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OUB-43 30-1-71 5,000 

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PERKIN AND KIPPINjG'S 

ORGANIC CHEMISTRY 



PERKIN AND KIPPING'S 

ORGANIC CHEMISTRY 

Part III 

BY 

F. STANLEY KIPPING 

PROFESSOR EMERITUS OF CHEMISTRY, UNIVERSITY COLLEGE 
NOTTINGHAM 

AND 

F, BARRY KIPPING 

UNIVERSITY LECTURER IN CHEMISTRY, CAMBRIDGE 
FELLOW OF ST. JOHN'S COLLEGE 



NEW EDITION 



W. flf R. CHAMBERS, LTD. 

11 THISTLE ST., EDINBURGH : 6 DEAN ST., LONDON, W.I 



PERKIN AND KIPPING'S 
ORGANIC CHEMISTRY 

NEW EDITION 

Part I 416 pages 

Part II 368 pages 

Part III 496 pages 

Parts I and II in one Volume 
744 pages 

W. & R. CHAMBERS, LTD. 

EDINBURGH AND LONDON 



W. & R. CHAMBERS, LTD. 


New Edition, 1958 



Pr'r.iril i:i A WAI II" 1 . 
by T, and A. (Y^-iiiMi: I ;: II : ,i: 
Printers 1o il:<> I r.lm-i'i < i II ::>.! 



PREFACE 

THE present volume was first written in 1934 as a continuation of 
Parts I and II of Perkin and Kipping's Organic Chemistry, and 
was intended mainly for the use of students who are working for 
an Honours Degree Examination. It was hoped that it might also 
be helpful to teachers, and to others who are interested in the more 
recent developments of certain branches of organic chemistry. 
These aims are unchanged and the main plan remains as before. 

The difficulty of selecting the subjects which should be dealt 
with in such a book, and of deciding the space to be allotted to each, 
will be appreciated by all those who are confronted with this 
particular problem in preparing their courses of lectures, and since 
the first edition this difficulty has grown, as new fields of chemistry, 
at that time unknown or of little importance, have assumed pro- 
minence. There is still the same limit, however, to what a student 
can remember, and certain deletions have therefore been made of 
what appeared to be out-of-date material. 

Whether the selection of subjects included in this book is the 
best or otherwise is no doubt a matter of opinion, but it is based 
on the results of many years of experience in teaching this branch 
and grade of chemistry. 

For the present edition the whole work has been reset, thus 
allowing complete freedom. In particular almost all the formulae 
have been redrawn and the opportunity has been taken of intro- 
ducing a new, and it is hoped, simplified, method of writing many 
of them. 

Two chapters have disappeared : one on the Electronic Formulae 
of Organic Compounds, as it is considered that the electronic theory 
of valency is now so well known to students that its inclusion in a 
text-book of organic chemistry is superfluous ; the other, on the 
Theory of Resonance, has not been deleted but has been transferred 
piecemeal to appropriate places in Parts II or III. Certain other 
short sections have been also transferred to Part II where their 
position seemed more logical, and two short chapters on Alkali 
Metal Compounds and Free Radicals have been combined. 

The two largest additions are the sections on Plastics 
Nucleoproteins : the former has been incorporated in a 




VI PREFACE 

with the revised section on Rubber and the latter with an extended 
section on Vitamins, which have been covered in more detail than 
before. 

The whole of the old text has been entirely rewritten and im- 
portant additions have been made on the Synthesis of Large Ring 
Compounds, the Oxidation of defines, the Nomenclature of Bridged 
Ring Compounds, the fnterconversion of Sugars, the Oxidation of 
Sugars with Periodic Acid, Synthetic Sesquiterpenes, Resin Acids, 
Azulenes, the Synthesis of Poly cyclic Compounds, Antibiotics and 
Adrenal Hormones : to avoid excessive length only the more salient 
advances in organic chemistry have been included. 

By his death in May 1949 I was deprived of the invaluable 
collaboration of my father, but fortunately the first proof had been 
received by then and I feel that any merit the present work may 
have is largely due to him, as he had a critical faculty and a flair for 
writing which were always my envy. 

I am greatly indebted to Dr C. P. Stewart, who read the whole 
of Part III in proof and made many valuable suggestions : also to 
Professor C. W. Shoppee for reading Chapter 64, and Professor 
A. R. Todd, who read Chapters 62 and 63. 



NOTE ON 1958 EDITION 

In the 1958 edition a new Chapter on the Applications of the 
Electronic Theory to Organic Chemistry has been added at the 
beginning. In many places modern electronic interpretations of 
organic reactions have been given, as, for example, in discussions 
of racemisation, the Walden inversion, aromatic substitution, etc. 
The Chapter on Physical Properties of Organic Compounds has 
been rewritten to give more prominence to those properties most 
used nowadays for determining constitution. Modern views of 
strainless ring structures are given and a short account of tropolones 
and ferrocene. Various other small alterations have been made in 
an endeavour to bring the matter thoroughly up to date in so far 
as possible without too extensive alterations. 

My very best thanks are due to Professor D. H. Peacock for 
valuable advice and many discussions throughout, to Professor G. W. 
Kenner for reading Chapter 43 and parts of Chapter 59 and to Dr. 
N. Sheppard for comments on parts of Chapter 44. F. B. K. 



CONTENTS 

PAOE 

CHAPTER 43. APPLICATIONS OF THE ELECTRONIC THEORY 

TO ORGANIC CHEMISTRY . . . ' . . 695a 

Substitution Reactions, 695/z. Hydrolysis and Esterifica- 
tion, 69S&. Addition to the Carbonyl Group, 695w. 
Reactivity of a-Hydrogen Atoms, 695w. Addition to the 
Ethylenic Linkage, 695o. Ferrocene, 695#. Tropolones, 
695r. 

CHAPTER 44. THE PHYSICAL PROPERTIES OF ORGANIC 

COMPOUNDS ....... 695w 

Melting-point, 695w. Boiling-point, 697. Solubility, 698. 
Molecular Volume and Parachor, 699. Molecular Re- 
fraction, 699. Absorption Spectra, 700. X-ray Crystal 
Analysis, 702. Dipole Moments, 702. Nuclear Magnetic 
Resonance, 705. Magnetic Susceptibility, 706. Heat of 
Combustion, 706. 

CHAPTER 45. GEOMETRICAL ISOMERISM .... 708 

Cis- and trans- Additive Reactions, 711. Interconversion of 
Geometrical Isomerides, 713. Stereochemistry of Cyclic 
Compounds, 716. 

CHAPTER 46. GEOMETRICAL ISOMERISM OF THE OXIMES AND 

OTHER COMPOUNDS OF TERVALENT NITROGEN . . 724 

The Beckmann Transformation, 729. Configurations of 
Ketoximes, 730. Configurations of Aldoximes, 732. 
Stereoisomerism of Hydrazones and Semicarbazones, 737. 
Metallic Diazotates and /sodiazotates, 739. 

CHAPTER 47. OPTICAL ISOMERISM ..... 742 

Racemic Substances and Conglomerates, 742. Variation 
in the Specific Rotation, 743. Relation between Structure 
and Specific Rotation, 744. Optical Superposition, 745. 
Asymmetric Synthesis, 746. Racemisation and Epimeric 
Change, 748. The Walden Inversion, 751. The Pheno- 
menon of Restricted Rotation, 757. Stereochemistry of 
Quaternary Ammonium Compounds, 762. 

vii 



vili CONTENTS 

FAOB 

Optical Isomerism of Amine Oxides, 764. 
Stereochemistry of Tervalent Nitrogen, 765. 
Stereochemistry of Tin and Silicon, 767. 
Stereochemistry of Sulphur and Selenium, 768. 
Stereochemistry of Organic Co-ordination Compounds, 
769. 

CHAPTER 48. CYCLOPARAFFINS AND CYCLO-OLEFINBS . . 777 
Qyc/oparaffins and their Derivatives, 777. 
Large Ring Compounds, 784. 
CycZo-olefines, 788. 
The Strain Theory, 789. 

The Theory of Strainless Ring Structures, 791. 
The Reduction Products of Aromatic Compounds, 797. 
Qyc/ohexane and its Derivatives, 797. 
OycZohexene, QycZohexadienes and their Derivatives, 798. 
QycZohexene- and Qyc/ohexadiene-dicarboxylic Acids, 801. 

CHAPTER 49. OLEFINIC COMPOUNDS ..... 804 
Oxidation of Olefmes, 808. 
Ozonides and Ozonolysis, 809. 
Conjugated Systems, 813. 
The Diels-Alder Reaction, 818. 

Nomenclature and Stereochemistry of Bridged Ring Com- 
pounds, 819. 

CHAPTER 50. KETONES, KETONIC ACIDS, AND KETENES . . 822 
Ketones, 822. 

Diacetyl, 822. Acetylacetone, Acetonylacetone, 823. 

Pentantrione, 824. 
Ketonic Acids, 825. 
Ketenes, 827. 

CHAPTER 51. ISOMERIC CHANGE 831 

Keto-enol Tautomerism, 831. 

Ethyl acetoacetate, 831. Dibenzoylacetylmethane, Di- 
ethyl diacetylsuccinate, 832. Benzoylcamphor, 833. 
Keto-lactol and Keto-cyclo-Tautomerism, 834. 

The Tautomerism of Nitro-compounds, 836. 

Lactam-lactim Tautomerism >V 83 8 . 

Three-carbon-atom Tautomerism, 838. 

The Tautomerism of Diazoamino-compounds, 840. 

Anionotropic Changes, 840. 



CONTENTS IX 

PAGE 

Reversible and Irreversible Isomeric Change, 841 . 

Benzidine transformation, 842. Diazoamino-amino- 
azo change, 843. Hofmann-Martius conversion, 844. 
Fries and Claisen reactions, 845. Hofmann, Curtius, 
and Lessen reactions, 846. Benzil-benzilic acid trans- 
formation, 847. Pinacol-pinacolone change, 848. 
Wagner- Meerwein reaction, 849. 

CHAPTER 52. THE CONFIGURATIONS, SYNTHESIS, AND GLYCO- 

SIDIC STRUCTURES OF THE MONOSACCHARIDES . .851 
The Configurations of the Monosaccharides, 851 . 
The Relationship between Glucose and Gulose, 859. 
Ketoses, 860. 

The Synthesis of Sugars and their Derivatives, 861 . 
The Glycosidic Structures of the Monosaccharides, 864. 
Butylene Oxide or Furanose Structures, 873. 
Ketoses and Methylpentoses, 874. 

Acetone and Other Derivatives of the Monosaccharides, 876. 
Interconversion of the Sugars, 879. 
Ascorbic Acid, 880. 

CHAPTER 53. DISACCHARIDES AND POLYSACCHARIDES . . 886 
Disaccharides, 886. 
The Synthesis of Disaccharides, 894. 
The Oxidation of Sugars with Periodic Acid, 895. 
Vegetable Glycosides, 897. 
Polysaccharides, 897. 

Starch, 898. Cellulose, 899. Inulin, Chitin, Alginic 

Acid, 900. Pectin, 901. 
Fermentation, 901. 

CHAPTER 54. THE MONOCYCLIC TERPENES AND RELATED COM- 
POUNDS ........ 909 

General Properties and Reactions of the Terpenes, 910. 

Nomenclature, 911. 

Formulation, 912. 

Limonene and its Derivatives, 913. 

The Synthesis of Terpenes, 915. 

Terpineol, Terpinolene, Terpin, 917. Cineole, 918. 
Sylvestrene, 919. 

Ketones and Alcohols derived from p-Menthane, 920 

Menthone, 920. Menthols and Menthylamines, 921. 
Pulegone, Carvone, 922. Piperitone, 923. 



X CONTENTS 

PAGE 

CHAPTER 55. DICYCLIC TERPENES AND RELATED COMPOUNDS . 924 
Pinene, 925. 
Camphor and its Derivatives, 927. 

Camphor, 927. Camphoric Acid, Camphoronic Acid, 

930. Camphorsulphonic Acids, 931. Borneol and 

/soborneol, 932. 
Other Dicyclic Terpenes, 933. 

Bornylene, Camphene, 933. 
Isoprene Theory, 935. 

CHAPTER 56. OPEN CHAIN TERPENES AND SESQUITERPENES . 940 
Open Chain Terpenes, 940. 

Myrcene, Ocimene, 940. Citral, 940. Geraniol and 

Nerol, 941. Linalool, 941. Geranic Acid, 942. 
Sesquiterpenes, 943. 

Farnesene, 944. Zingiberene, Bisabolene, Cadinene, 

944. Selinene, 945. Eudesmol, 946. 
Synthetic Sesquiterpenes, 947. 
Resin Acids, 948. 

Abietic Acid, 948. 
Natural and Artificial Perfumes, 949, 

Irone and lonones, 952. 
Azulenes, 954. 

Vetivazulene, 954. Azulene, 955. 

CHAPTER 57. PLASTICS AND RUBBER 956 

Plastics, 956. 

Condensation Plastics, 957. Polymerisation Plastics, 

960. Silicones, 963. 
Rubber, 964. 
Synthetic Rubber, 968. 

Butadiene, 969. Isoprene, 970. 

CHAPTER 58. CAROTENOIDS, PYRONES, ANTHOCYANINS, AND 

DEPSIDES 972 

Carotenoids, 972. 

Lycopene, 972. Bixin,974. Crocetin, 975. Carotene, 

976. Vitamin A, 978. 
Diphenylpolyenes, 980. 
Pyrones, 983. >, 

Dimethylpyrone, 984. Chelidonic Acid, 985. Chro- 

mone, 986. Xanthone, Flavone, 987. 
Anthoxanthidins and Anthoxan thins, 988. 



CONTENTS XI 

PAGE 

Anthocyanidins and Anthocyanins, 989. 
Depsides, 994. 
Tannins, 998. 

CHAPTER 59. AROMATIC STRUCTURE AND SUBSTITUTION . 1001 
Aromatic Structure, 1001. 
Substitution in the Benzene Series, 1004. 

CHAPTER 60. THE ORIENTATION OF BENZENE DERIVATIVES. 

POLYCYCLIC HYDROCARBONS 1018 

Orientation of Benzene Derivatives, 1018. 
Polycyclic Hydrocarbons, 1022. 

Pyrene, Chrysene, Fluorene, Dibenzanthracenes, 1023. 

Coronene, 1024. Rubrene, 1026. 
Terphenyl, Quaterphenyl, etc., 1027. 
Synthesis of Di- and Poly-cyclic Compounds, 1028. 

CHAPTER 61. ALKALI METAL COMPOUNDS, FREE RADICALS AND 

STERIC HINDRANCE 1037 

Alkali Metal Compounds, 1037. 

Free Radicals, 1040. 

Compounds of Tervalent Carbon, 1040. 

Compounds of Other Elements with Abnormal Valency, 

1042. 

Metallic Ketyls, 1046. 
Free Radicals of Short Life, 1047. 
Steric Hindrance, 1048. 

CHAPTER 62. HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS . 1051 
Azoles, 1051. 

Pyrazoles, 1052. Glyoxalines, 1053. Hydantoin, 

Histidine, 1054. Triazoles, 1055. Tetrazoles, 1056. 

Oxazoles, Isoxazoles, 1057. Thiazoles, 1057. 
Diazines, 1058. 

Pyridazines, Pyrimidines, 1058. Pyrazines, Quin- 

oxalines, 1060. 
Antibiotics, 1060. 

Penicillin, 1061. Chloromycetin, Streptomycin, 1064. 

CHAPTER 63. VITAMINS AND CONJUGATED PROTEINS . . 1065 

Vitamins, 1065. 

Vitamin B, 1065. Aneurin, 1066. Riboflavin, Pyri- 
doxin, 1068. Pantothenic Acid, Biotin, 1070. Folic 
Acid, 1072. Vitamins E and K, 1073. 

Conjugated Proteins, 1074. 



Xll CONTENTS 

PAGE 

Nucleic Acids, 1075. 

Nucleosides, 1075. Nucleotides, 1078. 
Haemin and Chlorophyll, 1080. 

CHAPTER 64. STEROIDS 1087 

Sterols, 1087. 

Cholesterol, 1087. Stigmasterol, Ergosterol, Copro- 
stanol, 1088. 

Structures of the Sterols, 1089. 

Bile Acids, 1098. 

Vitamin D, 1099. 

Sex Hormones, 1101. 

Oestriol, 1102. Oestradiol, 1103. Equilin, Equilenin, 
1104. Androsterone, 1105. Testosterone, Proge- 
sterone, 1106. 

Adrenal Hormones, 1108. 

Saponins, 1109. 

APPENDIX 

Some Examination Questions . , . .1112 
Note on Consulting the Literature . . , .1126 

LIST OF ABBREVIATIONS . . . . , . .1130 

OXIDISING AND REDUCING AGENTS 1131 

INDEX 1132 



PUBLISHER'S NOTE 

Chapter 43 bears page numbers 695a to 695* : the device, ad- 
mittedly awkward, is for technical reasons unavoidable. 



ORGANIC CHEMISTRY 
Part III 



CHAPTER 43 

APPLICATIONS OF THE ELECTRONIC THEORY 
TO ORGANIC CHEMISTRY 

THE introduction of Kekute's structural theory of organic chemistry 
nearly a century ago provided a valuable framework for the system- 
atic study of the subject and led to rapid and major developments ; 
the ideas of stereochemistry of van't Hoff and Le Bel extended the 
theory to account for the existence of isomerides for which, up to 
that time (1874), there was no explanation. In spite of these great 
advances the theory was handicapped in providing an interpretation 
of the behaviour of organic compounds by an incomplete knowledge 
of atomic structure and of the nature of valency : such phenomena 
as the Walden inversion and /raws-addition were completely inex- 
plicable. The introduction of the Rutherford-Bohr atom (1913), 
subsequently modified by de Broglie, Dirac, Heisenberg and 
Schrodinger, led to the ideas of valency of Lewis and Langmuir 
which were later extended by others. Gradually a theory to explain 
the nature of the reactions of organic compounds and of linking these 
reactions with the Kekule" structures has been developed largely 
by Lowry, Lapworth, Robinson, Ingold, Pauling and others. 

The fundamental postulates of this theory are based on assump- 
tions of movements of electrons within the molecules leading to 
the development of positive and negative charges at certain atoms, 
which thereby become reactive. It is assumed in the first place 
that the electrons taking part in a co-valent bond may be shared un- 
equally. In the C Cl bond, for example, the condition may be 
represented by C > Cl, and the result will be a permanent polarisa- 
tion of. this complex ; but such a change is not restricted to the 
heteropolar bond in question, and may be transmitted along a 

695* 



695J APPLICATIONS OF THE ELECTRONIC THEORY 

saturated chain until damped out, C > C > C Cl. This is 
known as the inductive effect: 1 it is to be noted that it does not 
produce an actual transfer of electrons from one atom to another and 
that the usual valencies of the elements concerned are maintained. 

In compounds containing multiple links there is more scope for 
the movement of electrons and mesomeric effects are present ; the 
basic principles of mesomerism or resonance have already been 
pointed out in a consideration of the structure of benzene, and it 
has been mentioned that compounds in which mesomerism is 
present are more stable than*they would otherwise be. 

As a simple example of a group with a multiple link the carbonyl 
radical may be considered ; this is usually represented by >C=O, 
but it could change into (i) by a transfer of two of the electrons 
of the double bond entirely to the oxygen atom. The theory assumes 
that there is a tendency for this change to occur and that these 

+ - 



two forms contribute to the final mesomeric state of the radical ; 
this may be indicated by (n). At the instant of reaction with 
any reagent the group undergoes electromeric change into (i) in 
which the carbon and oxygen atoms have positive and negative 
charges respectively. Although the oxygen atom maintains its 
octet of electrons, it acquires a negative charge and the carbon 
atom is left with a sextet of electrons until reaction has taken place. 
In mesomeric molecules such as this the contribution to the meso- 
merism or resonance of the form in which the octets are not main- 
tained is small until electromeric change occurs, on the demand of 
a reagent. It will be seen in the sequel that the electromeric change 
which precedes reaction is controlled by the inductive and mesomeric 
effects in the molecules concerned. 

As shown above and as previously indicated (p. 517) the mesomeric 
effect is usually shown by the use of curved arrows and in the case 
of a chain of alternate single and double bonds (conjugated chain, 
p. 815) such mesomerism extends along the whole length of the 

1 The inductive effect is often denoted by the letter I and its direction 
by a positive or negative sign : unfortunately there is no general agreement 
as to whether electron attraction is to be called +1 or I. A similar ambi- 
guity is found in the sign of the mesomeric effect (above), denoted by M. 
These symbols are, however, unnecessary and are not further employed in 
this book. 



TO ORGANIC CHEMISTRY 695c 

chain, (in), so that the atoms at the ends become charged when 
electromeric change takes place, (iv). 



ni >c=C-*-y=!=O IV >C C=C O v 

The above may be summarised thus : 

The inductive effect gives rise to unequal sharing, but no transfer, 
of the electrons of co-valent bonds between atoms ; it is a permanent 
state of the molecule. 

The mesomeric effect is present only in molecules containing 
multiple links and means that the actual state of the molecule is 
somewhere between those of the end forms; it also is a permanent 
state. Both the inductive and mesomeric effects cause permanent 
dipole moments (p. 702) and the latter alterations in bond lengths. 

The electromeric effect is only brought about at the instant of 
reaction, when the molecule goes over into one of the contributors 
to the mesomeric state. 

In order to apply these ideas to an explanation of the mechanism 
of organic reactions it is obviously necessary to find out in which 
direction inductive and mesomeric effects act : it might be thought, 
for example, at first sight equally plausible to write the carbonyl 
group (v) ; this seems unlikely, however, as the oxygen atom has 
a higher nuclear charge than carbon and will probably therefore 
demand a larger share of the bonding electrons. More definite 
information on the subject may be obtained from quite simple 
considerations, among which may be mentioned the ease with 
which a hydrogen atom leaves a molecule as a proton. 

When an acid ionises its acidic 1 '.*':<,.,, -i atom separates from the 
rest of the molecule as a proton which carries a positive charge, 

HA ^ H++A- 

or more correctly, in aqueous solution, as a hydrated proton ; it 
is largely the tendency of water to form hydrated ions which provides 
the energy for ionisation, but the argument is the same whether 
the ions are hydrated or not and this factor need not be further 
considered. The ease with which ionisation occurs will therefore 
depend primarily on the demand made by the group A on a share of 
the pair of electrons forming the co-valent link between H and A ; 
the greater the attraction of A f6r electrons the stronger will be the 
acid, HA. In a molecule of hydrogen the- two electrons of the co- 



APPLICATIONS OF THE ELECTRONIC THEORY 

valent link must clearly be shared equally between the two atoms ; 
similarly in ethane it is reasonable to assume equal' sharing of the 
two electrons forming the bond between the two carbon atoms (but 
not necessarily equal sharing in the carbon-hydrogen bonds). In 
the case of hydrogen chloride the sharing is very unequal and the 
chlorine atom demands a far greater share ; the electrons are 
withdrawn from the hydrogen atom which can therefore separate 
as a proton when the gas is dissolved in water. The inductive 
effect of chlorine is thus shown to be, H > Cl or H :C1. Water 
ionises to a much smaller extent so that it may be assumed that 
the oxygen atom is demanding a smaller share of the electrons than 
does chlorine, but there is still some inductive effect. Methanol, 
in which one of the hydrogen atoms in water is replaced by a methyl 
group, ionises much less still ; it is surely reasonable to assume 
therefore that the methyl radical repels electrons and thereby satisfies 
the demands of the oxygen atom, which in its turn does not demand 
a large share from the hydrogen atom of the hydroxyl group, 
CH 3 *--OH. 

Phenol is a much stronger acid than water and at first sight it 
would seem that the phenyl radical has a strong electron attracting 
inductive effect ; this is so, but it does not cover all the facts. In 
considering the mechanism of any reaction the stability of the final 
product or products and of any transition state (p. 695*) there may 
be, must be considered. Now when the phenolate ion is produced 
by the separation of a proton, the ionic charge can be distributed 
over several atoms instead of being localised and increased stability 
results ; the ion is a mesomeric form of possible structures as 
indicated : 






Similar mesomerism exists in phenol itself (p. 1012), but the meso- 
merism of phenol is less complete than that of the phenolate ion ; 
that is to say the contribution of forms such as the second two 
above to the mesomerism of the ibn is greater than that of similar 
forms in phenol itself, so that stabilisation of the ion displaces the 
equilibrium in the direction of ionisation. 



TO ORGANIC CHEMISTRY 6950 

The acidity of a carboxylic acid can be explained as due to the 
electron attraction of the carbonyl group and rnesomerism of the 
resulting ion (p. 517) ; this implies that the carbonyl group has a 
mesomeric effect (n, p. 6956) and not *(v, p. 695*). The relative 
strengths of various acids under similar conditions are as shown 

Dissociation Constants of Acids (x 10 5 ) 

Formic acid 17 

Acetic acid 1-7 Benzoic acid 6-3 

Propionic acid 1-3 Phenylacetic acid 4-9 

w-Butyric acid !$ /3-Phenylpropionic acid 2-2 

Monochlorpacetic acid 138 a-Chloropropionic acid 158 

Dichloroacetic acid 5130 $-Chioropropionic acid 8*3 

Trichloroacetic acid 224000 

and the relationships between some of these figures may be 
explained qualitatively as follows : 

(1) The electron- repelling inductive effect of the alkyl groups is 
shown by the fall as the series of fatty acids is ascended ; the large 
initial fall from formic acid to acetic acid, however, is perhaps 
unexpected and may not be due entirely to the inductive effect 
(p. 1013). The slightly larger value for butyric acid as compared 
with propionic acid is anomalous, but insignificant. 

(2) The electron-attracting effect of the phenyl group is shown 
by the greater strength of benzoic acid as compared with acetic 
acid and the damping of the inductive effect in a saturated chain by 
the fall in strength in passing to phenylacetic acid and j8-phenyl- 
propionic acid. 

(3) The strong electron attracting inductive effect of chlorine is 
well shown by the figures for the chloroacetic acids and chloro- 
propionic acids and the damping effect of the saturated chain is 
illustrated by the much l<m cr fiir.nv for ]3- than for a-chloropropionic 
acid. 

The most important organic bases are the amines and amino- 
compounds, and their basic character is due to the unshared pair of 
electrons on the nitrogen atom, which can be used to attach a proton 
to give an ammonium salt : 

RgNi+H-^-fCh > [R 3 NH]+4-CK 

The strength of the base will depend on the availability of the 
unshared pair of electrons of the nitrogen atom. When one of the 

Org. 11143$ 



69S/ APPLICATIONS OF THE ELECTRONIC THEORY 

hydrogen atoms of ammonia is replaced by an alkyl group the induc- 
tive effect of the latter should act to make the unshared pair more 
available, CH 3 > NH 2 , and in accordance with this premise, 
methylamine is in fact a stronger base than ammonia. In dimethy- 
lamine the effect is increased with a consequent increase in basic 
strength, but trimethylamine, although a stronger base than 
ammonia, is weaker than methylamine, whereas it might be expected 
that the inductive effect of three methyl groups would cause it to 
be the strongest base of the four compounds considered. There is 
no very clear explanation of this anomaly, but it has been suggested 
that the presence of the three relatively large methyl groups round 
the nitrogen atom may prevent the approach of the proton by a 
steric effect. This seems most unlikely. 

The very weakly basic character of the aromatic amino-compounds 
is accounted for by the tendency of the unshared pair of electrons 
of the nitrogen atom to participate in the mesomerism of the 
aromatic nucleus : aniline may be represented by the mesomeric 
form of (i) and (n), but in addition forms (in), (iv) and (v) contribute 
to the mesomerism : 




fH 2 




II 




NH a 





IV 



Forms (in) (and (iv), which are in fact identical) and (v) may be 
indicated by (vi) and (vn) respectively and (VHI) shows the final 
mesomeric form combining all the contributors, 




VI 





This example illustrates how it is permissible and useful to use the 
Kekule* formula for benzene in dealing with such problems. It 



TO ORGANIC CHEMISTRY 695g 

is to be noted that in (in), (iv) and (v) all the octets are maintained. 
In consequence of the contributions of forms (m)-(v) the unshared 
pair of electrons is not available for the attachment of a proton : in 
the anilinium ion, Ph-NH 8 +, such participation in the mesomerism 
of the ring is impossible so that energy would be required for its 
formation and there is little tendency for it to form. 

In diphenylamine the demands of the two aromatic nuclei on the 
unshared pair of the nitrogen are so great that it will not give salts 
in aqueous solution and indeed such is the mesomeric effect that 
the hydrogen atom of the amino-group is incipiently ionisable and 
diphenylamine gives salts with alkali metals ; in the anion of these 
salts the negative charge is distributed over the two phenyl groups 
and thereby stabilised by mesomerism. Triphenylamine is not 
basic. 

The very weakly basic nature of amides in contrast to that of 
amines is another example of the electron attraction of the carbonyl 
group and the forms contributing to the mesomerism have already 
been mentioned (p. 517). The presence of two carbonyl radicals 
in an imide, such as succinimide or phthalimide, has the effect of 
producing an acidic hydrogen atom and a mesomeric anion, and in 
the sulphonamides one SO 2 group is sufficient to give solubility 
in alkali. 

In all the above cases of acidity or incipient acidity the mobile 
proton was attached to oxygen or nitrogen, but if the ion formed 
can be sufficiently stabilised by resonance it is possible for a proton 
to be liberated from a ^C H link. A simple example of this is, 
of course, hydrogen cyanide (p. 366), but such ionisation is also 
shown in the aliphatic nitro- compounds, the anion of which (in 
the case of nitromethane) may be represented by the mesomeric 
form with contributors, ~CH 2 -~NO 2 and CH 2 =NO 0" : in this 
case there is also the usual mesomerism of the nitro-group (p. 438). 
The j3-diketones and j8-ketonic esters (p. 831) are similar in that 
the mesomeric ion is formed from the keto-form by direct ionisation 
of a hydrogen atom attached to carbon, due to the electron attraction 
of the two carbonyl groups, OC-*-CH 2 --CO , and then stabilisa- 
tion of the ion by resonance. Almost all reactions of ionisation are, 
to all intents and purposes, instantaneous, but this is not so in the 
case of ionisation of hydrogen attached to carbon, a fact which 
accounts for the relatively slow solution of aliphatic nitro-compounds, 
ethyl acetoacetate, etc., in alkali. 



69SA APPLICATIONS OF THE ELECTRONIC THEORY 

The formation of metallic derivatives of cycfopentadiene (p. 789) 
is another excellent example of stabilisation of an ion by resonance ; 
when the proton is lost from the >CH 2 group the anion is left with 
six electrons which are not required for any definite links and are 
free to form the same system as in benzene (aromatic sextet), with 
its very great stability. 

Substitution Reactions 

Substitution of one of the groups attached to a carbon atom by 
another as for example, 



where R is a hydrocarbon radical and the group A displaces the 
group B, may occur in various ways depending on how the bond 
between R and B is broken ; thus 

(1) one electron may remain with each, giving free radicals R' 
and B* (p. 1044), 

(2) both electrons may remain with B, giving R+ and B~, 

(3) both electrons may remain with R, giving R~ and B+. 

The first of these modes of fission is known as homolytic and 
the last two as heterolytic and the type of reaction occurring in any 
particular case depends on the nature of A and of RB and on the 
experimental conditions, etc. Homolytic and heterolytic reactions 
are governed by different principles and laws. Homolytic reactions 
are favoured by light, high temperatures and such catalysts as 
organic peroxides which themselves tend to produce free radicals. 
Heterolytic reactions are unaffected by light, free radicals and 
peroxides, but are often catalysed by acids and bases which tend 
to promote ionisation. Homolytic reactions are inhibited by 
substances such as quinol which combine with free radicals thereby 
stopping the chain mechanism ; such substances have no effect on 
heterolytic reactions. Homolytic reactions usually occur in the 
vapour phase or in non-polar solvents, whereas ionising solvents 
are usually best for heterolytic reactions. 

As examples of homolytic or free radical reactions the halo- 
genation of paraffins and of toluene in the side chain in sunlight 
may be mentioned : in each case a photochemical decomposition of 



TO ORGANIC CHEMISTRY 695* 

the halogen molecule into atoms is assumed, which initiates a chain 
reaction as follows : 

cr+cH 4 * Hci-f-cn;, 

CHg+CLj - > CH 3 Cl-f-Cr, 
Cl'-f CH 3 C1 - HCl+CH 2 Cr, etc. 

The high temperature halogenation of defines, previously ascribed 
to addition followed by dehydrohalogenation (p. 246), is probably 
a direct homolytic substitution of the same type, as is the high 
temperature nitration of paraffins. Other examples of free radicals 
are given later (pp. 1040 seq.). 

Most aliphatic substitutions are heterolytic, and of a type in which 
the entering group A supplies both electrons for its union with R, 
type 2, (p. 695A) ; this is shown in the following examples : 



RBr-hCN- = R-CN+Br~, 
R-NH 2 +NO++Br- = RBr+H 2 O+N 2 , 
RBr+-CH(COOEt) 2 = R- CH(COOEt) 2 +Br-. 

In all cases the entering group A (OR-, CN~, Br~, -CH(COOEt) 2 ), 
has a negative charge and brings with it a pair of unshared electrons ; 
a slightly different type of reaction is shown by the addition of a 
halide to ammonia or amines, 

RBr+R 3 N = R 3 RN++Br~ ; 

here the entering group is neutral but it has unshared electrons 
which are used to create the new bond. In both the above cases 
the entering group is known as nucleophilic, because it is seeking a 
nucleus with which to combine, and a substitution of this sort is 
nucleophilic substitution. 

Investigation of nucleophilic substitution (Hughes, Ingold and 
others) by various physico-chemical processes has shown that the 
reactions may proceed in two different ways. 

Firstly RB may be attacked by A and a transition state reaction 
complex A ... R ... B formed from which B is then eliminated : 
this reaction goes in one step, the union of A with R being synchro- 
nous with the elimination of B. Two entities, A and RB are con- 
cerned, the reaction is bimolecular and is called S#2 (substitution 
nucleophilic bimolecular). 

Secondly RB may ionise, RB ^ R + +B~, and then A- combines 



695; APPLICATIONS OF THE ELECTRONIC THEORY 

with R + : in this case there are two steps and of these the former, 
the splitting of RB, is much slower than the latter. The slow stage 
controls the speed of the overall reaction and as only one molecule 
is concerned in this the reaction is known as S N 1 (substitution 
nucleophilic unimolecular). It is clear therefore that the rate of an 
S N 2 reaction will be given by k[A][RB], and of an S N 1 reaction by 
k[RB] and a careful study of the reaction kinetics enables a decision 
to be reached as to the mechanism of a given reaction ; it is of 
course obvious that as usual, if one component of a bimolecular 
reaction is in such an excess that its concentration remains virtually 
constant during reaction, then that reaction will appear to be of 
the first order (pseudounimolecular). 

There are various factors which affect the mechanism of reactions 
and some of these may be illustrated by considering the hydrolysis 
of alkyl halides. When such compounds are hydrolysed in aqueous 
ethanol with dilute alkali the reaction may be S N 2 or S N 1 ; in the 
case of methyl and ethyl bromides it is entirely S N 2, but tertiary 
butyl bromide is hydrolysed by the S N 1 mechanism and uopropyl 
bromide may be hydrolysed by either mechanism. It is clear that 
for an S N 1 reaction there must be a tendency for a bromide ion to be 
split off from the alkyl halide and this is assisted by the electron 
repulsion of the methyl groups in tertiary butyl (and to a less extent 
in tropropyl) bromide. Another factor is a steric one : in an S N 2 
reaction the attacking group, ~OH in this case, approaches the mole- 
cule at the face of the carbon tetrahedron opposite to the released 
group, thus giving a linear arrangement of the transition state, 
A ... R ... B. It has been shown theoretically that such an approach 
requires less energy than any other. This approach is clearly 
hindered in tertiary butyl bromide by the screening effect of the 
three methyl radicals. In the series CH 3 Br, MeCH 2 Br, Me 2 CHBr, 
Me 3 CBr the reaction mechanism therefore gradually changes from 
S N 2 to S N 1 owing to two factors, that is to say, the electron repulsion 
of the alkyl groups and the steric effect. The screening effect is 
also shown by the fact that neopentyl halides, Me 3 C 'CH 2 X, react 
only very slowly by an S N 2 mechanism (X= halogen). 

When the ionisation of hydrogen was considered it was shown 
how great an effect was produced by the stabilising of the anion by 
resonance and the same factor mus"t be considered with regard to 
R + in an S N 1 reaction ; in an alkyl halide no stabilisation of this 
cation by mesomerism is possible (except possibly by hyper- 



TO ORGANIC CHEMISTRY 695k 

conjugation, p. 1013), but in an allyl halide, CH 2 :CH- CH 2 X, it is so 
stabilised by dispersal of the charge over the whole molecule, 
which is a mesomeric form of CH 2 :CH-CH,/ and +CH 2 -CH:CH 2 
(in this case the contributors to the mesomeric form are identical, 
as in the case of benzene). Allyl halides therefore often react 
rapidly by an S N 1 reaction and in the case of a substituted allyl 
compound the product of hydrolysis may be a mixture (pp. 695 m, 
840) as the entering group, A, can combine with the mesomeric ion 
in either of two different positions. The benzyl radical is similarly 
stabilised by resonance and the benzyl halides are very reactive. 

Consideration of the vinyl and acyl halides shows how the facts 
must first be known before the theory can be applied. In a vinyl 
halide it is assumed that there is mesomerism between CH 2 =CH X 
and ~CH 2 CH=X + and this is shown to be so by the fact that 
the carbon-halogen bond length is shorter than in an alkyl halide ; 
this mesomerism prevents ionisation and hence an S N 1 reaction. 
In the case of an S N 2 reaction the ease of such change will depend 
on the positive charge on the carbon atom to which the halogen is 
attached and that charge is partially neutralised by the mesomerism 
so that this type of mechanism is also difficult. 

Acyl halides, O=CR X, might appear at first sight to be similar 
to the vinyl halides, and in order to account for the easy hydrolysis 
of the halogen atom in such compounds the stability of the transition 
state in the S N 2 reaction must be considered : this will be 
-O-CR(OH) X from an acyl halide and ~CH 2 CH(OH) X 
from a vinyl halide, and it may be assumed that as oxygen is more 
electron attracting than carbon, the transition state with the charge 
on oxygen (from the acyl halide) is more stable than that with it on 
carbon (from the vinyl halide). An acyl halide is thus hydrolysed 
readily. Similarly the ready hydrolysis of esters and amides as 
compared with ethers and amines respectively is explained by the 
electron attraction of the carbonyl group and the fact that the 
charge of the transition state can be on an oxygen atom in esters 
and amides but not in ethers and amines. The steric consequences 
of the two types of nucleophilic substitutions are considered later 
(p. 753). 

Hydrolysis and Esterification 

It has been described above how the hydrolysis of esters of halogen 
acids can proceed by either an S N 1 or S N 2 mechanism : in the case 



6957 APPLICATIONS OF THE ELECTRONIC THEORY 

of esters of carboxylic acids the reaction is more complex, and 
similarly with the reverse process of esterification. 

Firstly there are two ways in which the ester or carboxyl group 
may be split, as indicated by the dotted lines (M and R=hydrocarbon 
radicals), 

M-COjOR+HOJH ^ M-COjOH-l-HjOR (1) Ac 
M-COOjR+HjOH ^ M-COOjH-fHQiR (2) Al 

The former of these is known as acyl-oxygen (Ac) fission as union 
of the acyl group to oxygen is broken both in hydrolysis and esteri- 
fication ; the latter is alkyl-oxygen (Al) fission as the union of the 
alkyl group to oxygen is broken. 

It has been found that alkaline hydrolysis of esters usually, but 
not invariably, involves Ac fission, (1), whilst acid hydrolysis or 
esterification (alkaline esterification, of course, does not occur) may 
proceed by either route according to the nature of M and R and 
the experimental conditions. In addition either reaction may be 
unimolecular or bimolecular and of the eight possibilities for 
hydrolysis, acid or alkaline, Ac or Al, unimolecular or bimolecular, 
six different mechanisms have been observed. 

It is unnecessary to discuss all these, but some interesting points 
may be illustrated by a comparison of two modes of hydrolysis by 
alkali involving the bimolecular Ac and the unimolecular Al fission 
respectively ; the mechanisms suggested for these processes are as 
follows : 

Bimolecular Acyl-oxygen Fission 

M.COOR o- M.CO M-CO 

slow I fast I fast I 

^ M.C.OR ^ OH > o- (i) 

fast | slow 

-OH OH -OR H-OR 



Unimolecular Alkyl-oxygen Fission 

slow fast (+H a O) 

M.COOR ^ M.COO-+R+ ^ M.COO-+R.OH/ 

fast slow(-HaO) 

fast 

* M.COOH+R.OH (2) 



TO ORGANIC CHEMISTRY 695w 

In the former case the reaction is driven from left to right by the 
neutralisation of the acid by the alkali and in the latter by the final 
rapid transfer of a proton from R-OH 2 + to M'COO~ : the order 
of the reactions is found in the usual way from kinetic experiments 
and is, of course, as usual controlled by the slowest stage. 

The mode of fission is proved by using water containing isotopic 
oxygen (indicated by an asterisk) in the hydrolysis : if it is acyl- 
oxygen, (1), none of the isotopic oxygen appears in the alcohol 
produced, but in alkyl-oxygen fission, (2), the alcohol contains 
such oxygen : 

M-COjOR+HOH = M-COOH+R-OH (1) 

M-COOjR+HOH^M-COOH+R-OH (2) 

Another difference between the two types of fission is that in (1) 
the group R is never parted from the oxygen to which it is attached, 
whereas in (2) the R O bond is broken and during the reaction a 
free ion R + is produced. Two consequences follow. Firstly, if 
the alcohol is optically active and its hydroxyl group is one of the 
four radicals of an asymmetric carbon group, the alcohol formed by 
hydrolysis of an optically active ester by mechanism (1) retains its 
optical activity ; in mechanism (2), however, the positive ion R + 
i.e. (CXYZ) + , cannot retain its configuration and combines with the 
hydroxyl ion in the two possible ways to give the d- and /-alcohols 
in equal quantities, and racemisation results. Secondly, if R + has 
a structure which is mesomeric, as for example CH 3 CH:CH CH 2 4 
(cf. p. 695), the product of mechanism (2) may be 

CH 3 -CH:CH-CH 2 'OH or CH 3 -CH(OH)-CH:CH 2 

or a mixture of the two, whereas in mechanism (1) no such 
isomeric change is possible (cf. p. 840). These differences have 
been observed experimentally and one of the factors which de- 
termines whether mechanism (1) or (2) occurs is the concentration 
of the alkali ; the rate of the slow stage of reaction (1) is controlled 
by the rate of attack of the carbon atom of the carboxyl group by the 
hydroxyl ion, but the rate of the slow stage of (2) is independent of 
the reagent. If then the concentration of hydroxyl ions is gradually 
diminished the rate of (1) will decrease and may finally fall below 
the rate of (2) ; the mechanism will then change from (1) to (2). 



695 APPLICATIONS OF THE ELECTRONIC THEORY 

It thus often happens that racemisation of an optically active alcohol 
occurs when dilute alkali is used in the hydrolysis, (2), but not with 
concentrated alkali, (1), a result which was very difficult to under- 
stand before the mechanisms of the reactions had been elucidated. 

Addition Reactions to the Carbonyl Group 

Lapworth, from a kinetic investigation of the interaction of 
acetone and hydrogen cyanide, in which it was found that the rate 
of reaction was greatly increased by the addition of alkali, concluded 
that the first stage in the addition process was 

Me 2 C-6+CN- > Me 2 C(CN)O- ; 

the intermediate ion then combines with a proton to give the cyano- 
hydrin. Such an addition is therefore nucleophilic as the attacking 
negative ion is nucleus seeking. In the same way the addition of 
sodium hydrogen sulphite to aldehydes or ketones is initiated by 
~SO 3 H which attaches itself to the positive carbon atom of the 
carbonyl group. With ammonia the unshared electron pair acts in 
a similar manner and the common condensations of the carbonyl 
radical with hydroxylamine, hydrazines, etc., are of the same type, 
only in these cases the final change is an elimination of water ; 

CH 3 - CHO > CH 3 - CH(6) NH 2 OH > CH 3 CH:NOH+H 2 O. 

Reactivity of a-Hydrogen Atoms 

One of the most useful groups of reactions in organic chemistry 
is that due to the reactivity of the hydrogen atoms on a carbon 
atom a- to a carbonyl, carbethoxy, cyano-, or other group of a 
similar kind or those hydrogen atoms attached to the same carbon 
atom as a nitro-group : these groups are often spoken of as negative 
groups and they are, in fact, all strongly electron attracting. Some 
of the reactions coming under this heading are the aldol reaction, 
the Claisen condensation and the Perkin reaction ; the occurrence 
of them all, usually in the presence of a basic catalyst, is due to 
incipient ionisation of an a-hydrogen atom. In the aldol reaction, 
for example, the strong electron attraction of the carbonyl group 
allows a basic catalyst (~OH) to remove a proton from the a-position 
to form a mesomeric anion, 



TO ORGANIC CHEMISTRY 69So 

CH 3 -~CH=b-hHO- 



3 - 

which then undergoes nucleophilic addition to another molecule of 
the aldehyde. Addition of a proton completes the reaction, 

CH 3 -~CH 6 + -CH 2 CHO * CH 3 CH(6) CH 2 CHO 

> CH 3 CH(OH)~CH 2 -~CHO. 

The Claisen reaction is very similar and is discussed later (p. 826). 

Addition to the Eihylenic Linkage 

Addition to an ethylenic linkage is similar to that to a carbonyl 
group in that polarisation or electromeric change precedes addition. 
That this is in fact the mechanism of addition was indicated by the 
experiments of Lowry and Norrish on the interaction of bromine 
and ethylene : it was found that combination only occurs very 
slowly in a vessel coated internally with paraffin wax, faster when 
stearic acid was the coating agent and still more rapidly in an un- 
coated glass vessel. The explanation is that the surface of the 
containing vessel acts catalytically in bringing about the polarisation 
of the ethylenic linkage and the more polar the surface the greater 
the effect. The mechanism of the addition of bromine to ethylene 
is now assumed to be 

CH 2 CH 2 +Br+ > CH 2 CH 2 Br ^ CH 2 BrCH 2 Br 

and there is further evidence for this view. That it is indeed the 
positive bromide ion which adds first is indicated by the fact that 
bromine in the presence of aqueous sodium chloride gives a chloro- 
bromide, in the presence of water gives a bromohydrin, and of a 
nitrate gives a bromo-nitrate, 

+CH 2 CH 2 Br+Ch CH 2 ClCH 2 Br, 
+CH 2 CH 2 Br+OH- * CH 2 (OH)~-CH 2 Br, 
+CH 2 CH 2 Br-fN0 3 ~ > CH 2 (NO 3 )~~CH 2 Br. 

The formation of the bromohydrin is suppressed by the addition 
of potassium bromide which, of course, increases the concentration 
of negative bromide ions required for the second stage of the 
addition of bromine. It is to be noted that this type of addition is 

1 The contributors to the mcsomeric ion (molecule) are separated by the 
sloping line /. 



695p APPLICATONS OF THE ELECTRONIC THEORY 

initiated by an electrophilic reagent, Br+, and is quite different 
from the nucleophilic addition to the carbonyl group, but there is 
no clear explanation of this ; in ethylene an electromeric change 
giving a negative charge to one carbon atom must obviously give 
an identical positive charge to the other, which should then be 
reactive towards nucleophilic reagents. When the double bond is 
conjugated with a carbonyl group (p. 825), it is so reactive, but not 
otherwise. 

It is assumed by analogy from the addition of bromine (and 
other halogens) that when a halogen acid adds to ethylene the 
reaction is also electrophilic and that a proton adds first, followed 
by a negative halide ion. In substituted ethylenes the direction 
of the electromeric change is controlled by the substituents : in 
propylene, for example, the electron repelling inductive effect of the 
methyl group gives (i) and the positive hydrogen adds to the 



n 



CH 2 group (Markownikoff rule, pp. 95, 804). In acrylic acid the 
carbonyl group controls the electromeric change (n) and the pro- 
duct is j8-bromopropionic acid. If the carboxyl group is further 
away from the double bond the inductive effect is lost and 
undecylenic acid, CH 2 :CH [CH 2 ] 9 COOH, for example, gives 
CH 3 CHBr [CH 2 ] 9 COOH with hydrogen bromide. 

When the case of styrene is considered difficulties arise. Electro- 
meric change could give either (in) or (iv), and might be expected 
to give the former ; when substitution in the nucleus is considered 
(p. 1012), in fact, (in) is assumed to occur. If this were the direction 
of change when hydrogen bromide is added the intermediate state 
would be Ph-CH 2 -CH 2 +, and the final product Ph-CH 2 -CH 2 Br 
whereas it is in fact Ph-CHBr-CH 3 ; it is assumed that the inter- 
mediate ion, (v), from (iv) is stabilised by mesomerism (v, vi and 
vii) which cannot be so with Ph- CH 2 - CH 2 + : 




in 




TO ORGANIC CHEMISTRY 6950 

at first sight it seems very unsatisfactory to have to bring in new 
assumptions to account for the facts, but it can be shown that in the 
cases considered earlier the intermediate states in the explanations 
given are also the most stable. In the vinyl halides electromeric 
change to ~CH 2 CH=X + has already been assumed and the 
product of addition would therefore be CH 3 CHX 2 in accordance 
with experiment. The stereochemistry of additions to ethylenic 
linkages is considered later (p. 712), as are the peroxide effect 
(p. 805) and additions to a conH.-jirn! chain (p. 813). 

Ferrocene 

Cyc/opentadiene reacts with Grignard reagents in a similar 
manner to acetylene and with methyl magnesium iodide, for 
example, yields ryc/opentadienyl magnesium iodide ; when this 
Grignard reagent reacts with ferric chloride, some of the latter is 
reduced and the ferrous chloride so formed is further changed by 
excess of the Grignard reagent, 

2C 5 H 5 MgBr+FeCl 2 =(C 5 H 5 ) 2 Fe+M g Br 2 +MgCl 2 ; 

a very interesting compound, diryc/opentadienyl iron, which has 
been given the name ferrocene, is produced. 

Ferrocene is a typical co-valent compound ; it melts at 173, is 
soluble in organic solvents, is readily volatile, and may be distilled 
in steam. Its chemical reactions are those of an aromatic compound ; 
it shows no additive reactions, but it can be sulphonated, undergoes 
acetylation by the Friedel-Crafts method and can be mercurated. 
Other typical aromatic substitutions such as nitration and chlorina- 
tion are complicated by the fact that ferrocene is readily oxidised. 
The structure of ferrocene cannot be written in a classical manner, 
but the iron atom is bound symmetrically to all five carbon atoms 
of each ring by a single co-valent bond resonating equally between 
the five carbon atoms of each ring : each ring therefore has the 
aromatic sextet with consequent aromatic properties. It is interest- 
ing to note that it has been shown that in solution (or in the molten 
state) the two rings are free to rotate about an axis vertical to the 
planes of the rings. Compounds similar to ferrocene have been 
obtained in which the metal atom is cobalt, nickel, chromium, 
vanadium, magnesium and other metals, and in some such compounds 
the metal carries a charge, e.g. (C 5 H 6 ) 2 Ti + . 



695r APPLICATIONS OP THE ELECTRONIC THEORY 



Tropolones 

Tropolone, a-hydroxy^cfoheptatrienone, (HI), and its derivatives 
are a very interesting group of compounds the chemistry of which 
has been studied mainly in the last ten years after their fundamental 
structure had been suggested by M. J. S. Dewar. Various methods of 
preparation are known, but on the whole they are not very readily 
accessible as either the starting products for syntheses are themselves 
difficult to make or the yields in the syntheses are poor. 

Tropolone itself has been prepared as follows : ryc/oheptanone 
is oxidised with selenium dioxide to ry/ohepta-l:2-dione and the 
latter is brominated ; the product, (i), which is probably formed 
by the elimination of hydrogen bromide from a tribromide, is 
treated with alkali to give (n) which on reduction with hydrogen in 
the presence of palladium-charcoal gives tropolone, (in) : 



OH 






II 



III 



Another general method for the preparation of tropolone deriva- 
tives involves enlarging an aromatic ring by the use of diazomethane 
or ethyl diazoacetate : using this method Johnson and his co- 
workers synthesised stipitatic acid, an important naturally occurring 
tropolone derivative, by the series of reactions shown : 




VI 



l:2:4-Trimethoxybenzene with ethyl diazoacetate gives first a sub- 
stance with a rycfopropane ring fused to the six membered ring 
(p. 781) which then spontaneously gives the seven membered ring 
compound, (iv) ; the addition of bromine causes demethylation and 
oxidation to give (v), which is demethylated with hydrobromic acid 



TO ORGANIC CHEMISTRY 



695* 



to stipitatic acid, (vi). It is to be noted that this synthesis does not 
prove conclusively the structure of the acid, but there is other 
evidence for this. 

The properties of tropolone are very interesting ; it gives salts 
with acids such as the hydrochloride and benzoate and is also acidic : 
the ion present in its salts with acids is a mesomeric form of (i), 
(n), etc., in which the seven ring carbon atoms have six unlocalised 
electrons between them forming an aromatic sextet. The positive 
charge is distributed over the whole system. The anion of the 
sodium salt is also mesomeric, (m) and (iv) : 




OH HO 




OH 





II 



III 



IV 



Tropolone shows the high volatility of an internally hydrogen 
bonded compound (compare o-nitrophenol and enol ethyl aceto- 
acetate) and is also tautomeric, (v) and (vi) ; it is also probable that 
forms such as (vn) contribute to the final mesomeric structure giving 
the ring once again an aromatic sextet : 





VII 



In agreement with these views X-ray analysis of the copper salt 
of tropolone shows the ring to be an almost regular heptagon with 
a carbon-carbon bond length of 1.4 A.U. and calorimetric measure- 
ments give a resonance energy of 33,000-36,000 cal. compared with 
that of 36,000 cal. for benzene. 

Tropolone shows no ketonic properties and when the hydroxyl 
group is methylated with diazomethane, dimethyl sulphate and alkali 
or methyl alcoholic hydrogen chloride the product is easily hydro- 



695* APPLICATIONS OF THE ELECTRONIC THEORY 

lysed and reacts with ammonia like an ester rather than like an 
ether : similarly the acyl derivatives are not easily prepared by 
direct acylation and behave as acid anhydrides rather than as esters. 
If the structure of tropolone is studied it will be seen that the 
>CO and >O OH groups are joined round the ring by a conjugated 
chain and might then be expected to behave like a simple carboxyl 
radical. 

Tropolone shows no ethylenic properties : with bromine in 
acetic acid it gives a mono-substitution derivative. It also shows 
aromatic properties in that it can be nitrated and sulphonated in 
the a- and y-positions and couples with diazonium salts in the 
y-position ; y-aminotropolones can be diazotised in the usual way. 
jg-Aminotropolones, however, give the corresponding hydroxy 
compounds with nitrous acid even at 20 and the a-amino- 
compounds usually undergo isomeric change and give derivatives 
of salicylic acid : 



Br" 






VIII 



Similar rearrangements to benzene derivatives are shown by many 
tropolone derivatives with alkaline reagents. Many tropolone deriv- 
atives are products of mould metabolism. 

Another very interesting compound related to tropolone has been 
prepared by heating the dibromide of ryc/oheptatriene : a molecule 
of hydrogen bromide is lost and tropylium bromide is formed. In 
this substance so great is the tendency to form the aromatic system 
that it is salt like, soluble in water, insoluble in organic solvents and 
gives an instantaneous precipitate with silver nitrate ; it should 
therefore be represented as a mesomeric cation combined with the 
bromide ion (vin). 



CHAPTER 44 

THE PHYSICAL PROPERTIES OF ORGANIC 
COMPOUNDS 

FROM the earliest days of structural organic chemistry relationships 
between physical properties and structure have been examined, and 
attention has already been drawn in Part I to regular variations in 
the melting-point, boiling-point and solubility in water of members 
of a homologous series. Such relationships are for the most part 
more or less limited and empirical and afford little evidence of 
structure in the case of compounds whose constitutions are unknown. 
A study of the behaviour of molecules towards electro-magnetic 
waves has, however, given much more valuable results, and in 
many cases, theoretical considerations support the experimental 
findings. Among such effects are molecular refraction, molecular 
rotation, absorption spectra, X-ray analysis, dipole moments, 
nuclear magnetic resonance and magnetic susceptibility. One 
on :*;! nil in <.? advantage of physical methods for the determination of 
structure, particularly in the case of natural products whose isolation 
and purification except in very small quantities may be a very difficult 
task, is that all the material used in the examination is recovered 
unchanged ; another is that the compound examined is not sub- 
mitted to the action of reagents which might produce structural 
changes. 

A brief account of the more important of these methods follows 
and also a mention of heats of combustion ; this is strictly speaking 
a chemical method, but it gives the most direct evidence of the 
relative stabilities of molecules. 

Melting-point. The melting-points of corresponding members 
of a homologous series either rise continuously, or rise and fall 
alternately as the series is ascended ; in both cases they finally attain a 
nearly constant value. The paraffins afford an example of a con- 
tinuous rise, the fatty acids of an alternating one (p. 183), since those 
normal acids containing an odd number of carbon atoms melt at a 
lower temperature than the preceding normal member containing 
an even number of carbon atoms ; the melting-points gradually 

* 44 69511 



696 THE PHYSICAL PROPERTIES OF 

approach constancy at 60-70. A similar alternation holds for the 
normal dibasic acids, as is shown in the following table : 

Melting-points of Normal Dibasic Acids 

No. of carbon atoms M.p. No. of carbon atoms M.p. 

3 136 4 185 

5 97 6 151 

7 105 8 144 

9 106 10 133 

11 110 12 129 

13 114 14 126-5 

15 114 16 123 

17 118 18 124 

X-ray investigation has shown that this alternation of melting- 
points depends on the way in which the long zig-zag chain molecules 
are arranged in the crystals and that those of the even-numbered 
are more closely packed than those of the odd-numbered acids ; 
this is confirmed by the values for the heats of crystallisation of 
the acids (Piper, J. 1929, 234). 1 

Of any three isomeric di-substitution products of benzene, the 
^-derivative usually melts at the highest temperature. When the 
two substituents are both op- or both w-directing then the melting- 
point of the o-derivative is often higher than that of the m- y but if 
the two substituents are of different directing power then the m- 
isomeride has the higher melting-point : 

M.p. o- M.p. m- M.p. p- 

Nitrophenols 45 96 112 

Dibromobenzenes 7-8 -6-5 89 

Dinitrobenzenes 118 90 173 

Dihydroxybenzenes 104 119 169 

Nitroanilines 71 114 147 

Phenylenediamines 102 63 147 

The melting-points of geometrical isomerides are considered on 
p. 710. 

1 A list of the abbreviations used in references to the literature is given 
on p. 1130. 



ORGANIC COMPOUNDS 697 

The determination of a melting-point is not only of great practical 
importance for ascertaining the purity or the identity of a compound, 
but may also be used for finding the proportions of two compounds 
in a mixture (thermal analysis). Thus, in the investigation of 
aromatic substitution the proportions of, say, 0- and ^-derivatives 
may be ascertained without separating the two substances, provided 
that the complete melting-point curve of the mixture has been 
ascertained with the aid of the two pure compounds ; the observed 
melting-point of the unknown mixture lies somewhere on that curve, 
and its position, determined experimentally, may show the pro- 
portions of the two components. 

Many organic substances, particularly azo- and azoxy-compounds, 
melt first to a doubly rcfrnninir * crystalline liquid ' or * liquid 
crystal/ which when further heated becomes clear. When the 
liquid is cooled the reverse changes are observed. 

Boiling-point. In a homologous series, the boiling-point usually 
rises in a regular manner as the series is ascended, with an approxi- 
mately constant difference between the boiling-points of successive 
members except the first two (pp. 63, 121, 181). 

In the case of isomerides, the normal compound has the highest, 
and that in which the largest number of carbon atoms is attached 
to a single atom has usually the lowest, boiling-point : 

w-Pentane b.p. 36 w-Valeric acid b.p. 186 

/sopentane b.p. 28 /wvaleric acid b.p. 176 

Tetramethylmethane b.p. 9-5 Methylethylacetic acid b.p. 175 

Trimethylacetic acid b.p. 163 

Similarly, with isomeric alcohols (and isomeric halides), the 
primary compounds have the highest, and the tertiary the lowest, 
boiling-point : 

w-Butyl alcohol b.p. 117 Methylethyl carbinol b.p. 99 

Isobutyl alcohol b.p. 108 Trimethyl carbinol b.p. 83 

The substitution of a hydroxyl group for a hydrogen atom of a 
hydrocarbon usually raises the boiling-point by about 80-120 : 

w-Butane b.p. -0-5 Oyt/ohexane b.p. 81 

f*-Butyl alcohol b.p. 117 Q^fohexanol b.p. 161 

Benzene b.p. 80 

Phenol b.p. 183 



698 THE PHYSICAL PROPERTIES OF 

In this case the attraction between the molecules is increased by 
hydrogen bonding and by large dipole moments and often causes 
association ; in the ethers where hydrogen bonding is absent, the 
boiling-point is usually below that of the isomeric alcohols. Com- 
pounds in which internal hydrogen bonding is possible often have 
lower boiling-points than isomeric compounds in which such 
bonding is impossible ; thus o-nitrophenol is more volatile than 
the ^-compound, and the enol-form of ethyl acetoacetate boils at a 
lower temperature than the keto-form (p. 833). 

Solubility. Organic compounds are usually good examples of the 
rule that similar compounds dissolve one another. Hydrocarbons 
and their halogen derivatives are usually sparingly soluble in water 
but soluble in one another. The introduction of oxygen, especially 
in the form of hydroxyl groups, increases the solubility in water 
owing to the combined effects of hydrogen bonding (between solute 
and solvent) and dipole attractions. Polyhydroxy compounds 
(glycerol, sugars, polyphenols) show this effect very markedly. The 
long chain alcohols such as dodecyl alcohol exhibit surface solubility, 
the effect of one hydroxyl group is not sufficient to make the whole 
molecule soluble in water, but the water surface becomes covered 
with an orientated film of molecules with the hydroxyl groups 
immersed in the water. In macromolecules like starch the attraction 
between water and the large molecule leads to the formation of a 
jelly. Molecules containing two or more hydroxyl groups in not 
too large a hydrocarbon skeleton usually have a sweet taste (glycol, 
glycerol, sugars). 

Other groups which notably enhance the solubility in water are 
NH 2 , COOH, and particularly SO 3 H, and here, as in the case 
of hydroxy-compounds, the solubility depends on the molecular 
weight (and structure) of the hydrocarbon radical as well as on the 
number and nature of the substituent groups. The sulphates and 
sulphonates of the higher hydrocarbons show surface solubility 
(detergents). Ethers are generally very sparingly soluble, and esters 
also, except those very rich in oxygen, such as dimethyl oxalate. 

Compounds which are soluble in water may also be soluble in 
the lower alcohols and ketones ; those which are sparingly soluble 
or insoluble in water, salts excepted, usually dissolve in benzene, 
chloroform, carbon tetrachloride, and other compounds free from 
oxygen. 

As a general rule compounds containing atoms united by electro- 



ORGANIC COMPOUNDS 699 

valencies (electrolytes) are insoluble in hydrocarbons and allied 
solvents, comparatively non-volatile and have a high mclimu-poiiri. 
whereas those containing only atoms united by co-valencies are 
usually soluble in hydrocarbon solvents, volatile, and have a low 
melting-point. 

Molecular Volume and Parachor. The molecular volume is the 
volume in cubic centimetres occupied by one gram molecule of a 
compound, and more than a century ago Kopp worked on this 
property. Sugden (1942) introduced the term parachor to denote 
a constant which compares molecular volumes under conditions 
of equal surface tension. Both these properties were at one time 
used for the determination of structure, because both depend on 
constitution, but few useful results were obtained from their use. 
They are dealt with more fully in previous editions of this book. 

Molecular Refraction. The molecular refraction (R) of a com- 
pound is calculated from the formula R=(n 2 -l)M/(n z -\-2)D, where 
n = refractive index, Af = molecular weight, and D = density (Lorentz 
and Lorenz). It is necessary to use monochromatic light in deter- 
mining n, since its value depends on the wave-length. From the 
results of determinations made with suitably chosen compounds of 
known structure it has been found' that the molecular refraction is 
dependent on constitution and, for example, an open chain olefine has 
a higher value than an isomeric 5- or 6-membered ring compound : 
it is possible to ascertain, therefore, from the molecular refraction of 
a substance of unknown structure whether the compound is cyclic or 
an open chain olefine, a point of very considerable importance 
in the study of the sesquiterpenes. It is also possible to distinguish 
between ketonic and enolic forms, since the values of R for 
CO CH 2 - and C(OH)=CH show a sufficient difference. 

More delicate constitutive effects are often shown ; open chain 
conjugated systems (p. 815), for example, may show optical exalta- 
tion, and give a value of./?, greater than that calculated for two isolated 

double bonds : 

R obs. R calc. 

Diallyl CH 2 =CH -CH 2 -CH 2 -CH=CH 2 28-77 7R _ 

Hexa-2:4-diene CH 3 -CH=CH-CH=CH-CH 3 3046 ^''* 

Thfe exaltation is greatly reduced by the substitution of alkyl 
groups for the central hydrogen atoms of the system, but is increased 
when the substituents are OH or OMe. A similar exaltation 



700 THE PHYSICAL PROPERTIES OF 

is shown by conjugation of the double bond with the carbonyl group 
as in carvone and pulegone (p. 922). 

Qy^/opentadiene (p. 789), instead of exaltation, shows optical 
depression, and gives a molecular refraction less than that calculated 
for two isolated double bindings, as do furan, pyrrole and thiophene. 
A-l:4-Qyc/ohexadiene (p. 799) shows the normal behaviour of a 
non-conjugated diolefine, but benzene shows a slight optical 
depression. 

Molecular Rotation. The method for the determination of the 
specific and the molecular rotations of compounds has already 
been given (p. 308), and the relations between molecular rotation 
and structure are briefly referred to later (p. 744) ; the phenomenon 
of rotatory dispersion is also mentioned (p. 743). 

Absorption Spectra. The internal energy of the molecules of 
an organic compound is increased by light absorption and the 
molecules thereby become excited ; the absorbed energy may 
increase either the electronic or the vibrational or the rotational 
energy of the molecules and with a given molecule only radiation of 
particular wave-lengths is effective for increasing each sort of 
energy, and from continuous radiation absorption spectra are 
therefore produced. In studying absorption spectra it is usual to 
divide the spectrum more or less arbitrarily thus : 

Micro-wave 100-1 cm. 

Infra-red 1-100 //, (1 ju= 10~ 4 cm.) 

Visible 4,000-8,000 A.U. (1 A.U. = 10- cm.) 

Ultra-violet 1 ,000-4,000 A.U. 

The energy required to increase the electronic energy of a molecule 
is greatest, and to increase the rotational energy the least ; and in 
general, absorption in the visible and ultra-violet indicates changes in 
the electronic energy, whereas infra-red absorption causes only 
changes in vibrational and rotational energy. Electronic changes 
require more energy the more firmly bound are the electrons, and 
hence the alkanes with their very firmly bound electrons absorb in 
the far ultra-violet whereas the alkenes show fairly strong absorption 
at 1,800-2,000 A.U. due to the less firmly bound electrons of the 
double bond. In the conjugated dienes such as butadiene a very 
strongly absorbing band at 2,170 A.U. appears which is characteristic 
and has been used for confirming the structure of terpenes, steroids 
and other compounds, as it lies in the more readily accessible ultra- 



ORGANIC COMPOUNDS 70l 

violet region (>2,000 A.U.). Conjugation of a double bond with an 
aromatic nucleus as in styrene also produces a strongly absorbing 
band in the same region. Carbonyl unsaturation gives rise to a 
fairly strong absorption band at about 1,850 A.U., characteristic of 
aldehydes and ketones, and strongly affected by conjugation either 
with aromatic systems as in benzaldehyde or with ethylenic systems 
as in mesityl oxide and crotonaldehyde. These bands have been 
used in the determination of structure, thus it was found that the 
absorption spectra of mesityl oxide and of carvone showed similar 
bands, confirming the similarity of structure. 

The relation between colour and structure in organic compounds 
has already been considered in Chapter 42 and since absorption in 
the visible region is broadly speaking due to transitions similar to 
those giving rise to ultra-violet absorption a close relation between 
absorption in these two regions is indicated. This has been confirmed 
by studies on the polyenes (p. 982). 

Absorption in the infra-red region depends upon the inter-atomic 
vibrational and the rotational frequencies of the molecule. From 
observations of such spectra the inter-atomic forces, distances and 
angles may be calculated. Although molecules vibrate as a whole, 
yet in some cases the vibration of part of the molecule may be little 
affected by changes in the rest of the molecule. Thus in the alcohols 
there is a characteristic band at 2-73-2-83 p whose presence can 
be used to detect the hydroxyl group and whose removal to about 3jj, 
provides evidence of hydrogen bonding. In o-nitrophenol the band 
is at even longer wave-length and difficult to observe, indicating 
chelation. 

Closely connected with infra-red absorption is the Raman effect. 
When light of a given frequency is incident upon a dust-free liquid 
a portion of the scattered light is observed to have its frequency 
altered by an amount depending on the nature of the compound. 
These changes in frequency of Raman lines relative to that of the 
incident light correspond to vibrational and rotational frequencies. 
They are often complementary to the infra-red absorption effects 
and in a similar way show characteristic values for particular groups. 
The Raman and infra-red spectra of ferrocene are important as 
indicating that it has a highly symmetrical molecular structure. 

Colorimetric methods have long been used in organic chemistry, 
pure and applied, and with the improvements in ultra-violet and 
infra-red spectroscopy similar methods are now used in these 



702 THE PHYSICAL PROPERTIES OF 

spectral regions. Infra-red spectroscopy has proved especially 
valuable in the examination of hydrocarbon mixtures in the petroleum 
industry, the intensities of the bands giving quantitative data of the 
occurrence of individual compounds. It may be added that absorp- 
tion spectra may be mapped not only for pure liquids but also for 
solutions of solids or liquids in solvents which have little (known) 
absorption and even for crystalline powders by suspending them in 
liquids of known absorption. 

X-ray Crystal Analysis. The diffraction of X-rays by the mole- 
cules of a crystal, suitably examined in an apparatus more or less 
analogous to a spectrometer, and recorded on a photographic plate, 
give a pattern from which a picture of the structure of the molecules 
may be deduced ; X-ray analysis, as shown by W. H. and W. L. 
Bragg, is, in fact, a very valuable method for determining the 
disposition of the atoms in a molecule, but the interpretation of X- 
ray data is by no means easy. A unique answer to the problem 
of the structure of the compound examined is rarely given, but a 
decision between two or more suggested formulae is usually possible 
and the method was of very great value in the examination of the 
sterols, penicillin and vitamin B 12 . In the case of the phthalo- 
cyanines, examined by J. M. Robertson, a complete answer was 
provided. 

X-ray analysis has also shown that many substances which were 
hitherto classed as amorphous, as, for example, cellulose, rubber 
and some of the fibrous proteins, have a structure approaching that 
of crystals, which can be seen when the molecules are suitably 
aligned. The now generally accepted helical structure of certain 
proteins is based mainly on the work of Astbury and Pauling. 

The values of inter-atomic distances may often be found from 
X-ray data and those of carbon to carbon are important. Carbon 
atoms united by single, double and treble bonds are said to have 
bond orders of one, two and three respectively and each type of 
bond has a characteristic length, C C, 1-54 ; C=C, 1-33, C=C, 
1-21 A,U. ; the bond order may therefore be found by measuring 
the bond length. In compounds where the nature of the bond is 
intermediate between single and double owing to mesomerism, the 
bond order is between one and two and the bond length also inter- 
mediate, as in benzene (p. 1002). 

Dipole Moments. When, in a molecule, the electrical centre 
(analogous to the centre of gravity) of all the protons does not coin- 



ORGANIC COMPOUNDS 703 

cide with that of all the electrons, the molecule has a permanent 
electrical moment, which is known as its dipole moment, /i. If the 
electrical charges be represented by +e and e respectively, and the 
distance between them by rf, it follows that fjv=ed. This conception 
is due to Debye, who has published many papers on the subject. 

The theoretical considerations involved in the experimental 
determination of p are not given here, but it may be noted that 
measurements of the dielectric constant and refractive index of a 
compound afford the necessary data. 

Determinations of the dipole moments of a large number of 
substances have now been made, by several different methods, and 
among other results, important conclusions with regard to the 
spatial arrangements of some of the atoms of certain molecules have 
been drawn. In the case of water, for example, if the oxygen and 
the two hydrogen atoms lie in a straight line, then it would appear 
that the electrical centres of the protons and electrons must coincide 
and the dipole moment would be zero ; actually, however, water 
has an appreciable moment. This result can be explained if the 
atoms, instead of being in a line, are situated at the corners of a 
triangle, and* on the assumption that the four pairs of electrons of 
the oxygen octet occupy the corners of a tetrahedron, the molecule 
of water may be represented by Fig. 24, and the angle between the 
two H O bonds (valency angle of oxygen) would be 109 for a 
regular tetrahedron. 




Fig. 24 

Such a spatial arrangement does not in fact agree very well with 
the actual value for the dipole moment, but the results show that 
the molecule is not linear. Wave-mechanical calculations and infra- 
red spectra lead to the conclusion that the H O H angle is in 
fact about 105. 

From a measurement of the dipole moment of ammonia, it is 
concluded that the three hydrogen atoms are arranged at three 
corners of a tetrahedron of which the nitrogen atom occupies the 
fourth, a conclusion which is confirmed by spectroscopic evidence. 



704 THE PHYSICAL PROPERTIES OF 

Methane and carbon tetrachloride have zero moments, in accord- 
ance with their accepted configurations, and a further study of other 
physical properties of the hydrocarbon confirms the regular tetra- 
hedral configuration of the molecule. All saturated aliphatic hydro- 
carbons derived from methane have a zero moment, and this is also 
true in the case of benzene, diphenyl, and some symmetrically 
substituted benzene derivatives such as ^-dichlorobenzene and 
l:3:5-trichlorobenzene. Certain symmetrical benzene derivatives, 
such as />-diethoxybenzene, have, however, a dipole moment ; this 
fact may be accounted for in a manner similar to that given in the 
case of water, that is to say, by assuming that the bonds joining 
the oxygen atom to the ethyl group and to the benzene nucleus are 
not in a line. Dipole moments are also shown by />-dialkylamino- 
derivatives of benzene, and may be accounted for in a similar manner. 

Dipole moments have been of great value in the detection of 
restricted rotation. The cis- and trans- isomerides of substituted 
ethylenes, where free rotation is prevented show marked differences 
(p. 711). 1 :2-Dichloroethane has a dipole moment which varies 
with the temperature and as the latter is raised approaches that 
calculated for uninhibited rotation of the two CH 2 C1 groups ; an 
energy barrier to free rotation is thus indicated (p. 796). 

Evidence of resonance is also afforded by dipole moments. Thus 
in the nitro-group the dipole moment of (i) would be directed 
along the line of the co-ordinate bond, and not along that of the 
union of the : : \ \ o \\ r< : ; to the rest of the molecule. If that structure 
were correct, therefore, ^-dinitrobenzene would be analogous to 
p-diethoxybenzene, and would show a dipole moment ; actually it 
appears to have a zero moment. Now in the mesomeric state repre- 
sented here by (n) the moment of the nitro-group will lie along the 
line of the bond joining the group to the rest of the molecule ; in 
/>-dinitrobenzene, therefore, the two moments will exactly oppose 
one another and the result will be in accordance with experiment. 




Measurements of the electron diffraction 1 of methyl azide vapour 

1 A beam of electrons is diffracted by the atoms in much the same way 
as a beam of light by a diffraction grating. 



ORGANIC COMPOUNDS 70S 

have shown that the three nitrogen atoms are linear, and a similar 
structure may, therefore, be inferred for all azides. It is possible, 
however, to write two linear formulae for an organic azide, namely, 
(i) and (n), and both structures will represent molecules having 

/N 
! R_ N =N=>N n R-N-NssN m R-N || 



large dipole moments, in opposite directions in the two cases. Now 
it can be calculated that if R is C 6 H 5 , each would have a moment of 
at least 4xlO~ 18 e.s.u. ; but the actual value is l-5xlO~ 18 e.s.u., 
with the negative end remote from the nucleus. These facts indicate 
that resonance occurs and that the actual state of the group probably 
approaches more nearly to (i) than to (n). A tautomeric mixture 
of (i) and (n) would give a moment between those of the two forms, 
as a mixture of highly polar substances will also be highly polar. 

A study of their heats of combustion confirms the view that the 
azides exist in the mesomeric form of (i) and (n), and cannot be 
represented by the conceivable ring structure (m). 

Dipole moment measurements have also shown that the aliphatic 
diazo-compounds cannot have either of the structures (iv) or (v), 
but might exist in their mesomeric state or else have the ring 
structure, (vi). Electron diffraction measurements, however, prove 
conclusively that (vi) is untenable, so that the resonance form of 
(iv) and (v) is inferred. 

/N 

iv R 2 C=N = N v R 2 C N==N vi 



Measurements of the dipole moments of tsonitriles point to the 
formula R N=C. Further examples of the application of dipole 
moments to questions of structure or configuration are given later 
(see index). 

Nuclear Magnetic Resonance. When an atom is placed in a 
magnetic field its nucleus may absorb electromagnetic radiation of a 
definite frequency, depending on the environment of the atom ; 
this causes absorption lines in the field spectrum and is known as 
nuclear magnetic resonance. Particularly important from the 
point of view of organic chemistry is proton magnetic resonance 
shown by the hydrogen nucleus, whilst carbon and oxygen nuclei 



706 THE PHYSICAL PROPERTIES OF 

show no resonance and hence cause no magnetic resonance spectra. 
The spectrum of hydrogen varies according to the neighbouring 
groups : in ethyl alcohol, for example, different resonance peaks of 
intensities in the ratio 3:2:1 correspond to the protons in the methyl, 
methylene and hydroxyl groups respectively. It is possible therefore 
to detect these groups and to determine their number even in quite 
complex molecules, such as sugars. It would appear that this method 
of investigating structure may prove of very great value in the 
future as it is one of the most direct ways in which hydrogen atoms 
show up, as it were. 

Magnetic Susceptibility. Electrons in an atom or molecule give 
rise to two magnetic effects. The so-called spin of the electron 
produces a magnetic field so that each electron behaves like a 
small magnet. Secondly, the electrons in the various orbitals 
produce by their motion another magnetic field. This is much 
smaller than the spin field. In an ordinary two-electron single bond 
the two electrons must be of opposite spin and so their electrical 
moments cancel. When an odd electron is present as in a free radical, 
the molecule behaves like a magnet and the compound shows para- 
magnetic susceptibility, that is to say, it is attracted by a magnet. 
The measurement of paramagnetism has been of great use in the 
detection of free radicals and the determination of the extent of 
dissociation of molecules into such radicals. 

In a normal organic molecule in which no unpaired electrons 
exist the molecule as a whole is repelled weakly by a magnet, i.e. it 
shows diamagnetic susceptibility. Pascal has shown that this 
property is additive and constitutive and it has been used in resolving 
questions of constitution. In measuring paramagnetic susceptibility 
correction has to be made for the (usually much) smaller diamagnetic 
effect. 

Heat of Combustion. An important regularity observed in a 
study of the heats of combustion or organic compounds is that, in 
a homologous series, the addition of a methylene group, (>CH 2 ), 
to the molecule produces a nearly constant increase (154 Cal. per 
gm. mol.) in the heat of combustion. That the property is not 
entirely additive, however, is seen from the difference between the 
heats of combustion of isomeric substances. Further, a molecule 
in any condition of strain, such as is due to a double or treble bond, 
or to a small ring structure, gives a greater heat of combustion than 
that calculated from the values obtained for corresponding saturated 



ORGANIC COMPOUNDS 707 

open-chain compounds (p. 790), and indeed the heat of combustion 
is a direct measure of the stability of a molecule. Consequently a 
molecule showing resonance has a smaller heat of combustion than 
that calculated for any one of its contributors, and the difference is 
the resonance energy, as in the case of benzene (p. 391). 

Another example is that a molecule containing a conjugated 
system of double bonds (p. 815) has generally a smaller heat of 
combustion than that of an isomeric compound with the same number 
of isolated double bonds ; the conjugated system is thus more stable 
and this is also due to resonance. 

The determination of resonance energies from heats of com- 
bustion involves the subtraction of two large quantities and leads 
to considerable errors in these differences. Kistiakowsky (1935) 
measured the heats of hydrogenation of unsaturated compounds ; 
these are much smaller than heats of combustion; as apart from 
other causes only the unsaturated bonds are affected, and allow 
of more accurate calculations of resonance energy. 

Heats of formation may be calculated from heats of combustion 
and from them bond energies and bond strengths. 



CHAPTER 45 
GEOMETRICAL ISOMERISM 

A SHORT description has already been given (pp. 347, 528) of the 
phenomenon of geometrical isomerism in the case of compounds, 
CRX=CR'X', where R and R' or X and X' are either identical or 
different atoms or groups of any kind. Even a simple substance, 
such as symmetrical dichloroethylene, CHC1:CHC1, may exist in 
cis- and trans- forms, and corresponding isomerides are known in 
the case of stilbene (diphenylethylene), CHPhiCHPh (p. 565), and 
many other ethylenic derivatives. 

The presence of a second ethylenic linkage in a substituted carbon 
chain increases considerably the number of possible isomerides. 
Thus the most familiar diolefinic derivatives, namely those such as 
the compound, CHX=CH CH CHY, which contain con- 
jugated systems (p. 813), may exist in the four stereoisomeric forms 
shown below : * 



G Hx C^ X 

"T 

C 



I II HI IV 

In general the number of geometrical isomerides of this type ot 
olefinic compound is 2 n , where n = the number of double bonds. 
If, however, the two ends of the chain are identical (X = Y), the 
number of possible forms is reduced ; in the above case, for instance, 
(i) would be identical with (in). More complex examples of this 
sort of isomerism are mentioned later (p. 982). 

Now it is possible in many cases to determine the configurations 
of such cis- and ra/w-isomerides, and one example of this has already 
been given, namely that of maleic and fumaric acids (p. 349). 

Another of a similar type is that of the two stereoisomeric 
o-hydroxycinnamic acids, known as coumarinic acid and coumaric 

1 This and many other matters concerning geometrical isomerism should 
be studied with the aid of the models already mentioned (p. 297). 

708 



GEOMETRICAL ISOMERISM 709 

acid respectively. The former loses a molecule of water spontane- 
ously, yielding coumarin (p. 986), which is reconverted into a salt of 
coumarinic acid by alkali ; coumaric acid also yields coumarin, but 
only when it is heated with hydrobromic acid. Concentrated boiling 
alkalis convert coumarinic acid into coumaric acid. These facts seem 
to prove that coumaric acid is the fra/w-isomeride, as shown below, 
because it is only in the m-acid that the carboxyl and hydroxyl groups 
are suitably situated in space for the formation of a closed chain. 





Coumarin 

The stereoisomeric o-aminocinnamic acids behave in a similar 
manner ; one (the cw-form) loses a molecule of water, yielding a 
closed chain. lactam, a-hydroxyquinoline (carbostyril), whilst the 
other (the trans- form) does not. 

These examples show that if one of the stereoisomerides is readily 
converted into a closed chain and the other is not, their configura- 
tions may be determined with a high degree of probability. In 
many cases, however, the two forms cannot be distinguished in 
this way, and other methods must be used. Thus, of the two stereo- 
isomeric crotonic acids (p. 350), one (crotonic acid, m.p. 72) may 
be obtained by the reduction of one of the stereoisomeric trichloro- 
cro tonic acids ; l this trichlorocrotonic acid, on hydrolysis, gives 
fumaric acid, the configuration of which is known. It follows, 
therefore, that this crotonic acid (m.p. 72) and the trichloro- 
crotonic acid from which it is formed are the *ra$-isomerides, 

H^ X CH 3 H^ X CC1 3 H^ ^ 

I *~ I ~" 8 

HOOC" ^H HOOC X ^H HOOC X ^ 

The other crotonic acid (as- or wocrotonic acid) melts at 15. 
Similarly the o-aminocinnamic acid which gives carbostyril yields 

1 Chloral is condensed with diethyl malonate giving diethyl trichloro- 
ethylidenemalonate, which, boiled with hydrochloric acid, gives trichloro- 
crotonic acid. 



710 GEOMETRICAL ISOMERISM 

a/focinnamic acid by the elimination of the amino-group ; the latter 
is therefore the ay-compound. Other chemical methods for deter- 
mining configurations are given later (p. 730). 

In their chemical properties ay- and frafw-isomerides are usually 
very similar, as most of their reactions depend, of course, on their 
constituent groups, and are therefore determined by their structures 
rather than by their configurations (compare pp. 848, 922). In 
their physical properties, however, such isomerides differ very con- 
siderably, so that if they are solids they can usually be separated 
from one another by fractional crystallisation ; liquid stereo- 
isomerides, such as many dihydroxy-derivatives, may first be 
converted into some crystalline ester, with the aid of, say, phthalic, 
dinitrobenzoic, or toluene-/>-sulphonic acid, or they may be trans- 
formed into crystalline urethanes, and then separated by fractional 
crystallisation. 

When the physical properties of as- and Jra/w-isomerides of 
known configurations are compared, the following regularities are 
observed : The oV-isomerides, as a rule, are less stable, have a lower 
melting-point, a greater heat of combustion and, if they are acids, 
a greater dissociation constant than the tfra/w-forms, as shown below: 

,yr Heat of Dissociation 

p * combustion constant (x 10 6 ) 

Maleic acid (ay-) 130 327 Cal. 1 170 

Fumaric acid (trans-) 287 320 Cal. 93 

/yocro tonic acid (ay-) 15 486 Cal. 3 '6 

Crotonic acid (trans-) 72 478 Cal. 2-0 

Oleic acid (as-) 14 2682 Cal. 

Elaidic acid (trans-) 51 2664 Cal. 

^[//ocinnamic acid (cis-) 68 1048 Cal. 13-8 

Clnnamic acid (trans-) 133 1041 Cal. 3-5 

The ay-forms are also more readily reduced by hydrogen and a 
catalyst than the tomy-isomerides. 

On the assumption that these rules hold good in all cases, the con- 
figurations of oy-frww-isomerides, including those of cyclic com- 
pounds, may be ascertained from a study of such physical properties. 

The measurement of the dipole moments of ay-tams-isomerides 
may afford more conclusive evidence of configuration, since a 
symmetrical frww-isomeride should f clearly have a zero (or very 
small) moment, whilst that of the ay-form should be considerable. 



GEOMETRICAL ISOMERISM 711 

Actual measurements with the halogen substitution products of 
ethylene gave the following results (/*x 10 18 ), from which it is con- 
cluded that the configurations of the compounds are as shown : 

cis- trans- cis- tram- 

Dichloroethylene 1-9 H^+yX Hs^+^/X 

Vs \~> 

Dibromoethylene 14 || || 

Di-iodoethylene 0-8 H^+^X X^+Ntf 

This conclusion has been confirmed by Debye, in the case of 
the dichlorides, by X-ray methods, since it is found that the distance 
between the chlorine atoms in the as-compound is 3*6, and in the 
fnww-isomeride 4*7 A.U. 

Cis- and trans- Additive Reactions 

It was at one time believed that the configurations of the cis- and 
/raws-forms could be determined by an investigation of the additive 
products of the two compounds. Thus, if the cis- and trans- 
forms of Cab~Cab, are separately converted into CabX CabX 
by the addition of X 2 , it would seem that different results 
should be obtained with the two isomerides, provided that addition 
brings about only a partial fission of the ethylenic bond. From 
the ct$-form, no matter which half of the double bond undergoes 
fission, identical w^o-configurations would be produced, but from 
the tozws-isomeride equal quantities of two enantiomorphously 
related compounds should be obtained : 

a a X aX a a a 

C==C + X 2 * C - C or C - C 

/ / / /4,'i 

cis- meso- (identical) 



X a\ b 



x, 



/ / / / A / A 

b a b a b Xfl X 

trans- <#- 

Org. 45 



712 



GEOMETRICAL ISOMERISM 



These changes may also be represented (and examined) with the 
aid of the tetrahedral models (Fig. 25) : 

x 
a 6 a b 





or 




meso- 



a b 






dl- 



Fig. 25 



Now it has been found that, on oxidation with permanganate 
(X = OH), maleic acid yields wesotartaric acid, whereas fumaric 
acid gives racemic acid : in both cases, therefore, the addition of 
the two HO-groups takes place in the expected manner (m-addition) 
as shown above. A similar ' normal ' or ay-addition occurs in 
many, probably in all, other cases in which an olefinic compound 
is converted into its dihydroxy-derivative by oxidation with per- 
manganate ; this reaction, therefore, may be used with some 
assurance to determine the configurations of the isomerides. 

When, however, maleic acid is treated with bromine it gives 
mainly rf/-dibromosuccinic acid, and fumaric acid gives mainly the 
weso-compound, an ' abnormal ' or Zrans-addition taking place ; 
halogens (and halogen acids) usually give a fra/w-addition, but in 
most of such additive reactions mixtures of the meso- and dl- 



GEOMETRICAL ISOMERISM 713 

isomerides are formed. Thus, dimethylmaleic add is reduced by 
hydrogen in the presence of a catalyst giving mainly m^o-dimethyl- 
succinic acid (os-addition) ; dimethylfumaric add yields a mixture 
containing both the meso- and ^/-reduction products, but trans- 
addition predominates. 

Unexpected, or * abnormal,' reactions also occur when the 
elements of water, or of a halogen acid, are eliminated from a 
saturated compound with the production of an olefinic derivative ; 
thus in the case of some cyclic cis- and /ram-hydroxy-compounds, 
trans- takes place more readily than as-elimination (p. 848). It 
has also been shown that os-dichloroethylene (p. 711) loses the 
elements of hydrogen chloride very much more readily than does 
the /raws-isomeride, the opposite of what might have been expected. 

Such /ra/w-additions and eliminations cannot be accounted for 
with the aid of the ordinary formulae and their models, but can be 
explained by the applications of the electronic theory. The addition 
of bromine to an ethylenic linkage has been shown (p. 695o) to 
involve the initial formation of a positive ion ; if there is an attraction 
between the -bromine atom and the positive carbon atom, as would 
appear not unlikely, the configuration of the molecule will be rigidly 
held. Now when the Br~ attacks this group it must approach from 
the far side to the bromine atom already present, as in an S N 2 
reaction. Addition therefore occurs in the /raws-position to the 
first bromine atom : 

Br 




\b 

no matter which end of the double bond is attacked first the final 
result will be tram-addition. If the conf uunition of the intermediate 
ion is not very firmly held, mixtures of ds- and /raws-additive products 
may be formed. 

Interconversion of Geometrical Isomerides 

The change of a ds- into a *ra/w-isomeride often takes place very 
readily in the presence of a suitable reagent, while the reverse 
change, involving an increase of energy (p. 710), is often brought 
about by the action of light, heat, etc. Traces of halogen or halogen 



714 GEOMETRICAL ISOMERISM 

acid convert diethyl maleate into diethyl fumarate, as does also 
potassium ; nitrous acid at ordinary temperatures coaverts oleic 
into elaidic acid, although the former can be distilled unchanged 
in superheated steam at 250. Cold mineral acids convert maleic 
into fumaric acid, and copper maleate, with hydrogen sulphide, 
gives fumaric acid ; conversely fumaric acid yields maleic anhydride 
when it is heated. On exposure to ultra-violet light, both maleic and 
fumaric acids are converted into an equilibrium mixture of the two 
forms. 

Wislicenus suggested that first an addition and then an elimina- 
tion of the reagent takes place during such changes ; after addition 
has occurred the carbon atoms are singly bound and consequently 
free to rotate around their common axis. Assuming that a certain 
rotation has taken place, the subsequent elimination of the reagent 
would give a stereoisomeride of the original substance. The con- 
version of maleic into fumaric acid by hydrochloric acid might 
therefore be represented as follows : 

Cl 

H v /COOH I 
X C X H CCOOH 

* H C COOH * 



\ 
N COOH | 



HOOC 



Cl 

I HOOC V /H 
C H X C X 



H C i 



COOH yCx 

W X COOH 



It is known, however, that chlorosuccinic acid is stable towards 
hydrochloric acid at the temperature at which the conversion of 
maleic into fumaric acid occurs. Further it has been shown that 
when deuterium chloride is used instead of hydrogen chloride, the 
resulting fumaric acid is free from deuterium. The above simple 
explanation of the transformation, therefore, cannot be adopted. 

It is possible nevertheless that in some cases addition of the 
reagent does in fact occur, and it has been suggested that the con- 



GEOMETRICAL ISOMERISM 715 

version of cis- into trans- stilbene *by boron trifluoride, takes place 
in the following manner : 



Ph\ H Phv-hH Ph 

Ph 



BF 3 ;= \ ;= || + BF 3 

-~C *BF 



/ x 
W N Ph 



H 



The occurrence of electromeric change would also account 
for the facts, as the more stable //Yww-isomeride would then be 
produced. 

An interesting example of the readiness with which a cis- may be 
converted into a fra/w-isorneride is met with in the case ofglutaconic 
acid. 1 The trans-compound, (i), m.p. 138, has long been known, 
but its configuration was not established, and during many years 
all attempts to prepare its geometrical isomeride were fruitless. 
When the trans-acid is heated with acetyl chloride containing some 
phosphorus trichloride, it does not give a normal anhydride but is 
converted into hydroxy-a-pyrone, (n), as shown by Bland and 
Thorpe (J. 1912, 856). This compound, with cold sodium car- 
bonate, gives a salt of the original acid (which was therefore supposed 
to be the m-isomeride), but when it is very cautiously treated with 
cold water and the solution is then evaporated as quickly as possible 
under low pressure, the or-acid, (in), m.p. 136, is obtained 
(Malachowski, Ber. 1929, 1323) : 

2 




HOOC X X H H^ ^ H' X COOH 

I II III 

The latter, however, is extraordinarily unstable in aqueous solution, 
being quickly converted into the /ram-acid, apparently as the result 
of tautomeric change (p. 839). This example shows clearly that 

1 Acetonedicarboxylic acid is first reduced to j9-hydroxyglutaric acid, and 
the latter is then converted into glutaconic acid by the elimination of a 
molecule of water. 



716 GEOMETRICAL ISOMERISM 

unexpected phenomena may occur in what seem to be very simple 
reactions, in consequence of which entirely erroneous conclusions 
may be drawn. 

Stereochemistry of Cyclic Compounds 

When a saturated homocyclic ring system, C w H 2w , where n = 3, 
4, or 5, is constructed with the usual models, it will be seen that all 
the carbon atoms lie in one plane and the hydrogen atoms are dis- 
tributed symmetrically on both sides of this plane, as shown below : 



H 





Cyclopropane Cyc/obutane 

Fig. 26 

In the case of rings containing 6 (or more) carbon atoms, the 
mean positions of the carbon atoms of the ring may also be planar 
(p. 792), and similar configurational formulae may be used to 
represent these structures ; for clarity, however, the symbols of 
the carbon atoms are usually omitted. In all such compounds the 
displacement of two atoms of hydrogen of different > CH 2 groups, 
by two atoms or radicals, with the formation of a complex 

CHa CH# (where a and b may be identical or different) gives 

rise to the possibility of stereoisomerism, just as in the case of 
corresponding derivatives of ethylene (the simplest ryt/oparaffin, 
p. 789). 

The first example of such isomerism was observed by Baeyer, 
who found that hexahydroterephthalic acid (cyclohexane-l:4-di- 
carboxylic acid 1 ) existed in two forms, one of which melted at 162, 
whereas the other melted at about 300 and was much more sparingly 
soluble than its isomeride. These acids were distinguished as the 
els- and trans-forms respectively, and from analogy with other 
substances whose configurations had already been proved (p. 710), 
the isomeride of higher melting-point was assumed to be the trans- 
form. This view was confirmed by Malachowski (Ber. 1934, 1783), 

For the system of numbering see p. 777. 



GEOMETRICAL ISOMERISM 717 

who showed that the acid, m.p. 162, gives a monomolecular 
anhydride, which yields the same acid on hydrolysis. 

The molecules of both these acids possess at least one plane of 
symmetry, and are therefore optically inactive : 




cis trans- 



Corresponding forms of cyclopropane-l;2-dicarboxyKc acid have 
also been obtained : 



HOOC COOH HOO 





cts- trans- 

In this case also one of the acids yields an anhydride, which with 
water regenerates the original compound ; this, therefore, is the 
as-acid, in which the carboxyl groups are suitably disposed for 
anhydride formation. The molecule of the as-acid has a plane of 
symmetry, whereas that of the trans-form has neither a plane nor a 
centre of symmetry, and should therefore be a ^//-substance (p. 299) ; 
this is, in fact, the case, as the trans-zcid has been resolved into its 
d- and /-forms with the aid of brucine. It might be thought at first 
sight that the ay-acid should also be optically active, as its molecule 
contains two asymmetric carbon-groups : it is, however, a meso- 
compound, and, like m^otartaric acid, its molecule contains two 
identical asymmetric groups of opposite sign. 

In dealing with the optical isomerism of cyclic compounds, how- 
ever, instead of considering asymmetric groups, it is better to 
study the configuration of the molecule as a whole ; one having 
neither a plane nor a centre of symmetry is non-superposable on 
its mirror image and exists in anttmeric forms, as in the case of 
open chain compounds. 

A simple method of showing the number of forms of such cyclic 
compounds is to represent the ring in the plane of the paper, and 



718 



GEOMETRICAL ISOMERISM 



substituents by a positive sign, if above, and a negative sign, if below, 
this plane. Thus, cydobutanedicarboxylic acid, C 4 H 6 (COOH) 2 , 
exists in three structurally isomeric forms, namely, the 1:1-, (i), 
1:2-, (n), and 1:3-, (in): 



CH 2 -C(COOH) a 
CH a --CH 2 



CH 2 CH-COOH 
CH 9 CH-COOH 



n 



HOOC 



CH 2 CH-COOH 

CH CH 2 
in 



In the case of (i) no geometrical or optical isomerism is possible, 
but both (n) and (in) give cis- and trans-isomerides, as can be easily 
seen from the following four figures : 






II, CIS- 



II, trans- 



, cts- 



III, trans- 



of these only the /raws-modification of (n) lacks a plane (indicated 
by the dotted lines) or centre of symmetry and exists, therefore, in 
d- and /-forms, 

A rather more complex case is presented by truxillic acid, which 
occurs in nature in coca-leaves (p. 604) and which can also be formed 
by the polymerisation of cinnamic acid. Truxillic acid is a 1:3- 
diphenylcyclobutane-Z'A-dicarboxylic acid, and it exists in the follow- 
ing five stereoisomeric forms, in which X represents COOH : 





GEOMETRICAL ISOMERISM 



719 





Ph 




m 



IV 



These stereoisomerides are also shown below in the simpler form, 
in which the carboxyl group is indicated by 4- or and the phenyl 
radical by or : 



+ 1 I + r~7l' 

I -' I 

' i - / L 1 

l II 



' 



IV 



It will thei) be seen that each of the acids, (n) to (v) inclusive, has 
at least one plane, and (i) has a centre of symmetry : none of these 
acids, therefore, is resolvable. When, however, one of the carboxyl 
groups is converted into the anilido-group, CONHPh, those 
acids, (i) and (n), in which the phenyl groups are in /raw- 
positions become dissymmetric, whilst the others retain a plane 
of symmetry. The two rf/-anilido-acids so formed have been re- 
solved and possess therefore the configurations (i) and (n) ; from 
a study of the stability and ease of anhydride formation of each 
acid, configurations have been definitely assigned to all the five 
isomerides. 
Five stereoisomeric 2'A-dicarboxycyclobutane-)i:3-diacetic acids, 

HOOC - CH 2 - CH CH - COOH 

HOOC - CH CH CH 2 COOH 

corresponding with the truxillic acids, have been isolated by Ingold, 
Perren, and Thorpe (J. 1922, 1765). 

Inositol (hexahydroxycyclohexane), C 6 H 6 (OH) 6 (p. 798), exists 
theoretically in eight geometrical forms, the configurations of which 
may be indicated as on p. 720, only the atoms and groups above the 



720 



GEOMETRICAL ISOMERISM 



plane of the ring being shown ; the four atoms of any >CH-OH 
group lie in a plane at right angles to that of the ring. 




OH 

O" 

OH 



Planes of symmetry are indicated by the dotted lines, which show, 
therefore, that all the isonierides are optically inactive, except the 
last, which has no plane or centre of symmetry. The active inositols 
and two of the inactive compounds occur in nature (p. 798). 

The fact that the cyclohexane ring is really puckered (p. 792) 
makes no difference to the number of isomerides theoretically 
obtainable, provided that, as with cyclohexane itself, there is equi- 
librium between the boat and chair forms. When, however, many 
large atoms or groups are attached to the ring the change from boat 
to chair or vice versa may thereby be rendered impossible, or certain 
isomerides, otherwise capable of existence, may be inhibited owing 
to the space requirements of the large groups. 

In the case of benzene hexachloride (hexachlorocyc/ohexane) seven 
of the eight theoretically possible forms have been isolated ; the 
configurations of the first five to be prepared are shown below and 
the letters indicate the disposition (axial or equatorial, p. 792) of the 
chlorine atoms starting in each case at the top of the hexagon and 
working clockwise, assuming that the rings are in the chair form. 



a o 




o 



(a) aeeeea (/3) eeeeee (y) aaeeea (d) aeeeee (e) aeeaee 



*, is by far the most active insecticide 
of the various isomerides ; it is remarkable that in any chair form 



GEOMETRICAL ISOMERISM 721 

of this two m-chlorine atoms in the l:3-position must both be 
axial on the same side of the ring, and if a model is made there is 
no room for such atoms, without some distortion of the ring. The 
configurations of the isomerides were determined by X-ray methods. 
The considerations which have just been applied to saturated 
homocyclic ring systems may be extended to saturated heterocyclic 
rings containing, for example, nitrogen or oxygen. The configura- 
tion of the piperazine molecule (p. 1060), for example, assuming the 
planar arrangement, or at any rate a mean planar position, of the 
three nitrogen bonds, may be represented by a plane ring ; 2:5- 
dimethylpiperazine, (i), would therefore exist in two forms, namely, 
trans-, (ll), and as-, (in), of which the trans- has a centre of symmetry, 
which is lacking in the cw-isomeride ; the latter, consequently, is 
resolvable into its antimeric forms (Kipping, F. B., and Pope, 
J. 1926, 1076), whereas the former affords another example of a 
compound which has a centre, but no plane, of symmetry : 



H H 2 

McC C 

HN NH 

CCMe 
H 2 H 


HN NH 
VV 


HN NH 



II III 



A model of an allene derivative of the structure, (iv), shows that 
the four groups, Rj, R 2 , RS, R4, are situated in two planes at right 
angles to one another and occupy the corners of an irregular tetra- 
hedron (Fig. 27) : 



R/ 




IV Fig. 27 



The stereochemical problem involved here is different from that 
concerned with one carbon atom, inasmuch as the tetrahedron is 
irregular, and therefore the four groups need not all be different 
to cause dissymmetry. A compound, R^CiCrCRgRi, in fact, 
should exhibit enantiomorphism. 
The unsaturated alcohol, (i, p. 722), can be prepared by treating 



722 GEOMETRICAL ISOMERISM 

the diketone, Ph-CO-CH 2 'CO'Ph, with a-naphthyl magnesium 
bromide (1 mol.) and then with dilute acid, which brings about 
hydrolysis, followed by the elimination of the elements of water : 
the product, with a-naphthyl magnesium bromide (1 mol.) and 
dilute acid successively then gives (i), which boiled with a solution 
of rf-camphorsulphonic acid is converted into a strongly dextro- 
rotatory diphenyldi-a-naphthylallene y (n). This last change is an 
extremely interesting example of an asymmetric dehydration (Mills 
and Maitland, J. 1936, 987). 

Ph Ph Ph /Ph 



C 10 H 7 C 10 H 7 C 10 H 7 C 10 H 7 

i n 

The acid, C 10 H 7 (Ph)C:C:C(Ph).COO.CH 2 .COOH, has also 
been resolved by the fractional crystallisation of its brucine salt 
(Kohler, Walker and Tishler,?. Am. Ghent. Soc., 1935, 57, 1743). 

In such allene compounds there is no asymmetric group ; it is 
the molecule as a whole which exhibits dissymmetry. 

Certain compounds containing a carbon atom which forms a 
link in a saturated ring, and which also has a group =CR 1 R 2 
directly attached to it, exhibit similar optical isomerism. 

The first compound of this kind, 4-methylcyc\ohexylideneacetic 
acid, 1 




OOH 

was prepared by Perkin, Pope, and Wallach (J. 1909, 1789), who 
resolved it into its d- and /-components by the crystallisation of its 
brucine salt. In the molecule of this compound the hydrogen atom 
and the methyl group on the left-hand side of the formula lie in a 
plane which is at right angles to that in which are situated the 
hydrogen atom and the carboxyl group on the right-hand side, as 
indicated. As this was the first case of a compound which could be 
resolved and which did not contain an asymmetric group, its 
resolution was a milestone in the history of stereochemistry. 
A substance in the molecule of which one atom forms a part of 

1 The bonds represented by dotted lines lie in a plane which is at right 
angles to the plane of the ryc/ohexane ring. 



GEOMETRICAL ISOMERISM 



723 



two closed chains is known as a spirocyclic compound or spirane. 
The stereochemistry of such compounds is very similar to that of 
allene derivatives and suitable structures may exist in antimeric 
forms. The first compound of this type to be resolved was the 
keto-dilactone of a benzophenonetetracarboxylic add, 1 (i, Mills and 
Nodder), and a very simple spirane, spirodihydantoin, (n), has been 
resolved, in its acidic lactim form, by Pope and Whitworth, 



HOOC 




COOH 



H 




II 



Such compounds lack a plane or a centre of symmetry ; further 
examples of optically active spiranes are given later (pp. 763, 775). 

* Obtained by heating the acid with hydrochloric acid. 



CHAPTER 46 

GEOMETRICAL ISOMERISM OF THE OXIMES AND 
OTHER COMPOUNDS OF TERVALENT NITROGEN 

THE question of the arrangement in space of the atoms or groups 
which are directly united to a tervalent nitrogen atom in a com- 
pound, NR 3 , is discussed later (p. 765) ; in the case of many 
compounds, in which a nitrogen atom is doubly bound to another 
atom, there is abundant evidence that the spatial distribution of the 
nitrogen valencies determines the existence of optically inactive 
isomerides. 

The first example of this phenomenon was observed in 1883 by 
Goldschmidt, who found that the dioxime of benzil, heated with 
alcohol at 170, was converted into an isomeride. Shortly after- 
wards Beckmann discovered a second benzaldoxime, and later a 
great many aromatic aldoximes and ketoximes were obtained in 
isomeric forms, generally i' : -.': -..i- 1 .v J by the letters a and j8. 

In those days it was thought that the three valencies of the 
nitrogen atom were symmetrically distributed in one plane and on 
this basis, in spite of the relative simplicity of their molecules, an 
explanation of the existence of such isomerides was impossible ; 
many years elapsed before the problem was solved satisfactorily. 

Both isomerides seemed to be produced by a simple interaction, 

>CO+NH 2 -OH - >C=:N.OH+H 2 0, 

and both were often formed simultaneously. Nevertheless they 
were not merely tautomeric, since they retained their individuality 
in solution, could be recovered unchanged from solvents, and could 
be separated by fractional crystallisation. Both seemed to be 
hydroxy-compounds ; they gave isomeric acyl derivatives with 
acid chlorides and isomeric alkyl derivatives with sodium ethoxide 
and an alkyl halide. Further, one of the two oximes could some- 
times be transformed into the isomeride under conditions which 
seemed to exclude or render improbable a structural change. 
Notwithstanding this difficulty it was suggested that the two forms 

724 



GEOMETRICAL ISOMERISM OF THE OXIMES 



725 



might be represented respectively by two of the following structurally 
different formulae : 

R C R' R C R' R CR' R CH R' 



OH 
I 



\ 

NH 

n 







HNO 

in 



NO 

IV 



The first compound, (i), might be produced by a direct condensa- 
tion, as indicated above, whereas (n) might be obtained if an additive 
compound, RR'C(OH)-NH-OH, were first formed and then lost 
the elements of water (compare p. 727) ; the structure, (n), might 
then pass into (in or iv) by isomeric change. 

It was then suggested by Hantzsch and Werner (1890) that the 
isomerism of the oximes was due, not to a difference in structure, 
but to a difference in configuration. It was pointed out that in a 
closed chain compound, such as pyridine, the nitrogen atom, N< , 
takes the place of a HC< group of benzene, with very little alteration 
in the stability of the ring ; it was therefore probable that the three 
nitrogen valencies concerned in ring formation have the same 
spatial directions as those of a carbon atom, and if so, they would 
be directed towards three corners of a tetrahedron. 

Aldoximes and certain ketoxirnes might then exist in geometric- 
ally isomeric forms, as indicated by the configurations, (v) and (vi) : 



R 



R' R 



R' R. 



R. 







N OH HO N OH HO* 

V VI VII VIII 

Fig. 28 

This hypothesis, after a great deal of discussion and investigation, 
b now generally accepted, but in a slightly modified form. Since 



726 GEOMETRICAL ISOMERISM OF THE OXIMES AND 

in compounds, NR 4 X, the four atoms or radicals linked by co- 
valencies are believed to be tetrahedrally arranged around a central 
nitrogen atom (p. 763), the molecules of the geometrically isomeric 
oximes are represented in a corresponding manner, as shown in (vn) 
and (vni). For convenience, the configurations of the two isomerides 
are usually indicated by the projection formulae, (ix) and (x), 

R C R' R C R' 

II II 

N-OH HO-N 

ix x 

which correspond with those of the cis- and trans-forms of certain 
olefinic compounds ; as shown by models, the three radicals R, 
R', and OH, all lie in one plane, as do the four atoms or radicals 
in ay- and frww-isomerides. 

The stereoisomeric oximes, however, are distinguished by the 
prefixes syn- and anti-. Thus, if in a ketoxime, R represents phenyl, 
and R' tolyl, the compound (ix) is called awfr'-phenyltolyl or syn- 
tolylphenyl ketoxime, whereas (x) would be 0wfr'-tolylphenyl or 
syw-phenyltolyl ketoxime. In the case of aldoximes, if R represents 
hydrogen, (ix) is called the anti- and (x) the syw-aldoxime, according 
to the juxtaposition or otherwise of the hydrogen atom and the 
hydroxyl group ; the letters a and j3, however, are also used, in 
which case the isomeride directly produced by the action of hydroxyl- 
amine on the aromatic aldehyde is generally distinguished as the 
a-compound ; this is the more stable form, which according to 
present views (p. 733) is the syw-modification. 

The evidence that the oximes are geometrically and not structur- 
ally isomeric seems to be conclusive, as will be seen from the 
following facts. The isomerism cannot be due to structural differ- 
ences of the nature shown on p. 725 ; if this were so there should 
be the same number of isomerides whether R and R' are the same 
or different, whereas, in fact, two oximes have never been obtained 
from a symmetrical ketone. Compounds of the formulae, (n) and 
(iv) (p. 725), should both give rise to optically active oximes if the 
two hydrocarbon radicals are different, as in each case the molecule 
contains an ordinary asymmetric carbon-group ; no such optically 
active oximes have, however, been obtained. 

On the other hand, Mills and Bain (J. 1910, 1866) have provided 
very strong evidence in favour of the Hantzsch-Werner hypothesis 



OTHER COMPOUNDS OF TERVALENT NITROGEN 727 

by resolving the oxime of cyclohexanone-4-carboxy& arid into 
optically active components : 



^'* 



HTJ 
2 **1 

CC OH 

H x / \ _ / 

HOOC^ C \ / C ~ N 
C C 
H 2 H a 


"SJ 

' 



This compound can show dissymmetry only if the hydroxyl 
radical is not in the same plane as the hydrogen atom and carboxyl 
group which are attached to the carbon atom in the 4-position. It 
will be seen, therefore, that the spatial relationship of these sub- 
stituents is similar to that of any three of the four terminal groups 
in 4-methykjyc/ohexylideneacetic acid (p. 722). 

Although there is no evidence of any structural differences be- 
tween isomeric oximes, it has been proved that a given pair of 
isomerides may afford structurally isomeric derivatives. The two 
benzaldoximes, for example, give two such benzyl derivatives, in 
one of which the benzyl group is directly united with oxygen, 
whereas in the other it is combined with nitrogen. These facts, if 
taken alone, would" afford strong evidence that the syn- and anti- 
benzaldoximes are themselves structurally different, but further 
investigation has shown that another explanation is necessary ; 
either or both of a pair of stereoisomerides may give two structurally 
isomeric alkyl or benzyl derivatives. Benzophenoneoxime, of which 
only one form is actually known, gives two isomeric methyl deriva- 
tives, and both the syn- and antt- forms of />-nitrobenzophenone- 
oxime give two analogous structural isomerides (below). That such 
isomeric alkyl derivatives are structurally different is proved by the 
fact that, when they are decomposed with mineral acids, the one 
gives an O-alkylhydroxylamine, NH 2 -OR, and the other an N- 
alkyl derivative, NHR-OH ; it must be concluded, therefore, that 
in one case the alkyl group has displaced hydrogen of a hydroxyl 
radical, in the other hydrogen of an HN-group. The existence of 
AT-methyl derivatives of oximes is confirmed by the fact that they 
may sometimes be obtained by treating an aldehyde or ketone with 
N-methylhydroxy famine, NHMe-OH ; in such cases it would seem 
that an additive compound is first produced and then loses the 
elements of water (p. 725). 

Org. 46 



728 GEOMETRICAL ISOMERISM OF THE OXIMES AND 

The formation of structurally isomeric alkyl derivatives from a 
given oxime may also be accounted for by assuming that, in the 
case of one, namely the TV-compound, the reaction involves the 
initial formation of an additive product : 

R C R' R_C-R' -i R C R' 



CRCR' -| 
MeN.ONaJ 



N - ONa L MeN - ONa J MeNO 

It is now known, therefore, that a given aromatic aldehyde or 
unsymmetrical ketone may form two stereoisomeric oximes, each 
of which may yield O-alkyl and N-alkyl derivatives. Complete 
series of such compounds have been obtained by Semper and 
Lichtenstadt (Ber. 1918, 928) from phenyl-p-tolyl ketone, and by 
Brady and Mehta (J. 1924, 2297) from p-nitrobenzophenone (phenyl- 
p-nitrophenyl ketone) ; the configurations of the isomerides on the 
basis of the Hantzsch- Werner hypothesis are shown below 
(X = CH 3 or NO 2 and R = C 6 H 4 X) : 

.Syw-phenyl-R ketoxime 
C 6 H 6 C CflH 4 X 

ii 

HO-N 



C fl H 5 C CH 4 X C 6 H 5 C C 6 H 4 X 

II II 

MeO-N ONMe 



-R ketoxime 
C 6 H 5 C C 6 H 4 X 

ii 

N-OH 



I 




C 6 H 5 C C 6 H 4 X 

II 

N-OMe MeNO 

It will be seen that the AT-alkyl derivatives which contain the group, 
R.NO=, may be compared with the amine oxides (p. 764), the 
doubly bound carbon atom, combined with this group, having taken 



OTHER COMPOUNDS OF TERVALENT NITROGEN 729 

the place of two of the hydrocarbon radicals in the oxide ; but as 
C e H 6 , C 6 H 4 X, Me, and O (above) are all in one plane, the molecule 
does not exist in enantiomorphously related forms. In the pro- 
duction of these JV-alkyl derivatives, it is assumed that the oxygen 
atom retains its position in the tetrahedral arrangement around the 
nitrogen atom, while the alkyl group takes the unoccupied corner 
(vii and vin, Fig. 28, p. 725). 

The Beckmann Transformation 

When the only known form of acetophenoneoxime is treated 
with phosphorus pentachloride in ethereal solution, or merely 
dissolved in concentrated sulphuric acid, it is almost completely 
transformed into acetanilide. Under similar conditions many other 
ketoximes undergo an isomeric change of this type giving substituted 
amides, and the change is known as the Beckmann transformation. 
A simple way of regarding the conversion of acetophenoneoxime 
into acetanilide is to assume that the ketoxime is a syw-phenyl 
derivative, (i), and that by some means the phenyl and hydroxyl 
groups are transposed, giving (n), which then by another isomeric 
change is converted into (in) : 

C 6 H 6 . C CH 8 HO - C CH 3 OC - CH 3 C 6 H 6 C - CH 3 

HO-N C 6 H 6 -N C 6 H 6 -NH N-OH 

I II III IV 

It seemed possible, therefore, that the Beckmann transformation 
might be used to determine the configurations of any two stereo- 
isomeric ketoximes on the assumption that the syw-radical changed 
places with the hydroxyl group. If, for example, acetophenone- 
oxime has not the jryw-phenyl but the $yw-methyl (or awfr'-phenyl) 
configuration, (iv), it might be expected to give methylbenzamide, 
C 6 H 6 -CO-NH-CH 3 , by the transposition of the methyl and 
hydroxyl groups as assumed above. 

When, for this purpose, the two stereoisomerides of a ketoxime 
are separately submitted to the Beckmann transformation, it is 
found that, as expected, two different substituted amides are 
obtained ; in some cases, however, a given syn- or anti-form 
affords both the isomeric amides (of which one is produced only 
in relatively small proportions), possibly as the result of the prior 
conversion of the one oxime into the other, ^wtf-phenyl-^-nitro- 



730 GEOMETRICAL ISOMERISM OF THE OXIMES AND 

phenyl ketoxime (p. 728), for example, gives />-nitrobenzanilide 
(hydrolysed to p-nitrobenzoic acid and aniline), but the syn-phenyl 
oxime gives a mixture of this anilide with a larger quantity of 
benzoyl-p-nitroaniline (hydrolysed to benzoic acid and />-nitro- 
aniline). 1 

Determination of the Configurations of Ketoximes 

It will be obvious that the formation of two substituted amides 
from a given ketoxime, even if one is produced in small proportions 
only, lessens the value of the Beckmann transformation as a means 
of determining configuration, but there is an even greater difficulty 
to be considered. It was first assumed (p. 729) that it was the 
adjacent $yn-radical which changed places with the hydroxyl group, 
and the question arose, has this assumption any justification ? 
Fortunately it is possible to obtain experimental evidence on this 
point, as has been done by Meisenheimer and his co-workers (Ber. 
1921, 3206 ; Ann. 446, 205 ; 495, 249), and others. 

Of the two benzilmonoximes, the one of lower melting-point can 
be obtained in the form of its benzoyl derivative, (n), by treating 
triphenylisoxazole, (i, cf. p. 1057), with ozone and then decomposing 
the ozonide : 



6 .C-CO.C 6 H 6 
N s X CO-C 6 H 5 



II 

CO-CgHj OC CO- 

NH-C 6 H 6 

III IV 

As it seems very probable that the fission of the ethylenic binding 
by ozone takes place in the usual way (p. 810) and does not involve 
any change in configuration, it must be inferred that the benzoyl 
derivative, (n), corresponds with the awfr'-phenyl-oxime, (in). 

But when this same oxime undergoes the Beckmann transforma- 
tion with phosphorus pentachloride it gives (a chloro-derivative of) 

1 It is assumed here that the anti-radical and the hydroxyl groups are 
transposed (p. 732), and that the oximes are respectively represented by 
the configurations shown on p. 728. 



OTHER COMPOUNDS OF TERVALENT NITROGEN 731 

(iv), the anti- ( C 6 H 5 ) and not the ^-radical ( CO-C 6 H 6 ) having 
changed places with the hydroxyl group. 

A second method for studying the Beckmann transformation is 
based on the possibility or otherwise of ring formation. Of the 
two oximes of 2-bromo-$-nitroacetophenone, one, (i), is immediately 
decomposed by caustic alkalis giving a closed chain compound, 
(n), with the elimination of hydrogen bromide, whereas the other, 
(in), is only very slowly attacked. 1 



N0 2 




NO 2 





OC'CHs 

HN'C 6 H 3 Br'NO a 
IV 



Clearly the more stable ketoxime must be regarded as the syn- 
methyl isomeride, (in), as already assumed ; when, however, this 
compound undergoes the Beckmann transformation it gives (iv), 
that is to say the flttfr'-radical and the hydroxyl group have changed 
places as in the preceding case. 

A third method, illustrating various interesting points, is based 
on a consideration of steric interference or restricted rotation. 2 Two 
oximes are derived from \-acetyl-2-hydroxynaphthakne-'$-carboxylic 
acid (p. 845), and their configurations may be represented as follows : 




:OOH 



R e CH $ 
U.OH 



OC CH, 
NH-R 



1 A halogen atom in the ^-position to a nitro-group is often particularly 
reactive (p. 425). 
1 This phenomenon is described later (p. 758). 



H, 




732 GEOMETRICAL ISOMERISM OF THE OXIMES AND 
*N>H 

R C CHa R CO 

HO'N CH 3 -NH 

II 

Of these, one can be resolved into rfA/B and /A/B forms by the 
crystallisation of its salts with active bases, but the other cannot. 
It is obvious, therefore, that the ^/-compound must be represented 
by (n), because it is only in this oxime that the free rotation of the 
group C(CH 3 )=NOH is rendered impossible owing to steric 
interference (just as in the case of certain other naphthalene deriva- 
tives, p. 760). 1 The occurrence of optically active forms of this 
compound affords, therefore, further evidence in favour of the 
Hantzsch- Werner hypothesis ; if the =N OH group were linear 
no clashing could occur. Now the oxime, (n), in the form of its 
methyl ester, undergoes the Beckmann transformation, giving 
R CO NH CH 3 , whereas the isomeride, (i), gives R NH CO CH 3 , 
the antf-radical and the hydroxyl group changing places in each 
case. 

From all these results it seems justifiable to conclude that the 
Beckmann transformation always takes place by an anti- or trans- 
interchange, and may therefore be safely used for determining the 
configuration of a ketoxime. This conclusion is strongly supported 
by Mills (British Association Reports, 1932) from a consideration of 
the changes involved from a mechanical point of view. 

The Configurations of the Aldoximes 

Aldoximes do not undergo the usual Beckmann transformation, 
although certain of their additive compounds with metallic salts can 
be converted into substituted amides ; benzaldoxime, for example, 
may be transformed into benzamide with the aid of cuprous 
chloride (Comstock, Amer. Chem. J. 1897, 485). As a rule, however, 

1 This interference is not apparent in the ordinary graphic formulae ; 
the hydroxyl group attached to the nitrogen atom in (n) collides both with 
the o-hydroxyl group and with the hydrogen atom (not shown) in the 
8-position. 



OTHER COMPOUNDS OF TERVALENT NITROGEN 733 

when isomeric aldoximes are treated with various reagents, one of 
them loses the elements of water, giving a cyanide, whereas the 
other does not ; the acetyl derivative of the less stable aldoxime also 
loses the elements of acetic acid, when it is treated with alkalis, 
whereas the isomeric acetyl derivative is unchanged or merely 
hydrolysed. 

It was at first assumed that the unstable oxime (which gives the 
unstable acetate) is the iyw-compound, with the hydrogen atom and 
the hydroxyl group in juxtaposition. This view, however, is con- 
trary to the results obtained by Brady and Bishop (J. 1925, 1357) 
with the isomeric 2-chloro-5-nitrobenzaldoximes ; of these two 
compounds one is completely converted into 5-nitrosalicylonitrile 
when it is boiled with sodium hydroxide solution during thirty 
minutes, whilst the stereoisomeride is only slightly changed. The 
oxime which is thus decomposed should, apparently, be the anti- 
form, (i), on the assumption that the halogen reacts with the sodium 
derivative of the oxime to give (n), which then undergoes isomeric 
change to (in) ; but this same oxime is given the $jw-formula, (iv), 
when its configuration is based on the fact that it readily loses the 
elements of water. It seems, therefore, that those stereoisomerides 
which show this behaviour have in fact the anta'-configuration and 
that the elimination of water occurs trans- or crossways. 





II 





V-OH 



In a similar manner Meisenheimer (loc. cit.) has shown that of 
the two oximes of 3-nitro-2:6-dtchlarobenzaldehyde, (i and iv, p. 734), 
one is decomposed by ice-cold 0'25 normal sodium hydroxide solu- 
tion with the elimination of hydrogen chloride, giving first a ring 



734 GEOMETRICAL ISOMERISM OF THE OXIMES AND 

compound and then 2-hydroxy-3-nitro-6-chlorobenzonitrik, (n) ; 
the other isomeride is not attacked under these conditions. The 
former therefore must be represented by (i) ; but the same oxime, 
(i), is readily converted into 3-nitro-2:()-dichlorobenzonitrile, (in), 
by acetic anhydride and sodium carbonate, whereas (iv) yields an 
acetyl derivative. Here again it is the anti-form which loses the 
elements of water ; consequently such reactions are trans- and not 
ai-eliminations as previously believed. 




II 



in 



IV 



Mills (loc. ctt.) has also discussed this problem, and concludes 
that the elimination of water must be crossways. 

When the configurations of various pairs of stereoisomerides 
have been determined, by methods such as those given above, the 
physical properties of the syn- and 0wfr'-compounds may be com- 
pared or contrasted ; if, then, there are any constant differences of 
any kind, a study of these properties may be. employed to determine 
unknown configurations. Very little use can be made of such 
methods at the present time ; the unstable aldoximes generally 
melt at a lower temperature than their stereoisomerides, but regu- 
larities in other physical properties such as viscosity, dissociation 
constant, and absorption spectra, have not been observed. It has 
been suggested, however (Sutton and Taylor, J. 1931, 2190), that 
measurements of the dipole moments of certain derivatives of 
stereoisomeric ketoximes might afford evidence of the configurations 
of the latter ; thus in the case of the TV-methyl derivatives of the 
p-nitrobenzophenoneoximes, (v) and (vi), since the dipole moments 
of the two N >O groups are comparable, (v) should have a larger 
dipole moment than (vi). As actual measurements gave (v), fix 10 18 , 
6-60, and (vi), 1*09, the results confirmed the configurations, which 
had been previously assigned to the compounds on chemical 
evidence. 



OTHER COMPOUNDS OF TERVALENT NITROGEN 735 



-C 6 H 4 C C 6 H 5 N-C 6 H 4 . C - C 6 H 5 

0< N-CH 3 CH 3 .N *O 

(m.p. 159) (m.p. 136) 

v vi 

It has also been shown by Taylor and Sutton (J. 1933, 63) that 
a comparison of the electric moments of the isomeric O-ethers of 
a given aldoxime, with those of the corresponding derivatives of a 
ketoxime, may afford information as to the configurations of the 
aldoximes, provided that those of the O-ethers of the ketoximes are 
known, and that the conversion of the aldoxime into its ether is not 
accompanied by a change in configuration. Thus in the case of the 
compounds shown below, the following results have been obtained : 

/>tx 10 18 JLCX 10 18 

NO 2 .C 6 H 4 .C-C 6 H 5 3-75 NO 2 -C 6 H 4 .CH 3-39 

MeO-N MeO-N 

NO 2 - C 6 H 4 . C C 6 H 5 4-26 NO 2 - C 6 H 4 . CH 3-88 

II II 

N-OMe diff< . 51 N-OMe diff . . 49 



It may therefore be concluded that the ketoxime and aldoxime 
derivatives having the larger moments correspond in configuration, 
as shown above ; this conclusion accords with other evidence. 

The conditions which determine the production and inter- 
conversion of stereoisomeric oximes are very varied. Sometimes 
only one isomeride (then called the a-compound) is produced when 
the aldehyde or ketone is treated with hydroxylamine, but very 
often both are formed and their separation may be very trouble- 
some. The transformation of one into the other may sometimes be 
brought about by merely heating the compound with a solvent, 
such as alcohol or benzene, or by exposure to ultra-violet light, but 
as a rule treatment with mineral acids, or occasionally with alkalis, 
is required. 

The non-existence of stereoisomerides of symmetrical aromatic 
ketones is of course in accordance with the Hantzsch-Werner 
hypothesis ; crystalline aliphatic aldoximes and the oximes of most 



736 GEOMETRICAL ISOMERISM OF THE OXIMES AND 

aliphatic unsymmetrical ketones are also known in one form only, 
contrary to what might have been expected. 

It has been shown, however, by Hiickel and Sachs that certain 
cyclic ketoximes (from methykyclopentanone and trans-fi-decalone) 
exist in stereoisomeric forms, and Furukawa has prepared stable 
stereoisomeric oximes of ethylpalmityl, propylpalmityl, and ethyl- 
stearyl ketones. 

To account for the customary non-existence of aliphatic iso- 
merides, Raikowa has pointed out that such oximes may undergo 
a simple tautomeric change, whereby one isomeride might be trans- 
formed into the other so readily as to render impossible the isolation 
of the unstable form. If, for example, the compound, (i), actually 
existed in a stereoisomeric form, (in), either might change into 
the other by passing through the form, (n), where R represents H 
or a hydrocarbon group : 

R.C-CH 2 R.C=CH R.C.CH 2 

I! 1 II 

N-OH Jtt HO-N 



i ii in 

So far as is known, all aliphatic aldoximes readily lose the elements 
of water ; nevertheless the liquid compounds might be mixtures 
of stereoisomerides and the decomposition of the syn-form might 
be due to its previous transformation into the isomeride in the 
manner just suggested. When oximes of unsymmetrical aliphatic 
ketones undergo the Beckmann transformation, the one form gives 
both the theoretically possible substituted amides ; this fact might 
also be accounted for by adopting Raikowa's views. 

Diketones, such as benzil, in accordance with the Hantzsch- 
Werner hypothesis, give three stereoisomeric dioximes, which are 
distinguished by the prefixes shown below : 

C 6 He C - C C$H 5 C 6 H 6 C - C C0H 5 

ii ii ii ii 

N-OH HO-N HO-N N-OH 

jyti-Benzildioxime anft-Benzildioxime 

C 6 H 6 C - C'C 6 H 5 
N-OH N-OH 

<2mj>At*Benzildioxime 



OTHER COMPOUNDS OF TERVALENT NITROGEN 



737 



The Beckmann transformation has been applied to bring about 
an isomeric change of certain cyclic oximes ; the monoxime of 
phenanthraquinone (p. 567), for example, heated with hydrochloric 
and acetic acids is converted into diphenimide, which on hydrolysis 
gives diphenic acid. Similarly a-indanoneoxime with phosphorus 
pentachloride gives dihydrocarbostyril, which is the lactam of 
Q-aminophenylpropiontc acid : 





The elimination of water from an aldoxime has also been utilised 
for ring formation. Thus when cinnamaldoxime is treated with 
phosphorus pentoxide it seems to undergo an isomeric change, 
giving a product which loses water and passes into woquinoline : 




H 



OH 





Stereoisomerism of Hydr ozones and Semicarbazones 

Since the group, >C=N-OH, in oximes gives rise to stereo- 
isomerides, it is clear that the group, >C=N-NH-C 6 H 5 , of the 
phenylhydrazones of aldehydes and unsymmetrical ketones might 
determine the existence of corresponding syn- and 0wfr-forms, (i) 
and (n) : 



R_C R' 

N-NH.C 6 H 6 
i 



C 6 H 6 .NH'N 
H 



R_CH R' 

N=N.C 6 H 5 
in 



Such isomerides have, in fact, been obtained ; that they are not 
structurally different as would be the case if one had the constitu- 
tion, (in), is shown by the existence of isomeric diphenylhydrazones, 



738 GEOMETRICAL ISOMERISM OF THE OXIMES AND 
R C-R' 




(C 6 H B ) 2 N-N N-N(C 6 H 5 ) a 



(iv), in the molecules of which there is no possibility of isomeric 
change due to the migration of a hydrogen atom in this way. It has 
also been proved by Mills and Bain (J. 1914, 64) that the benzoyl 
derivative of the phenylhydrazone of cyclohexanone-4-carboocyltc acid, 
(v), can be resolved into optically active components ; this fact shows 
that the double and single bonds of the nitrogen atom are inclined 
to one another, and therefore, that stereoisomeric hydrazones are 
capable of existence. 




This hydrazone and the corresponding oxime (p. 727) might con- 
ceivably undergo isomeric change, giving the group, 

-CH ^ -CH ^ 

>C-NH.NR 2 or ^C-NH-OH 

CH/ CH/ 

respectively, and the compounds so formed would be dissymmetric 
whatever the disposition of the nitrogen valencies ; to meet this 
possible objection Mills and his co-workers also resolved a hydrazone 
and an oxime in which such a transformation is impossible (.7. 1923, 
312 ; 1931, 537). 

Isomeric semicarbazones, >C:N-NH-CONH 2 , presumably 
syn- and awft'-compounds, have also been obtained. 

Molecules in which there occurs the complex N=N also 
exist in the cis- and frww-stereoisomeric forms shown below, in 
which R and R' may be identical or different : 

R N R N 

i II n || 

R' N N R' 

Azobenzene, the simplest azo-compound, has been known since 
832. From its zero dipole moment, and the X-ray examination 



OTHER COMPOUNDS OF TERVALENT NITROGEN 739 

of its crystal structure, it was assigned the Jrafw-configuration, (n). 
It was not until 1938, however, that the corresponding os-isomeride 
was isolated by G. S. Hartley. 

frww-Azobenzene is partially converted into the orange-red as- 
isomeride when its solutions are exposed to light and the two forms 
can be separated by chromatographic analysis (p. 980) ; the 
unstable as- is readily converted into the trans-modification in 
solution. 

Azoxy-compounds are also known in two physically different 
forms (Miiller, Ann. 493, 167 ; 495, 132), and from an examination 
of their absorption spectra it is inferred that they are geometrical 
isomerides, 

R-N RN 

II and || 

R-NO ON-R 

and not dimorphous forms of one substance. 

Metallic Diazotates and Isodiazotates 

When phenyldiazonium chloride is treated with an equivalent 
of silver oxide, or phenyldiazonium sulphate with an equivalent of 
barium hydroxide, in aqueous solution, strongly alkaline solutions 
of the diazonium hydroxide are produced ; these solutions couple 
immediately (p. 463), but the hydroxides rapidly decompose, even 
at ordinary temperatures, giving resinous products. 

On adding a solution of a phenyldiazonium salt to concentrated 
potassium hydroxide solution at 0, a crystalline (normal) potassium 
diazotate, C 6 H 6 -N 2 -OK, is precipitated, but if this salt is then 
heated with the alkali at 130-140, it undergoes a quantitative 
isomeric change and gives potassium isodiazotate (Schraube and 
Schmidt, Ber. 1894, 514). 

Corresponding metallic diazotates and tsodiazotates can be pre- 
pared from other diazonium salts, but in the case of />-nitrophenyl- 
diazonium chloride the conversion of the former into the latter 
may occur even at 10, so that the isodiazotate only can be isolated. 
The normal diazotates couple immediately with phenols, etc., but 
the tsodiazotates do so only very slowly. On treatment with mineral 
acids, the normal diazotates give diazonium salts ; the tsodiazotates, 
on the other hand, afford solutions which at first couple only very 
slowly, but which do so immediately when they have been kept 



740 GEOMETRICAL, ISOMERISM OF THE OXIMES AND 

during some time. Hydroxides, corresponding with the normal 
diazotates, cannot be isolated ; the alkali salts, with one equivalent 
of acid under certain conditions, give explosive oils which seem to 
be anhydrides and which, with alkali, regenerate the diazotates, 
and with acids, the diazonium salts. The metallic wodiazotates, 
with acetic acid, give oils which have acidic properties and which 
slowly change into neutral nitrosoamines. The normal alkali 
diazotates yield O-ethers, R-N 2 'OCH 3 , whilst the tsodiazotates 
give JV-ethers, R-N(CH 3 )'NO ; the former are yellow oils which 
couple readily, and regenerate the diazotates with alkali, whereas 
the latter are identical with the nitroso-derivatives of secondary 
amines and do not couple, or do so only very slowly. The silver 
salts, prepared either from the normal or from the wodiazotates by 
precipitation with silver nitrate, yield O-ethers with methyl iodide. 
When the AT-ethers are fused with alkali they afford wodiazotates. 

Various explanations of the above facts have been put forward 
by Bamberger, Angeli, and others, but the following, due to 
Hantzsch, is now generally accepted : 

Diazonium salts, (i), give both normal diazotates, (n), and iso- 
diazotates, (in), which are syn- and 0fr'-stereoisomeric forms 
respectively corresponding with those of the oximes, 

Ar.N-Cl Ar-N Ar-N 

III > II II 

N KO-N N-OK 

I ii in 

but, since all the substances concerned are ionised, they may also 
be represented by (iv), (v), and (vi) respectively : 

[Ar-N : .N]Cl Ar-N Ar-N Ar N N:O 

"O-N N-CT 

IV V VI VII 

It may be inferred, moreover, that the antf-diazotate can also 
react in the form (vn) because, as already mentioned above, it 
gives N-ethers. 

The existence of three isomeric cyanides, R*N 2 CN, has been 
proved ; one of these is colourless, readily soluble in water and 
behaves like a salt, whereas the other two are sparingly soluble, 



OTHER COMPOUNDS OF TERVALBNT NITROGEN 741 

coloured compounds, which are not electrolytes. It would seem, 
therefore, that the soluble cyanide is of the type (i), the other two 
being the syn- and 0wfr-isomerides corresponding with (n) and (in) 
respectively ; it has been shown by dipole moment measurements 
that the syn-form is the less stable (Le Fivre, J. 1938, 431). It 
does not follow, however, that the metallic diazotates and iso- 
diazotates are also syn- and flnfr-compounds, because in this case 
structural isomerism, unlikely in the cyanides, is conceivable. 



CHAPTER 47 
OPTICAL ISOMERISM 

Racemic Substances and Conglomerates 

WHEN a solution of equal quantities of the two crystalline antimeric 
forms of any compound is evaporated, the ^//-deposit may be either 
a racemic substance or a ^/-conglomerate, and in some cases there 
is a transition temperature which determines the nature of such a 
deposit (p. 299). Now the ^//-crystals thus obtained may be so small 
or ill-defined as to be unsuitable for goniometrical examination, and 
other methods must be used to ascertain which of the two <//-types 
has been formed. For this purpose, if one of the active isomerides 
is available, the following methods, mainly due to Roozeboom, 
may be used. 

(1) The densities of the active and inactive modifications are 
determined under the same conditions ; if these are different the 
^/-substance is racemic. 

(2) The melting-point of the ^//-substance alone, and mixed 
with different proportions of one of the active modifications, is 
observed ; if the melting-points of all mixtures are higher than that 
of the ^//-substance alone, the latter is a conglomerate, but if the 
melting-point of any mixture is lower, then the ^//-substance is 
racemic. This method is based on a study of the melting-point 
curves of mixtures of the two enantiomorphs in variable proportions. 
The curve thus obtained with a conglomerate is of the type shown 
in (i), Fig. 29, with a minimum when equal quantities of the d- and 



M.p. 






o/ 
/o 



Z- df- 



742 



o/ 
/o 

II 
Fig. 29 



J- d> 



% 
III 



OPTICAL ISOMERISM 743 

/-forms are present, so that the addition of either isomeride raises 
the melting-point. The curves for a racemic substance are shown in 
(n) and (in), according as its melting-point is higher or lower than 
(or the same as) that of the d- or /-form ; in either case, with certain 
proportions of either of the isomerides, the melting-point is depressed. 

The conclusions drawn from such observations refer only to the 
nature of the ^//-substance at the observed melting-point, since a 
conglomerate at the ordinary temperature might become a racemic 
substance when it is heated, and vice versa. 

(3) A saturated solution of the ^/-substance is shaken with a 
small proportion of one of the active isomerides, and after filtration, 
if necessary, is then examined in a polarimeter ; if the solution 
shows optical activity the ^//-substance is racemic, whereas it is a 
conglomerate if no rotation is observed. A determination of the 
weight of substance in a given volume of the saturated solution 
before and after it has been shaken with the active form, also dis- 
tinguishes between the two possibilities. If the substance is a 
conglomerate the two quantities are identical, but if it is racemic 
this will not be so. Both these methods depend on the fact that a 
mixture of equal quantities is more soluble than any other mixture 
of the d- and /-forms, and a saturated solution of such a mixture 
cannot dissolve either isomeride ; a solution saturated with a racemic 
substance, however, is still unsaturated with regard to either the 
d- or the /-form. 

Variation in the Specific Rotation with Experimental Conditions 

The specific rotation of a substance varies with the temperature, 
in some cases increasing, in others diminishing, as the temperature 
rises. It also varies with the wave-length of the light with which 
it is observed (footnote, p. 309), a phenomenon which is known as 
rotatory dispersion ; when, therefore, a specific rotation is given, 
the wave-length of the light and the temperature must be indicated 
as in [a]* 5 , where D refers to the sodium line, or Hsiei > wnere *he 
lower figures refer to the green line of the mercury-vapour spectrum. 
The specific rotation may vary very considerably with the nature of 
the solvent ; also with the concentration of the solution, but except 
in the case of optically active electrolytes dissolved in ionising 
liquids, the variation is quite irregular. 

In aqueous solution, however, in the case of electrolytes important 

Org. 47 



744 OPTICAL ISOMERISM 

regularities have been established. It was observed by Landolt that 
the molecular rotations, [M] (p. 309), of all normal salts of rf-tartaric 
acid were practically the same in sufficiently dilute aqueous solution, 
and Oudemans showed that this was also true of the salts of quinic 
add (l:3:4:5-tetrahydroxycyc/ohexanecarboxylic acid) ; further, it 
was found that the molecular rotations of various salts of a given 
active alkaloid with mineral or with organic acids were also prac- 
tically identical in sufficiently dilute solution, but varied with the 
concentration. These observations were explained by Hadrich, 
who concluded that in a completely ionised state the specific rotation 
is independent of the inactive ion ; in concentrated solutions the 
observed rotation may be greater or less than the value in dilute 
solution, because it is due both to the active ion and to the non- 
ionised molecule, but as dilution and ionisation increase, it becomes 
practically constant. This explanation cannot be accepted nowadays 
as all salts are completely ionised under all conditions, but as the 
rotation of solutions of optically active non-electrolytes in non- 
ionising solvents frequently varies with the concentration it is not 
surprising that similar variations occur with electrolytes in aqueous 
solution. 

All salts of the very strong acid, d-a-bromocamphor-n-sulphonic 
acid (p. 931), which were examined by Walden, gave a constant 
value [M D ]-f 270 for the rf-a-bromocamphor-7r-sulphonate ion 1 in 
aqueous solution. It is thus possible to determine the unknown 
molecular rotation of one of the ions of such a salt when that of the 
other is known. If, for example, the rf-bromocamphorsulphonate 
of a base gives [M] D +180, the ion of the base would have 
[M] D -90 (compare p. 762). 

Relation between Structure and Specific Rotation 

The pronounced influence of temperature, solvent, and con- 
centration of the solution, and also the facts observed in the case 
of electrolytes, show clearly that the Observed specific rotation 
depends on the state of the optically active molecules under the 
experimental conditions, as well as on their structure. It is not 

1 This value is probably too low and should be about [M]0 280, 
because, as usually prepared, the acid contains a small proportion of an 
optical isomeride having a much lower [M] D than 270 (F. S. Kipping, 
y. 1905, 628). 



OPTICAL ISOMERISM 745 

surprising, therefore, that in consequence of the disturbing in- 
fluences of association and other factors, attempts to determine the 
relation between the specific rotation of a substance and its con- 
stitution have so far met with little success. Even in the case of 
homologous compounds, such as the alcohols, CH 3 CH(OH)R 
and C 2 H 5 -CH(OH)-R, where R is a normal alkyl radical, there 
does not appear to be any simple numerical relation between the 
molecular rotations, whether determined in the liquid state or in 
solution (Pickard and Kenyon, J. 1913, 1923). This is also true as 
regards other closely related compounds such as derivatives of 0-, 
m-, and ^-nitrobenzoic acids containing structurally identical 
optically active groups (Frankland and Harger, J. 1904, 1571). 

The addition of borax, boric acid, certain metallic hydroxides, 
acids, or salts such as molybdates, tungstates, uranates, etc., to a 
solution of an optically active substance, often causes a great change 
in the specific rotation, owing to the interaction of the active and 
inactive compounds ; the specific rotation of malic acid, for example, 
is increased to about 500 times its original value by the addition of 
a uranate. In the case of some optically active compounds, such as 
the sugars, the effect of the addition of boric acid on the specific 
rotation may be utilised to distinguish between cis- and /raw- 
configurations of a group CH(OH)-CH(OH) , since the former 
only may react with the acid, giving a cyclic complex of very different 
rotatory power. 

Optical Superposition 

When one of the atoms or radicals in an asymmetric group is 
displaced by an atom or radical of a very different nature, as, for 
example, when lactic acid is converted into a-chloro-, bromo-, or 
amino-propionic acid, it may be presumed that there will be a 
considerable change in the molecular rotation. If, however, in an 
asymmetric group one of the radicals were displaced by another, 
which is different in configuration only, it would seem that little 
change in molecular rotation should occur, unless the entering group 
is itself optically active ; in the latter case the molecular rotation 
should be increased or diminished according as the rotation of the 
entering group is d- or /-, and the observed value should be the 
algebraic sum of those of the two dissymmetric radicals. This is 
the principle of optical superposition, formulated by van't Hoff ; it 
has been found to hold good approximately in many cases. 



746 OPTICAL ISOMERISM 

The ester of /-lactic acid with rf/-amyl alcohol, for example, has 
[M] D = 10 '2, a value which may be assigned to the /-lactyl complex ; 
the /-amyl ester of <//-lactic acid has [M] D = +4*2, and this value 
may be attributed to the /-amyl group. The molecular rotation of 
the /-amyl ester of /-lactic acid should therefore be the algebraic 
sum of the above values for the two radicals, and is, in fact, 
[M] D 6-3. The principle of optical superposition is of con- 
siderable importance in the study of the sugars (p. 868), but many 
exceptions to the rule have been observed. 

Asymmetric Synthesis 

When lactic acid is synthesised from acetaldehyde or by the 
reduction of pyruvic acid, the dl-add is obtained ; similarly when 
tartaric acid is synthesised from glyoxal or from succinic acid, an 
optically inactive dihydroxy-acid is produced, because in all these 
reactions the d- and /-groups in the molecule are generated in 
almost exactly equal quantities. 1 When, however, an optically active 
aldehyde, such as /-arabinose (p. 335), is combined with hydrogen 
cyanide, the two cyanohydrins, and the two acids (gluconic and 
mannonic) obtained from them by hydrolysis, are not produced in 
equal quantities ; the original molecule is dissymmetric and directs 
the course of the additive reaction. If, therefore, a symmetrical 
molecule is temporarily transformed into a dissymmetrical molecule 
by the introduction of some optically active radical and is then 
treated in such a way that a new asymmetric group is formed, 
unequal quantities of this group may result and, after the removal 
of the optically active radical, a product which shows some activity 
may be obtained ; in extreme cases only the rf- or the /-form of the 
new group might be generated (p. 747). 

Now methylethylmalonic acid is decomposed when it is heated, 
giving dl-methylethylacetic acid and the product is inactive. When, 
however, the methylethylmalonic acid is converted into its brucine 
hydrogen salt and the mixture of the two diastereotsomerides 2 is then 
heated, unequal quantities of the salts of rf- and /-methylethylacetic 

1 According to the laws of probability, the quantities of the d- and /-forms 
will not be exactly equal, but the excess of either will be so small that it 
cannot be detected (Mills, J. Soc. Chem. Ind. 1932). 

1 Structurally identical compounds which are optically active but not 
enantiomorphously related are said to be diastereoispmeric, as, for example, 
the + + and + forms of chlorohydroxysuccinic acid and salts dAlB 
and dAdB> or dAtB and IAIB in general. 



OPTICAL ISOMERISM 747 

acids are formed, and, after the removal of the brucine, the product 
is distinctly laevorotatory (Marckwald). 

When benzoylformic acid, C 6 H 5 -CO-COOH, is reduced it gives 
equal quantities of d- and /-mandelic acids ; when, however, the 
acid is converted into its /-menthyl ester and the latter is reduced 
with aluminium amalgam and water, unequal quantities of the d- 
and /-forms of the > CH(OH) group are generated and the product 
contains an excess of the ester of the /-acid : on hydrolysis, however, 
after the removal of the menthol, an optically inactive mandelic acid 
is obtained owing to racemisation (p. 748). In a similar manner, 
when \-menthyl benzoylformate is treated with methyl magnesium 
iodide, the product is a mixture of unequal quantities of the esters 
of methylphenylglycollic acid, but in this case, after hydrolysing the 
ester and removing the /-menthol, there remains an acid, which 
consists of about 60% of the /-, to 40% of the </-isomeride 
(McKenzie). It has also been shown that when l-bornyl fumarate 
is oxidised with permanganate it yields a bornyl ester from which 
unequal quantities of d- and /-tartaric acids are obtained (McKenzie). 

Syntheses of this kind which, starting from a symmetrical molecule, 
convert it into unequal quantities of d- and /-isomerides, are termed 
asymmetric syntheses. 

These results show that the dissymmetry of a molecule may 
determine the course of reactions brought about by symmetrical 
substances only, a fact which seems to have an important bearing 
on the syntheses which occur in animals and plants ; in the synthesis 
of aldohexoses in plants, for example, only very few of the sixteen 
optically active isomerides seem to be produced or else the other 
isomerides, if formed, are selectively decomposed. Even in labora- 
tory syntheses such dissymmetric influences may be very pro- 
nounced ; when, for example, mannoheptose is prepared from 
J-mannose (p. 320) only one of the two theoretically possible aldo- 
heptoses is obtained because, in the addition of the elements of 
hydrogen cyanide to the aldehyde group, the course of the reaction 
is directed by the dissymmetry of the molecule. 

Since a dissymmetric group may direct symmetrical reagents, it 
would seem that dissymmetric reagents should show a very different 
behaviour towards a given optically active molecule ; this, in fact, 
is so, and enantiomorphously related compounds often show 
differences in smell, in taste, and in physiological activity in general, 
properties which no doubt depend on their reactions towards other 



748 OPTICAL ISOMERISM 

optically active compounds contained in animal matter. Of great 
importance also is the difference in the behaviour of d- and /-enantio- 
morphs, and of optical isomerides in general, towards enzymes 
(pp. 863, 890, 902), but perhaps the most interesting fact is that 
these dissymmetric agents may convert a symmetrical molecule into 
one only of two enantiomorphously related derivatives (p. 90S). 

It was found by Cotton in 1896 that d- and /- circularly polarised 
beams of light are unequally absorbed by solutions of certain 
coloured, optically active compounds, a phenomenon which he 
called circular dichroim. It seemed, therefore, that if the optically 
active compound is decomposed by the light, the d- and /-forms 
might be changed at different rates by a given beam, in which case 
a solution of a (//-substance would become optically active. This 
was found to be so ; when dl-a-azidodimethylpropionamide, 
CH 3 -CH(N 8 )-CO'NMe 2 , is treated in this way in hexane solution, 
one of the forms is decomposed more rapidly than the other, and 
in consequence the unchanged material shows optical activity ; an 
asymmetric photochemical resolution has thus been accomplished 
(Kuhn, W. and Knopf). In a similar manner, as was shown by 
Mitchell (J. 1930, 1829), the ^/-nitrosite of a sesquiterpene, caryo- 
phyllene (from hop-oil), undergoes photochemical decomposition, 
with the evolution of nitrogen, and the original solution of the dl- 
substance becomes optically active. More recently Mitchell and 
Dawson (y. 1944, 452) have shown that when jS-chloro-jS-nitroso* 
aS-diphenylbutane, Ph - CH 2 - CCl(NO) - CH 2 - CH 2 Ph, dissolved 
in methyl alcohol is irradiated with circularly polarised light 
until about 90% of it is decomposed, the unattacked portion is 
optically active ; the decomposition products, of which the chief 
is a8-diphenyl-j8-butanoneoxime, contain no asymmetric group. 

Racemisation and Epimeric Change 

The </- and /-forms of many compounds are convertible one into 
the other, with the aid of heat or of a suitable reagent. When the 
change is carried to completion the product is a mixture of equal 
quantities of the two forms and is optically inactive ; the optically 
active compound is then said to have racemised or to have undergone 
racemisation. The first case of racemisation was observed by 
Pasteur, who found that, when the cinchonine salt of d- or of /- 
tartaric acid is heated at 170 during some hours, it gives a mixture 



OPTICAL ISOMERISM 749 

of salts from which rf/-tartaric acid can be isolated ; rf-tartaric acid, 
heated during many hours with water at 175, is also converted into 
dl- (and meso) tartaric acids, and /-tartaric acid, of course, behaves 
like the rf-acid. Mandelic acid, and other acids, the optical activity 
of which, as in the case of tartaric acid, is due to the presence of an 
asymmetric group, CH(OH)'COOH, undergo racemisation when 
they are heated, and certain esters such as methyl a-chloropropionate 
and dimethyl bromosuccinate undergo spontaneous racemisation 
(autoracemisatwri) at ordinary temperatures in the presence of traces 
of mineral acids. Methylbenzylacetyl chloride also racemises when 
it is heated at 120. Optically active j8-methyl-a-indanone is stable 
in alcoholic solution, but is immediately racemised on the addition 
of a little alkali ; many other optically active ketones behave similarly. 

In all these cases a hydrogen atom is one of the four different 
groups associated with optical activity and racemisation is probably 
due either to the formation of a planar mesomeric anion (p. 831), 
>C~ CR=O/>C=CR 0~ whose formation is catalysed by bases, 
or to the formation of a planar enolic form >C= CR OH. If there 
is no hydrogen atom associated with the asymmetric centre, as, for 
example, in atrolactic acid, Ph 'C(OH)Me 'COOH, then racemisation 
does not usually occur and in general when a mesomeric ion or 
an enolic form cannot be produced, an asymmetric carbon-group 
retains its configuration, and an optically active compound does 
not racemise unless it is submitted to very vigorous treatment. 

The racemisation of /-limonene at high temperatures is probably 
due to the lability of the hydrogen atom in position 6 (p. 912), 
which is sufficiently easily ionised to give a mesomeric anion 
-CH CMe= CH /--CH= CMe CH~ to which a proton may 
be added in position 2 or 6. 

The sodium derivative of optically active amyl alcohol is racemised, 
but only at a high temperature (about 200). In this case it is possible 
that a trace of the aldehyde is formed by oxidation and that then 
a reversible change occurs, as in the Ponndorf-Meerwein re- 
action, whereby each molecule of the alcohol is oxidised to one of 
the aldehyde at some stage in the process and then reduced again ; 
the aldehyde is racemised by the formation of a mesomeric ion. 
Other cases of racemisation of compounds which owe their optical 
activity to restricted rotation are mentioned later (p. 759, 760). 

The phenomenon of racemisation is closely related to that of 
epimeric change. When rf-gluconic acid is heated with quinoline 



750 OPTICAL ISOMERISM 

(to prevent the formation of lactone) at 140 it gives rf-mannonic 
acid ; the >CH(OH) group, directly combined to the carboxyl 
radical, undergoes a change, giving >C(OH)H, up to a condition 
of equilibrium, but the three other >CH(OH) groups in the 
molecule retain their original configurations (d- or /-). The product, 
therefore, although a mixture of optical isomerides, is not a dl- 
compound and is not enantiomorphously related to the original 
substance. An optical inversion of this kind is a reversible reaction 
and is known as an epimeric change ; the two substances concerned 
are epimerides. At the condition of equilibrium the product is not 
necessarily, or usually, a mixture of equal quantities of the two 
epimerides because the two forms differ in stability. 

Many other examples of epimeric change are met with in studying 
the acids derived from the sugars and also the sugars themselves, and 
many of the latter show mutarotation (p. 866) in aqueous solution 
owing to transformations of this nature. Some camphor derivatives 
also undergo epimeric changes and, in consequence, show mutarota- 
tion (p. 836). 

Interesting cases of optical change of an exceptional character 
have been observed during the resolution of certain ^/-substances. 
&\-Chloroiodomethanesulphonic aicd, CHIC1 'SO 3 H, has been resolved 
into its d- and /-components by Pope and Read (,7. 1914, 811), who 
found that the active acids were stable at the ordinary temperature 
and thus proved that optical activity may occur in a compound 
containing one carbon atom only. The corresponding ^/-chloro- 
bromo-acid, CHBrCl *SO 3 H, was investigated by Read and McMath 
(7. 1925, 1572), who prepared its \-hydroxyindylamine 1 salt and 
found that in undried acetone solution the rf-acid was partly con- 
verted into the /-isomeride, giving an equilibrium mixture of about 
81% of the /B/A and 19% of the lEdA salt. Under similar con- 
ditions, but with rf-hydroxyindylamine, the /-acid was converted 
into the rf-acid until a corresponding condition of equilibrium was 
reached ; the pure /B/A and dBdA salts, therefore, showed muta- 
rotation in aqueous alcoholic solution owing to the transformation of 
each into the equilibrium mixture. A similar phenomenon had 
been previously studied by Pope and Peachey (Proc. Ghent. Soc. 
1900, 42, 116) during the resolution of dl-methylethylpropyktannic 

1 <tf-a-Hydroxy-0-indylamine is prepared by shaking indene with bromine 
water and treating the bromohydroxyindane thus formed with ammonia ; 
it is resolved with the aid of rf-a-bromocamphor-Tr-sulphonic acid. 



OPTICAL ISOMERISM 751 

d-a-bromocamphor-7T-sulphonate (p. 767) from solutions of which 
only the </-base rf-acid crystallised. In this case the interconversion 
of the </- and /-forms is probably due to the existence of the ion 
MeEtPrSn + and the lesser solubility of the salt of the </-base causes 
it to crystallise from the solution. Another interesting case is 
described on p. 760. 

The Walden Inversion 

It was observed by Walden in 1896 that /-chlorosuccinic acid, 
treated with moist silver oxide gave /-malic acid, but with potassium 
hydroxide solution it afforded (/-malic acid ; further, it was found 
that /-malic acid was converted into J-chlorosuccinic acid by the 
action of phosphorus pentachloride. The two malic acids, and the 
two chlorosuccinic acids, could thus be converted one into the other 
as shown below : 

KOH 
/-Chlorosuccinic acid ...... "'"_,* rf-Malic acid 



A g2 A g2 

KOH I 

/-Malic acid * - rf-Chlorosuccinic acid 



Such a transformation of a d- into an /-isomeride, or vice versa, 
was known as a Walden inversion. 

Corresponding inversions were observed by Fischer in the case of 
*/-alanine, which can be converted into the /-isomeride and vice versa : 

</-Alanine </-Bromopropionic acid 

CH 3 CH(NH 2 ) . COOH - CH 3 - CHBr - COOH 

NOBr NH NOBr 



/-Bromopropionic acid /-Alanine 

CH 3 - CHBr- COOH - > CH 3 .CH(NH 2 ).COOH 

NH 8 

Aspartic acid shows similar behaviour : 

rf-Aspartic acid * - /-Bromosuccinic acid 
I NOBr NH " J NOBr 

rf-Bromosuccinic acid - * /-Aspartic acid 
NH 8 



752 OPTICAL ISOMERISM 

In all the above examples the Walden inversion occurs with 
compounds in which the asymmetric group is directly combined 
with the carboxyl radical, but this is not a necessary condition as 
is shown for example in the following transformations of f$-phenyl- 
fi-hydroxypropionic acid studied by McKenzie : 

PC1 8 or HC1 

rf-Ph-CHCl-CH 2 .COOH ' /-Ph-CH(OH).CH a -COOH 

H a O 



SOClj 



H,O 



SOC1, 



rf-Ph-CH(OH)-CH a -COOH . /-Ph-CHCl-CH 2 -COOH 

PC1 6 or HC1 

It should be carefully noted that in all the above examples the 
letters d- and /- show only whether the substance is dextro- or 
laevorotatory, and it cannot be assumed that because dextro- 
rotatory malic acid is converted into laevorotatory chlorosuccinic 
acid, an inversion of configuration has in fact occurred ; the chlorine 
atom may occupy the same position in the molecule as the hydroxyl 
group which has been displaced, and yet the sign of the rotation 
may be changed. A change of configuration is not established until 
the /-chloro-acid has been converted into /-malic acid. It is also clear 
that either the reaction of malic acid with phosphorus pentachloride 
or that of the resulting chloro-acid with silver oxide must involve 
an inversion of configuration, but that both reactions cannot do so. 

As stated above, the term Walden inversion was originally applied 
to the change of a d- into an /-isomeride (or vice versa), but it is 
now more commonly applied to any single reaction in which an 
inversion of configuration occurs : for example, as will be shown 
later, such an inversion of configuration occurs in the conversion of 
/-chlorosuccinic acid into rf-malic acid and hence a Walden inversion 
is said to have taken place in this one reaction. 

A great many explanations of the Walden inversion have been 
suggested. Fischer and Werner, for example, assumed that the 
first stage is the formation of an additive product, the configuration 
of which determines the course of the final substitution. If, for 
example, the compound C(abcd) is treated with a reagent, XY, 
the latter is attracted to the face ode, or to that of one of the other 
three faces of the tetrahedron, according to the nature of the inter- 
acting compounds. When now the second stage of the reaction 
occurs and d is displaced from the molecule, if the substituent is in 



OPTICAL ISOMERISM 753 

one of the positions close to rf, it will take the place of d and no 
inversion will occur ; if, however, the substituent is in position 
on the distant face abc, one of the atoms or groups 0, i, or c may 
slip into the position previously occupied by d, and its place will 
then be taken by X so that a Walden inversion results. 

Another suggestion was made by Holmberg (Ber. 1926, 125) which 
does not assume the formation of an additive compound, but supposes 
that the. course of the reaction is determined by the length of the 
molecule of the substituting reagent, X Y. When this is large com- 
pared with the distance C d t and Y removes </, one of the atoms or 
groups a, by c will be nearer than X to the d corner and will slip into 
the unoccupied space, while X takes up the new position which has 
been vacated. In this case a Walden inversion will occur, whereas 
if the distance X Y is small compared with C rf, X takes the 
place of d and there will be no change in configuration. 

Theories of this kind were the only ones possible at that time 
and it was only after the mechanism of substitution in aliphatic 
compounds in general had been more fully studied that a satis- 
factory explanation could be given. 

It has already been pointed out that in an S N 2 reaction, 

A+RB > RA+B, 

the entering group A approaches RB towards the face of the 
tetrahedron remote from B ; when B leaves the transition state there 
is therefore an inversion of configuration by a sort of " umbrella 
turning inside out effect ", as shown in the accompanying figure 
representing the action of an alkyl halide with ammonia (Mills, 
1932), 




Fig. 30 




754 OPTICAL ISOMERISM 

That this is in fact the case has been shown by Hughes and his 
co-workers (J. 1935, 1525) who studied the reversible reaction 
between 2-n-octyl iodide and sodium iodide containing radioactive 
iodine (indicated by an asterisk) in acetone solution, 

C 8 H 17 I+I- ^ C 8 H 17 I+I-, 

and the racemisation of d-2-n-octyl iodide by sodium iodide in 
acetone, which is caused by a similar reversible interchange of 
iodine atoms of the alkyl halide with iodide ions. Assuming that 
every individual substitution gives inversion of configuration the 
rate of iodine exchange was calculated from the rate of racemisation ; 
this rate was found to be equal to the measured rate of exchange 
using radioactive iodine. In this particular case, therefore, the S N 2 
reaction leads to inversion and it is now assumed that this is always so. 

In an S N 1 reaction the carbonium ion, R+, is planar and when union 
with A~~ occurs there is an equal chance of A~" combining on either 
side of this plane : equimolecular amounts of the two configurations 
will be formed and complete racemisation results. In fact the 
situation is not quite so simple because if B~ has not moved far from 
R+ before the approach of A~, the latter will tend to be at the side 
remote from B~~ and inversion will occur with some racemisation. 

Another complication is present if the group R+ contains certain 
configuration holding groups, the most important of which is the 
a-COO~ ion. This group is electron repelling and therefore 
promotes S N 1 substitution and as soon as B~ has been split off a 
weak bond, a sort of lactone, is formed between the carbon atom 
which B~ has left and the -COO~ ion on the side remote from that 
occupied previously by B~ ; this side is therefore protected from 
attack by A- which must wait until B~ has moved sufficiently far 
for A" to take its place. Reaction therefore occurs with retention 
of configuration, 






Fig. 31 

Another way of regarding a reaction of this sort is that it consists 
of two successive S N 2 processes each involving inversion : the first 



OPTICAL ISOMERISM 755 

leads to the formation of the lactone and the second to its decom- 
position by the group A. It is clear that two inversions will repro- 
duce the original configuration. 

Reaction can occur with retention of configuration in another 
way as is illustrated by the action of thionyl chloride on an alcohol : 
an intermediate may be formed which then decomposes by an 
internal reaction in which the chlorine atom takes the place of the 
hydroyxl group, 

R R \ R \ 

R'-C-- ' 



- - > -j-- \ - > - 

R"/ R'/Cl - SO R*/ 

the thionyl chloride is acting as a configuration holding reagent 
It is possible that this is the mechanism of the action of thionyl 
chloride on /3~phenyl-f3-hydroxyproptonic acid (p. 752), which, as 
will be seen later, does not involve an inversion ; thionyl chloride, 
however, does not always act in this way and in some cases causes 
inversion. 

The other examples of the Walden inversion given all involve 
compounds which contain a carboxyl group as one of the four 
different groups of the asymmetric centre and it is now clear why 
the phenomenon was first observed in such cases. If the result 
of two successive reactions is to convert a d- into its /-antimer one 
of the changes must involve inversion, and one retention, of con- 
figuration ; the commonest way in which the latter can occur is 
with an S N 1 reaction with a configuration holding group. Without 
such a group two successive S N 2 reactions would both give inversion 
and the final product would be identical in configuration with the 
starting material ; or if either reaction were S N 1, racemisation with 
possibly some inversion would occur at each such step. 

The next matter to consider is in which of the two reactions 
involved in converting a d- into an /-antimer or vice versa does the 
actual change of configuration occur. Kenyon and Phillips and 
their co-workers approached this problem as follows. When an 
alcohol, (i), is converted into its ^-toluenesulphonate, (n), by the 
action of />-toluenesulphonyl chloride the carbon-oxygen link of 
the alcohol is not broken and it can be assumed that no change of 
configuration occurs in the asymmetric group ; if it is similarly 
assumed that conversion of an alcohol into an acetate, (iv), by 
acetic anhydride also produces no change in configuration, it 



756 OPTICAL ISOMERISM 

follows that the alcohol, its j>-toluenesulphonate and its acetate 
all have the same configuration. It is not, of course, obvious that 
the action of acetic anhydride, like that of ^-toluenesulphonyl 
chloride, involves no break in the carbon-oxygen linkage, but a 
careful study of esterification has shown that the assumption is 
justified (p. 695k seq.). Now it was found that when an optically 
active alcohol was converted directly into its acetate the sign of 
rotation of the latter was opposite to that of the acetate, (in), obtained 
from the />-toluenesulphonate by the action of potassium acetate ; 
inversion of configuration must therefore have occurred in this last 
change (n mi), by an S N 2 reaction, 



O-CO-CHg 



> 

OH IT X O-S0 2 -C 7 H 7 IT X H 



II HI 



R \ C / H R \ C / C1 

/ C \ /\ 

R'' X 0-COCH 3 R ;/ X H 

IV V 

Assuming that a similar inversion occurs in the analogous reaction 
of the/>-toluenesulphonate with lithium chloride to give the chloride, 
(v), this chloride will be opposite in configuration to the original 
alcohol. 

In many other cases it can be shown by kinetic investigations 
that reactions are of the S N 2 type and assuming that this always 
gives inversion, relative configurations can be determined ; if, for 
example, a dextrorotatory halide is converted by an S N 2 hydrolysis 
into a laevorotatory hydroxy-compound, the halide and alcohol of 
like rotations are of the same configuration and so on. Working in 
this way it has been shown that substances of the same configuration 
have the signs of rotation as indicated : 

X=Ci Br OH NH 2 

HOOC-CH 2 -CHX-COOH + + + + 

CH 3 -CHX-COOH + + 

Ph-CHX-CH 2 -COOH + + + 



OPTICAL ISOMERISM 757 

It is thus clear that in the examples on pp. 751-752, the reactions 
of caustic potash on the halides, of phosphorus pentachloride on 
the alcohols and of ammonia on the halides all occur with inversion 
of configuration, whereas those of silver oxide on the halides and of 
nitrosyl bromide on the amines do not involve such a change. In 
some of the reactions, such as those of phosphorus pentachloride 
on alcohols, which do not admit of kinetic investigation, the mechan- 
ism may be S N 2 or S N 1 involving predominant inversion : the silver 
oxide reaction is S N 1 with a configuration holding group. The 
schemes on pp. 751-752 have been so arranged that all the changes 
represented by horizontal arrows involve inversion, whilst those 
shown vertically do not. 

The foregoing considerations also explain facts such as the follow- 
ing, which were very puzzling to earlier workers : although d- 
alanine gives /-bromopropionic acid with nitrosyl bromide (no 
inversion), its ethyl ester gives an ester of the d-bromo-acid (inver- 
sion) ; this is due to the configuration holding power of the carboxyl 
group which is not shown by the carbethoxy-radical. Again, when 
sodium a-bromopropionate is hydrolysed with concentrated alkali 
in aqueous solution an S N 2 reaction with inversion occurs, but with 
dilute alkali the configuration is retained by an S N 1 configuration 
holding reaction. 

Other examples of the Walden inversion are encountered in the 
carbohydrates (p. 880) and the sterols, and the theories outlined 
above apply equally to all fields of organic chemistry where optical 
activity is due to asymmetric carbon-groups ; it is possible, therefore, 
to correlate the absolute configuration of a particular group of this 
kind in any compound with that in related substances. 



Optically Active Diphenyl Derivatives and the Phenomenon of 
Restricted Rotation 

As the benzene molecule is planar (p. 1001), the configuration of 
diphenyl should presumably be represented by two plane rings, 
capable of free rotation about their point of union. Various com- 
pounds obtained from benzidine, NH 2 'C 6 H 4 'C e H 4 'NH a , how- 
ever, appeared to be formed by reactions which required the 
proximity of the two jp-amino groups; in consequence Kaufler 
(1907) proposed for diphenyl the configuration (i, Butterfly formula), 



758 OPTICAL ISOMERISM 

in which the two rings are situated in parallel planes, and the two 
p-amino-groups are closer together than in other possible con- 
figurations. 

The experimental evidence on which Kaufler's suggestion had 
been based was afterwards found to be valueless, and his formula 
has also been disproved by measurements of the dipole moments 
of p'-diphenyl derivatives, X'C e H 4 C e H 4 'X, which give values 
almost the same as those of the corresponding ^-derivatives of 
benzene, and, in particular, when X = Cl or Br, the dipole moment 
is zero (p. 705) : the Kaufler formula would require a relatively 
large moment in the case of $p'-dichlorodiphenyl. 

In the meantime, however, it had been shown by Christie and 
Kenner that certain simple substitution products of diphenyl could 
be resolved into optically active forms. This fact might be accounted 
for on the basis of Kaufler's formula, but an alternative explanation 
was put forward almost simultaneously by Turner and Le F&vre, 
Bell and Kenyon, and Mills, who suggested that, in certain diphenyl 
derivatives, the free rotation of the phenyl groups was in some way 
prevented. This view is now established : when a diphenyl 
derivative contains sufficiently large substituents in the o-positions 
to the junction of the rings, these substituents cannot pass one 
another (provided the molecule is sufficiently rigid), but clash or 
collide when either of the rings is turned around the C C axis ; 
free rotation is therefore blocked. 



p 

o 




II 

Fig. 32 



Thus in the case of a compound, (n), containing three substituents, 
A, B, and C, when C (the dark disc) cannot pass either A or B, the 
two benzene rings cannot be, or become, co-planar. Whatever their 
position, therefore, the compound will exist in two enantiomorph- 
ously related forms, (in), in both of which the rotation of either ring 
is confined to an arc of less than 180. 



OPTICAL ISOMERISM 



759 




III 




The first example of optical isomerism of this kind was observed 
in the case of 2:2 -dinitro-fatt -diphenic acid, (rv), which was resolved 
by Christie and Kenner ; since then many analogous compounds, 
including 2-nitrO'b\& -diphenic acid, have been proved to exist in 
optically active forms, as indicated in (m). 

Later Lesslie and Turner (J. 1932, 2021, 2394) resolved diphenyl 
benzidine-2:2'-disulphonate, (v), and also diphenyl~2:2 -disulphonic 
add, (vi)t in which the groups in the 2- and ^-positions are suffi- 
ciently large to clash with the o-hydrogen atoms of the nuclei 
indicated by (a) in (n), Fig. 32. 

NHi 




PhO,S 




SO 3 Ph 



HO*S 




IV 



VI 



rf-Diphenyl-2:2'-disulphonic acid is racemised at 100 C., a fact 
which shows that the obstruction is not very large and the molecule 
not completely rigid. The compound (vii) has also been resolved ; 
here restricted rotation is due to the clashing of the Me 3 As group 
with the o-hydrogen atoms only, and the bromine atom causes 
dissymmetry. 




Org. 48 



760 



OPTICAL ISOMERISM 



Similar phenomena have been observed in the case of certain 
dinaphthyl derivatives. 1 :\' -Dinaphthyl-%&' -dicarboxylic acid, (vm), 
has been resolved by the crystallisation of its brucine salt, but the 
sodium salt of the active acid slowly racemises in aqueous solution. 
1:1' '-Dinaphthyl-8-carboxylic acid, (ix), gives a brucine salt which, 
when crystallised from ethyl acetate, gives either the salt of the d- 
or that of the /-acid, and finally the whole acid may be deposited in 
the form of one component ; either salt can be obtained by ' seeding ' 
the solution with a crystal of the d- or /-isomeride. The sodium 



COOH 




:OOH 



HOOC 




VIII 



IX 



salt racemises in aqueous solution. In (vm) obstruction is caused 
by the hydrogen atoms (a) at 2 and 2', and in (ix) by those at 2' 
and 8'. 

Mills and his co-workers have also demonstrated restricted 
rotation in />m'-derivatives of naphthalene, (x), and quinoline, (xi), 
and in o-derivatives of benzene, (xn) and (xni) : 



Ph- 




COOH 




XI 



OPTICAL ISOMERISM 



761 



Me 





XII 



XIII 



Lesslie and Turner (J. 1934, 1170) have resolved W-methyl- 
phenoxarsine-2-carboxylic acid, (xiv) ; the dissymmetry is here 
ascribed to a folding of the molecule along a line joining the oxygen 
and the arsenic atoms : 



'COOK HOOC' 





xv 

Dipole moment measurements indicate similar folded molecules 
for those analogues of the above in which the MeAs< group is 
displaced by an oxygen or a sulphur atom. 

A final example of optical activity due to restricted rotation is 
that of (xv) ; here the full rotation of the benzene ring is prevented 
by its 2:5-substituents which clash with the large l:4-ring. 

In 1947 Newman showed that the acid (xvi) could be obtained 



[ 2 COOH 



fle Me 

XVI 




'CH 2 -COOH 



XVII 



optically active ; solutions of the brucine salt deposited the salt 
of the rf-acid only and the optically active acid racemised easily. 
The activity of this acid proves that its molecule cannot be planar. 
A model of the molecule shows that there is no room for the two 



762 OPTICALLY ACTIVE COMPOUNDS OF 

methyl groups at 4- and 5- if the phenanthrene system and the 
methyl groups all lie in one plane, as would be expected. Either 
one or both the methyl groups must be forced out of the plane of 
the ring by this overcrowding, or the ring is buckled. The acid 
(xvn) has also been obtained optically active. 

Stereochemistry of Quaternary Ammonium Compounds 

For many years after the formulation of Le Bel and van't Hoff' s 
hypothesis in 1874, the only compounds which were optically active 
in solution were those which contained in their molecules one or 
more asymmetric carbon-groups. In 1891, Le Bel prepared methyl- 
ethylpropylisobutylammonmm chloride, NMeEtPrBuCl, and, on the 
supposition that the quaternary salt might exist in enantiomorph- 
ously related forms, he attempted to obtain one of these by leaving a 
solution of the compound in contact with Penicillium glaucum (p. 306). 
In this way he obtained a solution which was very feebly laevorotatory , 
but which lost its activity when it was kept during a short time. 

Pope and Peachey (J. 1899, 1127) prepared methylallylphenyl- 
benzylammonium iodide, a compound which had been studied by 
Wedekind (Ber. 1899, 517), and heated it in acetone-ethyl acetate 
solution with silver J-camphor-j3-sulphonate (p. 932) ; after the 
silver iodide had been separated, the salt in the solution was frac- 
tionally crystallised, and the more sparingly soluble fraction was 
found to have [M] D +208 in aqueous solution. Since the acid ion 
has [M] D -f 51-7, it was concluded that the salt had been resolved 
and that the ammonium radical in the salt was dextrorotatory, having 
approximately [M] D +156 in aqueous solution (p. 744). The first 
conclusion was confirmed by converting the camphorsulphonate 
into the iodide, which in acetone-methyl alcoholic solution gave 
[M] D -f 192 . 1 The original mother liquors from the salt of the 
</-base gave finally the camphorsulphonate of the /-base, not quite 
free from the i-isomeride, having [M] D -87 in aqueous solution ; 
from this impure preparation the pure iodide of the /-base was 
prepared and found to correspond with that of the rf-base. It was 
thus proved that a compound NR 1 R 2 R 3 R 4 X exists in optically active, 
enantiomorphously related forms. 

1 As the [M] of this salt was not determined in aqueous solution, its 
value is not that of the substituted ammonium radical, but rather that of 
the molecule of the salt. 



NITROGEN, TIN, SILICON, SULPHUR, ETC. 



763 



The manner in which the five radicals in such compounds are 
arranged in space had previously given rise to much discussion. 
Willgerodt had suggested that they occupied the corners of a double 
pyramid on a triangular base (i, Fig. 33), with the acid radical 
situated at an apex. Other postulated arrangements were that the 
five groups occupied positions at certain corners of a cube (n, van't 
Hoff) or at the corners of a square pyramid (in, Bischoff). In each 
case the nitrogen atom was regarded as being situated at the centre 
of the given figure. 

Later (1906) Werner suggested a tetrahedral configuration, (iv), 
for the four non-acidic groups, with the acidic ion not concerned in 
the spatial arrangement. This view gradually became more gener- 
ally accepted with the development of the electronic theory of 
valency, 4>ut even in 1925, although (i) and (n) had been discarded, 
no definite decision had been made between (in) and (iv), both of 
which provided an explanation of the facts known at that time. 





II in 

Fig, 33 



IV 



The resolution of 4-phenyl-4'-carbethoxybispiperidinium- 1:1'- 
spiran bromide, 



H 2 H 2 H 2 H 2 

\r\r\ 



4-A 

H2 Hj HI 



[ 2 H 2 



COOEt 



Br 



by Mills and Warren (J. 1925, 2507) finally disposed of the pyra- 
midal configuration. It will be clear from the diagrams, Fig. 34, that 
if the pyramidal structure, (in), represents the molecule and the 
acidic ion occupies the apex of the pyramid, the two hydrogen atoms, 
the phenyl, and the carbethoxy-groups (RR]RR 2 ) all lie in one 



764 OPTICALLY ACTIVE COMPOUNDS OF 

plane and the compound has a plane of symmetry : in the tetrahedral 
arrangement, (iv), on the other hand, the four groups occupy the 
corners of an irregular tetrahedron and enantiomorphously related 
forms should exist : 





III IV 

Fig. 34 

It can therefore be regarded as established that the four co-valently 
linked atoms or groups of quaternary ammonium compounds are 
arranged tetrahedrally round the nitrogen atom, a conclusion fully 
confirmed by X-ray crystal analysis. 

Many nitrogen derivatives of the type NR^RsRiX have now 
been resolved into their d- and /- isomerides, and an unstable optic- 
ally active arsenic compound, [AsMePhBz-C 10 H 7 ]I has been de- 
scribed by Burrows and Turner (J. 1921, 426). 

Optical Isomerism of Amine Oxides 

When a tertiary amine is oxidised by hydrogen peroxide under 
certain conditions it affords an amine oxide of the type, R 3 NO. 
Meisenheimer (Ber. 1908, 41, 3966) oxidised methylethylaniline in 
this way and obtained a crystalline substance, MeEtPhNO, which 
gave salts, [NMeEtPh-OH]X ; the J-camphorsulphonate of this 
base was fractionated, and the base was thus resolved into optically 
active forms. Since that time many other amine oxides containing 
three different alkyl or aryl radicals have been resolved. In these 
compounds the three hydrocarbon groups and the oxygen atom are 
arranged tetrahedrally round the nitrogen atom. 

A compound of phosphorus, MeEtPhPO, analogous to the amine 
oxides, has been resolved by Meisenheimer and Lichtenstadt (Ber. 
1911, 356), and a derivative of arsenic, MeEt(C e H 4 -COOH)AsS, 
by Mills and Raper (J. 1925, 2479). 

Before any very definite conclusions had been drawn regarding 



NITROGEN, TIN, SILICON, SULPHUR? ETC. 765 

the arrangement in space of the atoms or groups in a quaternary 
salt, Meisenheimer had shown that two of the valencies of the 
nitrogen atom are not identical. He treated (1) trimethylamine 
oxide with methyl iodide, and from the salt so formed liberated the 
base with alkali, and (2) trimethylamine oxide with hydrochloric 
acid, and displaced the chlorine atom by OMe with the aid of 
sodium methoxide : 

,OCH 3 y OCH 3 (4) 

(1) Me 3 NO+ CHJ > Me 3 N<Q * Me 3 N\ (A) 

xOH ,OH (4) 

(2) Me 8 NO+HCl > Me s N\ > Me 3 N\ (B) 

X C1 X OCH 8 (5) 

If the two nitrogen valencies (distinguished above as 4 and 5) 
concerned in these changes are identical, the same result must clearly 
be obtained by the two series of reactions, but this was not so. The 
final products could not be isolated, but the properties of their 
solutions were not the same : when their aqueous solutions were 
evaporated, the substance (A) yielded trimethylamine, formaldehyde 
and water, while (B) gave trimethylamine oxide and methyl alcohol, 
and in each case the change was quantitative. Similar results were 
obtained with other isomerides of the same type, and also with those 
of the structure Me 3 N(OEt)OMe. 

That the two products A and B should be different is in accord- 
ance with the accepted tetrahedral configuration for the quaternary 
ammonium compounds ; in (A) the hydroxyl group is combined 
to the co-valent complex, [Me 3 N-OMe], by an electro-valency, 
while in (B) the methoxyl group is so united to the complex, 
[Me 3 N'OH], as shown below : 

tMe v /Me "I + _ T Me \ / Me "l + - 

>N< OH >N< OMe 

Me/ X OMeJ LMe^ N OHJ 

There is no experimental evidence, however, that either of these 
compounds is an electrolyte. 

Stereochemistry of Tervalent Nitrogen 

The disposition in space of the three nitrogen valencies in com- 
pounds, NR 3 , has been the subject of much experimental work. If 



766 OPTICALLY ACTIVE COMPOUNDS OF 

the nitrogen atom, and the three atoms or groups to which it is 
united, do not lie in one plane, compounds of the type, NR 1 R 2 R 3 , 
should exist in antimeric forms, but of the numerous attempts to 
resolve such substances (secondary and tertiary bases, alkylhydroxyl- 
amines, unsymmetrical hydrazines) by the crystallisation of their 
salts with optically active acids, none has succeeded. It is clear that 
in such experiments the compounds actually examined are deriva- 
tives of ' quinquevalent ' nitrogen, [NRjRgRg^X, and it is very 
remarkable that salts of this type, where X is an optically active 
radical, have not been obtained in diastereoisomeric forms, dBdA. 
and /BrfA, corresponding with those of the type, [NR 1 R 2 R 3 R 4 ]X. 
For, even if the molecule, NR^^, is planar, it would appear to 
be necessary that, during its conversion into a salt, the original 
directions of the valencies of the tervalent nitrogen would be changed, 
giving the tetrahedral configuration. On the other hand, the libera- 
tion of the amine from its salt would probably be accompanied by 
a reversal of this change in configuration ; so that even if salts, 
dBdA. and IBdA, could be separated, they might give the same planar 
base, NR^Rg, or the same inactive mixture of non-planar iso- 
merides. 

In view of this difficulty attempts have been made to obtain 
evidence of the disposition in space of the nitrogen valencies in 
another way (Kipping and Salway, J. 1904, 438). A base such as 
methylaniline or ^-toluidine was treated with a <//-acid chloride (R 3 ), 
and was thus converted into a substituted amide, NR 1 R 2 R 3 (Ri or 
R 2 may represent H), in which R 3 is either </-(+) or /-(-). If the 
three nitrogen valencies are not in one plane, the </-acid chloride 
would give the two diastereoisomerides, (i) and (n), 

N N N N 



+R 1 R a R 3 + 
i n in iv 

and the /-acid chloride would give the two corresponding /-deriva- 
tives, so that two different ^/-substituted amides should be formed ; 
only one was obtained. An optically active base (i.e. a base in which 
Rj is an optically active radical) such as d-indylamine or /-menthyl- 
amine was also treated with an optically active acid chloride (R 3 ) ; 
here again, two substituted amides, (in) and (iv), should have been 
formed, but only one was obtained. 



NITROGEN, TIN, SILICON, SULPHUR, ETC. 767 

Meisenheimer (Ber. 1924, 1744) also failed to resolve derivatives 
of anthranilic acid, R 1 R 2 N'C 6 H 4 'COOH, by the crystallisation of 
their salts with optically active bases, although in such experiments 
no use is made of the salt-forming power of the NRjR 2 R 3 group. 

All these results seem to show that the three valencies of the 
tervalent nitrogen atom lie in a plane, and that the salts of tetrahedral 
configuration, [NR 1 R 2 R 3 H]X, are either partially racemic (p. 307) 
in all cases which have been studied or are so easily racemised that 
only one salt, dBdA. or /IWA, separates from the solution of the two, 
and gives both when it is redissolved. On the other hand, it is 
known (p. 70S) that the molecule of ammonia is pyramidal so that 
the failure to resolve certain compounds is more probably due to 
the ease with which the nitrogen atom can pass through the plane 
of the three attached groups (p. 754), thus causing racemisation : 



JL^| 

/T 

RlR: 



N 
, 2 R 3 



Stereochemistry of Tin and Silicon 

Optically active methylethylpropylstannic iodide, MeEtPrSnl, 
was obtained by Pope and Peachey (Proc. Ghent. Soc. 1900, 42 and 
116). When the solution, prepared by treating the ^/-iodide with 
silver rf-camphorsulphonate, is evaporated, only the dAdB com- 
ponent is deposited, owing to the transformation of the rfA/B salt 
into its diastereoisomeride ; this dAdB salt, treated with potassium 
iodide, gave an optically active iodide which, however, rapidly 
racemised (p. 751). 

Silicon compounds of the two types shown below have been 
obtained in d- and /-forms (Kipping, J. 1907, 209 ; Challenger and 
Kipping, J. 1910, 755): 

f ? R\ /CH,.CH 4 .S0 3 H 

SO 8 H - C 6 H 4 CH a Si O Si - CH, C e H 4 SO 3 H /Si<f 

Rt N CH,.C t H. 



Nearly all the salts of the <f/-acids with an optically active base are 
partially racemic, and the two compounds, rfArfB and lA.dB (or 



768 OPTICALLY ACTIVE COMPOUNDS OF 

dAlB and /Affi), are so similar that they cannot be easily distinguished 
(J. 1908, 457). 

An optically active germanium, compound, phenylethylisopropyl- 
germanium bromide, has also been described (Ber. 1931, 2352). 

Stereochemistry of Sulphur and Selenium Compounds 
The first optically active sulphur compound, A-methylethylthetine 
platinichloride, was prepared by Pope and Peachey (J. 1900, 1072), 
and very shortly afterwards Smiles (J. 1900, 1174) obtained optically 
active picrates of methylethylphenacylsulphine. The structures of 
these substances were represented respectively by (i) and (n), in 
which the sulphur atom occupies the centre of a tetrahedron and 
is surrounded by four different groups : 

CH 3V /CH 2 .COOH\ CH 3X .CU^CO^h 

>S< J PtCl 4 , >S<f 

C 2 H/ X C1 /, C 2 U/ X C 6 H(N0 2 ) 3 .OH 

i ii 



_CH 3 C 2 H 5 CH 2 .COOHJ 

in 

According to modern views, however, the acid radical is combined 
with the sulphur atom by an electro-valency, and the compound, (i), 
is regarded as a sulphonium salt, [(CH 3 )(C 2 H 5 )S(CH 2 COOH)] 2 PtCI 6 , 
in which the sulphur atom is tri-covalent and situated at one 
corner of a tetrahedron ; this view is expressed in (m). 

An optically active selenium compound, methylphenyhelenetine 
bromide, [PhMeSe(CH 2 COOH)]Br, was obtained by Pope and 
Neville (Proc. Chem. Soc, 1902, 198), and phenyl-p-tolylmethyl- 
telluronium iodide, [PhMeTe-C 6 H 4 Me]I, has also been resolved by 
Lowry and Gilbert (J. 1929, 2867) ; the configurations of these 
compounds are believed to be similar to that of a sulphonium salt. 

Optically active derivatives of sulphur of a somewhat different 
character have been obtained by Phillips (J. 1925, 2552), who showed 
that when ethyl p-toluene$ulphinate, CH 3 C e H 4 SO - OC 2 H 6 , (2 mol.) 
is heated with /-j3-octanol (1 mol.) or /-menthol (1 mol.), and the 
product is then fractionated, a laevorotatory ethyl jp-toluenesulph- 



NITROGEN, TIN, SILICON, SULPHUR, ETC. 769 

inate is obtained. This result shows that the ethyl ester exists in 
d- and /-forms which react with the optically active alcohol with 
different velocities, the ethyl group being displaced by an octyl or 
menthyl radical ; when, therefore, the unchanged ethyl ester is 
separated, it no longer consists of equal quantities of the d- and 
/-forms, a partial resolution having been accomplished. This is 
another interesting example of the general phenomenon that d- 
and /-isomerides do not behave in the same way towards a given 
optically active compound (p, 747). 

The optical activity of ethyl />-toluenesulphinate shows that the 
molecule is non-planar : the groups are probably arranged pyrami- 
dally, as in the sulphonium salts. Various sulphoxides, RR'SO 
(one of the radicals of which contains a basic or acidic group), 
and also sulphilamines, RR'SNR", have been resolved. Further 
evidence supporting this view of the arrangement of the groups in 
such sulphur compounds was provided by the isolation of cis- and 
frvww-isomerides of the disulphoxide of \-A-dithian (Bell and Bennett, 
J. 1927, 1798) ; this result shows that the two oxygen atoms may 
lie either on the same or on different sides of the plane of the ring : 

3* 



os 7 ^o 

H 



Stereochemistry of Organic Co-ordination Compounds 

It has long been known that from aqueous solutions of mixtures 
of certain salts, well-defined crystalline products, such as the alums, 
M 2 'S0 4 ,M 2 ''XS0 4 ) 8 ,24H 2 O, and sulphates, M 2 'SO 4 ,M''SO 4 ,6H 2 O, 
are deposited ; similarly a solution of potassium chloride and 
platinic chloride gives a salt, K 2 PtCl 6 , and a mixture of potassium 
and ferrous cyanides gives K 4 Fe(CN) 6 . Such products were at one 
time regarded as having been formed by * molecular association, 1 
by an attraction between the molecules as such, without any change 
having occurred in their structures : it was thus implied that the 
atoms in the associated molecules retained their original state of 
combination. This view was clearly unsatisfactory, and it did not 
indicate the great differences which were shown by various so-called 
4 double salts ' of this nature. The alums, for example, give the 



770 OPTICALLY ACTIVE COMPOUNDS OF 

reactions of the acid ion and those of both the constituent metal ions, 
whereas potassium ferrocyanide gives no reactions of the ferrous ion, 
but those only of potassium and of a complex ion, Fe(CN) e ; salts 
of the former kind, therefore, might be regarded as mere crystalline 
aggregates comparable with racemic substances, whereas those of 
the latter are certainly of a different type. Between these two 
extremes many ' double salts ' of an intermediate character could 
be recognised. 

In 1893 Werner suggested that in such * molecular compounds,' 
which exist in solution, the atoms, radicals, or molecules are arranged 
round a central atom, usually a metal, some combined by ordinary 
(principal) valencies, and others by ' residual affinity ' or auxiliary 
valencies. The formula of potassium chloroplatinate, for example, 
is then written K 2 [PtCl e ], to indicate that the platinum atom is 
combined with the six chlorine atoms by auxiliary valencies, while 
the potassium atoms are united to the platinum by principal valencies. 
The atoms or groups inside such a bracket are not, whereas those 
outside are, ionised in aqueous solution. The group in the bracket 
is known as the co-ordination complex or co-ordinate group, and the 
number of atoms, radicals, or molecules (any of which is possible) 
inside the co-ordinate group is known as the co-ordination number 
of the atom at the centre of such a group. This co-ordination 
number is not directly related to the ordinary valency of the atom, 
but is usually either four or six. 

According to the electronic theory, the atoms or groups outside 
the bracket are held by electro-valencies or polar bonds, those inside 
by co-valencies or co-ordinate co-valencies. In the case of a com- 
plex having a co-ordination number four, the central atom has 
presumably an octet of electrons, but with a co-ordination number 
six, it has apparently twelve shared electrons. 

Many compounds, known as ammines, have been prepared in 
which a metal is co-ordinated with ammonia or with amines ; the 
compositions and relationships of these substances can be explained 
as follows : 

Potassium chloroplatinate, K 2 [PtCl 6 ], ionises (as denoted by the 
brackets) into 2K + and PtCl 6 ~~. If now an ammonia molecule is 
substituted for one of the chlorine atoms in the co-ordination com- 
plex, the electrons associated with the platinum atom are increased 
by one, because the chlorine takes out seven and the ammonia brings 
in a complete octet ; the co-ordinate group, therefore, requires, 



NITROGEN, TIN, SILICON, SULPHUR, ETC. 771 

instead of two, only one electron to complete its stable arrangement 
and combines with only one potassium atom, giving the compound, 
K[Pt C1 5 NH 3 ] . A repetition of this process produces [PtCl 4 - 2NH 3 ] , 
which is a non-electrolyte. 

The introduction of the next molecule of ammonia produces a 
group with one extra electron, which is lost to a negative element 
such as chlorine, forming [PtCl 3 -3NH 3 ]Cl, and so on, until all the 
six chlorine atoms have been displaced by ammonia molecules. The 
whole series of compounds is shown below in the second column ; 
platinous ammines and corresponding derivatives of many other 
metals, such as cobalt and chromium, can also be obtained. 

Platinous ammines Platinic ammines Cobaltic ammines 

Co-ordination Co-ordination Co-ordination 

number 4 number 6 number 6 



K 2 [PtCl 4 ] KJPtCy K 3 [CoCl 6 ] 

K[PtCl 3 NH 3 ] K[PtCl 5 - NH 3 ] K 2 [CoCl 5 NH 3 ] 

[PtCl 2 - 2NH 3 ] [PtCl 4 - 2NH 3 ] K[CoCl 4 - 2NH 3 ] 

[PtCl 3NH 3 ]C1 [PtCl 3 3NH 3 ]C1 [CoCl 3 . 3NH 3 ] 

[Pt 4NH 3 ]C1 2 [PtCl 2 4NH 3 ]C1 2 [CoCl 2 - 4NH 3 ]C1 

[PtCl - 5NH 3 ]C1 3 [CoCl 5NH 3 ]C1 2 

[Pt.6NH 3 ]Cl 4 [CO-6MIJC1, 

Cryoscopic and conductivity measurements with aqueous solutions 
of such compounds show that in every case the number of ions 
present in the solution is in agreement with the above formulae, and 
it should be noted that, as already stated, atoms, radicals, or molec- 
ules can form parts of the co-ordinated group. 

In agreement with the general rule that co-valency is directional 
whilst electro-valency is not, the groups inside the co-ordination 
complex are arranged in a particular manner round the central 
metallic atom ; consequently isomerism and stereoisomerism should 
be exhibited in certain cases. 

Now long before Werner's hypothesis had been put forward, 
isomerism had, in fact, been discovered in compounds of this kind ; 
[PtCl 4 -2NH 3 ], for example, was shown by Cleve, in 1871, to exist 
in two isomeric forms, which he regarded as structural isomerides 
When, however, this complex salt is considered in the light of 
Werner's theory, it will be seen that in the case of an atom, M, with 
a co-ordination number six, there are at least four ways in which 
the co-ordinated groups might be arranged in space (Fig. 35). 



772 



OPTICALLY ACTIVE COMPOUNDS OF 



namely at the corners of a hexagon, (i), a hexagonal pyramid, (n), 
a triangular prism, (in), or an octahedron, (iv) : 




Fig. 35 



In a complex of the formula, MA 2 B 4 , each of the arrangements (i), 
(11) and (in) gives three possible configurations for this group ; 
such a complex should therefore exist in three isomeric forms related 
to the 0-, TH-, and p- derivatives of benzene. The regular octahedral 
configuration, (iv), however, gives rise to only two isomerides, (v 
and vi, Fig. 36), which may be distinguished as cis- and trans-forms : 



B 




B 



CIS- 



VI 




B 



or 



B 



trans- 
Fig. 36 



NITROGEN, TIN, SILICON, SULPHUR, ETC. 773 

The fact that only two isomerides have been isolated in the numerous 
cases examined, and the stereochemical evidence described below, 
seem to prove that such molecules have the octahedral arrangement, 

(IV). 

Two molecules of ammonia in the ammines may be displaced by 
one molecule of a diamine, such as ethylenediamine (en), which 
then occupies two places in the co-ordinated complex ; such a 
combination is known as a chelate (claw-like) group and may be 
formed by a dibasic acid (oxalic acid) as well as by a diacidic amine. 
Further, a compound [Coen 2 Cl 2 ]Cl, which contains two en-chelate 
groups, exists in two stereoisomeric forms, (i) and (n), related 
respectively to the trans- and os-isomerides mentioned above : 

Cl 

eiT Pen 



en 

i 



en/ 

J L 

Cl 
I II 

Fig. 37 

A third form, in which one of the chelate groups would occupy 
extreme corners of the octahedron, probably does not exist, as the 
distance is too great to be bridged in this way. 

Now a study of configurations (i) and (n) shows that whereas 
the *ra;w-isomeride, (i), has a centre and several planes of symmetry, 
the os-form, (n), has only an axis of symmetry and should therefore 
exist in the antimeric forms represented above. 

A compound of this type, namely Qfe-chloroamminQdi(eihykne- 
diamine)cobaltic dichloride [Coen 2 Cl-NH 3 ]Cl 2 , was therefore in- 
vestigated by Werner (1911), who resolved it into its optically active 
components by the fractional crystallisation of the corresponding 
rf-a-bromocamphor-7r-sulphonate. Since that time many organic 
substances of this type, including the a&-dichlorodi(ethylene- 
diamine)cobaltic chloride, (n), shown above, have been obtained 
in optically active forms. 

Complexes containing three chelate groups, as for example, 



774 



OPTICALLY ACTIVE COMPOUNDS OF 



[Coen 8 ], also lack a plane or centre of symmetry and have been 
obtained in antimeric forms, indicated in Fig. 38. 





Fig. 38 

Chelation has also been observed in the case of compounds 
such as l:2:3-triaminopropane, which are capable of triple attach- 
ment to a single metallic atom (tridentate groups) ; di(l:2:3-iri- 
aminopropane)cobaltic trichloride , for example, has been prepared 
by Mann and Pope, and from ^'^-tnaminotriethylamine^ 
N(CH 2 -CH 2 -NH 2 ) 3 , dichlvro(ffifi f -triaminotriethylamine) platinic 
dichloride, [Cl 2 PtN(CH 2 .CH 2 .NH 2 ) 3 ]Cl 2 , which contains a quadri- 
dentate group, has been obtained. The first entirely inorganic 
substance to be isolated in optically active forms was (in, Fig. 39), 
in which each Co(NH 3 ) 4 (OH) 2 < plays the part of a chelate group ; 
the molecular rotation of this compound is exceptionally high, 
namely [M] 5600 about -47, 500. Later Mann (J. 1933, 414) resolved 
a much more simple rhodium compound (iv, Fig. 39), in which 
sulphamide, SO 2 (NH 2 ) 2 , is used as the chelate group : 



To (OH 1 1 

Co Co(NH s )4 Br e ,2 

L (OH J ,J 



Na 



III 



Fig. 39 



H 2 O 



y?" 
O, 



IV 



Co-ordination compounds of the following elements, Al, Cr, Fe, 
Co, Ru, Rh, Ir, Pt, Ni, As, have now been obtained in optically 
active forms, in all of which the co-ordination number is six. 

In a compound of an atom having a co-ordination number of 
four, either a square, or a tetrahedral spatial arrangement of the 



NITROGEN, TIN, SILICON, SULPHUR, ETC, 775 

co-ordinated group would appear to be probable, and in most cases 
of this kind the tetrahedral arrangement has been established by 
the resolution of suitable compounds. 

The more important of these substances are the metallic deriva- 
tives of j8-diketones. Metals displace one hydrogen atom from the 
enolic form of j3-diketones (p. 823), giving salts, and, in particular 
cases, the metal then co-ordinates with the remaining ketonic 
oxygen atom ; in this way there is produced a partially co-ordinated 
complex, (i, Fig. 40), which is that of a spirocyclic compound (p. 723), 
since the metallic atom is common to the two rings. Mills and Gotts 
(J. 1926, 3121) have resolved such a compound, namely, the beryllium 
derivative of benzoylpyruvic arid, (n), by the fractional crystallisation 




of its brucine salt. The existence of this substance in antimeric 
forms proves that thexarbonyl oxygen atom is united to the metal ; 
if this were not so dissymmetry would not occur. Similar spiro- 
cyclic compounds of boron, palladium and platinum have been 
resolved. 

The tetrahedral arrangement for 4-covalent, and the octahedral 
one for 6-covalent elements has been confirmed by the examination 
of crystal structures, but in the case of some 4-covalent elements, 
there is conclusive evidence of a planar arrangement. A compound 
MA 2 B 2> in which A 2 and B 2 all lie in one plane (whether co-planar 
with the metallic atom or not), will exist in cis- and ^raw-forms, 
and such isomerism has been observed in certain derivatives of 
4-covalent platinum, palladium, and nickel. The compound, 
Ptpy a Cl 2 (py = pyridine), for example, exists in two forms (as 
possibly does Pdpy 2 Cl 2 ), which have the same molecular weight ; 
furthermore the results of X-ray analysis indicate a square arrange- 
ment of numerous 4-covalent derivatives of bivalent Ni, Pd, Pt, Cu 
and Ag, and of tervalent Au, 

On* 49 



776 OPTICALLY ACTIVE COMPOUNDS OF NITROGEN, ETC. 

Sugden (J. 1932, 246) has obtained two isomeric compounds of 
nickel with benzylmethylglyoxime, 



O+N ^r-OH 

- 




-OH 



HO-NO 
Me-C C-Bz 



under conditions which appear to preclude any other explanation 
of their isomerism than that of different planar arrangements about 
the nickel atom. The compounds are diamagnetic, whereas a 
tetrahedral arrangement should give optical antimers, which would 
be paramagnetic. Similar derivatives of palladium have been 
prepared. 

Proof of the planar distribution of the valencies of 4-covalent 
platinum and palladium has been provided by Mills and his co- 
workers : mesodiphenylethylenediamine (1 mol.) and unsymmetrical 
dimethylethylenediamine (1 mol.) were combined in the complex 
shown, and this compound was then resolved : 



Ph 
Ph- 



U Tf 

u/^-^N. xN 1 *^^,. 

i X 

'Ht~~.rf* V-CM 

Hj H2 



If the valencies of the metal were directed towards the corners of 
a regular tetrahedron a resolution would be impossible, but with a 
planar arrangement the complex is dissymmetric. 



CHAPTER 48 
CYCLOPARAFFINS AND CYCLO-OLEFINES 

IT has been pointed out that benzene, and many other aromatic 
substances, can combine directly with hydrogen under suitable 
conditions (p. 406). The closed chain hydrocarbons which are 
formed from benzene and its derivatives in this way, and by many 
other methods, are classed as cycloparaffins when they are fully 
saturated, and as cyclo-olefines when they are unsaturated. Hexa- 
hydrobenzene, C 6 H 12 , for example, is called cyclohexane, whereas 
tetrahydrobenzene, C 6 H 10 , is called cyclohexene, and dihydrobenzene, 
C 6 H 8 , is cyclohex&diene. 

The terms cycloparaffm and ryc/o-olefine are also applied to 
corresponding compounds, the molecules of which contain closed 
chains of 3, 4, 5, 7, etc. carbon atoms. As already mentioned, it 
may be assumed that the carbon atoms of the simpler molecules lie 
in one plane, but as regards the higher members evidence to the 
contrary will be given later (p. 792). 

Cycloparaffins and their Derivatives 

The cycloparaffins are frequently referred to as the polymethylenes ; 
their nomenclature may be illustrated by the following examples : 

H, gi# 

CH, H.C-CH, H.C-C, / V 

^CH, Hji-CH, H,C / V / 

a, srs, 

CV/opropane Qyc/obutane Cyc/opentane Cyc/ohexane 

(Trimethylene) (Tctramethylene) (Pentamethylene) (Hexamethylene) 

Derivatives of the hydrocarbons are named in the ordinary way, 
the positions of the substituents being shown by numbering the 
carbon atoms as usual, and using these numbers in the name of the 
compound ; it is immaterial, of course, from which carbon atom 
the numbering starts, but as a rule it begins with one which is com- 
bined with some main substituent. 

Preparation. Many of the reactions which bring about the union 

777 



778 CYCLOPARAFFINS AND CYCLO-OLEFINES 

of carbon atoms of two different molecules, and result in the forma- 
tion of an open chain compound, may be applied to bring about the 
union of two carbon atoms of one and the same molecule, to give a 
cyclic compound, as is illustrated by many of the following methods 
of preparation : 

The lower cycloparaffins may be prepared by treating certain aoj- 
dihalogen derivatives l of the paraffins with zinc or with sodium 
(Freund), but other dibromides, such as CH 3 CHBr (CH 2 ) n CH 2 Br, 
may also be employed, 

/CH a Br /CH a 

CH a <^ +Zn(or2Na) CH a <^ | +ZnBr a (or 2NaBr). 

N CH a Br X CH a 

Cy/0propane is now manufactured by this reaction and is used 
as an anaesthetic. 

ffyrfrojcy-derivatives of the cycfoparaffins may be obtained by 
treating halogen derivatives of certain open chain ketones with 
magnesium, in the presence of ether ; S-acetylbutyl bromide, for 
example, gives a Grignard compound, which with a dilute acid 
affords 1-methylcyclopentan-l-ol, 

?' rw. B* 

\>-MgBt 




H 2 

Similarly the Grignard reagent from 1 :5-dibromopentane, with 
ethyl acetate, gives finally l-methylcyclohexanol* 



MgBr 

+ CHvCOOEt 





H, 

may be prepared by reducing certain open 



1 The letter w denotes a terminal position in any chain. 
1 When, as in this case, one substituent is not numbered, that particular 
group is in the 1 -position. 



CYCLOPARAFFINS AND CYCLO-OLEFINES 779 

chain diketones (Perkin and Kipping) ; this reaction is analogous 
to that which occurs in the formation of pinacol from acetone, 





2:8-Nonandione 1 :2-DimethyloK/oheptan-l:2-diol 

Xeto-derivatives may be prepared by heating the calcium (or other) 
salt of certain dicarboxylic acids, a reaction which corresponds with 
that employed in the preparation of ketones from monocarboxylic 
acids (Wislicenus) ; the calcium salt of adipic acid, for example, 
gives cydopentanone, 



CaCO. 



This method of formation is referred to in more detail later (p. 784). 

Adipic and pimelic anhydrides, on distillation, give carbon di- 
oxide and cyclic ketones (Blanc, cf. p. 1089). 

CVzr0#y-derivatives may be prepared by treating certain dihalides 
of the paraffins with the sodium derivative of diethyl malonate, 
ethyl acetoacetate, or cyanoacetate (Perkin), 



CH 8 Br 

+CH 2 (COOEt) 2 +2NaO-C a H 5 
2 Br 



V^ 1 *. A 2 J. 

CH 2 E 



2 v 

>C(COOEt) 2 +2NaBr+ 2C 2 H 8 OH. 
/ 



Diethyl o'c/opropane-l : 1-dicarboxylate 



Such reactions occur in various stages, but for the sake of brevity 
are summarised in the one equation ; the operations are carried out 
in much the same way as in the synthesis of open chain derivatives 
of ethyl acetoacetate and diethyl malonate. Another method is by 
treating certain dihalogen derivatives of the paraffins (1 mol.) with 
diethyl sodiomalonate (2 mol.), and then submitting the sodium 



780 CYCLOPARAFFINS AND CYCLO-OLEFINBS 

derivatives of the products to the action of bromine, iodine, or di- 
halides, such as methylene di-iodide or ethylene dibromide (Perkin) : 




+ 2 CH Na <COOEt), - 



Ha 
/-*^H 




g 
/^CN 



/ C 



H 2 C + Br a - H 2 C 

\- x -'CNa(COOEt)a V^* 1 

S 

Hi H 2 



Tetra-ethyl cyc/opentane- 
1 : 1 :2 :2-tetracarboxylate 



Carboxy-derivatives of ryc//V ketones may be prepared by treating 
the esters of certain dicarboxylic acids with sodium, 

H 2 




2 

y 9 

H 2 C T 

\ ^CH-COOEt 



This reaction is Dieckmann's modification of a Claisen condensa- 
tion (p. 827), and the sodium derivative of the enol is formed, as in 
the case of the preparation of ethyl acetoacetate ; the product, 
treated with a dilute acid, gives the keto-isomeride, ethyl cyclo- 
pentan-2-onecarboxylate. 

Similar condensations occur with other dicarboxylic esters and keto- 
esters and give usually a five- or a six-membered ring ; thus ethyl 
e-acetylhexoate gives 2-acetyl^fohexanone. 

Carboxy-derivatives of cyclic diketvnes (diones) may be prepared 
in a somewhat analogous manner, by condensing the esters of 
certain dicarboxylic acids with diethyl oxalate, with the aid of 
sodium or of sodium ethoxide (compare p. 929), 



CYCLOPARAFFINS AND CYCLO-OLEFINBS 781 

COOEt CHrCOOEt O( ,^CH.COOEt 

| + tH 2 * I H 2 

OOEt . OCS . COOEt 



Diethyl cycfopentan-l:2- 
dione-3:5-dicarboxy!ate 

This reaction corresponds with that which occurs in the prepara- 
tion of diethyl oxaloacetate and, like the preceding one, represents 
a Claisen condensation. 

Diketones are also obtained by the destructive distillation of the 
salts of dibasic acids (p, 784). 

Qyc/opropanecarboxylic acids may be prepared from pyrazoline 
derivatives, produced from aliphatic diazo-compounds and un- 
saturated esters (p. 1053), 

N--CH' COOEt 
EtOOOCHN 2 + CH 2 :CH COOEt -* l CH 2 ^ 



- COOEt 

CH- COOEt 
H 2 CCi + N 2 

rw ^CH* COOEt 

CH'COOEt N V 2 

CH 2 N 2 4-jJ -H CH-COOEf* 

tH-COOEt 



Qycfoparaffin rings may also be enlarged with the aid of these 
diazo-compounds . 

Derivatives of ryc/obutane are formed by the dimerisation of 
cinnamic acid and from ketene, etc. (pp. 718, 829) ; the Diels-Alder 
reaction is also an important method for obtaining 6-membered 
rings (p. 818). 

A method of great general importance for the preparation of 
cytf/ohexane and many of its derivatives is that of Sabatier and 
Senderens, already described (p. 405). Another method, particu- 
larly useful for the reduction of compounds which might be decom- 
posed by heat, such as certain terpene derivatives, consists in treating 
the unsaturated compound with hydrogen in the presence of col- 
loidal platinum or palladium. Under these conditions most cyclo- 
olefinic compounds unite with hydrogen rapidly at ordinary tempera- 
tures, and are transformed into the corresponding cycfoparaffin 
derivatives (p. 804). 

Properties of the Cycloparaffins. The rycfoparaffins and their 
derivatives usually boil at higher temperatures than the correspond- 



782 CYCLOPARAFFINS AND CYCLO-OLEFINES 

ing normal saturated open chain compounds, as shown in the 
following table : 

Oycfopentane, C 6 H 10 50 Pentane, C 5 H 12 37 

Cycfohexane, C 6 H 12 81 Hexane, C 6 H 14 71 

Cycfobutanol,C 4 H 7 .OH 123 Butyl alcohol, C 4 H 9 - OH 117 

Qycfopropanecarboxylic Butyric acid, 

acid, C 3 H 6 - COOH 183 C 3 H 7 - COOH 163 

In other physical properties, the two classes of compounds 
resemble one another rather closely ; the stereoisomerism of some 
ryc/oparaffin derivatives has already been discussed (p. 716). 

In certain chemical properties some of the ryc/oparaffins and 
their derivatives differ considerably from the corresponding open 
chain compounds, inasmuch as they form additive products, the 
closed chain undergoing fission. Cyclopropane, for example, is 
slowly attacked by bromine at ordinary temperatures, yielding tri- 
methylene dibromide (l:3-dibromopropane), but cyclobutane and 
the higher homologues are either unchanged or yield substitution 
products. Hydrogen bromide immediately converts cyc/opropane 
into propyl bromide, but does not attack the higher homologues. 
Cyc/opropane and cyclobutane are reduced by hydriodic acid, giving 
the corresponding paraffins, but the higher members are not attacked ; 
similarly cyclopropane is reduced by hydrogen in the presence of 
nickel more readily than is ryc/obutane, and again the larger rings 
are not attacked. 

These results (which may vary greatly with the temperature) 
and other facts show that the stability of the closed chains increases 
with the number of carbon atoms in the ring up to five, and then 
remains almost constant (p. 791). It is noteworthy, however, that 
the stability of a rycfoparafEn derivative depends not only on the 
size of the closed chain, but also on the positions of the substituents. 
Thus, whereas cyclopropane-lil-dicarboxylic add is very readily 
attacked by hydrobromic acid, giving fi-bromoethylmalonic add) 
CH 2 Br-CH 2 -CH(COOH) 2 , the isomeric l:2-dicarboxylic acid is 
not changed, even when it is heated with the halogen acid. 

In nearly all those reactions which do not involve a fission of the 
closed chain, the cycloparaffm derivatives behave like the corre- 
sponding open chain compounds. The cyclic akohols, for example, 
may be oxidised to ketones, and obtained from the latter by reduc- 
tion ; they may be converted into esters by the usual methods, and 



CYCLOPARAFFINS AND CYCLO-OLBFINES 783 

their halogen derivatives may form, and also react, with Grignard 
reagents. As a rule, however, halides cannot be converted into the 
corresponding cyanides, amines, etc., by the action of potassium 
cyanide, ammonia, etc. The cyclic ketones react with the usual 
ketonic reagents, and their oximes may be reduced to cyclic amines ; 
on oxidation, the closed chain of a ketone undergoes fission and an 
aliphatic dicarboxylic acid is formed. It is thus possible to pass 
from one of the higher cyclic ketones to the next lower homologue. 
Cycloheptanone, for example, is oxidised by potassium perman- 
ganate, giving pimelic acid, from the calcium salt of which cyclo- 
hexanone may be obtained. 

The ryc/oparaffin carboxylic acids are very similar to the aliphatic 
acids in their reactions, and give salts, esters, amides, etc., in a 
normal manner. They may be converted into their a-bromo-sub- 
stitution products, with the aid of bromine and red phosphorus, 
and from these compounds cyclic olefinic acids may be obtained ; 
all the dicarboxylic acids which contain the group > C(COOH) 2 
give monocarboxylic acids when they are heated alone or with water. 

In a few cases the direct conversion of a closed chain of n carbon 
atoms into one containing n 1 or w-f 1 carbon atoms has been observed; 
when, for example, benzene is reduced with hydriodic acid at 250, it 
yields methylcyclopentane, as well as tyr/ohexane, and under similar 
conditions wopropylidenecyc/obutane gives 1 rl-dimethylcycfopentane, 1 

M e, -> ry e 

k^/^Me 

Changes in the size of the ring also occur when certain alcohols are 
heated with oxalic acid or zinc chloride, as shown in the following 
examples : 



CHMea. 





1 These formulae are explained on p. 912. 



784 CYCLOPARAFFINS AND CYCLO-OLEFINBS 

Oxidation, combined with a pinacol-pinacolone transformation 
(p. 848), may produce similar changes : 










Me 



When cyclic amines, such as cycfobutylmethylamine, containing 
a CH 2 -NH 2 side chain, are treated with nitrous acid, they yield 
not only the corresponding alcohol, but also one containing another 
carbon atom in the ring (Demjanov), 

?' $ 

X \. H C*"* \ 

HA CH-CH 2 -NH 2 * 2 T CH-OH 



Large Ring Compounds 

Before 1926 no pure compound containing a single ring of more 
than eight carbon atoms was known ; since that date substances 
containing 30 or more carbon atoms in a single closed chain have 
been obtained and the following methods are available for their 
preparation : (1) Certain salts of aliphatic dicarboxylic acids are 
distilled in a vacuum ; the yield of cyclic ketone is often much 
better if, instead of the calcium salt, the thorium or yttrium salt, 
mixed with copper filings, is employed, but even then the yield may 
be less than 4% of the theoretical (Ruzicka and co-workers). 

Symmetrical cyclic diketones are often formed together with the 
monoketones ; distillation of the thorium salt of azelaic acid, (i), 
for example, yields not only cyclo-octewon*, (n), but also cyclo- 
hexadecan- 1 :9-dwne y (ill) , 

yCOOH / CH t\ / C \ 

[CHJ 7 <( [CHJ < >CO [CHJ 7 < >[CHJ, 

N COOH X CH,/ X CCK 

1 II HI 



CYCLOPARAFFINS AND CYCLO-OLBFINES 785 

(2) Greatly improved yields result when a dinitrile undergoes con- 
densation in very dilute solution in the presence of the alkali metal 
derivative, RaNK, of a secondary ainine, and the products are then 
hydrolysed (Ziegler and co-workers), 



/CN /C:NH /CO 

< > [CHJ/I * [CHJ/I 

X CH,-CN X CH-CN X CH, 



(3) oj-Iodo-derivatives of j8-ketonic esters are treated with 
potassium methoxide in methylethyl ketone (Hunsdiecker) ; ethyl 
2-keto-16-iodohexadecanecarboxylate thus yields finally cyclo- 
hexadecanone 

/CO /CO 

I[CH,] 14 .CO.CH a .COOEt [CH,] 14 < | * [CH 2 ] 14 t( | 

x CH-COOEt x CH a 

(4) A very dilute ethereal solution of the dichloride of a dibasic 
acid is slowly added to a gently boiling solution of triethylamine in 
ether : complex reactions occur in which cyclic ketones and di- 
ketones (and other products) are formed. Thus the dichloride of 
suberic acid gives cycloheptanone and cyc\otetradecan-l:8-dione 
(Blomquist) : 

/COC1 / CH \ / CO V 

[CH 8 ]/ [CH 2 ]/ >CO + [CH.K >[CH 2 ] 6 

X COC1 ^CH/ ^CO' 

(5) Esters of the higher dibasic acids are treated with sodium in 
an inert solvent (xylene) in the complete absence of oxygen, and 
the resulting sodium compounds decomposed with water ; cyclic 
a-hydroxyketones (acyloins) are thus formed : 

/COOMe /C-ONa 

[CH,],/ +4Na - [CH 8 ](|| +2NaOMe, 



/C-ONa /CO 

[CH,] n < || +2H.O - [CH 8 ] n < | +2NaOH. 

\rw.ryH 



This method does not require the high dilution of some of the 
other methods and the yields may be as high as 96% (Stoll and 
Prelog). 

Thedicarboxylicacidsordinitriles used in this workmaybeprepared 



786 CYCLOPARAFFINS AND CYCLO-OLEFINES 

as follows : Esters of the higher dicarboxylic acids, [CH 2 ] n (COOH) 2 , 
are reduced with the aid of sodium and alcohol, giving dihydroxy- 
compounds, which are then converted into acids, [CH 2 ] n ., 2 (COOH) 2 
and [CH 2 ] W + 4 (COOH) 2 , by the usual reactions for passing up a 
homologous series : 

/COOEt yCH a -OH 

[CHJ n < ~ + [CH 2 ] n < H> 

X COOEt X CH a -OH 

CH a Br xCH a .CN /CH a -COOH 

X 



/ a r x a . / 

<; [CH 2 ] n <( - * [CH a ] n <( 

X CH a Br X CH a -CN X CH 2 -COOH 



/CH a .CH(COOEt) a y CH 2 .CH a <COOH 

[CHJ n < * [CH 2 ] n <( 

X CH 2 - CH(COOEt) 2 X CH 2 CH a COOH 

The dibromides (above) may also be converted into the (di) Grignard 
compounds, which react with chlorodimethyl ether, C1CH 2 OMe, 
giving ethers ; these products are decomposed with hydrobromic 
acid and the operations are repeated : 

[CHJ n (CH 2 <MgBr) a --> [CH a ] n (CH 2 .CH 2 .OMe) 2 -> [CH 8 J n (CH a .CH a Br) a 

The dibromides are finally converted into acids as above. 

The co-iodo-derivatives required for method (3) are prepared as 
follows : The dimethyl ester of a dibasic acid is carefully hydrolysed 
to the monomethyl ester, the silver salt of which is treated with 
bromine in carbon tetrachloride solution, 

MeOOC-[CH a ] n -COOAg+Br a - MeOOC-[CH a ] n -Br+CO a +AgBr. 

The resulting w-bromo-ester is converted into the acid chloride by 
the ordinary methods, and the latter treated with ethyl sodio- 
acetoacetate in ether: the product, hydrolysed with sodium 
methoxide, gives an co-bromoketonic ester which is transformed into 
the iodo-compound in the usual way, 

Br.[CH a VCO'Cl * Br.[CH a ] n .CO.CH(CO.CH 8 )-COOEt 
Br (CH a ) n - CO - CH a - COOEt 

The cyclic monoketones obtained by such methods range from 
gtf/b-octanone, C 8 H M O, up to about cydononacosanone, C 29 H 56 O. 
Those containing 10, 11, and 12 carbon atoms have an odour of 
camphor, that with 13, a faint smell of cedar wood, which increases 



CYCLOPARAFFINS AND CYCLO-OLBFINES 787 

with the size of the ring up to 18 atoms ; when the vapour is more 
dilute, however, the substances containing 14, and especially 15 
carbon atoms smell of musk, while those with 16, 17, and 18 
carbon atoms respectively smell of civet. Cydopentadecanone, 
CisHagO, is manufactured under the name Exaltone, as a substitute 
for musk (below). 

The rings containing more than 7 carbon atoms are as stable as 
those containing only 5 or 6 ; thus no change occurs when the ketones 
containing from 7 to 18 carbon atoms are heated with concentrated 
hydrochloric acid at 180-200, or when the ketone, C 17 H 32 O, is 
passed over thoria heated at 400-420 ; further, the cyclic hydro- 
carbons, C 15 H 30 and C 17 H 34 , are unchanged by concentrated 
hydriodic acid at 250. 

The ketones, diketones, etc., show the usual chemical properties 
of such cjycfoparaffin derivatives : in addition, when cyclic ketones 
containing from 8 to 30 atoms in the ring are shaken for some days 
with nitromalonodialdehyde in aqueous-alcoholic solution con- 
taining sodium hydroxide, a very interesting reaction gives />-nitro- 
phenols bridged in the w-position. 

OHC 

+ CH'NOa - 

CH 2 OHC 

Compounds containing large rings in which some of the links are 
NH < groups have also been described. 

Until 1926 no monocyclic compound containing a ring of more 
than 6 carbon atoms had been found in nature ; muscone, or 
muskone, C^H^O, however, which occurs in vegetable musk, is now 
known to be l-3-methylexaltone, (iv), and civetone, C^H^O, a 
perfume obtained from civet, has been shown to be a cyclo-olefimc 
ketone, (v), 

CH 2 CH 2 - CHMe CH 2 CH [CH 2 ] 7V 

I [ II >co 

[CH 2 ] 10 CO CH-[CH 2 ]/ 

rsr v 

On reduction civetone yields cycloheptadecanone, and on oxidation 
it gives azelaic acid as one of the products ; its constitution, thus 
established, has been confirmed by synthesis 





788 CYCLOPARAFFINS AND CYCLO-OLEFINES 

Cyclo-olefines 

The cyc/o-olefines are related to the ryr/oparaffins just as the 
defines are related to the paraffins. They may be prepared from 
ketones and alcohols of the ry^/oparaffin series by reactions corres- 
ponding with those used in the formation of olefines from open 
chain compounds ; either of the following series of changes, for 
example, may be brought about by the usual methods : 



-CH 2 

jt -CHBI 

-%*2 ""^"Z I ** -p vt ?" 

-CO -CHOH v ^ -CH "* -CBr ~* -C 

Ni -rw COOH COOH 6 



-CHBr 

-CH 



Derivatives of cyclohexene may also be prepared from certain types 
of aromatic compounds which are first reduced to the corresponding 
cy/ohexane derivatives ; the latter may then be transformed into 
cyclo-oleinic compounds as above, 

C 6 H 6 - OH > C 6 H n OH > C.H u Br * C 6 H 10 , 

C 6 H 5 - COOH > C fl H n - COOH > C 6 H 10 Br COOH C 6 H 8 COOH. 

The cyc/o-olefines, like ethylene, readily form additive products 
with bromine, hydrogen bromide, ozone, etc., and unlike the cyclo- 
paraffins, they are very easily oxidised to acids, the closed chain 
undergoing fission. The more important ryc/o-olefine derivatives 
are those of ryc/ohexene, which are described later (p. 798) ; in 
addition the following are of interest. 

Qyc/obutene, a gas, may be obtained from ryc/obutanecarboxylic 
acid, the amide of which, treated with bromine arid alkali (Hof- 
mann's reaction), gives rydMbutylamine ; when this compound is 
exhaustively methylated (p. 597) and the quaternary hydroxide is 
heated, rycfobutene is formed, 





NMe 8 OH H 2 C^ yH 4- NMe, + H a O 
H a 

Oyrfobutene is reduced by hydrogen in the presence of nickel, 
giving cyclobutane, b.p. 11-12. 



CYCLOPARAFFINS AND CYCLO-OLEFINBS 789 

Cyc/opentadiene, (i), is an interesting cyclic diolefine which 
occurs in coal-tar ; it boils at 41 and is extremely unstable, readily 
undergoing polymerisation at ordinary temperatures (p. 819). It 
reacts with aldehydes and ketones, in the presence of sodium 
ethoxide giving condensation products, which are derived from the 
unknown methylene derivative (>C=CH 2 ), and are termed 
fulvenes ; dimethylfulvene, (n), for example, is an orange-coloured 
liquid (b.p. 46), whereas diphenylfulvene is a deep-red crystalline 
compound (m.p. 82). The fulvenes are conjugated compounds 

H H 



H H 

(p. 813), and, like the polyenes (p. 980), are examples of coloured 
hydrocarbons. Cydbpentadiene in benzene solution gives a potass- 
ium derivative, C 5 H 6 K (p. 695h) and interesting compounds with 
other metals (p. 695q) also exist. 

Qyf/o-octatraene is described later (p. 1001). 

The Strain Theory 

In order to account for the graded stability of the trycfoparaffins 
and their derivatives known in his time, Baeyer (1885) proposed a 
strain theory y which was based on the arrangement in space of the 
four valencies of the carbon atom. The (normal) angle between 
any two such valencies is 109 28' ; when, therefore, a carbon atom 
forms part of a planar saturated closed chain, the directions of two 
of its valencies must be deflected, causing, presumably, a strain in 
the molecule, as can be demonstrated with the aid of the usual 
models. In that of cj^foethane (ethylene), which may be regarded 
as the simplest closed chain, each of the two bonds must be deflected 
through an angle of 109 28'/2, in order to bring them parallel with 
one another. In the model of cyclopropane, the bonds would form 
an equilateral triangle, and the deflection of each would be 109 28'- 
60/2. Similarly, in the cases of the models erf closed chains com- 
posed of 4, 5, 6, etc. atoms, certain deflections of the bonds would 
occur. These angular deflections, which Baeyer regarded as 
measures of the strains set up in the molecules, are tabulated on the 
next page, the minus values indicating that the bonda are bent 
outwards instead of inwards ; 



790 CYCLOPARAFFINS AND CYCLO-OLEFINES 

Qycfoethane (ethylene) 54 44' (109 28'/2) 
Cyclopropane 24 44' (109 28'-60/2) 
Cydbbutane 9 44' (109 28'-90/2) 
Cjycfopentane 44' (109 28'-108/2) 
Qydbhexane -5 16' (109 28'-120/2) 
Qyc/oheptane -9 33' (109 28'-128 34'/2) 
Cy^fo-octane -12 51' (109 28'-135/2) 

It is evident from the above values that the deflection is greatest 
in ryc/oethane ; this molecule, therefore, should be the least stable, 
since ring-formation is accompanied by the greatest strain. In 
accordance with this view, the ryc/oethane ring (the ethylenic bond) 
is readily broken as, for example, when ethylene combines with 
bromine or with hydrogen bromide. From the other deflections 
(strains) given in the table, it would also be inferred that the relative 
stabilities of the rycfoparaffins gradually increase up to ^fopentane, 
and then decrease again. 

The great difference in behaviour between a-, /?-, y-, 8-, etc. 
hydroxy-acids, as regards the readiness with which they form 
lactones, and of dicarboxylic acids, as regards the readiness with 
which they form inner anhydrides, is also accounted for by the strain 
theory ; in molecules, such as those of y-valerolactone and succinic 
anhydride, which are very readily formed, there is presumably a 
smaller strain than in those which contain similar smaller closed 
chains. The facility with which various types of closed chains are 
produced from certain o- and peri- derivatives, but not usually from 
m- or ^-compounds, is also accounted for in a similar manner ; and 
in general, the strain theory may also be applied to heterocyclic rings, 
provided that the valencies of the oxygen, nitrogen, or other atom, 
which form links in the closed chain, are normally directed at an 
angle of about 109, as in the case of carbon. 

The most definite information regarding the relative stabilities 
of analogous molecules is afforded by their heats of combustion 
(p. 706), and the data given in the following table agree on the whole 
with Baeyer's theory ; as the strain diminishes the heat of com- 
bustion calculated for each >CH 2 group becomes smaller up to 
rydbpentane, but does not increase again, as was to be expected, 
and cycfoheptane, which ought to have the same heat of combustion 
as ryvfobutane, k as> * m f act> a sma il er one . 



CYCLOPARAFFINS AND CYCLO-OLEFINES 791 

Number of atoms 
in ring 234567 8 

Heat of combus- 
tion per CH 2 
group (Cal.) 170 168 165 158-7 157-4 158-3 158-6 

Angle of valency 

deflection 54 44' 24 44' 9 44' 44' -5 16' -9 33' -12 51' 

The Theory of Strainless Ring Structures 

Although Baeyer's strain theory thus seemed to correlate and 
account for many facts, it was not, as just shown, altogether satis- 
factory, and, as time went on, it became untenable in its original 
form. The work of Ruzicka, for example, had shown that even 
closed chains of 32 carbon atoms can be obtained, and are remarkably 
stable (p. 787), whereas, according to the strain theory, they should 
be highly unstable. 

Now it had been suggested by Sachse in 1890 (before the existence 
of such compounds was known) that if, in the case of those rings 
from ryc/ohexane upwards (where there is an outward deflection), 
it is assumed that the carbon atoms may take up a multiplanar 
arrangement, all strain might be avoided ; cyclic molecules contain- 
ing 6, 7, 8, 9 and more carbon atoms might then be as stable as 
ryc/opentane. This suggestion of the existence of strainless systems 
led to the further assumption that the strainless molecules might 
exist in two or more stereoisomeric forms. Cyc/ohexane, for 
example, might have either of the forms shown (Fig. 41, p. 792), 
known respectively as the chair and boat forms ; and similarly in 
the cases of the higher cyc/oparaffins, two (or more) strainless 
arrangements might be possible. 

When models of the two forms of ryc/ohexane are constructed it 
will be found, however, as pointed out by Mohr, that they can be 
converted into one another, without breaking any bonds, by very 
gentle pressure, suitably applied. These two stereoisomeric forms 
differ in configuration in a special way. Stereoisomeric substances 
such as d- and /-lactic acids, maleic and fumaric acids, glucose and 
mannose, rf-a-glucose and rf-j8-glucose, etc. also differ respectively in 
configuration, but cannot be interconverted merely by twisting or 
rotating single bonds or by alteration of valency angles as in the 
case of the forms of rycfohexane : stereoisomerides which can be 
so interconverted are said to differ in conformation. Conformational 
isomerides are usually so readily interconvertible that their isolation 
is impossible, but nevertheless important consequences follow from 

Org. 50 



792 CYCLOPARAFFINS AND CYCLO-OLEFINES 

their study : the d- and /-forms of those substances which owe 
their optical activity to restricted rotation about a single bond are 
examples of stable compounds which differ in conformation. 





Chair Boat (Bed) 

Cyclohexane 

Fig. 41 

In the diagrams (Fig, 41) the carbon atoms are, for clarity, drawn 
too far apart and if a scale model of the boat (bed) form is con- 
structed it will be found that the hydrogen atoms (not shown in the 
Fig.) attached to the valencies in the l:4-position within the boat 
so to speak (x, x, Fig. 41) are very close together : it is now thought 
that rysfohexane and its derivatives exist almost entirely in the 
chair form to avoid this crowding, which, of course, would be worse 
with larger atoms than hydrogen attached at x. There is experi- 
mental evidence for this view from X-ray data, electron diffraction 
spectra and dipole moments of ryc/ohexane and its derivatives. 

Further examination of the chair form shows that three of the 
carbon atoms (1:3:5) lie in one plane and three (2:4:6) in another 
very near (and parallel to) the first. The hydrogen atoms lie in three 
groups : three at a l above the mean plane of the carbon atoms, six 
at e nearly in this plane and three at a 2 below it. Those at a l and 
a 2 are known as axial (attached by axial bonds) and those at e as 
equatorial (attached by equatorial bonds) : the term polar has been 
used instead of axial, but to avoid confusion with the electrochemical 
use, the term is no longer employed. 

A substituent in cycfohexane may occupy either an axial or an 
equatorial position and this often has an important bearing on its 
chemical reactions, as, for example, the ease of dehydration of a 
cyclic alcohol. Furthermore in a cw-l:2-disubstituted cyi/ohexane 



CYCLOPARAFFINS AND CYCLO-OLEFINES 793 

one substituent must be axial and one equatorial, whereas in the 
trans-form both must be either axial or equatorial, and the latter is 
usually the preferred arrangement as the substituents then have more 
room. It is to be noted that none of the above considerations affect 
the number of possible stable position or stereoisomerides of cyclo- 
hexane derivatives, or the existence or otherwise of optical activity 
in these compounds as previously discussed (Chapter 45). For 
such purposes the ring may still be regarded as planar, as it is 
sufficiently flexible for any one chair form to change into another : 
when such a change occurs it will be found that the axial bonds 
become equatorial and vice versa. The geometrical considerations 
just described have also been applied to heterocyclic compounds, 
Mich as the pyranose sugars. 

Now when two such strainless rings are condensed together, as in 
decahydronaphthalene, two stable stereoisomerides should exist. 
The one might be regarded as having been formed by a as- addition, 
the other by a /raws-addition, of hydrogen to the carbon atoms 
common to the two rings of naphthalene ; further, in both com- 
pounds the two rings are so interlocked that the stereoisomerides 
cannot be converted one into the other, except by a fission of one 
of the closed chains. 

Figures of the models of the strainless cis- and /raws-forms of 
decahydronaphthalene (decalane) are given below : 




os-Decalane 
Fig. 42 

It is to be noted that in both forms of decalane both 
systems are chair forms. In toww-decalane the rings are joined 
entirely by equatorial bonds leaving the axial bonds of the two 
carbon atoms common to the two rings to carry the trans-hydrogen 



794 CYCLOPARAFFINS AND CYCLO-OLEFINES 

atoms (the only two shown in the figure) : it is also clear that 
frawj-decalane is a very flat molecule in which there are roughly 
three planes of atoms : 

(a) axial hydrogen atoms at 2:4:5:7:9, 

(b) all the carbon atoms and the equatorial hydrogen atoms, 

(c) axial hydrogen atoms at 1:3:6:8:10. 

In cw-decalane union of the two rings is accomplished by one 
axial and one equatorial bond in each case : with reference to ring A 
bond b is equatorial and c axial, while for ring B bond d is equatorial 
and f axial. It is also seen that os-decalane is not a flat molecule 
as is the trans-form. Mohr, who first pointed out that the rings 
would be locked in the dicyclic systems (1918) assumed that cis- 
decalane was made up of two boat forms of rycfohexane and it was 
Bastiansen and Hassel (1946) who suggested the above modification 
of the theory. 

Experimental evidence of the existence of such cis- and trans- 
forms of a dicyclic structure had already been afforded by Baeyer, 
who had found that both cis- and *raw$-hexahydrophthalic acids 
gave anhydrides. The behaviour of the trans-acid, however, was 
regarded as abnormal, because the ryc/ohexane ring was then 
assumed to be planar, and anhydride formation would involve con- 
siderable strain. If, however, the ring is in the chair form the two 
carboxyl groups are equidistant from one another in the cis- and 
trans-acids, and anhydride formation can occur with both. 

Further evidence of a similar kind was provided by Windaus, 
Hiickel, and Reverey (Ber. 1923, 91), who found that both the 
cis- and the trans-isomerides of 2-carboxycyclohexylacetic acid, 
HOOC-C 6 H 10 -CH 2 -COOH (hexahydrohomophthalic acid), gave 
its own anhydride ; here again, if the cy<rfohexane ring is planar, 
the two carboxyl groups in the trans-acid are widely apart, but in 
the chair form the two carboxyl radicals are brought into such 
positions that both acids can form anhydrides. 

The existence of stable cis- and /raws-forms of a dicyclic structure 
was fully established by the results of Huckel's work on decalane 
and its derivatives. It had been found that fi-decalol, C 10 H 17 OH, 
prepared by reducing j3-naphthol, existed in stereoisomeric forms, 
but this, of course, was to be expected. In a dicyclic structure, 
such as that of decalane, it was assumed that the two rings were 
inclined to one another at an angle of 109 28', and the hydroxyl 
grtmp in decalol might therefore be situated either within or without 



CYCLOPARAFFINS AND CYCLO-OLEFINES 



795 



this angle, as indicated in Fig. 43 (in which the symbols for the two 
hydrogen atoms of the >-CH groups are omitted) : 




Decalol 



Decalol 



But the isomeric decalols gave different ketones (decalones) on oxida- 
tion, whereas, had they been merely cis- and trans-forms which were 
related as indicated above, they must have been converted into one 
and the same decalone, when the H C OH and HO C H 
groups were converted into >C=O. The existence of the two 
decalones, therefore, proved the existence of two decalanes, which 
can differ in configuration only ; moreover, one of the decalones 
must be derived from the cis- and the other from the fraws-decalane. 
In accordance with this view, one of the decalones, on oxidation, 
gave the ay-, and the other the trans-form of 2-carboxycydohexyl- 
propionic acid, HOOC - C 6 H ]0 CH 2 CH 2 - COOH. These results are 
summarised below, and they are all readily accounted for by the 
theory described above : 



oy-Decalane 



oy-j8-Decalone 



(cis (m)-jS-Decalol 
cis (*ra;w- 



/nww-Decalane &ww-/J-Decalone 



/ trans (2ra/w)-/?-Decalol 
I trans (o$)-j8-Decalol 



It will thus be seen that four decalols should be obtainable, and 
since each of these is a ^/-compound, eight optically isomeric forms 
of j3-decalol should be capable of existence. These optical isomerides 

S ! 



Xwv. WjX^V. ^ 
^/'jjc ^/"*XT f 

$Jk 

H, " H 




0-Dec*lol 



[:- U* 

From w-/3-Decalone From trans-fl-'Decalonc 



796 CYCLOPARAFFINS AND CYCLO-OLEFINBS 

may be indicated as on p. 795, the configurations of the groups 
attached to the carbon atoms marked by asterisks being distinguished 
by the positive and negative signs. 

The four rf/-forms have been obtained, and also the four corre- 
sponding dl-p-decalylamines (reduction products of j8-naphthylamine); 
analogous isomerides have also been prepared from a-naphthol. 
Further, it has been shown that cts- and trans-forms of hydrindane 
and of 0,3,3-rf/ry/o-octane (cf. p. 820) are capable of existence. 



Configurations of Open Chain Compounds 

If one of the methyl groups of ethane is rotated relative to the 
other an infinite number of different conformations are possible : 
there is, however, only one compound C 2 H 6 and this can be explained 
by assuming either that rotation is perfectly free or that the molecule 
exists in one stable position, which will be that having the least 
energy of all possible forms produced by rotation. The hydrogen 
atoms of one methyl group may, for example, start directly over 
those of the other (eclipsed position) and gradually rotate until the 
bonds joining carbon to hydrogen in one methyl group bisect the 
angle between similar bonds in the other group (staggered position). 
All other positions lie between these two extremes. It is now believed 
that mutual repulsion of the C H bonds causes the staggered 
position to be preferred. In ethylene dichloride it has been shown 
by infra-red and Raman spectral measurements that the anti- 
(staggered) form in which the chlorine atoms are as far apart as 
possible is the most stable : it should be pointed out that the 
energy differences between forms of this sort are too small (1-2 Cal. 
per mole) to allow any hope of separating such isomerides. 

The heat of combustion per CH 2 group of cycfohexane is less than 
that of ryc/opentane (p. 791) which indicates a greater strain in 
the latter hydrocarbon. This is possibly explained when it is 
realised that in the chair form of rydohexane all C H bonds are 
staggered (and indeed cyc/ohexane is the only rycfoparaffin in which 
this can be so) whereas if rycfopentane is planar all C H bonds 
are eclipsed. Thermal and spectral data suggest that cyclo- 
pentane is not planar, and therefore Gtrained, presumably in order 
to avoid the eclipsed positions of the hydrogen atoms. The 
larger heat of combustion of rydbheptane, as compared with cyck- 
hexane, is probably due to similar causes. 



CYCLOPARAFFINS AND CYCLO-OLEFINES 797 

Reduction Products of Aromatic Compounds 
Cyclohexane and its Derivatives 

ne, <ry<:fohexene, ^fohexadiene, and their derivatives 
may all be regarded as reduction products of aromatic substances 
and classed as hydroaromatic compounds. Cyc/ohexane and some 
of its homologues occur in large proportions in Caucasian petroleum, 
and are sometimes known as naphthenes. 

Cyclohexane, C 6 H 12 (hexahydrobenzene, hexamethylene), was first 
obtained by Berthelot in an impure state by the reduction of benzene 
with hydriodic acid and red phosphorus ; at the high temperature 
which is required, the closed chain of six atoms undergoes an 
isomeric change, to a certain extent, and some methylcyclopentane 
is also formed. It was not until 1893 that the pure hydrocarbon 
was prepared by Baeyer (p, 798) ; later, it was obtained by Perkin 
by the action of sodium on hexamethylene dibromide (l:6-dibromo- 
hexane), and it is now easily prepared commercially by the reduction 
of benzene with nickel and hydrogen. 

Qyc/ohexane boils at 83-84 and is very stable : it is not attacked 
by potassium permanganate solution, or by bromine at ordinary 
temperatures, but it is oxidised by hot nitric acid, giving adipic acid. 

The stereoisomerism of hexachlorocyc/ohexane, CjE^Clg, has 
already been described (p. 720) ; the a-isomeride has been shown 
to be capable of optical activity by treating it with half the amount 
of brucine required to convert it completely into trichlorobenzene. 
The base reacts more rapidly with the d-form and the unattacked 
hexachloride is laevorotatory. This is an interesting example of how 
different rates of reaction may be used to show optical activity. 

Cyc/ohexanol, C 6 H U -OH, is now prepared on a large scale by 
the reduction of phenol with hydrogen and nickel at about 170. 
It boils at 161 (m.p. 15), does not react with sodium hydroxide, 
and with hydrobromic acid gives cyclohexyl bromide, C 6 H 11 Br. On 
oxidation it first gives cyclohexanone and then adipic acid* The 
Grignard reagents obtained from the cyclohexyl halides are used 
for the preparation of many cyclohexyl derivatives. 

Cycfohexan-l:4-diol, C 6 H 10 (OH) 2 (quinitol), may be obtained 
by reducing quinol with hydrogen and nickel, and was first prepared 
from cyc/ohexandione (p. 798) ; it exists in cis- and trans-forms, 
melting at 102 and 139 respectively, both of which are oxidised 
by chromic acid, giving benzoquinone. 



798 CYCLOPARAFFINS AND CYCLO-OLEFINES 

Cycfohexanpentol, C 6 H 7 (OH) 6 , is an interesting compound 
which occurs in nature. A dextrorotatory form, quercitol, (m.p. 
235), is found in acorns, and a laevorotatory isomeride (m.p. 174) 
in the leaves of Gymnema sylvestre, but obviously the two stereo- 
isomeric alcohols are not enantiomorphously related. 

Qyc/ohexanhexol, C 6 H 6 (OH) 6 (inositol), exists theoretically in 
eight stereoisomeric forms (p. 719), one of which is a ^/-substance. 
The d-compound occurs in the sap of certain pine trees in the form 
of its monomethyl ether, and an /-ether is found in quebracho bark ; 
mesoinositol (fourth configuration, p. 720) occurs in human muscle, 
in various plants, and sometimes in the urine, and another non- 
resolvable inositol is present in certain fish and plants. 

Cy/ohexanecarboxylic acid, C 6 H 1X -COOH (hexahydrobenzoic 
acid), may be obtained by reducing benzoic acid with sodium 
amalgam and water ; it melts at 31, and its bromide C 6 H 11 COBr, 
gives an a-bromo-substitution product, C 6 H 10 Br COBr. 

Cydohexene, Cydohexadienes, and their Derivatives 

Many important reduction products of benzene were obtained 
synthetically by Baeyer from diethyl succinate. When this ester 
(2 mol.) is heated with sodium it gives diethyl sticcinylosuccinate 
(1 mol.) and sodium ethoxide, as the result of a Claisen condensation. 
Diethyl succinylosuccinate or diethyl l'A-cydohexandione-2:5-dicarb- 
oxylate, (i), affords on hydrolysis a j3-ketonic acid, which, like 
acetoacetic acid, readily loses carbon dioxide, giving l:4-cyclo- 
hexandione, (n) ; this diketone may be reduced with sodium amalgam 
and water, and is thus converted into l:4-cyc/ohexandiol (quinitol), 
On), 



EtOOC 








III 



When quinitol is heated with hydriodic acid it gives a di-iodide, 
which is reduced by zinc-dust and acetic acid to cye/ohexane. With 
cold hydriodic acid it gives an iodohydroxy-compound, which can 



CYCLOPARAFFINS AND CYCLO-OLEFINBS 799 

be reduced to cy^fohexanol ; if this alcohol is converted into cyclo- 
hexyl bromide, and the product heated with quinoline, cydohexene 
or tetrahydrobenzene is formed, whereas l'A-dibromocydohexane y 
prepared directly from quinitol and treated in a similar manner, 
gives a mixture of two structurally isomeric cydohexadienes (di- 
hydrobenzenes). The following four compounds were thus syn- 
thesised from diethyl succinate : 

g* H H H 

H 2 C X 



^ X 
H 2 H a H H 

Cyc/ohexane Cyctohexene A-l:3- and A-l:4-Cyc/ohexadicnc8 

Cycfohexene, C e H 10 , usually obtained by treating cyc/ohexanol 
with sulphuric acid, boils at 83-84 ; it combines directly with 
bromine, with nitrosyl chloride (p. 914), and with ozone, and is 
readily oxidised, giving adipic acid. Its ozonide (m.p. 75) is 
decomposed by water giving adipic acid and adipic aldehyde. 

A-l:3- and A-l:4-Qyc/ohexadienes, C 6 H 8 , have practically the 
same boiling-point (81-82), and both readily undergo polymerisa-^ 
tion ; they differ, however, in their behaviour towards bromine, 
inasmuch as the A-l:3-isomeride (a conjugated compound, p. 815) 
is mainly converted into a 1 :4-dibromide (l:4-rf$row0-A-2-cyclo- 
hexene), whereas the A-l:4-cyclic di-olefine gives a saturated tetra- 
bromide (tetrabromocydohexane). 

All these reduction products of benzene differ fundamentally from 
the parent hydrocarbon, and do not show the characteristic reactions 
of aromatic compounds towards halogens, nitric acid, and sulphuric 
acid. 

Many derivatives of cyc/ohexene and ryc/ohexadiene may be 
obtained from open chain aliphatic compounds. When ethyl 
acetoacetate, diethyl acetonedicarboxylate, or similar j3-ketonic 
compounds are treated with aldehydes, or di-iodides, RCHI 2 , in 
the presence of diethylamine or piperidine, derivatives of 1:5- 
diketones are formed (Knoevenagel). These compounds, (i, X 
COOEt, when ethyl acetoacetate is used), readily undergo inner 
condensation with the loss of the elements of water, yielding deriva- 
tives of cycfohexene, (n) ; the latter, treated with dilute acids, 



800 CYCLOPARAFFINS AND CYCLO-OLEFINES 

undergo hydrolysis and then lose carbon dioxide (2 mol,). 1 The 
product, (in), obtained in this way from acetaldehyde (R * CH 3 ) 
and ethyl acetoacetate is 2:4-dimethyl-&-l-cyc\ohexen~6-one y or, if 
in the enolic form, 2 t A-dimethyl-&-l:5-cyclohexadien-6-ol, that is to 
say it may be regarded either as a keto-derivative of ryc/ohexene 
or as a hydroxy-derivative of ryc/ohexadiene, and its properties 
accord with these structures. 



X 



K*I***U v*v/ Jiv*Jrlvx \*\J R**iv wO R*HC 

CH 3 X'HC xH H 2 C 



HaC 



CH 3 ~* X-HC ~* ~ "* - - 



CH, CH 8 CH 8 CH 3 

I II HI 

Diketo-derivatives of cyc/ohexane may be obtained by the con- 
densation of diethyl sodiomalonate or of ethyl sodioacetoacetate 
with aj8-unsaturated ketones, such as mesityl oxide, or analogous 
esters (Vorlander), an application of the Michael reaction (p. 807) ; 
when the product, (iv), is hydrolysed, the resulting j3-ketonic acid 
loses carbon dioxide, giving a cyclic diketone, (v), which in 
the dienolic form is l:l-dtmethyl-&-3:5-cyclohexadien-3:5-diol or 
5:5-dtmethyl'dihydroresorcmol, (vi) : 

COOEt COOEt 

CHa 
Me 2 C XOOEt Me 2 C 



COOEt 
Me T 

.-Pv i 

y- v 




IV V VI 

1 One of the carboxyl groups in the hydrolysis product is /9 to a carbonyl 
radical and the other part of a group CO-CH:CR-CHR'-COOH ; both 
such groups readily lose carbon dioxide. 



CYCLOPARAFFINS AND CYCLO-OLEFINES 



801 



In a similar manner the condensation of ethyl sodioacetoacetate with 
ethyl crotonate finally leads to the synthesis of a methykydohexan- 
dtone, which, in the enolic form, is 5-methyldihydroresorcinol : 



Me-H 



COOEt 



CH 8 
Et 



Mc- 



( C 
XOO 



HC 

T 



COOEt 

.A, 



COOEt 



CH 

CO MeHCT CO Me-HC 
T - T I -* I 

^ CH $ H 2 C.^CHa H 2 

COOEt CO 



CO 

I 



Cydohexene- and Cydohexadiene-dicarboxylic Acids 
Reduction of the Phthalic Acids 

The reduction products of phthalic, wophthalic, and terephthalic 
acids formed the subject of a long investigation by Baeyer, who 
obtained the di-, tetra-, and hexa-hydro-derivatives of all the three 
isomerides ; his results may be illustrated by a short summary of 
those obtained in the case of terephthalic acid, the reduction products 
of which are represented by the following seven structural formulae : 



COOK 






COOH 



COOH 




A-l:5-acid A-l:4-acid 

Dihydro-acids 



A-l:3-acid 




COOH 



COOH 




COOH 

A-l-acid A -2 -acids 

Tetrahydro-acids 




Hexahydro-acids 



Of the above the A-2:5-dihydro-, the A-2-tetrahydro-, and the 
hexahydro-acid exist in cis- and trans-forms (p. 716) and some of 
them are ^/-compounds. 

When terephthalic acid in alkaline, neutral, or acid solution is 
reduced with sodium amalgam at various temperatures, it yields 



802 



CYCLOPARAFFINS AND CYCLO-OLEFINES 



different dihydro-acids, according to the experimental conditions. 
It was ultimately proved that the first reduction product is a mixture 
of the els- and trans-forms of the A-2:5-acid, formed by the addition 
of hydrogen to the two carbon atoms in the l:4-position. In the 
molecules of these acids the double bindings in the /3y-position are 
labile, and, whether present in an open or a closed chain structure, 
pass into the ajS-position when they are heated with aqueous 
alkalis (p. 838) : 

CH:CH-(!;H.COOH > CH 2 .CH:i-COOH 

One such change takes place even when the A-2:5-acid is boiled 
with water, and the A-l:5-acid, which is thus produced, then under- 
goes a similar transformation when its alkaline solution is boiled, 
with the formation of the A-l:4-acid. 

The A-l:3-acid is prepared from hexahydroterephthalic acid 
which is converted into l'A-dibromocyclohexane-1'A-dicarboxylic 
acid (aa'-dibromohexahydroterephthalic acid) ; this product, treated 
with boiling alcoholic potash, loses two molecules of hydrogen 
bromide and gives A-l:3-dihydroterephthalic acid. 

Both the or- and /ra/w-A-2-tetrahydro-acids are produced by 
the reduction of A-l:3- or A-l:5-dihydroterephthalic acid with 
sodium amalgam and cold water ; they both undergo isomeric 
change when they are boiled with a solution of sodium hydroxide, 
the double binding passing from the j3y- to the aj8-position in the 
usual manner, with the formation of the A-l-acid. 

A mixture of the cis- and trans-hexahydroterephthalic acids is 
produced when the tetrahydro -acids are combined with bromine 
and the dibromo -additive products are reduced with zinc-dust and 
acetic acid. 

These relationships are tabulated below : 



Terephthalic acid 



Reduction 



Boiling 



l:2-Dibromo- 

hexahydro- 
tereDhthalic acid 

I Zinc and 
acetic acid 

Hexahydro- 
terephthalic adds 




A-2:5-Acids 



A-l-Acid 



+ l:4-Dibromo- 

hcxahydro- KOH 
terephthalic acids 



> A -1:5- Acid 
Water I Ni 


1 Reduction 
Cold 
Boiling + 
A -2- Acids 
NaOH | 




Reduction 
Cold 


Alcoholic 


,:3-Acid 



Boiling 



A-l:4-Acid 



CYCLOPARAFFINS AND CYCLO-OLEFINES 803 

The structures of the various di- and tetra-hydro-acids were 
determined from their methods of formation, their behaviour 
towards alkalis, the results of their oxidation with permanganate, 
and in several other ways. Thus, one of the tetrahydroterephthalic 
acids must be the A-2-compound since it isomerises, giving the 
A-1-compound when it is heated with aqueous alkali ; also it 
combines with bromine, and the additive product, with alcoholic 
potash, is converted into a stable dihydroterephthalic acid which 
must be the A-l:3-compound. The latter is thus distinguished 
from the other stable dihydro-acid, which, therefore, is the A-l:4- 
isomeride. 

From all the results obtained with the three phthalic acids, it 
was found that sodium amalgam and water reduce a double binding 
only when it is in the aj8-position to a carboxyl group. Further, 
terephthalic acid, instead of giving a A-3:S-dihydro-derivative, as 
might have been expected if hydrogen were added to the carbon 
atoms 1 and 2, gave the A-2:5-compound, one hydrogen atom only 
combining with each of the >C-COOH groups, just as if the two 
carbon atoms 1 and 4 were directly united ; a rearrangement of 
the two remaining ethylenic bindings had also occurred. This and 
other reactions of conjugated systems are considered later (p. 813). 

^ : . . ", working with pure sodium amalgam (a reagent very 
different from that used by Baeyer), found that the first reduction 
product of terephthalic acid which can be isolated is the A-2-acid. 
These discordant results may be due to the different lengths of time 
during which the initial product is exposed to the action of the alkali 
hydroxide. 



CHAPTER 49 
OLEFINIC COMPOUNDS 

SOME of the more important methods of preparation and additive 
reactions of the >C=C< group of olefines and certain olefinic 
derivatives have already been described (pp. 85, 337) ; the following 
account amplifies what is there given. 

All olefinic groups combine with hydrogen, but not under the 
same conditions ; hydrogen in the presence of catalysts (Ni, Pt, 
Pd, etc.) reduces all olefinic (also in many cases aromatic) compounds 
(p. 405), but nascent hydrogen (from sodium amalgam and water, 
etc.) does not combine with ethylene (or benzene). On the other 
hand, derivatives of ethylene, such as acrylic and maleic acids (and 
aromatic acids), are reduced by sodium amalgam and water, as the 
properties of the ethylenic group are profoundly modified by the 
substitution of carboxyl for hydrogen (p. 816). 

Olefinic compounds which cannot be reduced with nascent 
hydrogen can generally be converted into saturated compounds by 
first adding halogen or halogen acid (HBr, HI) to the molecule and 
then displacing the halogen by hydrogen with reducing agents 
(p. 802). 

The combination of olefines with halogens (C1 2 , Br 2 ) is a general 
property, to which, however, there are important exceptions ; tetra- 
phenylethylene and l:2-dibromo-l:2-diphenylethylene, for example, 
as well as certain aliphatic olefinic compounds, such as tetrachloro- 
ethylene and dimethyl- and dibromo-fumaric acids, do not react 
with bromine ; the symbol, > C=C <, in such cases may therefore 
be misleading. 

The addition of a molecule of a halogen acid to an olefine usually 
takes place more slowly than that of a halogen, and the rule which 
summarises the usual course of the reaction for hydrocarbons 
(Markownikoff, p, 95) is not invariable, as the nature of the 
product depends largely on the experimental conditions ; in the 
absence of oxygen or peroxides, such as benzoyl peroxide or per- 
benzoic acid, propylene unites slowly with hydrogen bromide, 
giving /?-bromopropane (normal reaction), but in the presence of 

804 



OLEFINIC COMPOUNDS 805 

oxygen or peroxides combination occurs much more rapidly and 
a-bromopropane is formed by an abnormal addition (Kharasch, 
McNab and Mayo, J. Am. Chem. Soc. 1933, 2531). 

Similarly allyl bromide and vinyl bromide show slow normal 
(Markownikoff) additions with hydrogen bromide in the absence 
of oxygen or peroxides, giving aj8-dibromopropane and ethylidene 
dibromide ; but in the presence of peroxides rapid abnormal re- 
actions give ay-dibromopropane and ethylene dibromide respect- 
ively. Many further examples of this interesting peroxide effect 
have been observed, and in molecules which do not contain a strongly 
directing group either the normal or the abnormal reaction can be 
induced by suitable conditions ; in some cases it is necessary to add 
an anti-oxidant, such as hydrogen, catechol, quinol or diphenyl- 
amine, in order to suppress the abnormal reaction. 

In the combination of an aj8-unsaturated acid with a halogen acid 
Markownikoff s rule does not apply. The usual behaviour is that 
the halogen unites with that carbon atom of the olefinic group which 
is the further removed from the carboxyl group ; thus acrylic and 
crotonic acids with hydrogen bromide give only j3-bromo-deriva- 
tives, but in the acids, CH 2 :CH-[CH 2 ] n -COOH, the carboxyl group 
has little effect on the reaction, and normal or abnormal effects are 
observed. 

Hydrogen fluoride, chloride and iodide, unlike hydrogen bromide, 
do not show abnormal reactions catalysed by oxygen or peroxides. 

It has been shown that the mechanism of a normal reaction with 
hydrogen bromide is probably the addition of a proton followed by 
that of a bromide ion (p. 695p) : 



CHjr-CH - 1 

CH 8 -CH-CH 8 +Br CH 8 -CHBr-CH 8 . 

In an abnormal reaction, the oxygen or peroxide liberates a 
bromine atom from the hydrogen bromide and this atom then 
combines with the olefine, 



CH 8 ~- CH CH 2 Br; 
a reaction with hydrogen bromide follows with the liberation of 



806 OLEFINIC COMPOUNDS 

another bromine atom and so on, leading to a rapid homolytic 
chain reaction (p. 695t) : 

CHr-CH CH 2 Br+HBr > CH 8 CH a CH 2 Br+Br. 

In the presence of an anti-oxidant, which combines with bromine 
atoms, the chain is readily broken and a normal slow addition occurs. 
Abnormal reactions do not occur with the other halogen acids, as 
hydrogen fluoride and chloride are not attacked by oxygen or 
peroxides, and iodine atoms produced from hydrogen iodide do not 
react with oiefines. 

Although the complex, (i), usually gives additive products with 
halogens, numerous cases are known in which the methylene 
group is preferentially attacked. If, for example, one of the two 
olefinic carbon atoms is not combined with hydrogen, halogens 
at ordinary temperatures may give substitution ; thus wobutylene 
with chlorine gives jS-methylallyl chloride and bromine displaces 
hydrogen of the methyl group in triphenylmethylethylene : 

3 ~* CH2;C< CH 



Even very simple oiefines often undergo substitution at high temp- 
eratures, propylene, for example, at 300-600 gives allyl chloride 
(p. 246). 

Af-chloro-substituted anilides such as JV-chloro-4-chloroacetanilide, 
C 6 H 4 C1 NCI - CO CH 3 , and N- chloro -2:4- dichloroacetanilide, 
C 6 H 3 C1 2 -NC1-CO-CH 3 , are very useful reagents for substituting 
chlorine for hydrogen in groups such as (i, above) ; AT-bromo- 
succinimide reacts similarly, and, with rycfohexene, for example, 
gives a good yield of l-bromo-A-2-cyc/ohexene, 

Hydrogen cyanide does not combine with oiefines, but it reacts 
with ajS-unsaturated aldehydes and ketones giving either cyano- 
hydrins, or cyano-derivatives of the saturated compound. Cinnamic 
aldehyde, for example, gives a cyanohydrin, but mesityl oxide is 
converted into the cyanide, CN-CMe 2 *CH 2 >CO-CH 3 (p. 816). 
Other compounds which unite directly with oiefines are HOC1, 
NOC1, N 2 O 3 , and N 2 O 4 ; some of the additive products so formed 



OLEFINIC COMPOUNDS 807 

from nitrosyl chloride are of considerable importance in the study 
of the terpenes (pp. 914, 925). 

The addition of alkali metals, and of metallic alky Is, to certain 
types of olefmic compounds is described later (pp. 1038-39). Of 
much greater practical importance is the addition to a/S-unsaturated 
esters and aj8-unsaturated ketones of the sodium derivative of di- 
ethyl malonate or of ethyl acetoacetate (Michael reaction). Diethyl 
sodiomalonate, for example, combines with ethyl cinnamate, giving 
a sodium derivative, which is immediately decomposed by dilute 
acids, the sodium atom being displaced by hydrogen : 

C 6 H 5 CH CH(COOEt) 2 C 6 H 5 CH CH(COOEt) 2 

II 
EtOOC-CH 



Na EtOOC-CHo 



The tricarboxylic acid obtained from this ester, like all such 
derivatives of malonic acid, decomposes when it is heated, with 
the formation of fi-phenylglutaric acid. 

Other examples of this most useful general reaction have been 
given (p. 800), and it should be noted that when addition takes 
place the sodium atom of the ester seems to unite with that carbon 
atom, which is directly combined with the COOEt or >CO 
group. The course of the reaction depends, however, on the nature 
of the unsaturated ketone or ester, and also on the experimental 
conditions. From diethyl citraconate, (i), for example, with diethyl 
sodiomalonate, both the compounds, (n) and (ill), may be obtained, 
and the same two esters may also be produced from diethyl itaconate, 
(iv), under the same conditions, probably because the two olefinic 
esters are tautomeric in the presence of sodium ethoxide (Hope, 
J. 1912, 892 ; Ingold, Shoppee, and Thorpe,?. 1926, 1477). 



CH 3 


CH 3 


CH(COOEt) 2 




C- COOEt 


CH- COOEt 


CH 2 


CH 2 


CH. COOEt 


CH. COOEt 


CH- COOEt 


C- COOEt 




CH(COOEt) 2 


CH 2 - COOEt 


CH 2 . COOEt 


i 


ii 


in 


IV 



The polymerisation of olefines is considered later (p. 960) and 
also the isomeric change of olefinic acids (p. 838). 

Org. 51 



808 OLEFINIC COMPOUNDS 

Oxidation of Okfines 

The oxidation of olefines with potassium permanganate and 
chromic acid has already been mentioned (p. 95), but there are 
many other reagents which oxidise such compounds in various 
ways. With perbenzoic acid or monoperphthalic acid (p. 813), for 
example, olefines usually give cyclic oxides (epoxides) which can be 
hydrolysed to l:2-glycols, 

V X X C-H 

II ' I/O I 
C C' C OH 

/\ /\ /\ 

Hydrogen peroxide, in alkaline solution, often effects a similar 
change, especially with aj3-unsaturated ketones. 

In the presence of catalysts, such as osmium tetroxide or per- 
vanadic acid, a solution of hydrogen peroxide in ether or acetone, 
may convert an olefine either into an oxide, as shown above, a glycol, 
or a mixture of carbonyl compounds. 

The glycol formed in this (or in other) ways may be oxidised to 
the carbonyl compounds with a solution of lead tetra-acetate in 
acetic acid (Criegee's reagent), 1 



>C-OH 

+Pb(O-CO-CH 8 ) 4 - 
OH 

>CO 

+2CH 3 COOH+Pb(O - CO CH 3 ) 2 , 
>CO 



T 

>6.i 



which often attacks olefines directly giving the diacetate of the diol, 

C C-O-CO-CHs 

II | 

C C-O-CO-CHj 

/\ /\ 

Just as the group (i) may undergo substitution instead of addition, 

* The oxidation of glycols with periodic acid is discussed later (p. 895). 



OLEFINIC COMPOUNDS 809 

so may it be oxidised abnormally to (n), by selenium dioxide or 
chromic acid, and by Criegee's reagent to (in) : 

> C=C CH 8 > C=C CO 

i n 

;> C=C CH(0 - CO - CH 3 ) 
in 

Oycfohexene, for example, with the last-named reagent, gives a 
mixture of acetates which can then be hydrolysed to the unsaturated 
alcohol and saturated diol respectively, 



O-CO'CHj 

OfS^l 
- Q * 




Qzvnides and Ozonolym 

As previously stated (p. 96) an essential step in the determination 
of the structure of an olefinic compound is to ascertain the position 
in the molecule of the double bond ; for this purpose oxidation with 
an alkaline solution of permanganate is very commonly employed. 
Another highly important method, the various stages of which are 
summarised in the term ozonolysis, involves the preparation of the 
ozonide of the unsaturated compound* 

The ozonides (p. 96) were first investigated by Harries, who 
found that ozone combined directly with olefinic and acetylenic 
compounds, one molecule of ozone uniting with each unsaturated 
binding of the substance. They may be prepared by dissolving 
the unsaturated compound in an inert solvent, such as chloroform, 
and passing into the cooled solution ozonised oxygen, diluted with 
carbon dioxide if it is necessary to moderate the reaction. Under 
such conditions ethylene, allyl alcohol, mesityl oxide, and oleic acid, 
for example, give mono-ozonides, whereas diallyl and other di- 
olefinic derivatives give di-ozonides. 

The ozonides of the simpler olefines may be distilled in a vacuum, 
but most ozonides are very explosive ; they behave like peroxides, 
liberating iodine from potassium iodide, and they are decomposed 



810 OLEFINIC COMPOUNDS 

by water (yielding aldehydes, ketones, acids, etc., p. 811) in such a 
way that the carbon atoms, originally united by a double bond, are 
completely separated from one another. The formation of an 
ozonide, followed by its decomposition with water, is therefore a 
most valuable method (ozonolysis) of determining the positions of 
the double bindings in all types of unsaturated compounds ; for 
such a purpose the isolation of the ozonide is unnecessary, and the 
process may often be carried out by treating the compound with 
ozone in aqueous or acetic acid solution. 

Ethylene ozonide, decomposed with water, gives formaldehyde 
and formic acid ; diallyl ozonide gives succindialdehyde and/or 
succinic acid, together with formic acid and/or formaldehyde : 



CH 2 -=CH 2 CH 2 =CH CH 2 CH 2 CH=CH 2 

CH 2 O CH 2 O 2 CH 2 O 2 CHO-CH 2 .CH 2 .CHO CH 2 O 2 

The ozonides of oleic acid and elaidic acid (p. 710) yield nonylic 
aldehyde (or acid), and azelaic acid (or semialdehyde), 

CH 3 [CH 2 ] 7 CH=CH [CH 2 ] 7 COOH 
CH 3 - [CH 2 ] 7 - CHO COOH - [CH 2 ] 7 COOH 

and those of crotonic acid and wocrotonic acid (p. 709) give acet- 
aldehyde and glyoxylic acid ; the two stereoisomerides are thus 
proved to be structurally identical in both cases. Similarly the 
ozonides of stearolic acid, CH 3 .[CH 2 ] 7 -C:C-[CH 2 ] 7 -COOH, and 
phenylpropiolic acid, C 6 H 6 C:CCOOH, are decomposed by water, 
the former giving pelargonic (nonylic) and azelaic acids, and the 
latter, benzoic and oxalic acids. 

Qyc/o-olefines yield ozonides which are relatively stable towards 
water ; rycfohexene ozonide, C 6 H 10 ,O 3 , for example, is only slowly 
decomposed even at 100. Aromatic hydrocarbons also give 
ozonides : benzene forms a tri-ozonide, C 6 H e ,3O 3 , which explodes 
with warm water, but decomposes more slowly with cold water, 
yielding glyoxal, 

C fl H 6 ,30 8 +3H 2 - 3C 2 H 2 O 2 
Naphthalene yields a diozonide only. 



OLEFINIC COMPOUNDS 811 

Ozonolysis was first used by Harries in his investigation of the 
constitution of rubber, and is now a process of great importance in 
the study of olefinic compounds in general ; in the case of some 
diolefinic derivatives, one only of the double bonds may undergo 
fission, if graded ozonolysis is applied, and further information as 
to the structure of the compound is thus obtained. 

Various structural formulae might be assigned to a given ozonide, 
if valency alone is considered and it is assumed that oxygen may 
be di- or quadri-valent, but most of them need not be discussed. 
According to Staudinger the action of ozone on an ethylenic com- 
pound, R 2 C=CR 2 , leads finally to the formation of an ozonide, (i) : 



\ / 
0-0 



II 



All the relatively stable mono-ozonides seem to have this structure, 
because on reduction they yield ketones (or aldehydes), and not 
glycols, as would be the case if they were represented by (n), as 
suggested by Harries. Many ozonides, however, undergo poly- 
merisation, giving viscous or solid amorphous polyozonides, 



f-Oa-CRj-O'CRa'Oa-CRa * ' ~ -' V 



i or \ 

n [O CR* 

M 

the molecular weights of which in benzene solution range from 
about 3000 to 6000. 

Oxozonides are sometimes formed by the combination of ozon- 
ides with oxygen, and are probably polymerides of the structure, 



4-Oa-CR* -Oj-CRa - 2 CR2-4 



The initial decomposition of an ozonide, (i), by water is a fission 
of one of the links of CR^-O-CRg giving a dihydroxydialkyl 



812 OLEFINIC COMPOUNDS 

peroxide, (in), which is then converted into a monohydroxyalkyl 
hydrogen peroxide, (iv), and a ketone, (v) ; , 



_ 
\Q - O/ \R R/ \OOH \R 

III IV V 

the former then decomposes into a ketone and hydrogen peroxide. 
When, however, either of the radicals, R, represents hydrogen, 
(v) is an aldehyde instead of a ketone, and (iv) gives an acid, 
R'COOH, and water instead of a ketone and hydrogen peroxide. 
Sometimes the products of decomposition are obtained in the form 
of their peroxides (p. 966). 

Ozonolysis of acetylenic compounds usually gives (a mixture of) 

acids, R.c;C.R'-t-O 3 +H 2 - R-COOH+R'-COOH. 

The importance of the process of ozonolysis can hardly be over- 
rated ; in addition to its use in the case of mono-, di-, and poly- 
olefinic compounds (compare citral, sesquiterpenes, and polyenes), 
it has been employed in attempts to determine the structures of 
unstable olefinic enols. The ozonide of the enolic form of benzoyl- 
acetone, C e H 6 -CO-CH 2 -CO'CH 3 , for example, with water gives 
methylglyoxal, benzoic acid, and hydrogen peroxide ; it may 
therefore be concluded that the*enol probably has the structure, 
C 6 H 5 -C(OH):CH.CO-CH 3 . 

Ozone also reacts with certain types of saturated compounds ; 
it oxidises primary alcohols to aldehydes and then to acids, and 
converts di-isoamyl ether, for example, into isoamyl isovalerate, 
C 4 H 9 .COOC 6 H n . 

Many unsaturated compounds combine slowly with oxygen in 
the dark, more quickly in the light, yielding peroxides ; the changes 
involved are probably as indicated below : 

CH 2 :CPh 2 > CH 2 CPh 2 * Polymeride. 

o 6 

Acetyl peroxide, CH 3 -CO-O-O-CO-CH 3 , benzoyl peroxide, 
C 6 H 5 *CO'O'OCO-C e H 6 , and many analogous compounds are 
obtained by the action of metallic peroxides on anhydrides, acid 
chlorides, etc. ; the former is a thick explosive liquid, but the latter 



OLEFINIC COMPOUNDS 813 

is crystalline and relatively stable, and is used as an oxidising 
agent and disinfectant. 

When benzoyl peroxide is treated with sodium methoxide it 
yields sodium perbenzoate and methyl benzoate, and the salt, with 
dilute sulphuric acid, gives perbenzoic acid> 

(Ph-CO) 2 O 2 +MeONa = Ph-CC^Na+Ph-COOMe. 

Monoperphthalic acid, C 6 H 4 (COOH)-CO-OOH, is obtained by 
treating phthalic anhydride with alkaline hydrogen peroxide and 
liberating the acid at a low temperature. 

Conjugated Systems 

Of the two di-olefinic hydrocarbons, isoprene and diallyl, which 
have already been briefly described (p, 105), the latter may be 
said to show a normal behaviour : that is to say its chemical pro- 
perties might have been foretold from its structural formula, in- 
asmuch as each of its olefinic bindings behaves on the whole like 
that of ethylene. Isoprene, however, under various conditions, 
gives certain additive products which were at first regarded as 
abnormal, and many other di-olefines and their derivatives behave 
in this respect like isoprene. 

Such unexpected reactions were first observed by Fittig (1885) 
in the case of piperic acid (p. 601) ; on reduction with sodium 
amalgam and water this compound gave the j8y-unsaturated acid 
shown below, instead of one of the expected products, which would 
have been formed by the normal addition of two hydrogen atoms to 
one, or to both of the olefinic bonds : 

CH 2 <Q>C 6 H 3 -CH:CH-CH:CH.COOH-f2H 

^TT ^O 



It will be seen that in this reaction both the original double bonds 
are changed by combination with hydrogen, but a new one is formed 
in a different position in the molecule. 

Baeyer's work on the reduction of the phthalic acids afforded 
other examples of the same kind ; terephthalic acid, (i), for example, 
gave a A-2:5-dihydro-derivative, (u), and A-l:3-dihydroterephthalic 
acid, (in), gave the A-2-tetrahydro-acid, (iv), the two hydrogen 



814 OLEFINIC COMPOUNDS 

atoms having been added in the Imposition, with the formation of 
a new double binding in both cases (p. 802) : 

COOH COOH COOK COOH 







In order to obtain further information regarding these reactions, 
Baeyer examined the reduction of open chain di-olefinic acids, 
having a A-l:3 -structure analogous to that of terephthalic acid. 
Muconic acid may be obtained by condensing glyoxal with malonic 
acid in the presence of pyridine and then heating the tetracarboxylic 
acid so formed ; it has the structure, (v), given below, and is 
reduced by sodium amalgam and cold water to dihydromuconic 
acid, (vi). The constitution of dihydromuconic acid is shown by 
the fact that it yields malonic acid on oxidation ; also, when heated 
with alkali, it undergoes isomeric change, and the double bond 
passes from the /?y- to the a/5-position (p. 838), with the formation of 
(vn), which, on oxidation, gives a mixture of oxalic and succinic acids : 

v HOOC-CH:CH.CH:CH-COOH 

vi HOOC.CH 2 .CH:CH-CH 2 -COOH 

vii HOOC-CH 2 .CH 2 .CH:CH.COOH 

It is clear from these results that the behaviour of terephthalic acid 
on reduction is strictly comparable with that of a A-l:3- open chain 
di-olefinic acid, and that in both cases hydrogen atoms are added in 
the 1 :4-position with the formation of a new double binding. Further 
investigations by various workers proved that other di-olefinic acids 
behaved in the same way. Cinnamylidenemalonic acid (p. 529), for 
example, gave on reduction the product shown below : 

Ph-CH:CH.CH:C(COOH) 2 > Ph-CH 2 .CH:CH-CH(COOH) 2 

This phenomenon of l:4-addition is not confined to acids, but is 
observed in the case of many di-olefinic compounds of a particular 
type ; thus both 1-phenylbutadiene and symmetrical 1 :4-diphenyl- 
butadiene, with nascent hydrogen, yield l:4-dihydro-derivatives, 

Ph-CH:CH.CH:CH 2 +2H - Ph-CH 2 .CH:CH-CH 3 , 
Ph CH:CH CH:CH - Ph+2H = Ph CH 2 . CH:CH CH 2 - Ph. 
Similarly, pyrrole is reduced to pyrroline (p. 588), 



OLEFINIC COMPOUNDS 815 

It will be seen later that 1:6-, and even l:10-addition may take 
place in the case of certain polyenes (p. 982). 

In order to account for all the reactions of this nature, which were 
then known, Thiele suggested that the atom-fixing powers of the 
two carbon atoms in an olefinic group are not completely exhausted 
or satisfied by the combined affinities of the atoms forming that 
group : that the two unsaturated carbon atoms have some * residual 
affinity/ to which their reactivity is due. If, in the following scheme, 
these residual affinities, or partial valencies, are represented by 
dotted lines, the combination of an olefinic derivative with hydrogen 
may be represented thus : 

RCH:CHR+H 2 - R CH:CH R * R CH 2 .CH 2 R. 

H H 

In the case of a molecule, which contains the group 
CH:CH-CH:CH , it may be supposed that the partial valencies 
of the two central carbon atoms neutralise one another, those of 
the end carbon atoms remaining free, as indicated below, (l) ; 1:4- 
addition then takes place because of the two partial valencies of the 
two terminal carbon atoms of the system, with the formation of a 
new olefinic bond, (n, Thiele's rule) : 

CH;CH*CH;CH~- + 2H - CH 2 -CH:CH.CH 2 



ii 

An arrangement of alternate double and single bonds of this 
kind is known as a conjugated system. 

The addition of bromine (1 mol.) to a conjugated system may also 
follow Thiele J s rule : Cyr/opentadiene, for example, and A-l:3- 
dihydrobenzene (cycfohexadiene) form 1 :4-dibromo-additive pro- 
ducts, but l:2-addition often occurs ; in most reactions of this kind, 
however, a mixture of 1:4- and 1 :2-dibromo-derivatives is f ormed 
although one type of addition may predominate. Thus butadiene 
and 1:3-, 2:3-, and l:4-dimethylbutadienes all give mixtures 
of 1:2- and l:4-derivatives ; (symmetrical) 1 :4-diphenylbutadiene 
gives the former only but yields a 1 :4-additive product with nitrogen 
peroxide. 

In general, the course of such reactions of conjugated systems 
depends both on the nature of the unsaturated substance and on 



816 OLEFINIC COMPOUNDS 

that of the addendum ; thus l:4-addition occurs so generally with 
nascent hydrogen, in various types of compounds, that it is possible 
to infer the presence or absence of a conjugated system from the 
behaviour of a compound on reduction. In the case of the addition of 
bromine or an unsymmetrical compound such as hydrogen bromide, 
however, the results are very irregular ; the exceptions to Thiele's 
rule gradually became so numerous that the rule lost its value. 

According to modern ideas in a conjugated compound such as 
butadiene forms such as +CH 2 -CH:CH-CH 2 - contribute to the 
mesomeric state of the molecule and the fact that the length of the 
central (single) carbon-carbon bond in butadiene is 146 A.U. as 
compared with the length of 15 A.U. of an unconjugated single 
bond confirms this view. The central bond thus has some double 
bond character. If this form of butadiene is the most reactive the 
first attack by an electrophilic reagent leads to the addition of, for 
example, Br+ or H + to one end of the conjugated system and to the 
formation of an ion which is mesomeric and thereby stabilised, 

CH 8 :CH-CH:CH a +Br+ > CH 2 :CH-CH-CH 2 Br/CH,-CH:CH-CH 2 Br, 

CH 2 :CH-CH:CH 2 +H+ > CH 2 :CH-CH-CH 8 /CH 9 -CH:CH-CH 8 . 

An ion formed by addition of bromine or hydrogen to one of the cen- 
tral carbon atoms, CH 2 :CH-CHBr-CH 2 + or CH 2 :CH-CH 2 -CH 2 + 
cannot be stabilised by mesomerism. That this view is correct is 
supported by the fact that the final product of addition as found 
experimentally, is always one during the formation of which such a 
mesomeric ion may be assumed ; with butadiene, for example, no 
l-bromobut-3-ene, CH 2 :CH -CHa'CH^Br, is formed with hydrogen 
bromide, and with 1-phenylbutadiene similarly the product is 
Ph-CH:CH-CHBr-CH 3 and not Ph-CH:CH-CH 2 -CH 2 Br while 
l:4-dimethylbutadiene and hydrogen bromide give a mixture of 
Me-CH 2 -CHBr-CH:CH-Me and Me-CH 2 -CH:CH-CHBr-Me. 

The second stage of the reaction is the combination of the bromide 
ion with the mesomeric cation and the final product depends on 
various factors : the structure of the first formed product depends 
on the relative rates of addition of Br~ at the two possible positions 
and that isomeride which is the more rapidly formed will pre- 
dominate. This compound may, however, ionise again and if there 
is sufficient time the final product will consist mainly or entirely of 
the more stable isomeride. Whether the first formed addition 



OLEFINIC COMPOUNDS 817 

compound re-ionises or not depends on the structure of the original 
conjugated substance, the solvent in which addition is taking place, 
the temperature, etc. and the composition of the final mixture may 
also depend on the time of reaction. The case of 1-phenylbutadiene 
may be cited as an example of the control of addition by very 
different stabilities of the final products ; Ph'CH:CH-CHBr-CH 3 
is more stable than Ph-CHBr'CH:CHCH 8 as in the former 
compound the ethylenic linkage is conjugated with the aromatic 
ring whereas in the latter it is not ; the former, as already stated, 
is the sole product of reaction of hydrogen bromide with 1-phenyl- 
butadiene. 

When an ethylenic linkage is conjugated with a carbonyl group, 
>C=CR CR'=O, certain nucleophilic additions to the former, 
which do not occur with an isolated double bond, are possible ; addi- 
tions to unsaturated aldehydes and ketones of hydrogen cyanide 
(CN~), and of diethyl malonate(~CH(COOEt) 2 ), the Michael reaction, 
have already been mentioned (pp. 806-807) and the reactions with 
ammonia, hydroxylamine and Grignard reagents (R~) are described 
later (p. 825). In these reactions the carbonyl group causes the 
j8-carbon atom to assume a positive charge by mesomeric change 
and that carbon atom is active towards nucleophilic reagents, 



It is interesting to recall that Thiele applied his views to explain 
the great stability of benzene, in comparison with that of olefinic 
compounds ; he suggested that the molecule of benzene, represented 
by the Kekute formula, may be regarded as an extended conjugated 
system, (i), in which the partial valencies neutralise one another, as 
indicated in (n) ; corresponding symbols may be written for 



m 



naphthalene and other benzenoid compounds, as well as for hetero- 
cyclic compounds, such as pyridine. Such explanations, however, 
are found wanting when further* cases are considered. Cycle- 
octatetrene, for example, may be represented by the symbol, (in), 
in which, as in (it), all the partial valencies are neutralised, but this 
hydrocarbon is very reactive and olefinic in character ; thus, it 






818 



OLEFINIC COMPOUNDS 



reduces permanganate, combines readily with bromine, is decom- 
posed when it is heated, and gives tarry products with nitric acid. 

Modern views explain the difference between the two hydro- 
carbons, benzene and cyc/o-octatetrene (p. 1001). 

The Diels-Alder Reaction 

Very interesting additive reactions have been described by Diels, 
Alder, and their collaborators, who found that substances containing 
the group, CH=CH CO , such as maleic anhydride, ethyl 
acrylate, and />-benzoquinone, unite directly with conjugated systems, 
the addition always occurring in the l:4-position. Isoprene and 



O3 




maleic anhydride, for example, give the anhydride of 4-methyl- 
&-4-cyc\ohexene-l:2-dicarboxylic acid, (i, methyltetrahydrophthalic 
anhydride) ; similarly butadiene and quinone give a hydronaph- 
thalene derivative, (n). Maleic anhydride, acetylenedicarboxylic 
acid (or its ester), and certain other unsaturated substances, also 
react with cyclic conjugated systems giving bridged ring compounds 
(p. 819). 

Thus the products of the combination of maleic anhydride with 
cycfopentadiene, (in), hexatriene, (iv), and furan, (v), and those 
of acetylenedicarboxylic acid (or ester) with anthracene, (vi, 
X - COOH), rycfopentadiene, (VH), and furan, (vm), are shown 
below ; the dotted lines indicate where combination has taken place. 



CH:CH 2 






III 



IV 




COOMc 



VI 




VII 



OLEFINIC COMPOUNDS 819 

Reactions with maleic anhydride, such as those indicated above* 
are so general that this compound may be used for determining the 
presence or absence of a conjugated system in di- and poly-olefines 
of unknown structure, such as members of the terpene and sesqui- 
terpene groups ; additional very interesting examples of the Diels- 
Alder reaction are given later (pp. 1028, 1035). 

Two or more molecules of a given conjugated hydrocarbon may 
also unite by l:4-addition (Alder and Stein, Ann, 496, 197). A-l:3- 
Qyc/ohexadiene, for example, ! ,i:i-,:o >- Lr<u i . i polymerisation, giving (ix), 
and two molecules of rycfopentadiene give the hydrocarbon, (x), 
which may then combine with a third molecule (A) forming the 
compound (xi) : 





IX X XI 



Benzene, however, does not undergo polymerisation in this way, 
and does not react with maleic anhydride, facts which, like many 
others, show the unique character of the molecular structure of 
this hydrocarbon. 

Polymerides are often termed dimerides, trimerides, etc., according 
to the number of molecules of the original substance from which 
they are formed. 

Nomenclature and Stereochemistry of Bridged Ring Compounds 

In the structural formulae of many of the polycyclic compounds 
just considered, one or more carbon atoms of one of the rings may 
be regarded as forming a link or bridge between two of those of 
another ring; such molecules are said to have a bridged ring 
structure, of which many more examples are found among the 
dicyclic terpenes and their derivatives (p. 924). 

In the systematic nomenclature of such compounds the presence 
of the bridge is denoted by the prefix meso (Bredt) or endo (Diels), 
followed by the name of the group which forms the bridge across 
the higher membered or parent ring ; this latter is numbered, 
starting from one of the carbon atoms common to all three rings, 



820 OLEFINIC COMPOUNDS 

and the position of the bridge is then indicated by numerals as 
shown: 





- 
1 -A-Endoethylenecyclohexane 1 :5-J?mfomethylenecyc/o-octane 



An alternative system names the compound as a derivative of 
that dicyclic hydrocarbon which contains the same number of carbon 
atoms as the entire bridged ring structure (all substituents excluded) ; 
the number of carbon atoms forming the bridge, followed by that 
of each of the links which connects the two carbon atoms common 
to the three rings is then given before the name. Thus (l) is 2,2,2- 
diryc/o-octane and (n) 1,3,3-dicy^/ononane, the first figure in each 
case indicating the number of carbon atoms in the bridge. 

Systematic names may now be given to the compounds men- 
tioned on p. 818 : (v), for example, is l-A-meso-oxy-A-5-cyclo- 
hexene-2:3-dicarboxylic anhydride and (vn) is lA-meso (or endd) 
methylene-2:5-c3>c/0hexadiene-2:3-dicarboxylic acid, or 1 ,2,2-di- 
ryc/ohepta-2:5-diene-2:3-dicarboxylic acid. 

The second system of nomenclature (above) can be applied to 
decahydronaphthalene, hydrindane and other structures of a similar 
type, which may be regarded as bridged rings ; decalane, for 
example, would then be 0,4,4-diryc/odecane and hydrindane 
0,3,4-dicycfononane since the bridges here are bonds and do not 
contain carbon atoms. In the latter case the numbering starts with 
the smaller ring and finishes with those carbon atoms common to 
the two rings. 



^^r C 

? k s, , H, 

Hydrindane Spiro-3,5-nonane 



OLEFINIC COMPOUNDS 821 

The nomenclature and numbering of spirocyclic compounds (p. 723) 
may also be seen from the above example. 

It has already been seen that the molecule of decalane is not 
planar (p. 793) : similarly bridged ring compounds are rigid tridi- 
mensional structures, as indicated in the case of 1,2,2-dicycfoheptane, 
(i) ; the planes of the three rings (two of four and one of three 
atoms) which would be formed if certain atoms were joined as in- 
dicated by the dotted line are inclined to one another and meet at 
that line. The same structure is indicated in a somewhat different 
way in (n). The stereochemistry of such tridimensional structures 
is therefore very complex. 





II 



CHAPTER 50 
KETONES, KETONIC ACIDS, AND KETENES 

Ketones 

THE symbol > C=O which occurs in the formulae of various types 
of compounds, as already mentioned, does not represent or sum- 
marise a constant set of properties or reactions, since this group, 
like >C=C<, behaves very differently according to the nature 
of the atoms or radicals with which it is combined. When, for 
example, it is directly united to OH, OEt, NH 2 , or Cl, as 
well as to a carbon atom, it is very inert, and its properties are 
quite different from those which it shows in ketones and in aldehydes, 
probably because of resonance (p. 517) ; in the two types just men- 
tioned the carbonyl group is highly reactive, and, in consequence, 
the study of its reactions in such compounds is of importance. 

In addition to the simple mono-ketones, di-, tri-, etc., ketones 
are known. The diketones are classed according to the relative 
positions of the two carbonyl groups, and are distinguished as a- 
or 1:2-, )8- or 1:3-, y- or 1:4-, etc., diketones ; a more systematic 
nomenclature is illustrated below. 

Diacetyl, CH 3 -CO-CO-CH 3 (dimethylglyoxal, butandione), is 
the simplest l:2-diketone and is obtained by the hydrolysis with 
dilute sulphuric acid of its monoxime, isonitrosomethylethyl ketone, 1 
which is prepared by the interaction of methylethyl ketone, amyl 
nitrite, and hydrochloric acid : 

CH 3 CO CH a - CH 3 CH 3 - CO C(:N OH) CH 8 * CH 3 CO CO CH 3 . 
Diacetyl is a yellow, volatile liquid, b.p. 87-89, with a character- 
istic quinone-like smell ; with alkalis it yields first diacetylaldol and 
then p-xyloquinone : 

O 
CH S -OC X V CH, 

H,C V x CO-CH a H 2 C X X CO-CH, 

8 8 

1 The group, >C:N-OH, if produced from >CO and hydroxylamine, is 
usually called the oximino-group, but when formed from >CH t and nitrous 
acid, as in this case, it is called the isonitroso-group. 

822 




KETONES, KETONIC ACIDS, AND KETENES 823 

It condenses with o-phenylenediamine, yielding dimethylquin- 
oxaline (p. 1060), a reaction which is shown by most substances 
containing the CO -CO group, and it reacts with hydroxyl- 
amine and with phenylhydrazine, as do other l:2-diketones, such 
as benzil, in a normal manner. 

Dimethylglyoxime, CH 3 - C(:N OH) C(:N OH) - CH 3 (diacetyl- 
dioxime), is prepared by the interaction of wonitrosomethylethyl 
ketone and hydroxylamine, and melts at 234. It is used in the 
detection and estimation of nickel, as it yields an almost insoluble 
red compound, (C 4 H 7 O 2 N 2 ) 2 Ni, with nickel salts in neutral solution. 1 
On reduction the dioxime yields a mixture of meso- and dl-2:3- 
diaminobutanes . 

Acetylacetone, CH 3 CO CH 2 CO - CH 3 (2-A-pentandione), is a 
l:3-or jS-diketone, and is prepared by the condensation of acetone 
and ethyl acetate in the presence of sodamide (Claisen condensation), 

CH 8 .COOEt+CH 3 .CO-CH 8 = C^-CO-CHs-CO-C^-fEt-OH. 

It boils at 139, and is decomposed into acetone and acetic acid 
when it is heated with water : like ethyl acetoacetate, it forms a 
sodium derivative which reacts with alkyl halides and many other 
halogen compounds. Derivatives of acetylacetone with metals 
such as beryllium, copper, zinc, and aluminium are remarkably 
stable, and many of them can be vapourised unchanged. They have 
therefore been used for the determination of the atomic weight and 
valency of various metals. They are regarded as partly co-ordinated 
compounds rather than as mere salts because of their volatility and 
from stereochemical evidence (p. 775). The behaviour of acetyl- 
acetone and other l:3-diketones towards hydroxylamine and phenyl- 
hydrazine is described later (pp. 1052, 1057), 

Many other l:3-diketones may be prepared by the condensation 
of esters with ketones, as in the case of acetylacetone ; thus a mixture 
of ethyl benzoate and acetone, or of ethyl acetate and acetophenone, 
gives benzoylacetQW) C 6 H 5 -CO'CH 2 -CO'CH 3 , which closely re- 
sembles acetylacetone in its reactions. 

Acetonylacetone, CH 3 - CO CH 2 CH 2 CO CH 3 (2:5-hexan- 
dione), is a l:4-diketone, prepared by treating ethyl sodioaceto- 

1 a-Benzildioxime also reacts with nickel salts and gives a precipitate, 
which is so sparingly soluble in water that one part of the metal in two 
million pans of water can thus be detected (compare p. 776). 

Qrg. 52 



824 KETONES, KETONIC ACIDS, AND KETENES 

acetate with iodine, and submitting the product, diethyl diacetyl- 
succinate, to ketonic hydrolysis : 

CH 8 CO CHNa - COOEt CH 3 CO CH COOEt CH 3 CO CH a 

CH 8 CO -CHNa- COOEt ~~" CH 3 CO CH COOEt """* CH 3 .CO-CH 2 

It can also be obtained from ethyl acetoacetate in another way 
(p. 211). It boils at 192, and has no acidic properties, as its mole- 
cule does not contain the active group, CO CH 2 CO ; it reacts 
normally with one or with two molecules of hydroxylamine or 
phenylhydrazine. 

Acetonylacetone and other 1 :4-diketones are of very considerable 
importance owing to the great readiness with which they form five- 
membered heterocyclic compounds (p. 589). 

Derivatives of 8- or l:5-diketones are formed by the condensation 
of aldehydes with ethyl acetoacetate, but these products undergo 
inner condensation and are converted into derivatives of cyclo- 
hexenone (p. 799). 

Triketones and tetraketones are known ; dibenzoylacetylmethane 
is described later (p. 832), and triketoindane has already been 
mentioned (p. 556). 

Pentantrione, CH 3 CO - CO CO CH 3 (triketopentane), has been 
obtained by condensing acetylacetone with p-nitrosodimethylaniline 
and hydrolysing the product, CAc 2 :N C fl H 4 NMe 2 ; it is an orange 
liquid, and condenses with acetylacetone to give the hydroxy- 
tetraketone, 

CH 3 .CO-C(OH).CO-CH 3 

CH 3 -CO.CH.CO.CH 8 

Most of the reactions of simple aldehydes have already been given 
and the tautomerism of hydroxyaldehydes is discussed later (p. 834) ; 
both the CHO groups of dialdehydes, such as glyoxal and succin- 
dialdehyde show, as a rule, the normal behaviour. 

Many of the higher aldehydes of the C n H 2n O series, from heptyl- 
aldehyde upwards, are used in perfumery. 

afi-Unsaturated ketones are readily prepared by the condensation 
of ketones either alone or with aldehydes ; acetone, for example, 
gives mesityl oxide and phorone, whereas acetone and benzaldehyde 
in the presence of sodium hydroxide give benzylideneacetone, 
C 6 H 5 .CH:CH.CO-CH 8 . 



KETONES, KETONIC ACIDS, AND KETENES 825 

aj3-Unsaturated ketones are conjugated substances (p. 816) and 
readily give additive products ; from mesityl oxide and ammonia, 
diacetonamine is formed (pp. 148, 606), whereas phorone and 
ammonia give triacetonamine (p. 60S) and trtacetonediamme, 

Me 2 C:CHCO-CH;CMe 2 



NH 2 
H 
Triacetonamine Triacetonediamine 

Mesityl oxide reacts with hydroxylamine, giving a hydroxylamino- 
additive compound and an oxime, 

Me 2 C CH 2 - CO CH S Me 2 CH:CH C CH 3 

I II 

NH-OH N-OH 

ajS-Unsaturated ketones may also form ethylenic additive pro- 
ducts with hydrogen cyanide, instead of cyanohydrins (p. 806) and 
may combine similarly with Grignard reagents, such as phenyl 
magnesium bromide, 

C 6 H B .CO.CH:CH.C e H 6 - > C 6 H 6 -C(OMgBr):CH-CH(C 6 H 6 ) 2 - > 
C 6 H 6 - CO - CH 2 - CH(C 6 H 6 ) 2 

Ketonic Acids 

It has already been pointed out (p. 210) that jS-ketonic acids and 
their esters differ from the corresponding a- and y-ketonic com- 
pounds in certain very important respects. Ethyl acetoacetate is a 
]8-ketonic ester of exceptional interest and the mechanism of its 
formation by the action of sodium on ethyl acetate, as well as its 
structure, were at one time widely discussed. It was first assumed 
by Frankland and Duppa that sodium displaced hydrogen from the 
molecule of ethyl acetate, giving CH 2 Na'COOEt, which then 
reacted with unchanged ethyl acetate. Much later, Claisen sug- 
gested that in the first place sodium ethoxide was formed, from 
traces of alcohol contained in the ethyl acetate or produced by its 
decomposition, and that this compound gave, with ethyl acetate, 



826 KETONES, KETONIC ACIDS, AND KETENES 

an additive product, which then condensed with unchanged ester, 
as shown below : 

CH 3 .COOEt+NaOEt - CH 8 .C(ONa)(OEt) 2 , 

CH 8 .C(ONaXOEt) 2 +CH 3 .COOEt - 

CH 3 C(ONa):CH COOEt+2Et - OH. 

In accordance with this view it was found that benzyl benzoate 
and sodium methoxide gave the same compound as methyl benzoate 
and sodium benzyloxide : 

C 6 H 5 'CO-OCH t 'C 6 H 5 -fCH 3 .ONa 

^ C 6 H 5 C(ONa)(OCH 3 )(O - CH a - C,H 6 ) 
C 6 H 8 - CO OCH 3 + C 6 H B CH a ONa 

It was also shown that when the ethyl acetate, used in the prepara- 
tion of ethyl acetoacetate, is free from alcohol, the reaction with 
sodium is very slow at first, but becomes more rapid as soon as some 
alcohol (sodium ethoxide) has been formed, in accordance with 
Claisen's view. 

Michael disputed the existence of Claisen's intermediate product, 
and Nef assumed the formation of a sodium compound of an enolic 
form of ethyl acetate, which combines with ethyl acetate, 

CH 2 :C(ONa)(OEt)+CH 3 -COOEt - CH 3 -C(ONa)(OEt).CH a -COOEt ; 

the additive compound so formed might then lose a molecule of 
alcohol, giving CH 3 -C(ONa):CH-COOEt. This explanation has 
been slightly modified by Arndt and Eistert (Ber. 1936, 2381) : a 
small proportion of an anion which is the mesomeric form of (i) 
and (n) is first produced by the action of the sodium (or sodium 
ethoxide) on ethyl acetate, 



1 
tJ 





OEt OEt 



A reversible reaction then occurs between (i) and an active form of 
ethyl acetate, (in), to give an anion, (iv), which loses alcohol and 
affords (v, one of the contributors of a mesomeric ion) : 

+/ CH. f /CHri T /CH 8 1 

C<rOEt EtOOC-CHi-C^-OEt -* EtOOC-CHtC/ 

XT L \o~ J L \o~ J 

III IV V 



KETONES, KETONIC ACIDS, AND KETENES 827 

A sodium derivative of ethyl acetate has been isolated by 
Scheibler. 

Whatever may be the mechanism of the reaction between ethyl 
acetate and sodium, it is known that many analogous condensations 
may be brought about ; two molecules of the same or of different 
esters of monocarboxylic acids (below), or one molecule of an ester 
and one molecule of a ketone (p. 823), or two molecules of the esters 
of different dicarboxylic acids (p. 781), may condense in the presence 
of sodium, sodium ethoxide, or sodamide, giving ketonic esters or 
diketones ; such reactions, of which many examples have been 
given, are described as Claisen condensations. In most of the cases 
already considered only the final stage of the change is indicated. 

Ethyl benzoylacetate, C 6 H 6 -CO-CH 2 -CQOEt, can be prepared 
by the condensation of ethyl benzoate with ethyl acetate in the 
presence of sodium or alcohol-free sodium ethoxide. It boils at 
148 (11 mm.) and closely resembles ethyl acetoacetate in its chemical 
behaviour ; its sodium derivative reacts with alkyl halides as does 
ethyl sodioacetoacetate, and the products undergo acid and ketonic 
hydrolysis ; the ester is therefore of service in the synthesis of many 
aromatic ketones and other compounds. 

Ketenes 

Ketenes are compounds which contain the group >C:CO, and 
the simplest ketene, CH 2 :CO, was first obtained by decomposing 
acetic anhydride with a white-hot platinum wire (Wilsmore), 

CH 8 .C(\ 

>O - 2CH 2 :CO+H S O. 



It is more conveniently prepared by passing the vapour of acetone 
through a tube, partially filled with earthenware, at a dull red heat, 

CHj-CO-CH, - CH 8 :CO+CH 4 . 

Ketene, and some of its homologues, may be obtained by treating 
a solution of an a-bromoacyl bromide with zinc, 

(CH 8 ) 2 CBr.COBr+Zn - (CH 3 ) 2 C:CO+ZnBr, ; 
dialkylketenes are formed when dialkylmalonic anhydrides (obtained 



828 KETONES, KETONIC ACIDS, AND KETENES 

from the acid chlorides with pyridine and sodium carbonate solution) 
are heated, 

/ C0 \ 

(C 2 H 6 ) 2 C< >0 - (C 2 H 5 ) 2 C:C(H C0 2 . 



Ketenes are usually yellow , mobile liquids with a characteristic 
odour. Ketene is a gas (b.p. 56), and diethyl ketene, CEt 2 :CO, 
a liquid (b.p. 92). Ketenes do not show the reactions character- 
istic of ketones, but they combine directly with many compounds, 
addition taking place to the ethylenic linkage ; thus with acetic 
acid, for example, ketene gives acetic anhydride, 

CH 2 :CO+CH 3 -COOH = (CH 3 .CO) 2 O, 

which is thus prepared on the large scale. With water, alcohol, and 
ammonia or amines, ketenes yield acids, esters, and amides respect- 
ively, the group >C:CO in these reactions behaving like the 
N:CO group of the carbimides, 

CH 2 :CO+R-OH = CH 3 .CO-OR, 
CH 2 :CO+NH 3 - CH 3 .CO-NH 2 . 

With bromine, bromo-acid bromides are formed, and halogen acids 
give acyl halides. 

Dimethyl ketene combines with tertiary bases, such as pyridine, 
forming additive compounds, which are decomposed by boiling 
hydrochloric acid, yielding the base and wobutyric acid, by the addi- 
tion of the elements of water. 

Ketenes are oxidised to peroxides by oxygen ; they combine 
directly with olefines, and with various other substances which 
contain double linkages, as, for example, with ketones and with 
Schiifs bases (p. 499), 

R 2 C CO 



I I 

c-6 



R 2 C:CO+R'-CH:NR" - I I 

R'CH J 



R 2 C CO 

NR" 



When ketene is passed into a dry ethereal solution of diazo- 
me thane, it gives cyclobutanone, probably in two stages, 



KETONES, KETONIC ACIDS, AND KETENES 829 

CH a \ 

CH a :CO+CH 8 N 2 - I ^CO+Ng 
CH 2 

CH 2V CH 2 .CO 

I >CO+CH 2 N 2 - [ I +N 2 

CH/ CH 2 -CH 2 

The great reactivity of ketenes is shown by the fact that di- 
methyl ketene combines with carbon dioxide at low temperatures, 
giving products such as 2(CH 3 ) 2 C:CO,CO 2 , 3(CH 3 ) 2 C:CO,2CO ? , 
and 4(CH 3 ) 2 C:CO,3CO 2 . The first of these three compounds is 
crystalline and is tetramethylacetonedicarboxylic anhydride, (i), since, 
on hydrolysis, it is decomposed into dimethylmalonic acid and 
wobutyric acid, and it is formed when dimethylmalonic anhydride 
is heated with a little methylamine ; in the latter reaction it may be 
assumed that the anhydride is first decomposed giving dimethyl 
ketene and carbon dioxide, which then combine again, but in 
different proportions. When dimethylmalonic anhydride is heated 
alone it is converted into tetramethylcyclobutandione, (n), and carbon 
dioxide, the diketone being formed by the polymerisation of di- 
methyl ketene : 

8 

Me 2 C x ^CMca OC-CMea 

OC X ^CO Me 2 C CO 

I II 

Most ketenes polymerise with great facility, either spontaneously 
or in the presence of a catalyst. Ketene, for example, gives diketene, 
which melts at -6-5, boils at 127, and is stable at very low tem- 
peratures ; in the presence of acids, diketene combines with alcohols, 
giving esters of acetoacetic acid, which are thus prepared com- 
mercially, 

CH 2 

C 2 H 5 -OH - CH 3 -CO CH 2 COOEt, 



and on reduction it gives j3-butyrolactone, a reaction which confirms 
the given structure. Under ordinary conditions diketene gives a 
dark tarry polymeride. 



830 KETONES, KETONIC ACIDS, AND KETENES 

In benzene solution in the presence of pyridine, ketene or diketene 
is converted into dehydracetic acid (p. 984), which, like tetramethyl- 
rycfobutandione, might be classed as a polyketene> (CR 2 :CO) n . 

Diphenyl ketene, Ph 2 C:CO, prepared by treating diphenyl- 
chloroacetyl chloride with zinc, is a reddish-yellow liquid, boiling 
at 146 (12 mm.) ; unlike the aliphatic ketenes, it does not undergo 
polymerisation, but it shows the general reactions of those com- 
pounds. It was the first ketene to be obtained, and was discovered 
by Staudinger in 1905. 

Carbon suboxide, C 3 O 2 (p. 276), boils at 7 and polymerises to a 
red solid. Its chemical behaviour is similar to that of the ketenes. 



CHAPTER 51 

ISOMERIC CHANGE 

Keto-enol Tautomerism 

THE phenomenon of keto-enolic tautomerism, a type of dynamic 
isomerism, of which some account has already been given (pp. 
203-205), is shown by many substances, such as j3-ketonic esters 
(ethyl acetoacetate, diethyl oxaloacetate, diethyl acetonedicarb- 
oxylate) and jS-diketones, the molecules of which contain the group, 
_CO CH 2 -CO - or -CO -CHR - CO -, and it has been very 
extensively studied by many chemists, among whom may be men- 
tioned Knorr, Claisen, W. Wislicenus, Kurt Meyer, and Dimroth. 

From the allelotropk mixture of the ketonic and enolic forms 
of ethyl acetoacetate the two desmotropes (p. 205) have been isolated ; 
they are both stable in the pure condition, but are readily converted 
into an equilibrium mixture by various catalysts. 

This change was discussed by Laar, who introduced the term 
tautomerism, as long ago as 1885 ; he suggested that the molecule 
of ethyl acetoacetate contained a very mobile hydrogen atom, which 
oscillated perpetually between the two positions represented in the 
isomeric structures. According to present views the first change is 
probably the separation of a proton from the molecule, giving the 
resonance or mesomeric form of the anions, (i), (il), and (ill) ; the 
proton can then recombine with the anion in either one of two ways : 

CH 8 .CO.CH 8 .COOEt - [OVCO.CH.COOEt I 

iCH 3 -C(O):CH.COOEt n 
CH,C(OH ): CH.COOEt ^ {^ ^ .^^ 

The resonance of the ion is an essential feature of all such tautomeric 
changes. This view of the mechanism is supported by the fact that 
the change is catalysed by ions and does not occur in the solid or 
vapour state. The resonance of the ion may also account for the 
fact that in some reactions the ester gives C-, and in others O- 
derivatives. Thus when ethyl acetoacetate is treated with benzoyl 
chloride in the presence of pyridine it gives an O-benzoyl derivative, 
CH 8 C(O*CO-C e H 5 ):CH'COOEt, but when its sodium derivative 

831 



832 ISOMERIC CHANGE 

reacts with benzoyl chloride or with alkyl halides, a C-derivative, 
CH 3 -CO-CHR-COOEt, is produced. The alkali derivatives of 
such tautomeric substances are mainly ionic compounds in which 
the metal is associated with the mesomeric form of analogues of 
(i), (n), and (in). The copper, beryllium and other metal derivatives 
of j8-diketones are, however, co-valent and chelated (p. 775), as, 
indeed, are the enolic forms themselves (p. 833). 

Some other interesting examples of the phenomenon of des- 
motropism are given below. 

Dibenzoylacetylmethane, CH 3 .CO-CH(CO-C e H 5 ) 2 (dibenx- 
oylacetone), is prepared by treating an ethereal solution of benzoyl- 
acetone (p. 823) with benzoyl chloride in the presence of sodium 
carbonate, and decomposing an aqueous solution of the sodium 
derivative thus formed with acetic acid. The. precipitated impure 
enolic form melts at 80-85, but the liquid slowly solidifies and 
melts again at 99-101 (equilibrium mixture). The enol gives an 
immediate colouration with ferric chloride in alcoholic solution and 
is immediatelv soluble in alkalis. The ketonic form melts at 150, 
and only gives these reactions after it has passed into the enoi. 

When either isomeride is dissolved in hot anhydrous alcohol and 
the solution is rapidly cooled, the deposit is a mixture of both, but 
when the solution of the enol in aqueous alcohol evaporates slowly 
at ordinary temperatures, the pure keto-form is deposited. In the 
latter case the solution becomes saturated with the keto-isomeride, 
and, as this form then separates in crystals, the equilibrium is 
disturbed and more keto-isomeride is produced, until finally the 
change is complete. 

Diethyl diacetylsuccinate, EtOOC - CHAc - CHAc COOEt, 
prepared from ethyl sodioacetoacetate (p. 824), may be a dl- or a 
meso-compound in its diketonic form, because the molecule contains 
two asymmetric carbon-groups of identical structure, but these 
two forms, which melt at 30 and 90, are in equilibrium in solution 
owing to keto-enol change. The mono-enolic form, which owing 
to chelation (p. 833) would not be expected to exhibit cts-trans- 
isomerism, is a ^/-compound and the di-enolic form (m.p. 45) 
is probably doubly chelated. Two mono-enolic forms have been 
described ; one is a liquid, the purity of which is doubtful, and the 
other melts at 20. 

Diethyl dibenzoylsuccinate, EtOOC [CH(COPh)] 2 - COOEt, 
obtained from ethyl sodiobenzoylacetate (p. 827), also exists in 



ISOMERIC CHANGE 833 

desmotropic ketonic and enolic forms, and the two types show 
considerable differences in their absorption spectra. 

Benzoylcamphor has also been obtained in two crystalline 
desmotropic forms, which may be represented as below, but the 
enol is probably chelated (below) : 

v'CHCO'C 6 H 5 ^ /C:C(OH)'C0H B 

C 8 H H\ I C 8 H H\ I 

x co * x co 

Owing to the readiness with which tautomeric change usually 
occurs in the presence of traces of alkalis or acids, attempts to 
determine the proportion of the tautomerides in any given allelo- 
tropic mixture by colorimetric methods with ferric chloride, by 
titrating the enol with bromine, or by precipitating it with cupric 
acetate (p. 200), give only approximate results, which, however, 
may sometimes be supplemented by a study of the physical pro- 
perties of the mixture (density, molecular refraction, etc.)* 

It has thus been found that the proportion, keto : enol, in the 
case of a given allelotropic mixture, usually varies considerably 
with the temperature ; but in the case of ethyl acetoacetate, the 
equilibrium is practically unaltered by changes of temperature, 
even up to the boiling-point of the ester. When in solution, the 
nature of the solvent and the concentration of the solution also 
influence the proportion of the isomerides ; in general, the per- 
centage of enol is low in water, formic acid, and acetic acid, :: , .*' : 
in the order given, and is greatest in non-dissociating solvents such 
as benzene and hexane. It has already been seen that the boiling- 
point of the enol is lower than that of the keto-form (p. 205). 

These facts, which at first sight appear to be anomalous, are 
accounted for by the assumption that the enol is not a hydroxy- 
compound, but resembles rather an ether, owing to the occurrence 
of chelation (p. 489) : 



L H 

*c* * OEt 

H 

chelation would also explain the stabilities of the enolic forms of 
l:3-diketones, which can give a practically strainless six-atom ring 
containing two double bonds. 
Keto-enolic tautomeric change of a modified type may take place 



834 ISOMERIC CHANGE 

even when the CO and CH a groups are separated from 
one another by one or more carbon atoms ; the two acids, 

/CO COOH yC(OH) - COOH 

CEt 2 ( * CEt 2 < I 

X CH 2 -COOH * X CH.COOH 

for example, are converted one into the other by concentrated alkali 
and the same equilibrium mixture is obtained from either compound ; 
as the hydroxy-form is not an unsaturated alcohol (enol), this change 
is known as keto-cyclol tautomerism. 

Keto-lactol tautomerism, in which a hydrogen atom passes from 
a carboxyl to a carbonyl group, with the formation of a lactone, also 
involves ring closure ; laevulic acid, for example, behaves like a 
ketone in most of its reactions, but gives an acetyl derivative of the 
hydroxy- or lactol form, 

otx *f*f\mf*vt - u *^^^* **** *^ r **JI 

VH a *1A/ VllJ XlON* \ 

I * I p 

CHa'COOH H a c ^c& 

J&to-cytffo-tautomerism, in which a hydrogen atom passes from 
a hydroxyl group to a carbonyl oxygen atom, with the formation of 
a closed chain, is of particular interest (Helferich and Malkomes, 
Ber. 1922, 702), y-Acetylpropyl alcohol, (i), for example, prepared 
by the ketonic hydrolysis of ethyl p-bromoethylacetoacetate, 
CH 8 .CO-CH(COOEt)-CH 2 .CH 2 Br, gives an oxime, but in other 
reactions it behaves as if it had the structure of the tetrahydrofuran 
derivative, (n), 

CHjCOCH s ^ 

CHa'CHa'OH * 

I II 

Similarly y-hydroxy-n-valer aldehyde, (in), is tautomeric with 
methylhydroxytetrahydrofuran, (iv), and S-hydroxycaproaldehyde, (v), 
with methylhydroxytetrahydropyran 9 (vi) : 

CHa'CHO > 

CHaCH(OH)'CH, * 

III IV 



ISOMERIC CHANGE 835 

.CH..CHO _^ H,C-CH.OH 

CHa< Z3 H,C 

N CH 1 .CH(OH).CH, 



V VI 

Both these substances, (in) and (v), give the reactions of aldehydes, 
but do so only slowly, and judging from their physical properties 
(molecular refraction), their allelotropic mixtures consist almost 
entirely of the closed chain structures, (iv) and (vi) ; both of them, 
like a sugar, can be methylated with methyl alcohol and hydrogen 
chloride, a reaction which does not occur in the case of a simple 
alcohol. 

Keto-cyclo-tautomeric changes, strictly analogous to the above, 
are observed in the molecules of the polyhydric ketones and alde- 
hydes, that is to say, in the sugars ; the ketonic or aldehydic form 
apparently exists in solution in equilibrium with the furanose or 
pyranose structure (pp. 874, 873). In all such cases, two (a- and ]8-) 
diastereoisomeric forms of the closed chain molecule are possible, 
so that the solution contains an equilibrium mixture of three com- 
pounds, of which the ketonic or aldehydic form is probably present 
in small proportions only. 

It was at one time believed that the mutarotation of certain sugars 
was due to the conversion of the a- into the j3-form, or vice versa, 
by the addition to, and subsequent elimination of a molecule of 
water from, the carbonyl group, but the study of the keto-cyclo- 
tautomerism of simple ketones and aldehydes seems to show that 
such an assumption is unnecessary ; the two epimeric sugars may 
be regarded as keto-cyclo-tautomeric forms of the hydroxy-aldehyde 
or ketone, and it has been found that the conversion of one into the 
other may occur in the absence of water. 

Desmotropes of simple mono-ketones are rare, or unknown, 
and their molecules seem to exist almost entirely in the ketonic form ; 
nevertheless, such compounds may show tautomerism and give 
derivatives of both isomerides. Acetone, for example, forms a 
sodium derivative and behaves towards bromine like an enol ; cyclo- 
hexanone gives an acetyl derivative of the enolic form with acetic 
anhydride, and methylindanone (p. 749) is doubtless partly converted 
into the enol by alkali ; in all these cases the liquid substance is 
probably an allelotropic mixture, consisting almost entirely of the 
carbonyl form. 



836 ISOMERIC CHANGE 

On the other hand, phenols, naphthols, etc., exist as enols owing 
to the stability of the benzene ring ; if they passed into ketonic 
modifications, unstable dihydro-aromatic rings would be produced. 
Phloroglucinol, a tri-enol, however, can form a non-olefinic triketo- 
cyc/ohexane and derivatives of both forms are known (p. 493) ; in 
the solid state phloroglucinol is probably an enol. 

The Tautomerism of Nitro-compounds 

The tautomerism of primary and secondary nitroparaffins has 
already been mentioned (p. 194). In the case of phenylnitro- 
methane, the isolation of the normal, Ph-CH 2 'NO 2 , and aci-forms, 
Ph.CH:NO-OH, has been described (p. 437); the former is an 
oil and gives no colour with ferric chloride, whereas the latter 
melts at 84, gives a red colour with ferric chloride and is an 
electrolyte. 

TT-Bromo-a-mtrocamphor has also been obtained in two forms. 
The one melts at 142 and has [a] D 4-188, the other melts at 108 
and has [a] D 51 ; both compounds show mutarotation and the 
equilibrium mixture from either has [a] D 39 (all the specific 
rotations refer to a benzene solution). When either of the desmo- 
tropes is dissolved in chloroform and the solution is evaporated at 
ordinary temperatures, the deposit finally contains both forms, an 
unusual phenomenon, due to the slowness with which the one is 
converted into the other in the absence of any added catalyst (p. 833) ; 
in alcoholic solution in the presence of ferric chloride, however, the 
change is very ra]pid, and both forms give an immediate colouration. 
These observations may be accounted for by assuming that the 
structure, (i), is tautomeric with a chelated form, (n), or (in) : 



^ C ,H ls B< 

o" 

i ii in 

a-Nitrocamphor also shows mutarotation in the presence of traces 
of catalysts, but is known in only one form. 

It was at one time considered that optically active j3-nitrobutane, 
Et-CHMe-NO 2 , and j8-nitro-octane, C 6 H 13 -CHMe-NO 2 , yielded 
optically active sodium salts ; if this were so the salts could not 



ISOMERIC CHANGE 837 

have the structure [RR'C:NO-O]Na because the anion would not 
then show optical activity. As it now seems probable that these 
salts are not in fact optically active, the structures given above still 
serve to explain all the facts. 

According to Hantzsch, tautomerism is also observed in the case 
of o- and ^-nitrophenols. o-Nitrophenol, which has a light yellow 
colour, and p-nitrophenol, which is colourless, give highly coloured 
salts ; from the alkali metal salts, with alkyl halides, colourless 
alkyl derivatives, NO 2 -C e H 4 -OR, are produced, but in certain 
cases from the silver salts and alkyl halides, intensely coloured 
unstable alkyl compounds are formed. The latter are believed to 
be esters of quinonoid acids, (iv), which are formed from the nitro- 
phenols by a complex tautomeric change, but their nature is still 
unsettled. The chelation of o-nitrophenols has already been 
mentioned (p. 489). 



,NO-OH 




p-Nitrosophenol, prepared from phenol and nitrous acid, or from 
/>-nitrosodimethylaniline (p. 451), would seem to be represented 
by NO-C 6 H 4 -OH, but as the same compound is formed by the 
action of hydroxylamine on quinone, it might be quinone monoxime, 
HO*N:C 6 H 4 :O. It crystallises from ether in green plates, but 
can also be obtained in colourless crystals from aqueous solution ; 
both forms give the same green solution in these solvents, and as 
the compound gives the reactions of both the above structures, 
it is regarded as tautomeric. From a comparison of the absorp- 
tion spectra of ^-nitrosophenol with that of />-nitrosoanisole, 
NO'C 6 H 4 -OMe and the O-methyl ether of quinone monoxime, 
MeO-N:C 6 H 4 :O, it has been inferred that />-nitrosophenol exists 
as quinone monoxime. 

Tautomerism similar to that just described is shown by other 
nitrosophenols, as for example a-nitroso-/?-naphthol, but here 
presumably chelation is also possible. 

Other examples of isomeric change in which atoms or groups 
pass from the 1- to the 4-position in the benzene nucleus are given 
later (p. 844). 



838 ISOMERIC CHANGE 

Lactam-lactim Tautomerism 

The phenomenon of lactam-lactim tautomerism, expressed by 
CO-NH ^~7 C(OH):N , is observed in many ring com- 
pounds (pp. 580, 634, 1052, 1058), and indeed the first recorded 
case of tautomerism was that of isatin (Baeyer). As a rule such 
substances seem to have the lactam structure in the solid state, 
but usually give alkyl derivatives of both the forms ; the O-alkyl 
derivatives are hydrolysed by acids, but the N-alkyl compounds 
are not, so they are easily distinguished. Even simple amides, 
such as acetamide, give sodium salts and from urea, methylisourea, 
NH 2 'C(OMe):NH, may be obtained by the action of dimethyl 
sulphate. 

Imino-ethers, R-C(OR'):NH, are derived from the aci-forms of 
amides ; they may sometimes be obtained by treating the silver 
derivative of an amide with an alkyl halide, but more conveniently, 
by the interaction of a cyanide and an alcohol in the presence of 
hydrogen chloride, 

R-CN+ R'-OH R.C(OR'):NH. 

Amidines, R'C(NHR'):NH, are also derived from aci-amides, 
and may be obtained by the action of ammonia, or of an amine, on an 
imino -ether, or by heating an amide with an amine and phosphorus 
pentachloride ; in the latter reaction the amide is converted into 
the dichloro-derivative, R-CC1 2 *NH 2 , and then, by the loss of 
hydrogen chloride, into the imino-chloride> R-CC1:NH, which with 
the amine gives R-C(NHR'):NH. 

The anions of the alkali metal salts of imides, CO-NH-CO , 
such as succinimide and phthalimide, probably exist in mesomeric 
forms, 

CO-N CO or COrN-CO or CO N:CO-~ , 

which with alkyl halides give JV-alkyl derivatives. Similarly sulphon- 
amides, R-SO 2 .NHR', and disulphones, R-SO 2 .CH 2 -SCyR', 
both of which are soluble in alkali, probably give mesomeric anions. 

Three-carbon-atom Tautomerism 

It was found by Fittig that various j8y-unsaturated acids, 
ReH:CH'CH 2 -COOH, which are stable under most conditions, 



ISOMERIC CHANGE 839 

are converted into the aj3-isomerides when their solutions in aqueous 
alkali are heated ; during his study of the reduction products of 
the phthalic acids, Baeyer observed several cases of a similar kind, 
in which a j3y- is transformed into an aj8-isomeride, sometimes even 
by boiling water (p. 802). The resulting a|9-unsaturated acid, like 
the j8y-compound, is usually stable, both in the solid and in the 
dissolved state, except that it may be partially reconverted into the 
j8y-compound by boiling aqueous alkalis, and equilibrium between 
the two forms is then established ; the reaction, therefore, is a 
reversible one, and is an example of three-carbon-atom tautomerism y 

CH:CH-CH a ^ CH 2 -CH:CH 

In the case of such unsaturated acids, however, the alkaline 
solution does not contain a simple allelotropic mixture ; the salts 
of the two acids are in equilibrium with that of the j8-hydroxy-acid, 
which is formed by the addition of the elements of water to the 
aj8-unsaturated compound. 

Some aromatic jSy-olefmic acids, such as fi-benzylidenepropionic 
acid, C e H 6 'CH:CH-CH 2 -COOH, change into the aj8-isomeride 
only very partially, and the latter, y-phenykrotonic acid, is almost 
completely converted into the j8y-acid when it is merely warmed 
with pyridine. Certain aj3-olefinic acids, derived from cyclo- 
paraffins, are also practically completely converted into the /?y- 
cyc/o-olefimc isomerides by alkalis (Kon and Linstead, J. 1925, 616, 
815), as in the example given below, 



r**^^* 

2 X 



Vtijf*^^ 

C:CH-CQOH + \ X>CH,-COOH 



Particularly facile tautomerism of this type is shown by glutaconic 
acid derivatives, HOOC*CR:CH a .CHR'.COOH. 

Three-carbon-atom isomeric change is also shown by various 
allyl derivatives of benzene, in which the group CH 2 -CH:CH 2 
passes into CH:CH-CH 8 , when the compound is treated with 
alcoholic potash at high temperatures ; eugenol, for example, is 
converted into isoeugenol and safrole into i&osafrole, in this way 
(p. 951). These changes, however, seem to be non-reversible. 

Org. 53 



840 ISOMERIC CHANGE 

The Tautomerism of Diazoamino-compounds 

The group, N:N-NH , of diazoamino-compounds, under- 
goes tautomeric change, which may be compared with that of the 
three-carbon-atom system. When phenyldiazonium chloride is 
treated with />-toluidine the same compound is obtained as when 
p-tolyldiazonium chloride is treated with aniline : 

C 6 H 5 .N 2 C1+NH 2 .C 6 H 4 .CH 3 CH 5 .N:N.NH.C 6 H 4 .CH 3 i 
C 6 H 5 .NH 2 +C1N 2 .C 6 H 4 .CH 3 = C 6 H 6 .NH-N:N-C 6 H 4 .CH 3 n 

As two different products, having respectively the structures 
shown above, might be expected if the reaction is merely an elimina- 
tion of a molecule of hydrogen chloride, it must be inferred that 
one of the forms passes into the other by an isomeric change. On 
hydrolysis with acids, this product yields aniline, ^>-toluidine, phenol, 
and/>-cresol, and on reduction it gives aniline, ^>-toluidine, phenyl- 
hydrazine and />-tolylhydrazine ; it thus behaves as if it were a 
mixture of (i) and (n), which, therefore, are tautoijieric. Tauto- 
merism of this kind, in which both tautomerides are of the same type, 
is sometimes known as virtual tautomerism. 

The group, R N:CH-NH R', also undergoes tautomeric 
change into R NH-CHiNR' (p. 1051). 

Anionotropic Changes 

In all the above cases it is a hydrogen atom (or proton) which 
migrates and the changes may be termed prototropic ; many examples 
are known, however, in which a negative group migrates and such 
reactions are known as anionotropic. Thus the ^-nitrobenzoate 
of phenylvinyl carbinol, Ph-CH(OH)-CH:CH 2 , in boiling acetic 
acid solution gives the corresponding ester of y-phenylallyl alcohol, 
Ph CH:CH CH 2 OH , whereas under other conditions an equilibrium 
mixture of the two esters is produced. Similar changes often occur 
during reactions of allyl compounds as in the following examples, 

HBr 

CIVCHiCH-CHssOH - CH 8 -CH:CH-CH 2 Br 

+CH 3 -CHBr-CH:CH 2> 

Me CH:CH CHR' O CO R -^^ Me - CH:CH - CHR' - OH 

+Me-CH(OH)-CH:CHR', 

and another case has already been mentioned (p. 816). 



ISOMERIC CHANGE 841 

The conversions of linalool into geraniol (p. 942) and of nerolidol 
into farnesol (p. 947) are also of this type. 

A very interesting example described by Kenyon and his co- 
workers is that shown below, and in many cases, if the original 
alcohol is optically active, activity is also shown by the product 
although it is due to a different asymmetric group. 

R \ c / CH v/ Me 

/*"\ ^\ " 
W N OH X H W HCT H 



Reversible and Irreversible Isomeric Change 

In the preceding examples some of the substances which show 
tautomerism give allelotropic mixtures with great rapidity at 
ordinary temperatures in the presence of catalysts, and the mixtures 
may contain considerable proportions of both forms. In other 
cases the change is brought about only slowly even by concentrated 
reagents, the one form may be present in the equilibrium mixture 
in very small proportions, and the only evidence of its presence is 
that some of its derivatives can be isolated ; the unknown, unstable, 
or labile isomeride is then called the pseudo-form (p. 437). There 
are also many cases in which a compound can be transformed into 
an isomeride with the aid of heat, or reagents, or both, but this 
isomeride cannot be reconverted into the original compound under 
the same, or other, conditions ; the isomeric change is complete and 
irreversible. When, for example, a ketoxime undergoes the Beck- 
mann transformation, and is converted into a substituted amide, 
the latter cannot be reconverted into the oxime. Similarly, when 
hydrazobenzene is transformed into benzidine, the latter is not 
reconverted into the parent substance, when it is heated with strong 
acids or treated in other ways. 

All grades of behaviour between clearly defined examples of 
dynamic equilibrium on the one hand, and completed irreversible 
isomeric changes on the other, are known, and in many cases it is 
difficult to decide under which heading the change should be classed. 
Ammonium cyanate is stable in the dry state, but when it is dissolved 
in water or gently heated, it is almost completely transformed into 
urea ; the latter is also stable in the dry state and seems to crystallise 
from water unchanged, but in fact, at 100, in aqueous solution, 



842 ISOMERIC CHANGE 

4-5% of the urea is converted into ammonium cyanate. The appar- 
ently irreversible completed change, 

NH 4 .O-CN * NH 2 .CO-NH 2 , 

is in fact reversible and incomplete. 

It is also difficult to decide in many cases whether the trans- 
formation is merely a rearrangement of the atoms of a molecule 
(awJramolecular), or whether it is the final result of several inter- 
mediate stages in which two or more different molecules take part 
(wtermolecular). 

Some further important types of isomeric change and the methods 
by which these problems are investigated may now be considered ; 
many of them are associated with the names of those by whom they 
were first described or investigated. 

The benzidine transformation occurs in the case of various 
hydrazo-compounds in which both p-positions are free (p. 464 and 
footnote, p. 678) ; if, however, one of these is occupied, the change 
proceeds in one of three ways : (1) The group in the ^-position is 
displaced and the normal change occurs, as in the case of 4-carboxy- 
hydrazobenzene, C e H 5 .NH-NH.C 6 H 4 -COOH, which yields benz- 
idine. (2) An ottho-semidine, 





NH-NH 

~ C a H 6 

or (3) a pzra-semidine transformation occurs, 




NH-NH 





In some cases, however, both ortho- and ara-semidine changes 
take place together, and in others a 2:4'-diamino-derivative of a 
substituted diphenyl may be formed : 




843 



NHi 
(CH 3 ) 2 N ~~ 

If both jp-positions are occupied, either the or/Ao-semidine change 
takes place or fission occurs, so that when a pp'-a*o-derivative is 
reduced with tin and concentrated hydrochloric acid, the hydrazo- 
compound which is first formed does not undergo any of the above 
changes, but is converted into a mixture of two amines, 

CH 3 - C 8 H 4 N:N - C 6 H 4 - O - Bz+4H - 

CH 3 .C 6 H 4 .NH 2 +H 2 N.C 6 H 4 .O.Bz. 

That the benzidine transformation is infra- and not wter-molec- 
ular has been shown by Ingold and Kidd (J. 1933, 984), who found 
that 2:2'-dimethoxy- and 2:2' -diethoxy-hydrazobenzene underwent 
the change when mixed together but not a trace of an unsymmetrical 
benzidine could be detected in the product. 

The benzidine change has also been carried out with many 
unsymmetwcal hydrazo-compounds, XC 6 H 4 NH NH C 8 H 4 Y, in 
which X and Y are not/)- to the nitrogen atoms, but no symmetrical 
benzidine, 

NH 2 -C 6 H 3 X.C 6 H 3 X.NH 2 or NH 2 -C 6 H 3 Y.C 8 H 8 Y.NH 2 , 

has been isolated from such reactions. 

In the structure of hydrazo-compounds as usually written the 
distance between the two ^-positions at which union occurs appears 
to be very large, but in fact the molecule is not linear and it is 
probable that during the change the two nuclei are in parallel planes. 
In this event the intramolecular nature of the change can be readily 
understood and the o-seinidine and ^-semidine transformations 
would require only a rotation of the nuclei relative to one another. 

The diazoamino-aminoazo transformation (p. 462) is inter- 
molecular and takes place in two stages ; the evidence for this seems 
conclusive. Firstly, if the change is carried out in the presence of 
an amino-compound different from that to which the ArN 2 -group 
is attached, a mixture of two aminoazo-derivatives is often formed ; 
this is easily accounted for by the suggested mechanism, 

Ph-N 2 .NH.Ph+HCl - Ph'N 2 Cl+PhNH 2 , 
Ph-N 2 Cl+C 8 H 4 X.NH a - Ph.N 2 *C 6 H 3 X.NH 2 +HCl. 



844 ISOMERIC CHANGE 

Secondly, the formation of phenyldiazonium chloride during such 
a reaction has been proved by Kidd, who, by the addition 
of a solution of diazoaminobenzene in hydrochloric acid to an 
alkaline solution of j3-naphthol, obtained a high yield of benzeneazo- 
j3-naphthol. 

Lastly, it has been shown that phenyldiazonium chloride and 
aniline condense to give diazoaminobenzene, aminoazobenzene or 
mixtures of the two compounds under different conditions of 
acidity of the solution.. 

The Hofmann-Martius conversion of methylaniline into o- 
and p-toluidine (p. 450), and of methylpyridiniuin iodide into a- 
and y-rnethylpyridines (p. 570), may also occur in two stages and 
Hickinbottom has suggested that an alkyl radical separates as a 
positive ion, which may then react with the base to give a nuclear 
substituted amine or be converted into an olefine : 

CH 6 NH a [CH 2n+1 - C 6 H 4 NHJ+ 

[C 6 H 6 .NH a .C n H 2n+1 ]+ + or 

CJHi+i [C 6 H 6 -NH 8 ]+ + C n H lw 

In the comparable isomeric change of AT-alkylpyrroles into 
C-alkyl derivatives (pp. 588, 600), by passing the former through 
a strongly heated tube, it would seem, however, that the irreversible 
isomeric change involves a simple transposition of an alkyl group 
and a hydrogen atom. 

The formation of />-chloroacetanilide from the chloroamide, 
C 6 H 5 NCI CO CH 3 (p. 1016), of anilinesulphonic acid (sulphanilic 
acid) from sulphamic acid C 6 H 5 -NH-SO 3 H (p. 1015), and of p- 
aminophenol by treating phenylhydroxylamine (p. 465) with 
sulphuric acid, seem to be simple transpositions, but in the first 
case, at least in aqueous solution, this is not so ; the chloroamide 
undergoes isomeric change owing to the intermediate formation of 
chlorine (Orton and Bradfield, J. 1927, 986) which then reacts with 
the acetanilide : 

C 6 H 5 .NCl-CO.CH 3 -f HC1 - C 6 H 5 .NH-CO-CH 3 +C1 2 , 
C 6 H 6 .NH.CO-CH 3 +C1 2 - C 6 H 4 C1.NH.CO-CH 8 +HC1. 

This view is confirmed by the fact that chloroamides in the 
presence of hydrochloric acid, chlorinate amines, phenols, etc. 



ISOMERIC CHANGE 845 

The conversion of phenylmethylnitrosoamine, C 6 H 5 NMeNO, 
into />-nitrosomethylaniline by alcoholic hydrogen chloride, is also 
probably due to reactions between different molecules. 

Many cases are known in which isomeric change occurs owing 
to the migration of an acetyl, benzoyl, or other acyl radical (Fries 
reaction) ; in some of these there is direct evidence that the change 
takes place in stages between different molecules, whereas in others 
the mechanism is doubtful. Ethyl 2-acetoxy-3-naphthalenecarb- 
oxylate, for example, treated with aluminium chloride in nitro- 
benzene solution, is transformed (after the addition of water) into 
ethyl l-acetyl-2-hydroxynaphthalene-3-carboxylate, 





Apparently this is the result of a simple migration of the acetyl 
group; but since acetyl-a-naphthol, C 10 H 7 -OAc, under similar 
conditions, gives not only \-hydr oxy-2-acetylnaphthalene y by 
* isomeric change/ but also l-hydroxy-2:4-diacetylnaphthalene, it 
must be concluded that the acetyl group is eliminated as acetyl 
chloride, which then reacts with the aromatic nucleus of the same 
or of a different molecule, giving 2- and 2:4-diacetyl derivatives. 

When phenylallyl ether is heated at about 200, o-allylphenol is 
formed (Claisen) and in similar cases the product is always the 
0-compound. That this transformation is intramolecular is shown 
by the fact that when a mixture of phenylcinnamyl ether and 
jS-naphthylallyl ether is heated, the two compounds undergo iso- 
meric change independently of one another. The product from 
phenylcinnamyl ether is o-a-phenylallylphenol, 





in which the carbon atom originally combined with oxygen is not 
attached to the nucleus in the product. In cases where both 
o-positions are occupied the hydrocarbon group migrates to the 



846 ISOMERIC CHANGE 

/^-position, but the carbon atom of this group, which was combined 
with oxygen, now becomes directly united to the nucleus, 

0-CH 2 -CH:CHPh 
COOH 





CH a -CHJCHPh 



If both o- and />-positions are occupied decomposition into a 
phenol and a mixture of unsaturated hydrocarbons occurs. 

When the benzoyl derivative of o-nitrophenol is reduced with 
tin and hydrochloric acid, it gives o-benzoylaminophenol, 

N0 2 .C 6 H 4 .O.CO.C 6 H 6 > C 6 H 5 .CO-NH.C 6 H 4 .OH; 

but although apparently the benzoyl radical in the initial reduction 
product, NH 2 'C 6 H 4 -O'COC 6 H 5 , passes directly from oxygen to 
nitrogen, it is more probable that, after reduction, ring-closure 
occurs, and subsequently ring-fission, by hydrolysis. 

On the other hand the conversion of triphenylacetaldehyde into 
phenyldesoxybenzoin (diphenylacetophenone) , 

(C,H S ) 3 C.CHO * (C 6 H B ) 2 CH.CO.C 6 H 5 , 

which is brought about by acids, appears to be the result of a simple 
transposition of a hydrogen atom and a phenyl radical. 

In certain aliphatic compounds the displacement of an amino- 
by a hydroxyl group, with the aid of nitrous acid, is often accom- 
panied by an apparent isomeric change ; propylamine, for example, 
gives both propyl and tsopropyl alcohols, and in Demjanov's re- 
action (p. 784) changes in ring-structure take place. 

The Beckmann transformation is intramolecular, as is shown 
by the formation of optically active acetyl-y-heptylamine from 
active methyl-y-heptyl ketoxime (Kenyon and Young, J. 1941, 264), 

C 4 H, - CH(Et) . C . Me OC Me 

II I 

NOH NH.CH(Et).C 4 H, 

since it is clear that the heptyl group is never free during the change, 
otherwise racemisation would have occurred. 

The Hofmann and Curtius reactions, summarised in the 
following equations, have already been briefly mentioned, 



ISOMERIC CHANGE 847 

R-CO-NH 2 + Br a +4KOH - R-NH 2 + K 2 CO 3 -h2KBr+2H 2 O, 
R.COOH+N 3 H - R.NH a +C0 2 +N 2 . 

Another change of a similar type, known as the Lessen rearrange- 
ment, occurs when hydroxamic acids or their salts or esters are 
heated, or treated with reagents such as thionyl chloride, 

R-CO-NH.OH > R-NCO+H 2 * R-NH 2 -hC0 2 . 

In all these reactions a radical migrates from carbon to nitrogen 
at some stage and an tyocyanate is produced, 

R.CO-NHBr > R-NCO+HBr, 
R.CON 3 > R-NCO+N 2 . 

Wallis and his co-workers (J. Am. Chem. Soc. 1926, 169 ; 1931, 
2787 ; 1933, 1701) found that if the reactions are performed on an 
amide, azide and hydroxamic acid in which the a-carbon-group is 
asymmetric, optical activity is retained and the rotation of the amine 
so produced is the same in all three cases, 



Furthermore when the amide of optically active 2-a-naphthyl- 
3:5-dinitrobenzoic acid, in which the activity is due to restricted 
rotation (for which the presence of groups in the phenyl radical in 
both positions ortho to the union with the naphthyl radical is 
essential), is submitted to the Hofmann reaction, an active amine 
is formed without any racemisation, 

NO, 
NOj 




These facts prove that at no time is the migrating radical detached 
from the molecule and the change therefore is entirely intra- 
molecular, 
The benzil-benzilic acid transformation occurs when benzil, 



848 ISOMERIC CHANGE 

heated with concentrated aqueous alkali, is converted into a salt of 
benzilic acid, and is undergone by certain other l:2-diketones. 
The ketone combines with a hydroxyl ion, and the product then 
undergoes isomeric change : 



Ph Ph Ph 

The pinacol-pinacolone transformation (p. 155) is an important 
general reaction in which isomeric change takes place, together with 
the elimination of the elements of water. The mechanism may be 
represented as similar to that of the benzil-benzilic acid change : 

^A? J 



Bartlett and his co-workers have found that the cw-form of 1:2- 
dimethykycfopentan-l:2-diol gives an 87% yield of 2:2-dimethyl- 
cyc/opentanone with dilute sulphuric acid, whereas the trans- 
isomeride gives tars only ; in other words, the change can only 
occur when the methyl group can expel a hydroxyl radical from the 



Glycols, CR 2 (OH)-CHR.OH, like pinacols, CR 2 (OH).CR 2 -OH, 
also undergo interesting changes, some of which resemble the 
pinacol-pinacolone transformation, but proceed in various ways 
according to the nature of the glycol, and the experimental con- 
ditions. These changes are : 

i CRPh(OH).CHPh-OH * CRPh 2 .CHO4-H 2 O, 
ii CRPh(OH).CHPh-OH CHRPh.CO-Ph+H 2 O, 
in CRPh(OH).CHPh-OH > R-CO.CHPh 2 +H 2 O. 

In (i) and in (in) the results may be brought about by a pinacol- 
pinacolone change of the usual kind, but in (n) there is no trans- 
ference of a phenyl group, and the formation of the ketone may be 
due to the direct elimination of the elements of water, followed by 
an enol-keto-change. 

Some very interesting results with related compounds have been 
obtained by McKenzie and his co-workers (J. 1923, 79 ; 1924, 844), 



ISOMERIC CHANGE 



849 



who have shown that when the amino-alcohol, (iv), is treated with 
nitrous acid, it does not give the glycol, CPh 2 (OH)-CHPh-OH, as 
might have been expected, but is converted into the ketone, (v). 
Similarly, when the amino-alcohol, (VT), is treated with nitrous acid, 
it gives the ketone, (vn), and the optically active amino-alcohol, 
(vin), is transformed into the optically active ketone, (ix) : 



iv Ph 2 C(OH).CHPh-NH 2 
vi PhCMe(OH)-CHPh-NH 2 
vin Ph 2 C(OH)-CHMe-NH 2 



PhCO-CHPhjj v 
MeCO-CHPh 2 vn 
PhCO-CHMePh ix 



All these results may be accounted for by assuming that the amino- 
group is displaced by hydroxyl in a normal manner, and that the 
glycol then undergoes change by a mechanism corresponding with 
that suggested for the ordinary pinacol-pinacolone transformation, 
and the reactions (i) and (in) shown on p. 848. When, however, the 
glycol, PhCMe(OH)-CHPh-OH, corresponding with the amino- 
alcohol, (vi), is actually prepared (by another method) and sub- 
mitted to dehydration, it does not give the ketone, (vn), as might 
have been expected, but is converted into an isomeric ketone, (ix). 
The Wagner-Meerwein rearrangement (p. 933) is of the same 
type as the pinacol-pinacolone change and may be represented 
similarly, 1 





It is possible that an organic ion with a mesomeric structure is first 
formed, which, in the case of pinacol and camphene hydrochloride, 
may be respectively represented as below : 



Me 



Me 



Me 



6H 




Whitmore (J. Am. Chem. Soc. 1932, 54, 3274) has put forward a 
general theory correlating many intramolecular rearrangements and 
1 These formulae are explained on p. 912. 




850 ISOMERIC CHANGE 

other abnormal reactions. The first stage in all such changes is the 
rupture of a non-ionic link between a carbon or a nitrogen atom, X, 
and an electronegative atom or group, Y, which is split off with its 
complete shell of electrons, thus leaving the carbon (or nitrogen) 
atom deficient, 

R.... 

rC.CX>Y. mmf^ 

...... 

If a negative ion :Z:~is then taken up directly, obviously no re- 
arrangement occurs, but if X has a greater attraction for electrons 
than C, then isomeric change occurs leaving C with the incomplete 
shell : 

[$*]* - [*H* 

finally a negative ion is recombined from the reaction mixture or 
a proton is lost. 

The production of oa-dimethylpropyl acetate from j8/J-dimethyl- 
propyl iodide with sodium acetate is thus represented as follows : 



Me H I Me H I I Me H Me H 

Mc:C : C: I - Mc:C : C -> C : C:Me - CH 8 CO:O*:C : c:Me 

I I I I 

Me H Me H Me H Me H 



The Hofmann reaction may be shown in a similar way : 



H 
[ - R:C:N:Br ->|R:C:N|-^IC:N:Rl-^C:N;R - O:ON:R 



From most of the examples given above it is obvious that there 
are many difficulties to be overcome in attempting to formulate the 
stages of what seem to be comparatively simple transformations. 
Isomeric change, reversible or irreversible, and in many cases 
preceded, or followed by other reactions, is, however, such a 
common phenomenon of organic chemistry, that it is met with in 
nearly all types of compounds ; other interesting examples, not 
given in this chapter, will be found on pp. 715, 934, and 1024. 



CHAPTER 52 

THE CONFIGURATIONS, SYNTHESIS, AND GLYCO- 
SIDIC STRUCTURES OF THE MONOSACCHARIDES * 

The Configurations of the Monosaccharides 

THE molecule of an aldohexose, like that of the wonocarboxylic 
acid derived from it, contains four structurally different asymmetric 
carbon-groups, and theoretically, therefore (p. 307), there will 
be sixteen optically isomeric aldohexoses of the constitution 
CH 2 (OH)-[CH(OH)] 4 -CHO, and sixteen optically active mono- 
carboxylic acids corresponding with them. These sixteen optically 
isomeric forms may be classed in eight pairs of enantiomorphously 
(antimerically) related compounds. 

The molecules of a hexahydric alcohol (hexitol) of the constitu- 
tion, CH 2 (OH)-[CH(OH)] 4 -CH 2 -OH, and those of the corres- 
ponding dfcarboxylic acids also contain four asymmetric groups, 
but in the case of these compounds only ten optical isomerides are 
theoretically possible. The reason for this is, that whereas all the 
four asymmetric carbon-groups in the molecule of an aldohexose 
or monocarboxylic acid are structurally different, in the molecule 
of a hexitol or of a dicarboxylic acid this is not so ; two optically 
isomeric aldohexoses may correspond with, and be converted into, 
one hexitol or one dicarboxylic acid only. This difference can be 
made clear with the aid of the usual projection formulae. 2 Thus, 
the configurations (i) and (n), and (in) and (iv), represent the rf- 
and /-forms respectively of two hexoses, configurations (v)~(vin) 
those of the corresponding hexitols : 



CHO CHO CHO CHO 



OH HO 

OH HO 

OH HO 

OH HO 



H H 

H HO 

H H 

H H 



OH HO 

H H 

OH HO 

OH HO 



H 
OH 
H 
H 



CH.-OH CH.-OH CH,-OH CH.-OH 
I II III IV 

1 This and the following chapter should be read as a continuation of 
Chapter 19, p. 310, 

8 Some of the C symbols are for clarity omitted in such projection formulae. 

851 



852 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 
CHa-OH CHj-OH CH a -OH CH 8 -OH 



OH HO 

OH HO 

OH HO 

OH HO 



H H 

H HO 

H H 

H H 



OH HO 

H H 

OH HO 

OH HO 



H 
OH 
H 
H 



CH a .OH CHa-OH CHa-OH CH a -OH 

V VI VII VIII 

An examination of these shows, however, that when the two ends 
of the chain in (i) and in (n) have been made the same (in the 
hexitols), configurations (v) and (vi), which result, are identical ; 
for, after rotating either through 180 in the plane of the paper it 
can be superposed on the other, whereas this is not the case with 
(i) and (n), (in) and (iv), or (vn) and (vin). 

It should be clearly understood in using these projection formulae 
that whilst they may, for comparison, be rotated in the plane of the 
paper without changing their significance, rotation in other ways is 
inadmissible; thus by turning (in) through 180 about its long 
axis, it gives a configuration apparently, but not actually, identical 
with (iv) ; similarly for (i) and (n), or (vn) and (vm). That these 
pairs are not, in fact, identical, will be understood when it is remem- 
bered that the molecule does not actually lie wholly in one plane ; 
such a rotation will not, therefore, produce coincidence. 

The configuration (v or vi) corresponds with that of meso- 
tartaric acid, and the molecule has a plane of symmetry which is 
lacking in (i) and (11). 

The molecule of an aldopentose, such as /-arabinose, and that of 
the corresponding w00carboxylic acid, contain three structurally 
different asymmetric carbon-groups, and eight optical isomerides 
of both of these types are possible ; in each case these eight iso- 
merides constitute four pairs of enantiomorphously related com- 
pounds. 

The molecule of a pentitol, 

CH 2 (OH) CH(OH) - CH(OH) CH(OH) - CH 2 OH , 
and that of an ajSy-trihydroxyglutaric acid, 

COOH CH(OH) - CH(OH) - CH(OH) - COOH, 

derived from an aldopentose, contain, however, two asymmetric 
carbon-groups only, because in these compounds the central carbon 
atom is combined with two structurally identical groups namely, 
either [ CH(OH) CH 2 - OH] or [ CH(OH)-COOH], and has 



STRUCTURES OF THE MONOSACCHARIDES 853 

lost its asymmetry. When the two outer CH(OH) groups have 
the same configurations, d- and d-> or /- and /-, the compound is 
optically active, just as in the case of the tartaric acids ; when, 
however, these two asymmetric groups have different configurations 
(one being d- and the other /-), although optical inactivity results, 
the presence of the central >CH(OH) group renders possible the 
existence of two stereoisomeric (inactive) forms. There are, there- 
fore, only four stereoisomeric pentitols, of which two, (ix) and (x), 
are enantiomorphously related and optically active, and two, (xi) 
and (xu), are inactive w^ro-compounds, each possessing a plane of 
symmetry. 1 The four stereoisomeric ajSy-trihydroxyglutaric acids 
correspond with the pentitols, only two of them being optically active. 



HO 
H 
H 



H H 

OH HO 
OH HO 



OH HO 
H HO 

H HO 



H HO 
H H 

H HO 



H HO 

OH HO 
H H 



H H 

H H 

OH HO 



OH 
OH 

H 



IX X XI XII XIII XIV 

It should be noted that formulae (xm) and (xiv), which might 
appear at first sight to represent two more pentitols, are identical 
with (ix) and (x) respectively, and can be superposed on the latter 
after their rotation in the plane of the paper. 

Now it has been found possible to establish not only the structural 
relationships of the various aldoses and those of their immediate 
derivatives, but also to determine the manner in which these 
compounds are related in configuration, and to assign to each a 
definite configurational formula. 

There are various ways in which this can be done, but whatever 
method is used, it is necessary to bear in mind certain facts which 
have been established experimentally ; with these as a basis the 
configurations may then be deduced in a relatively simple manner. 

The basic facts required for the method employed below are as 
follows : (1) There are four stereoisomeric pentitols (ix, x, xi, xu, 
above) ; of these, two (d- and /-arabitol) are optically active, whereas 
the other two (xylitol and adonitol) are inactive. 

(2) /-Arabinose combines with hydrogen cyanide, and the cyano- 
hydrin thus obtained is converted on hydrolysis into optically 
isomeric, epimeric acids (p. 749), namely, /-gluconic acid and 
/-mannonic acid, formed respectively by the oxidation of /-glucose 

1 The carbon symbols and the CH 2 OH (or COOH) groups are con- 
veniently omitted in these configurations. 



854 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

and /-inannose. The formation of two optically isomeric acids in 
this way is explained as follows : By the combination of the aldehyde 
with hydrogen cyanide, a new asymmetric group is synthesised, and 
consequently both the theoretically possible forms of this new group 
may be produced, just as in the synthesis of lactic acid from acet- 
aldehyde. There are, therefore, two optically isomeric products, 
both of which contain the three asymmetric groups of the original 
aldopentose, but which differ in configuration as regards the new 
asymmetric group. If, for example, the original aldopentose had 
the configuration (xv), the epimeric products would be (xvi) and 
(xvn) : 

COOH COOH 



CHO 



H 
HO 
HO 



OH 

H 

H 



CHa-OH 



H 
H 

HO 
HO 



OH 
OH 
H 
H 



CHa-OH 



HO 
H 

HO 
HO 



H 
OH 
H 
H 



XV 



XVI 



CHa-OH 
XVII 



(3) Glucose and gulose are related to one another in the manner 
shown on p. 860. Both these aldohexoses give on oxidation one 
and the same optically active dicarboxylic acid (saccharic acid), and 
on reduction one and the same active hexitol (sorbitol). It is clear, 
therefore, that any configuration which would lead to the production 
of an optically inactive (mwo)dicarboxylic acid or hexitol cannot 
represent either of these aldohexoses. With these facts in mind, 
the configurations of the more important members of the mono- 
saccharides may now be considered. 

Since the molecules of the two optically inactive pentitols (xylitol 
and adonitol) must have a plane of symmetry, they must be repre- 
sented by configurations A and B, whereas rf- and /-arabitol must 
be represented by C and D, which are antimeric. 



HO H 
HO;H 
HO|H 

A 



HO 

H 

HO 



H 

OH 

H 



H 

HO 
HO 



OH 

H 

H 



HO 
H 
H 



H 

OH 

OH 



Now, let C represent /-arabitol, and D, rf-arabitol ; this is, of 
course, an arbitrary choice (p. 859), but according to a convention 
all members of the ^/-series are represented as having the hydroxyl 
radical of the bottom H C OH group on the right-hand side, 
and as derived from d-glyceraldehyde (p. 874) by extending the 



STRUCTURES OF THE MONOSACCHARIDES 



855 



molecule upwards from the CHO-group. In such projection 
formulae, moreover, the main carbon chain is considered to lie in 
the plane of the paper so that the hydrogen atoms and hydroxyl 
groups are above this plane, as indicated below. This becomes 
important when the ring structures of the sugars are considered 
(p. 872). 



H C OH 

H C OH represents H 

H C -OH 




Each of the four pentitols gives rise to two aldopentoses, because 
when either the upper or the lower CH 2 -OH group (not shown) 
is changed into CHO, the configuration of the aldopentose which 
results will depend on which of the two CH 2 *OH groups has 
been transformed. 

The two aldopentoses derived from /-arabitol are therefore C x 
and C2, 1 according as the upper or the lower CH 2 -OH group is 
transformed into CHO : 



H 
d HO 



HO 



CHO 
OH 
H 
H 



CH,-OH 



H 
HO 
HO 



CH.-OH 



^n a - 

OH 
H 
H 
CHO 



C, 



CHO 
HIOH 
H OH 
HOIH 

CH 2 -OH 



Since /-arabinose is formed by the oxidation of /-arabitol, and 
is converted into the latter on reduction, the configuration of 
/-arabinose must be expressed by C x or C 2 . 

/-Arabinose can be converted into a mixture of /-gluconic and 
/-mannonic acids, from which /-glucose and /-mannose respectively 
are obtained (p. 853) ; since /-arabinose has the configuration Cj 
or C 2 , the configurations of /-glucose and of /-mannose must be 

1 The central formula is given to show how C s is arrived at, namely, 
by changing the lower CH 8 'OH group into CHO, and then turning 
the configuration through 180 in the plane of the paper in order to bring 
the CHO groups in C x and C 8 into corresponding positions for purposes 
of comparison. 

Org. 54 



856 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

among the following, all of which are obtained by changing the 
CHO group in C x or C 2 into CH(OH)-CHO : 



HO 

H 

HO 

HO 



CHO CHO CHO CHO 



H H 

OH H 

H HO 

H HO 



OH HO 

OH H 

H H 

H HO 



H H 

OH H 

OH H 

H HO 



OH 
OH 
OH 
H 



J A A iiW J.J. J.J.VS J.A AAV/ A A 

CH 2 -OH CHg-OH CH 2 -OH CH a -OH 

Derived from C 4 Derived from C a 

I II III IV 

Now, /-glucose on reduction gives /-sorbitol, and on oxidation, 
first /-gluconic acid and then /-saccharic acid. /-Mannose similarly 
gives /-mannitol, /-mannonic acid, and /-mannosaccharic acid. All 
these compounds are optically active, whereas an aldohexose having 
the configuration (in) would give an optically inactive (meso)htxitol 
and an optically inactive (wwo)dicarboxylic acid, because when the 
terminal groups are made the same, the molecule has a plane of 
symmetry ; therefore the configuration (in) cannot represent either 
/-glucose or /-mannose, and since these two aldohexoses are derived 
from a single aldopentose (C A or C 2 ), the configuration (iv) is also 
excluded. 

/-Glucose and /-mannose, therefore, are represented by the 
configurations derived from C x ; C x , therefore, and not C 2 (p. 855), 
represents /-arabinose. 

Now, the aldohexose, gulose, is formed from glucose by trans- 
posing the groups CH 2 -OH and CHO (p. 860). If /-glucose 
had the configuration (u), such a transposition could not result in 
the formation of a new aldohexose (gulose) ; an aldohexose identical 
with /-glucose would be formed, as can be seen by transposing the 
groups and then rotating the configuration in the plane of the paper. 
Hence l-glucose must have the configuration (i), and l-mannose the 
configuration (n). 

The configuration of \-fructose is also established from its relation 
to /-glucose and /-mannose (p. 317), and because, on reduction, it 
gives a mixture of /-sorbitol and /-mannitol. The production of 
two optically isomeric hexitols in this reaction is due to the synthesis 
of both forms of a new asymmetric group, >CH-OH, from the 
> CO group ; these two epimerides, however, are not necessarily 
formed even in approximately equal proportions, since the molecule 
of the ketone is asymmetric (compare p. 747). 



STRUCTURES OF THE MONOSACCHARIDES 



857 



The configurations of /-glucose, /-mannose, and /-arabinose, 
and those of the corresponding hexitols and mono- and di-carboxylic 
acids, having been settled, those of the other aldohexoses and 
aldopentoses can be deduced, and are given in the table below. 
The C symbols and also those of the CHO and CH 2 -OH 
groups are omitted to save space, but it must be remembered that 
the CHO group is at the top of the configuration in all cases. 



Configurations of Members of the l-Family of Aldohexoses 



HO 

HO 
HO 



H 
HO 
HO 



OH 

H 

H 



HO 

H 

HO 



H 

OH 

H 



Adonitol 



/-Arabitol 



Xylitol 




HO 
HO 



OH 
H 



/-Altrose /-Allose /-Mannose /-Glucose /-Talose /-Galactose Mdose /-Gulose 

The experimental facts and arguments used in these further 
deductions are briefly as follows : /-Arabinose gives on very careful 
oxidation l-arabonic acid, CH 2 (OH)-[CH(OH)] 3 .COOH, which 
undergoes epimeric change, giving ribonic acid ; the lactone of 
ribonic acid, on reduction, gives an aldopentose, l-ribose, which, 
therefore, must have the given configuration, and which on further 
reduction gives (optically inactive) adonitoL 

From /-ribose two aldohexoses namely, /-allose and /-altrose 
can be derived, just as /-arabinose gives /-glucose and /-mannose. 
Since \-allose on oxidation gives an optically inactive Acarboxylic 
acid Q-altrose would give an active one), the configurations of these 
two aldohexoses must be respectively as shown. 

The aldopentose, l-lyxose, gives /-arabitol on reduction ; its 
configuration is therefore represented as above. 1 On oxidation, 
/-lyxose gives \-lyxonic acid, and the latter undergoes epimeric 
change, giving \-xylonic add, which is identical with the oxidation 
product of /-xylose ; the configuration of l-xylose, and that of its 

1 It will be seen that this configuration is C 2 (p. 855). 



858 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

reduction product, optically inactive xylitol, are thus determined. 
From /-xylose, just as from /-arabinose (p. 853), two aldohexoses 
namely, /-gulose and \-idose can be prepared. Since \-gulo$e on 
oxidation gives rf-saccharic acid, and is obtained from </-glucose * 
in the manner described (p. 859), its configuration, and consequently 
that of /-idose, is established. 

Of the remaining two aldohexoses, \-galactose y on oxidation, 
gives first \-galactonic acid and then optically inactive mucic acid 
(p. 313) ; as, moreover, it can be transformed into /-lyxose by the 
method already described (p. 321), its configuration and that of 
\-talose must be as above ; further, /-galactonic acid can be con- 
verted into \-talonic acid by epimeric change, and /-talonolactone 
can be reduced to /-talose. 

The four optically isomeric aldotetroses are d- and l-erythrose 
and d- and \-threose, which on reduction give three tetritols (d-, /-, 
and meso-) and three dihydroxydicarboxylic acids (</-, /-, and 
W$o-tartaric acids). /-Erythrose can be obtained from /-arabonic 
acid by either of the methods for the descent of the aldose series 
(p. 320), and on oxidation it gives wwotartaric acid. /-Threose can 
be obtained from /-xylose in a similar manner. The configurations 
of the tetroses are thus established : 



HOIH 
HOIH 



H 
HO 



OH 
H 



/-Erythrose /-Threose 

The d- and \-Families 

The configuration of d-glucose and that of any member of the 
(/-family, is, of course, enantiomorphously related to that of the 
/-isomeride. The configurations of the ten optically isomeric 
hexitols (or dicarboxylic acids) correspond with those of the aldo- 
hexoses from which they are derived. /-Glucose and rf-gulose give 
/-sorbitol (^/-glucose and /-gulose give rf-sorbitol), d- and /-galactose 
give (inactive) dulcitol, and d- and /-allose also would give one 
hexitol only ; rf-talose and rf-altrose would give the same hexitol 
(rf-talitol), whereas /-talose and /-altrose would give /-talitol. 

In the above discussion it has been assumed that every chemical 

1 If the gulose derived from J-glucose (i.e. from d-saccharic acid) be 
classed as rf-gulose, then either the xylose from which this d-gulose is ob- 
tained must be called /-xylose, or the lyxose derived from this (rf-)xylose by 
epimeric change must be classed as /-lyxose, because it is enantiomorphous 
with the J-lyxose corresponding with cf-arabitpl. It is better, therefore, to 
call it /-gulose, according to the given convention (p. 854). 



STRUCTURES OF THE MONOSACCHARIDES 859 

or epimeric change which has actually been carried out with a 
member of either the /- or the ^-family is also possible in the case 
of the enantiomorphously related isomeride. 

It may also be noted that an arbitrary choice was made in selecting 
one of two enantiomorphously related configurations to represent 
the pentitol, /-arabitol. If D (compare p. 854) had been chosen for 
/-arabitol instead of C, the only difference would have been that 
/-arabinose, /-glucose, /-mannose, and all the other compounds of 
the /-family would have been represented by configurations enantio- 
morphously related to those actually used. The choice between 
two enantiomorphously related configurations once made, however, 
must be adhered to throughout. 

In some examples already given, as in that of ordinary fructose, and 
in that of arabinose (p. 335), the laevorotatory form is distinguished 
by rf, and the dextrorotatory by /. This is because ordinary (laevo- 
rotatory) fructose is directly related to ^/-glucose in configuration, 
and the dextrorotatory form of arabinose is directly related to /- 
glucose. As suggested by Fischer, the choice between the letters, 
d and /, is based on the configurational relationships of the compound 
rather than on the direction in which the substance rotates the plane 
of polarised light. It is therefore customary, where necessary, to 
employ positive and negative symbols to indicate the sign of the 
rotation, as in /(-f-)-arabinose, d( )-fructose, etc., the letter showing 
the group or family relationship. 

In studying the above table, and the sugar group in general, it 
should be remembered that the names of many of the aldohexoses 
and aldopentoses are based on the epimeric relations (p. 749) of the 
compounds. The name talose, for example, is taken from that of 
galactose, ribose from arabinose, lyxose from xylose, the names of 
any pair of epimerides having many letters in common. This is also 
so in the case of glucose and gulose because the latter was first 
obtained from the former, but the two sugars in this case are not 
epimeric. On the other hand, glucose and mannose, which are 
epimeric, have unrelated names. The alcohols, except adonitol, 
sorbitol, and dulcitol, and the monocarboxylic acids have names 
derived from those of the aldoses from which they may be obtained. 

The Relationship between Glucose and Gulose 
When saccharic acid, an oxidation product of glucose, is reduced, 
in the form of its lactone, C 6 H 8 O 7 , it is partly converted first into 



860 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

glucuronic acid l and then into gulonic acid, an optical isomeride 
of gluconic acid ; on reduction, in the form of its lactone, gulonic 
acid yields gulose, an optical isomeride of glucose. The constitu- 
tional relationship between these compounds is therefore as follows : 



CHO 
[CH-OH] 4 

Glucose 



COOH 
> [CH-OH] 4 
CH 2 -OH 

Gluconic acid 
CH 2 -OH 
[CH-OH] 4 

COOH 

Gulonic acid 



COOH 

* [CH-OH] 4 

COOH 

Saccharic acid 
CH a -OH 

* [CH-OH] 4 

CHO 

Gulose 



CHO 

[CH-OH] 4 



:OOH 

Glucuronic acid 



Gulose, (n or in), is thus formed from df-glucose, (i), by a 
transposition of the groups CH 2 -OH and CHO. In order to 
compare their configurations, that of gulose, (11), may be rotated 
through 180 in the plane of the paper, giving (in), and it will then 
be seen that this configuration is that of /-gulose (footnote, 
p. 858). 

CH 2 -OH 



H 

HO 

H 

H 



CHO 

OH 

H 

OH 

OH 
CH 2 -OH 
I 



H 


OH 


HO 


H 


H 


OH 


H 


OH 


CHO 


II 



HO 
HO 
H 
HO 



CHO 

H 

H 

OH 

H 

CH 2 -OH 
III 



Ketoses 

Although d( )-fructose (p. 313) is the only ketose of much im- 
portance, others are known, and have been obtained, as already 
stated (p. 335), with the aid of the sorbose bacterium (Bacterium 
xylinwri), which was identified by Bertrand. This organism ferments 
certain polyhydric alcohols, in which process one of the CH(OH) 
groups is oxidised to CO ; J-mannitol is thus converted into 
rf-fructose, whereas rf-sorbitol (p. 258), obtained from the juice of 
the mountain ash, gives l-sorbose y and on reduction this ketose gives 
a mixture of d-sorbitol and /-iditol, the hexahydric alcohol obtained 
from /-idose. 

1 This acid is sometimes called glycuronic acid ; it occurs in a combined 
form in nature. 



STRUCTURES OF THE MONOSACCHARIDES 



861 



The structural and firfiuur.itin-ial relationships of rf-glucose, 
d'-sorbitol, /-sorbose, /-iditol, and /-idose are shown below : 



H 

HO 
H 
H 



CHO 



OH 
H 
OH 
OH 



CHa-OH 

^/-Glucose 



HO 

H 

HO 



CHa-OH 
CO 



H 

OH 

H 



CHa-OH 

/-Sorbose l 



H 

HO 

H 

H 



CHa-OH 



OH 
H 
OH 
OH 



CHa-OH 

d-Sorbitol 



H 
HO 

H 
HO 



CHa-OH 



OH 
H 
OH 
H 



CH a .OH 

Mditol 



H 

HO 

H 



CHa-OH 



OH 

H 
OH 



CO 
CHa-OH 

/-Sorbose 1 



H 
HO 

H 
HO 



CHO 



OH 
H 
OH 
H 



CHa-OH 

/-Idose 



The Synthesis of Sugars and their Derivatives 

The complete synthesis of the naturally-occurring sugars, glucose, 
mannose, and fructose, and of many related compounds, including 
aldohexoses, which were not known to occur in nature, was one of 
the brilliant triumphs of organic chemistry, and was accomplished 
by Fischer ; the more important results of this work may be very 
briefly summarised. 

As already stated (p. 318), various sugar-like mixtures can be 
obtained by treating aqueous solutions of formaldehyde with milk 
of lime ; from one of these mixtures (formose), Fischer isolated 
an osazone, which was isomeric with glucosazone and proved to be 
identical with a-acrosazone (see below). In the meantime he had 
been investigating other methods of synthesis, and, in conjunction 
with Tafel, had found that acraldehyde dibromide, with ice-cold 
barium hydroxide solution, gave a mixture of sugars from which 
two osazones, named acrosazones (a- and ]8-) could be isolated ; 
from a-acrosazone, by the method already described (p. 318), he 
obtained a sugar, C 6 H 12 O 6 , which he named a-acrose. The experi- 
mental difficulties in preparing a-acrose from the dibromide were, 
however, very formidable, and since it seemed that this sugar 
might have been formed by an aldol condensation of glycer aldehyde, 
CH 2 (OH)-CH(OH)-CHO, attempts were made to obtain it from 

glycerol. 

1 These two projections are identical 



862 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

Glycerol, carefully oxidised with dilute nitric acid or bromine 
water, gave a product, glycerose (a mixture of a little glyceraldehyde 
with dihydroxyacetone), which was treated with alkalis in the cold ; 
from the mixture of condensation products so obtained, a-acrosazone 
was isolated, and converted into a-acrose. This sugar fermented 
with yeast, and on reduction was converted into a hexahydric 
alcohol, C 6 H 14 O 6 , which was found to be very similar in properties 
to naturally occurring </-mannitol (p. 258) ; but, whereas */-mannitol 
was optically active, a-acritol was of course optically inactive. 

The possibility suggested itself that a-acritol might be (//-mannitol ; 
but as <//-mannitol was then unknown, and as only about 0-2 gram 
of a-acritol was obtained from 1 kilo of glycerol, even if the identity 
of a-acritol and ^/-mannitol were established, the preparation of 
considerable quantities of this synthetical product for further in- 
vestigation would be a very laborious task. 

Now, rf-mannitol, on oxidation, gave first the corresponding 
aldohexose, rf-mannose (which was afterwards obtained more easily 
from vegetable-ivory nuts), and then the corresponding mono- 
carboxylic acid, df-mannonic acid. The enantiomorphously related 
/-mannonic acid was obtained (together with /-gluconic acid) from 
/-arabinose, with the aid of hydrogen cyanide (p. 853). 

A mixture of equal quantities of d- and /-mannonic acids when 
reduced (in the form of their lactones) gave first an aldohexose, 
<//-mannose, and on further reduction a hexitol, rf/-mannitol ; the 
rf/-mannitol thus prepared was proved to be identical with a-acritol. 
It was thus possible to obtain a-acritol, which had already been 
synthesised, by comparatively easy methods, and to investigate it 
further. 

J/-Mannonic acid, which could be prepared from a-acritol, just 
as rf-mannonic acid is prepared from e/-mannitol (but which was 
actually obtained by mixing the d- and /-acids), was resolved into 
its enantiomorphously related components with the aid of its 
strychnine or morphine salt, and the d-mannonic acid (in the form 
of its lactone) was then reduced, first to rf-mannose, and then to 
rf-mannitol. 

In a similar manner /-mannose and /-mannitol were obtained 
from /-mannonic acid. 

rf-Mannonic acid was heated with quinoline, and was partly 
transformed into rf-gluconic acid (epimeric change) ; the lactone 
of the latter was then reduced to d-glucose and rf-sorbitol. In a 



STRUCTURES OF THE MONOSACCHARIDES 



863 



similar manner /-gluconic acid was obtained from /-mannonic acid, 
and reduced to /-glucose and /-sorbitol. 

rf-Fructose was obtained from J-glucose with the aid of the 
osazone in the manner already described (p. 318), and /-fructose 
was prepared from a-acrose, as stated below. 

These brilliant results are summarised below ; the starting-point 
is a-acrose, and the arrows indicate the directions in which the 
transformations occur : 



{//-Fructose 
(a-acrose) 

I 
<//-Mannitol 



d/-Mannose 



<//-Mannonic_ 
acid 



/-Fructose 



rf-Mannitol 



</-Sorbitol 



</-Mannose 



J-Mannonolactone 






rf-Mannonic acid 
/-Mannonic acid 



^-Glucose - > d'-Glucosazone 
J-Gluconolactone {/-Fructose 



> d- Gluconic acid 
'+ /-Gluconic acid 



/-Mannonolactone 

i 

/-Mannose 

i 

J-Mannitol 



/-Gluconolactone 

i 

/-Glucose - > /-Glucosazone 

i 

/-Sorbitol (/-Fructose) 



In addition to these compounds, Fischer also synthesised manno- 
heptose, manno-octose, and mannononose (p. 320). 

The fact that a-acritol is identical with <//-mannitol proved con- 
clusively that a-acrose was dl- fructose, since the sugar had been 
obtained from a-acrosazone. 

The original product from glycerose, however, might have been 
^/-glucose, d/-mannose, or ^/-fructose, since the osazones of all 
these hexoses give fructose when the sugar is regenerated (p. 318). 
In order to settle the nature of the original condensation product, 
the solution of some of the latter was treated with yeast ; fermenta- 
tion occurred and the solution became dextrorotatory. Now, had 
the original product been ^/-glucose or rf/-mannose, the ordinary 



864 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 



)-form would have fermented, the /( )-form being unchanged, 
whereas ^/-fructose, as was proved by separate experiments, would 
give a dextrorotatory solution, because only laevorotatory (/-fructose 
(d( )<-fructose) is fermentable (p. 902). The original product from 
glycerose, therefore, is ^/-fructose, which is probably formed by an 
aldol condensation of glyceraldehyde and dihydroxyacetone, or 
from dihydroxyacetone alone, which is known to give a- and 
$-acrose when it is treated with dilute alkali. 

From the above brief description of work which occupied many 
chemists during many years, it will be seen that although the 
synthesis of the sugars was accomplished mainly with the aid of 
glycerose, it was also proved that the same compounds could have 
been obtained from formose, and therefore from formaldehyde. 
Baeyer's view that natural sugars are produced by an aldol con- 
densation of formaldehyde, a transient reduction product of carbon 
dioxide, was thus supported, but the actual conversion of carbon 
dioxide into a sugar, independently of plant life, had still to be 
accomplished. 

Experiments with this object in view were made by Moore and 
Webster (1913-18), who proved that carbonic acid is reduced to 
formaldehyde by exposing it to ultra-violet light in the presence of 
certain inorganic catalysts, and that, on exposure to ultra-violet 
light of longer wave-length, an aqueous solution of formaldehyde 
gives reducing ' sugars ' ; such reactions are photosyntheses. Baly, 
Heilbron, and Barker (J. 1921, 1025) then stated that these two 
stages could be combined in one vessel, and carried out in the 
absence of any inorganic catalysts, but although more recent in- 
vestigations seem to support these conclusions, they do not afford 
convincing evidence that the changes are due solely to the action 
of light or that the products are sugars. 

The Glycosidic Structures of the Monosaccharides 

It has already been mentioned (p. 316) that the view that mono- 
saccharides are pblyhydric aldehydes does not account for all their 
properties and some of the facts bearing on this question have been 
stated ; these facts are recapitulated here for the sake of clarity. 

When rf-glucose is warmed with methyl alcohol in the presence 
of a little hydrogen chloride, a mixture of two, a- and fi-methyl- 
glucosides, C 6 H 11 O 6 CH 3 , is produced; these glucosides lack the 



STRUCTURES OF THE MONOSACCHARIDES 



865 



reducing action of glucose on Febling's solution, do not show muta- 
rotation, do not react with phenylhydrazine, and do not ferment 
with yeast ; although fairly stable towards dilute alkalis, they are 
hydrolysed by dilute acids, regenerating d-glucose. 

It was suggested by Fischer that these glucosides were ring 
structures, (i) and (n), and that their isomerism was due to the 
production from the CHO group of the rf- and /-forms of a new 
asymmetric complex, shown in (in) and (iv) : 



H C OMe 
HCOH Q 
HO C H 



MeO C~H 



H-i- 



H C O 
CHj- 



1 C OH 
OH 
I 




Suggested structures, now discarded, for o- and /3-methylglucosides 





H C OH 
CH 2 -OH 

IV 
Suggested structures, now discarded, for a- and /? -glucoses 

The glucosidic or oxide ring was assumed to contain five atoms 
merely from analogy with the lactones (pp. 287, 319), of which the 
commonest and most easily formed were y-lactones ; such a struc- 
ture, containing a closed chain of five atoms, was termed a y- or 
butylene oxide ring. 

It was afterwards found that ^-glucose itself exists in two forms, 



866 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

both of which may be obtained by crystallisation under different 
conditions. When it separates slowly from water below 30-35 the 
sugar is deposited in hydrated crystals, C 6 H 12 O e ,H 2 O, but from 
cold alcohol in anhydrous crystals ; both these products show an 
initial rotation of about [a] D -f-110, but this value falls slowly (very 
rapidly if traces of alkali are added) and becomes constant at 
[a] D -fS2'6. When, however, a solution of glucose is rapidly 
evaporated at 100, and the residue is dissolved in ice-cold water, 
the addition of ice-cold alcohol precipitates anhydrous crystals, 
which have an initial and final specific rotation, [a] D -f-52-6, no change 
in rotation taking place. Lastly, when an aqueous solution of 
glucose is crystallised slowly above 98, or when the sugar is crystal- 
lised from hot pyridine, the product shows an initial rotation, 
[a] D +17-5, which rises to and becomes constant at 4-52-6. 

The form produced at ordinary temperatures is called a-glucose, 
the other is /?-glucose, and the product of the rapid evaporation of 
solutions at 100 is the equilibrium mixture of the two (purified by 
solution and reprecipitation in the cold) ; it will be seen from the 
values for [a] D that the equilibrium mixture (once believed to be a 
distinct substance), which is produced when either is dissolved, 
consists, roughly, of equal quantities of the two forms. 

A substance like glucose, which gave different initial and final 
values for its specific rotation, was said to show ' bi-rotation/ and 
a great many other sugars (having a ' free carbonyl ' group, p. 886) 
showed this phenomenon, now known as mutarotation. 

It was suggested by Tollens, long before the two forms of glucose 
had been isolated, that mutarotation was due to the formation or 
fission of an oxide ring structure (m and iv, p. 865), but this view 
could not be established experimentally. 

The discovery of the two methyl glucosides, however, seemed to 
show that a- and j8-glucose corresponded with the a- and /?-methyl- 
glucosides, but that in solution the oxide ring structures of both the 
sugars underwent fission, giving an equilibrium mixture of the two 
forms and, in consequence, causing mutarotation ; the ring 
structures of the methylglucosides were more stable in solution, so 
that these compounds did not show mutarotation. This view was 
confirmed by E. F. Armstrong (J. 1903, 1305), who showed that 
when the glucosides were carefully hydrolysed by the action of 
enzymes, the changes in rotatory power which occurred could be 
explained on the assumption that the a-glucoside gave a-glucose, 



STRUCTURES OF THE MONOSACCHARIDES 867 

and the /J-glucoside, ]8-glucose. Similar a- and j3-methyl isomerides 
are also formed from the other aldohexoses, and from aldopentoses 
and ketohexoses; ethyl, propyl, etc., glycosides (p. 316) can also 
be prepared. 

It should be noted that in spite of their glycosidic structure, in 
which the aldehyde group CHO is no longer present, the a- and 
/J-sugars retain most of the reactions of aldehydes and behave in 
solution as if their molecules contained a ' free aldehyde ' or ' free 
carbonyl ' group. 

Now, if a y-glycosidic ring of the type shown on p. 865 is formed 
either in a sugar or in a y-lactone of a sugar acid, it would seem that 
all the asymmetric groups will retain their configurations, and when 
that of the product is expressed in the usual way, the glycosidic or 
lactone ring will be shown on the right- or on the left-hand side of 
the carbon chain of the projection formula, according to the position 
of the y-hydroxyl group on atom 4. 1 In the case of d^-gluconic 
acid, for example, the lactone ring would be on the right, whilst 
in the lactone of </-galactonic acid it will be on the left, because of 
the position of the 4- or y-hydroxyl group : 



1 CO 



H C C 



2 H C OH 



CO 
H C OH 



| O O I 

3 HO-CH | | HO-C H 

4 H-C 1 ' C-H 

5 H-C-OH H C-OH 

6 CH 2 -OH CH 2 -OH 

rf-Gluconolactone rf-Galactonolactone 

Mo+68 [a] -78 

From an examination of the lactones of twenty-four monobasic 
acids, obtained by the oxidation of the aldehyde group of sugars, 
Hudson (J. Am. Chem. Soc. 1910, 338) found that on the assumption 
that they were all y-lactones, those in which the lactone ring ap- 
peared on the one side of the chain of the projection formula were 
all dextrorotatory, the others, laevorotatory (Hudson's lactone rule). 

1 The numbering of the carbon atoms always starts from the aldehyde 
or carboxyl group, as shown here. 



868 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

Evidence in support of this assumption was afforded by a study of 
the rates of hydrolysis of lactones and methylated lactones derived 
from sugars. In the case of the latter, whose structures are estab- 
lished by oxidation experiments (see later), the y-, are hydrolysed 
much more slowly than the 8-lactones ; as the lactones of the sugar 
acids are only hydrolysed slowly, it may be assumed that they are 
also the y-compounds. Hudson also pointed out that ring com- 
pounds, such as the lactones and the oxide forms of sugars, had 
very much higher specific rotations than open chain molecules such 
as the hexitols and sugar acids ; that is to say, the ring structure 
had the predominating optical effect. 

It could be argued, therefore, that the aldoses in their oxide forms 
should follow the lactone rule, provided that they also were y-ring 
compounds of the structures, (in) and (iv), already shown (p. 865). 
For, if it be assumed that the total effect on the rotatory power is 
the algebraic sum of the separate effects of each of the asymmetric 
groups in the molecule (compare optical superposition, p. 745), 
and that the same hydroxyl group takes part in the formation of 
the ring both in the sugar and in the lactone of the acid, then this 
total effect would be due to the asymmetric groups, 1, 2, 3, 4, 5 in 
the case of the glycosidic sugar, and to the groups 2, 3, 4, 5 in the 
case of the lactone ; the difference between them would thus be 
caused by the configuration of group 1 . Now if the algebraic mean 
of the rotations of the a- and j8-forms of a sugar is taken it can be 
assumed that the effects (d- or /-) of the configuration of group 1 
has been eliminated (this value may not be the same as the equili- 
brium value of the rotation, as the proportions of the two forms at 
equilibrium are not usually identical, p. 866). It may be inferred, 
therefore, that the sign, at least, of the rotation due to the groups 
2, 3, 4, 5 will be the same in the two cases, and will depend on the 
right- or left-handedness of the ring structure as shown in the 
configurational formulae. 

When, however, these assumptions were tested, it was found 
that they were not in accordance with the experimental evidence, 
if the sugars were represented as y- or butylene oxides, as in (in) 
and (iv) (p. 865), It was then pointed out by Drew and Haworth 
(J. 1926, 2303) that if the glycosidic ring of the sugars is composed 
of six atoms instead of five, that is to say if a 8- or amylene oxide ring 
is formed, then Hudson's rule would hold good with the sugars 
just as with the y-lactones. Thus, if rf-galactose were a y-oxide, as 



STRUCTURES OF THE MONOSACCHARIDES 869 

represented in (n), 1 the ring would be on the left-hand side, because 
of the position of the y- or 4-hydroxyl group, and according to the 
rule the sugar should have the same sign of rotation as y-rf-galactono- 
lactone, (i) : 



H C-OH 



-i-H 



H C OH 




-CO I CH(OH) CH(OH) 



H C OH 



Oil I 

HO C H HO C H HO CH 



HO C H 



H T~ 

CH,-< 







CH a OH CHj-OH CH,-OH 

I II III 

if, on the other hand, </-galactose is a S-oxide, as shown in (in), 
the ring would be on the right and its rotation should be, as it is, 
of opposite sign to that of the lactone ; the actual values are 
^-galactose [a] D +98, and d-galactonolactone [a] D -78. Other 
cases in which a sugar and the y-lactone of its monocarboxylic acid 
had specific rotations of different signs were found to conform to 
Hudson's rule, provided that the sugar was represented by the 
,8-oxide structure, but clearly further evidence on this point was 
required ; such evidence was obtained from a study of the 
methylated sugars. 

In 1903 Purdie and Irvine made the very important discovery 
that glucose could be converted into a crystalline tetramethyl 
derivative by treating a-methylglucoside with methyl iodide and 
silver oxide, and hydrolysing the tetramethyl-methylglucoside 
with dilute acid ; later, similar compounds were obtained, not only 
from other mono-, but also from di-saccharides. Denham and 
Woodhouse then found that cellulose could be methylated with 
dimethyl sulphate and alkali, a method which, applied to the simpler 
saccharides by Haworth, has given compounds of the greatest use 
in the investigation of the carbohydrates in general. 

In the preparation of these compounds great care must be taken 

1 When, as in this case, the configuration of the 1 -group is not shown, the 
configuration represents either the a- or the /3-form. 



870 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

to avoid the presence of much free acid or alkali ; acids may bring 
about the hydrolysis of disaccharides, and alkalis may cause isomeric 
and other changes, especially with monosaccharides. It has been 
shown, for example, that glucose, mannose, and fructose all give 
the same equilibrium mixture in the presence of dilute alkalis 
(Lobry de Bruyn), probably as a result of keto-enolic changes : 



CH-OH 
CHO 



C-OH 
CH-OH 



CO 

CH a .OH 



and concentrated alkalis produce a series of complex changes, as 
has been shown by Nef. 

The polymethyl derivatives of the saccharides are more easily 
dealt with than the parent hydroxy-compounds, since they are 
soluble in various organic solvents, with which they may be ex- 
tracted from their aqueous solutions ; they usually crystallise well 
and have definite melting-points, and some of them may even be 
distilled under greatly reduced pressure. 

Now when a- or j8-methylglucoside is treated with dimethyl 
sulphate and dilute alkali, all the hydroxyl groups are methylated 
and a tetramethyl-methylglucoside, (i), is formed. This product is 
hydrolysed by very dilute acid, giving tetramethylglucose, (n), the 
glucosidic methyl group alone being displaced, with the formation 
of a * free carbonyl ' group (p. 867) ; these compounds, as will 
now be shown, are represented by the following structural formulae : x 



H C OMe 

MeO C H O 

,H C OMe 

H C 



1 CH(OMe) 
2 H C OMe 
3 MeO C H ( 
4 H C OMe 
; 14 P 


1 

CH(OH) 

H C OMe 
> MeO C H ( 

H C OMe 

1 

u r 


6 CHj-OMc CHj-OMe 
I II 



CH 2 -OMe 
III 



1 In studying the structures of the glycosidic sugars, it is usually unneces- 
sary for the student to trouble about configurational formulae, although the 
latter are used in this chapter. 



STRUCTURES OF THE MONOSACCHARIDES 871 



COOH 
H COMe 
MeO C H 
H COMe 
COOH 

IV 


r i 

J3 COMe 
MeO C H 
H COMe 
H COMe 

V (unknown) 


1 COOH 
H COMe 
MeO C H 
H COMe 
H COMe 
CH.-OH 
VI 


COOH 
H COMe 
MeO C H 
H COMe 
H COMe 
COOH 
VII 



Tetramethylglucose, (11), on careful oxidation, yields first, tetra- 
methylgluconolactone, (in), and afterwards xylotrimethoxyglutaric 
acid? (iv), which may also be obtained directly from xylose ; the 
formation of this acid, of which one carboxyl group must be that 
combined in the lactone ring of the tetramethylgluconolactone, 
shows that three of the methoxy-groups in the lactone and also in 
the tetramethylglucose must be in the 2, 3 and 4 positions ; other- 
wise this acid could not have been produced. The lactone ring 
could not have been in the 4- or y-, but must have been either in 
the 5- (as shown) or the 6-position, (v) ; in the latter case the 
6-group must have been lost, and the 5-group oxidised to COOH. 

That the lactone ring is not 1:6 is shown by many facts, perhaps 
the simplest being that 2:3:4:5-tetramethylgluconic acid, (vi), which 
has been prepared from other sources (p. 891), gives tetramethyl- 
saccharic acid, (vn), on oxidation, and cannot be converted into the 
lactone, (in), mentioned above. 

The closed chain in tetramethylgluconolactone, (ill), and in 
tetramethylglucose, (n), and tetramethyl-methylglucoside, (i), is 
therefore a l:5-ring, and assuming that its structure is unchanged 
during the methylation of the glucoside, the a- and j8-glucosides 
and glucoses are also of the 1:5 or amylene oxide type, as shown in 
(i) and (11), and not of the butylene oxide type as represented 
on p. 865. 

Evidence that no change occurs during methylation has been 
provided by (Miss) Isbell, who has shown, mainly by polarimetric 
methods, that when a sugar, which from other evidence is believed 

1 The stereoisomeric r -:MI. ,:ro\ ^,:"j. :---:c acids and their methyl 
derivatives are distinguished as xylo-, nbo-, or arabo- in order to show to 
which of the pentoses they are related in configuration. 

Org. 55 



872 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

to be of the amylene oxide type, is oxidised with bromine water 
the 8-lactone of the sugar acid is formed rapidly and almost 
quantitatively. 

By similar methods it has been proved that the methylglycosides 
of other hexoses, such as galactose and mannose, and of the pentoses 
(arabinose, lyxose, and xylose), all contain 6-atom-, 8-, or amylene 
oxide ring structures ; methylarabinoside, (vni), for example, gives 
trimethyl-methylarabinoside, (ix), which, with dilute acids, yields 
trimethylardbinose, (x) ; on oxidation this compound is then con- 
verted into ardbotrimethoxyglutaric acid, (xi) : 




CH(OMe) 
MeO C H 



VIII 




I 
CH(OH) 

MeO C H 
H C OMe 





The amylene oxide sugars and their derivatives may therefore 
be represented by configurations such as (xn, a-glucose) and (xm, 
/J-glucose), in which there is a nearly planar ring of 5 carbon atoms 
and one oxygen atom. These configurations, (xn) and (xm), give, 
of course, a much more accurate representation of the actual spatial 
distribution of the atoms than those hitherto used. 1 

1 The models (p. 855) must be bent backwards in order to convert them 
into the ring structures : the hydrogen atoms in positions 4 and 5 are then 
trans to one another, as shown. 



STRUCTURES OF THE MONOSACCHARIDES 873 

CHa-OH CHa-OH 






OH H OH 

a-4-Glucopyranose /3-rf-Glucopyranose 
XII XIII 

In the molecule of a-glucose, the hydroxyl groups, 1 and 2 (p. 870), 
are in the ay-position to one another, and trans- in /?-glucose. This 
is known from the effect of boric acid on the specific rotation (p. 745) 
and electrical conductivity of their solutions (Boeseken), and also 
from the results of X-ray analysis. 

The pentoses and hexoseS of the amylene oxide type may there- 
fore be regarded as derivatives of pyran, (xiv), and are called 
pyranose (or normal) sugars (Haworth). Further examples of the 
use of the pyranose configurations will be given later, but in dealing 
with many points the conventional projection formulae are perhaps 
easier to follow and will be retained. 

Butylene Oxide or Furanose Structures 

In 1914 Fischer (Ber. 1914, 1980) isolated a liquid, y-methyl- 
glucoside, 1 from the products of the interaction of glucose and 
methyl alcohol ; two crystalline pentabenzoyl-y-glucoses have since 
been prepared (Ber. 1927, 1487). This y-methylglucoside gives a 
tetramethyl-methylglucoside, (i), which is hydrolysed to a liquid 
tetramethylglucose ; on oxidation this liquid product is converted 
first into tetramethyl-gluconolactone, (n), and then into a dimethyl- 
tartaric acid, (m). These facts seem to show that the y-compound* 
have a 1:4- or butylene oxide structure. 

CH(OMe) CO 1 COOH 

H-C-OMe o H-C-OMe | H~C-OMe 

MeO --C--- H I MeO C H I MeO C- H 

H-C 1 H-C 1 COOH 




H C OMe 

CHa-OMe 

II III 

1 The letter y here signifies merely a difference from the a- and /3-forms. 



874 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

The dimethyltartaric acid referred to above is dextrorotatory, but 
is related to /-glucose if both substances are regarded as configura- 
tionally derived from glyceraldehyde ; it should therefore be called 
/(+ )-dimethyltartaric acid. 

CHO 



HO H 
H OH 
HO H 
HO H 
CHa-OH 
/Glucose 


CHO 
H|OH 
CHa-OH 

<J-Glyceraldehyde 


COOH 
HO H 
H OH 
COOH 

<*(-)-Tartaricacid 


COOH 
H OH 
HO H 
COOH 

/(+)-Tartaric acid 



These butylene oxide sugars may be regarded as derived from 
furan (p. 585), just as the normal sugars are derived from pyran and 
are classed as furanoses (Haworth) ; * their configurations may be 
represented as shown below : 



:H(OH)CH 2 OH 




:H 2 OH 




Similar derivatives of other y-sugars are known, and Haworth 
and Porter have prepared crystalline a- and fi-ethylglucosides 
(p. 879) which are derived from the butylene oxide structure, but 
the y-sugars themselves do not appear to exist. 

Ketoses and Methylpentoses 

d-Fructose, treated with methyl alcohol and hydrogen chloride, 
yields d-methylfructoside, (i), which exists in a- and j8-forms 
just as do the methylglucosides. The tetramethyl-methylfructosides, 
prepared in the usual way, are hydrolysed to l:3A:5-tetramethyl- 
fructose, (H), which is then oxidised in stages to d-3:4:5-trimethyl- 
fructuronic acid, (in), d-23'A-trimethylarabolactone, (iv), and finally 
to d-arabotrimethoxyglutaric acid, (v). These results show that the 

1 There are, theroetically, a- and /3-forms of both these furanose sugars. 
The names pyran and furan suggest saturated structures, but as the latter 
is used for the unsaturated compound (footnote, p. 585), the furanose 
sugars are derivatives of tetrahydrofuran (p. 834) ; similarly, if the name 
pyran is given to the unsaturated ring shown above (p. 873), as seems 
to be advisable from its relation to the pyrones (p. 983), the pyranose sugars 
are derived from tetrahydropyran. 



STRUCTURES OF THE MONOSACCHARIDES 



875 



molecule of the fructoside, and presumably that of fructose, contains 
a 6-atom amylene oxide or pyranose ring, corresponding with that 
of the normal aldohexoses : 



:H 8 OH 
: OMe 
HO CH 
O H C OH 
H C OH 




!OOH 
I OH 




II 



III 



-co 



MeO CH 
O H C OMe 

IH C OMe 
I 
CH a 

IV 



COOH 
MeO CH 
H C OMe 
H C OMe 

COOH 
V 



A l:3:4:6-tetramethyl-y-fructose, (vi), structurally isomeric with 
the compound (n), has been obtained from methylated sucrose 
(p. 893) ; on oxidation, this compound is converted into (vn), then 
into (vin), and finally into d( )-dimethyltartaric acid, (ix) ; it has, 
therefore, a butylene oxide or furanose structure, and is derived 
from a y-fructose or fructofuranose (p. 874), of which a crystalline 
y-methylfructoside has been isolated. 



CHj-OMe 
HO C > 



COOH 



MeO CH 
H C 
H C 



HO-C 

MeO CH 
H C OMe 
H C 



CH 8 - 



OMe 



VI 



CH 2 -OMe 
VII 



876 "THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 



MeOC-~H 
H C O 
H C 




CHfOMe 
VIII IX 

In addition to the aldoses and ketoses of the types already described 
(in which every carbon atom in the molecule is directly combined 
with an oxygen atom), various sugars of a somewhat different 
character are known. Thus, several met hy /pen loses, such as 
\-rhamnose, CH 3 [CH OH] 4 CHO, occur in nature in the form of 
glycosides. These compounds resemble the aldopentoses very 
closely in their chemical behaviour ; they may be reduced to the 
corresponding alcohols, oxidised to the corresponding mono- 
carboxylic acids, etc., and when heated with mineral acids they give 
a-methylfurfuraldehyde. /-Rhamnose has been shown to be a 
pyranose sugar like the normal hexoses, 
Other important sugars are mentioned later (pp. 1076, 1110). 

Acetone and Other Derivatives of the Monosaccharides 
When hexoses are shaken with acetone in the presence of a 
catalyst, such as hydrogen chloride or zinc chloride, condensation 
readily occurs (Fischer), giving products, many of which are 
crystalline and relatively stable towards alkalis, but are more easily 
hydrolysed by acids than the methyl derivatives. 

The structures of such mono- and di-acetone compounds have been 
determined by methods analogous to those employed in the case of 
the sugars themselves ; methylation is followed by the removal of 
the acetone groups by acid hydrolysis, and the resulting methylated 
sugars are identified. It has thus been found that condensation usually 
occurs with adjacent hydroxyl groups, which are in the ay-position, 






OH 

>C-OH 



but the original oxide ring in the sugar may be broken, with the 
formation of a new one, having, of course, a different structure. 
a-Glucose, (i), for example, gives a diacetone derivative, (n), in which 



STRUCTURES OF THE MONOSACCHARIDES 



877 



the acetone residues are present at positions 1 ,2 and 5,6, the oxide ring 
having changed from position 5 (normal glucose) to 4 (y-glucose). 



i 

2 H C OH 
3 HO C H 

4y T f** f\1 J 
rl Ly-r-vJJtt 

6 CH 8 -OH 


H-n-C O^ 
1 >CMe 8 
H C O c 
> 1 
HO C H 

H- C 


1 

H C O 



" _!>* 1 



I 
H C- 



II 



H C OH 

CH,-OH 
III 



It appears probable, therefore, that the acetone residue cannot 
bridge the f raws-position, so that condensation cannot occur in the 
2,3 or 3,4 position ; in solution, however, the oxide ring undergoes 
fission, 5,6 condensation then occurs, and afterwards the oxide ring 
is re-formed at atom 4, giving a derivative of y-glucose. When 
cautiously hydrolysed with acids, the diacetone derivative gives 
glucose monoacetone, and as this compound does not reduce 
Fehling's solution, and does not, therefore, contain in its molecule 
a ' free carbonyl,' it must be the 1,2-derivative, (in). 

1 ,2:5,6-Di-wopropylideneglucofuranose (glucose diacetone) on 
methylation and hydrolysis gives 3-methylglucose and 1,2-wo- 
propylideneglucofuranose (glucose monoacetone) similarly yields 
3 :5 :6-trimethylglucose . 

In the case of fructose, a diacetone compound can be formed 
from either the a- or the j8-sugar without the fission of the oxide 
ring, and the structurally different diacetone compounds are both 
derived from normal fructose. 



CH.- 
1 



OH 



CM CI1 H 



CH,0. 

I ^CMe. 




1 
HO C H 

H-C 



CH $ - 



-CH, 



Diacetone derivatives of normal fructose 



878 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

In the molecule of normal rf-xylose there is only one pair of 
hydroxyl groups suitably placed for condensation with acetone : 



-OH 



H C- 
H C OH 
HO~C~ H 
H COH 



H C < 



O 



CH,- 



OH 



HC-OH 
HO C H 



HO'CH a C- 
H 



Normal xylose y-Xylose 



I 

H C O v 

| >CMe 2 
H C-0^ 



CMe a < I 

^ ~ 



O 

: H 



H 

y-Xylose diacetone derivative 

In a y-xylose the hydroxyl groups at 1 ,2 are suitable and also those 
at 3,5, since the latter are separated from one another by about 
the same distance as the former ; with acetone, therefore, xylose 
gives a diacetone y-xylose, the oxide ring undergoing fission and 
re-formation after condensation has occurred, as with glucose. 

Benzaldehyde condenses with sugars in a similar manner to 
acetone, but it often reacts with alternate hydroxyl groups ; with 
glucose, for example, 4,6-benzylideneglucopyranose is produced 
and this compound, on methylation and hydrolysis, gives 2:3- 
dimethy Iglucose . 

Sugar carbonates are formed by the condensation of sugars with 
phosgene in pyridine solution : they are usually crystalline and in 
contradistinction to the acetone derivatives are stable towards dilute 
acids, but are hydrolysed by alkalis, a fact of some importance, as 
is illustrated by the preparation of glucofuranosides. Thus, 1,2- 
wopropylideneglucofuranose (p. 877) yields 1,2-tropropylidene- 
glucofuranose 5,6-carbonate, and when this is heated with alcohol 



STRUCTURES OF THE MONOSACCHARIDES 879 

and hydrogen chloride the acetone residue is removed and a mixture 
of a- and j8-ethylglucofuranoside 5,6-carbonates is formed by the 
usual glycoside reaction. After separation the two carbonates can 
be hydrolysed with dilute alkali to a- and j8-ethylglucofuranosides. 
Ethyl mercaptan does not react with glucose to form thiogluco- 
sides, but condensation occurs with the open chain aldehydo-form 
of the sugar to give a thioacetal : 

CHO > CH(SEt) a 

Methylation of the thioacetal then gives a pentamethyl derivative 
from which the two SEt groups can be removed by treatment 
with aqueous mercuric chloride ; an open chain 2:3:4:5:6-penta- 
methylglucose is thus produced. 

The penta-acetyl and pentabenzoyl derivatives of the hexoses, 
like the sugars themselves, are oxide structures and exist in a- 
and j8-forms, corresponding with those of the alkyl glycosides ; 
consequently they do not show aldehyde characteristics. 

Acetobromoglucose, C 6 H 7 O(OAc) 4 Br, tetra-acetylbromoglucose, is 
formed by the action of hydrobromic acid on penta-acetylglucose, 
the glycosidic acetoxy-group being displaced by a bromine atom, 
so that it is a derivative of the normal or amylene oxide form of 
glucose. The bromine atom may be easily displaced by other 
groups, for which reason acetobromoglucose (or acetochloroglucose) 
and corresponding derivatives of other sugars have been used in 
the syntheses of disaccharides and glycosides (pp. 895, 897). 

Inter conversion of the Sugars 

It has already been seen how inversion of the configuration of 
the groups on the 2-carbon atom of an aldose may be effected 
(epimeric change, pp. 749, 857) and a sugar thereby converted into 
an optical isomeride : the transformation of glucose into gulose 
has also been mentioned (p. 859). Now there are other ways 
in which interconversions may be performed and possibly one of 
the most important uses the ^-toluenesulphonates (tosyl esters) of 
the sugars or of suitable derivatives ; such esters are formed by 
treating the sugar with />-toluenesulphonyl chloride in pyridine 
solution. The esters may then be hydrolysed by mild alkali, but 
configurational changes often occur during the process. If there 
is a free hydroxyl radical on the next carbon atom to that directly 



880 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

united to the tosyloxy-group and in the fra/w-position, an ethylene 
oxide ring is first formed on hydrolysis, with an inversion of the 
groups around the carbon atom to which the tosyloxy-radical was 
united : 

HO-C-H .C-H 

I 0/| 

H-C-O-S(VC 6 H 4 .Me X C-H 



When, for example, a tosyl group at the 3 -position in glucose is 
removed, an anhydro -derivative of allose is produced, with inversion 
of the configuration around carbon atom-3 ; 3-tosyl-4,6-benzyl- 
idine-a-methylglucoside, (i), thus yields 4,6-benzylidene-2,3- 
anhydro-a-methylalloside, (n). 

The oxide ring of an anhydro-sugar may then be opened by the 
action of alkali, and Walden inversion again takes place at one of the 
carbon atoms concerned in the oxide ring; (n) therefore gives 
4,6-benzylidene-a-methylaltroside (inversion at 2, in) or 4,6- 
benzylidene-a-methylglucoside (inversion at 3). A mixture con- 
taining about 84% of (in) is in fact produced and from (in), a- 
methylaltroside and altrose may be obtained. 

By methods such as this rare sugars may often be prepared from 
common ones. 



B-t 



! OMe 



H C OMe 



H C OH 
TO C H 



Q 




H C 



I \ 



CH r O-CHPh 
I, T=Me.CeH 4 -SO 2 



HO C H 



CH a -O CHPh 
II 




Ascorbic Acid 

/-Ascorbic acid, C 6 H 8 O e , was first isolated by Szent-Gy6rgyi in 
1928 from the adrenal glands, and later, in considerable quantity, 
from paprica (Hungarian pepper) ; it occurs widely distributed in 
animals and plants. It has strong antiscorbutic properties (p. 653) 



STRUCTURES OF THE MONOSACCHARIDES 881 

and has been identified as Vitamin C. It melts at 192, has 
[a] 578 o-f-24 in aqueous solution, and behaves like an unsaturated 
carboxylic acid. 

The constitution of ascorbic acid was elucidated mainly as a 
result of the work of Haworth and Hirst and their collaborators. 
The acid is a very powerful reducing agent and is attacked by 
oxygen in alkaline, but only very slowly in acid solution ; with 
iodine in the presence of acid, a reversible oxidation takes place, 

C OH ^ HO-COH C:O 

|| + Ii + 2H 2 O I or | + 2HI, 

C OH " HO C OH C:O 

I I I 

the oxidation product being reduced to ascorbic acid by hydrogen 
iodide or by hydrogen sulphide. 

Ascorbic acid is only a weak monobasic acid and gives a sodium 
salt, C 6 H 7 O 6 Na, whereas the oxidation product just mentioned is 
neutral and behaves like the lactone of a hydroxycarboxylic acid, 
thus showing that the acidity of ascorbic acid is due to an enolic 
hydroxyl group. When the primary oxidation product is further 
oxidised with sodium hypoiodite, or when ascorbic acid is oxidised 
with permanganate, oxalic acid and a trihydroxybutyric acid are 
obtained. 





COOH 
OOH 



Vx 

i 




HO C H 
CH 8 -OH 

/Ascorbic acid 

The trihydroxybutyric acid can be methylated and the product 
converted into its crystalline amide ; this compound is identical 
with trimethyl-l-threonamide, derived from /-threose (p. 858). Its 
configuration is further confirmed by its oxidation to /(-h)-tartaric 
acid, and that of /-ascorbic acid is therefore as shown above. 

When ascorbic acid is methylated first with diazomethane (p. 469) 



882 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

and then with methyl iodide and silver oxide, a tetramethyl derivative, 
(i), is obtained which, on ozonolysis, yields a derivative of threonic acid, 
(n) ; on treatment with alcoholic ammonia this substance is quan- 
titatively converted into oxamide and S'A-dimethyl-l-threonamide, (in), 

CO - CO 1 CO-NH, 

A I io-OMe I CO-NH, 






The structure of the 3:4-dimethyl-Z-threonamide is proved by 
the fact that with sodium hypochlorite, sodium cyanate is produced 
(Weerman), a reaction which has been shown to be characteristic 
of a-hydroxy-amides, 

H COH+NaClO+NaOH = HO+NaNCO+2H 2 O+NaCl. 

CO-NH a 
The a-hydroxyl group, therefore, is not methylated. 

When (n) is hydrolysed with baryta it gives barium oxalate and 
barium dimethylthreonate, and from the latter the amide, previously 
prepared from the direct oxidation product of ascorbic acid, may be 
obtained. 

The presence of the unmethylated hydroxyl group in the 
ex-position to the amide radical in the dimethylthreonamide proves 
that the lactone ring in tetramethylascorbic acid, and by inference 
that in ascorbic acid itself, is furanose or 1:4, as shown in the above 
formula. That ascorbic acid is not a carboxylic acid with a 2:4- 
oxide ring is shown by many considerations, among which may be 
mentioned the great strain which would be involved in such a ring, 
and the fact that the first oxidation product of ascorbic acid is a 
lactone and not an acid. 

From the evidence given above it is clear that the structure of 
tetramethylascorbic acid is as indicated, (i), and that ascorbic acid 
itself has either the corresponding structure (p. 881), or that in 



STRUCTURES OF THE MONOSACCHARIDES 



883 



which the group, (iv), has changed into one of the possible tauto- 
meric forms, (v), (vi), or (vn). 



co-, 

H0 ~ 



HO 



O J ] 01 

H-fc I H~C - 1 H 




IV 



VI 



VII 



Formulae (vi) and (vn) should give rise to stereoisomerides, which 
have not been detected in the study of ascorbic acid, and neither 
configuration represents a flat molecule, such as is revealed by an 
X-ray examination of the compound (Cox). Further, ascorbic acid 
gives, with diazomethane, a dimethyl derivative which, from its 
properties, is no doubt derived from (iv), and this dimethyl deriva- 
tive has an absorption spectrum very similar to that of the acid 
itself. This is a very good example of the important part played 
by a study of physical properties in the elucidation of structure. 

The above formula (p. 881) was established by the synthesis of 
/-ascorbic acid by Haworth, Hirst, and their collaborators (J. 1933, 
1419). An examination of the configuration of the acid showed that 
it might be synthesised from /-lyxose or /-xylose, but even the 
preparation of one of these pentoses in sufficient quantity was a 
task of considerable difficulty. For this purpose, </-galactose, which 
is easily obtained, is converted into its diacetone derivative, (i) ; 
this compound is then oxidised to the corresponding derivative of 
galacturonic acid, from which d-galacturonic acid, (n), is obtained 
by hydrolysis, 



CMe 




H C <X 

| >CMe 

H-c-cr 



O C H 

CMe a < I 

^0-C-H 

H C 

coo 



H 



884 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC 

CHO 
H C OH 



HO < 

HO \ 
H 



: H 

H 

>- OH 
OOH 
II 



The reduction of the y-lactone of this aldehydic acid, (in), yields 
\-galactonolactone > (iv), 





.CHO 
H C OH 

r+ TJT 


CH a .OH 
H C OH 

i H 

c 


P. 

HO C I- 
H C C 


n 







~uf\ r* u 


n Y v 

or 1 
II C 


HO C H 
H C-OH 
CO 


HO y H 
H C OH 
Co 


HO-C H 
CH 2 OH 



in 



IV 



which is first converted into its amide and then into /-lyxose, (v), 
by the Weerman reaction (p. 882) ; the osazone of /-lyxose gives 
\-xylosone (l-lyxosone, vi), on hydrolysis, 







CN 
| 




C{NH)~ 


CHO 


CHO 


JH(OH) 


HO- 


4 


H C OH 


CO 


O 


HO- 


-1 


H C OH 


H C OH 


OH 


H- 


-C 


HO C H 
CH,-OH 


HO C H 
CH t OH 


HO C H 
CH,.OH 


HO- 


i H 

1 
CHj-OH 


V 


VI 


VII 




VIII 



and this osone, with potassium cyanide and calcium chloride in 
aqueous solution, in the course of twenty minutes, is almost quanti- 

1 The two configurations shown here are identical. 



STRUCTURES OF THE MONOSACCHARIDES 885 

tatively converted into the compound, (vm), the intermediate 
nitrile, (vn), undergoing isomeric change. This product is hydro- 
lysed by 8% hydrochloric acid at about 40-50, and from the result- 
ing solution /-ascorbic acid (p. 881), identical in all respects with 
the natural substance, is obtained. 

A much simpler synthesis of /-ascorbic acid has been achieved 
(Helferich and Peters, Ber. 1937, 45) by condensing the tetra- 
acetate of the cyanohydrin of /-threose with ethyl glyoxylate in the 
presence of sodium methoxide ; the ethyl radical and the acetyl 
groups are removed during the process, which is similar to the 
benzoin reaction : 




HO 






H-C- 
HO- 

2 OH 



>-C.H 

CH 8 C 



Other syntheses of the vitamin, which are now used commercially, 
have also been devised, and various compounds analogous to 
ascorbic acid in structure have been prepared, but most of them 
are either inert or have little antiscorbutic activity. 



CHAPTER 53 
DISACCHARIDES AND POLYSACCHARIDES 

THE disaccharides (pp. 321-325) are hydrolysed by acids and by 
enzymes, giving two molecules of the same or of different hexoses ; 
maltose, for example, gives two molecules of glucose, whereas lactose 
gives glucose and galactose, and sucrose gives glucose and fructose. 

Many other disaccharides are known, such as cellobiose, gentio- 
biose, and melibiose. 1 Cellobiose is obtained by treating cellulose 
with acetic anhydride and sulphuric acid, when acetolysis occurs, 
and octa-acetylcellobiose is formed ; this compound is readily 
hydrolysed giving cellobiose. Gentiobiose is formed, together with 
^-fructose, by the partial hydrolysis with an enzyme of a trisaccharide, 
gentianose, which occurs in the roots of the gentian. Melibiose is 
obtained also, together with rf-fructose, from a trisaccharide, 
rajfinose, which occurs in the molasses from beet-sugar and in 
Australian manna, from eucalyptus. 

Two different types of disaccharides are known : 

Type I. Those such as lactose and maltose, which show muta- 
rotation, give osazones, and may be oxidised with bromine and water 
to monocarboxylic acids of the molecular formula, C 12 H 22 O 12 . 
Lactose, for example, gives lactobionic acid, and maltose, malto- 
bionic acid, so that the molecule of each of these sugars must contain 
a so-called ' free carbonyl ' group, that is to say a modified aldehyde 
group corresponding with that in a- and j8-glucose, etc. Hence, 
when lactose and maltose are produced by the condensation of two 
aldohexose molecules, the aldehyde group of one of the aldohexoses 
is not directly concerned in the process. Lactobionic acid and 
maltobionic acid, like the disaccharides from which they are derived, 
are readily hydrolysed ; lactobionic acid is thus transformed into 
rf-galactose and J-gluconic acid, whereas maltobionic acid is con- 
verted into (/-glucose and d-glueomc acid. From these facts, and 
from a consideration of the formulae of the alkylglycosides, it would 
seem that lactose is a glycoside derived from rf-galactose, and 
maltose a glycoside derived from rf-glucose. 

Type II. Sucrose, unlike lactose and maltose, does not show 

1 The suffix ' biose ' is often used to denote a disaccharide. The term 
* biose link ' is employed below to denote the group C O C by which the 
two hexose residues are united in the disaccharide. 

886 



DISACCHARIDES AND POLYSACCHARIDES 887 

mutarotation, does not give an osazone, and cannot be oxidised to 
an acid of the molecular formula, C 12 H 2 2O 12 ; consequently, its 
molecule does not contain a ' free carbonyl * group and must differ 
considerably in type from that of lactose or of maltose ; the modified 
aldehyde group of glucose as well as the ketonic group of fructose 
have both been changed as a result of the combination of the two 
hexoses, Trehalose, which occurs in various plants, is also a di- 
saccharide of Type II. ; on hydrolysis it gives ^-glucose only. 
The two types of disaccharides may therefore be classified as follows: 

I. Glucose-glycoside type (with a * free carbonyl ' group). 
(a) Maltose, Lactose, Cellobiose. (b) Gentiobiose, 

Melibiose. 

II. Glycosido-glycoside type (with no ' free carbonyl '). 
Sucrose, Trehalose. 

Theoretically there are many different ways in which members 
of Type I. might be formed, since the elimination of a molecule of 
water from two molecules of the glycosidic forms of the same or of 
different aldohexoses might involve any one of the four hydroxyl 
groups of one of the compounds ; the first step, therefore, is to 
ascertain which of these hydroxyl groups takes part in the production 
of the biose link of the disaccharide. 

This can be done by first submitting the disaccharide to complete 
methylation, and then hydrolysing the product carefully so that two 
methylated hexoses are obtained ; these compounds are tri- and 
tetra-methyl derivatives, the structures of which can be (and have 
been) determined by studying their products of oxidation, and in 
other ways. The results of such experiments show which of the 
four hydroxyl groups of each aldohexose were not concerned in the 
disaccharide formation because hydroxyl groups which are methyl- 
ated in the fission products must have been present as such in the 
disaccharides. This method of investigation is illustrated by the 
examples given below. 

Maltose, exhaustively treated with dimethyl sulphate and alkali, is 
converted into methyl-heptamethylmaltoside, a compound which lacks 
the reducing power of the parent sugar because the * free carbonyl ' 
group has been methylated. The hydrolysis of methyl-heptamethyl- 
maltoside gives heptamethylmaltose, the glycosidic methyl group being 
displaced by hydrogen, and on further hydrolysis the disaccharide 
derivative gives 2:3:4:6-tetramethylglucose and 2:3:6-trimethylglucose, 

Org. 66 



888 DISACCHARIDES AND POLYSACCHARIDES 

The production of 2:3:4:6-tetramethylglucose shows that the 
linkage of the hexose molecules occurs through carbon atom 1 in 
the case of the A-part of the molecule (see below), because carbon 
atom 5 is a part of the oxide-ring structure ; the formation of 
2:3:6-trimethylglucose shows that B is linked to A through the 
oxygen of carbon atom 4 or 5, as the 4 and 5 hydroxyl groups of 
the B-part of the disaccharide are not methylated. 

Now if it be assumed that the glucose residue B is of the normal 
amylene oxide type, the formula of maltose must correspond with 
(i) ; but this might not be so, since the molecule of maltose might 
contain a labile y-glucose residue (p. 873) as shown in (n), which 
structure would give the same products of fission as (i). 



i I:H 
2 CH-OMe 
3 CH-OMe < 
4 CH-OMe 

5J~*1T 


^ii^ii; 1 
CH-OMe 
) O CH-OMe < 
1 CH 

/-itr 


6 CH 2 -OMe CH-OMe 

1 Heptamethylmaltose 1 

2:3:4:6- 2:3:6- 

Tetramethylglucose Trimethylglucose 



A B 


i 
2 CH-OMe 

3 CH-OMe ( 

4 CH-OMe 

? ATT , , 


CH-OMe 

) O CH-OMe O 
1 1 

/^TT 1 


1 CH 
CH 2 'OMe 

2:3:6- 
Trimethylglucoie 


6 CH 2 -OMe 
2:3:4:6- 

Tetramethylglucoee 



DISACCHARIDES AND POLYSACCHARIDES 



889 



That (i) represents heptamethylmaltose is proved as follows : 

When maltobionic acid, obtained by oxidising maltose, is methyl- 
ated, it yields the methyl ester of octamethylmaltobionic acid, (in), 
which on hydrolysis gives the same 2:3:4:6-tetramethylglucose, (iv), 
as before (from A), together with a 2:3:5:6-tetramethylgluconic acid, 
(v, from B), instead of a 2:3:6-trimethylglucose ; the carbon atom 5 
which escaped methylation in the disaccharide is methylated in 
maltobionic acid because the 5 oxide-ring underwent fission in the 
formation of the latter. The 2:3:5:6-tetramethylgluconic acid, (v), 
forms a y-lactone, (vi), identical with tetramethyl-y-gluconolactone 
(p. 873). Clearly, then, the y- or 4-hydroxyl group of the B mole- 
cule takes part in the formation of the biose link, as shown in (i) 
and (in). 



A 


B 
COOH 

CH-OMe 


IH-OMe 





iH-OMe 
:H-OMe 



CH 2 - 



OMe 



:H-OMe 




OMe 



Til 



CH(OH) 



;H(OH) 1 

:H-OMe 
:H-OMe O 



CH-OMe 
CH-OMe 

CH 

CHj- 



OMe 
IV 



B 

COOH 

CH-OMe 
CH-OMe 
CH-OH 
CH-OMe 
CH 2 -OMe 
V 



B 



CO- 



OMe 
CH-OMe 



CH-OMe 
CH 2 -OMe 



VI 



Maltose, therefore, is a glucose-glucoside, but it remains to be 
decided whether the glucoside structure of A is a- or j8-, that is to 
say whether the configuration of A corresponds with that of a- 



890 DISACCHARIDES AND POLYSACCHARIDES 

methyl- or j8-methyl-glucoside. Now maltose is hydrolysed by 
maltase (p. 332), an enzyme which has been found to attack a- but 
not /?-glucosides ; it is therefore glucose-a-glucoside, as shown 
below. 




>H 



The structures of lactose and cellobiose (p. 886) have been 
elucidated in a similar manner and are identical with that of maltose. 
The heptamethyl derivatives of these sugars, obtained from the 
methyl-heptamethyldisaccharides, are hydrolysed, giving the following 
products : 

TT 111 A f2:3:4:6-tetramethylgalactose. 

Heptamethyllactose i -3 /: * ^.11 
r J \2:3:6-trimethylglucose. 

TT ^ - , ,. (2:3:4:6-tetramethylglucose. 
Heptamethylcellobiose \ ~ ~ , A . A i t , 
v J [2:3:6-tnmethylglucose. 

These results show that in both disaccharides, just as in the case 
of maltose, the two aldobexose residues (A and B) are linked together 
through the 4 or 5 carbon atom of B ; the position of the biose link 
is proved to be the same as that in maltose by a study of the fission 
products of octamethyllactobionic and octamethylcellobionic acids 
respectively ; the former gives 2:3:4:6-tetramethylgalactose and 
2:3:5:6-tetramethylgluconic acid, and the latter gives 2:3:4:6-tetra- 
methylglucose and 2:3:5:6-tetramethylgluconic acid. 

Though structurally identical with maltose, lactose and cello- 
biose differ from maltose in configuration. Lactose is hydrolysed by 
lactose, and is a j3-galactoside ; cellobiose is hydrolysed by emulsin 
(p. 499), not by maltase, and is therefore a j8-glucoside (compare 
p. 903). 

The structure of melibiose has been established by the same 
methods as those used for maltose, lactose, and cellobiose. The 
disaccharide is completely methylated, and the octamethyl deriva- 
tive is then converted into heptamethylmelibiose by graded hydrolysis ; 
this compound undergoes fission, giving 2:3:4:6-tetramethyl- 
galactose and 2:3:4-trimethylglucose. 



DISACCHARIDES AND POLYSACCHARIDES 8V1 

The two hexose molecules are therefore linked together through 
carbon atoms 5 or 6 of the glucose residue B, probably 6, if the 
glucose residue is the normal pyranose form. 

Now methyl octamethylmelibionate^ on hydrolysis, affords 2:3:4:6- 
tetramethylgalactose and 2:3:4:5-tetramethylgluconic acid which 
can be oxidised to tetramethylsaccharic acid. 

These facts prove that the biose linkage must be from atom 1 in 
the galactose residue, A, to atom 6 in the glucose residue, B. 




6 CH 8 OH 

Melibiose and Gentiobiose 



CH: 

I 

CH-OMe 

OMe 
OMe 

CH 

CH a OMe 



CH-( 
CH-C 



COOH 

I 
CH'OMe 

I 
O CH OMe 

CH OMe 
CH OMe 



L CH a 
Octamethylbionic acid 



CH(OH) 1 
CH-OMe 
CH-OMe 


COOH 
CH-OMe 
CH-OMe 


CH-OMe 


CH-OMe 


CH ' 
CH a - OMe 


CH OMe 
CH, OH 


2:3:4:6- 


2:3:4:5- 


Tetramethylhexose 


Tetrarncthyl- 
uluconic acid 



In a similar manner gentiobiose has been shown to be structur- 
ally identical with melibiose, but its molecule contains a glucose, 
in place of the galactose residue, A ; this structure has been con- 
firmed by synthesis (p. 895), and from its behaviour towards emulsin, 
the biose link of A is that of a j3-glucoside. 

It will be seen that the disaccharides of Type I. may be classed 



892 



DISACCHARIDES AND POLYSACCHARIDES 



in two groups (p. 887), and the results of their investigation may 
be summarised as follows : 




Maltose a -Glucose Glucose 
Lactose /?-Galactose Glucose 
Cellobiose ^-Glucose Glucose 

I I 

Methylated Methylhexoses 

bioses give : 2, 3, 4, 6 2, 3, 6 

Methylated 
bionic acids 
give : 



Melibiose a-Galactose Glucose 
Gentiobiose ^-Glucose Glucose 



I ! 



Methyl- Methylhexonic 
hexose acid 

2, 3, 4, 6 2, 3, 5, 6 



Methylhexoses 
2, 3, 4, 6 2, 3, 4 

Methyl- Methylhexonic 
hexose acid 

2,3,4,6 2,3,4,5 



The 1 carbon atom of the * free carbonyl * group is indicated by 
the dark circle. The hydroxyl group of this carbon atom is methyl- 
ated in the octamethyl derivative of the disaccharide, but not in its 
first product of hydrolysis (heptamethyl derivative) ; it is this 
* free carbonyl ' which gives the carboxyl group of the bionic acid. 

With the aid of this summary most of the experimental data given 
in this chapter are easily reproduced, since the above symbols are 
based on the facts there recorded. It is easily seen, for example, 
that methylated lactose will give 2:3:4:6-tetramethylgalactose and 
2:3:6-trimethylglucose ; that lactobionic acid will give 2:3:4:6- 
tetramethylgalactose and 2:3:5:6-tetramethylgluconic acid, the 5- 
hydroxyl group which is * blocked ' in the disaccharide, owing to 
the oxide ring, being methylated in lactobionic acid, in which this 
ring is no longer present. 

Disaccharides of Type II., the molecules of which do not contain 
a * free carbonyl,' must have been formed by the elimination of 
water from the reducing groups of both monosaccharides, so that 
it is only necessary to determine the structure of the oxide rings in 
the two hexoses. 



DISACCHARIDES AND POLYSACCHARIDES 893 

This is accomplished by methods corresponding very closely 
with those used in the case of the disaccharides of Type I. ; that is 
to say the compounds are completely methylated, under conditions 
which do not bring about any change in structure, and the products 
of fission of the methylated compounds are then identified. 

Sucrose, with dimethyl sulphate and alkali, yields octamethyl- 
sucrose, which is hydrolysed by very dilute (0*4%) hydrochloric acid, 
giving a 2:3:4:6-tetramethylglucose and a l:3:4:6-tetramethyl-y- 
fructose ; the former compound is identical with normal 2:3:4:6- 
tetramethylglucose (p. 870), and the constitution of the latter was 
proved in the manner already described (p. 875). 

Octamethylsucrose, therefore, consists of normal tetramethyl- 
glucose condensed with y-tetramethylfructose, and these two mole- 
cules must be linked by the elimination of water from the 1-hydroxyl 
group of tetramethylglucose and the 2-hydroxyl group of y-tetra- 
methylfructose, as will be seen from the following formula : 



1 
2 
3 
4 
5 
6 


*H 

H C OMe 
MeO-C H ( 
H C OMe 
H i 


1 "-^O*" 

^^**r 


UMC 


1 ? 1 
) MeO C H 1 

H C OMe 1 

u r I 


CH a -OMe CH, 

Octamethylsucrose 


OMe 



Sucrose itself is represented by a formula corresponding with 
that of its octamethyl derivative. 

Octamethylsucrose, [a] D 4-67, is hydrolysed to a mixture of 
methylated hexoses, which has [a] D -f57, so that no inversion occurs 
as with the unmethylated sugar (p. 323). This fact is readily ex- 
plained by the above structural and configuration^ formula, since 
both the methylated hexoses produced are dextrorotatory (Hudson's 
rule) ; when, however, the unmethylated sugar is hydrolysed, the 
dextrorotatory y-fructose which is first formed immediately passes 
into normal rf( )-fructose with a change of the oxide-ring structure, 
and as rf()-fructose has a larger laevo-specific rotation than dextro- 
rotatory rf-glucose, inversion occurs. 



894 DISACCHARIDES AND POLYSACCHARIDES 

1 CH a .OMe CHfOH 

2 HO C * | C OH 

3 MeO C H HO C H 

loll 

4 H C OMe | Q H C OH 



5 H C J I H C OH 

6 CH a OMe I CH, 

Tetramethylfructofuranose Normal fructopyranose 

The above constitutional formula represents sucrose as a fructo- 
sido-glucoside, or glucosido-fructoside, both the hexoses being 
united through their glycosidic groups ; as, therefore, the molecule 
contains no * free carbonyl,' sucrose does not show those reactions 
of disaccharides of Type I. which are due to such a group. Since 
a glycoside (or fructoside) may exist in a- and j8-forms, the con- 
figuration of sucrose is not settled until it has been determined 
whether this linkage is a- or j8- in the glucose residue and a- or 
j8- in the fructose residue clearly four possibilities ; conclusive 
evidence on this point, however, is still lacking, but sucrose is 
probably a j8-fructosido-a-glucoside. 

The Synthesis of Disaccharides 

Several methods for the synthesis of disaccharides have been 
investigated. Thus the hydrolysis of a disaccharide by an enzyme 
is a reversible process, and if a mixture of the constituent mono- 
saccharides is submitted to the action of the enzyme some of the 
disaccharide is produced ; maltose is thus obtained from rf-glucose. 

Pictet and his collaborators synthesised a sugar, which they 
believed to be maltose, by heating a mixture of a- and j8-glucose at 
160 in a vacuum, and, similarly, a product, thought to be lactose, 
from a mixture of j3-glucose and j8-galactose. By the condensation 
of tetra-acetyl-y-fructose and tctrn-acctylglucosc, they obtained a 
sugar, now known as wosucrose, which differs from sucrose only as 
regards the biose link. 

Syntheses such as the above do not give much information as to 
the structure of the disaccharide, and as an illustration of a more 
definite synthesis that of gentiobiose (Helferich and Klein, Ann, 
450, 219) may be given. 



DISACCHARIDES AND POLYSACCHARIDES 



895 



2:3:4:6-Tetra-acetyl-l-bromoglucose, (i), and l:2:3:4-tetra-acetyl- 
/?-glucose, (n), compounds of proved constitution, react in the 
presence of silver oxide, and when the product is very cautiously 
hydrolysed in order to displace the acetyl groups, it gives a glucose- 
j8-glucoside 1 which was proved to be identical with gentiobiose 
(p. 892). 



C 

{ 



CHBr- 
IH-OAc 
OAc 

:H-OAC 
I 

CH- 



CH a - 



OAc 



CH(OAc) 
CH-OAc 
CH-OAc O 
CH-OAc 



n 



CHj-OH 



II 



The Oxidation of Sugars with Periodic Acid 

Very interesting results have been obtained by the oxidation of 
sugars or their derivatives, with periodic acid ; one or more groups 
CH(OH) CH(OH) undergo fission with the formation of 
dialdehydes, and the reactions are quantitative. 

Thus, with a methylhexosepyranoside fission occurs between 
carbon atoms 2 and 3 and also between 3 and 4 with the elimination 
of the CH(OH) group at 3 as formic acid and the formation of (i) : 

C 7 H 14 6 +2HI0 4 - C 6 H 10 5 +H.COOH-f2HI03+H 2 0, 



1 

2 


CH(OMe) 
CH-OH 


CH(OMe) 
CHO 

"V f 


3 


CH-OH ( 


3 C 


4 
5 
6 


CH-OH 

PIT 


CHO 


CH,-OH CH,-OH 




I 



CH(OMe) 
O CO 






O CO 
CH- 



CH.-OH 

II 



1 2:3:4:6-Tetra-acetylbromoglucose gives glucosides derived from ^-glucose. 



896 



DISACCHARIDES AND POLYSACCHARIDES 



When the dialdehyde, (i), is then oxidised with bromine water in 
the presence of strontium carbonate, the crystalline strontium salt, 
(u), is obtained. 

Both a- and j3-methylglycosides give such oxidation products 
and, in either the rf- or the /-series, the corresponding derivatives 
are distinguished merely by the different configurations of their 
1 -group ; as all a-methylglycosides of the ^-series (so far examined) 
give the same strontium salt, (n), it follows that they all have the 
same configuration at carbon atom-1. Methylpentosefuranosides, 
(in), give the same oxidation products, with a fission of the 
molecule as indicated, but without, of course, any production of 
formic acid, 





CH- 
CH 2 -OH 



III 



IV 



The application of this method has fully confirmed the structure 
of sucrose, (iv) : with three molecules of periodic acid the sugar 
gives (v) together with one molecule of formic acid. On further 
oxidation with bromine water, followed by hydrolysis, glyoxylic, 
glyceric, and hydroxypyruvic acids are formed (Fleury and Courtois, 
Compt. Rend. 1942, 214, 366) : 



CHj-OH 




CHO 
COOH 

COOH 

CH-OH 

CH.-OH 




DISACCHARIDES AND POLYSACCHARIDES 897 

Vegetable Glycosides 

Several naturally-occurring glycosides, such as amygdalin (p. 354), 
salicin (p. 535), arbutin (p. 491), ruberythric acid (p. 562), and 
indican (p. 681), have already been mentioned, and their products 
of hydrolysis have been given ; such compounds are derived from 
sugars by the condensation of the glycosidic hydroxyl group with 
a hydroxyl group of the non-sugar part of the molecule or aglycone, 
just as the disaccharides are derived from two monosaccharides. 
The structures of many glycosides have been determined by isolat- 
ing the products of hydrolysis obtained with enzymes or acids, and 
also applying the methods used in investigating the structures of 
the saccharides. In the case of arbutin, for example, hydrolysis 
yields glucose and quinol, and as hydrolysis is effected by emulsin, 
arbutin is a ]8-glucoside ; arbutin gives a pentamethyl derivative, 
which is hydrolysed with methyl alcohol and hydrogen chloride to 
a- and j3-2:3:4:6-tetramethyl-methylglucosides. Arbutin, there- 
fore, is a quinol-j3-glucoside, C 6 H 11 O 5 -O'C 6 H 4 -OH, derived from 
normal glucopyranose, and during its hydrolysis, in the presence 
of methyl alcohol, both the a- and j8-glucosides are produced. 
Michael has synthesised methylarbutin from quinol monomethyl 
ether and . *\ / * :'.,* > , (p. 879), and Macbeth and Mackay 
have obtained pentamethylarbutin by condensing tetramethyl- 
glucose and quinol monomethyl ether, thus confirming the above 
structure. 

Amygdalin has been proved to be a gentiobioside (p. 892) of 
/-mandelonitrile, C 6 H 5 -CH(CN)-O-C 12 H 21 O 10 , and has been syn- 
thesised by Campbell and Haworth (J. 1924, 1337). 

Various other types of glycosides, such as the tannins (p. 998), 
anthocyanins (p. 989) and cardiac poisons (p. 1110), occur in nature. 

Polysaccharides 

The polysaccharides, such as starch (p. 325) and cellulose (p. 328), 
are hydrolysed by acids and by enzymes, and their molecules are 
finally resolved into monosaccharides ; during this process many 
intermediate products are formed, and from starch, for example, 
various soluble, comparatively simple substances, composed of 
only eight or fewer monosaccharide molecules closely related to 
maltose have been isolated. From this and much other evidence it 
has been inferred that the polysaccharides are highly complex 



898 DISACCHARIDES AND POLYSACCHARIDES 

condensation products of the oxide forms of the monosaccharides 
(generally glucose), the molecules of which are linked together by 
the elimination of the elements of water, as indicated below : 

HO C fl H 10 O 5 H!K> C fl H 10 O 6 HlSb C 6 H 10 O 6 iTSo - C 6 H 10 O 5 H etc. 

If, then, as seems very probable, the polysaccharides are open 
chain compounds, their empirical formulae will approach the more 
nearly to C 6 H 10 O 5 , the larger the number of monosaccharide residues 
in their molecules ; if, as is conceivable, they are closed chain 
compounds, the elimination of the elements of water from the ends 
of the chain will give a product, (C 6 H 10 5 ) n , whatever the number 
of monosaccharide residues in the molecule. It is not to be inferred, 
however, that all the links indicated above by <~> are of the same 
nature ; they may be formed by either the a- or the ^-configuration 
and may vary alternately or otherwise, so that hydrolysis may bring 
about the fission of the less stable links only, giving products which 
are still polysaccharides. 

The determination of the structures of such complex molecules 
is obviously a task of the greatest difficulty, but a good deal of 
information has been gained by employing methods similar to 
those used in the study of the disaccharides. 

Starch. By the hydrolysis of starch under suitable conditions 
an 80% yield of maltose is obtained, a fact which would appear to 
show that the polysaccharide consists wholly of linked maltose 
molecules ; on methylation, starch yields nearly 90% of trimethyl- 
starch, (C 6 H 7 O 6 Me 3 ) n , which, on hydrolysis, is converted mainly 
into 2:3:6-trimethylglucose. 

When starch is heated at 120 with butyl alcohol, amylose (20-25%) 
separates ; amylopectin passes into solution and can be precipitated 
by ethyl alcohol. These two components differ in many respects ; 
although amylose may be dissolved from starch with warm water 
(p. 326), when it has been thoroughly dried it is more sparingly 
soluble than is amylopectin ; the former gives an intense blue with 
iodine and is completely converted into maltose by j8-amylase ; * 
the latter gives a red-brown colour with iodine and yields only 50% 
of maltose with j3-amylase, together with a residue of dextrin-A. 

Now Haworth and his collaborators have shown that when fully 
methylated amylose is hydrolysed, in addition to 2:3:6-*ranethyl- 

1 Diastase is a mixture of enzymes of which one is /?-amylase. 



DISACCHARIDES AND POLYSACCHARIDES 



899 



glucose, which is the main product, a small proportion of 2:3:4:6- 
/f/^rrt::\!::*iicoso is obtained; the latter, apparently, must have 
been formed from the commencing group l of an open chain structure, 
such as that shown below, and by determining its proportion, 
the number of hexose units in the chain may be estimated. It was 
found by this method (end-group assay) that the amylose molecule 
contains about 100 or more hexose units, and molecular weight 
determinations by osmotic pressure measurements agree with this 
value. The structure of amylose may therefore be expressed as 
below, the maltose units being united by a-glucose linkages : 




Amylose 

Amylose has been obtained crystalline and the results of its X-ray 
examination suggest a helical arrangement of the chain. 

In amylopectin, end-group assay gives a chain length of about 
20 glucose units, whereas osmotic pressure measurements show a 
very much higher molecular weight ; this and other evidence 
indicate that the relatively short chains are bound to one another 
by l:6-a-linkages, thus giving a sort of tree-like structure. 

Cellulose. Evidence of a like nature points to the conclusion 
that the structure of cellulose is similar to that of amylose, but that 
the linked hexose molecules are those of j8-glucose, since cellulose 
consists of cellobiose units. 





1 It is to be noted that the other terminal group yields fnmethylgiucose, 
as the methyl group attached to the glucosidic oxygen atom is displaced on 
hydrolysis. 



900 DISACCHARIDES AND POLYSACCHARIDES 

Molecular weight determinations of cellulose by various methods 
give values from about 300,000-500,000, and the molecules have a 
long thread-like structure. 

Some interesting results have been obtained by Hess and Schultze 
(Ann., 448, 99 ; compare Pringsheim, Ann., 450, 255) during their 
investigations of crystalline cellulose diacetate, a compound obtained 
by treating cellulose triacetate with sulphuric and acetic acids. 
Molecular weight determinations in acetic acid solution in the 
absence of dissolved air give values corresponding with those 
required for C 6 H 8 O 5 Ac 2 , but in the course of a few days the molecular 
weight gradually increases and becomes infinitely large ; the com- 
pound then recovered from the solution is identical with the original 
one, and gives the same small molecular weight as before. Cellulose 
triacetate shows a similar behaviour. 

Inulin (p. 327), like starch and cellulose, yields on methylation a 
trimethyl-derivative, which on hydrolysis gives 3:4:6-trimethyl-y- 
fructose (over 90% yield) ; inulin, therefore, is represented as a 
condensation product of a- or j8-fructofuranose. In addition to 
fructose, on hydrolysis inulin gives a very small proportion of 
glucose ; it is not yet known how this is combined in the molecule. 

Chitin, a polysaccharide which is contained in the shells of 
crustaceans, yields glucosamine and acetic acid on hydrolysis ; it is 
probably composed of units of JV-acetylglucosamine joined in the 
same way as the glucose units of cellulose. As will be seen from 
the formula, glucosamine is theoretically formed by displacing the 
hydroxyl group on carbon atom 2 of glucose by the amino-group. 



CH(OH) 
H C NH, 
HO C H 
H C OH 



H-C. 



CH,-OH 

Glucosamine 

Algimc Acid, (C 6 H 8 O 6 ) n , occurs both in the free state and as the 
calcium salt in many seaweeds. The sodium salt gives a very 



DISACCHARIDES AND POLYSACCHARIDES 901 

viscous solution in water even at a concentration of only 2% and 
is used in the dyeing, textile and explosives industries and in making 
ice-cream, etc. On hydrolysis alginic acid gives rf-mannuronic 
acid, C 6 H 10 O 7 , and its molecule consists of units of this acid com- 
bined in the same way as the glucose units of cellulose. 

Pectin is widely distributed in plants, especially in fruit juices, 
and the setting or jellying of jams is due to its presence. It is 
composed of units of ^-galacturonic acid, C 6 H 10 O 7 (p. 883), and its 
methyl ester linked in the same way as the mannuronic acid in 
alginic acid. 

Fermentation 

The production of intoxicating liquors from various natural sweet 
substances by the process of fermentation (compare p. 330) has 
been known from the very earliest times, but it was not until some 
150 years ago that Lavoisier showed that, in this process, a sugar is 
decomposed, roughly quantitatively, into alcohol and carbon dioxide. 
This result was confirmed by Gay-Lussac some twenty years later, 
and in 1860 Pasteur proved that small proportions of glycerol, 
succinic acid, and other substances are also produced ; it is now 
known that whereas the alcohol, carbon dioxide, and glycerol are 
formed from the sugar (p. 332), fusel oil and succinic acid are pro- 
duced from the amino-acids (leucine, tyoleucine, glutamic acid, 
pp. 623-625) contained in the yeast, malt, potatoes, or other material, 
which is used in this process for manufacturing alcohol. 

In order that fermentation may take place, the temperature must 
be kept within certain limits ; there must also be present certain 
mineral salts, particularly those of potassium and magnesium, 
sulphates, and phosphates, and some source of combined nitrogen, 
which serve as food for the yeast organism. 

The sugars in the materials generally used for the production of 
alcohol are sucrose, glucose, and maltose, the last two of which are 
formed from starch ; it was believed at one time that the di- 
saccharides, sucrose and maltose, must first be hydrolysed to mono- 
saccharides (by invertase and maltase respectively) before they could 
ferment, but from the results of investigations by \Yillstattcr and 
his co-workers it would seem this is not so, and that such di- 
saccharides may be directly fermented by particular enzymes. 

In addition to the sugars just mentioned, J-mannose is fermented 
by yeast ; rf-galactose ferments only very slowly at first, but as the 



902 DISACCHARIDES AND POLYSACCHARIDE8 

yeast becomes accustomed to this sugar the rate of change increases 
and ultimately may surpass that of {/-glucose. 

When Fischer prepared new aldoses, which were not known in 
nature, he investigated their behaviour towards yeast and found that 
glycerose (p. 862) fermented slowly but that tetroses and pentoses 
were not attacked ; the new aldohexoses, /-glucose, /-mannose, and 
/-fructose (p. 864), did not ferment, but rf-mannononose (p. 320) 
gave alcohol and carbon dioxide ; mannoheptose and manno-octose, 
however, were unfermentable. It was thus shown (a) that only 
those sugars containing 3 or a multiple of 3 carbon atoms are acted 
on by yeast, and (b) that, of two enantiomorphously related com- 
pounds, only the one form ferments. These facts led Fischer to 
suggest that the sugar, and the enzyme which attacks it, might be 
compared with a lock and key, since a very slight alteration in the 
configuration of the one prevents the proper working of the other. 

Little progress was made in the investigation of this subject until 
Buchner showed in 1897-98 that the alcoholic fermentation of certain 
sugars can take place in the absence of any living yeast cells. By 
grinding yeast with quartz sand and kieselguhr and submitting the 
mixture to great pressure, he obtained a yeast extract which was 
passed through a kieselguhr filter ; although this extract did not 
contain any living cell, it was capable of bringing about the decom- 
position of certain sugars into alcohol and carbon dioxide. This 
important discovery proved that, contrary to Pasteur's views, the 
presence of a living organism is not essential to fermentation ; 
although the living cell produces the active agent, the latter works 
independently. This active agent or zymase, a mixture of enzymes, 
although inanimate, has, as stated above, a highly selective action ; 
it can only attack a very few of the sixteen optically isomeric aldo- 
hexoses. Its action is restricted and specific, and this is true of the 
numerous other enzymes which are known. These nitrogenous 
' organic catalysts ' are usually named after the substance on which 
they act (the substrate), or to which they give rise ; inverts or 
sacchanwe produces invert sugar by the hydrolysis of sucrose ; 
amylose hydrolyses starch (amylose), and so on. Further examples 
of the specific action of enzymes are afforded by the sorbose bac- 
terium (p. 335), which can oxidise to a ketose, /-arabitol, and d- 
sorbitol, but not xylitol or dulcitol ; by malted (p. 332), which 
hydrolyses maltose and a-, but not jS-methylglucoside, and a- but 
not j8-biose links of the diaaccharides (p. 890) ; by emulsin (p. 354) 



DISACCHARIDES AND POLYSACCHARIDES 903 

or synaptase, which hydrolyses the ]8- but not the a-forms of glu- 
cosides, including disaccharides. Many enzymes have now been 
obtained crystalline and are proteins. 

Buchner's discovery, important though it was, threw no light on 
the mechanism of alcoholic fermentation, and it was not until 1906 
that any substantial advance was made. It was then found by 
Harden and Young that, in the presence of alkali phosphates, the 
evolution of carbon dioxide from a fermenting sugar is greatly 
accelerated, and further investigation has proved that a diphosphoric 
ester of a hexose is produced in the solution ; this ester is derived 
from ^-fructose, whether the original sugar is ^/-glucose, *f-mannose, 
or ^/-fructose (which may be converted one into the other), and 
Robison has shown that it is a l:6-ester of fructose. 

In more recent years, owing mainly to the work of Neuberg, 
Embden, Meyerhof, and others, much has been learned about the 
mechanism of alcoholic fermentation. It is now known that zymase 
contains various enzymes, some of which can act only in the presence 
of co-enzymes^ formerly known collectively as co-zymase. 

These co -enzymes are relatively simple substances and unlike 
the enzymes themselves are not destroyed by heat. One is a 
phosphate carrier, adenosine triphosphate, 1 (ATP), which gives up 
a part of its phosphate content to the sugars undergoing fermenta- 
tion and is thereby converted into adenosine diphosphate, (ADP) ; l 
this latter is reconverted into ATP at a subsequent stage. Another, 
co-enzyme I or co-zymase, (Co), adenine-nicotinamide dinucleotide * 
is capable of combining with two atoms of hydrogen per molecule 
to form Co,2H and giving them up again, thus acting as a hydrogen 
carrier. Aneurin pyrophosphate, co-carboxylase, is mentioned 
later (p. 1067). 

According to current views, the first step (a) in the fermentation 
of glucose is its phosphorylation by ATP : 

Glucose+2ATP (g) , fructofuranose l:6-diphosphate+2ADP; 

the liberated ADP becomes rephosphorylated at a later stage (e 
and g) and is then available for the phosphorylation of more glucose. 
This change, (a), actually occurs in three stages : 

Glucose > glucopyranose 6-phosphate + fructofuranose 
6-phosphate > fructofuranose l:6-diphosphate. 

1 The structures of these compounds are shown in the table, p. 906. 
Org. 57 



904 DISACCHARIDES AND POLYSACCHARIDES 

Each stage is brought about by a specific enzyme and the first 
and last require ATP as co-enzyme. 

The next transformation (b) is the fission of the fructose diphos- 
phate into (two 3 -carbon atom chains of) triose phosphate, which 
consists of an equilibrium mixture of dihydroxyacetone phosphate 
and glyceraldehyde phosphate?- Both reaction (b) and the inter- 
conversion of the triose phosphates are catalysed by enzymes. 



OP QH 2 -OP 

CHo-OP 

W 






CHOP 
CH-OH 
ip- OH 



In the next stage (c), the glyceraldehyde phosphate combines 
with inorganic phosphate to give a diphosphate (i), of the hydrated 
form, which in the presence of an enzyme and co-zymase, (Co), 
gives Co,2H and a mixed anhydride of phosphoric acid and glyceric 
acid phosphate, (u, commonly called \;3-diphospfioglyceric acid) : 

CH 2 -OP CH 2 -OP 

I (d) | 

CH-OH + Co - > CH-OH + Co,2H 

CO-OP 



I II 

The diphosphoglyceric acid, (n), now loses a phosphate radical 
to ADP, which is reconverted into ATP and the resulting glyceric 
acid ^-phosphate is transformed into the a-ester, both changes being 
catalysed by enzymes. 

CH a -OP CH a -OP CH 2 -OH 

CH-OH + ADP ^ ATP 4- CH-OH - > CH-OP 
CO-OP COOH COOH 

1 These compounds are also called phosphodihydroxyacetone and 
phosphoglyceraldehyde respectively ; the more systematic names are used 
here and in the following pages. 

8 P - OPO(OH) a . 



DISACCHARIDES AND POLYSACCHARIDES 905 

The glyceric acid a-phosphate now loses a molecule of water (/) 
and is converted into (enol) pyruvic acid phosphate : this product then 
reacts (g) with ADP to form pyruvic acid and ATP. Under the 
influence of an enzyme, carboxylase, which requires as co-enzyme 
aneurin pyrophosphate, the pyruvic acid is converted into acet- 
aldehyde and carbon dioxide (h). In the last stage (t), reduced 
co-zymase (Co,2H), produced in reaction (d) t converts acetaldehyde 
into alcohol, and the co-zymase returns to (d). 

CH 2 -OH CH a CH 3 CH 3 

I (/) II to) I (h) \ 

CH'OP > C-OP CO (+ ATP) > CHO 

| I + ADP I 

COOH COOH COOH CO 2 



| + Co,2H > T +Co. 

CHO CH 2 -OH 



These reactions, summarised in the accompanying table, account 
for about 90% of the products of normal fermentation. The normal 
yield (2%) of glycerol (p. 901) can be increased to as much as 
37% by the addition of sodium sulphite at the beginning of the 
process (see table) ; advantage was taken of this fact in Germany 
during the war of 1914-18, when glycerol was so urgently needed 
for the manufacture of explosives. 

Another variation of the fermentation process can be brought 
about by the addition of ammonium or potassium carbonate or 
dipotassium hydrogen phosphate ; acetic acid is then produced, 
together with glycerol, alcohol and carbon dioxide, as shown in the 
table (p. 907). 

In all these cases glyceraldehyde phosphate may be regarded as 
the primary and acetaldehyde as the secondary product of fermenta- 
tion, their fates depending on the conditions. 

Certain bacteria yield butyric acid and butyl alcohol, and their 
formation is often accompanied by that of acetone and hydrogen ; 
a suggested mechanism for these processes is shown in the table. 

/-Lactic acid is produced when certain micro-organisms act on 
glucose, and also by the enzymes of muscle acting on glycogen ; 
this is an example of asymmetric synthesis (p. 746), common among 
reactions brought about by enzymes, as the lactic acid is probably 
formed by the reduction of pyruvic acid by Co,2H. 



906 



DISACCHARIDES AND POLYSACCHARIDES 



FERMENTATIONS 



Ethyl Alcohol 
C 6 H 12 6 - 2C2H5-OHH-2C02 



C 6 H 12 + 



Glycerol 
C 6 H 12 O e - C 3 H 8 O 3 +CO 2 +CH 3 .CHO 



H,N 



N-C 

/ 



N k 



CH 2 OP 
2 CH-OH 
CHO 

i 


;H 2 -OP 
H-OH 
CHO 

/ \ 


;H 2 -OP 
H-OH 
COOH 


CH 2 .OP CH 2 -OP 
CH-OH CH-OH 
COOH CH 2 -OH 


i 


i I HOH 


QH 3 
2 1 +2C0 2 
CHO 

i 


CHO 2 CH-OH 
CH 2 OH 


CH 2 -OH 


The sodium sulphite, with carbon dioxide, 
gives bisulphite, which unites with the acet- 
aldehyde; the reaction (i) being thus in- 
hibited, the glyceraldehyde phosphate is 
reduced to glycerol phosphate by Co,2H 
which itself returns to (a) ; the glycerol 
phosphate so produced is convened into 
glycerol by an enzyme. 


[L-CH-OH 
| CH-OH 





Adenine 



Ribose 



ADP, R - -PO(OH) 8 

ATP, R - -PO(OH)-O-PO(OH)t 



DISACCHARIDES AND POLYSACCHARIDES 



907 



FERMENTATIONS 



Mixed 

2C 6 H 12 6 +H 2 - 2C 3 H 8 3 +2CO* 
+ CH 3 - COOH-f C 2 H 5 OH 

CH 2 -OP 

2C 6 Hi 2 O 6 4 CH-OH 
CHO 



\ 



5 


:iH 2 .op 


CH 2 -OP 


2 C 


:H-OH 


2 CH-OH 




:OOH 


CH 2 -OH 




\ 


I 


2 1 


%2C0 2 


CH 2 OH 


C 


:HO 

\ 


2 CH OH 
CH 2 -OH 


?H 3 


CHa 




COOH 


CH 2 -OH 





Butyric Acid, Butyl Alcohol 
and Acetone 

2CH 3 -CHO 
CH 3 CH(OH) CH 2 CHO 



CH 3 -CH:CH-CHO 

i 

CH 3 .CH 2 .CH 2 -CHO 

/ \ 

C 3 H 7 COOH C 3 H 7 CH 2 OH 
2CH 3 -CHO 



2 CH 3 - COOH-f 2H 2 



In alkaline solution the acetaldehyde under- 
goes a Cannizzaro reaction, giving acetic acid 
and alcohol, and as reaction (i) cannot then 
occur the glyceraldehyde phosphate undergoes 
the same changes as those shown in the case 
of the glycerol fermentation. 

Co-zymase, R 



CH,-CO-CH 2 .COOH 

i 

CH 3 CO-CH 3 +C0 2 



[OH 
OH 







908 DISACCHARIDES AND POL YSACCHARIDES 

At the present time large quantities of sugar are fermented, 
mainly for the production of yeast, which is required in bread- 
making ; in this operation ammonium sulphate is added to the 
fermenting liquid, which is vigorously aerated. The result is a 
very rapid increase in the growth of the yeast, which utilises the 
ammonium sulphate and the whole of the alcohol, for the formation 
of protein matter ; it is thus possible to manufacture valuable 
nitrogenous food material from carbohydrates and (synthetic) 
ammonium salts and at the same time to obtain a supply of carbon 
dioxide, which is solidified (dry ice) and used for refrigerating 
purposes. 



CHAPTER 54 

THE MONOCYCLIC TERPENES AND RELATED 
COMPOUNDS 

ALTHOUGH the carbohydrates, the proteins, and the non-volatile 
fatty glycerides (olive, linseed, palm oil, etc.) form by far the greater 
part of dry vegetable matter, many plants contain various other 
types of most interesting compounds ; among these are certain 
volatile, odoriferous liquids, called essential oils, most of which occur 
in the flower, fruit or leaves, possess a pleasant odour or taste, and 
are used in the preparation of essences and perfumes (p. 949) ; 
some of them are also employed in medicine. 

A few essential oils have already been mentioned as, for example, 
oil of wintergreen (p. 533), oil of mustard (p. 339), oil of bitter 
almonds (p. 499), and oil of aniseed (p. 503) and some of their 
components have been described. Many such oils, however, are 
complex mixtures of many different types of compounds, the separa- 
tion and identification of which are tasks of great difficulty ; in 
their investigation, Wallach, Baeyer, Semmler, Perkin jun., Wagner, 
Ruzicka, and many others have taken part. 

A very abundant and well-known, but not a typical, essential oil 
is the liquid, turpentine, which is obtained by making shallow cuts 
in the bark of pine-trees (coniferae), and collecting the liquid which 
exudes. Turpentine consists of a solution of various resins in liquid 
oil of turpentine ; when the crude oil is distilled in steam, ' spirit of 
turpentine ' passes over, leaving a residue of rosin or colophony 
(p. 948). 

Spirit of turpentine is a mobile, optically active liquid of sp. gr. 
about 0-86, boiling from about 155 to 165 ; it is, however, a mixture, 
and shows considerable variations in properties according to the 
species of pine from which it has been obtained. It has a well- 
known, rather pungent odour, which is probably not due to its 
principal component, but to small quantities of substances formed 
from the latter by oxidation. On exposure to moist air, the oil 
gradually changes ; it darkens in colour, becomes more viscous, 
and is slowly converted into resinous oxidation products. 

Spirit of turpentine is practically insoluble in water, but is 

909 



910 THE MONOCYCLIC TERPENES 

miscible with most organic liquids ; it is an excellent solvent for 
many substances, which are insoluble in water, such as phosphorus, 
sulphur, and iodine, and it also dissolves resins and caoutchouc ; 
it is used on the large scale in the preparation of varnishes and 
oil-paints. 

The principal component of spirit of turpentine is a hydro- 
carbon, pinene, C 10 H 16 . This substance occurs not only in all 
pine-trees, but also in the essential oils of a great many other plants 
as, for example, those of eucalyptus, laurel, lemon, parsley, sage, 
juniper, and thyme. These, and other essential oils, may also con- 
tain hydrocarbons, such as Kmonene, camphene, etc., which are 
isomeric with, and more or less closely related to, pinene. 

Such hydrocarbons, C 10 H 16 , obtained from plants, and certain 
related isomerides, which have been prepared synthetically, are 
classed together as (true) terpenes. Other types of naturally- 
occurring hydrocarbons, (C 6 H 8 ) n related to the terpenes, C 10 H 16 , 
are classed as sesquiterpenes, C 15 H 24 , or polyterpenes, (C 5 H 8 ) n , where 
n > 3 ; in addition, many derivatives of these hydrocarbons occur 
in essential oils, and will be considered in due course. 



General Properties and Reactions of the Terpenes, |C 10 H 16 

These compounds are mostly highly refractive liquids, readily 
volatile in steam and having a pleasant odour ; their boiling-points 
range from about 155 to 185. Most of them are optically active 
and occur in both d- and /-forms. They are very reactive, easily 
oxidised, combine with ozone, and show the general behaviour of 
unsaturated compounds. Thus, they unite directly with bromine, 
hydrogen chloride, hydrogen bromide, and nitrosyl chloride, 
forming additive products, which, as a rule, are crystalline and 
serve for the isolation and identification of the hydrocarbons. But 
whereas some of the terpenes combine directly with four atoms of 
bromine or two molecules of hydrogen bromide, others unite with 
only two atoms of bromine or one molecule of hydrogen bromide. 
This behaviour affords strong evidence that the terpenes, C 10 H 16 , 
are not open chain hydrocarbons ; if they were they should unite 
directly with six atoms of bromine or with three molecules of a 
halogen acid, because their molecules would contain either three 
olefinic or one olefinic and one acetylenic binding. They are there- 
fore cyclic olefines and are classed in two groups : 



AND RELATED COMPOUNDS 911 

I. Monocyclic di-olefinic terpenes, which combine with 2Br 2 or 
with 2HBr. Limonene, terpinolene, phellandrene, syl- 
vestrene. 

II. Dicyclic mono-olefinic terpenes, which combine with Br 2 or 
with HBr. Pinene, camphene, bornylene. 

Many other members of each of these types, as well as a few 
open chain terpenes, C 10 H ]6 (p. 940), are known. 

Important evidence as to the nature of the closed chains in the 
molecules of the monocyclic terpenes was obtained at a compara- 
tively early stage of their investigation, since it was found that some 
terpenes and some of their simpler derivatives could be converted 
into cymene (/>-wopropylrnethylbenzene), C 10 H 14 ; ^>-toluic acid 
and terephthalic acid could also be obtained from them by oxidation 
in other ways. It was inferred, therefore, that such terpenes are 
closely related to cymene that is to say, that their molecules 
probably contain the same framework of carbon atoms as that 
which occurs in cymene. Further iMM'-jium'H, more especially 
the study of the products of their graded oxidation, served to con- 
firm this view, and, in the course of time, it was proved that some 
of the terpenes are, in fact, dihydro-p-cymenes, the structures of 
which were finally established. 

Nomenclature. For the nomenclature of the monocyclic ter- 
penes, the fully saturated cycloparaffm, hexahydrocymene, C 10 H 20 , 
which may be regarded as the parent hydrocarbon, is called p- 
menthane, derived from that of its well-known derivative menthol ; 
the cjrfo-olefines derived from it are known as p-mentkenes, 
C 10 H 18 , or p-menthadienes, C 10 H 16 , according as their molecules 
contain one or two ethylenic linkages respectively. Substances of 
a corresponding type, namely, 0- or w-menthenes, and o- or 
m-menthadienes, as the case may be, may also be derived from 
o- and 7/2-menthanes. 

In order to express the structures of the monocyclic terpenes, 
and those of their derivatives, the carbon atoms of the corresponding 
parent menthanes are numbered in a conventional manner as shown 
(p. 912) ; the presence and positions of the double bonds are then 
indicated by A, with the addition of the numerals of those carbon 
atoms from which the double binding starts, when these atoms are 
taken in the conventional order (compare pp. 799, 801). Limonene, 



912 THE MONOCYCLIC TERPENES 

for example, is A-l:8(9) 1 -p-menthadiene, and sylvestrene is 
A-l:8(9)-w-menthadiene : 

7 CH 3 



rw 8 w r rw 3 

C / CH * $ H2C ^ C / CH V 

H * 



Limonene, Sylvestrene, 

A-l:8(9)-/>-menthadiene A-l:8(9)-m-menthadiene 

I II 

it will be seen that many structurally isomeric 0-, w-, and p-mentha- 
dienes are theoretically possible. 

Formulation. The structures (i) and (n) may also be con- 
veniently represented by, and should be carefully compared with, 
(in) and (iv) respectively : 





Sylvestrene 
IV 

It will then be clear that the C and H symbols, omitted from both 
ends of every (single or double) bond in (in) and (iv), can be readily 
pictured and that the number of hydrogen atoms combined with 
any carbon atom follows from the quadrivalency of carbon. 

Many other formulae can be conveniently represented in this 
way ; for open chain compounds a zig-zag framework is used as 
shown : 2 

1 The number in brackets, (9), is to show without ambiguity that the 
carbon atoms 8 and 9, and not 8 and 4, are united by the olefinic binding. 

2 The angles (about 90) of the zig-zag are purely arbitrary. 



AND RELATED COMPOUNDS 913 

JL f*ir r>u OTT PW pnOH 

C Cn2 CH 3 CH 3 ^^2 AAivn 

cC\f Vo HOOCT \^ 




v ^ *%. s* \. * s\. ^COOH 



Propane Isoprene Acetone Succinic acid 

Here, however, as in all cases, substituents of the parent hydro- 
carbons are shown (by their symbols with numbers) in the ordinary 
way ; thus although a CH 3 group is shown merely by a line 
a CH 2 C1, CH 2 -OH, COOH, etc., are usually shown in full. 

Limonene and its Derivatives 

Limonene, C 10 H 16 (A-l:8(9)-p-mew///a^we), is a pleasant- 
smelling, mobile liquid, boiling at 175. 

J-Limonene is found in oil of lemon, orange, caraway, cummin, 
etc., whereas /-limonene occurs in pine-needle oil and in oil of 
peppermint. J/-Limonene occurs in Oleum cinae and was named 
dipentene before its relation to the optically active forms was known. 
Dipentene is formed (as the result of racemisation) when either of 
the active modifications is heated at 250-300 ; it is also produced 
when pinene (p. 925) is treated in a similar manner, and may be 
prepared by heating terpineol (p. 917) with potassium hydrogen 
sulphate. 

Limonene (d- or /-) combines with one molecule of hydrogen 
chloride in the absence of water, giving an optically active limonene 
(mono)hydrochloride (8-chloro-&-l-p-menthene) y C 10 H 17 C1, 1 but in 
the presence of water it unites with two molecules of hydrogen 
chloride or bromide, and the crystalline products, limonene di- 
hydrochloride, C 10 H 18 C1 2 and limonene dihydrobromide, C 10 H 18 Br 2 , 
are optically inactive and identical with those obtained from di- 
pentene. Both these compounds exist in cis- and trans- forms and it 
is the latter which are produced from limonene ; the cw-compounds 
are formed from cineole (p. 918). With bromine the limonenes yield 
tetrabromides, C 10 H 16 Br 4 , which are optically active and melt at 

1 The trivial names of such additive products of the terpenes are generally 
used, and formulae such as C 10 H 16 ,HC1, C 10 H 16 ,2HC1, etc., are often em- 
ployed instead of these given here. 



914 



THE MONOCYCLIC TERPENES 



104, whilst dipentene tetrdbromide melts at 125 and is, of course, 
optically inactive. 

The limonenes and dipentene also combine directly with nitrosyl 
chloride, as was first shown by Tilden, giving well-defined crys- 
talline nitrosochlorides, C 10 Hi 6 ONCl (p. 923) ; these compounds 
may be prepared more easily by treating the terpene with an alkyl 
nitrite in the presence of hydrochloric acid. Each of the active 
terpenes gives a mixture of two (a- and ]8-, or cis- and trans-) 
optically active isomeric nitrosochlorides, all of which are bi- 
molecular, and probably contain in their molecules the group 
>CH-NO:NO-CH<. In the formation of the mono-hydro- 
chloride, the halogen atom combines with the 8-carbon atom, 
whereas with nitrosyl chloride the chlorine atom takes up the 1- 
and the NO-group the 2-position (p. 912). 

The structure of limonene is based mainly on the results of the 
investigation of the oxidation products of a-terpineol, C 10 H 18 O, a 
compound which is formed, by the addition of the elements of water, 
when limonene or dipentene is shaken with a 5% aqueous solution 
of sulphuric acid. With potassium permanganate, terpineol yields 
trihydroxyhexahydrocymene, which, with other oxidising agents, 
gives homoterpcnyhncthyl ketone, terpenylic acid (m.p. 90), and 
finally terebic acid (m.p. 175), as shown below : 




OH 



-Terpineol Trihydroxy- 

hexahydrocymene 





Terpenylic acid 



Homoterpenylmethyl ketone * 



HOOC 



Terebic acid* 




Terebic acid* 



1 The alternative formulae of homoterpenylmethyl ketone and of terebic 
acid are merely set out differently. 



AND RELATED COMPOUNDS 915 

Terebic acid is the lactone of a hydroxydicarboxylic acid and is 
formed by the oxidation of wopropylsuccinic acid ; its constitution 
is established by the following synthesis (Simonsen) : Diethyl 
acetylsuccinate, obtained from ethyl sodioacetoacetate and ethyl 
chloroacetate, is treated with methyl magnesium iodide (1 mol.) ; 
the product gives on hydrolysis a hydroxydicarboxylic acid, the 
lactone of which is terebic acid : 

COOEt 
EtOOC J HOOC J HOOC 






Diethyl acetylsuccinate Terebic acid 

In a similar manner terpenylic acid is formed by the oxidation of 
j3-ttopropylglutaric acid, and has been synthesised from diethyl 
]8-acetylglutarate x with the aid of methyl magnesium iodide. 

Now from a general knowledge of the behaviour, on oxidation, 
of compounds of known constitution (olefines, glycols, ketones, 
etc.) it is possible, from the structure of terpenylic acid, to deduce 
that of homoterpenylmethyl ketone and then those of trihydroxy- 
hexahydrocymene, and a-terpineol respectively, as shown above. 
This is an important example of the use of graded oxidation, for the 
determination of structure. 

It is to be noted, however, that the structure of limonene is not 
completely decided by this series of changes as terpinolene (p. 917) 
might also give a-terpineol by the addition of water. The optical 
activity of limonene, however, shows that the double binding which 
was concerned in the formation of a-terpineol must be 8:9, and 
not 4:8, in the molecule of the terpene. 

The Synthesis of Terpenes 

The structures of a-terpineol, and of limonene, having thus been 
determined with a high degree of probability, were fully established 
by Perkin, who accomplished complete syntheses of these and various 
other naturally occurring terpenes by the methods given below. 

Ethyl cyanoacetate reacts with two molecules of ethyl j8-iodo- 

1 /S-Acetylglutaric acid is obtained, in the form of a dilactpne, when the 
sodium salt of tricarballylic acid is heated with acetic anhydride. 



916 



THE MONOCYCLIC TERPENES 



propionate, in the presence of sodium ethoxide, giving triethyl 
3-cyanopentane-l :3 :5-tricarboxylate, 

CN.CH 2 .COOEt + 2CH 2 I.CH 2 .COOEt + 2NaOEt = 
CN.C(COOEt)(CH 2 .CH 2 .COOEt) 2 + 2NaI + 2EtOH ; 

this ester, on hydrolysis with hydrochloric acid, yields pentane- 
l:3:S-tricarboxylic acid, (i), as the group >C(COOH) 2 , produced 
by the hydrolysis of the > C(COOEt) CN complex, decomposes 
with the loss of carbon dioxide. This acid is converted into 4-keto- 
hexahydrobenzoic acid, (n), when it is heated with acetic anhydride, 
or when its ester is treated with sodium (Dieckmann) and the 
resulting j8-keto -ester is submitted to ketonic hydrolysis. The 
ethyl ester of (n), treated with methyl magnesium iodide and then 
with dilute acid, yields the ester of a hydroxyhexahydro-p-toluic 
acid (4-methyl-4-hydroxycyclohexanecarboxyltc acid, in) : 



HOOC 





v 

COOH 



The last-named hydroxy-compound, (in), gives, with hydro - 
bromic acid, the corresponding bromo -derivative, which, on 
treatment with pyridine, loses one molecule of hydrogen bromide 
and is converted into a tetrahydro-p-toluic acid (4-methyl-&-3- 
cyclohexenecarboxylic acid, iv). The ester of this acid reacts with 
methyl magnesium iodide, and when the product is decomposed 
with dilute acid it gives d\-a-terpineol, (v), which is converted into 
dipentene when it is treated with potassium hydrogen sulphate. 






AND RELATED COMPOUNDS 



917 



Theoretically, this loss of the elements of water might occur in one 
of two ways, giving either (vi) or (vn), but as dipentene is a 
^/-mixture it must have a dissymmetric structure and cannot there- 
fore be represented by (vn). 

The d7-acid, (iv), was resolved with the aid of strychnine or 
brucine, and the active esters were both prepared ; these com- 
pounds, treated with methyl magnesium iodide, gave d- and /-ter- 
pineol respectively (Fischer and Perkin, J. 1908, 1871). 

The preparation of 4-methyl-A-3-c)/c/0hexenecarboxylic acid, (iv), 
as above, was very laborious ; later the necessary material for the 
resolution was obtained by a simpler method : p-Toluic acid was 
sulphonated and the sulphonic acid converted into 3-hydroxy-4- 
methylbenzoic acid by fusion with potash ; this acid was then 
reduced with sodium and alcohol to the corresponding hexahydro- 
compound of which the hydroxyl group was displaced by bromine. 
The product, with pyridine, gave (iv) : 



,S0 3 H 





COOH 



COOH 




OOH 



COOH 



The active terpineols melt at 38-40, boil at 219 and have a 
very strong smell of hyacinths. 

J/-a-Terpineol (k-l-p-menthen-$-ol) l melts at 35 ; it can be 
prepared on the large scale by boiling terpin hydrate (p. 918) or 
dipentene with dilute sulphuric acid and is used in perfumery. 

Terpinolene (k-l'A(S)-p-menthadiene, vn, p. 916), an optically 
inactive structural isomeride of limonene, is produced when terpineol 
is dehydrated with alcoholic sulphuric acid or oxalic acid ; it occurs 
in various essential oils, and when treated with acids it undergoes 
isomeric change, giving * terpinene/ which is a mixture of various 
/>-menthadienes (a or A-l:3-, j8 or A-l(7):3-, y or A-l:4-). 

m-Terpin, C 10 H 20 O 2 (p-menthan-l:8-diol), is produced by the 
addition of the elements of water, when terpineol is shaken with 
dilute sulphuric acid, and its structure is as shown (p. 918); it may be 
prepared by treating oil of turpentine (pinene) with dilute sulphuric 



1 /3-Terpineol is A-8(9)-p-wwf/H?w-l-0/ and has not been found in nature. 



918 THE MONOCYCLIC TERPENES 

acid and alcohol at ordinary temperatures, as a result of complex 
changes. It has been synthesised by treating ethyl 4-ketohexa- 
hydrobenzoate (cf. n, p. 916), with an excess of methyl magnesium 
iodide and decomposing the product with water, a method which 
establishes its constitution. m-Terpin melts at 104, boils at 258, 
and combines readily with water, giving crystalline terpin hydrate, 
C 10 H 20 O 2 ,H 2 O, which melts at 117. frww-Terpin melts at 158- 
159 and is formed from fra/w-dipentene dihydrobromide ; it does 
not unite with water. When os-terpin is dehydrated, terpineol, 
dipentene, terpinene, terpinolene, and cineole are produced. 






or 



Cineole 

Cineole, C 10 H 18 O, occurs in many oils (eucalyptus, rosemary, 
etc.) and in Oleum cinae ; it boils at 172 and has a camphor-like 
odour. With phosphorus pentoxide it yields cymene, and with an 
acetic acid solution of hydrogen bromide it gives m-dipentene 
dihydrobromide. 

Two other />-menthadienes may be mentioned. a-Phellandrene 
occurs in both d- and /-forms in many essential oils ; it is A-l:5-p- 
menthadiene, and is very unstable. 

ft-Phellandrene is A-l(7):2-p-menthadiene, and occurs in water- 
fennel oil. 

Terpenes which are not known to occur in nature can also be 
prepared from the toluic acids (Perkin) : />-Toluic acid, for example, 
is first reduced to hexahydrotoluic acid, which is then brominated 
in the a-position ; the product, treated with quinoline, yields 
a tetrahydro-p-toluic acid (4-methyl-A-l-cyc\ohexenecarboxylic acid, 
i), the ester of which, with methyl magnesium iodide, yields 
&-3-p-menthen-8-ol, (n). This isomeride of terpineol, on de- 
hydration, gives &-3:8-p-menthadiene y (in), an isomeride of limonene, 
which has not been discovered in plants. In a similar manner 
o-toluic acid yields an o-menthenol and an o-menthadiene. A 



AND RELATED COMPOUNDS 



919 





OH 



II 




m-menthadiene has also been synthesised (Perkin) as follows : 
w-Hydroxybenzoic acid is reduced to the hexahydrohydroxy-acid, 
which is then oxidised to the corresponding keto acid, (iv). The 
ester of this acid is treated with methyl magnesium iodide in the 
usual way and is finally converted into a w-menthadiene, carvestrene, 
or dl-sylvestrene, (v). 1 




COOH 




COOEt 




COOEt 






VI 



Various menthadienes have also been synthesised by Henderson 
and his co-workers (J. 1920, 144). 

*/-Sylvestrene was first obtained from Swedish pine-needle oil 
prepared from the wood of Pinus sylvestris ; the oil, treated with 
hydrogen chloride, gave a crystalline optically active dihydrochloride, 
from which, with aniline, there was formed a dextrorotatory terpene, 

1 Both sylvestrene and carvestrene probably consist of mixtures of (v) 
and (vi). 

Org. 58 



920 THE MONOCYCLIC TERPENES 

named sylvestrene from its origin. It was afterwards shown by 
Simonsen that rf-sylvestrene does not actually occur in the essential 
oil obtained from Swedish turpentine, but that it is formed from a 
dicyclic terpene, carene (p. 924) ; when the oil is treated with 
hydrogen chloride the rydfopropane ring undergoes fission, and the 
dihydrochloride thus obtained gives rf-sylvestrene, together with 
dipentene, when it is decomposed with aniline. 

Ketones and Alcohols derived from p-Menthane 

/-Menthone, C 10 H ]8 O (p-menthan-3-one), is one of the numerous 
components of oil of peppermint, the essential oil of Mentha 
piperita, which also contains menthol, pinene, cadinene (p. 944), 
and many other compounds It boils at 208, and its chemical 
behaviour shows that it is a ketone ; on reduction with sodium and 
alcohol, it is converted into the secondary alcohol, menthol, and on 
oxidation with permanganate it gives ketomenihylic acid, (i), and 
d-p-methyladipic acid, (n). 

The structures of these products having been determined, that 
of menthone may be deduced, and is shown below. 






COOK L COOH 

OOH 



Menthone I II 

An optically inactive menthone has been synthesised as follows : 
2-Hydroxy-^-methylbenzoic acid, (in), 1 is reduced with sodium and 
amyl alcohol to fi-methylpimelic acid, (iv) : 2 the ester of this acid 
with sodium ethoxide undergoes the Dieckmann condensation, 
yielding the j8-ketonic ester, (v), which on treatment with sodium 
ethoxide and tsopropyl iodide gives (vi) ; the ketonic hydrolysis of 
this ester yields optically inactive menthone, a mixture of cis- and 
tran$-dl-forms : 

1 Prepared by treating the sodium derivative of m-cresol with carbon 
dioxide ; compare salicylic acid (pp. 531, 533). 
8 Compare p. 534. 



AND RELATED COMPOUNDS 



921 




:OOH 





/-Menthol, C 10 H 19 -OH (p-menthan-3-ol), occurs in oil of pepper- 
mint both in the free state and as menthyl acetate, and it is prin- 
cipally to the presence of these compounds that oil of peppermint 
owes its very powerful odour. Menthol melts at 44 ; on reduction 
with hydriodic acid, it is converted into hexahydrocymene. On 
oxidation with chromic acid it yields a mixture of two active men- 
thones, because the > CH CO group of the latter undergoes 
keto-enolic change, giving both cis- and trans-forms of the cyclic 
ketone. On oxidation with permanganate, however, it gives keto- 
menthylic acid and fi-methyladipic acid. With some dehydrating 
agents menthol affords a mixture of isomeric menthenes, and with 
hydrogen chloride it forms menthyl chloride. It is used in pharmacy. 

The menthones, menthols and menthylamines furnish interesting 
examples of stereochemical relationships ; thus, from each of the 
two (as- and trans-) (//-menthones, two (//-menthols (or (//-menthyl- 
amines) are derived, as shown below (R=OH or NH 2 ) for the 
members of the d- or the /-series : * 





Menthone (tram-) 



/wnienthone (as-) 



d a a a 



Menthol 



JVeomenthol 



/jomenthol 



Neoisomenthol 



1 The meaning of the + and - signs in these formulae is explained on 
p. 718. 



922 THE MONOCYCLIC TERPENES 

/-Menthylamine, C 10 H 10 -NH 2 , is formed, together with three 
optical isomerides, by heating /-menthone with ammonium formate 
or by the reduction of /-menthoxime with sodium and alcohol. It 
is a strongly basic liquid, and has been much used for the resolution 
of J/-acids. 

The four <//-menthylamines were first prepared by Kipping and 
Tutin in 1904 and have since been studied, together with the 
menthols, by Read. The configurations (p. 921) have been assigned 
to them from a comparison of their physical and chemical pro- 
perties with those of similar compounds of known configurations. 

It is interesting to note that when weomenthol is treated with 
phosphorus pentachloride or formic acid, a good yield of A-3-p- 
menthene is obtained, whereas the stereoisomeric menthol, under 
the same conditions, gives menthyl chloride or menthyl formate ; 
it is therefore from the compound in which the hydrogen and 
hydroxyl groups are believed to be in the /raws-position that water 
is readily eliminated. Similarly, menthylamine gives menthol 
with nitrous acid, whereas weomenthylamine gives A-3-/>-menthene. 

Three other ketones derived from />-menthane, namely pulegone, 
carvone andpiperitone, may be mentioned ; their structures and their 
relationship to menthone are shown below : 







Menthone Pulegone Carvone Piperitone 



</-Pulegone, C 10 H 18 O (A-4(8)-p-wn*fow-3-0we), occurs in oil of 
Mentha Pulegium (pennyroyal), and boils at 221. On reduction 
it yields menthone or menthol, and on oxidation j3-methyladipic 
acid and acetone, reactions which prove its constitution. 

/-Carvone, C 10 H 14 O (&-6:S-p-menthadien-2-one) occurs in cara- 
way oil, spearmint oil, etc., and boils at 230. With phosphorus 
pentoxide it is readily converted into carvacrol (hydroxycymene) 
by isomeric change, a fact which shows that the carbonyl is in the 
o-position to the methyl group. 



AND RELATED COMPOUNDS 923 

When limonene nitrosochloride (p. 914) is treated with alcoholic 
potash it is converted into carvoxime, with the elimination of 
hydrogen chloride and the conversion of the group >CH-NO 
into the oximino-group > C=NOH : 



;NOH 





Limonene Carvoxime Bcnzyhdcne- 

nitrosochloride pipentone 

/-Piper itone occurs in eucalyptus oils. It gives thymol on 
oxidation with ferric chloride and menthone or menthol on 
reduction. It condenses with benzaldehyde to give the benzyl idene 
derivative (above), a very interesting example of the activation of a 
methyl group which is united to a carbon atom conjugated with a 
carbonyl radical. It is also to be noted that pulegone, carvone and 
piperitone are all aj8-unsaturated ketones and behave as such 
towards, for example, hydroxylamine (p. 825). 



CHAPTER 55 
DICYCLIC TERPENES AND RELATED COMPOUNDS 

THE dicyclic terpenes, C 10 H 16 , as already stated (p. 911), combine 
with one molecule of bromine or hydrogen bromide only and are 
bridged ring structures (p. 819) which contain one olefinic binding. 
One of the closed chains always consists of six carbon atoms but 
the other may contain three, four or five atoms only. Those which 
form the cyclopropane or cyclobutene rings (carene, pinene) are in 
a condition of strain (p. 789) and consequently may readily undergo 
fission. 







Carene a-Pmene Bornylene Camphene 

The dicyclic terpenes and their derivatives are usually known by 
their trivial names, as those based on the system applied to bridged 
rings in general (p. 819) are too cumbersome. 1 

The chemistry of the dicyclic terpenes and their derivatives is 
much more difficult than that of the monocyclic compounds, as 
will be seen from the account given later of the behaviour of some 
of the more important members of this group ; some of the changes 
which these compounds undergo are very remarkable, one of the 
rings undergoing fission, giving products, which sometimes pass 
again into bridged ring structures of a different kind. Owing to 
such transformations, at one time quite novel and unexpected, the 
determination of the constitutions of the dicyclic terpenes was a 
task of great difficulty and was only accomplished by the work of 
many chemists, not only on the terpenes themselves, but on many 
related compounds, particularly camphor. 

1 a-Pinene, for example, is l:3-endodimethylmethylene-4-methyl-&-4-cyc\o- 
hexeneor 2:6:6-trimethyl-l,l t 3-dicyclo-&-2-heptene, and camphor is l:4-endo- 
dimethylmethylene-l -methylcyclohexan-2-one or 1 :7:l-trimethyl-l ,2,2-dicyclo- 
heptan-2-one. 

924 



DICYCLIC TERPENES AND RELATED COMPOUNDS 925 

Pinene 

a-Pinene, C 10 H 16 , is the most abundant and important dicyclic 
terpene, and its separation from turpentine, in a crude form, has 
been described. The oils from some varieties of pine are dextro- 
rotatory, others laevorotatory, and the isolation of optically pure 
d- or /-pinene is a task of great difficulty. 

rf/-Pinene is obtained from the nitrosochloride (below) by treat- 
ment with aniline and is a mobile liquid of sp. gr. 0-858 at 20, 
having an odour of * turpentine.' It boils at 155-156, and is readily 
volatile in steam. 

Pinene combines directly with two atoms of bromine, giving a 
crystalline dibromide, C 10 H ]6 Br 2 , which when heated alone, at a 
moderately high temperature, is converted into cymene and hydrogen 
bromide. Cymene is also produced, together with various other 
hydrocarbons, when pinene is heated with iodine. In light petroleum 
solution at 70, pinene forms, with dry hydrogen chloride, a 
crystalline pinene hydrochlonde, 1 C 10 H 17 C1 ; this compound gives 
pinene on treatment with alcohol at a very low temperature, but at 
10 it passes into an isomeric hydrochloride, bornyl chloride, 
which is formed directly from pinene and dry hydrogen chloride at 
ordinary temperatures (p. 934). With moist hydrogen chloride, 
dipentene dihydrochloride is formed, the cyclobutane ring undergoing 
fission. 

Pinene also combines directly with nitrosyl chloride, giving a 
crystalline dl-pinene nitrosochloride , C 10 H 16 ONC1, which is probably 
bimolecular in the solid state (compare limonene nitrosochloride, 
p. 914). The active nitrosochlorides are very much more soluble 
than the dl-form and so the latter separates first when a mixture 
containing both d- and /-pinene is treated with nitrosyl chloride ; 
it serves for the preparation of the pure ^/-compound. 

When pinene is heated at 250-270 it yields dipentene ; with 
sulphuric acid in alcoholic solution at ordinary temperatures, it 
gives a-terpineol, and with dilute nitric and sulphuric acids, terpin 
hydrate. When heated with organic acids it yields esters of borneol 
and woborneol (p. 932), from which camphor can be obtained. 

Pinene readily undergoes oxidation, yielding various compounds, 
the simpler of which are p-toluic, terephthalic, terpenylic, and 
terebic acids (p. 914). In moist air in sunlight it gives sobrerol or 

1 Compare pp. 930, 933. 



926 DICYCLIC TERPENES AND RELATED COMPOUNDS 

pinol hydrate, C 10 H 16 (OH) 2 , which, treated with dilute mineral acids, 
is converted into pinol, C 10 H 16 O. 

The formation from pinene of cymene and of various other 
compounds obtainable from limonene, including the two aliphatic 
acids named above, seemed to show that pinene and limonene were 
closely related in structure, and various formulae were suggested 
for the former in accordance with this view. Finally, from a study 
of the first oxidation products of pinene, sobrerol and pinol, Wagner, 
in 1894, concluded that the terpene must be represented by the 
structure already given, and is related to sobrerol and pinol as 
shown below : 



.OH 






Pinene Sobrerol Pinol 



This conclusion was confirmed by Baeyer : Pinene, on careful 
oxidation with potassium permanganate, is converted into a-pinonic 
acid, which, on treatment with an alkali hypobromite, gives pinic 
acid ; this product, on further oxidation by indirect methods, is 
converted into cis-norpinic acid 1 (dimethylcyclobutanedicarboxylic 
acid), a very stable compound which resists further oxidation. A 
synthesis by Kerr (J. Am. Chem. Soc. 1929, 614) confirmed Baeyer's 
formula for worpinic acid. 



COOH 
HOOC 






HOOC N 

Pinonic acid Pinic acid Norpinic acid 

Accompanying a-pinene in most of the turpentine oils, there is 
found a variable and small proportion of a closely related terpene, 
\-fi-pinene ; in the molecule of this compound the group, > C CH 3 , 

1 The prefix nor generally, but not invariably, indicates the next lower 
homologue of some fairly well-known compound. 



DICYCLIC TERPENES AND RELATED COMPOUNDS 927 

of pinene becomes > C CH 2 and the 6-carbon atom ring does 
not contain any olefinic binding, but the cyc/obutane structure 
remains as before, 

Of the other dicyclic terpenes, shown on p. 924, bornylene and 
camphene will be briefly described when the chemistry of camphor 
has been considered. 

Camphor and iis Derivatives 

{/-Camphor, C 10 H 16 O, is a component of oil of camphor, and is 
obtained from the wood of the tropical camphor-tree (Cinnamomum 
camphor a) , by distillation in steam. 

It is a soft, crystalline solid, melting at 178-179, and boiling at 
209 ; it is very volatile, sublimes readily even at ordinary tempera- 
tures, and has a highly characteristic smell. It is only sparingly 
soluble in water, but sufficiently so to impart to the solution a 
distinct taste and smell (Aqua camphorae), and it dissolves readily 
in alcohol and most ordinary organic solvents. It is used in medicine, 
in the manufacture of xylonite or celluloid, and also in the prepara- 
tion of a few explosives ; in the laboratory it is employed in the 
determination of molecular weights. 

/-Camphor also occurs in certain essential oils ; a mixture of the 
d- and /-forms is manufactured from oil of turpentine (p. 930). 

Camphor is a saturated ketone, and its molecule contains the 
group CH 2 CO, as is proved by the following reactions : It 
is reduced by sodium and alcohol, giving two stereoisomeric 
secondary alcohols, borneol and woborneol (p. 932), from which 
it is formed by oxidation. It reacts with hydroxylamine, giving 
camphoroxime (m.p. 119), and, when treated with uoamyl nitrite 
and sodium ethoxide, it affords syn- and anti-iso/wfrwo-derivatives, 
C(:N-OH) CO , which are converted into a diketone, camphor- 
quinone, CO CO , by boiling dilute sulphuric acid. With 
chlorine and with bromine it gives, in the first place, stereoisomeric 
monohalogen compounds, CHX CO . 

Sodiocamphor, CH=C(ONa) , reacts with esters of formic 
acid, giving an acidic substance, hydroxymethylenecamphor, 
C(:CH-OH)-CO or C(CHO):C(OH) , x which condenses 
with primary and secondary bases and has been utilised for the 

1 The complete formulae of all these derivatives can be obtained from 
that of camphor (p. 928), since only the --CH 2 CO group of this 
compound undergoes change in the reactions just mentioned. 



928 DICYCLIC TERPENES AND RELATED COMPOUNDS 

resolution of ^/-compounds of such types. Some other camphor 
derivatives are mentioned later (p. 931). 

When camphor is heated with iodine, it is converted into car- 
vacrol, and when it is distilled with phosphorus pentoxide, it is 
transformed into jp-cymene, reactions which seemed to give im- 
portant clues to its structure, but as it could also be changed into 
w-cymene, m-xylene, />-acetyl-o-xylene, and other benzene deriva- 
tives, such indications had to be accepted with caution. The 
determination of the constitution of camphor was, in fact, a problem 
of very great difficulty ; during a period of more than twenty years, 
many formulae were assigned to it only to be discarded as further 
experimental data were accumulated. Although few of the deriva- 
tives just mentioned had been prepared in those days, it was known 
that camphor could be oxidised by boiling nitric acid, giving a 
dicarboxylic acid, ^.-camphoric acid, C 10 H 16 O 4 , which was easily 
converted into its anhydride ; on further oxidation, this dicarboxylic 
acid gave a tricarboxylic acid, camphoronic acid, C 9 H 14 O 6 , but for 
a long time no conclusive evidence as to the structures of these 
compounds could be obtained. In 1893, however, Bredt found that 
when camphoronic acid is heated slowly it decomposes into carbon 
dioxide, water, carbon, wobutyric acid, and trimethylsuccinic acid ; 
from this result he deduced for camphoronic acid, camphoric acid, 
and camphor respectively the structures shown below : 





H C COOH 

Camphoronic acid l Camphoric acid Camphor 

The synthesis of camphoric acid by Komppa in 1903 fully established 
Bredt's formula, and was accomplished as follows : 5:5-Dimethyl- 
dihydroresorcinol, prepared by the method already described 
(p. 800, and therefore obtainable from its elements), is treated with 
an alkaline solution of sodium hypobromite, whereby it is converted 
into bromoform and Pfi-dimethylglutaric acid. The ester of this 
acid, (i), condenses with diethyl oxalate in the presence of sodium 
ethoxide, yielding the (di-)/J-ketonic ester, (il), which is treated 

1 The dotted lines indicate the various points at which the molecule 
seemed to undergo fission. 



DICYCLIC TERPENES AND RELATED COMPOUNDS 929 

with sodium and methyl iodide. The oil thus produced is a mixture 
of the monomethyl, (in), and dimethyl derivatives, with the un- 
changed compound ; when it is extracted with dilute sodium 
carbonate solution the inert dimethylated product is left undissolved. 
The extract contains the sodium derivatives of the enolic forms of 
(n) and (in) ; these are separated by making use of the fact that 
the copper derivative of the methylated product, (in), only is soluble 
in ether. 



:H 2 -COOEt ^ COOEt 

COOEt ' ^ v 

I ' + 
COOEt 

CH 2 -COOEt 



COOEt 

oCx 



II 




From this soluble copper salt the ester is regenerated and reduced 
in alkaline solution, when it gives an alkali salt of (iv), the ester 
having undergone hydrolysis. Hydriodic acid and red phosphorus 
convert (iv) into (v), which is treated first with hydrobromic acid 
and then with zinc-dust and acetic acid. The product, (vi), is an 
oil, which must have the given constitution, whatever the position 
of the double bond in (v), or that of the bromine atom in the hydro- 






bromide ; it is a mixture of cis- and /ra/M-^/-camphoric acids and 
is separated into its components by heating it with acetyl chloride, 
when only the or-form gives an anhydride. On hydrolysis, this 
anhydride gives oy-rf/-camphoric acid, which is resolved with the 
aid of cinchonidine. Another synthesis of J-camphoric acid, by a 
different method, was accomplished by Perkin and Thorpe, almost 
at the same time as that of Komppa. 

Camphor can be obtained from camphoric acid : Camphoric 
anhydride, treated with sodium amalgam and water, is reduced to 
campholide, (vn), which, when heated with potassium cyanide, 
gives the cyano-acid, (vni) ; from this compound, by hydrolysis, 



930 DICYCLIC TERPENES AND RELATED COMPOUNDS 

homocamphoric acid, (ix), is obtained, and the destructive distillation 
of the calcium salt of this acid gives camphor : 

Me Me Me 

,C^ /9x x?x 

TT f+~ I f*f\ UT C* I f*f\f\V V * I f*f\t\\3 

Ht. I CU ri 2 C I CUUii H 2 C | COOH 

CMe 2 ^O | CMe 2 | CMe 2 

, I X CH 2 H 2 C^ I ^CH 2 -CN H 2 C X KCH 2 -COOH 

H H H 

VII VIII IX 

The conversion of camphoric anhydride into campholide might 
occur in two ways, either as shown above (which is actually the 
case), or by the reduction of the other carbonyl group. This 
synthesis, therefore, is not by itself a complete proof of the structures 
of campholide and the first two substances obtained therefrom ; 
but as camphor gives carvacrol with iodine, the methyl group must 
be attached to the carbon atom a to the carbonyl group in camphor, 
and the above reactions, therefore, take place as shown. 

Commercial Preparation of Camphor from Pinene. Pinene, from 
oil of turpentine, saturated with hydrogen chloride at 0, yields 
bornyl chloride (p. 933), which, heated with sodium acetate and 
acetic acid, is converted into isobornyl acetate, /soborneol, prepared 
by the hydrolysis of the acetate, on oxidation with chromic acid, is 
transformed into camphor. Pinene also gives camphene when its 
vapour is passed over a heated catalyst ; camphene can then be 
converted into bornyl acetate and hence into borneol and camphor. 

It was thought at one time, before pinene hydrochloride (p. 925) 
was known, that in the formation of bornyl chloride a molecule of 
hydrogen chloride was merely added to that of pinene without the 
occurrence of any other change, and the product was therefore 
misnamed ' pinene hydrochloride ' ; it was also called ' artificial 
camphor ' because it resembled camphor in smell and in other 
outward properties. 

dW-Camphoric acid, C 10 H 16 O 4 (p. 928), crystallises very read- 
ily, melts at 187, and when heated alone, or with acetyl chloride, is 
converted into its anhydride (m.p. 221). The formula, (vi, p. 929), 
shows that four optically active forms (d- and l-cis~ y and d- and 
/-frans-camphoric acid), as well as two ^/-modifications, should be 
obtainable ; all of these are known. 

d-Camphoronic acid, C 9 H 14 O 6 (p. 928), melts at 137, is readily 
soluble in water and when strongly heated is decomposed into 



DICYCLIC TERPENES AND RELATED COMPOUNDS 931 

trimethylsuccinic acid, wobutyric acid, carbon dioxide, water, and 
carbon, as already stated (p. 928). rf/-Camphoronic acid has been 
prepared synthetically (Perkin and Thorpe). Ethyl acetoacetate 
condenses with ethyl bromoisobutyrate in the presence of zinc 
(Reformatsky reaction) to form, after treatment with dilute acid, 
diethyl p-hydroxy-aaf}-triinethylglutarate, (i). The hydroxyl group 
in this ester is first displaced by chlorine, with the aid of phosphorus 
pentachloride, and the halogen atom is then displaced by a CN 
group with the aid of potassium cyanide ; the product, on hydrolysis, 
yields rf/-camphoronic acid, (n) : 

CH 3 CH 3 CH 3 



H 2 C X H 2 C X I X OH H 2 C^ PCOOH 

I CBrMe 2 -> I CMe 2 -+ I CMe 2 

EtOOC I 2 EtOOC | HOOC | 

COOEt COOEt COOH 

I II 

As might have been anticipated, these changes proved exceedingly 
difficult to carry out ; (i) and the corresponding chloro-acid readily 
lose the elements of water or hydrogen chloride respectively, giving 
aa/J-trimethylglutaconic acid, and the yield of the cyanide, even 
under special conditions, was very bad. 

Camphorsulphonic acids. Various optically active sulphonic 
acids have been obtained from camphor and from its monohalogen 
derivatives, and as these compounds are strong acids, the salts of 
which usually crystallise very readily, they have often been used in 
the resolution of <//-bases (pp. 762, 767, 773). 

rf-a-Chloro- and rf-a-bromo-camphor-7r-sulphonc acids, 
C 10 H 14 OX-SO 3 H, are obtained by the sulphonation of the 
0-halogen derivatives ; they are crystalline and give well-defined 
sulphonyl chlorides, sulphonyl bromides, and sulphonamides. On re- 
duction, the a-bromo-acid gives d-camphor-7T-sulphonic acid, whereas 
the direct sulphonation of ^/-camphor with anhydrosulphuric acid 
yields the d7-7r-sulphonic derivative. When gently heated the 
a-halogen-7r-sulphonyl halides are decomposed, with the evolution 
of sulphur dioxide, giving cwr-dihalogen derivatives of camphor. 1 

1 The halogen derivatives, C 10 H 14 OX 2 , obtained from the sulphonyl 
halides, C 10 H U OX-SO 2 X, were distinguished by the letter v (before their 
structures were known), because of their pyrogenic origin : hence the acids 
from which they were formed were classed as ir-acids (Kipping and Pope). 



932 DICYCLIC TERPENES AND RELATED COMPOUNDS 

All these compounds contain the group CHX CO , and in 
the presence of alkalis they give solutions of cis- and trans- 
isomerides, as the result of a tautomeric change (p. 835). d-Camphor- 
ft-sulphontc acid (Reychler's acid) is easily obtained by treating 
camphor with sulphuric acid in acetic anhydride solution ; in 
aqueous solution it gives [M] D +51-7. 

It is interesting to note that the sulphonic group of the -TT-acids 
has displaced a hydrogen atom of one of the twin or gem-dimethyl 
groups of camphor, whereas, in Reychler's acid, hydrogen from 
the solitary methyl group is displaced. 

Nowadays the positions of substituents in the camphor molecule 
are often indicated by numerals ; it will be seen from the numbered 
formula that the letters a, ]8 and TT correspond respectively with 
3, 10 and 8 (or 9) : 




J-Borneol, C 10 H 17 - OH, occurs as bornyl acetate in many essential 
oils, as, for example, in those of thyme, valerian, and pine-needle, 
and, in a free condition, in the oils of spike and rosemary ; its 
principal source, however, is Dryobalanops aromatica, a tree growing 
in Borneo and Sumatra. /-Borneol occurs in baldrian oil. 

rf-Borneol can be obtained, together with troborneol, by reducing 
rf-camphor with sodium and alcohol ; it is also formed when bornyl 
magnesium chloride is treated with oxygen, and the product is 
decomposed with a dilute acid. It is rather like camphor in outward 
properties, but is more distinctly crystalline, and, although it has 
an odour recalling that of camphor, it also smells faintly of pepper- 
mint. It melts at 208, boils at 212, and is readily volatile in 
steam. 

Borneol is a secondary alcohol ; when treated with phosphorus 
pentachloride, it is converted into a mixture of bornyl and isobornyl 
chlorides, and when this product is heated with aniline, it gives 
camphene, with the elimination of the elements of hydrogen chloride 
(p. 934). 

/wborneol, C 10 H 17 -OH, is a stereoisomeride of borneol, the 
secondary alcohol group in conjunction with the rigid ring structure 



DICYCLIC TERPENES AND RELATED COMPOUNDS 933 

giving rise to cis- and trans-forms (compare p. 821). It melts at 
217 and resembles borneol in physical and chemical properties, 
but it has not been found in nature. 

Bornyl chloride and wobornyl chloride are related in the same 
way as the alcohols. 

Other Dicyclic Terpenes 

Bornylene, C 10 H 10 , is a dicyclic terpene (p. 934) closely related 
/o camphor and the stereoisomeric borneols, and is formed by 
heating bornyl iodide with alcoholic potash. It melts at 133 and 
on oxidation with nitric acid it gives camphoric acid ; it does not 
occur in nature. 

Camphene, C 10 H 16 , is a dicyclic terpene (m.p. 51) which is 
found in a number of essential oils (ginger, citronella, spike, valerian 
oil), either in the </-, /-, or d7-form. It is formed when bornyl or 
wobornyl chloride is warmed with aniline, or heated at 200 with 
sodium acetate and glacial acetic acid, and it may also be obtained 
by heating borneol with potassium hydrogen sulphate ; from the 
formulae on p. 934, it will be seen that these reactions involve 
changes in the cyclic structures (Wagner-Meerwein rearrangement, 
p. 849). 

Camphene unites directly with one molecule of hydrogen chloride, 
forming camphene hyZrochloride, C 10 H 17 C1, which is unstable and 
passes into wobornyl chloride (p. 934). It is much more stable than 
pinene, and is only oxidised with difficulty, giving many products, 
among others camphor, the formation of which involves complex 
changes. 

The structural relationships of the more important dicyclic 
terpenes and a few of their derivatives are shown on p. 934, 
and it will be seen that the bridged rings in these compounds 
sometimes undergo unusual changes, which are all the more note- 
worthy because they take place in solution at ordinary temperatures. 

Pinene hydrochloride, prepared at 70 (p. 925), undergoes a 
remarkable transformation in solution even at 10, and passes 
into bornyl chloride, which is therefore easily obtained by treating 
pinene, dissolved in chloroform, with hydrogen chloride at 0. 
Bornyl chloride at 130, in chlorobenzene solution, gives a small 
proportion of tsobornyl chloride, which, in its turn, is very partially 
converted into camphene hydrochloride ; on the other hand, the 



934 DICYCLIC TERPENES AND RELATED COMPOUNDS 







Pinene 



Pincne Bornyl chloride and Camphene 

hydrochloride /sobornyl chloride hydrochloride 







Camphene 1 



Camphene * 



Camphor 



Borneol and 
/soborneol 







Bornylene 



Camphane 



Pinane 



Tricyclene 



last-named compound, prepared from camphene (p. 933), passes 
into tsobornyl chloride rapidly and almost completely, when it is 
merely dissolved in cresol, and a large proportion of the tso-com- 
pound is then slowly transformed into bornyl chloride. In solution, 
therefore, there is an equilibrium mixture of the three compounds, 
bornyl chloride, isobomyl chloride, and camphene hydrochloride, 
of which, at ordinary temperatures, the bornyl chloride is by far 
the largest component (Meerwein and Emster, Ber. 1922, 2520). 

Many of the monocyclic terpenes have been converted into 
saturated substituted ryc/oparaffins by reduction under suitable 
conditions. Limonene (p. 913), for example, has been reduced to 
hexahydro-/>-cymene (/>-menthane) with hydrogen and a nickel 
catalyst, and phellandrene gives a mixture of />-menthane and 
p-menthene with colloidal palladium. Dicyclic terpenes can be 
similarly reduced to saturated bridged ring structures ; bornylene, 
for example, with nickel and hydrogen, gives camphane y and cam- 

1 These two formulae for camphene represent identical structures which 
are merely set out differently. 



DICYCLIC TERPENES AND RELATED COMPOUNDS 935 

phene gives isocamphane, a saturated hydrocarbon which corre- 
sponds with camphene in structure. Pinene, in contact with 
palladium black at 190-200, in an atmosphere of carbon dioxide, 
is converted into a mixture of cymene and pinane, 

2C 10 H 16 = C 10 H 14 -h C 10 H 18 . 

Tricyclene (p. 934) is an interesting example of a saturated tricyclic 
hydrocarbon ; it does not occur in nature but has been obtained 
from various terpene derivatives. It has also been prepared by the 
oxidation of camphor hydrazone with mercuric oxide ; on reduction, 
using a nickel catalyst, it is converted into wocamphane. 

The mono- and di-cyclic terpenes and some of their derivatives, 
which have been described above, are merely the more important 
representatives of those particular types of naturally-occurring 
compounds. It is interesting to note that all, or nearly all, these 
optically active substances occur in nature in both the d- and the 
/-form, whereas in the case of the sugars and optically active alkaloids 
only the one enantiomorph, either d- or /-, is found in the vegetable 
kingdom. 

Isoprene Theory 

In addition to the foregoing mono- and di-cyclic compounds, 
C 10 H 16 , various other classes of terpenes are known, namely open 
chain terpenes, C 10 H 16 (p. 940), and sesquiterpenes, C 15 H 24 (p. 943), 
as well as numerous 'derivatives of each type. All the parent hydro- 
carbons have the empirical formula C 5 H 8 , and, as suggested by 
Wallach during his long study of the sesquiterpenes, they may all 
be regarded as derived from isoprene. 

Thus, by some unknown mechanism, two molecules of isoprene 
might give rise to a/>-menthadiene, (i),such as limonene, terpinolene, 
etc. ; to a w-menthadiene, (n), such as carvestrene ; or to a dicyclic 
terpene such as pinene or bornylene, (in). 



CH 3 





I II III 

Or*. 69 



936 DICYCLIC TERPENES AND RELATED COMPOUNDS 

The dotted lines indicate where combination might occur, followed 
of course by a redistribution of some of the hydrogen atoms and the 
olefinic links, and with the simplified formulae (p. 912) these 
hypothetical syntheses may be expressed as follows : 






Now it is known that isoprene can be obtained by heating di- 
pentene at about 300 (as also by the destructive distillation of 
rubber, p. 970), and it has been proved that isoprene, treated with 
a little sulphuric acid in acetic acid solution, gives cyclic (a-terpineol, 
cineole) and open chain (geraniol, linalool, p. 941) terpene deriva- 
tives. In spite of such facts it seems to be unlikely that this di- 
olefine is really the starting-point in the natural production of 
terpenes and their derivatives, since isoprene is not known to 
occur in plants ; other views have therefore been advanced 
(p. 942). 

Nevertheless Wallach's hypothesis is of very considerable aid 
in memorising the formulae of the various types of terpenes 
and their derivatives, as well as those of related substances 
such as natural rubber, the carotenoids (p. 972), etc. It has also 
been employed in deciding between various possible formulae 
for a natural product (pp. 945, 974). Some of its applications are 
given below. 

From isoprene, by a head-to-tail union x of two molecules, the 
structures of many open chain (acyclic) terpenes, such as ocimene 
and myrcene and related compounds such as citral (p. 940), are 
easily derived : 




Isoprene Ocimene 

1 Isoprene is 2-methylbutadiene and the ' head ' is the 1 -carbon atom. 



DICYCLIC TERPENES AND RELATED COMPOUNDS 937 





Myrcene 



Citral 



By curling the formula of, say, ocimene in various ways the carbon 
skeletons of numerous monocyclic terpenes, such as limonene, and 
of dicyclic terpenes such as bornylene, pinene, etc., are obtained : 




Ocimene 




Ocimene 



\ 





Carene 



Ocimene 







Limonene Bornylene Pinene Camphene 

In the case of the m-menthadienes the union is tail-to-tail, 





Sylvestrene 



The addition of a third isoprene molecule to ocimene, again head- 
to-tail, gives the structure of an acyclic sesquiterpene such as 



938 DICYCLIC TERPENES AND RELATED COMPOUNDS 

farnesene and by curling this in various ways the different groups 
of mono- and di-cyclic sesquiterpenes (p. 943) are produced : 




Bisabolene Cadinene Selinene 

Another arrangement of farnesene gives vetivazulene (p. 954), 





Farnesene 



Vetivazulene 



If now a fourth isoprene skeleton is added to farnesene in the 
same head-to-tail manner, the skeleton of phytol (p. 1083), a reduced 
diterpene alcohol, is obtained while rubber is represented by an 
extended isoprene chain. Squalene, a dihydro/nterpene (p. 948), 
is made up of two farnesene skeletons joined tail-to-tail and a 
similar union of two phytol molecules gives lycopene (p. 972) : 



DICYCLIC TERPENES AND RELATED COMPOUNDS 939 



Phytol Rubber Squalene Lycopene 



CHAPTER 56 
OPEN CHAIN TERPENES AND SESQUITERPENES 

Open Chain Terpenes 

COMPARATIVELY few open chain terpenes, C 10 H 16 , are known, but 
many of their derivatives occur in essential oils and are of com- 
mercial importance in the perfume industry. 

Myrcene, C 10 H 16 (b.p. 166), occurs in bay oil and ocimene, 
C 10 H 16 (b.p. 177), in the oil of Ocimum basilicwn ; both are open 
chain tri-olefinic terpenes and are respectively represented by the 
following formulae : 

CH 3 CH 2 

CH 3 .C:CH-CH 2 -CH 2 -C-CH:CH 2 

Myrcene 




r i - 

CH 2 :C.CH 2 .CH 2 .CH:C.CH:CH 2 



Ocimene 

Both hydrocarbons are reduced to dihydro-derivatives by sodium 
and alcohol by the addition of two hydrogen atoms to the ends of 
the conjugated system. 

Citral, C 10 H 16 O, occurs in many essential oils, particularly in 
lemon-grass oil, of which it forms about 80%. It is a liquid, having 
a pleasant odour of lemons, and can be distilled under reduced 
pressure. It combines directly with sodium hydrogen sulphite, 
and when heated with potassium hydrogen sulphate it yields 
cymene. When boiled with alkalis it yields 2-methyl-k-2-hepten- 
6-one, and acetaldehyde, (n), and on oxidation with permanganate, 
followed by chromic acid, it gives acetone, and oxalic acid ; when 
submitted to ozonolysis it yields acetone, laevulic aldehyde, and 
probably glyoxal, (in). These, and other results prove that citral 
has the constitution, (i) ; later, formaldehyde was also found among 
the products of ozonolysis and it was therefore inferred that the 
natural oil contains a structural isomeride, (iv) : 

940 



OPEN CHAIN TERPENES AND SESQUITERPENES 941 





cff 




Crude citral was therefore regarded as a mixture of (i) and (iv), each 
of which exists in ay- and trans-forms ; these four components are 
geranial or citral a (m-2:6-dimethyl-A-l:6-octadien-8-al) and 
neral or citral b (*ra/-2:6-dimethyl-A-l:6-octadien-8-al) and the 
corresponding A-2:6-isomerides : 



H C-CHO OHC C H 

Geranial Neral 

Studies of absorption spectra, however, seem to indicate that there 
is very little, if any, of form (iv) in either stereoisomeride, and it 
appears that migration of the double bond from (i) to (iv) may occur 
to some extent during ozonolysis, to account for the production of 
formaldehyde, 

Geraniol and Nerol, C 10 H 18 O, occur in many essential oils, and 
are the stereoisomeric alcohols corresponding respectively with 
geranial and neral ; the configurations of these alcohols, and hence 
of the citrals, are inferred from the fact that nerol gives fl-terpineol 
much more easily with dilute sulphuric acid than does geraniol, 




CH 2 -OH k. CH 2 -OH 




Nerol 




Linalool, C 10 H 18 O, is a tertiary alcohol which occurs notably 
in oils of lavender and bergamot. It is optically active, and both 
d- and /-forms occur in various oils. It is represented by the formula: 




942 OPEN CHAIN TERPENES AND SESQUITERPENES 

When linalool is treated with acetic anhydride it gives (an ester 
of) geraniol, by an isomeric change which is commonly shown by 
all alcohols of the same type as linalool (p. 840), 




Geranic acid, C 10 H 16 O 2 , is formed by the oxidation of citral 
with silver oxide, but is better prepared by the conversion of the 
aldehyde into the oxime, dehydration to the nitrile and hydrolysis, 

R-CHO > R-CH:NOH > R-CN * R-COOH. 

It has been synthesised from 2-methyl-A-2-hepten-6-one by the 
Reformatsky reaction with ethyl iodoacetate and zinc, followed by 
dehydration of the resulting hydroxy-acid, 





A/S/V 



COOH 



Its calcium salt heated with calcium formate yields citral. 

When citral is treated with potassium hydrogen sulphate it is 
converted into cymene, and from geraniol, with the aid of various 
dehydrating agents, dipentene (p. 913) and other />-menthadienes 
are obtained ; linalool, under various conditions, gives a-terpineol, 
terpin hydrate, dipentene, and other menthadienes. 

Facts such as these and the lack of experimental evidence in sup- 
port of the isoprene hypothesis have led to the suggestion that such 
open chain aldehydes and alcohols are intermediate products in 
the formation of the cyclic terpenes and their derivatives, and that 
the former are produced from acetone and aldehyde by reactions 
such as the following (i and n) : 



OPEN CHAIN TERPENES AND SESQUITERPENES 943 




CHO j CHO 
C H 3 = 





The aldehyde, C 10 H 14 O, formed according to (n), might undergo 
reduction, first to citral, C 10 H 16 O, and then to nerol, C 10 H 18 O, and 
it is known that the latter can be converted into a-terpineol, di- 
pentene, etc. 

Against this view there is the fact that the condensation of 
acetaldehyde and acetone in the laboratory leads to the formation 
of ethylideneacetone, and not to j3-methylcro tonal as represented 
above, as an aldehyde group is far more reactive than a ketone 
group in such a mixed condensation. Finally, there is no evidence 
of the occurrence of acetaldehyde or acetone in the vegetable 
kingdom. 

Sesquiterpenes 

The sesquiterpenes, C 15 H 24 , are of three chief types : open chain, 
monocyclic and dicyclic. They occur in essential oils, together 
with innumerable derivatives, and their molecules may be regarded 
as based on isoprene units as suggested by Wallach (p. 938). 

For the determination of their structures in bygone times the 
first step was usually a study of the physical properties of the 
compound, more especially its molecular refraction (p. 702), from 
the value of which the presence of one or more closed chains in the 
molecule could be inferred ; the results were then confirmed (or 
otherwise) by an examination of the behaviour of the compound 
towards hydrogen chloride, hydrogen bromide, and other reagents 
for olefinic bindings. Further information might then be obtained 
by submitting the substance to ozonolysis and graded oxidation, 
but the products were generally either too simple or too complex 
to give useful information. 

It was not until 1921 that rapid progress was made. About that 
time Ruzicka found that sulphur, first used by Vesterberg, was an 
invaluable reagent for the dehydrogenation of sesquiterpenes and 
their derivatives, many of which at moderately high temperatures 



944 OPEN CHAIN TERPENES AND SESQUITERPENES 

were thereby transformed into substituted naphthalenes. Later it 
was shown that selenium could be used instead of sulphur. The 
structure of the aromatic oxidation product could then be determined 
without much difficulty and that of the parent sesquiterpene could 
be deduced with some assurance. 

Farnesene, C 16 H 24 , is an example of an open chain sesquiterpene; 
it is formed by the dehydration of farnesol, C 15 H 26 O, an alcohol 
which occurs in oil of ambrette seeds. These two compounds may 
be respectively represented as follows, but both are probably 
mixtures of structural and stereoisomerides : 




Farnesene Farnesol 

Zingiberene, C 16 H 24 , is the main component of ginger oil and 
may be taken as an example of a monocyclic tri-olefinic sesquiterpene. 
It is optically active, and boils at 134 (14 mm.). When it is heated 
with sulphur, oxidation and ring-closure occur, and it gives a hydro- 
carbon, cadalene, C 15 H 18 , which has been synthesised and proved 
to be l:6-dtmethyl-4-isopropylnaphthalene, (i). From the results of 
further investigation, involving ozonolysis, etc., it has been proved 
that zingiberene has the structure, (n). 




I II ill 

Bisabolene, C 15 H 24 , occurs in oil of bergamot and myrrh and is 
very closely related to zingiberene, from which it differs in that 
the olefinic binding, A (n), in zingiberene is at B in bisabolene. 

Cadinene, Ci 6 H 24 , occurs in oil of cubebs, etc,, and is a repre- 
sentative of the dicyclic di-olefinic sesquiterpenes ; when it is heated 
with sulphur it gives cadalene, and from other results it would 



OPEN CHAIN TERPENES AND SESQUITERPENES 945 

seem that the natural product, purified so far as possible, is 
mainly (in). 

Cadinoly C 15 H 26 O, is a mixture of structural isomerides, which 
may be regarded as derived from cadinene by the addition of the 
elements of water. 

Selinene, C 16 H 24 , which occurs in celery oil, is a representative 
of a rather different type of dicyclic di-olefinic sesquiterpenes. It 
combines with two molecules of hydrogen in the presence of 
platinum and gives with hydrogen chloride a dihydrochloride ; its 
molecular refraction accords with that of a dicyclic structure con- 
taining two ethylenic linkages. When oxidised with sulphur 
selinene yields eudalene, C 14 H W , or l-methyl-7-wopropylnaph- 
thalene, (iv), and in this change one carbon atom is eliminated. 
From a study of many similar cases it is inferred that this carbon 
atom is attached to the 1, 7, 9, or 10 position in the reduced naph- 
thalene ring of selinene, from any of which it must be displaced in 
the formation of the naphthalene derivative. An examination of 
the possibilities shows that 10 is the only position which conforms 
to the isoprene rule, so that the framework of selinene is very 
probably represented by (v), in which case the only matter remaining 
to be decided is the distribution of the two double bonds : 





IV 



But when selinene dihydrochloride is reconverted into selinene 
the product is different from the original sesquiterpene ; and from 
a study of their oxidation products, the isomerides have been given 
the following structures : 





0-Seltnene 



a-Selmtne 



946 OPEN CHAIN TERPENES AND SESQUITERPENES 

Eudesmoly C 15 H 26 O, melts at 82-83 and is very closely related to 
selinene ; it is a mixture of two alcohols, the proportion of which 
appears to show considerable variations without any change in 
the melting-point : 





a-Eudesmol 



/3-Eudesmol 



As an example of the way in which the structure of a naphthalene 
derivative, obtained by the dehydrogenation of a sesquiterpene is 
established, the synthesis of eudalene is given : Ethyl p-wopropyl- 
cinnamate is reduced to the saturated alcohol, which is converted 
successively into the bromide, cyanide and acid, (i), the chloride 
of which undergoes an internal Friedel-Crafts reaction giving an 
isopropyltetralone, (n). The tertiary alcohol formed from (n) after 
treatment with methyl magnesium iodide is dehydrated and the 
resulting dihydronaphthalene derivative, (in), dehydrogenated with 
sulphur, gives eudalene, (iv), which must therefore be 1-methyl- 
7-tsopropylnaphthalene : 





II 





III 



IV 



OPEN CHAIN TERPENES AND SESQUITERPENES 947 

Synthetic Sesquiterpenes 

Very interesting syntheses of sesquiterpenes and their derivatives 
from geraniol have been accomplished. This alcohol, with phos- 
phorus trichloride, gives the chloride, (i), 1 from which, with the aid 
of ethyl sodioacetoacetate in the usual way, aj8-dV/ry</ropseudo- 
ionone (n, cf. p. 952), is obtained : 



CH 2 C1 





This ketone is then converted into (in) by treatment with acetylene 
in the presence of sodamide, a most important method for the 
preparation of tertiary alcohols of this type ; reduction by sodium 
and moist ether 1 converts the acetylenic into an olefinic link and the 
product, (iv), is a sesquiterpene alcohol, dl-nerolidol, which occurs 
notably in neroli oil from bitter oranges : 



OH 





The dehydration of nerolidol gives farnesene, which on treatment 
with formic acid gives a monocyclic sesquiterpene the hydrochloride 
of which is identical with that of naturally occurring bisabolene 
(p. 944). 

Farnesol (p. 944) is produced by an isomeric change (p. 840) 
when nerolidol is treated with acetic anhydride ; the corresponding 

1 Reductions of this kind may also often be conveniently and almost 
quantitatively accomplished by using hydrogen in the presence of a palladium 
catalyst which has been partially poisoned with a lead salt and quinoline : 
also by using sodium in liquid ammonia. 



948 OPEN CHAIN TERPENES AND SESQUITERPENES 

bromide, farnesyl bromide, when treated with magnesium in ether 
gives a mixture of hydrocarbons from which squalene hexahydro- 
chloride, identical with that from natural squalene, can be isolated ; 
squalene, C 30 H 60 , is an important dihydrotriterpene which occurs in 
the livers of the shark. 



Squalene 

Resin Acids 

The non-volatile residue of colophony or rosin from turpentine 
(p. 909) is a brown, brittle mass largely used for sizing paper and 
cotton and for the manufacture of plastics, varnish, soap, etc. ; it 
consists largely of a complex mixture of resin acids, derived from 
diterpenes, C 20 H 32 , of which abietic acid may be taken as typical. 

Abietic acid, C 20 H 30 O 2 , is laevorotatory and melts at 173. 
When it is dehydrogenated with sulphur or palladium-charcoal it 
yields retene (l-methyl-7-wopropylphenanthrene), C 18 H 18 , and 
when it is hydrogenated it gives a mixture of tetrahydroabietic 
acids ; on oxidation with permanganate it is converted into two 
isomeric tetrahydroxy-acids, C 19 H 29 (OH) 4 COOH ; these facts 
prove the presence of two double bonds in the molecule of abietic 
acid. When it is oxidised with nitric acid, abietic acid gives the 
two cyc/ohexane acids, (i) and (n), together with some wobutyric 
acid : 




Retene 



II 



OPEN CHAIN TERPENES AND SESQUITERPENES 949 

The framework of abietic acid can thus be shown by (in), the 
heavy lines serving to indicate those parts of the molecule within 
which the double bonds must be situated ; the two carbon atoms 
which are lost (as carbon dioxide and methane respectively) in the 
conversion of abietic acid into retene are therefore those of the 
carboxyl group at 1 and the methyl group at 12 : 



X COOH 



,COOH 




III 



IV 



The production of tsobutyric acid as one of the products of 
oxidation points to one of the double bonds being 6:7 or 7:8. The 
position of the carboxyl group is confirmed by the fact that esteri- 
fication of the acid is difficult, as in other tertiary compounds, 
CR 3 -COOH ; moreover, if the carboxyl is converted into a methyl- 
group by the following series of changes (compare p. 954) : 



COOEt > CH 2 OH 



CHO 



CH:N-NH a > CH 3 , 



and the product is then dehydrogenated, retene is again formed. 

The molecular refraction and absorption spectrum of abietic 
acid give only indecisive evidence as to whether the double bonds 
are conjugated or not, and although abietic acid combines with 
maleic anhydride, it only does so at 130, a temperature at which 
isomeric change might occur before reaction. 

As a result of much further work, however, it is concluded that 
the structure of abietic acid is that shown in (iv). 



Natural and Artificial Perfumes 

The extraction of essential oils from plants, for their use as 
perfumes and essences, is an art which has been carried out from 
the remotest times, and is now a very important industry. 

In many countries considerable tracts of land are utilised for the 



950 OPEN CHAIN TERPENES AND SESQUITERPENES 

cultivation of the plants required, and particularly in the South of 
France, tuberoses, violets, jasmine, etc., are grown in large quan- 
tities for the sake of their delicate perfumes. It seems probable, 
however, that before very long such natural products will be 
almost entirely displaced by synthetic ones, just as those of the 
indigo and the madder plant have been superseded by coal-tar 
products, and many natural medicinal compounds by manufactured 
substitutes. 

The essential oils are extracted from the vegetable products in 
various ways. The oldest process for their separation was by steam 
distillation ; the vegetable matter was boiled with water in an earthen- 
ware still, and the oil was then collected from the aqueous distillate ; 
large metal stills are now used for this purpose, and in the case of 
oranges, lemons, limes, and other large fruits, the peel is first dis- 
integrated mechanically in order to set free the essential oils. 
Another process, which is particularly useful when the proportion 
of perfume is very small, is to extract the vegetable matter with a 
volatile, odourless solvent, such as light petroleum, and then to 
distil the solvent. When such methods do not give good results, 
enfleurage is used ; the flowers (roses, violets, orange-blossoms, etc.) 
are placed in melted odourless fat (such as purified lard), and the 
latter is then separated from the flowers in hydraulic presses ; the 
essences are afterwards extracted from the fat with alcohol. Some 
flowers (jasmine, tuberose, etc.), however, continue to produce 
their perfume for a long time after they have been picked ; in such 
cases they are left in contact with a layer of cold fat (cold enfleurage), 
until the formation and absorption of perfume ceases. 

Nearly all types of compounds composed of carbon, hydrogen, 
and oxygen are found in essential oils, and most of these naturally 
occurring substances, whether aliphatic or aromatic, have a pro- 
nounced and agreeable smell. Some of the simpler odoriferous 
aliphatic esters (p. 198) can be prepared from other sources, and 
have long been manufactured for use in confectionery. 

The artificial production or partial synthesis of such compounds 
is an expanding and important branch of industry which, as already 
mentioned, may lead to the complete supersession of the natural 
products. 

The first important partial synthesis in this field was that of 
coumarin (m.p. 67), which occurs in the Tonka-bean, and in sweet 
vernal grass, to which the pleasant smell of new-mown hay is partly 



OPEN CHAIN TERPENES AND SESQUITERPENES 951 

due ; this compound was prepared (Perkin, 1868) from salicyl- 
aldehyde and sodium acetate by a Perkin reaction, followed by 
the conversion of the resulting coumarinic acid into its lactone 
(p. 709). 

Some years later various important perfumes were prepared 
from certain cheap and abundant naturally occurring substances. 
Vanillin, C 6 H 3 (OMe)(OH).CHO[OMe:OH = 3:4], for example, 
which occurs in vanilla pods, was prepared by Tiemann and Haar- 
mann from coniferin, C 16 H 22 O g ,2H 2 O, which occurs in the sap of 
various coniferae ; this compound is a phenolic glucosidc of coniferyl 
alcohol, C 6 H 3 (OMe)(OH).CH:CH.CH 2 .OH, and, on oxidation, 
gives glucovanillin (the group CH:CH'CH 2 -OH being converted 
into CHO) ; this product is hydrolysed by acids, yielding vanillin 
and glucose. Vanillin is now manufactured from eugenol, 
C 6 H 3 (OMe)(OH).CH 2 .CH:CH 2 [OMe:OH - 3:4], an important 
component of oil of cloves ; the eugenol is first heated with caustic 
alkali, to convert it into its isomeride, woeugenol (p. 839), and the 
latter, in the form of its acetyl derivative, is then oxidised. 

Heliotropin, (i), or piperonal (p. 602), which occurs in heliotrope 
(Cherry Pie), is manufactured in a similar manner from safrole, (n), 
a component of sassafras officinale and other essential oils ; the 
allyl is converted into the propenyl radical by isomeric change, as 
in the case of eugenol, and the latter is then oxidised with chromic 
acid. 



CH 2 <> C 6 H 3 - CHO CH 2 <> C 6 H 3 - CH 2 - CH:CH 2 

I ii 

Terpineol is also manufactured from turpentine (p. 917). 

A very interesting synthetic perfume was discovered by Baur 
(Per. 1891, 2832), who found that the 2:4:6-trinitro-derivative, 
obtained by nitrating w-tertiary butyltoluene, C 6 H 4 (CH 3 ) CMe 8 , 
had a pronounced odour recalling that of musk, a very expensive 
perfume obtained from certain glands of the musk-deer. This 
artificial ' Muse Baur,' or some nearly related nitro-compounds 
having a similar odour, are now manufactured in large quantities 
and are very cheap compared with exaltone (p. 787), a far superior 
musk substitute. 

The possible preparation of the odoriferous principle of violets 

Org. 60 



952 OPEN CHAIN TERPENES AND SESQUITERPENES 

at one time occupied much attention and an optically active ketone, 
irone, was first isolated from the roots of Iris fiorentina by Tiemann 
and Kriiger (Ber. 1893, 2675) ; this product was given the formula 
C 13 H 20 O, but in the light of later experiments it seems more probable 
that the molecular formula is C 14 H 22 O and that it is a mixture of 
isomerides, (la) and (ib). 





la 



Later it was found that two compounds, a- and fi-ionones, both 
having an intense smell of violets, and related to irone in structure, 
could be cheaply prepared from citral, an abundant component of 
oil of lemon-grass and of lemon oil : Citral condenses with acetone 
in the presence of baryta, giving pseudo/owowe, (n), 1 which combines 
with water, giving pseudotowowe * hydrate' (in) ; when this com- 
pound is heated with dilute acid, ring-closure occurs, with the 
elimination of one molecule of water, and by the loss of another, in 
different ways, a-ionone, (iv), and jS-ionone, (v), are formed. 





ii in 

The structures of a- and j8-ionone follow from those of their 
oxidation products ; the former yields wogeronic acid, and the 
latter geronic acid, both of which are further oxidised by sodium 
hypobromite to ]8j8-dimethyladipic and aa-dimethyladipic acids 
respectively : 

1 A mixture of or- and trans-forms from citral a and citral b. 



OPEN CHAIN TERPENES AND SESQUITERPENES 953 



IV 





VI HOO 



,COOH 




:OOH VII 




/rogeronic acid 



:OOH 



Geronic acid 



COOH COOH 

"Uc CT 



^-Dimethyladipic acid 



aa-Dimethyladipic acid 



The initial products of oxidation, (vi) and (vn), are unstable and 
cannot be isolated. 

The ionones are now prepared on the large scale for use in 
perfumery, and some of their derivatives, the carotenes and vitamin 
A, for example (pp. 976, 978), are very important. 

Many other compounds, differing greatly from one another in 
structure, are prepared by the ordinary processes of organic chemistry 
and used in perfumery ; as examples, anisaldehyde (aubepine, 
hawthorn blossom), phenylethyl alcohol (which occurs in roses), 
methyl anthranilate (a component of orange flowers and of jasmine), 
and esters of salicylic acid may be mentioned. 



954 OPEN CHAIN TERPENES AND SESQUITERPENES 

Azulenes 

The blue colour of camomile oil was first observed about five 
hundred years ago and it is now known that many essential oils 
contain violet or blue compounds, or yield such substances on 
dehydrogenation with selenium, sulphur, etc. The colouring 
matters may be extracted from a petrol or ethereal solution of the 
oils with aqueous phosphoric acid and precipitated from the latter 
with water ; with picric and styphnic acids, trinitrobenzene, etc., 
they give crystalline derivatives which may be used for their puri- 
fication. These compounds are known as azulenes and are of great 
interest because of their colour and structure. 

Vetivazulene, C 16 H 18 , is obtained by the action of sulphur on 
vetiver oil (from andropogon muricatus) ; it crystallises in violet 
needles, m.p. 32. On catalytic reduction it unites with four 
molecules of hydrogen to give a hydrocarbon, C 16 H 26 ; its refrac- 
tivity and other physical properties suggest that it is dicyclic and 
if so one of the five double bonds which it would contain is resistant 
to reduction. With potassium permanganate it is oxidised to acetic, 
wobutyric and oxalic acids, and acetone ; tetrahydrovetivazulene 
with ozone gives acetone, formic, wobutyric and a-methylglutaric 
acids. All such products give little information concerning its 
structure. 

When vetiver oil is fractionated and appropriate ketonic fractions 
are purified by means of their semicarbazones, a ketone, p-vetivone, 
C 16 H 2 2O> can be isolated. As a result mainly of the work of St. Pfau 
and Plattner, j3-vetivone has been shown to be (i), and its molecule 
contains both a seven- and a five-membered ring. 



O: 





II 



When its hydrazone is heated with sodium ethoxide and alcohol 
(Wolff-Kishner method), 

> C=N - NH 2 - > CH 2 +N a , 



OPEN CHAIN TERPENES AND SESQUITERPENES 955 

it gives a hydrocarbon, C 16 H 24 , which on dehydrogenation yields 
vetivazulene, (n), and eudalene (p. 946) : the formation of the latter 
illustrates how changes in ring structures may occur during high 
temperature dehydrogenations. Conclusive evidence for the 
structure of vetivazulene is therefore not afforded by such a result, 
but the given constitution has, in fact, been confirmed by synthesis. 
Azulene y C 10 H 8 , of which vetivazulene is a dimethylwopropyl 
derivative, has been synthesised by a most ingenious method : 
j8-decalol, dehydrated with zinc chloride, gives a mixture of isomeric 
octahydronaphthalenes, from which the A-9:10-compound, (i), 
can be separated and converted into yr/0decan-l:6-dione, (n), by 
ozonolysis : 



CO"- CO 




II 



When this diketone is treated with aqueous sodium carbonate it 
undergoes an internal condensation giving 0,3,5-dicyr/0-A-9-decen- 
4-one, (in). The corresponding saturated alcohol, (iv), obtained 
by reduction gives azulene, (v), on dehydrogenation with palladium- 
charcoal : 






III IV 



Other azulene derivatives have been obtained by treating the 
ketone (in) with Grignard reagents and dehydrogenating the 
products. 



CHAPTER 57 
PLASTICS AND RUBBER 

Plastics 

A PLASTIC substance is one which, like putty, plasticine or celluloid, 
can be moulded by pressure or other mechanical means, at a suitable 
temperature, into a required form, which is then retained ; the word 
plastic, however, is now used as a noun to denote those materials 
which can be thus treated at some stage in their manufacture, and 
afterwards hardened if necessary (below). Some plastics are also 
known as synthetic resins, but the latter term is more restricted and 
cannot be applied, for example, to the cellulose plastics, since 
cellulose has not yet been synthesised. 

Plastics are nearly always mixtures of substances of high molecular 
weight, ranging probably beyond 100,000 or so, and with rare 
exceptions they are amorphous. Those which soften when heated 
and harden again in the cold, without having undergone chemical 
change (so that the operations may be repeated many times), are 
classed as thermoplastic, and generally consist of ribbon-like mole- 
cules. Those which change in structure when they are heated, at 
some stage in their manufacture, and gradually harden as a result 
of irreversible chemical reactions, are termed thermosetting, and in 
their final condition are probably composed of lattice-like or tri- 
dimensional molecules. 

The finished manufactured products may be colourless, or 
coloured ; transparent, or opaque. In addition to the organic com- 
pounds of which they are mainly composed, they may contain other 
ingredients, such as plasticisers, fillers and pigments. Plasticisers, 
as their name implies, are added to increase the fluidity or mobility 
of the material and thus facilitate the moulding or other mechanical 
operations ; also sometimes to decrease brittleness and impart 
flexibility. They are generally esters of high boiling-point, such as 
gl} collates, phthalates and organic phosphates, or other viscous and 
high boiling liquids such as the polyglycols ; camphor is an im- 
portant plasticiser, especially for cellulose esters (p. 962). Fillers, 
such as wood flour, lampblack, asbestos and mica, are often incor- 
porated in order to modify the physical properties, such as brittle- 

956 



PLASTICS AND RUBBER 957 

ness, resistance to shock, heat resistance and electrical character- 
istics ; the desired ornamental effect is generally attained by the 
addition of organic or mineral pigments. 

The use of plastics is extending rapidly ; they are chemically 
inert, stable under ordinary conditions, insoluble in water, generally 
good thermal and electrical insulators, rigid or flexible, and not 
easily broken ; they can be cut to shape but are mostly moulded into 
the required form. They are employed for the production of 
articles of domestic and industrial use far too numerous to mention 
and are of particular importance in the electrical industry, in the 
manufacture of aeroplane parts, non-splintering glass, fabrics, 
photographic films, etc. 

The reactions involved in the manufacture of plastics are mainly 
of two types, namely (1) condensation, and (2) polymerisation, as 
will be seen from the following brief account of some of the more 
important commercial products. 

Condensation Plastics. In the process of condensation, as already 
shown, two or more molecules, identical or different, unite with the 
elimination of the elements of water, alcohol or some other simple 
compound, as in the formation of crotonaldehyde from acetaldehyde, 
and of mesityl oxide and phorone from acetone. Theoretically, in 
these and many other examples of this very common reaction, the 
process might continue indefinitely ; actually, as a rule, it very soon 
comes to an end and there is nothing unusual in the properties of 
the relatively simple products, which if solid are crystalline. When, 
however, formaldehyde (formalin) is heated with phenol in the 
presence of an acid or alkali, a long series of condensations results 
in the gradual formation of a mixture of various amorphous, very 
complex plastics. This material, first manufactured by Baekeland 
about 1908, and hence called Bakelite, was the first entirely synthetic 
industrial plastic. 

The initial change in the production of Bakelite is probably a 
simple reaction between formaldehyde and phenol, which gives 
o-hydroxymethylphenol (saligenin), two molecules of which then 
condense, again in the o-position : 

C 6 H 5 .OH-fCH 2 > HO-C fl H 4 .CH 2 .OH, 

2HO.C 6 H 4 -CH 2 .OH + HO-C 8 H 4 .CH 2 .C 6 H 3 (OH).CH 2 .OH. 

As this last compound, like saligenin, contains a CH 2 -OH 
group and a C 6 H 4 radical in which a position ortho to the phenolic 



958 PLASTICS AND RUBBER 

hydroxyl is unsubstituted, a similar condensation may be repeated, 
and so on indefinitely with successive products. The result is the 
formation of a mixture of substances, the molecules of which are 
composed of very long chains, consisting (except at the ends) of the 
identical units shown between the dotted lines, 

HO C 6 H 4 - CH 2 C 6 H 3 (OH) CH a CH 3 (OH) - CH 2 j CH 4 OH. 

When, therefore, the molecule is sufficiently large its empirical 
formula is practically identical with that of one of these units, since 
the composition of the slightly different end groups may be left 
out of consideration. Owing to its very high molecular weight the 
substance differs from ordinary crystalline compounds in its physical 
characteristics ; it is a plastic. 

Now the properties of the products formed by the condensation 
of phenol and formaldehyde (formalin) vary very considerably with 
the nature (acid or alkali) of the condensing agent, proportions of 
the reactants and the temperature ; when instead of equimolecular 
quantities an excess of formalin is used, the aldehyde may react 
with some of the hydrogen atoms para to the hydroxyl radicals and 
the linear condensation products may thus become united by 
CH 2 groups at intervals throughout their length ; this would 
give rise to a sort of ladder arrangement and, by a continuation of 
such a reaction, lattice arrangements and tridimensional structures 
would be produced : 



C,H 2 (OH) - CH a CH a (OH) CH a C 6 H 2 (OH) - CH 2 - CH 2 (OH) 

CH 2 



a 
CH a 

a C 6 



CH 2 (OH) CH a C 6 H a (OH) CH a CH 2 (OH) - CH 2 C 6 H 2 (OH) 

Crow linkages of this kind have an important effect on the properties 
of the plastic, rendering it much more sparingly soluble and raising 
the softening point, until finally a thermosetting material is obtained, 
Other phenols, such as the cresols, give similar substances. 
Formaldehyde reacts with urea, in the presence of a catalyst, 

CH 2 O+NH 2 -CO-NH 2 - NH a .CO-NH.CH 2 -OH, 
and by repeated condensations of the product there might be formed 



PLASTICS AND RUBBER 959 

molecules consisting of long chains of the units indicated by the 
dotted lines, 

NH a -CO-NH-CH a NH-CO-NH.CH a NH-CO.NH.CH 2 NH.CO-NH 2 ; 

further condensation might then occur between the NH < groups and 
the formaldehyde whereby the chains become linked together. As the 
products are thermosetting plastics it is probable that they are cross- 
linked structures, formed from the linear molecules shown above. 

A most important plastic of an amide type, but otherwise quite 
different from the urea-formaldehyde product, is obtained when a 
solution of adipic acid (prepared from phenol, p. 797) and hexa- 
methylenediamine l is heated under pressure (Carothers) ; the 
liquid gradually becomes more and more viscous and the product, 
when melted, can be formed into threads and finally spun into 
fibres, which, structurally and physically, are very like those of silk, 
but twice as strong and unchanged by water. This material (and the 
fabric made therefrom) is known as nylon and was the first successful 
entirely synthetic fabric. The reactions which occur here are 
probably simple condensations which, repeated many times, give 
complex chain molecules, the units of which are as indicated : 

JCO - [CH 2 ] 4 CO - NH JCHJ. NH \ CO - [CH 2 ] 4 - CO NH [CHJ . NH j . .. . 

In spite of its apparent simplicity the satisfactory manufacture of 
nylon was only accomplished after vast expenditure of time and 
money, as the technical difficulties, etc., were very considerable. 

A different type of condensation plastic, in which the units are 
linked by ester groups is produced from glycerol and phthalic 
anhydride or in general from polyhydric alcohols and polybasic 
acids or their anhydrides. Theoretically there are many different 
ways in which reactions between these two components may occur, 
giving either comparatively simple products, incapable of further 
change, or complex substances still capable of undergoing condensa- 
tion. Considering the latter possibility only, two molecules of 
glycerol may react with one molecule of phthalic anhydride, 

HO CH a - CH(OH) CH a - O - CO - C 6 H 4 CO - O CH 2 - CH(OH) - CH a - OH ; 

1 Hexamethylenediamine is also obtained from phenol, since it is pre- 
pared from adipic acid through the amide and nitrile. 



960 PLASTICS AND RUBBER 

this product may condense with phthalic anhydride and then with 
glycerol (at either end) and theoretically these processes may con- 
tinue indefinitely ; there would thus be formed long linear molec- 
ules of the units indicated above by the dotted lines, and these 
might then become cross-linked by condensation with the anhydride, 
giving lattice or tridimensional structures. The plastics obtained 
in this way are theglyptals or alkyd resins, which are used principally 
as varnishes and for joining sheets of asbestos and other materials. 

Terephthalic acid and ethylene glycol give a linear condensation 
product which can be made into fibres and fabrics (Terylene) in 
a similar manner to nylon. 

Polymerisation Plastics. In many cases of polymerisation, as, for 
example, in that of aldehydes, the process soon comes to an end 
because of the formation of closed chain compounds, such as 
trioxymethylene and paraldehyde ; but when an aldol is formed 
this linear product still contains an aldehyde group and polymerisa- 
tion might theoretically continue indefinitely ; actually, so far as is 
known, it proceeds to a limited extent only, as in the production of 
formose from formaldehyde. 

Ethylene and other olefinic compounds, however, give polymerides 
by a reaction indicated below, which seems to continue indefinitely, 

CH 2 :CH a +H-CH:CH a = CH 3 .CH 2 .CH:CH a , 

CH 8 -CH 2 .CH:CH 2 +H-CH:CH a = CH 3 -CH 2 -CH 2 .CH 2 .CH:CH 2 . 

Straight chain molecules of high molecular weight which have the 
structure, CH 3 .CH 2 .[CH2-CH 2 ] n .CH:CH 2 , are thus produced. 
When n is very large the difference between the molecular formula 
of the polymer and that of the corresponding normal paraffin, is 
negligible, since the composition of the latter is also expressed so 
very closely by [CH 2 ] n . Such polyethylenes, therefore, are very 
similar to the paraffins in chemical properties, although their mole- 
cules contain one ethylenic link ; they are thermoplastics and are 
used largely for insulating electrical cables, etc. Polythene, manu- 
factured from ethylene, is an example of such polymerisation, but 
unlike the great majority of plastics it is crystalline. 

Polywobutylenes, such as vistanex, are formed from tsobutylene, 
CMe 2 :CH 2 , in a similar manner ; they consist of units CMe 2 CH 2 
and resemble the paraffins in their chemical behaviour. 



PLASTICS AND RUBBER 961 

Styrene (phenylethylene, vinylbenzene), C 6 H 5 -CH:CH 2 , under- 
goes ethylenic polymerisation, in which the phenyl group takes no 
part and gives a resinous plastic, polystyrene, composed of units 
CH 2 -CHPh ; this product is extensively used for electrical 
purposes as it has a very high dielectric constant. 

The polymerisation of all such unsaturated hydrocarbons is 
usually carried out at elevated temperatures under high pressure 
in the presence of a catalyst as, for instance, boron trifluoride or 
aluminium chloride ; but others such as peroxides, concentrated 
sulphuric acid, phosphates and silicates are also used. 

Simple vinyl derivatives, such as vinyl chloride, CH 2 :CHC1, and 
vinylidene dichloride, CH 2 :CC1 2 , also polymerise in the same way 
as ethylenic hydrocarbons, giving linear products composed of 
the units CH 2 -CHC1 and CH 2 -CC1 2 respectively. 

Vinyl acetate, CH 2 :CH-O-CO-CH 3 , is also a source of various 
plastics : by the usual ethylenic polymerisation it gives polyvinyl 
acetate, a product composed of units CH 2 CH(O CO CH 3 ) ; 
the ester groups can then be hydrolysed, giving polyvinyl alcohol, 
two units of which, (i), react with one molecule of an aldehyde to 
form an acetal, (u), 

CH 2 .CH(OH).CH a -CH(OH) - - CH a CH CH 2 CH 

O-CHR-O 
I II 

Various thermoplastics of different properties may thus be manu- 
factured from polyvinyl alcohol ; formaldehyde gives polyvinyl 
formal (Formvar, R=H), acetaldehyde, polyvinyl acetal (Alvar, 
R== CH 3 ), and butyraldehyde, polyvinyl butyral (Butvar, R= C 3 H 7 ). 
The last-named product is used mainly as a laminator, for joining 
sheets of glass, in the manufacture of safety glass (Triplex), which 
does not splinter when it is broken, and many of these vinyl plastics 
have found wide application. 

The polymerisation of esters of acrylic acid and alkyl substituted 
acrylic acids gives the important group of acrylate plastics ; those 
from ethyl acrylate and methyl methylacrylate (p. 343), for example, 
consist of units CH 2 - CH(COOEt) and CH 2 - CMe(COOMe) 
respectively, and the latter (Perspex) is used more particularly in the 
manufacture of windows for aeroplanes, etc. 

In the examples given above all the units of the complex molecules 



962 PLASTICS AND RUBBER 

are identical, but there is no reason why this should be so. A 
mixture of two (or more) simple olefinic compounds may give 
linear polymerides formed by the combination of molecules of 
both the components ; a mixture of equimolecular proportions of 
vinyl chloride and vinyl acetate, for example, might give a product 
composed of the units (i), whereas that from a mixture of methyl 
methylacrylate and ethyl acrylate might consist of the units (n) : 



CH a - CHC1 CH 2 CH CH a CMe - CH 2 CH 

O-CO-CHs COOMe COOEt 



I II 

Such mixed polymers are called inter- or co-polymers. 

As the proportions of the two components can be varied at will, 
plastics having almost any desired physical properties may thus be 
produced from vinyl derivatives alone. 

Many vinyl plastics can be converted into materials with rubber- 
like properties by the incorporation of plasticisers, but the products, 
although plastic and elastic, cannot be vulcanised (p. 965). 

Passing now from olefinic substances containing only one active 
double bond in the molecule to those which contain two, it will be 
seen that a linear polymer formed from the latter still retains one 
ethylenic link in every unit ; butadiene, for example, would give 
(in) and chlorobutadiene, (iv) : 

CH a .CH:CH-CH, CH a -CCl:CH-CH a 

III IV 

The properties of the unsaturated plastics thus formed are different 
from those of the saturated polymerides of mono-olefinic compounds, 
and are similar in many respects to those of natural rubber ; it it 
mainly from such di-olefines and their substitution products that 
the very important synthetic rubbers are manufactured (p. 968). 

The complex molecules of cellulose consist of long chains which 
are possibly cross-linked, and the units of which have the empirical 
formula, C 6 H 10 O 5 (p. 899) ; these units contain alcoholic hydroxylic 
groups which can be esterified with acetic anhydride, nitric acid, 
etc., or made into ethers, and some of the products are used in the 
manufacture of plastics such as cordite, celluloid, xylonite, etc. Of 
the partly synthetic compounds of this kind cellulose acetate is 
perhaps the most important because of its use in the manufacture 



PLASTICS AND RUBBER 963 

of artificial silk (rayon), cinema films and many other commercial 
products. Other fibres derived from cellulose have already been 
described (p. 330). 

Casein (p. 645) is a highly complex substance of animal origin 
composed of units having an amide structure, comparable to that 
of nylon ; after it has been moulded it can be hardened by treatment 
with formaldehyde. It is commonly used for the manufacture of 
buttons, umbrella handles, ash trays, etc. Other proteins are also 
used for the production of fibres, films, etc. 

Plastics containing Silicon. Mono-, di-, and tri-alkyl and aryl 
substitution products of silicon tetrachloride, prepared with the 
aid of Grignard reagents, are readily hydrolysed by water, and the 
corresponding hydroxides quickly undergo condensation in the 
presence of acids or alkalis giving open and closed chain products. 
The mono-hydroxy-compounds (silicols) thus give the simple 
oxides, SiR 3 -O- SiR 3 , only, but the diols, SiR 2 (OH) 2 , afford complex 
mixtures of both types, 

HO . SiR 2 - [O SiR 2 ] n O - SiR 2 OH SiR 2 < ; 

and the trihydroxides are rapidly converted into highly complex 
products of unknown structure (Kipping). 

The mixtures so obtained from the lower alkyl derivatives are 
oils (known as silicones), soluble in many organic liquids, and do not 
crystallise at polar temperatures ; they have characteristics different 
from those of mineral and vegetable oils, show very little change in 
viscosity with changes in temperature, and are now manufactured, 
mainly in the U.S.A., for various commercial purposes. 

When oxidised with air and a catalyst, or treated in various other 
ways, these oils, mainly open chain compounds, afford gelatinous or 
resinous plastics as the result of further condensation and of the 
displacement of alkyl groups by oxygen with the formation of cross- 
linked molecules. These products differ from the generality of 
plastics in being much more stable towards heat ; as they have 
exceptional electrical insulating properties, are very inert chemically 
and do not attack metals, they are of considerable importance, par- 
ticularly in the electrical industry. The more volatile substituted 
silicon chlorides, in the state of vapour or dissolved in an organic 
liquid, may be applied directly to glass, porcelain, etc., for the pro- 
duction of a water-repellant film ; the halide is decomposed by the 



964 PLASTICS AND RUBBER 

moisture on the article so treated and an adherent film of silicone is 
thus produced. 

The Manufacture of Plastic Materials. There are four main 
mechanical methods by which plastic articles may be manufactured ; 
they vary with the nature of the plastic and the shape of the article 
to be made. 

(1) Moulding. This is the chief method and employs mainly a 
phenol-formaldehyde plastic. A moulding powder is prepared by 
mixing a partly condensed (still thermoplastic) phenol -formaldehyde 
product with a filler (usually wood-flour), plasticiser, pigment, etc. 
This mixture is then placed in a mould and submitted to pressure 
and heat (up to 180 or so) whereon the thermosetting process 
(cure) occurs. The cure requires from 1 minute to 1 hour or more, 
according mainly to the thickness of the moulded article : the two 
halves of the mould are separated and the finished product ejected. 
This operation requires very heavy and expensive equipment. 

(2) Casting. This method is also largely used for phenol-formal- 
dehyde resins which, in the liquid (partially condensed) state are 
mixed with a plasticiser, poured into moulds and maintained at 
60-80 during several days until cured ; as a rule no filler is used. 
The moulds are often made of lead. 

(3) Injection Moulding. A granulated thermoplastic material is 
fed into a heated cylinder and forced into moulds (cooled if neces- 
sary). This is a very rapid method and is used largely for cellulose 
acetate and methyl methylacrylate plastics. 

(4) Extruding. A thermoplastic material, either alone or mixed 
with a suitable solvent, is heated and forced through a die by a screw ; 
rods, tubing, etc., are thus made and wire, etc., may be coated with 
plastic. 

Rubber 

India Rubber, Rubber, or Caoutchouc, is prepared from a watery 
emulsion, known as rubber latex, a product of many tropical and 
sub-tropical trees, such as the Euphorbiaceae, of which Hevea 
brasiliensis is the main species and the almost exclusive source of 
commercial natural rubber. Guttapercha and balata are closely 
related to rubber, but differ from it in physical properties. 

The latex is obtained by making incisions in the bark of the tree 
and collecting the ' milky ' liquid which exudes ; it consists mainly of 
rubber, 27-35%; fatty matter soluble in acetone,! -2-1 ?%; protein- 



PLASTICS AND RUBBER 965 

like substances, 1*5-2% ; water, and a very little mineral matter. 
Some samples also contain inositol (p. 798) and/or /-methylinositol 
and dimethylinositol. When it is treated with very dilute acetic 
acid, the latex coagulates and the precipitated rubber is then boiled 
with water, kneaded, and pressed into blocks or rolled into sheets ; 
the latter may be cured (rendered aseptic) by a smoking process. 

This crude material may be purified by extracting it with boiling 
acetone, to remove fats and resins, and then treating it with chloro- 
form or benzene ; the proteins are not dissolved and, from the 
decanted colloidal solution, the rubber may be precipitated by the 
addition of alcohol. The product still contains some protein 
matter, which may be removed by hydrolysis with cold methyl 
alcoholic potash, but the rubber cannot then be obtained completely 
free from alkali. 

According to Pummerer the preparation of ' pure ' rubber is 
best carried out as follows : Uncoagulated latex is stirred with 8% 
sodium hydroxide solution, in an atmosphere of nitrogen ; the 
liquid is then diluted with three times its volume of water, stirred 
at 50 during 8-10 hours, and then placed aside. The rubber 
separates at the surface as a cream, and, after having been treated 
in this way several times, it is free from protein. The cream is then 
diluted with water, stirred, separated, and left in a dialyser during 
several hours ; after coagulation with acetone or acetic acid it is 
extracted with acetone, to remove resins, dissolved in benzene and 
fractionally precipitated with a mixture of alcohol and acetone. 

Rubber thus purified is colourless, optically inactive, and has no 
definite melting-point ; it is ' soluble ' in benzene, chloroform, and 
carbon disulphide. Its remarkable elasticity under ordinary con- 
ditions is gradually lost with a rise or fall of temperature ; this 
behaviour seriously impaired its usefulness for most purposes, and 
the great importance of rubber at the present time is due to a dis- 
covery of Goodyear in 1839 ; namely, that if rubber is heated with 
white-lead and sulphur, elasticity is retained over a greater range of 
temperature than before and it is also less readily attacked by 
chemical reagents. Such vulcanised rubber is now manufactured 
by heating the natural material with sulphur (2-5-15%) under 
pressure, at about 130-155, during 6 to 12 hours ; by increasing 
the proportion of sulphur to 25-40%, ebonite and vulcanite are 
obtained, and coloured vulcanised products may be prepared by 
the incorporation of various substances, such as the sulphides of 



966 PLASTICS AND RUBBER 

antimony and mercury. Rubber may also be vulcanised by treating 
it (thin sheets or tubing) with a solution of sulphur monochloride 
in carbon disulphide, or by the successive action of sulphur dioxide 
and hydrogen sulphide (Peachey). The process of vulcanisation 
may be very much hastened and thus cheapened by the addition of 
certain accelerators, such as thiocarbanilide, but very little is known 
as to the chemical changes which result. 

Nowadays increasing quantities of rubber latex are concentrated 
by evaporation or centrifugion to save carriage, sterilised by the 
addition of ammonia and shipped to countries where it can be 
more efficiently treated ; the manufactured articles there produced 
are superior in quality to those made from sheets of imported 
rubber. 

Rubber has the empirical formula, C 5 H 8 , but its molecular 
formula is not known. It gives with hydrogen bromide a compound, 
(C 5 H 9 Br) n , and with bromine, (C 5 H 8 Br 2 ) n . Samples ' purified by 
ordinary methods give no appreciable depression of the freezing- 
point in benzene solution, but various specimens, obtained by 
Pummerer's process, gave values by Rast's method in camphor or 
benzylidenecamphor, and by Beckmann's method in menthol, 
corresponding with a molecular weight of 600-2400. 

When rubber is destructively distilled it yields a complex mixture 
of hydrocarbons, which contains isoprene, dipentene, and a sesqui- 
terpene, hevene ; isoprene at ordinary temperatures slowly poly- 
merises, giving a rubber-like product, as observed by Tilden. 

Harries treated rubber, dissolved in chloroform, with ozone and 
obtained an explosive oil, which gradually solidified in a vacuum 
to a glassy mass ; the molecular weight of this substance agreed 
with that of an ozonide, C 10 H 16 ,O 3 ,O 3 ; when decomposed with 
water this ozonide gave laevulic aldehyde and its peroxide. These 
facts accord with the view that the ozonide is derived from 1:5- 
dimethyl-k - 1 iS-cyclo-octadiene, 



H,C CH a 
3 -(f CH 



CH 3 -( CH CHa-OC 



"HC j>C 

H CH a 



CH, OHC CO-CH, 

H 2 0-CH 2 



but it seems to be more probable that the rubber molecule, as 
suggested by Pickles, is an open chain structure, composed of modi- 



PLASTICS AND RUBBER 967 

fied isoprene units, from which such an ozonide might well be 
formed : 

CH 2 - CH:C CH 2 CH 2 CH:C CH 2 CH 2 - CH:C - CH 2 

CH 3 CH 3 CH 3 

When rubber is heated with hydrogen at about 270 under high 
pressure, in the presence of platinum or palladium, it is converted 
into a hydrocarbon, named hydrocaoutchouc, (C 6 H 10 ) n , which is 
still colloidal and cannot be distilled in a vacuum. This compound 
is not acted on by bromine, concentrated nitric acid, or potassium 
permanganate in the cold, and thus behaves like a paraffin or a cycle- 
paraffin. It is slowly decomposed at about 350-400, giving a 
mixture of many olefmes, (C 5 H 10 ) n ; the most complex component 
of this mixture has a molecular formula of C 60 H 100 , or thereabouts, 
and the simplest component is ft-methylbutene, which, on oxidation, 
gives methylethyl ketone. The transformation of isoprene into 
rubber, of rubber into hydrocaoutchouc, and of the latter into 
j8-methylbutene, may be represented in the following manner 
(Staudinger, Ber. 1924, 1203) : 

CH 2 :CH C:CH 2 CH 2 .CH-C:CH 2 CH 2 :CH-C:CH 2 Isoprene 

CH 3 ins (^Ha I t 

- CH 2 -CH 2 C:CH CHjrCH2-C:CH CH a -CH 2 -C:CH Rubber 

CH 3 CH 3 CH 3 



CH 2 -CH 2 CH CH 2 CH 2 CH 2 CH-CHa CH-CH 2 CH-CH 2 Hydrocaoutchouc 

CH 3 CH 3 CH 3 



CH 3 -CH 2 -C:CH 2 CH 3 -CH 2 -C:CH 2 CH 3 -CH 2 -C:CH 2 0-Methylbutene 

CH 3 CH 3 CH 3 

It seems very probable, therefore, that rubber is a mixture of various 
compounds derived from isoprene, but no definite conclusion can 
yet be drawn as to the number of isoprene units which form the 
molecules ; as far as is known the latter are long open chain struc- 
tures, but if so, it would be difficult to account for the formation of 
the ozonide, C 10 H 16 ,O 3 ,O 3 , unless it is a dimeride of an ozonide, 
C 5 H 8 ,0 8 . 

Later investigations with certain synthetic rubbers showed that 
their behaviour towards ozone is similar to that of the natural 
product. Thus the ozonide of rubber from butadiene yields 

Org. 61 



968 PLASTICS AND RUBBER 

(succindialdehyde and) succinic acid, and that from dimethyl- 
butadiene rubber gives mainly acetony lace tone, while the ozonide 
of natural rubber gives laevulic aldehyde, as already stated : 

Butadiene rubber 

CH 2 -CH:CH-CH 2 CH 2 -CH:CH-CH 2 > COOH-CH 2 CH a -COOH 

Dimethylbutadiene rubber 

CH 2 -CMe:CMe-CH 2 CH 2 CMerCMe CH a > COMe CH a -CH a -COMe 

Natural rubber 

CH a -CH:CMe-CH 2 CH 2 CH:CMe CH 2 . COMe-CH 2 CH 2 -CHO 

These results seem to show that the natural and the synthetic 
products have much the same type of structure : on the other hand, 
isoprene rubber, destructively distilled, gives mixtures which differ 
from those obtained from natural rubber, since they contain satur- 
ated hydrocarbons. 

Synthetic Rubber 

Towards the close of the nineteenth century there were indications 
that the supply of rubber, at that time obtained almost entirely 
from the Amazon district, would not meet the ever-increasing 
demands, and there was therefore a probability that if a suitable 
method could be devised, synthetic rubber could be profitably 
manufactured. During the interval between the two great wars, 
however, owing to the extensive plantations which had been laid 
out in many tropical countries, there was more than enough natural 
rubber (about one million tons in 1932) to provide all the world's 
needs, and its price was so low that it would have been impossible 
for any synthetic product to compete with it. 

In spite of such economic considerations, however, much research 
had been done during this period both in Germany and elsewhere, 
partly because it was always possible that a more useful material 
even than natural rubber might be discovered, and indeed several 
processes were being worked for the manufacture of rubbers with 
special properties. Following the fall in 1941 of the chief rubber- 
growing countries, Malaya, the Dutch East Indies, etc., the more 
promising syntheses were put into very large-scale operation, mainly 
in the U.S.A. 

The first synthetic rubbers were obtained by the polymerisation 
of simple dienes (p. 962), such as butadiene and isoprene, but later 



PLASTICS AND RUBBER 969 

work has shown that better results are usually obtained by the co- 
polymerisation of mixtures of butadiene and various mono-olefinic 
compounds such as styrene. The more important products, their 
components and a few of their trade designations are shown below : 
they have a structure probably allied to that of natural rubber, 
contain double bonds and can be vulcanised. 

Butadiene-Styrene co-polymer Buna-S, Perbunan 

Butadiene-Acrylonitrile co-polymer Buna-N 

Butadiene-Trobutylene co -polymer Butyl rubber 

Chlorobutadiene polymer Duprene, Neoprene 

In the earlier processes polymerisation either in the liquid or 
vapour phase, or in solution, was effected with suitable catalysts 
such as sodium ; nowadays emulsion polymerisation is used in 
which the diene or a mixture of it with an olefine is emulsified in 
water with soap or other similar reagent and then heated at 40-60 
during 10-15 hours with hydrogen peroxide, ammonium per- 
sulphate or an organic peroxide or peracid, with the addition of a 
trace of carbon tetrachloride, sodium cyanide, etc. The product 
is a latex which resembles that of natural rubber and can be co- 
agulated in a similar manner. 

The various synthetic rubbers differ from one another and also 
from natural rubber* in many ways, and by suitable compounding a 
material having almost any desired character can be obtained. 

The preparation of two of the most important compounds used 
in the manufacture of synthetic rubbers, butadiene and chloroprene, 
is described below, together with interesting proposals for that 
of isoprene ; styrene has already been mentioned (p. 419) and 
acrylonitrile is prepared from cyanoethanol (p. 244). 

Butadiene, CH 2 :CH-CH:CH 2 , (b.p. -3), is formed in small 
proportions when a mixture of ethylene and acetylene is passed 
through a red-hot tube. It was at one time manufactured from 
butyl alcohol, obtained from starch (p. 119). This alcohol, with 
hydrogen chloride, gave butyl chloride which was subsequently 
chlorinated ; the mixture of dichlorides, which probably contained 
the compounds shown below, yielded crude butadiene when it was 
passed over heated soda-lime : 

(CH 3 .CH 2 .CHC1.CH 2 C1 

CH 3 -CH 2 .CH 2 .CH 2 C1 > JcH 8 .CHCi.CH 2 .CH 2 Cl 

tCH 2 Cl-CH 2 .CH a .CH 2 Cl 



970 PLASTICS AND RUBBER 

In the case of l:2-dichlorobutane, the formation of butadiene 
would also involve some isomeric change. 

Butadiene is now manufactured by three methods : (1) Aldol, 
from acetaldehyde, is converted into l:3-butylene glycol by 
catalytic reduction, and the latter, passed over heated lime, gives 
the diolefine, 

CH 3 -CH(OH)-CH 2 -CHO CHs-CH(OH)-CH 2 -CHa-OH > CHaiCH-CHiCHr 

(2) Acetylene is polymerised to vinylacetylene, by treatment 
with cuprous and ammonium chlorides, and by catalytic reduction 
this hydrocarbon is converted into butadiene, 

2C 2 H 2 * CH 2 :CH.C;CH > CH 2 :CH-CH:CH 2 . 

(3) Petroleum is cracked under such conditions that it yields 
directly 5-12% of butadiene, or the butane and butene, formed 
under the usual conditions, are employed. In the latter case the 
butane is dehydrogenated at 600 with a catalyst of aluminium and 
chromium oxides, and the butene thus formed is converted into 
butadiene with a similar catalyst at a slightly higher temperature. 
The butene from butane (and that obtained directly from petroleum) 
may also be converted into butadiene by combining it with chlorine 
and then heating the 2:3-dichlorobutane with barium chloride. 

2-Chlorobutadiene, CH 2 :CH CC1:CH 2 (chloroprene), is obtained 
on the large scale by treating vinylacetylene with hydrochloric acid 
under particular conditions, 

CH C . CH:CH 2 -hHCl = CH 2 :CC1 - CH:CH 2 . 

Isoprene, CH 2 :CMe CH:CH 2 (2-methylbutadiene) y boih at 33-34 
and is formed by strongly heating turpentine or rubber, or by 
passing dipentene (p. 913) over heated platinum. It may be manu- 
factured from the crude amyl alcohol obtained from fusel oil 
(p. 120), by a method analogous to that by which butadiene is 
obtained from butyl alcohol ; the amyl chlorides, produced by 
treating the alcohols with hydrogen chloride, are chlorinated and 
the mixture of dichlorides is passed over heated soda-lime. 

Isoprene may also be prepared in various other ways : 
(1) />-Cresol is reduced with hydrogen in the presence of nickel, 
and the 4-methylcyclohexanol so obtained is oxidised to methyl- 
cyclohexanone, and then to fi-methyladipic acid, 



PLASTICS AND RUBBER 971 





- I I 

H 2 C. COOH 
COOH 

The diamide of this acid with sodium hypochlorite gives 2-methyl- 
l:4-dtaminobutane, and the quaternary hydroxide, obtained from 
this base by exhaustive methylation, is then destructively distilled : 

CH 3 CH CH a NH a CH 3 - CH CH 2 NMe 3 - OH CH 3 - C:CH a 

CH.-CHa.NH, ~~" CH a -CH 2 .NMe 3 -OH """" CH:CH a 

(2) o-Cresol is reduced catalytically to 2-methylcydohexanol ; 
this product, passed over heated alumina, yields k-\-tetrahydro- 
toluene (methylryc/ohexene), which is decomposed at a high temper- 
ature, giving isoprene and ethylene, 




CH 3 

HC' 



O 



CH, 



H 2 



As the last two methods start from materials which are not 
abundant, it seems unlikely that they could be used successfully in 
the large scale operations for which they were devised ; the manu- 
facture of a synthetic rubber from isoprene has therefore been 
abandoned. 



CHAPTER 58 

CAROTENOIDS, PYRONES, ANTHOCYANINS, 
AND DEPSIDES 

Carotenoids 

THE term carotenoid (or lipochrome) is applied to certain yellow, 
orange, red or brown pigments of a particular type which occur 
widely distributed in the animal and vegetable kingdoms. Such com- 
pounds are found in all kinds of plants, and, in those which also 
contain chlorophyll, are intimately associated with that most 
important substance ; in others, such as the fungi, in which chloro- 
phyll is absent, the carotenoids are mainly responsible for the 
colour. In the animal kingdom the yellow colour of many fats 
butter, for example is due to their presence. 

Mainly from the results of the work of Kuhn, Karrer, and their 
collaborators, it has been shown that all carotenoids possess in their 
molecules numerous (7-11) conjugated double linkages, to which they 
owe their colour. Some of the carotenoids are hydrocarbons, some 
are di- or poly-hydroxy-compounds, and some are carboxylic acids. 

Lycopene, C 40 H 56 , forms carmine prisms, melting at 175, and 
was first isolated by Willstatter from tomatoes, which owe their 
colour to its presence ; it also occurs in bitter-sweet and rose hips 
and many other plants. On exposure to dry oxygen it rapidly 
absorbs 32-5% of its weight (11 atoms) of this gas and becomes 
colourless. When a solution of lycopene in cyclohexane is treated 
with hydrogen in the presence of a platinum catalyst, each molecule 
of the hydrocarbon combines with thirteen molecules of hydrogen, 
and a colourless paraffin, perky drolycopene* C 40 H 82 , is produced. 
This fact proves that lycopene is an open chain polyene, in the 
molecule of which there are thirteen double bindings. 

On ozonolysis lycopene (1 mol.) gives acetaldehyde, acetic acid, 
acetone (at least 1*6 mol.), and laevulic acid, whereas with chromic 
acid it gives acetic acid (6 mol.). These products show that the 
molecule contains the following groups : 

2Me 2 C=, =CMe CH 2 CH 2 CH=, 6 CMe= 

1 The prefix ' perhydro * denotes that all the double (or treble) bonds in 
the lycopene molecule have been reduced. 

972 



CAROTENOIDS, PYRONES, ANTHOCYANINS, DEPSIDES 973 

Cautious oxidation with chromic acid gives 2-methyl-A-2-hepten- 
6-one (1 mol.) and lycopenal, C 32 H 42 O (1 mol.), and the latter is further 
broken down into methylheptenone (1 mol.) and bixin dialdehyde, 
C 2 4H 28 O 2 (1 mol.) ; it is clear, therefore, that the two molecules of 
methylheptenone have originated from the ends of the lycopene chain 
and that of bixin dialdehyde from the middle portion, thus : 

8 24 8 



Now the formation of each methylheptenone molecule involves 
Acetone 



Methyl- 
hep tenone 



Laevulic 
Acid 




Methyl- 
heptenone 



Acetone 



Lycopene 



Dihydrophytyl 
bromide 



Perhydro- 
lycopcne 



974 CAROTENOIDS, PYRONES, 

the loss of one CMe= group and two double bonds from the 
lycopene molecule, so that the central portion (C 24 ) must contain 
four CMe= groups and an uninterrupted series of conjugated 
linkages to account for the nine remaining double bonds. The 
application of the isoprene rule then leads to the symmetrical 
formula for lycopene (p. 973). 

The absorption spectrum and other physical properties of 
lycopene, when compared with those of synthetic polyenes in 
general, accord with the given structure, which is now fully estab- 
lished. 

A hydrocarbon, b.p. 240 (0-3 mm.), probably identical with 
perhydrolycopene, has been synthesised from phytol (p. 1083), the 
structure of which has been established by synthesis : Phytol, 
which occurs in chlorophyll, is reduced catalytically to dihydro- 
phytol, which is converted into its bromide with phosphorus penta- 
bromide ; bromine is then eliminated from two molecules of the 
bromide by the Wurtz-Fittig reaction, yielding a hydrocarbon, 
C 40 H 82 , as indicated (p. 973). 

It should be noted that the molecule of lycopene is built up 
from eight isoprene residues which form two identical groups, 
C 2 oH 28 , united together symmetrically, although lycopene, unlike 
terpenes, could not be formed by the mere polymerisation of 
isoprene. 

Burin, C 25 H 30 O 4 , occurs in Bixa orellana and crystallises in 
violet needles, m.p. 198 ; on hydrolysis it gives methyl alcohol and 
norbtxin (footnote, p. 926), C 24 H 28 O 4 , a dibasic acid of which there- 
fore bixin is the monomethyl ester. On catalytic hydrogenation 
bixin unites with nine molecules of hydrogen and the perhydrobixin 
which is thus formed gives perhydronorbixtn on hydrolysis. 

Perhydro#0rbixin has been synthesised as follows : Trimethylene 
dibromide is condensed with diethyl sodiomethylmalonate and the 
product is converted into the diethyl ester of aa'-dimethylpimelic 
acid, in the usual manner ; this ester is then reduced to the alcohol 
which is treated with phosphorus tribromide. From the resulting 
dibromide, (i), with the aid of diethyl malonate, the dibasic acid, 
(n), is prepared and converted into its monoethyl ester, (in) ; the 
electrolysis of the potassium salt of this acid gives perhydrowor- 
bixin diethyl ester, (iv), which, although it contains four asym- 
metric groups, is identical with that prepared from natural 
bixin. 



ANTHOCYANINS, AND DEPSIDES 975 



BrH 2 C 

Jr 




11 HOOC \S v \s v cOOH 



I** ,x"v y~v x"v x"v >x^. - ^ ^-^ ^. ^ ^--^ ^-^ ^L.UUJit 




IV 



This synthesis not only proves the constitution of bixin but also 
confirms that of lycopene, as the bixin dialdehyde obtained from 
the latter can be oxidised to worbixin. 

A very interesting paraffin, C^l:!, go, has been synthesised from 
the potassium salt of perhydrobixin by the following reactions : 
COOMe COOMe 

C 22 H 44 COOMe C 44 H 88 COOMe C(OH)Me a CHMe a 

COOK ! C 22 H 44 2 COOH 3 C 44 H 88 4 C 44 H 88 6 C 44 H 88 

COOK " C 22 H 41 * COOH ' C 44 H 88 * C 44 H 88 ' C 44 H 88 

C 22 H 44 COOMe C 44 H 88 COOMe C(OH)Me a CHMe a 

COOMe COOMe 

1 and 3. Electrolysis (Kolbe reaction). 2. Partial hydrolysis. 4. MeMgl. 5. HI. 

Crocetin, C 2 oH 24 O 4 , is found in saffron, in the form of its digentio- 
bioside. Its constitution has been established by the conversion of 
perhydroworbixin into perhydrocrocetin by a series of well-known 
reactions. A carboxylic acid, R-CH 2 -COOH, is converted into 
the a-hydroxy-acid, which is esterified (methylated) with diazo- 
methane ; the resulting methyl ester is then treated with an excess 
of methyl magnesium iodide and the tertiary alcohol so formed is 
oxidised (with lead tetra-acetate) first to the next lower aldehyde 
and then to the corresponding acid : 

R-CH a -COOH * R-CHBr-COOH - > R-CH(OH)-COOH * 
R-CH(OH)- COOMe - > R-CH(OH)-C(OH)Me 2 - * 
R.CHO - - R-COOH. 



976 CAROTENOIDS, PYRONES, 

By the application of this series of reactions, and then repeating 
them with the product, the molecule of perhydroworbixin, C 2 4H 48 O 4 , 
loses four CH 2 groups (two at each end of the structure) and 
gives perhydrocrocetin, C 20 H 40 O 4 . 

When perhydrocrocetin, (i), is submitted to the same series of 
reactions (shown above), the product is a diketone, (n), the pro- 
duction of which, in the place of a dialdehyde, obviously proves 
the presence of methyl (or other alkyl) groups at these points in 
the chain : 



COOH 
HOOC' 





il 



Carotene, C 40 H 56 , usually occurs with chlorophyll, and also gives 
rise to the colour of many yellow flowers, roots (such as carrots), 
and fats (such as butter). Three isomeric carotenes have been 
isolated, and they are most easily separated by the very important 
method of chromatographic analysis (p. 980). a-Carotene, m.p. 184, 
is more soluble in petroleum than the /J-isomeride ; it is highly 
dextrorotatory and shows a very high rotatory dispersion (p. 743), 
M0563+ 284 Meo75+458. j8-Carotene, m.p. 187, and y-caro- 
tene, m.p. 178, are optically inactive. The proportion of the forms 
varies in different plants. 

The a- and /?-isomerides are closely related, and the structural 
formulae assigned to them (p. 977) are based on the following 
results, obtained mainly from an investigation of the mixture : 

On exposure to dry oxygen, carotene absorbs about 35% of its 
weight (12 atoms) of the gas, with the emission of a distinct odour 
of violets (p. 952). When reduced with hydrogen in the presence of 
a platinum catalyst, each molecule combines with eleven molecules 
of hydrogen, giving a colourless saturated hydrocarbon, perhydro- 
carotene, C 40 H 78 ; from this fact it is concluded that the molecule 
of carotene contains eleven olefmic bindings, and two closed chains. 
The ozonolysis of (jS-)carotene gives geronic acid (p. 952), the yield 



ANTHOCYANINS, AND DEPSIDES 



977 



of which corresponds with that calculated for the oxidation of two 
j8-ionone rings. Oxidation with permanganate under various con- 
ditions gives acetic, oxalic, aa-dimethylsuccinic, and aa-dimethyl- 
glutaric acids, together with j8-ionone (p. 952). 

From these results, the structure of ]8-carotene is represented by 
the symmetrical formula shown below, which is closely related to 
that of lycopene, and indeed may be derived from the latter by 
ring-closure of the two ends of the chain. The molecule of a-caro- 
tene, which is dissymmetric, differs from that of the j8-isomeride 
only as regards the structure of that ionone ring which gives iso- 
geronic acid on oxidation. y-Carotene is monocyclic, and, struc- 
turally, consists of half a molecule of j8-carotene joined to half a 
molecule of lycopene. 

COOH 




Jiogeronic acid 



HOOC-\ X 

-O 

Geronic acid 



t 




a-Carotene 



0-Ionone 



0-Carotene 



The given structures have been fully confirmed by a series of 
brilliant investigations by Kuhn and his collaborators. 



978 CAROTENOIDS, PYRONES, 

Many of the carotenoids are converted into an equilibrium 
mixture of isomerides when their solutions in, for example, benzene 
or petroleum ether are boiled during 30-60 minutes ; a similar 
isomerisation occurs under the influence of catalysts such as iodine, 
or heat. During these changes decompositions also take place. 
Such isomerism is probably due to changes of configuration about 
one or more of the double bonds. 

Vitamin A, C 2 oH 30 O, occurs in the free state, and as esters, in the 
liver oils of many fish, notably the cod and halibut, and also in 
whale oil ; it may be prepared by removing the hydrolysable matter 
and sterols from the liver extracts, followed by a chromatographic 
separation or distillation in a molecular still under 0-00001 mm. 
pressure. It has been obtained in crystals, m.p. 63-64, from ethyl 
formate at a low temperature. Both a- and j3-carotene yield vitamin 
A in the animal body, as does indeed any carotenoid which contains 
a j8-ionone ring and five conjugated double bonds. With a sol- 
ution of antimony trichloride in dry chloroform, vitamin A gives 
a deep blue colour (Carr-Price reaction, p. 653), which has been 
much used for estimating the vitamin ; carotenoids give a similar 
colour. 

When submitted to ozonolysis, vitamin A yields geronic acid in 
the amount required by one j8-ionone ring per molecule and on 
catalytic hydrogenation it absorbs five molecules of hydrogen. 
From such facts, an examination of physical data, and relationship 
to the carotenes, the given structure of the vitamin was proved 
(Karrer) : 



,CH 2 -OH 





Vitamin A 



:H 2 -OH HO-H 2 C: 




ANTHOCYANINS, AND DEPSIDES 979 

In the presence of hydrochloric acid and alcohol, vitamin A 
(concentrate) is transformed into a cyclic derivative which, on 
dehydrogenation with selenium, gives l:6-dimethylnaphthalene ; 
these changes are accounted for by Karrer's formula from which 
such a substance could be derived in either (or both) of the ways 
indicated (p. 978). 

Vitamin A, identical in all respects with the natural product, has 
been synthesised as follows (Isler et al., Helv., 1947, 30, 1911) : 

(1) j3-Ionone is treated with ethyl chloroacetate and sodium 
methoxide at 60, the resulting glycidic ester, (i), is hydrolysed, 
and the acid is heated with copper powder under reduced pressure ; 
the product is an aldehyde, (li), during the formation of which the 
ethylenic linkage migrates and occupies the aj8-position to the 
aldehyde group : 



COOEt 





ii 



(2) Acetylene is condensed with methylvinyl ketone in liquid 
ammonia solution in the presence of sodium, and the product of 
hydrolysis, the tertiary alcohol, (in), is isomerised with sulphuric 
acid (p. 942), and thus converted into (iv), which, treated with an 
excess of ethyl magnesium bromide gives (v) : 




Vv 




CH 2 -OH - BrM g ,v Jx CH 2 -OMgBr 



III IV V 

(3) The aldehyde, (n), reacts normally with (v), and in the 
product of hydrolysis, (vi), the acetylenic link is then partially 
reduced to an olefinic bond ; the acetyl derivative, (vn), 1 heated 
with iodine in petrol solution is converted into the acetate of vitamin 
A, from which, after hydrolysis, the pure crystalline vitamin is 
isolated with the aid of its crystalline /?-naphthoate. 

1 A CHj-OH group is much more easily acetylated than a >COH 
group. 



980 CAROTENOIDS, PYRONES, 




VI VII 

Vitamin A 2 occurs associated with vitamin A in fresh-water fish : 
its structure only differs from Vitamin A in that it has another 
conjugated double bond in the ring. 

Chromatographic Analysis. When a solution of an organic solid 
is filtered through a tightly packed column of a suitable absorbent 
such as alumina, calcium carbonate or lime, the solute is often 
deposited on the absorbent in a particular layer or zone (Tswett) : 
the location of this zone depends upon the nature of the solute and 
that of the solvent and it may be made to travel gradually down the 
column by successive washings with the same (or a different) solvent. 
If now a mixture of two or more solutes in a suitable solvent (often 
benzene or petroleum ether) is submitted to the same process, the 
solutes are deposited in bands which may be further separated from 
one another by suitable washing (development). In the case of 
differently coloured solutes the bands may be cut off and the 
separated solutes extracted therefrom ; such a process has proved 
invaluable in the separation of carotenoids (p. 976), chlorophylls 
(p. 647), and other pigments from one another (chromatographic 
analysis). 

With colourless compounds a separation occurs in the same way, 
but as it is impossible to see the limits of the bands, various methods 
are used to determine their boundaries. Thus various colourless 
compounds may exhibit different fluorescent effects in ultra-violet 
light ; or the whole column may be extruded from the tube and 
painted longitudinally with some indicator which reacts differently 
with the contents of the various zones. 

Diphenylpolyenes 

Some most interesting diphenylpolyenes, the molecules of which 
contain several conjugated systems of carbon atoms, have been 
prepared by Kuhn, R., and his collaborators (.7. 1938, 605), princip- 
ally in order to compare their behaviour with that of the carotenoids. 



ANTHOCYANINS, AND DEPSIDES 981 

The molecules of these compounds contain two phenyl groups each 
of which is combined with a terminal carbon atom of the open chain ; 
unlike the di-olefines, butadiene, isoprene, etc., they do not poly- 
merise readily, so that they are more suitable than such compounds 
for the object in view. 

1 :6-Diphenylhexatriene,C 6 H 5 - CH:CH - CH:CH - CH:CH - C 6 H 5 , 
has been prepared in many different ways ; it can be obtained from 
cinnamic aldehyde, which on reduction is converted into hydro- 
cinnamoin, 

C 6 H 5 - CH:CH - CH(OH) - CH(OH) - CHrCH - C 6 H 5 , 

just as benzaldehyde is transformed into hydrobenzoin (p. 501) ; 
this dihydroxy-compound is converted into diphenylhexatriene 
when its suspension in ether is treated with phosphorus di -iodide, 
as the organic di-iodide which is probably formed, spontaneously 
loses iodine. In a similar way, 

Ph CHrCH - CH(OH) - CH:CH - CH(OH) - CHrCH - Ph, 

prepared from acetylene dimagnesium bromide and cinnamic 
aldehyde, followed by a partial reduction of the acetylenic linkage, 
gives diphenyloctatetrene. 

An important general method for the preparation of polyenes is, 
by the condensation of aromatic aldehydes (2 mol.) with a dicarb- 
oxylic acid (1 mol.) in the presence of acetic anhydride and litharge, 
at temperatures above about 140 ; in this reaction two molecules 
of carbon dioxide, as well as 2H 2 O, are eliminated : 

C 6 H 5 - CH:CH - CHO H 2 C CH 2 OCH CHrCH - C 6 H 6 

COOH COOH 

Instead of cinnamic aldehyde, its condensation product with 
acetaldehyde, C 6 H 5 - CHrCH CHrCH CHO or crotonaldehyde, 
C 6 H 5 - CHrCH- CHrCH CHrCH CHO, may be employed; the 
former, with succinic acid, gives C 6 H 5 -[CH:CH] 6 -C 6 H 5 , and the 
latter, C 6 H 5 -[CH:CH] 8 .C 6 H 5 (l:\b-diphenylhexadecaoctene) ; other 
dicarboxylic acids, such as dihydromuconic acid (p. 814), may also 
be used instead of succinic acid, and by this method compounds, 
Ph-(CH:CH) n -Ph, in which n = 1 to 8 were obtained, but the 
reaction cannot be used for the higher analogues. 



982 CAROTENOIDS, PYRONES, 

Some of the latter have been prepared as follows : Unsaturated 
aromatic aldehydes such as those mentioned above are converted 
into thio -aldehydes with the aid of hydrogen sulphide, and the 
products are heated with copper, 

2Ph-(CH:CH) n .CHS > Ph.(CH:CH) 2n+1 -Ph ; 

in this way compounds in which n = 5 and 7 were prepared. 

It is noteworthy that in such syntheses the resulting diphenyl- 
polyene is only obtained in one form, although theoretically manj 
might be expected, owing to the possibilities of os-raw$-isomerism ; 
l:4-diphenylbutadiene, prepared by various other methods, is 
known in the three forms predicted by theory, but of the six possible 
stereoisomerides of diphenylhexatriene, only one is obtained by 
the above general methods and this has been shown by X-ray 
analysis to be the all trans-compound. 

Diphenylethylene or stilbene is colourless, and l:4-diphenyl- 
butadiene is only faintly yellow, but diphenylhexatriene is distinctly 
yellow, and the higher diphenylpolyenes are intensely coloured, yellow, 
orange, or copper-red compounds, in which respect they resemble 
the carotenoids ; 1 : 22-diphenyldocosaundecene, Ph - (CH:CH) n Ph, 
however, is violet-black (m.p. 318) and 1 :30-diphenyltriaconta- 
pentadecene, Ph-(CH:CH) 15 -Ph, is greenish-black. The poly- 
enes dissolve in concentrated sulphuric acid, giving solutions the 
colours of which pass from yellow to blue as the number of olefinic 
bindings in the molecule increases ; the more complex carotenoids 
also give blue colourations. 

On reduction with sodium- or aluminium-amalgam, the diphenyl* 
polyenes behave in a very remarkable manner ; a hydrogen atom i& 
added at each end of the chain, whereby both the C 6 H 5 -CH:CH 
groups become C 6 H 5 -CH 2 CH:, so that not only 1:4- (p. 813), 
but 1:6-, 1:8-, and l:10-addition may take place in a complex con- 
jugated system. The dibenzylpolyenes thus obtained are colourless 
and, unlike the diphenyl derivatives, readily undergo atmospheric 
oxidation, especially when they are slightly impure ; when sub- 
mitted to ozonolysis they give phenylacetic acid, together with a 
little phenylacetaldehyde, and the yield of the former alone is more 
than 75% of that theoretically possible on the assumption that the 
two hydrogen atoms are added at the ends of the chain only ; in 
the presence of a catalyst the dibenzylpolyenes are completely 
reduced by hydrogen to the saturated hydrocarbons. 



ANTHOCYANINS, AND DEPSIDES 983 

On reduction with molecular, instead of nascent, hydrogen, with 
the aid of a palladium catalyst, the diphenylpolyenes behave quite 
differently ; some of their molecules undergo complete reduction, 
according to the quantity of hydrogen absorbed, whilst the others 
are unchanged. 

The addition of bromine to the diphenylpolyenes has not been 
fully investigated, but seems to take a different course from that 
of nascent hydrogen ; that is to say, two bromine atoms do not 
combine with the terminal C 6 H 5 -CH:CH groups only. 

The diphenylpolyenes are oxidised by permanganate, but appar- 
ently less readily than the simple olefines ; diphenylhexatriene, 
one of the more stable of these compounds, in acetone solution, is 
not attacked by permanganate at ordinary temperatures until after 
the lapse of some forty minutes. 

Another very interesting reaction of the diphenylpolyenes is 
described later (p. 1027). 

Pyrones 

The term pyran is applied to the unknown unsaturated closed 
chains represented below, and the pyranose sugars are derived from 
the corresponding saturated structure (p. 874). The unsaturated 
closed chain compounds related to the pyrans are named a-pyrone 
and y-pyrone respectively : 

?Y H f 'V 

.^H, HCji^H HC{i 

a-Pyran y-Pyran a-Pyrone y-Pyrone 

Many derivatives of a- and y-pyrone occur in nature, and many 
have also been prepared synthetically ; such compounds, although 
containing olefinic bindings, do not behave like olefines, and do 
not react with hydroxylamine and other ketonic reagents. It is 
clear from its structure that a-pyrone is an unsaturated lactone and 
in the y-isomeride the carbonyl group is conjugated with the cyclic 
oxygen atom ; both substances, therefore, behave like lactones 
rather than like ketones. 

Both a- and y-pyrone derivatives give with ammonia the cor- 

Org. 62 



984 CAROTENOIDS, PYRONES, 

responding derivatives of a hydroxypyridine (or of its tautomeride, 
pyridone) ; coumalic acid, for example, gives 6-hydroxynicotinic acid, 



x H H 

^ N x-^ HC v N ^* OH 

H 



and 2:6-dimethyl-'y-pyrone gives 4-hydroxylutidine (p. 985). 

a-Pyrone-5-carboxylic acid (coumalic acid) is formed by the action 
of concentrated sulphuric acid on malic acid, possibly with the inter- 
mediate production of hydroxymethyleneacetic acid : 



CH(OH).COOH CH.QH 

CHvCOOH CH-COOH 



SH- 
. 

>4 



HOOOHC 

II I II I 

HC^ COOH HC TO 

OH O^ 

It melts at 206, gives yellow salts with alkalis, and when heated 
alone is converted into a-pyrone (coumaliri) and carbon dioxide. 
6-Phenyl-a-pyrone occurs in coto bark. 

2:6-Dimethyl-y-pyrone can be obtained by treating the copper 
derivative of ethyl acetoacetate with carbonyl chloride and hydro- 
lysing the product with sulphuric acid ; the acid thus formed readily 
loses carbon dioxide, giving diacetylacetone, which, probably in a 
di-enolic form, then loses the elements of water : 

COClj O Q 

^,C*^ MX* XCX , 

EtOOCCHa CH 2 COOE^ fitOOCHC CHCOOEt HC 



-CH 2 OVCOOEt fitOOC-HCCH-COOEt HC 
II -* | | -> H 

Me-CO CO'Me Me-OC CO-Me Me-C CMe 

Dimethylpyrone can also be obtained from dehydracetic add, 
C 8 H 8 O 4 , which is produced, together with other compounds, when 
the vapour of ethyl acetoacetate is passed through a suitably heated 
iron tube. This so-called ' acid/ which has probably the given 



ANTHOCYANINS, AND DEPSIDES 985 

structure, is decomposed by hydriodic acid, with the loss of carbon 
dioxide and the formation of diacetylacetone, which then gives 
dimethylpyrone : 

O O 

-C^ H 2 C' ^CH* 

3 CH 3 -OC CO-CH 3 



Dimethylpyrone (m.p. 132), as shown by Collie and Tickle (J. 
1899, 710), combines directly with mineral and with organic acids, 
giving crystalline salts, such as the hydrochloride, C 7 H 8 O 2 ,HC1, and 
the oxalate, (C 7 H 8 O 2 ) 2 ,C 2 H 2 O 4 ; these salts are partially, but not 
completely, hydrolysed in aqueous solution, as shown by cryoscopic 
and conductivity measurements. 

From time to time various formulae have been assigned to the 
cation of these salts ; that shown, (i), is supported by the fact that 
the methiodide y C 7 H 8 O 2 , Mel, corresponding with the hydro- 
chloride, is transformed into methoxylutidine, (n), by treatment with 
ammonium carbonate in the cold : 

OH 9Me 

[tf 
CH 3 - 



II 



The ring common to such (symmetrical) compounds is possibly a 
mesomeric form of two identical contributors as suggested for 
benzene. 

Other oxonium derivatives are known, such as the compound 
Me 2 O,HCl (formed from dimethyl ether and hydrogen chloride), 
and possibly the Grignard reagents. 

y-Pyrone-2:6-dicarboxylic acid (chelidonic acid) occurs in 
Chelidontum maius. It is obtained from diethyl acetonedioxalatc, 
which is prepared by the condensation of acetone with diethyl 
oxalate in the presence of sodium ethoxide ; when this ester is 
heated with hydrochloric acid, it is hydrolysed and also loses the 
elements of water : 



986 



CAROTENOIDS, PYRONES, 
O O 



I 
EtOOC-OC 



[ ' -> H H N H 

COOEt EtOOC-C CCOOEt 
HO 



OH 



HC" 
HOOC-C 



CH 
C-COOH 



Chelidonic acid gives acetonediacetic acid and pimelic acid on 
reduction, and is decomposed by hot alkalis giving oxalic acid and 
acetone. When heated alone it loses carbon dioxide, giving first, 
y-pyrone-2-carboxylic acid (comanic acid), and then y-pyrone 
(m.p. 32, b.p. 215). 

$-Hydroxy-y-pyrone-2\(>-dicarboxylic acid, or meconic acid, occurs 
in opium (p. 610). 

Benzopy rones are formed, theoretically, by the condensation of 
the benzene and the pyrone nuclei. In this way a-pyrone gives rise 
to the coumarins (p. 709) and the less important wocoumarins. 





Chromone or /;ii/:,o-y-/vf'w/'. is derived from y-pyrone. It has 
been synthesised as follows : o-Hydroxyacetophenone, 1 (i), is con- 
densed with diethyl oxalate in the presence of sodium, and the 
product, (n), is treated with alcoholic hydrochloric acid ; the 
chromonecarboxylic acid, (iv), which is thus formed (from in) gives 
chromone, (v), when it is heated : 




CO-CHj 



OEt 

io. 



COOEt 




COOEt 



1 Ethyl sodioacetoacetate is condensed with o-nitrobenzoyl chloride, 
and the product, NO 2 -C 6 H 4 .CO-CH(COOEt).CO-CH3, is hydrolysed: 
the resulting o-nitroacetophenone is converted into o-hydrpxyacetophenone 
by the usual method. o-Hydroxyacetophenone is also obtained from phenyl 
acetate by the Fries reaction (p. 845). 



ANTHOCYANINS, AND DEPSIDES 
<^ 



987 




in 



Xanthone, dibenzo-y-pyrone, is produced when oo'-diamino- 
benzophenone is diazotised and the solution of the diazonium 
salt is heated, as the 00'-dihydroxybenzophenone, which is first 
formed, loses the elements of water ; it is also produced when a 
mixture of phenol and salicylic acid is heated with concentrated 
sulphuric acid. It crystallises in colourless needles, melting at 173. 

One of its dihydroxy-derivatives, euxanthone, occurs as a glycoside, 
euxanthic acid, the , i ::,:: salt of which is a yellow pigment 
(piuri, Indian yellow), deposited from the urine of oxen fed on 
mango leaves. 



HO 



Flavone (2-phenylchromone) was first obtained synthetically by 
Kostanecki. o-Hydroxyacetophenone is condensed with benz- 
aldehyde in the presence of alcoholic potash, and the product, 
benzylidene-o-hydroxyacetophenone, is converted into its acetyl 
derivative ; when the latter is brominated and the dibromo- 
derivative is treated with alkali, flavone is produced : 



CH 







Flavone melts at 97 and occurs on the stalks and leaves of primula. 



988 



CAROTENOIDS, PYRONES, 



Anthoxanthidins and Anthoxanthins 

The anthoxanthidins are pigments derived from flavone, and 
many of them occur in plants, usually as their glycosides, the 
anthoxanthins : chrysin, 5:7-dihydroxyflavone, in the buds of the 
poplar ; luteolin, 5:7:y'A'-tetrahydroxyflavone, in mignonette ; and 
quercetin, 3:5:7:3' :4' -pentahydroxyflavone, as its rhamnoside, quer- 
citrin, in the blossom of the horse-chestnut. 

Many such substances were first synthesised by Kostanecki. 

Chrysin, for example, is formed by heating with hydriodic acid 
the product of the condensation of phloroacetophenonetrimethyl 
ether with ethyl benzoate in the presence of sodium ethoxide : 



CH 3 O 




'CH 3 

EtOOCC 6 H 6 
OCH 3 





CH 3 O 



C 6 H ft 



Anthoxanthidins have also been synthesised by Robinson and his 
co-workers by heating phloroacetophenone (2'A:6-trihydroxyphenyl- 
methyl ketone), or one of its derivatives, with a mixture of the 
sodium salt and the anhydride of an aromatic acid. Thus phloro- 
acetophenone, sodium benzoate, and benzoic anhydride yield a 
product which on hydrolysis gives chrysin ; similarly a>-methoxy- 
phloroacetophenone and the sodium salt and anhydride of veratric 
acid (p. 612) give a product which, when demethylated, yields 
quercetin (J. 1926, 2334), 




OH Q 
s?^ ^C 




ANTHOCYANINS, AND DEPSIDES 989 

Many of the anthoxanthidins are decomposed when air is passed 
through their alkaline solutions, the pyrone nucleus undergoing 
disintegration ; a substituted benzoic acid and phloroglucinol * are 
thus obtained, and from the known structures of the products that 
of the anthoxanthidin may often be determined. 

Anthocyanidins and Anthocyanins 

The many beautiful colours of flowers and fruits are due mainly 
to a group of pigments known as the anthocyanins. These com- 
pounds combine phenolic and basic properties and form both alkali 
salts and well-crystallised salts with acids ; the latter are usually 
employed in their isolation. The free anthocyanins are violet, their 
alkali salts blue, and their salts with acids, red. A single anthocyanin, 
therefore, may often give rise to very different colours, which 
depend on its state of combination ; the colour of the blue corn- 
flower, for example, is due to a metallic salt of cyanin, but, in the 
form of its salts with acids, cyanin gives rise to the colour of the red 
rose and geranium. The colour, however, is not entirely dependent 
on the degree of acidity of the cell-sap ; it may also be affected by 
the presence of colloids, other pigments, and the physical condition 
of the anthocyanin. 

The anthocyanins are hydrolysed by hydrochloric acid, giving a 
sugar and a salt of an anthocyanidin ; cyanin, for example, yields 
glucose, and the anthocyanidin salt, cyanidin chloride. When they are 
further broken down by hot alkali they give phloroglucinol or one of 
its methyl ethers, and in addition a phenolic acid, or a methyl ether 
of a phenolic acid, which is characteristic of the particular antho- 
cyanidin : pelargoniditi) for example, gives />-hydroxybenzoic acid, 
cyanidin gives protocatechuic acid, and delphinidin gives gallic acid. 

Mainly as a result of the researches of \\ ."!-i <.;:<:, it has been 
found that the anthocyanidin salts are substituted hydroxybenzo- 
pyrylium or hydroxyflavylium compounds of the general formula, 



HO 



1 Phloroglucinolcarboxylic acid, the formation of which might be expected, 
is decomposed in boiling aqueous solution, carbon dioxide being eliminated. 





990 



CAROTENOIDS, PYRONES, 



in which the group R is an aromatic residue, containing one or 
more hydroxyl or/and methoxyl radicals, as shown below, and X 
is an acidic radical (compare p. 985) : 



Pelargonidin, R is 



Cyanidin* R is 




OH 



Delphinidin, R is 



Malvidin 
(synngidin), R is 




Almost all the anthocyanidins are derived from pelargonidin, 
cyanidin, or delphinidin, by the substitution of methyl radicals for 
hydroxylic hydrogen atoms. 

The anthocyanidin salts were first synthesised by long and 
troublesome methods, but Robinson and his collaborators worked 
out simpler processes of which the synthesis of cyanidin chloride 
(J. 1928, 1526) may be taken as an example. PlilorouliKriii.iKlcliulc, 
prepared from phloroglucinol by Gattermann's reaction (p. 502), is 
first benzoylated by the Schotten-Baumann method, and the 
product, 2-benzoyloxy-4:6-dihydroxybenzaldehyde 9 (i), is condensed 
with wil'A-triacetoxyacetophenone, (n) (p 993), in the presence of 
hydrogen chloride in ethyl acetate solution ; 5-benzoylcyantdin 
chloride , (in), is thus produced, as the acetyl groups are eliminated 
during the reaction : 



0-CO-Ph 




II 



III, 5-Benzoylcyanidin chloride 



The benzoyl group is then hydrolysed with aqueous-alcoholic alkali, 
which also breaks the pyrylium ring, giving (iv) ; on treatment 
with hydrochloric acid the pyrylium ring is re-formed with the 
production of cyanidin chloride, (v), 



ANTHOCYANINS, AND DEPSIDES 



991 



HO 




OH 



V, Cyanidin chloride 



Using similar methods, pelargonidin chloride and delphinidin 
chloride have also been synthesised from the appropriate hydroxy- 
acetophenone derivatives. 

The anthocyanins are mono- or di-hexosides, or biosides, of the 
anthocyanidins, containing sugar residues in the 3- or 3:5-positions 
(p. 989) : a single anthocyanidin may therefore give rise to two or 
more anthocyanins. The positions of the sugar residues in the 
molecules have been conclusively proved by the synthesis of the 
anthocyanins themselves (Robinson and Robertson,^. 1928, 1460) : 

<v-\fetra-acetyl-p-glucosidoxy~\-\-acetoxyacetophenone, (vi), pre- 
pared as described later (p. 993), is treated as before with 2-benzoyl- 
oxy-\\b-dihydroxybenzaldehyde (i, p. 990), and the acetyl derivative, 
(vn), so formed is converted into the anthocyanin salt, (vin), by 
successive treatment with alkali and acid. 




Ph.CO-O 




O*C 6 H 7 0(OAc) 4 



OAc 



VI 



vn 



OH 




VIII, Callistephin chloride 

The product is identical with the naturally-occurring anthocyanin 
salt, callistephin chloride ; it yields pelargonidin chloride and 
glucose on hydrolysis. 

Pelargonin chloride, a diglucoside, has been synthesised as follows 
(Robinson and Todd, J. 1932, 2488) : 2-Monoacetyl-fi-glucosidyl- 



992 



CAROTENOIDS, PYRONES, 



phloroglucinaldehyde, (ix) (p. 993), is condensed in the usual manner 
with to-[tetra-acetyl-f$-glucosidoxy]4-acetoxyacetophenone^ (vi), 




HO 



. 



and the product, (x), is converted into the anthocyanin salt, pelar- 
gonin chloride, by successive treatment with cold alkali and acid, 



C 6 H U 5 -0 




HO 

Cl 

Pelargonin chloride 

The presence of a free hydroxyl group in the 3-position (p. 989) 
apparently renders an anthocyanin open to attack by oxidising 
agents, such as ferric chloride, and this reaction may therefore be 
used to ascertain whether or not a sugar residue occupies that 
position. 

Conclusions as to the positions of the sugar groups can also be 
drawn from a careful comparison of the colour changes, with a 
variation of hydrogen ion concentration, of anthocyanins of known 
and unknown structures. 

The anthocyanidins are closely related to the flavone pigments 
(anthoxanthidins), and the latter may often be converted into the 
anthocyanidins by reduction : rutin, for example, a glycoside of 
quercetin (p. 988), treated with sodium amalgam and alkali, is 
converted into a product which, with air and hydrochloric acid, 
yields cyanidin chloride, rhamnose and glucose, 



ANTHOCYANINS, AND DEPSIDES 993 

DH OH H 

N^ 




Rutin (R = Ci 2 H 2 iO 9 ) Cyanidin chloride 

The changes in the pyrone nucleus probably involve reduction 
(1), loss of water (2), atmospheric oxidation (3), salt formation (with 
its redistribution of valencies), and hydrolysis (4), 




The preparation of some of the compounds used in the syntheses of 
the anthocyanidins and anthocyanins is very briefly described below. 

a>:3'A-Trtacetoxyacetophenone (p. 990) has been obtained by 
condensing chloroacetic acid with catechol in the presence of 
phosphorus oxychloride and then heating the resulting halogen 
derivative with acetic anhydride and potassium acetate : 

CH 4 (OH) a - > CH 2 C1.CO-C 6 H 3 (OH) 2 - AcO-CH 2 .CO-C 6 H 3 (OAc) a 

o)-Hydroxy-4r-acetoxyacetophenone has been prepared as follows: 
Chloroacetyl chloride is treated with anisole and an excess of an- 
hydrous aluminium chloride ; during the reaction the methyl group 
is displaced by ".,' :. The OAc group is then substituted 
for the chlorine atom as above, the acetyl compound is hydrolysed, 
and the sodium derivative of the phenolic product is acetylated : 

MeO-CH 5 - > HO-C 6 H 4 .CO.CH a Cl - 

HO-C e H 4 .CO-CH a -OAc - * AcO-C,H 4 .CO-CH a .OH 

This acetyl derivative, treated with tetra-acetyl-1-bromo-a-glucose 
(p. 879) in benzene solution in the presence of silver carbonate, 
gives (x)-[tetra-acetyl-f3-gliicosidow]-4-acetoocyacetophenone (p. 991). 

2-Monoacetyl-fi-glucosidylphloroglticinaldehyde is obtained (to- 



994 CAROTENOIDS, PYRONE8, 

gather with the corresponding tetra-acetyl derivative) by the con- 
densation with potash of phloroglucinaldehyde and tetra-acetyl-a- 
bromoglucose in acetone solution ; during this reaction the hydrolysis 
of three acetyl groups takes place. It is to be noted that the phloro- 
glucinaldehyde derivatives are j3-glucosides, although an a-glucoside 
is used in their preparation (footnote, p. 895), because a Walden 
inversion has occurred. 

Depsides 

By the interaction of the hydroxyl group of one molecule of a 
phenolic acid and the carboxyl group of another, a carboxy-deriva- 
tive of a phenolic ester, HOOC-C 6 H 4 -O-CO-C 6 H 4 .OH, may be 
obtained ; theoretically this compound might react with another 
molecule of the same or of a different phenolic acid, and by repeti- 
tions of such reactions there would be formed highly complex 
products, 

HOOC - C 6 H 4 - O . [CO C 6 H 4 - O] n - CO C 6 H 4 - OH, 

related to the phenolic acids, just as the polypeptides are related 
to the amino-acids (p. 620). To such compounds Fischer and 
Freudenberg gave the name depside (Gr. depsein, to tan), because 
many of them resembled the tannins (p. 998) ; they are dis- 
tinguished as di-, tri-, etc. depsides, according to the number of 
their constituent phenolic acid residues. 

Certain depsides had been previously obtained by the action of 
phosphorus oxychloride on a phenolic acid, but such products were 
indefinite in character and probably complex mixtures. Fischer 
controlled the course of depside formation by first * protecting ' or 
* blocking ' the phenolic group with the carbomethoxy-mdical, 
CO-OMe, which could be easily removed again by hydrolysis 
without bringing about the fission of the more stable depside link. 

The phenolic acid is first treated with methyl chloroformate 
and cold dilute aqueous alkali; the resulting carbomethoxy- 
derivative, (i), is converted into the acyl chloride, (n), by treatment 
with phosphorous pentachloride in chloroform solution, and the 
product is then condensed with another molecule of the same or of 
a different phenolic acid in the presence of alkali. The substituted 
didepside thus formed, (in), may be hydrolysed with cold aqueous 
normal alkali, and thus converted into a didepside, or may be 
transformed into its acid chloride, and utilised in further analogous 
syntheses of tri-, tetra-, and poly-depsides. 



ANTHOCYANINS, AND DEPSIDES 995 

I MeO-CO.O-C 6 H 4 .COOH n MeO-CO.O.C 6 H 4 .COCl 
m MeO-CO.O.C 6 H 4 .CO-O.C 6 H 4 .COOH 

The acid chloride, (n), may also be used for many other 
preparations ; it reacts with esters of ammo-acids, for example, 

MeO CO O - C e H 4 - COC1 + 2NH a - CH a - COOEt 
MeO - CO O C 6 H 4 CO - NH CH a - COOEt + HC1,NH, CH a - COOEt, 

and with benzene in the presence of aluminium chloride it gives 
substituted benzophenones. The carbomethoxy-group in the 
product is then displaced by careful hydrolysis. 

Phenolic groups situated in the m- or />-position to a carboxyl 
radical are easily carbomethoxylated, but those in the o-position are 
not ; thus protocatechuic acid and gallic acid (p. 536) are both fully 
substituted by the method given above, whereas salicylic acid 
remains unchanged ; by using a large excess of methyl chloro- 
formate in benzene solution in the presence of dimethylaniline, 
however, the carbomethoxy-derivatives of salicylic acid and other 
o-phenolic acids may be prepared. Partially carbomethoxylated 
polyphenolic acids are prepared either by the use of carefully 
controlled quantities of the reagents, or by the graded hydrolysis of 
the fully substituted compounds ; in the latter process, a carbo- 
methoxy-group in the />-position to the carboxyl radical is often 
the more or the most easily displaced. 

In some cases the hydroxyl in the o-position to a carboxyl group 
does not react readily with the acid chloride ; this difficulty is over- 
come by condensing a carbomethoxy-derivative of a phenolic 
aldehyde with that of the acid chloride and then oxidising and 
hydrolysing the product. 

o-Di-orsellinic acid was thus prepared from dicarbomeihoxyorsel- 
linyl chloride (p. 997) and p-monocarbomethoxyorsellinaldehyde : 




MeO-COO{ 

"" 0-COOMe 
CH, OHC CH a 

O-CO'OMe b-CO-OMc OH OH 





996 CAROTENOIDS, PYRONES, 

The orientation of partially carbomethoxylated phenolic acids, 
and of the depsides, may be accomplished with the aid of diazo- 
methane. A dicarbomethoxylated gallic acid, (i), for example, 
yields the methyl derivative, (n), which, on hydrolysis, gives (in) : 

:OOH 

OOMe 





The structure of (in), and hence that of (n) and of (i), can then be 
established, because (in) can give only one monomethyl ether, or 
other phenolic derivative, whereas (iv) could give two isomerides. 
Similarly a study of the hydrolysis products of a completely methyl- 
ated depside will settle the constitution of that compound. 

Now, when the pentacarbomethoxy-derivative of j)-digallic acid 
is hydrolysed, instead of giving />-digallic acid, as would be expected, 
it is converted into w-digallic acid ; similarly, when penta-acetyl- 
/>-digallic acid, (v), is hydrolysed with cold dilute ammonia, the 
product is not the expected p-galloylgallic acid, but m-galloylgallic 
acid, (vi), as hydrolysis is accompanied by the transference of the 
galloyl group from the />- to the w-hydroxy-group : 

HO 

coon - 





Such isomeric changes (p. 845) are quite common among the depsides, 
the investigation of which is thus rendered much more difficult. 

Most of the didepsides, such as di-orsellinic acid, are crystalline, 
sparingly soluble in cold water, and give colour reactions with 
ferric chloride. They are easily hydrolysed by an excess of dilute 



ANTHOCYANINS, AND DEPSIDES 997 

alkali, and with diazomethane they yield first their methyl esters, 
and then methyl ethers of these esters, all the phenolic being con- 
verted into OMe groups. The didepsides of gallic, protocatechuic, 
and j3-resorcylic acid (2:4-dihydroxybenzoic acid) precipitate dilute 
gelatine solutions, and solutions of quinine acetate (properties shown 
by tannin). 

Tri- and tetra-depsides may also be prepared by the general 
methods. The tetradepside, 

HO.(MeO)C 6 H 3 .CO.O.C 6 H 4 .CO.O.C 6 H 4 .CO.O.C 6 H 4 .COOH, 

for example, is obtained by condensing carbomethoxyvanilloyl-p- 
hydroxybenzoyl chloride, (i), 1 with p-hydroxybenzoyl-p-hydroxy- 
benzoic acid, (n), and then displacing the carbomethoxy-group by 
hydrogen, 

I MeO - CO O (MeO)C 6 H 3 - CO - O C 6 H 4 - COC1 
ii HO.C 6 H r CO-O.C 6 H 4 .COOH 

The chief natural sources of the depsides so far discovered are 
the lichens ; lecanoric acid, C 16 H 14 O 7 , for example, occurs in 
Roccella and Lecanora, and evernic acid, C 17 H 16 O 7 , together with 
orsellinic acid, in Evernia prunastri. The constitutions of these 
acids have been established by the following syntheses : 

Orcinol, C 6 H 3 (CH 3 )(OH) 2 , (i), which can be obtained from 
3:5-dinitrotoluene; is treated with chloroform and potash (Reimer- 
Tiemann), or with hydrogen cyanide and hydrogen chloride in the 
presence of aluminium chloride (Gattermann), and the resulting 
orsellinaldehyde, (n), is converted into its dicarbomethoxy-derivative 
which is oxidised ; the product, (ill), the dicarbomethoxy-derivative 
of orsellinic acid, is converted into its chloride, which, condensed 
with orsellinic acid, gives (iv) : a 

CH 3 





MeO-OCO( 

~~"OCO-OMe 
I II III 

* Vanillic acid is CeH 8 (COpH)(OCH 8 ) - OH[OCH 3 :OH - 3:4]. 

1 Orsellinic acid yields two isomeric monomethyl ethers and must there- 
fore have the structure assigned to it : if it were 2:6-dihydroxy-4-methyl- 
benzoic acid, as would be possible from its method of synthesis from orcinol, 
only one ether could exist. 



998 



CAROTENOIDS, PYRONES, 



MeO-COO 




HO 




OH 



The didepside, (v), thus obtained, after the displacement of the 
carbomethoxy-groups, is identical with naturally-occurring lecanoric 
acid, which, therefore, is a />-diorsellinic acid, because it differs 
from o-diorsellinic acid prepared as described above (p. 995), and 
yet gives orsellinic acid on hydrolysis. 

Lecanoric acid and evernic acid yield, with diazomethane, the 
same ester, methyl trimethyllecanorate, so that evernic acid is a 
methyl derivative of lecanoric acid, (v). Further, evernic acid, on 
hydrolysis, yields orsellinic acid together with everninic acid, which 
is known to be a ^-methyl derivative of orsellinic acid ; the con- 
stitution of evernic acid, therefore, is 



MeO 




OH 



The above, and many other interesting syntheses, were rendered 
possible by the application of Fischer's simple method of protecting 
or blocking a phenolic group by the introduction of a radical which, 
subsequently, could be easily displaced. 

Tannins 

A brief description of tannin has already been given (p. 536) 
As long ago as 1854, Strecker suggested that some tannins were 
compounds of glucose and gallic acid, but owing to experimental 
difficulties it was impossible to prove that these two substances were 
not merely mixed together in the natural product. By dissolving 
pure commercial tannin from Chinese galls (oak-apples) in a slight 
excess of alkali carbonate and extracting the solution with ethyl 
acetate, Fischer obtained preparations containing no free carboxyl 
groups and which, on hydrolysis with 5% sulphuric acid, gave 
7-8% of glucose and 93-92% of gallic acid ; it was thus shown that 
this particular tannin is probably a compound of one molecule of 



ANTHOCYANINS, AND DEPSIDES 999 

glucose with five molecules of digallic acid (a didepside), correspond- 
ing in structure with penta-acetyl or pentabenzoyl glucose. 

Pentagalloylglucose was then prepared by carefully hydrolysing 
the carbomethoxy-derivative, obtained by the condensation of 
tricarbomethoxygalloyl chloride with glucose, in the presence of 
chloroform and quinoline, 

C H 12 O 6 +5C 6 H 2 (O-CO 2 Me) 3 COCl > 

C 6 H 7 O[O CO C 6 H 2 (O-CO 2 Me) 3 ] 5 * C 6 H 7 O[O-CO-C 6 H 2 (OH) 3 ] 6 

This compound showed a strong resemblance to tannin in that it 
had an astringent taste, and precipitated solutions of gelatin and 
of alkaloids ; it was probably a mixture of a- and j8-tetra-galloyl- 
galloy Iglucosides . 

When tannin is methylated with diazomethane, a methylotannin 
is obtained (Herzig) which is indifferent towards alkali and therefore 
contains no free phenolic or carboxyl groups ; on hydrolysis it 
yields glucose, trimethylgallic acid, and a dimethylgallic acid, in which 
the methoxy-groups are in positions 3 and 4 (COOH =1). The 
digallic acid component of tannin, therefore, is probably a m-digallic 

acid, 

HO COOH 

~ 




HO HO OH 



Pentamethyl-m-digallic acid was therefore prepared from tri- 
methylgalloyl chloride and 3'A-dimethylgallic acid, and its acid chloride 
was condensed with both a- and j8-glucose in the manner described 
above. Two isomeric penta[pentamethyl-m-dtgalloyl]-glucoses (both 
of which were probably mixtures of a- and jS-glucosides) were thus 
obtained ; the preparation from /J-glucose was very similar to 
methylotannin, but their identity could not be established. 

Attempts to synthesise tannin itself, by the condensation ofpenta- 
acetyl-m-digalloyl chloride with j8-glucose, followed by the displace- 
ment of the acetyl groups, gave a penta-m-digalloylglucose which 
was possibly an isomeride of natural tannin, but it differed from the 
latter in specific rotation ; the structure of gallotannin, therefore, 
was not established. Certain tannins are derived from the catechins, 
which are hydrogenated anthocyanidins. 

In the course of these experiments on the synthesis of tannin 

Org. 63 



1000 CAROTENOIDS, PYRONES, ANTHOCYANINS, DEPSIDES 

various compounds of very high molecular weight were prepared, 
as, for example, penta[pentamethyl-m-digalloyl]glucose, M.W. 2050 
(p. 999). By the condensation of tribenzoylgalloyl chloride (a sub- 
stance which is easily prepared, and which crystallises well) with 
mannitol, a compound of molecular weight 2966 was probably 
obtained, but its composition could not be proved by analysis. 
When, however, p-iodophenylmaltosazone is similarly condensed 
with tribenzoylgalloyl chloride, the product contains halogen, and 
its composition can be fixed by iodine determinations. 
Hepta[tnbenzoylgalloyl]-^'iodophenylmaltosazone^ 

C 12 H 13 2 (:N 2 HC 6 H J) 2 [O - CO - C 6 H 2 (O CO - C 6 H 5 ) 3 ] 7 

thus prepared, has a (calculated) molecular weight of 4020 ; that 
found from measurements of the freezing-points of its bromoform 
solutions agreed with this value, a fact which shows that the results 
of cryoscopic measurements are trustworthy even in the case of 
such complex molecules. The molecular weight of this compound, 
moreover, far surpassed that of any substance of known constitu- 
tion which at that time had been synthesised. 



CHAPTER 59 
AROMATIC STRUCTURE AND SUBSTITUTION 

Aromatic Structure 

THE theory of resonance as applied to benzene and other aromatic 
compounds has been briefly outlined in Part II, but it must not be 
thought that the problems of the structure and reactions of benzene 
and its derivatives are thereby solved. 

Prior to the advent of this theory the chemical behaviour of the 
aromatic hydrocarbon had been compared or contrasted with that 
of various unsaturated compounds such as dipropargyl (p. 379). 
The inferences drawn from such studies were however of question- 
able value because of the possible effects of the ring structure on all 
the properties and reactions of one of the compounds only. 

In order to avoid this obvious disadvantage \\ ' , - and his 
collaborators (Ber. 1911, 3423 ; 1913, 517), after a very laborious 
investigation, prepared a hydrocarbon, C 8 II 8 , which they regarded 
as ryc/o-octatetrene (p. 817) x and which therefore could be regarded 
as far more comparable with benzene in structure than any open 
chain hydrocarbon ; but here again there was a complete dissimil- 
arity in practically every respect. Cyc/o-octatetrene combines with 
hydrogen in the presence of palladium, whereas benzene does not ; 
it reduces permanganate, immediately forms an additive compound 
with bromine, and in other ways has nothing in common with the 
aromatic hydrocarbon. This contrast is now explained as follows : 
The molecule of benzene fulfils the conditions of resonance and 
exists in the mesomeric form. It is a symmetrical planar molecule 
as is shown by the X-ray examination of the crystal structure of 
benzene derivatives ; also by the study of their infra-red spectra 
and measurements of their electron diffraction. The fact that 
substances such as diphenyl, />-dimethyl-, />-dichloro- and />- 
dibromo-benzenes, l:3:5-trialkyl- and tribromo-benzenes have 
zero dipole moments also points to the planar distribution of the 
ring and the substituents. On the other hand, it has been shown 
mathematically that the molecule of rytfo-octatetrene cannot assume 

1 Cyc/o-octatetrene has since been obtained by the polymerisation of 
acetylene and all the pioneer results of Willstatter have been confirmed. 

1001 



1002 AROMATIC STRUCTURE AND SUBSTITUTION 

a mesomeric state ; a wide difference in properties between benzene 
and the cyclic olefine might therefore be expected. 

Some experimental evidence, in addition to that already given, 
that benzene has the postulated mesomeric structure (p. 390), is 
afforded by measurements of the carbon to carbon distances in its 
molecule ; if there were alternate double and single links in the 
ring, as in Kekule's formula, the carbon-carbon distances should 
also alternate between 1-54 A.U., the single bond distance found 
in paraffins, and 1'33 A.U., the double bond distance found in 
olefines. In fact the bonds are all of equal length, namely 1-39 A.U., 
a value which lies between that of a single and that of a double bond. 

Further physical evidence that the carbon atoms in benzene are 
not united by ordinary ethylenic bonds is afforded by the value of 
the heat of combustion of the hydrocarbon, which, as already stated, 
is 39,000 cal. less than that calculated for a compound of the Kekule 
structure. Moreover, the heats of hydrogenation of benzene, 
cyc/ohexene and ethylene are respectively 49,800, 28,590 and 
32,580 cal. ; if benzene contained three ethylenic linkages similar 
to that of ryc/ohexene, the heat of hydrogenation would be expected 
to be of the order of 86,000 cal., giving a value of nearly 36,000 cal, 
for the resonance energy. 

Chemical evidence that benzene is a mesomeric compound is, of 
course, impossible to obtain as all the reactions of the hydrocarbon 
may be considered as the normal behaviour of such a structure. 
Nevertheless an interesting attempt to obtain such evidence was 
made by Levine and Cole (J. Am. Chem. Soc. 1932, 338) who 
studied the ozonisation of o-xylene. They found that the ozonide 
of this hydrocarbon when decomposed with water, gives glyoxal, 
methylglyoxal and diacetyl, all of which can be isolated in the form 
of their />-nitrophenylhydrazones, and it was shown later by Wibaut 
that the relative quantities of the products are such as would be 
expected from a mixture of equal quantities of (i) and (n) : 





II 



This result might be accounted for by assuming (1) That the 
mesomeric bonds, as such, undergo fission during ozonisation ; 



AROMATIC STRUCTURE AND SUBSTITUTION 



1003 



since all bonds are of the same type, the results would be as stated ; 
(2) That the mesomeric molecule passes into its Kekuld contributors, 
(i and ii), prior to reaction and that ozonisation then proceeds 
normally ; if so, the postulated structurally isomeric o-xylenes are 
formed in equal quantities. 

Unfortunately, therefore, the results are of little value as evidence 
either for or against the view that the benzene molecule exists in a 
mesomeric state. 

An attempt to show that the chemical behaviour of a mesomeric 
substance is determined by that of all its theoretically possible 
contributory forms has been made by Pauling, Brockway and Beach 
(J. Am. Ghent. Soc. 1935, 2708) in the case of condensed ring hydro- 
carbons. Naphthalene, for example, may be represented by the 
following structures, all of which may contribute to the mesomeric 
state : 






I n 

In (i) and (n) double bonds connect the aj8-atoms (a, a) and in 
(in) a single bond does so ; the reverse conditions apply to the 
j8j3-atoms (a, b). t)n the assumption that each structure contributes 
about equally, as doubtless do the identical structures (n) and (in), 
the a/J-links in the mesomeric form will have two -thirds, and the 
]8j3-links (and others) one-third of the character of a double bond as 
indicated in (iv) by the given numerical fractions. These con- 
clusions are supported by the known facts concerning the positions 
at which naphthalene derivatives couple. 

In the cases of anthracene and phenanthrene the characters of 
the various bonds in the respective resonance forms, (v) and (vi), 
can be deduced in a similar manner and indicated as before : 





IV 




1004 AROMATIC STRUCTURE AND SUBSTITUTION 

Here again the results give bond characters apparently in agree- 
ment with the known chemical properties of the hydrocarbons, such 
as the nearly olefmic nature of the 9:10-link in phenanthrene, which 
is shown by the ready oxidation of the hydrocarbon to diphenic 
acid ; such deductions, however, are open to criticism (Lennard- 
Jones and Coulson, Transactions of the Faraday Society, 1939, 35, 
817). 

Substitution in the Benzene Series 

The orientating or directing influence of an atom or group, already 
combined with the benzene nucleus, on the position which is taken 
up by a second substituent, has already been considered, and a 
simple empirical rule, concerning the position taken up by the 
entering group, has been given (p. 433). 

Hammick and TT- jjuo-.li (J. 1930, 2358) proposed another 
empirical rule : A mono-substitution product of benzene may 
be represented by C 6 H 5 -A (A = halogen) or C 6 H 5 -AB ; in the 
latter A is any atom directly united to the nucleus and B is an atom, 
or one of several atoms, directly combined with A, as for example 
the H of a CH 3 or the O of an NO 2 . If now any atom B is in a 
higher group of the periodic table than is A, then further substituents 
enter the meta-position : when A and B are in the same periodic 
group, then if B is of lower atomic weight than A, we/a-substitution 
again occurs. If no such atom B satisfies one of these conditions, 
substitution is ortho-para, and the same occurs if B is absent : 
further, if AB carries an ionic charge, a positive charge gives m- 
and a negative charge op-substitution. The following table gives a 
few illustrations of the application of this rule : 

Group AB NOa CN Cl CH 8 OH CH:CH CHClj 

A NCC1COC C 

B O N H H C&H H&C1 

Substitution occurs m- m- op- op- op- op- op- wi- 

lt must not be forgotten that in a great many cases both op- and 
m-substitution occur at the same time in variable proportions, so 
that the above rules only give an indication of which is the pre- 
dominant reaction. 

Many explanations or theories of aromatic substitution based 
mainly on Kekute's formula have been put forward during the last 
sixty to seventy years ; of these, only a few of the more important 
are considered here. 



AROMATIC STRUCTURE AND SUBSTITUTION 1005 

Holleman (1910), after prolonged investigation, summarised his 
conclusions as follows : 

In every compound, C 6 H 5 X, X is directly united with a doubly- 
bound carbon atom, and it is known that the behaviour of such an 
atom or group is very greatly influenced by the immediate proximity 
of the ethylenic binding ; the chlorine atom in CH 2 =CC1 CH 3 , 
for example, is very resistant to double decomposition compared 
with that in CH 2 =CH CH 2 Cl. It may be assumed, therefore, 
that X influences the double binding, since a mutual action between 
different groups in a molecule is a general phenomenon. 

Now in such a group, C 6 H 5 X, the substituent X may facilitate or 
hinder addition, and from what is known about conjugated bindings 
(p. 813), addition in the 1:4, (n), as well as in the 1:2, (i) position 
may be influenced, whereas addition in the 2:3-position, (in), will 
not, since X is not directly combined with the olefinic linkage. 
Consequently, the velocity of the additive reaction in the o- and 
^-positions will be increased or decreased, but addition in the 
w-position will not be influenced. 

It is very probable that substitution is preceded by addition . Thus, 
in nitration, the first products may be those shown below ; these lose 
the elements of water, whereby the less stable olefinic 6-ring reverts 
to the benzene structure. The velocity of the additive reactions in 
the three cases represented will determine the type of substitution, 






I II in 

If X increases the velocity, substitution is op (i and n), and 
exclusively so if X has a very large accelerating effect, for in that 
case the quantity of w-product will be negligible. If the effect of 
X is not so great, the proportion of m-derivative, (HI), will be 
greater. If, on the other hand, X retards addition, the proportion 
of w-derivative will be large, and the slowness of w-substitution in 
general will be explained. 

Just as in processes of addition to conjugated systems, the forma- 
tion of 1:4- products is accompanied by that of 1:2-, so also in the 



1006 AROMATIC STRUCTURE AND SUBSTITUTION 

aromatic compounds. The relative proportions in which o- and 
p-compounds are formed varies within very wide limits and depends 
on the nature of X, on that of the substituting reagent, on the tem- 
perature, and other conditions. All these factors influence the 
results but do not cancel the accelerating effect of X. If the m- 
compound is the main product, the o-derivative is often formed at 
the same time. This is also explained since primary addition may 
give NO 2 at 2 or at 3. 

Holleman himself points out that his views do not make it possible 
to predict the effect of a given substituent any more than it is possible 
to predict the nature of the effect of a catalyst. 

In 1919 Vorlander discussed the question whether or not electrical 
charges within the molecules of the reacting substances were the 
directing agents in aromatic substitution (Ber. 1919, 263). This 
possibility had been considered previously by Hiibner, Nolting, and 
others, and it had been pointed out that groups such as NO 2 , 
SO 3 H, and COOII, which are w-orientating, might be regarded 
as electro-negative (or acidic) because they occurred in the anions 
of acids : _ + _ + _ + 

NO 3 H, SO 4 H 2 , R-COOH. 

The basic group, NH 2 , which is op-orientating, was then con- 
sidered to be electro-positive, and by implication or otherwise the 
halogens, OH, CH 3 , and other op-orientating groups were also 
regarded as electro-positive. 

Such a classification of aromatic substituents, however, was an 
arbitrary one ; the OH group and the halogens might at that 
time, with much more reason perhaps, have been considered to be 
negative radicals. 

Vorlander also discussed this question as to whether a given atom 
or group should be labelled positive or negative, and he represented 
some of the principal aromatic substituents as follows : 

_+ -+ -+ - + 
op-Orientating NH 2 , OH, OMe, CH 3 and the halogens ; 

m-Orientating NO 2 , CO -OH, SO 2 -OH. 

+ -+- 

He argued that nitric acid should be represented by HONO 2 , 
and that when it reacts with benzene it behaves like a true hydroxy- 
base, the benzene playing the part of an acid ; similarly in the case 



AROMATIC STRUCTURE AND SUBSTITUTION 1007 

of sulphuric acid. He also pointed out that in acyl chlorides the 
R.CO group plays the part of, say, Na in NaCl, and is therefore 
positive. As further evidence that the three w-orientating groups 
given above should be regarded as positive, he drew attention to the 
fact that their directive action is the same as that of the very strongly 
positive quaternary ammonium radical. 

He then classified some forty aromatic substituents as positive 
or negative according to their known orientating effect on nitration 
or bromination ; when represented in the manner shown above, 
the positive or negative character of the substituent is that of the 
atom which is directly combined with carbon of the nucleus, so 
that substituents previously regarded as negative were now classed 
as positive and vice versa. On such a basis Vorlander founded the 
following rules of substitution : 

I. In the formation of disubstitution products of benzene by 
halogenation or nitration, the entering substituent is directed mainly 
into the /w-position by positive, into the o- and ^-positions by 
negative side chains already present in the molecule. 

II. The carbon atoms of the nucleus behave negatively towards 
a positive, and positively towards a negative substituent. 

In order to account for this behaviour he assumed that the positive or 
negative influence of the substituent extended to all the carbon atoms 
of the nucleus, which become alternately or + as shown below : 





H 



The nuclear H atoms in any such substitution product are now 
no longer bound with equal, but by different strengths, as indicated 
by the light and heavy lines ; those joined to the carbon atoms by 
heavy lines are in a state of greater tension (electrical potential differ- 
ence), and will be more readily displaced than the others ; they have 
stronger positive charges and will react more energetically with 
bromine, for example, to form HBr, or with nitric acid to form H 2 O. 
Consequently the positive substituent, NO 2 - , causes w-, whereas 
the negative substituent, NH 2 , causes op-orientation. 



CN H 



1008 AROMATIC STRUCTURE AND SUBSTITUTION 

At about the same time, in order to explain certain abnormal 
reactions of aliphatic compounds, Lapworth (Proc. Manchester 
Literary and Philosophical Society, Vol. 64, 1920) put forward his 
views on induced alternate polarities. According to him a particular 
atom (the ' key ' atom) at the end of a chain in a molecule, may 
have a positive or a negative effect, which is transmitted along that 
chain. In the molecule of an aj8-unsaturated ketone, for example, 
the * key ' atom, oxygen, induces an alternating effect, so that in 
its reactions the compound shows, or appears to show, polar pro- 
perties ; thus the combination of such a ketone with hydrogen 
cyanide often does not give a cyanohydrin but may be expressed by 

c c=c o >c 6 c=o 

CN H CN H 

The signs -f and , however, do not imply that the atoms so 
marked actually carry electrical charges, but that these atoms seem 
to display these relative polar characters at the instant of the chemical 
change in which they take part. 

These views were then applied to benzene derivatives, and that 
atom of the substituent which is directly united to carbon of the 
nucleus was given a -f- or sign according to that which had been 
assigned to the ' directive ' or ' key ' atom. Thus in the nitro- and 
aldehyde groups the oxygen atom is the key atom, whereas in the 
cyanogen group the key atom is nitrogen and in a quaternary chloride 
it is the nitrogen atom of the positively charged ammonium group ; 
the substituent is therefore + in all these cases : 

NO 6, CHO, CN, NMe 3 
The polarity induced by the ' key ' atom is then extended to all 
the carbon and hydrogen atoms of the nucleus, which are marked 
+ or alternately : 





AROMATIC STRUCTURE AND SUBSTITUTION 1009 

+ - + 

Compounds of the type (i), reacting with HO*NO 2 , HO-SO 3 H, 
or halogen will therefore give op- t whereas those of type (n) will 
give m- derivatives, ll + combining with the negative, and C~ with 
the positive radical or atom, as , ,' by Holleman. 

Modern views on aromatic substitution are based on considerations 
of how the inductive and mesomeric effects of substituents will 
influence the availability of electrons at different positions in the 
nucleus. Aliphatic hydrocarbons do not readily undergo substitution 
and their derivatives of the type RX usually react by a nucleophilic 
mechanism in which a negative reagent of ion attacks where there is 
a deficiency of electrons. Aromatic hydrocarbons in general are 
readily substituted and the ease of substitution is frequently increased 
by groups which are not themselves displaced ; the very different 
behaviour of benzene and of phenol towards nitrating and halogenat- 
ing agents is an example. Aromatic substitution is usually brought 
about by electrophilic reagents which are themselves deficient in 
electrons and which therefore attack where electrons are most 
available ; such groups are Br+, NO 2 +, HSO 3 +, CH 3 -CO, Ph-N 2 +, 
etc. Simultaneously with the electrophilic attack on the nucleus, or 
immediately after it, a proton is lost from the point of attack, as is 
shown in the following examples : 

C 6 H 6 fBr+=C 6 H 5 Br+H+, 
C 6 H 6 +N0 2 + = C 6 H 5 -N0 2 +H+, 

C.HI+HSO.+ = c 6 H 5 -so 3 H+H+, 

C 6 H 6 -hCH 3 -CO+ = C 6 H 5 -CO -CH 3 +H+, 

Me 2 N -C 6 H 5 +Ph -N 2 + = Me 2 N -C e H 4 -N 2 -Ph+H+, 

The evidence for nitration being effected by the nitronium ion, 
NO 2 + , is strong and the existence of this ion has been proved in 
many ways. Firstly, cryoscopic measurements of solutions of nitric 
acid in sulphuric acid show that the depression of the freezing- 
point is four times larger than would be produced by undissociated 
nitric acid : this is explained by the following reaction, 

HN0 3 +2H 2 S0 4 ^ N0 2 ++ H 3 O++2HSO 4 - ; 

secondly, examination of the Raman spectra of solutions of nitric 
acid in sulphuric acid and comparisons with many other spectra have 
shown the presence of the NO 2 + ion in such solutions, and thirdly, 
the kinetics of nitration can only be explained by assuming that 
the nitronium ion is the nitrating agent. In cases of substitution 



1010 



AROMATIC STRUCTURE AND SUBSTITUTION 



other than nitration the evidence is less conclusive, but, for example, 
in halogenation and in the Friedel- Crafts reaction where catalysts 
are employed, these probably act by removing the negative ion as a 
complex, A1C1 4 ~~, FeCl 3 Br~, or by forming complexes with one of the 
reactants, RA1C1 4 . 

The influence of a substituent on the distribution of electrons in 
the nucleus depends on the nature of the substituent and may be 
considered under four headings. 

(1) The substituent A has an electron-repelling inductive effect. 
The end forms which, with the usual Kekule forms, contribute to 
the total mesomeric state are (i), (n) and (in) and the final mesomeric 
form is represented by (iv), 






II 



in 



IV 



At the instant of reaction electromeric change to (i), (n) or (in) 
occurs and an elect rophilic reagent attacks at the 2-, 4-, or 6- 
positions where electrons are available : op-substitution results. 
It is seen that in (i), (il) and (in) the 1-carbon atom to which A is 
attached has only a sextet of electrons so that probably the con- 
tributions of these forms to the total mesomerism will not be great, 
but sufficient to control the orientation of further substitution. It 
is also to be noted particularly that the 3- and 5 -carbon atoms are 
unaffected in all cases : it is impossible to write a structure with a 
negative charge on these atoms without exceeding the octet rule. 
The general inductive effect will, however, cause a drift of electrons 
away from A increasing their availability over the whole nucleus, 
but to a much greater extent in the o~ and p-positions, making sub- 
stitution more rapid than in benzene itself. Toluene, which is a 
compound containing a group of this sort, for example, is converted 
into mononitrotoluene nearly 25 times as fast as benzene is nitrated 
to nitrobenzene. 

(2) The substituent A has an electron-attracting inductive effect. 
The end forms are (v), (vi) and (vn) and the final mesomeric form 

(VIII), 




AROMATIC STRUCTURE AND SUBSTITUTION 1011 

A A A A 






VII 



VIII 




Again octets are not maintained in (v), (VT) and (vn) as the 2-, 4- 
and 6-carbon atoms respectively have only a sextet of electrons ; 
the only atom with available electrons is that at 1- to which the group 
A is attached and at which substitution cannot occur without 
displacement of A : such a displacement does indeed sometimes 
occur. In the electromeric forms the 3- and 5 -positions are again 
unaffected, but owing to the deficiency of electrons at the 2-, 4- and 
6-carbon atoms electrons are most available at the w-positions ; even 
here, however, their availability is not great and is diminished and 
made less than in any position in benzene itself by the general 
inductive effect towards A. Substitution cannot therefore occur at 
2-, 4- or 6- and is forced to take place at 3- and 5- : it will however 
be slower than in benzene. Examples of compounds containing 
groups with this effect are the quaternary salts of Ph'NMe 3 + , 
PhPMe 3 + , Ph-AsMe 3 + , etc., all of which show slow w-substitution. 
It might be thought that forms such as (ix) in which the 3 -position 
has a negative charge and is therefore activated would be possible 
contributors to the mesomerism, but in this there are two carbon 
atoms with only a sextet of electrons and it is assumed that it is too 
unstable to make an appreciable contribution. 

(3) The substituent A has an unshared pair of electrons on the atom 
directly attached to the nucleus. In this case the unshared pair can 
be concerned in the mesomerism and forms (x), (xi) and (xn) are 
contributors to the final state indicated by (xin) (compare p. 695/), 
Octets are maintained in all forms (even on the group A) which 






XI 



XII 



XIII 



1012 



AROMATIC STRUCTURE AND SUBSTITUTION 



therefore probably contribute more to the final mesomeric state 
than the forms discussed above in which sextets of electrons are 
found. In the electromeric forms (x), (xi) and (xn) electrons are 
available at the 2-, 4- and 6-positions respectively and op-substitution 
will occur ; furthermore it will be much more rapid than in benzene 
owing to the high electron density at these positions. Aniline and 
phenol are examples of compounds containing groups of this sort 
and their extremely easy and rapid op-substitution is familiar and 
illustrated by the formation of tribromo-derivatives in cold aqueous 
solution, by diazo-coupling, etc. 

(4) The atom A directly attached to the nucleus has another atom 
attached to it by a multiple link. Here a pair of electrons of the 
double (or triple) bond can participate in the mesomerism in either 
of two ways as indicated in (xiv)-(xvn) or (xvm)-(xxi), 



A 



A B T 





XIV 



A B 




XV 



A B 



XVI 



A B 



XVII 





XX 



In none of the contributors are all octets maintained : the atom 
with the positive sign has only a sextet of electrons. It is clear that 
case (a) represented by (xiv)-(xvn) resembles type (1) and op- 
substitution will result : styrene, C 6 H 5 'CH:CH 2 , is a substance of 
this kind. The case (b) represented by (xvm)-(xxi) is similar to 
type (2) and slow ^-substitution will occur : all compounds con- 
taining the carbonyl group directly attached to the nucleus, as, for 
example, benzaldehyde, acetophenone, benzoic acid and ethyl 
benzoate are of this type, owing to the mesomeric effect of that 
group. Benzene is mononitrated nearly 300 times as fast as is ethyl 
benzoate, under the same conditions. 



AROMATIC STRUCTURE AND SUBSTITUTION 1013 

The various effects described above may be summarised as follows: 

Type Example Orientating Effect 

(1) Ph < A Ph-CH 3 op- 

(2) Ph > A Ph-NMe 3 X m- 

(3) Ph-^A Ph-OH op- 
(4a) Ph-^A^B Ph-CH:CH 2 op- 

ph^-A=^B Ph-COOEt m- 



Such then is the general theory of aromatic substitution and it 
remains to examine some individual cases in more detail and to see 
how some of the separate effects just described may be superimposed 
on one another. 

The inductive effect of the halogens might be expected to place 
them in type (2), but they are, in fact, op-directing : it must there- 
fore be assumed that a mesomeric effect of type (3) is more powerful, 
but as the inductive effect is in the opposite direction the mesomeric 
effect is partly nullified and the slow op-substitution found experi- 
mentally results. Chlorobenzene is mononitrated at only 3 per 
cent, of the speed of benzene under the same conditions. It usually 
happens that when an inductive and a mesomeric effect are both 
present the latter controls the electromeric effect. 

In nitrobenzene and benzenesulphonic acid the substituents both 
have strong dipoles, -+NO 2 ~ and -+SO 2 --OH respectively; their 
inductive effect is of type (2) and their mesomeric effect of type 
(46). The effects therefore reinforce one another and slow m- 
substitution results, which is, of course, in accord with experiment. 

It has been suggested that the strong op-directive effect in toluene 
may not be entirely due to the inductive effect, but that a methyl 
group attached to a conjugated system may exert a mesomeric 
effect by a process known as hyperconjugation : the electrons of the 
C H bonds of the methyl group are assumed to be less localised 
than those of a C C bond and permit of greater electron release 
in the op-positions (xxn). The same effect might account for the 
large fall in acid strength in passing from formic to acetic acid. 



XXII 




1014 AROMATIC STRUCTURE AND SUBSTITUTION 

When the series toluene, benzyl chloride, benzylidene dichloride, 
benzotrichloride is considered it might be expected that the inductive 
effect of the halogen atoms would gradually convert the electron 
repulsion of the unsubstituted side chain into an attraction, with 
consequent change from predominantly op- to predominantly m- 
substitution. That this is indeed the case is shown by the following 
figures for the percentage of w-compound formed by nitration of 
the relevant substances, 

C 6 H 5 -CH 3 C 6 H 5 -CH 2 C1 C 6 H 5 -CHC1 2 C 6 H 5 -CC1 3 
4 14 34 64 

Experiment therefore confirms the theoretical conclusions, but it 
might perhaps have been expected that benzotrichloride would 
have been more strongly w-directing than it is in fact. 

The inductive effect of the chlorine atoms in the above cases has 
only been transmitted through one carbon atom and it might be 
anticipated that such an effect would gradually diminish if a saturated 
side chain of increasing length is introduced between a chlorine 
atom or a group with a similar inductive effect, and the nucleus. 
That this is so is shown by the figures for the percentage of m- 
nitration in two series of compounds which both have a strongly 
electron attracting group in the side chain, 

Ph -NMe 3 X Ph -CH 2 -NMe 3 X Ph -CH 2 -CH 2 -NMe 3 X 
100 88 19 

Ph -CH 2 -CH 2 -CH 2 -NMe 3 X 
5 

Ph -N0 a Ph -CH 2 -NO 2 Ph -CH 2 -CH 2 -NO 2 
93 48 13 

Incidentally these figures are entirely opposed to the alternate 
polarity views, according to which the second compound in each 
series should give op-, and the third should give predominantly 
w-substitution. 

It would not, however, be anticipated that the same damping of 
the inductive effect would be shown in an unsaturated side chain in 
which the substituent is conjugated with the nucleus, but in fact 



AROMATIC STRUCTURE AND SUBSTITUTION 1015 

such is even more the case. Thus benzole acid is TW-, but cinnamic 
acid op-directing, as is Ph 'CH:CH *NO 2 ; the effect of the strongly 
electron attracting carboxyl or nitro-group is completely lost 
although it is directly conjugated with the nucleus and the following 
(most unlikely) state (i) must be assumed, instead of the much more 
obvious (n), 





H 



The mononitration of cinnamic acid is however about ten times 
slower than that of benzene and there must then be a general 
inductive effect in the opposite direction to the mesomeric effect. 

A case which falls well in line with theory is the decrease of 
reactivity produced by acetylating aniline ; this is due to the 
electron attraction of the carbonyl group which makes the unshared 
pair of the nitrogen atom less available for participation in the 
mesomerism of the nucleus. 

The theory outlined above may be extended to polycyclic com- 
pounds such as naphthalene and diphenyl and to heterocyclic 
aromatic substances. Thus the substitution of a-naphthol and 
a-naphthylamine in the 2- and 4-positions is easily understood and 
the substitution of j8-naphthol at 1- or 6- is also clear (in) : in 
diphenyl forms such as (iv) contribute to the mesomerism and 
give op- direction in both rings, 





iv v 

In the case of pyridine the strongly acidic solutions used in 
nitrations, etc., convert the base into a salt (v) in which the nitrogen 
atom then has a similar w-directing and deactivating effect to that 
in the quaternary ammonium derivatives and nitrobenzene. In 
pyrrole, however, where the lone pair is already participating 
in the mesomerism of the ring no salt formation is possible and 

Org. 64 



1016 



AROMATIC STRUCTURE AND SUBSTITUTION 



forms such as those shown on p. 591 account for the great reactivity 
of both the a- and /J-positions. 

As an example of a nucleophilic, as contrasted with the usual 
electrophilic, substitution in the aromatic series the action of 
potash on nitrobenzene in the presence of air to give nitrophenol 
may be mentioned ; in this case the substituting group is the OH~ 
ion, and an oxidising agent (air) must be present to oxidise the H~ 
which is formed, to water. Attack should therefore be at positions 
of least electron density, that is to say the 0- and /^-positions from 
which electrons are withdrawn ; the product is in fact o-nitro- 
phenol. The action of sodamide on pyridine to give a-aminopyridine 
is similarly nucleophilic. 

A few other applications of the electronic theory to aromatic 
chemistry may be considered. 

The stability of the aromatic halides is attributed to contributions 
of forms such as (i) and (n) to the mesomerism ; both the S N 1 
and S N 2 reactions are made difficult as in the vinyl compounds. 






II 



III 



When electron-attracting groups such as NO 2 are present in the 
o- and/or />-position it would appear that the above effect should 
be enhanced and the halides be more stable ; the reverse is, of 
course, the case and it must be assumed that the carbon atom of the 
nucleus to which the halogen is attached becomes more positive 
by withdrawal of electrons, (in), thus allowing easier S N 2 reaction 
by a nucleophilic reagent. A more convincing explanation is 
perhaps found if the transition state is considered ; this is as shown, 






AROMATIC STRUCTURE AND SUBSTITUTION 1017 

(iv), and the negative charge can be on oxygen, whereas on the 
unsubstituted halide it must be on carbon, (v). 

A similar case of easy hydrolysis is provided by />-nitrosodimethyl- 
aniline and here again the negative charge of the transition state 
can be on oxygen, (vi). Such considerations show how the electronic 
theory can rarely be applied with complete safety unless all the 
experimental facts are known ; almost as many new facts can be 
predicted from applications of analogy to organic reactions as from 
theoretical considerations. 

A case of activation of hydrogen atoms in a side chain is provided 
by 2:4-dinitrotoluene which condenses with benzaldehyde to give 
2:4-dinitrostilbene, 

Ph -CHO+H 3 C -C 6 H 3 (N0 2 ) 2 = Ph -CH:CH -C 6 H 3 (NO 2 ) 2 +H 2 O ; 

the strongly electron-attracting nitro-groups conjugated through 
the nucleus with the methyl group cause incipient ionisation of the 
hydrogen atoms of the latter, (i). Similar activation is shown by 
the 2- and 4-methylpyridines, (n), and quinolines by the electron 
attraction of the heterocyclic nitrogen atom, 







II 



CHAPTER 60 

THE ORIENTATION OF BENZENE DERIVATIVES. 
POLYCYCLIC HYDROCARBONS 

Orientation of Benzene Derivatives 

IT may be taken for granted that practically every known di-sub- 
stitution product of benzene, C 6 H 4 X 2 or C 6 H 4 XY, has already been 
orientated by the methods described on pp. 394-399, and that the 
structure of a new di-derivative might be readily determined by con- 
verting the compound into one of those of known orientation. Many 
tri-substitution products, in which two, or all, of the substituent atoms 
or groups are identical, have also been orientated by Korner's method. 
There are, however, various simpler processes by which the 
structures of compounds, C 6 H 3 XYZ, may be determined. When 
toluene is nitrated it gives three mononitro-derivatives ; the o- and 
p-compounds, which are the principal products, can be converted 
into one and the same dinitro -derivative, which, therefore, must be 
the l:2:4-compound, (i). This dinitro-derivative, on reduction 
with ammonium sulphide, affords a mixture of two bases, 
C 6 H 3 (NH 2 )(NO 2 )-CH 3 ; one of these is also obtained by the 
nitration of o-toluidine, in the form of its acetyl derivative, and must 
therefore be represented by (n), whereas the other base is produced 
in a similar manner fromp-toluidine and must have the structure (in). 






From each of these bases many other compounds may be prepared, 
such as CH 3 :NH 2 :NH 2 , CH 3 :OH:NO 2 , and CH 3 :C1:NO 2 , and the 
orientation of all such derivatives is thus established by synthesis. 

In many cases such simple methods are not available, and the 
following procedure is adopted : One of the substituents, say X, 
in the compound, C 6 H 3 XYZ, is displaced by hydrogen ; the 
product, C 6 H 4 YZ, is then identified as the o-, m-, or />-compound, 

1018 



THE ORIENTATION OF BENZENE DERIVATIVES, ETC. 1019 

as the case may be, from a study of its properties, especially, if 
possible, by a mixed melting-point determination. A second sub- 
stituent, say Y, in the compound, C 6 H 3 XYZ, is then displaced by 
hydrogen, and, as before, the product, C 6 H 4 XZ, is identified as the 
0-, m-y or p-compound. The data may then be sufficient for the 
orientation of the tri-derivative, but if not, the substituent Z is 
displaced by hydrogen and the nature of the product, C 6 H 4 XY, is 
established. 

A compound, C 6 H 3 (NH 2 )(NO 2 )-CH 3 , for example, might be 
first converted into C 6 H 4 (NO 2 ) - CH 3 by ,'.:-.p-. s\:\:. the amino-group 
by hydrogen with the aid of the diazonium salt ; the product is, 
say, ^>-nitrotoluene. The original compound is then acetylated, the 
nitro- is reduced to an amino-group, and the latter is then displaced 
by hydrogen as before ; the product is (the acetyl derivative of), 
say, o-toluidine. These data show that the compound is (l). 
Similarly, it will be seen that each of the compounds, (ll) to (vi) 
inclusive, could be orientated by identifying the products of two 
such operations, but in the case of the remaining four, (vn), (vni), 
(ix), and (x), the results would be inconclusive, because (vn) and 
(vin) would give o-nitrotoluene and w-toluidine, and (ix) and (x) 
would give w-nitrotoluene and o-toluidine : 



CH 3 



CH 3 




NO 2 



CH 8 CH 3 CH 3 

^ N0j i^HQ, f 

JNH, NH^ }> U^J^NOj 





VII 



VIII 



IX 



1020 THE ORIENTATION OF BENZENE DERIVATIVES 

In order, therefore, to distinguish between (vn) and (vm), or 
between (ix) and (x), it would be necessary to determine the relative 
positions of the NH 2 and NO 2 groups. For this purpose the 
NH 2 group might be displaced by bromine, and the product 
oxidised to the acid, C fl H 3 Br(NO 2 )-COOH, which is then reduced 
to C 6 H 3 Br(NH 2 ) COOH with stannous chloride and hydrochloric 
acid ; this compound, heated with soda-lime, might give either 
o- or ^-bromoaniline, p. 1022). The relative positions, CH 3 :NO 2 , 
CH 3 :NH 2 , and NO 2 :NH 2 , having thus been determined, the 
orientation of the original compound has been accomplished. 

Although only well-known general reactions are applied in such 
operations, it may happen that one or more of them may not take 
place in a normal manner ; in the case just considered, the oxidation 
of the methyl group might be difficult or might involve the complete 
decomposition of the compound, and the results of the high tem- 
perature reaction with soda-lime might be very unsatisfactory. If so, 
a different procedure might be tried : The original compound might 
be reduced to the diamine and the diacetyl derivative of the latter 
submitted to oxidation ; the product, heated with soda-lime, might 
then give 0- or p-phenylenediamine, for the identification of which 
the diacetyl or dibenzoyl derivative might be used ; the structure of 
the tri-derivative, (vn), (vm), (ix) or (x), would then be determined. 

A similar but more restricted series of operations is often necessary 
even when the tri-substitution product has been prepared from a 
known di -derivative. Thus when m-nitrotoluene is chlorinated it 
may give one or more of the following isomerides, 




NO 2 




N0 2 



II 




and, for its orientation, each of the products must be converted either 
into one, or into two di-derivatives, as the case may be. If, when 
the nitro-group is displaced by hydrogen, one of the products gives 
p-chlorotoluene, it must be (l), whereas if w-chlorotoluene is formed 
it must be (11) ; if, however, the di-derivative is o-chlorotoluene, it will 
be necessary to ascertain the relative positions of the chlorine atom 
and the nitro-group in order to distinguish between (in) and (iv) ; for 



POLYCYCLIC HYDROCARBONS 1021 

this purpose the nitrochloro-derivative might be oxidised to the acid, 
C ft H 3 Cl(NO 2 ) COOH, and the latter reduced to the amino-compound 
with stannous chloride and hydrochloric acid. The amino-acid might 
then give o- or j>-chloroaniline, when it was heated with soda-lime, 
a result which would decide between formulae (in) and (iv). 

When two of the substituents in the tri-derivative are identical 
the orientation of the latter cannot of course be carried out on the 
lines just given, unless one of these substituents can be converted 
into another, which is readily displaceable by hydrogen. The 
orientation of a compound, C 6 H 3 Me(NO 2 ) 2 , would be possible in 
that way, because one of the nitro-groups may be reduced, leaving 
the other unchanged, and a compound, C 6 H 3 XYZ, would thus be 
formed. When, however, one of the two identical groups cannot 
be thus differentiated, the tri-derivative may often be orientated by 
making use of other compounds of known structure. 

The nitrophthalic acid (m.p. 219) obtained by the oxidation of 
nitronaphthalene gives an anhydride, and is therefore a derivative 
of o-phthalic acid ; further, it can be prepared by the nitration of 
phthalic acid and must therefore be represented by (i) or (n). 



COOH COOH 





Now from the base (ix, p. 1019), with the aid of the Sandmeyer 
reaction, the amino- is displaced by the cyano-group and the latter 
is hydrolysed to COOH ; the methyl group is then oxidised and 
a nitrophthalic acid identical with that obtained from nitro- 
naphthalene results. The nitrophthalic acid from naphthalene has 
therefore the structure (i). 

An alternative process, namely the conversion of the tri- 
derivative of unknown structure into one which has already been 
orientated, is often used. Thus w-cresol is readily chlorinated, 
giving a mixture of monochloro-derivatives, which may contain 
four isomerides, corresponding with those obtained from m-nitro- 
toluene (p. 1020). One of these compounds (which can be isolated 
by fractional distillation) is treated with dimethyl sulphate and 
alkali and the product is then oxidised with permanganate ; the 



1022 THE ORIENTATION OF BENZENE DERIVATIVES 

chloromethoxybenzoic acid which is thus obtained is found to be 
identical with the acid, COOH:OMe:Cl = 1:3:4, so that the chlorine 
atom in this chloro-w-cresol is in the ^-position to the methyl radical. 

This last method, as a rule, is the most convenient one for such 
orientations, as it may be necessary to change one group only of the 
tri-derivative ; its applicability becomes more and more general, of 
course, with every increase in the number of compounds which 
have been orientated. 

The structures of the higher substituted benzene derivatives are 
determined by analytical, synthetical, and comparative methods 
similar to those used in the case of the tri-derivatives. 

The displacement of an aromatic substituent by hydrogen is a 
very important operation in many orientations. This is a simple 
matter in the case of halogens (p. 426) and NH 2 or NO 2 groups 
(p. 455), but for the displacement of COOH and of OH by 
hydrogen a high temperature is required, and the operations may 
lead to unsatisfactory results ; for such processes nitro -compounds 
must first be reduced to amino -compounds, otherwise complete 
decomposition may occur. For the displacement of an alkyl group, 
the compound must usually be oxidised to the corresponding acid ; 
this is not always possible, and in any case an amino-group, if present, 
must be protected by acetylation or benzoylation, and a hydroxyl 
group by methylation, before oxidation is attempted. Alkyloxy- 
groups cannot be directly displaced, and must be converted into 
phenolic groups before the compound is heated with zinc-dust. 

Poly cyclic Hydrocarbons 

Some of the many hydrocarbons obtained from coal-tar have 
been described, but others of a more complex nature have been 
isolated from this source and many have been synthesised. 

Those obtained from coal-tar usually contain condensed benzene 
nuclei, as in the examples shown below : 





Pyrcnc, CieHio Chrysenc, 



POLYCYCLIC HYDROCARBONS 



1023 





Picene, 



Fluorene, 



Pyrene crystallises in pale yellow plates, m.p. 149, and is formed 
by treating diphenyl-oo'-diacetyl chloride with aluminium chloride 
and reducing the resulting diketone with hydriodic acid and red 
phosphorus. 

Chrysene (l:2-benzphenanthrene), m.p. 250, may be synthesised 
by strongly heating l-phenyl-2-a-naphthylethane or indene, or by 
other methods which are mentioned later (pp. 1030, 1033, 1034). 

Picene (l:2:7:8-dibenzphenanthrene), m.p. 365, is formed, among 
other compounds, by heating a-methylnaphthalene with sulphur 
or by the interaction of naphthalene, ethylene dibromide, and 
aluminium chloride. 

Fluorene, m.p. 116. is produced by passing diphenylmethane 
through a heated tube or from diphenyl, methylene dichloride and 
aluminium chloride. 

The two isomeric dibenzanthracenes, (i) and (n), are of interest 
in that (i) is colourless, reacts slowly with maleic anhydride, and 
causes cancer when applied to the skin (of mice), whereas (n) is 
deep blue, reacts instantly with maleic anhydride, and has no 
carcinogenic activity : 





II 



Other powerfully carcinogenic compounds are methylchol- 
anthrene, a derivative of the steroids (p. 1087), and benzpyrene, 



1024 THE ORIENTATION OF BENZENE DERIVATIVES 

which has been isolated from pitch ; all these carcinogenic sub- 
stances are derivatives of l:2-benzanthracene, which itself has no 
carcinogenic activity. 





Methylcholanthrene 



Benzpyrene 




Benzanthracene 



Coronene (' hexabenzobenzene *) is a very interesting and highly 
complex hydrocarbon, which has been synthesised by Scholl and 
Meyer, K. (Ber. 1932, 902). The chloride of anthraquinone-l:5- 
dicarboxylic acid reacts in a tautomeric form, (m), with m-xylene 
in the presence of aluminium chloride, yielding chiefly (iv), 



p CO 




Me 



OC O 



III 




POLYCYCLIC HYDROCARBONS 



1025 



This product is oxidised to the corresponding tetracarboxylic- 
dilactonic acid, which, on reduction, is converted into the hexa- 
carboxylic acid, (v). 

When (v) is treated with 20% oleum, it gives (vi), from which 
(vn) is formed, on reduction with hydriodic acid and phosphorus : 



COOH 



COOH 



HOOC 



COOH 




OC 



COOH 



HOOC 




HOOC 



H 2 C 



CH 2 




H 2 C 



CH, 



VII 



This compound (VH), heated with soda-lime and copper powder, 
loses four atoms of hydrogen, giving a coronene derivative, in the 
molecule of which there are nine closed chains. On oxidation with 
nitric acid, two of the closed chains undergo fission and a tetra- 
carboxylic acid, (vm), is formed ; when this acid is heated with soda- 
lime it gives coronene, (ix). 



1026 THE ORIENTATION OF BENZENE DERIVATIVES 
HOOC COOH 




HOOC 



COOH 




VIII 



IX 



Coronene is pale yellow, fluorescent, and exceedingly stable. 

Some other very iiiiciv-'.ir.u hydrocarbons have been investigated 
by Moureu, Dufraisse, and their collaborators (Compt. Rend. 1926, 
1440, and later). One of these compounds, rubrene or 9:10:11:12- 
tetraphenylnaphthacene (tetraphenylbenzanthracene), is formed by 
heating the chloride of diphenylphenylethinyl carbinol (see below) 
in a vacuum, 



Ph Ph 





Rubrene, as its name implies, is a red compound, which shows 
a yellow fluorescence in benzene solution ; it is oxidised by chromic 
acid to o-dibenzoylbenzene and carbon dioxide. A solution of 
rubrene (R) in benzene absorbs oxygen when it is exposed to light, 
and a colourless peroxide, oxyrubrene (RO 2 ), which crystallises with 
half a molecule of benzene, can be isolated from the solution. When 
it is suddenly heated at about 180, oxyrubrene decomposes into 
rubrene and oxygen with the emission of a greenish-yellow light. 
The interconversion of rubrene and oxyrubrene in the above simple 
manner recalls that of haemoglobin and oxyhaemoglobin. 

The carbinol mentioned above can be obtained by treating benzo- 
phenone with sodiophenylacetylide, CNajCPh, and decomposing 
the additive compound with water ; the carbinol is converted into 
the chloride with the aid of phosphorus trichloride. 



POLYCYCLIC HYDROCARBONS 1027 

Terphenyl, Quaterphenyl, etc. 

Chain-like polycyclic aromatic hydrocarbons can be obtained 
from nuclear aromatic halogen compounds by the Wurtz-Fittig 
reaction, or by the Ullmann modification of that reaction 
(p. 420). Terphenyl or l:4-diphenylbenzene, C 6 H 5 -C 6 H 4 -C 6 H 5 , is 
formed when a mixture of />-dibromobenzene and bromobenzene 
is heated with sodium, and quaterphenyl, C 6 H 5 -C 6 H 4 -C 6 H 4 -C 6 H 5 , 
is obtained, together with some sexiphenyl, when 4:4'-di-iodo- 
diphenyl is heated with silver powder at about 240 ; in this latter 
reaction some of the iodine is displaced by hydrogen. 

O.i ; / / . j/7. /, -. 7, C 6 H 5 C 6 H 4 C 6 H 4 C 6 H 4 - C 6 H 5 , is prepared from 
a mixture of 4-iodoterphenyl and 4-iododiphenyl with the aid of 
silver at high temperatures, whereas sexiphenyl^ C 6 H 5 [C 6 H 4 ] 4 C 6 H 5 
(m.p 465), is obtained from 4-iodoterphenyl alone, under similar 
conditions, or by heating a mixture of 4-iododiphenyl (2 mol.) and 
4:4 / -di-iododiphenyl (1 mol.) with copper at 220. 

Methyl derivatives of hydrocarbons of this type may be obtained 
similarly ; 4A'-dimethylsexiphenyl, CH 3 C 6 H 4 [C ? H 4 ] t - C 6 H 4 CH 3 , 
for example, is prepared from 4:4'-methyliododiphenyl (2 mol.) 
and 4:4'-di-iododiphenyl (1 mol.) with the aid of copper. 

The methyl groups in the molecules of such compounds can be 
oxidised with chromic anhydride in glacial acetic acid solution ; 
the carboxylic acids thus derived from quaterphenyl and higher 
members of this polycyclic series are very sparingly soluble in 
ordinary solvents, and their sodium salts are practically insoluble in 
boiling water. A summary of the more important work on these 
compounds is given by Pummerer and SHiihb<TjriT (Ber. 1931, 2477). 

A much more interesting general method for the preparation of 
such polycyclic aromatic hydrocarbons is based on the Diels-Alder 
reaction. l:4-Diphenylbutadiene combines directly with maleic 
anhydride, giving a product which can be hydrolysed to the 
corresponding acid ; when the calcium salt of the latter is strongly 
heated with lime and zinc-dust, it is converted into terphenyl : 



C 6 H 6 






1028 THE ORIENTATION OF BENZENE DERIVATIVES 

Kuhn and Wagner-Jauregg applied this method to the diphenyl- 
polyenes (p. 980) and found that these compounds combined with 
maleic anhydride, one molecule of the latter being added to every 
complete conjugated system, CH:CH-CH:CH , of the polyene, 
during which reaction the pronounced colour of the hydrocarbon 
disappeared ; the l:4-additive products thus obtained were hydro- 
lysed, and the calcium salts of the acids were heated with lime and 
zinc-dust, and thus converted into polycyclic hydrocarbons (Ber. 
1930, 2662). 

Diphenylhexatriene, like diphenylbutadiene, combines with only 
one molecule of maleic anhydride, but diphenyloctatetrene, in the 
molecule of which there are two complete conjugated systems, 
combines with two, giving an additive product, 

HC=CH HC=CH 

-HC^ / CH * HC v H-CeH - C 6 H 5 .C 6 H 4 .C 6 H 4 -C 6 H 5 

HC CH 

OC. .CO 




from which quaterphenyl can be obtained by the given method. 
It is interesting to note that derivatives of terphenyl occur in the 
colouring matter of certain fungi. 

Synthesis of Di- and Poly-cyclic Compounds 

Many methods are available for the synthesis of (di- and) poly- 
cyclic aromatic or hydroaromatic ring systems ; the most important 
general reactions for the production of the former are the following : 

(1) The condensation of two molecules of an aromatic hydro- 
carbon by the direct elimination of hydrogen at relatively high 
temperatures : examples are the preparation of diphenyl from 
benzene, phenanthrene from o-ditolyl or stilbene, fluorene from 
diphenylmethane, chrysene from phenylnaphthylethane or indene 
and of picene from a-methylnaphthalene (p. 1023). 

(2) The Wurtz-Fittig reaction, as in the production of diphenyl 
from bromobenzene and of anthracene and phenanthrene from 
o-bromobenzyl bromide ; the yields are usually poor, but are 
improved when copper is used instead of sodium (Ullmann, p. 420). 

(3) The Friedel-Crafts reaction, as in the preparation of anthra- 
cene from benzyl chloride, or from benzene and tetrabromoethane ; 



POLYCYCLIC HYDROCARBONS 1029 

also of fluorene from diphenyl and methylene dichloride and of 
picene from naphthalene and ethylene dibromide (p. 1023). 

(4) The use of diazonium salts, as in the Pschorr synthesis of 
phenanthrene. This reaction has been extended to the preparation 
of derivatives of that hydrocarbon and other diazonium salts may 
behave in an analogous manner. o-Nitrophenyldiazonium chloride, 
for example, with cuprous chloride gives mainly oo'-dinitrodiphenyl 
and not o-chlorobenzene ; similarly many phenyldiazonium salts, 
which give a normal Sandmeyer reaction, afford diphenyl deriva- 
tives with alcohol and copper powder ; phenyldiazonium sulphate 
with the latter gives diphenyl, and with formic acid and copper 
powder, a mixture of diphenyl, terphenyl, quaterphenyl, etc. 

(5) The decomposition of o-methylbenzophenones by heating 
them alone or with zinc-dust (Elbs) : 





H 2 O 



(6) The dehydrogenation of hydroaromatic ring systems (below) 
with sulphur or selenium, or with palladium-charcoal, a method of 
great importance in the determination of the structure of the 
sesquiterpenes, e,tc. 

The more important general methods for the production of 
hydroaromatic compounds are : 

(1) The cyclisation of compounds such as geraniol, linalool, 
nerolidol, etc., as already shown (p. 941), readily gives six-membered 
ring compounds, and illustrates a general type of change which 
occurs when (a) two double bonds or (b) one double bond and a 
>C(OH)-CH< group (which easily loses water) are suitably 
situated in the same molecule. Simple examples are the conversion 
of the methylheptenol, (i), into 1:1 -dimethyl- A-3-cyc/ohexene, (n), 
with phosphoric acid, and of the unsaturated tertiary alcohols, (ill) 
and (iv), into 9-methyl-A-2-octahydronaphthalene : 







1030 THE ORIENTATION OF BENZENE DERIVATIVES 



cb 




cb 



III 



OH 
IV 



A reaction of a very similar type occurs when a suitable side chain 
aromatic alcohol or olefine is treated with sulphuric acid, stannic 
chloride, aluminium chloride, etc. : 




VI 



VII 



The synthesis of naphthalene from phenylbutylene (p. 541) is of a 
similar type, but dehydrogenation also occurs. The compound, (v), 
used in the synthesis of (vi), was prepared by condensing the 
potassium derivative of ethyl cyc/0hexanone-2-carboxylate with 
j3-phenylethyl bromide followed by ketonic hydrolysis and reduction, 
whereas (vn) was obtained by the dehydration of the alcohol from 
j8-phenylethyl n.;ii?iu':>iuin bromide and ry^/ohexanone. On de- 
hydrogenation (vi) gives phenanthrene. Retene (p. 948) and cyclo- 
pentenophenanthrene (cf. p. 1089), as well as chrysene, picene, 
etc., have been synthesised by a similar method : 





Darzens has performed many syntheses of a like nature in which 
sulphuric acid at about 45 is used as the condensing agent ; thus 
(vm), in which R=Me, CHMe 2 , or OMe, gives (ix) : 




POLYCYCLIC HYDROCARBONS 



COOH 



1031 




COOH 



VIII 



IX 



A very interesting hydrocarbon in which condensation had occurred 
in the meta-position was synthesised by Cook and Hewett from 
1-benzylryc/ohexanol with phosphorus pentoxide at 160 ; 





This reaction is one of the very rare cases in which ring formation 
occurs in other than the o- position. 

(2) Many cyclic 1:5 -ketonic esters or diketones undergo inner con- 
densations in the same way as their open chain analogues (p. 799), 
as illustrated by the following examples (Linstead, Kon, Ruzicka) : 



NaCH(COOEt) 

CO'CH; 



o 

^sX^^ 




Org.65 



1032 THE ORIENTATION OF BENZENE DERIVATIVES 

In the first case acetyl-A-1-ryc/ohexene 1 is condensed with diethyl 
sodiomalonate and in the second with ethyl sodioacetoacetate 
(Michael reactions) : cyclisation then occurs with the elimination 
of alcohol and water respectively. 

A slightly different method has been used by Robinson : the 
sodio-derivative of a saturated ketone, usually prepared with the 
aid of sodamide, is added to an aj8-unsaturated ketone, by a modified 
Michael reaction, whereon the resulting l:5-diketone undergoes 
spontaneous ring formation. Thus, sodiocyc/ohexanone condenses 
with methylstyryl ketone (benzylideneacetone) to give finally (x) : 



a 




k 




Attempts to extend this method to simple unsaturated ketones, such 
as methylvinyl ketone, were unsuccessful as such substances were 
polymerised by sodamide ; it was found, however, that a Mannich 
base methiodide could be used as a source of such a ketone. Thus 
when acetone is heated with diethylamine hydrochloride and form- 
aldehyde, condensation to the hydrochloride of a compound known 
as a Mannich base occurs, 

CH 3 .CO-CH a +CH 2 Of Et 2 NH,HCl - 

CH 3 -CO-CH 2 .CH 2 .NEt 2 ,HCl+H 2 O : 

the free base, with methyl iodide, gives the quaternary salt, which is 
then condensed with the ketone in the presence of sodamide : 

H ? C 





Presumably the methiodide decomposes into the unsaturated ketone 
during the reaction and is acted on by the sodioketone before poly- 
merisation can occur. 

1 Cyc/ohexene with acetyl chloride in the presence of stannic chloride 
yields 2-chloroacetylcycfohexane which is heated with pyridine. 



POLYCYCLIC HYDROCARBONS 



1033 



A more complex synthesis is exemplified by the condensation of 
acetylcyc/ohexene and a-tetralone to give finally a ketodecahydro- 
chrysene, which may be reduced (Clemmensen) and dehydro- 
genated to chrysene, 





(3) Suitable aromatic ketonic esters also undergo cyclisation, in 
which water is eliminated from the enolic form ; thus the condensa- 
tion product of j3-phenylethyl bromide and ethyl sodioacetoacetate, 
(i), yields (n) : 





COOEt 



ii 



Ruzicka and his co-workers condensed jS-1-naphthylethyl bromide 
with ethyl ryc/ohexanone-2-carboxylate to give (in), which when 
boiled with 50% sulphuric acid gave (iv) and then yielded chrysene 
on dehydrogenation and decarboxylation : 




,CH 2 Br 



COOEt 

JO 



COOEt 




III 



COOEt 




IV 



1034 THE ORIENTATION OF BENZENE DERIVATIVES 

(4) Cyclic ketones have been made from acids with sulphuric 
acid as the condensing agent or from acid chlorides and aluminium 
chloride in the same way as a-indanone and its homologues (F. S. 
Kipping). These reactions may be typified by the preparation of 
a-tetralone and are very general: 





The resulting ketones may be reduced by Clemmensen's method 
and the products dehydrogenated to aromatic hydrocarbons ; or 
the ketone may be acted on with a Grignard reagent and afterwards 
dehydrated and dehydrogenated. In this way numerous naph- 
thalene and phenanthrene derivatives have been prepared. R. D. 
Haworth and his co-workers have condensed naphthalene deriva- 
tives with succinic anhydride (aluminium chloride), reduced the 
keto-acid and cyclised the product with sulphuric acid : 

CO-CH 2 'CH 2 COOH 





CHj-CHj-CHfCOOH 




Phthalic anhydride can be condensed in the same way (cf. p. 561), 
and the quinone may then be converted into benzanthracene : 





C 10 H, 



A slightly more complex case is presented by the double cyclisation 
of (v) by either method ; the product on reduction and dehydro- 
genation yields chrysene : 



POLYCYCLIC HYDROCARBONS 



1035 



.COOK. 




COOH 




Similar reactions have been carried out with hydroaromatic acids : 
thus the chloride of (vi) gives (vn) on treatment with stannic chloride : 




OH 




VI 



VII 



(5) The Diels-Alder diene synthesis has been applied to the 
preparation of many polycyclic hydroaromatic compounds : 
examples which need no description are appended : 



oc 




1036 THE ORIENTATION OF BENZENE DERIVATIVES, ETC. 

(6) Numerous polycyclic compounds have been prepared by 
the application of the methods of cyclic ketone formation from 
dibasic acids, either by the destructive distillation of a suitable salt 
of the acid or by the Dieckmann process (p. 780). 



CHAPTER 61 

ALKALI METAL COMPOUNDS, FREE RADICALS 
AND STERIC HINDRANCE 

Alkali Metal Compounds 

THE alkyl derivatives of zinc and mercury which have already been 
described (p. 233) were discovered by Frankland in 1849, and, until 
they were superseded by the much more accessible Grignard re- 
agents, were compounds of great importance in many ways. In 
1858, Wanklyn showed that sodium decomposed zinc diethyl with 
the separation of zinc, but a sodium alkyl was not isolated ; later, 
Acree found that, with sodium, mercury diphenyl in boiling benzene 
solution yielded sodium phenyl as an insoluble powder. During 
more recent times, Schlenk and Ziegler (and their co-workers) have 
studied such metallic compounds independently, and the following 
is a brief account of their results. 

Sodium ethyl, C 2 H 5 Na, is gradually formed when mercury diethyl, 
dissolved in light petroleum, is heated with sodium in the absence 
of oxygen. Other sodium and potassium alkyls can be obtained in 
a similar manner. They are colourless solids, insoluble in organic 
solvents, decompose when they are heated, and inflame on exposure to 
the air ; when treated with water, alcohol, or ether, they give paraffins, 

RNa+(C 2 H 5 ) 2 O = RH+C 2 H 4 f C 2 H 5 -ONa. 

The corresponding lithium alkyi compounds, with the exception 
of lithium methyl, are soluble in petroleum and benzene without 
decomposition. Lithium ethyl, C 2 H 5 Li, crystallises from benzene, 
has a sharp melting-point, and distils unchanged in the absence of 
oxygen. Sodium phenyl and lithium phenyl, prepared from mercury 
diphenyl, are colourless, insoluble in indifferent solvents, and 
inflame in the air, but sodium benzyl is an intensely red crystalline 
compound, which reacts with tetramethylammonium chloride, 
giving tetramethylbenzylammonium, which is also a red solid, 

C 6 H 5 .CH 2 Na+NMe 4 Cl = NMe 4 .CH 2 -C 6 H 5 +NaCl. 

Another method for the preparation of alkali metal organic 
compounds is by the action of the metal on certain ethers, 

RNa+R-ONa. 

1037 



1038 ALKALI METAL COMPOUNDS 

Potassium phenyldimethylmethyl) CMe 2 PhK, for example, is prepared 
by treating methylphenyldimethylmethyl ether in ethereal solution 
with a sodium-potassium alloy, in an atmosphere of nitrogen ; 
the solution gradually turns red owing to the formation of the 
potassium derivative, 

CMe 2 Ph-OCH 3 +2K = CMe 2 PhK+CH 3 .QK. 

This compound combines directly with various olefinic substances, 
giving products which are usually highly coloured ; with phenyl- 
and diphenyl-ethylene, for example, it gives, respectively, 

C e H 5 .CHK-CH 2 -CMe 2 Ph and C 6 H 5 - CHK - CHPh - CMe 2 Ph. 

Certain lithium alky Is and aryls may also be prepared by treating 
an alkyl or aryl halide with the metal in the presence of ether or 
benzene. The alkyl chlorides are most suitable for this purpose, 
as the bromides, and especially the iodides, readily undergo the 
Wurtz-Fittig reaction, which occurs in two stages : 

RI+2Na = RNa+Nal, 
= R-R+NaI. 



A solution of lithium butyl, prepared from the chloride, gives 
additive compounds with various defines ; with unsymmetrical 
diphenylethylene, for example, the product is C 4 H 9 CH 2 -CLi(C 6 H 5 ) 2 , 
as is shown by the fact that, when treated first with carbon dioxide 
and then with acids, it is converted into aa-diphenyl-n-heptylic acid, 
C 4 H 9 .CH 2 .C(C 6 H 5 ) 2 .COOH. 

A potassium derivative of triphenylmethyl (p. 1040) is obtained 
by treating triphenylmethane with potassamide in liquid ammonia, 

Ph 3 CH+KNH 2 = Ph 3 CK+NH 3 . 

Sodium and potassium combine with certain olefinic compounds, 
giving either a simple additive product or a compound formed from 
two molecules of the olefine : 

Ph 2 C:CPh 2 +2Na = Ph 2 CNa-CNaPh 2 , 
2Ph 2 C:CH 2 +2Na - Ph 2 CNa CH 2 - CH 2 - CNaPh 2 . 
The second type of reaction occurs in two stages, as shown, 

Ph 2 CNa-CH 2 Na+Ph 2 C:CH 2 = Ph 2 CNa-CH 2 .CH 2 .CNaPh 2 . 
The polymerisation of olefines by sodium (p. 969) is probably due 



FREE RADICALS AND STERIC HINDRANCE 1039 

to a reaction of this kind, which, theoretically, may be repeated 
indefinitely with other molecules of the olefine. 

As a rule only those ethylenic compounds in which aryl groups 
are combined with one or both of the olefinic carbon atoms, form 
additive derivatives with the alkali metals ; an exception, however, 
occurs in the case of di-wobutylene-ethylene, which reacts in the 
following manner : 

Me a C:CHy 

2 >C:CH 2 +2Na 

MeaCrCH/ 

Me a C:CHx yCH:CMe a 

/ CNa - CH 2 - CH, - CNa<" 
H/ N CH:CMe, 



It is also noteworthy that certain purely aromatic compounds 
may give metallic derivatives ; 4-phenyldiphenyl(terphenyl,p. 1027), 
for example, gives the compound, 




All these alkali metal compounds are decomposed by water, alcohol, 
and other substances containing a hydroxyl group, or capable of 
existing in an enolic form, and the metal is displaced by li\ti 012011. 
When treated with carbon dioxide, they give salts of carboxylic 
acids, and, as shown above, the identification of the product of such 
a reaction serves to establish the constitution of the metal derivative. 
They react with alkyl halides in different ways according to 
their structure, as illustrated by the following examples : 

Ph 2 CNa-CNaPh 2 4-2CH 3 I = Ph 2 C:CPh 2 +C 2 H 6 +2NaI, 

Ph 2 CNa.CH 2 .CH 2 .CNaPh 2 +2CH 3 I = 

Ph 2 C(CH 3 ) - CH 2 - CH 2 - C(CH 3 )Ph 2 + 2NaI. 

The alkali metal compounds described above may be classed as 
follows : (1) Simple colourless alkyl or aryl metal compounds, 
such as potassium ethyl and sodium phenyl, insoluble in organic 
solvents and decomposed by ether (p. 1037). (2) Coloured com- 
pounds usually stable towards ether and soluble in organic solvents 
to form conducting solutions ; those compounds in which the 
carbon atom combined with the metal is directly united to a benzene 



1040 ALKALI METAL COMPOUNDS 

nucleus (or to an olefinic carbon atom) belong to this group, as 
for example sodium benzyl, potassium phenyldimethylmethyl, and 
di-sodium l:2-diphenylethylene. (3) Colourless substances soluble 
in organic solvents, some of which, such as lithium ethyl, may be 
distilled or sublimed ; such compounds are similar to the alkyl 
derivatives of the metals of the second periodic group ; they are 
non-electrolytes, and even when mixed with zinc dialkyls are poor 
conductors of electricity. 

Free Radicals 

The fundamental assumption that carbon is quadrivalent in all its 
compounds is the basis of the structural formulae of organic 
chemistry, and the use of double and treble bonds is not only a 
necessary consequence of this assumption but seemed to be justified 
by the fact that, until 1900, it had not been possible to obtain any 
substance in which such quadrivalency could not be postulated. 
It is true that, before that time, Nef had questioned this assumption 
and, in a series of papers published in the Annalen from 1890 onwards, 
had argued that the molecules of hydrogen cyanide, alkyl wocyanides, 
fulminic acid, and halogen substitution products of acetylene, 
contained bivalent carbon atoms. His experimental evidence no 
doubt seemed to justify his conclusions, but as it was also possible 
to explain his results with the aid of the orthodox formulae, his 
arguments did not carry conviction. 

In 1900, however, Gomberg prepared triphenylmethyl, the 
existence of which seemed to demand a modification of the accepted 
views ; since then it has been shown by various workers that not 
only carbon, but also several other elements, give rise to compounds 
of greater or less stability in which the ordinary valency of the 
element is not shown ; a brief account of some of these cases of 
* abnormal valency * is given below. 

Compounds of Tervaknt Carbon 

In attempting to prepare hexaphenylethane, Gomberg treated 
triphenylmethyl chloride, in benzene solution, with copper, silver, 
zinc, or mercury in the absence of air ; the product had the com- 
position of hexaphenylethane , but its properties were not those of 
such a compound. Its solution was yellow, but on evaporation in 
an indifferent atmosphere gave a colourless substance, m.p. about 



FREE RADICALS AND STERIC HINDRANCE 1041 

95, which crystallised with benzene ; the yellow solution rapidly 
absorbed oxygen, giving a colourless peroxide, Ph 3 C-O-O-CPh 3 , 
m.p. 185, which yielded triphenyl carbinol with concentrated 
sulphuric acid. The solution also reacted with iodine, giving tri- 
phenylmethyl iodide, and with nitric oxide and nitrogen peroxide 
yielding substances, Ph 3 C NO and Ph 3 C NO 2 respectively ; with 
sodium a red salt, sodium triphenylmethyl y Ph 3 C-Na, was produced, 
and with concentrated hydrochloric acid, p-diphenylmethyltetra- 
phenylmethane, Ph 2 CH - C 6 H 4 CPh 3 (p. 1045). 

This new type of highly reactive compound was named triphenyl- 
methyl and represented by the formula, CPh 3 , because it seemed 
that it could not be hexaphenylethane, CPh 3 CPh 3 . Cryoscopic 
determinations, however, gave results considerably higher than 
those required for triphenylmethyl. It was therefore concluded 
that the colourless solid (m.p. 95) is hexaphenylethane, which 
partly dissociates in solution, giving two molecules of yellow 
triphenylmethyl , 

Ph 3 C-CPh 3 T* 2Ph 3 C; 

as : ,'", dissociation would take place on treatment with 
reagents this view would account for the additive reactions given 
above. 

In ionising solvents, such as sulphur dioxide, colourless hexa- 
phenylethane affords a coloured conducting solution in which it is 
assumed that triphenylmethyl cations exist, an electron having been 
lost to the solvent, 

Pri 3 C-CPh 3 7-* 2Ph 3 C+ + 2e, 
or that both cations and anions have been formed, 

Ph 3 C-CPh 3 ^! Ph 3 C+ + Ph 3 C-. 

Triphenylmethyl halides similarly give conducting solutions in 
sulphur dioxide, while triphenylmethyl anions are furnished by 
sodium triphenylmethyl, 

Ph 3 CNa ^ Ph 3 C- + Na+. 

The triphenylmethyl complex can thus exist as an uncharged 
radical, as a carbanion, or as a carbcation. 

Tri-4-diphenylmethyl, (C 6 H 6 C 6 H 4 ) 3 C, is obtained from the corre- 
sponding chloride by treatment with copper and exists in the solid 
form in dark green crystals ; cryoscopic determinations show that 



1042 ALKALI METAL COMPOUNDS 

in benzene solution almost the whole of the compound is present 
in the ' monomolecular ' form. 

Tri-4-nitrophenylmethyl y (NO 2 - C 6 H 4 ) 3 C, and pentaphenylcydo- 
pentadienyl, (in), are respectively deep green and violet, and do not 
seem to associate. The latter is prepared by reducing the diketone, 
(l), formed from desoxybenzoin (phenylbenzyl ketone) and formal- 
dehyde to a cyclic pinacol, (n), eliminating water (2 mol.), con- 
densing with />-nitrosodimethylaniline and hydrolysing the product 
to 2:3:4:5-tetraphenylryrfopenta-A-2:4-dienone ; this compound 
reacts with phenyl magnesium bromide giving the tertiary alcohol 
which is converted into the chloride and treated with silver, 

HO OH 

Ph-OC CO-Ph Ph-C C-Ph Ph-C-C-Ph 

t \ > / \ > // \\ 

Ph-HC CH-Ph Ph-HC v CH-Ph Ph-C C-Ph 

C X C X X C X 

H 2 H 2 - h 

I II III 

Diphenyl-f$-naphthylmethyl y Ph 2 (C 10 H 7 )C, on the other hand, is 
* bimolecular ' in the solid state, but dissociates to the extent of 
from 15 to 50% in various solvents. 

7Y/i//j/>//</f i/< /in/. Ph 3 C-CPh 2 , is formed by the action of sodium 
triphenylmethyl on benzophenone dichloride in ethereal solution 
in an atmosphere of nitrogen (Schlenk and Mark, Ber. 1922, 2285), 

2Ph 3 CNa+Ph 2 CCl 2 = Ph 3 C.CPh 2 -CPh 3 +2NaCl ; 

on evaporation, the solution gives a mixture of pentaphcnylethyl 
(golden yellow crystals) and hexaphenyle thane (triphenylmethyl). 

Many iiiiii1(M^- l i> compounds containing (tervalent) carbon atoms 
of abnormal valency have been prepared, and they all show additive 
reactions analogous to those of triphenylmethyl. In all such cases 
it would seem that the normal or ' bimolecular 9 compounds are 
colourless or nearly so, whereas the radicals (or ions) containing 
tervalent carbon atoms are highly coloured, but the changes in 
colour of the solutions are not always parallel to the changes in the 
extent of the dissociation. 

Compounds of other Elements with Abnormal Valency 

When a solution of diphenylsilicon dichloride, SiPh 2 Cl 2 , in 
toluene is heated with sodium, various compounds are formed ; 



FREE RADICALS AND STERIC HINDRANCE 1043 

among others two crystalline substances of the composition, (SiPh a ) n . 
One of these is relatively very stable, and gives cryoscopic results 
which correspond with those required for an octaphenylcyclosilico- 
tetrane, Si 4 Ph 8 ; the other is so sparingly soluble that its molecular 
weight cannot be determined cryoscopically, but as it is readily 
attacked by iodine in benzene solution at the ordinary temperature, 
giving a compound, Si 4 Ph 8 I 2 , it is regarded as an octaphenylsilico- 
tetrane, SiPh 2 -SiPh 2 -SiPh 2 -SiPh 2 , the molecule of which contains 
two tervalent silicon atoms. This compound differs from those which 
contain tervalent carbon atoms in being colourless, both in the solid 
state and in solution, but it is extraordinarily reactive, and even 
when it is boiled with benzyl alcohol, benzaldehyde, nitrobenzene, 
ethylene dibromide, etc., it muK-iuoos change, giving oxides, 
Si 4 Ph 8 O 2 , Si 4 Ph 8 O, and other products. 

When trimethylstannic bromide, dissolved in liquid ammonia, is 
treated with sodium, a colourless solid, m.p. 23, is obtained ; from 
the results of cryoscopic measurements, it is concluded that dilute 
solutions of this product contain trimethyltin, (CH 3 ) 3 Sn, which, in 
more concentrated solutions, gives ' bimolecular ' hexamethyl- 
dislannane, (CH 3 ) 3 Sn Sn(CH 3 ) 3 . The compound combines with 
chlorine, giving trimethylstannic chloride , and with sodium, yielding 
sodium trimethyltin, (CH 3 ) 3 SnNa. Organic compounds of bivalent 
tin are also known. 

The interaction of />-xylyl magnesium bromide and lead dichloride 
yields a compound of the composition of a hexaxylyldiplumbane, 
(C 6 H 3 Me 2 ) 3 Pb Pb(C 6 H 3 Me 2 ) 3 , and cryoscopic results in benzene 
solution correspond with this formula. As, however, the com- 
pound gives coloured solutions and combines with bromine in 
pyridine solution at 40, yielding trixylylplumbic bromide, it 
probably dissociates in solution, giving Pb(C 6 H 3 Me 2 ) 3 . Cyclohexyl 
magnesium bromide reacts with lead dichloride, giving a compound 
which in dilute solution has a molecular weight corresponding with 
that of tricyclohexyllead, Pb(C fl H n ) 3 ; this product combines with 
iodine, yielding tricyclohexylplumbic iodide. 

Wieland, in 1911, showed that tetraphenylhydrazine, which is 
colourless in the solid state, gives in boiling toluene a green solution ; 
as treatment with nitric oxide results in the formation of diphenyl- 
nitrosoamine, NPh 2 -NO, it was concluded that the solution contained 
a free radical : 

Ph 2 N.NPh 2 ;H 2Ph 2 N. 



1044 ALKALI METAL COMPOUNDS 

Tetra-anisylhydrazine, (MeO - C 6 H 4 ) 2 N N(C 6 H 4 - OMe) 2 , and tetra- 
p-dimethylaminophenylhydraztne, (Me 2 N C 6 H 4 ) 2 N N(C 6 H 4 NMe 2 ) 2 , 
also dissociate in solution but to a rather larger extent. 

Hexaphenyltetrazane, Ph 2 N - NPh NPh - NPh 2 , gives dark blue 
solutions the colour of which increases when they are warmed or 
diluted ; with nitric oxide it gives nitrosotriphenylhydrazine, 
Ph 2 N-NPh-NO. It is inferred from these facts that the tetrazane 
dissociates, giving 2Ph 2 N-NPh. 

Diphenylpicrylhydrazyl, Ph 2 N-N-C 6 H(NO 2 ) 3 -OH, crystallises in 
dark-violet prisms, which resemble potassium permanganate, and 
has probably the given molecular formula even in the solid state. 
It is reduced by quinol to the corresponding hydrazine. 

Diphenyl nitric oxide was prepared by Wieland by the oxidation 
of diphenylhydroxylamine with silver oxide, 

2Ph 2 N.OH+Ag 2 = 2Ph 2 NO+H 2 0+2Ag. 

It crystallises in deep red needles. 

Goldschmidt, in 1922, oxidised guaiacol with lead dioxide and 
obtained a green solution, which was decolourised by the addition 
of quinol or triphenylmethyl, 



OMc QMc C 

- C 6 H 4 ^ -* C 6 H 

OH O 

Green Colourless 



\CJHi 

O O 



Neither the green nor the colourless compound could be isolated. 

9-Hydroxy-lQ-methoxyphenanthrene, oxidised with ferricyanide, 
was converted into a colourless substance, which was isolated ; this 
product gave a yellowish-green solution of the equilibrium mixture 
of the two products, analogous to those shown above. 

9-Chloro-lQ-hydroxyphenanthrene gave on oxidation a correspond- 
ing product in which a state of equilibrium was reached so slowly 
that both the blue (* monomolecular ') and the colourless (' bi- 
molecular ') forms could be isolated by fractional precipitation, 



Cl Cl 

/ - CM H/ 



Cl Cl Cl Cl 

C 14 H 



OH O 00 

All the compounds of abnormal valency so far described are 
examples of free radicals, which may be defined as uncharged 



FREE RADICALS AND STERIC HINDRANCE 



1045 



complexes showing additive properties and having an odd number 
of electrons. The stability of those of long life may usually be 
ascribed at any rate partially to a redistribution of the electrons by 
resonance ; triphenylmethyl, for example, might exist as a meso- 
meric form of the following structures, in which resonance could 
occur with any one of the three nuclei : 





Ph 2 C 




II 



III 



The formation of ^-diphenylmethyltetraphenylmethane (p. 1041) 
might then be attributed to the union of (i) and (in), followed by 
isomeric change. 

In the case of the hydrazine derivatives (p. 1043) there is the 
possibility of a complex resonance, corresponding with that of 
Iriphenylmethyl , 



PM.-Q 



PhN: 





in which one of the forms is regarded as derived from bivalent 
nitrogen and the others from tervalent carbon ; similarly diphenyi 
nitric oxide is a mesomeric form of structures containing univalent 
oxygen, ' bivalent ' nitrogen, and tervalent carbon, 



Ph 2 N O 



Ph 2 N-*0 



Ph-NO: 




The ketyls (p. 1046) may also be represented as mesomeric 
structures. 

All molecules which contain an odd number of electrons are 
paramagnetic and the percentage dissociation of a hexa-arylethane, 
for example, can be calculated from its magnetic susceptibility ; in 
this way it has been shown that tri-4-diphenylmethyl is almost 
completely dissociated both in the solid state and in solution. 



1046 ALKALI METAL COMPOUNDS 

Metallic Ketyk 

When an ethereal or benzene solution of a ketone or an aldehyde 
is treated with an excess of sodium, in the absence of air and moisture, 
there is formed an insoluble, coloured, metallic compound which 
readily undergoes atmospheric oxidation, and is immediately 
decomposed by water (Beckmann and Paul, Ann., 266, 1). The 
product from benzophenone, for example, with water, gives 
benzophenone, benzhydrol, (C 6 H 5 ) 2 CH-OH, and benzopinacol, 
(C 6 H 5 ) 2 C(OH).C(OH)(C 6 H 5 ) 2 ; when its suspension in ether is 
treated with dry carbon dioxide, it gives equimolecular quantities of 
benzophenone and the sodium salt of benzilic acid. 

From these reactions it was inferred that the sodium derivative 
had the structure, CPh 2 Na-O-CPh 2 -ONa. Benzaldehyde also 
gives a sodium compound, from the reactions of which it 
seemed that its structure was NaO CHPh CHPh ONa. 

Schlenk and his colleagues (Ber. 1913, 2840; 1914, 486) 
stated that such sodium compounds are not formed from two 
molecules of the ketone or aldehyde, because on the addition of 
potassium to a boiling ethereal solution of p-phenylbenzophenone, 
C 6 H 5 -C 6 H 4 -CO-C 6 H 5 , there is no change in the boiling-point, 
although the potassium derivative, C 6 H 5 - C 6 H 4 - C(OK) - C e H 6 , is 
produced. This compound is readily soluble in ether, and its 
molecule, KO-CR 2 , contains a tervalent carbon atom, but in solu- 
tion there is an equilibrium between the mono- and bi-molecular 
forms and the percentage dissociation varies with the conditions, 

2Ph 2 CONa 7-* Ph 2 C(ONa)-C(ONa)Ph 2 . 

Such substances are called metal ketyls. 

The sodium (and potassium) ketyls obtained from ^-phenyl- 
benzophenone and from ^p'-diphenylbenzophenone are highly 
coloured, like other compounds containing tervalent carbon ; 
they combine avidly with oxygen, probably giving peroxides, 
NaO-CR 2 -O'O-CR a -ONa, since the products, with water, give 
sodium peroxide and a ketone ; when treated directly with water, 
they are probably first converted into the corresponding hydroxide, 
R 2 C(OH), because the final products are a pinacol, or a ketone 
and a secondary alcohol, 

2R 2 C(OH) = R 2 C(OH).CR 2 .OH, 
2R 2 C(OH) - R 2 CO+R 2 CH.OH. 



FREE RADICALS AND STERIC HINDRANCE 1047 

They react with methyl iodide, 

2R 2 C(ONa)4 CH 3 I - R 2 C(ONa)l4-R 2 C(ONa).CH 8 , 

and the subsequent addition of water gives a ketone, a tertiary 
alcohol, sodium iodide, and sodium hydroxide. 

When an ethereal solution of the potassium ketyl of phenyl- 
benzophenone is added to various compounds such as dimethyl- 
pyrone, xanthone, etc., highly coloured insoluble ketyls are formed 
by a transference of the potassium atom. 

Free Radicals of Short Life 

In addition to those relatively stable radicals described above, the 
transitory existence of other free radicals has been demonstrated, 
in the first instance, by Paneth and his collaborators (Ber. 1929, 
1335; 1931,2702). 

When the vapour of lead tetramethyl under 1-5-2 mm. pressure 
is passed through a tube heated by a narrow flame, a mirror of lead 
is produced ; when the gas which is simultaneously formed is 
immediately passed over a mirror, previously deposited in the same 
tube a little further from the flame, this older film disappears ; it 
can be caused to reappear still further along by heating the tube 
with a second burner. These and other facts seem to establish the 
existence, for a short time, of methyl radicals. 

Pb(CH 3 ) 4 7~* 4CH 3 +Pb, 

which are capable of forming lead tetramethyl if passed over a film 
of lead before they have combined to form ethane. The free 
methyl radical, containing a tervalent carbon atom, also attacks zinc, 
with the formation of zinc dimethyl. The half-life period of the 
methyl radical has been estimated to be 0-006 second. Similar 
experiments have shown the transitory existence of the ethyl radical. 

Norrish and his collaborators have shown that free radicals are 
produced in a number of photochemical reactions. Thus, when 
the vapour of methylethyl ketone is exposed to ultra-violet light, it 
decomposes into free methyl and ethyl radicals, together with carbon 
monoxide ; the radicals then combine with one another to give 
ethane, propane, and butane. 

At low temperatures acetone is decomposed, giving acetyl radicals 
which unite to form diacetyl. In solution in iso-octane at 80-100, 

Or*. 66 



1048 ALKALI METAL COMPOUNDS^ 

the radicals from methylethyl ketone react with the solvent, giving 
methane and ethane, and an olefine is formed from the iso-octane ; 
the formation of free radicals is thus conclusively demonstrated, 
and the transitory existence of free radicals is now assumed in many 
reactions . 

Steric Hindrance 

As a rule tertiary amines unite readily with methyl iodide yielding 
a quaternary ammonium salt ; it has been found, however, that 
of the six isomeric dimethylxylidines, C 6 H 3 (CH 3 ) 2 N(CH 3 ) 2 , the 
2:6-compound [NMe 2 = 1] is incapable of forming a quaternary 
salt, whereas the other isomerides react with methyl iodide in a 
normal manner. The same difference in behaviour is observed 
with the corresponding bromotoluidine derivatives, and whereas 
trobutyltoluidine [Me:NH 2 :Bu^ = 1:2:5] readily gives a quaternary 
salt, the isomeride [Me:NH 2 :Bu 3 = 1:2:3] is hardly attacked by 
methyl iodide at 150. 

As it is difficult to suggest any chemical effect of the alkyl groups 
which could account for these facts, it has been supposed that their 
influence is spatial or steric : that in the di-ortho- or 2:6-compounds, 
the substituents, by reason of their size, block the approach of the 
methyl iodide and prevent salt formation, but when the substituent 
radicals are further removed from the dimethylamino-group, 
blocking does not occur. 

This phenomenon, in which chemical reactions appear to be 
hindered or entirely suppressed by the mere presence of neigh- 
bouring atoms or groups, which have no apparent chemical effect, 
is called steric hindrance or the ortho effect when the groups are o- 
in a benzene ring ; as will be seen, however, from the examples 
given below, it would appear unlikely that the whole effect is due 
to such mechanical action, and it seems possible that the substituents 
have an influence on the mesomerism of the molecule, but the 
evidence relating to this phenomenon is very conflicting. 2:5- 
Dimethylxylidine, C e H 3 Me 2 -NMe 2 , for example, is more reactive 
towards methyl iodide than is dimethyl-o-toluidine, C 6 H 4 Me NMe 2 , 
and 2:3-dimethylxylidine is more reactive than either, differences 
which cannot be due to a merely mechanical effect. It has also been 
found that, in the case of 0-substituted dimethylanilines, the yield 
of quaternary salt obtained under comparable conditions is very 
roughly parallel with the yield of substituted p-dimethylaminobenzyl 



FREE RADICALS AND STERIC HINDRANCE 1049 

alcohol, obtained by condensation with formaldehyde, in the presence 
of acids, 

Me 2 N - C 6 H 4 X+ CH 2 O - Me 2 N - C 6 H 3 X - CH 2 - OH 
(X = Me, Cl, Br, or OMe) 

Derivative of dimethyl- 
aniline o-Me o-Cl o-Br o-OMe 
Yield of quaternary salt 7-6 15-6 16 100 
Yield of alcohol 6 36 45 60 

It is not easy to see why a group in the o-position to the tertiary 
amino -radical should have a steric influence on the condensation 
in the ^-position to the latter. 

The hydrolysis of aromatic nitriles and amides is very greatly 
hindered by the presence of halogen atoms or of alkyl or nitro- 
groups in one or both o-positions to the nitrile or amide radical ; 
thus 2:3:5:6-tetramethylbenzonitrtle and pentamethylbenzonitrile resist 
hydrolysis by the usual methods. 2'A:6-Trimethylbenzonitrtle is 
hydrolysed only with great difficulty, whereas mono- and dinitro- 
2 t A:6-trimethylbenzomtriles are hydrolysed comparatively readily. 

Apparent steric effects are also observed in the case of oxime 
formation ; thus while quinone easily gives a dioxime, 2:6-dichloro- 
quinone gives a monoxime only, and tetrachloroquinone (chloranii, 
p. 509) does not react with hydroxylamine ; further, although 
2A:6-trimethylbenzaldehyde gives an oxime, phenylmesityl ketone, 
C 6 H 5 .CO.C 6 H 2 (CH 3 ) 3 , [2:4:6], does not. 

The most exhaustive inquiries into the effects attributed to steric 
hindrance have been made in the case of the esterification of acids 
(Meyer, V., and Sudborough, Ber. 1894, 510, 1580, 3146). Thus, 
with the substituted benzoic acids the presence of methyl, halogen, 
nitro- or other groups in both o-positions to the carboxyl radical 
hinders esterification by alcohol and hydrogen chloride ; even with 
only one substituent in the o-position, the yield of ester under 
comparable conditions is substantially less than with the cor- 
responding m- or/-acids. On the other hand, phenylacetic acid is 
esterified more rapidly than benzoic acid, and it is difficult to imagine 
that the o-hydrogen atoms of benzoic acid exert a steric effect. 

2A:6-Trtchloro- 9 tribromo-, and trinitro-bemoic acids yield no 
ester with boiling alcohol and hydrogen chloride, whereas mesit- 
ylenecarboxylic acid and pentamethylbenzoic add give esters slowly. 
It may also be noted that the rate of esterification of substituted 



1050 ALKALI METAL COMPOUNDS 

acetic acids diminishes with the number of substituents in the 
methyl group. In general the rate of hydrolysis of the esters is 
parallel to their speed of formation. 

Although in many of the above-mentioned cases the effect appears 
to be steric, some other examples of chemical inactivity, such as 
the resistance to oxidation with chromic acid of the cresols (p, 487), 
cannot be due to a steric effect, because all three isomerides behave 
alike ; furthermore, the protection is withdrawn when the hydroxyl 
group is methylated, although an increase in the size of the group 
occurs. 

Examples of a different kind are met with in many cases in which 
an atom of carbon or other quadrivalent element is directly com- 
bined with radicals, the shape or volume of which seems to affect 
the course of a reaction, and the existence of compounds in which 
certain elements show abnormal valencies may, in some cases, 
possibly be due, at any rate in part, to such steric effects ; 
in addition, the following examples, which are very suggestive, 
may be mentioned : When triphenyl carbinol is reduced cata- 
lytically under pressure it is converted into tricyclohexyl carbinol, 
C(C 6 H n ) 3 -OH, but tetraphenylmethane, treated in the same way, 
does not give tetraryc/ohexylmethane. Germanium tetrachloride and 
phenyl IM.SJJMI ,<:um bromide give tetraphenylgermane y Ge(C 6 H 6 ) 4 , 
but the tetrachloride and cydohexyl magnesium bromide give tri- 
cyclohexylchlorogermane, Ge(C 6 H n ) 3 Cl, and the tetraodbhexyl 
derivative is not formed. Similarly, although tetraphenylsilicane 
is easily obtained from silicon tetrachloride and phenyl magnesium 
bromide, phenylsilicon trichloride does not give tricyc/ohexyl- 
phenylsilicane with cyclohzxyl magnesium bromide, but is con- 
verted into dkydohexylphenyhilicane, SiH(C 6 H n ) 2 *C 6 H 5 ; on the 
other hand, the bromide, SiBr(C 6 H u ) 2 -C 6 H 6 , reacts normally with 
ethyl magnesium bromide, apparently because the ethyl occupies a 
smaller volume than the cydohexyl group. 

Many examples of undoubted steric influences which hinder the 
free rotation of groups have already been given (pp. 731, 758), and 
it can also be shown with the aid of models that the existence of 
otherwise possible stereoisomerides is sometimes inhibited by the 
size of the atoms or groups (p. 720), but such purely physical effects 
do not seem to be related to the phenomena of steric hindrance. 



CHAPTER 62 
HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 

MANY different types of heterocyclic organic compounds are known, 
in addition to those which have already been described, because 
one or more atoms of various elements may take the place of the 
carbon atoms in many closed chain structures ; the more important 
of these elements are oxygen, nitrogen, and sulphur. Some hetero- 
cyclic compounds are so closely allied to certain open chain com- 
pounds, into which they may be easily converted, that they are 
more conveniently classed with the latter ; as, for example, the 
oxides of the glycols, the anhydrides and imides of dibasic acids, 
the lactones and lactides, and the glycosidic forms of the sugars. 
Other heterocyclic compounds, such as furan, thiophene, pyrrole, 
etc., are not related in this way to open chain compounds, but form 
stable nuclei, of which many derivatives are known ; such structures 
are usually unsaturated, but nevertheless are often of very great 
stability, and show the behaviour of aromatic rather than that of 
olefinic substances. 

Of the compounds of this kind a few only are described and one 
or two of tHe many methods for the preparation of each type ; it 
will be seen that various unsaturated five-membered rings are 
formed with great facility, a fact which seems to show that the 
valencies of the nitrogen, oxygen, and sulphur atoms are directed 
in space similarly to those of the carbon atom. 

Azoles 

The term azole is used to denote those five-membered hetero- 
cyclic structures containing two double bonds and more than one 
nitrogen atom, or nitrogen atoms together with those of oxygen 
(oxazoles) or sulphur (thiazoles) ; the atoms of the ring are 
numbered in a conventional manner, always starting with one of 
the hetero-atoms, for the usual purpose. 

The substances of this kind containing two nitrogen atoms are 
classed as pyrazoles or gyloxalines (iminazoles) iiccording to the 
relative positions of the two nitrogen atoms : 

1051 



1052 HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 



JCH 



Pyrazole Glyoxaline (iminazole) 

Now although in the pyrazoles the 3- and 5-positions are appar- 
ently different, this is not so, as l-phenyl-3 -methyl- and 1-phenyl- 
5-methyl-pyrazoles yield the same methylpyrazole when the phenyl 
group is displaced by hydrogen (p. 1053) ; the given structures 
are therefore tautomeric. The same phenomenon occurs in the 
glyoxalines in which the 4- and 5-positions are identical. Another 
kind of tautomerism is observed in these structures, as the hydroxy- 
derivatives are tautomeric with the keto-compounds : owing to this 
complex tautomerism, the formula of oxalylurea (parabanic acid, 
p. 633), for example, can be written in any one of several ways, 

OC NH ^""u HO-C=N HO-C=N 

i < HO-CX X C-OH <? or 



Similar changes are observed in analogous six-membered ring 
compounds and in those with condensed rings, as, for example, the 
purines (p. 637). 

Pyrazoles are formed by the condensation of l:3-diketones 
or j3-ketonic esters with hydrazines ; thus acetylacetone and 
hydrazine give 3:5-dimethylpyrazole, 



f 

|-C NH 8 



CH|-C NH 8 CHj-C-NH 



CH, CH, 

whereas a keto-pyrazoline (below) orpyrazolone derivative (1-phenyl- 
3-methylpyrazolone) is formed from ethyl acetoacetate and phenyl- 
hydrazine (p. 591). An ester of a pyrazoletricarboxylic acid results 
from the interaction of ethyl diazoacetate (p. 468) and diethyl 
acetylenedicarboxylate , 



HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 1053 

C-COOEt EtOOC-C fl 

EtOOC'CHN, + (I) -> II 

C'COOEt EtOOC-C, 

COOEt 

Similarly acetylene and diazomethane yield pyrazole, m.p. 70. 

Pyrazoles are weakly basic and those with an unsubstituted 
imino group give metallic derivatives and can be acetylated ; they 
have a benzenoid character in that they can be halogenated, 
nitrated and sulphonated. Alkylpyrazoles can be oxidised to 
carboxylic acids, and even phenylpyrazoles on oxidation yield 
pyrazolecarboxylic acids ; the acids lose carbon dioxide when they 
are heated. Aminopyrazoles can be diazotised and the resulting 
diazonium compounds couple with amines and phenols. 

Derivatives of pyrazoline, (i), can be obtained by reducing the 
pyrazoles with sodium and alcohol or by condensing unsaturated 
esters, etc., with aliphatic diazo-compounds, 

H 2 C NH EtOOC-CH EtOOC'HC N 

T / ^_ LL. ~~* I v. 



/L 

N v^ CH 2 

a 



they are much less stable than the pyrazoles and have an aliphatic 
character. Many pyrazoline derivatives decompose when they are 
heated, giving nitrogen and cyclopropane derivatives (p. 781), 



EtOOOHC N EtOOC-HC 

/ \\ -* l 

EtOOC'HC N EtOOC-HC 



:cH 2 + N 2 

N J&tOUC -HC' 

H 2 



Glyoxaline, (11), is formed by the condensation of glyoxal with 
formaldehyde and ammonia, 



CHO 



CHO HC NH 

I + 2NH, 4- H-CHO -^ // \ 

CHO HC v N ^ H " 

in a similar manner 1 :2-diketones give substituted glyoxalines, 
R- 



-CO 

T 
CO 



/ 

-I- 2NM 3 * R-CHO 




1054 HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 

Glyoxalines are more strongly basic than the pyrazoles, but the 
hydrogen atom of the imino-group can be displaced by metals ; 
they can be halogenated and nitrated. 

Hydantoin (2'A-diketotetrahydroglyoxaline or 2A-dihydroxygly- 
oxaline) is prepared by the electrolytic reduction of parabanic 
acid, or by converting ethyl glycine into the substituted urea with 
potassium cyanate and heating the latter with hydrochloric acid, 

H 2 C NH 2 H 2 C NH H 2 C NH 

COOEt + HCNO - EtOOC X CO -* OC V ,CO 

3, H 

Such cyclic urea derivatives are readily hydrolysed, giving open 
chain compounds, and are therefore usually classed with the latter. 
\-Histidine (p. 626) has been synthesised as follows : Diamino- 
acetone hydrochloride l is heated with potassium thiocyanate, and 
the resulting compound, (i), is treated with dilute nitric acid a : 

H 2 N CH 2 HN CH 2 

HCNS 4- CO-CH 2 NH 2 SC S CO'CH 2 'NH 2 



HN-CH _ ^ HN -CH 

N C-CH 2 -NH 2 ^HS-Qv X C- 



II 



The hydroxymethyl derivative, (H), which is thus formed, is con- 
verted into the chloro-compound and condensed with diethyl sodio- 
chloromalonate to give (in) ; the 4- (or 5-) glyoxalinechloropro- 
pionic acid, (iv), formed by the hydrolysis of (in), is converted by 
ammonia into ^/-histidine, (v), which is resolved with tartaric acid : 

HN- 

~~* >CH 2 -CCl(COOEt) a 



N^ N x 

III 

1 Acetonedicarboxylic acid and nitrous acid give di-isonitrosoacetone, 
with the elimination of carbon dioxide, and the product is reduced to 
diaminoacetone. . . . 

The amino- is converted into the hydroxy-group by nitrous acid which 
is produced during the reaction. 



HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 1055 

T~^ -* H 

^ }>CH 2 -CHOCOOH 4x 1>CH 2 CH(NH 2 )'COOH 

X N N^ 

IV V 

Benzoglyoxalinesor benziminazoles are produced from o-phenylene- 
diamines and acids, 





Benzoglyoxaline is oxidised to glyoxaline-4:5-dicarboxylic acid with 
permanganate. 

Triazoles. When three nitrogen atoms and two carbon atoms 
form a five-membered ring, four different arrangements would 
appear to be possible : 



HN * yr-NH 

O O 



I II III IV 

But (i) and (n), and also (ill) and (iv), are tautomeric and so the 
triazoles are usually divided into two classes only, namely triazoles 
(i and n) and osotriazoles (ill and iv). When, however, the imino- 
hydrogen atom in either class is displaced by some radical tauto- 
merism is no longer possible, and two derivatives of each type can 
be obtained. 

Both triazoles and osotriazoles are very weakly basic and the 
imino-hydrogen atom can be displaced by metals ; the C-alkyl 
compounds can be oxidised to the corresponding acids. 

Triazoles are produced by heating amides with hydrazides, which 
are themselves prepared by the action of hydrazine hydrate on 
esters : 

H 2 N OCH HN CH 



" ~ s> 

Also by the interaction of diacetamide or one of its homologues (in 



1056 HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 

the enolic form), and semicarbazidc hydrochloride, in the presence 
of sodium acetate, 



N=CMc 

MeC^N-CO-NHi 



JI=CMe 
Me-OC OH _. f ' 



H 2 N 
K=iCMe 



M 

c 



N=CMe 

1 VT + H 2 N-CONH.NHCONH, 
iC ^ NH 

^M^ 



Osotriazoles are produced by oxidising the osazones of (1:2-) 
diketones and heating the products with dilute acid, 



| - | | + H,0 

Phc * N x NHPh phC ^ N x NPh 

PhC=N 
Ph^ NPh 

^NX- 

Some of the osotriazole is oxidised by the liberated oxygen. 

Osotriazole may be obtained by the condensation of acetylene 
and hydrazoic acid, 

CH HC=N HC NH 

'&* N x - H 

Tetrazoles may be obtained by the condensation of phenyl 
azide (p. 470), with the phenylhydrazones of aldehydes in the 
presence of alcoholic sodium ethoxide, aniline being eliminated, 

McHC=NNHPh MeC=NNHPh MeC=N 

N 3 Ph * 



Ammotetrazole is formed from aminoguanidine and nitrous acid, 
in nitric acid solution, the azide which is first produced, undergoing 
isomeric change, 



HETBROCYCLIC COMPOUNDS AND ANTIBIOTICS 1057 
H 2 N-C-NH-NH 3 H 2 N-C-N 3 H a N-C--NH H 2 N-C=N 



or 



As with the triazoles, tautomerism occurs in those tetrazoles in 
which there is an unsubstituted imino-group. 

Tetrazole and its derivatives are not basic, and in fact the imino- 
hydrogen atom is strongly acidic. The nucleus exhibits benzenoid 
characteristics, and aminotetrazoles can be diazotised. 

As examples of heterocyclic rings containing two elements other 
than carbon, the following may be mentioned : 

Oxazoles are formed from (the enolic forms of) a-halogen ketones 
and amides, 

T OH \\ H _ T~" 

CHBr x CMe * HC N x CMe 

HO 0' 

Isoxazoles are produced from the monoximes of j8-diketones, 

PhC-CH, P h/ C-C f PHC-CH 

CPh * N^ CPh 



'H OH 

Thiazoles are formed by the action of phosphorus pentasulphide 
on the acyl derivatives of a-aminoketones or by condensing thio- 
amides with a-halogen ketones, etc., 

H 2 C NH HC N 

R'OC CO-R' ^ R-C C-R' 

N S X 

R-CO H 2 Nv R '/9"~u 

/ * V./ _ // \\.. R/ 



2-Aminothiazole is prepared from thiourea and aj3-dichloro- 
diethyl ether (which gives chloroacetaldehyde). 

Various thiazole derivatives, such as sulphathiazole (p. 477), 
penicillin (p. 1061) and vitamin Bj (p, 1066), are very important. 



1058 HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 

Benzothiazoles are formed from o-aminothiophenols and acids, 



C*R + 2H 2 O 





Primuline (p. 680) is an example of a complex which contains 
two benzothiazole rings. 

Diazines 

The diazines are six-membered heterocyclic compounds of the 
structures shown below. 

Orf/zo-diazines, or pyridazines, are produced from enolic 1:4- 
diketones and hydrazine, the dihydrodiazines which are formed 
intermediately undergoing atmospheric oxidation, 

R 

^CX NH 

T ^ - 

R R R 

Maleic anhydride and hydrazine yield diketotetrahydropyridazine, 

o 

Hr ^CO X ^IMH 

flv* \ Iili2 ill-' INri 

II 0+1 > H I + H 2 

Hr / Krur ur Wru 

V.^PQ nri 2 riL.^ ^WJtl 

8 

M^^a-diazines, or pyrirnidines, are the most important diazines ; 
many, usually hydroxypyrimidines, such as alloxan, barbituric acid, 
uracil, thymine, cytosine (2-hydroxy-6-aminopyrimidine), etc., 
occur naturally, some of them as constituents of nucleic acids 
(p. 1075), Such hydroxypyrimidines show lactam-lactim tautom- 
erism (p. 838) and the method of writing their formulae is arbitrary : 

H H 

OC^CO ^HO-C^OOH OC X 

' i 6 5 ! ^ N "H HN 

O OH u OH 

lja:!' ri -;r!c nrH. - .- 1 -P ^ ^ Uractl 

(2:4~ti- 1 nkctonexahydropyrimiainc) (2 t\ I ).\r <i.r!: .is^ ,i- JF|:> i ! s.line) 



HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 1059 

Syntheses of barbituric acid and 4-methyluracil have already been 
given (pp. 634, 635) as examples of a general method, which con- 
sists in the condensation of urea with an ester of the malonic or 
acetoacetic type or with a j3-diketone (in the enolic form), 

u W u W 

ri 2 * jn 2 

OC' COOEt OC' ^CO OC' HO-C;CH 3 OC' ^C-CH 3 

Ji JH, * ^ J* 4 > ^ JH 

COOEt g COOEt g 

Barbituric acid 4-Methyluracil 

These reactions may be extended by condensing amidines (and 
other amino-compounds) instead of urea with the esters mentioned 
above or with certain unsatu rated esters ; acetamidine, for example, 
with ethyl acetoacetate gives 6-hydroxy-2:4-dimethylpyrimidine, 
while urea and ethyl aery late give dihydrouracil, 

H H 2 H 



HO.C-CH 3 CH 3 .C^ Nx C-CH 3 OC' CH 2 ^ OC'CH,' 

JH "* L,JH H 2 N ^ HN CH, 

COOEt 6 H COOEt g 



Dihydrouracil, treated with bromine and pyridine successively, 
gives uracil (p. 1058). 

Aminopyrimidines may be prepared by various reactions of a 
similar type of which the following may serve as examples : thio- 
acetamide and aminomethylenemalononitrile x give a cyanoamino- 
methylpyrimidine, 



Me *S B S 

H CN Me-C^ CN Mc-C^ 1 C-NH 

W^C-C"^ HN VC ^C'CN~~* 
H H 



1 Ethyl orthoformate condenses with malononitrile in the presence of 
acetic anhydride to give ethoxymethylenemalononitrile which is treated 
with ammonia. 



1060 HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 

while ethyl acetate and malonodiamidine give ^&-diamino-2-methyl- 
pyrimidine (Todd and co-workers) : 



Mei! 



H 9 H 

H^ - L 

f *- 




NH 2 &H 2 NH 2 NH 2 



Pyrimidine, m.p. 20-22, b.p. 124, may be prepared by the 
reduction of the trichloro-compound obtained from barbituric acid 
and phosphorus oxychloride ; it gives a neutral solution in water, 
but combines with acids giving salts. Homologous pyrimidines 
can be oxidised to carboxylic acids. Hydroxypyrimidines are 
phenolic and basic and with phosphorus oxychloride give chloro- 
pyrimidines. Purine and its derivatives contain a pyrimidine 
condensed with a glyoxaline ring. 

Para-diazines, or pyrazines, are formed spontaneously from 
a-aminoketones, with the intermediate production of dihydro- 
pyrazines, which are very easily oxidised, 

H 2 

HjC^ 1 ^ CO-Me 
Me-OC X CH 2 
H 2 

On reduction with sodium and alcohol, pyrazines yield hexahydro- 
pyrazines or piperazines. 

Benzqpar^diazines, or quinoxalines, result from the condensa- 
tion of o-phenylenediamines and l:2-diketones, l:2-dialdehydes, 



4- 2H 2 



a-ketoacids, etc. o-Quinones condense similarly with l:2-diamines 
(cf . p. 1071) ; mauveine (p. 679) is a derivative of dibenzqpflradiazine. 

Antibiotics 

During recent years a number of organic compounds which are 
termed by micro-organisms and which have the power of inhibiting 





HBTEROCYCLIC COMPOUNDS AND ANTIBIOTICS 1061 

the growth or activity of other micro-organisms have been isolated ; 
such substances are known as antibiotics and their use has opened 
new vistas in the treatment of disease. Probably penicillin, of which 
a short description has already been given (p. 654), is the best known 
and most important compound of this type, but the field is very 
fertile and it is possible that even more useful substances may be 
discovered in the future. 

A short account of some of the work which led to the determina- 
tion of the structure of penicillin follows, together with a mention 
of two other antibiotics, chloromycetin and streptomycin. 

Penicillin. This name has been given to a mixture of closely 
related acids, C 9 H U O 4 N 2 SR, which differ only in the nature of the 
group R, and three of which are mentioned here : 

British Name American Name R 

Penicillin-I F-penicillin CH 2 - CH:CH CH 2 - CH, 

Penicillin-II G-penicillin CH 2 - C e H 6 

Penicillin-Ill X-penicillin CH 2 C 6 H 4 - OH (1 :4) 

Their structures have been established by the combined and 
sustained efforts of many workers both here and in the U.S. A. and 
many of their important decomposition products have been syn- 
thesised ; they are generally used medicinally in the form of their 
sodium salts. 

The penicillins are hydrolysed by hot dilute mineral acids giving 
equimolecular quantities of penicillamine (d-pj3-dimethy Icy stein), 
carbon dioxide and an aldehyde which contains the group R : 

COOH COOH 



/"?""? 

Mc a C || + H 2 O = Me 2 C 

X S-g CH-NH.CO.R V SJJ 

Penicillins Penicillamine 



C0 2 + OCH*CH a -NH-CO-R 
Aldehyde 



When they are treated with methyl alcohol methyl esters are 
produced and biological inactivation occurs ; the methyl ester 



1062 HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 

from penicillin-II undergoes hydrolysis giving penicillamine and 
methyl penaldate which by catalytic reduction and hydrolysis yields 
cydohexylacetylalanine (synthesised) ; the structure of methyl 
penaldate is thus established and R, in penicillin-II, is CH 2 - C 6 H 6 : 

COOH 

^"-R COOMc _^ COOMe ^ 

62 \ ^.C CH'NHCO*CH 2 *Ph OCH-CH-NHCO-CH 2 Ph 

Methyl penaldate-II 
COOH 



I 3 -CH.] 



CH 3 CH NH - CO - CH 8 - C.H U 

Cvc/ohexylacetylalanine 

With diazomethane, the penicillins give monomethyl esters which 
with mercuric chloride solution yield the methyl ester of penicil- 
lamine : this proves that the acidic group in the penicillins is the 
carboxyl radical of penicillamine and the formation of methyl 
penaldate shows that a new carboxyl group, esterified by methyl 
alcohol, is produced by the gentle hydrolysis of the penicillins. It 
also proves that the carbon dioxide evolved when the penicillins 
are hydrolysed with mineral acids is formed from this new carboxyl 
group by the decomposition of a penaldic acid : 



R-CONH*CH< > R-CO-NH-CHj-CHO + CO 2 



When the penicillins are treated with alkali, salts of dicarboxylic 
acids, penicilloic acids , are formed ; these dicarboxylic acids have 
been synthesised, 

COOH COONa 

9 C ^N CO ^^N COONa 

Me,C I I +2NaOH=Me 2 C I I + H a O 

X S ^C CHNH'COR N s C "~ CH-NH'CO-R 

Penicillins Penicilloic acids 

(sodium salt) 

Finally the sodium salt of penicillin-II, treated with hydrogen 
and Raney nickel in aqueous solution, gives desthiopemcillin-II, 
C 16 H 2 oO 4 N 2 i m which the sulphur has been exchanged for two 



HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 1063 

hydrogen atoms ; a part of this product undergoes hydrolysis 
giving phenylacetyl-\-alanyl-d-valme : 

COOH COOH 



MdC I I * Me 2 HC | I 

X S-~"~ CHNH*CO-CH 2 -Ph H 2 C CHNH-COCH 2 -Ph 

H 

Penicillin-II Desthiopenicillin-II 

COOH 

*/ C *^N COOH 
Me 2 HC | | 

H 2 C CH-NHCO-CH 2 -Ph 

Phenylacetyl-/-alanyl-rf-vahne 

The formation of the last-named compound, which has been 
synthesised, affords very strong evidence of the structure of the 
penicillins (including that of R in penicillin-II), since it contains 
all the atoms of the penicillin molecule except that of sulphur. The 
results also show that the molecules of the penicillins contain certain 
complex groups which are present in some well-known protein 
amino-acids (alanine and valine). 

In the presence of dilute mineral acids at 30, the penicillins show 
mutarotation" and give crystalline isomerides, penillic acids ; these 
products with cold aqueous mercuric chloride evolve carbon dioxide 
and give penillamines, which resist hydrolysis : 

? OOH CO-R ? OOH ? OOH 

' TT I I R I R 



MejC | >J "" Me 2 C 



Penillic acids Penillamines 



Penillic acids with hot dilute acids give penicillamine, carbon 
dioxide and an aldehyde in the same way as the penicillins, but 
with baryta water they are isomerised to isopenillic acids : 



Me 2 C 
Org.67 



COOH 

A R 

/C-N-4 
IN 



1064 HETEROCYCLIC COMPOUNDS AND ANTIBIOTICS 

Chloromycetin (chloroamphenicol) was first isolated from Strepto- 
myces venezuelae and has proved of value in the treatment of some 
forms of typhus. It is laevorotatory, melts at 150, and its structure, 



- C 6 H 4 CH(OH) CH(NH - CO - CHC1 2 ) CH 2 - OH, 

has been proved by synthesis : the presence of an aromatic nitro- 
group in the molecule is noteworthy. 

Streptomycin, C 21 H 39 O 32 N 7 , is isolated from cultures of Strepto- 
myces griseus ; it is a complex glycoside of known structure and has 
given promising results in cases of tuberculous meningitis. 



CHAPTER 63 
VITAMINS AND CONJUGATED PROTEINS 

Vitamins 

THE immense amount of work which has been done since the 
existence and importance of vitamins was proved has led to the 
discovery of many new vitamins and a better understanding of their 
function in the living organism : our knowledge of the chemistry 
of the vitamins has also made rapid progress and many of them 
have been synthesised. Some of these developments are described 
in this chapter, but vitamins A, C and D are found elsewhere 
(pp. 978, 881, 1099) owing to their close relationship to other com- 
pounds of outstanding importance. 

Vitamin B, The active substance, originally called vitamin B, 
proved to be a complex mixture, which contains a vitamin now 
known as B 1? and various other components, referred to collectively 
as the vitamin B 2 complex. 

Vitamin B x , or aneurin, called thiamin in the U.S.A., is the anti- 
beri-beri factor (p. 653), and is destroyed by heat. 

The vitamin B 2 complex is much more stable towards heat, and 
from it the following components have been isolated ; the names 
in parentheses were formerly used : 

Riboflavin (lactoflavin, vitamin G) Nicotinamide 

Pyridoxin (vitamin B 6 , adermin) Meso'mositol (p. 798) 

Pantothenic acid />-Aminobenzoic acid 

Biotin (vitamin H) Folic acid (vitamin B c ?) 

Of these riboflavin is a growth factor for rats, pyridoxin prevents 
dermatitis in rats and pantothenic acid in chicks, etc. ; nicotin- 
amide is the anti-pellagra component. It should be noted, however, 
that in these and other cases the effects mentioned are those by 
which the compounds are usually most easily recognised, but 
doubtless do not cover the whole activity. Many of these substances 
are also bios factors, in that they promote the growth of yeast and 
other micro-organisms, but it is not yet known whether or not they 
are true vitamins, that is to say are necessary for the growth and 
health of human organisms; possibly they would be better called 
biotics rather than vitamins (cf. antibiotics, p. 1060). 

1065 



1066 VITAMINS AND CONJUGATED PROTEINS 

Most, if not all, of these substances, are present in living matter 
as more complex molecules, combined with one another and often 
also with phosphoric acid and a sugar ; they then form the pros- 
thetic groups of conjugated proteins. Such proteins are often 
enzymes or co-enzymes, and it may well be that vitamin activity is 
due to some simple chemical change brought about by enzyme 
action. Co-carboxylase (aneurin pyrophosphate) and co-zymase 
have already been mentioned (p. 903) in this connection, 

Aneurin, vitamin B 1 , was first isolated in the crystalline state in 
1926 in the form of its ' hydrochloride ' (Jansen and Donath), to 
which the formula, C 6 H 10 ON 2 ,HC1, was assigned ; six years later 
it was shown that the vitamin contained sulphur, but it was not 
until about 1934 that much progress was made with the determination 
of its structure. It was then found (R. R. Williams and co-workers) 
that the chloride, of which the correct formula was C 12 H 18 ON 4 C1 2 S, 
could be quantitatively converted by sodium sulphite containing 
sulphurous acid into an oily base, C 6 H 9 ONS, and a sulphonic acid, 
C 6 H 9 O 3 N 3 S. The structures of both these compounds were then 
determined by physical methods and degradations and established 
by synthesis ; the synthesis of aneurin itself was then accomplished. 

The basic decomposition product of aneurin was obtained as 
follows : The sodium derivative of ethyl acetoacetate is treated 
with j8-bromodiethyl ether and the product is converted into the 
compound, (i), with the aid of sulphuryl chloride, 

COMe CO'Me COMc 

CHNa-COOEt CH-COOEt CClCOOEt I 

CH 2 Br-CH 2 -OEt CH a CH a -OEt CH 2 CH 2 OBt 

The carbethoxy-group of (l) is then displaced by hydrogen 
(ketonic hydrolysis), and the product (in its enolic form) is con- 
densed with thioformamide, to give the thiazole ether, which is 
converted into the alcohol, with hydrochloric acid ; the hydro- 
chloride of the resulting base, l-methyl-S-fi-hydroxyethylthiazole, 
(n), is identical with that of the base obtained from aneurin : 

MeC=OCH 2 CH 2 OEt MeC=OCH 2 CH 2 OEt MeC=C-CH 2 CH,'OH 

"V ~ 



VITAMINS AND CONJUGATED PROTEINS 1067 

The vitamin itself was synthesised by R. R. Williams and Cline 
in the following manner : Ethyl j8-ethoxypropionate is converted 
into its hydroxymethylene derivative with the aid of ethyl formate 
and this product, (in), is condensed with acetamidine. The resulting 
compound, (iv), in its lactim form, (v), gives with phosphorus 
oxychloride a chloro-derivative, which on treatment with alcoholic 
ammonia is converted into an amine, (vi) ; the ethoxy-group of 
this base is then displaced by bromine, with the aid of hydrogen 
bromide, and finally the salt of the bromo-derivative, (vn), which 
is thus formed, is combined with the thiazole, (n). The final 
product, (vm), gives a corresponding chloride, which is identical 
with that of the naturally occurring vitamin B x in antineuritic action. 



NH 2 HO-HC HN CH 

\>CH,-OEt - Me(^ V 
EtOOc' V-CO 



Me( + 
NH 




III IV 

- Me/~\CH 2 -OEt -* 

N=4 H2 N=/ N H 2 




VI VH 



QMe. 
CH 2 -N 
H 2 



VIII 



Co-carboxylase, the co-enzyme of carboxylase which plays such 
an important role in alcoholic fermentation (p. 905), is the pyro- 
phosphoric ester of aneurin. 

Thiochrome, C 12 H 14 ON 4 S, was isolated from yeast by Kuhn and 
his co-workers in 1935 ; it is a yellow basic compound, the solutions 
of which show an intense blue fluorescence. It is also obtained 
when aneurin is oxidised in alkaline solution, and is probably formed 
by such a reaction during its extraction from natural sources. 
Thiochrome has the structure shown (p. 1068) and has been synthe- 
sised by Todd ; this synthesis, and the relation between thiochrome 
and aneurin, confirm the structural formula assigned to the latter. 



1068 VITAMINS AND CONJUGATED PROTEINS 

H H 2 
CxCx 



Riboflavin has been isolated from whey, and forms orange- 
brown crystals which show a yellowish-green fluorescence. Its 
structure is proved by various syntheses, of which those of Karrer 
and of Kuhn appeared almost simultaneously. In one method, 
nitroxylidine is converted into its carbethoxy-derivative, which is 
reduced catalytically ; the resulting amino-compound is then 
condensed with d-ribose in the presence of hydrogen and palladium, 
which reduce the N~CH-group 





NH-COOEt 

The amine produced by the alkaline hydrolysis of this ribose 
derivative condenses with alloxan, in the presence of boric acid, 
and gives riboflavin : 

CH 2 *[CH -OH] 3 'CH 2 -OH CH 2 [CHOHJ 3 CH 2 OH 

Mer*^ 





In another synthesis the reduced condensation product of J-ribose 
and 4-amino-o-xylene is coupled with a />-nitrophenyldiazonium 
salt and the resulting compound is catalytically reduced with 
hydrogen and nickel under pressure ; the amine is then condensed 
with alloxan as before : 

CH 2 -[CH-OH] 3 .CH 2 'OH CH 2 -[CH'OH] 3 -CH 2 -OH 

NH ^^ ^NH 





Pyridoxin, (n) , previously called vitamin B 6 or adermin, is the com- 
ponent of the vitamin B 4 complex which prevents dermatitis in rats. 



VITAMINS AND CONJUGATED PROTEINS 1069 

It is usually prepared from rice bran and is obtained as (the hydro- 
chloride of) a weak tertiary base, C 8 H U O 3 N. One of its oxygen 
atoms is phenolic and the other two form primary alcoholic groups ; 
its absorption spectrum is very similar to that of 3-hydroxypyridine 
and different from those of the 2- and 4-isomerides. Its phenolic 
methyl ether is oxidised by alkaline permanganate to a methoxy- 
Pyridinetricarboxylic acid, which gives a red colour with ferrous 
sulphate and readily loses carbon dioxide (1 mol,), two character- 
istics of pyridine-2-carboxylic acids (p. 575). 

Under slightly different conditions pyridoxin methyl ether is 
oxidised to a methoxymethylpyridinedicarboxylic acid, (i), which does 
not give a reaction with ferrous sulphate ; this acid is also obtained 
by the oxidation of 4-methoxy-3-methylwoquinoline, a synthetic 
compound of known structure, 

OMe COOH CH 2 -OH 






I II 

The constitution of pyridoxin, established by these and other 
facts, is therefore represented by (n), and confirmed by the following 
synthesis : - Cyanoacetamide is condensed with ethoxyacetylacetone 
in the presence of piperidine and the product, (in), after having 
been nitrated in the free j3-position, is converted into (iv) with the 
aid of phosphorus pentachloride ; this chloride is then reduced to 
(v), which, treated successively with nitrous acid and hydrobromic 
acid, gives the (hydrobromide of) pyridoxin (n), 

CH 2 -OEt 

H 2 C^ CH 2 CN HC^^OCN 

MeCO ^CO * MeC^ ^CO 

H 
III 

CH 2 -OEt 
MeV 






1070 VITAMINS AND CONJUGATED PROTEINS 

Pantothenic acid is the chick anti-dermatitis factor of the 
vitamin B 2 complex and its usual source is liver, from which it is 
extracted only with very great difficulty ; its investigation is mainly 
due to R. J. Williams and his collaborators. On hydrolysis with 
alkali it gives j8-alanine and an ay-dihydroxy-acid (as a salt) ; the 
latter passes into a hydroxy-y-lactone, (i), C 6 H 10 O 3 , m.p. 91-92, 
[a] 260 -~49-8. The structure of this lactone was proved by con- 
verting it into the trihydric alcohol, (n), with methyl magnesium 
iodide, oxidising this alcohol to the hydroxyaldehyde, (in), with 
lead tetra-acetate, and then into aa-dimethyl-/?-hydroxypropionic 
acid, (iv), by further oxidation : 

C ^CH-OH 
2 1 X C * CH 2 (OH) CMe, - CH(OH) C(OH)Me f * 



CH 2 (OH).CMe a -CHO > CH 2 (OH) - CMe, - COOH 

III IV 

Pantothenic acid has been synthesised by the following method : 
wobutyraldehyde is condensed with formalin in the presence of 
potassium carbonate and the bisulphite compound of the resulting 
hydroxyaldehyde is converted into the cyanohydrin, 

CHaO+CHMej-CHO CH a (OH)-CMe 2 -CHO * 

CH 2 (OH) CMe 2 CH(OH) CN ; 

this product, hydrolysed with concentrated hydrochloric acid, gives 
the rfMactone, (i, above), from which by resolution with quinine, 
a /-lactone, identical with that from pantothenic acid is obtained. 
After condensation with |8-alanine ethyl ester and hydrolysis of the 
ester with cold baryta, J-pantothenic acid, (v), identical chemically 
and physiologically with the natural substance is obtained, 

CH 2 (OH) CMe 2 CH(OH) CO NH CH 2 - CH 2 COOH 
V 

Biotin prevents injury to rats caused by the ingestion of large 
quantities of egg-white ; it is also one of the bios substances which 
promotes the growth of yeast, etc., and for this it is effective at a 
dilution of one in 5x 10 11 . It was first isolated as its methyl ester 



VITAMINS AND CONJUGATED PROTEINS 1071 

from egg-yolk and subsequently from liver extracts : 1 million eggs 
would be required to obtain 1 g. It has recently been shown that 
the sources mentioned above furnish two isomeric biotins, a-biotin 
from egg-yolk and j3-biotin from liver. 

The structure of j8-biotin was determined mainly by the work of 
du Vigneaud. /2-Biotin methyl ester, C n H 18 O 3 N 2 S, is readily 
hydrolysed to the acid, biotin, C 10 H ]6 O 3 N 2 S, m.p. 230-231, 
[a] 22 = +92 in 0-1 AT. sodium hydroxide solution; the acid is 
reconverted into the ester by diazomethane. With baryta or con- 
centrated hydrochloric acid biotin gives carbon dioxide and a 
diamino-acid, C 9 H 18 O 2 N 2 S, m.p. 186-190, which is reconverted 
into biotin by phosgene. Biotin, therefore, is a cyclic ureide : 

>C-NH 2 >C-NH X 

+ COC1, > >CO 

>C-NH 2 >C-NH 

On oxidation it gives a sulphone, and biotin methyl ester, with 
methyl iodide, gives a sulphonium salt ; the sulphur atom is 
therefore present as a thio-ether group. 

The diamino-acid, on oxidation, gives adipic acid and that its 
carboxyl group remains as such in the adipic acid is proved by the 
fact that when the carboxyl group of biotin methyl ester is displaced 
by NH 2 by the Curtius method and the product is hydrolysed, 
the resulting triamine does not give adipic acid on oxidation. 

Partial formulae, (i) or (H), for j8-biotin may therefore be written : l 



S< J 

I 

CO/"! |>C-(CH,),.COOH 



II 

Now the diamino-acid combines with phenanthraquinone to 
give a substituted quinoxaline (p. 1060), so that the NH 2 groups 
are combined with adjacent carbon atoms ; further, the ultra- 
violet absorption spectrum of this quinoxaline is very similar to 

1 In the case of (n) adipic acid would be formed from a substituted 
malonic acid or /3-keto-acid. 



1072 VITAMINS AND CONJUGATED PROTEINS 

that of the quinoxaline, (iv), from j8/?'-diaminotetrahydrothiophene, 
and different from that of the intermediate rfi'Ay^roquinoxaline, (in, 
which gave iv when heated in the air) : 





IV 



The carbon atoms attached to the simino-group< in the diamino- 
acid, therefore, are also directly united to hydrogen atoms ; possible 
formulae (v) and (vi) follow for biotin : 



HN CH 2 -CH 2 -CH 2 'CH 2 

>C \ jT S 
HN****'*'*"" 1 "**/ 



oc; | s oc; 

HN-^Xx 

VI 




VII 

Finally, when the nitrogen atoms of the diamino-acid are dis- 
placed by exhaustive methylation, the product (which was syn- 
thesised later) is a[oo-carboxy-n-butyl]thiophene, (vn) ; these 
results prove that the structure of j8-biotin is expressed by the 
formula (v), which has been confirmed by the synthesis of the 
^//-compound. 

a-Biotin is shown at (vm). 

CHMe, 




VIII 



Folic acid. The chemistry of this component of the vitamin B 
mixture has not yet been clearly elucidated and confusion has arisen 



VITAMINS AND CONJUGATED PROTEINS 1073 

because the name folic acid has been used for several different, but 
closely related, compounds. One of these, vitamin B c , is probably 
identical with the synthetic product, pteroylglutamic acid, shown 
below : 



OH 



COOH 



Pteroylglutamic acid is beneficial in cases of pernicious anaemia. 

Vitamin B 12 , also effective against pernicious anaemia, forms red 
crystals and is remarkable in that it contains cobalt : its structure has 
been elucidated by Todd and his co-workers (Nature, 1955, 176, 329). 

Vitamin E, which occurs in wheat germ oil (p. 654), is also found 
in other seed oils, such as cotton seed and its absence from a diet 
brings about sterility. It is now known that there are at least two 
and possibly more naturally occurring compounds which possess 
vitamin E activity, and these have been called tocopherols (Gr. tokos, 
childbirth ; phero, to bear). a-Tocopherol has been synthesised 
by the interaction of 2:3:5-trimethylquinol and phytyl bromide 
(cf. p. 973) and its structure is shown below ; it is a derivative of 
dihydrobenzopyran or chroman, 




a-Tocopherol 



j3-Tocopherol is a lower homologue of the a-compound. 

Vitamin K occurs in hog's liver fat, and green \cgct, sWcs, such 
as spinach and alfalfa ; it is concerned in the clotting of blood and 
its absence from a diet lengthens the time of blood clotting. Vitamin 



1074 



VITAMINS AND CONJUGATED PROTEINS 



Kj has been synthesised : Phytol reacts with 2-methyl-l:4-di- 
hydroxynaphthalene in the presence of oxalic acid and the resulting 
methylphytylnaphthoquinol is oxidised to the corresponding 
quinone with silver oxide in the presence of magnesium sulphate : 




Vitamin KI 

Vitamin K 2 is a related compound of the structure : 




Conjugated Proteins 

Conjugated proteins (p. 645) contain, in addition to the protein 
matter, a small proportion of some relatively simple substance 
known as the prosthetic group, which may be separated from the 
protein by gentle hydrolysis or even in some cases by dialysis. The 
chief types of conjugated proteins and their prosthetic groups are 
the following : 



Conjugated proteins 
Nucleoproteins 
Chromoproteins 
Glycoproteins 



Prosthetic groups 
Nucleic acids 
Haem, chlorophyll 
Carbohydrates or carbohydrate 
derivatives 



VITAMINS AND CONJUGATED PROTEINS 1075 

In addition, many, if not all, the B vitamins and the lecithins 
probably constitute the prosthetic group of proteins ; many pros- 
thetic groups, such as that of caseinogen, have not yet been identified. 

The nucleoproteins form the chief constituents of the cell nucleus 
in both plants and animals, and it seems very probable that many 
of the viruses, responsible for so many diseases, are nucleoproteins. 
The chromoproteins, haemoglobin and chlorophyll, 1 have already 
been briefly described ; the glycoproteins or mucins occur in the 
mucous membrane of animals. 

In the sequel a brief account is given of the prosthetic groups of 
the nucleoproteins and chromoproteins and allied compounds. 

Nucleic Acids 

The nucleoproteins are weak acids as their molecules contain 
phosphoric acid residues, and they undergo progressive hydrolysis 
with various reagents as indicated below : 

Nucleoprotein 
Nucleic acids-f Protein 

I 

Nucleotides 
Nucleosides+Phosphoric acid 

Base 4- Sugar 

In considering the structure of the nucleic acids it will be con- 
venient to start with the nucleosides. 

Nucleosides. Many nucleosides are very readily hydrolysed by 
dilute acids to a base (purine or pyrimidine) and a sugar and are 
thus shown to be glycosides ; others are resistant to such reagents, 
and when hydrolysed with concentrated acids give a product from 
which a sugar cannot be isolated. The glycosidic nature of such 
nucleosides has, however, been shown in other ways ; uridine 
(p. 1076), for example, can be hydrogenated to dihydrouridine, which 
hydrolyses normally giving a base and a sugar. 

The identification of the basic decomposition product of the 

1 The term chlorophyll is often applied either to the chromoprotein or 
to the prosthetic group. 



1076 VITAMINS AND CONJUGATED PROTEINS 

molecule (aglycone) is a fairly simple matter and the bases which 
are thus obtained are either : 

(a) Purine derivatives (adenine, guanine, p. 639). 

(b) Pyrimidine derivatives (uracil, cytosine, p. 1058, thymine 

or 5-methyluracil). 

The sugar component is isolated with more difficulty, but it is 
now known that it is either d-ribose or rf-2-deoxyribose, two sugars 
which are not known to occur elsewhere in nature. Nucleosides 
are therefore rf-ribosides or rf-deoxyribosides, and some of the more 
important are shown below : 

J-Ribonucleosides 

9-Guanine rf-ribofuranoside, guanosine 
9- Adenine rf-ribofuranoside, adenosine 
3 -Cytosine ^/-ribofuranoside, cytidine 
3-Uracil </-ribofuranoside, uridine 

rf-Deoxyribonucleosides 

9-Guanine rf-deoxyribofuranoside 
9-Adenine rff-deoxyribofuranoside 
3-Cytosine rf-deoxyribofuranoside 
3 -[5-methyluracil] J-deoxyribofuranoside 

Now, before a structure and configuration can be assigned to a 
nucleoside the following points have to be settled : 

(a) To which atom of the base the sugar is united, (b) whether 
the sugar is pyranose or furanose, (c) the nature, a- or j3-, of the 
glycoside link. 

(a) As an example guanosine may be considered ; when this 
substance is treated with nitrous acid, an amino-group is displaced 
and xanthosine (9-xanthine J-ribofuranoside) is formed ; this 
compound, with diazomethane, gives a dimethyl derivative, which 
on hydrolysis yields theophylline (l:3-dimethylxanthine, p. 638), 



Hor 



Me 
Guanine Theophylline 




VITAMINS AND CONJUGATED PROTEINS 1077 

This result proves that in xanthosine, positions 1 and 3 were free and 
that, probably, 7 (or 9) was occupied by the sugar residue : had the 
sugar residue been at 8, leaving 7 (or 9) free, a trimethyl derivative, 
caffeine (1 :3:7-) or 1 :3:9-trimethylxanthine would have been expected. 

But since the 7 and 9 positions in unsubstituted purines are 
tautomeric, the ribose residue might be attached to either of these 
nitrogen atoms. A comparison of the ultra-violet absorption 
spectrum of guanosine with those of 7-methyl- and 9-methyl- 
guanine shows, however, a close resemblance to that of the 9- 
derivative ; guanosine, therefore, is 9-guanine riboside (p. 1078). 
It has been shown in a similar manner that in all nucleosides derived 
from purine bases, the sugar residue is in the 9-position (Gulland), 
and this physical evidence has been confirmed in other ways (p. 1078). 

On the other hand, cytidine, with nitrous acid gives uridine, the 
methyl derivative of which yields 1-methyluracil on hydrolysis ; 
the ribose residue must therefore be in the 3 -position of the pyri- 
midine base. 

Inconclusive spectroscopic evidence has shown that the sugar 
residue in the 2-deoxyribosides is also probably in the 9- or the 
3 -position according to the type of base. 

(b) The glycosidic structure of a nucleoside is determined as follows : 

The compound is completely methylated and the product is 
hydrolysed* with dilute acid : the 2:3:5-trimethyW-ribose thus 
produced is oxidised to a y-lactone, which is proved on further 
oxidation to afford w^odimethyltartaric acid : 



1 CH(OH) 



COOH 

H-C OMe | H- 

O 



2 H-C OMe 

3 H-C OMe T H OMe j H-< 

4 H-C 

5 CH 2 OMe CH 2 OMe 




? OMe 
tOOH 



The sugar, therefore, is a furanoside (as shown) and similar sugar 
residues are assumed to be present in all nucleosides ; the structures 
of guanosine and cytidine, which represent the two types of nucleo- 
sides, are therefore as shown (p. 1078). In the deoxyribonucleosides 
there is a hydrogen atom instead of the hydroxyl group at the 
2-position in the sugar molecule. 



1078 



VITAMINS AND CONJUGATED PROTEINS 



N=CH 



0-CH-CH 2 -OH 



OH 
^CHj-OH 



NH 2 



Guanosine 



Cytidine 



(c) Todd and his co-workers have shown that when adenosine, (i), 
is oxidised with sodium periodate, a dialdehyde, (ll), is formed. 
This confirms the furanose structure of the rihose : a pyranose 
sugar would have been oxidised with the elimination of one carbon 
atom (p. 895). Further, adenine J-glucopyranoside, (ill), synthe- 
sised by a method which proves conclusively that the sugar residue is 
in the 9-position, gives the same dialdehyde, (n), with the loss of one 
carbon atom, when it is oxidised with periodate ; the 9-position of 
the ribose in adenosine is thereby proved conclusively (p. 1077). 

Another synthesis of (in) starts from 2:3:4:6-tetra-acetyl-l- 
bromoglucose which gives ~ ' ' (p. 895) ; .'.^Miming this to 

be so in the present instance, (in), is a j8-glucopyranoside. The 
configuration of carbon atom 1 of the sugar molecules in (i) and 
(in) must be the same as they both yield (n) on oxidation ; adenosine 
is therefore a j8-riboside and the other ribonucleosides have been 
shown to have the same configuration. 




CHI 
CH( 



CH a -OH 



EiO 

a -OH 



o 




I II 

R - C B H 4 N 5 

The structures of the ribonucleosides have been finally confirmed 
by their syntheses (Todd and co-workers,^. 1947-48). 

Nucleotides are phosphoric esters (hydrogen phosphates) of 
nucleosides, and as the structures of the nucleosides are known the 



VITAMINS AND CONJUGATED PROTEINS 



1079 



only matter to settle concerning the nucleotides is the point of 
attachment of the phosphoric acid residue. In the case of the 
typical nucleotides, the adenylic acids, this has been done as follows : 

The nucleotide is treated with nitrous acid and the product is 
carefully hydrolysed ; a base and a ribose phosphate are thus 
obtained. The latter is then oxidised to a ribonic acid phosphate, 
or reduced to a ribitol (adonitol) phosphate, from the nature of 
which the structure, i.e. the position of the phosphate residue, may 
be determined. Thus the <f-ribose phosphate, (i), of the nucleotide, 
adenylic acid obtained from muscle, gives a rf-ribonic acid phos- 
phate, (ll), on oxidation and */- ribitol phosphate on reduction, so 
that the phosphate residue must be at 5 : had it been at 2 or 3, rf-ribo- 
trihydroxyglutaric acid phosphate would have been formed. 

On the other hand, the </-ribose phosphate, (in), obtained from 
the adenylic acid of yeast, gives on reduction an (inactive) meso- 
ribitol phosphate, (iv), in which the phosphate group must be at 3, 
the only position which could give a weso-compound. 



F> 
"I 



(OH) 
OH 
OH 



O 



H- 



CH 2 



0-P0 8 H, 
I 



OOH 



U-C OH 
H-C OH 
H-C OH 

CH 2 0-P0 3 H 4 



II 



CH(OH) 
H-C OH 
H-C 0-P0 3 H, 
H-C- 



1 



CH 2 -OH 
III 



CH 2 OH 

:-OH 

:-o.po 8 H 

:-OH 

CH 2 OH 

IV 



The position of the phosphate groups is also shown by the 
action of sodium periodate on the nucleotides, A glycoside 
derived from ribose 5 -phosphate, (l), has free hydroxyl groups 



Orjj. 68 



1080 VITAMINS AND CONJUGATED PROTEINS 

at 2 and 3, whereas one derived from the 3 -phosphate, (in), has 
no CH(OH)-CH(OH) group; only the former, therefore, 
should be attacked by periodate, and experiments show that this is 
so. The final proof of the structures of the adenylic acids is furnished 
by their synthesis (Todd and co-workers, J. 1947, 648 : 1949, 2746). 

In other nucleotides the phosphate group is also either at 5 or 3. 

Nucleic acids (polynucleotides) are hydrolysed by enzymes or 
very gentle treatment with acids or alkalis, giving equimolecular 
quantities of four different nucleotides, each of which may then 
undergo further hydrolysis as already described : yeast ribonucleic 
acid, for example, gives finally approximately equimolecular propor- 
tions of guanine, adenine, cytosine and uracil, together with d-ribose. 
The molecular weights of nucleic acids have been determined by 
many methods, such as viscosity, X-rays, etc., and minimum values 
corresponding with at least 30 nucleotide residues have been 
obtained, but it is not yet known how such residues are united in 
the nucleic acids. 

Haemin and Chlorophyll 

The structures of haemin and of the closely related chlorophylls 
have been established mainly by the work of Hans Fischer, Kiister, 
Neucki, Piloty and Willstatter, which extended over nearly forty 
years ; the following very brief summary of this work may give 
some idea of the immense difficulties which were overcome and the 
cpoch-mak'ni* results which were achieved. 

Perhaps the best thing to do in order to understand these results is 
to start with a study of haemin, (i), and some of its degradation pro- 
ducts, (n), referred to later ; it will then be seen that after the elimin- 
ation of the FeCl group, while the framework of the haemin molecule 
remains intact (in n), the groups R and R' undergo various simple 
changes which result in the formation of the different porphyrins. 



CH 2 :HC 




HOOC-CH 2 -H 2 C H CH 2 -CH 2 'COOH 
Haemin, I 




VITAMINS AND CONJUGATED PROTEINS 1081 

Protoporphyrin 

(R - CH:CH 2 ; R' - CH 2 -CH 2 COOH) 
Haematoporphyrin 

(R - CH(OH)-CH 3 ; R' - CH a -CH 2 COOH) 
Mcsoporphyrin 

(R - CH a CH 3 ; R' = CH 2 -CH 2 -COOH) 
Aetioporphyrin 

(R = R' = CHa CHa) 
Porphin 

(R R' = II ; Me H) 
Deuteroporphyri n 

(R = H ; R' - ~CH 2 CH 2 COOH) 

When haemin (p. 647) is treated with dilute acids the iron is 
eliminated and protoporphyrin is produced ; with concentrated 
hydrobromic and acetic acids, the two vinyl groups are converted 
into CH(OH)-CH 3 groups and haematoporphyrin is formed, 
whereas with hydriodic acid they are both reduced to CH 2 -CH 3 , 
giving mesoporphyrin. The last-named compound can also be 
produced from protoporphyrin by direct reduction ; when it is 
decarboxylated it gives aetioporphyrin. These compounds are all 
derivatives of the parent structure porphin shown on p. 1084. 

The presence of two carboxyl groups in haemin and (some of) 
the above-mentioned porphyrins is shown by the formation in each 
case of a dimethyl ester (the melting-point of which serves for its 
identification), and the presence of two olefinic groups in haemin 
is shown by its absorption of four atoms of hydrogen on its reduction 
with palladium and hydrogen. 

Under the prolonged action of bacteria in alkaline solution, the 
vinyl groups of haemin are displaced by hydrogen (and the FeCl 
group eliminated) with the formation of deuteroporphyrin, which 
can be oxidised to a mixture of two molecules of citraconimide (m, 
methyl maleimide) and two molecules of haematic acid, (iv), 

MeC=CH MeC=C-CH 2 -CH 2 COOH 

OC^ CO OC. .CO 
Y rf 

III IV 



When haemin is reduced vigorously with hydriodic acid it gives 
a mixture of four pyrroles, 






Hacmopyrrole Phyllopyrrole Opsopyrrole Cryptopyrrole 



1082 



VITAMINS AND CONJUGATED PROTEINS 



and the four corresponding carboxylic acids ( CH 2 -CH 2 'COOH 
instead of -CH 2 -CH 3 in the above formulae). During this 
reaction the vinyl are reduced to ethyl groups and the CH= 
uniting the pyrrole nuclei remain attached to one or other of those 
nuclei and are at the same time reduced to CH 3 . 

From these and many other facts the structure of haemin , (i , p . 1 080) , 
was deduced and then fully established by the following synthesis 
(H. Fischer and collaborators) : (a) 2:3-Dimethylpyrrole is con- 
densed with 2:4-dimethylpyrrole-5-aldehyde in the presence of 
alcoholic hydrobromic acid to give 4:5:3':5'-tetramethylpyrro- 
2:2'-methene hydrobromide, (v), 



Me 



Me, 



e/ * 
OHC0M, 



Me 




Me 



Br 



(b) 2:4-Dimethylpyrrole-j8-propionic acid (cryptopyrrolecarboxylic 
acid) treated with bromine gives 5:5'-dibromo-3:3'-di--carboxy- 
ethyl-4:4'-dimethylpyrro-2:2'-methene hydrobromide, (vi), with 
the loss of one carbon atom, 



Br 



HN==\Br 




Br 

HOOC-CH 2 -CH 2 H CH 2 CH 3 COOH 
VI 

The compounds (v) and (vi) heated together with succinic acid at 
180-190 give a mixture from which deuteroporphyrin (p. 1081) is 
isolated ; in this reaction (v) forms the top and (vi) the bottom 
of the structure (as printed) and the two methyl groups in the 
a-positions in (v) supply the carbon atoms of the CH= groups 
uniting the nuclei in (n, p. 1081). 

Deuteroporphyrin, treated in acetic acid solution with ferrous 
acetate, sodium chloride and hydrochloric acid, takes up FeCl and 
gives deuterohaemin (i, CH:CH 2 -= H) which, unlike deutero- 
porphyrin, is converted into a diacetyl derivative by acetic anhydride 
and stannic chloride ; this compound, reduced with alcoholic potash, 
gives haematoporphyrin, the FeCl group being eliminated. Finally 
haematoporphyrin, distilled at 105* in a vacuum, loses two molecules 



VITAMINS AND CONJUGATED PROTEINS 



1083 



of water giving protoporphyrin, from which haemin is obtained by 
the ^introduction of the Fed group. 

Chlorophyll a, C 66 H 72 O 6 N 4 Mg, is hydrolysed by alkali, giving 
a green magnesium compound, chlorophyllin a, together with equi- 
molecular proportions of methyl alcohol and phytol ; it is therefore 
an ester of a dibasic acid. With acids chlorophyll a loses magnesium 
affording phaeophytin a from which chlorophyll a can be regenerated 
with methoxy in.Hjjiicsiiiiii bromide (from methyl alcohol and methyl 
magnesium bromide). When hydrolysed with acids and then heated 
strongly with alkalis phaeophytin a gives three porphyrins, closely 
related to those obtained from haemin under various conditions, 
namely rhodoporphyrin, phylloporphyrin and pyrroporphyrin. 



CH 2 :HC 




Et H 




HC CO 
COOMc 



VII 



HOOOCHjfCHj 



VIII 



8 ) 

lorophyll a (R - Me) 
Chlorophyll b (R - CHO) 



TV 



: V ' (R - COOH ; R' - H) 
! , (R = H; R' -Me) 

Pyrroporphyrin (R - H ; R' H) 



Rhodoporphyrin gives pyrroporphyrin when it is heated with alkali 
and on being heated with soda-lime both pyrroporphyrin and 
phylloporphyrin lose the carboxyl group of the propionic acid residue 
to give pyrroaetioporphyrin and phylloaetioporphyrin respectively. 
By the following series of reactions : 



R .H , R.CH,OMe - R-CH.Br 

SnCU R-CH a .CH(COOEt) a - R.CH a -CH a .COOH 

a second propionic acid residue can be introduced into pyrropor- 
phyrin (in place of R, vin) giving mesoporphyrin, thus supplying a 
link with the haemin series. 

Pyrroporphyrin, obtained from rhodoporphyrin by decarboxyl- 
ation, has been synthesised by a method similar to that for deutcro- 



1084 VITAMINS AND CONJUGATED PROTEINS 

porphyrin (p. 1082) : its structure is thus proved and therefore also 
that of rhodoporphyrin ; phylloporphyrin has also been synthesised. 

From the above and much other evidence the structure, (vii), 
has been assigned to chlorophyll a (R = Me) and a similar structure 
(R = CHO) to chlorophyll b. The chief differences between these 
structures and that of haemin are the presence of an extra carbon 
ring containing a carbonyl group and the partial reduction of the 
pyrrole ring IV. 

The presence of the extra carbon ring is proved by the following : 
(a) By careful hydrolysis it is possible to remove the phytyl group 
and the magnesium atom from chlorophyll a giving phaeophorbide 
a ; this last compound with hydrogen iodide yields an isomeric 
compound phaeoporphyrin a 6 , 1 the two hydrogen atoms in ring IV 
being lost and the vinyl group reduced. 

(b) Phaeoporphyrin a 5 is obtained from phylloporphyrin methyl 
ester, already synthesised (above), by oxidising the latter with 
iodine and sodium acetate, thus converting the methyl group at y 
(vm, R') into CHO ; the CHO was then converted through 
the cyanohydrin, etc., to CH 2 - COOMe, which condensed with 
dichlorodimethyl ether in the presence of ferric chloride, 







CH 3 0-CHC1 2 HCCHC1 HC CHOH 

>Mc COOMe COOMe 

oxidation finally gives phaeoporphyrin 6 dimethyl ester. 

It will be seen that the structures given to haemin, the por- 
phyrins, the chlorophylls and the phthalocyanines (p. 683) may all 




1 The numeral used in this and similar cases signifies the number of 
oxygen atoms in the compound in question. 



VITAMINS AND CONJUGATED PROTEINS 1085 

be regarded as being derived from the fundamental structure, (ix). 
In the case of the porphyrins and allied compounds, Y is CH 
throughout and various substituents are attached at the numbered 
positions. The parent compound of this group is porphin (ix, 
Y = CH). In the phthalocyanines the group Y is N in all cases and 
benzene nuclei are fused to the pyrrole rings in the 1,2 ; 3,4 ; 5,6 ; 
and 7,8 positions. Other compounds are known, as, for example, 
phthalocyanine without the benzene rings and substances in which 
some of the Y groups are CH and some are N. 

Now the degradation results and the various syntheses do not 
completely prove the structures of the naturally occurring deriva- 
tives of type (ix) : many of the syntheses, for example, are carried 
out at a high temperature at which isomeric changes, etc. might 
occur. Direct evidence for the given structures of the phthalo- 
cyanines has however been furnished by X-ray examinations and 
molecular weight determinations, and it has been shown that the 
compounds consist of flat molecules with the four pyrrole residues 
and the four Y groups all in one plane and arranged as shown in (ix). 
It will be seen that such molecules contain an inner heterocyclic 
ring of sixteen atoms, similar to those suiux-'cd by Drew for the 
higher cycloparaffins (p. 796), and a system of completely con- 
jugated double and single bonds of the same type as that in aromatic 
hydrocarbons, etc. ; thus although the double bonds are of necessity 
shown in a particular position in (ix), others are equally possible 
and the conditions necessary for resonance are satisfied. The actual 
state therefore may be that of a mesomeric form, which may account 
for the strong colours exhibited by all such substances and also for 
their great stability, ease of formation, and chemical behaviour in 
general : the porphyrins, for example, like aromatic compounds, 
can be halogenated, nitrated and sulphonated and show none of the 
instability of the pyrroles. The indicated positions of the hydrogen 
atoms on the nitrogen atoms are also arbitrary, as it may be assumed 
that each hydrogen atom is held also by a hydrogen bond to another 
nitrogen atom : no porphyrin has been found to exist in the two 
forms which would be possible if the hydrogen atoms were attached 
to opposite nitrogen atoms in one form (as in ix) and to adjacent 
nitrogen atoms in the other (as in II, p. 1081, and vni, p. 1083). In 
the case of the metallic derivatives, haemin, the chlorophylls and the 
metallic phthalocyanines also, different modes of union of the nitrogen 
atoms to the metal are apparently possible, but do not in fact exist 



1086 VITAMINS AND CONJUGATED PROTEINS 

as each bivalent metal is shared equally by all four nitrogen atoms ; 
when the metal or metallic radical takes the place of the two hydro- 
gen atoms of the NH groups it does so without changing the shape 
or size of the structure as a whole. 

Many porphyrins occur naturally in, for example, yeast, pearl- 
oysters, mussels, feathers, etc., and even in minerals : many of 
these compounds were synthesised during the investigation of 
haemin. 

Treibs has shown that certain porphyrins occur in various 
petroleums, shales and coals : a bituminous marl from Switzerland, 
for example, contained 04% of total porphyrins, which contain 
vanadium (as > VO) as the central atom. It appears very probable 
that these porphyrins have originated from chlorophyll or haemin, 
and Treibs concludes that plants were the main source of petroleum 
as the quantity of chlorophyll- is greater than that of haemin- 
derivatives ; since mesoporphyrin, which is found in such sub- 
stances, is decarboxylated slowly at about 200 he infers that this is 
the maximum temperature to which the oil has been subjected. 

As might be expected various degradation products of haemo- 
globin and of chlorophyll have been found to occur in vivo, the 
latter particularly in various parts of the body, and especially in the 
faeces of ruminants and herbivora such as cattle, elephants, sheep 
and silk- worms. An interesting example of a degradation product 
of haemoglobin is bilirubin, C 33 H 36 O fl N 4 , which is best obtained 
from ox gall-stones. It has a very different absorption spectrum 
from that of haemin and hence does not contain the porphyrin 
ring system ; its structure has not yet been completely determined, 
but is probably as shown : 




R-CH,'CH,'COOH R'=-CH:CH, 



CHAPTER 64 
STEROIDS 

THE sterols are alcohols derived from a complex hydrocarbon, 
cyclopentanoperhydrophenatithrene. They occur in nature in 
association with fats, carbohydrates and proteins, partly in the free 
state, and partly as esters of the higher fatty acids ; about 20 such 
compounds are known, and like so many products of living organisms 
they are optically active. 

They may be divided into three classes : 

Zoosterols, which occur in animals ; cholesterol in bile, gall- 
stones, etc. 

Phytosterols, which occur in plants ; stigmasterol in calabar bean, 
soya bean, etc. 

Mycosterols, which occur in fungi ; ergosterol in ergot, yeast, etc. 

As, however, some are found in both animals and plants, this 
classification cannot be rigidly applied. 

Closely related to the sterols, and doubtless formed from them 
in the animal organism, are the important bile acids, some of which 
have long Been known and which are now classed with the sterols, 
as steroids , because they are derived from the same hydrocarbon 
framework as the former. 

The group of steroids also includes the sex hormones, compara- 
tively recently discovered compounds of very great interest and 
physiological importance ; other naturally occurring substances 
such as the adrenal hormones, saponins and cardiac poisons of the 
same fundamental structure are also included in the steroid group. 

Sterols 

Cholesterol, C 27 H 46 -OH (Gr. chole, fat ; stereos, solid), occurs in 
bile, in the brain, and in considerable proportions (up to 98%) in 
certain gall-stones and cancerous and tubercular deposits ; it is also 
found in the yolk of egg and in some vegetable oils. The fat 
(lanoline) obtained from wool is a mixture of cholesteryl palmitate, 
stearate, and oleate. 

Cholesterol is very easily prepared by extracting common gall- 

1087 



1088 STEROIDS 

stones with alcohol, boiling the extract with a little potassium 
hydroxide, and precipitating the product from the concentrated 
solution with water ; it is washed with water and crystallised from 
a mixture of ether and alcohol. 

It separates from ether in plates, melts at 148, and distils at about 
360 without appreciable decomposition ; it is laevo rotatory and 
insoluble in water. In the lower intestine it is reduced to copro- 
stanol, C 27 H 47 -OH. 

A cold saturated solution of cholesterol in acetic anhydride, to 
which is added concentrated sulphuric acid, turns red and then 
blue and finally green. Concentrated sulphuric acid, containing a 
little iodine, colours cholesterol violet, then blue, then green, and 
lastly red. Warmed with dilute (20%) sulphuric acid, cholesterol 
crystals are coloured red at the edges. 

Stigmasterol, C 29 H 47 -OH, m.p. 170, occurs in the soya and 
calabar bean ; it is laevorotatory. 

Ergosterol, C 28 H 43 -OH, is probably widely diffused in animals 
and plants and occurs particularly in ergot and yeast, from the 
latter of which it is usually extracted ; it melts at 154 and is 
laevorotatory. 

On exposure to ultra-violet light, it is partly converted into a 
resinous or waxy product, which is a mixture of various isomerides 
of the sterol (produced successively) and from which calciferol was 
isolated in 1931. 

Coprostanol (coprosterol), C 27 H 47 -OH, occurs in facets ; it melts 
at 102 and is dextrorotatory. 

The investigation of cholesterol and the bile acids was a task of 
exceptional difficulty, not only because of the great complexity of 
the compounds but for many other reasons. Although the sterols 
crystallise readily, traces of impurities may prevent them from 
doing so and different sterols often form mixed crystals or molecular 
compounds, so that their isolation was particularly troublesome, 1 
They also proved to be compounds of an entirely novel type and 
new processes had to be devised for their degradation to substances 
of known structure. Thus although cholesterol was first analysed 
by Chevreul as long ago as 1823, it was only in 1859 that it was 
proved to be a monohydric alcohol, and a secondary alcohol in 1903. 

1 It is interesting to note that Pregl developed his method of micro- 
analysis to deal with a bile acid product which was only available in minute 
quantities. 



STEROIDS 1089 

During the years immediately following, mainly as the result of 
the work of Wieland and Windaus, many new facts concerning 
the structures of the steroids were established, but the data were 
disconnected and progress was still comparatively slow ; it was not 
until about 1932 that notable advances were made. In that year, 
after it had been shown by Diels that cholesterol could be partly 
converted into chrysene (p. 1022) and Diels' hydrocarbon (p. 1090), 
and Bernal's X-ray measurements of ergosterol had been published, 
it was suggested by Rosenheim and King, and also by Wieland and 
Dane, that cholesterol and other sterols were derivatives of a cyclo- 
pentanoperhydrophenanthrene. This view, fully confirmed by further 
evidence, threw a flood of light on the chemistry of these and other 
natural products and rendered possible the striking advances which 
immediately ensued. 

The following is a brief account of the methods and reactions 
by which the structures of the sterols and more particularly that 
of cholesterol were determined, and the synthesis of many im- 
portant steroids, including that of the fundamental framework, 
was accomplished. 

Structures of the Sterols 

The catalytic reduction of the olefmic binding of cholesterol 
yields chokstanol, C 27 H 47 -OH ; this alcohol cannot be reduced 
further by ordinary direct methods, but when it is oxidised to the 
corresponding ketone, the latter can be reduced to a saturated 
hydrocarbon, cholestane, C 27 H 48 , by Clemmen sen's method ; choles- 
terol, therefore, is tetracyclic, for, had it been an open chain 
compound, it would have given a hydrocarbon, C 27 H 56 . 

The procedure just given, by means of which a secondary alcohol 
group, >CH-OH, is converted into >CH 2 by oxidation, followed 
by reduction, is of great importance in the investigation of the 
steroids. 

The size of the rings in the cholesterol molecule was decided in 
early investigations mainly by the Blanc rule (cf. p. 779), according 
to which 1:4- and l:5-dicarboxylic acids, when heated with acetic 
anhydride and then distilled, yield anhydrides, whereas 1:6- (and 
1:7-) acids give cyclic ketones. Cyfohexanone, for example, on 
oxidation yields adipic acid (1:6), which gives ^fopentanone, 
whereas the latter gives glutaric acid (1:5), which yields its anhydride 



1090 STEROIDS 

and not ryc/obutanone. It is therefore possible to distinguish a 
six- from a five-membered ring, provided that the ring contains a 
CH 2 'CO or CH 2 -CH(OH) - group and can therefore be 
oxidised to the desired dicarboxylic acid. Fortunately various 
compounds (the bile acids), derived from cholesterol and con- 
taining hydroxyl groups in different rings, are known, so that 
this procedure is of fairly general application. Blanc's method, 
however, is unreliable when the carboxyl groups of the acid are 
attached to different rings, as they would be, for example, in the 
acid obtained by the oxidation of ring C of cholesterol at 11 or 
12 j 1 in such cases a l:6-acid may give an anhydride instead of a 
ketone. 

The structural framework of cholesterol was finally decided by 
the results of oxidation experiments on the sterol and on the 
bile acids, but more particularly by the study of the Diets' 
hydrocarbon. 

This most important compound, C 18 H 16 , was obtained by the 
dehydrogenation of cholesterol with selenium (p. 944) at 320, a 
very complex reaction during which chrysene and picene (p. 1023) 
are also formed. In such dehydrogenations a methyl group attached 
to a carbon atom common to two rings (angular methyl group) must 
of necessity be eliminated (as selenide) when the ^/oparaffin or 
rycfo-olefine rings become aromatic (except in certain cases where 
ring enlargement can occur or where the methyl group migrates to 
a new position, cf. p. 1104). The production of chrysene here does 
not prove, as might have been expected, the existence of four six- 
membered closed chains in cholesterol ; only three are originally 
present as the fourth is formed from the cyclopentane ring and the 
angular methyl group at 13. 

The results of oxidation experiments, X-ray crystal analysis, etc., 
showed that Diels* hydrocarbon was probably methylcyclopenteno- 
phenanthrene, (n), and it was then synthesised by Harper, Kon, 
and Ruzicka : j8-[a-Naphthyl]ethyl magnesium bromide was treated 
with 2:5-dimethylyc/opentanone and the hydrolysed product was 
distilled with phosphorus pentoxide under reduced pressure ; ring 
closure occurred, giving (i), which was then dehydrogenated to 
the Diels' hydrocarbon, (n), with selenium : 

1 The numerals used in this chapter to show the positions of substituents 
and the capital letters by which the rings are distinguished refer throughout 
to those in the formula on p. 1095. 



STEROIDS 



1091 



2*MgBr 



Me 





The di-methyl derivative of cyc/opentanone is used here to ensure 
the presence of a methyl group in the position shown in the final pro- 
duct ; the other methyl group being in an angular position is elimin- 
ated when the group > CMe is converted into > C^. 

The X-ray examination of the Diels* hydrocarbon and the 
synthetic compound proved their identity ; x the two preparations 
also gave the same nitroso- and tribromo-derivatives. When the 
Diels' hydrocarbon is formed from cholesterol it seems likely that the 
methyl group at 13 passes to 17 and the long side chain is eliminated. 

The structure of the long side chain in the molecule of cholesterol 
(at position 17) is proved by the production of methylwohexyl 
ketone, CH 3 -CO-CH 2 .CH 2 .CH 2 -CHMe 2 , from cholesteryl acetate 
or cholesterol on oxidation ; the formation of this compound also 
shows that the side chain is saturated and that it is united to the 
cyc/opentane ring by that carbon atom which forms the carbonyl 
group in the oxidation product. 

The structure of the side chain of cholesterol and of many other 
compounds has also been determined by an important method due 
to Wieland (cf. p. 975) : when an ester is treated with an excess of 
phenyl magnesium bromide it gives a tertiary alcohol, which can 
be dehydrated in one way only, 

R.CH 2 -COOEt > R.CH 2 .C(OH)Ph 2 > 

R.CH:CPh 2 R-COOH+COPh 2 

The oxidation of the resulting olefine then yields, as shown, benzo- 
phenone and an acid containing one carbon atom less than that of 

1 The mixed melting-point method is useless, because here, as in many 
other cases, related substances do not depress each other's melting-point. 



1092 STEROIDS 

the original ester. If, however, there is a branch in the chain in the 
a-position of the acid, the oxidation products of the olefine obtained 
from the tertiary alcohol will be benzophenone and another ketone 
instead of an acid : 

R \ *\ 

CH-COOEt -> jpH'C(OH)Ph 2 -> 

"O' "D* 

* RI Rv R x 

CtCPh 2 - CO + COPhj 

R/ -n/ 

\ R l 

The branching of the side chain having thus been established, 
the new ketone can then be oxidised further and the process of 
degradation continued. 

When cholestane (p. 1089) is oxidised with chromic acid the 
CHMe 2 group is attacked, acetone and a//ocholanic acid x being 
produced. The latter can be degraded by Wieland's method and 
then gives successively, wora/focholanic acid, biswora/focholanic 
acid, and finally aetioaZ/ocholylmethyl ketone. This ketone is 
oxidised with the loss of one carbon atom to aetioa/focholanic acid : 

^> CHMe - CH 2 - CH 2 CH 2 - CHMe 2 Cholestane 
\-CHMe CH 2 CH 2 - COOH ^/focholanic acid 

\-CHMe CH 2 - COOH Afora/focholanic acid 

\-CHMe - COOH Biswora//ocholanic acid 

y CO Me Aetiofl/focholylmethyl ketone 

\ COOH Aetioa//ocholanic acid 

These results show that the side chain in cholestane and, therefore, 
that in cholesterol has the given constitution. 

Aetioa/focholanic acid, further degraded by Wieland's method, 
gives a cyclic ketone which on oxidation affords a dibasic acid ; as 
this product gives an anhydride with acetic anhydride, the ring to 
which the side chain is attached is probably five-membered (p. 1089), 

1 The prefix allo denotes the stereochemical nature of the compound 
only (p. 1C 



STEROIDS 1093 

an inference which is established by the synthesis of the Diels' hydro- 
carbon already described. 

The position of the side chain in the five-membered ring, first 
suggested by X-ray and surface film measurements, has been deter- 
mined in the following manner : Cholesterol is oxidised by copper 
oxide to a ketone, cholestenone* C 27 H 44 O (i, p. 1094), which is then 
converted into coprostanol, C 27 H 47 OH (a stereoisomeride of choles- 
tanol,p. 1097), by the reduction of the carbonyl group (to > CH OH) 
and the ethylenic binding. The oxidation of coprostanol to the 
ketone, followed by a Clemmensen reduction of the latter, gives 
coprostane, C 27 H 48 , a stereoisomeride of cholestane, which yields 
cholanic acid on oxidation. 

Now deoxycholic acid, a bile dihydroxy-acid (p. 1098), also 
affords cholanic acid when its two >CH(OH) groups are both 
converted into > CH 2 in the usual way ; the side chains of de- 
oxycholic acid and cholesterol are therefore in the same position. 

Cholesterol > Coprostanol Coprostane-^. 01 _ , . ., 

Deoxycholic Cholamc aacL 



When the two >CH-OH groups of deoxycholic acid are both 
oxidised to ]> CO, and only the carbonyl radical at 3 is reduced by 
the Clemmensen method, the product is \2-ketocholanic acid (below) ; 
this compound undergoes internal condensation at 330 with the 
loss of carbon dioxide, giving dehydronorcholene, which on dehydro- 
genation with selenium loses two angular groups and yields methyl- 
cholanthrene. The structure of this hydrocarbon was proved by 
its oxidation to anthraquinone-l:2:5:6-tetracarboxylic acid, and 
subsequently by its synthesis. 

,,CxH ^ 
HOOOH 2 CT ^ 





Ketocholanic acid Dehydronorcholenc 



1 It will be been that the 5:6-olefinic binding of cholesterol takes up a 
different position in cholestenone : such changes are common in compounds 
of this type, but as the double bond is finally reduced, its position is im- 
material in the present instance. 



1094 



STEROIDS 





Methylcholanthrene 



Anthraquinone- 
tetracarboxyhc acid 



These results can be explained only if the position of the side 
chain in ketocholanic acid, and therefore in cholesterol, is, as shown, 
at 17 (p. 1095). 

The synthesis of methylcholanthrene also confirms the presence 
of the cyc/opentanophenanthrene skeleton in cholesterol, a fact of 
great importance in view of the very poor yield of the Diels' hydro- 
carbon when the sterol is dehydrogenated. 

The position of the hydroxyl group in cholesterol is fixed in the 
following manner : Cholestenone, (i), formed by the oxidation of 
cholesterol, can be proved to be an a/J-unsaturated ketone ; further 
oxidation yields a ketonic acid, (n), which can be reduced to a 
saturated acid, (in). The degradation of the latter by the Wieland 
method to give (iv) shows that the newly formed side chain has the 
constitution CH 2 CH 2 COOH ; the partial structure of choles- 
tenone, which accounts for these results, is shown below, and the 
fact that the final acidic product is esterified only with difficulty 
(steric hindrance) confirms the presence of the methyl group in 
the a-position. 




HOOC 




X 



II 



HOOC 




HOOC 



III 



IV 



STEROIDS 



1095 



Kon has proved the position of the hydroxyl group in a very 
simple way : cholestanol (below) is oxidised to cholestanone which 
is treated with methyl magnesium iodide. When the resulting 
tertiary alcohol is heated with selenium at 350, 7-methyl-l:2- 
ryc/opentenophenanthrene, which has been synthesised, is one of the 
products : the methyl group in this phenanthrene derivative obviously 
occupies the same position as the hydroxyl group of cholestanol. 

The above is an outline of the way in which the main features of 
the structure of cholesterol have been decided ; the position of the 
double bond and those of the methyl groups at 10 and 13 can only 
be proved by very difficult methods which illustrate no new important 
principles. 



HO 1 




Cholesterol 1 



It may be noted in conclusion that the structural formula of 
cholesterol is based, not only on the results of experiments with 
the sterol itself, but also, of course, as usual, on a consideration of 
all relevant evidence obtained in the study of allied compounds. 

The relationship of cholesterol, ergosterol, and stigmasterol is 
shown below : 



Cholesterol 
C 27 H 45 -OH 



Ergosterol 



Cholestanol 

(Dihydrocholesterol) 



Ergostanol 

(Hexahydro- 

ergosterol) 



3-j8-Hydroxyfl//o- 
cholanic acid 2 



Wieland's 
method 



' 3-/?-Hydroxyw0ra//0- 
cholanic acid 2 



Stigmasterol 
C M H 47 -OH 



Stigmastanol- 
(Tetrahydrostigmasterol) 



1 Sometimes the numbering of positions 18 and 19 is reversed. 
1 The letter ft refers to the configuration of the acid (p. 1097). 



Org. 69 



1096 



STEROIDS 



Each sterol can be reduced catalytically to the corresponding 
saturated alcohol, which is acetylated ; the acetyl derivative is then 
oxidised and the acetyl group displaced by hydrolysis. The product 
is a hydroxy-acid : when that from cholesterol is degraded one 
stage by Wieland's method, the same compound as that obtained 
directly from the other two sterols is produced. 

All three sterols, therefore, have the hydroxyl group in the same 
position and the same configurations about atoms 3, 9, 10, 13, 14, 
17 and 20 ; their catalytic reduction products differ solely as regards 
the structure of the side chain. 

On ozonolysis CIL'-II :i'l yields ajS-dimethylbutyraldehyde, whilst 
stigmasterol gives a-ethyl-j8-methylbutyraldehyde ; the nature of 
the side chains and the position of the double bonds in these sterols 
are therefore as shown. Ergosterol combines with maleic anhydride 
and on oxidation yields a benzene derivative : these facts show that 
there are conjugated double bonds in one ring of the sterol molecule. 
From all the evidence the following structures are assigned to the 
two sterols and the related hydroxy#0ra//0cholanic acid respectively. 




Ergosterol 




COOH 



Stigmasterol 



3-Hydroxy w>ra//0cholanic acid 



STEROIDS 



1097 



An examination of the formula of cholesterol (p. 1095) reveals 
the presence of eight asymmetric groups in the molecule, namely 
those at 3, 8, 9, 10, 13, 14, 17, 20 ; there are, therefore, 256 possible 
stereoisomerides. The chief point to decide, however, is the cis- 
or f raws-relationship of the four rings. Now sterols can be degraded 
in a suitable manner to a f raws-acid, derived from ryc/opentane ; 
the rings C and D are therefore trans- to one another. X-ray 
measurements reveal a flat molecule, which is only possible if the 
rings B and C are trans-. A comparison of the physical properties 
of cholestane and coprostane with those of cis- and Jraws-decalane 
shows that rings A and B are trans- in cholestane (the a//0-series) 
and cis- in coprostane. Thus cholestane is trans-trans-trans- and 
coprostane is cis-trans-trans-. 

It has also been shown that the hydroxyi group of cholesterol 
(at position 3) is in the ds-position relatively to the methyl radical 
at 10. A similar stereochemical arrangement is found in all the 
naturally occurring sterols, and this configuration is denoted when 
necessary by the prefix j8, the trans-form by a or epi. 

The stereochemical relationships of the steroids are usually 
indicated in formulae by showing atoms or groups projecting in 
one direction from the rings by continuous, and in the other by 
dotted, lines ; two groups cis to one another will therefore both be 
shown eitheK by continuous or by dotted lines. 



Me 



HO 




HO 




jB-Cholestanol 

fl//o-serie8 
Rings all trans 



R - C 8 H 17 



Coprostanol 

normal series 

Rings A and B CM 



As it is necessary to consider the stereochemical arrangement at 
5, 8, 9 and 14, where no substituents occur, the hydrogen symbols 
cannot be omitted as usual from the formula : in such cases lines 
or dots are therefore used to represent hydrogen atoms and methyl 
groups are then shown by Me. Compounds of the epi- or a-series, 
such as #*cholestanol, would have the hydroxyi group at 3 attached 
by a dotted line. 



1098 STEROIDS 

Digitonin (p. 1109) forms a very stable insoluble complex with 
j8-steroids, a fact which is extensively employed in stereochemical 
studies and also for effecting the separation of stereoisomerides. 



Bile Adds 

A brief description of some of the compounds found in the bile, 
including the bile acids, has been given (p. 629). Cholic acid and 
all the related bile acids are hydroxy-acids and, when heated, they 
yield the corresponding olefinic compounds, all of which can be 
reduced to cholanic or a//ocholanic acid ; they can also be converted 
into cholanic acid by oxidation to ketones followed by a Clemmensen 
reduction. 

The structure of cholanic acid being known from its relationship 
to cholesterol, and the positions of their hydroxyl groups having 
been determined in much the same way as in the case of that sterol, 
the bile acids may now be represented : 



COOH 




Cholanic acid or oftocholanic acid 

Cholic acid, 3:7:12-trihydroxycholanic acid 
Deoxycholic acid, 3:12-dihydroxycholanic acid 
Hyodeoxycholic acid, 3 :6-dihydroxy cholanic acid 
Chenodeoxycholic acid, 3:7-dihydroxycholanic acid 
Lithocholic acid, 3 -hydroxy cholanic acid 

The first two acids, and the last, occur notably in human bile ; 
hyodeoxycholic acid in that of swine ; chenodeoxycholic acid in 
that of geese and fowls ; lithocholic acid is also found in the bile 
of cattle. It is thought that all these compounds may be formed in 
the animal by the oxidation of cholesterol. 

Some important relationships between cholesterol and its deriva- 
tives and the bile acids may be seen from the following table : 



STEROIDS 1099 

Cholesterol < Diels' hydrocarbon 
\ (also synthesised) 

Coprostanol (p. 1093) Cholestanol (p. 1089) 
Coprostane (p. 1093) Cholestane (p. 1089) 
Cholanic acid (p. 1093) ^f/focholanic acid (p. 1092) 
Deoxycholic acid (p. 1098) 

Methylcholanthrene (p. 1093) 
(also synthesised) 

It will be observed that these interrelationships demonstrate 
clearly a common framework, the structure of which is proved by 
the syntheses indicated. Coprostane and cholestane, and also 
cholanic and a//ocholanic acids, are stereoisomerides, differing only 
in the ds or trans arrangement of the rings A and B (p. 1097). 

Vitamin D 

A short account of this vitamin has already been given (p. 653). 
Crystalline vitamin D 2 , now known as calciferol, was first isolated 
from irradiated ergosterol in 1931 and it is now clear that there are 
several compounds with vitamin D activity ; a numerical suffix is 
therefore used to distinguish them. 

When ergosterol is irradiated with ultra-violet light various 
isomeric compounds are successively produced, but of these only 
calciferol shows antirachitic activity : 

Ergosterol > Lumisterol > Tachysterol > Calciferol * 

Suprasterols. 

All have the same side chain, which gives ajS-dimethylbutyraldehyde 
on ozonolysis. Ergosterol and lumisterol have almost identical 
absorption spectra and both give the Diels' hydrocarbon on de- 
hydrogenation ; they are stereoisomeric, the confirm, n ion at C 10 
undergoing inversion during the transformation. The other 
isomerides have absorption spectra different from those of ergosterol 
and lumisterol and do not yield the Diels' hydrocarbon. During 
the change of lumisterol into tachysterol ring B is broken and the 
double bonds take up new positions in calciferol. 



1100 



STEROIDS 




Tachysterol 

Calciferol combines with four molecules of hydrogen in the presence 
of a catalyst giving a saturated compound, C 2 8H 61 -OH, and is there- 
fore tricyclic ; its structure is based mainly on its relationship to ergos- 
terol. On ozonolysis it yields formaldehyde (evidence of the presence 
of a CH 2 group in the vitamin), and the keto-acid shown below. 

Other important decompositions are summarised in the following 
scheme : 



C 9 H 17 



Calciferol : CHn same 
olefinic chain as in 
ergosterol 



CHMe-COOH 




C.H,, 1 
1 The side chain is reduced before ozonolysis is carried out. 



STEROIDS 1101 

In the reaction with maleic anhydride addition occurs to the 
conjugated system (a, a,) with the formation of the cyc/ohexene 
ring and, in the formula of the (hydrolysed) product, the CH- 
group attached to this ring is shown below it for the sake of con- 
venience. The reduction of carboxyl groups to methyl radicals, which 
occurs in the selenium reaction, also takes place in other compounds. 

Sodium and alcohol reduce calciferol and tachysterol to the same 
product so that their skeletons are identical, but the positions of 
the double bindings in tachysterol have not been decided. 

An antirachitic product distinguished as vitamin D 3 (isolated by 
chromatographic analysis from tunny-liver oil) has been prepared 
by irradiating 7-dehydrocholesterol with ultra-violet light ; the last- 
named compound can be obtained from cholesterol as indicated below : 




Cholesteryl acetate 7-Ketocholesteryl acetate 





'OH 

7-Dehydrocholesterol 

The oxidation of the > CH 2 group (7) of cholesteryl acetate to 
> CO by chromic acid in the manner shown is a type of reaction 
which often occurs in the sterol series (cf. p. 809) ; the kctone is 
then reduced by aluminium wopropoxide, and the dibenzoate of the 
resulting diol is heated. 7-Dehydrocholesterol benzoate is pro- 
duced (with the loss of benzoic acid) and the remaining (3) benzoyl 
group is displaced by hydrolysis. 

Sex Hormones 

Oestrogenic (female) hormones. In 1929 Doisy and Butenandt, 
independently, prepared in the pure state from pregnancy urine 
a substance, oestrone, C 18 H 22 O 2 , which has the property of producing 
oestrus in castrated female rodents. This discovery led to the 



1102 STEROIDS 

isolation of other sex hormones, and in the short space of ten years 
the structures of many of these most important and interesting 
compounds were determined, and pure materials became available 
for clinical use. 

Oestriol, C 18 H 24 O 3 , was isolated in 1930 (Marrian), also from the 
urine of pregnancy, and later oestradiol, equilin, and equiknin 
were discovered, all of which had physiological properties similar 
to those of oestrone. 1 As an illustration of the great difficulties 
involved in such work, it may be mentioned that only 25 mg. of 
oestradiol (p. 1103) were obtained from 4 tons of swine ovaries. 

Oestriol contains in its molecule one phenolic hydroxyl radical 
(and therefore an aromatic nucleus) and two secondary alcohol 
groups ; with potassium hydrogen sulphate it yields oestrone, the 
complex CH(OH)-CH(OH) becoming CO-CH 2 , and this 
phenolic ketone gives chrysene on distillation with zinc-dust. 
From this fact, X-ray data, and other physical measurements, it 
was concluded that these sex hormones were structurally related 
to the sterols. 

When oestriol is fused with potash the ring containing the 
alcoholic hydroxyl groups undergoes fission and oxidation, and the 
dibasic acid thus formed gives a dimethylhydroxyphenanthrene on 
dehydrogenation ; in the last reaction both the carboxyl radicals 
are eliminated as carbon dioxide. 




Oestriol Marrianolic acid 




Dimethylhydroxyphenanthrene 

1 It will be seen that some of these sex hormones have names which 
indicate the presence of carbonyl or more than one hydroxyl group in the 
molecule. 



STEROIDS 



1103 



The methyl ether of this dimethylhydroxyphenanthrene has been 
synthesised by Cook, and the structure of oestriol is thus established ; 
further evidence, moreover, is provided by Cook's synthesis of the 
methoxycycfopentenophenanthrene, which is formed by the reduc- 
tion and dehydrogenation of methylated oestrone. 



MeO 





Methyloestrone 



MeOV 

Methoxyc^c/opentenophenanthrene 



Oestradiol, (i), is formed by the reduction of oestrone, and when 
its phenolic monomethyl derivative, (n), is heated with zinc 
chloride an olefinic binding is produced, accompanied by the 
migration of the angular methyl group ; on dehydrogenation with 
selenium this cyc/opentene derivative, (in), yields methylmethoxy- 
cycfopentenophenanthrene, (iv), which has been synthesised. 



OH 



HO 




MeO 




II 




MeO 




HI 



IV 



Similarly methyloestrone gives with methyl magnesium iodide 
a tertiary carbinol, which, heated with selenium, yields a dimethyl- 
methoxycjtffopentenophenanthrene ; this product has also been 
synthesised. 





1104 STEROIDS 

Me 
OH 



MeO 



These changes can be explained only by assuming the presence 
at C ]: , of an angular methyl group (which migrates) and a carbonyl 
group at C 17 in oestrone. 

The structures of equilin and equilenin shown below have been 
proved by similar methods ; like oestrone and its derivatives, to 
which they are closely related, these substances are phenols. 

O 



HO 1 




Equilin 



Equilenin 



A complete synthesis of equilenin, identical in all respects with the 
natural product, was accomplished by Bachmann in 1940. 

Many synthetic oestrogenic compounds have been prepared. 
The first substances of this type (Cook and Dodds) were deriva- 
tives of tfg-dibenzanthracene, in which R = Me, Et, Pr a , Pr^, etc. : 




The most active compound is that in which R is Pr a , and this shows 
a biological activity nearly as great as that of oestriol, as does also 
(fraw$)stilboestrol (diethylstilboestrol, iv), a very important simpler 
compound, which is now synthesised for clinical use as follows : 
Anisaldehyde is converted into anisoin, which is reduced to 4- 
methoxyphenyl-4'-methoxybenzyl ketone, (i), and then ethylated 
with sodium ethoxide and ethyl iodide ; the product, (n), when 



STEROIDS 



1105 



converted into the tertiary alcohol, (in), dehydrated and finally 
demethylated, gives stilboestrol, (iv) : 




OMe 









Androgenic (male) hormones. Androsterone, C 19 H 30 O 2 , was 
isolated by Butenandt in 1931, from male urine of which 100,000 
litres were required ; it is a male hormone and it can be detected 
and estimated by the increase in the area of the combs of capons 
which is brought about by its administration. Later, dehydroiso- 
androsterone 1 and androstenedione were discovered, and in 1935 
Lacqueur isolated testosterone (10 mg. from 100 kilos of testes). These 
substances have important effects on certain male characterstics, such 
as the pitch of the voice, hair on the body, and the sex glands. 

The structures of the androgenic hormones have been determined 
mainly by the preparation of the compounds from known sterols ; 
androsterone, for example, can be obtained from cholesterol (overall 
yield up to 0-2 per cent.) by converting it into Qtocholestanol and 
oxidising (the acetate of) this alcohol with chromic acid (Ruzicka) : 
Cholesterol * j3-cholestanol * cholestanone > a-cholestanol 



HO 




(a. or) E/Hcholestanol 



Androsterone 



1 Whereas androsterone belongs to the a- or cpt'-series, dehydrowo- 
androsterone has the ^-configuration at position 3. 



1106 



STEROIDS 



Dehydroisoandrosterone is obtained by the oxidation of the acetyl 
derivative of cholesterol dibromide followed by denomination and 
hydrolysis ; the overall yield is about 2-8%. The dibromide is 
used to prevent the oxidation of the double bond in ring B and the 
group > CBr CHBr is subsequently reconverted into > C=CH 
with the aid of zinc. 

The oxidation of dehydrowoandrosterone then yields androstene- 
dione, the double bond changing its position, as in other cases (foot- 
note, p. 1093, and p. 1094) : 




HO 

DehydroMoandrosterone 



Androstenedione 



Testosterone can be obtained from the acetate of dehydro&oandro- 
sterone, which is reduced to an alcohol and then benzoylated ; the 
product is partially hydrolysed to eliminate the acetyl group 
(giving i) and then oxidised to the benzoylated ketonic alcohol, 
which yields testosterone on hydrolysis: 




OCOPh 




I Testosterone 

Testosterone is usually used clinically in the form of one of its esters. 
Progesterone, the corpus luteum hormone, which prepares the 
uterus for the implantation of the fertilised ovum, was isolated by 
Butenandt in 1934 ; 50 mg. were obtained from 10 kilos of swine 
ovaries. Its structure is shown by its preparation from stigmasterol 
(and other compounds) ; the dibromo-additive product of the 
acetylated sterol is oxidised to an acid, which is debrominated 
(above) and the acetyl group is then displaced by hydrogen. 



STEROIDS 



1107 




:OOH 



Stigmasterol 



The acid, (ll), so formed is degraded by the Wieland method 
(after protecting the nuclear double bond by bromination), and the 
resulting ketonic alcohol (pregnenolone, in), in the form of its di- 
bromide, is oxidised to a diketone, which is finally debrominated : 




:0'CH 3 




:oCH 3 



in 



Progesterone 



Pregnenolone is more easily oxidised to progesterone by heating 
it with acetone and aluminium wopropoxide (Oppenauer). This is 
an important general method for the oxidation of alcohols and is 
the reverse of the Ponndorf reaction (p. 156) : it depends on the 
use of a large excess of acetone. 

Progesterone is now manufactured by this method for clinical 



use. 



Although the steroids so briefly described above are directly 
responsible for the ::.:! :: of the various sexual processes, their 
formation in its turn is controlled from the pituitary (brain) gland 
by certain other hormones, which pass in the blood to the testes 
and ovary and stimulate the functions of these organs. It is interest- 
ing to note that androstenediol which has high male activity is also 
oestrogenic ; most of these compounds, in fact, have certain bi-sexual 
characteristics. 



1108 STEROIDS 

Adrenal Hormones 

When the adrenal glands are removed from an animal death ensues, 
but life may be prolonged by the administration of extracts from 
the cortex of the gland ; the hormone which produces this effect 
was originally called cortin, but it is now known to be a complex 
mixture of at least 20 steroids, only some of which are physiologic- 
ally active. These active compounds, hormones of the adrenal 
cortex, were investigated mainly by Reichstein, Kendall and Winter- 
steiner and shown to be derivatives of progesterone : 

Corticosterone or ll:21-dihydroxyprogesterone 
Dehydrocorticosterone or ll-keto-21-hydroxyprogesterone 
Deoxycorticosterone or 21-hydroxyprogesterone 

In addition, a 17-hydroxy-derivative of each steroid also occurs in 
the gland. 

The isolation of such substances from the complex natural mixture 
is accomplished only with very great difficulty and the so-called 
Girard reagents proved of great value for this purpose. 

The Girard reagent-T is prepared by mixing trimethylamine and 
ethyl chloroacetate and then adding hydrazine, 1 

Me 8 N+Cl.CH 2 .COOEt+H 2 N.NH 2 = 

[Me 3 N - CH 2 - CO - NH - NH 2 ]Cl+EtOH. 

The resulting hydrazide combines readily with ketones giving pro- 
ducts which are soluble in water ; non-ketonic compounds may then 
be extracted from the aqueous solution with a solvent, after which 
the hydrazide is hydrolysed and the required ketone extracted. 

The structures of the cortical hormones have been proved by 
their partial synthesis from steroids of known structure. Deoxy- 
corticosterone, for example, has been prepared as follows : The 
hydroxyketone (in, p. 1107), prepared from stigmasterol, is further 
degraded to (i) and the acid chloride of the acetyl derivative of this 
compound is treated with diazomethane ; the product, (11), is 
hydrolysed with alkali and treated with acetic acid, whereon the 
acetate, (in), is produced : this compound is then converted into 
deoxycorticosterone, (iv), by the Oppenauer oxidation (p. 1107), 
followed by the hydrolysis of the acetyl group : 

1 The Girard reagent-P is made with pyridine instead of trimethylamine. 




1109 



:oCHN 2 



ii 



COCH 2 OAc 



HO 1 




CO-CHa-OH 



III 



IV 



The synthesis of cortical hormones with a hydroxyl group at 11 
proved much more difficult as the few known steroids substituted 
in this position are unsuitable as starting materials. 

17-Hydroxydehydrocorticosterone (cortisone, compound E) has 
proved of value in the treatment of rheumatoid arthritis. 



Saponins 

Saponins and sapogenins. The saponins are vegetable glycosides, 
which act as emulsifiers of oils and produce stable foams when their 
aqueous solutions are shaken ; they also dissolve the red corpuscles, 
poison fish and the lower animals, and irritate the eyes and organs 
of taste. On hydrolysis they yield a sapogenin and a sugar or sugars. 

The sapogenins are all closely related structurally, and like the 
sterols they give the Diels' hydrocarbon on dehydrogenation ; they 
are hydroxy-derivatives of the framework shown (p. 1110). 

Digitonin is a saponin which occurs in Digitalis purpurea, the 
purple foxglove ; on hydrolysis it yields the >. p w' <\\u\\nt>i-\m 
(1 mol.), glucose (2 mol.), galactose (2 mol.) and xylose (1 mol.). 
D/.'/Vv. < //:. is a 2:3:15 (?)-trihydroxy-derivative of the first structure 
shown below. In the same plant occur gitonin and tigonin, which are 



1110 



STEROIDS 



respectively glycosides of the 2:3- and the 3-hydroxy-derivatives of 
this same structure. 

o 




Framework of Sapogenins 



Digitoxigenin 



Cardiac poisons. Since very early times certain plant extracts 
have been used as arrow-poisons and are now employed medicinally 
to revive the action of the heart. The potent principles of such 
extracts have been isolated and their structures have been deter- 
mined by Jacobs, Tschesche and Windaus. 

Digoxin, digitoxin and gitoxin, for example, are isolated from 
Digitalis purpurea, and Digitalis lanata ; these substances are glyco- 
sides, and on hydrolysis yield agly cones (or genins) and sugars. 



CHO 

CH 2 

CH-OH 

CH-OH 

CH-OH 

CH 3 

Digitoxose 



CHO 

CH-OH 

CH-OMe 

CH-OH 

CH-OH 

CH 3 

Digitalose 



The sugar obtained from these glycosides is digitoxose, and 
from others digitalose has been isolated. As will be seen, these 
aldoses are of a novel type ; they do not occur except in these 
cardiac poisons. The aglycones yield cholanic acid derivatives on 
degradation and have a structure similar to that shown for digitoxi- 
genin, the aglycone of digitoxin (above) ; the sugar residues are 



STEROIDS 1111 

attached to the hydroxyl group at 3. In the plant these glycosides 
are present as still more complex compounds combined with other 
sugars. 

The unsaturated 5-membered ring is very important from a 
physiological standpoint ; when the olefmic bond is saturated little 
activity remains, and a fission of the lactone ring also causes a loss 
of activity. The steroid part of the molecule of the so-called toad 
poisons, such as bufotoxm, is probably structurally similar to that 
of the genins. 



Org. 70 



APPENDIX 

Some Examination Questions 

MANY examination questions on organic chemistry relate to general 
methods of preparation, general reactions, and general properties 
of important types of compounds, and can be answered if the 
student is able to reproduce the facts which he has studied in his 
text-books. Others, however, are of a different character, and are 
set with the object of testing the ability of the student to apply his 
text-book knowledge in an intelligent manner ; those of the latter 
type only are considered below. 

1. Methods for the preparation of di-substitution derivatives of 
benzene are often required, as, for example : * Suggest methods for 
the preparation of m-mtroanitine, p-sulphobenzoic acid, and m-di- 
bromobenzene* 

In answering such questions, it is of course essential to bear in 
mind the rules of aromatic substitution (pp. 433, 1004) and to 
remember that many di-derivatives, C 6 H 4 XY, cannot be obtained 
directly from certain mono-substitution products, C 6 H 5 X, owing 
to the orientating effect of X. 

m-Nttroamline cannot be obtained by the nitration of aniline 
except under very particular conditions (p. 1013), because the amino- 
or NHAc-group is op-orientating. It may, however, be prepared 
from nitrobenzene because the nitro-group is /H-orientating, and 
one of the nitro-groups in the dinitro-compound can be reduced 
without changing the other. 

p-Sulphobenzoic acid cannot be obtained by sulphonating benzoic 
acid, and the carboxyl group cannot be introduced into the molecule 
of benzenesulphonic acid in the p-position by the general method, 

NO 2 > NH 2 N 2 X CN > COOH, because both the 

carboxyl radical and the sulphonic group are m-orientating. On 
the other hand, the methyl radical is op-orientating and can then be 
converted into COOH ; the suggested method therefore might be : 

/CH 3 /COOH 

C 6 H 5 -CH 3 C 6 H/ > C 6 H 4 <; 

X S0 8 H X S0 3 H 

1112 



APPENDIX 1113 

When, as in this case, it is known that the product would probably 
be a mixture, a method for the separation of the two or more com- 
ponents at one or other stage of the operations should be suggested, 
if possible. If, as would commonly be the case, the actual process 
could not be given, it would be known, nevertheless, that for 
volatile liquids, fractional distillation, and for soluble solids, frac- 
tional crystallisation of the actual components of the mixture, or of 
some simple derivatives, are generally employed, and a statement 
to that effect should be made. As a rule, details of the isolation of 
a product need not be given (except in the case of ordinary * pre- 
parations ') but are sometimes required. 

m-Dibromobenzene cannot be prepared by the direct bromination 
of benzene or of bromobenzene, or by nitrating bromobenzene and 
then displacing the NO 2 group by bromine by the usual series of 
reactions, because bromine is 0/>-orientating. It might, however, 
be obtained by brominating nitrobenzene and then substituting 
Br for NO 2 by reducing the compound to wz-bromoaniline with 
stannous chloride and hydrochloric acid and then displacing the 
amino-group by bromine. 

How could (a) m-aminophenol and (b) p-hydroxybenzoic acid be 
obtained ? m-Aminophenol cannot be obtained by nitrating phenol 
and then reducing the nitro-compound, or by sulphonating aniline 
and then (1i>placin<r the sulphonic group by hydroxyl, since both 
the HO and the NH 2 groups are op-orientating ; its preparation 
by the following series of reactions might therefore be -:.:.:*" <: : 

/N0 2 /NO 2 /NH, 

C 6 H 6 -* C fl H 4 (N0 2 ) a -+ C 6 H/ --* C 6 H/ -+ C 6 H 



X NH 8 N OH OH 

p-Hydroxybenzoic acid cannot be obtained by first nitrating or 
sulplinn.'ii injr benzoic acid and then displacing the nitro- or sulphonic 
group by the usual methods ; it might, however, be prepared by 
nitrating toluene and then submitting the product, a mixture of 
isomerides, to the following changes : 

/CH 3 /COOH 

C e H/ " C e H/ * 

X NO a X NO 2 

yCOOH /COOH /COOH 

4Ns NH t * 4Nx N 8 X 6 4Nx OH 



1114 APPENDIX 

The isomerides would probably be separated most easily as nitro- 
benzoic acids. 

2. Methods for the synthesis, or the complete synthesis 1 of 
compounds of a given structure, other than simple substitution 
products of benzene, have often to be siimr.-u d. To do so success- 
fully a knowledge of the important general reactions is of course 
essential, particularly of those which bring about the union of carbon 
atoms ; among the latter the following may be mentioned, but there 
are many others : The uses of hydrogen cyanide and its salts ; 
simple condensations of aldehydes and ketones with one another 
and with acids, including the aldol condensation (pp. 141, 148, 158) 
and the Perkin reaction (p. 526) ; the uses of Grignard reagents 
(pp. 236, 431, 497), and of diethyl malonate and ethyl acetoacetate 
(pp. 200-210) ; the Tiemann-Rcimer reaction (p. 502); the Claisen 
condensation (p. 827) ; the Michael reaction (p. 807) ; the Re- 
formatsky reaction (p. 286). 

The first step in answering such questions is to set out the 
structural formula of the required substance, possibly in the various 
ways in which it might be written and then to examine it carefully. 
A relationship to some better-known compound may then be seen, 
and a method of preparation may suggest itself. If not, the 
formula is resolved into various imaginary fragments or residues, 
which occur in certain simpler, commonly available, compounds and 
methods for bringing about their union, and for the subsequent 
modification, if necessary, of the resulting structure, are then con- 
sidered. 

This procedure may be illustrated by the following examples : 

* Suggest a method for the synthesis of each of the following 
compounds : (a) CHMe 2 - N:CHPh, (b) CPhMe(O COPh) COOEt 
(c) N(CH 2 .CH 2 .OH)3, (d) CMe 3 .COOH.' 

The molecule of (a) is related to that of benzylideneaniline (p. 499) ; 
it contains an wopropyl residue and also a benzal group, which is 
present in benzaldehyde. Since aldehydes condense with primary 
amines, tsopropylamine might be prepared from acetoxime (obtained 
from acetone), and could then be condensed with benzaldehyde to 
give the desired product. 

1 The word ' synthesis ' is often used to denote any method of preparation, 
except from some natural source ; the words * complete synthesis * usually 
imply the production of the compound from its elements. 



APPENDIX 1115 

The molecule of (b) is that of a benzoyl derivative of the ester of 
an a-hydroxy-acid. Now a-hydroxy- acids are obtained from 
aldehydes or ketones, with the aid of hydrogen cyanide, followed 
by the hydrolysis of the hydroxy cyanide. In this case a ketone, 
acetophenone, might be the starting-point ; the hydroxy-acid, 
prepared from it, is then benzoylated and esterified, or esterified 
and then benzoylated. 

(c) The molecule of this compound is closely related to that of 
triethylamine, obtained from ethyl bromide and alcoholic ammonia, 
but instead of the ethyl radicals it contains three hydroxyethyl 
groups. If, therefore, instead of ethyl bromide, ethylene bromo- 
hydrin, obtained from ethylene and hypobromous acid, were used, 
the desired compound might be obtained, since alcoholic ammonia 
does not react with alcoholic hydroxy 1 groups. It is probable, of 
course, that the primary and secondary hydroxyamino-compounds, 
as well as the quaternary salt, might be produced at the same time ; 
it is also conceivable that the bromohydrin might be converted into 
ethylene oxide. Such considerations, however, do not necessarily 
invalidate the suggested method, which is based on reasonable 
assumptions. On the other hand, to suggest that the hydroxy- 
amine, (c), might be obtained by chlorinating triethylamine, and 
K,S '.,'/ the product, would be most unsatisfactory, since it 
should be known that a hydrogen atom of a CH 2 <group would be 
displaced rather than that of a CH 3 group. What is required in 
such answers is not necessarily a method which must give the 
desired product, but one which is based on sound analogies : if the 
process involves improbable (or unknown) reactions, or if it is more 
likely that at any stage the reaction will take a course different from 
that which is assumed, then the suggested method is of course 
unsatisfactory. 

(d) As this compound is trimethylacetic acid, a possibility which 
might suggest itself would be to start with acetic acid, convert it 
into trichloroacetic acid, and then to treat an ester of this compound 
with methyl magnesium iodide ; or to treat ethyl aa-dichloro- 
propionate with methyl magnesium iodide. Neither project, how- 
ever, would be satisfactory as the carbethoxy-group might also react 
with the Grignard compound. 

Now the required acid is related to trimethyl carbinol, CMe 3 -OH, 
which could be obtained from acetone and methyl magnesium 
iodide, or from ethyl acetate and the same Grignard reagent ; the 



1116 APPENDIX 

displacement of hydroxyl by COOH might then be accomplished 
by the usual series of changes, but the displacement of a tertiary 
bromine by the CN radical is likely to prove very difficult : 

OH > Br > CN * COOII or 

OH Br > MgBr > COOMgBr COOH 

If perchance the formula of trimethylacetic acid recalls that of 
pinacolone, which can be prepared from acetone, it might also be 
remembered that this ketone can be oxidised to trimethylacetic acid. 
Such a method, however, would not be arrived at by deduction and 
would not be based on a general reaction, since, from the usual 
behaviour of ketones on oxidation, it might be expected that 
pinacolone would give acetic acid, acetone, and carbon dioxide. 

' Suggest methods for the preparation of (a) Ph CH 2 CH 2 CO Me 
and (b) CMe 2 :CH-CH 2 -CH 3 , and for a complete synthesis of 
(c) CHMe 2 -CH 2 .CH 2 .CHEt-COOH.' 

(a) This molecule contains an acetone residue and a benzyl 
group and is that of a mixed ketone. It might be obtained by the 
destructive distillation of a mixture of the calcium salts of acetic 
acid and j8-phenylpropionic acid (hydrocinnamic acid) ; destructive 
distillations, however, generally give very poor results, and, in 
addition, three products might be obtained, of which the desired 
compound might form only a very small proportion. Now the ketone 
(a) is closely related to benzylideneacetone, which is easily prepared ; 
it might possibly be obtained from this unsaturated compound by 
treating the latter with a suitable reducing agent, which would 
saturate the olefinic binding without affecting the carbonyl group ; 
alternatively, by treating the olefinic compound with hydrogen 
bromide and reducing the additive product. But many ketones 
containing the group, CH 2 -CO-CH 3 , are obtainable from ethyl 
acetoacetate, and such reactions generally give good results ; the 
desired compound might therefore be prepared from that ester and 
benzyl chloride by the usual procedure. 

(b) An important fragment of this molecule is an acetone or 
wopropyl residue, but it should be known that the substance could 
not be obtained by the condensation of acetone with propane or 
by the condensation of propane with propaldehyde. The compound 
is related to mesityl oxide, which is easily prepared from acetone, 
but to obtain it from the unsaturated ketone the carbonyl group 



APPENDIX 1117 

must be reduced to >CH 2 . Various processes for bringing about 
such a change are known, but as the reduction of the carbonyl 
radical might involve the saturation of the olefinic binding, the use 
of mesityl oxide would not be very promising. Further considera- 
tion might then suggest that the olefinic compound (b) might be 
obtained from the alcohol, CMe 2 (OH)-CH 2 -CII 2 -CH 3 , or from 
the corresponding halogen derivative, by the elimination of the 
elements of water or of halogen acid ; in such operations it is not 
likely that an isomeride, CH 2 :CMe-CH 2 -CH 2 -CH 3 , would be 
formed in large proportions owing to the general inactivity of the 
CH 3 in comparison with that of a CH 2 < group. Now many 
tertiary alcohols can be easily prepared from ketones or esters with 
the aid of Grignard reagents. It is therefore suggested that (b) 
might be obtained by treating acetone with propyl magnesium 
bromide, decomposing the additive compound, and then heating 
the alcohol with, say, zinc chloride or potassium hydrogen sulphate 
(or alone) to bring about the elimination of the elements of water ; 
or the tertiary alcohol might be treated with hydrobromic acid and 
the product heated with quinoline or alcoholic potash. The tertiary 
alcohol might also be prepared from ethyl butyrate and methyl 
magnesium iodide. 

Very many other secondary and tertiary alcohols, such as 
CHMe 2 - CH 2 . CH(OH) - CH,, C 2 H 5 - CH(OH) - CH 2 - CH 2 CH,, 
CeH 5 .CH(6H)-CH 2 .CH 3 , C a H 5 .CH a .CMe I -OH, CMe 2 Ph-OH, 
might of course be obtained by corresponding methods, and then 
converted into olefines and subsequently into paraffins by reduction . 

(c) It will be seen that this compound may be regarded as ethyl- 
woamylacetic acid. It might therefore be prepared (as an ester) 
from diethyl malonate with the aid of ttoamyl bromide and then 
ethyl bromide, in two separate operations as usual (p. 207). Since 
a complete synthesis of (c) is required, it would also be necessary to 
give methods for the synthesis of diethyl malonate and of the two 
alkyl halides from their elements. The troamyl iodide might be 
obtained from synthetic acetone by converting it into wopropyl 
alcohol, and then into wobutyl alcohol by the usual series of reactions, 

OH, Br, CN, CH 2 *NH 2 , CH 2 -OH, 

for passing up a series, repeating these operations in order to convert 
the tsobutyl into tyoamyl alcohol ; or more shortly from wopropyl 
magnesium bromide and ethylene oxide, etc. (p. 225). 



1118 APPENDIX 

1 How might the compound CMe 2 (CH 2 -COOH) 2 be obtained ? ' 
This molecule contains an acetone or wopropyl residue and two 
radicals derived from acetic acid, but it does not seem possible to 
unite such residues by general reactions. A group, CH 2 -COOH, 
however, is easily formed from CH(COOH) 2 , a residue of malonic 
acid, and the CH 2 < group of the latter is very reactive. The 
required compound might therefore be obtained from acetone by 
converting it into CMe 2 Br 2 and then treating the dibromide with 
diethyl sodiomalonate (2 mol.) ; the resulting ester would then be 
hydrolysed and the tetracarboxylic acid decomposed in the ordinary 
way : 

/CH(COOEt) 3 

CMe a Br a CMe^ * 

X CH(COOKt), 

/CH(COOII), ,CH,-COOH 

CMe,/ * CMe/ 

X C11(COOH) 2 X CH,-COOII 

A further examination of the formula of the acid shows that 
the molecule contains a residue of wovaleric acid united to a 
CH 2 -COOH group, and that of wovaleric acid, residues of acetone 
and acetic acid. Now wovaleric acid could be synthesised from 
ethyl acetoacetate or diethyl malonate, but a saturated acid such as 
this does not lend itself to further synthetical operations. It might 
be transformed into an unsaturated acid, CMe 2 :CH-COOH, how- 
ever, by bromination and subsequent elimination of the elements 
of halogen acid, and the ester of this product would be expected to 
give the compound, (COOEt) 2 CH-CMe 2 -CH 2 .COOEt, by direct 
combination with diethyl sodiomalonate (Michael reaction). The 
unsaturated acid might also be prepared from the condensation 
product of acetone and diethyl malonate (but not by the condensa- 
tion of acetone and acetic acid). It might also be possible to convert 
the unsaturated acid into CMe 2 Br CH 2 COOH with the aid of 
hydrobromic acid and then to treat the ester of this compound with 
diethyl sodiomalonate ; if the ester of the tricarboxylic acid were 
thus obtained it could be easily converted into the desired compound. 
It will be seen from the examples given above that every stage of 
a suggested method must be carefully considered in order to avoid 
the use of operations which, although they may bring about the 
desired change, may also cause others which would defeat the end 
in view. 



APPENDIX 1119 

3. Another type of question is that which deals partly or mainly 
with isomerism and which often causes unnecessary trouble owing 
to the haphazard manner in which it is treated ; some simple 
examples may serve to show the best procedure. 

' Write the structural formulae of the alcohols, C 5 H ir OH, and 
of the amines, C 5 H 13 N.' 

In answering all such questions the formulae should be deduced 
systematically, otherwise some of the possible isomerides may be 
omitted, or two formulae, which are merely set out differently, 
may be returned as those of two isomerides, when they are in fact 
identical. 

Now the alcohols, C 5 H U -OH, arc derived from the pentanes, 
C 5 H 12 , and the first step, therefore, is to write the formulae of these 
hydrocarbons ; in this, and similar cases, skeleton formulae of 
carbon atoms alone might suffice. 



I CH 3 .CH 2 .ClVcH 2 -CH, H *JJ a > CH-CH.-CH, 

a' ft' V n' a <-H 3a ' V c' 

III C(CH,) 4 

It is then obvious that from (i), three isomerides, 0, b y c, and from 
(n), four isomerides, a, b, c, d, are derived by snl^ii: I'V.-.r HO 
for hydrogen, whereas (ill) gives one alcohol only. 

Of the amines, C 5 H 13 N, there will be eight primary bases, each 
of which corresponds with one of the alcohols ; in addition, there 
are secondary and tertiary amines to be considered. The structures 
of the former are obtained by introducing an > NH group between 
two carbon atoms in the various possible ways ; from (i) two such 
bases are obtained, since there are two different positions a' and b r ; 
from (n) there are derived three isomerides by introducing the 
>NH group at a', V, or c' ; from (in) only one secondary base 
could be formed. The structures of the tertiary amines are easily 
found because the group, C 5 H 13 , must consist of three radicals 
which can only be CH 3 , CH 3 and C 3 H 7 or CH 3 , C 2 H 6 and 
C 2 H 5 ; the group C 3 H 7 , however, may be either the normal or 
tsopropyl group, so that there would be three tertiary bases. 
Altogether, therefore, 17 compounds, C 6 H 13 N, are theoretically 
possible. 



1120 APPENDIX 

1 Write the structural formulae of the benzene derivatives, 
CgHj^O.' 

If the compound is a mono-substitution product of the hydro- 
carbon, it may be represented by the formula, C 6 H 5 (C 2 H 5 O), 
and the various isomerides of this class are first obtained by con- 
sidering the possible arrangements of the group, C 2 H 5 O. These 
would be : 

CH a .CH 2 -OH CH(OH)-CH 3 CH 2 -O-CH 3 OCH a -CH 3 

If the compound is a di-substitution product, its molecule may 
contain one side chain of two carbon atoms, or two side chains, 
each containing one carbon atom ; in other words, the di-substituted 
derivatives are isomerides obtained from A 9 C fl H 5 C 2 H 5 , by displacing 
a nuclear hydrogen atom by hydroxyl, or from B, C 6 H 4 (CH 3 ) 2 , by 
displacing side chain hydrogen by hydroxyl, or by interposing an 
oxygen atom. 

Now from A, o-, m- y and />-ethylphenols, C 6 H 4 Et-OH would be 
obtained. From B, which may be cither o-, m- y or />-xylene, the 
three corresponding xylcnols, CH 3 -C 6 H 4 -CH 2 -OH, may be 
derived and also the three isomeric, o-, m-, and />-ethers, 
CH 3 .C 6 H r OMe. 

Lastly, if the compound is a tri-substitution product of benzene, 
it must be represented by C 6 H 3 (CH 3 ) 2 -OH, and of such phenols 
there are six isomerides, two derived from o-, three from m- y and 
one from />-xylene. 

An alternative procedure would be to start from the possible 
hydrocarbon structures, C 6 H 4 *CH 2 -CH 3 and C 6 H 4 (CII 3 ) 2 , and 
then to derive the isomerides by (a) ' ,, -j : : '.-. an oxygen atom 
between two carbon atoms, and (b) di.-pl.iriiiL! a hydrogen atom by 
hydroxyl, in all the possible ways. From ethylbenzene two ethers, 
two alcohols, and three phenols are thus obtained, whereas each of 
the xylenes gives rise to one ether and one alcohol, and in addition 
o-xylene gives two phenols, w-xylene three, and p-xylene one. 

A systematic procedure thus gives the possible structural formulae 
without difficulty, and there is no need to compare any two of them 
to see whether or not they are identical 

' What possible structures can be assigned to a compound of the 
molecular formula, C 9 H 8 O 3 , which gives terephthalic acid on 
oxidation ? ' 



APPENDIX 1121 

As the substance must be a di-derivative of benzene containing 
the group, C 6 H 4 <, the residue, C 3 H 4 O 3 , must form two side chains 
in the ^-position, of which, obviously, one carbon atom in each 
case must be directly combined with the benzene nucleus. Further, 
one of these side chains, A, must contain one and the other, J5, 
must contain two carbon atoms. 

If A is COOH, Bis C 2 H 3 O, namely -CO - CH 3 or CH 2 -CIIO. 

If A is CHO, B is C 2 H :J O 2 , namely CH 2 COOH, 
CH(OH).CHO, CO-CH 2 .OH, or COOC1I 3 . 

If A is CH 2 -OH, B is C 2 HO 2 , namely CO-CIIO. 

If A is CH 3 , B is C 2 HO 3 , namely CO-COOII. 

By thus proceeding from the highest to the lowest stage of 
oxidation of A, the required isomerides are easily obtained. 

In answering such questions it may be possible to write one or 
more formulae in which the valency of each atom is correctly 
shown, but which represent compounds, the existence of which is 
improbable ; thus, in the above example, when B is C 2 H ;J O 2 it 
might be written -CH 2 -O-CHO. In such case the improbable 
formula should be given with suitable comments. 

4. A few examples of questions on research problems may now 
be considered. 

1 A substance, neutral to litmus, of the empirical formula, 
C 7 H 7 O 2 N, boiled with alkalis, gave a solution from which acids 
liberated a compound, A, free from nitrogen. 0-207 g. of A gave 
0462 g. CO 2 and 0-081 g. of H 2 O ; 0-25 g. of A in 25 g. of acetic 
acid gave A = 0-35 (K for acetic acid is 39). From these data find 
the molecular formula of A and that of the original substance, and 
give the possible structural formulae of the compound A.' 

As the original compound is neutral, and loses nitrogen when it 
is boiled with alkalis, giving apparently an acid, it is probably an 
ammonium salt, an amide, or a nitrile. From the combustion data, 
the composition of A is found to be C - 60-9, H ==. 4-35, and 
O = 34-8%, corresponding with the empirical formula, C 7 H 6 O 3 , 
which requires C, 60-85, H, 4-35, 0, 34-8%. From the experimental 
data the molecular weight of A is 111, and C 7 H 6 O 3 requires 138 ; 
as, however, the observed value for an acid would probably be low 
owing to the ionisation of the compound in acetic acid solution, the 
cryoscopic result may be taken to show clearly that the molecular 
formula of the acid is C 7 H 6 O 3 or C 6 H 4 (OH)-COOH. The acid, A, 



1122 APPENDIX 

therefore is o-, w-, or />-hydroxybenzoic acid and the original 
compound, C 7 H 7 O 2 N, is the corresponding amide. 

It should be noted that as the results of cryoscopic determinations, 
apart from other experimental errors (which may be more than, 
say, 10%) are influenced by ionisation or association, they only 
serve to show the value of n in the expression (E.F.) n = M.F. 

' A hydrocarbon containing C - 85-7 and H - 14-3% combines 
directly with bromine, giving an oil, which contains 74-1% of 
bromine. This bromo-derivative is boiled with a solution of sodium 
carbonate and the product is oxidised with potassium permanganate 
solution. Acetic acid is formed. Give the possible formulae of 
the hydrocarbon and of the substance formed by the hydrolysis of 
the bromo-derivative.' 

From the percentage composition, the empirical formula, CH 2 , 
is obtained ; the compound is therefore an olefine or possibly a 
rycfoparaffin. In either case, since the hydrocarbon combines 
directly with bromine, 74-1 : 160 : : 25-9 : x, where x is the equiva- 
lent weight of the (CH, 2 ) n radical ; as x is 56 the M.F. of the radical 
is (CH 2 )i. Alternatively the molecular weight of the hydrocarbon 
radical may be found by calculating that of the dibromide, which 
is 74-1 : 160 : : 100 : x, and then subtracting 160 for Br 2 . The 
molecular formula of the hydrocarbon, therefore, is C 4 H 8 , and, if 
an olefine, its structure may be represented by one of the following 
formulae : 



CH a :CH-CH 2 .CH 3 CH 3 -CH:CH-CH 3 or 

I II III 

Now the dibromide would probably give the corresponding 
glycol when it is boiled with sodium carbonate solution ; if so, 
since the product gives acetic acid on oxidation it could hardly be 
derived from (i), as such a derivative would be expected to give 
propionic and carbonic acids ; on the other hand, a glycol, 
CH 3 -CH(OH).CH(OH)-CH 3 , from (n) would probably give acetic 
acid only, and a glycol, (CH 3 ) 2 C(OH).CH 2 -OH, from (in), acetone 
and carbonic acid, the former of which might then be oxidised 
further to acetic and carbonic acids. 

The hydrocarbon, therefore, is probably (n) or (in) ; it could not 
be ryc/obutane, but it might be methylryc/opropane from which 



APPENDIX 1123 

a glycol, CH 3 .CH(OH)-CH 2 .CH 2 .OH or CH 3 .CH(CH 2 .()H) 2 , 
might be obtained and oxidised to acetic acid. 

* 0-2 g. of a neutral compound gave 0-3521 g. CO 2 and 0-072 g. 
H 2 O. When the compound was boiled with ammonium hydroxide 
solution and the concentrated neutral solution was treated with 
silver nitrate solution, there was formed a colourless silver salt which 
contained 65-06% of metal (Ag = 107-9), From these data assign 
a formula to the neutral compound and to the substance which 
forms a silver salt.' 

The combustion results give C - 48-0, H - 4-0, and O - 48-0% 
(by difference) ; the E.F. is therefore C 4 H 4 O 3 . Obviously the 
compound is converted directly or indirectly into an ammonium 
salt, and from the percentage of metal in the silver salt the 
equivalent of the radical (combined with one atom of silver) 
is 65-06 : 107-9 : : 34-94 : x, or 58. This radical must contain 
CO-O , E = 44, which apparently is combined with one atom 
of carbon and two atoms of hydrogen, giving C 2 H 2 O 2 , E = 58 ; its 
molecular formula therefore is (C 2 H 2 O 2 ) n and that of the acid is 
(C 2 H 3 O 2 ) W . As the original compound is (C 4 H 4 O 3 ) W the molecular 
formula of the acid is probably (C 2 H 3 O 2 ) 2 or CJI 6 O 4 , unless some 
fission of the molecule has occurred ; this molecule would contain 
two COOH groups and may be written C 2 H 4 (COOH) 2 . 

The acid is therefore either succinic or zsosuccinic acid, and since 
it is obtained from a compound, (C 4 H 4 O 3 ) n , by hydrolysis, the latter 
must be an anhydride and the acid is succinic acid. It will be seen 
that the acid cannot have the molecular formula, (C 2 H 3 O 2 ) W , where 
n is greater than 2, but the original compound might possibly have 
been (C 4 H 4 O 3 ) W where n is 2, 3, or more. 

* 0-2 g. of a compound containing carbon, hydrogen, and oxygen, 
gave 0-2933 g. of CO 2 and 0-1200 g. of H 2 O. When boiled with 
acetic anhydride it gave a derivative which afforded the following 
data : 0-1741 g. gave 0-3080 g. CO 2 and 0-0902 g. H 2 O : 0-25 g. 
dissolved in 10 g. of acetic acid gave A = 0-56 (K = 39) : 0-261 g. 
on hydrolysis neutralised 30 c.c. of N/10 alkali. 

Find the empirical and molecular formulae of the derivative and 
of the original compound, and assign a possible constitution to the 
latter/ 

The combustion results for the original compound give C = 40-0, 



1124 APPENDIX 

H = 6-7, and O 53-3%, from which the E.F., CH 2 O, is immedi- 
ately deduced. As this compound is changed by acetic anhydride, 
the product might be an acetyl derivative or an anhydride. This 
product contains C = 48-25, H = 5-75, and O = 46-0% and seems 
to have the empirical formula, C 7 H 10 O 6 . The cryoscopic value for 
its M.W. is 174, a result which is probably not influenced by 
ionisation or association and which agrees with that required for 
C 7 H 10 O 5 . On the assumption that the product is an acetyl derivative, 
the weight of the substance which gives one equivalent of acetic 
acid on hydrolysis would be 3 : 1000 : : 0-261 : x = 87. As this 
value should be free from any considerable error, the M.W. may 
be taken as 174, which agrees with the cryoscopic result. The 
compound, C 7 H 10 O 5 , is therefore a diacetyl derivative. Now 
C 7 H 10 O 6 -2(O.CO-CH 3 ) = C 3 H 4 O, which may be written 

CH 2 .CO-CII 2 , CH 2 .CH-CHO, or CH 2 - CH 2 CO , 

and the molecule of the original compound will contain one of these 
groups combined with two hydroxyl radicals. The acetyl derivative 
is therefore that of dihydroxyacetone or of glyceraldehyde, C 3 H 6 O 3 ; 
it cannot be derived from the group CH 2 -CH 2 -CO because 
an acetyl derivative, AcO-CH 2 -CH 2 -CO-OAc, if obtainable, 
would neutralise three and not two equivalents of alkali. 

The deduction of an E.F., not always a very easy matter, is of 
course very much simplified if the (approximate) M.W. is known ; 
it is often better, therefore, to calculate the molecular weight before 
to find the E.F. 



* An optically active compound, A, containing C = 44-1, H = 8-8, 
and O = 47-1%, heated with acetic anhydride and sodium acetate 
gave a crystalline derivative the M.W. of which, determined cryo- 
scopically, was found to be 300. When hydrolysed with alkali, 
l-064g. of this derivative neutralised 28 c.c. of N/2 caustic soda. 
On oxidation, A gave malonic acid as one of the products. What is 
the probable structure of A ? ' 

The E.F. of A is found to be C 5 H 12 O 4 . Since 1-064 g. of its 
derivative neutralises 14 c.c. of N. alkali, the weight which gives one 
equivalent of acetic acid is 14 : 1000 : : 1-064 : x, and x is 76. As 
the molecular weight is (approximately) 300, the molecule of the 
acetyl derivative must contain 4 acetyl groups, and that of A, which 



APPENDIX 1125 

is C B H 12 O 4 , 4 hydroxyl groups ; the latter, therefore, is a tctra- 
hydroxypentane, C 5 H 8 (OH) 4 , in the molecule of which, presumably, 
no two hydroxyl groups can be combined with the same carbon 
atom. 

Now from the three isomeric pentanes, 8 isomeric tetrahydroxy- 
compounds can be derived ; this will be seen by writing the struc- 
tural formulae of the three isomeric hydrocarbons (p. 1 1 19), imagining 
that each is converted into a pentahydroxy-derivativc and that one 
hydroxyl group is then displaced by hydrogen in all the possible 
ways. Three isomeric tetrahydroxy-compounds are thus obtained 
from normal pentane, four from wopentane, and one from tetra- 
methylmethane. Of these, only those compounds which contain 
in their molecules a group, C CH 2 C, could give malonic acid 
on oxidation, that is to say, the isomcrides, 

CH 2 (OH)-CH 2 -CII(OH)-CII(OH)-CH a .OH 
CH 2 (OH) - CH(OH) . CII 2 -CI I(OI I) - Cl I 2 OH 

1 10 ' cnP C(OH) CH ' 2 ' CI Ia ' OH 

But as only the first two of these isomerides could show optical 
activity the structure of A must be represented by one of those 
formulae. 



NOTE ON CONSULTING THE LITERATURE 

IT is often necessary, especially for those engaged in research, to 
consult dictionaries, works of reference and various chemical 
journals to find out whether some particular compound (A) has or 
has not been described, and if it can be traced, to read all that has 
been published about it. This may be a very troublesome task 
and the procedure will vary according to circumstances. 

When (A) is known by name a preliminary search may be made in 
the alphabetical indexes of the following : 

Dictionary of Organic Chemistry, Heilbron and Bunbury. 
Dictionary of Applied Chemistry, Thorpe. 

The first of these, published in 1943, and revised ten years later, 
lists a large number of organic compounds and gives their physical 
characteristics, together with some literature references. Thorpe's 
dictionary (1937-54) is especially useful for commercial products, 
methods, etc. 

A compound may be indexed alphabetically under a trivial or 
a systematic name, and in the latter case especially, there may be 
various ways of doing so. Thus, even ethyl chloride might be 
indexed as such, or as chloroethane 1 or monochloroethane, and 
hydroxyaminopropionic acid as aminohydroxypropionic acid ; the 
compound C 6 H ? (COOII)(NH 2 )(OH) 2 [1:2:4:5] 2 might be indexed 
as dihydroxyaminobenzoic acid, as aminoprotocatechuic acid, or 
as dihydroxyanthranilic acid, and Ph-NH-CH 2 -NH-Ph as di- 
phenylmethylenediamine, dianilinomethane, and so on. 

Usually, however, the substituent elements or groups contained 
in recorded compounds are named in a given order, and if so the 
sequence should be carefully noted ; in Heilbron's dictionary, for 
example, this order is set out at the beginning. 

Very often (A) is some apparently new (unnamed) compound, the 
structure of which is known from its method of formation in the 
course of research or it may be a compound which it is desired to 

1 Ethyl is aethyl or athyl, ethane is aethan or athan and hydroxy is oxy 
in German ; as a rule the systematic English and German names of a 
compound are practically the same. 

2 All such numbers are often omitted in an index (as are also salts in 
general). 

1126 



NOTE ON CONSULTING THE LITERATURE 1127 

synthesise, if it has not already been described. In either case it may 
be given one or more systematic names and looked for under each. 

Another important work of reference is Traitt de Chimie Organ- 
ique, Grignard, in 23 vols. The main subjects dealt with therein are 
shown on the cover of each volume, to which there is also an alpha- 
betical, formula and author index ; very comprehensive lists of the 
literature references to the matter described in the various sections 
are also included. The treatise is not meant to be an encyclopaedia 
of organic compounds ; it deals systematically and critically with 
facts, methods and theories and is especially useful when information 
is required on some particular subject. 

Elsevier's Encyclopaedia of Organic Chemistry is useful for finding 
information concerning condensed carbocyclic ring compounds ; 
this is the only part of this work published to date. 

As the above-named works do not claim to be exhaustive the 
search should always be continued elsewhere, and Beilstein's 
Handbuch der Organischen Chemie (4th edition) may next be con- 
sulted. This work covers the literature to the end of 1909, but has 
two addenda, one (E I) from 1910 to the end of 1919 and the other 
(E II) from 1920 to the end of 1929 ; there arc 4 volumes concerned 
with aliphatic, and 23 volumes with aromatic and other cyclic com- 
pounds, in the main work and in each addendum. The number of 
each volume of the addenda corresponds with that of the main work : 
that is to say a compound found for example in vol. vi of the main 
work will be described in the same volume of each addendum. 
On the cover of each volume of the main work there is a summary of 
the types of compounds therein described and all volumes con- 
tain an alphabetical index ; there is also a general alphabetical 
index (vol. E II, xxviii) and formula index (vol. E II, xxix) 
covering the main work and the two addenda and covering also 
vols. xxx and xxxi which deal with rubber, carotenoids and 
carbohydrates to the end of 1938. A list of the abbreviations used 
will be found in vol. i. 

When (A) is unknown by name, or it seems likely that it might 
be indexed under many headings, a formula index must be con- 
sulted, and time may often be saved by doing so in the first place. 
Also, when the name of any author associated with (A) is known, 
a literature search may sometimes be shortened by consulting any 
author indexes which may be available, but this should not take the 
place of the formula index search. 

Org. 71 



1128 NOTE ON CONSULTING THE LITERATURE 

In a formula index compounds are arranged according to the 
number and nature of the atoms in their molecules, starting with 
the number of carbon atoms, followed immediately by the number 
of hydrogen atoms (if any) and then any other elements which are 
present arranged alphabetically. 

All compounds containing one carbon atom are first given, then 
those with two atoms of carbon, and so on. Indexes constructed 
on this plan, which should be consulted in the given order, are : 

Beihtein (vol. E II, xxix). 

Formula indexes of the American Chemical Abstracts, 1920-46, 
and thereafter one for each year. Similar indexes will be 
found in Chemisches Zentralblatt, 1922-24, 1925-29, and for 
later years, at the end of each annual volume. 1 

Most of the books of reference mentioned above are generally 
to be found only in the libraries of large institutions such as the 
Patent Office, Colleges (technical and otherwise) and Universities ; 
here also more or less complete sets of many of the important 
journals may be consulted. 

A common reason for consulting the literature is to find the best 
method for the preparation of some required compound ; this may 
often be found in Beilstein or one of the other quoted works, but 
it is always advisable to consult Organic Syntheses, in which the 
best-known method for the preparation of each of a large number 
of compounds is given in great detail. 

The following two examples may serve to illustrate the general 
procedure suggested above : 

(1) It is desired to find out whether or not a compound (A) of 
the following structure has been described: 

CHMe-CHMe v 
HN<; )NH 

X CHMe-CHMe X 

It is obviously likely be called tetramethylpiperazine, and it will in 
fact be found in the alphabetical index to Beilstein (vol. E II, xxviii) 
under that name ; the page references here given are 23, 23 ; I, 8 ; 

1 These are arranged rather differently from those of Beilstein and the 
American Chemical Abstracts, but a few moments study of them will afford 
all necessary guidance. 



NOTE ON CONSULTING THE LITERATURE 1129 

II, 19, 22, 23, 24. The figure 23 refers to the volume of the main 
work and 23 to the page. I and II refer respectively to the first and 
second addenda and the page figures to the same volume, i.e. 23, of 
these addenda as before. The reference 23, 23, will be found to 
describe all that was known about the compound (A) up to the end 
of 1909. The reference I (23), 8, will be found to describe an 
isomeric tetramethylpiperazine, as also will II, 19 ; further informa- 
tion on the required substance, complete up to the end of 1929, is 
found in references II, 22, 23, 24. Later references must be sought 
in the American Chemical Abstracts formula index where the 
compound will be found listed as piperazine, tetramethyl and 
reference must be made to each entry; these, of course, are abstracts 
only, but at the beginning the title of the original paper and the 
name of its author are given. 

(2) Information is required about a substance (A) which is thought 
to be />-CH 3 .C 6 H r SO ? -CH 2 .SO 2 .C 6 H 5 , but for which a probable 
name may not suggest itself. 

Under C 14 H 14 O 4 S2, in the formula index to Beilstein(vol.E II,xxix) 
there will be found the following five compounds named as shown : 

aj8-Bis-phenylsulfon-athan, C 6 H 5 - SO 2 - CH 2 CH 2 - SO 2 - C 6 H 5 . 
aa-Bis-phenylsulfon-athan, (C 6 H 5 - SO 2 ) 2 CH - CH 3 . 
4:4'-Dimethyl-diphenyldisulfon, CII 3 - C 6 H 4 - SO 2 . SO 2 - C 6 H 4 - CH 3 . 
Phenylsulfon-benzylsulfon-methan, PhSO 2 - CH 2 - SO 2 - CH 2 Ph. 
/>/>-Diphenylen-bis-methylsulfon, CH 3 - SO 2 - C 6 H 4 - C 6 H 4 - SO 2 CH 3 . 

From these names formulae can be written as indicated. It is 
clear that the desired compound had not been described up to the 
end of 1929. 

A further search is made in later formula indexes and it will be 
found under the name Methane (phenylsulfonyl) (/>-tolylsulfonyl), 
in the collective index of American Chemical Abstracts, 1920-46. 
Further search will then be made in the annual indexes of the same 
work. 



ABBREVIATIONS USED IN THE REFERENCES 
TO JOURNALS 



Amer. Chem. J. 

Ann. 

Ber. 

Compt. Rend. 

Helv. 

* 

y. Am. Chem. Soc. 

J. pr. Chem. 

J. Soc. Chem. Ind. 

Proc. Chem. Soc. 

Proc. R.S. 



American Chemical Journal. 

Justus Liebig's Annalen der Chemie. 

Berichte der deutschen chemischen Gesell- 

schaft. 
Comptes rendus hebdomadaires des Seances 

de PAcademie des Sciences. 
Helvetica Chimica Acta. 
Journal of the Chemical Society. 
Journal of the American Chemical Society. 
Journal fur praktische Chemie. 
Journal of the Society of Chemical Industry. 
Proceedings of the Chemical Society. 
Proceedings of the Royal Society. 



1130 



OXIDISING AGENTS 



Acetone and aluminium woprop- 

oxide, 1107, 1108. 
Air, 1058. 

Benzoyl peroxide, 812. 
Bromide water, 862, 872, 886. 
Chromic acid, 797, 809, 921, 930, 

940, 951, 972, 1026, 1027, 1089, 

1092, 1100, 1101, 1105. 
Ferric chloride, 923, 992. 
Hydrogen peroxide, 764, 808. 
Hypoiodites, 881. 
Iodine, 881, 1084. 
Lead dioxide, 1044. 
Lead tetra-acetate, 808, 809, 975, 

1070. 
Mercuric oxide, 935. 



Monoperphthalic acid, 895, 1078, 

1079. 
Nitric acid, 797, 862, 928, 933, 948, 

1025. 
Ozone, 799, 809, 812, 940, 954, 955, 

966, 967, 972, 976, 978, 982, 1096, 

1099, 1100. 
Perbenzoic acid, 808. 
Periodic acid, 895, 1078, 1079. 
Potassium ferricyanide, 1044. 
Potassium permanganate, 712, 747, 

783, 809, 881, 914, 920, 921, 926, 

940, 948, 954, 977, 983, 1001, 

1055, 1069. 

Selenium dioxide, 695, 809. 
Silver oxide, 942, 1074. 



REDUCING AGENTS 



Aluminium amalgam, 747, 982. 
Aluminium tsopropoxide and iso- 

propyl alcohol, 1101. 
Electrolytic reduction, 1054. 
Hydriodic acid, 782, 783, 797, 881, 

921, 929, 975, 1023, 1025, 1081. 
Hydrogen and a catalyst, 710, 713, 

804, 954, 970, 974, 978, 982, 1050, 

1062, 1089, 1096, 1100. 
Hydrogen and nickel, 782, 788, 797, 

804, 934, 935, 970, 1062, 1068. 
Hydrogen and palladium, 695r, 781, 

804, 934, 947, 967, 983, 1001, 

1068, 1081. 
Hydrogen and platinum, 781, 804, 

945, 967, 972, 976. 
Hydrogen sulphide, 881. 



Quinol, 1044. 

Sodium and alcohol, 786, 920, 922, 

927, 932, 940, 1053, 1060, 1101. 
Sodium amalgam and alkali, 992. 
Sodium amalgam and water, 798, 

801, 802, 803, 804, 813, 814, 929, 

982. 

Sodium and liquid ammonia, 947. 
Sodium and moist ether, 947. 
Stannous chloride (anhydrous), 1113. 
Stannous chloride and hydrochloric 

acid, 1020, 1021. 
Tin and acid, 843, 846. 
Zinc and acid, 798, 802, 929. 
Zinc amalgam and hydrochloric acid, 

1033, 1034, 1089, 1093, 1098. 



1131 



INDEX 

Heavy type indicates the more important of two or more references to a 
compound or subject. 



Abietic acid, 948. 
Abnormal addition, 805. 
Abnormal valencies, 1040. 
Absorption spectra, 700 seq., 739, 833, 

837, 883, 941, 974, 1001, 1069, 1071, 

1077, 1086, 1099. 
Accelerators (rubber), 966. 
Acetaldehyde, 905 seq., 961. 
Acetamide, 838. 
Acetamidme, 1059, 1067. 
Acetic acid, 695*, 905. 
Acetic anhydride, 827, 828. 
Acetobromoglucose, 879, 896, 993, 994, 

1078. 

Acetochloroglucose, 879, 897. 
Acetolysis, 886. 
Acetone, 695w, 827, 835, 905, 907, 

1047. 

Acetone compounds of sugars, 876. 
Acetonediacetic acid, 986. 
Acetonedicarboxylic acid, 715, 1064. 
Acetonedioxalic acid, 985. 
Acetonylacetone, 823, 968. 
Acetophenoneoxime, 729. 
Acetylacetone, 823, 824, 1052. 
Acetylbutyl bromide, 778. 
Acetylcyc/ohexanone, 780. 
Acetylcyc/ohexene, 1032, 1033. 
Acetylene V-' 1 * 1 '":- '' 970,1001. 
Acetylene MIH- will, , 947, 979, 

981, 1053, 1066. 
Acetylenedicarboxylic acid, 818. 
Acetylenic compounds (ozonolysis), 812. 
Acetylglucosamine, 900. 
Acetylglutaric acid, 916. 
Acetylheptylamme, 846. 
Acetylhydroxyiiaphthalene carboxylic 

acid, 731, 846. 
Acetylnaphthol, 845. 
Acetyl peroxide, 812. 
Acetylpropyl alcohol, 834. 
Acetyl radical (free), 1047. 
Acetylsuccmic acid, 916. 
Acetylxylene, 928. 
Acids, 895c seq. 
Acraldehyde dibromide, 861. 
Acre*, 1037. 
Acritol, 862 seq. 
Acrosazones, 861 seq. 
Acrose, 861 seq. 

1132 



I Acrylate plastics, 961. 
Acrylic acid, 695/>, 804, 805, 961 
Acrylonitnle, 969. 
Acyclic terpenes, 936, 940. 
Acyl hahdes, 695/5. 
Acyloms, 785. 
A< \l-o\\fijon fission, 6950 
Addition to carbon yl group, 696n. 
Addition to conjugated systems, 813 

seq., 818, 982. 

Addition to ethylenic linkage, 695o. 
Additive reactions of cis-trans-isn- 

merides, 711. 
Additive reactions of olefines, 65()o, 

804 seq. 

Adenine, 906, 1076, 1080. 
Adenine deoxyribofuranoside, 1070 
Adenine glucopyranoside, 1078. 
Adenine - nicotinamide dinucleotido, 

903. 

Adenine nbofuranoside, 1076, 1078 
Adenosine, 1076, 1078. 
Adenosmc diphosphate, 903. 
Adenosine triphosphatc, 903. 
Adenylic acids, 1079. 
Adermin, 1065, 1068. 
Adipic acid, 779, 797, 799, 959, 1071, 

1089. 

Adipic aldehyde, 799. 
Adipic anhydride, 779. 
Adonitol (ribitol), 853 seq., 1079. 
Adrenal glands, 880, 1108. 
Adrenal hormones, 1087, 1108. 
Aetio0//ocholanic acid, 1092. 
Aetioa//ocholylmethyl ketone, 1092. 
Aetioporphyrin, 1081. 
Affinity (residual), 770, 815. 
Agylcones, 897, 1076, 1110. 
Alanine, 761, 757, 1063. 
Alanine (-), 1070. 
Alcoholic fermentation, 901. 
Alder, 818, 819, 1027, 1036. 
Aldohexoses (configurations), 851. 
Aldohexoses (synthesis), 746, 861. 
Aldol, 970. 
Aldol reaction, 695n. 
Aldopentoses, 862 seq. t 867. 
Aldotetroses, 858. 

Aldoximes (configurations), 732, 736. 
Alginic acid, 900. 



INDEX 



1133 



Alkali metal compounds, 1037 seq. 

Alkyd resins, 960. 

Alkyl halides (hydrolysis) 605;. 

Alkylhydroxylamines, 727, 766. 

Alkyl-oxygen fission, 695*. 

Alkylpyrazoles, 1053. 

Alkylpyrroles, 844. 

Allelotropic mixtures, 831 scq. 

Allene derivatives, 721. 

4/Jocholanic acid, 1092, 1098, 1099. 

A //ocinnamic acid, 710. 

Allose, 857, 858, 880. 

.4 //asteroids, 1097. 

Alloxan, 1058, 1068. 

Allyl alcohol, 809. 

Allyl bromide, 805. 

Allyl chloride, 806. 

Allyl compounds, 695&. 

Allylphenol, 845. 

Alternate polarities, 1008, 1014. 

Altrosc, 857, 858, 880. 

Aluminium (stereochemistry), 774. 

Aluminium tsopropoxide, 1101, 1107. 

Alvar, 961. 

Amides, 695, 838. 

Amidmes, 838, 1059. 

Amine oxides, 764. 

Amines, 695c. 

Amino-acids, 901, 995. 

Amino-alcohols (isomeric change), 849. 

Aminoazoberizene, 844. 

Aminobenzoic acid, 1065. 

Aminocinnamic acids, 709. 

Aminoguanidine, 1056. 

Aminohydroxypynmidine, 1058. 

Ammoke tones, 1054, 1057, 1060. 

Aminomethylenemalononitrile, 1059. 

Aminophenol, 1113. 

Aminophenylpropionic acid, 737. 

Aminopropionic acids (see Alanines). 

Aminopyrazoles, 1053. 

Aminopyrimidines, 1059. 

Aminotetrazoles, 1066, 1067. 

Aminothiazole, 1057. 

Ammothiophenols, 1058. 

Aminotropolones, 695J. 

Aminpxylene, 1068. 

Ammines, 770. 

;4w/>At-benzildioxime, 736. 

Amygdalin, 897. 

Amyl alcohols, 746, 749, 970. 

Amylase, 898, 902. 

Amyl chlorides, 970. 

Amylene dichlorides, 970. 

Amylene oxide ring, 871 seq. 

Amyl lactate, 746. 

Amylopectin, 898, 899. 

Amylose, 898, 902. 

Androgenic hormones, 1105. 

Androstenediol, 1107. 

Androstenedione, 1105, 1106. 

Androsterone, 1105. 

Aneurin, 1065, 1066 seq. 



Aneurin pyrophosphate, 903, 905, 1066, 

1067. 

Angeli, 740. 

Angular methyl group, 1090. 
Anhydro-sugars, 880. 
Aniline, 696/. 
Anilmium ion, 696g. 
Anils, 828. 

Anion tropic changes, 840, 942, 947. 
Amsaldehyde, 953, 1104. 
Anisoin, 1104. 
Anthocyamdins, 989, 999. 
Anthocyanms, 989, 991. 
Anthoxanthidins, 988, 992. 
Anthoxanthins, 988. 
Anthracene, 818, 1003, 1028. 
Anthraquinonedicarboxylic acid, 1024. 
Anthrequinonetetracarboxylic acid , 

1093. 

Antibiotics, 1060 scq., 1065. 
Anti-oximcs, 726. 
Aqua camphorae, 927. 
Arabinose, 746, 852 seq., 872. 
Arabmose ' " . -.'. 865 <*g. 859. 
Arabitol, 8o3 wq. t uu2. 
Arabitol ' " " 864 seq. 

Arabomc , ., 
Arabotrimethoxyghitaric acid, 871, 

872, 874. 
Arbutin, 897. 
Armstrong, E. F., 866. 
Arndt, 826. 

Aromatic compounds '' 797. 

Aromatic sextet, 695/t . 
Aromatic structure, 1001. 
Aromatic substitution, 1004. 
Arsenic (stereochemistry), 761, 704, 

774. 

Ascorbic acid, 880 seq. 
Aspartic acid, 751. 
Astbury, 702. 

Asymmetric synthesis, 746, 905. 
Atrolactic acid, 749. 
Autoracemisation, 749. 
Auxiliary valencies, 770. 
Axial bonds, 792. 
Azelaic acid, 784, 787, 810. 
Azelaic semialdehyde, 810. 
Azides, 705, 1066. 
Azidodimethylpropionamide, 748. 
Azo- (compounds, stereochemistry), 738. 
Azobenzene, 738. 
Azoles, 1051 seq. 
Azoxy- (compounds), 739. 
Azulene, 955. 
Azulenes, 938, 954. 

Bachmann, 1104. 

Baekeland, 957. 

Baeyer, 716, 789, 794, 797, 798, 801, 813, 

814, 838, 839, 864, 909, 926. 
Bain, 726, 738. 
Bakelite, 957. 



1136 



INDEX 



Chlorobromomethanesulnhonic acid, 

760. 

Chlorobutadiene, 962, 969, 970. 
Chlorocamphorsulphonic acid, 931. 
AT-Chlorochloroacetanilide, 806. 
Chlorocresols, 1021. 
AT-Chlorodichloroacetanilide, 806. 
Chlorodimethyl ether, 786. 
Chlorohydroxyphenanthrene, 1044. 
Chlorohydroxysuccinic acids, 746. 
Chloroiodomethanesulphonic acid, 760. 
Chloromenthene, 913. 
Chloromethoxybenzoic acids, 1022. 
Chloromycetin, 1061, 1064. 
Chloromtrobenzaldoximes, 733. 
Chloronitrosodiphenylbutane, 748. 
Chlorophyllin, 1083. 
Chlorophylls, 1074,1075,1080, 1083 seq. 
Chloroprene, 970. 
Chloropropionic acids, 6950. 
Chloropyrimidines, 1060. 
Chlorosuccinic acid, 714, 761. 
Cholamc acid, 1093, 1098, 1099. 
Cholcstane, 1089, 1092, 1097, 1099. 
Cholcstanol, 1089, 1095, 1097, 1099, 

1105. 

Cholcstanone, 1095, 1105. 
Cholestenone, 1093, 1094. 
Cholesterol, 1087 seq., 1095 seq., 1098, 

1101, 1105. 

Cholesterol dibromide, 1106. 
Cholesteryl acetate, 1091, 1101. 
Cholesteryl palmitate, 1087. 
Cholic acid, 1098. 
Christie, 758, 759. 
Chroman, 1073. 
Chroma tographic analysis, 739, 976, 

978,980, 1101. 

Chromium (stereochemistry), 774. 
Chromone, 986. 
Chromonccarboxyhc acid, 986. 
Chromoproteins, 1074. 
Chrysene, 1022 seq., 1028, 1030, 1033, 

1034, 1089, 1090, 1102. 
Chrysin, 988. 
Cineole, 918, 936. 
Cinnamaldoxime, 737. 
Cinnamic acid, 710, 718, 1016. 
Cmnamic aldehyde, 806, 981. 
Cinnamylideneacetaldehyde, 981. 
Ciimamylidenecrotonaldehyde ,981. 
Cinnamylidenemalonic acid, 814. 
Cinnamylphenyl ether, 845. 
Circular dichroism, 748. 
Cis- and /raws-additive reactions, 711. 
Cis- and frans-isomerides, 708 seq. 
Citraconic acid (ester), 807. 
Citraconimide, 1081. 
Citral, 936, 940, 942, 943, 952. 
Civetone, 787. 
Claisen, 825, 831, 845. 
Claisen condensation, 695, 780, 798, 

823, 827. 



Clemmensen, 1033, 1034, 1089, 1093. 

1098. 

Cleve, 771. 
Cline, 1067. 

Cobaltic ammines, 771 seq. 
Co-carboxylase, 903, 1066, 1067. 
Co-enzymes, 903 seq.. 1066, 1067. 
Cole, 1002. 
Collie, 985. 
Colophony, 909, 948. 
Comanic acid, 986. 
Combustion (heat of), 705, 706, 710. 

790, 1002. 
Compound E, 1109. 
Comstock, 732. 
Condensation plastics, 957. 
Configuration holding group, 764. 
Configurations of aldoxirnes, 732. 
Configurations of geometrical iso- 

merides, 708. 

Configurations of ketoximes, 730. 
Configurations of monosaccharides, 

851. 

Conformation, 791. 
Cm 'uii'ci.iK*. 742. 
O I.I-.MIII, ,">!. 
Coniferyl alcohol, 951. 
Conjugated proteins, 1066, 1074 seq. 
Conjugated systems, 707, 708, 813, 818, 

825, 972, 980, 1005, 1028, 1085. 
Cook, 1031, 1103, 1104. 
Co-ordination complex, 770. 
Co-ordination compounds, 769. 
Co-ordination number, 770. 
Co-polymers, 962, 969. 
Copper (stereochemistry), 775. 
Coprostane, 1093, 1097, 1099. 
Coprostanol, 1088, 1093, 1097, 1099. 
Coprosterol, 1088. 
Coronene, 1024 seq. 
Corpus luteum hormone, 1106. 
Corticosterone, 1108. 
Cortm, 1108. 
Cortisone, 1109. 
Cotton, 748. 
Coulson, 1004. 
Coumalic acid, 984. 
Coumalin, 984. 
Coumaric acid, 708. 
Coumarm, 709, 950, 986. 
Coumarmic acid, 708, 961. 
Courtois, 896. 
Cox, 883. 

Co-zymase, 903 seq., 907, 1066. 
Cresols, 920, 958, 970, 971, 1050. 
Criegee's reagent, 808, 809. 
Crocetin, 976. 
Cross linkages, 958. 
Crotonalcohol, 840. 
Crotonic acid, 709, 710, 806, 810. 
Cryptopyrrole, 1081. 
Cryptopyrrolecarboxylic acid, 1082. 
Cure (of plastics), 964. 



INDEX 



1137 



Cure (of rubber), 965. 

Curtius reaction, 846, 1071. 

Cyanidin, 989, 990, 992. 

Cyanin, 989. 

Cyanoacetamide, 1069. 

Cyanoaminomethylprimidine, 1059. 

Cyanohydrin formation, 696. 

Cyclic alcohols, 778, 782. 

Cyclic amines, 783, 784. 

Cyclic compounds (stereochemistry), 

716. 

Cyclic diketones, 780, 784, 785. 
Cyclic halides, 783. 
Cyclic hydroxyke tones, 785. 
Cyclic ketones, 779, 780, 783, 784, 785. 
Cyclic olefines, 777, 788, 910, 911. 
Cyclic olefmic acids, 783. 
Cyc/obutane, 716, 777, 782, 788, 790. 
Cyc/obutanecarboxylic acid, 788. 
Cyc/obutanedicarboxylic acids, 718. 
Cyc/obutanol, 782. 
Cyc/obutanone, 828, 1090. 
Cyc/obutene, 788. 
Cyc/obutylamine, 788. 
Cyc/obutylmethylamino, 784. 
Cyc/odecandione, 955. 
Cyc/oethane, 798, 790. 
Cyc/oheptadecanone, 787. 
Cyc/oheptadione, 696*'. 
Cyc/oheptane, 790, 796. 
Cyc/oheptanone, 695?, 783, 785. 
Cyc/oheptatriene, 695/. 
Cyc/ohexadecandione ,784. 
Cyc/ohexadecanone, 785. 
Cydtohexadienedicarboxvhc acids, 801 

seq. 
Cyc/ohexadienes, 700, 777, 798 seq., 815, 

819. 

Cyc/ohexandiol, 797, 798. 
Cyc/ohexandione, 797, 798. 
(7yc/ohexandionedicarboxylic acid, 

(ester), 798. 

Cyctohexane, 777, 782, 790, 797 seq. 
Cyc/ohexane (stereochemistry), 720, 

791, 796. 

Cyc/ohexanecarboxylic acid, 798. 
Cyc/ohexanedicarboxyhc acids, 716, 

794, 801 seq. 

Cyc/ohexanhexol, 719, 798, 965. 
Cyctohexanol, 797, 799. 
Cyc/ohexanone, 783, 797, 835, 1030, 

1032, 1089. 
Cyc/ohexanonecarboxylic acid, 916 

919. 
Cyc/ohexanonecarboxylic acid oxime, 

727, 738. 
Cyc/ohexanonecarboxylic acid phenyl- 

hydrazone, 738. 
Cyctohexanpentol, 798. 
Cyc/ohexene, 777, 788, 798 seq., 806, 

809, 1002, 1032. 

Cyc/ohexenedicarboxylic acids, 801 seq. 
Cyc/ohexene ozonide, 799, 810. 



Cycfohexylacetylalanine, 1062. 
Cycfohexyl bromide, 797, 799, 1050. 
Cyc/ononacosanone, 786. 
Cyc/b-octane, 790. 
Cyc/o-octanone, 784, 786. 
Cyc/o-octatetrene, 817, 1001. 
Cyc/o-octene, 783. 
Cyc/o-olefines, 777, 788, 910, 911. 
Cyc/o-olefines (ozomdes), 810. 
Cyc/oparaffin carboxylic acids, 783. 
Cyc/oparaffins, 716, 777, 911, 934. 
Tyc/opentadecanone, 787. 
Cyc^opentadiene, 695A, 695^, 700, 789, 

815, 818, 819. 
CysJopentadienyl niagncsiiini iodide, 

6950. 
Cyc/opentandionedicarboxylic acid 

(ester), 781. 

Cyc/opentane, 777, 782, 790, 796. 
Cyc/opentanetetracarboxyhr acid 

(ester), 781. 
Cyc/opcntanol, 784. 
Cyc/opentanone, 779, 1089. 
Cyc/opentanonecarboxylic acid (ester), 

780. 
Cyc/opentanoperhydrophenanthreiie, 

1087, 1089. 

Cyc/opentenophenanthrene, 1030. 
Cyc/opropane, 716, 777, 778, 782, 789, 

790. 

Cyc/opropanecarboxyhc acids, 781, 782 
Cyc/opropanedicarboxylic acids , 717, 

779, 782, 1063. 
Cyc/otetradecandione, 786. 
Cymene, 911, 918, 925, 928, 935, 940. 
Cytidine, 1076, 1077. 
Cytosine, 1058, 1076, 1080. 
Cytosine deoxyribofuranoside, 1076. 
Cytosine ribofuranoside, 1076. 

Dane, 1089. 

Darzens, 1030. 

Dawson, 748. 

de Broglie, 695a. 

Debye, 702, 711. 

Decahydronaphthalene, 793 seq., 820. 

Decalanes, 793 seq., 820, 1097. 

Decalols, 794 seq., 955. 

Decaloneoxime, 736. 

Decalones, 794 seq. 

Decalylamines, 796. 

Dehydracetic acid, 830, 984. 

Dehydrocholesterol, 1101. 

Dehydrocorticosterone, 1108. 

Dehydrogenation, 943, 944, 945, 946, 
948, 954, 955, 979, 1029, 1030, 1033, 
1034, 1090, 1093, 1096, 1099, 1100, 
1102, 1103, 1109. 

Dehydrowoandrosterone, 1105 seq. 

Dehydroisoandrosterone acetate, 1106. 

Dehydronorcholene, 1093. 

Delphmidm, 989, 090, 991. 

Demjanov, 784, 846. 



1138 



INDEX 



Denham, 869. 

Deoxycholic acid, 1003, 1098, 1009. 
Deoxycorticosterone, 1108. 
Deoxyribonucleosides, 1076 seq. 
Deoxyribose, 1076. 
Depression (optical), 700. 
Depsides, 094 seq. 
Desmotropic forms, 831 seq. 
Desoxybenzoin, 1042. 
Desthiopenicillms, 1062. 
Detergents, 608. 
Deuterohaemin, 1082. 
Deuteroporphyrin, 1081, 1082. 
Dewar, M. J. S., 696r. 
Dextrin, 808. 
Diacetarnides, 1056. 
Diacetonamine, 825. 
Diacetone fructose, 877. 
Diacetone galactose, 883. 
Diacetone glucose, 876. 
Diacetone xylose, 878. 
Diacetyl, 822, 1002, 1047. 
Diacetylacetone, 084, 985. 
Diacetylaldol, 822. 
Diacetyldioxime, 823. 
Diacetylsuccinic acid (ester), 824, 832. 
Dialdehydes, 824, 896. 
Dialkylketenes, 827. 
Dialkylmalonic anhydrides, 827. 
Diallyl, 609, 809, 813. 
Diallyl ozonide, 810. 
Diamagnetic compounds, 706, 776. 
Diamines, 1060. 
Diaminoacetone, 1064. 
Diaminobenzophenone, 987. 
Diaminobutancs, 823. 
Diaminohexane, 959. 
Diaminomethylpyrimidme, 1060. 
Diaminotetrahydrothiophene, 1072. 
Diastase, 898. 
Diastereoisomerides, 746. 
Diazines, 1058. 

Diazo-aliphatic compounds, 705, 781. 
Diazoamino-aminoazo transformation, 

843. 

Diazoaminobenzene, 844. 
Diazoamino-compounds ( tan tomerism) , 

840. 

Diazocyanides, 740. 
Diazomethane, 696r, 695s, 781, 828, 

881, 975, 996, 997, 998, 999, 1053, 

1062, 1071, 1076, 1108. 
Diazonium salts, 1029. 
Diazotates (metallic), 739. 
Dibasic acids, 696, 785, 1089. 
Dibenzanthracenes, 1028, 1104. 
Dibenzo/wrodiazine, 1060. 
Dibenzopyrone, 987. 
Dibenzoylacetone, 832. 
Dibenzoylacetylmethane, 832. 
Dibenzoylbenzene, 1026. 
Dibenzoylme thane, 722. 
Dibenzoylsuccinic acid (ester), 832. 



Dibenzphenanthrene, 1023. 
Dibenzylpolyenes, 982. 
Dibromobenzenes, 1001, 1027, 1113. 
Dibromocyc/ohexane, 799. 
Dibromocyc/ohexanedicarboxylic acid, 

802. 

Dibromocycfohexene, 799. 
Dibromodiphenylethylene, 804. 
Dibromoe thylenes ,711. 
Dibromofumaric acid, 804. 
Dibromohexahydroterephthalic acid, 

802. 

Dibromohexane, 797. 
Dibromopentane, 778. 
Dibromopropanes, 782, 805. 
Dibromosuccmic acid, 712. 
Dicarbomethoxygallic acid, 99C. 
Dicarbomethoxyorsellinaldehyde , 907. 
Dicarbomethoxyorsellinic, acid, 997. 
Dicarbomethoxyorsellmyl chloride, 

996, 997. 
Dicarboxycydobutanediacetic acids, 

719. 

Dicarboxylic acids, 696, 786, 1089. 
Dichloroacetic acid, 8950. 
Dichlorobenzenes, 704, 1001. 
Dichlorobutanes, 969, 970. 
Dichlorodi (e thylenediamine) cob al tic 

chloride, 773. 

Dichlorodiethyl ether, 1057. 
Dichlorodimethyl ether, 1084. 
Dichlorodiphenyl, 768. 
Dichloroethane, 704, 796. 
Dichloroethylenes, 711, 713. 
Dichloronitrobenzaldoximes, 733. 
Dichloroquinone, 1049. 
Dichloro(triaminotriethylamine) pla- 

tinic dichloride, 774. 
Dicyclic compounds, 820. 
Dicyclic terpenes, 911, 924. 
Dkyc/odecane, 820. 
Dicyc/odecenone, 965. 
Dicyc/oheptadienedicarboxylic acid, 

820. 

Dicyc/oheptane, 821. 
Dicyc/ohexylphenylsilicane, 1050. 
Dicyc/ononane, 820. 
Dicyc/o-octane, 796, 820. 
Dicyc/opentadiene, 819. 
Dicyc/opentadienyl iron, 695^. 
Didepsides, 944 seq. 
Didiphenyl ketone, 1046. 
Dieckmann, 780, 916, 920, 1036. 
Diets, 818, 819, 1089. 
Diets-Alder reaction, 818, 1027, 1035. 
Diets' hydrocarbon, 1089, 1090, 1094, 

1099, 1109. 

Diethoxybenzene, 704. 
Diethoxyhydrazobenzene, 843. 
Diethyl acetonedicarboxylate, 799, 831. 
Diethyl acetonedioxalate, 985. 
Diethyl acetylenedicarboxylate, 1062. 
Diethyl acetylglutarate, 915. 



INDEX 



1139 



Diethyl acetylsuccinate, 916. 
Diethylarainobutanone, 1032. 
Diethyl chloromalonate, 1064. 
Diethyl citraconate, 807. 
Diethyl cyctohexandionedicarboxyla te , 

798. 
Diethyl cyctopentandionedicarboxylate , 

781. 
Diethyl cycfopropanedicarboxylate, 

779. 

Diethyl diacetylsuccinate, 824, 832. 
Diethyl dibenzoylsuccinate, 832. 
Diethyl fumarate, 714. 
Diethyl hydroxytrimethylglutarate, 

931. 

Diethyl itaconate, 807. 
Diethyl ketene, 828. 
Diethyl maleate, 714. 
Diethyl malonate, 1059. 
Diethyl oxaloacetate, 831. 
Diethylstilboestrol, 1104. 
Diethyl succinate, 798. 
Diethyl succinylosuccinate, 798. 
Diethyl trichloroethylidenemalonate, 

709. 

Digallic acids, 990, 999. 
Digitalose, 1110. 
Digitogenin, 1109. 
Digitonin, 1098, 1109. 
Digitoxigenin, 1110. 
Digitoxin, 1110. 
Digitoxose, 1110. 
Digoxin, 1110. 

Dihydrobenzenes, 777, 799, 816, 819. 
Dihydrobcnzopyran, 1073. 
Dihydrocarbostyril, 737. 
Dihydrocholesterol, 1095. 
Dihydrocymenes, 911. 
Dihydrodiazincs, 1068. 
Dihydromuconic acid, 814, 981. 
Dihydrophytol, 974. 
Dihydrophytyl bromide, 973, 974. 
Dihydro/>s*wrfoionone, 947. 
Dihydropyrazines, 1060. 
Dihydroquinoxalines, 1072. 
Dihydroterephthalic acids, 801 scq., 

Dihydrouracil, 1069. 
Dihydrouridine, 1076. 
Dihydroxyacetone, 862, 864. 
Dihydroxy acetone phosphate, 904. 
Dihydroxybenzoic acids, 997. 
Dihydroxybenzophenone, 987. 
Dihydroxycholanic acids, 1098. 
Dihydroxydialkyl peroxides, 811. 
Dihydroxyflavone, 988. 
Dihydroxyglyoxaline, 1064. 
Dihydroxymethylbenzoic acid, 997. 
Dihydroxyprogesterone, 1108. 

TN.M 3 __~._:_~:j:.r>^ IAKQ 



Di-iododiphenyl, 1027. 
Di-iodoethylenes, 711. 
Di-woamyl ether, 812. 



Di-wobutyiene-ethylene, 1039. 
Di-tsonitrosoacetone, 1064. 
Di-isopropylidenegalactopyranose ,883. 
Di-isopropyhdeneglucofuranose, 877. 
Di-tsopropylidenexylofuranose, 878. 
Diketene, 829. 
Diketones, 696#, 780, 822 seq., 831 scq. t 

848, 1062, 1053, 1057, 1058, 1069, 

1060. 
Diketones (metallic derivatives), 776, 

823, 832. 

Diketotetrahydroglyoxaline, 1054. 
Diketotetrahydropyridazme, 1058. 
Diketotetrahydropyrimidme, 1058. 
Dimerides, 819. 

Dimethoxyhydrazobenzene, 843. 
Dimethyladipic acids, 962. 
Dimethylamme, 695/. 
Dimethylammobenzyl alcohol, 1048. 
Dimethylascorbic acid, 883. 
Dimethylbenzcnes, 1001. 
Dimethyl brornosuccmate, 749. 
Dimethylbutadiene rubber, 968. 
Dimethylbutadienes, 815, 816. 
Dimethylbutyraldehyde, 1096, 1099. 
Dimethylcyc/obutanedicarboxylic acid, 

926. 

Dimethylcyc/oheptanediol, 779. 
Dimethylcyc/ohexadiendiol, 800, 928. 
Dimethylcyc/ohexadienol, 800. 
Dimethylcyc/ohexene, 1029. 
Dimethylcyc/ohexenone, 800. 
Dimethylcyc/o-octadiene, 966. 
Dimethylcyc/opentandiol, 848. 
DimethylcycJopentanc, 783. 
Dimethylcyc/opentanones, 848, 1090. 
Dimethylcystein, 1061. 
Dimethyldihydroresocrinol, 800, 928. 
Dimethylethylenediainme, 776. 
Dimethylfulvene, 789. 
Dimethylfutnaric acid, 713, 804. 
Dimethylgallic acid, 999. 
Dimethylglucose, 878. 
Dimethylglutaric acid, aa, 977; /3/3, 928. 
Dimethylglyoxal, 822. 
Dimethylglyoxime, 823. 
Dimethylhydroxyphenanthrene, 1102. 
Dimethylhydroxypropiomc acid, 1070. 
Dimethylhydroxypyrimidme, 1059. 
Dimethylinositol, 798, 965. 
Dimethylwopropylazulene, 965. 
Dimethylwopropylnaphthalene, 944. 
Dimethyl ketene, 828, 829. 
Dimethylmaleic acid, 713. 
Dimethylmalonic anhydride, 829. 
Dimethylmethoxycyc/opentenophen- 

anthrene, 1103. 
Dimethylnaphthalene, 979. 
Dimethyloctadienal, 941. 
Dimethylpimelic acid, 974. 
Dimethylpiperazine, 721. 
Dimethylpyrazole, 1052. 
Dimethylpyrone, 984, 1047. 



1140 INDEX 



Dimethylpyrone methiodide, 985. 
Dimethylpyrrole, 1082. 
Dimethylpyrrolealdehyde, 1082. 
Dimethylpyrrolepropionic acid, 1082. 
Dimethylquinoxaline, 823. 
Dimethylsexiphenyl, 1027. 
Dimethylsuccinic acid, aa, 977 ; aa', 

713. 
Dimethyltartaric acids. 873. 874, 875, 

1077. 

Dimethyl threonamide, 882. 
Dimethyltoluidmes, 1048. 
Dimethylxanthinc, 1076. 
Dimethylxylidines, 1048. 
Dimroth, 831. 

Dinaphthylcarboxylic acid, 760. 
Dinaphthyldicarboxylic acid, 760. 
Dinitnles, 786. 
Dinitrobenzenes, 704. 
Dinitrodiphenic acid, 769. 
Dinitrodiphenyl, 1029. 
Dinitrotoluenes, 997, 1018. 
Dinitrotrimethylbenzonitrile, 1049. 
Di-olefines, 813, 962, 969 seq. 
Di-olefinic acids, 813. 
Diones, 780. 

Di-orsellinic acids, 995, 996, 998. 
Dipentene, 918, 916, 917, 918, 920, 925, 

936, 942, 966. 

Dipentene dihydrobromides, 913, 918. 
Dipentene dihydrochlorides, 913, 925. 
Dipentene nitrosochloride, 914. 
Dipentene tetrabromide, 914. 
Diphenic acid, 737, 1004. 
Diphenimide, 737. 
Diphenyl, 704, 1001, 1015, 1023, 1028, 

1029. 
Dighenyl (derivatives, optically active), 

757. 

Diphenylacetophcnone, 846. 
Diphenylamine, 695g. 
Diphenylbenzene, 1027. 
Diphenyl benzidinedisulphonate, 759. 
Diphenylbenzophenone, 1046. 
Diphenylbutadienes, 814, 815,982, 1027. 
Diphenylbutanoneoxime, 748. 
Diphenylcarbinol , 1 046. 
Diphenylchloroacetyl chloride, 830. 
Diphenylcyc/obutanedicarboxylic acids, 

Diphenyldiacetyl chloride, 1023. 
Diphenyldi-a-naphthylallene ,722. 
Diphenyldisulphonic acid, 759. 
Diphenyldocosaundecene, 982. 
Diphenyldodecahexene, 981. 
Diphenylethylene, aa-, 1038 ; afl-, 708, 

715, 982, 1038. 

Diphenylethylenediamine, 776. 
Diphenylfulvene, 789. 
Diphenylheptylic acid, 1038. 
Diphenylhexadecaoctene, 981. 
Diphenylhexatriene,981, 982,983, 1028. 
Diphenylhydrazones, 737. 



Diphenylhydroxylamine, 1044. 

Diphenyl ketene, 830. 

Diphenylme thane, 1023, 1028. 

Diphenylmethyltetraphenylmethane, 
1041,1046. 

Diphenylnaphthylmethyl, 1042. 

Diphenyl nitric oxide, 1044, 1045. 

Diphenylnitrosoamine, 1043. 

Diphenyloctatetrene, 981, 1028. 

Diphenylphenylethinyl carbinol, 1026. 

Diphenylpicrylhydrazyl, 1044. 

Diphenylpolyenes, 980 seq., 1028. 

Diphenylsilicon dichloride, 1042. 

Diphenyltricontapentadecene ,982. 

Diphosphoglyceric acid, 904. 

Dipole moments, 702, 710, 734, 738, 
741, 768, 761, 792, 1001. 

Dirac, 695a. 

Disaccharides, 886. 

Disaccharides (synthesis), 894. 

Di-sodmm diphenylethylene, 1040. 

Dispersion (rotatory), 743. 

Disulphones, 838. 

Diterpenes, 948. 

Dithiandisulphoxides, 769. 

Ditolyl, 1028. 

Di(triaminopropane)cobaltic tri- 
chloride, 774. 

Dodds, 1104. 

Doisy, 1101. 

Donath, 1066. 

Drew, 868, 1085. 

Dufraisse, 1026. 

Dulcitol, 858, 902. 

Duppa, 825. 

Duprene, 969. 

Du Vigneaud, 1071. 

Dynamic isomensm, 831 seq. 

Ebonite, 965. 

Eclipsed bonds, 796. 

Eistert, 826. 

Elaidic acid, 710, 714. 

Elaidic acid ozonide, 810. 

Elbs, 1029. 

Electromeric change, 6966. 

Electron diffraction, 704, 706, 792, 1001. 

Electrophilic reagents, 696/>, 1009. 

Embden, 903. 

Emster, 934. 

Emulsin, 890, 891, 897, 902. 

Emulsion polymerisation, 969. 

End-group assay, 899. 

JEnrfo-compounds, 819. 

Efufoethylenecyc&hexane, 820. 

Enrfomethylenecyc/ohexadienedicar- 

boxylic acid, 820. 
E^ndomeihylenecyclo-octane, 820. 
Enfleurage, 950. 
Enohc forms (estimation), 833. 
Enzymes, 902 seq., 1066. 
E^icholestanol, 1097, 1105. 
Epimeric change, 750 seq., 835, 857, 862. 



INDEX 



1141 



Epimeric sugars, 859. 

Epimerides, 750, 853. 

Asteroids, 1097. 

Epoxides, 808. 

Equatorial bonds, 792. 

Equilenin, 1102, 1104. 

Equilin, 1102, 1104. 

Ergostanol, 1095. 

Ergosterol, 1087, 1088, 1089, 1095 seq., 

1099. 

Erythrose, 858. 
Essential oils, 009, 949. 
Esterification (mechanism of), 695/f seq. 
Ethoxyacetylacetone, 1069. 
Ethoxymethylenemalonomtnle, 1059. 
Ethyl acetoacetate, 825 seq., 1059. 
Ethyl acetoacetate (formation), 825. 
Ethyl acetoacetate (manufacture), 829 
Ethyl acetoacetate (tautomerism), 831 

seq., 833. 

Ethyl acetonedicarboxylate, 799. 
Ethyl acetoxynaphthalenecarboxylate, 

845. 
Ethyl acetylenedicarboxylate, 818, 

1052. 

Ethyl acetylglutarate, 915. 
Ethyl acetylhexoate, 780. 
Ethyl acetylhydroxynaphthalenecar- 

boxylate, 845. 
Ethyl acetylsuccinate, 915. 
Ethyl acrylate, 818, 901, 902, 1059. 
Ethyl benzoylacetate, 827. 
Ethyl bromoethylacetoacetate, 834. 
Ethyl bromowobutyrate, 931. 
Ethyl chloroacetate, 979, 1108. 
Ethyl tinnairiate, 807. 
Ethyl citraconate, 807. 
Ethyl copper acetoacetate, 832. 
Ethyl cyanoacetate, 915. 
Ethyl cyanopentanetricarboxylate, 916. 
Ethyl cyc/ohexandionedicarboxylate, 

798. 
Ethyl cyc/ohexanonecarboxylate, 916, 

918, 919, 1030, 1033. 
Ethyl cyc/opentandionedicarboxylate, 

Ethyl cyc/opentanetetracarboxy late , 

780. 

Ethyl cyc/opentanonecarboxylate, 780. 
Ethyl cyc/opropanedicarboxylate, 779. 
Ethyl diacetylsuccinate, 824, 882. 
Ethyl diazoacetate, 695r, 1052, 1053. 
Ethyl dibenzoylsuccinate, 832. 
Ethylene, 6950, 1002. 
Ethylene (polymerisation), 960. 
Ethylenediamine, 773. 
Ethylene dichloride, 704, 796. 
Ethylene glycol, 960. 
Ethylene ozonide, 810. 
Ethylenic linkage (addition to), 695o. 
Ethyl ethoxypropionate, 1067. 
Ethyl fumarate, 714. 
Ethylglucofuranoside carbonate, 879. 



Ethylglucofuranosides, 874, 879. 

Ethylglycosides, 867. 

Ethyl glyoxylate, 885. 

Ethyl hydroxytrimethylglutarate, 931. 

Ethylideneacetone, 943. 

Ethylidene dibromide, 806. 

Ethyl iodoacetate, 942. 

Ethyl iodopropionate, 915. 

Ethyl isopropylcinnamate, 946. 

Ethyl itaconate, 807. 

Ethyl ketohexahydrobenzoate, 916, 

918, 919, 1030, 1033. 
Ethyl ketoiodohexadecanecarboxylate , 

785. 

Ethyl mercaptan, 879. 
Ethylmethylbutyraldehyde, 1096. 
Ethyl orthoforrnate, 1059. 
Ethyl oxaloacetate, 831. 
Ethylpalmityl ketoxime, 736. 
Ethyl radical (free), 1047. 
Ethyl sodioacetoacetate (structure), 

832. 

Ethylstearyl ketoxime, 736. 
Ethyl succinylosuccinate, 798. 
Ethyl tetrahydrotoluate, 916, 918. 
Ethyl toluenesulphinate, 708. 
Eudalene, 945, 946, 955. 
Eudesmol, 946. 
Eugenol, 839, 951. 
Euxanthic acid, 987. 
Euxanthone, 987. 
Evernic acid, 997, 998. 
Evernmic acid, 998. 
Exaltation (optical), 699. 
Exaltone, 787, 951. 
Exhaustive methylation, 1072. 

Farnesene, 938, 944, 947. 

Farnesol, 841, 944, 947. 

Farnesyl bromide, 948. 

Female hormones, 1101. 

Fermentation, 901. 

Fermentation (alcoholic), 901. 

Fermentation (butyric), 905, 907. 

Fermentation (lactic), 906. 

Ferrocene, 695tf, 701. 

Fillers, 956, 964. 

Fischer, 751, 752, 859, 861, 863, 865, 

873, 876, 902, 917, 994, 998. 
Fischer, H., 1080, 1082. 
Fittig, 813, 838. 
Flavone, 987, 988. 
Fleury, 896. 

Fluorene, 1028, 1028, 1029. 
Folic acid, 1065, 1072. 
Formaldehyde, 861, 864, 1070. 
Formaldehyde plastics, 957 seq. t 961. 
Formic acid, 6960. 
Fonnose, 861, 864. 
Formvar, 961. 
Frankland, 745, 825, 1037. 
Free radicals, 706, 1040 seq. 
Freudenberg, 994. 



1142 



INDEX 



Freund, 778. 

Friedel-Crafts reaction, 946, 1010, 1028. 

Fries reaction, 845, 986. 

Fructofuranose, 874, 875, 900. 

Fructofuranose diphosphate, 903. 

Fructofuranose phosphate, 903. 

Fructose, 856, 860, 870, 902 seq. 

Fructose " . ' /. -'" 859. 

Fructose i , .. 874 seq. 

Fructose (synthesis), 861 seq. 

Fructose diacetone, 877. 

Fructose diphosphate, 903 seq. 

Fructose phosphate, 903. 

Fructosides, 874, 894. 

Fulvencs, 789. 

Fumaric acid, 709, 710, 712, 714. 

Furan, 700, 818, 874. 

Furanose structures, 873 seq. t 1076 seq. 

Furukawa, 736. 

Fusel oil, 901, 970. 

Galactonic acid, 858. 

Galactonolactone, d-, 867, 869 ; /-, 884. 

Galactose, 883, 901, 1109. 

Galactose ' .' v 857, 858. 

Galactose nicture), 868 

seq., 872. 

Galactose diacetone, 883. 

Galactosides, 890. 

Galacturonic acid, 883, 901. 

Gallic acid, 989, 995, 997, 998. 

Gallotannin, 999. 

Galloylgallic acids, 996. 

Gammexane, 720. 

Gattermann, 990, 997. 

Gay-Lussac, 901. 

Gm-dimethyl (groups), 932. 

Genins, 1110. 

Gentianose, 886. 

Gentiobiosc, 886, 887 seq., 891, 894. 

Gentiobipsides, 897, 975. 

Geometrical isomerides (additive re- 
actions), 711. 

Geometrical isomerides (determination 
of configuration), 708. 

Geometrical isomerides (dipole mo- 
ments), 710. 

Geometrical isomerides (heat of com- 
bustion), 710. 

Geometrical isomerides (interconver- 
sion), 718, 978. 

Geometrical isomerides (melting- 
points), 710. 

Geometrical isomerides (oxidation), 
712. 

Geometrical isomerides (physical prop- 
erties), 710. 

Geometrical isomerism, 708, 724. 

Geranial, 941. 

Geranic acid, 942. 

Geraniol, 841, 936, 941, 942, 947, 1029. 

Geranyl chloride, 947. 

Germanium (stereochemistry), 768. 



Geronic acid, 952, 976, 978. 

Gilbert, 768. 

Girard reagents, 1108. 

Gitonin, 1109. 

Gitoxin, 1110. 

Glucofuranose, 874. 

Glucofuranosides, 878. 

Gluconic acid, 750, 853, 855, 856, 860, 

862 seq. 

Gluconolactone, 863, 867. 
Glucopyranose, 873. 
Glucopyranose phosphate, 903. 
Glucosamine, 900. 
Glucosazone, 861 seq. 
Glucose, 864 seq., 870, 901 seq. 
Glucose (configuration), 853 seq , 869, 

872. 
Glucose (glycosidic structure, 864 seq. 

873, 874. 

Glucose .^iniN-i-), 861. 
Glucose (I i. . i : .:<', 876, 
Glucose glycosides, 887, 889, 895. 
Glucose monoacetone, 877, 878. 
Glucose phosphate, 903. 
Glucosides, 864, 870 seq., 890. 
Glucovanillin, 951. 
Glucuronic acid, 860. 
Glutaconic acid, 715, 839. 
Glutamic acid, 901. 
Glutaric acid, 1089. 
Glyceraldehyde, 854, 861 seq., 874. 
Glyceraldehyde diphosphate, 904. 
Glyceraldehyde phosphate, 904, 905 seq. 
Glyceric acid, 896. 
Gluceric acid phosphate, 904. 
Glycerol, 862, 901, 905 seq. 
Glycerol phosphates, 906. 
Glycerol plastics, 959. 
Glycerose, 862 seq., 902. 
Glycidic esters, 979. 
Glycogen, 905. 
Glycollates, 956. 
Glycols (isomeric change), 848. 
Glycols (oxidation), 808, 895. 
Glycoproteins, 1074, 1075. 
Glycosides, 884, 872, 876, 886, 890, 

987, 988, 991, 992, 994, 1064, 1075, 

1109, 1110. 

Glycosides (vegetable), 897, 951, 1109. 
Glycosidic structures of monosac- 

charides, 864 seq. 
Glycuronic acid, 860. 
Glyoxal, 1002, 1053. 
Glyoxaline, 1053. 

Glyoxalinechloropropionic acid, 1054. 
Glyoxalinedicarboxylic acid, 1055. 
Glyoxalines, 1061 seq. t 1054, 1060. 
Glyoxylic acid, 896. 
Glyptals, 960. 

Gold (stereochemistry), 775. 
Goldschmidt, 724, 1044. 
Gomberg, 1040. 
Goodyear, 965. 



INDEX 



1143 



Gotts, 775. 

Guaiacol, 1044. 

Guanine, 1076, 1080. 

Guanine deoxyribofuranoside, 1076. 

Guanine ribofuranoside, 1076. 

Guanosine, 1076 sea. 

Gulland, 1077. 

Gulonic acid, 860. 

Gulose, 854, 856 seq., 859, 860. 

Guttapercha, 964. 

Haarmann, 951. 

Hddrich, 744. 

Haem, 1074. 

Haematic acid, 1081. 

Haematoporphyrin, 1081, 1082. 

Haemin, 1080 seq., 1084 seq. 

TT.it :..<-.'1- -Mil. 1026, 1086. 

H.i< irnp.rolr, 1081. 

Halides (hydrolysis), 695;. 

TT.il'>-;, 11,11:0:1, 695A. 

HammiLK, 1U04. 

Hantzsch, 726, 740, 837. 

Hantzsch-Werner hypothesis, 725 seq., 

732, 735. 
Harden, 903. 
Harger, 745. 
Harper, 1090. 
Harries, 809, 811, 966. 
Hartley, 739. 
Hassel, 794. 
Haworth, K. D., 1034. 
Haworth, W. N., 868, 869, 873, 874, 881, 

883, 897, 898. 
Heat of combustion, 705, 706, 710, 791, 

1002. 

Heat of hydrogenation, 707, 1002. 
Heilbron, 864. 
MI/MI vrr,, 095a. 
H.tjtruh, 3I, 885, 894. 
Heliotropin, 961. 
Henderson, 919. 
Heptamethylcellobiose, 890. 
Heptamethyllactose, 890. 
Heptamethylmaltose, 887 seq. 
Heptamethylmehbiose, 890. 
Hepta[tribenzoyl]galloyliodophenyl- 

maltosazone, 1000. 
Heptylaldehyde, 824. 
Herzig, 999. 
Hess, 900. 

Heterocyclic compounds, 1051 seq. 
Heterolytic reactions, 695A. 
Heterpolar bonds, 695. 
Hevene, 966. 
Hewett, 1031. 
Hexabenzobenzene, 1024. 
Hexachlorocyc/ohexane, 720, 797. 
Hexadiene, 699. 
Hexahydric alcohols, 851 seq. 
Hexahydrobenzene, 777, 797. 
Hexahydrobenzoic acid, 798. 
Hexahydrocymene, 911, 921, 934. 
Org. 72 



798, 



Hexahydroergosterol, 1096. 
Hexahydrohomophthalic acids, 794. 
Hexahydrohydroxybcnzoic acid, 919. 
Hexahydroketobenzoic acid, 727, 738. 

916, 919. 

Hexahydrophthalic acids, 794. 
Hexahydropyrazines, 1060. 
Hexahydroterephthalic acids, 716, 801, 

seq. 

Hexahydrotoluic acid, 918. 
Hexahydroxycyc/ohexane, 719, 

965. 

Hexamethyldistannane, 1043. 
Hexamethylene, 777, 797. 
Hexamethylenediamme, 959. 
Hexamethylene dibromide, 797. 
Hexandione, 823. 
Hexaphenyle thane, 1040 seq. 
Hexaphenyltetrazane, 1044. 
Hexatriene, 818. 
Hexaxylyldiplumbane, 1043. 
Hexitols, 851 seq., 868, 862. 
Hexose phosphates, 903 seq. 
Hexoses, 851 seq. 
Hickinbottom, 844. 
Hindrance (steric), 1048. 
Hirst, 881, 883. 
Histidine, 1054. 

Hofmann-Martius transformation, 844. 
Hofmann's bromoamide reaction, 788, 

846. 

Holleman, 1005, 1006, 1009. 
Holmberg, 753. 
Homocamphoric acid, 930. 
Homolytic reactions, 695A. 
Homoterpenylmethyl ketone, 914. 
Hope, 807. 
Hormones, 1087, 1101 seq. 



Hormones 
Hormones 
Hormones 
Hormones 
Hormones 



adrenal), 1108. 
androgemc), 1105. 
female), 1101. 
male), 1105. 
ocl!o iyi.ii i. 1101. 



Hormones (sex;, llul seq. 
Hitbner, 1006. 
Huckel, 736, 794. 
Hudson, 867, 868. 

Hudson's lactone rule, 867 seq., 893. 
UA 'V. OOos, 764. 
// fi:f.v. -'if, 786. 
Hydantoin, 1054. 
Hydrazides, 1056. 
Hydrazines, 766, 1043, 1045. 
Hydrazo-compounds, 842. 
Hydrazoic acid, 1056. 
Hydrazones (stereoisomerism), 737. 
Hydrindane, 796, 820. 
Hydrindoneoxime, 737. 
Hydroaromatic compounds, 797, 1029. 
Hydrocaoutchouc, 967. 
Hydrocarbons (carcinogenic), 1023. 
Hydrocarbons (polycyclic), 1022 seq. 
Hydrocinnamoin, 981. 



1144 



INDEX 



Hydrogenation (heat), 707, 1002. 
Hydrogen bonding, 695s, 698, 833, 836, 

1085. 
Hydrolysis (mechanism of), 695;, 695/5 

seq. 

Hydroxamic acids, 847. 
Hydroxyacetophenone, 986, 987. 
Hydroxyacetoxyacetophenone, 993. 
Hydroxyacetylnaphthalene, 845. 
Hydroxylalkylhydrogen peroxides, 812. 
Hydroxyfl/focholanic acid, 1095. 
Hydroxyammopyrimidine, 1058. 
Hydroxybenzoic acids, 919, 989, 1113. 
Hydroxybenzopyrylmm compounds, 

989. 
Hydroxybenzoylhydroxybenzoic acid, 

997. 

Hydroxycaproaldehyde, 834. 
Hydroxycholanic acid, 1098. 
Hydroxycmnamic acids, 708. 
Hydroxycyc/oheptatnenonc , 695r . 
Hydroxycymene, 922. 
Hydroxydehydrocorticosterone, 1 109. 
Hydroxydiacetylnaphthalene , 845. 
Hydroxydimcthylpyrimidinp, 1059. 
Hydroxyflavylium compounds, 989. 
Hydroxyglutaric acid, 715. 
Hydroxyhexahydrotoluic acid, 916. 
Hydroxyindylanune, 750. 
Hydroxylutidine, 984. 
Hydroxymethoxyphenanthrene, 1044. 
Hydroxymethylbenzoic acids, 917, 920. 
Hydroxymethyleneacetic acid, 984. 
Hydroxymethylenecamphor, 927. 
Hydroxymethylphenol, 957. 
Hydroxynicotmic acid, 984. 
Hydroxymtrochlorobenzomtrile, 734. 
HydroxyworaZ/ocholanic acid, 1095, 

1096. 

Hydroxyprogesterone, 1108. 
Hydroxypyridmes, 984, 1069. 
Hydroxypyrimidmes, 1058, 1060. 
Hydroxypyrone, 715. 
Hydroxypyronedicarboxylic acid, 986. 
Hydroxypyruvic acid, 896. 
Hydroxyquinoline, 709. 
Hydroxyvaleraldehyde, 834. 
Hyodeoxycholic acid, 1098. 
Hyperconjugation, 1013. 

Iditol, 860. 
Idose, 857, 858, 860. 
nhnifrortli, 1004. 
Imides, 69.n?, 838. 
Iminazoles, 1051 seq. 
Imino-chlorides, 838. 
Imino-ethers, 838. 
Indanone, 1034. 
Indanoneoxime, 737. 
Indene, 750, 1023, 1028. 
India rubber, 964. 

Induced alternate polarities, 1008, 
1014. 



Inductive effect, 6956 seq. 

Indylamine, 766. 

Ingold, 695a, 695t, 719, 807, 843. 

Inositol, 719, 798, 966, 1065. 

Intermolecular changes, 842. 

Interpolymers, 962. 

Intramolecular changes, 842. 

Inulin, 900. 

Inversion, 893. 

Invertase, 901, 902. 

lododiphenyl, 1027. 

lodophenylmal tosazone , 1 000. 

lodopropionic acid, 915. 

lodoterphenyl, 1027. 

lonones, 952, 977, 978, 979. 

Indium (stereochemistry), 774. 

Iron (stereochemistry), 774. 

Irone, 952. 

Irvine, 869. 

Isatin, 838. 

I shell, 871. 

Isler, 979. 

/soamyl isovalerate, 812. 

/soborneol, 927, 930, 932, 934. 

/sobornyl acetate, 930. 

/sobornyl chloride, 932, 933, 934. 

/sobutylene, 806, 960, 969. 

/sobutyltoluidme, 1048. 

/sobutyraldehyde, 1070. 

/socamphanc, 935. 

/socoumarins, 986 

/socrotonic acid, 709, 710, 810. 

/sodiazotates (metallic), 739. 

/soeugenol, 839, 951. 

/sogeromc acid, 952, 977. 

/soleucme, 901. 

/somenthol, 921. 

/somenthone, 921. 

Isomenc change, 831 seq. 

Isomerism ' : . ' ,i'/ . T^s seq. 

Isomerism ' . . ~\'2 -i : 

/sonitriles tii. I i 'is-i-.TOS. 

/sonitroso- (group), 822. 

/sonitrosocamphor, 927. 

/sonitrosomethylethyl ketone, 822, 823. 

/sopenillic acids, 1063. 

/sophthalic acid (reduction products), 

801. 
Isoprene, 813, 818, 935, 936, 966, 967, 

968, 970. 

Isoprene theory, 935, 942, 945, 974. 
/sopropyl bromide, 804. 
/sopropyldimethylazulene, 955. 
/sopropyldimethylnaphthalene, 944. 
/sopropylglutaric acid, 915. 
/sopropyhdenecyc/obutane, 783. 
/sopropylideneglucofuranose, 877, 878. 
/sopropylidenegtucofuranose carbonate, 

878. 

/sopropylmethylbenzcne ,911. 
/sopropylmethylnaphthalene, 945, 946. 
/sopropylmethylphenanthrene, 948. 
/sopropylsuccmic acid, 915. 



INDEX 



1145 



/sopropyltetralone, 946. 
/soqumolme, 737. 
/sosafrole, 839. 
/sosucrose, 894. 
/sourea, 838. 
Isoxazoles, 1057. 
Itaconic acid (ester), 807. 

Jacobs, 1110. 
Jansen, 1066. 
Johnson, 695^. 

Karrer, 972, 978, 1062. 

Kaufler, 757. 

Kekule, 695a, 695/, 817, 1002, 1003, 

1004. 

Kendall, 1108. 
Kenner, 758, 759. 
Kenyan, 745, 755, 758, 841, 846. 
Kerr, 926. 
Ketene, 827, 829. 
Ketenes, 827 seq. 
Ketocholanic acid, 1093 seq. 
Ketocholestcryl acetate, 1101. 
Keto-cyclol tautomensm, 834 
Keto-cyclo-tautomerism, 834. 
Ketodecahydrochrysene, 1033. 
Keto-enohc change, 831 seq. 
Ketohexahydrobenzoic acid, 727, 738, 

916, 919. 

Ketohexoses, 860, 867, 874. 
Ketohydroxyprogesterone, 1108. 
Keto-lactol tautomensm, 834. 
Kctomenthyhc acid, 920, 921. 
Ketones, 822 seq. 
Ketones (uhsaturated), 806, 807, 808, 

824. 

Ketonic acids, 825 seq. 
Keto-pyrazolines, 1052. 
Ketoses, 860, 867, 874. 
Ketoximes "-:i r . .: .: -n . 730, 735. 
Ketyls (mei.ilV., li.-, 1046 
Key atom, 1008. 
Kharasch, 805. 
Kidd, 843, 844. 
King, 1089. 
Kipping, F. B., 721. 
Kipping, F. S., 744, 766, 767, 779, 922, 

931, 963, 1034. 
Kishner, 954. 
Kistiakowsky, 707. 
Klein, 894. 
A'i. . '. 799. 
A' i ;. 71-* 
A'i: *', - II 
Kohler, 722. 

Kolbe reaction, 947, 975. 
Komppa, 928. 
Kon, 839, 1031, 1090, 1095. 
Kopp, 699. 
Kdrner, 1018. 
Kostanecki, 987, 988. 
Krtger, 952. 



| Kuhn, R., 972, 977, 980, 1028, 1067, 

1068. 

Kuhn, W., 748. 
Kustcr, 1080. 

Laar, 831. 

Lacqueur, 1105. 

Lactam-lactim tautomensm, 838, 1052, 

1058. 

Lactase, 890. 
Lactic acid, 746, 905. 
Lactobionic acid, 886. 
Lactoflavin, 1005 
Lactols, 834. 
Lactone rule, 867 
Lactoiics, 790, 834, 865. 
Lactones of sugar acids, 867 srq. 
Lactose, 886, 887 $eq. t 894. 
Laevulic acid, 834, 972. 
Laevuhc aldehyde, 940, 966. 
Landolt, 744. 
Langmuir, 696<i. 
Lanoline, 1087. 
Lapworth, 695a, 69Cw. 
Latex, 964. 
Lavoisier, 901. 
Lead (tervalent), 1043. 
Lead tetra-acetate, 808. 
Lead tetramethyl, 1047. 
Le Bel, 695a, 762. 
Lecanonc acid, 997, 998. 
Lecithins, 1075. 
Le Fevre, 741, 758. 
Lennard- Jones, 1004. 
Lesshe, 759, 761. 
Lewis, 695a. 
Leucine, 901. 
Levine, 1002. 
Lichens, 997. 
Lichtenstadt, 728, 764. 
Limonene, 749, 910, 911, 913, 934, 935, 

937. 

Limonene hydrobromides, 913. 
Limonene hydrochlorides, 913. 
Limonene nitrosochlorides, 914, 923. 
Limonene tetrabromide, 913. 
Linalool, 841, 936, 941, 942, 1029. 
Linstead, 839, 1031. 
Lipochromes, 972. 
Liquid crystals, 697. 
Lithium butyl, 1038 
Lithium ethyl, 1037, 1040. 
Lithium methyl, 1037. 
Lithium phenyl, 1037. 
Lithocholic acid, 1098. 
Lobry de Bruyn, 870. 
Lorentz, 699. 
Lorenz, 699. 
Lossen reaction, 847. 
Lowry, 696a, 695, 768. 
Lumisterol, 1099. 
Luteolin, 988. 
Lycopenal, 973. 



L146 



INDEX 



Lycopene, 938, 972 seq., 975. 
Lyxonic acid, 857. 
Lyxosazone, 884. 
Lyxose, 857, 858, 872, 883, 884. 
Lyxosone, 884. 

Macbeth, 897. 

Mackay, 897. 

Magnetic resonance (nuclear), 705. 

Magnetic susceptibility, 706. 

Maitland, 722. 

Malachowskt, 715, 716. 

Maleic acid, 710, 712, 714, 804. 

Maleic anhydride, 714, 818, 1023, 1027, 

1028, 1058, 1096, 1100. 
Malic acid, 745, 751 seq., 984. 
Malkomes, 834. 
M ,! :, , * / 1060. 
M .;..-: .:,-. I". 9. 
Malonylurea, 1058. 
Maltase, 890, 901, 902. 
Maltobiomc acid, 886, 889. 
Maltose, 886, 887 seq., 894, 898, 001, 

902. 

Malvidin, 999. 
Mandelic acid, 747, 749. 
Mandelonitrile, 897. 
Mann, 774. 
Mannich, 1032. 

Mannitol, 866, 860, 862 seq., 1000. 
Mannoheptose, 747, 863, 902. 
Mannonic acid, 750, 853, 866, 856, 



Mannonolactonc, 862 seq. 

Mannononose, 863, 902. 

Manno-octose, 863, 902. 

Mannosaccharic acid, 866. 

Mannose, 747, 870, 901 seq. 

Mannose (configuration), 854 seq. 

Mannose (glycosidic structure), 872. 

Mannose (synthesis), 861 seq. 

Mannuronic acid, 901. 

Marckwald, 747. 

Mark, 1042. 

'..'.if' , :'" ''. 695/>, 804, 805. 

Maman, Ilu2. 

Marrianolic acid, 1102. 

Martins 844. 

Mauveine, 1000. 

Mayo, 806. 

McKenzie, 747, 762, 848. 

McMath, 750. 

McNab, 806. 

Meconic acid, 986. 

Mceneein, 749, 849, 934. 

Mehta, 728. 

Meisenheimer, 730, 733, 764, 766, 767. 

Melibiose, 886, 887 seq., 891. 

Melting-point, 695w, 710, 742. 

Menthadienes, 911 seq., 917, 918, 919, 

935. 

M ' ,.,V: ":-. 022. 
Me:.:: \ ,: '. !" 



Menthane, 911, 934. 
Menthanol, 921. 
Menthanone, 920. 
Menthenes, 911, 921, 922, 934. 
Menthenols, 917, 918. 
Menthenone, 922. 
Menthols, 768, 920, 921, 922, 923. 
Menthones, 920, 921, 923. 
Menthoxime, 922. 
Menthyl acetate, 921. 
Menthylamines, 766, 921, 922. 
Menthyl benzoylformate, 747. 
Menthyl chloride, 921, 922. 
Menthyl formate, 922. 
Mercury diethyl, 1037. 
Mercury diphenyl, 1037. 
Mesitylenecarboxylic arid, 1049. 
Mesityl oxide, 806, 809, 824, 825. 
A/eso-compounds, 819. 
Mesoethylenecyc/ohexane, 820. 
Mesoinositol, 798, 1065. 
Mesomeric effect, 6956 seq. 
Mesomerism, 6956, 704, 749, 826, 831, 

838, 849, 985, 1001 seq., 1045, 1048, 

1086. 
Afesomethylenecyc/ohexadienedicar- 

boxylic acid, 820. 
Mesomethylenecyc/o-octane, 820. 
Af<jso-oxycyc/ohexenedicarboxylic an- 
hydride, 820. 

Mesoporphyrin, 1081, 1083, 1086. 
M0to-diazines, 1058. 
Metals (organic derivatives), 1037 seq. 
Methanol, G95rf. 
Methoxycyc/opentenophenanthrene, 

1103. 

Methoxylutidine, 985. 
MethoxymethyKsoquinoline, 1069. 
Methoxyhethylpyridinedicarboxylic 

acid, 1069. 
Methoxyphenylmethoxybenzyl kctone, 

1104. 

Methoxyphloroacetophenone, 988. 
Methoxypyndinetricarboxylic acid, 

1069. 

Methyl (radical, free), 1047. 
Methyladipic acid, 920, 921, 922, 970. 
Methylallyl chloride, 806. 
Methylallylphenylbenzylammonium 

iodide, 762. 
Methylaltroside, 880. 
Methylamine, 695/. 
Methylaniline, 766, 844. 
Methyl anthranilate, 953. 
Methylarabinoside, 872. 
Methylarbutin, 897. 
Methylated sugars, 869 seq., 887 seq. 
Methylation, 869, 881, 887, 1072. 
Methyl azide, 704. 
Methylbenzamide, 729. 
Methylbenzophenones, 1029. 
M- V.y.H'it^lf.-ftvl r'-l-v-id-, 749. 
M. : .>" i- .!:::< ,i- -\ ;-.- 936,970. 



INDEX 



1147 



Methylbutene, 967. 

M'ethyl chloroformate, 994, 995. 

Methyl chloropropionate, 749. 

Methylcholanthrene, 1023, 1092 seq., 
1099. 

Methylcrotonal, 943. 

Methylcyc/ohexandione, 801. 

Methylcyc/ohexanccarboxyhc acid, 918. 

Methylcyc/ohexanol, 778, 970, 971. 

Methylcyc/ohexanone, 970. 

Methylcyc/ohexene, 971. 

Methykyc/ohexenecarboxylic acids , 
916, 917, 918. 

Methylcyc/ohexenedicarboxylic an- 
hydride, 818. 

Methylcyc/ohexylideneacetic acid, 722. 

Methylcyc/opentane, 783, 797. 

MethylcycJopentanol, 778. 

Methykyc/opentanoneoxime, 736. 

Methylcyc/opentenophenanthrenes, 
1090, 1095. 

Methyldiaminobutane, 971. 

Methyldiaminopyrirnidine, 1060. 

Methyldihydroresorcinol, 801. 

Methyldihydroxynaphthalcne, 1074. 

Methylethylactic acid, 746. 

Methylethylaniline, 764. 

Methylethylaniline oxide, 764. 

Methylethyl ketone, 822, 1047. 

Methylethylmalonic acid, 746. 

Methylethylphenacylsulphine picrate, 

Methylethylphenylphosphine oxide, 

764. 
Methylethylpropyh'sobutylamnionium 

chloride, 763. 
Methylethylpropylstaimic bromocam- 

phorsulphonate, 760. 
Methylethylpropylstanmc iodide, 767. 
Methylethyl thetine platimchlonde, 768. 
Methylexaltone, 787. 
Methylfructosides, 874, 875. 
Methylfurfuraldchyde, 876. 
Methylgalactosides, 872. 
Methylglucose, 877. 
Methylglucosides, 864 seq. t 869, 870, 

873, 902. 

Mi'll:\hl\r.".iric.. S72, 896. 
Methylglyoxal, 812, 1002. 
Methyl group, 695rf. 
Methylguanines, 1077. 
Methyl-heptamethyldisaccharides, 890. 
Methyl-heptamethylmaltoside, 887. 
Methylheptenol, 1029. 
Methylheptenone, 940, 942, 973. 
Methylheptyl ketoxine, 846. 
Methylhydroxybenzoic acids, 917, 920. 
Methylhydroxycyc/ohexanecarboxylic 

acid, 916. 

Methylhydroxyethylthiazole ,1066. 
Methylhydroxylamine, 727. 
Methylhydroxytetrahydrofuran, 834. 
Methylhydroxytetrahydropyran, 834. 



Methylindanone, 74y, 836. 
Methylinositol, 798, 965. 
Methyliododiphenyl, 1027. 
Methylisohexyl ketone, 1091. 
MethyU'sopropylbenzene, 911. 
Methyhsopropylnaphthalene, 945, 946. 
Methylisopropylphenanthrene, 948. 
Methyh'sourea, 838. 
Methyllyxoside, 872. 
Methylmaleimidc, 1081. 
Methylmannosides, 872. 
Methylniethoxycyc/opentenophen- 

anthrene, 1103. 

Methyl methylacrylate, 961, 902, 964. 
Methylnaphthalcne, 1023, 1028. 
Methyloctahydronaphthalene, 1029. 
Methyl octamethylmehbionate, 891. 
Methyloestrone, 1103. 
Methylorsellimc acid, 997. 
Methylo tannin, 999. 
Methyl penaldate, 1062. 
Methylpentoses, 874, 876. 
Methylphenoxarsinecarboxylic acid, 

761. 
Methylphenyldimethylmethyl ether, 

1038. 

Methylphenylgly collie acid, 747. 
Methylphenylnitrosoamine, 845. 
Methylphenylpyrazoles, 1052. 
Methylphenylselenetme bromide, 768. 
Methylphytylnaphthoquinol, 1074. 
Methylpimelic acid, 920. 
Methylpyrazoles, 1052. 
Methylpyridines, 844. 
Methyl radical (free), 1047. 
Methylstyryl ketone, 1032. 
Methyltetrahydrophthalic anhydride, 

818. 

Methyl trimethyllccanorate, 998. 
Methyluracil, 1059, 1076, 1077. 
Methyluracil deoxynbofuraiioside, 

1076. 

Methylvinyl ketone, 979, 1032. 
Methylxyloside, 872. 
Meyer, K., 831, 1024. 
Meyer, Victor, 1040. 
Meyerhof, 903. 
Michael, 826, 897. 

Michael reaction, 800, 807, 817, 1032. 
Micro-analysis, 1088. 
Mills, 722, 723, 726, 732, 734, 738, 746, 

753, 758, 760, 763, 764, 776, 776. 
Mitchell, 748. 
Mohr, 791, 794. 
Molecular refraction, 699, 835, 943, 

945, 954. 

Molecular volume, 699. 
Monoacetylglucosidylphloroglucin- 

aldehyde, 991, 993. 
Monocarbomethoxyorsellinaldehyde, 

995. 

Monochloracetic acid, 6950. 
Monocyclic terpenes, 909 seq. 



1148 



INDEX 



Monomethylglucose, 877. 

Monomethyllorsellinic acid, 997. 

Monoperphthalic acid, 808, 818. 

Monosaccharides, 851 seq. 

Monosaccharides (acetone compounds), 
876. 

Monosaccharides 861. 

Monosaccharides struc- 

tures), 864. 

Moore, 864. 

Moureu, 1026. 

Mucic acid, 858. 

Mucins, 1075. 

Muconic acid, 814. 

Muller, 739. 

Muse Baur, 951. 

Muscone, 787. 

Musk, 787, 951. 

Mutarotation, 760, 835, 836, 866, 886. 

Mycosterols, 1087. 

Myrcene, 936, 940. 

Naphthalene, 1030. 
Naphthalene (derivatives), 1034. 
Naphthalene (derivatives, optically 

active), 760. 

Naphthalene (structure), 1003. 
Naphthalene diozonide, 810. 
Naphthenes, 797. 
Naphthylallyl ether, 845. 
Naphthyldmitrobenzoic acid, 847. 
Naphthylethyl bromide, 1033, 1090. 
Nef, 826, 870, 1040. 
\\ ;,iii\ '.: M,!>-. fl06. 
A,- ..-,..:. -:-l.'.l, ItJi 
Neomcnthol, 921, 922. 
A^omenthylamine, 922. 
JV>0pentyl halides, 69 5j. 
Neoprene, 969. 
Neral, 941. 
Nerol, 941, 943. 
Nerolidol, 841, 947, 1029. 
Neroli oil, 947. 
Neuberg, 903. 
Neucki, 1080. 
Neville, 768. 
Newman, 761. 

Nickel (stereochemistry), 774, 775, 776. 
Nicotinamide, 902, 1065. 
Nitration, 1005, 1009. 
Nitro- (compounds), 695g, 836. 
Nitro- (group), 695g, 704. 
Nitroacetophenone, 986. 
Nitroanilmes, 1112. 
Nitrobenzanilide, 730. 
Nitrobenzophenoneoximes, 727, 728, 

734. 

Nitrobenzoyl chloride, 986. 
Nitrobutane, 836. 
Nitrocamphor, 836. 
Nitrochlorobenzaldoximes, 733. 
Nitro-compounds (tautomerism), 695g, 

836. 



Nitrodichlorobenzaldoximes, 733. 
Nitrodichlorpbenzonitrile, 734. 
Nitrodiphenic acid, 759. 
Nitrogen (bivalent), 1043, 1045. 
Nitrogen (optically active compounds), 

762. 
Nitrogen (stereochemistry of tervalent), 

765. 

Nitromalonodialdehyde, 787. 
Nitrome thane, 695g. 
Nitronium ion, 1009. 
Nitro-octane, 836. 

Nitroparaffins (tautomerism), 695^,836. 
Nitrophenols (tautomerism), 837. 
Nitrophenyldiazonium chloride, 739, 

1029, 1068. 
Nitrophenylphenyl ketoximes, 728, 

729, 734. 

Nitrophthalic acid, 1021. 
Nitrosalicylonitrile, 733. 
Nitrosoammes, 740. 
Nitrosoanisole, 837. 
Nitrosochlorides, 914, 925. 
Nitrosodimethylamlme, 824, 1017, 1042. 
Nitrosonaphthol, 837. 
Nitrosophenol, 837. 
Nitrosotriphenylhydrazme, 1044. 
Nitrotoluencs, 1017, 1018, 1020. 
Nitrotoluidines, 1018 seq. 
Nitrotnmethylbenzonitnles, 1049 
Nitroxylidme, 1068. 
Nodder, 723. 
Netting, 1006. 
Nonandione, 779 
Nonyhc acid, 810. 
Nonyhc aldehyde, 810. 
JVom//ocholamc acid, 1092. 
Norttxm, 974, 975. 
Normal sugars, 873. 
Norpimc acid, 926. 
Nornsh, 696w, 1047. 
Nuclear magnetic resonance, 705. 
Nucleic acids, 1068, 1074, 1075 seq., 

1080. 

Nucleophilic addition, 695n, 817. 
Nucleophilic groups, 695t. 
Nucleophilic substitution, 695t seq., 

1016. 

Nucleoproteins, 1074, 1075 seq. 
Nucleosides, 1075 seq. 
Nucleotides, 1075 seq., 1078 seq. 
Nylon, 969. 

Ocimene, 936, 937, 940. 
Octa-acetylcellobiose, 886. 
Octahydronaphthalenes, 955. 
Octamethylcellobionic acid, 890. 
Octamethyllactobionic acid, 890. 
Octamethylmaltohionic acid, 889. 
Octamethylsucrose, 893. 
Octanol, 768. 

Octaphenylcyc/osilicotetrane, 1043. 
Octaphenylsilicotetrane, 1043. 



INDEX 



1149 



Qctyl iodide, 754. 

Oestradiol, 1102, 1103. 

Oestriol, 1102, 1104. 

Oestrogenic hormones, 1101 seq. 

Oestrone, 1101 seq. 

Oil of ambrette seeds, 944. 

Oil of bay, 940. 

Oil of bergamot, 941, 944 

Oil of camomile, 964. 

Oil of camphor, 927. 

Oil of caraway, 913, 922. 

Oil of celery, 945. 

Oil of citronella, 933. 

Oil of cloves, 951. 

Oil of cubebs, 944. 

Oil of cummin, 913. 

Oil of eucalyptus, 910, 918, 923. 

Oil of ginger, 933, 944. 

Oil of juniper, 910. 

Oil of laurel, 910. 

Oil of lavender, 941. 

Oil of lemon, 910, 913, 952. 

Oil of lemon-grass, 940, 952. 

Oil of Mentha pipenta, 920. 

Oil of MentJta Pulegium, 922. 

Oil of myrrh, 944. 

Oil of Ocimum basihcum, 940. 

Oil of orange, 913. 

Oil of parsley, 910. 

Oil of pennyroyal, 922. 

Oil of peppermint, 913, 920, 921. 

Oil of pine-needle, 913, 919, 932. 

Oil of rosemary, 918, 932. 

Oil of sage, 910. 

Oil of spearmint, 922. 

Oil of spike /932, 933. 

Oil of thyme, 910, 932. 

Oil of turpentine, 909, 917, 925. 

Oil of valerian, 932, 933. 

Oil of vetiver, 954. 

Oil of waterfennel, 918. 

Olefines, 804 seq. 

Olefines (additive reactions), 695o, 804 

seq. 

Olefines (oxidation), 808. 
Olefinic compounds, 804 seq. 
Oleic acid, 710, 714, 809. 
Oleic acid ozonide, 810. 
Oleum cinae, 913, 918. 
Oppenauer, 1107, 1108. 
Ospopyrrole, 1081. 
Optical depression, 700. 
Optical exaltation, 699. 
Optical inversion, 750. 
Optical isomerism, 742 seq. 
Optical superposition, 746, 868. 
Orcinol, 997. 

Organo-metalhc compounds, 1037 seq. 
Orientation of aromatic compounds, 

1018 seq. 

Orientation rules, 1004 seq. 
Orsellinaldehyde, 997. 
Orsellinic acid, 997, 998. 



OMo-diazines, 1058. 

Ortho effect, 1048. 

CM&o-semidinc transformation, 842. 

Orion, 844. 

Osazones, 1056. 

Osotnazoles, 1055, 1056. 

Oudemans, 744. 

Oxalylurea, 1062, 1054. 

Oxazoles, 1051, 1057. 

Oxide rings, 865 seq. 

Oxidising agents, 1131. 

Oximcs (geometrical isomerism), 724 

seq. 

Oximino-(group), 822. 
Oxomuin salts, 985. 
Oxozonides, 811. 

Oxygen (stereochemistry), 703, 761. 
Oxygen (univalent), 1044, 1045. 
Oxy haemoglobin, 1020. 
Oxyrubrene, 1026 
Ozonides, 730, 809 wq 
O/.onolysis, 730, 809 seq., 940, 943, 954, 

966, 967, 972, 978, 982, 1002, 1096, 

1099, 1100. 

Palladium (stereochemistry), 775, 776. 
Palladium-charcoal (dehydrogenation) , 

948, 955, 1029, 1100. 
Paneth, 1047. 

Pantothemc acid, 1065, 1070. 
Parabanic acid, 1052, 1054. 
Parachor, 699. 
Aira-dmzmes, 1060. 
Paramagnetic compounds, 706, 776, 

1045. 

Pflra-semidme transformation, 842. 
Partial valencies, 815. 
Pascal, 706. 
Pasteur, 748, 901, 902. 
Paul, 1046. 

Pauhng, 69Sa, 702, 1003. 
Peachey, 750, 762, 767, 768, 966. 
Pectin, 901. 
Pelargonic acid, 810. 
Pelargomdin, 989, 990, 991. 
Pelargonin, 991, 992. 
Penaidic acids, 1062. 
Penicillamine, 1061 seq. 
Penicillins, 1061 seq. 
Penicilloic acids, 1062. 
Penillammes, 1063. 
Pemllic acids, 1063. 
Penta-acetyldigallic acid, 996. 
Penta-acetyldigalloyl chloride, 999. 
Penta-acetylglucose, 879. 
Penta-acetylhexoses, 879. 
Pentabenzoylglucoses, 873. 
Pentabenzoylhexoses, 879. 
Pentacarbomethoxydigallic acid, 996. 
P i:t,"! .MlloxUlii' <. 999. 
Pentagalloylglucose, 999. 
Pentahydroxyflavone, 988. 
Pentamethylarbutin, 897. 



1150 



INDEX 



Pentamethylbenzoic 'acid, 1049. 
Pentamethylbenzonitrile, 1049. 
Pentamethyldigallic acid, 999. 
Pentamethylene, 777. 
Pentamethylglucose, 879. 
Pentandione, 823. 
Pentanetricarboxylic acid, 916. 
Pentantrione, 824. 
Penta[pentamethyldigalloyl]glucose, 

Pentaphenylcyc/opentadienyl, 1042. 

Pentaphenylethyl, 1042 

Pentitols, 852 seq. 

Pentoses, 852 seg., 872, 883, 896, 902. 

Perbenzoic acid, 804, 808, 813. 

Perbunan, 969. 

Perfumes, 949. 

Perhydrobixin, 974, 975. 

Perhydrocarotene, 976. 

Perhydrocrocetin, 975, 976. 

Perhydrolycopene, 972, 973, 974. 

Perhydronorbixin, 974, 975, 976. 

Perkin, 951. 

Perkin, junr., 722, 779, 780, 797, 909, 

915, 917, 918, 919, 929, 931. 
Perkin reaction, 696w, 951. 
Permonophthalic acid, 808, 813. 
Peroxide effect, 805. 
Peroxides, 804, 812, 828, 1041, 1046. 
Perren, 719. 
Perspex, 961. 
Peters, 885. 
Phaeophytin, 1083. 
Phaeoporphyrin, 1084. 
Phellandrenes, 911, 918, 934. 
Phenanthraquinone, 1071. 
Phenanthraquinonemonoxime, 737. 
Phenanthrene, 1003, 1028, 1029, 1030, 

1034. 

Phenol, 696d, 957, 959. 
Phenol-formaldehyde plastics, 957, 964. 
Phenolic acids, 994. 
Phenolic aldehydes, 995. 
Phenylacetaldehyde, 982. 
Phenyl acetate, 986. 
Phenylacetic acid, 695*, 982, 1049. 
Phenylacetylalanylvaline, 1063. 
Phenylacetylene, 1026. 
Phenylallyl alcohol, 840. 
Phenylallyl ether, 845. 
Phenylallyl phenol, 845. 
Phenyl azide, 1056. 
Phenylbenzophenone, 1046, 1047. 
Phenylbenzyl ketone, 1042. 
Phenylbutadeine, 814, 816, 817. 
Phenylbutylene, 1030. 
Phenylcarbethoxybispiperidinium- 

spiran bromide, 763. 
Phenylchloropropionic acid, 752. 
Phenylchromone, 987. 
Phenylcinnamyl ether, 845. 
Phenylcrotonic acid, 839. 
Phenyldesoxybenzoin, 846. 



Pbenyldiazonium chloride, 739. 
Phenyldiphenyl, 1027 seq., 1039. 
Phenylenediamines, 823, 1055, 1060. 
Phenylethyl alcohol, 953. 
Phenylethyl bromide, 1030, 1033. 
Phenylethylene, 961, 969, 1038. 
Phenylethyltsopropylgermanium bro- 

Phenylglutaric acid, 807. 
Phenyl group, 695d. 
Phenylhydrazones, 1056. 
Phenylhydrazones (stereochemistry) , 

737. 

Phenylhydroxylamine, 844. 
Phenylhydroxypropionic acid, 752, 755. 
PhenyU'sopropylmethyl ether, 1038. 
Phenyhnesityl ketone, 1049. 
Phenylmethylnitrosoamine, 845. 
Phenylmethylpyrazoles, 1052. 
Phenylmethylpyrazolone, 1052. 
Phenylnaphthylethane, 1023, 1028. 
Phenylnitromethane, 836. 
Phenylnitrophenyl ketoximes, 728, 729, 

734. 

Phenylpropiolic acid, 810. 
Phenylpropiomc acid, 9650. 
Phenylpyrazoles, 1053. 
Phenylpyrone, 984. 
Phenylsihcon trichloride, 1050. 
Phenyltolyl ketone, 728. 
Phenyl tolylmethyltelluronium iodide , 

Phenylvinylcarbinol, 840. 

Phillips, 755, 768. 

Phloroacetophenone, 988. 

Phloroacetophenonetrimethyl ether. 
988. 

Phlorogiucinaldehyde, 990, 994. 

Phloroglucinol, 836, 989, 990. 

Phloroglucinolcarboxylic acid, 989. 

Phorone, 824, 825. 

Phosphates, 956. 

Phosphodihydroxyacetone, 904. 

Phosphoglyceraldehyde, 904. 

Phosphoglyceric acid, 904. 

Phosphopyruvic acid, 905. 

Phosphorus (optically active com- 
pounds), 764. 

Photosynthesis, 864. 

Phthalates, 956. 

Phthalic acids (reduction products), 
801 seq., 813. 

Phthalic anhydride, 959, 1034. 

Phthalimide, 695g, 838. 

Phthalocyanines, 702, 1084 seq. 

Phylloaetioporphyrin, 1083. 

Phylloporphyrin, 1083, 1084. 

Phyllopyrrole, 1081. 

Physical properties of organic com- 
pounds, 6950. 

Phytol, 938, 974, 1074, 1083. 

Phytosterols, 1087. 

Phytyl bromide, 1073. 



INDEX 



1151 



Pjcene, 1028, 1028, 1029, 1030, 1090. 

Pickard, 745. 

Pickles, 966. 

Picric acid, 964. 

Pictet, 894. 

Piloty, 1080. 

Pimelic acid, 783, 986. 

Pjmelic anhydride, 779. 

Pinacol-pinacolone transformation, 784, 

848, 849. 

Pinacols, 1042, 1046. 
Pinane, 934, 935. 
Pinene, 910, 911, 913, 917, 920, 924, 

925, 930, 933, 935, 937. 
Pinene (#-), 926. 
Pinene dibromide, 925. 
Pinene hydrochloride, 925, 930, 933, 934. 
Pinene nitrosochlonde, 926. 
Pinic acid, 926. 
Pinol, 926. 
Pinol hydrate, 926. 
Pinonic acid, 926. 
Piper, 696. 

Piperazines, 721, 1060. 
Piperic acid, 813. 
Piperitone, 922, 928. 
Piperonal, 951. 
Pituitary gland, 1107. 
Plasticisers, 966, 964. 
Plastics, 956 seq. 
Platinic ammines, 771. 
Platinous ammines, 771. 
Platinum (stereochemistry), 771 seq. t 

775, 776. 
Plattner, 964. 
Polar bonds, 792. 
Polycyclic hydrocarbons, 1022 seq. 
Polydepsides, 994. 
Polyenes, 815, 972, 980 seq., 1028. 
Polyethylenes, 960. 
Polyglycols, 956. 
Polytsobutylenes, 960. 
Polyketenes, 830. 
Polymerisation of hydrocarbons, 819, 

960, 969, 1038. 

Polymerisation plastics, 960 seq. 
Polymethylenes, 777. 
Polynucleotides, 1080. 
Polyozonides, 811. 
Polysaccharides, 897 seq. 
Polystyrene, 961. 
Polyterpenes, 910. 
Polythene, 960. 
Poly vinyl acetal, 961. 
Polyvinyl acetate, 961. 
Polyvinyl alcohol, 961. 
Polyvinyl butyral, 961. 
Polyvinyl chloride, 961. 
Polyvinyl formal, 961. 
Ponndorf, 749, 1107. 
Pope, 721, 722, 723, 750, 762, 767, 768, 

774, 931. 
Porphin, 1081, 1086. 



Porphyrms, 1080 &q., 1083 seq., 1085. 

Porter, 874. 

Potassium ethyl, 1039. 

Potassium ketyls, 1046. 

Potassium phenyldimethylmethyl, 

1038, 1040. 

Potassium tnphenylmethyl, 1038. 
Pregl, 1088. 
Pregnenolone, 1107. 
Prelog, 785. 
Primuline, 1058. 
Principal valencies, 770. 
Pringsheim, 900. 
Progesterone, 1106 s^., 1108. 
Propionic acid, 6960. 
Propylamine, 846. 
Propyl bromide, 806. 
Propylene, 696/>, 804, 806. 
Propylglycosides, 867. 
Propylpalmityl ketoxime, 736. 
Prosthetic groups, 1066, 1074. 
Proteins, 702, 963. 

Proteins '''iiiu.'.iKtll. 1066, 1074 seq. 
Protocatechiuc acid, 99, 996, 997. 
Protoporphyrin, 1081, 1083. 

PrototrojM <! .: -, 840. 

Pschorr, !<:>!. 
Pseudo-forms, 841. 
Pseudoiononc, 952. 
Pseudoionone hydrate, 952. 
Pseudoummolecular reaction, 695;. 
Pteroylglutamic acid, 1073. 
Pulegone, 700, 922, 923. 
Pummerer, 965, 1027. 
Purdie, 869. 

Purines, 1052, 1060, 1075 seq. 
Pyranose sugars, 793, 878, 874, 875. 
Pyrans, 873, 874, 983. 
Pyrazines, 1060. 
Pyrazole, 1053. 

Pyrazolecarboxylic acids, 1053. 
Pyrazoles, 1051 seq. 
Pyrazoletricarboxylic acid, 1052. 
Pyrazoline, 781, 1053. 
Pyrazolone, 1052. 
Pyrene, 1022 seq. 
Pyridazines, 1058. 
Pyridone, 984. 
Pyridoxin, 1065, 1068. 
Pyndoxin methyl ether, 1069. 
Pyrimidine, 1060. 
Pyrimidines, 1058 seq., 1075 seq. 
Pyronecarboxylic acids, 984, 986. 
Pyronedicarboxylic acid, 985. 
Pyrones, 983 seq. 
Pyroxonium salts, 985. 
Pyrroaetioporphyrin, 1083. 
Pyrroles, 700, 814, 1081 seq. t 1085. 
Pyrroline, 814. 
Pyrroporphyrin, 1083. 
Pyruvic acid, 906 seq. 
Pyruvic acid phosphate, 905. 
Pyrylium compounds, 990. 



1152 INDEX 



Quadridentate group, 774. 
Quaternary ammonium derivatives 

(stereochemistry), 762. 
Quatcrphenyl, 1027, 1029. 
Quercetin, 088, 992. 
Suercetrin, 988. 

uercitol, 798. 

nic acid, 744. 
Ljuinitol, 797, 798. 
3uinol, 797, 897, 1044. 
~ uinol diethyl ether, 704. 
v umol glucoside, 897. 
Quinoline (derivatives, optically active), 

760. 

8 uinol monomethyl ether, 897. 
uinone, 818, 1049. 
Qumone monoxime, 837. 
Quinone monoxime methyl ether, 837. 
Quinones, 1034, 1060, 1074. 
Quinoxahnes, 823, 1060, 1071. 
Quinquipheny], 1027. 

Racemic compounds, 742. 

Racemisation, 748. 

Radicals (free), 1040 seq. 

Raffinose, 886. 

Raman spectra, 701, 796, 1009. 

Raikowa, 736 

Raper, 764. 

Rast, 966. 

Rayon, 963. 

Read, 750, 922. 

Reducing agents, 1131. 

Reformatsky reaction, 931, 942. 

Refraction (molecular), 699, 835, 943, 

945, 954. 
ReichMn, 1108. 
Reimer-Tumann reaction, 997. 
Residual affinity, 770, 815. 
Resin acids, 948. 
Resins, 909. 

Resins (svnthctir), 956 seq. 
Resonanc'e, 6956, 707, 826, 931, 985, 

1001 seq., 1045, 1085. 
Resonance energy, 695s, 707, 1002. 
Resorcylic acids, 997. 
Restricted rotation, 731, 757. 
Retene, 948, 1030. 
Reverey, 794. 
Reychler's acid, 932. 
Rhamnose, 876, 992. 
Rhamnosides, 988. 
Rhodium (stereochemistry), 774. 
Rhodoporphyrin, 1083, 1084. 
Ribitol (adonitol) phosphates, 1079. 
Riboflavin, 1065, 1068. 
Ribonic acid, 857, 1079. 
Ribonic acid phosphates, 1079. 
Ribonucleic acid, 1080. 
Ribonucleosides, 1076 seq. 
Ribose, 857, 906, 1068, 1076 seq., 1080. 
Ribose phosphates, 1079. 
Ribotrihydroxyglutaric acid, 871. 



Ribotrihydroxyglutaric acid phosphate, 

1079. 

Robertson, 991. 
Robertson, J. A/., 702. 
Robinson, 695a, 988, 990, 991, 1032. 
Robison, 903. 
Roozeboom, 742. 
Rosenheim, 1089. 
Rosin, 909, 948. 
Rotation (molecular), 700. 
Rotation (restricted), 731, 757. 
Rotation (specific), 743. 
Rotatory dispersion, 700, 743. 
Rubber, 702, 811, 936, 938, 964 seq. 
Rubber (synthetic), 962, 968. 
Rubrene, 1026. 

Ruthenium (stereochemistry), 774. 
Rutherford, 695a. 
Rutm, 992. 
Ruzicka, 784, 791, 909, 943, 1031, 1033, 

1090, 1105. 

Sabatier, 781. 
Saccharase, 902. 

Saccharic acid, 854, 856, 858, 859. 
Sachs, 736. 
Sachse, 791. 
Safrole, 839, 951. 
St. Pfau, 954. 
Salicy aldehyde, 951. 
Salicyclic acid, 995. 
Saligenm, 957. 
Salway, 766. 

Sandmeyer reaction, 1029 
Sapogenms, 1109. 
Saponins, 1109. 
Scheibler, 827. 
Schiff's bases, 828. 
Schlenk, 1037, 1042, 1046. 
Schmidt, 739. 
Scholl, 1024. 
Schraube, 739. 
Schrodinger, 695a. 
Schultze, 900. 

Selenium ' " ' "19, 954, 

979, ici'j, i -, : , ' 1100, 

1103. 

Selenium (stereochemistry), 768. 

Seligsberger, 1027. 

Selinene, 938, 945. 

Semicarbazide, 1056. 

Semicarbazones (sterepisomerism), 737. 

Semidine transformation, 842. 

Semmler, 909. 

Semper, 728. 

Sender ens, 781. 

Sesquiterpenes, 910, 943. 

Sex hormones, 1087, 1101 seq. 

Sexiphenyl, 1027. 

Shoppee, 807. 

Sihcols, 963. 

Silicon (stereochemistry), 767. 

Silicon (tervalent), 1043. 



INDEX 



1153 



Silicones, 963. 

Silicon plastics, 063. 

Silk (artificial), 063. 

Silver (stereochemistry), 775. 

Simonsen, 915, 920. 

Smiles, 768. 

S N 1 reactions, 696; . 

S N 2 reactions, 695*. 

Sobrerol, 925, 926. 

Sodium benzyl, 1037, 1040. 

Sodium ethyl, 1037. 

Sodium ketyls, 1046. 

Sodium phenyl, 1037, 1039. 

Sodium trimethyltin, 1043. 

Sodium triphenylmcthyl, 1041, 1042. 

Solubility, 698. 

Sorbitol, 854, 856, 858, 860, 862 s^., 
902. 

Sorbose, 860. 

Sorbose bacterium, 860, 902. 

Specific rotation, 743. 

Spiranos, 723, 820. 

Spirit of turpentine, 909. 

Spirocyclic compounds, 728, 775, 820. 

Spirodihydantom, 723. 

Spirononane, 820. 

Squalene, 938, 948. 

Staggered bonds, 796. 

Starch, 897, 898, 901 

Staudinger, 811, 830, 967. 

Stearohc acid ozomde, 810. 

Stein, 819. 

Stereoisomerism of cyclic compounds, 
716 seq. 

Stereoisomerism of elements other than 
carbon, 762 seq. 

Stereoisomerism of unsaturated com- 
pounds, 708 seq. 

Steric hindrance, 1048, 1094. 

Steric interference, 731, 757 seq 

Steroids, 1087. 

Sterols, 1087 seq. 

Stigmastanol, 1095. 

Stigmasterol, 1087, 1088, 1095 seq. t 
1106, 1108. 

Stilbene, 708, 715, 982, 1028. 

Stilboestrol, 1104. 

Stipitatic acid, 695r. 

Stoll, 785. 

Strain theory, 789. 

Strainless ring structures, 791. 

Strecker, 998. 

Strepromycin, 1061, 1064. 

Styphnic acid, 964. 

Styrene, 695/>, 961, 969, 1038. 

Styrylmethyl ketone, 1032. 

Suberic acid, 785. 

Substitution (aromatic) 1004. 

Substitution reactions, 695A seq. 

Substitution (rules), 1004. 

Substrate, 902. 

Succinic acid, 901, 968. 

Succinic anhydride, 1034. 



Succmimide, 695 J 838. 

Succinylosuccinic acid (ester), 798. 

Sucrose, 886, 887, 893, 896, 901 

Sudborough, 1049. 

Sugar carbonates, 878. 

Sugars (sMitlirsi**-. 861. 

Sugden, 699, 776. 

Sulphamic acid, 844 

Sulphamide, 774. 

Sulphilamines, 769. 

Sulphobenzoic acids, 1112. 

Sulphonamides, 695g, 838. 

Sulphoncs, 838, 1071. 

Sulphonium salts, 768, 1071. 

Suphoxidcs, 769. 

Sulphur ' " " 943, 944, 

945, 94- , \ , ' 
Sulphur (stereochemistry), 761, 768. 
Suprasterols, 1099. 
Sutton, 734, 735. 
Sylvestrenc, 911, 912, 919, 937. 
Synaptase, 903. 
Syw-oximes, 726. 
Synthetic resins, 956 seq 
Syringidm, 990. 
Szent-Gydrgyi, 880 

Tachysterol, 1099 seq. 

Tafel, 861. 

Talitol, 858.* 

Talonic acid, 858. 

Talonolactone, 858. 

Talose, 857, 858. 

Tannins, 994, 997, 998. 

Tartaric acids, 744, 746, 747, 748, 858, 

874. 

Tartaric acids (optical i&omerism), 874. 
Tautonierism, 831 seq. 
Tautomerism (virtual), 840. 
Taylor, 734, 735. 

Tellurium (stereochemistry), 768. 
Terebic acid, 914 seq., 925. 
Terephthalic acid, 911, 925, 960. 
Terephthalic acid (reduction products), 

801 seq., 813. 

Terpenes (acyclic), 936, 940. 
Terpenes (dicyclic), 911, 924. 
Terpenes (monocyclic), 909, 935 seq. 
Terpenes (open chain), 936, 940. 
Terpenes (synthesis), 915 seq., 947. 
Terpenylic acid, 914 seq., 925. 
Terphenyl, 1027, 1028, 1029, 1039. 
Terpin, 917, 918. 
Terpinene, 917, 918. 
Terpmeol, 913, 914 seq., 917, 918, 925, 

936, 941, 942. 
Terpineol (synthesis), 916. 
Terpin hydrate, 917, 918, 925, 942. 
Terpinolene, 911, 915, 917, 918, 935. 
Tervalent carbon, 1040 seq., 1046, 1046. 
Tervalent lead, 1043. 
Tervalent nitrogen (stereochemistry), 

766. 



1154 



INDEX 



Tervalent silicon, 10 J 3. 
Tervalent tin, 1043. 
Terylene, 960. 
Testosterone, 1106, 1106. 
Tetra-acetylbromoglucose, 879, 896, 

993, 994, 1078. 

Tetra-acetylchloroglucose, 879. 
Tetra-acetylfructose, 894. 
Tetra-acetylglucose, 894, 896. 
[Tetra-acetylglucosidoxy]acetoxy- 

acetophenone, 991, 992, 993. 
Tetra-anisylhydrazine, 1044. 
Tetrabromocyc/ohexane, 799. 
Tetrachloroethylene, 804. 
Tetrachloroquinone, 1049. 
Tetracyc/ohexylme thane, 1050. 
Tetradepsides, 994, 997. 
Tetra[dimethylaminophenyl]hydra- 

zine, 1044. 
Tetra-ethyl cyc/opentanetetracar- 

boxylate, 780. 

Tetragalloyl-galloylglucosides, 999. 
Tetrahydroabetic acids, 948. 
Tetrahydrobenzene, 777, 799. 
Tetrahydrofuran, 874. 
Tetrahydrofurans, 834. 
Tetrahydropyrans, 834, 874. 
T I.,,! .,:; .- 1095. 
*] ::.':... ! : A ... '.'. acids, 801 seq. t 

1813. 

Tetrahydrotoluene, 971. 
Tetrahydrotoluic acids, 916, 917, 918. 
Tetrahydrovetivazulene, 954. 
Tetrahydroxycyc/ohexanecarboxylic 

acid, 744. 

Tetrahydroxyflavone, 988. 
Tetraketones, 824. 
Tetralone, 1033, 1034. 
Tetramethylacetonedicarboxylic an- 
hydride, 829. 

Tetramethylascorbic acid, 882. 
Tetramethylbenzonitrile, 1049. 
Tetramethylbenzylammonium, 1037. 
Tetramethylcyc/obutandione, 829, 830. 
Tetramethylene, 777. 
Tetramethylfructose (1:3:4:5-), 874. 
Tetramethylfructose (1:3:4:6-), 875, 

893. 

Tetramethylgalactose, 890, 891. 
Tetramethylgluconic acid (2:3:4:5-), 

871, 891. 
Tetramethylgluconic acid (2:3:4:6-), 

871. 
Tetramethylgluconic acid (2:3:5:6-), 

889, 890. 
Tetramethylgluconolactone (2: 3:4:6-), 

871. 
Tetramethylgluconolactone (2:3:5:6-), 

873, 889. 

Tetramethylglucose, 869, 887, 897. 
Tetramethylglucose (2:3:4:6-), 870 seq., 

890, 893, 899. 
Tetramethylglucose (2:3:6:6-), 873. 



Tetramethyl-methylfructosides, 874. 

Tetramethyl-methylglucoside, 869. * 

Tetramethyl-methylglucoside (2:3:4:6-) , 
870, 897. 

Tetramethyl-methylglucoside (2: 3: 5: 6-), 
873. 

Tetramethylpyrromethene hydro- 
bromide, 1082. 

Tetramethylsaccharic acid, 871, 891. 

Tetraphenylcyc/opentadienone, 1042. 

Tetraphenylethylene, 804. 

Tetraphenylgermane, 1050. 

Tetraphenylhydrazine, 1043. 

Tetraphcnylme thane, 1050. 

Tetraphenylnaphthacene, 1026. 

Tetraphenylsilicane, 1050. 

Tetrazanes, 1044. 

Tetrazoles, 1056. 

Tetritols, 858. 

Tetroses, 858, 902. 

Theophylline, 1076. 

Thermal analysis, 697. 

Thermoplastics, 966. 

Thiamin, 1065. 

Thizaoles, 1061, 1057, 1066. 

Thiele, 815, 816, 817. 

Thiele's rule, 815. 

Thioacetals, 879. 

Thioacetamide, 1059. 

Thioaldehydes, 982. 

Thioamides, 1057, 1059. 

Thiochrome, 1067. 

Thio-ethers, 1071. 

Thioformamide, 1066. 

Thioclucosides, 879. 

Thiophene, 700. 

Thiourea, 1057. 

Thorpe, 715, 719, 807, 929, 931. 

Three-carbon-atom tautomerism, 838. 

Threonic acid, 882. 

Threose, 858, 881, 885. 

Thymine, 1058, 1076. 

Thymol, 923. 

Tickle, 985. 

Tiemann, 951, 952. 

Tiemann-Reimer reaction, 997. 

Tigonin, 1109. 

Tilden, 914, 966. 

Tin (stereochemistry), 767. 

Tin (tervalcnt), 1043. 

Tishler, 722. 

Tocopherols, 1073. 

Todd, 991, 1060, 1067, 1073, 1078, 1080. 

Tollens, 866. 

Toluenesulphinic acid (ester), 768. 

Toluenesulphonates of sugars, 879. 

Toluic acids, 911, 917, 918, 925. 

Tolyphenyl ketone, 728. 

Tosylbenzylidenemethylglucoside, 880. 

Tosyl esters of sugars, 879. 

Trans-addition, 695a, 712 seq. 

Trans-elimination, 714, 733 seq., 848. 

Transition state, 695*, 695&. 



INDEX 



1155 



Tifchalose, 877. 
Treibs, 1086. 
Triacetonamine, 825. 
Triacetonediamine, 825. 
Triacetoxyacetophenone, 990, 993. 
Triaminopropane, 774. 
Triaminotriethylamine, 774. 
Triazoles, 1055. 

Tribenzoylgalloyl chloride, 1000. 
Tribromobenzenes , 1001. 
Tribromobenzoic acids, 1049. 
Tricarballylic acid, 915. 
Tricarbomethoxygalloyl chloride, 999. 
Trichloracetic acid, 695*. 
Trichlorobenzenes, 704. 
Trichlorobenzoic acids, 1049. 
Trichlorocrotinic acids, 709. 
Trichloropyrimidine, 1060. 
Tricyclene, 934, 935. 
Tricyc/ohexyl carbinol, 1050. 
Triryc/ohexylchlorogerniane , 1 050. 
Tricyc/ohexyllead, 1043. 
Tricyc/ohexylphenylsilicane, 1 050. 
Tricyc/ohexylplumbic iodide, 1043. 
Tridentate group, 774. 
Tridepsides, 994, 997. 
Tridiphenylmethyl, 1041, 1045. 
Triethyl cyanopentanetricarboxylate , 

916. 

Trihydroxybutyric acid, 881. 
Trihydroxycholanic acid, 1098. 
Tnhydroxyglutaric acids, 852 seq., 871. 
Trihydroxyhexahydrocymene, 914. 
Trihydroxyphenylmethyl ketone, 988. 
Trihydroxypyrimidine, 1058. 
Triketocyc/ohexane, 836. 
Triketohexahydropyrimidine, 1058. 
Triketones, 824. 
Triketopentane, 824. 
Trimerides, 819. 
Trimethoxybenzene, 696f. 
Trimethoxyglutaric acids, 871. 
Trimethylamine, 695/, 1108. 
Trimethylamine oxide, 765. 
Trhnethylarabinose, 872. 
Trimethylarabolactone, 874. 
Trimethylbenzaldehyde, 1049. 
Trimethylbenzonitrile, 1049. 
Trimethylene, 777. 
Trimethylene dibromide, 782, 974. 
Trimethylfructose, 900. 
Trimethylfructuronic acid, 874. 
TrimethylgalUc acid, 999. 
Trimethylgalloyl chloride, 999. 
Trimethylglucose (2:3:4-), 890. 
Trimethylglucose (2:3:6-), 887, 890, 898. 
Trimethylglucose (3:5:6-), 877. 
Trimethylglutaconic acid, 931. 
Trimethylinulin, 900. 
Trimethyl-methylarabinoside, 872. 
Trimethylquinol, 1073. 
Trimethylribose, 1077. 
Trimethylstannic bromide, 1043. 



Trimethylstannic cnloride, 1043. 
Trimethylstarch, 898. 
Trimethylsuccinic acid, 928. 
Trimethylthreonamide, 881. 
Trimethyltin, 1043. 
Tnmethylxanthine, 1077. 
Trinitrobenzcne, 954. 
Trinitrobenzoic acids, 1049. 
Trinitrobutyltolucne, 951. 
Trimtrophenylmethyl, 1042. 
Triose phosphates, 904. 
Triphenylacetaldehyde, 846. 
Tnphenylamme, 696g. 
Tnphenyl carbine], 1041, 1060. 
Triphenylisoxazole, 730. 
Triphenylmethyl, 1038, 1040 seq., 1045. 
Triphenylmethyl chloride, 1040. 
Triphenylmethylethylene, 806. 
Triphenylmethyl iodide, 1041. 
Triplex, 961. 
Trisacchandes, 886. 
Triterpenes, 938, 948. 
Trixylylplumbic bromide, 1043. 
Tropolones, 695r. 
Tropylium bromide, 695*. 
Truxillic acids, 718. 
Tschesche, 1110. 
Tswett. 980. 

Turner, 758, 759, 761, 764. 
Turpentine, 909, 925. 
Tutin, 922. 

Ullman, 1027, 1028. 

Undecylenic acid, 696. 

Univalent oxygen, 1044. 

Unsaturated acids (isomeric change), 

802, 814, 838. 

Unsaturated acids (reduction), 813 seq. 
Unsaturated aldehydes, 806. 
Unsaturated compounds, 804 seq. 
Unsaturated esters, 806. 
Unsaturated hydrocarbons, 804 seq. 
Unsaturated ketoncs, 806, 807, 808, 

824, 923, 1008. 

Uracil, 1058, 1069, 1076, 1080. 
Uracil ribofuranoside, 1076. 
Urea, 841, 1059. 

Urea-formaldehyde plastics, 968 seq. 
Uridine, 1075, 1076, 1077. 

Valerolactone, 790. 

Valine, 1063. 

Vanillic acid, 997. 

Vanillin, 951. 

van't Hoff, 6950, 745, 762, 763. 

Veratric acid, 988. 

Vesterberg, 943. 

Vetivazulene, 938, 954. 

Vetivone, 954. 

Vinyl acetate, 961, 962. 

Vinylacetylene, 970. 

Vinylbenzene, 961. 

Vinyl bromide, 805. 



1156 



INDEX 



Vinyl chloride, 961, 962. 
Vinyl compounds, 695fc, 6950. 
Vinylidene dichloride, 961. 
Vinylmethyl ketone, 979. 
Vinyl plastics, 961 seq. 
Virtual tautomerism, 840. 
Viruses, 1075. 
Vistanex, 960. 
Vitamin A, 978 seq. 
Vitamin A,, 980. 
Vitamin B, 1065 seq., 1075. 
Vitamin B lt 1065 seq. 
Vitamin B a , 1065 seq. 
Vitamin B a , 1065, 1068. 
Vitamin B lt , 702, 1073. 
Vitamin B c , 1065, 1073. 
Vitamin C, 881. 
Vitamin D, 1099 seq. 
Vitamin D,, 1099 seq. 
Vitamin D,, 1101. 
Vitamin E, 1073. 
Vitamin G, 1065. 
Vitamin H, 1065. 
Vitamin K, 1073. 
Vitamins, 1066 seq. 
Vorlander, 800, 1006, 1007. 
Vulcanisation, 965. 
Vulcanite, 965. 

Wagner, 849, 909, 926. 
Wagner-Jauregg, 1028. 
Wagner- Merewein rearrangement, 849, 

933. 

Walden, 744, 751. 
Walden inversion, 695a, 751 seq., 880, 

994. 

Walker, 722. 

Wallach, 722, 909, 935, 943. 
Wallis, 847. 
Wanklyn, 1037. 
Warren, 763. 
Webster, 864. 
Wedekind, 762. 
Weerman, 882, 884. 
Werner, 725, 762, 763, 770, 773. 
Whitmore, 849. 



Whitworth, 723. 

Wibaut, 1002. 

Wieland, 1043, 1044, 1089, 1091, 1094, 

1095, 1107. 
Willgerodt, 763. 
Williams, R. J., 1070. 
Williams, R. R., 1066, 1067. 
Willstatter, 803, 901, 972, 989, 1001, 

1080. 

Wilsmore, 827. 
Windaus, 794, 1089, 1110. 
Wintersteiner, 1108. 
Wislicenus, 714, 779, 831. 
Wolff-Kishner method, 954. 
Woodhouse, 869. 
Wurtz-Fittig reaction, 974, 1027, 1028, 

1038. 

Xanthme ribofuranosidc, 1076. 

Xanthone, 987, 1047. 

Xanthosine, 1076 seq. 

X-ray investigation, 6955,702, 711, 721, 

738, 764, 775, 792, 873, 883, 899, 982, 

1001, 1080, 1085, 1089, 1090, 1091, 

1093, 1097, 1102. 
Xylenes, 928, 1002. 
Xylidine, 1068. 
Xylitol, 863 seq., 902. 
Xylonic acid, 857. 
Xyloquinone, 822. 
Xylose, 857, 868, 871, 872, 878, 883, 

1109. 

Xylose diacetone, 878. 
Xylosone, 884. 
Xylotrimethoxyglutaric acid, 871. 

Yeast, 901 seq. 
Young, 903. 
Young, D. P., 846. 

Ziegler, 785, 1037. 
Zinc dimethyl, 1047. 
Zinc diethyl, 1037. 
Zingibcreiie, 944. 
Zoosterols, 1087. 
Zymase, 902 seq.