ketone, and this suggests that the position of the double bond 
is 4 : 5 (see below). Finally, progesterone has also been synthesised from 
diosgenin and from pregnanediol, and the preparation from the latter, taken 
in conjunction with the others, definitely shows that the position of the 
double bond in progesterone is 4 : 5. 

(i) Progesterone from stigmasterol (Butenandt et al., 1934, with improve- 
ments by other workers). 



CHj-COO 



CH 3 CO 




acetate of 3p -hydro xybisnorchol-5- 
enic acid 



CH 3 
N C=C(C 6 H 5 ) 2 



CH 3 
CO 




pregnenolone progesterone 

Pregnenolone has also been isolated from the corpus luteum. 



§19] STEROIDS 411 

(ii) Progesterone from cholesterol (Butenandt et al., 1939). Cholesterol is 
first converted into dehydroepiandrosterone (see §13), and then as follows: 



HO' 




(i)(CH 3 -CO) 2 Q 
(ii) HCN 



cholesterol 



HO 

dehydroepiandrosterone 



HO v CN 



CH 3 COO 



HO 




CH,M g Br 



pregnenolone 



progesterone 



412 



ORGANIC CHEMISTRY 



[CH. XI 

(iii) Progesterone from diosgenin (Marker et al., 1940, 1941). Diosgenin 
(a sapogenin) occurs as a glycoside in the root of Trillium erectum. 




diosgenin 



CrO, 



CH,COO 




pregnenolone 




progesterone 

Saponins and Sapogenins. Saponins are plant glycosides, and the aglycon 
is known as the sapogenin (cf. §24. VII). Saponins are very powerful emulsifiers, 
and derive their name from this property; they are used as detergents.; There 
are two groups of saponins, the steroid and the triterpenoid saponins, and these 
two groups may be distinguished by the fact that only the former group gives 
Diels' hydrocarbon on distillation with selenium; the triterpenoid group gives 
mainly naphthalene or picene derivatives (cf. §1). 

Digitonin is a steroid saponin; it causes haemolysis of the red blood cells. 



§19] 



STEROIDS 



413 



(iv) Progesterone from pregnanediol (Butenandt et al., 1930). 



CH, 

I 



CHOH 



CH, 



HO 




H 
pregnanediol 



CH,COO 




IHO-COCH. 



KOII 



HO' 



CH 3 
CHO-COCH 3 




(ii)CrOa 



O" 



Br 





CH 3 
CO 








CH 3 
CO 




C,H 6 N 
(-HBr) * 






-I 


<y 










pro 


jesteroiu 


* 



In the above reactions, bromination might have occurred in position 2; in 
this case the position of the double bond would have been 1:2. This is 
impossible, since the preparation of progesterone by methods (i) to (iii) shows 
that the double bond must be 4 : 5 or 5 : 6. Thus the preparation from 
pregnanediol proves that the double bond is 4:5. 



414 



ORGANIC CHEMISTRY 



(v) Progesterone from ergosterol (Shepherd et al., 1955). 
be the most practical synthesis. 



[CH. XI 
This appears to 



HO 




ergosterol 



ergosterone 



MeO 1 





jjoergosterone 
CHO 




C 6 H 10 NH 



CH, 




progesterone 

§20. Pregnane-3ot : 20a-diol, C^HsgOa, was isolated from human preg- 
nancy urine by Marrian (1929) ; it is biologically inactive, and is the main 
metabolic product of progesterone. The functional nature of the two oxygen 
atoms was shown to be secondary alcoholic, and since pregnanediol is satur- 
ated, the parent hydrocarbon is C 21 H3 6 , and so the molecule is tetracyclic. 
Pregnanediol gives the haloform reaction; thus a CH 3 'CHOH- group is pre- 



§22] STEROIDS 415 

sent (see Vol. I) . When oxidised, pregnanediol is converted into the diketone 
pregnanedione and this, on the Clemmensen reduction, forms pregnane, 
C 21 H 36 . This is identical with 17-ethylsetiocholane, a compound of known 
structure. Thus pregnanediol contains the steroid nucleus, and the position 
of the side-chain is 17. Finally, the relationship between pregnanediol and 
progesterone shows that the former contains one hydroxyl group at position 3. 
Further work showed that the configuration of the 3-hydroxyl group is a. 
Thus: 



CH 3 
CHOH 



HO' 




H 
pregnanediol 



pregnanedione 



Zn-Hg ; 
HCl 




ADRENAL CORTICAL HORMONES 

§21. Introduction. In the adrenal glands (of mammals) there are two 
regions, the medulla which produces adrenaline (see §12. XIV), and the cortex 
which produces steroid hormones. The production of these adreno-cortical 
hormones is controlled by the hormone produced in the anterior lobe of the 
pituitary, the so-called adrenocorticotrophic hormone, ACTH. The absence 
of the corticoids causes loss of sodium from the body. 

§22. Adrenal cortical hormones. About 28 steroids have been isolated 
from the extract of the adrenal cortex, and their structures have been eluci- 
dated mainly by Kendall et al. (1935), Wintersteiner (1935- ) and Reichstein 
et al. (1936- ). Only six of these 28 compounds are physiologically active, 
fourteen are inactive and are produced by the reduction of the active horm- 
ones, and the remaining six are cestrone, progesterone, 17oc-hydroxypro- 
gesterone and adrenosterone, and two other compounds that are apparently 
produced by oxidation during the isolation of the hormones from the cortical 
extract. Adrenosterone is as shown, and possesses androgenic activity 
(see overleaf). 



416 



ORGANIC CHEMISTRY 



[CH. XI 




andrenosterone 

The six active compounds are as follows (they have been designated by 
letters as well as named systematically). 




Substance Q ; 

1 1 -Deoxycorticosterone ; 
2 1 -Hy droxyprogesterone 



Substance H; 

Corticosterone ; 
11 : 21-Dihydroxy- 
progesterone 



Compound A; 

1 1 -Dehydrocorticosterone ; 
2 1 -Hydroxy- 1 1 -keto- 
progesterone 




Substance S; 

1 l-Deoxy-17-hydroxy- 
corticosterone 



Substance M; 

1 7-Hydroxy- 
corticosterone 



Substance F; 

Compound E; 
1 1 -Dehydro- 1 7-hydroxy- 
corticosterone ; 
cortisone 



Owing to the presence of the a-hydroxyketone group, the adrenal cortical 
hormones are strong reducing agents. The hydroxyl group at position 21 
behaves in the usual way, but the 11-keto group does not form an oxime or 
a phenylhydrazone. The 11-keto group is resistant to catalytic reduction 
in neutral solution, but can be reduced in acid solution ; it is readily reduced 
to a hydroxyl group by lithium aluminium hydride, and to a methylene 
group by the Clemmensen reduction. 

The keto-hormones are separated from non-keto compounds by means of 
Girard's reagents P and T (see Vol. I). 

The structures of the cortical hormones have been elucidated by degrada- 



§22] 



STEROIDS 



417 



tion and by partial syntheses from sterols of known structure, e.g., deoxy- 
corticosterone from stigmasterol (Reichstein et al., 1937, 1940). The first 
step is the conversion of stigmasterol to pregnenolone (see §19 i). 



C0 2 H 



HO 




HO 




(i)(CHyCO)»Q 
(ii) SOCl a 



pregnenolone 



COC1 



CHa-COO' 




(i)CH 2 N g 
(ii)KOH 



HO 




O-0HN 2 











CH 2 OH 


COCHN 2 CO 

/\ A y\ A 


( X 

Oipenauer 


\ H 2 SO t> 






^n 


n 









0' 



o v 



deoxycorticosterone 



A very interesting point about the above synthesis is the unusual stability 
of the diazoketone. 

Cortisone (Substance F, Compound E) has been used for the treatment 
of rheumatoid arthritis and rheumatic fever. Many partial syntheses are 
known, and there is also a total synthesis; e.g., the following partial synthesis 
starts from 3a : 21-diacetoxypregnane-ll : 20-dione (Sarett, 1948) (see over- 
leaf). 



418 



CH 3 COO v H 




ORGANIC CHEMISTRY 

CH 2 0-COCH 3 

I 
CO 

o 



CH 3 -COO' 




[CH. XI 
CH2OCOCH3 

C(OH)-CN 



CH 2 OH 

I 



C-CN 



(i) POClf-C»H,N(-H a O ) 
(ii) KOH 



HO' 



CH 2 OCOCH 3 

I /ON 

°-°>o 2 
-o 



(i)(CH,-CO) a O 




CH 2 0-COCH 3 

00 
-OH 



CH 2 0-COCH 3 

I 
OCN 




CHoOH 




CHjOH 




(i)-HBr 



cortisone 



A UXINS 



§23. It had been suggested for some years by botanists that various substances 
had plant growth-promoting properties, but it was not until 1933 that such 
compounds were actually isolated. In 1933, K6gl et at. isolated an active com- 
pound from human urine, and they named it auxin a and showed that its struc- 
ture is I. Soon afterwards, Kogl et al. isolated auxin b (II) from maize germ oil. 



§23] STEROIDS 419 

C,H,-CH-^ ^-CH-CsHs 

^CHOH-CHuCHOHCHOHCOjH 

I 

auxin a 

C.H.- CH~<; >- CH-C 2 H 5 

^CHOH-CHjCOCHjCOjH 
II 
auxin b 

The name auxin is now taken as the generic name for the plant hormones. 
Auxins generally occur in the plant kingdom, but are also present in urine, etc. 
Further work by Kogl et al. (1934) led to the isolation from urine of another 
growth-promoting substance which the authors named " hetero-auxin ", and 
subsequently showed that this compound is indole-3-acetic acid. 



to 



CH,-C0 8 H 



indole-3-aoetic acid 

The discovery that indole-3-acetic acid had plant growth-promoting properties 
led to the examination of compounds of related structure, and it was soon found 
that various derivatives of indole-3-acetic acid are also very active; it was also 
found that a number of arylacetic acids and aryloxyacetic acids are active, e.g., 
phenylacetic acid, III, 1-naphthaleneacetic acid, IV, and 2-naphthoxyacetic 
acid, V. 

pH 2 -COjH CHjCOjH 

^jOCHjCOaH 





IV V 

Recent work has suggested that indole-3-acetic acid is the natural plant 
hormone, and not auxins a and b. In fact, there now appears to be some doubt 
as to the existence of auxin a (auxentriolic acid) and auxin b (auxenolonic acid) ; 
neither of these compounds has been isolated since Kogl obtained them. 

The relation between chemical structure and growth-promoting properties has 
still to be solved, but nevertheless much progress has been made in this direction. 
Koepli et al. (1938) believe that a plant hormone must have a ring structure 
containing at least one double bond, and a side-chain containing a carboxyl 
group (or a group capable of being converted into a carboxyl group) removed 
from the ring by at least one carbon atom (cf. compounds I-V) . These require- 
ments, however, have been modified by Veldestra (1944- ). 



READING REFERENCES 

Fieser and Fieser, Steroids, Reinhold (1959). 

Gilman (Ed.), Advanced Organic Chemistry, Wiley (1943, 2nd ed.). Ch. 19. The 

Steroids. 
Rodd (Ed.), Chemistry of Carbon Compounds, Elsevier. Vol. IIB (1953). Ch. 17. 

Sterols and Bile Acids. Ch. 18. Sex Hormones; Adrenocortical Hormones. 
Stewart and Graham, Recent Advances in Organic Chemistry, Longmans, Green. Vol. Ill 

(1948, 7th ed.). Ch. I. The Bile Acids and Sterols. Ch. III. The Hormones. 
Vitamins and Hormones, Academic Press (Vol. I, 1943- ). 



420 ORGANIC CHEMISTRY [CH. XI 

Cook (Ed.), Progress in Organic Chemistry, Butterworth. Vol. II (1953). Ch. 4. The 
Partial Synthesis of Cortisone and Related Compounds from Accessible Steroids. 
Ch. 5. The Relationship of Natural Steroids to Carcinogenic Aromatic Com- 
pounds. Vol. Ill (1955). Ch. 1. Total Synthesis of Steroids. Vol. 5 (1961). 
Ch. 4. The Chemistry of the Higher Terpenoids. 

Shoppee, Chemistry of the Steroids, Academic Press (1958). 

Klyne, The Chemistry of the Steroids, Methuen (1957). 

Lythgoe, Some Recent Advances in the Chemistry of the D-Vitamins, Proc. Chem. Soc, 
1959, 141. 

Butenandt, The Windaus Memorial Lecture, Proc. Chem. Soc, 1961, 131. 

Loewenthal, Selective Reactions and Modifications of Functional Groups in Steroid 
Chemistry, Tetrahedron, 1959, 6, 269. 

Handbook for Chemical Society Authors, Chem. Soc. (1960). Ch. 4. Nomenclature of 
Steroids. 

Dodds, Synthetic (Estrogens, /. Pharm. Pharmacol., 1949, 1, 137. 

Wicker, The Mechanism of Catalytic Hydrogenation of Cyclic Compounds, J.C.S., 1956, 
2165. 

Popjak, Chemistry, Biochemistry and Isotopic Tracer Technique, Royal Institute of 
Chemistry Monograph, No. 2 (1955). 

Ciba Foundation Symposium on the Biosynthesis of Terpenes and Sterols, Churchill 
(1959). 

Skoog (Ed.), Plant Growth Substances, University of Wisconsin (1951). 

Pincus and Thimann (Ed.), The Hormones, Academic Press. Vol. I (1948). Plant 
Growth Hormones (p. 5). 

Audus, Plant Growth Substances, Leonard Hill Ltd. (1953). 



CHAPTER XII 

HETEROCYCLIC COMPOUNDS CONTAINING 
TWO OR MORE HETERO-ATOMS 

§1. Nomenclature, (i) When the heterocyclic compound contains two 
or more hetero-atoms, the starting point for numbering is the hetero-atom 
of as high a group in the periodic table and as low an atomic number in 
that group. Thus the order of naming will be O, S, Se, N, P, As, Sb, Si, 
Sn, Pb, Hg. 

(ii) With the atom of the preferred kind as number 1, the ring is numbered 
in such a way that the hetero-atoms are given the lowest numbers possible. 

(iii) Of two or more numberings conforming to rules (i) and (ii), the one 
that is chosen is that which assigns low numbers more nearly in the order 
of precedence established by rule (i). 

(iv) Of two or more numberings conforming to rules (i)-(iii), the one that 
is chosen is that which gives hydrogen atoms the lowest numbers possible. 

(v) When a heterocyclic compound containing at least one nitrogen atom 
does not end in ine and gives basic compounds on progressive hydrogenation, 
the latter derivatives will be indicated by the successive endings ine, idine; 
e.g., pyrazole, pyrazoline, pyrazolidine. 

The hetero-atoms in heterocyclic compounds are indicated by prefixes, 
e.g., O by oxa, S by thia, N by aza. 

AZOLES 

Azole is the suffix used for five-membered rings containing two or more 
hetero-atoms, at least one of which is nitrogen. 

PYRAZOLE GROUP 

§2. Pyrazole. Pyrazole may be synthesised in a number of ways, some 
of the more convenient methods being the following: 

(i) By passing acetylene into a cold ethereal solution of diazomethane 
(von Pechmann, 1898). 



III + CH 2 N 2 
CH 



CH- 
ti* 



CH 



CH 5 . 2N 
H 



(ii) By heating epichlorohydrin with hydrazine in the presence of zinc 
chloride (Balbiano, 1890). 



CH 2 ^ 
1 > + NH 2 \NH 2 *- 

ch/ 

| 


CH 2 -NH-NH 

CHOH 

1 


CH 2 C1 


CH 2 C1 


N 2 H 4 ^ n n 

*■ H II + H 2 + 2NH 3 


H 





CHOH -CH 2 

CH 2 NH 

\ / 
NH 



421 



422 ORGANIC CHEMISTRY [CH. XII 

(iii) By the decarboxylation of various pyrazolecarboxylic acids, e.g., by 
heating pyrazole-3 : 4 : 5-tricarboxylic acid (see also §2a ii). 



HO,C 
HO 






|C0 2 H gjjO 



o- 



3 CO, 



(iv) Jones (1949) has shown that pyrazole may be conveniently prepared 
by the condensation of 1:1:3: 3-tetraethoxypropane, 

(C a H B 0) a CH.CH a -CH(OC a H 6 ) a , 

with hydrazine dihydrochloride. 

Properties of pyrazole. Pyrazole is a colourless solid, m.p. 70°. It 
is a tautomeric substance; the existence of tautomerism cannot be demon- 
strated in pyrazole itself, but it can be inferred by the consideration of pyr- 
azole derivatives. If pyrazole is tautomeric, then the positions 3 and 5 will 
be identical; if pyrazole is not tautomeric, then these positions are different. 
Now Knorr et al. (1893) showed that on oxidation, both 3-methyl-l-phenyl- 
pyrazole and 5-methyl-l-phenylpyrazole gave the same product, viz., methyl- 
pyrazole. Thus positions 3 and 5 must be equivalent in pyrazole, and this 



o 



3 II 

N 
H 



^H 



II 



can only be explained by assuming that pyrazole is tautomeric (I and II). 
It therefore follows that in pyrazole there can only be two carbon-alkyl 
derivatives, 3- (or 5-) and 4-. If, however, the imino hydrogen is replaced 
by an alkyl or aryl group, then three carbon-alkyl derivatives are possible, 
3, 4 and 5, since tautomerism is now impossible, and so positions 3 and 5 
are no longer equivalent. 

Pyrazole exhibits aromatic properties, e.g., it is readily halogenated, 
nitrated and sulphonated; the group enters at position 4. The following 
resonating structures are possible for pyrazole. 



v" 



H 



-Q 1 

H 



H 



If these structures are contributed equally, then electrophilic attack should 
occur equally well at positions 3, 4 or 5 (in pyrazole itself, positions 3 and 5 
are equivalent). As we have seen above, electrophilic attack occurs ex- 
clusively at position 4. The reason for this is not certain. Possibly the 
resonating structures are not contributed equally (as was assumed). On 
the other hand, Dewar (1949) has suggested that substitution occurs in the 
4-position because the transition state for 4-substitution is more symmetrical, 




3-substitution 




4-substitution 



and consequently more stable, than the transition state for 3- (or 5-) sub- 



§2a] HETEROCYCLIC COMPOUNDS 423 

stitution. Orgel el al. (1951), however, have calculated the electron dis- 
tribution in pyrazole, and it can be seen from their results that 4-substitu- 
tion will be favoured by electrophilic reagents. Brown (1955, 1960) has 
also calculated the electron densities in pyrazole. 

-Oil, ,0-07 



V 



0-06 k /N-0-38 
W 
H 
0-36 

It is interesting to note that pyrazole-4-diazonium salts are stable to boil- 
ing water. Pyrazole is feebly basic, and forms salts with inorganic acids; 
the imino hydrogen may be replaced by an acyl group. Pyrazole is very 
resistant to oxidising and reducing agents, but may be hydrogenated cata- 
lytically, first to pyrazoline, and then to pyrazolidine. Both of these com- 
pounds are stronger bases than pyrazole. 

# catalyst ^ N catalyst C H 2 /NH 

H H H 

pyrazoline pyrazolidine 

§2a. Synthesis of pyrazole derivatives. 

(i) A very important method for preparing pyrazole derivatives is by the 
reaction between /J-diketones (or /3-ketoaldehydes) and hydrazines (Knorr 
et al, 1883). 

R R R 

1 I „ I 

/CO COH HNR ^C— NR" 

(a) CH 2 =^^= CH + | *■ CH | + 2H 2 

X CO V CO H 2 N X C=N 

I, I, ', 

R R' R 

R R R 

I I I 

/CO CO H 2 N /C=N 

(b) CH 2 =?=^ CH + I *- CH | + 2H 2 

N CO "^COH HNR" ^C— NR" 

R' R' R' 

Thus, according to the above, a mixture of isomeric pyrazoles will be pro- 
duced. Contrary to general opinion, the product is usually only one of 
the isomers, e.g., benzoylacetone and phenylhydrazine form only 3-methyl- 
1 : 5-diphenylpyrazole (Drumm, 1931). 

CH 2 -CO-CH 3 CH— COCH 3 CH-C-CH 3 

T =f=*= II *~ || || 1 Q xt 

C 6 H 5 -CO C 6 H 5 COH +/NH 2 C 6 H 5 C s ^N ^"^ 

NH N 

CeH 5 C 6 H 5 

In a few cases, two isomers have been isolated, e.g., 3-a-benzoylacetyl-l : 5- 
diphenylpyrazole, I, reacts with phenylhydrazine to produce a mixture of 
1 : 1' : 5 : 5'-tetraphenyl-3 : 3'-dipyrazolyl, II, and 1 : 1' : 3' : 5-tetraphenyl- 
3 : 5'-dipyrazolyl, III (Finar, 1955). 



424 ORGANIC CHEMISTRY [CH. XII 

C 6 H 5 -CO-CH 2 -CO-C CH 

|| II + C 6 H 5 NH-NH 2 *■ 

N C-C 6 H 5 

I 
I C 6 H 5 

CH— C— C — OH C 6 H 5 -C CH 

II II II II + 11 II 
C 6 H 5 -0 .N N CC 6 H 5 N C-C CH 

V V V II ll 

II IN. X>C 6 H 5 
C 6 H 5 6 6 H 5 C 6 H 5 \ N / 

II III C 6 H 5 

If /S-ketoesters are used instead of /S-diketones, then 5-pyrazolones are 
formed (Knorr et al., 1883), e.g., ethyl acetoacetate reacts with hydrazine 
to form 3-methylpyrazol-5-one. 

CH 2 C'Cri3 CH 2 C'Gri3 CH 2 C'CH3 

I Jl >-H 2 0+ | B — »-| II +C 2 H 6 OH 

C2H 5 2 C O C 2 H 5 2 C JZ CO N 

/NH 2 H 2 N W 

H 2 1T H 

(ii) Pyrazolecarboxylic acids are produced by the reaction between diazo- 
acetic ester and acetylenic compounds, e.g., with ethyl acetylenedicarb- 
oxylate, ethyl pyrazole-3 : 4 : 5-tricarboxylate is formed. 

C 2 H 5 2 C-C CH-C0 2 C 2 H 5 C 2 H 5 2 C-C — C-C0 2 C 2 H 5 

III + II *- II II 

C 2 H 5 2 C-C N 2 C 2 H 6 2 C-C s N 

y 

H 

If an ethylenic compound is used instead of an acetylenic one, then a 
pyrazoline derivative is produced, e.g., ethyl fumarate gives ethyl pyrazoline- 
3:4: 5-tricarboxylate. 

C 2 H 5 2 C-CH CH-C0 2 C 2 H 6 C 2 H 6 2 C-CH— CC0 2 C,H 5 

+ " — ' 1 



CH-00 2 C 2 H 6 N 2 2 H 5 2 CCH 

N l 
H 



\ N / 



(iii) Pyrazoles are produced by the reaction between acetylenic carbonyl 
compounds and hydrazines (Moureu et al., 1903) ; a mixture of isomers is 
said to be obtained. 

r-c=c-co-r' R-C=CC-r' R-CCH 2 C0R' 



r"-nh-nh 2 R"-NH X 'nh-r" 



i 



\ I 

CH— C-R' R-C CH 

II II II II 

R-C /N N C-R' 

1* N 

i- i- 



§2a] HETEROCYCLIC COMPOUNDS 425 

(iv) Pyrazolines are obtained by the condensation of a : /^-unsaturated 
ketones or aldehydes with hydrazines, e.g., acraldehyde and hydrazine give 
pyrazoline. 

OH — CHO CH — CH CH 2 — OH 

CH 2 + NH 2 CH 2 N CH 2 # 

NH 2 H 2 lT V 

H 

Pyrazolines may be oxidised to pyrazoles by bromine or mercuric oxide. 
Properties of the pyrazole derivatives. Pyrazoles with substituent 
methyl groups may be oxidised by potassium permanganate to the corre- 
sponding pyrazolecarboxylic acids, e.g., 

I I 

6 H 5 6 H5 

Pyrazole-3- and 5-carboxylic acids are readily decarboxylated by heating 
above their melting points ; the pyrazole-4-carboxylic acids are more stable, 
but can nevertheless be decarboxylated at elevated temperatures, e.g., 



HO.C^CO.H^ HO^ ^ J—! 

H0 ° C V V V N 

H H H 

Although pyrazole itself is not reduced by sodium and ethanol, 2V-phenyl 
substituted pyrazoles are readily reduced to the corresponding pyrazolines, 
e.g., 

CHr-CH 

N / C,H,OH ^*/ 

I I 

CeH 5 CeHs 

1-Unsubstituted pyrazoles apparently cannot be chloromethylated; carbinols 
are produced, e.g. (Dvoretzky et al., 1950): 

n CH 3 HC , 

+ CH 2 *- 



o 



CH 3 V N/ N 
H 



n nCH 3 HOOH 2 n nCH 3 HOCH 2 n [rCH 3 

? H 7 

CH 2 OH CH 2 OH 

(main product) 

On the other hand, 1-phenylpyrazole can readily be chloromethylated in 
the 4-position (Finar et al., 1954). 



426 



ORGANIC CHEMISTRY 



[CH. XII 



™CH 2 C1 



N + CH 2 + HCI 
N 

C,H 6 



I 



+ H 2 



4-Chloromethyl-l-phenylpyrazole can be converted into 1-phenylpyrazole- 
4-aldehyde by means of the Sommelet reaction (see Vol. I). The 4-aldehyde 
is more conveniently prepared by the direct formylation of 1-phenylpyra- 
zole with dimethylformamide and phosphoryl chloride (Finar et al., 1957). 
1-Phenylpyrazole can also be mercuratedin the 4-position (Finar et al., 1954). 
When boiled with concentrated aqueous potassium hydroxide, quaternary 
pyrazoles are converted into hydrazines (Knorr et al., 1906), e.g., 



O + cH 3 i-^ri 



I 
C 6 H B 



SCHsfr-^V H-C0 2 H+C e H s NH-NH-CH s 

N 
I 
c bH s 



Knorr used this reaction to prepare syw.-disubstituted hydrazines; at the 
same time, this reaction proves the structure of the pyrazole-quaternary 
salts. 

Esters of the pyrazolinecarboxylic acids eliminate nitrogen on heating 
to give cyclopropane derivatives; sometimes much better results are achieved 
if the compound is heated with copper powder. 

R-CH CHC0 2 C 2 H 6 RCH— C-C0 2 C 2 H 5 

R-CH N. 



RCH, 



RCH- 
RCH N 
H 



Cu 
heat 



RCH 



I CH-C0 2 C 2 H 5 + N 2 



Antipyrine (2 : 3-dimethyl-l-phenylpyrazol-5-one), m.p. 127°, is very 
much used in medicine as a febrifuge. It is prepared industrially by con- 
densing ethyl acetoacetate with phenylhydrazine, and methylating the pro- 
duct, 3-methyl-l-phenylpyrazole-5-one, with methyl iodide in alkaline 
ethanolic solution, or with methyl sulphate in the presence of sodium 
hydroxide. 



CH 3 - C • OH 2 

CO.C 2 H 5 



+ C.H.NH-NH, 



Oxlg" C " CHg 



N C0 2 C 2 H 6 
NH 



I 
C 6 H 5 



CH,C- 



-CH 2 + 



C 2 H 5 OH 



CH 3 I 



CH,C= 



?H 



I 
C 6 H 5 

3-methyl- l-phenylpyrazol-5-one 



CH 3 JJ CO 
N 
I 
CeHs 

antipyrine 



At first sight one might have expected to obtain the O-methyl or the 4-methyl 
derivative, since the tautomeric forms IV (keto) and V (enol) are theoretically 



HETEROCYCLIC COMPOUNDS 



427 



§2b] 

possible. Methylation of 3-methyl-l-phenylpyrazole-5-one with diazo- 
methane results in the formation of the 0-methyl derivative (this is also 

CH 3 C=CH 

HN CO 

V 

I 

C 6 H 5 

VI 

produced in a small amount when methyl iodide is used as the methylating 
reagent). This raised some doubts as to the structure of antipyrine, since 
for its formation, the tautomeric form VI must also be postulated. The 
structure of antipyrine was shown to be that given above by its synthesis 
from sym.-methylphenylhydrazine and ethyl acetoacetate. 



CH 3 C 0H 2 
N CO 

NT 

i 


i- 


CH 3 C OH 

II 11 
N COH 


i 

CsHs 




C 6 H 5 


IV 




V 



CH. 



rc=c: 



H 



OH CO 

OC 2 H 5 ' 

CH 3 -NH V 

N NH 

C 6 H 6 



CH 3 C — CH 
CH 3 N CO 

I 
C«H« 



+ H 2 + C 2 H 6 OH 



The pyrazole nucleus has always been considered to be a synthetic one, 
but Fowden et al. (1959) have now isolated a-amino-j8-l-pyrazolylpropionic 
acid from water-melon seed; this acid has been synthesised in good yield 
by Finar et al. (1960). 

§2b. Indazoles (benzopyrazoles). Indazole may be prepared by the 
removal of a molecule of water from o-toluenediazohydroxide in neutral 
solution (the yield is very poor). 

H 

-HjO 





Indazole may conveniently be prepared by heating o-2V-nitroso-2V-benzoyl- 
toluidine in benzene solution. 



kAcH 3 



CO-C 6 H 5 
NO 




J*+C 6 H s -C0 2 H 



Indazole, m.p. 146°, exhibits the same type of tautomerism that exists 
in pyrazole, since two series of 2V-derivatives (1 and 2) are known: 





Nitration and sulphonation of indazole produce the 5-substitution product ; 
bromination gives the 3 : 5-dibromo compound. 



428 ORGANIC CHEMISTRY [CH. XII 

IMIDAZOLE GROUP 

This group of compounds is also known as the iminazoles or the glyoxalines. 

§3. Imidazole (iminazole, glyoxaline) is isomeric with pyrazole, and 
occurs in the purine nucleus and in the amino-acid histidine; 4-amino- 
imidazole-5-carboxamide occurs naturally as a riboside (or ribotide). 

Imidazole may be prepared by the action of ammonia on glyoxal. The 
mechanism of this reaction is uncertain, but one suggestion is that one mole- 
cule of glyoxal breaks down into formic acid and formaldehyde, and then 
the latter reacts as follows: 

(i) CHO-CHO + H 2 >- H- CHO + H- C0 2 H 

(ii) CHO NH 3 CH-N 

| + h-CHO >- II II + 3H 2° 

CHO „„ CH CH 

NH 3 \ N / 

H 

A certain amount of support for this mechanism is given by the fact that 
glyoxaline may be prepared directly from glyoxal, ammonia and formalde- 
hyde. 

A general method for preparing imidazoles is by the reaction between 
an oc-dicarbonyl compound, ammonia and an aldehyde (Radziszewsky, 1882). 

R— c=0 „ RC N 

, | +2NH 3 + R-CHO — ->• ,|| || + 3H 2 
R— C=0 RC CR 

H 

Imidazole itself is best prepared by the action of ammonia on a mixture of 
formaldehyde and tartaric acid dinitrate (" dinitrotartaric acid "), and then 
heating the dicarboxylic acid thereby produced. 

C0 2 H C0 2 H 

I I 

cho-no 2 _ 2MN0 ^ co 2NH3 ho 2 c-c — a 3oo°, n — n ann 

<W>, "Ao ^^H0 2 CC 1h~^U 2 

C0 2 H - C0 2 H $ H 

Another good method is to brominate paraldehyde in ethylene glycol 
and to heat the product, 2-bromomethyl-l : 3-dioxalan, with formamide in 
the presence of ammonia (Bredereck et al., 1958) ; bromoacetaldehyde is 
probably an intermediate: 



CH«— O. CHO 

| >H.CH 2 Br — ^ I -S» 

CH.-0 7 CH 2 Br NHs 



-N 

) 



Imidazole, m.p. 90°, is a weak base, but it is more basic than pyrazole. 
Imidazole is a tautomeric substance, since positions 4 and 5 are equivalent 
(positions 5, 4 and 2 have also been designated a, /5 and fi, respectively). 



CH* 2Cf 



3H5 2CHf $CH*2CHm 

H 



§3a] HETEROCYCLIC COMPOUNDS 429 

Methyl iodide attacks imidazole in potassium hydroxide solution to form 
1-methylimidazole which, when strongly heated, isomerises to 2-methyl- 
imidazole (cf. the Hofmann rearrangement; see Vol. I). 



n — F 





ch 3 i 



o ^ a 



KOH „ „ „ 1))CH 



'N W 

! H 3 



i. 



An interesting method of preparing 4(5)-methylimidazole is by the action 
of zinc hydroxide and ammonia on glucose; the reaction is assumed to occur 
via the breakdown of glucose into methylglyoxal and formaldehyde, which 
then react as follows: 



CH 3 -CO CH 3n N 

/ I xr/ +2NH 3 +CH 2 ^ I J + 3H2 ° 

H 



CHO 



The imidazole ring is extremely stable towards oxidising and reducing 
agents ; hydrogen peroxide, however, readily opens the ring to form oxamide. 



o 



N h 3 q, , CONH 2 



CO-NH 2 

'N' 
H 

Acetyl chloride and acetic anhydride have no action on imidazole, but 
benzoyl chloride in the presence of sodium hydroxide opens the ring to 
form dibenzoyldiaminoethylene. 



ntnj/ 



N CH-NH-COC 6 H: 

CH-NH-COC 6 H, 

li 



[J + 2C 6 H 6 -COCl+3NaOH H| + H-C0 2 Na+2NaCl 



Nitration and sulphonation of imidazole produce the 4(5)-derivative. 
Electrophilic attack at positions 4 or 5 can be accounted for by the con- 
tributions of the resonating structures II and IV. Resonating structure III 



n N " : | N f=^ [=N 



H H H H 

I II III IV 

shows that position 2 should also be subject to electrophilic attack. This 
is found to be the case with halogenation, e.g., bromine reacts with imidazole 
in chloroform solution to give 2:4: 5-tribromoimidazole. 



Brn N 

+ 3HBr 

Br 



H H 

Imidazole couples with diazonium salts in the 2-position, but iV-alkyl- 
imidazoles do not couple at all. 

§3a. Benzimidazoles (benziminazoles). These are readily formed by 
heating o-phenylenediamines with carboxylic acids, e.g., benzimidazole itself 



430 ORGANIC CHEMISTRY [CH. XII 

(m.p. 170°) is produced by heating o-phenylenediamine with 90 per cent, formic 
acid. 

+ jm »- [ H CH+2H 2 

NH 2 (f W 

OXAZOLE GROUP 

§4. wo-Oxazoles. tso-Oxazoles are formed by the dehydration of the 
monoximes of /?-diketones or /?-ketoaldehydes. 



R-C CH 2 R-C CH RC, .CH 

I T ^=^ H >■ II II 

ft COR N C-R N2 5CR 

OH OH OH O' 



+ H 2 



*so-Oxazole itself may be prepared by the action of hydroxylamine on 
propargylaldehyde. 



C-CHO 

III + NH 2 OH- 

CH 



C CH 

III II 
CH N 

HO 



CH — CH 
II II 

CH N 



wo-Oxazole is a colourless liquid, b.p. 96°, and smells like pyridine; it is 
weakly basic. wo-Oxazoles, when substituted in the 3 : 5-positions, are 
stable to alkalis, but when the 3-position is vacant, the ring is opened to 
form ketonitriles (cf. oximes, §§2f, 2g. VI). 

OH— CH 



II II -Ss^R-CO-CH^ON 

RC. 2T 
XT 

§4a. Oxazoles. Oxazoles may be prepared by the condensation of acid 
amides with oc-halogenoketones, e.g., acetamide and co-bromoacetophenone 
form 2-methyl-4-phenyloxazole ; the mechanism of the reaction is not certain 
but it may occur through the enol forms. 

C 6 H 5 -CO NH 2 __ C 6 H 5 -C0H + NH 

CH 2 Br OC-CH s CHBr HOCCH 3 



C 6 H 5 C-i— jN 
II II 
(coCHs 2CCH3 



+ HBr + H 2 



A better method of preparation is the dehydration of oc-acylamidocarbonyl 
compounds with sulphuric acid or phosphorus pentachloride. 



CH-NH ^_ CH N _ Hl0 > 



n — N 



R-CO COR' RC V C-R R VJ R 

X OH HO' 

Oxazoles have basic properties similar to those of pyridine, but are less 
resistant to oxidation. They possess aromatic properties, and the stability 
of the ring towards hydrolytic reagents depends on the nature of the sub- 



§5] HETEROCYCLIC COMPOUNDS 431 

stituents in the ring (c/. t'so-oxazoles). The parent compound, oxazole, has 
not yet been prepared. 

5-Oxazolones. The oxazolones are keto derivatives of the oxazolines, 
the most important group being the 5-oxazolones or azlactones. These 
azlactones are very important intermediates in the preparation of oc-amino- 
acids (see §2 va. XIII) and keto-acids (see Vol. I). 

§4b. Benzoxazoles. These may be prepared by the reaction between o-amino- 
phenols and carboxylic acids, e.g., o-aminophenol and formic acid form benz- 
oxazole, m.p. 31°. 

NH> % Ay\. 

+ ^CH >- [ | ^CH+aHjO 

OH H0 / VN/ 

THIAZOLE GROUP 

§5. Thlazoles. A general method for preparing thiazoles is the con- 
densation between oc-halogenocarbonyl compounds (particularly the chloro 
derivatives) and thioamides; the mechanism of the reaction is uncertain, 
but it may occur through the enol forms. 

r-co m 2 ^b-coh r _ R |r- 3 N HC1 

R'-CHC1 >R" R'CCl PR" R'&, «CR* 

S^ HS' N S/ 

Thiazole itself may be prepared from chloroacetaldehyde and thioformamide. 

CHO NH 2 Q H0H n 11 n — tf 

I +1 ^=^ II + II »* +H 2 0+HC1 

CH 2 C1 CH CHCI JCH ^ / 

If thiourea or its substitution products are used instead of thioamides, 
then 2-aminothiazoles are produced, e.g., thiazole may be prepared from 
chloroacetaldehyde and thiourea as follows: 



CHO NH 2 

CH 2 C1 + i-NH 2 " 



CHOH NH n — N 

II + \\ » + H 2 0+HC1 

CHCI C-NH 2 l^ ^NH 2 



NaNO; 
HCI 



OL •*- n 




Another general method for preparing thiazoles is by the action of phos- 
phorus pentasulphide on a-acylamidocarbonyl compounds. 

CH 2 — NH ^ CH N 

R-CO CO-R' " R-C C-R' 

\>H HO 

2-Mercaptothiazoles may be prepared by the condensation between a- 
chloroketones and ammonium dithiocarbamate. 

R-CO NH 2 Rn N „ . , XTTI _, 

I + | >- I +H 2 + NH 4 C1 

R'-CHC1 C-SNH 4 R'V >SH 



432 



ORGANIC CHEMISTRY 



[CH. XII 



Thiazole is a weakly basic liquid, b.p. 117°; it occurs in vitamin B v 
It is a very stable compound, and is not affected by the usual reducing 
agents; sodium and ethanol, however, open the ring to form thiols (or 
hydrogen sulphide) and amines. Thiazole is very resistant to substitution 
reactions, but if a hydroxyl group or an amino group is in position 2, then 
the molecule is readily attacked by the usual electrophilic reagents to form 
5-substitution products, e.g., 2-hydroxy-4-methylthiazole is readily bromi- 
nated in chloroform solution to give 5-bromo-2-hydroxy-4-methylthiazole. 



CH, 



OOH 



+ Br 2 



chci 3 



CH 3 , 
Br' 



n — N 



+ HBr 



§5a. Thiazolines. These may be prepared by the reaction between 
/S-halogenoamines and thioamides, e.g., 



CHjj-NH, NH 

I + II 

CHjjBr OR 



HS 



/ 



CH. 

A 



■N 



2 CR 
S 



II + NH 4 Br 



A characteristic reaction of the thiazoles is their ring opening by the action 
of acids, e.g., 



CH 2 — N 

II 
.CCH 3 






HCl 



2-methylthiazoltne 



CH 2 -NH 2 
CH 2 SH 

2 -ami noethanethiol 



§5b. Thiazolidines. These are readily formed by the condensation of 
carbonyl compounds with cysteine. 



,HO- 2 C-CH-NH 2 
CH 2 SH 



+ R-CO-R 



H0 2 C-CH — NH 

■*" ' J, + 



H,0 



The thiazolidine ring is very easily opened, sometimes by boiling with 
water, or with an aqueous solution of mercuric chloride (see also penicillin, 
§6a. XVIII). 

§5c. Benzothiazoles. These may be prepared by the action of acid 
anhydrides or chlorides on o-aminothiophenols, e.g., benzothiazole from 
o-aminothiophenol and formic acid in the presence of acetic anhydride. 



/y NH 



o 



v 



CH 



(CH 3 -CO)jO 



HO 



/ 




2JCH+2H 2 



V 



Benzothiazoles are also formed by the action of phosphorus pentasulphide 
on o-acylamidophenols, e.g., 




p s s« 



NH-CO-CH. 




C-CH, 



§6] 



HETEROCYCLIC COMPOUNDS 



433 



2-Mercaptobenzothiazole is a vulcanisation accelerator (§33a. VIII); it 
may be prepared as follows: 



\AoH 



+ CS 2 




C-SH+H 2 



§5d. iso Thiazoles. Benzwothiazoles have been known for many years, 
but no derivatives of isothiazole itself have been obtained until very recently 
when Adams et al. (1956) prepared the parent compound and a number of 
its simple derivatives, e.g., 




iNH, 



[o] 



OC0 2 H -2co 2 



fCOjH 



N 



/soThiazole is a colourless liquid which smells like pyridine. 



TRIAZOLE GROUP 



§6. Osotriazoles and triazoles. Triazoles are five-membered rings 
which contain two carbon and three nitrogen atoms. Two structural iso- 
meric triazoles are known, the 1:2: 3-(l : 2 : 5-) and the 1 : 2 : 4- (1 ; 3 : 4-), 
the former being known as osotriazole, and the latter as triazole. Each 
exists in two dissimilar tautomeric forms. 



* 



CH- . 

Ill 3 
CH^N 

H 



osotriazole 



CH=N 



l 



W 



iNH 



FT 

CHs zN 
H 



HNj 5 CH 

CHz A 



triazole 

Replacement of the imino hydrogen atom by an alkyl or aryl group prevents 
tautomerism, and thereby gives rise to the possibility of two AT-substituted 
triazoles and two iV-substituted osotriazoles. All four types of compounds 
have been prepared. 

Osotriazole may be prepared by the reaction between acetylene and 
hydrazoic acid. 

CH CH — N 



HN S 



CH 



CH N 

V 

H 



On the other hand, a general method for preparing osotriazoles is the con- 
densation of azides with j8-ketoesters, e.g., phenyl azide and ethyl aceto- 
acetate form ethyl 5-methyl-l-phenylosotriazole-4-carboxylate. 

CH 2 -C0 2 C 2 H 5 N CC0 2 C 2 H 6 

C 6 H 5 -N 3 + J^ TI *- I | c „ + H 2 



CO-CH 3 



N CCH 3 
N 



C«H S 



434 



ORGANIC CHEMISTRY 



[CH. XII 



Derivatives of osotriazole may also be prepared by the oxidation of osazones 
with dichromate and sulphuric acid, or with dilute copper sulphate solution, 
e.g., benzilosazone gives 1:3: 4-triphenylosotriazole. 



C 6 H 5 -C=N-NH-C 6 H 6 
C 6 H 6 -C=N-NH-C 6 H 6 



C 6 H 5 -C=N 
■*■ | >C 6 H 6 + C 6 H 5 -NH 2 

C 6 H 5 -C=N 



The formation of osotriazoles from sugar osazones provides a good derivative 
for the characterisation of sugars (see Vol. I). 

Triazoles may be prepared by heating acid hydrazides with amides, 
e.g., formyl hydrazide and formamide give triazole. 



NH, 



OCH 



N= 



HC=0 H,N 



NH 



CH NH 



CH 

I + 2H 2 



Triazoles are also formed when sym.-diacylhydrazines are heated with 
ammonia or amines in the presence of zinc chloride, e.g., syw.-diacetyl- 
hydrazine and methylamine give 1:2: 5-trimethyltriazole. 



NH— NH 
I I 

CH 3 -CO CO-CHs 

V 

I 

CH, 



N- 



-N 



ZnCla 



K N 



CH 3 -C ^C-CHs 

OH HO 



H v- H 



CH 3 C ^CCHa 

N N 

I 
CH, 



II +2H 2 



CH, 



Both triazoles are weak bases, and are very stable compounds. 
Benzotriazole is formed by the action of nitrous acid on o-phenylene- 
diamine. 






HNO, 



HCl . 



\K 



=NC1 




+HC1 



§7. Oxadiazoles. These are five-membered rings containing two carbon 
and two nitrogen atoms and one oxygen atom; four types are known. 



CH— N 
II II 

CH N 

\>' 

1:2:3- 
oxadiazole 



f— ff H 

c v 

1:2:4- 

oxadiazole 



\/ 

1:2:5- 
oxadiazole 



N N 

II II 

CH 6h 
\> 

1:3:4- 
oxadiazole 



The furazans (1 : 2 : 5-oxadiazoles) may be prepared by the action of sodium 
hydroxide on the dioximes of cc-diketones. 



R-C— CH 
NOH noh 



NaOH R|? _ 



-C-B 



V 



II + h 2 o 



§8. Sydnones. The sydnones were first prepared by Earl et al. (1935) 
by the action of cold acetic anhydride on 2V-nitroso-2V-phenylglycines ; 



§8] HETEROCYCLIC COMPOUNDS 435 

Earl formulated the reaction as follows: 

y CHiC0 2 U CH— 0=0 

/ ' * (CH,CO),0 / | T 

c ^\ m ( _ Ha0) » W^l 

Earl (1946) proposed the name sydnone for compounds of this type; thus 
the above compound is iV-phenylsydnone. 

Sydnones are white or pale yellow crystalline compounds, which are 
hydrolysed by hot 5 per cent, sodium hydroxide to the original iV-nitroso- 
2V-ary]glycine, and by moderately concentrated hydrochloric acid to an 
arylhydrazine, formic acid and carbon dioxide. 

The structure proposed by Earl is similar to that of a yS-lactone, but 
Baker et al. (1946, 1949) offered a number of objections to this structure, 
e.g., 

(i) A system containing fused three- and four-membered rings would be 
highly strained, and consequently is unlikely to be produced by dehydration 
with acetic anhydride; /?-lactones are not produced under these conditions. 

(ii) Many /3-lactones are unstable to heat; sydnones are stable and so 
the /S-lactone structure is unlikely. 

(iii) If the /S-lactone structure is correct, then sydnones should be capable 
of existing in optically active forms. Kenner and Baker (1946) prepared 
(+)-2V-nitroso-2V-phenylalanine, and when this was converted into a syd- 
none, the product was optically inactive. If Earl's structure were correct, 
then the sydnone would be expected to be optically active. 

CH, CH 3 



Jm 



>C0 2 H C CO 

C 6 H B -K *" Ctf.-N I 

X N0 N N — O 

(iv) The aryl nucleus in sydnones is very resistant to substitution by 
electrophilic reagents. Since the above structure is similar to that of an 
arylhydrazine, this resistance is unexpected. 

Baker et al. (1946) therefore proposed a five-membered ring which cannot 
be represented by any one purely covalent structure; they put forward a 
number of charged structures, the sydnone being a resonance hybrid, e.g., 
three charged resonating structures are: 

+/ CH=C-0 ^=0-0 +/ CH-C-0 

Ar-N -«-»► Ar-N. I -«— »- Ar-N. | 

^N — O X N=0 + ^N— + 

I II III 

Now Simpson (1945) had proposed structure IV for 3-methyl-5 : 6-di- 
methoxyanthranil; Baker et al. (1949) adopted this ± sign and suggested 
that sydnones be represented by structure V. Baker also proposed the 



CH— C=0 
Ar-N^ + 

N — O 




436 ORGANIC CHEMISTRY [CH. XII 

term meso-ionic to describe the sydnone structure. Baker et al. (1955) 
have, however, revised the definition of the term meso-ionic, and have 
proposed formula Va instead of V. This is based on the fact that sydnones 
are aromatic in character, and the circle and plus sign represent the sextet 

CH— C— 
Ar-N (+) | 
N — O 

Va 

of jr-electrons in association with a positive charge (the " aromatic sextet " 
is the essential feature of aromatic compounds). 

Dipole moment measurements of various sydnones have shown that the 
positive end of the dipole is situated on the nitrogen atom attached to the 
aryl group (Sutton et al., 1947, 1949; Le Fevre et al, 1947). This is in 
keeping with Baker's structure. 

The meso-ionic structure would necessitate a planar, or almost planar 
molecule; such a molecule would not be optically active (cf. iii above). 
Earl (1953) has suggested that, from the available evidence, sydnones can 
be represented as a resonance hybrid, the two main contributing structures 
being VI and VII. 

CH-C=0 5h-c=o 

Ar-N/. | Ar-IST _ | 

N N O X N— O 

VI VII 

Sutton et al. (1949), however, have shown that VI probably contributes 
to the resonance hybrid, but to a lesser extent than I, II and III. 



TETRAZOLE GROUP 

§9. Tetrazole. Tetrazole is a five-membered ring which contains one 
carbon and four nitrogen atoms. There are two tautomeric forms of tetra- 
zole, and replacement of the imino hydrogen by, e.g., an alkyl group gives 
rise to two iV-alkyltetrazoles (cf. triazoles, §6). 

CH— N CH=N 

||« 3 || ^=^ !• *| 
N5 ! 2N HNi 2 »N 

H 

Tetrazole may be prepared by heating hydrogen cyanide with hydrazoic 
acid in benzene solution at 100°. 



CH CH— ¥ 

I +HN 3 "I 1 



\n- 

H 



Derivatives of tetrazole may be prepared by the condensation of phenyl 
azide with phenylhydrazones of aldehydes in the presence of ethanolic 
sodium ethoxide, e.g., benzaldehyde phenylhydrazone and phenyl azide 
form 1 : 4-diphenyltetrazole. 



§11] HETEROCYCLIC COMPOUNDS 437 

C 6 H 5 -CH=N-NH-C 6 H 5 r H ON C 6 H 6 -C=N-NH-C 6 H 6 

. C a H 5 QNa^ I ^_ 

C 6 H 6 -N 3 N=N-NH-C 6 H 5 



°< H ^ + C 6 H,NH 2 



^ % >C 6 H 6 



Tetrazole is a colourless solid, m.p. 156°; it has no basic properties, but 
the imino hydrogen is acidic, e.g., tetrazole forms a silver salt [CHNJ-Ag -1 ". 



AZINES 

The suffix azine is used for six-membered rings which contain two or 
more hetero-atoms, at least one of which is nitrogen. 

DIAZINE GROUP 

§10. Introduction. The diazines are six-membered rings containing two 
nitrogen atoms. Three isomeric diazines are theoretically possible, and all 
three are known. 





o-diazine ; »»-diazine ; />-diazine ; 

pyridazine miazine; piazine; 

pyrimidine pyrazine 

The above formula are now usually written with a nitrogen atom at the 
top, i.e., the formulae of pyridazine and pyrimidine are inverted. 

§11. Pyridazines. These may be prepared by the action of hydrazine 
on 1 : 4-diketones, the intermediate dihydro compound being readily oxidised 
by atmospheric oxygen. 

R R R 

CO COH /\ 

CH 2 CH H^N CH NH 

R R R 

Pyridazine itself may be prepared from maleic dialdehyde and hydrazine 
hydrate. 

CHO 
CH NH a 

II +1 * 

CH NH Z 

CHO 
Pyridazine is a colourless liquid, b.p. 208°. 



^ 





438 ORGANIC CHEMISTRY [CH. XII 

PYRIMIDINES 

§12. Ureides. Ureides are acylureas, and may be prepared by the action 
of an acid anhydride or acid chloride on urea, e.g., 

.NH 2 /NH-00-CH 3 JSIH-COCHs 

G / (CH,-CO),0 , ^ (CH,-CO),0 > c / 

X NH 2 V NH 2 N NHCO-CH 3 

acetylurea diacetyJurea 

The simple ureides resemble the amides in properties. 

Allophanic acid, NH 2 -CONH'C0 2 H, is not known in the free state, but 
many of its esters have been prepared: 

(i) By the action of chloroformates on urea. 

NH 2 -CONH 2 + Cl-CO a R— v NH 2 -CONH-C0 2 R + HC1 

(ii) By the reaction between urethans and cyanic acid. 

HNCO + NH 2 -C0 2 R— ► NH 2 -CONH-C0 2 R 

The alkyl allophanates are well-defined crystalline compounds, and so are 
frequently used to identify alcohols. They are prepared by passing cyanic 
acid vapour into the dry alcohol; urethans are intermediate products. 

TTTWO 

ROH + HNCO -> NH 2 -C0 2 R — > NH 2 -CONH-C0 2 R 
According to Close et al. (1953), allophanate formation occurs via a concerted 
attack of two molecules of cyanic acid to form a chelate intermediate. 



0. 



O 



§13. Cyclic ureides. Many cyclic ureides are known; some occur 
naturally and others are synthetic (a number of cyclic ureides — alloxan, 
allantoin, parabanic acid and hydantoin — are discussed in §2. XVI, in 
connection with the purines, which are cyclic diureides). 

The cyclic ureides containing a six-membered ring behave, in a number 
of ways, as pyrimidine derivatives. 

§13a. Barbituric acid. A very important pyrimidine derivative is bar- 
bituric acid (malonylurea). It was originally prepared by condensing urea 
with malonic acid in the presence of phosphoryl chloride (Grimaux, 1879). 

.CO. 
.NH 2 H0 2 C / \ 

^ + W ^0£^ fH CH 2 

x nh 2 ho 2 c x %ra /C ° 

A much better synthesis is to reflux ethyl malonate with urea in ethanolic 
solution in the presence of sodium ethoxide. 

.CO. 



/NH 2 C 2 H 6 2 C v j^ \ H 

CO + >H 2 C '"° ONa > | | + 2C 2 H 5 OH 

\H 2 C^Ac' CO CO 

X NH X 



CH 



§13b] HETEROCYCLIC COMPOUNDS 439 

Barbituric acid is a solid, m.p. 253°, and is not very soluble in water. It 
is strongly acidic due to enolisation (lactam-lactim tautomerism) ; some 
possible lactim forms are II-IV. Structure IV represents barbituric acid 

OH OH 

/a°\ / C °\ A A 

NHi 5CH 2 __ NH CH 2 __ N Ctt, ^ N 

COa 4CO HOC. CO HOC! CO HOC COH 

W V V V 

I II III IV 

as 2 : 4 : 6-trihydroxypyrimidine, and this structure has been proposed be- 
cause of the acidic nature of barbituric acid. On the other hand, barbituric 
acid contains an active methylene group, since it readily forms an oximino 
derivative with nitrous acid. Thus barbituric acid behaves as if it had 
structure I, II or III. Furthermore, it is very difficult to acylate hydroxy- 
pyrimidines containing hydroxyl groups in the 2-, 4- or 6-positions, thus 
indicating that structure I is more probable than II or III. This is sup- 
ported by the fact that methylation of hydroxypyrimidines with, e.g., 
methyl iodide in the presence of sodium hydroxide, results in the formation 
of iV-methyl derivatives ; this indicates the probable presence of imino groups. 
On the other hand, it is possible to replace three hydroxyl groups by three 
chlorine atoms by means of phosphoryl chloride; this suggests barbituric 
acid behaves as IV. Barbituric acid also forms O-alkyl derivatives, thereby 
indicating structures II, III and IV. 

Barbituric acid can be nitrated and brominated in the 5-position, and 
also forms metallic derivatives (at position 5). By means of the sodio 
derivative, one or two alkyl groups may be introduced at position 5 (this 
reaction is characteristic of the — CH 2 *CO — group). Barbituric acid and 
5 : 5-dimethylbarbituric acid have no hypnotic action. On the other hand, 
5 : 5-diethylbarbituric acid (Barbitone, Veronal) has a strong hypnotic action ; 
it is best prepared as follows: 

/CO\ 
/NH 2 C 2 H 5 2 C x ch.on« W C(C 2 H 5 ) 2 

CO + £(C 2 H 5 ) 2 CiH,ONa > 1 I 5/2 

\ra 2 c 2 h A c^ W 

5-cycZoHexyl-3 : 5-dimethylbarbituric acid (Evipan) is a better hypnotic 
than Barbitone and is not so toxic. 5-Ethyl-5-phenylbarbituric acid (Lumi- 
nal) is also used in medicine. 

§13b. Derivatives of barbituric acid. Violuric acid (5-oximino- 
barbituric acid) is formed when barbituric acid is treated with nitrous acid; 
it is the oxime of alloxan (see §2. XVI). Violuric acid gives a violet colour 

CO t /C 

NH CH 2 NH C=NOH 

I | + HN0 2 »- I I + H,0 

CO CO CO CO 

X NH 7 ^H^ 

in water, and forms deeply coloured salts with various metals, e.g., the 
potassium salt is blue and the magnesium and barium salts are purple. 
Dilituric acid (5-nitrobaibituric acid) may be prepared by nitrating 
barbituric acid with fuming nitric acid, or by the oxidation of violuric 
acid with nitric acid. 



440 ORGANIC CHEMISTRY [CH. XII 

/ C0 \ / C0 \ /*\ 

NH CH 2 hno 3 NH CH-N0 2 hno 3 NH C=NOH 

I I >■ I I ■< II 

CO CO CO CO CO CO 

N NH / ^NH 7 X NH 

barbituric acid dilituric acid violuric acid 

Uramil (5-aminobarbituric acid) is formed by the reduction of either 
dilituric acid or violuric acid. 

/C o CO CO 

NH CHN0 2 [h]^ NH CHNH 2 jh]_ NH C=NOH 

CO CO CO CO CO CO 

N NH X X NH X N NH / 

dilituric acid uramil violuric acid 

Uramil may also be prepared by the action of ammonium hydrogen sulphite 
on alloxan, and then boiling the product, thionuric acid, with water. 

CO v CO MTT 

NH N CO NH V H0 

I | + NH 4 -HS0 3 >- | l x S0 3 H -^^- 

CO CO CO CO 

N NIT X NH X 



alloxan thionuric acid 

H-NH 2 



/ C0 \ 



NH OH' 

CO CO 
X Nff 
uramil 



+ H 2 S0 4 



Dialuric acid (5-hydroxybarbituric acid) is produced by the action of 
nitrous acid on uramil; it is also formed when alloxan is reduced with hydro- 
gen sulphide or with zinc and hydrochloric acid. 

/CO\ /C O x DO 

NH CH-NH 2 HWOi> NH CHOH ^^ NH CO 

co do " bo co co Co 

\NH / ^NH/ ^NH^ 

urainil dialuric acid alloxan 

§14. Pyrimidine, m.p. 22-5°, b.p. 124°/758 mm., was first prepared from 
barbituric acid as follows (Gabriel, 1900). 

? H CI 

/ C0 \ / C / C \ / C 6 H 

NH CH 2 __ n' X CH pqc^ N^ CH Zn dust ^ Ni' ' N CH 
CO CO Hoi JloH *~ClA ' CC1 h ° twater .CHt. «CH 



jy vu hou ooh cic cci cm, 

x nh/ <*n' V ^/ 



4.CH 

pyrimidine 



§14] 



HETEROCYCLIC COMPOUNDS 



441 



Pyrimidine may also be prepared by the oxidation of alkylpyrimidines, 
followed by decarboxylation. A recent preparation is the catalytic reductive 
dechlorination of 2 : 4-dichloropyrimidine ; the latter is heated with hydrogen 
under pressure in the presence of Pd — C and magnesium oxide (Whittaker, 
1953). 




H a 



Pd-C 




Pyrimidine is neutral in solution, but forms salts with acids. Pyrimidine 
is probably a resonance hybrid of the following resonating structures: 




~ v ~ 



Thus the ring is deactivated, and position 5 has the greatest electron density 
(cf. nitrobenzene and pyridine, Vol. I). It can therefore be expected that 
attack by electrophilic reagents will be difficult, but attack by nucleophilic 
reagents (at positions 2, 4 and 6) will be facilitated. Chlorine atoms at 
2, 4 or 6 are readily replaced by hydroxyl or amino groups, and an amino 
group in position 2 or 6 is readily replaced by a hydroxyl group merely on 
boiling with water (c/. vitamin B 1( §3. XVII). 

When a hydroxyl or an amino group is present in the pyrimidine nucleus, 
the compound no longer behaves entirely as an aromatic derivative. The 
introduction of hydroxyl or amino groups into positions 2, 4 and 6 progres- 
sively diminishes the aromatic properties of the compound (cf. barbituric 
acid, §13a, and uracil, §15). 

Pyrimidine derivatives. A very important general method for pre- 
paring pyrimidines is the condensation between /3-carbonyl compounds of 
the type R-COCH a -COR', where R and R' = H, R, OR, CN, and com- 
pounds having the amidine structure R>C(= NH)*NH 2 , where R = R (an 
amidine), OH (urea), SH or SR (thiourea or its S-derivative), NH 3 (guani- 
dine) ; the condensation is carried out in the presence of sodium hydroxide 
or sodium ethoxide. Thus: 



X NH 2 OC<R' 

R-C. + -CH, 

^NH OCXR" 



/ 



NH 2 OC;R' 
%H HOC^R" 



R' 



R 



N- 



R' 



+ 2H 2 



This general reaction may be illustrated by the condensation of acetamidine 
(R = CH 3 ) with ethyl acetoacetate (R' = OC 2 H 5 , and R" = CH 3 ) to form 
6-hydroxy-2 : 4-dimethylpyrimidine. 

CO. 
yNH 2 C 2 H 6 2 (I -tfcr y>h 

CH 3 -o( + \ H -£Hhm* f 1 f 1 , 

"^NH HOC^CH 3 CH 3 C CCH 3 

4 : 5-Diaminopyrimidines, which are intermediates in purine synthesis 
(see §4. XVI), may be prepared by condensing formamidine with phenyl- 
azomalononitrile (Todd et al., 1943). 



CH; 




442 



ORGANIC CHEMISTRY 



[CH. XII 



NH CN 

4 + >H-N=N-C 6 H B *^> 
X NH 2 NC X 



NH e 

aN=N-C«H 5 



"NH 2 



NH, 






Schaeffer et al. (1962) have shown that s-triazine reacts with amidines, 
amidine salts and imidates having oc-acidic methylene groups to produce 
4 : 5-disubstituted pyrimidines (yield: 51-100 per cent.): 



X— CHg-C 



/* 



N^N 



•V 



NH 



X N X 




X = C0 2 R, CONH 2 , CN, COPh 
Y «= NH„ OR, SR 



Z = Y or NH, 



§15. Uracil (2 : 6-dihydroxypyrimidine) is a hydrolytic product of the 
nucleic acids (§§13, 13b. XVI). It has been synthesised in many ways, e.g., 

(i) Fischer and Roeder (1901). 



/NH.J C 2 H 6 2 C x 
tip + ^CH 

N NH 2 CH 2 

urea ethyl 

acrylate 



ao° 



/ C0 \ 
*H 



dihydrouracil 



Nra' 



CH 2 
CH 2 



/ C0 \ 



Br t 



CH s -CO s H 



NH CH 

CO CH 

\nh' 



CHBr 

2 



.CO 



boil in C 6 H C N 
(-HBr) 



Ah 



NH "CH 

Ao 

X NH 

uracil 

(ii) Wheeler and Liddle (1908). 



/NH 2 c 2 H 5 o 2 a 

CS + .CH 



\ 



•NH 2 



NaO< 



CH 



sodioformyl- 
thiourea acetic ester 

/ C °\. 



x eo 

NH CH 

I II 

CS CH 

\nh/ 

2-thiouracil 



NH 



CH 



aq. CHjCI-CO a H C Q CH 

^nh' 

uracil 



]| _ + CH 2 SH-C0 2 H 
CI 



§17] HETEROCYCLIC COMPOUNDS 443 

Four tautomeric structures are theoretically possible for uracil. 

OH OH 

/ C0 \ A\ / C0 \ // C \ 

NH CH __ N N CH ^ NH CH _^ IT N CH 

co ch ^~" co ch " hoc. ch "~ hoc ch 
\nh x \kh/ "Ni/ % / 

I II III IV 

The ultraviolet absorption spectrum of uracil (in ethanol) is different from 
that of 1 : 3-dimethyluracil (a derivative of I), from that of 6-methoxy-3- 
methyluracil (a derivative of II), and from that of 2 : 6-diethoxyuracil (a 
derivative of IV). Thus uracil is probably III, and this is supported by 
the fact that the ultraviolet absorption spectrum of 1-methyluracil (a 
derivative of III) is similar to that of uracil (Austin, 1934) (but see also 
§13b. XVI). 

§16. Thymine (5-methyluracil, 2 : 6-dihydroxy-5-methylpyrimidine) is a 
hydrolytic product of the nucleic acids. It has been synthesised by methods 
similar to those used for uracil. 

(i) Fischer and Roeder (1901); in this case ethyl methacrylate is used 
instead of ethyl acrylate. 

CO /CO N Br 

/NH 2 C a H,0,C N NH CH-CH 3 Br NH (f 

nn + r-rn h ' at > I I 2a — ^ | N CH 3 

CO + ^OCHs »"l l ch,-co,h* I ' 

^NH 2 CH 2 °Vh^ W 2 



_/ 



COv 



OH 



J ^^ NH \jOH. __ /W 

(-HBr) C0 CH " H0 



^nh/ 



V 



(ii) Wheeler and Liddle (1908); in this case sodioformylpropionic ester 
is used instead of sodioformylacetic ester. 



/ C V _„ ^°°v 



/NH 2 C 2 H 5 2 C^^ t ^^NH \>CH 3 C H, a -co,H > NH X CCH 3 

S CH CO C 

^SK N NIT 



08 + >CH 3 — *-| II "*"—"> | 

^NH 2 NaOci? CS CH CO CH 



§17. Cytosine (6-aminouracil, 6-amino-2-hydroxypyrimidine) is a hydro- 
lytic product of the nucleic acids. It has been synthesised by Wheeler and 
Johnson (1903) starting from S-ethyhsothiourea and sodioformylacetic ester 
(see also §13b. XVI). 



444 



ORGANIC CHEMISTRY 
.CO 



/NH 2 C 2 H 6 2 C 
C 2 H 5 S-C + CH 

NH NaOCH 



^ ^ 



CH 

■*■ I II 

C 2 H 6 SC CH 



pocu 



[CH. XII 

CI 
N CH 
c7h 6 SC .CH 



NHs 



NH 2 
I 

SK. 

N CH 



NH, 



N CH ^ 

c,HfOH C,H fi SC.. CH "*" CO .CH "" HO^ 



%' " \nh/ 



NH, 



N 



N' 
cytosine 



Pyrazlnes 

§18. Pyrazines may be prepared by the self-condensation of an a-amino- 
ketone in the presence of an oxidising agent such as mercuric chloride; the 
intermediate dihydro compound is readily oxidised to the pyrazine (Gabriel 
et al., 1893). 



RCO 



/NH 2 

THg OO-R 

.CH, 



H,N 



/ 



H 2 CR Hgci 



R \S H > 




Actually, only the salts of a-aminoketo compounds are known; addition of 
alkali liberates the free base which immediately forms a pyrazine in the 
presence of mercuric chloride. 

Pyrazine itself may be prepared from aminoacetaldehyde (R = H in the 
above equations). The best method, however, for preparing pyrazine is 
as follows (Wolff et al, 1908). 



JSTHv 



CH 2 C1 
2 I + 

CH(OC 2 H 5 ) 2 

ehloroacetal 



NH 3 



HCl 



NH N 
3H, 



heat 



CH 2 CH 2 
)CH CHC 



CH 2 CH 2 

CH(OC 2 H 5 ) 2 CH(OC 2 H B ) 2 
diacetalylamine 



NH 2 OH-HCl 




HOCH CHOH 

2:6-dihydroxymorpholine 

A convenient general method for preparing pyrazines is to heat an a-amino- 
acid with acetic anhydride in the presence of pyridine, hydrolyse the product 
(an acetamidoketone) with acid and then warm with sodium hydroxide in 
the presence of mercuric chloride (Dakin et al., 1928). This method is thus 
similar to the first general method given above, but offers a convenient 
method of preparing a-aminocarbonyl compounds. 



§19] 



HETEROCYCLIC COMPOUNDS 



445 



R-C 



i 



NH a 



(CH,-CO)tO 



C0 2 H 



C H B N 



*~R-Cf 



,NH-CO-CH 3 

../ HCl 



CO-CH, 



/NHu-HCl 
*■ R-CH 

CO-CH 3 



HgCI. 



r/\ch 3 

^ch^JJr 



Pyrazine is a solid, m.p. 55° ; pyrazines (and pyrazine) are readily reduced 
by sodium and ethanol to hexahydropyrazines or piperazines. Piperazine, 
m.p. 104°, is a strong diacid base. 2 : 5-Diketopiperazines are produced 
from a-amino-acids (see §4 C. XIII). 




Na 



CjH 5 OH 



C!H 2 CH 2 

CH 2 CHjj 
N Nir 

piperazine 



BENZODIAZINES 



§19. The following benzodiazines are theoretically possible, and all are 
known ; the first two are derived from pyridazine, the third from pyrimidine 
and the fourth from pyrazine. 







phthalazine 



quinazoline 



quinoxaline 



Cinnolines may be prepared by the cyclisation of diazotised o-amino- 
acetophenones (Schofield el al., 1948), e.g., 



2 N 




•CO-CH, 



•N 2 C1 




2 N 



+ HCl 



Phthalazines are formed by heating the benzoyl derivative of benzalde- 
hyde hydrazones, e.g., 





+ H 2 



0.H, 



Quinazolines may be prepared by the action of ammonia on acylated 
o-aminobenzaldehydes or o-aminoacetophenones (Isensee et al., 1948), e.g., 



446 



ORGANIC CHEMISTRY 



[CH. XII 



"CH, 



aco-c 
+ NH 3 
NH-CO-CHg 




+ 2H 2 



Quinoxalines are formed by the condensation of o-phenylenediamines 
with a-dioxo compounds, e.g., 

glyoxal 

The formation of quinoxalines is used to identify aromatic o-diamines and 
1 : 2-diketones (see, e.g., §9. XVII). 






^.NH 2 

\Anh 2 + 



OC-R 

I , 

OC-R 




, + 2H 2 



Of the dibenzodiazines, only the phenazines (dibenzopyrazin.es) are impor- 
tant. Phenazine, m.p. 171°, may be prepared by condensing o-phenylene- 
diamine with catechol in the presence of air. 

9 10 1 

,x NH 2 HC 



^A 





+ 3H 2 



Phenazine forms unstable salts (coloured red or yellow) in excess of strong 
acids. Many dyes are derived from phenazine, e.g., the safranines (see 
Vol. I). 

DIAZINES CONTAINING ONE NITROGEN ATOM AND 
AN OXYGEN OR SULPHUR ATOM 

§20. Oxazines. Morpholine is tetrahydro-1 : 4-oxazine, and it may be 
prepared as follows: 



2CH 2 —CH 2 + NH 3 " 

ethylene 
oxide 



HO OH ' ^ 

- CH 2 (fH 2 -!iF- I I +H 2 



CH 2 .CH. 
X NH 



X N 
H 



diethanolamine 

Morpholine is a liquid, b.p. 128°, and is strongly basic. It is miscible with 
water in all proportions, and is widely used as a solvent. 

§21. Phenoxazines. These are formed by condensing o-aminophenols 
with catechols at 260°, e.g., 

H 

aNH 2 ho yX ^ ^ 

OH + HO A/ 

phenoxazine 




i\ +2H 2 



§24=] 



HETEROCYCLIC COMPOUNDS 



447 



Phenoxazines axe also produced by the action of alkali on 2-hydroxy-2'- 
nitrodiphenylamines, e.g., 



,NH« 



\J 0H W\J 




Phenoxazine is a solid, m.p. 156°; it is the parent substance of a number 
of dyes, e.g., Meldola's Blue (see Vol. I). 

§22. Thiazines. Phenothiazines may be prepared by heating o-amino- 
thiophenols with catechols, e.g., 

\AsH HO^V 

phenothiazine 

Phenothiazine may also be prepared by fusing diphenylamine with sulphur. 




.NH. 



cno 



+ 2S 




+ H 2 S 



Phenothiazine, m.p. 185°, is used as an insecticide; it is the parent sub- 
stance of a number of dyes, e.g., Methylene Blue (see Vol. I). 



TRIAZINES AND TETRAZINES 

§23. Triazines. Three triazines are theoretically possible; the parent com- 
pounds are unknown, but derivatives of each have been prepared. 



l:2:3-triazine; 


l:2:4-triazine; 


l:3:5-triazine; 


p/c.-triazine; 


(W.-triazine; 


sym.-triazine; 


p-triazine 


a-triazine 


cyanidine 



Cyanuric acid, cyamelide and hexamethylenetetramine are derivatives of sym.- 
triazine (see Vol. I). 

§24. Tetrazines. Only derivatives of two tetrazines are known. 



l:2:4:5-tetrazine; 
sym.-tetrazine 



V 

l:2:3:4-tetrazine; 
osotetrazine 



448 ORGANIC CHEMISTRY [CH. XII 

§25. Some important condensed systems containing two fused heterocyclic 
systems are: 






These occur in natural products (see Ch. XVII, Vitamins). It appears that 
isoalloxazine, the tautomer of alloxazine, does not exist as such; only when the 
hydrogen atom is substituted is the isoalloxazine form retained (see §6. XVII). 

READING REFERENCES 

Gilman (Ed.), Advanced Organic Chemistry, Wiley. Vol. IV (1953). Ch. 8. Hetero- 
cyclic Chemistry. 
Morton, The Chemistry of Heterocyclic Compounds, McGraw-Hill (1946). 
Acheson, An Introduction to the Chemistry of Heterocyclic Compounds, Interscience (1960). 
Badger, The Chemistry of Heterocyclic Compounds, Academic Press (1961). 
Rodd (Ed.), Chemistry of the Carbon Compounds, Elsevier. Vol. IVA, B and C (1958- 

1960). Heterocyclic Compounds. 
Elderfield (Ed.), Heterocyclic Compounds, Wiley (1951- ). 
Patterson and Capell, The Ring Index, Reinhold (1940). 
Handbook for Chemical Society Authors, Chem. Soc. (1960). Pp. 90-106. Heterocyclic 

Systems. 
Finar and Simmonds, The Reaction between Aroylacetones and Arylhydrazines, J.C.S., 

1958, 200. 
Wright, The Chemistry of the Benzimidazoles, Chem. Reviews, 1951, 48, 397. 
Wiley, The Chemistry of the Oxazoles, Chem. Reviews, 1945, 37, 401. 
Organic Reactions, Wiley, Vol. VI (1951). Ch. 8. The Preparation of Thiazoles. 
Benson and Savell, The Chemistry of the Vicinal Triazoles, Chem. Reviews, 1950, 46, 1. 
Potts, The Chemistry of 1,2,4-Triazoles, Chem. Reviews, 1961, 61, 87. 
Baker and OUis, Meso-ionic Compounds, Quart. Reviews [Chem. Soc), 1957, 11, 15. 
Benson, The Chemistry of the Tetrazoles, Chem. Reviews, 1947, 41, 1. 
Nineham, The Chemistry of Formazans and Tetrazolium Salts, Chem. Reviews, 1955, 

55, 355. 
Franklin, Heterocyclic Nitrogen Compounds; Part I. Pentacyclic Compounds, Chem. 

Reviews, 1935, 16, 305. 
Johnson and Hahn, Pyrimidines; Their Amino and Amino-oxy Derivatives, Chem. 

Reviews, 1933, 13, 193. 
Shriner and Neumann, The Chemistry of the Amidines, Chem. Reviews, 1944, 35, p. 395; 

The formation of substituted pyrimidines. 
Lythgoe, Some Aspects of Pyrimidine and Purine Chemistry, Quart. Reviews (Chem. 

Soc), 1949, 3, 181. 
Krems and Spoerri, The Pyrazines, Chem. Reviews, 1947, 40, 279. 
Leonard, The Chemistry of the Cinnolines, Chem. Reviews, 1945, 37, 269. 
Vaughan, The Chemistry of the Phthalazines, Chem. Reviews, 1948, 43, 447. 
Gates, The Chemistry of the Pteridines, Chem. Reviews, 1947, 41, 63. 
King, Three- and Four-Membered Heterocyclic Rings, J.C.S., 1949, 1318. 



CHAPTER XIII 

AMINO-ACIDS AND PROTEINS 

§1. Classification of the amino-acids. When hydrolysed by acids, 
alkalis or enzymes, proteins (§6) yield a mixture of amino-acids. Acid 
hydrolysis destroys certain amino-acids, particularly tryptophan. On the 
other hand, alkaline hydrolysis causes complete racemisation and also the 
destruction of a number of amino-acids, e.g., serine, threonine, cysteine, 
etc. Enzymic hydrolysis has also difficulties, particularly the long time 
that is usually needed and the fact that the hydrolysis is often not com- 
plete. Thus acid hydrolysis is the most satisfactory, but enzymic hydrolysis 
is very useful for the isolation of tryptophan. Gurnani et al. (1955) have 
introduced an improved method for the hydrolysis of proteins. The tissue 
is first dissolved in 85 per cent, formic acid and then 2N hydrochloric acid 
is added; all the amino-acids, except tryptophan, are liberated within two 
hours. The number of amino-acids so far obtained from proteins appears 
to be about twenty-five, all of which except two are a-amino-acids ; the 
two exceptions are proline and hydroxyproline, which are imino-acids (see 
list of amino-acids below). Ten of the amino-acids are essential acids, i.e., 
a deficiency in any one prevents growth in young animals, and may even 
cause death. The amino-acids are classified in several ways; the table on 
pages 452 and 453 shows a convenient classification; the letters g, I and e 
which follow the name of the acids indicate that the acid is respectively of 
general occurrence, lesser occurrence and essential (to man). 

The a-amino-acids listed in the table have been isolated from proteins. 
Plants have continued to provide new amino-acids of diverse structure; 
between 1950 and 1960 about fifty amino- or imino-acids have been identi- 
fied as components of higher plants. About 20 more have been recognised 
as constituents of micro-organisms or have been obtained as fragments of 
the antibiotics excreted by the micro-organisms. These discoveries are the 
result of the application of paper and ion-exchange chromatography to the 
examination of plant extracts. 

§2. General methods of preparation of the amino-acids. There are 
many general methods for preparing a-amino-acids, but usually each method 
applies to a small number of particular acids ; many acids are also synthesised 
by methods special to an individual. It should also be noted that very often 
a synthesis is a more convenient way of preparing an amino-acid than pre- 
paring it from natural sources. 

(i) Amination of a-halogenated acids (Perkin et al., 1858). 
(a) An a-chloro- or bromo-acid is treated with concentrated ammonia, 
e.g-, 

CH 2 Cl-CO a H + 2NH S — ► CH 2 (NH 2 )-CO a H + NH 4 C1 

This method is convenient for the preparation of glycine, alanine, serine, 
threonine, valine, leucine and norleucine. 

(6) The yields obtained by the above method are variable because of 
side-reactions. Better yields are obtained by using Gabriel's phthalimide 
synthesis (1889) with a-halogeno-acids (see also Vol. I), e.g., 

449 



450 



ORGANIC CHEMISTRY 



[CH. XIII 




\ - ?^ 3 

NK+BrCH-COiAHs- 
CO 



CH a 



aNCH-C0 2 C 2 H 6 -&&** 




,C0 2 Na 



'CO-NH-CH'C0 2 Na 
CH, 



HCI 



-A 



C0 2 H 



L1)co 2 h 



+ CH 3 -CH(NH 2 )-C0 2 H 



(ii) Strecker synthesis (1850). A cyanohydrin is treated with con- 
centrated ammonia, and the resulting amino-nitrile is then hydrolysed with 
acid. In practice the amino-nitrile is usually prepared from the oxo com- 
pound in one step by treating the latter with an equimolecular mixture of 
ammonium chloride and potassium cyanide (this mixture is equivalent to 
ammonium cyanide), e.g., 



CH,-CHO -^U CH 3 -CH( 

KCN \ CN 



2 HCI 



r 3" 



>CH 3 -CH(NH 2 )-C0 2 H 



This method is useful for preparing the following amino-acids: glycine, 
alanine, serine, valine, methionine, glutamic acid, leucine, norleucine and 
phenylalanine. 

(iiia) Malonic ester synthesis. This method is really an extension of 
(i) a; it offers a means of preparing a-halogeno-acids, e.g., 

CH 2 (C0 2 C 2 H 6 ) a -^> R-CH(C0 2 C 2 H 6 ) 2 -^> R. C H(C0 2 H) 2 -^ 



EX 



(ii) HCI 



R-CBr(C0 2 H) 2 -^> R-CHBr-C0 2 H -^> R-CH(NH 2 )-C0 2 H 

This method offers a means of preparing, from readily accessible materials, 
the following acids: phenylalanine, proline, leucine, woleucine, norleucine 
and methionine. 

The malonic ester synthesis may also be combined with the Gabriel 
phthalimide synthesis to prepare phenylalanine, tyrosine, proline, cystine, 
serine, aspartic acid, methionine and lysine, e.g., 



Cystine. 

CgHg-CHjiSH + HCHO + HCI 
benzylthio] 

CH 2 (C0 2 C 2 H 5 ) 2 -^ 5 -*-CHBr(C0 2 C 2 H 5 ) 2 



-*"C 6 H 5 CH 2 -S-CH 2 C1 
benzylthiomethyl chloride 

0c> K 




CO 

\ 

N-CHtCOAHs), 

CO 




CNa(C0 2 C 2 H 5 ) 2 



C.Hp-CHs-S-CHaCl 




CO 
\ 

N-C(C0 2 C 2 H 5 ) 2 
O CHa-S-CHjj-QsHs 



§2] 



COgH 



(ii) HCI 



AMINO-ACIDS AND PROTEINS 

C0 2 H 

NH 2 CH-CH 2 SH 



451 



S- benzyl cysteine 
C0 2 H C0 2 H 

NH 2 - CH-CH 2 S- S • CH 2 - CH-NH 2 



(±) -cysteine 



Proline. 





N-C(COAH 6 ) 2 
CO CH 2 -CH 2 CH 2 Br 



(i)NaOH > NH 2 - CH-C0 2 H 
<"> HC1 * CH 2 -CH 2 -CH 2 OH 



(±) -cystine 



;N-0Na(CO 2 2 H i ) 2 +-Br(CH 2 ) 3 Br ■ 



\ 

^N-C(C0 2 C 2 H B ) 2 

CH 2 -CH 2 CH 2 0-CO-C!H3 



CH 2 CH -GOgH 



Acylamido derivatives of malonic ester may also be used to synthesise 
amino-acids; the usual derivative employed is ethyl acetamidomalonate 
(Albertson, 1946). 

CH a (CO a C a H 6 ) a -2% HON=C(C0 2 C a H 6 ) a . H * 



NH a -CH(CO a C a H B ) a -^^ 

CH 3 -CO-NH-CH(CO a C a H 5 ) a C ' H ' OTa > 
ethyl acetamidomalonate 



m 



RBr 



HBr 



CHa-CO-NH-CR^OaQjH^a > R-CH(NH a )-CO a H 

The following acids may be prepared by this method: serine, leucine, valine, 
methionine, lysine, glutamic acid and ornithine. 

A special application of this method is the preparation of tryptophan 
from benzamidomalonic ester and gramine methosulphate (Albertson et al., 
1945; Tishler et al, 1945). 

|CH 2 -N(CH s ) 3 } + S0 4 CHl+ C 6 H 5 -CO-NH-CH(C0 2 C 2 H 5 ) 2 ctfuoN^ 



Ccr 




CH 2 -0(CO 2 C 8 H 5 ) 2 (;) Na OH. 



NH-COC.H, 



(ii) HCI 




CH 2 -CHC0 2 H 

I 
NH, 



H 

tryptophan 



462 



ORGANIC CHEMISTRY 



[CH. XIII 



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l?a§\lra 

■ i n ■ i 



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a a <? a a 

aa-T-a a 

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§2] 



AMINO-ACIDS AND PROTEINS 



453 















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464 ORGANIC CHEMISTRY [CH. XIII 

A more recent method of preparing ethyl acetamidomalonate is to reduce 
oximinomalonic ester in a mixture of acetic anhydride, pyridine and sodium 
acetate with hydrogen in the presence of Raney nickel (Vignau, 1952). 

(iiifi) oc-Amino-acids may be synthesised by means of the Curtius re- 
action (see also Vol. I). 



/ C0 * K N H 

rx " ■" uinwjvji^ - o.v «a^ 

CO2C9H5 



CH 2 (C0 2 C 2 H 6 ) 2 c * H R ° Na > R-CH(C0 2 C 2 H 6 ) 2 ^^*- R-CH( -^*- 



C0 2 K C0 2 H C0 2 H 

R-Ch' -i™2^R. C H c ' H ' OH > RCH ^*- 

X CONHNH 2 X CON 3 NH-C0 2 C 2 H s 

acid azide 
R-CH(NH 2 )-C0 2 H 

Glycine, alanine, phenylalanine and valine can be prepared by this method. 
Instead of malonic ester, the starting material can be ethyl cyanoacetate. 

CN CN ON 

CH / CiH R '° M % RCH Na " 4 > RCh' 

\>0 2 C 2 H 5 X CO 2 2 H 6 CONH-NH 2 

CN CN 

hno Vr . oh / c » H ' OH > r-ch -^U-R-CH(NH 2 )-C0 2 H 

N CON 3 N NHC0 2 C 2 H 6 

Phenylalanine and tyrosine are conveniently prepared by this method. 

Another variation is the use of the Hofmann degradation on ester amides 
(see also Vol. I). 

/ C0 2 C 2 H 5 C0 2 C 2 H 6 

R ' c \ -mh*" R ' CH X *" R-CH(NH g ) -C0 2 H 

CO-NH 2 NH 2 

(iiic) The Darapsky synthesis (1936). In this method an aldehyde is 
condensed with ethyl cyanoacetate and simultaneously hydrogenated; the 
product, an alkylcyanoacetic ester, is then treated as above (for the cyano- 
acetic ester method). 

CN /CN 

R-CHO+CH 2 -$-*- R-CH.-CH US/ 

N C0 2 C 2 H 5 C0 2 C 2 H 6 



CN 
R-CH 2 CH 11?) hci*°" * * R-CHg-CHfNHjJ-COjH 

CON 3 

(iv) Amino-acids may be prepared by reducing a-ketonic acids in the 
presence of ammonia; the reduction may be performed catalytically, or 
with sodium and ethanol. The mechanism of the reaction is not certain, 
but it probably occurs via the imino-acid. 



§2] AMINO-ACIDS AND PROTEINS 455 



R-COCO a H + NH 3 M 



H » .-• 



ROC0 2 H" 

II 
NH 



R-CH(NH a )-C0 2 H 



This method works well for alanine and glutamic acid. 

Oximes of oc-keto-acids may also be reduced to a-amino-acids. The 
advantage of this method is that the oximes may readily be prepared in 
good yield by the action of sulphuric acid on a mixture of an alkylacetoacetic 
ester and an alkyl nitrite (Hartung et ah, 1942). 

H SO 

CH 3 -COCHR-CO a C a H 5 + RONO -±-> 



Zn— CjH.OH 



R-OCO a C a H 5 + CH 3 -CO a H + ROH 

II 
NOH 

The reduction of phenylhydrazones made by the action of a diazonium 
salt on an alkylacetoacetic ester also may be used to prepare a-amino-acids 
(c/. the Japp-Klingermann reaction, Vol. I); e.g., 

CH 3 -CH-C0 2 C a H 6 + C 6 H 5 -N a Cl-^ 

COCH 3 

CH 3 -CO a H + CH 3 -C-CO a C a H 5 

II 
N-NH-C 6 H 5 

CH 3 -CH-CO a C 2 H 5 J^^Lt. CH 3 -CH(NH a )-CO a H 

NH a 

Thus alanine, phenylalanine, leucine, woleucine, valine and hydroxyproline 
may be prepared in this way. 

Alkylacetoacetic esters may also be converted into a-amino-acids by means 
of the Schmidt reaction (see also Vol. I). 

H SO 

CH 3 -COCHR-CO a C a H 5 + HN 3 -^-4- 

CH 3 -CONH-CHR-CO a C a H 6 + N,-^^% R-CH(NH a )-CO a H 

(va) The Azlactone synthesis (Erlenmeyer synthesis, 1893). Azlactones 
are usually prepared by heating an aromatic aldehyde with hippuric acid 
(benzoylglycine) in the presence of acetic anhydride and sodium acetate, 
e.g., benzaldehyde forms benzoyl-a-aminocinnamic azlactone (4-benzyhdene- 
2-phenyloxazol-5-one) . 



C,H s CHO + CH 2 -C0 2 H (CHs . C o) a o C,H 5 -CH= 



rr 



NH-CO-C 6 H 5 CH > COjNa N < 2 >° 

I 
C 6 H 5 

This reaction is usually referred to as the Erlenmeyer azlactone synthesis. 
Aceturic acid (acetylglycine) may also be used instead of hippuric acid. 
Furthermore, it has been found that aliphatic aldehydes may condense with 
hippuric acid to form azlactones if lead acetate is used instead of sodium 
acetate (Finar et al., 1949). 

When azlactones are warmed with one per cent, sodium hydroxide solu- 
tion, the ring is opened, and if the product is reduced with sodium amalgam 
followed by hydrolysis with acid, an a-amino-acid is produced, e.g., 



456 



ORGANIC CHEMISTRY 



CeEt-CH^ CO C 6 H 5 -CH=C • C0 2 H 

II NaOf^ 6 | 2 Na-H g> 

N^ NH-CO-C 6 H 5 



[CH. XIII 

CgIi5*CPl2' CH'COgH 

NH-CO-C 6 H 5 



HCI 



C 6 Hs 
CeHj-CHg-OEKNH^-COaH + C 6 H 5 -C0 2 H 



The azlactone synthesis offers a convenient means of preparing phenyl- 
alanine, tyrosine, tryptophan and thyroxine. 

(v&) Aromatic aldehydes also condense with hydantoin, and reduction of 
the product with sodium amalgam or ammonium hydrogen sulphide, followed 
by hydrolysis, gives an a-amino-acid, e.g., tryptophan may be prepared by 
first converting indole into indole-3-aldehyde by means of the Reimer- 
Tiemann reaction (see Vol. I). 



OHO 





-NH 



+ T >co- 

CH 2 -NH 

hydantoin 



(CH 3 -CO).jO, 




CH 2 CH-NH hci 
I ^CO-^ 

CO-NH 




CH=C — NH 
I > 

CO-NH 



;co 



CH 2 -CHC0 2 H 



NH, 



This method has been improved by using acetylthiohydantoin instead of 
hydantoin. 

CO— NH 

I >» 

CH— N-CO-CHj 

acetylthiohydantoin 

The above method may be used to prepare phenylalanine, tyrosine, trypto- 
phan and methionine. 

Another modification of the hydantoin synthesis is the Bucherer hydan- 
toin synthesis (1934). In this method an oxo compound is converted 
into the cyanohydrin and this, on treatment with ammonium carbonate, 
produces a 5-substituted hydantoin which, on hydrolysis, gives an a-amino- 
acid. 



RCHO + HCN 



-^R-CHOH-CN fNH,) ° C ° 3 > 



RCH— CO 



NH— CO 



>NH 



HCI. 



R-CH(NH 8 )-C0 2 H 



(vc) Aromatic aldehydes may be condensed with diketopiperazine, and 
the product converted into an amino-acid by heating with hydriodic acid 
and red phosphorus, e.g., 



§3] AMINO-ACIDS AND PROTEINS 457 

/C0 N /CO 

awoHotf ?^j£2^v r v BsoH ■ o • H • 

CH 2 NH C 6 H 6 -CH=C NH 

\o' CO 



HI 



2C 6 H 5 -CH 2 -CH(NH 2 )-C0 2 H 



Phenylalanine, tyrosine and methionine may be prepared by this method. 

§3. Isolation of amino-acids from protein hydrolysates. Many 
amino-acids can be detected colorimetrically, and these colour reactions 
have now been developed for quantitative estimation. Also, amino-acids 
containing a benzene or pyrrolidine nucleus have characteristic absorption 
spectra; thus the presence of such acids can readily be ascertained. 

The actual quantitative isolation of amino-acids from their mixtures is a 
difficult problem. The earliest method was the fractional distillation of the 
amino-acid esters in vacuo (Fischer, 1901). This method is very little used 
now, and is only satisfactory for the neutral amino-acids {i.e., those con- 
taining one amino-group and one carboxyl group). 

Neutral amino-acids may be extracted by w-butanol saturated with water, 
and then separated by fractional crystallisation or by the fractional distilla- 
tion of the esters. After the butanol extraction, the residue may be treated 
with phosphotungstic acid, whereupon the basic amino-acids are precipitated 
(Dakin et al., 1913). 

A number of individual amino-acids can be obtained by means of selective 
precipitation as salts, e.g., lysine is precipitated by picric acid. 

Mixtures of amino-acids may be separated into fractions consisting of 
the neutral, basic and acidic acids by means of the electrical transport method. 
In this method a P.D. is applied to the mixture at the proper pK; the basic 
acids (positively charged) migrate to the cathode compartment, the acidic 
acids (negatively charged) migrate to the anode compartment, and the 
neutral acids remain in the centre compartment. 

The most satisfactory method of analysing amino-acid mixtures is parti- 
tion chromatography carried out on paper (Martin et al., 1944). The mixture 
of amino-acids is partitioned between a stationary water phase adsorbed on 
a strip or sheet of filter paper and a moving phase of some organic solvent 
(butanol, phenol, etc.). The moving phase either ascends or descends the 
paper strip (according to the way the experiment is performed). A small 
amount of the amino-acid solution is applied to one end of the paper, the 
strip then placed in a suitable glass container containing the organic solvent 
saturated with water, and when the solvent front has progressed a suitable 
distance, the distance moved by the solvent is measured, the strip dried, 
and then sprayed with a dilute solution of ninhydrin in butanol (see also 
§4C). Coloured spots are produced at the positions of the various amino- 
acids. The ratio of the distance travelled by the amino-acid to the distance 
travelled by the solvent is characteristic of each amino-acid, and is known 
as the R F value (this value depends on the experimental conditions). 

A very interesting analytical method is the microbiological assay. This 
depends on the fact that micro-organisms can be " trained " to feed on a 
specific amino-acid in the nutrient medium. The rate of growth of the 
micro-organism is first measured by breeding in a medium containing the 
particular amino-acid, and then the rate of growth is measured in the 
mixture of amino-acids to be analysed. In this way it is possible to deter- 
mine the amounts of various amino-acids in protein hydrolysates without 
isolation of the acids. Another method of analysis is that of isotopic dilution. 



468 



ORGANIC CHEMISTRY 



[CH. XIII 



Suppose the amount of glycine is to be estimated. A weighed amount 
of labelled glycine is added to the hydrolysate, and then glycine is isolated 
by one of the standard methods. The amount of labelled glycine in this 
specimen is now measured, e.g., say it is 1 per cent. Thus for every 1 g. 
of labelled glycine there are 99 g. of ordinary glycine. Since the weight 
of the added labelled glycine is known, the total weight of glycine in the 
mixture can therefore be calculated (see also Vol. I). 

§4. General properties of the amino-acids. The amino-acids are 
colourless crystalline compounds which are generally soluble in water but 
sparingly soluble in organic solvents; most melt with decomposition, but 
Gross et al. (1955) have shown that sublimation is possible with a number of 
amino-acids. All except glycine contain at least one asymmetric carbon 
atom, and all (except glycine) occur naturally in their optically active forms. 
It has been mentioned in §5b. II that natural (— )-serine was chosen as the 
arbitrary standard for correlating the configurations of amino-acids, the 
relationship to this acid being indicated by D g or t s . It has now been shown 
that l, = L 8 , i.e., natural (— )-serine belongs to the L-series (with glyceralde- 
hyde as absolute standard). The correlation between the two standards 
was established as follows. (+)-Alanine has been correlated with l(+)- 
lactic acid (for the correlation of the latter with l(— )-glyceraldehyde see 
§5b i. II); and L(+)-alanine has been correlated with l(— )-serine: 



C0 2 H 



HO- 



C0 2 H 



-H -*^-H- 



Me 

l(+) -lactic acid 



-Br -*&*+ N,- 



C0 2 H 



-H -%+■ NH; 



C0 2 H 



Me 



cat.' -""j 

Me Me 

l(+) -alanine 



C0 2 H 



NH 2 



H 



CH 2 OH 

l(— )-serine 



MeOH , 
HC1 : 



ClNHg" 



C0 2 Me 
H 



PCI. 



ClNHs 



C0 2 Me 



CH 2 OH 



CH 2 Cl 



(!) NaOH 



C0 2 H j 
-H 



NHr 

Me i 
!.(+) -alanine 

A new method for determining the configuration of an a-amino-acid is by 
studying the rotatory dispersion curves of the 2V-alkylthio derivatives. 
L-Compounds show a positive Cotton effect, whereas the D-compounds show 
a negative effect (see §12a. I). It has been shown that the a-carbon atom, 
i.e., the carbon atom attached to the amino-group, has, in almost all the 
amino-acids, the same configuration as L(— )-glyceraldehyde. The specific 
rotation of the amino-acids depends on the pH of the solution, the tempera- 
ture, the presence of salts and the nature of the solvent (see §12. I), The 
racemic amino-acids may be resolved by first formylating and then resolving 
the formyl derivatives via the salt with an optically active base, and finally 
removing the formyl group by hydrolysis (see also C i). Alternatively, 
racemic amino-acids may be resolved by means of enzymes (see §10 iv. II). 
A more recent method is the selective destruction of one or other enantio- 
morph of a racemate by a specific D- or L-oxidase (Parikh et al., 1958); the 
optical purity of the product is greater than 99*9 per cent. As pointed 
out above, most natural amino-acids are l; these are obtained by acid or 



§4] AMINO-ACIDS AND PROTEINS 459 

enzymic hydrolysis of proteins. Alkaline hydrolysis of proteins gives the 
DL-amino-acids (§1), and so does the synthetic preparation; it is by resolu- 
tion of the synthetic racemic modification that the D-amino-acids are 
frequently prepared. 

The symbols d and l are used for the configuration of the a-carbon atom 
(see above), and the symbols (+) and (— ) are used to indicate the direction 
of the rotation (c/. §5. II). When two asymmetric centres are present, then 
D and L still refer to the a-carbon atom, and the naturally occurring acid 
is known as the L-amino-acid. The a«o-form is the name given to that 
form in which the configuration of the second asymmetric carbon atom is 
inverted, e.g., l(— )-threonine (the naturally occurring form), D(+)-threonine, 
L-«Wothreonine and D-aWothreonine. 

C0 2 H C0 2 H C0 2 H C0 2 H 

NHj-G-H H-C-NH 2 NHrC~H H~C-NH 2 

H-G-OH HO-C-H HO-C-H H-C-OH 



I L 



CH 3 CH S CH 3 CH ; 



L(-)-threonine D(+)-threonine L-atfothreonine D-a/Zothreonine 

Since they contain amino and carboxyl groups, the amino-acids possess 
the properties of both a base and an acid, i.e., they are amphoteric. 

A. Reactions due to the amino-group. 

(i) The amino-acids form salts with strong inorganic acids, e.g., 

Cl{H 3 N-CH a -CO g H. 

These salts are usually sparingly soluble in water, and the free acid may be 
liberated from its salt by means of a strong organic base, e.g., pyridine, 
(ii) Amino-acids may be acetylated by means of acetyl chloride or acetic 
anhydride. 

R-CH(NH 2 )-C0 2 H + (CH 3 -CO) 2 -> 

RCH(NH-COCH 3 )-C0 2 H + CH s -C0 2 H 

Similarly, benzoylchloride produces the benzoyl derivative. These acetylated 
derivatives are acidic, the basic character of the amino-group being effectively 
eliminated by the presence of the negative group attached to the nitrogen. 
It should also be noted that the carboxyl group of one molecule can react 
with the amino-group of another molecule of an amino-acid to form a 
peptide (see §9). Sanger (1945) has shown that l-fluoro-2 : 4-dinitrobenzene 
combines with amino-acids to form dinitrophenyl derivatives (see §11). 
(iii) Nitrous acid liberates nitrogen from amino-acids. 

R-CH(NH a )-C0 2 H + HNO a -*. R-CHOH-CO a H + N 2 + H 2 

The nitrogen is evolved quantitatively, and this forms the basis of the van 
Slyke method (1911) for analysing mixtures of amino-acids. 

(iv) Nitrosyl chloride (or bromide) reacts with amino-acids to form chloro- 
(or bromo) acids. 

R-CH(NH 2 )-C0 2 H + NOC1-* R-CHC1-C0 2 H + N a + H 2 

(v) When heated with hydriodic acid at 200°, the amino-group is elimi- 
nated with the formation of a fatty acid. 

R-CH(NH 2 )-C0 2 H -^U. R.CH 2 -C0 2 H + NH 3 



460 ORGANIC CHEMISTRY [CH. XIII 

B. Reactions due to the carboxyl group. 

(i) Amino-acids form salts; the salts of the heavy metals are chelate 
compounds, e.g., the copper salt of glycine (deep blue needles) is formed 
by heating copper oxide with an aqueous solution of glycine. 




The amino-acids may be liberated from their alkali salts by treatment in 
ethanolic solution with ethyl oximinocyanoacetate (Galat, 1947). 

(ii) When heated with an alcohol in the presence of dry hydrogen chloride, 
amino-acids form ester hydrochlorides, e.g., 

NH 2 -CH 2 -C0 2 H + C 2 H 6 OH + HC1-* C1{H 3 N-CH 2 -C0 2 C 2 H 5 + H 2 

The free ester may be obtained by the action of aqueous sodium carbonate 
on the ester salt. The esters are fairly readily hydrolysed to the amino- 
acid by aqueous sodium hydroxide (even at room temperature). These 
esters may be reduced to the amino-alcohols by means of sodium and ethanol, 
or hydrogenated in the presence of Raney nickel. Amino-acids may be 
reduced directly to the amino-alcohol with lithium aluminium hydride, and 
in this case no racemisation occurs (Vogel et al., 1952). 

R-CH(NH 2 )-CO a H UAm '> R-CH(NH a )-CH 2 OH 

(iii) When suspended in acetyl chloride and then treated with phosphorus 
pentachloride, amino-acids form the hydrochloride of the acid chloride. 

R-CH(NH 2 )-CO a H + PC1 5 — ► Cl{H 3 N-CHR-COCl + POO, 

(iv) Dry distillation, or better by heating with barium oxide, decarboxyl- 
ates amino-acids to amines. 

R-CH(NH a )-C0 2 H-^ R-CH 2 -NH 2 + C0 2 

(v) When heated with acetic anhydride in pyridine solution, amino-acids 
are converted into methyl a-acetamidoketones (Dakin et al., 1928; see also 
§18. XII) ; this reaction is often referred to as the Dakin-West reaction. 

NH 2 NH-CO-CHs 

„ / (CHj-CO)aO / 

R-CH c,h 5 n > R'CH 

C0 2 H COCH 3 

C. Reactions due to both the amino and carboxyl groups. 

(i) When measured in aqueous solution, the dipole moment of glycine 
(and other amino-acids) is found to have a large value. To account for 
this large value it has been suggested that glycine exists, in solution, as 
an inner salt: 

NH 2 -CH 2 -C0 2 H + H 2 ^ NH 3 -CH 2 -c6 2 + H 2 

Such a doubly charged ion is also known as a zwitterion, ampholyte or a 
dipolar ion. This dipolar ion structure also accounts for the absence of 
acidic and basic properties of an amino-acid (the carboxyl and amino-groups 
of the same molecule neutralise each other to form a salt). The properties 
of crystalline glycine, e.g., its high melting point and its insolubility in 
hydrocarbon solvents, also indicate that it exists as the inner salt in the 
solid state. 



§4] AMINO-ACIDS AND PROTEINS 461 

Each amino-acid has a definite pH at which it does not migrate to either 
electrode when a P.D. is applied. This pH is known as the isoelectric 
point, and at this point the amino-acid has its lowest solubility. 

Owing to their amphoteric character, amino-acids cannot be titrated 
directly with alkali. When formalin solution is added to glycine, methylene- 
glycine is formed. 

NH 2 -CH 2 -C0 2 H + H-CHO — >■ CH 2 =N-CH 2 -C0 2 H + H 2 

Although some methyleneglycine is probably formed, it appears that the 
reaction is more complex; the main product appears to be dimethylol- 
glycine. 

NH 2 -CH 2 -C0 2 H + 2H-CHO -> (CH 2 OH) 2 N-CH 2 -C0 2 H 

These glycine derivatives are strong acids (the basic character of the amino- 
group being now suppressed), and can be titrated with alkali. This method 
is known as the Sorensen formol titration. 

(ii) When heated, a-amino-acids form 2 : 5-diketopiperazines ; esters give 
better yields; e.g., diketopiperazine from glycine ester. 

CH 2 -C0 2 C 2 H 5 NH 2 /CH 2 -CO\ 

I + I *- NH NH + 2C 2 H s OH 

NH 2 C 2 H 5 2 OCH 2 XJO-CH^ 

(iii) iV-alkyl or arylamino-acids form iV-nitroso derivatives with nitrous 
acid, and these may be dehydrated to sydnones by means of acetic anhydride 
(see §8. XII). 

R R 

I I 

CH-C0 2 H /C C=0 

ArN / (CH3CO)3 °> Ar-N ± | 

N N0 X N O 

(iv) Betaines. These are the trialkyl derivatives of the amino-acids; 
betaine itself may be prepared by heating glycine with methyl iodide in 
methanolic solution. The betaines exist as dipolar ions; thus the formation 
of betaine may be written: 

HaN-CHa-COs + 3CH 3 I — ► (CH 3 ) 3 N-CH 2 -c62 + 3HI 

Betaine is more conveniently prepared by warming an aqueous solution of 
chloroacetic acid with trimethylamine. 

+ - 

(CH 3 ) 3 N + C1CH 2 -C0 2 H -> (CH 3 ) 3 N-CH 2 -C0 2 -f- HC1 

Betaine is a solid, m.p. 300° (with decomposition). It occurs in nature, 
especially in plant juices. It behaves as a base, e.g., with hydrochloric acid 

- + 

it forms the stable crystalline hydrochloride, Cl^CH^aN'CH^COaH. 

(v) Amino-acids react with phenyl wocyanate to form phenylhydantoic 
acids, and these, on treatment with hydrochloric acid, readily form hydan- 
toins (see §2. XVI): 

Ph-NCO + R-CH(NH 8 )-C0 2 H -^ R-CH-NH-CONHPh -52L> R-CH— NH 

\co 

C0 2 H CO— NPh 

If phenyl wothiocyanate is used instead of the wocyanate, then thiohydan- 
toins are produced (see §11). 



462 ORGANIC CHEMISTRY [CH. XIII 

(vi) Ninhydrln reaction. Ninhydrin (indane-1 : 2 : 3-trione hydrate) 
reacts with amino-acids as follows: 

CO 

CO + RCHNH 2 -C0 2 H — >~ RCHO+ C0 2 + NH 3 + 





CO 

\hoh ni :i drin > 



2NH, 




The amino-acid is oxidised to aldehyde and the ninhydrin is reduced to 
1 : 3-diketoindan-2-ol. The latter then reacts with another molecule of 
ninhydrin and with ammonia (which is produced in the first reaction) to 
form a coloured product. This reaction is the basis of a colorimetric method 
for estimating amino-acids. 

§5. Thyroxine (thyroxin). Thyroxine is a hormone; it is the active 
principle of the thyroid gland and was first isolated by Kendall (1919). 
It was later isolated by Harington (1930) as a white crystalline solid, 
m.p. 235°, with a laevorotation. 

The structure of thyroxine was established by Harington (1926). This 
author showed that the molecular formula of thyroxine is C 16 H u 4 NI 4 . 
When treated in alkaline solution with hydrogen in the presence of colloidal 
palladium, the iodine in thyroxine is replaced by hydrogen to form thyronine 
(thyronin), C 1B H 15 4 N. This behaves as a phenol and an oc-amino-acid. On 
fusion with potassium hydroxide in an atmosphere of hydrogen, thyronine 
gives a mixture of ^-hydroxybenzoic acid, quinol, oxalic acid and ammonia. 
When fused with potassium hydroxide at 250°, thyronine gives ^-hydroxy- 
benzoic acid, quinol and a compound with the molecular formula C 13 H M O a 
(II). A structure for thyronine which would give all these products is I. 

m \^/-° ~\^y>~CH 2 - CH-C0 2 H 



I 

thyronine 



NH, 



Thyronine (provisionally structure I) was subjected to the Hofmann ex- 
haustive methylation (see §4. XIV) and the product thereby obtained was 
then oxidised. The final product would be III (on the assumption that I 
is thyronine). 



HO \__\-0-\__\ C0 2 H 



III 

The structure of III was confirmed by synthesis, starting from p-bTomo- 
anisole and ^>-cresol. 



§5] AMINO-ACIDS AND PROTEINS 463 

cH *° < C3 >Br+K0< C3 >cH3 Cu ~ 



*3 bronze 



ch s o<j3^- o -<3 >ch » J ^~ 

CH 3 0<^>-0-^>C0 2 H- a ^ 

HO \^y > — O — \__y > °0 2 H 
III 

Furthermore, when 4-methoxy-4'-methyldiphenyl ether is heated with 
hydriodic acid, compound II (CnHuO,; see above) is obtained; thus the 
structure of II is also established. 

CH 3 0<3-0-<3cH3-^ H0<^O^3cH 3 

II 

Now when thyroxine is fused with potassium hydroxide, no ^>-hydroxybenzoic 
acid is obtained; instead, compounds of the pyrogallol type are formed. 
These facts suggest that two atoms of iodine are adjacent to the hydroxyl 
group, and that the two remaining iodine atoms are in the other benzene 
ring. This, together with the analogy with di-iodotyrosine, leads to the 
suggestion that thyroxine is IV. 

I I 

HO \ 7~°~\ ^-0H 2 CHCO 2 Hi 

I I NH 8 

IV 

thyroxine 



464 ORGANIC CHEMISTRY [CH. Xllf 

This structure for thyroxine has been confirmed by synthesis (Harington 
et al., 1927). 



KoCO.in >0H 3°\ ?—0-\ /JNOa (ii)C t 



I 



Clj-HCl 



C 5 HuONO-HCr 



I I 



SnCla-HCI -,„ „ yf ^v_«_^ N\ „„„ C t H s CONH-CH a CO,H , 



►ch 3 o \^y -o — \ ^ cho 

I 



1 

azlactone 



CO— O 

CCjHs 



1 

HO<^^— Q-\ ^-0H 2 CH-CO 2 H 



I I 

coJV HO^^-0-^^>-CH 2 -CH-C0 2 H 
I I NH 2 

(±) -thyroxine 

The racemic modification was resolved via the formyl derivative (Harington, 
1938). 
The synthesis of thyroxine has been improved, e.g., by Hems et al. (1949). 

,7—t. ,C0 2 H „„„ s?-\^ /C0 2 H 



" NH * noT ^ 



L-tyrosine 



§6] AMINO-ACIDS AND PROTEINS 465 

N°* /COAH 5 

■ P)(ch,-co),o-n.oh ^ H0< ^ ^_CH 2 -CH 

(ii) c,H a oH;cH,^^so,n no =,/ ^ X NH-CO-CH s 

W ^ CH 3 0< ^0-< VCH 2 CH 

^ >SO.CI: heat NzzrzX N ^=^ N l 



ch,< >so 3 ci; heat >==^ g^ v NH-CO-CH 3 

•<" H '- W ^ caofVo/ >-CH 2 GH 

(ii) NaN0 2 -H 2 S0 4 0±l3U \ / ^\ == / * \ xm . rrv . rw 

(iii)Ij-Nal ' ' Y^ NH-CO-CH 3 



(i) HI-CH 3 -CO,H 
(ii) I, in CjHjNHj 



HO^^-0-^^CH 2 -CH 



I 

L-thyroxine 



C0 2 H 
NH 2 



The thyroid gland also contains 3 : 5-di-iodotyrosine, and this compound 
is believed to be the precursor of thyroxine. Deficiency in thyroxine causes 
myxcedema. 

PROTEINS 

§6. General nature of proteins. The name protein was introduced by 
Mulder (1839), who derived it from the Greek word proteios (meaning first). 
Proteins are nitrogenous substances which occur in the protoplasm of all 
animal and plant cells. Their composition varies with the source; an 
approximate composition may be given as: carbon, 47-50%; hydrogen, 
6-7%; oxygen, 24-25%; nitrogen, 16-17%; sulphur, 0-2-0-3%. Other 
elements may also be present, e.g., phosphorus (nucleoproteins), iron (haemo- 
globin). 

Proteins are colloids and have no characteristic melting points; some 
have been obtained in crystalline form. All proteins are optically active 
(laevorotatory), their activity arising from the fact that they are complex 
substances built up of amino-acids. It appears likely that all enzymes 
are proteins (see §12); many hormones are also proteins, e.g., insulin. 

Proteins may be coagulated, i.e., precipitated irreversibly, by heat and 
by strong inorganic acids and bases, etc. When proteins are precipitated 
irreversibly, they are said to be denatured, but the chemical changes that 
occur in this process are still uncertain. The results of denaturation may 
be a change in any of the following properties: solubility, molecular shape 
and size, biological activity, or susceptibility to enzymic reactions. One 
point that appears to be reasonably certain is that a critical number of 
hydrogen bonds must be broken before irreversible denaturation can occur. 
Proteins may be precipitated by ethanol or concentrated solutions of am- 
monium sulphate or sodium chloride. In this case, the precipitation is 
reversible, i.e., the precipitated proteins may be redissolved; thus they are 
not denatured by these reagents. Proteins are also precipitated by the 
salts of the heavy metals, e.g., mercuric chloride, copper sulphate, etc., and 
they give many characteristic colour reactions with various reagents, e.g., 



466 ORGANIC CHEMISTRY [CH. XIII 

(i) Biuret reaction. Addition of a very dilute solution of copper sulphate 
to an alkaline solution of a protein produces a red or violet colour. 

(ii) Milloris reaction. When a solution of mercuric nitrate containing 
nitrous acid is added to a protein solution, a white precipitate is formed 
and slowly turns pink. 

(iii) Xanthoproteic reaction. Proteins produce a yellow colour when 
treated with concentrated nitric acid. 

Proteins are amphoteric, their behaviour as an anion or a cation depend- 
ing on the pH. of the solution,. At some definite pH, characteristic for each 
protein, the solution contains equal amounts of anion and cation. In this 
condition the protein is said to be at its isoelectric point, and at this pH. the 
protein has its least solubility, i.e., it is most readily precipitated (cf. amino- 
acids, §4 C i). The osmotic pressure and viscosity of the protein solution 
are also a minimum at the isoelectric point. The amphoteric nature of 
proteins is due to the presence of a large number of free acidic and basic 
groups arising from the amino-acid units in the molecule. These groups 
can be titrated with alkali or acid, and by this means it has been possible 
to identify acidic and basic groups belonging to the various amino-acid 
units (see also §11). 

The molecular weights of proteins have been determined by means of 
the ultracentrifuge, osmotic pressure measurements, X-ray diffraction, light 
scattering effects and by chemical analysis. Chemical methods are based 
on the estimation of a particular amino-acid, e.g., casein contains cystine; 
hence the estimation of the percentage of this amino-acid and of sulphur will 
lead to the evaluation of the molecular weight of casein. The most reliable 
values of the molecular weights are those obtained by the ultracentrifuge 
method; thevalues recorded vary considerably for the individual proteins, rang- 
ing from about 40,000 for egg albumin to about 5,000,000 for haemocyanin. 

§7. Classification of proteins. Several arbitrary classifications of the 
proteins are in use. On