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PERKIN AND KIPPINjG'S

ORGANIC CHEMISTRY

PERKIN AND KIPPING'S

ORGANIC CHEMISTRY

Part III

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.

Pr'r.iril i:i A WAI II"1.
by T, and A. (Y^-iiiMi: I ;:• II • : ,i:
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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what appeared to be out-of-date material.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 >V83 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,
CH3— *--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 105)

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 > [R3NH]+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. 111—43$

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, CH3 — >— NH2, 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 :

fH2

NHa

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,

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-NH8+, 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 — SO2 — 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, ~CH2-~NO2 and CH2=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-*-CH2-»-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 >CH2 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+cH4 — * Hci-f-cn;,

CHg+CLj - > CH3Cl-f-Cr,
Cl'-f CH3C1 - » HCl+CH2Cr, 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-NH2+NO++Br- = RBr+H2O+N2,
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+R3N = R3RN++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 SN1 (substitution
nucleophilic unimolecular). It is clear therefore that the rate of an
SN2 reaction will be given by k[A][RB], and of an SN1 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 SN2 or SN1 ; in the
case of methyl and ethyl bromides it is entirely SN2, but tertiary
butyl bromide is hydrolysed by the SN1 mechanism and uopropyl
bromide may be hydrolysed by either mechanism. It is clear that
for an SN1 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 SN2
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 CH3Br, MeCH2Br, Me2CHBr,
Me3CBr the reaction mechanism therefore gradually changes from
SN2 to SN1 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, Me3C 'CH2X, react
only very slowly by an SN2 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 SN1 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, CH2:CH- CH2X, it is so
stabilised by dispersal of the charge over the whole molecule,
which is a mesomeric form of CH2:CH-CH,/ and +CH2-CH:CH2
(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 SN1 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 CH2=CH — X
and ~CH2— 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 SN1 reaction.
In the case of an SN2 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 SN2 reaction must be considered : this will be
-O-CR(OH)— X from an acyl halide and ~CH2— 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 SN1 or SN2 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 (+HaO)

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-OH2+ 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 CH3 • CH:CH • CH24
(cf. p. 695£), the product of mechanism (2) may be

CH3-CH:CH-CH2'OH or CH3-CH(OH)-CH:CH2

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

Me2C-6+CN- >• Me2C(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
~SO3H 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 ;

CH3 - CHO — > CH3 - CH(6) • NH2OH — > CH3 • CH:NOH+H2O.

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

CH3-~CH=£b-hHO- —

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

CH3-~CH— 6 + -CH2— CHO — * CH3— CH(6)— CH2— CHO

— > CH3— CH(OH)~CH2-~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

CH2— CH2+Br+ — > CH2—CH2Br ^ CH2Br—CH2Br

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,

+CH2— CH2Br+Ch — » CH2Cl—CH2Br,
+CH2— CH2Br+OH- — * CH2(OH)~-CH2Br,
+CH2— CH2Br-fN03~ — > CH2(NO3)~~CH2Br.

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

CH2 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, CH2:CH • [CH2]9 • COOH, for example, gives
CH3 • CHBr • [CH2] 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-CH2-CH2+, and the final product Ph-CH2-CH2Br
whereas it is in fact Ph-CHBr-CH3 ; 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- CH2- CH2+ :

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 ~CH2 — CH=X+ has already been assumed and the
product of addition would therefore be CH3 — CHX2 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,

2C5H5MgBr+FeCl2=(C5H5)2Fe+MgBr2+MgCl2;

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. (C5H6)2Ti+.

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) :

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 :

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

III

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
— NH2, — COOH, and particularly — SO3H, 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=(n2-l)M/(nz-\-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 — CH2-— 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 CH2=CH -CH2 -CH2 -CH=CH2 28-77 7R _

Hexa-2:4-diene CH3-CH=CH-CH=CH-CH3 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 10—0-1 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 B12. 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 — CH2C1 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 diffraction1 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 C6H5, 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.

iv R2C=N =± N v R2C «— 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, (>CH2),
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 HxC^X

I II HI IV

In general the number of geometrical isomerides of this type ot
olefinic compound is 2n, 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^ XCH3 H^ XCC13 H^ ^

I *~ I ~" 8

HOOC" ^H HOOCX ^H HOOCX ^

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 1018), from which it is con-
cluded that the configurations of the compounds are as shown :

cis- trans- cis- tram-

Dichloroethylene 1-9 0 H^+yX Hs^+^/X

Vs \~>

Dibromoethylene 14 0 || ||

Di-iodoethylene 0-8 0 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 X2, 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 + X2 — * C - C or C - C

/ / / /4,'i

cis- meso- (identical)

X a\ b

/ / / / 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

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 SN2
reaction. Addition therefore occurs in the /raws-position to the
first bromine atom :

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 :

Hv /COOH I
XCX H— C—COOH

* H— C— COOH *

\
NCOOH |

HOOC

I HOOCV /H
— C— H XCX

H— C— i

COOH yCx

W XCOOH

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

BF3 ;=± \ ;=± || + BF3

-~C— *BF

/x
W NPh

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) :

HOOCX XH H^ ^ H' XCOOH

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, CwH2w, 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 :

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 > CH2 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 acid1) 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, C4H6(COOH)2,
exists in three structurally isomeric forms, namely, the 1:1-, (i),
1:2-, (n), and 1:3-, (in):

CH2-C(COOH)a
CHa--CH2

CH2— CH-COOH
CH9— CH-COOH

HOOC

CH2— CH-COOH

• CH— CH2
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

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

'©

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, — CO«NHPh, 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 - CH2 - CH— CH - COOH

HOOC - CH— CH • CH2 • COOH

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

Inositol (hexahydroxycyclohexane), C6H6(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.

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 0

(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 H2

McC C

HN NH

C—CMe
H2 H

HN NH
VV

HN NH

II III

A model of an allene derivative of the structure, (iv), shows that
the four groups, Rj, R2, RS, R4, are situated in two planes at right
angles to one another and occupy the corners of an irregular tetra-
hedron (Fig. 27) :

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-CH2'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-naphthylalleney (n). This last change is an
extremely interesting example of an asymmetric dehydration (Mills
and Maitland, J. 1936, 987).

Ph Ph Ph /Ph

C10H7 C10H7 C10H7 C10H7

i n

The acid, C10H7(Ph)C:C:C(Ph).COO.CH2.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 =CR1R2
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

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, NR3, 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+NH2-OH - >C=:N.OH+H20,

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— C—R' R— CH— R'

•OH
I

HNO

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.

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, NR4X, 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

C—C OH

Hx / \ _ /

HOOC^C\ /C~N
C— C
H2 Ha

"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, NH2-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'

CR—C—R' -|
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 = CH3 or NO2 and R = C6H4X) :

.Syw-phenyl-R ketoxime
C6H6 — C — CflH4X

HO-N

CflH5 — C — C«H4X C6H5 — C — C6H4X

II II

MeO-N ONMe

-R ketoxime
C6H5 — C — C6H4X

N-OH

C6H5 — C — C6H4X

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
CeH6, C6H4X, 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) :

C6H6 . C • CH8 HO - C • CH3 OC - CH3 C6H6 • C - CH3

HO-N C6H6-N C6H6-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,
C6H6-CO-NH-CH3, 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.C6H6
Ns XCO-C6H5

— CO-CgHj OC— CO-

NH-C6H6

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- (— C6H5) and not the ^-radical (— CO-C6H6) 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

N02

NO2

OC'CHs

HN'C6H3Br'NOa
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).

732 GEOMETRICAL ISOMERISM OF THE OXIMES AND
*N>H

R — C — CHa R — CO

HO'N CH3-NH

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(CH3)=N«OH 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 • CH3, whereas the isomeride, (i), gives R • NH • CO • CH3,
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.

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.

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 1018,
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

-C6H4 • C • C6H5 N-C6H4 . C - C6H5

0<— N-CH3 CH3.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 1018 JLCX 1018

NO2.C6H4.C-C6H5 3-75 NO2-C6H4.CH 3-39

MeO-N MeO-N

NO2 - C6H4 . C • C6H5 4-26 NO2 - C6H4 . CH 3-88

II II

N-OMe diff< 0.51 N-OMe diff. 0.49

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-CH2— R.C=CH— R.C.CH2—

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 :

C6He • C - C • C$H5 C6H6 • C - C • C0H5

ii ii ii ii

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

jyti-Benzildioxime anft-Benzildioxime

C6H6 • C - C'C6H5
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 :

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-C6H5, 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.C6H6
i

C6H6.NH'N
H

R_CH— R'

N=N.C6H5
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'

(C6HB)2N-N N-N(C6H5)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.NR2 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-CO«NH2, 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 R«N

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, C6H6-N2-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-N2'OCH3, whilst the tsodiazotates
give JV-ethers, R-N(CH3)'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 0«fr'-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*N2«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 [MD]-f 270° for the rf-a-bromocamphor-7r-sulphonate ion1 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, CH3»CH(OH)«R
and C2H5-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, C6H5-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,
CH3-CH(N8)-CO'NMe2, 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 - CH2 - CCl(NO) - CH2 - CH2 • 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 'SO3H, 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 *SO3H, was investigated by Read and McMath
(7. 1925, 1572), who prepared its \-hydroxyindylamine1 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

Ag20 Ag20

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

CH3 • CH(NH2) . COOH « - CH3 - CHBr - COOH

NOBr NH» NOBr

/-Bromopropionic acid /-Alanine

CH3- CHBr- COOH - •> CH3.CH(NH2).COOH

NH8

Aspartic acid shows similar behaviour :

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

rf-Bromosuccinic acid - *• /-Aspartic acid
NH8

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 :

PC18 or HC1

rf-Ph-CHCl-CH2.COOH ' /-Ph-CH(OH).CHa-COOH

HaO

SOClj

H,O

SOC1,

rf-Ph-CH(OH)-CHa-COOH . /-Ph-CHCl-CH2-COOH

PC16 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 — dt 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 SN2 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,

C8H17I+I- ^ C8H17I+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 SN2
reaction leads to inversion and it is now assumed that this is always so.

In an SN1 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 SN1 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 SN2 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-- 0 '

-— - > -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 SN1 reaction with a configuration holding group. Without
such a group two successive SN2 reactions would both give inversion
and the final product would be identical in configuration with the
starting material ; or if either reaction were SN1, 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 SN2 reaction,

O-CO-CHg

— — >

OH IT XO-S02-C7H7 IT XH

II HI

R\C/H R\C/C1

/C\ /°\

R'' X0-COCH3 R;/ XH

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 SN2 type and assuming that this always
gives inversion, relative configurations can be determined ; if, for
example, a dextrorotatory halide is converted by an SN2 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 NH2

HOOC-CH2-CHX-COOH + + + +

CH3-CHX-COOH + +

Ph-CHX-CH2-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 SN2 or SN1 involving predominant inversion : the silver
oxide reaction is SN1 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 SN2 reaction with inversion occurs, but with
dilute alkali the configuration is retained by an SN1 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, NH2'C6H4'CeH4'NHa, 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'CeH4«CeH4'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.

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

SO3Ph

HO*S

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 Me3As 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

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

OPTICAL ISOMERISM

761

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'

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

'CH2 -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 1920.1 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 NR1R2R3R4X exists in optically active,
enantiomorphously related forms.

1 As the [M]0 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

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

H2 H2 H2 H2

\r\r\

4-A

H2 Hj HI

[2 H2

COOEt

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]RR2) 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-C10H7]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, R3NO.
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(CeH4-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 :

,OCH3 yOCH3 (4)

(1) Me3NO+ CHJ — > Me3N<Q — * Me3N\ (A)

xOH ,OH (4)

(2) Me8NO+HCl > MesN\ > Me3N\ (B)

XC1 XOCH8 (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 Me3N(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, [Me3N-OMe], by an electro-valency,
while in (B) the methoxyl group is so united to the complex,
[Me3N'OH], as shown below :

tMev /Me "I + _ TMe\ /Me"l + -

>N< OH >N< OMe

Me/ XOMeJ LMe^ NOHJ

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, NR3, 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, NR1R2R3,
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, [NR1R2R3R4]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 (R3),
and was thus converted into a substituted amide, NR1R2R3 (Ri or
R2 may represent H), in which R3 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

+R1RaR3+
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 (R3) ;
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, R1R2N'C6H4'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 NRjR2R3 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, [NR1R2R3H]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^|

RlR:

N
,2R3

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,.C«H4.S03H

SO8H - C6H4 • CHa • Si • O • Si - CH, • CeH4 • SO3H /Si<f

Rt NCH,.CtH.

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 :

CH3V /CH2.COOH\ CH3X .CU^CO^h

>S< J PtCl4, >S<f

C2H/ XC1 /, C2U/ XC6H(N02)3.OH

i ii

_CH3C2H5CH2.COOHJ

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, [(CH3)(C2H5)S(CH2 • COOH)]2PtCI6,
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(CH2 • COOH)]Br, was obtained by Pope and
Neville (Proc. Chem. Soc, 1902, 198), and phenyl-p-tolylmethyl-
telluronium iodide, [PhMeTe-C6H4Me]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, CH3 • CeH4 • SO - OC2H6, (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 :

os7 ^o

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,
M2'S04,M2''XS04)8,24H2O, and sulphates, M2'SO4,M''SO4,6H2O,
are deposited ; similarly a solution of potassium chloride and
platinic chloride gives a salt, K2PtCl6, and a mixture of potassium
and ferrous cyanides gives K4Fe(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 K2[PtCle], 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, K2[PtCl6], ionises (as denoted by the
brackets) into 2K+ and PtCl6~~. 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 C15 • NH3] . A repetition of this process produces [PtCl4 - 2NH3] ,
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 [PtCl3-3NH3]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

K2[PtCl4] KJPtCy K3[CoCl6]

K[PtCl3 • NH3] K[PtCl5 - NH3] K2[CoCl5 • NH3]

[PtCl2 - 2NH3] [PtCl4 - 2NH3] K[CoCl4 - 2NH3]

[PtCl • 3NH3]C1 [PtCl3 • 3NH3]C1 [CoCl3 . 3NH3]

[Pt • 4NH3]C12 [PtCl2 • 4NH3]C12 [CoCl2 - 4NH3]C1

[PtCl - 5NH3]C13 [CoCl • 5NH3]C12

[Pt.6NH3]Cl4 [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 ;
[PtCl4-2NH3], 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, MA2B4, 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 :

CIS-

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 [Coen2Cl2]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 :

eiT Pen

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 [Coen2Cl-NH3]Cl2, 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

[Coen8], 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(CH2-CH2-NH2)3, dichlvro(ffifif-triaminotriethylamine) platinic
dichloride, [Cl2PtN(CH2.CH2.NH2)3]Cl2, 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(NH3)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, SO2(NH2)2, is used as the chelate group :

To (OH 1 1

Co Co(NHs)4 Bre,2

L (OH J ,J

III

Fig. 39

H2O

y?"
O,

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
MA2B2> in which A2 and B2 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,
PtpyaCl2 (py = pyridine), for example, exists in two forms (as
possibly does Pdpy2Cl2), 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 T«f

u/^-^N. xN1*^^,.

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, C6H12, for example, is called cyclohexane, whereas
tetrahydrobenzene, C6H10, is called cyclohexene, and dihydrobenzene,
C6H8, 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 CH3 • CHBr • (CH2)n • CH2Br,
may also be employed,

/CHaBr /CHa

CHa<^ +Zn(or2Na) » CHa<^ | +ZnBra(or 2NaBr).

NCHaBr XCHa

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

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

•MgBr

+ CHvCOOEt

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).

CVzr£0#y-derivatives may be prepared by treating certain dihalides
of the paraffins with the sodium derivative of diethyl malonate,
ethyl acetoacetate, or cyanoacetate (Perkin),

CH8Br

+CH2(COOEt)2+2NaO-CaH5
2Br

V^1*. A2J.

CH2E

>C(COOEt)2+2NaBr+ 2C2H8 • 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) :

+ 2CHNa<COOEt), -

Ha
/-*^H«

g»
/^CN

H2C + Bra «- H2C

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

£ S

Hi H2

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,

„ y 9°

H2C 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

| + tH2 * I £H2

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
EtOOOCHN2 + CH2:CH» COOEt -* l CH2 ^

- COOEt

CH- COOEt
H2CCi + N2

rw ^CH* COOEt

CH'COOEt N V2

CH2N2 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, C6H10 50° Pentane, C5H12 37°

Cycfohexane, C6H12 81° Hexane, C6H14 71°

Cycfobutanol,C4H7.OH 123° Butyl alcohol, C4H9- OH 117°

Qycfopropanecarboxylic Butyric acid,

acid, C3H6 - COOH 183° C3H7 - 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)
CH2Br-CH2-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

Me, -> rye

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— CH2-NH2 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-CH2-NH2 — * 2T 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-dwney (ill) ,

yCOOH /CHt\ /C°\

[CHJ7<( [CHJ§< >CO [CHJ7< >[CHJ,

NCOOH XCH,/ XCCK

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

XCH,-CN XCH-CN XCH,

(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.CHa.COOEt — »[CH,]14< | * [CH2]14t( |

xCH-COOEt xCHa

(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»\ /COV

[CH8]/ — » [CH2]/ >CO + [CH.K >[CH2]6

XCOC1 ^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 - [CH8]»(|| +2NaOMe,

/C-ONa /CO

[CH,]n< || +2H.O - [CH8]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, [CH2]n(COOH)2,
are reduced with the aid of sodium and alcohol, giving dihydroxy-
compounds, which are then converted into acids, [CH2]n.,2(COOH)2
and [CH2]W+4(COOH)2, by the usual reactions for passing up a
homologous series :

/COOEt yCHa-OH

[CHJn< ~ + [CH2]n< — H>

XCOOEt XCHa-OH

CHaBr xCHa.CN /CHa-COOH

/ar xa. /

<; — » [CH2]n<( - * [CHa]n<(

XCHaBr XCHa-CN XCH2-COOH

/CHa.CH(COOEt)a yCH2.CHa<COOH

[CHJn< — * [CH2]n<(

XCH2 - CH(COOEt)2 XCH2 • CHa • COOH

The dibromides (above) may also be converted into the (di) Grignard
compounds, which react with chlorodimethyl ether, C1CH2 • OMe,
giving ethers ; these products are decomposed with hydrobromic
acid and the operations are repeated :

[CHJn(CH2<MgBr)a--> [CHa]n(CH2.CH2.OMe)2-> [CH8Jn(CHa.CHaBr)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-[CHa]n-COOAg+Bra - MeOOC-[CHa]n-Br+COa+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.[CHaVCO'Cl — * Br.[CHa]n.CO.CH(CO.CH8)-COOEt
— » Br • (CHa)n - CO - CHa - COOEt

The cyclic monoketones obtained by such methods range from
gtf/b-octanone, C8HMO, up to about cydononacosanone, C29H56O.
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, C17H32O, is
passed over thoria heated at 400-420° ; further, the cyclic hydro-
carbons, C15H30 and C17H34, 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 -

— CH2 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),

CH2 • CH2 - CHMe • CH2 CH— [CH2]7V

I [ II >co

[CH2]10 CO CH-[CH2]/

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 :

-CH2

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,

C6H6 - OH — > C6Hn • OH •> C.HuBr — * C6H10,

C6H5 - COOH > CflHn - COOH > C6H10Br • COOH » C6H8 • 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,

NMe8«OH • H2C^ yH 4- NMe, + HaO
Ha

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=CH2), 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

(p. 813), and, like the polyenes (p. 980), are examples of coloured
hydrocarbons. Cydbpentadiene in benzene solution gives a potass-
ium derivative, C5H6K (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 0° 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 >CH2 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, kas> *m fact> a smailer one.

CYCLOPARAFFINS AND CYCLO-OLEFINES 791

Number of atoms
in ring 234567 8

Heat of combus-
tion per CH2
group (Cal.) 170 168 165 158-7 157-4 158-3 158-6

Angle of valency

deflection 54° 44' 24° 44' 9° 44' 0° 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 al above the mean plane of the carbon atoms, six
at e nearly in this plane and three at a2 below it. Those at al and
a2 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,

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-C6H10-CH2-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, C10H17«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

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 - C6H]0 • CH2 • CH2 - 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 C2H6 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 CH2 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, C6H12 (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, C6HU-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, C6H11Br. 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, C6H10(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, C6H7(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, C6H6(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, C6H1X-COOH (hexahydrobenzoic
acid), may be obtained by reducing benzoic acid with sodium
amalgam and water ; it melts at 31°, and its bromide C6H11«COBr,
gives an a-bromo-substitution product, C6H10Br • 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-dibromocydohexaney
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

H2CX

^ X
H2 Ha H H

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

Cycfohexene, CeH10, 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, C6H8, 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, RCHI2, 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 *» CH3)
and ethyl acetoacetate is 2:4-dimethyl-&-l-cyc\ohexen~6-oney or, if
in the enolic form, 2tA-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.

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

CH3 X'HC x£H H2C

HaC

CH3 ~* X-HC ~* ~ "* - -

CH, CH8 CH8 CH3

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
Me2C XOOEt Me2C

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

CH8
Et

Mc-

( C
XOO

COOEt

.A,

COOEt

CO Me«HCT CO Me-HC
T -» T I -* I

^ CH$ H2C.^CHa H2

COOEt CO

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

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

Dihydro-acids

A-l:3-acid

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 — •> — CH2.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 (C12, Br2) 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, CH2:CH-[CH2]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

CH8-CH-CH8+Br »• CH8-CHBr-CH8.

In an abnormal reaction, the oxygen or peroxide liberates a
bromine atom from the hydrogen bromide and this atom then
combines with the olefine,

» CH8~- CH— CH2Br;
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— CH2Br+HBr — > CH8— CHa— CH2Br+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,
C6H4C1 • NCI - CO • CH3, and N- chloro -2:4- dichloroacetanilide,
C6H3C12-NC1-CO-CH3, 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-CMe2*CH2>CO-CH3 (p. 816).
Other compounds which unite directly with oiefines are HOC1,
NOC1, N2O3, and N2O4 ; 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 :

C6H5 • CH CH(COOEt)2 C6H5 • 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).

CH3

CH(COOEt)2

C- COOEt

CH- COOEt

CH2

CH. COOEt

CH- COOEt

C- COOEt

CH(COOEt)2

CH2- COOEt

CH2. COOEt

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 XC-°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-CH8)4-
• OH

>CO

+2CH3 • COOH+Pb(O - CO • CH3)2,
>CO

>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— CH8— > C=C— CO—

i n

;> C=C— CH(0 - CO - CH3)—
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 :

CH2-=CH2 CH2=CH— CH2— CH2— CH=CH2

CH2O CH2O2 CH2O2 CHO-CH2.CH2.CHO CH2O2

The ozonides of oleic acid and elaidic acid (p. 710) yield nonylic
aldehyde (or acid), and azelaic acid (or semialdehyde),

CH3— [CH2]7— CH=CH— [CH2]7— COOH
CH3 - [CH2]7 - CHO COOH - [CH2]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, CH3.[CH2]7-C:C-[CH2]7-COOH, and
phenylpropiolic acid, C6H6«C:C«COOH, 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, C6H10,O3, for example, is only slowly
decomposed even at 100°. Aromatic hydrocarbons also give
ozonides : benzene forms a tri-ozonide, C6He,3O3, which explodes
with warm water, but decomposes more slowly with cold water,
yielding glyoxal,

CflH6,308+3H20 - 3C2H2O2
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, R2C=CR2, leads finally to the formation of an ozonide, (i) :

\ /
0-0

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* —

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 - 02— 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/ \O—OH \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-O3+H20 - 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, CeH6-CO-CH2-CO'CH3, for example, with water gives
methylglyoxal, benzoic acid, and hydrogen peroxide ; it may
therefore be concluded that the*enol probably has the structure,
C6H5-C(OH):CH.CO-CH3.

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,
C4H9.COOC6Hn.

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 :

CH2:CPh2 — > CH2— CPh2 — * Polymeride.

o — 6

Acetyl peroxide, CH3-CO-O-O-CO-CH3, benzoyl peroxide,
C6H5*CO'O'O«CO-CeH6, 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)2O2+MeONa = Ph-CC^Na+Ph-COOMe.

Monoperphthalic acid, C6H4(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 :

CH2<Q>C6H3-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.CH2.CH:CH-CH2-COOH

vii HOOC-CH2.CH2.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-CH2.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:CH2+2H - Ph-CH2.CH:CH-CH3,
Ph • CH:CH • CH:CH - Ph+2H = Ph • CH2 . CH:CH • CH2 - 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 :

R—CH:CH—R+H2 - R— CH:CH— R — * R— CH2.CH2—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 — - — CH2-CH:CH.CH2—

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 Js 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 formed
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 +CH2-CH:CH-CH2- 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 1»5 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,

CH8:CH-CH:CHa+Br+ > CH2:CH-CH-CH2Br/CH,-CH:CH-CH2Br,

CH2:CH-CH:CH2+H+ > CH2:CH-CH-CH8/CH9-CH:CH-CH8.

An ion formed by addition of bromine or hydrogen to one of the cen-
tral carbon atoms, CH2:CH-CHBr-CH2+ or CH2:CH-CH2-CH2+
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, CH2:CH -CHa'CH^Br, is formed with hydrogen
bromide, and with 1-phenylbutadiene similarly the product is
Ph-CH:CH-CHBr-CH3 and not Ph-CH:CH-CH2-CH2Br while
l:4-dimethylbutadiene and hydrogen bromide give a mixture of
Me-CH2-CHBr-CH:CH-Me and Me-CH2-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-CH3
is more stable than Ph-CHBr'CH:CH»CH8 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

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:CH2

III

COOMc

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<ui.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.

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, — NH2, 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, CH3-CO-CO-CH3 (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 :

CH3 • CO • CHa - CH3 — » CH3 - CO • C(:N • OH) • CH8 — *• CH3 • CO • CO • CH3.
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
CHS-OCX VCH,

H,CV xCO-CHa H2CX XCO-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 >CHt 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, CH3 - C(:N • OH) • C(:N • OH) - CH3 (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, (C4H7O2N2)2Ni, with nickel salts in neutral solution.1
On reduction the dioxime yields a mixture of meso- and dl-2:3-
diaminobutanes .

Acetylacetone, CH3 • CO • CH2 • CO - CH3 (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),

CH8.COOEt+CH3.CO-CH8 = 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) C6H5-CO'CH2-CO'CH3, which closely re-
sembles acetylacetone in its reactions.

Acetonylacetone, CH3 - CO • CH2 • CH2 • CO • CH3 (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 :

CH8 • CO • CHNa - COOEt CH3 • CO • CH • COOEt CH3 • CO • CHa

CH8 • CO -CHNa- COOEt ~~" CH3 • CO • CH • COOEt """* CH3.CO-CH2

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 • CH2 • 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, CH3 • CO - CO • CO • CH3 (triketopentane), has been
obtained by condensing acetylacetone with p-nitrosodimethylaniline
and hydrolysing the product, CAc2:N • CflH4 • NMe2 ; it is an orange
liquid, and condenses with acetylacetone to give the hydroxy-
tetraketone,

CH3.CO-C(OH).CO-CH3

CH3-CO.CH.CO.CH8

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 CnH2nO 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,
C6H5.CH:CH.CO-CH8.

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,

Me2C:CH«CO-CH;CMe2

NH2
H
Triacetonamine Triacetonediamine

Mesityl oxide reacts with hydroxylamine, giving a hydroxylamino-
additive compound and an oxime,

Me2C • CH2 - CO • CHS Me2CH:CH • C • CH3

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,

C6HB.CO.CH:CH.CeH6 - > C6H6-C(OMgBr):CH-CH(C6H6)2 - >
C6H6 - CO - CH2 - CH(C6H6)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 CH2Na'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 :

CH3.COOEt+NaOEt - CH8.C(ONa)(OEt)2,

CH8.C(ONaXOEt)2+CH3.COOEt -

CH3 • 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 :

C6H5'CO-OCHt'C6H5-fCH3.ONa

^ C6H5 • C(ONa)(OCH3)(O - CHa - C,H6)
C6H8 - CO • OCH3+ C6HB • CHa • 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,

CH2:C(ONa)(OEt)+CH3-COOEt - CH3-C(ONa)(OEt).CHa-COOEt ;

the additive compound so formed might then lose a molecule of
alcohol, giving CH3-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 /CH81

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, C6H6-CO-CH2-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, CH2:CO, was first obtained by decomposing
acetic anhydride with a white-hot platinum wire (Wilsmore),

CH8.C(\

>O - 2CH2:CO+HSO.

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, - CH8:CO+CH4.

Ketene, and some of its homologues, may be obtained by treating
a solution of an a-bromoacyl bromide with zinc,

(CH8)2CBr.COBr+Zn - (CH3)2C: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\

(C2H6)2C< >0 - (C2H5)2C:C(H C02.

Ketenes are usually yellow , mobile liquids with a characteristic
odour. Ketene is a gas (b.p. —56°), and diethyl ketene, CEt2: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,

CH2:CO+CH3-COOH = (CH3.CO)2O,

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,

CH2:CO+R-OH = CH3.CO-OR,
CH2:CO+NH3- CH3.CO-NH2.

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),

R2C— CO

I I

c-6

R2C:CO+R'-CH:NR" - I I

R'CH— J

R2C — 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

CHa\

CHa:CO+CH8N2 - I ^CO+Ng
CH2

CH2V CH2.CO

I >CO+CH2N2 - [ I +N2

CH/ CH2-CH2

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(CH3)2C:CO,CO2, 3(CH3)2C:CO,2CO?,
and 4(CH3)2C:CO,3CO2. 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 :

Me2Cx ^CMca OC-CMea

OCX ^CO Me2C— 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,

CH2

C2H5-OH - CH3-CO • CH2 • 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> (CR2:CO)n.

Diphenyl ketene, Ph2C: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, C3O2 (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— CH2— -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 :

CH8.CO.CH8.COOEt - [OVCO.CH.COOEt I

iCH3-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,
CH8«C(O*CO-CeH5):CH'COOEt, but when its sodium derivative

831

832 ISOMERIC CHANGE

reacts with benzoyl chloride or with alkyl halides, a C-derivative,
CH3-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, CH3.CO-CH(CO-CeH5)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'CH«CO'C6H5 ^ /C:C(OH)'C0HB

C8HH\ I C8HH\ I

xco *— xco

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

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 — CHa — groups are separated from
one another by one or more carbon atoms ; the two acids,

/CO • COOH yC(OH) - COOH

CEt2( * CEt2< I

XCH2-COOH * — XCH.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 « — Hac^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,
CH8.CO-CH(COOEt)-CH2.CH2Br, gives an oxime, but in other
reactions it behaves as if it had the structure of the tetrahydrofuran
derivative, (n),

CHj«COCHs ^

CHa'CHa'OH *

I II

Similarly y-hydroxy-n-valer aldehyde, (in), is tautomeric with
methylhydroxytetrahydrofuran, (iv), and S-hydroxycaproaldehyde, (v),
with methylhydroxytetrahydropyran9 (vi) :

CHa'CHO >

CHa«CH(OH)'CH, *

III IV

ISOMERIC CHANGE 835

.CH..CHO _^ H,C-CH.OH

CHa< Z3 H,C 0

NCH1.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-CH2'NO2, 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]D4-188°, 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,HlsB<

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-NO2, and j8-nitro-octane, C6H13-CHMe-NO2, 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, NO2-CeH4-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-C6H4-OH, but as the same compound is formed by the
action of hydroxylamine on quinone, it might be quinone monoxime,
HO*N:C6H4: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'C6H4-OMe and the O-methyl ether of quinone monoxime,
MeO-N:C6H4: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,
NH2'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-CC12*NH2, 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-SO2.NHR', and disulphones, R-SO2.CH2-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,
R«eH:CH'CH2-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 tautomerismy

— CH:CH-CHa— ^± — CH2-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, CeH6'CH:CH-CH2-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:CHa.CHR'.COOH.

Three-carbon-atom isomeric change is also shown by various
allyl derivatives of benzene, in which the group — CH2-CH:CH2
passes into — CH:CH-CH8, 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 :

C6H5.N2C1+NH2.C6H4.CH3 « C«H5.N:N.NH.C6H4.CH3 i
C6H5.NH2+C1N2.C6H4.CH3 = C6H6.NH-N:N-C6H4.CH3 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-CHiN—R' (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:CH2, in boiling acetic
acid solution gives the corresponding ester of y-phenylallyl alcohol,
Ph • CH:CH • CH2 • 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 - CH8-CH:CH-CH2Br

+CH3-CHBr-CH:CH2>

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/CHv/Me

/*"\ ^\ — "
W NOH XH 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,

NH4.O-CN — * NH2.CO-NH2,

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, CeH5.NH-NH.C6H4-COOH, which yields benz-
idine. (2) An ottho-semidine,

NH-NH

~ CaH60

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
(CH3)2N ~~

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,

CH3 - C8H4 • N:N - C6H4 - O - Bz+4H -

CH3.C6H4.NH2+H2N.C6H4.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, XC6H4 • NH • NH • C8H4Y, in
which X and Y are not/)- to the nitrogen atoms, but no symmetrical
benzidine,

NH2-C6H3X.C6H3X.NH2 or NH2-C6H3Y.C8H8Y.NH2,

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 ArN2-group
is attached, a mixture of two aminoazo-derivatives is often formed ;
this is easily accounted for by the suggested mechanism,

Ph-N2.NH.Ph+HCl - Ph'N2Cl+PhNH2,
Ph-N2Cl+C8H4X.NHa - Ph.N2*C6H3X.NH2+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 :

C«H6 • NHa [C«H2n+1 - C6H4 • NHJ+

[C6H6.NHa.CnH2n+1]+ + » or

CJHi+i [C6H6-NH8]+ + CnHlw

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,
C6H5 • NCI • CO • CH3 (p. 1016), of anilinesulphonic acid (sulphanilic
acid) from sulphamic acid C6H5-NH-SO3H (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 :

C6H5.NCl-CO.CH3-f HC1 - C6H5.NH-CO-CH3+C12,
C6H6.NH.CO-CH3+C12 - C6H4C1.NH.CO-CH8+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, C6H5«NMe»NO,
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, C10H7-OAc, under similar
conditions, gives not only \-hydr oxy-2-acetylnaphthaleney 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-CH2-CH:CHPh
COOH

CHa-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,

N02.C6H4.O.CO.C6H6 — > C6H5.CO-NH.C6H4.OH;

but although apparently the benzoyl radical in the initial reduction
product, NH2'C6H4-O'CO«C6H5, 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,HS)3C.CHO — * (C6HB)2CH.CO.C6H5,

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),

C4H, - CH(Et) . C . Me OC • Me

II — I

NOH NH.CH(Et).C4H,

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-NH2+ Bra+4KOH - R-NH2+ K2CO3-h2KBr+2H2O,
R.COOH+N3H - R.NHa+C02+N2.

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+H20 — * R-NH2-hC02.

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.CON3 — > R-NCO+N2.

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, CR2(OH)-CHR.OH, like pinacols, CR2(OH).CR2-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 — * CRPh2.CHO4-H2O,
ii CRPh(OH).CHPh-OH — » CHRPh.CO-Ph+H2O,
in CRPh(OH).CHPh-OH — > R-CO.CHPh2+H2O.

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, CPh2(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 Ph2C(OH).CHPh-NH2
vi PhCMe(OH)-CHPh-NH2
vin Ph2C(OH)-CHMe-NH2

PhCO-CHPhjj v
MeCO-CHPh2 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 :

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.C««X>«Y. m»mf^

......

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 -» CH8»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
CH2(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, CH2(OH)-[CH(OH)]4-CH2-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

H H

H HO

H H

OH HO

H H

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 CHa-OH CH8-OH

OH HO

H H

H HO

H H

OH HO

H H

OH HO

H
OH
H
H

CHa.OH CHa-OH CHa-OH CHa-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 w0«0carboxylic 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,

CH2(OH) • CH(OH) - CH(OH) • CH(OH) - CH2 • 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) • CH2 - 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

OH HO
H H

H H

OH HO

OH
OH

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 — CH2 • 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

CHa-OH

H
H

HO
HO

OH
OH
H
H

CHa-OH

HO
H

HO
HO

H
OH
H
H

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

HO
HO

HO
H
H

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 — CH2-OH group (not shown)
is changed into — CHO, the configuration of the aldopentose which
results will depend on which of the two — CH2*OH groups has
been transformed.

The two aldopentoses derived from /-arabitol are therefore Cx
and C2,1 according as the upper or the lower — CH2-OH group is
transformed into — CHO :

H
d HO

CHO
OH
H
H

CH,-OH

H
HO
HO

CH.-OH

^na-

OH
H
H
CHO

CHO
HIOH
H OH
HOIH

CH2-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 Cx or C2.

/-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 C2, the configurations of /-glucose and of /-mannose must be

1 The central formula is given to show how Cs is arrived at, namely,
by changing the lower — CH8'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 Cx and C8 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 Cx or C2 into — CH(OH)-CHO :

CHO CHO CHO CHO

H H

OH H

H HO

OH HO

OH H

H H

H HO

H H

OH H

H HO

OH
OH
OH
H

J A A iiW J.J. J.J.VS J.A AAV/ A A

CH2-OH CHg-OH CH2-OH CHa-OH

Derived from C4 • Derived from Ca

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 (CA or C2), the configuration (iv) is also
excluded.

/-Glucose and /-mannose, therefore, are represented by the
configurations derived from Cx ; Cx, therefore, and not C2 (p. 855),
represents /-arabinose.

Now, the aldohexose, gulose, is formed from glucose by trans-
posing the groups — CH2-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 — CH2-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

H
HO
HO

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, CH2(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 C2 (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, C6H8O7, 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
CH2-OH

Gluconic acid
CH2-OH
[CH-OH]4

COOH

Gulonic acid

COOH

* [CH-OH]4

COOH

Saccharic acid
CHa-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 — CH2-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).

CH2-OH

CHO

OH
CH2-OH
I

CHO

HO
HO
H
HO

CHO

CH2-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-sorbosey 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 :

HO
H
H

CHO

OH
H
OH
OH

CHa-OH

^/-Glucose

CHa-OH
CO

CHa-OH

/-Sorbose l

CHa-OH

OH
H
OH
OH

CHa-OH

d-Sorbitol

H
HO

CHa-OH

OH
H
OH
H

CHa.OH

Mditol

CHa-OH

H
OH

CO
CHa-OH

/-Sorbose 1

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, C6H12O6, 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,
CH2(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, C6H14O6, 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

/-Mannose

J-Mannitol

/-Gluconolactone

/-Glucose - > /-Glucosazone

/-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, C6H11O6«CH3, 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
H—C—OH 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
CH2-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, C6H12Oe,H2O, 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-C—H | | HO-C— H

4 H-C 1 ' C-H

5 H-C-OH H— C-OH

6 CH2-OH CH2-OH

rf-Gluconolactone rf-Galactonolactone

Mo+680 [a]0-78°

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— C—H

HO— C— H

HT~

CH,-<

CHa 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

CHa.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

CH(OH)

H— C— OMe
> MeO— C— H (

H— C— OMe

u r«

6 CHj-OMc CHj-OMe
I II

CH2-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— C—OMe
MeO— C— H
H— C—OMe
COOH

r — i

J3— C—OMe
MeO— C— H
H— C—OMe
H— C—OMe

V (unknown)

1 COOH
H— C—OMe
MeO— C— H
H— C—OMe
H— C—OMe
CH.-OH
VI

COOH
H— C—OMe
MeO— C— H
H— C—OMe
H— C—OMe
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)»CH2OH

:H2OH

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 :

:H8«OH
:— OMe
HO— C—H
O H— C— OH
H— C— OH

!OOH
I— OH

III

-co

MeO— C—H
O H— C— OMe

IH— C— OMe
I
CHa

COOH
MeO— C—H
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— C—H
H— C— 0
H— C

HO-C

MeO— C—H
H— C— OMe
H— C

CH8-

OMe

CH2-OMe
VII

876 "THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC

MeO—C-~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, CH3 • [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,

>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).

2 H— C— OH
3 HO— C— H

4y T f** f\1 J
rl— Ly-r-vJJtt

6 CH8-OH

H-n-C— O^
1 >CMe8
H— C— O c
> 1
HO— C— H

H- C

H— C O

" _!>*•• 1

I
H— C-

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

CM«CI1H

CH,0.

I ^CMe.

1
HO— C— H

0 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— C—OH

H— C— <

CH,-

H—C-OH
HO— C— H

HO'CHa— C-
H

Normal xylose y-Xylose

H— C— Ov

| >CMe2
H— C-0^

CMea< I

^ ~

:— 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, C6H7O(OAc)4Br, 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(VC6H4.Me XC-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

H— C

I \

CHrO-CHPh
I, T=Me.CeH4-SO2

HO— C— H

CHa-O CHPh
II

Ascorbic Acid

/-Ascorbic acid, C6H8Oe, 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]578o-f-240 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-C—OH C:O

|| + Ii + 2H2O 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, C6H7O6Na, 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

HO— C— H
CH8-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— C—OH+NaClO+NaOH = £HO+NaNCO+2H2O+NaCl.

CO-NHa
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~

OJ ] 01

H-fc— I H~C - 1 H

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

CMea< I

^0-C-H

H— C

coo

884 THE CONFIGURATIONS, SYNTHESIS, AND GLYCOSIDIC

CHO
H— C— OH

HO— <

HO— \
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

CHa.OH
H— C— OH

i H

HO— C— I-
H C C

~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
CH2 OH

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

JH(OH)

HO-

H— C— OH

HO-

-1

H— C— OH

—OH

H-

-C

HO— C— H
CH,-OH

HO— C— H
CHt OH

HO— C— H
CH,.OH

HO-

i H

1
CHj-OH

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 :

H-C-
HO-

2OH

>-C.H

CH8C

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, C12H22O12.
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, C12H22O12 ; 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 CH2-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
CH2'OMe

2:3:6-
Trimethylglucoie

6 CH2-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).

B
COOH

CH-OMe

IH-OMe

iH-OMe
:H-OMe

CH2-

OMe

:H-OMe

OMe

Til

CH(OH)

;H(OH) 1

:H-OMe
:H-OMe O

CH-OMe
CH-OMe

CHj-

OMe
IV

COOH

CH-OMe
CH-OMe
CH-OH
CH-OMe
CH2-OMe
V

CO-

•OMe
CH-OMe

CH-OMe
CH2-OMe

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.

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 0 -3 /: * • ^.11
r J \2:3:6-trimethylglucose.

TT ^ - , „ ,. (2:3:4:6-tetramethylglucose.
Heptamethylcellobiose \ ~ ~ , A . Ai 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 CH8 OH

Melibiose and Gentiobiose

CH:

CH-OMe

OMe
OMe

CHa OMe

CH-(
CH-C

COOH

I
CH'OMe

I
O CH OMe

CH OMe
CH OMe

L— CHa
Octamethylbionic acid

CH(OH) 1
CH-OMe
CH-OMe 0

COOH
CH-OMe
CH-OMe

CH-OMe

CH '
CHa- 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— 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

CHa-OMe CH,

Octamethylsucrose

•OMe

Sucrose itself is represented by a formula corresponding with
that of its octamethyl derivative.

Octamethylsucrose, [a]D4-67°, 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 CHa.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 CHa • 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).

{

CHBr-
IH-OAc
OAc

:H-OAC
I

CH-

CHa-

OAc

CH(OAc)
CH-OAc
CH-OAc O
CH-OAc

CHj-OH

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) :

C7H1406+2HI04 - C6H1005+H.COOH-f2HI03+H20,

CH(OMe)
CH-OH

CH(OMe)
CHO

"V f

CH-OH (

3 C

4
5
6

CH-OH

PIT

CHO

CH,-OH CH,-OH

CH(OMe)
O— CO

O— CO
CH-

CH.-OH

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-
CH2-OH

III

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, C6H11O5-O'C6H4-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, C6H5-CH(CN)-O-C12H21O10, 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 • CflH10O5 • H!K> • CflH10O6 • HlSb • C6H10O6 • iTSo - C6H10O5 • H etc.

If, then, as seems very probable, the polysaccharides are open
chain compounds, their empirical formulae will approach the more
nearly to C6H10O5, 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, (C6H1005)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, (C6H7O6Me3)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 C6H8O5Ac2, 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, (C6H8O6)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, C6H10O7, 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, C6H10O7 (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» QH2-OP

CHo-OP

CH»OP
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) :

CH2-OP CH2-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.

CHa-OP CHa-OP CH2-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).

CH2-OH CHa CH3 CH3

I (/) II to) I (h) \

CH'OP > C-OP » CO (+ ATP) > CHO

| I + ADP I

COOH COOH COOH CO2

| + Co,2H > T +Co.

CHO CH2-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
C6H1206 - 2C2H5-OHH-2C02

C6H120« — +

Glycerol
C6H12Oe - C3H8O3+CO2+CH3.CHO

H,N

N-C

•Nk

CH2«OP
2 CH-OH
CHO

;H2-OP
H-OH
CHO

/ \

;H2-OP
H-OH
COOH

CH2.OP CH2-OP
CH-OH CH-OH
COOH CH2-OH

i IHOH

QH3
2 1 +2C02
CHO

CHO 2 CH-OH
CH2 OH

CH2-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

2C6H1206+H20 - 2C3H803+2CO*
+ CH3 - COOH-f C2H5 • OH

CH2-OP

2C6Hi2O6 — » 4 CH-OH
CHO

:iH2.op

CH2-OP

2 C

:H-OH

2 CH-OH

:OOH

CH2-OH

2 1

%2C02

CH2 OH

:HO

2 CH OH
CH2-OH

?H3

CHa

COOH

CH2-OH

Butyric Acid, Butyl Alcohol
and Acetone

2CH3-CHO
CH3 • CH(OH) • CH2 • CHO

CH3-CH:CH-CHO

CH3.CH2.CH2-CHO

/ \

C3H7 • COOH C3H7 CH2 • OH
2CH3-CHO

2 CH3- COOH-f 2H2

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-CH2.COOH

CH3 CO-CH3+C02

[•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, C10H16. 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, C10H16, obtained from plants, and certain
related isomerides, which have been prepared synthetically, are
classed together as (true) terpenes. Other types of naturally-
occurring hydrocarbons, (C6H8)n related to the terpenes, C10H16,
are classed as sesquiterpenes, C15H24, or polyterpenes, (C5H8)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, |C10H16

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, C10H16,
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 2Br2 or
with 2HBr. Limonene, terpinolene, phellandrene, syl-
vestrene.

II. Dicyclic mono-olefinic terpenes, which combine with Br2 or
with HBr. Pinene, camphene, bornylene.

Many other members of each of these types, as well as a few
open chain terpenes, C10H]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), C10H14 ; ^>-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, C10H20,
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,
C10H18, or p-menthadienes, C10H16, 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 :

7CH3

rw 8 w r rw 3

C/CH* $ H2C^C/CHV

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 CH3 CH3 ^^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 CH3 — group is shown merely by a line
a — CH2C1, — CH2-OH, —COOH, etc., are usually shown in full.

Limonene and its Derivatives

Limonene, C10H16 (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 C10H17C1,1 but in
the presence of water it unites with two molecules of hydrogen
chloride or bromide, and the crystalline products, limonene di-
hydrochloride, C10H18C12 and limonene dihydrobromide, C10H18Br2,
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, C10H16Br4, 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 C10H16,HC1, C10H16,2HC1, 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, C10Hi6ONCl (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, C10H18O, 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 :

« -Terpineol Trihydroxy-

hexahydrocymene

Terpenylic acid

Homoterpenylmethyl ketone *

HOOC

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.CH2.COOEt + 2CH2I.CH2.COOEt + 2NaOEt =
CN.C(COOEt)(CH2.CH2.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

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) :

,S03H

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, C10H20O2 (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,
C10H20O2,H2O, 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.

Cineole

Cineole, C10H18O, 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-menthadieney (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

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

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, C10H]8O (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, C10H19-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 NH2) 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, C10H10-NH2, 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, C10H18O (A-4(8)-p-w£n*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, C10H14O (&-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, C10H16, 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,lt3-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, C10H16, 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, C10H]6Br2, 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 C10H17C1 ; 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 , C10H16ONC1, 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, C10H16(OH)2, which, treated with dilute mineral acids,
is converted into pinol, C10H16O.

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 acid1 (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

HOOCN

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 — CH3,

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— CH2 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, C10H16O, 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 — CH2 — 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 --CH2— 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, C10H16O4, which was easily
converted into its anhydride ; on further oxidation, this dicarboxylic
acid gave a tricarboxylic acid, camphoronic acid, C9H14O6, 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.

:H2-COOEt ^ COOEt

COOEt ' ^ — v

I ' +
COOEt

CH2-COOEt

COOEt

oCx

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

H«t. I CU ri2C I CUUii H2C | COOH

CMe2 ^O | CMe2 | CMe2

, I XCH2 H2C^ I ^CH2 -CN H2CX KCH2-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, C10H16O4 (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, C9H14O6 (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) :

CH3 CH3 CH3

H2CX H2CX I XOH H2C^ PCOOH

I CBrMe2 -> I CMe2 -+ I CMe2

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-sulphon£c acids,
C10H14OX-SO3H, 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, C10H14OX2, obtained from the sulphonyl
halides, C10HUOX-SO2X, 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, C10H17- 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, C10H17-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, C10H10, 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, C10H16, 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, C10H17C1, 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 camphaney 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,

2C10H16 = C10H14 -h C10H18.

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,
C10H16, various other classes of terpenes are known, namely open
chain terpenes, C10H16 (p. 940), and sesquiterpenes, C15H24 (p. 943),
as well as numerous 'derivatives of each type. All the parent hydro-
carbons have the empirical formula C5H8, 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).

CH3

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

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, C10H16, are known, but
many of their derivatives occur in essential oils and are of com-
mercial importance in the perfume industry.

Myrcene, C10H16 (b.p. 166°), occurs in bay oil and ocimene,
C10H16 (b.p. 177°), in the oil of Ocimum basilicwn ; both are open
chain tri-olefinic terpenes and are respectively represented by the
following formulae :

CH3 CH2

CH3.C:CH-CH2-CH2-C-CH:CH2

Myrcene

r i -

CH2:C.CH2.CH2.CH:C.CH:CH2

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, C10H16O, 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, C10H18O, 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,

CH2-OH k. CH2-OH

Nerol

Linalool, C10H18O, 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, C10H16O2, 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
CH3 =

The aldehyde, C10H14O, formed according to (n), might undergo
reduction, first to citral, C10H16O, and then to nerol, C10H18O, 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, C15H24, 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, C16H24, is an example of an open chain sesquiterpene;
it is formed by the dehydration of farnesol, C15H26O, 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, C16H24, 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, C15H18, 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, C15H24, 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, Ci6H24, 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 C15H26O, is a mixture of structural isomerides, which
may be regarded as derived from cadinene by the addition of the
elements of water.

Selinene, C16H24, 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, C14HW, 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 :

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 C15H26O, 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 :

III

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 :

CH2C1

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 ether1 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 :

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, C30H60, 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, C20H32, of which abietic acid may be taken as typical.

Abietic acid, C20H30O2, is laevorotatory and melts at 173°.
When it is dehydrogenated with sulphur or palladium-charcoal it
yields retene (l-methyl-7-wopropylphenanthrene), C18H18, and
when it is hydrogenated it gives a mixture of tetrahydroabietic
acids ; on oxidation with permanganate it is converted into two
isomeric tetrahydroxy-acids, C19H29(OH)4COOH ; 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

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 :

XCOOH

,COOH

III

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,
CR3-COOH ; moreover, if the carboxyl is converted into a methyl-
group by the following series of changes (compare p. 954) :

— COOEt — > — CH2OH

— CHO

— CH:N-NHa — > — CH3,

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, C6H3(OMe)(OH).CHO[OMe:OH = 3:4], for example,
which occurs in vanilla pods, was prepared by Tiemann and Haar-
mann from coniferin, C16H22Og,2H2O, which occurs in the sap of
various coniferae ; this compound is a phenolic glucosidc of coniferyl
alcohol, C6H3(OMe)(OH).CH:CH.CH2.OH, and, on oxidation,
gives glucovanillin (the group — CH:CH'CH2-OH being converted
into — CHO) ; this product is hydrolysed by acids, yielding vanillin
and glucose. Vanillin is now manufactured from eugenol,
C6H3(OMe)(OH).CH2.CH:CH2[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.

CH2 <> C6H3 - CHO CH2 <> C6H3 - CH2 - CH:CH2

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, C6H4(CH3) • CMe8,
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
C13H20O, but in the light of later experiments it seems more probable
that the molecular formula is C14H22O and that it is a mixture of
isomerides, (la) and (ib).

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

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, C16H18, 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, C16H26 ; 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,
C16H22O> 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.

When its hydrazone is heated with sodium ethoxide and alcohol
(Wolff-Kishner method),

> C=N - NH2 - > CH2+Na,

OPEN CHAIN TERPENES AND SESQUITERPENES 955

it gives a hydrocarbon, C16H24, 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.
Azuleney C10H8, 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

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 :

C6H5.OH-fCH20 > HO-CflH4.CH2.OH,

2HO.C6H4-CH2.OH + HO-C8H4.CH2.C6H3(OH).CH2.OH.

As this last compound, like saligenin, contains a — CH2-OH
group and a C6H4 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 • C6H4 - CH2 C6H3(OH) • CHa C«H3(OH) - CH2 j C«H4 • 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
— CH2 — 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,H2(OH) - CHa • C«Ha(OH) • CHa • C6H2(OH) - CH2 - C«H2(OH)

CH2

«a
CHa

a • C6

C«H2(OH) • CHa • C6Ha(OH) • CHa • C«H2(OH) - CH2 • C6H2(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,

CH2O+NH2-CO-NH2 - NHa.CO-NH.CH2-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,

NHa-CO-NH-CHa NH-CO-NH.CHa NH-CO.NH.CH2 NH.CO-NH2;

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 - [CH2]4 • CO - NH JCHJ. • NH \ CO - [CH2]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 CHa - CH(OH) • CHa - O - CO - C6H4 • CO - O CH2 - CH(OH) - CHa - 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,

CH2:CHa+H-CH:CHa = CH3.CH2.CH:CHa,

CH8-CH2.CH:CH2+H-CH:CHa = CH3-CH2-CH2.CH2.CH:CH2.

Straight chain molecules of high molecular weight which have the
structure, CH3.CH2.[CH2-CH2]n.CH:CH2, 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 [CH2]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,
CMe2:CH2, in a similar manner ; they consist of units — CMe2 • CH2 —
and resemble the paraffins in their chemical behaviour.

PLASTICS AND RUBBER 961

Styrene (phenylethylene, vinylbenzene), C6H5-CH:CH2, under-
goes ethylenic polymerisation, in which the phenyl group takes no
part and gives a resinous plastic, polystyrene, composed of units
— CH2-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, CH2:CHC1, and
vinylidene dichloride, CH2:CC12, also polymerise in the same way
as ethylenic hydrocarbons, giving linear products composed of
the units — CH2-CHC1— and — CH2-CC12— respectively.

Vinyl acetate, CH2:CH-O-CO-CH3, is also a source of various
plastics : by the usual ethylenic polymerisation it gives polyvinyl
acetate, a product composed of units — CH2 • CH(O • CO • CH3) — ;
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),

CH2.CH(OH).CHa-CH(OH) - -•• CHa • CH • CH2 • 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== CH3), and butyraldehyde, polyvinyl butyral (Butvar, R= C3H7).
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 —CH2 - CH(COOEt)— and — CH2 - 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) :

CHa - CHC1 • CH2 • CH CHa • CMe - CH2 • 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) :

CHa.CH:CH-CH, CHa-CCl:CH-CHa •

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, C6H10O5 (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, SiR3-O- SiR3, only, but the diols, SiR2(OH)2, afford complex
mixtures of both types,

HO . SiR2 - [O • SiR2]n • O - SiR2 • OH SiR2 < ;

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, C5H8, but its molecular
formula is not known. It gives with hydrogen bromide a compound,
(C5H9Br)n, and with bromine, (C5H8Br2)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, C10H16,O3,O3 ; 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— CHa
3-(f CH

CH3-( CH CHa-OC

"HC j>C

H£— CHa

CH, OHC CO-CH,

H20-CH2

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 :

CH2 - CH:C • CH2— CH2 • CH:C • CH2— CH2 - CH:C - CH2

CH3 CH3 CH3

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, (C6H10)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, (C5H10)n ; the most complex component
of this mixture has a molecular formula of C60H100, 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) :

CH2:CH C:CH2 CH2.CH-C:CH2 CH2:CH-C:CH2 Isoprene

CH3 ins (^Ha I t

- CH2-CH2 C:CH CHjrCH2-C:CH CHa-CH2-C:CH Rubber

CH3 CH3 CH3

CH2-CH2 CH CH2 CH2 CH2 CH-CHa CH»-CH2 CH-CH2 • Hydrocaoutchouc

CH3 CH3 CH3

CH3-CH2-C:CH2 CH3-CH2-C:CH2 CH3-CH2-C:CH2 0-Methylbutene

CH3 CH3 CH3

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, C10H16,O3,O3, unless it is a dimeride of an ozonide,
C5H8,08.

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 —

— CH2-CH:CH-CH2— CH2-CH:CH-CH2— > COOH-CH2 CHa-COOH

Dimethylbutadiene rubber —

— CH2-CMe:CMe-CH2— CH2 CMerCMe CHa— >• COMe CHa-CHa-COMe

Natural rubber —

— CHa-CH:CMe-CH2— CH2 CH:CMe CH2— ». COMe-CH2 CH2-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, CH2:CH-CH:CH2, (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 :

(CH3.CH2.CHC1.CH2C1

CH3-CH2.CH2.CH2C1 — > JcH8.CHCi.CH2.CH2Cl

tCH2Cl-CH2.CHa.CH2Cl

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,

CH3-CH(OH)-CH2-CHO » CHs-CH(OH)-CH2-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,

2C2H2 — * CH2:CH.C;CH — > CH2:CH-CH:CH2.

(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, CH2:CH • CC1:CH2 (chloroprene), is obtained
on the large scale by treating vinylacetylene with hydrochloric acid
under particular conditions,

CH • C . CH:CH2-hHCl = CH2:CC1 - CH:CH2.

Isoprene, CH2:CMe • CH:CH2 (2-methylbutadiene)yboih 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

H2C. 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 :

CH3 • CH • CHa • NHa CH3 - CH • CH2 • NMe3 - OH CH3 - C:CHa

CH.-CHa.NH, ~~" CHa-CH2.NMe3-OH """" CH:CHa

(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,

CH3

HC'

CH,

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, C40H56, 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* C40H82, 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 :

2Me2C=, =CMe • CH2 • CH2 • 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, C32H42O (1 mol.), and the latter is further
broken down into methylheptenone (1 mol.) and bixin dialdehyde,
C24H28O2 (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 (C24) 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,
C40H82, 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,
C2oH28, united together symmetrically, although lycopene, unlike
terpenes, could not be formed by the mere polymerisation of
isoprene.

Burin, C25H30O4, occurs in Bixa orellana and crystallises in
violet needles, m.p. 198° ; on hydrolysis it gives methyl alcohol and
norbtxin (footnote, p. 926), C24H28O4, 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

BrH2C

11 HOOC \S v \s v cOOH

I** ,x"v y~v x"v x"v >x^. —— •»-•— ^ ^-^ ^. ^ ^--^ ^-^ ^L.UUJit

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

C22H44 COOMe C44H88 COOMe C(OH)Mea CHMea

COOK ! C22H44 2 COOH 3 C44H88 4 C44H88 6 C44H88

COOK " C22H41 * COOH ' C44H88 * C44H88 ' C44H88

C22H44 COOMe C44H88 COOMe C(OH)Mea CHMea

COOMe COOMe

1 and 3. Electrolysis (Kolbe reaction). 2. Partial hydrolysis. 4. MeMgl. 5. HI.

Crocetin, C2oH24O4, 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-CH2-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-CHa-COOH — * R-CHBr-COOH - > R-CH(OH)-COOH — *
R-CH(OH)- COOMe - > R-CH(OH)-C(OH)Me2 - *
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, C24H48O4,
loses four — CH2 — groups (two at each end of the structure) and
gives perhydrocrocetin, C20H40O4.

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'

Carotene, C40H56, 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, C40H78 ; 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

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, C2oH30O, 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) :

,CH2-OH

Vitamin A

:H2-OH HO-H2C:

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

(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) :

CH2-OH -» BrMg,v Jx CH2-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 >C»OH
group.

980 CAROTENOIDS, PYRONES,

VI VII

Vitamin A2 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,C6H5 - CH:CH - CH:CH - CH:CH - C6H5,
has been prepared in many different ways ; it can be obtained from
cinnamic aldehyde, which on reduction is converted into hydro-
cinnamoin,

C6H5 - CH:CH - CH(OH) - CH(OH) - CHrCH - C6H5,

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 2H2O, are eliminated :

C6H5 - CH:CH - CHO H2C CH2 OCH • CHrCH - C6H6

COOH COOH

Instead of cinnamic aldehyde, its condensation product with
acetaldehyde, C6H5- CHrCH • CHrCH • CHO or crotonaldehyde,
C6H5- CHrCH- CHrCH • CHrCH • CHO, may be employed; the
former, with succinic acid, gives C6H5-[CH:CH]6-C6H5, and the
latter, C6H5-[CH:CH]8.C6H5 (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 C6H5-CH:CH—
groups become C6H5-CH2 — 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 C6H5-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 Hf '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,

xH H

^Nx-^° HCvN^*OH

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-
„.

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,

EtOOC«CHa CH2«COOE^ fitOOC«HC CH»COOEt HC

-CH2 OVCOOEt fitOOC-HCCH-COOEt HC
II -* | | -> H

Me-CO CO'Me Me-OC CO-Me Me-C C«Me

Dimethylpyrone can also be obtained from dehydracetic add,
C8H8O4, 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^ H2C' ^CH*

3 CH3-OC CO-CH3

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, C7H8O2,HC1, and
the oxalate, (C7H8O2)2,C2H2O4 ; 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 methiodidey C7H8O2, Mel, corresponding with the hydro-
chloride, is transformed into methoxylutidine, (n), by treatment with
ammonium carbonate in the cold :

OH 9Me

[tf
CH3-

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
Me2O,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

[' -> HH NH

••COOEt EtOOC-C C«COOEt
HO

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

1 Ethyl sodioacetoacetate is condensed with o-nitrobenzoyl chloride,
and the product, NO2-C6H4.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

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.

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 :

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 :

CH3O

'CH3

EtOOC«C6H6
OCH3

CH3O

C6Hft

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,

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

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-dihydroxybenzaldehyde9 (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

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

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*C6H70(OAc)4

OAc

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),

and the product, (x), is converted into the anthocyanin salt, pelar-
gonin chloride, by successive treatment with cold alkali and acid,

C6HU05-0

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 0 OH H

Rutin (R = Ci2H2iO9) 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 :

C«H4(OH)a - > CH2C1.CO-C6H3(OH)2 - » AcO-CH2.CO-C6H3(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-C«H5 - > HO-C6H4.CO.CHaCl - ••

HO-CeH4.CO-CHa-OAc - * AcO-C,H4.CO-CHa.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-C6H4-O-CO-C6H4.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 - C6H4 - O . [CO • C6H4 - O]n - CO • C6H4 - 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-C6H4.COOH n MeO-CO.O.C6H4.COCl
m MeO-CO.O.C6H4.CO-O.C6H4.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 - CeH4 - COC1 + 2NHa - CHa - COOEt «
MeO - CO • O • C6H4 • CO - NH • CHa - COOEt + HC1,NH, • CHa - 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 CHa

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 :

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)C6H3.CO.O.C6H4.CO.O.C6H4.CO.O.C6H4.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)C6H3 - CO - O • C6H4 - COC1
ii HO.C6HrCO-O.C6H4.COOH

The chief natural sources of the depsides so far discovered are
the lichens ; lecanoric acid, C16H14O7, for example, occurs in
Roccella and Lecanora, and evernic acid, C17H16O7, together with
orsellinic acid, in Evernia prunastri. The constitutions of these
acids have been established by the following syntheses :

Orcinol, C6H3(CH3)(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

CH3

MeO-OCO(

~~"O«CO-OMe
I II III

* Vanillic acid is CeH8(COpH)(OCH8) - OH[OCH3: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

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

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,

C0H12O6+5C6H2(O-CO2Me)3COCl >

C6H7O[O CO C6H2(O-CO2Me)3]5 * C6H7O[O-CO-C6H2(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^

C12H1302(:N2HC6H J)2[O - CO - C6H2(O • CO - C6H5)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, C8II8, 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) :

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 :

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 C6H5-A (A = halogen) or C6H5-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 CH3 or the O of an NO2. 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 — CH8 —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, C6H5X, 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 CH2=CC1 — CH3,
for example, is very resistant to double decomposition compared
with that in CH2=CH — CH2Cl. 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, C6H5X, 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 NO2 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 — NO2,
— SO3H, and — COOII, which are w-orientating, might be regarded
as electro-negative (or acidic) because they occurred in the anions
of acids : _ + _ + _ +

NO3H, SO4H2, R-COOH.

The basic group, — NH2, which is op-orientating, was then con-
sidered to be electro-positive, and by implication or otherwise the
halogens, — OH, — CH3, 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 — NH2, — OH, — OMe, — CH3 and the halogens ;

m-Orientating — NO2, —CO -OH, — SO2-OH.

+ -+-

He argued that nitric acid should be represented by HONO2,
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 :

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 H2O.
Consequently the positive substituent, NO2-— , causes w-, whereas
the negative substituent, NH2— , 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, — NMe3
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*NO2, HO-SO3H,
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+, NO2+, HSO3+, CH3-CO, Ph-N2+,
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 : —

C6H6fBr+=C6H5Br+H+,
C6H6+N02+ = C6H5 -N02+H+,

C.HI+HSO.+ = c6H5-so3H+H+,

C6H6-hCH3 -CO+ = C6H5 -CO -CH3+H+,

Me2N -C6H5+Ph -N2+ = Me2N -CeH4 -N2 -Ph+H+,

The evidence for nitration being effected by the nitronium ion,
NO2+, 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,

HN03+2H2S04 ^ N02++ H3O++2HSO4- ;

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 NO2+ 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, A1C14~~, FeCl3Br~, or by forming complexes with one of the
reactants, RA1C14.

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),

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'NMe3+,
Ph«PMe3+, Ph-AsMe3+, 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

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— BT

XIV

A— B

XVI

A— B

XVII

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, C6H5'CH:CH2, 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-CH3 op-

(2) Ph— >— A Ph-NMe3X m-

(3) Ph-^A Ph-OH op-
(4a) Ph-^A^B Ph-CH:CH2 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, -+NO2~ and -+SO2--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,

C6H5 -CH3 C6H5 -CH2C1 C6H5 -CHC12 C6H5 -CC13
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 -NMe3X Ph -CH2 -NMe3X Ph -CH2 -CH2 -NMe3X
100 88 19

Ph -CH2 -CH2 -CH2 -NMe3X
5

Ph -N0a Ph -CH2 -NO2 Ph -CH2 -CH2 -NO2
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 *NO2 ; 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),

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 SN1
and SN2 reactions are made difficult as in the vinyl compounds.

III

When electron-attracting groups such as NO2 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 SN2 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+H3C -C6H3(N02)2 = Ph -CH:CH -C6H3(NO2)2+H2O ;

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,

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, C6H4X2 or C6H4XY, 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, C6H3XYZ, 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,
C6H3(NH2)(NO2)-CH3; 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 CH3:NH2:NH2, CH3:OH:NO2, and CH3:C1:NO2, 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, C6H3XYZ, is displaced by hydrogen ; the
product, C6H4YZ, 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, C6H3XYZ, is then displaced by
hydrogen, and, as before, the product, C6H4XZ, 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, C6H4XY, is
established.

A compound, C6H3(NH2)(NO2)-CH3, for example, might be
first converted into C6H4(NO2) - CH3 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 :

CH3

NO2

CH8 CH3 CH3

^N0j i^HQ, f

JNH, NH^ }> U^J^NOj

VII

VIII

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 — NH2 and — NO2 groups. For this purpose the
— NH2 group might be displaced by bromine, and the product
oxidised to the acid, CflH3Br(NO2)-COOH, which is then reduced
to C6H3Br(NH2) • COOH with stannous chloride and hydrochloric
acid ; this compound, heated with soda-lime, might give either
o- or ^-bromoaniline, p. 1022). The relative positions, CH3:NO2,
CH3:NH2, and NO2:NH2, 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,

NO2

N02

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,
CftH3Cl(NO2) • 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, C6H3Me(NO2)2, would be possible in
that way, because one of the nitro-groups may be reduced, leaving
the other unchanged, and a compound, C6H3XYZ, 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 — NH2 or — NO2 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 :

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

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

HOOC

COOH

HOOC

H2C

CH2

H2C

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

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 (RO2), 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, C6H5-C6H4-C6H5, is
formed when a mixture of />-dibromobenzene and bromobenzene
is heated with sodium, and quaterphenyl, C6H5-C6H4 -C6H4-C6H5,
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, C6H5 • C6H4 • C6H4 • C6H4 - C6H5, is prepared from
a mixture of 4-iodoterphenyl and 4-iododiphenyl with the aid of
silver at high temperatures, whereas sexiphenyl^ C6H5 • [C6H4]4 • C6H5
(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, CH3 • C6H4 • [C?H4] t - C6H4 • CH3,
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 SHii»hb<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 :

C6H6

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*HCv £H-CeH» -» C6H5.C6H4.C6H4-C6H5

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) :

H2O

(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

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. :

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, CHMe2, or OMe, gives (ix) :

POLYCYCLIC HYDROCARBONS

COOH

1031

COOH

VIII

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;

^sX^^

Org.65

1032 THE ORIENTATION OF BENZENE DERIVATIVES

In the first case acetyl-A-1-ryc/ohexene1 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) :

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,

CH3.CO-CHa+CH2Of Et2NH,HCl -

CH3-CO-CH2.CH2.NEt2,HCl+H2O :

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

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 :

,CH2Br

COOEt

III

COOEt

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-CH2'CH2«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 :

C10H,

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 :

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 :

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, C2H5Na, 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+(C2H5)2O = RH+C2H4f C2H5-ONa.

The corresponding lithium alkyi compounds, with the exception
of lithium methyl, are soluble in petroleum and benzene without
decomposition. Lithium ethyl, C2H5Li, 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,

C6H5.CH2Na+NMe4Cl = NMe4.CH2-C6H5+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) CMe2PhK, 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,

CMe2Ph-OCH3+2K = CMe2PhK+CH3.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,

CeH5.CHK-CH2-CMe2Ph and C6H5 - CHK - CHPh - CMe2Ph.

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 C4H9 • CH2-CLi(C6H5)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,
C4H9.CH2.C(C6H5)2.COOH.

A potassium derivative of triphenylmethyl (p. 1040) is obtained
by treating triphenylmethane with potassamide in liquid ammonia,

Ph3CH+KNH2 = Ph3CK+NH3.

Sodium and potassium combine with certain olefinic compounds,
giving either a simple additive product or a compound formed from
two molecules of the olefine :

Ph2C:CPh2+2Na = Ph2CNa-CNaPh2,
2Ph2C:CH2+2Na - Ph2CNa • CH2 - CH2 - CNaPh2.
The second type of reaction occurs in two stages, as shown,

Ph2CNa-CH2Na+Ph2C:CH2 = Ph2CNa-CH2.CH2.CNaPh2.
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 :

MeaC:CHy

2 >C:CH2+2Na »

MeaCrCH/

MeaC:CHx yCH:CMea

/ CNa - CH2 - CH, - CNa<"
H/ NCH: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 :

Ph2CNa-CNaPh24-2CH3I = Ph2C:CPh2+C2H6+2NaI,

Ph2CNa.CH2.CH2.CNaPh2+2CH3I =

Ph2C(CH3) - CH2 - CH2 - C(CH3)Ph2+ 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, Ph3C-O-O-CPh3,
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, Ph3C • NO and Ph3C • NO2 respectively ; with
sodium a red salt, sodium triphenylmethyl y Ph3C-Na, was produced,
and with concentrated hydrochloric acid, p-diphenylmethyltetra-
phenylmethane, Ph2CH - C6H4 • CPh3 (p. 1045).

This new type of highly reactive compound was named triphenyl-
methyl and represented by the formula, CPh3, because it seemed
that it could not be hexaphenylethane, CPh3 — CPh3. 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 ,

Ph3C-CPh3 T* 2Ph3C;

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,

Pri3C-CPh3 7-* 2Ph3C+ + 2e,
or that both cations and anions have been formed,

Ph3C-CPh3 ^! Ph3C+ + Ph3C-.

Triphenylmethyl halides similarly give conducting solutions in
sulphur dioxide, while triphenylmethyl anions are furnished by
sodium triphenylmethyl,

Ph3CNa ^ Ph3C- + Na+.

The triphenylmethyl complex can thus exist as an uncharged
radical, as a carbanion, or as a carbcation.

Tri-4-diphenylmethyl, (C6H6 • C6H4)3C, 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-nitrophenylmethyly (NO2 - C6H4)3C, 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-HCv CH-Ph Ph-C C-Ph

C XCX XCX

H2 H2 -h

I II III

Diphenyl-f$-naphthylmethyly Ph2(C10H7)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/. Ph3C-CPh2, 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),

2Ph3CNa+Ph2CCl2 = Ph3C.CPh2-CPh3+2NaCl ;

on evaporation, the solution gives a mixture of pentaphcnylethyl
(golden yellow crystals) and hexaphenyle thane (triphenylmethyl).

Many iiiiii1(M^-li> 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, SiPh2Cl2, in
toluene is heated with sodium, various compounds are formed ;

FREE RADICALS AND STERIC HINDRANCE 1043

among others two crystalline substances of the composition, (SiPha)n.
One of these is relatively very stable, and gives cryoscopic results
which correspond with those required for an octaphenylcyclosilico-
tetrane, Si4Ph8 ; 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, Si4Ph8I2, it is regarded as an octaphenylsilico-
tetrane, SiPh2-SiPh2-SiPh2-SiPh2, 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,
Si4Ph8O2, Si4Ph8O, 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, (CH3)3Sn, which, in
more concentrated solutions, gives ' bimolecular ' hexamethyl-
dislannane, (CH3)3Sn • Sn(CH3)3. The compound combines with
chlorine, giving trimethylstannic chloride , and with sodium, yielding
sodium trimethyltin, (CH3)3SnNa. 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,
(C6H3Me2)3Pb • Pb(C6H3Me2)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(C6H3Me2)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(CflHn)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, NPh2-NO, it was concluded that the solution contained
a free radical :

Ph2N.NPh2 ;H 2Ph2N.

1044 ALKALI METAL COMPOUNDS

Tetra-anisylhydrazine, (MeO - C6H4)2N • N(C6H4 - OMe)2, and tetra-
p-dimethylaminophenylhydraztne, (Me2N • C6H4)2N • N(C6H4 • NMe2)2,
also dissociate in solution but to a rather larger extent.

Hexaphenyltetrazane, Ph2N - NPh • NPh - NPh2, gives dark blue
solutions the colour of which increases when they are warmed or
diluted ; with nitric oxide it gives nitrosotriphenylhydrazine,
Ph2N-NPh-NO. It is inferred from these facts that the tetrazane
dissociates, giving 2Ph2N-NPh.

Diphenylpicrylhydrazyl, Ph2N-N-C6H(NO2)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,

2Ph2N.OH+Ag20 = 2Ph2NO+H20+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 0C

-» C6H4^ -* C6H

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

/ -» CMH/

Cl Cl Cl Cl

C14H

OH O 0—0

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 :

Ph2C

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,

Ph2N— O

Ph2N-*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, (C6H5)2CH-OH, and benzopinacol,
(C6H5)2C(OH).C(OH)(C6H5)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, CPh2Na-O-CPh2-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,
C6H5-C6H4-CO-C6H5, there is no change in the boiling-point,
although the potassium derivative, C6H5 - C6H4 - C(OK) - CeH6, is
produced. This compound is readily soluble in ether, and its
molecule, KO-CR2, 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,

2Ph2CONa 7-* Ph2C(ONa)-C(ONa)Ph2.

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-CR2-O'O-CRa-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,
R2C(OH), because the final products are a pinacol, or a ketone
and a secondary alcohol,

2R2C(OH) = R2C(OH).CR2.OH,
2R2C(OH) - R2CO+R2CH.OH.

FREE RADICALS AND STERIC HINDRANCE 1047

They react with methyl iodide,

2R2C(ONa)4 CH3I - R2C(ONa)l4-R2C(ONa).CH8,

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(CH3)4 7~* 4CH3+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, C6H3(CH3)2 • N(CH3)2, the
2:6-compound [NMe2 = 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:NH2:Bu^ = 1:2:5] readily gives a quaternary
salt, the isomeride [Me:NH2:Bu3 = 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, CeH3Me2-NMe2, for example, is more reactive
towards methyl iodide than is dimethyl-o-toluidine, C6H4Me • NMe2,
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,

Me2N - C6H4X+ CH2O - Me2N - C6H3X - CH2 - 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-
2tA: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,
C6H5.CO.C6H2(CH3)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(C6Hn)3-OH, but tetraphenylmethane, treated in the same way,
does not give tetraryc/ohexylmethane. Germanium tetrachloride and
phenyl IM.SJJMI ,<:um bromide give tetraphenylgermaney Ge(C6H6)4,
but the tetrachloride and cydohexyl magnesium bromide give tri-
cyclohexylchlorogermane, Ge(C6Hn)3Cl, 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(C6Hn)2*C6H5 ; on the
other hand, the bromide, SiBr(C6Hu)2-C6H6, 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 XC-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,

|-C NH8

CH|-C NH8 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,

H2C— NH EtOOC-CH EtOOC'HC— N

T „ / ^_ LL. ~~* „ I v.

Nv^ CH2

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

:cH2 + N2

N J&tOUC -HC'

Glyoxaline, (11), is formed by the condensation of glyoxal with
formaldehyde and ammonia,

CHO

CHO HC— NH

I + 2NH, 4- H-CHO -^ // \

CHO HCvN^H "

in a similar manner 1 :2-diketones give substituted glyoxalines,
R-

-CO

T
CO

-I- 2NM3 * 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,

H2C— NH2 H2C— NH H2C— NH

COOEt + HCNO -» EtOOC XCO -*• OCV ,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 :

H2N— CH2 HN— CH2

HCNS 4- CO-CH2«NH2 SCS CO'CH2'NH2

HN-CH _ ^ HN -CH

N C-CH2-NH2 ^HS-Qv XC-

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-

~~* >CH2-CCl(COOEt)a

N^ Nx

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

^ }>CH2-CHOCOOH 4x 1>CH2«CH(NH2)'COOH

XN 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 :

H2N 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 '

H2N
K=iCMe

N=CMe

1 VT« + H2N-CO«NH.NH«CO«NH,
iC ^ NH

^M^

Osotriazoles are produced by oxidising the osazones of (1:2-)
diketones and heating the products with dilute acid,

| - »» | | + H,0

Phc*NxNHPh phC^NxNPh

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=N»NHPh MeC=N«NHPh MeC=N

N3Ph *

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
H2N-C-NH-NH3 H2N-C-N3 HaN-C--NH H2N-C=N

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,

TOH \\H _ T~"

CHBr xCMe * HCN xCMe

HO 0'

Isoxazoles are produced from the monoximes of j8-diketones,

PhC-CH, Ph/C-Cf 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.,

H2C— NH HC— N

R'OC CO-R' ^ R-C C-R'

NSX

R-CO H2Nv 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 + 2H2O

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,

^CXNH

T ^ -

R R R

Maleic anhydride and hydrazine yield diketotetrahydropyridazine,

Hr^CO „ X ^IMH

flv* \ Iili2 ill-' INri

II 0+1 > H I + H20

Hr» / Krur ur» Wru

V.«^PQ nri2 riL.^ ^WJtl

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 OCX

' 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

ri2 »* jn2

OC' COOEt OC' ^CO OC' HO-C;CH3 OC' ^C-CH3

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 H2 H

HO.C-CH3 CH3.C^NxC-CH3 OC' CH2 ^ OC'CH,'

JH "* L,JH H2N ^ HN CH,

COOEt 6H 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"^ HNVC^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 9H

H^ - L

f *-

NH2 &H2 NH2 NH2

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,

HjC^1^ CO-Me
Me-OC XCH2
H2

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- 2H20

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, C9HUO4N2SR, 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 — CH2 - CH:CH • CH2 - CH,

Penicillin-II G-penicillin — CH2 - CeH6

Penicillin-Ill X-penicillin — CH2 • C6H4 - 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

™ /"?""?0

McaC || + H2O = Me2C

XS-g— CH-NH.CO.R VSJJ

Penicillins Penicillamine

C02 + OCH*CHa-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 — CH2- C6H6 :

COOH

^"-R COOMc _^ COOMe ^

62 \ ^.C— CH'NH»CO*CH2*Ph OCH-CH-NH«CO-CH2«Ph

Methyl penaldate-II
COOH

I3-CH.]

CH3 • CH • NH - CO - CH8 - C.HU

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-CO«NH*CH< > R-CO-NH-CHj-CHO + CO2

When the penicillins are treated with alkali, salts of dicarboxylic
acids, penicilloic acids , are formed ; these dicarboxylic acids have
been synthesised,

COOH COONa

9C^N— CO ^^N COONa

Me,C I I +2NaOH=Me2C I I + HaO

XS^C— CH«NH'CO«R Ns— 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,
C16H2oO4N2i 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 * Me2HC | I »

XS-~£"~ CH»NH*CO-CH2-Ph H2C— CH«NH-CO«CH2-Ph

Penicillin-II Desthiopenicillin-II

COOH

*/C*^N COOH
Me2HC | |

H2C— CH-NH«CO-CH2-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 "" Me2C

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 :

Me2C
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,

- C6H4 • CH(OH) • CH(NH - CO - CHC12) • CH2 - OH,

has been proved by synthesis : the presence of an aromatic nitro-
group in the molecule is noteworthy.

Streptomycin, C21H39O32N7, 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 B1? and various other components, referred to collectively
as the vitamin B2 complex.

Vitamin Bx, or aneurin, called thiamin in the U.S.A., is the anti-
beri-beri factor (p. 653), and is destroyed by heat.

The vitamin B2 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 B6, adermin) Meso'mositol (p. 798)

Pantothenic acid />-Aminobenzoic acid

Biotin (vitamin H) Folic acid (vitamin Bc ?)

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 B1, was first isolated in the crystalline state in
1926 in the form of its ' hydrochloride ' (Jansen and Donath), to
which the formula, C6H10ON2,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 C12H18ON4C12S,
could be quantitatively converted by sodium sulphite containing
sulphurous acid into an oily base, C6H9ONS, and a sulphonic acid,
C6H9O3N3S. 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 CO«Mc

CHNa-COOEt CH-COOEt — » CCl«COOEt I

CH2Br-CH2-OEt CHa • CHa -OEt CH2« CH2 •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=OCH2«CH2«OEt MeC=OCH2«CH2«OEt MeC=C-CH2«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 Bx in antineuritic action.

NH2 HO-HC HN— CH

\>CH,-OEt -» Me(^ V
EtOOc' V-CO

Me( +
NH

III IV

-» Me/~\CH2-OEt -*

N=4H2 N=/NH2

VI VH

QMe.
CH2-N
H2

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, C12H14ON4S, 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 H2
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 :

CH2*[CH -OH]3'CH2-OH CH2«[CH«OHJ3«CH2»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 :

CH2-[CH-OH]3.CH2'OH CH2-[CH'OH]3-CH2-OH

NH ^^ ^NH

Pyridoxin, (n) , previously called vitamin B6 or adermin, is the com-
ponent of the vitamin B4 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, C8HUO3N. 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 CH2-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),

CH2-OEt

H2C^ CH2«CN HC^^OCN

MeCO ^CO * MeC^ ^CO

H
III

CH2-OEt
MeV

1070 VITAMINS AND CONJUGATED PROTEINS

Pantothenic acid is the chick anti-dermatitis factor of the
vitamin B2 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), C6H10O3, 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 XC0 — * CH2(OH) • CMe, - CH(OH) • C(OH)Mef *

CH2(OH).CMea-CHO •> CH2(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 » CHa(OH)-CMe2-CHO *

CH2(OH) • CMe2 • 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,

CH2(OH) • CMe2 • CH(OH) • CO • NH • CH2 - CH2 • 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 1011. 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, CnH18O3N2S, is readily
hydrolysed to the acid, biotin, C10H]6O3N2S, 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, C9H18O2N2S, m.p. 186-190°, which is reconverted
into biotin by phosgene. Biotin, therefore, is a cyclic ureide :

>C-NH2 >C-NHX

+ COC1, — > >CO

>C-NH2 >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 — NH2 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

CO/™"! „„ |>C-(CH,),.COOH

Now the diamino-acid combines with phenanthraquinone to
give a substituted quinoxaline (p. 1060), so that the — NH2 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) :

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 CH2-CH2-CH2'CH2«

>C\ jT S
HN****'*'*""1"**/

oc; | s oc;

HN-^Xx

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 Bc, is probably
identical with the synthetic product, pteroylglutamic acid, shown
below :

COOH

Pteroylglutamic acid is beneficial in cases of pernicious anaemia.

Vitamin B12, 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 K2 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

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-

2 H-C OMe

3 H-C OMe T H £ OMe j H-<

4 H-C

5 CH2 OMe CH2 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-CH2-OH

OH
^CHj-OH

NH2

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(

CHa-OH

EiO
—
a -OH

I II

R - CBH4N5

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

H-

CH2

0-P08H,
I

OOH

U-C OH
H-C OH
H-C OH

CH20-P03H4

CH(OH)
H-C OH
H-C 0-P03H,
H-C-

CH2-OH
III

CH2 OH

:-OH

:-o.po8H§

:-OH

CH2 OH

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.

CH2:HC

HOOC-CH2-H2C H CH2-CH2'COOH
Haemin, I

VITAMINS AND CONJUGATED PROTEINS 1081

Protoporphyrin

(R - — CH:CH2 ; R' - — CH2-CH2 COOH)
Haematoporphyrin

(R -— CH(OH)-CH3; R' -— CHa-CH2 COOH)
Mcsoporphyrin

(R - —CHa CH3 ; R' •= — CH2-CH2-COOH)
Aetioporphyrin

(R = R' = —CHa CHa)
Porphin

(R » R' = II ; Me « H)
Deuteroporphyri n

(R = H ; R' - ~CH2 CH2 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)-CH3 groups and haematoporphyrin is formed,
whereas with hydriodic acid they are both reduced to — CH2-CH3,
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-CH2 -CH2 • 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 ( — CH2-CH2'COOH
instead of — -CH2-CH3 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 — CH3.

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,

e/— — *
OHC0M,

(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,

HN==\Br

HOOC-CH2-CH2 H CH2«CH3«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:CH2 -= 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, C66H72O6N4Mg, 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.

CH2:HC

Et H

HC— CO
COOMc

VII

HOOOCHjfCHj

VIII

8»)

lorophyll a (R - —Me)
Chlorophyll b (R - — CHO)

•: 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-CHa.CH(COOEt)a - » R.CHa-CHa.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 a6,1 the two hydrogen atoms in ring IV
being lost and the vinyl group reduced.

(b) Phaeoporphyrin a5 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 — CH2- COOMe, which condensed with
dichlorodimethyl ether in the presence of ferric chloride,

CH30-CHC12 HC—CHC1 HC— CHOH

>Mc COOMe COOMe

oxidation finally gives phaeoporphyrin 06 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, C33H36OflN4, 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, C27H46-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, C27H47-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, C29H47-OH, m.p. 170°, occurs in the soya and
calabar bean ; it is laevorotatory.

Ergosterol, C28H43-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), C27H47-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, C27H47-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, C27H48, by Clemmen sen's method ; choles-
terol, therefore, is tetracyclic, for, had it been an open chain
compound, it would have given a hydrocarbon, C27H56.

The procedure just given, by means of which a secondary alcohol
group, >CH-OH, is converted into >CH2 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
— CH2'CO— or — CH2-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 j1 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, C18H16, 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-dimethyl£yc/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

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, CH3-CO-CH2.CH2.CH2-CHMe2, 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.CH2-COOEt — > R.CH2.C(OH)Ph2 — >

R.CH:CPh2 — » R-COOH+COPh2

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)Ph2 ->

"O' "D*

*» RI Rv Rx

CtCPh2 -» CO + COPhj

R/ -n/

\ Rl

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
— CHMe2 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 - CH2 - CH2 • CH2 - CHMe2 Cholestane
\-CHMe • CH2 • CH2 - COOH ^/focholanic acid

\-CHMe • CH2 - 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* C27H44O (i, p. 1094), which is then
converted into coprostanol, C27H47 • 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, C27H48, 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 > CH2 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 ^
HOOOH2CT ^

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 — CH2 • CH2 • 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

III

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.

HO1

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
C27H45-OH

Ergosterol

Cholestanol

(Dihydrocholesterol)

Ergostanol

(Hexahydro-

ergosterol)

• 3-j8-Hydroxyfl//o-
cholanic acid 2

Wieland's
method

' 3-/?-Hydroxyw0ra//0-
cholanic acid 2

Stigmasterol
CMH47-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.

jB-Cholestanol

fl//o-serie8
Rings all trans

R - C8H17

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 D2, 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 C10
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, C28H61-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 — CH2 group in the vitamin), and the keto-acid shown below.

Other important decompositions are summarised in the following
scheme :

C9H17

Calciferol : C»Hn « 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 D3 (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 > CH2 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, C18H22O2, 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, C18H24O3, 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-CH2— , 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.

MeO

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 C17 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.

HO1

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 tf«g-dibenzanthracene, in which R = Me, Et, Pra, Pr^, etc. :

The most active compound is that in which R is Pra, 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, C19H30O2, 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

(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) :

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'CH3

:o«CH3

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

Me8N+Cl.CH2.COOEt+H2N.NH2 =

[Me3N - CH2 - CO - NH - NH2]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

:o«CHN2

CO«CH2«OAc

HO1

CO-CHa-OH

III

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.

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

CH2

CH-OH

CH3

Digitoxose

CHO

CH-OH

CH-OMe

CH-OH

CH3

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, C6H4XY, cannot be obtained
directly from certain mono-substitution products, C6H5X, 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,

NO2 > NH2 » N2X » 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 :

/CH3 /COOH

C6H5-CH3 — C6H/ — > C6H4<;

XS08H XS03H

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 NO2 — 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 NO2 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 NH2 — groups are op-orientating ; its preparation
by the following series of reactions might therefore be -•:.:•.:«•*"« <: :

/N02 /NO2 /NH,

C6H6 -* CflH4(N02)a -+ C6H/ --* C6H/ -+ C6H

XNH8 NOH 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 :

/CH3 /COOH

CeH/ " CeH/ *

XNOa XNO2

yCOOH /COOH /COOH

4NsNHt * 4NxN8X 6 4NxOH

1114 APPENDIX

The isomerides would probably be separated most easily as nitro-
benzoic acids.

2. Methods for the synthesis, or the complete synthesis1 of
compounds of a given structure, other than simple substitution
products of benzene, have often to be siim»r.-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) CHMe2 - N:CHPh, (b) CPhMe(O • COPh) • COOEt
(c) N(CH2.CH2.OH)3, (d) CMe3.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 CH2 <group would be
displaced rather than that of a CH3 — 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, CMe3-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 • CH2 • CH2 • CO • Me
and (b) CMe2:CH-CH2-CH3, and for a complete synthesis of
(c) CHMe2-CH2.CH2.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, — CH2-CO-CH3, 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 >CH2. 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, CMe2(OH)-CH2-CII2-CH3, 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, CH2:CMe-CH2-CH2-CH3, would be
formed in large proportions owing to the general inactivity of the
CH3 — in comparison with that of a CH2< 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
CHMe2 - CH2 . CH(OH) - CH,, C2H5 - CH(OH) - CH2 - CH2 • CH,,
CeH5.CH(6H)-CH2.CH3, CaH5.CHa.CMeI-OH, CMe2Ph-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, — CH2*NH2, — CH2-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 CMe2(CH2-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, — CH2-COOH,
however, is easily formed from — CH(COOH)2, a residue of malonic
acid, and the CH2< group of the latter is very reactive. The
required compound might therefore be obtained from acetone by
converting it into CMe2Br2 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

CMeaBra »• CMe^ *

XCH(COOKt),

/CH(COOII), ,CH,-COOH

CMe,/ * CMe/

XC11(COOH)2 XCH,-COOII

A further examination of the formula of the acid shows that
the molecule contains a residue of wovaleric acid united to a
— CH2-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, CMe2: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)2CH-CMe2-CH2.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 CMe2Br • CH2 • 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, C5HirOH, and
of the amines, C5H13N.'

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, C5HU-OH, arc derived from the pentanes,
C5H12, 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 CH3.CH2.ClVcH2-CH, H *JJa> CH-CH.-CH,

a' ft' V n' a<-H3a' V c'

III C(CH,)4

It is then obvious that from (i), three isomerides, 0, by 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, C5H13N, 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 br ;
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, C5H13, must consist of three radicals
which can only be CH3, CH3 and C3H7 or CH3, C2H6 and
C2H5; the group C3H7, however, may be either the normal or
tsopropyl group, so that there would be three tertiary bases.
Altogether, therefore, 17 compounds, C6H13N, 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, C6H5 — (C2H5O),
and the various isomerides of this class are first obtained by con-
sidering the possible arrangements of the group, — C2H5O. These
would be :

— CHa.CH2-OH — CH(OH)-CH3 — CH2-O-CH3 — OCHa-CH3

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 A9 CflH5 • C2H5, by displacing
a nuclear hydrogen atom by hydroxyl, or from B, C6H4(CH3)2, by
displacing side chain hydrogen by hydroxyl, or by interposing an
oxygen atom.

Now from A, o-, m-y and />-ethylphenols, C6H4Et-OH would be
obtained. From B, which may be cither o-, m-y or />-xylene, the
three corresponding xylcnols, CH3-C6H4-CH2-OH, may be
derived and also the three isomeric, o-, m-, and />-ethers,
CH3.C6HrOMe.

Lastly, if the compound is a tri-substitution product of benzene,
it must be represented by C6H3(CH3)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, C6H4*CH2-CH3 and C6H4(CII3)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, C9H8O3, which gives terephthalic acid on
oxidation ? '

APPENDIX 1121

As the substance must be a di-derivative of benzene containing
the group, C6H4<, the residue, C3H4O3, 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 C2H3O, namely —-CO - CH3 or — CH2-CIIO.

If A is — CHO, B is C2H:JO2, namely — CH2 • COOH,
— CH(OH).CHO, — CO-CH2.OH, or — COOC1I3.

If A is — CH2-OH, B is C2HO2, namely — CO-CIIO.

If A is — CH3, B is C2HO3, 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 C2H;JO2 it
might be written -CH2-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,
C7H7O2N, boiled with alkalis, gave a solution from which acids
liberated a compound, A, free from nitrogen. 0-207 g. of A gave
0462 g. CO2 and 0-081 g. of H2O ; 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, C7H6O3,
which requires C, 60-85, H, 4-35, 0, 34-8%. From the experimental
data the molecular weight of A is 111, and C7H6O3 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 C7H6O3 or C6H4(OH)-COOH. The acid, A,

1122 APPENDIX

therefore is o-, w-, or />-hydroxybenzoic acid and the original
compound, C7H7O2N, 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, CH2,
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 (CH2)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 Br2. The
molecular formula of the hydrocarbon, therefore, is C4H8, and, if
an olefine, its structure may be represented by one of the following
formulae :

CHa:CH-CH2.CH3 CH3-CH:CH-CH3 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,
CH3-CH(OH).CH(OH)-CH3, from (n) would probably give acetic
acid only, and a glycol, (CH3)2C(OH).CH2-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, CH3.CH(OH)-CH2.CH2.OH or CH3.CH(CH2.()H)2,
might be obtained and oxidised to acetic acid.

* 0-2 g. of a neutral compound gave 0-3521 g. CO2 and 0-072 g.
H2O. 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 C4H4O3. 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 C2H2O2, E = 58 ; its
molecular formula therefore is (C2H2O2)n and that of the acid is
(C2H3O2)W. As the original compound is (C4H4O3)W the molecular
formula of the acid is probably (C2H3O2)2 or CJI6O4, unless some
fission of the molecule has occurred ; this molecule would contain
two — COOH groups and may be written C2H4(COOH)2.

The acid is therefore either succinic or zsosuccinic acid, and since
it is obtained from a compound, (C4H4O3)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, (C2H3O2)W, where
n is greater than 2, but the original compound might possibly have
been (C4H4O3)W where n is 2, 3, or more.

* 0-2 g. of a compound containing carbon, hydrogen, and oxygen,
gave 0-2933 g. of CO2 and 0-1200 g. of H2O. When boiled with
acetic anhydride it gave a derivative which afforded the following
data : 0-1741 g. gave 0-3080 g. CO2 and 0-0902 g. H2O : 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., CH2O, 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, C7H10O6. 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
C7H10O5. 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, C7H10O5, is therefore a diacetyl derivative. Now
C7H10O6-2(O.CO-CH3) = C3H4O, which may be written

— CH2.CO-CII2— , — CH2.CH-CHO, or —CH2 - CH2 • 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, C3H6O3 ;
it cannot be derived from the group — CH2-CH2-CO — because
an acetyl derivative, AcO-CH2-CH2-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 C5H12O4. 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 CBH12O4, 4 hydroxyl groups ; the latter, therefore, is a tctra-
hydroxypentane, C5H8(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 — CH2 — C, could give malonic acid
on oxidation, that is to say, the isomcrides,

CH2(OH)-CH2-CII(OH)-CII(OH)-CHa.OH
CH2(OH) - CH(OH) . CII2-CI I(OI I) - Cl I2OH

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 C6H?(COOII)(NH2)(OH)2[1:2:4:5]2 might be indexed
as dihydroxyaminobenzoic acid, as aminoprotocatechuic acid, or
as dihydroxyanthranilic acid, and Ph-NH-CH2-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-CHMev
HN<; )NH

XCHMe-CHMeX

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 />-CH3.C6HrSO?-CH2.SO2.C6H5, but for which a probable
name may not suggest itself.

Under C14H14O4S2, 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, C6H5 - SO2 - CH2 • CH2 - SO2 - C6H5.
aa-Bis-phenylsulfon-athan, (C6H5 - SO2)2CH - CH3.
4:4'-Dimethyl-diphenyldisulfon, CII3 - C6H4 - SO2 . SO2 - C6H4 - CH3.
Phenylsulfon-benzylsulfon-methan, PhSO2 - CH2 - SO2 - CH2Ph.
/>/>-Diphenylen-bis-methylsulfon, CH3 - SO2 - C6H4 - C6H4 - SO2 • CH3.

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.
oc»l!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 "-:ir. .••: .:• -n • . 730, 735.
Ketyls (mei.ilV., l»i.-», 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, 9»9, 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.
vumol 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.

SN1 reactions, 696; .

SN2 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 Blt 1065 seq.
Vitamin Ba, 1065 seq.
Vitamin Ba, 1065, 1068.
Vitamin Blt, 702, 1073.
Vitamin Bc, 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.

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