Chemical Synthesis 1924

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OU_1 58459 >!J
LIBRARY
Call No,
Authot
This
^Manuals of Pure and Âpplied Chemistry

General Editor
R.
M. CAVEN,
D.Sc.(Lond.), F.I.C.
CHEMICAL SYNTHESIS
CHEMICAL SYNTHESIS
Studies in the Investigation of
Natural Organic Products
BY
HARRY
D.Sc.(Lond.), F.I.C.
Member
of the Research Staff of Nobel Industries, Ltd.
BLACKIE AND SON LIMITED

50
OLD
BAILEY,
LONDON; GLASGOW, BOMBAY

1924
Printed and bound tn Great Britain
PREFACE
have attempted to describe the more important investigations which have been made by the organic chemist in
In this work
I
modern times
this is
domain of natural organic products. The book covers only a limited field of organic chemistry, and even
in the
but partially surveyed.
During recent years the study of natural organic products has The results already attracted chemists in increasing numbers. obtained have opened out almost infinite possibilities and have
brought us face to face with new modes of chemical reaction about
which we know very
little
as yet.
account of the nature of the subject-matter and the fact that the book is intended 'for those who have a knowledge of organic
On
chemistry at least equal to that required for a pass B.Sc. degree, the usual textbook arrangement has not been adopted. I am indebted to Messrs. Merck, Schimmel & Co., and
particularly to
the
Wellcome Research Bureau,

at
for
information
which they have kindly placed Also, my thanks are due

general
editor
my
disposal.
to
for
Professor
R.
M.
Caven, the
suggestions,
of
the
series,
many
valuable
and
to
my
chief,
Mr. W.
Rintoul, F.I.C.,
Head
of the
Nobel
Research Laboratories, for the interest which he has taken in the preparation of the book. Finally, I am indebted to my wife for
her help in preparing the book for the press.
H.
THE RESEARCH
LABORATORIES, ARDEER, March, 1924.
HEPWORTH.
EDITOR'S NOTE
years of neglect chemistry is at length being recognized in this country as one of the most important factors of modern
After
many
life. Evidence of this recognition is shown by the increased notice which the subject is receiving in the public press, and by the large numbers of books that are being issued on various aspects of the
science.
It is
now
clearly seen that chemical science contributes
to the health, comfort, luxury,

citizen.
and
intellectual life of the
modern
bring the latest achievements of chemistry within the reach of minds untutored in its first principles; though this task should be attempted by those best
It is a difficult task, nevertheless, to
qualified to
perform
it.
of the present series of manuals, however, is to provide for those who have a working knowledge of chemistry for graduates in science and medicine, for workers in various branches of applied chemistry, for teachers, and for all who have an intellectual interest in the science for its own sake readable accounts of modern
The purpose
developments written by experts in the subjects with which they

deal.
Organic chemistry as a science

it
is
still
Wohler;
is not yet one hundred years old; four years to the centenary of the synthesis of urea by yet how amazing has been the advance in our knowledge
during ninety-six years!
started with the study of natural products, the exponents of this branch of chemistry, by elaborating artificial derivatives of the hydrocarbons, have deviated far from
Having
the path pursued by Nature herself. Nevertheless throughout this period there have always been chemists to whom the natural products
of the plant and animal world themselves proved the main attraction, chemists who studied these products because they were part of Nature, irrespective of whether the study would bring any kind of
gain beyond the knowledge
itself.
vii
Of
the labours and discoveries
viii
EDITOR'S NOTE
Hepworth gives an account in the present account begins where Nature begins, with the photovolume. This synthesis of plant products; it continues with the study of chlorophyll and other natural pigments, and of the formation of carboof these chemists, Dr.
hydrates, tannins, oils, fats, and waxes. After notice of the terpenes, and then of the amino acids and the natural bases which are elaborated from these, the volume concludes with an account of the alkaThus the work loids, and of recent research upon their synthesis. of Nature in the organic field, and the efforts of man to follow her
and elucidate her methods, are brought
to view.
R.
ROYAL TECHNICAL COLLEGE, GLASGOW,
March, 1924.
M. CAVEN.
CONTENTS
INTRODUCTION
-------CHAPTER
I
-
..-xv
i
Page
THE PHOTOSYNTHESIS OF PLANT PRODUCTS

Introduction
The
Presence of Formaldehyde in the Plant and the Function of the Chlorophyll Photocatalysis: the Synthesis of Formaldehyde from Carbon Dioxide and
Water
Photosynthesis of Nitrogen
Compounds from Nitrates and Carbon Dioxide
CHAPTER
CHLOROPHYLL
Amorphous and
Phytol
Extraction of Plant Pigments " "
Crystalline
II
CHLOROPHYLL AND OTHER NATURAL PIGMENTS

-
-'3
14 14
15
Chlorophyll
v
Chlorophyll-^ and Chlorophy 11-6
16
-
Nomenclature
-Êtiophyllin
-16
17
Action of Alkalies and Acids on Chlorophyll

and Êtioporphyrin Carotin, Xanthophyll, and Fucoxanthin Chlorophyll and Haemin
------
-19
20 20
22
23
THE ANTHOXANTHINS
7-Pyrone The Xanthones Flavones and Flavonols
.-.---.-.----..----24
-
-26
33
THE ANTHOCYANIN PIGMENTS

Introduction
Extraction
-..-.._..---.. ---
33
34
35
Nomenclature
Distribution
Salts of
Benzopyroxonium
Synthesis of Pelargonidin Origin of the Anthocyanins in Plants
.-.-...-..36 ........38 ._..-.. .40

-
40
ix
CONTENTS
CHAPTER
'
III
THE CARBOHYDRATES
Introduction
Classification
THE MONOSACCHAROSES
Natural Sources
Synthetic Preparation Synthesis of Glucose and Fructose Configuration of the Monosaccharoses
The
Pentoses and Hexoses
Enzymes
Fermentation of the Monosaccharoses
Methylglucosides Mutarotation and the Isomeric Forms of Glucose
..-.. -------------44 -------49 ------.53 ----.--....55 -------57

-
-42
43
Page
44
5^.
50
56
Methylated Sugars Glucosamines
-61 -62
63
59
Giucal Natural and Artificial Gluco sides Structure of the Glucosides Synthetic Glucosides
THE
DlSACCHAROSES Sucrose Maltose

Cellobiose
Lactose Trehalose Melibiose
THE
TRISACCHAROSES
Raffinose
Gentianose
Melecitose
Mannotriose
Rhamninose
Stachyose
TETRASACCHAROSES
THE POLYSACCHAROSES The Celluloses
Cotton Cellulose Starches and Dextrins
------- --67 ----------69 -?o -----------71 -----------72 -----------72 -----------73 -.--.------74 -----------75 -75 -75 -----------76 -----77 -------------
-------64 -65
-
73
74
76 76
77 78
81
CHAPTER
THE
Introduction
Isolation of the
IV
Classification of the
Tannins Tannins
The
Depsides Lichen Products Gallotannin
------.----84 ---------84 ......--.------------85 .--.--.----go

85
DEPSIDES, LICHEN PRODUCTS, AND TANNINS
88
CONTENTS
CHAPTER V
xi
Introduction and Classification
Occurrence
The
Constitution and Synthesis of the Glycerides Hydrolysis of the Oils and Fats
The Waxes The Sterols The Preparation
Fermentation Glycerol
The The The
Lipins
.-_--,_------------94 -------------------99 -----------99 -----------OILS, FATS,

94
95
9*7
ANIMAL AND VEGETABLE
AND WAXES
Page
of Fatty Acids from Hydrocarbons

-
100
101
Phosphatides Cerebrosides
-----
103
-104
105
CHAPTER
THE TERPENES AND
Introduction
Classification
-
VI
THEIR DERIVATIVES
-
106
-107
109
-
THE
OLEFINIC TERPENES AND THEIR DERIVATIVES
THE MONOCYCLIC TERPENES

Limonene
Synthesis of
-
114
Limonene
-
Terpinolene
The Terpinene Group The Phellandrene Group

Sylvestrene and Carvestrene
\-
-114 -115 -117 -117

-
118
Synthetic Monocyclic Terpenes The Menthenes and their Derivatives
-118 -119
-
122
THE DICYCLIC TERPENES

The Sabinane
or Tanacetane
-125
125
THE CARANE GROUP

THE PINANE GROUP
---
Group
128 129
THE CAMPHANE GROUP
-131
~
Synthesis of Camphoric Acid Conversion of Camphoric Acid into
*33
1
Camphor
-
34
Borneol and Isoborneol
-135
-
Bornylene and Camphane Fenchone and the Fenchenes
135
136
137
SESQUITERPENES AND POLYTERPENES
NATURAL AND SYNTHETIC PERFUMES
138
xii
CONTENTS
CHAPTER
VII
Introduction
Isolation of the
Classification
--------___
Amino Acids of the Amino Acids
-
THE AMINO ACIDS AND POLYPEPTIDES

-
Page
142
-143 -144
-
Resolution and Identification of the
Amino Acids
-
145
Amino Acids Monobasic Monamino Acids Synthesis of the
Diamino Acids
Dibasic
Monamino Acids
Hydroxy- and Thio-amino Acids Aromatic Amino Acids -
-146 -146 -149 -152 -153 -155

157
-
Heterocyclic Amino Acids Distribution of the Amino Acids in the Proteins
163
THE POLYPEPTIDES
-164
-
Synthesis of the Polypep tides Relation of the Polypeptides to the Simpler Proteins
164 167
CHAPTER
Introduction and Scope Occurrence and Isolation
-
VIII
SOME SIMPLE NATURAL ORGANIC BASES

-
170
-
-170
172
175
SIMPLE
MONO AMINO
Adrenaline
----------BASES
~
..
DIAMINO BASES
HETEROCYLIC BASES
-
-177 -17$
l8l
-
BASES DERIVED FROM TRYPTOPHANE
THE
BETA!NES
-
183
CHOLINE AND ALLIED BASES

CREATINE
-184
-
186
THE
w- AMINO ACIDS
187
CHAPTER IX
Introduction
-... ...-..PYRIMIDINE AND PURINE BASES

ITS
NucJeoproteins and Nucleic Acids
190 190
193
PYRIMIDINE AND SOME OF

Uracil
DERIVATIVES
-
and Thymine
. -
195
Cytosine
197
CONTENTS
THE PURINE
xiii
Purine Uric Acid
Occurrence and Structure of the Purine Bases Synthesis of the Purine Bases
----------------------BASES
-
Page
-198
200
201
204 205 208
SYNTHETIC NUCLEOSIDES AND NUCLEOTIDES
CHAPTER X
Introduction
Occurrence
------------
THE ALKALOIDS
-
-211
212 212
213
Extraction of the Alkaloids

Investigation of the Alkaloids
THE PYRROLE ALKALOIDS

Hygrine
Stachydrine
Betonicine and Turicine
-215
215 216
THE
PYRIDINE ALKALOIDS
Trigonelline
Piperine
Conine
Nicotine
------------------------------. -----
216 217 217

217 218 220
----~ -
THE TROPANE GROUP
-Atropine and its Allies Tropine Cocaine and some Synthetic Substitutes
THE POMEGRANATE ALKALOIDS THE NORHARMAN ALKALOIDS

Harmine and Harmaline
--------------------^
-221 -221
222
224 226
226
226 228
228
THE
ISOQUINOLINE ALKALOIDS
x/Papaverine
Laudanosine
Hydrastine
-----------
230
-231
232 232
THE QUINOLINE ALKALOIDS
The Cinchona Alkaloids Quinine and Cinchonine The Strychnos Alkaloids Strychnine and Brucine
234
234 234
235
THE PHENANTHRENE ALKALOIDS

Morphine and Codeine
Thebaine
----------SYNTHESIS OF THE ALKALOIDS

-
--
THE PHYTOCHEMICAL
INDEX OF AUTHORS
236
239
241
INDEX OF SUBJECTS
TABLE OF ABBREVIATIONS EMPLOYED IN THE REFERENCES

Abbreviated Title.
Journal.
Absts.
Amer. Chem. J. Amer. J. Physiol. Ann. Ann. Chim. Arch. Pharm.

Ber. Ber. Deut. hot. Ges. Ber. Deut. pharm. Ges.
Abstracts in Journal of the Chemical Society, London. American Chemical Journal. American Journal of Physiology.
Justus Liebig's Annalen der Chemie.
Biochem. J. Biochem. Z.
Bull. Soc. chim.
Annales de Chimie. Archiv der Pharmazie. Berichte der Deutschen chemischen Gesellschaft. Berichte der Deutschen botanischen Gesellschaft. Berichte der Deutschen pharmazeutischen Gesellschaft. The Biochemical Journal. Biochemische Zeitschrift. Bulletin de la Socie"t6 chimique de France.
Chem. Chim. C.r.
Zeit.
et Ind.
Chemiker Zeitung. Chimie et Industrie. Comptes rendus hebdomadaires des Stances de 1'Acad&nie des Sciences.
Deutsches Reichs Patent. Gazzetta chimica italiana. Helvetica Chimica Acta.
Journal of the American Chemical Society. Journal of Biological Chemistry.
D.R.P. Gazz. Helv. Chim. Acta. J. Amer. Chem. Soc. J. Biol. Chem. J. Ind. Eng. Chem.
y. Physiol. J. pr. Chem. y. Russ. Phys.
y. Soc. Proc.
Chem. Soc. Chem. Ind.
Journal of Industrial and Engineering Chemistry. Journal of Physiology. Journal fur praktische Chemie. Journal of the Physical and Chemical Society of Russia.
Journal of the Society of Chemical Industry.
Proc. Roy. Soc. Site. Preuss. Akad. Wiss.

Berlin.
Trans.
Proceedings of the Chemical Society, London. Proceedings of the Royal Society. Sitzungsberichte der Preussischen Akademie der Wissenschaften zu Berlin. Transactions of the Chemical Society, London.
Zeitschrift fur Biologic. Chemisches Zentralblatt.
Z. Biol.
Zentr.
Z. physiol. Chem.
Hoppe-Seyler's Zeitschrift
fiir
physiologische Chemie.
INTRODUCTION
As
early as the second half of the eighteenth century,
Lemery
divided substances, according to their origin, into three classes,
and animal, and thereby separated inorganic from organic chemistry. Even down to the third decade of the nineteenth century an important distinction was drawn between
viz. mineral, vegetable,
organic and mineral substances.
It
was supposed that the
latter
alone were producible artificially, while the synthesis of the former was wholly beyond the power of the chemist and was reserved for
the living organism, in which of a Vital Force.

It is easy to
it
was performed under the influence

in
its
was so
early youth organic chemistry connected with biology, for the materials which the closely chemist was called upon to investigate were mostly products of animal or vegetable origin. The isolation of urea from animal urine
understand
why
by Rouelle, the recognition of uric

glycerine
acid, lactic acid, malic acid,
and
by Scheele, the
isolation of asparagine
by Vauquelin and
Robiquet, of morphine by Sertiirner, together with many other similar discoveries during the first ten years of the nineteenth century,
are admirable examples of the
manner
in
which the
living
world
was drawn upon and made

pounds.
It is generally
to yield
up
its
treasure of chemical
com-
conceded that the doctrine of a special vital force was discredited as an outcome of the synthesis of urea, from lead
by Wohler in 1828;* and as, year by year, new synthetic products were added to the list of organic compounds, this last barrier, which separated organic from inorganic
cyanate and
chloride,
is not a little remarkable that John Davy had obtained urea several years before this by the action of carbonyl chloride on ammonia, but had not recognized it.
ammonium
* It
xvi
INTRODUCTION
chemistry, was swept away, and henceforth the former became the chemistry of carbon compounds.
The subsequent development

traced here, and
it
it
of organic chemistry cannot be will be sufficient to say that, in the form in which
chemistry may be deemed to have begun with the work of Frankland at the middle of the nineteenth century.
exists to-day, organic
Once
the
doctrine
of the
constancy of valency was
Couper,
Crum Brown, and Kekul6 were
accepted, able to bring order into
the vast mass of material which had already been accumulated. At a later date, van't Hoff and Le Bel extended existing ideas of
molecular arrangement into three dimensions, and laid the foundations of our present views. Thus it came about, as a result of the
enormous
theoretical
and
practical
developments which followed
these discoveries, that organic chemistry
became separated from
biology in the latter half of last century. The organic products enumerated in the text-books
number
is
of natural
indeed small in
comparison with the 150,000 carbon compounds of which organic chemistry can boast to-day.
With the dawn of the twentieth

been paid to the chemistry of other
century,
vital
more
attention has
products, with a view to the elucidation of the mechanism by which these substances are elaborated by the plant and animal. This return to the field of
early studies
by no means exclusively, to the pioneering researches of Emil Fischer; and the prospects which have been opened out seem almost infinite in variety.
is
due
principally, but
We
know
that in nature the construction of organic
compounds
begins with the carbon dioxide and nitrogen of the atmosphere, and the study of the mechanism by which the plant can assimilate
these substances, with the ultimate production of the
most complex
in
organic
compounds,
is
now
attracting
chemists
increasing
numbers.
The
investigation of plant pigments
and
especially chlorophyll
has been the subject of a the plant pigment par excellence series of brilliant researches by Willstatter, and these studies have
led to the development of
solvents.
"
"
an extraordinary technique in the use of
Several points with regard to the structure of chlorophyll
INTRODUCTION
have
still
to
be cleared up, but these must apparently await further
investigation of the pyrrole derivatives.
In the phytochemical * synthesis of plant products, the sugars
make
their appearance at a very early stage.
Since 1886, the inrapidly, princi-
vestigation of these
pally
compounds has proceeded very
owing
to the classic researches of
Emil Fischer.
the extensive results accomplished, we are still standing all the chemical possibilities of even the monosaccharoses,
In spite of far from under-
and the glucose molecule

and
his collaborators
is
almost as wonderful as that of
now assuming camphor. The

di-
a protean character recent work of Irvine
on the
cellulose,
demands
special
and poly-saccharoses, especially consideration, and valuable results may
be expected from the new methods which are being employed.

discovery of the methyl glucosides and acetobromoglucose may be regarded as the cardinal points in the recent studies of the synThe remarkable achievements in the investigation thetic glucosides.
of gallotannin are almost unsurpassed in the realm of synthetic
The
organic chemistry, yet gallotannin represents but one of the numerous members of the tannin family, about the majority of which we know
practically nothing.
Similar remarks apply to the natural
gums and
mucilages.
The chemical
reactivity of the
attention, especially at
enzymes has received considerable the hands of J2. Fischer, H. E. and E. F.
Armstrong, Bayliss, and Bourquelot, and the value of these sub" " chemical reagents of the organism has been stances as the repeatedly emphasized. The chemical investigation of these substances presents considerable difficulty largely owing to their colloidal
nature.
Willstatter has recently initiated a series of researches with
a view to the ultimate determination of the constitution of the
enzymes;
said that
it
and
will
if this
aim
is
eventually achieved,
it
may be
safely
which
this
outweigh even the extraordinarily chemist has already carried out.
brilliant researches
At first sight it would appear that the chemistry of the oils, fats, and waxes could almost be regarded as a closed chapter, but the
later
researches of
E.
Fischer
,
have shown that even such an

a plant.
xviii
INTRODUCTION
apparently simple problem as the preparation of the monoglycerides is in reality full of Of the chemical constitution of the pitfalls.
majority of the lipins we know practically nothing as yet, and much work remains to be done before we understand these substances
even from a purely chemical point of view. The statement that fats and sugars are converted in the body to carbon dioxide and water
is
no longer considered an
all-sufficient explanation of the role of
these substances in the animal economy. the breakdown of the higher fatty acids
No
all
one imagines that in the carbon atoms are
immediately or directly converted into carbon dioxide. Our views as to the mechanism of oxidation reactions, both in the laboratory
and in the
organism, have lately undergone considerable change, and there is a good deal of evidence in favour of the view that the first stage in the oxidation of organic substances consists
living
in the replacement of
hydrogen atoms by hydroxyl groups.
Following the synthesis of camphoric acid by
Komppa
in 1903,
and that of dipentene by Perkin,
jun., in the following year, the
progress in the investigation of the mono- and di-cyclic terpenes and their derivatives has been very rapid, and almost every year
new compounds belonging

natural sources.
to these classes are being isolated
from
In recent years the chemistry of the caoutchoucs has attracted considerable attention, more particularly with a view
to preparing synthetic rubber.
Although a good deal of progress
cannot be said that a thoroughly successful product has yet been prepared synthetically. Of the sesqui-terpenes we know very little, while we are equally ignorant of the mechanism
has been made,
it
by which the plant synthesizes its essential oils. The introduction of a new method of separating the mono-amino
acids obtained in the hydrolysis of the proteins,
1901, led to
numerous
investigations
by E. Fischer in of the nature of the amino

decade,
acids present therein.
the technique had been worked out, investigators began to consider the losses involved in the process of isolation, and more recently Dakin and
After the
first
when
Foreman have introduced alternative methods for the certain types of amino acids derived from the hydrolysis
Fischer's investigations of
isolation of
of proteins.
many
of the naturally occurring polypep-
INTRODUCTION
tides
xix
have been extended by a number of chemists, notably by Abderhalden. Perhaps the most interesting polypeptide so far
is
discovered
glutathione,
which has been
isolated
recently
by
Hopkins, and
this substance bids fair to revolutionize
our
ideas
concerning the possibilities of these compounds in the living organism. In spite of the rapid progress which has been made
study of the untouched.
in
the
proteins, vast
regions
still
remain almost
The
isolated
classification of the natural organic bases is
increasingly difficult problem.
The
alkaloids,
becoming an which were easily
on account of
their insolubility in water
and
their ready
solubility in organic solvents,
were amongst the
first
natural sub-
stances to attract the organic chemist.
Very substantial progress has been made in the study of these compounds, perhaps the most
cryptopine and protopine by W. H. Perkin, jun., and that of harmine and harmaline by the same author in collaboration with R. Robinson.
interesting investigation of recent years being the classic study of
Each year brings forward new alkaloids for investigation, and the Without doubt the most satisfield seems almost inexhaustible.
factory theory with regard to the phytochemical synthesis of the
been put forward is that due to R. Robinson, and a consideration of his paper cannot fail to suggest numerous problems which deserve the attention of the organic chemist. The
alkaloids
which has so
far
extraction of the simpler natural bases presented
more
difficulty
on
account of their solubility in water, and the necessary technique
was
initiated
by Brieger in 1885.
It is surprising to
what an extent
the study of ergot has resulted in the isolation of may be regarded as derived from amino acids.
new bases which The chemistry
of the purines has of late years received an increased stimulus from biology, and our interest in these compounds no longer centres
around
caffeine,
theobromine, and uric acid.
The study
of the
nucleic acids and the purine and pyrimidine bases which are con-
them has the same fascination as that which uric acid and the xanthine bases had sixty years ago. The preparation of synthetic nucleosides and nucleotides by E. Fischer must be regarded as a
tained in
valuable step towards the ultimate synthesis of the nucleic acids.
xx
It
INTRODUCTION
has been stated that the idea of a vital force was dispelled almost a century ago; but the chemist must bear in mind that until
he has shown that his synthetic methods are identical with those of Nature, and that he can prepare natural organic compounds from
materials likely to be
employed by the plant and within small

is
limits
of temperature, there
just as
much
scope for endeavouring to

vital
penetrate Nature's methods of synthesis as there was in the days
when
it
was believed that every organic compound required a

its
force for
elaboration.
ORGANIC CHEMICAL SYNTHESIS

CHAPTER
The
I
Photosynthesis of Plant Products

The
processes by
Introduction.
means
of
which green plants
are enabled to assimilate nitrogen and carbon have attracted the attention of chemists for a number of years, and whatever the nature
of these reactions may be, they constitute, indeed, the chemical " synthesis par excellence ". Although atmospheric nitrogen has been recognized as the ultimate source of supply of that long
is constructed, modern inhas indicated that nitroger^ is not drawn by the plant vestigation directly from the air, but is assimilatated in a combined state from
element from which phyto-protoplasm
with or without bacterial co-operation. The jmajority of chemists believe that the agency by which green plants are enabled to assimilate carbon is chlorophyll, operating under solar influence by some such mechanism as will be indicated in the
the
soil
by the
roots,
present chapter.
In 1870 Baeyer * put forward the hypothesis that the first product of plant assimilation is formaldehyde resulting from the photolysis of carbon dioxide in the presence of water, with the elimination of free oxygen:
CO + H O = HCHO + O
2
2,
and that the
resulting formaldehyde then polymerizes to give a hexose (C6 12O 6) (p. 42). This plausible hypothesis has influenced investigations on the synthetic aspects of carbon assimilation
*
,
Ber., 1870,3,63.
1
1
(D331)
and for many years the question of the of free formaldehyde in green leaves gave rise to the most presence contradictory answers. This particular point has lost a good deal of its original significance in view of the more recent results obtained,
to a remarkable extent,
and Baly and Heilbron. Laboratory experiments on the polymerization of formaldehyde to the hexoses are usually quoted in favour of the formaldehyde hypothesis, but in this connection it is noteworthy that the evidence in favour of the view that cane sugar & disaccharose is the first carbohydrate synthesized by the plant seems almost conclusive. Other authors consider that formic acid is the more likely interespecially
by
Willstatter,
mediate product of early origin. Erlenmeyer was the first to make the suggestion, but it is only in recent years that renewed attention has been given to this possibility. Spoehr has shown that carbon
dioxide and water are easily reduced to formic acid by means of radiant energy, and that a sugar-like product, which the plant can utilize as a foodstuff, is produced from formic acid under conditions such as may obtain in an active leaf.
The recent results obtained by Baly and Heilbron in their studies of the photochemical synthesis of nitrogen compounds from nitrates and carbon dioxide have given rise to a good deal of theoretical speculation as to the intermediate nitrogenous products which may possibly be formed in the plant, but these intermediate compounds are for the most part unknown to the organic chemist as yet. In
view of our limited knowledge of the chemistry of the proteins the degree of our ignorance respecting the synthesis of nitrogenous
compounds
is not surprising. Robinson's views on the phytochemical synthesis of the alkaloids will be dealt with in a later chapter (p. 237).
in the plant
The Presence
Function of
in the plant
Formaldehyde in the Plant and the the Chlorophyll. The presence of formaldehyde
of
first
* in Since that reported by Reinke 1883. time many investigators have reported its presence, and these statements have been taken as evidence of the truth of Baeyer's hypo-
was
thesis.
recent investigators have suggested, however, that this formaldehyde is a degradation product of chlorophyll. Schryver f has confirmed Ewart's view J that chlorophyll contains combined
More
formaldehyde.
* Ber. deut. hot.
The former
investigator
found that formaldehyde
Gesells., 1883, 1,
406. t Proc. Roy. Soc., 1910, 82 B, 226. t Ibid., 1908, 80 B, 30.

is
in chlorophyll films after exposure to bright than when exposed to a dull light. When glass plates sunlight covered with films of chlorophyll were kept in the dark no formaldehyde was produced, even when moist carbon dioxide was present. If such plates were exposed to sunlight in an atmosphere free from carbon dioxide a very minute quantity of formaldehyde was pro-
more abundant
duced, and the presence of moist carbon dioxide increased the quantity of formaldehyde very considerably. From these experiments Schryver concluded that in the presence of sunlight, water, and carbon dioxide, there is a continuous production of formaldehyde,
which
being continually condensed to sugar. If this condensation does not proceed rapidly enough to remove all the formaldehyde, the excess enters into combination with the chlorophyll, to be set free later. In this way the quantity of free formaldehyde is so
is
regulated that at no time is a toxic quantity present. * Wager has studied the decomposition of chlorophyll on exposure to oxygen both in sunlight and in the dark, and concludes
that the process is not catalytic. Oxygen is absorbed and aldehydes are formed, and it is suggested that the sugars produced during assimilation are not formed directly from carbon dioxide and water,
but by the polymerization of aldehydes produced in this way. Warner f states that formaldehyde is produced when chlorophyll is exposed to sunlight in air, either in the presence or absence of carbon dioxide, from which he concludes that the latter plays no part in the
production of formaldehyde by photosynthesis outside the plant, and that the formaldehyde is in reality an oxidation product of the
chlorophyll.
Jorgensen and Kidd J employed chlorophyll-^ and -b (p. 16), and on exposing an aqueous chlorophyll sol, contained in glass vessels and in contact with various gases, to light, they found that
formaldehyde was only produced in the presence of oxygen. In the case of carbon dioxide, phaeophytin (p. 17) was produced and there was no further change. These authors suggest that the formaldehyde arises chiefly from the phytol (p. 15) which is probably split off from the chlorophyll under the action of light and oxygen. These views have, however, been more recently superseded by the experiments of Willstatter and Stoll, who showed that no formaldehyde was formed if pure chlorophyll, in colloidal solution, was
employed
the colloidal solution being considered to approximate

f Ibid., p.
* Proc. Roy. Soc., 1914, 87 B, 386. t Proc. Roy. Soc., 1916, 89 B, 342.
Ber.
378. 1917, 50, 1791.

most
The formaldehyde
closely to the condition of the chlorophyll in the chloroplast. described by earlier workers is attributed to the
oxidation of impurities accompanying the chlorophyll they employed. The failure to obtain any trace of formaldehyde from pure chlorophyll in vitro is attributed to the absence of the essential
enzyme present in the green leaf. Experiments shown that carbon dioxide reacts with chlorophyll
solution to
-in
(i)
vitro
have
in colloidal
(ii).
form a compound of the nature of a bicarbonate
N
R
H o + co = R
2 2
,o
<
'OH
N
0)
It is
:NH
very unlikely that a compound of constitution (ii) would yield two atoms of oxygen with regeneration of chlorophyll, so that some intramolecular rearrangement must first take place, and this,
according to Willstatter and
Stoll, involves
the absorption of energy,
which
is
supplied by sunlight.
(iii) is
In this way a formaldehyde-peroxide
compound
assumed
to be formed:
,O
R
Ô
:NH
This compound should be easily capable of losing oxygen, either in one or two stages, with regeneration of unaltered chlorophyll and
formation of formaldehyde.
,O
,V.:_Mg-O-CH
*0

No
such peroxide
(iii)
has been observed
when experiments
"
are
carried out in vitro, but this is not considered surprising, of the essential difference between test-tube experiments
in view
and the
con-
of the living cell ". The chloroplast centrations of carbon dioxide which decompose
activity
will
tolerate
chlorophyll in collbidal solution to phaeophytin, with precipitation of magnesium carbonate, so that the chlorophyll in the chloroplast must be pro-
from photo-oxidation in some way. Evidence has been adduced that within the living cell the decomposition of the peroxide-formaldehyde compound (iii) is brought about by an enzyme. * has shown that certain plant acids, especially dibasic Spoehr to ultra-violet acids, readily undergo decomposition when exposed with the formation of acetaldehyde and acetic light in quartz vessels,
tected
acid,
and that the
latter
may undergo
further decomposition, yield-
ing formaldehyde and formic acid. The most satisfactory evidence that formaldehyde is the conbeen necting link between carbon dioxide and the carbohydrates has
supplied by Willstatter and Stoll.f Of all the possible primary products, formaldehyde is the only one in the formation of which the volume of carbon dioxide absorbed would be equal to the volume " of oxygen liberated. In other words, the assimilatory quotient ",
unity in the case of formaldehyde, 1-33 for glycollic acid, 2 for formic acid, and 4 for oxalic acid. This quotient has been determined experimentally and found to be unity, whether the in carbon temperature is 10 or 35, whether the atmosphere is rich
2
CO
/O 2
is
dioxide or even deprived of oxygen altogether, or whether ordinary foliage or succulent leaves, like cactus, are examined. It should be pointed out that although since the days of de
Saussure (1804) chlorophyll has been regarded as the fundamental agent in the photosynthesis of plant matter, there is no experimental evidence that the primary agent may not be contained in the colourless part of the chloroplast, chlorophyll thus being the result of a " The function of the chlorophyll may be later
synthetic stage.
a protective one to the chloroplast when exposed to light, it a light-screen as has been suggested by Pringsheim, or it
may be may be
concerned in condensations and polymerizations subsequent to the In this first act of synthesis with production of formaldehyde." J connection it is noteworthy that in 1892 Molisch showed that
* Biochem. Zeitsch., 1913, 57, 95.
J Biochemistry,
t Ber.,
191?, 50* 1777.
by B. Moore,
p. 55.
chlorosis of green plants will follow a deficiency of iron even in the presence of sunlight and that development of chlorophyll can be
restored
by supplying the
ponent of the darkness and then exposed to light regain their chlorophyll, which is therefore itself a product arising from photosynthesis. the Synthesis of Formaldehyde from Photocatalysis
:
deficiency, although iron is not a comGreen leaves etiolated by chlorophyll molecule.
Carbon Dioxide and Water.

light,
It is a well established fact that

is
an aqueous solution of carbon dioxide
unable to absorb visible
but that it absorbs ultra-violet light of extremely short waveIn order to gain the energy required for the first stage of length. the synthesis, the carbon dioxide and water must be exposed to
light of this very short wave-length.
Since sunlight includes at
the
most only a minute quantity of this light, the synthesis cannot be initiated by sunlight, and we have therefore to account
fact that
for the
the plant
is
able to accomplish this synthesis
in ordinary sunlight.
* have Baly and Heilbron suggested a theory which is based on the quantitative study of the formation of hydrogen chloride from
hydrogen and chlorine, f

reaction
is
It
was found that the velocity of
this
not proportional to the intensity of the light, but increases far more rapidly than the intensity; i.e. the amount of hydrogen
chloride formed with a given quantity of energy is not constant, but increases rapidly to an explosive maximum as the intensity of the light is increased. The reaction may be formulated:
H +
2
C1 2
+E =
2HC1
+E+
K,
where
is
the
molecule and
of hydrogen
amount of energy absorbed

is
in activating the chlorine
the normal heat of formation of two molecules
chloride.
The
total
energy
-)-
is
radiated
at
infra-red (heat) frequencies,
which are
characteristic of the
hydrogen
molecule.
has been proved, however, that many of the infrared frequencies of a compound molecule are identical with those of
It
its
component atoms, and consequently the molecules of hydrogen chloride and chlorine have some infra-red frequencies in common.
Part of the energy E will therefore be reabsorbed by the surrounding chlorine molecules, with the result that these become
partially or
+K
wholly activated.
Baly and Heilbron consider that the
principle
made
*
applicable to all photochemical reactions, and may be use of in promoting a reaction when the reactant molecules
is
t
Trans., 1921, 119, 1025.
Baly and Barker, Trans., 1921, 119, 653.

are screened
this
ultra-violet rays they normally require. For " the reactants are mixed with a " photocatalyst purpose (A), which absorbs rays different from those characteristic of the re-
from the
actants, but
which has the same infra-red frequencies as the reactants. When such a mixture is exposed to rays absorbed by the substance A, the energy thus absorbed will be radiated at the infra-red frequencies characteristic of A; and since these are the same as
those of the reactant molecules, the latter will reabsorb this radiation and the reaction will take place. Now Moore and Webster * have stated that a saturated
solution of carbon dioxide gives no formaldehyde on exposure to ultra-violet light, but that in the presence of certain inorganic
aqueous
"
e.g. colloidal ferric hydroxide, beryllium chloride, small quantities of formaldehyde are produced. Baly and &c., Heilbron have confirmed these experiments, and in addition have
catalysts ",
observed that if a solution of carbon dioxide in water is agitated by carbon dioxide during the exposure to ultra-violet light, distinct These authors have traces of formaldehyde can soon be detected. advanced two reasons why the solution must be agitated in order to obtain positive results: 1 In ultra-violet light the liberated oxygen would combine with water to give hydrogen peroxide, which would oxidize the formal.
dehyde
2.
to formic acid.
If the solution is not agitated, the formaldehyde which escapes oxidation is polymerized as fast as it^s formed, whereas agitation
carries a portion of the formaldehyde to the the actinic intensity of the light is less.
back of the vessel, where
These authors have found that formaldehyde is polymerized by long- wave ultra-violet light (290 //ft), while its synthesis requires short-wave ultra-violet light (200 pp). Paraldehyde and sodium phenate absorb the long-wave ultra-violet light, and therefore if added to the solution protect the formaldehyde from polymerization, and it has been shown that the so-called inorganic catalysts employed by Moore and Webster behave in a similar manner.
In ultra-violet light a photo-equilibrium
Carbohydrate
is
established:
t
In order that the
> Carbon Dioxide and Water 4

.
Formaldehyde
first
stage
may be
photocatalyzed, a substance
Proc. Roy. Soc., 1914, 87 B, 163, 556; 1918, 90 B, 168.

as
must be used which has the same infra-red frequencies and malachite green, methyl orange, and dioxide;
carbon
/>-nitroso-
dimethylaniline have been found to be suitable photocatalysts for suitable photocatalyst for the second stage of the this reaction.
reaction has not yet been found, but these authors suggest that chlorophyll is an ideal photocatalyst for both stages of the synthesis.
The Photosynthesis
ammonium
salts are
of
Nitrogen
Compounds from
Potassium nitrate and possibly the sources from which the plant derives its nitrogen, but nitrates as such are relatively inert substances which do not readily lend themselves to chemical change, whereas nitrites,
Nitrates and Carbon Dioxide.
on the other hand,
are
much more
reactive.
In 1890 Laurent observed that the plant is able to convert nitrate into nitrite, and this fact was soon afterwards confirmed by other workers. As early as 1883 Schimper found that nitrates were destroyed in green leaves exposed to daylight, but were not so destroyed if the leaves were kept in the dark. Furthermore, no
destruction of nitrate occurs in etiolated leaves exposed to sunlight. Thiele * first recorded the rapid conversion of nitrate into nitrite by the rays from a mercury quartz lamp, evolution of oxygen
occurring simultaneously.
Baudisch f exposed mixtures of potassium nitrite and methyl alcohol in aqueous solution to diffused daylight and to ultra-violet light, and found that the methyl alcohol
to
hyponitrite, and the latter, at the moment of its reacted with the formaldehyde to form the potassium formation, salt of formhydroxamic acid (i):
became oxidized was reduced to
formaldehyde
at the
expense of the
nitrite,
which
KN0 + CH OH - KNO + HCHO + HoO KNO + HCHO - H C OH N-OK

2
(i)
No
reaction took place in the dark even
if
the solutions were boiled,
so that the change was clearly photochemical. Moore found that, in solutions of nitrate undergoing this reduction, green leaves check the accumulation of nitrite, thus indicating their capacity to absorb the more active compound. Pro-
ceeding from the hypothesis that one of the organisms arising earliest in the course of evolution must have possessed, united in a
*
Ber., 1907, 40, 4914. t Ber., 1911, 44, 1009; 1916,49,1176; 1918,51,793.
single cell, the dual function of assimilating both carbon and nitrogen, Moore examined the simplest unicellular algae. He found that in
the absence of
all
sources of nitrogen except the atmosphere, and
in presence of carbon dioxide, these algae can fix nitrogen, grow, and form proteins by utilization of light energy. The rate of grotvth is accelerated by the presence of nitrites or oxides of
nitrogen.
Moore and Webster
* have also
made
the important
observation that the reduction of nitrates to nitrites takes place in the roots and stems where photochemical reaction is excluded.
recently Baly, Heilbron, and Hudson f have investigated the photosynthesis of nitrogen compounds from nitrates and carbon
More
dioxide by passing the latter through aqueous solutions of potassium nitrate or nitrite exposed to ultra-violet light. In these experiments the following observations were made:
1.
Activated formaldehyde, such as
is
photochemically produced,
reacts with potassium nitrite, and this reaction takes precedence over that in which formaldehyde is converted into sugars.
2. If formaldehyde is produced at a greater rate than it can react with the nitrite, reducing sugars are formed. In these circumstances activated formaldehyde is assumed to
have the structure

of reaction
OH,
bivalent carbon atom.
It is further
the activity being due to the assumed that the first product
is formhydroxamic acid (i), an atom of oxygen being evolved which oxidizes a further quantity of formaldehyde to formic These changes may be represented by the following equations: acid.
H - C - OH + O NOK
:
~>
H C OH -> H C OH +o N OK O N OK H. COOH
II
I!
(i)
Under
the conditions of the experiment, the potassium salt pletely hydrdlyzed to the free acid:
is
com-
H - C - OH N OH
II
and the
a
latter
compound
readily loses oxygen with the formation of
compound:
H - C - OH
NH
* Proc. Roy. Soc., 1919, 90 B, 158.
f
Trans., 1922, 121, 1078.
10
which may be regarded
as a hydrate of hydrocyanic acid. With the latter yields a labile ring compound (ii) which formaldehyde
undergoes rearrangement to give glycine
(iii):
HO CH-CHOH \/ NH
(ii)
CH NHoCOOH
2
(iii)
Aqueous
solutions of
formhydroxamic acid
prepared by the
action of ethyl formate on hydroxylamine in methyl alcoholic solution and formaldehyde were exposed to ultra-violet light, when a
reaction quickly ensued and a variety of products including methylamine and a mixture of a-amino acids (detected qualitatively only)
were formed. Methylamine is probably formed directly from ammonia and formaldehyde, the latter acting as a methylating agent
(P- 215)-
claimed that alkaloids have been produced. The authors explain the formation of these substances by assuming that formhydroxamic acid condenses with three or four molecules
it
In addition,
is
of activated formaldehyde to produce compounds (iv) and (v) which by loss of water and oxygen give pyrrole and pyridine compounds
respectively:
H-C-OH
I
H-C-OH
I
H-C-OH
/\
H-C-OH
HC-OH
H-C-OH
H-C-OH
H-C-OH H-C-OH
NH
By
the condensation of two
(v)\ NH
molecules of formhydroxamic acid with one molecule of formaldehyde, the compound (vi) would be produced which by loss of oxygen and water would yield glyoxaline
(vii) (p. 178).
H-C-OH
NH
HC
H-C-OH H-C-OH
x
<s
NH
(vi)

Evidence of the formation of (p. 145), has been adduced.
11
this substance, as well as histidine
The
authors summarize their views as follows:
Potassium nitrate
Carbon dioxide and water

4,
I
Dtassium nitrite
Formhydroxamic
Nitrogen bases
__
Alkaloids and xanthine bases
_
acid
all
2
Activated formaldehyde
a-amino acids
I
J"
(histidine, &c.)
Substituted a-amino acids

J,
Proteins
these reactions take place is assumed to be due to the cardinal fact that the various intermediate comreadiness with which
The
pounds are produced in highly reactive phases. * have obtained a Still more recently Baly, Heilbron, and Stern
number
of naturally occurring nitrogen compounds photosynthetically from carbon dioxide and ammonia. Although the products of the action of light on carbonic acid and ammonia differ from those
formed when carbonic acid and potassium nitrate are illuminated, the mechanism of the synthesis appears to be very similar in the two
During the first part of the investigation aqueous solutions of ammonia, saturated with carbon dioxide, were exposed for various periods of time to the light from a quartz mercury lamp, and the final product was found, in the main, to be methylamine. In addiThis photosyntion, nitric and probably nitrous acids are formed. thesis is supposed to take place in two stages: first, the photosynthesis of formaldehyde by the action of light on the carbonic acid,
cases.
H CO = H C OH + O
3
2;
and, secondly, the interaction of the activated formaldehyde and
ammonia,
NHs +
H c OH = CH NH +
. .
O.
The
oxidation of the
ammonia
*
to nitric acid
is
said to be
due to the
Trans., 1923, 123, 185.
12

is
oxygen that
set free in these
two
reactions.
Batteries of eight
quartz tubes, each containing 100 c. c. of 1-3 N-ammonia, saturated with carbon dioxide, were exposed to the light of a quartz mercury
lamp for different periods, and the presence of pyridine (or piperidine) Neither a- ami no was qualitatively confirmed in every instance. acids, sugars, hydroxylamine, nor hyponitrous acid was present. By the prolonged action of ultra-violet light on aN-ammonia and formaldehyde an alkaloid, which was thought to be conine, was
obtained.
These reactions have been carried out in daylight or ultra-violet light; but it should be remembered that the synthesis of proteins can also take place in the dark and in tissues free from chlorophyll, provided that an adequate supply of carbohydrate is available. Indeed, there is good evidence in favour of the view that nitrogen assimilation is not a photochemical process, and that light is only of indirect importance in providing one of the means for the
formation of carbohydrates.
REFERENCES.
Biochemie der Pflanzen, Vol. I, by F. Czapek (Jena, 1913). The Chemistry of Plant Products, Vol. II, by P. Haas and T. G. Hill
Biochemistry,
(London, 1922). by B. Moore (London, 1921).
Untersuchungen iiber die Assimilation der Kohlensanre, by R. Willstatter and A. Stoll (1918).
CHAPTER
II
Chlorophyll and other Natural Pigments
CHLOROPHYLL
role of chlorophyll in the realm of vital For synthesis has already been dealt with in the previous chapter. obvious reasons a correct knowledge of its constitution is of the
Introduction.
The
utmost interest to the organic chemist and the botanist. The chemical study of chlorophyll dates from the year 1819, when Pelletier and Caventou first applied this name to the green-leaf
pigment, without, however, isolating the substance. Since then numerous workers, amongst whom Schenck and Marchlewski may be mentioned, have attempted to prepare chlorophyll in a pure condition, but the methods employed in most cases were too drastic.
Previous to 1911, there was no chemical evidence to show that chlorophyll was not a single chemical individual, although Stokes, Sorby, and others had obtained spectroscopic evidence pointing
to the existence of
more than one substance.
During the
last
ten
years chlorophyll has been subjected to careful chemical investigation by Willstatter and his collaborators, and, although some minor points still remain to be cleared up, our knowledge of the chemistry
of chlorophyll has
made enormous
and
is
progress.
originally assigned the
In 1912 Willstatter and Isler * definitely showed that chlorophyll ,

as ordinarily obtained, to
formula
C55 H72 O 6 N4 Mg,
which they had
and that two
in reality a mixture of two substances, yellow pigments, carotin and xanthophyll, accompany
further pigment, fucochlorophyll in the chloroplast of plants. has been isolated from brown algae. xanthin,
presence of magnesium in chlorophyll is remarkable, and at once suggests other complex organic compounds containing traces
*
The
Ann., 1912,390, 269.

13
14
of metallic elements.
Of these the best known is haemoglobin, red colouring matter of blood, which contains iron, and yields the by chemical decomposition compounds having a fundamental structure similar to those obtained from chlorophyll. Haemocyanine, the main constituent of the blood of the octopus, contains 0-38 per cent of copper, while, according to Church, the red colour exhibited by a number of African birds called turacos is due to a pigment
turacine,
which contains 8 per cent of copper. Extraction of Plant Pigments. The usual method of extracting chlorophyll from green tissues consists in first steeping the fresh material in hot water to destroy oxidizing enzymes, and
then extracting the colouring matter with warm alcohol. Willstatter has shown that the operation of drying produces no change of
importance in the chlorophyll, and he accordingly recommends the use of dried in place of fresh material, and extraction by shaking with organic solvents (ethyl or methyl alcohol, ether, or acetone) in the cold. Organic solvents containing an appreciable amount of water are preferable to dry solvents. When cold alcohol is used for the extraction the so-called " " " is obtained, whereas with ether an amorcrystalline chlorophyll
phous chlorophyll results.* The yellow pigments may be eliminated by a regulated system of partition among solvents, finally making use of the insolubility of chlorophyll in petroleum ether. The green pigments may also be saponified by alkalies, and are then insoluble in ether. This method can be adopted to separate the from the yellow pigments. The separation of carotin from green xanthophyll is based on the fact that when a mixture of petrol and
methyl alcohol containing a little water is employed, the carotin passes into the petrol, whereas the greater part of the xanthophyll remains in the methyl alcohol layer. The distribution of the in plants may be roughly summarized thus: pigments
Green pigments * fo
pai ? per IO ? JSH^Wt' f part per 1000. tChlorophyll-&,
-
"
1000. Yellow pigments {Carotin, J part per *B 1 (Xanthophyll, J part per 1 000.
The common
frequently
large scale.
Nettle
been used
(Urtica) is the plant which has for the extraction of chlorophyll
most on a
" Amorphous and
Crystalline
"
Chlorophyll.
Willstatter
* Willstatter and Benz, Ann., 1908, 358, 267.
CHLOROPHYLL
15
and his collaborators obtained specimens of amorphous chlorophyll from upwards of two hundred plants drawn from numerous cryptogams and phanerogams. The formula suggested for this chlorophyll was C 55 H72 N4 O 5Mg, and on decomposition all the samples yielded about 30 per cent of an alcohol named phytol.* Hydrolysis with
colc^ dilute, caustic potash gave equimolecular quantities of methyl alcohol, phytyl alcohol, and a tribasic acid called chlorophyllin.f
Amorphous
chlorophyll therefore appears to be the di-ester of a tribasic acid. Since only five oxygen atoms are present in amorphous chlorophyll there cannot be more than two carboxyl groups present.
Internal anhydride formation is precluded, since phytochlorin-e, a decomposition product of chlorophyll, contains the same grouping
and does not form an amide with ammonia. J No amide is present, since chlorophyll gives no ammonia on hydrolysis, and it was finally suggested that the fifth oxygen atom forms part
of a lactam ring.
=N
C 31 H 30 N Mg3
-io
COOCH COOC oH
3
2
39
Amorphous
chlorophyll
+ 3 KOH
Hydrolysis
->
C 31H 30 N 3Mg
~ _ COOK + CH H + C H OH - COOK
3
20
30
Chlorophyllin'salt
Phytol
Crystalline chlorophyll was found to be a di-ester which contained an ethyl group in the place of the phytyl radicle, while the second
carboxyl group was esterified with methyl alcohol and the third carboxyl group resembled that of amorphous chlorophyll. Willstatter
found that during the extraction with alcohol " is set free, and this an enzyme chlorophyllase brings about the In other respects amorphous and crystalline chlorosubstitution.
Stoll
and
"
phyll are probably identical.
Phytol. According to the investigations of Willstatter, Schuppli, and Mayer phytol is a primary alcohol of the composition C 20H 39 OH. On oxidation with chromic acid a ketone, C17 H 34 O,
||
* Willstatter
t Willstatter
and Oppe*, Ann., 1911, 378, i. f Ann., 1910, 378, and Utzinger, Ann., 1911, 382, 129. Ann. 1910,378, 18. Ann., 1919, 418, 121.
9
||
18.
16
is

obtained, from which
it is
j8
bond between the a and
concluded that phytol contains a double carbon atoms of the chain (i).
C 16 H 31 C = C.CH 2 OH
C/O3
(i)
(W
()
txH->
further oxidation phytol gives phylenic acid and this acid forms a lactone. Such behaviour is characteristic of acids containing
On
the a and
methyl groups in the a and j3 carbon atoms.
j8
positions,
and a double bond between
Chlorophyll-^ and Chlorophyll -b. It has already been mentioned that as early as 1864 Stokes obtained spectroscopic evidence pointing to the existence of more than one substance in chlorophyll. The latter was separated into two substances termed Chlorochlorophyll-0 and chlorophyll-6 by Willstatter in 1912.*
phyll- a
is
blue-black
organic
a
solvents.
Chlorophyll- b
green solution. solubility in the

rated
The common
giving a green-blue solution in is a green-black solid giving two chloroph)41s have much the same
solid
organic
by
their
different solubilities
solvents, but can in methylalcohol.
be sepaBoth can
be obtained be written:
in
microscopic crystals.
These chlorophylls may
(C 32 30 ON 4 Mg) (COOCH 3 ) (COOC, H 39 ) (C 32H 28 2 4 Mg) (COOCH 3) (COOC 20 39 )
Chlorophylls
Chlorophyll-6.
Nomenclature. The magnesium atoms of either of the chlorophylls may be removed and replaced by two hydrogen atoms,
with the aid of alcoholic oxalic acid. In this reaction the ester groups remain intact, and the hydrogen derivative is known as a
phaeophytin.f
The
by magnesium,
agent. J
reverse change, can be carried out
i.e.
the replacement of hydrogen by means of the Grignard re-
radicle hydrolysis is allowed to proceed until the phytyl a phaeois removed, the monomethylester w hich remains is called phorbide;|| while the removal of the methyl radicle leaves a dibasic
r
When
acid phaeophorbin; e.g.

*
Ann., 1912, 390, 269. J Ann., 1913, 396, 180.

||
From Gr., #cu6s From Gr., <t>vr6i>
= =
dusky.
a plant.
From
Gr.,
<t>oppr)
food.
CHLOROPHYLL
[C 32H 30 ON 4 Mg]
17
COOCHg -Mg -> COOC 20 H 39 +H

2
[C 32
H 32 ON
COOCH 3
4]
COOC 20 H 39
Chlorophyll-a
Phseophytin-a (Phytyl phteophorbide)
Hydrolysis
->
[C 32H 32
ON
COOCH
4]
Hydrolysis
COOH
->
[C 32H 32 ON 4]
COOH COOH
Phaeophorbide-a
Phaeophorbin-a
chlorophyll derivatives may be classified in two main groups according as they contain magnesium or are derived from the latter
The
by replacing the magnesium by hydrogen.

Magnesium
Chlorophyll,
Derivatives.
3
Corresponding Hydrogen
Compounds.
Phceophytin,
fCOOCH MgR COOC 20 H 39 I COOH
H R \ COOC, H
2
"
fCOOCH
I
39
COOH"
Chlorophyllide,
Chlorophyllin,
MgRJ^^SJ'
,
Phaeophorbide,
HR
2 2
MgR(COOH) 3
2
Phoeophorbin,
H R(COOH)
Glaucophyllin* or) Cyanophyllin,
M RH COOfn jMgKMÛUH) Pyrophyllin, MgRH 2 (COOH) Êtiophyllin, MgRH 3
Glaucoporphyrinf of Cyanoporphyrin
Pyroporphyrin,
H,RH (COOH)
2
^tioporphyrin,
v
H RH 3
2
In the tricarboxylic derivatives one carboxyl group is, of course, masked by lactam formation. Action of Alkalies and Acids on Chlorophyll. It has dready been stated that when chlorophyll- a is treated with alkali
it
ordinary temperature the phytyl radical is displaced, that a methyl ^roup is then eliminated, and that finally a tribasic acid, chloroAt 140 carbon dioxide is split off and }hyllin-tf, is produced.
^laucophyllin, a dicarboxylic acid, is obtained.
At 165 rearrange-
ment occurs and rhodophyllin is produced, which in turn at 200 oses carbon dioxide, with the production of a monocarboxylic acid,
Tyrophyllin.J
hot alkali is allowed to react with chlorophyll-a, an intranolecular change occurs with the production of isochlorophyllin-<z, someric with chlorophyllin-a. In this reaction the green colour
If
*
From
bluish green. Gr., y\avKos f From Gr., 7ro/?0tf/)eo$ J Willstatter and Fritzsche, Ann., 1909, 371 , 33. (D331)
purple.
2
i8
changes to a yellowish-brown but, after a few minutes, the original * green colour reappears. Willstatter has suggested that this phenomenon is due to the presence of the lactam group which opens and re-forms in a new position. The original lactam group may be denoted:
NH - CO
hydrolysis the carboxyl y may enter into union with another nitrogen group 8, or another carboxyl a may combine with nitrogen The action of cold and hot alkali may be represented by the y.
On
scheme:
d
NH CO
a
COOH
CO-O-C
H NH CO
29
MgN
3
MgN C H CO-OCH
3 31
NH CO
Chlorophyll
ay III
s
C 3l H 29 CO-OH
Chlorophyll! n - a
COOH
MgN
C n H ao CO-OH
IsochloTophyllin -a
Willstatter assumes that at least three of the nitrogen atoms of chlorophyll are capable of taking part in lactam ring formation,
and since there are three carboxyl radicles also present in the molecule it can be seen that a very considerable number of lac tarns may be formed. This type of rearrangement has been termed " allomerization
"
by
Willstatter.
further action of alkali, at higher temperatures, on chlorophyll-# results in the successive formation of cyanophyllin, erythrophyllin, and phyllophyllin, which are isomeric with glaucophyllin,
The
rhodophyllin, and pyrophyllin respectively. By the action of acids on chlorophyll, the
magnesium is removed from the molecule and replaced by two hydrogen atoms. Similar results are obtained by the action of acids on the decomposition
products of chlorophyll, so that for each magnesium derivative there
is
a corresponding
hydrogen compound.
The
phyllins and porphyrins

*
Ann.,
when heated with soda-lime

129.
are
ign,382,
STANDING IN
PHAOPHYTIN-a
[3)
WITH ACIDS
(C0 8 C M H 3t ) WITH
MgCH 3 I
[C 31
ALCOHOL CHLOROPHYLL-a H 29 N 3 M g ](NH-CO)(CO 2CH 3 )(CO 2C 2oH39)

y
ALLOM -CHLOROPHYLL-a [C H3oON Mg](C0 CH )(C0 C H 39

31 4 2
20
ft
a.
I
a o r METHYL-PHAOPHORBIDE-a [C M H 33 ON ](CO CH 3 (CO CH
4 2
)
ACID
3)
g r
METHYL-CHLOROPHYLLIDE-a [C ,H 30 ON Mg](C0 CH (C0 CH 3 w

3 4 2
3)
PHAOPHORBIDE-a < 3 [C 32 H 32 ON 4 ](CO,CH 3 )(COOH)
ACID
<
CHLOROPHYLLIDE-a
[C 32 H 30 ON 4 Mg](C0 2 CH 3 )
(C0 2 I
PHYTOCHLORIN-e [C M H M ON ](C0 1 H) 1
1
ACID
ISOCHLOROPHYLLIN-a [C 31 H M N Mg](NH-CO) (COOH)

3
CHLOROPHYLLIN-a
a
ACID
2
PHYTOCHLORIN,
[C S2 H 32 ON,](C()
2
and g
|
J3
[C 31 H 29 N 3 Mg](NHCO) 8 y
(COOH)
ft
H) 2
CYANOPORPHYIUN
[C,,H 3 ,N 4 ](CO,H) 2
CYANOPHYLLIN
[C 3l H 32 N 4 Mg](C0 2 H) 2
I
GLAUCOPHYLLIN
[C 31 H 32 N 4 Mg](C0 2 H) 2
GLAUCOPORPHYLLIN
>
>
-Io
p<?
ERYTHROPHYRIN
3
[C 31 H M N 4 ](C0 2 H) t
ERYTHROPHYLLIN
[C M H M N.MgJ(C
t U),
SODA LIME
"He RHODOPHYLLIN
[C 31 H 3a N 4 Mg](C0 2 H) 2
RHODOPORPHYLLIN
[C 31 H 34 N 1 ](C0 2 II) 2
PHYLLOPORPHYRIN
[C 31
Ac it)
PHYLLOPHYLLIN
-
PYRROPHYLLIN
Ac_[
PYRRQPQRPHYLLIN
[C 3 iH M NJ(C0 2 H)
H M N,]{CO,H)
M^CHTl
[C^N.MgKCO.H)
#/$
VETIOPHYLLi [C 3l H M N 4 Mg]
AETIOPORPHYLLIN
[QiHagNJ
[Facing p. 18,
CHLOROPHYLL
converted
into
,
19
C31 H 36N4
The
aetiophyllin,
C 31 H34 N4 Mg,
and
astioporphyrin,
18 summarizes the various decomposition of chlorophyll- a. Some of the intermediate products products formed by the decomposition of chlorophyll-a do not to be
respectively. table facing p.
appear
fornfed
when
chlorophyll-6
is
similarly treated.*
-Êtiophyllin and Êtioporphyrin. The aetiophyllin molecule contains no oxygen, so that the magnesium atom is probably
attached to nitrogen. By the oxidation of phylloporphyrin, methyl-ethyl-maleinirnide and haematinic acid (ii) are formed. The structures of these (i) substances are known with certainty to be:
CH
C - C C 2H 5
OC
(0
CO
CH 3 C = C CH CH COOH OC CO
2
NH
NH
(ii)
Nencki and Marchlewski observed the production of haemopyrrole on the reduction of the porphyrins. Haemopyrrole is a mixture of
three pyrrole derivatives, namely, an ethyl trimethyl and two isomeric dimethylethylpyrroles of the following structures:
CH C - C C H
3 2
CH C
3
C-CH
CH C - C C H CH C CH
3
2
CH C - C C H 5
3
-
HC
C CH 3
NH
Phyllo-pyrrole
NH
Iso-hsemopyrrole
NH
Krypto-pyrrole
Willstatter concludes that aetioporphyrin is probably a compound of four pyrrole nucleii. Owing to the deficiency in hydrogen, these nucleii must be so combined and substituted by double bonds or the formation of rings that eight atoms of hydrogen less are required than if single bonds were present. These considerations lead to a skeleton framework of the type:
N
'
Willstatter, Ber., 1914, 47, 2854.
20
around which the methyl and ethyl groups are so disposed as the products obtained on oxidation and satisfactorily to account for
reduction.
In this
way
the following formulae are provisionally

setiophyllin:
given to
aetioporphyrin and
HC=CH
CH.-O-CH
ii
C,H-C-C 8 2
>
c
,C
0-CH
C-C-C.H.
G=OCII 3
CH 3
Êtioporphyrin
^tiophyllin
is
Carotin,
C 40 H 56
an unsaturated hydrocarbon.
It crystal-
lizes in lustrous
rhombohedra which are orange-red by transmitted
and blue by
exposure to the air it readily undergoes oxidation and becomes bleached. Carotin also occurs in the roots of carrot, and the colour of yellow or orange petals is not
reflected light.
On
infrequently due to
it.
Xanthophyll,
lustre.
On
C40 5G O 2 forms yellow crystals with a blue Like carotin, it undergoes bleaching on exposure to the air. reduction with magnesium powder and water xanthophyll is
,
converted into carotin.*
Fucoxanthin, C 40 H 54 O 6 was first isolated from fresh brown Unlike carotin and xanthophyll, algae by Willstatter and Page.f which are neutral substances, fucoxanthin has basic properties, and
,
forms blue
per
cent
salts
with mineral acids.
Chlorophyll
of
iron
and
Haemin.
Haemoglobin
"
contains
"
0-47
and consists of a colourless protein named

non-protein
of
globin, united to a coloured prosthetic or
group.
with
Haemoglobin carbon
oxidized
to
possesses
the
remarkable
nitric
property
monoxide
is
and
oxyhaemoglobin.
the
oxide, and is When treated with
combining most easily weak acids,
oxy haemoglobin
nature
*
easily resolved into globin
and haematin.
is
The
quite
of
union
between
these
two substances
unknown.
Ewart, Proc. Roy. Soc., 1915, 89 [B],
i.
Ann., 1914, 404, 237.
CHLOROPHYLL
21
The properties of haematin have been studied by Kuster, Fischer (H.), Piloty, and Willstatter, but its constitution is still obscure. When treated with hydrochloric acid it is converted into a crystalline substance haemin.
Both haematin and haemin are freed from iron by the action of strong acids, and the iron-free pigment is known as haematoporphyrin. The latter on complete reduction with hydriodic acid yields haemoWillstatter and M. Fischer* treated haematoporphyrin pyrrole. with alcoholic potash in the presence of pyridine and obtained hsemoporphyrin, C 33 H 36 O4 N4 which on distillation gave aetioThese observations are of special interest since they serve phyllin. to co-relate chlorophyll and haemin. Haemoporphyrin is a dicar,
been studied by Kuster. f Two haematinic acids, which eventually proved to be the anhydride and imide of carboxyethylmethylmaleic acid, were
obtained:
boxylic acid of aetioporphyrin. The oxidation products of
haematin have
CH 3 C COOH
CH C - CO
3
H0 C
2
CHo CHo C
-
COOH
HO C-CH
2
.CH. 2
C - CO
||
/NH
Carboxyethylmethylmaleic acid
Haematinic acid
(i)
CH 3 C - CO
CH, C
-
- CO
H0 C CH CH C - CO
2 2
-
C 2H 5 C - CO
Methylethylmaleic anhydride
Haematinic Acid
(ii)
Both haematinic acids may be readily converted into methylethylmaleic anhydride. It has not been found possible to eliminate the iron from haemin until hydrogen bromide has been introduced into the molecule, and this is explained by a change from a to a carbon linking: nitrogen
>
Zeil. Physiol.
Chem., 1913, 87, 423.
Ann., 1906, 345,
x.
22

The
following tabulation briefly illustrates the relation of chloroits derivatives to those of haemin:
phyll and
Chlorophyll
I
Chlorophyllin
Haemoglobin
> Haematm
A e t o p or pby rin
i
Pyrrophyllin
i
AetiopJby'Uin
Haematoporphyrin
following provisional formula which has been assigned to haemin should be compared with that of aetiophyllin:
The
CH 3 .C
COOH.CH .CH
2
.C
CBL.C
There are many facts which still require elucidation, and no doubt modifications in the above formulae will be introduced as our knowledge of the more complex pyrrole derivatives becomes more
complete.
THE ANTHOXANTHINS
In this section we shall consider the more important yellow pigments which occur in the vegetative organs and in the petals of
account of their close relationship to the natural blue colouring matters known as the anthocyanins (p. 33), Willstatter and Everest* have proposed the adoption of the term " " anthoxanthins to distinguish these yellow pigments.
many
plants.
On
These colouring matters occur naturally in combination with

*
Ann., 1913 401, 189.
THE ANTHOXANTHINS
glucose or rhamnose, associated with the tannins, and in some cases uncombined. The majority of these pigments are derived either from xanthone (i) or flavone (ii), and are consequently frequently
classified as the
xanthones and flavones:
CO
These compounds owe their chemical properties to the presence of the y-pyrone nucleus, so that we may briefly consider the preparation of y-pyrone, even although it is not itself a natural product. y-Pyrone. This compound is the anhydride of a i 5-dihydroxy:
3-ketone, and has been prepared synthetically from chelidonic ester * by Claissen as follows: Chelidonic ester (i)f is converted into 2:6-
pyrone carboxylic acid

acid:
(ii)
on treatment with fuming hydrochloric

2
CH - C(OH)CO C H CO CH = C(OH)CO C.,H

2
->
5
CO
CH - C CO,H
CH = C CO,H
(ii)
(i)
and on heating
this substance decarboxylation takes place,

(iii)
with the
successive formation of coumenic acid
and y-pyrone
(iv):
COOH
CH = C
CO
(iii)
CH
CO
x
CH
O
CH = CH
y-Pyrone
is
/ CH = CH
(iv)
pounds
salts
a colourless solid, and the basic properties of containing the y-pyrone nucleus are well marked.
com-
The
with inorganic acids, which may be represented as addition products of the base with mineral acids, are as a rule more highly coloured than the bases from which they are derived, and are generally
Ber., !89i,24, 118. Chelidonic acid (7-pyrone dicarboxylic acid) occurs in combination with the alkaloid chelidonine in the root of the common celandine.
t
24
* very unstable in the presence of water. In 1899 Collie and Tickle observed that dimethyl y-pyrone (v) readily forms salts with many
acids,
and they suggested that the existence of these the oxygen atom (a) becoming quadrivalent when
salts is
salt
due to
formation
occurs.
CH C - CH
3
CO
\ - / C CH
CH
3
O(a)
(v)
Xanthone was first obtained by Kolbe and Lautermann by the action of phosphorus oxychloride on sodium salicylate.f It is most conveniently prepared by distilling a mixture of acetic anhydride and salicylic acid. During this reaction some phenol is produced, and the reaction may be considered to consist of the condensation of phenol and salicylic acid:
HOOCX\
+
X
I
I
CO
>-
OH HO\X
O
acid
(i)
Ullmann and Zlokasoff J obtained 0-phenoxybenzoic
by the interaction of sodium phenate and sodium o-chlorobenzoate in the presence of copper powder, and this acid readily passes into
xanthone by elimination of water.
COOH
CO
o
(i)
Xanthone
crystallizes in long colourless needles, gives a blue
fluorescence in sulphuric acid, and readily forms By reduction under suitable conditions, xanthene
(iii),
oxonium
(ii),
salts.
xanthydrol
and dioxyxanthylene
*
(iv)
may
be obtained.
Trans., 1899, 75, 710. f Ann., 1860, 115, 197. J Ber., 1905,38, 21 ii.
THE ANTHOXANTHINS
CHOH
25
(iii)
(iv)
the hydroxyxanthones, and indeed all hydroxyketones, are alkylated, the hydroxyl group in the ortho position to the carbonyl group remains unaffected. This is a noteworthy example of steric
When
hindrance.
Indian Yellow or Piuri. This pigment is obtained by concentrating the urine of cows which have been fed upon mango leaves.
On
(C
19
account of
The
salt,
H On
pigment which is present in the form of its magnesium or calcium 18 ), for which Graebe * suggested the formula:
disagreeable smell it principal ingredient of this

its
is
seldom used
is
as a dye-stuff.
euxanthic acid
CO
HO C H <^>C H O
6
CH(OH)[CH(OH)] 4 COOH
On
treatment with dilute sulphuric acid, euxanthic acid yields euxanthone.f The latter has been synthesized by v. Kostanecki and Nessler J by the condensation of resorcinol and hydroquinone
carboxylic acid in the presence of acetic anhydride:
COOH
OH
CO
OH
HOr^Y
I
/\>
H0
X/OH
1-2H.O +
H0\/
O
Euxanthone
Gentisin. This pigment is the yellow colouring matter of Gentiana lutea, and its identity with 1:3: y-trihydroxyxanthone3-methylether has been established by v. Kostanecki.
>*v
>v
>N
)H
HOr
OCH,
*
Ann., 1889, 254, 267. J Ber., 1891, 24, 1894.
f Cf. Stenhouse, Ann., 1844, 51, 429. Monats., 1891, 12, 207; 1895, 16, 919.
26
FLAVONE AND FLAVONAL PIGMENTS

Name.
Structural Formula.
Occurrence.
OH
Several varieties of
Chrysin
poplar, especially
Populus nigra, P.
pyramidalis.
Bark
Quercetin
of
Quercus
leaves
tinctorius,
of horse chestnut, hop, &c.
Dried
Rhamnetin
Rhamnus
ticus,
berries of cathartinctoria.
R.
Wood
Morin
wood).
of
Morus
(yellow
tinctoria
HO
OH CO
Reseda
Luteolin
luteola,
OH
Genista "weld"; "

tinctoria,
dyer's
broom ".
Galangin
Galanga
root.
Kaempferol
of DelFlowers consolida, phinium Prunus spinosa;

berries of
Rham-
nus catharticus.

The Flavones and
on
Flavonols.
in the free state in nature.*
their flower stalks, leaves,
27
Flavone has been obtained
Many
varieties of the
primula possess
or meal.
and seed capsules a characteristic dust This powder, obtained from P. pulverulenta and P.japonica,
has been
shown to be identical with flavone. Flavone has been synthesized by several methods, of which one or two illustrations may be given: i. Von Kostanecki and Tamborf condensed ethyl-o-ethoxybenbenzoylacetophenone
(i):
zoate and acetophenone, in the presence of sodium, to give o-ethoxy-
X\ cooc H
2
.,
(0
which,
when
digested with boiling hydriodic acid, yielded flavone.
CO
CO
CO-CH 2
OH
2.
HO
acids,
employed esters of /? - hydroxyarylcinnamic which he prepared by the action of sodium phenolates on the
J
:
:
Ruhemann
esters of propiolic acid, e.g.
C 6H 5 C C C0 2 C 2H 5 + NaOC 6 H 5 = C 6 H 5 C(OC 6 H 5) C(Na)CO 2C 2H 5

\
were then converted into the corresponding acids and chlorides, and the latter on treatment with aluminium chloride gave
esters
The
the corresponding flavones:
HO CO CH n CH C-C H
6
\/
o
->
/ \CH CH \ /C-C H
6
CO
||
condensed benzoyl acetic ester and phenol in the presence of phosphorus pentoxide:
3.
Simonis
CJETp-CO 2 5 f
^n.
*"
+ C H OH + H O
2 5
* Trans. , 1915, 107, 872. J Ber., 1903, 36, 1913, 2188.
^^-, 1900, 33, 330.

Ber.> 1914, 47, 2229.
28

CO
Methylacetoacetic ester condenses in the same way to give dimethyl-chromone:
o
sulphuric acid is used in the condensation of phenols and j8-ketonic esters, the reaction takes a different course and derivatives of a-pyrone (coumarin) are obtained.
It is interesting to
note that
if
Flavonol differs from flavone in the fact that
it
contains a
hydroxyl group in the y-pyrone ring in the place of the hydrogen is present in the case of flavone. Flavonol has been obtained synthetically as follows: i. Von Kostanecki and Szabranski* converted flavanone into
atom which
isonitroso flavanone
dilute acids:
(i)
and thence
into flavonol
by the action of
co
co
CH
o
o
(i)
Flavonal
2.
Auwers and
Miiller
-f-
obtained
2-methyl flavonol by the
action of caustic potash on the dibromide of benzylidene-4-methyl
coumaranone:
CH C H <^)CBrCHBrC 6 H 5 CO
3 6 3
CO
>
CH 3 C a H
xOH
3
Br
I
\ X
>
5
CO-C=C-C 6 H
/ \C-OH CH -C H \ /C-C H
3 6 3
||
OH
This
is
On
a general reaction and has been applied extensively. hydrolysis flavonol gives o-hydroxybenzoyl carbinol
acid:
(ii)
and benzoic
CO
CTT 4 6 rl
/ \C-OH \ /C-C H
II
I)
>
,.
/~i
TT
CO - C(OH)
<-6*~i4\
O
t
X OH
HO - C C H
-
* Ber.
1904, 37, 2819.
f ^^"- 1908, 41, 4233.
FLAVONE AND FLAVONAL PIGMENTS 29 OH CO - CH(OH) C H4 + C H,COOH OH CO C H CO CHoOH

6
6
This reaction is typical of a whole series of flavonol derivatives, and has been generally applied in the determination of their structure. As a rule the compound is first fully methylated and then boiled with
alcoholic potash.
This pigment was first (i 3-dihydroxyflavone). from poplar buds, in which it is present to the extent of isolated about 0-25 per cent, by Piccard in 1873. For this purpose an alcoholic extract of the buds is treated, while hot, with lead acetate, and after standing some time the yellow precipitate is removed. The excess of lead is removed as sulphide and the filtrate evaporated to
Chrysin
dryness. The residue is then purified by recrystallization, after it has been successively extracted with carbon disulphide, benzene, and boiling water.
Chrysin crystallizes in colourless leaflets which in alkaline solution exhibit an intense yellow colour. It forms a diacetyl derivative.
boiling with concentrated potassium hydroxide solution, chrysin gives phloroglucinol, benzoic acid, acetic acid, and a
little
On
acetophenone:
C 15 H 10
The
+ 3 H O - C H O + C H COOH + CH COOH
2
researches of v. Kostanecki indicated that chrysin was i 3dihydroxyflavone, and this has been established by its synthesis by
:
Emilewicz,
v.
Kostanecki, and Tambor.*
acetophenone-trimethyl-ether (i) is in the presence of sodium to give
For this purpose phlorocondensed with ethyl benzoate
2:4: 6-trimethoxy-benzoyl-
acetophenone
(ii):
OCH 3
-
OCH
I
X\_CO_CH
'
CH 3 O\^/OCH 3
]
CH
^
2
Boiling, concentrated hydriodic acid de-
methylates this compound, and at the same time the ring is closed with the
production of chrysin:
*
Ber., 1899,32, 2448.

Quercetin (1:3 :3':4'-tetraoxyflavonol) has been the subject of several investigations. It gives a penta-acetyl derivative, both a mono- and a tetra-methyl ether, and when fused with alkali it
When pentamethyl yields protocatechuic acid and phloroglucinol. is treated with alcoholic potash it quercetin gives methoxyfisetoldimethyl-ether (iii) and veratric acid (iv), which indicates that
quercetin
is
a derivative of flavonol: *
3
OCH CO
COCH 3 CH 3
OCH 3
OCH L ~ OCH 3
fV +COOH o> k^kpH

111
co: CH 2 OCH 3
OCH,
CH,
iv
Quercetin has been synthesized from phloracetophenone dimethyl ether and veratric aldehyde by v. Kostanecki, Lampe, and Tambor
as follows :f
OCH,
OCH
JI0
COCH:CH-< \
v VOCH/
X)CI
OH
Hydroxytetramethoxy-benzalacetophenone
OCH,
OCH, CO
HC1
CO-CH
CH 3
CH 2
OH CH-/
OCH 3
CO
C:NOH
V-OCH 3
CH 3
O
OCH,
CHQ
C-OH
c
CO
H 2 S04
CH3O
CH-/
VoCH
^
CH 3
O
OCH 3
OCH 3
Tetramethoxyflavone
Herzig, Ber., 1909, 42, 155. % This is analogous to the reaction:
*
t Ber. 1904,37, 1402.

y
CO
CH
CH-C.H. o 6
HC1
CO
(Alcoholic)
OH
O
Flavanone
w - Beazal-o-oxyacetophenoae

OCR,
31
OH CQ
O
Quercetin
The
with
reduction of quercetin to cyanidin chloride will be dealt

(quercetin-3-methylether). fruit of various species of
later (p. 37).
Rhamnetin
seed-bearing
Persian Berries
the
Rhamnus
contain the
glucoside xanthorhamnin, which on hydrolysis gives a sugar and the colouring matters rhamnetin, rhamnazin, and quercetin. Isorhamnetin, which is a monomethylether of quercetin, occurs, together with other products, in the common red clover.*
OH CO
vC-OH
-OH
HOk
'OH
VA^>
"
<
)OH CH3 OCH 3
'
Rhamnetin
Isorhamnetin
Rhamnazin
Morin
is
obtained from
Old Fustic " the wood of Chloro-
phora tinctoria a tree found in tropical regions. Together with logwood it is one of the most importaht natural dye-stuffs. In alkaline solution it gives an intense yellow colour, an olive-green coloration with ferric chloride, and a bright orange coloured precipitate with lead acetate. Morin has been synthesized by v. Kostanecki, Larnpe, and
Tambor
in a similar
is
manner
to quercetin. f
Luteolin
the main colouring matter of
herbaceous plant known as Reseda luteola tributed in France, Germany, and Austria. Weld is probably the oldest European dye-stuff, and it was used by the Gauls in the time
of Julius Caesar. A. G. Perkin assigned to luteolin the constitution of a tetrahydroxyflavone, and this structure has been confirmed by its synthesis
weld "the dried which is widely dis-
"
by
v.
Kostanecki, Rozycki, and Tambor.

(i)
acetophenone trimethyl-ether
is
For this purpose phlorcondensed with ethyl-veratrate

f Ber.,
* Power and Salway, Trans., 1910, 97, 231.
1906, 39, 625.
32
(ii)

to give 2 14
:
3':4'-pentamethoxy-benzoyl-acetophenone (iii), which on long digestion with concentrated hydriodic acid gives
:
luteolin:
OCH 3
H.OOC-/ 8
0)
(dihydroxyflavonol) is obtained from galanga root the rhizome of Alpinia officinarum. It has been obtained synthetically by v. Kostanecki and Tambor in a similar manner to
Galangin
that of Kaempferol.
Kaempferol.
The
constitution of this
compound
as a tri-
hydroxyflavonol is due to v. Kostanecki,* and it has been obtained from the blue flowers of Delphinium consolida by Perkin and Wilkinson, f
Von Kostanecki and Tambor J have

/
obtained kaempferol syn:
on thetically as follows: Hydroxy-4 : 6 : 4 -trimethoxy chalkone (i), / boiling with alcoholic sulphuric acid, gives i 3 4 -trimethoxy:
flavanone
(ii):
OCH 3
OCH 3 CO
The
with
latter
on treatment with amyl

.'3
:
yields isonitroso-i
and hydrochloric acid 4-trimethoxyflavanone (iii), which on boiling

nitrite
/
ro-per-cent sulphuric acid gives

9
y
1:3: 4 -trimethoxyflavonol
y
*Ber. 1901,34, 3723. t Trans. 1902, 81, 585. J Ber. 1904,3?, 792. Chalkone or benzylidene acetophenone is readily prepared by the condensation of acetophenone and benzaldehyde:
C 6 H 5 COCH 3 + C 6 H 5 CHO = C 6 H 5 COCH 2 CHOHC 6 H 5 C H 5 COCH CHC 6 H 5 + ->

6
:
HO
2
(Claisen, Ber., 1887, 20, 257.)

(iv),
33
yields
and the
latter
on digestion with hydriodic acid
kaemp-
ferol (v).
OCH 3 CO
,C:NOH
OCH 3 CO
/\/\C-OH
CH a o

Introduction. In spite of the fact that as early as 1664 Robert Boyle published an investigation of the colour changes which take place when flower extracts are treated with alkalies and acids,
it
only within the last decade that the nature of the anthocyanins has been revealed.
is
The
to
recognition of glucosides
among
the anthocyanins appears
have been first made by Heise as recently as 1894. In 1909 Miss Wheldale first suggested that anthocyanins might be formed from glucosides of the flavone or xanthone series by the action of oxidases, and showed that there are a certain nujnber of anthocyanin types which give rise to a definite series of colour varieties. Prior to 1913, the most fruitful attempt to isolate a colouring matter from blossoms in quantity sufficient for detailed examination had been made by Grafe in 1911, but the conclusions to which it In 1913 Willstatter began to publish, with led were inaccurate. numerous collaborators, a series of investigations which have brought For the purthis subject within the realm of synthetic chemistry. of distinguishing the glucosidic from the non-glucosidic pigpose ments, the names anthocyanin and anthocyanidin were applied to the former and the latter respectively. The first of these papers was published in collaboration with Everest,* and dealt with the cornflower pigments. It was shown
that the distinct shades of colour
shown by
different parts of the
flower are due to various derivatives of one substance; thus the blue form is the potassium derivative of a violet compound which is
*
(D331)
Ann., 1913, 401, 189.
34
converted into the red form by oxonium salt formation with a mineral or plant acid. The chromogen, as found in blossoms, was combined with two molecular proportions of glucose and isolated
as
removed and
On hydrolysis, the sugar was chloride was obtained. crystalline cyanidine Continuing these investigations, it soon became evident that the
crystalline
cyanine
chloride.
almost infinite variety of colour and tint exhibited by flowers does not imply the existence of an equally diverse series of plant-colouring
appears that only comparatively few basal colouring materials are distributed throughout the flower kingdom, and from
materials.
It
colours
these simple foundations the endless variety of floral shades and is built up by slight alterations in structure.
colouring matter of a large number of flowers has been examined, and these investigations have now culminated in the
The
In the -early stages of the synthesis of pelargonidin by Willstatter. of the anthocyanins, the reduction of quercetin was investigation
shown
produce cyanidin, and in this way the genetic relationship between the anthoxanthin and the anthocyanine series was established. More recent experiments on these lines have led to most interesting results concerning the problem of flower
to
colorations.
Extraction of the Pigments. In practice it has been found more advantageous to employ the dried material than to use fresh
flowers.
The
solvents
is
to the plant
which
for the extraction vary according used as a starting material, but the essential
employed
part of the process is the formation of a sparingly soluble oxonium Water alone suffices in the case of the cornflower; hydrosalt.
chloric acid in methyl alcohol is used in the case of the rose and the hollyhock; while dilute alcohol is used to remove the pigments from
the larkspur and the scarlet pelargonium. In the case of the grape the skins are extracted with glacial acetic acid at ordinary temperature and the dark red filtrate is precipitated with ether.
investigation of the anthocyanins is rendered difficult by the fact that they are not very stable substances. Aqueous or
The
alcoholic solutions
of the pigments gradually lose their colour. Decolorization can be delayed by the addition of salts such as sodium
chloride,
it
and the addition of excess of mineral acid apparently stops
completely. Among the methods which have been employed for the purification of the extracted pigments may be mentioned: precipitation and
crystallization of the chloride; purification
by
suitable reagents
and

quent
crystallization of the chloride; and separation as picrate conversion into chloride.
35
and subse-
anthocyanins can be distinguished from the anthocyanidins in solution by the addition of amyl alcohol after acidification with sulphuric acid, when the anthocyanidins alone dissolve in the amyl
alcohol.
The
The
water, and
anthocyanins, as glucosides, are readily soluble in as a rule in alcohol, but are insoluble in ether and chloro-
The glucosides are hydrolyzed by heating with dilute acids, the resulting anthocyanidin salts are insoluble in ether but are and generally soluble in water and in alcohol. With one exception, the
form.
pigments themselves have not been obtained in the crystalline state. Nomenclature. It has already been pointed out that when
the anthocyanins are hydrolyzed by hydrochloric acid they are converted into sugars and the chlorides of a base these chlorides being
conveniently termed anthocyanidins. The scientific terminology, however, requires some explanation. We have already seen that dimethyl y-pyrone is a base which owes
basic properties to the fact that the oxygen atom may become quadrivalent with the formation of oxonium salts. These salts may
its
be written
formula:
(i)
or
(ii)
according as
)H
we
use the benzenoid or quinonoid
c-CH
The
(iii),
y-pyrones may also be regarded as derivatives of y-pyrone which again bears a resemblance to the pyrylium or pyroxonium
salts (iv):
CH
HcXN,CH
LJ
?
(iv)
Pyrylium salts such as the chloride and nitrate have been ob tained, but the parent base has not been isolated.
36

The
anthocyanidins
salts
may be
* which
benzopyroxonium
quinonoid
(ii)
regarded as derivatives of 2-phenylmay be given a benzenoid (i) or a
is interesting to note that 2-phenylhas not been isolated in a pure state. When its benzopyroxonium chloride, which itself is very hygroscopic and easily decomposed on exposure to the atmosphere, is treated with caustic soda, a very
structure. It
unstable crystalline precipitate
is
obtained.
CH
CH
--
o x
i
(Benzenoid)
(i)
(Orthoquinonoid)
(ii)
hydroxy or methoxy derivatives of 2-phenyl-benzopyroxonium salts; thus cyanidin chloride may be

are
The anthocyanidins
(iii)
written
or
(iv):
QH
PH
HO
OH CH ^f\ XV r.nuHO
QH
H
X/V/ C-\_/~OH
(iii)
-XXXX C -^ >
(iv)
ci (Orthoquinonoid)
ci (Benzenoid)
has been suggested that the blue anthocyanidin pigment is the potassium salt of a phenol betaine (i), but this view has been adversely criticized by Heilbron.f
It
OH
(0
Distribution of the Anthocyanins.

tion illustrates the distribution of
The
following tabula-
some of these pigments:

Dahlia, scarlet geranium. Aster.
Pelargonidin.
Pelargonin.
Callistephin.
*
Diglucoside of pelargonidin. Monoglucoside of pelargonidin.
salts of 2-phenyl-benzopyroxonium have been also termed polyflavylium or polyflavoxonium salts. In this way cyanidin chloride may also be designated as a pentahydroxy-flavoxonium chloride.
salts
The
fHeilbron and Buck, Trans. 1922, 121, 1198.

,

Cyanidin.
37
Cyanin.
Peonin.
Idaein.
Diglucoside of cyanidin. /Diglucoside of peonidin (mono\ ethyl ether of cyanidin). Monogalactoside of cyanidin.
Cornflower, dahlia.
Peony.
Fruit of cranberry.
Delphinidin.
Violanin.
Rhamnoside of delphinidin.
Delphinin.
Oenin.
/Diglucoside of delphinidin ( hydroxybenzoic acid. of oenidin (del| Monoglucoside \ phinidin dimethyl ether).
+-
Pansy.
Larkspur.
Fruit of grape.
Cyanidin Chloride.
Willstatter
and Mallison obtained a
small yield of cyanidin chloride by the reduction of quercetin with sodium amalgam or magnesium in alcoholic solution containing
hydrochloric acid and mercury:
OH CO
,C-OH
1LJ
H OH
V
OH
/X/ \C-OH
HO
OH OH
[Intermediate product]
Cyanidin chloride
Cyanidin
alcohol.
itself
is
insoluble in water,
it
but readily soluble in
With sodium carbonate
coming blue and then violet. cyanin and cyanidin are obtained by hydrolytic dissociation, and the colour may be restored by concentration or the addition of acid.
resembles cyanin in first beColourless modifications of both
Everest found that cyanidin chloride undergoes decolorization when heated for a short time in dilute alcohol at 80. In explanation of this phenomenon he suggests that in solution an equilibrium mixture
of the two forms
(i)
and
(ii)
is
present,
and that preponderance of
38
one or other of the two forms depends on the condition of the solution.
OH
HO
o
6
Coloured
(i)
Cl
(ii)
Colourless
Pelargonidin and Delphinidin Chlorides. Pelargonin is a monoglucoside of pelargonidin, and on hydrolysis with hydrochloric acid yields the chloride of the latter and glucose. Phloroglucinol and ^-hydroxybenzoic acid are obtained when
pelargonidin chloride
is
heated with acids.
with formula
thesis.
(i),
and
this
This is in agreement structure has been confirmed by its syn-
OH
CH
OH
Delphinin chloride yields glucose, delphinidin chloride, and />-hydroxybenzoic acid on hydrolysis, and by analogy with the glucoside populin (benzoyl salicin) it is assumed that the benzoylation takes place in the glucose and not in the delphinidin portion of
the molecule.
Delphinidin chloride gives phloroglucinol and gallic acid on treatment with hot acids, and Willstatter has proposed the
formula:
CH
,OH
HO
vatives.
Synthesis of Salts of Benzopyroxonium and its DeriThe following are the more important methods by which these compounds may be synthesized:

i
.
39
* obtained benzopyroxonium Fellenberg the condensation of salicylaldehyde with acetaldehyde chloride by in the presence of concentrated hydrochloric acid:
Decker
and
v.
CHO
C 6H4
<(
CH 3 +
I
CH:CH
6
I
OH
+ HC1 = C H 4<^ O CHO
CH + 2H O
2
The
salt
was analysed in the form of its double salts with ferric In moist air the ferric chloride double chloride and gold chloride.
salt
undergoes slow decomposition with the formation of cumarin, probably according to the scheme:
CH CH
:
CH CH
:
C.H
C6H
O
Cl
CH
CH CH
:
CH
OH
CH CH
:
I
->
Isomerization
C 6 H 4<
Au
rnu
Oxidation
o-co
replaced by acetone, salts of z-methylbenzopyroxonium are obtained, and it has been generally shown that any compound containing the CH
When
acetaldehyde
is
In group may be used. this way co-ethoxy- and phenoxyacetophenones have been converted
into
CH 2 CO
/
\
^^^T
compounds
2.
of the anthocyanidin
type.f
2-Methyl-benzopyroxonium chloride has been obtained by iodide in benzol solution: treating cumarin with magnesium methyl
PH'CH
^
CHaMgI
CH
C 6 H 4<
CH
O-CO
CH CH
:
OMgl COCH 8
O
i,
Ann., 1909, 364, 17.
f
C-CH
Pra tt and Robinson, Trans., 1922, 121, 1577.
40
2-Phenyl-benzopyroxonium chloride has been obtained in a similar manner, using magnesium phenyl bromide. Synthesis of Pelargonidin, Pelargonidin has been synthesized by Willstatter and Zachmeister * as follows: 2 4 6-trihydroxybenzaldehyde (i) is condensed with sodium methoxyacetate,
:
in the presence of the corresponding anhydride, to give 5 : y-dimethoxyacetyl-3-methoxycoumarin (ii), which on successive treat-
ment with caustic soda and diazomethane yields 3:5: y-trimethoxycoumarin (iii). This compound is then treated with magnesium anisyl bromide and converted into the chloride of anisyl-trimethoxybenzopyroxonium (iv). On demethylation with hydriodic acid and subsequent treatment with hydrochloric acid, pelargonidin chloride
is
obtained.
A(0
OH -
HI COCH
CH 3 0-CH 2 CO-0
CH
i"
CH
CII S O
CH 3
CH
()
HO
CH
c
/\/\C-OCH
ôkA/ 00 O
* *
âovUÎ)
O-C1
1V / (
/
*
vU -O
O-C.1
ll1 / (*
Pelargonidin chloride
The Origin of the Anthocyanin Pigments in Plants.
This
problem has attracted a good deal of attention, but up to the present no finality has been reached. In view of the frequent occurrence of
glucosides in the plant it is not surprising that the anthocyanins are glucosides, but the non-glucoside or anthocyanidin portion of these
compounds deserves
special attention. have already seen that the anthocyanidins have a structural formula closely related to that of the flavones, and this fact in con-
We
junction with the production of cyanidin on the reduction of quercetin has suggested that the anthocyanidins may be derived from the
flavones.
comparing the formulae of some of the anthocyanidins with those of the flavone and flavonol pigments, it is seen that they may be arranged in a series as follows:
Pelargonidin,
On
C 15 10 O 5 Luteolin, kaempferol, .... Quercetin, C 16 10 O 7 Cyanidin, C 15 10 O 6 Delphinidin, C 15 10 O 7 .... Myricetin, C 15 n O 8

.
fisetin,
H H
C 15 H 10 O
* Sits. Preuss. Akad. Wiss. Berlin, 1914, 34, 886.

From
this tabulation
it is
41
one atom of oxygen
evident that the anthocyanidins contain than the corresponding flavones, so that if the chemist ascertains which flavone, flavonol, and anthocyanin pigments are present in one and the same flower, and then deterless
mines whether the relationship is one of oxidation or reduction, the problem will be advanced at least one stage. Combes * has shown that if an acidified alcoholic solution of quercetin is treated with zinc dust, magnesium ribbon, or sodium amalgam, a brilliant crimson solution is obtained, which gives a green colour when treated with alkali. This red substance has been " artificial antermed allocyanidin or OH OH / / but Willstatter has stated /V/' thocyanin ",
o=r
not a true anthocyanin pigment and he proposes for it an open structural formula:
that
it is
\_ O H /
S^/S^/C-OH OH CH
Shibata f and his collaborators have studied the reduction of myricetin by magnesium in the presence of organic acids, and have
obtained a number of complex

light
salts
which appear
to
throw some
on the problem of plant
coloration.
Despite the definite evidence produced by Willstatter and others, that anthocyanins are reduction products of flavones, the known
correlation of distribution of oxydases and of anthocyanins used as an argument for the older oxidation hypothesis. It
possible, however, that the assumption that oxidation
may be
is
quite
two views may be reconciled on the is needed in* the earlier stages of the and that only the final stage is one of reduction of flavone synthesis,
derivatives to anthocyanin.
Finally, it should be remembered that the fact that small quantiof a natural anthocyanin pigment can be obtained artificially by the reduction of a hydroxyflavonol, does not necessarily imply that
ties
one
class is derived
from the other in the
plant.
REFERENCES.
The Chemistry of Plant Products, by P. Haas and T. G. Hill, 2 vols. (London, 1921, 1922). The Natural Organic Colouring Matters, by A. G. Perkin and A. E.
Everest (London, 1918). The Anthocyanin Pigments of Plants, by M. Wheldale (Cambridge, 1916). Untersuchungen iiber Chlorophyll, by Willstatter and Stoll (Berlin, 1913).
Ueber Pflanzenfarbstoffe, Willstatter (Ber., 1914, 47, 2831).

*
Comptes rendus, 1914, 158, 272.
J. Amer. Chem. Soc., 1919, 41, 208.
CHAPTER
III
The Carbohydrates
This group of compounds, which includes the sugars, starches, celluloses, and gums, constitutes one of the most important groups of organic compounds. The carbohydrates are among the principal products of plant life, and they are also elaborated, but to a much smaller extent, in the animal organism. The desire to produce grape-sugar artificially is coeval with organic chemistry itself, for Liebig had indicated the fascination of this problem. As early as 1811 Kirchhoff had found that starch may be transformed into a sugar, while more exact knowledge of the varieties of the sugars was obtained by Biot. The term glucose was suggested by Dumas, while laevorotatory fructose was termed Kekule eventually applied the term dexlaevulose by Berthelot.
Introduction*
trose to dextrorotatory grape-sugar.
In 1861 Butlerow obtained methylenitan by the action of lime water on a hot solution of trioxymethylene as a sweet, pale yellow syrup responding to the common tests for glucose, but differing from the latter by being optically inactive and unfermentable by yeast. In 1886 Loew subjected formaldehyde to the action of cold lime water and obtained a sugar-like product which he termed formose. At this time chemists recognized two aldohexoses (glucose and galactose), two ketohexoses (fructose and sorbose), and one aldopentose (arabinose). Three hexobioses (sucrose, lactose, and maltose) and one hexotriose (raffinose) were also known to be definite individuals. Kiliani had introduced the cyanhydrin reaction, and had determined the general structure of glucose and galactose as that
of straight-chained
pentahydroxyaldehydes, and of fructose as a
pentahydroxyketone. The subsequent development of the sugars from this chaotic mass of isolated facts is largely due to the masterly researches of
Emil Fischer.
The
discovery of plenylhydrazine was of enormous

42
THE CARBOHYDRATES
43
value in this direction, and it was perhaps fortunate that nothing of the nature of the Walden inversion disturbed the aldohexose configurations.
Step by step the structure of the monosaccharoses has been unravelled, and step by step they have been built up from the
simplest materials. Of late years the discovery of y-methylglucoside by Fischer and Irvine has opened the way to a multitude of contingent isomerides, by
those of df-glucose alone numbering eleven; and the work of Irvine on the substituted methyl derivatives of the carbohydrates has done much to increase our knowledge of their structure. Even to-day our knowledge of the starches, celluloses, and gums is little more than a collection of empirical observations. The recent work of Irvine on the alkylation of these substances deserves particular commendation, because it is on these lines that the constitutions of many of these compounds may eventually be
determined.
fall
Classification of the Carbohydrates, The carbohydrates naturally into two classes, the sweet and crystalline compounds
termed sugars and the tasteless amorphous carbohydrates. According to the old system of classification, the carbohydrates were
divided into three groups: the grape-sugar group, containing all the isomeric compounds of the formula C 6 12 O 6 ; the cane-sugar group, embracing all the compounds of the formula C 12 2 2O n ; and the
amylose or starch group, which contained the amorphous, complex The three carbohydrates of the general formuta (C6 10 5 ) W of carbohydrates are now termed monosacprincipal groups charoses * (formerly glucose), disaccharoses (formerly the canesugar group), and polysaccharoses (formerly the starches, &c.).
H O
Fischer succeeded in preparing a large number of new sugars, containing from two to nine carbon atoms, which possess the general characters of the monosaccharoses, and these are distinguished by
the terms biose, triose, tetrose, &c. While some of the monosaccharoses combine the properties of alcohols and aldehydes, others
have the characters of alcohols and ketones, and the additional terms aldose and ketose have been introduced. It should be noted that several recently discovered sugars, e.g. rhamnose and fucose, have the " " formula C6 12 O 5 so that the old term (hydrate carbohydrate
of carbon)
is
not
now
strictly applicable to all
compounds
",
classified
as carbohydrates.
" * Fischer uses the suffix " ide " in ose place of
glucosides.
by analogy with the
44
THE MONOSACCHAROSES
Glucose and fructose are among the most commonly occurring sugars in plants and animals. These and others may be obtained from the glucosides and polysaccharoses by the hydrolyzing action of acids and ferments. Thus rf-glucose is found in the majority of glucosides, while cane-sugar yields glucose and fructose on hydrolysis, and raffinose yields glucose, fructose, and galactose. Other monosaccharoses occur as follows:
Natural Sources.
ARABINOSE. As the pentosan araban, in cherry gum, gum arabic, &c. XYLOSE. As the pentosan xylan, in woody tissue. It may be readily prepared from cotton seed hulls with a yield of 8 to 10 per
cent.*
GALACTOSE.
As
a galactan in various gums, mucilages,
and
pectans, e.g. agar-agar.
As condensation products, the mannans, in certain mucilages, and in the cell walls of the endosperm of various seeds.
MANNOSE.
A convenient source for its preparation is vegetable ivory nut.f

Synthetic Preparation of the Monosaccharoses. The following are among the more important synthetic methods which have been elaborated for the preparation of monosaccharoses: 1. The Oxidation of the Polyhydric Alcohols. This may be effected by bromine and sodium carbonate,^ nitric acid, Fenton's reagent (hydrogen peroxide and a ferrous salt), bromine on the lead
salt
of the alcohol, platinum black. <J E.g. glycerol gives glycerose, a mixture of glyceric aldehyde and dihydroxy acetone, in which the
||
latter
" Sorbose Bacterium". This Oxidizing Action by organism was discovered by Bertrand** and found to exert a selective
2.
predominates.
action in the case of the polyhydric alcohols. Glycerol and z-erythritol are oxidized to the corresponding ketoses, while glycol, /-xylitol, and
dulcitol are unattacked.
*
Hudson, ^. Ind. Eng. Ghent., 1918, 10, 176. f Hudson,^. Anter. Ghent. Soc., 1917, 39, 470. j Fischer and Tafel, Ber. 1887, 20, 3384. Fischer and Tafel, Ber. 1887, 20, 1088. Fischer and Tafel, Ber., 1888, 21, 2634. Grimaux, Contptes rendus, 1887, 104, 1276. ** Bertrand, Ann. Chint. Phys. 1904, 8, 3, 181.
t
||
][
THE MONOSACCHAROSES
3.
45
Solution.
Aldol Condensation of the Lower Members in Alkaline Dilute sodium hydroxide solution is usually used as
e.g. glycollic
2
condensing agent,
2
aldehyde polymerizes
2
to erythrose:
CH (OH)CHO + CH (OH)CHO - CH
4,
(OH) CH(OH; CH(OH)
CHO
Conversion of a Lower to a Higher MonosaccRarose. The Cyanhydrin Reaction. This reaction was discovered
*,
and was widely applied by Fischer in the study of the sugar group. A typical example of its application is the conversion of /-arabinose into /-mannonic and 7-gluconic acids:
by Kiliani in 1885
COOH
HOH-H
HO
HO-
OH H
CH 2 OH
HCN.then
Hydrolysis
H HO
HO
CH,OH
/-Arabinosc
of the Cyanhydrin
CH OH
a
Z-Gluconic acid
/-Mannonic acid
is introduced in this reaction, and two products are formed. consequently This reaction opened the way to the artificial production of The method was found to be capable of /-glucose and /-mannose. wide extension, and is limited only by the diminishing amount of
new asymmetric carbon atom
material available for each succeeding step. were realized by Fischer: f

J-glucose
f
The
following series
a-glucoheptose
\ (3-glucoheptose
rf-mannose
^-"6^12^6
mannoheptose
/a-gluco-octose (p-gluco-octose rnanno-octose -
"
glucononose
mannononose
C H 14
7 -
C 8 H 16 O 8
rhamnoheptose
CoH 18 O 9
rharnno-octose
7
rhamnose
oc-rhamnohexose
C 6 H 12 O 5
5.
C H 14
7
C 8 H 16 O
Conversion of a Higher to a Lower Monosaccharose. The degradation of a sugar may be brought about in
four ways:
(a)
WohVs method.^
*
This method may be
conversion of glucose into </-arabinose.
by the In practice the oxime of

illustrated
9
Ber., 1886, 19, 3033. f Ber. 1890, 23, 2611. J Ber., 1893, 26, 730; 1897, 30, 3101; 1899, 32, 3666.
46

when
nitrile
the monosaccharose
chloride,
gluconic by treatment with ammoniacal silver oxide.
heated with acetic anhydride and a little zinc a vigorous reaction ensues and the pentacetate of is formed. Hydrogen cyanide is then eliminated
is
CHO
CH NOH
:
CN
CHOH
(CHOH) 3
->
CHOH
(CHOH) 3
->
CHOH
(CHOH) 3
->
CHO
(CHOH) 3
CH OH
2
CH OH
2
CH OH
2
CH OH
2
Glucose
Glucose oxime
Gluconic
nitrile
Arabinose
In
this
way glucose may be converted
successively into arabinose,
erythrose, glycerose, and glycollic aldehyde. In this method the calcium salt of the mono(b) Ruff's method* basic acid obtained from the higher monosaccharose is oxidized, by means of Fenton's reagent, to the lower sugar.
C 6 H 12
->
C 6 H 12
+ O -> C H 10 O + C0 + H O
5
Glucose
Gluconic acid
Arabinose
Neuberg's electrolytic method.-^ The sugar is converted into the corresponding acid, and the copper salt electrolysed between platinum electrodes. In this way gluconic acid may be converted
(c)
into t/~arabinose
and ultimately complete degradation to formaldehyde
achieved.
method^ An alcoholic solution of gluconolactone gives </-gluconamide on saturation with ammonia. When this is
(d) Weermanri's
treated with hypochlorous acid a 50 per cent yield of t/-arabinose
is
produced.
H 2O HC1O -CH(OH)CONH 2 -> -CH(OH)N:CO -> - CHO +
NH + CO
3
In this way the following transformations have been achieved: d-galactose to rf-lyxose, /-mannose to /-arabinose, and /-arabinose to
/-erythrose.
6.
Conversion of Aldoses into Ketoses.
be brought about with the aid of phenylhydrazine.

of glucose into fructose as carried out by Fischer
*
Ber., 1898, 31, 1573.
may The conversion may be considered.

24, 152.
This change
t Biochem.
Zeit., 1910,
%Absts.> 1915, 1, 387.
THE MONOSACCHAROSES
47
An excess of phenylhydrazine and glucose react with the formation of glucosazone as follows:
CHO CHOH
(CHOH) 3
CH N NHC 6 H 5
:
CHOH
+ C H NH-NH 2
6 5
""
(CHOH) 3
+ C H NH NH 2
6 5
CH OH
2
CH OH
2
Glucose
:
Glucose phenylhydrazone *
->
CH N-NHC H CO + C H NH + NH, (CHOH) CH OH

6
Intermediate product.
The phenylhydrazone
first formed has undergone oxidation at the of a second molecule of phenylhydrazine, and the interexpense mediate product thus formed then undergoes further condensation
with phenylhydrazine to give glucosazone, which on hydrolysis gives

glucosone.
CH N NHC H
:
CHO
Warm
cone.
C N NHC H 5
:
HC1
CO
|
->
(CHOH) 3
(CHOH) 3
CH OH
2
CH OH
2
Glucosazonef
Glucosone
its
The osone on
reduction of
lead salt with zinc dust
and
glacial
acetic acid is converted into fructose.
An
alternative
method
consists in reducing the osazone with
zinc dust
and
acetic acid,
when an osamine
is
formed.
The
latter
on treatment with nitrous acid gives
rise to fructose:
Fischer, Ber., 1887, 20, 821.
f Fischer, Ber., 1884, 17, 579.
J Fischer, Ber., 1889, 22, 87.
48

note that Fischer has shown that the sugars be conveniently purified by preparing the pure phenylhydrazone may and regenerating the sugar therefrom by heating it with benzaldehyde or formaldehyde, when the hydrazone group is transferred to the
aldehyde and oxygen takes its place.* 7. Reduction of the Lactones of
Mono- and Dibasic

acids,
Polyhydroxy Acids. f
The monocarboxylic
produced by
the oxidation of the aldoses, are readily soluble in water, and many of them pass spontaneously into their lactones; e.g. gluconic acid
These lactones are crystalline compounds ^ gives gluconolactone. in aqueous solution pass into the corresponding acids, until which
a condition of equilibrium
is
attained.
Many
of these lactones
with sodium amalgam and water, in the presence of carbonic acid, and thus converted into the corresponding aldoses. The solution should be kept acidic by the judicious addition of dilute
may be reduced
sulphuric acid from time to time as the sodium salt of the acid cannot be reduced. This is a reaction of great importance, since it serves as a means of passing from the acid to the corresponding aldose,
which may then be reduced

gives glucose:
to the alcohol, e.g. gluconic lac tone
CO
CHO
2
O (CHOH)
(CHOH) 2
H CHOH :H OH
2
+H
CHOH CHOH CH OH
2
Gluconic lactone
Glucose
Interconversion of Isomeric Polyhydric Monocarboxylic Acids. J These acids undergo a very interesting change
8.
when they
are heated with pyridine or quinoline at a temperature of 130 to 150, e.g. d-gluconic acid treated in this way is partly transformed into rf-mannonic acid, whereas d-mannonic acid under the
The partly converted into d-gluconic acid. asymmetric carbon group, to which the carboxylic group is directly united, undergoes optical inversion. As the process is reversible
same conditions
is
the original
and newly formed products are usually present

y
is
* Fischer and E. F. Armstrong, Ber.

t Fischer, Ber., 1890,
1902, 35, 3141.

J Fischer, ibid., 2611.
23, 930.
THE MONOSACCHAROSES
an equilibrium mixture.
follows:
49
represented as
The
reaction
may be
COOH
COOH
H-C-OH
:HOH)*
HO-C-H
(CHOH)*
CH OH
2
CH OH
2
This method has proved of great value, not only for synthetic purposes, but also as a means of ascertaining the configuration of
the monosaccharoses.
of Glucose and Fructose. Although it is impossible to give here an adequate description of these syntheses, or to convey more than an idea of the great difficulties which had to be overcome, the more important results of this work may be briefly
The Synthesis
summarized.
work, carried out by Butlerow and Loew, has already been referred to. Fischer himself has stated that the directive inearlier
The
work among the carbohydrates was the discovery of a- and j8-acrose. In 1887, associated with Tafel, he obtained from acrolein dibromide and baryta a syrup which yielded two osazones, isomeric with one another and with phenylglucosazone. They were called a- and ^8-phenylacrosazone, which corresponded to the two synthetic sugars a- and /?-acrose, having the composition C 6 H 12 O6
fluence
on
his
The former
sugar he subsequently identified with <//- fructose, whilst /3-acrose, which he suggested resembled sorbose, was proved by E. Schmitz in 1913 to be the dl form of that ketose. The acroses are
optically inactive, and although reducible to hexahydric alcohols the yields are very poor. /?-Phenylacrosazone was eventually
hydrolyzed to glucosone, and, on incomplete reduction, this product was obtained. By applying this process to a-acrosazone, in combination at subsequent stages with Pasteur's methods of separating optical antipodes, the passage from inactive synthetic a-acrose to sugars identical in all respects with ^/-glucose, d- fructose, and d'-mannose was ultimately effected. The following tabulated
fructose
scheme
illustrates the synthesis of
some of these
sugars.
(D331)
50

Acrolein dibromide
Formaldehyde
Glyeerose
I
â-Acrose
a-Acrosazoue
i
a-Acrosoae
dl- Fructose
1-
Fructose
dl-Marmitol
dl-
Mannonic Acid
d -Mannonic Acid
1-
Mannonic Acid
1-Gluconic Acid
1 1-Mannose
I
d-Mannose
d-Glucomc Acid
d- Glucose
1-
Glucose
d-Glucosazone
d-Glucosone
d- Fructose
of the Monosaccharoses. Before considering the stereochemical configurations of the monosaccharoses it is desirable to consider some simpler cases. Compounds of the type Cabcd which contain a single asymmetric carbon atom exist in
The Configuration
two forms
only.
These may be represented thus:
These two arrangements are
One may be
arbitrarily.
designated as
later,
and mirror image. or /, or d the other then becoming

related as object
y
the formulae assigned to d- and /-glucose are chosen in the d form the groups occupy a certain position, so that in the stereoisomeride they are in the reverse position. The prefix does not necessarily denote the sense of the rotation.
It is
* As will be shown
assumed that
THE MONOSACCHAROSES
If these two compounds are solids the choice being immaterial. of one are related to those of the other as object the crystals Such crystals are said to be hemihedral or to mirror image.
enantiomorphous (Gr.,
eVai/r/o?
opposite),
compounds
another.
If
are
said
to
be enantiomorphously related
and the d and / to one
two asymmetric carbon atoms are present a larger number of modifications may exist. The classic example of optical isomerism in substances containing two asymmetric carbon atoms is that of the tartaric acids. Four modifications, namely dextro, laevo, meso, and racemic, are known and the first three may be represented:
-^ OH
TT
HO 4^.
COOH
d- Tartaric Acid
1-
COOH
Tartaric Acid
COOH
Meso-Tartaric Acid
or by using projections of these models:
COOH
H-
COOH
-H
COOH
H
H-
-OH -OH
HO-
H-
-OH
COOH
Mesotartaric acid
is
COOH
COOH
It is inthe simple optically inactive form. active by internal compensation, and cannot be resolved into two optically active modifications because all the molecules of which it
is
composed
are
alike.
Racemic or
rf/-tartaric
acid
is
simply a
crystallographic union of equal quantities of the d and / acids. It is therefore inactive by external compensation and can be resolved
into the
which concarbon groups, exist in asymmetric three optically isomeric forms which may be represented by the and ~| fIf, however, the two , H respectively. signs asymmetric groups in this acid are made to have different structures,
like tartaric acid,
d and / forms. Thus it is evident that compounds

two structurally
,
tain
identical
52
as e.g.
CH 2 OH, the by reducing one of the COOH groups to are no longer identical, so that four and fconfigurations H and isomerides are now possible, viz. -j [-, H optical K Of these four optical isomerides, the first two are enantiomorphously related, optically active forms. The second two are also enantiomorphously related and both are optically active. Neither would correspond with mesotartaric acid, because in the molecule of the latter the + and groups are structurally identical and enantiomorphously related, as a result of which the acid is an internally compensated and optically inactive compound. The mole,
,
CH 2 OH CHOH CHOH CHO, or the corresponding monocarboxylic acids, CH 2 OH CHOH CHOH COOH,
cules of a tetrose,
contain two dissimilar asymmetric carbon groups and would therefore exist in four optically active forms, and two of these (the h
inactive dicarboxylic acid. An extension of this reasoning to the pentoses shows that the following tabulation represents the theoretical possibilities:
)
and the
would give one and the same
ASYMMETRIC CARBON ATOMS.

Pentoses
.
. .
OPTICAL ISOMERIDES.
8,
4 pairs of enantiomorphously
related isomerides.
Corresponding
boxylic acid
acids
. .
monocar. .
3
3
8,
,,
Corresponding dicarboxylic
. .
Hexoses Corresponding dicarboxylic

. .
.
.
4
4 4
16,
4,* 4 8
,,
,,
acids
Corresponding hexitols
10 10
Using the signs
and
as in the case of the tartaric acids r
* The molecules of a 2 2 OH, and pentitol, those of the corresponding dicarboxylic acid, contain two asymmetric carbon groups only, because the middle atom is combined with two structurally identical groups CHOH- COOH], and has therefore lost its asymmetry. or 2 [and or When the groups attached to i and 3 have the same configuration, the compound is optically active (compare the tartaric acids). When and and the these two asymmetric groups have different configurations (one being other ), internal compensation ensues and the presence of the middle group (2) renders possible the existence of two such internally compensated (inThere are thus four optically isomeric pentitols, of which two are active) forms.
-
CH OH CHOH CHOH CHOH CH
CHOH-CH OH
,
CHOH
enantiomorphously related and optically active, and two are inactive by internal compensation.
THE MONOSACCHAROSES
53
to distinguish any two enantiomorphously related groups, the configurations of the aldopentoses and aldohexoses may be represented
thus:
Aldopentoses.
CH OH
2
(X)
*
CHOH CHOH CHOH CHO
<Y)
Aldohexoses.
CHOH
CHOH CHOH
<P)
+ + + +
+
i
CHOH
CHO
II
Laevoxylose under suitable treatment gives one of the optically inactive pentitols and one of the optically inactive trihydroxy-dicarboxylic acids, and therefore
The Pentoses and Hexoses.
must be represented by i, 2, 3, or 4, since these are the only configurations from which it would be possible to derive an internally compensated pentitol, i.e. a pentitol in which the two asymmetric carbon groups (X) and (Y) are of different signs. Laevoarabinose, on the other hand, gives one of the optically active pentitols and therefore its configuration must be either 5, 6, 7, or 8. Laevoarabinose forms a cyanhydrin, which on hydrolysis gives the structurally identical but optically isomeric /-gluconic and mannonic acids. On reduction of the lactones of these acids, /-glucose and /-mannose are formed respectively. In these reactions the new The configurations of asymmetric carbon atom j8 is introduced. and /-mannose must therefore be included in the series /-glucose IX to XVI.
*
See p. 52.
54
Laevoglucose and /-mannose give optically active dicarboxylic acids and optically active hexitols. This excludes XII or XIII, because the dicarboxylic acids and hexitols derived from these would
be optically inactive by internal compensation.
COOH + - + - COOH
or
CH 2 OH + - + - CH OH,
2
(In the
compounds
the
asymmetric groups in corresponding positions, are enantiomorphously related and cause internal compensation.) Therefore /-glucose and
/-mannose must be IX, X, XI, XIV, XV, or XVL Dextroglucose and t/-mannose give one and the same osazone. Therefore the molecules differ in configuration only as that
regards
particular
(P) (P-
asymmetric group directly united to the aldehyde group 53)- This excludes structures XI and XIV, since on excluding
the
group the other three asymmetric groups are not identical. The configurations must therefore be chosen from IX, X, XV, or
/?
XVL
Dextroglucose and </-gulose give on oxidation one and the same optically active dicarboxylic acid (J-saccharic acid), and on reduction one and the same optically active hexitol
(</-sorbitol).
XVI, because a dicarboxylic acid or hexitol having the corresponding configurations could not be produced
from two
either
different aldohexoses.
This excludes
IX
or
Laevoglucose must therefore be
or
XV.
and were chosen quite arbitrarily and the same relationship would hold if all the signs had been reversed, one of these configurations may be arbitrarily assigned to rf-glucose,
the other to /-glucose.
Since the signs
assigned to /-glucose, d-glucose becomes X, J-mannose IX, /-mannose XVI, df-gulose V, /-gulose IV, while /-arabinose,
If
XV is
from which /-glucose and /-mannose are obtained, becomes d- arabinose 5, and /-xylose (from which /-gulose is derived) 2.
8,
The
group
projection formulae* in the tabulation on p. 55. As already mentioned, the choice between the letters d and / has been made by Fischer to depend on the
structural
optical relationships of the various are shown more fully by means of
members
of the hexose
relationship of these compounds rather than on the direction in which the substances rotate the plane of polarized light
IP-
5)* Cf. Tartaric Acids, p. 51.
THE MONOSACCHAROSES
CH
55
Configurations of the Aldohexoses.

r
v.
Enzymes.
saccharoses, it in yeast) (eVfJyUj;
Before discussing the fermentation of the would be advisable to briefly consider the enzymes
-the lifeless products of the living cells which induce these changes and act either in the presence or abdirectly sence of the living organism. Enzymes are substances of the utmost importance to all living " " chemical reagents of matter, and they may be regarded as the the organism. It has not been possible as yet to isolate an enzyme
has been impracticable to do more than investigate the effects produced when mixtures containing them are allowed to act upon substances of known composiIn many cases it is possible to obtain solid amorphous tion.
in the pure state, to the present
it
and up
preparations which when dissolved in

criterion
for their
enzyme solutions is no definite Unfortunately of purity for these colloids, and the methods available preparation are such as would not remove many known
extremely
water.
there
furnish
active
enzymes are thrown out of solution on addition of alcohol or salts such as ammonium and sodium sulphates, while they are frequently carried down with neutral precipitates such as calcium phosphate, when formed in their presence. Willstatter and Stoll* have endeavoured to improve the methods
*
impurities. As a rule
Ann., 1918, 416, 21.
56
for isolating

settled:
and purifying enzymes so that the following points (i) whether enzyme activity is possessed by an analytically pure compound or whether an enzyme is a system of co-operating substances; (2) whether a metal is an integral part of an enzyme; and eventually (3) what atomic groupings are associated with enzyme activity. It is too early as yet to answer any of these
may be
questions definitely. As a preliminary study the case of horseStill more recently the same authors * radish peroxydase was chosen. have devised an improved method of purification by means of
adsorption
acid,
compounds with aluminium or ferric hydroxide, silicic Similar methods have been applied to kaolin, or talc.
invertase.f
Enzymes can act only within a limited range of temperature. In general the enzymes of animal origin act best at 37, while a suitable temperature for those of vegetable origin. is 25 With few exceptions enzymes can act only in neutral solution, and a faintly acid medium is preferable to an alkaline one.
Many
which
neutral
substances
which are very poisonous
to
living
organisms are not nearly so prejudicial to the enzymes, so that substances of this kind are frequently added to solutions in
enzyme changes
are
in
progress
in
order
to
prevent
bacterial contamination.
Yeast juice containing zymase is a complicated mixture of enzymes. The process of dialysis serves to separate it into two parts, the dialysate, which has passed through the membrane, and the residue which has not. Each of these portions by itself is incapable of effective fermentation, but when mixed together they become active. The active substance contained in the dialysate
is
called the co-enzyme.
Fermentation of the Monosaccharoses.
During the course
of his experiments on racemic acid, Pasteur observed that aqueous solutions of the acid become laevorotatory in the presence of peni-
owing to the destruction of the dextrotartaric acid by the fungus, and this device has been frequently employed for the resolucillium,
tion of inactive mixtures.
Fischer has
shown
that this selective
action
is
tion of carbohydrates.
exhibited by invertase and zymase in producing fermentaOf the aldohexoses only the three natural
and rf-galactose are fermentable. The tetroses, pentoses, heptoses, and octoses are not attacked by yeast, while mannononose undergoes alcoholic fermentation and glycerose
sugars, c?-glucose, </-mannose,
*
Ann., 1921,422,47.
\Ann.> 1921, 425,
i.
THE MONOSACCHAROSES
is
57
partly transformed into propionic acid. It would seem, therefore, that the only molecules which are attacked are those which contain
three, or a multiple of three, carbon atoms. It is obvious that the action of the enzyme
the structure but also
depends not only on on the configuration of the molecule, and to
explain this selective action Fischer introduced the simile of a " lock and key ". When the asymmetric structure of the enzyme
corresponds to that of the organic compound to be acted upon, or "the wards of the key fit those of the lock", reaction may
occur.
The
selective action of Bertrand's sorbose bacterium has already
been mentioned.
The Methylglucosides. In 1893 Fischer observed that when a solution of glucose in cold methylalcohol was saturated with dry hydrochloric acid and allowed to stand, the mixture lost its characteristic
aldehydic property of reducing cupric solutions. On concentrating the solution, after neutralization with lead carbonate, crystals of a-methyl glucoside separated while the mother liquors
contained the isomeric ^-compound.

Melting Point.
Rotatory Power.
.... ....
a-Methyl glucoside
(3-Methyl glucoside
165 104
+157
33
The two
products are regarded as stereoisomeric y or butylene
oxides, and have the following structural formulae:
HO-C-H
H-C-OH HO-C-H
\
H-C-OH
CH 2 OH
a
-
H-C-OH
CH 2 OH
-
Methyl Glucoside
Methyl Glucoside
This type of ring is often termed the pentaphane or butylene oxide ring. When hydrolyzed by acids these glucosides yield methyl The action of enzymes towards them is alcohol and glucose. specific, for each form requires its own particular enzyme; thus,
a-methyl glucoside
is
hydrolyzed by maltase and jS-methyl glucoside
by emulsin.
$8
In 1914, Fischer isolated a third product from this reaction in the form of a syrup. He found that the syrup could be distilled in a high vacuum, and had the composition of a methyl glucoside
This isomeric methyl glucoside is scarcely attacked by emulsin or maltase. Irvine, Fyfe, and Hogg * have shown that this compound is a mixture of isomerides derived from an entirely new It readily condenses with acetone, reduces variety of glucose. alkaline potassium permanganate, and unites with oxygen to give a
methylated by the combined action of silver oxide and methyliodide, it gives a new tetramethyl-methylglucoside which, on hydrolysis, is converted into a liquid tetramethylglucose. This compound is very reactive but forms no phenylosazone. On reduction it gives a tetramethylhexitol which is probably correctly represented by the formula:
neutral product.
(C7 H 14 O 6 ).
When
CH (OCH
2
3)
[CH
OCH
3] 3
CHOH CH
OH.
On
new
this basis
an ethylene oxide structure must be assigned to the tetramethylglucose, and the new methylglucoside is a mixture
of stereoisomerides having the formulae:
CH O
3
-C-H
[CH OH] 3
H-C- OCH,
[CHOH] 3
CHoOH
The
state.
CHoOH
not yet been
isolated
parent
glucose has
in
the free
In addition to a- and j3-methyl glucosides, there are

derivatives of aditions
all
many
other
the a- or
Under proper experimental conjS-glucose. five hydroxyl groups in glucose become acetylated, j8-pentacetate predominating according to the method
and
adopted. In either isomeride, one of the acetyl groups that attached to the carbon atom marked with an asterisk is far more reactive
than the
rest.
When
either of these
liquid hydrogen action of a saturated solution

it
chloride
or
compounds bromide, or, more of these two acids

or
is
treated with
easily,
by the
or
in acetic acid,
is
converted
into
the corresponding a*
Trans., 1915, 107, 524.
jS-acetochloro-
acetobromo-glucose:
THE MONOSACCHAROSES
AcO-CH
Br-CH
59
H-C-OAc
H-CHBr
CH 2 OAc
a Glucose
pentacetate
CH 2 OAc
a Acetobromoglucose
/3
CH 2 OAc
Glucose pentacetate
j8
CH 2 OAo
Acetobromoglucose
Fischer and his collaborators have utilized acetobromoglucose and similar derivatives of other hexoses for obtaining a variety of
glucosides. In addition
to the isomeric forms of glucose pentacetate, acetochloro- and acetobromo-glucose, the following glucose derivatives are known: a- and ^8-acetonitroglucose, a- and /?-acetomethylglucoside, a- and /2-tetracetylglucose, and various methylglucoses
and methylglucosides. Mutarotation: the Isomeric

fall
Forms
of
Glucose.
The
when a gradual solution of glucose is allowed to stand is known The change takes place very slowly when highly
of optical rotation observed
is
freshly prepared as mutarotation.
purified glucose
used, but almost immediately if a small quantity of alkali is added. In 1890, Fischer noticed that certain lactones related to the sugars underwent a similar change, and he therefore ascribed the change with glucose to a like addition of a molecule of water, with the formation of a heptahydric alcohol.
CHO
HOH) 4 + H
2
CH(OH) 2
->
[CHOH] 4
CH OH
2
CH OH
2
In 1895, Tanret * described a further form of glucose of constant rotatory power, and three forms of glucose were now recognized:
a-glucose, [a] D p-glucose, [a] D
y-glucose, [a] D
+ no to + 52-5 + 19 to + 52-5 + 52-5

behaviour of a- and /J-glucose
f
Simon f compared the

* C.
r. t
optical
1895, 120, 1060.
C.
r.,
1901, 132, 487.
6o
with the corresponding methylglucosides and suggested that both contain a closed ring. Direct proof of the glucosidic structure of both a- and /?-glucose was afforded by their preparation from the corresponding glucosides by Armstrong,* who used appropriate
enzymes
for the hydrolysis. The change in rotatory power of glucose was shown by Lowry in he subse1899, to be a process of reversible isomeric change and
aquently concluded that Tanret's y-glucose is a mixture in which assumes that an in equilibrium. and ^-glucose are present Lowry f or hydrate is an intermediate stage in the establishment of aldehyde
equilibrium between the glucoses:
CH OH
2
CH OH
2
CH 2 OH
CHOH
CH
+ H 2 09
CHOH
I
CHOH
H-C-OH
a
-
CH(OH) 2
Form
This explanation involves the opening of the ring, and an alternative formulation has been put forward by Armstrong which does
not involve any disruption of the y-oxide ring. The stages through which our present views regarding the glucose molecule have developed may be expressed in historical
sequence as follows:
C H 12O
6
fl
(4)
(6)
*
Trans., 1903, 85, 1306.
t Trans.,
iQ3> 85, 1314.
THE MONOSACCHAROSES
Position
i
61
in the last formula plays a part in mutarotation, in the formation of glucosides, and in oxidation processes, while the pro-
perties of the
group indexed as 2 are revealed in the formation of of the group in position 6 is restricted to a few reactions such as oxidation to saccharic acid and the formaosazones.
Our knowledge
evident that the linkage of the ring-forming oxygen atom in the molecule need not remain exclusively in one position, but may connect different pairs of carbon
tion of dibromoderivatives.
It is
atoms, and thus

variables.
all
the groups from
to 6
must be regarded
as
For example:
Position
,,
2
3
may may
,>
possess either the a or (J configuration. be involved in an ethylene-oxide ring. a propylene-oxide ring. ,,

,, ,, ,, ,, ,,
,, ,,
4
5
a butylene-oxide ring.
an amylene-oxide ring.
a hexylene-oxide ring.
,,
,,
It follows, therefore,
glucose may isomerides.
that if we include an aldehydic variety, dreact in any one of eleven forms or as a mixture of these
of the hydroxyl groups in glucose can be masked by acetyl or benzoyl groups, but these groups are too easily removed in subsequent reactions, and moreover they render these compounds resistant
Methylated Sugars.
The
reactive properties
to enzymes.
In 1895, Fischer observed that sugars combine with one or two molecules of acetone and also with benzaldehyde to form welldefined isopropylidene and benzylidene
compounds containing the
groups:
\*s
V-J\
3) 2
>C(CH -C- /
|
-CI
CH C H
6
Purdie and Irvine have employed methylation, either by methyl iodide and silver oxide or, more generally, dimethyl sulphate and caustic soda, to introduce stable methyl groups into
Since
1901,
the hydroxyl positions of reducing sugars or into any hydroxyl groups which remain unsubstituted in a sugar derivative. The
all
sequence of operations leading to a fully methylated glucose expressed by the following scheme:
may be
62
CH OH
CH CH- OCH 3
CH- OH
CH OCH 3
CH OH
O
CH-OH CH-OH
CH
CH-OH
CH- OH
^H 2 OH
Glucoside formation
O
I
CH OCH 3
.
CH OCH 3
CH OCH 3 CH
in- OCH 3
CH-OCH,
CHOH
CHoOH
The
first
:H
OCH
^Hg
OCHs
CH OCH
Hydrolysis
Methylation
the formation of methylglucoside, a reaction which protects the reducing group, and this is; followed by the introduction of methyl groups into the remaining hydroxyl positions.
stage
is
Acid hydrolysis eliminates the glucosidic alkyl group only, with the result that a tetramethylglucose is produced. Extending these it is clear that if a sugar is substituted by any group or principles, groups capable of subsequent removal by hydrolysis, it is possible to methylate the unoccupied hydroxyl positions and ultimately to obtain definite partly methylated sugars, and this method has been extensively employed in the study of the di- and
poly-saccharoses
.
In general, it may be said that alkylated sugars are very suitable for exact and critical experimental study. In many cases the comreadily in highly characteristic forms, and, in addition, the sugars or their glucosides can be effectively purified by distillation in a high vacuum. Moreover, the presence of the
pounds
crystallize
alkyl groups increase the solubility in organic solvents.
In view of the manifold parts played by the substituted amino group in animal and vegetable metabolism, it is remarkable that few amino- derivatives of the sugars are known. In 1878, Lederhouse isolated an amino-sugar from lobster shells. This compound has the simple empirical relationship to glucose expressed by interchange of one hydroxl group in the glucose mole-
The Glucosamines.
amino group. Both the hydrochloride and the pentacetate of glucosamine exist in two forms. It is reasonable to conclude that if glucosamine is treated with nitrous acid, glucose will be obtained, but in reality dehydration occurs and a sugar named chitose is obtained. Fischer and Andrae * claim that chitose is a hydrated furfuran
cule for one
derivative rather than a true sugar: * Ber., 1903, 36, 2587.
THE MONOSACCHAROSES HO CH - CHOH
HO-CH CH
O
while Irvine and
CH CHO
formulate chitose, with the aldehydic radical present, as in the hexoses, in the butylene-oxide form:
Hynd
O CH OH CH CH CH(OH) CH CH(OH)
.
These authors* have succeeded in converting glucosamine into glucose by a long series of operations, and represent glucosamine by
a formula of the beta'me type:
H H OH H
CH 2OH
Fischer and Leuchs f have synthesized glucosamine from rf-arabinose by the following reactions:
CH OH
2
CH-OH
second glucosamine was obtained by Fischer and Zach J by the action of liquid ammonia on triacetylmethylglucoside, but its constitution is not known with certainty.
This branch of sugar chemistry retains a somewhat perplexing aspect, and this is all the more regrettable in view of the great biochemical interest attached to glucosamine as a connecting link between carbohydrates and amino acids. Glucal. In 1913, Fischer obtained a strongly reducing compound, C6 10 O4 which he named glucal, by the reduction of
Trans., 1912, 101, 1128.
J Ber., 1911, 44, 132.
Sitz. Preuss.
\Ber., 1903,86, 84. Akad. Wiss. Berlin, 1913, 311.
64
j8-acetobromoglucose with zinc dust and acetic acid. It is a slightly sweet, soluble syrup with aldehydic properties, and evidently possesses ethylenic unsaturation, since it decolorizes bromine water. The constitution of glucal has not been conclusively proved, but its * properties are satisfactorily explained by the formula:
HO-CH -CH(OH)-CH-CH(OH)-CH:CH o
2
l
The term glucoof substances having the property in common of furnishing a sugar (usually glucose) and one or more other products on hydrolysis. Glucosides occur in all parts of
Artificial Glucosides.
side
is
The Natural and
applied to a large
number
The extraction plants, but especially in the fruit, bark, and roots. is usually effected either by water or alcohol. In the former case
necessary to destroy the enzyme which accompanies the glucoside, or the latter may be hydrolyzed during the extraction. Glucosides are generally colourless crystalline solids, having a
it is first
and laevorotary optical power. In chemical structure resemble the simple a- and /?-methylglucosides, and may therethey fore be represented by the general formula:
bitter taste
CHoOH CHOH CH [CHOH] 2 CH-O-R o

i
where
R is
an organic
radical.
glucosides are all hydrolyzed by heating with .mineral acids, and in the majority of cases they may also be hydrolyzed by suitable enzymes. The appropriate enzyme is contained in the same plant
tissue but in different cells, gaining access to the glucoside only when the tissue is destroyed. The best known glucoside-splitting enzymes
The
are the emulsin of almonds and the myrosin of black mustard seed. Emulsin is also able to act upon certain synthetic glucosides. It
has already been mentioned that by the action of various alcohols upon sugars in the presence of hydrochloric acid, Emil Fischer was able to prepare two series of stereoisomeric glucosides, and that
the a-glucosides are exclusively attacked by maltase whereas the glucosides are exclusively attacked by emulsin.
/?-
From
Maltose
emulsin.
it is
these results
it
has been possible to draw conclusions as to
the configurations of
is
some of the natural sugars and glucosides. an a-glucoside, for it is hydrolyzed by maltase and not by Emulsin brings about the hydrolysis of lactose, from which
is
evident that this sugar

*
related to the
[B], 509.
-glucosides.
Alkyl
Ber., 1920, 53
THE MONOSACCHAROSES
unattacked glucosides derived from non-fermentable sugars are both maltase and emulsin.
by
The
better
known
glucoside-splitting
enzymes are shown
in the
following table.
ENZYMES CAPABLE OF HYDROLYZING GLUCOSIDES

Enzyme.
Hydrolyses.
Products.
Emulsin
Prunase
Many
natural and syn-
thetic glucosides.
.
Prunasin
Amygdalase
Gaultherase Tanriase
Amygdalin
Gaultherin
Glucose, d-mandelonitrile. Glucose, e/-mandelonitrile

glucoside.
Methyl
Gallic
salicylate, glucose.
Tannins
and
ellagic acids,
and
glucose.
Rhamnase
Myrosin
Indigo ferment
Xanthorhamnin
Sinigrin
Indican
Rhamnitin, rhamninose. Potassium Allylthiocyanate, hydrogen sulphate. Indoxyl and glucose.
majority of the glucosides are derived from dextroglucose, but in addition glucosides derived from d- and /-arabinose, ^/-xylose, and rf-ribose, from rhamnose and other methyl pentoses, and from In the glucosides all galactose, mannose, and fructose, are known.
The
types of organic substances are united to glucose; for example, Avnumber of the better alcohols, aldehydes, acids, phenols, &c.
known
ence will be
glucosides are given in the table on p. 66, and frequent refermade to some of these compounds throughout this book.
Three main points The Structure of the Glucosides. should be taken into account in the study of a glucoside. In the first place, the constituent sugar and the group with which it is combined must be identified, and the actual union of these compounds must be determined. This may be deduced from an examination of the products of hydrolysis, either by dilute acids or
the action of an enzyme, but when the non-sugar residue contains several hydroxyl groups the structure arrived at by such means is open to doubt. In the second place, the particular configuration of the glucoside must be determined, for the compound may exist in the a- or jS-stereoisomeric forms. This point may generally be settled by the study of enzyme action, for, since emulsin is the
specific
enzyme
for
/J- glucosides,
it it
may
reasonably be concluded
that
all
glucosides hydrolyzed
by
are derived
from
j8-glucose.
5
(D331)
66
Glucoside.

Products of Hydrolysis.
Phenols.
Arbutin
Phloridzin
Baptisin
Glucose Glucose
+ +
+ + +
hydroquinone.
Rhamnose
Qlucose Glucose Glucose
phloretin. baptigenin.
Alcohols.
Coniferin
Populin
Salicin
coniferyl alcohol. benzole acid. saligenin saligenin.
Aldehydes.
Amygdalin
Helicin
Linamarin
Prulaurasin
Sambunigrin
Gaultherin
mols Glucose + J-mandelonitrile. Glucose + salicylaldehyde. Glucose + acetonecyanhydrin. Glucose + racemic mandelonitrile. Glucose + /-mandelonitrile.
2
Acids.
Glucose
methyl
salicylate.
.
Oxyflavone Deriva lives
Apiin
Isoquercitin
Xanthorhamnin
Apiose + apigenin. Glucose + quercetin. 2 mols Rhamnose + galactose
rhamnetin.
Mustard
Sinigrin
Oils.
Glucose
allyl
isothiocyanate
+ KHSO
.
4.
Anthocyanins
Cyanin
Delphinin
Idaein
. .
2 mols Glucose 2 mols Glucose
+ cyanidin. + />-hydroxy
benzoic acid
+ del-
phinidin.
Galactose
cyanidin.
The
point to be settled is the nature of the sugar residue. have seen that the simple sugars and their derivatives may exist in
last
We
modifications other than the ordinary butylene oxide type. Reliable evidence on this point cannot be obtained from a study of the sugar resulting from the hydrolysis of the glucoside, for rearrangement of
the free hydroxyl groups of the carbohydrate may occur during this Trustworthy information regarding the internal structure process.
of the sugar constituents may most readily be obtained by a study of the products of hydrolysis of the alkyl derivatives of the glucosides, and the actual hydroxyl group involved in glucoside
formation
may
also
is
non-sugar residue
be determined by such methods, when the a substance containing several such groups.
*
Trans., 1906, 89, 814.
Irvine and Rose * obtained a pentamethyl salicin by methylation
THE MONOSACCHAROSES
67
of the natural glucoside, and showed that the sugar in the parent They supported glucoside possessed a butylene- oxide linking.
a synthesis of a pentamethyl salicin which proved to be identical with that derived from the natural glucoside
these observations
by
by methylation.
Macbeth and Pryde * have determined the structure of the glucoside indican, and this may be briefly considered. Earlier workers had shown that indican was an indoxyl glucoside, and that the constituent sugar was rf-glucose, but no evidence regarding the internal linking of the sugar had been adduced. Indican was
More
recently
methylated, by the action of methyl iodide and dry silver oxide, and the resulting tetramethylindican hydrolyzed to tetramethylOn hydrolysis of the methylglucoside and indoxyl derivatives.
former a crystalline tetramethylglucose was isolated which was

readily identified as the 2:3:5:6 or butylene oxide These results may be conveniently summarized:
Indican
compound.
_ Tetramethyl methylglucoslde
1
Tetramethyl indican
ladoxyl derivatives
Tetramethyl glucose
(2:3:5:6)
From
the results obtained
it is
evident that indican
is
derived from
a molecule of d- glucose combined with indoxyl, the internal linking of the sugar being of the butylene-oxide type. The following structure is therefore established for the glucoside:
CHoOH CHOH CH CHOH CHOH CH O C 8 H N O

-
and enzyme action and

is
optical properties indicate that the
compound
a derivative of jS-glucose.
Several of the natural glucosides have been prepared synthetically, and in addition a considerable number of artificial glucosides have been obtained, notably by Emil Fischer and his collaborators. Michael condensed crude acetochloroglucose with the In
The Synthetic Glucosides.
1879 potassium salts of various phenols, and in

*
this
way prepared phenyl
Trans., 1922, 122, 1660.
68
more satisfactory glucoside, helicin, salicin, and methylarbutin. condense the non-saccharose constituent and acetomethod is to
bromoglucose in the presence of
this
silver oxide.
By an
extension of
terpene glucosides, and cyanophoric glucosides have been synthesized. A new modification of the glucoside synthesis consists in warming acetobromoglucose in the presence of quinoline. with During this process a
method purine glucosides
(p.
208),
phenol rearrangement takes place, and a mixture of a- and jS-phenol glucosides is formed, which may be separated by crystallization from carbon This synthesis of a-glucosides is of considerable tetrachloride. importance, as hitherto it has been impossible to obtain them owing
to the fact that a-acetochloroglucose gave rise to j8 compounds. Considerable interest attaches to the synthesis of the glucosides
containing hydrogen cyanide.
This acid has been frequently isolated
from plant products, but it is only quite recently that its formation has been ascribed invariably to the decomposition of a glucoside.
perhaps the classic example of a glucoside, since it played such a conspicuous part in the early development of organic chemistry in the hands of Liebig and Wohler. Even to-day its constitution is not established with certainty, but in all probability it is
Amygdalin
is
a derivative of a disaccharose.
Sambunigrin was obtained from the leaves of Sambucus niger by Bourquelot and Danjou in 1905, and in the following year Herissey obtained prulaurasin from Prunus laurocerasus. Both these glucosides have been obtained synthetically by Fischer and * Bergmann according to the following scheme:
Ethyl
cfi-
mandelate
\^
Acetobromoeflucose
(Ag20)
Ethyl d- and
1-
tetra acetylglucosidomandelate
B
(CH 3CO)4 C8 H 7
d-
-0-CH(C6 H 5)C02 C 2 H8 )
and
1-
\ (NH 8) mandelamide glucoside
C6 H 115'- CH ( C6 H 5> CONH 2

I
(Crystallized from pyridine)

d-
1-
Mandelamide glucoside
I
I
y
1-
r acetic L
anhydride and"!
*
pyridine
tetra acetate
w
d-
Mandelamide glucoside tetraacetate
Ber., 1917, 50, 1047.
THE DISACCHAROSES
(POCl,)
1- Mandelonitrile
69
glucoside tetra acetate
d- Mandelonitrile glocoaide tetra acetate
d-
and
1-
MandelnitrUe glucoside (Prulaurasin)

(fractional crystallization)
1-
Mandelonitrile glucoside
d- Mandelonitrile glucoside
(Sambunigrin)
Soon
after this Fischer described the synthesis of glycollonitrile-
glucoside, the simplest of the cyanophoric glusocides, and that of linamarin (from flax), the glucoside of acetonecyanhydrin.
Bourquelot has obtained glucosides synthetically by means of enzymes. Whereas in dilute aqueous solution the hydrolysis of j8-methyl glucoside by emulsin
Finally
it
may be mentioned
that
complete, hydrolysis is retarded by increasing amounts of methyl alcohol until in the presence of a certain proportion of this alcohol
is
the
enzyme
is
alcohol.
The
able to synthesize glucoside from glucose and the reaction has been extended to other alcohols, the
enzyme being allowed to act on sugars dissolved in alcohols conIn this way crystalline taining varying amounts of water or acetone. glycol-, glycerol-, geranyl-, and cinnamyl-/?-glucosides have been obtained by means of emulsin.
THE DISACCHAROSES
disaccharoses are carbohydrates containing twelve carbon atoms, and consist of two simple six-carbon atom residues united through an oxygen atom. When hydrolyzed by acids or enzymes,
The
one of the constituent hexoses functions in the same manner as

glucose does in the methyl glucosides, while the aldehydic or ketonic group of the second hexose may remain functional or disappear. In
the former case
reduces cupric salts, exhibits e.g. maltose, lactose, and melibiose, while in the latter case the sugar has no reducing properties, e.g. sucrose and trehalose.
disaccharose
the
mutarotation, and forms an osazone,
Research work on the disaccharoses therefore centres round three points: determination of the nature of the component hexoses, the type of glucosides which they represent, and the hydroxyl group concerned in the attachment.

Irvine and his collaborators have employed five methylated hexoses as reference compounds to determine the constitution of the most important disaccharoses and polysaccharoses:
Of
these,
2:3:5: 6-tetramethylglucose has proved of greatest service. Structure of Sucrose (Cane Sugar). In conformity with
the absence of reducing properties of cane sugar, Fischer put forward a formula (i) in 1893:
CH OH
2
CHOH
-C!H
CH OH
2
CHOH CHOH
o
(ii)
CHOH CHOH CH
C - CH 2 OH
|
This formula remained unchallenged until his isolation of ymethylglucoside (p. 58), when he drew attention to the similar behaviour of these two substances towards acids. While it is assured
that the glucose residue has the same type of oxide ring as that of the a- and /?-glucosides, his inference was that the fructose com-
y form. This view has received confirmation by Haworth and Law,* who prepared octamethylsucrose and observed that when treated with dilute acid it gives tetramethylglucose and The methylated aldose proved to be the tetramethylfructose.
ponent
is
in the
tetramethylglucose of the butylene oxide type, while the ketose

* Trans. y 1916, 109, 1314.
THE DISACCHAROSES
which
displayed a rotatory power and reaction towards permanganate " at once stamped it as being allied in structure to y-glucose ". The new provisional formula (ii) shows a butylene oxide aldose
coupled
groups.
to
an
ethylene
oxide
ketose
through
their
reducing
Maltose is a reducing sugar which yields, on with dilute acids or with maltase, two molecular prohydrolysis
portions of glucose. Consequently it is regarded as a biose having the reducing group of one glucose molecule united through an
Maltose.
anhydride linking with a second glucose residue. assigned to maltose by Fischer was:
The
constitution
CH
CH 2
CHOH
CHOH
This structure has been confirmed by Haworth and Miss Leitch.* Starting from the free sugar, methyl maltoside was produced by the regulated action of methyl sulphate and sodium hydroxide, and the same reagents were then used to convert this
product
the
into
heptamethyl-methylmaltoside
(ii)
(i).
On
hydrolysis,
(iii)
tetramethylglucose obtained.
and
the
trimethylglucose
were
H OH
:
CH CH
CHOCH CHOCH
CH
CHOCH,
1
CHOH CHOCH
CHOCH
CHOCH
2
|
CH OH
2
CHOCH
CH +
CHOCH
2
O
3
CHOCH
UH
3
CHOCH.,
I
CHOCH,
-CHOCH.
CH OCH 3
(i)
CH OCH 3
U:HOCH HOH
(iii)
OHH
*
Trans., 1919, 115, 809.
72

Cellobiose.
In the same paper the following formula was
suggested for cellobiose:
CH OH
a
Haworth and Hirst * have prepared this sugar from cellulose (p. 79) and converted it into an octamethyl derivative which was shown to be heptamethyl-methylcellobiose. The hydrolytic products obtained from this compound are in accordance with the above
formula for cellobiose.
Lactose or milk sugar is present in the milk of all it has not been found in the vegetable kingdom. The preparation of lactose from milk is easily carried out. For this purpose rennet is added to milk to coagulate the casein, and the " " clear liquid or whey which separates is concentrated in vacuo. It is interesting to note that lactose was the first sugar of which the occurrence of more than one modification was observed. Three forms are known, and are designated a, /?, and y, the last being an
Lactose.
mammalia, but
equilibrium mixture of the a and ft forms. Hudson f has made a careful study of the modifications of lactose, and his papers should be consulted for further details.
Lactose resembles cane sugar and maltose in forming esters with Haworth and Miss Leitch J have ineight equivalents of acid,
vestigated the constitution of lactose in a similar manner to that already described in the case of sucrose. Lactose was completely
methylated and then hydrolyzed, according to the following scheme:

Lactose
> methyl lactoside
when products were obtained
> heptamethyl-methyl lactoside.
Tetramethylhexose (A). Methylalcohol. Trimethylhexose (B).

*
Tram., 1921, 119, 193.
\J. Amer. Chem.
Soc., 1908, 30, 1767.
I Trans., 1918, 113, 188.
THE DISACCHAROSES
Compound
73
(A) was shown to be the butylene oxide form of tetramethyl galactose, while (B) was shown to be identical with the
trimethyl glucose isolated by Denham from methylated cellulose From this evidence the following structural formula has (p. 79).
been assigned to
lactose:
pt_r VxJLJ.
CHOH CHOH
I
CH
CHOH
[Galactose residue]
CHOH CHOH CHOH

I
[Glucose residue] Lactose
Trehalose, mycose, or mushroom sugar was discovered by Wiggers, in 1832, in ergot, and has subsequently been found to be a constituent of most mushrooms, toadstools, and other fungi. It appears to replace sucrose in those plants which do not contain It is also found formed in chlorophyll and do not elaborate starch. trehala manna, a cocoon formed by certain species of beetles on several spiny plants native to Syria and Persia.
hydrolysis of trehalose with dilute #iineral acids takes place very slowly and produces a quantitative yield of ^/-glucose. Maltase, invertase, emulsin, and diastase are without action on trehalose,
The
but
it is
readily hydrolyzed
by the enzyme
trehalase,
which
is
con-
veniently obtained from the fungus Aspergillus niger. Trehalose does not reduce Fehling's solution and does not form
either hydrazones or osazones.
is
Melibiose has not been found naturally produced by the hydrolysis of raffinose:
in the free state, but
C 18 H 32
Melibiose
is
16
+H
= CH
6
12
+ CnHwOu
Melibiose
Raffinose
d-Fructose
reduced by sodium amalgam to melibitol, which on It is hydrolyzed by hydrolysis gives mannitol and ^/-galactose. strong acids to ^/-glucose and ^-galactose. With emulsin the hydroan enzyme found in bottom yeast, attacks lysis is slow, but melibiase, It reduces Fehling's solution and forms this disaccharose rapidly.
hydrazones and osazones.
74
Melibiose was the first disaccharose to be obtained synthetically. was prepared by Fischer and Armstrong * from acetochlorogalactose and sodium glucosate, which condense to give melibiose
It
tetracetate.
On
hydrolysis with caustic soda, melibiose
is
obtained.
H
-d-
H-d-O.
CH,CO O - C -
CH OH HO - C - H -H
2
H H
H - C - OH + C H ONa HO - C - H
2
H C O COCH 3
CH O COCH 3
2
Acetochlorogalactose
Glucose
NaCl
+ C H OH
2 5
H - C - O COCH
2
O
3
HO-C - H
AH
CH - O COCH 3
Melibiose tetracetate
Turanose and Gentibiose
are obtained
by the hydrolysis of
the trisaccharoses, melecitose and gentianose, respectively.
Raffinose,
THE TRISACCHAROSES C 18 H 32 O 16 is the best known

,
and most widely
It was first isolated by Johnston in 1843 from eucalyptus manna, and was later obtained from beet sugar in the refining process by Loiseau, who gave to it the name raffinose = to refine). It is most conveniently prepared from cotton(raffiner seed meal by precipitation from an aqueous extract with calcium
distributed trisaccharose.
Ber., 1902, 35, 3144.
TRISACCHAROSES
oxide
75
salt
and subsequent decomposition of the calcium
with
carbon dioxide.
Raffinose exhibits
dilute acids
it
no reducing
properties.
On
6
hydrolysis with
gives rf-fructose, (/-glucose,

16
and
6
df-galactose:
C 18 H 32
+ 2H
= CH
6
12
+ C H 12
+ C H 12 O 6
6
Raffinose
d-Fructose
rf-Glucose
d-Galactose
In practice the hydrolysis takes place in two stages, melibiose (p. 73) and fructose being the first products, and the melibiose then yielding Invertase hydrolyzes raffinose to fructose and galactose and glucose. while emulsin breaks it down to sucrose and galactose. melibiose, From these observations the following formula may be constructed:
C 6H U
-O- CH
6
10
- O - C Hn
6
Fructose
Glucose
Sucrose
Galactose
Melibiose
in 1882 in Gentian roots
Gentianose was discovered by Meyer
(Gentiana luted), and is most conveniently prepared by extraction of the dried roots with 95 per cent alcohol. Gentianose is a nonreducing sugar which possesses a slightly sweet taste. On hydrolysis
it
and two molecules of glucose, or, in stages, with the formation of either fructose and gentiobiose (by gentianase) or of sucrose and glucose (by emulsin).
splits
up
into fructose
CcHn
-O- CH
6
10
- O - C Hn
6
Fructose
Glucose
Sucrose
Glucose
Gentiobiose
Melecitose, or melezitose, was first observed by Bonastre in It is prepared from 1833 in the manna from the larch (Pinus larix). Turkestan manna by extraction with warm water and crystallization from methyl alcohol. It does not form osazones and is not a reducing sugar.
and turanose, hydrolysis with dilute acids it gives glucose the latter being further hydrolyzed to glucose and fructose. The manner of arrangement of the two glucose -and one fructose residues in this sugar is unknown. Mannotriose was found by Tanret in 1902 in the manna of
On
the ash (Fraxinus ornus). The manna contains up to 16 per cent of mannotriose, up to 60 per cent of mannitol, and small quantities of is tedious. stachyose, and the separation of these sugars Mannotriose reduces Fehling's solution and forms a phenyl-
76
osazone.

On
hydrolysis with dilute acids the sugar yields two molecules of galactose and one of glucose, while emulsin gives
glucose and digalactose:
OHC C H 10
-
-O-CH
6
10
- O - C H nO
6
Glucose
Galactose
Galactose
Gluco-galactose
Digalactose
along with rhamnetin, is a product of the hydrolysis of the glucoside xanthorhamnetin, found in the
,
Rhamninose, C 18 H 32 O 14
Persian berry (Rhamnus infectorid). The hydrolysis is effected by the enzyme rhamninase, which is present in the berries. Rhamninose is a reducing sugar which possesses a slightly sweet
taste.
hydrolysis with dilute acids it gives one molecule of J-galactose and two molecules of rhamnose:
On
OHC C H
5
1U
- O - C H 10
6
- O - C H nO 4
6
Galactose
Rhamnose
Rhamnose
TETRASACCHAROSES
Stachyose, lupeose, or mannotetrose, C 24 H42 O 2 i, was discovered by Planta in 1888 in the tubers of Stachys tubifera, in which
it
sometimes present to the extent of 70 per cent. Its occurrence in the manna of the ash has already been mentioned, and it has also been found in the roots of various Labiatae.
is
It is
not a reducing sugar.

it
On
6
hydrolysis with
weak
acids or
invertase
yields d- fructose
and mannotriose:
6
C 24H 42 O
2i
+ H O = C H 12O + C H
2
Stachyose
rf-Fructose
18 3 oO 16 Mannotriose
Stronger acids hydrolyze stachyose to the hexoses. According to * the gastro-intestinal juice of Helix pomatia effects the Bi6rry hydrolysis in the following stages:
rf-fructose and mannotriose. Mannotriose to */-galactose and a disaccharose. (II) (III) The disaccharose into galactose and glucose.
(I)
To
The formula of stacyhose may thus be provisionally represented: C 6 H n O 5 - O - C 6 H 10 O 4 - O - C 6 H 10 O 4 - O - C 6 H UO 5

Fructose
Glucose
^
Galactose
-v
Galactose
.^^^
Mannotriose
* Biochem. Zeitsch., 1912, 44, 446.
THE POLYSACCHAROSES
77
THE POLYSACCHAROSES
polysaccharoses are substances of high molecular weight, and most of them are amorphous and insoluble in water. On hydro-
The
they break down into sugars containing five or six carbon atoms, and may therefore be regarded as anhydrides of these substances. Since we have no reliable knowledge of the molecular
lysis
weights of these compounds, their formulae are written (C6 10 O6 ) or (C5 8 O4 ) W according as they give rise to hexoses or pentoses on
;J
hydrolysis.
The
1.
polysaccharoses
may be
classified as follows:
2.
(b)
Starches and dextrins, including glycogen, inulin, &c. Gums, which comprise (a) natural gums and pentosans, and
mucilages and pectic bodies.

3. Celluloses.
The importance
of these substances cannot be overestimated
and yet we have very little knowledge of the chemical constitution of any of them. Much might be written on the importance of these substances from the chemical, botanical, physiological, and commercial points of view, and indeed, in spite of our limited knowledge, the most remarkable devices have been successfully employed for the utilization of these substances, and especially the derivatives of cellulose, in industry. The consideration of these numerous applications is beyond the scope of this book, and the reader desiring information on these matters should consult one of the numerous treatises, of which Worden's Technology of Cellulose Esters is perhaps the most monumental. During the last few years the chemistry of cotton cellulose has received considerable attention, and since more progress has been made in the study of this polysaccharose than the
other
members
of this group,
all.
it
will
be well
to
consider
the
celluloses first of
The
Celluloses.
The term
cellulose
should
be taken in
general to connote a
as follows.
i.
group of substances rather than a single chemical compound, and used in this generic sense we may classify the celluloses
Normal or
typical celluloses of
the
cotton type, e.g. the
cellulose obtained
from cotton,
flax,
hemp, &c.
78
2.

Compound celluloses of the wood cellulose, jute, and cereal The natural celluloses occurring in jute, cereal straws, types.
some form of
which may be
cellulose
grass
esparto, &c., consist of non-cellulose constituent
combined with a
or a fatty sub-
either of the nature of lignin

(e.g. flax),
(e.g. jute fibre), a pectic or stance (e.g. cork).
gummy
substance
which represent a very heterogeneous collection of substances, are much more easily hydrolyzed than other celluloses and give rise to various sugars such as mannose, galactose, and certain pentoses. These celluloses occur
3.
Hemi-, pseudo-, or reserve
celluloses,
in the cell walls of the seeds of various plants, e.g. Soja hispida,
Cocos nucifera, beans, peas, &c.
The extensive study of the alkylated with which the names of Purdie, Irvine, and Haworth sugars (p. 61), are intimately connected, has opened out a hopeful method for the determination of the constitution of the polysaccharoses. Now that
Cotton Cellulose.
the properties and structure of a large number of alkylated aldoses and ketoses are known, the substances formed in the degradation of
the alkylated polysaccharoses
is
may be
identified.
The original method, employing silver oxide and methyl iodide, not always successful owing to the experimental difficulties frequently caused by the insolubility of the carbohydrate in methyl iodide, or to the presence of reducing sugars when the silver oxide
functions as an oxidizing agent, and in these cases, methylation by means of dimethyl sulphate and caustic soda gives better results.
Investigations of this type must include, (i) the identification of the constituent sugars, (2) their stereochemical form, (3) the hydroxyl
group involved in the coupling of the constituents, and (4) the position of the internal oxygen atom in each ring. These methods give more certain results than the investigation
of the acyl derivatives * of the sugars, or the acetolysis f of the polysaccharoses by the action of acetyl bromide in the presence of
hydrobromic and
acetic acids, since the latter brings
about simul-
taneous acetylation, hydrolysis, and bromination.

Willstatter J regards cellulose as a polyglucose, and has claimed that the complex may be quantitatively transformed into glucose.
This work has, however, been repeated by Miss Cunningham, who

has shown that
it is
impossible to estimate, by means of the polari-
* Hess and Messmer, Ber., 1921, 54 B, 499. t Bergmann and Beck, ibid., 1574. Trans. 1918, 113, 173. J Ber. 1913, 46, 2401.
t
THE POLYSACCHAROSES
79
meter, the amount of glucose produced in a system saturated with hydrochloric acid, as this acid produces profound constitutional changes in the sugar. Estimations based on reducing power are
equally valueless.
Denham and Woodhouse*
succeeded
in
alkylating
cotton
cellulose, and obtained a derivative which on hydrolysis yielded a mixture of methylated products from which 2:3: 6-trimethylglucose (i) was isolated.
-CH
OH
CH - O .......... (X)
CHOH CHOH CH
I
CHOH CH OCH
2
CH - O .......... (Y)
3
CH OH
2
(i)
(ii)
This
trimethylglucose
has
been
obtained
from
several
other
methylated sugars and its structure is well established.! This work gave the first clear evidence as to the linkage of part of the cellulose molecule which must contain the unit shown in formula (ii). Irvine and SoutarJ continued this work, and by the degradation of a purified methylated cellulose obtained an 85 per cent yield of The cellulose was treated with crystalline derivatives of glucose. acetic anhydride and sulphuric acid, and both the soluble and
>
insoluble portions were converted into methylglucoside, quite free from any isomeric methylhexoside. These results clearly showed
the absence of mannose and galactose residues in cellulose, and pointed to the following formula for cellobiose:
HO-CH.[CHOH] 2 -CH-CH - O - CH-[CHOH] 2 .CH-CHOH.CH OH

2
I
- _J
*
Haworth and Hirst obtained cellobiose in a yield of 30 per cent by an improved method of acetolysis of cellulose, and, as already shown (p. 72), confirmed the above structural formula.
Trans., 1914, 105, 235?-
t Trans., 1922, 121, 1213.

Trans., 1921, 119, 293.
J Trans., 1920, 117, 1489.
8o

More
recently Irvine
is
and Hirst * have shown that the
cellulose
molecule
entirely composed of glucose residues by obtaining an over-all yield of glucose derivative equal to 95 per cent of that theo-
retically available.
Cotton cellulose, 100 parts
I
Cellulose triacetate, 177 parts
.
99*5 per cent
(Methyl alcohol containing 0-75 per cent
HC1)
a- and p-methylglucosides, 114-1 parts \ 95 '5 P er cent Glucose equivalent, 106 parts J
continued by Irvine, Denham, and Hirst, and by the exhaustive methylation of cotton cellulose a product was obtained which contained 43-0 per cent of methoxyl
place of 45-6 per cent required by the trimethyl derivative. The material still preserved its fibrous nature, from which it was
in
Denham and Woodhouse's work was
concluded that no profound molecular change had taken place. The trimethylcellulose was then submitted to simultaneous depolymerization, hydrolysis, and conversion of the scission products into the corresponding methylglucosides. These were distilled in a high vacuum, and the distilled material consisted of 2:3:6-
On hydrolysis of the distilled trimethyl methylglucoside only. glucoside crystalline 2 : 3 : 6-trimethylglucose alone was obtained. These reactions may be summarized:
Cotton cellulose
4
Trimethyl
cellulose lulose
i
......
"j
[yield 90 per cent.

J
2 ~> 3-> 6-Trimethyl methylglucoside
^
2 "j 3"> 6-Trimethyl glucose
I
yield 89 per cent
The scheme
affords a proof that
all
the glucose residues in cellulose
are identical in structure
unsubstituted.
least
To
and have the hydroxyl groups 2, 3, and 6 satisfy this condition and to account for the
it is
necessary to include in the formula at In view of the fact that the highest (i). yield of cellobiose so far obtained does not approach that theoretically
formation of cellobiose,
two glucose residues
* Trans. , 1922, 121, 1585.
THE POLYSACCHAROSES
81
possible on the bases of formula (i), an alternate formula (ii), in which the symmetrical tri-i : 5-anhydroglucose is the unit of cellulose,
appears to be the more favourable.*
CH O
CHOH CHOH
CH - O - CH CHOH CHOH CH CH CH 2OH O CH OH
' I
CH OH CH - O - CH - CH CHOH CHOH CH CHOH

2
.
CHOH
CH - O CH OH
2
CH CHOH CHOH CH
I
CH OH
2
O(ii)
ohe of the most widely distributed substances in the vegetable kingdom. As a more or less permanent reserve food material it occurs in seeds, fruits, the vegetable parts such as tubers, &c., and in the latex of certain plants.
Starch
is
Starches and Dextrins.
It also
occurs in green leaves, presumably as a temporary reserve
material.
preparations, properties, and uses of starch need not be dealt with here, and in spite of the amount of work which has been
The
devoted to the study of its chemical constitution our knowledge of the nature of the starch molecule is very slight indeed.
that when starch is rethe reaction ceases when the methoxyl content peatedly methylated is 37 per cent. This value corresponds exactly with the theoretical amount calculated on the basis that one hexose residue has acquired
*
t
Irvine and
Macdonald f have shown
Irvine,
.7.
Soc. Chem. Ind. y 1922, 41

y
362 R.
6
J. Soc. Chem. Ind.
1922, 41, 362 R.
(D331)
82
three methyl groups whilst four are shared by two glucose residues. When digested with methyl alcohol containing hydrochloric acid, the
methylated starch was converted into trimethyl-methylglucoside and dimethyl-methylglucoside. These were separated by distillation in high vacuum and thereafter hydrolyzed to give the parent sugars. An unexpected result was encountered in that the trimethylglucose isolated proved to be the crystalline form in which the methyl groups
occupy the 2:3:6 positions. One glucose residue in starch must thus be substituted as shown in formula (ii) (p. 79). In order to accommodate the formation of maltose from starch, either one or two additional glucose residues must be present at X and Y in the unit. The reactions involved may be summarized:
Starch
Methylated starch
(OCH 3=36-2%)
Trimethyl: methyl glucoside
^
~cr
Y
Dimethylmethyl glucoside
^
Depolymerised methylated starch
\
2. 3. 6.
\
Dimethyl
glucose
Trimethyl glucose
2 - 3 S 6. Tetramethyl glucose
The work so far carried out has not been sufficient to justify a formula which will fit in with these facts and at the same time account for all the properties of the starch molecule.
Inulin
is
of
common
occurrence as a reserve food-stuff.
It is
very conveniently prepared from dahlia tubers, and in many of its It is derived from fructose, and until properties resembles starch. recently there was no reason to doubt that the parent hexose was the well known laevorotatory form of the ketose. Inulin has been submitted to examination on similar lines to that already described for cellulose and starch, by Irvine and his collaborators.
Very little is known of the chemical nature of the various natural gums and mucilages. The chemistry of the polysaccharoses offers an exceedingly wide field for future chemical research, and it is most
desirable that the chemist should obtain a knowledge of the constitution of these important natural compounds.
THE POLYSACCHAROSES
REFERENCES.
83
The Simple Carbohydrates and Glucosides, by E. F, Armstrong (London,

1919).
Sugars and
their
Simple Derivatives, by
J.
E. Mackenzie (London,
Alcoholic Fermentation,
by A. Harden (London, 1911). The Nature of Enzyme Action, by W. M. Bayliss (London, 1914). Untersuchungen uber Kohlenhydrate und Fermente, 1884-1908, by E.
Fischer (Berlin, 1909). Untersuchungen uber Kohlenhydrate und Fermente, 1908-19, by E. Fischer and M. Bergmann (Berlin, 1922).
The Chemistry of Plant Products, by P. Haas and T. G,

1921).
Hill
(London,
CHAPTER
The
Tannins
Introduction.
In very early times
IV
Depsides, Lichen Products, and
it
was known that certain
parts of plants possess a very astringent taste, give a black coloration with substances containing iron, and have the property of con-
verting
raw hides into

"
leather.
Some
tannin as the generic name for this of vegetable products, while others have unfortunately used denote a particular substance better described as gallotannin.
Gallic acid
galls to the air, in a
"
employ the term widely disseminated group

writers
it
to
was prepared by Scheele in 1786 by exposing nut warm place, and frequently removing the film of mould. Scheele's product was undoubtedly very impure, and gallic acid was first obtained in an almost pure state by Berzelius. Even earlier than this, Lewis, in 1763, had isolated gallotannin, and five years later Piepenbring had obtained gallic acid from it. Gallotannin, obtained from gall apples, has been the subject of
many
formula
In 1852 Strecker denoted gallotannin by the it as a compound of one molecule of grape sugar and three molecules of gallic acid. In 1871 Schiff denoted a tannin-like product which Lowe had obtained by heating as digallic acid, and for a long time gallic acid with arsenious acid afterwards gallotannin was assumed to be identical with digallic acid. This erroneous view was finally shattered by Flawitzki, who, in 1895,
investigations.
C 27 H 22O 17
and considered
showed
that gallotannin
was
optically active.
The subsequent development of the chemistry of gallotannin culminated in 1918 with the synthesis of the active gallotannin from Chinese tannin by Emil Fischer. In the course of his investigations,
which he termed Depsides synthesized two lichen products
Classification.
Fischer not only synthesized "
compounds with
"
(Seêtv
to
tannin-like properties, tan), but he also
Owing
Lecanoric and Evernic acids. to our present incomplete knowledge

it is
of the chemical constitution of the tannins,

84
difficult to
evolve a
DEPSIDES, LICHEN PRODUCTS,

proper chemical
fies
AND TANNINS
85
classification of these substances.
Proctor * classi-
the tannins in two main groups:
1. Pyrogallol Tannins, including divi-divi, galls, oak-wood, and chestnut tannins. These tannins give a dark blue colour with ferric salts, give no precipitate with bromine water, and on leather " " produce a bloom consisting of ellagic acid.
acacias,
pine barks, mimosas, oak barks (but not oak wood, fruits, or galls), quebracho wood, cassia and mangrove barks, cutch, and gambia. These tannins give a greenish-black colour with iron alum, a yellow " or brown precipitate with bromine water, and deposit no bloom ".
addition of concentrated sulphuric acid to a drop of the infusion produces a dark red or crimson ring at the junction of the two liquids.
of the tannins in this class contain phloroglucinol as one of the constituents of the molecule.
2.
Pyrocatechol Tannins, including
all
the
The
Some
Isolation of the Tannins. The majority of the tannins are soluble in hot water and may be precipitated with lead acetate. The plant infusion is treated with an aqueous solution of lead acetate and the precipitate decomposed, in the moist condition, with hydrogen sulphide. The solution of tannin thereby obtained is then concentrated in vacuo.
In
many
extraction.
preferable to employ an organic solvent for Various mixtures of alcohol, water, and ether may be
cases
it is
used, but acetone
probably the best solvent. Ethyl acetate is used extensively, but some tannin glucosides are insoluble in this The method used by Fischer and Freudenburg for the solvent. purification of Chinese tannin will be described later. The Depsides. The term " depside " was introduced by Fischer and Freudenburg f to denote a series of anhydrides formed by the condensation of a carboxylic group of a phenolcarboxylic acid with a hydroxyl group of the same or a similar acid, e.g.
is
HO-C 6 H 4 COOH + HOC 6 H 4COOH - H O+HO-C H 4 CO.O-C H 4 COOH

2
Hydroxybenzoic'acid
(a didepside)
This product may condense with another molecule of a phenolcarboxylic acid to give a tridepside, HO- C 6 4 CO-O-C6 4 CO-OC6 4 COOH, and by an extension of this reaction tetradepsides may
H
*
be obtained.
indeed, very similar to that employed for the polysaccharoses and the polypeptides.
is,
The nomenclature
Principles of Leather Manufacture,
London, 1903.
f Ann., 1910, 372, 35.
86

As
early as 1883, Klepl
had obtained di- and tri-depsides by heating p-hydroxybenzoic acid, and Schiff had prepared similar products by the action of dehydrating agents on phenolcarboxylic
acids.
In order to obtain a satisfactory yield in the preparation of the depsides, it is necessary to protect the hydroxyl group of one of the acids undergoing reaction, and for this purpose Fischer first employed
methylchloroformate
-
(C1COOCH 3 ), e.g. HO C H 4 COOH + C1COOCH 3 - CH CO

6 3
O C H 4 COOH + HC1
6
is
In the case of those phenolic acids in which the hydroxyl group meta or para position to the carboxyl group, this reaction may easily be brought about with the aid of caustic soda, but when
in the
the hydroxyl group is in the ortho position it is preferable to use dimethylaniline in an indifferent solvent for the removal of the ele-
ments of hydrochloric acid. This latter method was first devised by Fritz Hofmann in 1899. The following tabulation illustrates the applications of these methods of carbomethoxylation.
In aqueous solution.
Dimethylaniline method.
Salicylic acid.
-Hydroxybenzoic acid.f w-Hydroxybenzoic acid.

Vanillic acid.J
a-
and (3-Hydroxynaphthoic
acids.* *
o-Cumaric
acid.
p-Resorcylic acid. Phloroglucinol carboxylic
acid.l!
Protocatechuic acid.t
Orsellinic acid.* * Gallic acid.f
Partial carbomethoxylation
may be accomplished
in the case of
polyhydroxyphenolic acids;
e.g. using one molecule of chloroformic the ^-methylcarbonato or carbomethoxy derivatives of /Jester, resorcylic acid and orsellinic acid were obtained, while in the case of gallic acid the meta derivative was first obtained.
The methylcarbonato group is easily removed by an excess of cold aqueous alkali, and more slowly, as urethane, by a normal solution of ammonia. In some cases a selective removal of a methylcarbonato group
may be
accomplished.
substituted phenolic acids readily react with phosphorus pentachloride to give acid chlorides in the usual way.
had previously employed methylchloroformate for the protection of the hydroxyl group in tyrosine, in the preparation of tyrosylglycine. Ber. 9 1909, 42, 226. t Ber. 9 1908, 41, 2877. J Ann., 1910, 372, 47. \\Ann., 1912,391,366. **Iter., 1913,46,2400.
* Fischer
The
AND TANNINS
87
Before describing the synthesis of the depsides, two simple applications of these methods may be illustrated.
^-Hydroxyhippuric Acid.*
This acid was prepared from
^-hydroxybenzoic acid and glycine ester in the following stages: C1CO 2 CH 3 PC1 5 HO'C 6H 4 COOH-> CH 3 .CO 2 -O-C 6H 4 COOH - CH 3 CO 2 -O-C 6H 4 COCi
/>-Hydroxybenzoic acid
This acid chloride was then condensed with glycine ester, and on hydrolysis with caustic soda, p-hydroxyhippuric acid was obtained:
CH CO O C H COC1 + 2NH CH CO C H - CH CO O C H CO NH CH CO C H +HC1, NH CH COOC H 6 -> HO C H CO NH CH COOH

3
/>-Hydroxyhippuric acid.
/>-Hydroxybenzophenone.f
^>-hydroxybenzoic acid as follows:
This
was
PC1 5
synthesized
from
HO-C 6H 4COOH -> CH 3 CO 2 OC 6 H 4 COOH -> CH 3 CO 2 -O-C H 4 COC1

6
C1CO 2 CH 3
The
was then condensed with benzene by the usual Friedel Craft reaction and the product hydrolyzed.
acid chloride
CH C0
3
O C H 4 COC1 + C 6H 6 -> CH CO O C H CO C H -> HO C H 4 CO C H

6 3 2 6 4
6
-
In a similar way
2: 3:
4-trihydroxybenzophenone
(alizarin yellow)
was obtained from pyrogallolcarboxylic acid. Didepsides. The simplest didepside is obtained by the condensation of two molecules of ^-hydroxybenzoic acid J in cold alkaline solution as follows:
CH CO
3
O C H 4 COC1 + NaO C H 4 CO Na - CH 3 CO O C H 4 CO O C H
6
CO Na + NaCl
2
The product
didepside,
is
then hydrolyzed with w-alkali at 20
to give the
HO C H CO O C H COOH
6
Tri- and tetr a -depsides. These are obtained in a similar manner to the didepsides. In the case of the monophenolcarboxylic
acids only one class of polydepside compounds of the type:
is
possible, viz. straight-chain
HO C H CO
6
O-C 6 H 4 COOH
J Ber., 1909, 42, 216.
Ber., 1908, 41, 2880.
t Ber., 1909, 42, 1017.
88

di-
but with
and tri-phenolcarboxylic acids several types are theo-
retically possible, e.g.
CH CO O C H CH CO O C H
3
2 6
COC1 COC1
H(X
HO
C 6 H 3 COOH
HO \C H COOH HO C H CO O x
6 3
6
Compounds of such types are not yet known with certainty.* The following tabulation embraces the more important polydepsides prepared
by these methods:
Tridepsides.
Didepsides.
Tetrad epsides.
Di-/>-hydroxybenzoic acid.f Di-/>-hydroxybenzoyl-/>Di-protocatechuic acid. J

w-Digallic acid.
Di-^S-resorcylic acid. J
Tri-/>-hydroxybenzoyl-/>-
hydroxybenzoic acid.
-
||
hydroxybenzoic
-
acid.JI
Vanilloyl-/>-hydroxybenzoyl-/>
acid.ll
Vanilloyl di -p hydroxy -
hydroxybenzoic
benzoyl - p - hydroxybenzoic acid.y
Vanilloyl- vanillin.
1 1
In 1918 Fischer prepared several depsides in which acetylation of the phenolic hydroxyl groups had been used instead of carbomethoxylation.f f The acetyl derivatives of the phenolic acids are easily prepared, crystallize well, and may be converted into their chlorides without difficulty. After condensation the acetyl groups may be removed by dilute alkali at zero or ammonia at ordinary
temperature.
natural source of the depsides so far discovered is the Lichens, which are peculiar plant formations produced by the symbiosis of algae and fungi. Many species of
lichens have been used
food-stuffs.
Lichen Products.
The only
Two
early times in medicine, dyeing, and as acids, lecanoric and evernic, which are found in
y
from
the varieties Roccela and Lecanora, and Evernia prunastris have been the subject of several investigations by Fischer and his collaborators.
stituent of
"
Orcinol (sym. methylresorcinol) " lichens. litmus

.
is
an important con-
Orsellinic Acid.**
9
This acid has been synthesized from

9
* Ber. t Ann., 1911, 384, 238. t Ber. 1909, 42, 217. 1912, 45, 2712. B*r., 1913, 46, 1124. \\Ann., 1910, 372, 63. ** Ber., 1913, 46, 886. 1 1 Ber., 1918, 51, 46; 1919, 52, 809.

orcinol
AND TANNINS
89
by Hoesch. Orcinol is converted into orcylaldehyde by Gattermann's method, and, after protecting the two hydroxyl groups
is
by carbomethoxylation,
give orsellinic acid:
oxidized and subsequently hydrolyzed to
CHO
CH 3 /\OH
HC1,HCN
CHO COOH CH 3 /\0-C02 CH 3 CH 3 /\OH

CH CO O
3 2
_ OH
Orcinol
N/
OH
\/
folio wed
NaQH
by
OH
Orcylaldehyde
Orsellinic acid
Lecanoric Acid.
like
This acid has long been known as an ester-
anhydride of orsellinic acid. The acid has been studied and For this purpose orsellinic acid was synthesized by Fischer.*
converted into
its
dimethylcarbonato derivative and thence into the
corresponding acid chloride.
COOH
COOH
C1CO-CH-
COC1
PC1,
CH,X\OH
3
v
f
I
CH 3 X\0-CO 2 CH 3
3r
CH 3 X\O-CO CH 2 3
II
OH
O-CO 2 CII 3
O-CO 2 CH 3
Orsellinic acid
This chloride was then coupled with orsellinic acid in aqueous acetone solution, and on hydrolysis gave a diorsellinic acid identical with lecanoric acid. Since orsellinic acid contains two hydroxyl
evident that this synthesis alone does not establish the structure of lecanoric acid. The authors have however synthesized
groups,
it is
o-diorsellinic acid
from which
it is
be different from lecanoric acid, evident that in the above synthesis the acid chloride
it
and found
to
condenses with the />-hydroxyl group of orsellinic acid, and the constitutional formula of lecanoric acid thus becomes:
CO
OH
Lecanoric Acid
This acid, together with orsellinic acid, is obtained by the hydrolysis of evernic acid with baryta. Everninic
* Ber. 9 1913, 46, 1138.
Everninic Acid.
go

CHO
CHO
(CH 3 ) 2 SO,
and
f
1
acid has been synthesized from orcylaldehyde by Hoesch as follows:
PH
OH
Orcylaldehyde
CH 3/\OH
CHO COOH CH 3 /\0-C0 2 CH 3 CH,/\OH JC1C02 CH 3 ^ KMn04

I
NaOH
\/
>v/
and hydrolysis
3
\S
OCH 3
OCH
OCH 3
Everninic acid
Everninaldehyde
Evernic Acid. When natural evernic acid is methylated by means of diazomethane it gives a product identical with that obtained by the methylation of lecanoric acid, viz. the methyl ester of triEvernic acid must therefore be a monomethyl-lecanoric acid. methyl-lecanoric acid, and since on hydrolysis it gives everninic acid, the methyl group must be in the para position to the depside
group.
COOH OH
OH
O
CO /
Evernic acid
SOCH
Gallotannin. It has already been stated that Strecker had denoted gallotannin as a compound of one molecule of grape sugar with three molecules of gallic acid. For half a century there prevailed a conflict of opinion as to the presence of a glucose residue > the production of sugar on hydrolysis being denied by several chemists, and the proportions in which it was obtained the fol-
by
lowers of Strecker varying much amongst themselves. Before studying the hydrolysis of gallotannin it was, of course, necessary to obtain a sample as pure as possible. For this purpose Fischer and Freudenburg* employed Chinese tannin and purified it by extraction from a weak alkaline solution with ethyl acetate.
hydrolysis with 5 per cent sulphuric acid for 70 hours it yielded 7 to 8 per cent sugar, an amount which they regarded as probably too low in view of the extended period occupied in completing the
reaction.
On
They then expressed

is
stituent of tannin
the opinion that the principal connot a glucoside, but a sugar ester comparable
*
Ber., 1912, 45, 919,
AND TANNINS
is
91
with pentabenzoylglucose, in which the acyl group acid. Expressed by the formula
that of digallic
C 6H
[C 6
H (OH) CO O
2
C 6 H 2 (OH) 2 CO] 6
such a compound having a molecular weight 1700 would yield 10-6 per cent of glucose on hydrolysis. Somewhat later Fischer and Bergmann * made use of the
potassium
originally
salt of gallotannin as a
method of
purification
method
recommended by
Berzelius.
Pentagalloyl- glucose.
Fischer and Freudenburg then turned
For this purpose trimethylcarbonatogalloyl chloride was prepared from gallic

their attention to the synthesis of pentagalloyl-glucose.
acid as follows:
COOH
>
3
3 -J
COOH
CHXO.Ok 32
coci
OH CH yo.COL-CH, 23 OC1CO.CH,C0 Ok ^/ OH
2
>
O C0 2 CH 3
\^Ô-CO.CH, 0-C0 -CH

2
This acid chloride was then condensed with glucose in chloroform

solution in the presence of quinoline to give penta (trimethylcarbonatogalloyl) glucose, which on hydrolysis with alkali in aqueous acetone
forms were obtained by fractional crystallization and, although not identical with gall-nut tannin, closely resembled it in amorphism, taste, solubility, optical Moreover, the product precipitated activity, and feeble acidity. gelatin and alkaloids, became gelatinous with arsenic acid, and developed a colour with ferric chloride. Methylotannin. In 1905 Herzogf had obtained a compound " " which he termed methylotannin by the action of diazomethane on tannin. This compound was indifferent towards alkali and
gave pentagalloyl glucose.
ft
Both the a and
therefore contained no carboxyl or hydroxyl groups. On hydrolysis it gave trimethylgallic acid and acid. m-^>-dimethylgallic Taking
this evidence, in addition to his earlier
gallotannin probably consists of a
work, Fischer concluded that compound of one molecule of
glucose with five molecules of digallic acid. Methylotannin would then consist of one molecule of glucose with five molecules of
pentamethyl-w-digallic acid.
Pentamethyl-w- digallic acid was next synthesized by condensing

* Ber. 1919, 52 [B], 829.
y
f Ber., 1905, 38, 989.
92
trimethylgalloyl chloride with the m-/>-dimethyl ether of gallic acid in the presence of alkali:
CH 3O
COOH
,
CH O
'
COOH
CH 3CK CH3
The
CH 3O
OCH 3
CH 36
CH3 O~OCH3
/f-glucose
its
chloride of this acid
was then coupled with a- and
to give penta
(pentamethyl-m-digalloyl) glucose which, from
properties, appeared to be identical with methylotannin.
CHOR
--/ /i 'HOR
V>-
CH ---3
v 3
-,
CO--
\CHOR
CH
R=CH 0<^
CH 3
\CO-oY
CH 3
\
OCH
3
HOR
CH OR
2
Several unsuccessful attempts were then made to prepare />-digallic acid *, but owing to the wandering of an acyl group, the meta acid was invariably obtained, even when the most delicate methods were
used for hydrolysis. The Active Principle of Chinese Tannin. Valuable as the use of the methylcarbonato derivatives had proved, they did not
suffice to perfect the
aim in view, namely to synthesize the main This was accomplished in 1918, principle of Chinese tannin.
following the observation that the corresponding acetyl compounds are superior to the methylcarbonato derivatives for depside proIn making this advance, Fischer explained that the acetyduction.
been used much earlier had not he been misled by the statements of previous workers as to the difficulty of removing the acetyl group, which actually prolated phenolcarboxylic acids
would
certainly have
ceeds quite smoothly. The chloride of penta-acetyl-m-digallic acid
is
crystalline,
and
with jS-glucose yields the compound:
C 6H
This
[C 6
(0
COCH
3) 3
CO O C H
6
(O
CO CH
3) 2
CO-]
is
then de-acetylated by cold aqueous caustic soda at zero,

r.,
1918,51,45-
AND TANNINS
93
The resemblance between giving penta (w-digalloyl) jS-glucose. this artificial tannin and the principal constituent of Chinese tannin
is
much closer than that offered by pentagalloylglucose. More recently Nierenstein * has criticized Fischer's
alternative formula in
formula for
gallotannin, and suggested an
which four of
the hydroxyl groups of the glucose portion of the molecule are free, but the reader is referred to the original literature for an account of
need hardly be pointed out that Fischer's work deals only with one particular tannin, and that the constitution of many of the tannins, and especially the catechol tannins, is still
these criticisms.
It
obscure.
Many
of the intermediate
compounds described
in this chapter
are substances of very high molecular weight, e.g. the M,W. of penta (pentamethyl-w-digalloyl) glucose is 1810. During these
synthesized hepta (tribenzoyl-galloyl) pa freak molecule of gigantic dimensions iodophenylmaltosazone, (M.W. 4021), vastly exceeding that of any other synthetic product, f
investigations
Fischer
> ^-iodophenylmaltosazone > Maltose (-Iodophenylhydrazine) (tribenzoyl-galloyl chloride)
CH:N.NHC 6 H4 I C:N.NHC 6 H 4 I
CHOR
CHOR
|
I
|| || CHOR GO OIIO II CH0-CH- CH- CHCH- CH- CH

Hepta
where
R=-CO.C 6 H 2 (O'COC 6 H 5) 3
(tribenzoyl-galloyl) p-iodophenylmaltosazone
[XôHÔssNJ a ]
REFERENCES.
The Principles of Leather Manufacture, by Proctor (London, 1903). Die Chemie der natiirlichen Gerbstoffe, by Freudenburg (Berlin, Julius
Springer).
Nekrolog auf Emil Fischer, by Hoesch (Berichte, 1921).

c-
Chem.
2nd., 1922, 41,
29 T.
&&>
9 I 3> 4
CHAPTER V
Animal and Vegetable
Oils, Fats,
and Waxes
Introduction and Classification. Oils, fats, and waxes may be divided broadly into two natural groups, those of animal and plant origin, and those of mineral origin. The former may again be subdivided into two groups, according as they are volatile or non- volatile. The volatile oils, which are contained mainly in the leaves, stems, and flowers of the plant, are also termed essential oils and will be dealt with in a subsequent chapter. The non-volatile " " fixed oils, which are also termed oils, are contained in the seeds and fruits of plants and are obtained by means of expression, or by extraction with solvents. Considered chemically, all fixed oils and fats are esters of glycerol with fatty acids, and are termed glycerides. The animal and vegetable waxes are also esters, but the neutral radicle contained in these is an alcohol other than glycerol and no glycerol can be obtained from them. consequently The manufacture of glycerol, soap, and candles from natural
fats, as
and
here.
well as the hardening of oils with the production of edible hydrogenated oils, are too well known to require elaboration
During the Great War efforts were made to produce fatty acids the oxidation of suitable hydrocarbons, while in order to conby
serve glycerol supplies attempts were made to prepare edible fats containing ethylene glycol and other polyhydric alcohols in place of Considerable success was also achieved in the preparation glycerol. of glycerol by the fermentation of sugar.
A very short account will

it
from which
will
be given of the chemistry of the lipins, be seen that as yet we have very little knowledge
of the chemical constitution of these substances.
and waxes are very widely distributed in the vegetable kingdom, and they are found in especially
oils,
Occurrence.
The
fats,
94
OILS, FATS,
large
AND WAXES
95
The commonest
as spores and seeds. are those of oleic, palmitic, and stearic glycerides but the glycerides of many other acids such as, for instance, acids, Hnoleic and linolanic acids in linseed oil, erucic acid in colza and rape
lauric acid in laural oil, myristic acid in oil of nutmeg, and ricinoleic acid in castor oil are found in smaller quantities. The of vegetable fats are liquid at ordinary temperatures, but majority
oil,
amounts in the reproductive bodies such
a few, such as coco-butter, are solid. The oils and fats form one of the most important food reserves of plants, and they are probably formed from carbohydrates, of which glucose, sucrose, and starch
appear to be those most usually employed. The glycerides of fatty acids occur in animals, stored in the connective tissue cells of adipose tissue, and for the most part these
In certain glycerides are esters of stearic, palmitic, and oleic acids. animals the glycerides of other fatty acids occur; thus, lard contains
about 10 per cent of acids of the linoleic series, while in the fat of cows' milk the esters of butyric and caproic acids occur in fair
and those of the intermediate acids, caprylic, capric, and myristic acids in traces. lauric, The glycerides which occur in nature contain, in almost all cases, three fatty acid radicles, and are thus triglycerides. These triglycerides have frequently been supposed to be each a compound of glycerol with one and the same acid, that is, to be simple triglycerides; but several mixed triglycerides, or compounds containing more than one acid united with the same molecule pf glycerol, have now been separated from natural products. The Constitution and Synthesis of the Glycerides. The constitution of the oils and fats as triglycerides was established by the classic researches of Chevreul carried out between 1815 and
quantities,
1823.
Since glycerol is a trihydric alcohol it should be possible to obtain mono-, di-, and tri-glycerides; and, further, since glycerol is both a primary and a secondary alcohol, two different mono- and
di-glycerides should be obtainable from glycerol and an acid. perusal of the literature will show that many of these compounds
have been obtained.

for
The method most commonly employed
the
action
or on and subsequent exchange of the halogen atoms
preparation of monoglycerides depends either on the of glycerine chlorohydrins on the salts of fatty acids (i), the esterification of the fatty acid with the chlorohydrin
for the hydroxyl
groups
(ii).
9t>
CH
(i)
C1
CH O CO R
-
CHOH CH OH
2
+ AgOOC-R
CH
->
C1
CHOH CH OH
2
CH
C1
CHoOH
->
(ii)CHCl
CHC1
2
CH OH
2
+ HOOC-R
CH -O-CO-R
CHOH CH -O-CO-R
2
Both these methods have recently been shown to be unreliable by Fischer,* since the former method is complicated by side reactions, and no guarantee is afforded of the simple replacement of the halogen atoms by the fatty acid radicals, while in the second method the halogen atom can, in general, be only replaced under conditions which readily occasion further change.
Attention was drawn by Fischer to the fact that glycerol amonobenzoate is rapidly converted into a mixture of glycerol and a dibenzoate
carbonate.
when treated in ethereal solution with potassium The process is more conveniently followed with the
r
benzoyl derivatives of ethylene glycol in chloroform solution, whereby it may be show n that the change is balanced and attains an equili-
brium in the presence of the

and
glycol
and the mono- and di-benzoates.
Similarly, glycerol monoacetate is largely transformed into diacetin The action of the potassium carbonate appears to be glycerol.
definitely catalytic, since very small
amounts of
it
suffice to accelerate
the change.
by Purdie,f took place between simple esters and alcohols in the presence of a Grun J has shown that this small amount of sodium alkyloxide. interchange of alkyl groups between fats and alcohols can take place under certain conditions even in the absence of catalysts. Such phenomena explain to some extent the gradual change in
The phenomena are very similar to those first observed who found that an exchange of alkyl radicals readily
the melting-point observed by Grun to take place when diacyl derivatives of glycerol are preserved, and also of the so-called ageing of the natural fats. This, however, is not a complete explanation
of
all
the facts, as
as,
some of the
one form,
for
melting-points 55 these as examples of co-ordination isomerism, but this hypothesis
triglycerides are known in more than example, tristearin which exists in two forms, and 71 respectively. Grun prefers to regard
is
somewhat
*
intangible.
f Trans., 1887,
Ber., 1920, 53, 1589.
53, 391.
J Ber., 1921,
45
[B], 273, 290.
OILS, FATS,
AND WAXES
97
This circumstance has rendered the synthesis of pure monoglycerides a matter of considerable difficulty. As initial material for the synthesis of monoglycerides, Fischer, Bergmann, and Bar" acetone glycerol (i) (p. 61), the constitution of wind * adopted
which has been definitely established by Irvine, Macdonald, and Souter.f This substance readily reacts with acid chlorides in the presence of quinoline, yielding products from which the acetone residue is easily removed by mild treatment, thus giving undoubted For example, stearyl chloride condenses with a-monoglycerides.
isppropylidene glycerol in the presence of quinoline to give stearyl
isopropylidene glycerol (ii). On hydrolysis with semi-normal hydrochloric acid in the presence of ether, a-monostearin (iii) is obtained,
CH OH
2
C 17 H 35 COC1
->
3) 2
CH
!
O CO C 17 H 35
-
CH O CO C H 3&
2
17
CUO.
>C(CH CH O/
|
CH. >0(CH
->
3) 2
CHOH
CHoOH
(iii)
|
CH/
(i)
(ii)
Hydrolysis of the Oils and Fats. The glycerides are hydrolyzed by superheated steam in a few hours, and more readily
acid acts
in the presence of hydrochloric acid acting as a catalyst. Sulphuric more rapidly than hydrochloric acid probably because it
helps to bring the oil into a state of fine division or emulsification. Twitchell's reagent which is an aromatic derivative of sulphuric
acid obtained
by dissolving
oleic acid in
benzene or naphthalene in
is used very extensively oleic acid and adding strong sulphuric acid The aromatic sulphonic acid is the catalyst, and for this purpose.
rapidly than sulphuric acid because it is soluble in fat, The addition of small quantities of lime or fatty acid, and water. the hydrolyzing action of steam, and if similar magnesia accelerates
it
acts
more
small quantities of the alkalies which give soluble soaps be added, the acceleration is even more pronounced.
The removal of glycerol from its union with fatty acids in glycerides may be effected by alcohols containing as catalyst i to 2 per cent of hydrochloric acid. The following reaction takes place
in the case of methyl alcohol:
CH O CO R CH O CO R + sCH OH CH O CO R
2
-
CH OH
2
sCH 3 O CO R
-f
CHOH CH OH
2
* Ber. 1920, 53 [B], 1589.

y
f Trans., 1915, 107, 337.

7
331
98
The
excess of alcohol sets the equilibrium point very much towards the right-hand side of the equation, and the presence of hydrochloric acid causes this equilibrium to be rapidly approached. * Lapworth and Pearson have shown that glycerol can be quantitatively replaced by mannitol in fats by heating the fat with mannitol in the presence of sodium ethoxide under reduced pressure. An
almost theoretical yield of glycerol is obtained in the distillate, while the residue in the distillation flask may be treated so as to obtain a
synthetic mannitol fat. when the proportion is
The maximum
two
is
yield of glycerol is obtained molecules of fat to three of mannitol.
The
nature of the fat thus obtained
not
known with
certainty.
Enzymes which are capable of hydrolyzing fats occur in the seeds in which vegetable oils are found, and lipase is the most widely distributed of these enzymes. It is found in the pancreatic juice, the liver and blood of animals, and in most oily seeds particularly
Lipase is not only able to hydrolyze fats, but also many other esters, such as ethyl salicylate, ethyl acetate, and carbonate. There appears to be a distinct difference between ethyl
during germination.
the enzymes from different sources, and

lipase
it
has been stated that
separated into two substances, neither of which is independently capable of bringing about the hydrolysis. Lipase has a reversible action, and the fact whether it hydrolyzes or synthesizes fats
is
may be
merely a question of conditions, mainly the presence
or absence of water.
The
which extract contains the

a
fat;
glycerol extract of a fat-containing seed mixed with oleic acid will synthesize lipase
fat
while the addition of water results in the hydrolysis of this
into glycerol
and
fatty acid.
As
of the
early as 1855, Pelouze

oils
showed
that oil seeds contain a sub-
stance which
this subject
is capable of producing comparatively rapid hydrolysis contained in the seeds; but little attention was paid to
from a technical point of view until Constein, Hoyer, and Wartenberg,f by an extended series of experiments, showed
that the ferment contained in castor seeds
is capable of accelerating the hydrolysis of triglycerides, provided they be comconsiderably pletely emulsified in a slightly acid medium.
The enzymes
contained in animal organisms appear to act
much
more slowly than those occurring in the seeds of plants. The changes undergone by fats and oils when they become rancid are possibly initiated by enzymes that hydrolyze the glycerides, but there is, as yet, little definite information on this subject.
*
Biochem.J., 1919, 13, 296.
| Ber., 1902, 35, 3989.
OILS, FATS,
AND WAXES
99
has already been mentioned that the waxes formed by the combination of monoor di-hydric alcohols with higher fatty acids. The alcohols hitherto identified in waxes belong both to the aliphatic and cyclic series,
It
The Waxes.
must be considered
as esters
the latter being represented by the sterols. One of the best known vegetable waxes
South American palm (Copernicia pound, the constitution of which

ceryl
alcohol, 26 cerotic acid, acids,
,
carnauba wax from a a hard brittle comcerifera). is unknown. This wax contains
is
It is
C H 53 OH, myriscyl alcohol, C 30H61 OH, C 26 H52 O 2 and carnaubic acid, C 24 H48 O 2
Candelilla
and two
,
with a hydroxy acid.
wax
is
together obtained from the stem of
(Pedilanthus pavonis), growing chiefly in Mexico. Its composition is unknown, but a hydrocarbon, hentriacontane,
leafless plant
C 30H62
has been isolated from
it.
Animal waxes are obtained from a great variety of sources and have little in common with those from vegetable sources except the absence of glycerides. The following are some of the more important animal waxes: wool wax, wool fat, or lanoline, which is rich in cholesterol; bees- wax, which consists principally of myricyl palmitate and cerotic acid; spermaceti, which is obtained as a solid precipitate from the head oil of the sperm and bottle-nosed whale, and consists almost entirely of cetin and cetyl palmitate; and insect or Chinese wax, which consists mainly of ceryl cerotate. The Sterols : Cholesterol and Phytosterol. In addition to
the trihydric alcohol glycerol, all fats contain a small quantity of the monohydric cyclic alcohols cholesterol and phytosterol, which " " form what is known as the unsaponifiable residue of fats. These substances may be isolated from fats by treating an ethereal solution
with alcoholic sodium ethoxide,
and the soap

sterols.
The separates. All animal fats contain cholesterol, while vegetable fats contain either phytosterol itself or a closely allied substance belonging
frequently met with in the animal organism; thus, biliary calculi are almost wholly composed of cholesterol, while its presence has been further confirmed in human
to the
saponification takes place filtrate then contains glycerol and the
when
group of
sterols.
Cholesterol
is
bile,
may
It blood, brain, epidermis, in milk, and in the yolks of egg. be conveniently prepared by evaporating to dryness the ethereal
extract of gall-stones.
has been the subject of prolonged Windaus. Its constitution is as yet investigation especially by unknown, but it appears to be a poly cyclic, hydroaromatic, secondary
Cholesterol,
C 27 H45 OH,
ioo
alcohol containing four reduced rings. Windaus * considers that its constitution has been established to the extent indicated in the
expression:
(C 18
Hj
r
CH-OH CH
phytosterol was at one time employed to designate a definite chemical individual of the formula C 27 45 OH, but is
OTT
The term
now used
as a generic term to include a number of substances having Windaus and Hauth f showed that certain properties in common.
the substance obtained from calabar beans and
commonly known
as
phytosterol was in reality a mixture of two substances, sitosterol, of the formula C 27 45 OH, and stigmasterol, C 30 47 an observation which has been confirmed by Salway.J Sitosterol, the " cholesterol of plants ", is widely disseminated in the vegetable kingdom, and occurs in all seeds and fruits. It differs from choles-
H OH
terol in crystalline form, melting-point, magnitude of optical rotation, and chemical constitution, the latter being as yet unknown.
which have been -described include, isocholesterol, C 27 H46 O, brassicasterol, and stigmasterol. The Preparation of Fatty Acids from Hydrocarbons. During the late war strenuous efforts were made by the Central Powers to use paraffin wax as an initial material for the production of fatty acids and their esters in order to overcome the shortage of natural fats. The usual method was to heat the hydrocarbons of high molecular weight with oxygen or air, generally under pressure,
Other
sterols
in the presence of a catalyst.
Thus, in the presence of manganese C. Kelber converted a paraffin wax (m.p. 50), by compounds, the action of a stream of oxygen at 150, into a mass of which more than 35 per cent consisted of fatty acids insoluble in water, and about 25 per cent of the lower fatty acids (up to capric acid,
H. H. Franck
*
Ber., 1919,
||
used up to 5 per cent of various compounds

1906, 39, 4378; 1907, 40, 3681. &<*> 1920, 53 [B], 66, 1567. Chem. Zeit.> 1920, 44, 309.
f #er.,
52
[B], 162.
I Trans., 1911, 99, 2154||
OILS, FATS,
AND WAXES
101
of lead, mercury, vanadium, and chromium, and, working at 150 in an autoclave filled with oxygen, obtained from a paraffin of low
melting-point 40 per cent of fatty acids of higher, and 57 per cent of acids of lower molecular weight. mixture of the acids so obtained was esterfied with ethylene glycol, and yielded an edible fat said to resemble coco-nut oil. F. Fischer and W. Schneider *
employed a
steel autoclave,
and conducted the reaction
the presence of sodium carbonate, the mixture being by pumping in compressed air. In this way they obtained a yield of 90 per cent of fatty acids from crude paraffin, and these authors are of the opinion that iron, copper, and manganese have equal
catalytic effects.
at 170 stirred
in
A. Grunf has studied these reactions in more detail, and has that the results are dependent on many factors as yet little understood. In the absence of water the anhydrides of the higher fatty acids are formed, and in every case the neutral products contain ketones, such as stearone. The acids formed all appear to have a straight chain structure, while, according to Fischer and Schneider, the acids containing an uneven number of carbon atoms are formed in greater quantity than those with an even number. The latter type are those commonly derived from natural fats. Schaarschmidt and Thiele J have chlorinated paraffin at 160, and removed the hydrogen chloride either by treatment with alkali or by simply .heating at about 300. The resulting mixture of olefmes was then oxidized, preferably by t>zone, and under the best conditions a yield of 60 per cent of the higher fatty acids was obtained. Similar results were obtained by Granacher, who
shown
oxidized heated paraffin wax by a current of air containing 2 per cent of nitrogen peroxide. At 150 the process requires about four days. When /z-undecane is treated in the same manner, nonoic is the highest acid formed, and this is only obtained in small quantities. This method is therefore unsuitable for the degradation of hydroindicates that the higher paraffins in nature probably consist only to a small extent of normal hydrocarbons. Fermentation Glycerol. As early as 1858 Pasteur observed
it
carbons, but
the formation of small quantities of glycerol during the course of alcoholic fermentation. During the war, this circumstance assumed enormous importance in Germany, for it made possible the pro-
duction of glycerol from sugar on an industrial scale.

*
It
was
dis-
Ber., 1920, 53 [B], 922.
f Ibid-* 987. t Ber. Helv. Chim. Acta, 1920, 3, 721.
*92O, 53 [B], 2128.
102
covered that, under special conditions, the ordinary yield of glycerol of about 3 per cent can be increased at least tenfold. The essential feature of the industrial process, which has been
is
described by K. Schweizer,* and by W. Constein and K. Ludecke,f the employment of sugar solutions containing large quantities of
Crude sugar, or even molasses, may be used, and sulphite. neither the race of yeast nor the temperature appears to have much The monthly output in Germany influence on the yield of glycerol.
sodium
amounted to 1000 tons, 100 parts of sugar yielding 20 parts of purified glycerol, 27 of alcohol, and 3 of acetaldehyde. The process is based on the work of Neuberg and his pupils,
finally
and this chemist has furnished a theoretical explanation in a paper J which can only be briefly summarized here. In 1913 Neuberg and
Kerb put forward the hypothesis that dextrose, by loss of two molecules of water, furnishes the aldol of methylglyoxal, C6 8 O4 ,
which breaks down to two molecules of this one of which is reduced to glycerol, while the other
pyruvic acid:
H keto-aldehyde, C H O
3
2,
is
oxidized to
CH
The
C(OH)CHO + H 2 O
2
:
H
+
O
II
CH
(OH)
CH
C(OH)CHO
is
3
+ CH CO COOH
3
CH(OH) CH 2 OH
pyruvic acid
decarboxylated by carboxylase to acetaldehyde,
CH
and the
latter is
CO COOH - C0 + CH 3 CHO
2
reduced to alcohol, while from a further molecule

is
of methylglyoxal, pyruvic acid
regenerated:
CHa-CO-CHO CH CHO
3
II
=
2
CH CO COOH + CH CH OH
3 3
2
Hence methylglyoxal and pyruvic acid would be intermediate As stages, and glycerol and acetaldehyde necessarily by-products.
a matter of
fact,
the latter are always present during alcoholic ferit is
mentation, and the circumstance that the only known form of methylglyoxal does not ferment is not a fatal objection, since the most stable of the many possible forms.
It
probably
that slightly alkaline salts do not suppress the fermentation, but increase the yield of the by-products at the and then it was shown * * that of the main
||
was next found
expense
products;
by
* Helv. Chem.
J Ibid.) 1677.
||
Ada,
1919, 2, 167.
f Ber., 1919, 52
[B], 1385.
Biochem. Zeitsch., 1913, 58, 158. * * Biochem. Zeitsch., 1916, 78, 238. Ibid., 1918, 89, 365.
OILS, FATS,
AND WAXES
103
the use of sodium sulphite the acetaldehyde may be fixed in a yield of 70 per cent of the theoretical as the additive compound
CH 3 CH(OH) O SO 2 Na.
The
similar
additive
compound
of
pyruvic acid undergoes decarboxylation. As the acetaldehyde is now no longer reduced, the " hydrogen of fermentation " is used
up in forming more pound dissociates, its
Since the aldehyde-sulphite comand that of the glycerol, should depend yield, on the concentration of the sodium sulphite employed, but not be
glycerol.
proportional to it (mass action). The theory further demands that glycerol and acetaldehyde should be formed in molecular proportions. Both these postulates are fulfilled; thus, from 100 gm.
of dextrose and varying amounts of sulphite, the following yields were obtained:
Sodium
Sulphite Used.
Acetaldehyde
Glycerol
Grammes.
11*90 12-52
....
Grammes.
23*37 24-86 27-61 36-90
33
50
75 150
18-65
:
The molecular
glycerol is therefore 0-94 to 0*95 instead of i. The highest yield of glycerol corresponds with 35*06 per cent of hexose, or 70 per cent of the portion which could furnish
ratio acetaldehyde
For a 100 per cent conversion, the fermentation glycerol. have to proceed completely according to the equation:
would
C 6 H 12 O 6 + Na 2 SO 3 + H 2 O = C 3 H 8 O 3 + CH 3 CH(OH)OSO 2Na + NaHCO 3
The
shortage of 30 per cent is due to unsuppressed dissociation of aldehyde sulphite. With the same relative quantities of sugar and
sulphite in dilute solution, the dissociation yield of glycerol falls off considerably.
Still
is
much
greater
and the
more
recently
Neuberg and Reinfurth
state that insoluble
calcium sulphite suspended in the fermenting solution has advantages over the sodium salt.* The Lipins. When animal and vegetable tissues are extracted
with ether or with certain other organic solvents, the extract is composed of a heterogeneous collection of substances which include
the
and fatty acid; (2) substances having no relation to such as cholesterol and certain pigments; (3) substances fats, containing fatty acids, nitrogen, and phosphorus, known as phos(i) neutral fat
* For a summary of the methods by which the normal course of fermentation has been modified to produce glycerol, see Schweizer (Chim. et Industrie, 1921, 6, 149).
104
phatides;

and
(4)
cerebrosides, which are substances containing fatty acids, nitrogen, and a carbohydrate, but no phosphorus. The last two groups of fat-like bodies are often termed lipoids,
but
afc
these substances are difficult to separate
and
to obtain in a
confusion prevails regarding their number and pure state, " " has been used in such a chemical properties. The term lipoid
much
sometimes even including the neutral fats that it is better to consider the phosphatides and The lipins can then be defined as cerebrosides together as lipins. substances of a fat-like nature yielding on hydrolysis fatty acids or derivatives of fatty acids and containing in their molecule either nitrogen or nitrogen and phosphorus. The Phosphatides Lecithin. The phosphatides are of They plastic consistence and have distinctly fat-like properties. occur abundantly in eggs, brain, heart, muscle, liver, and other organs, and appear to be present in every animal and vegetable cell
vague and unsatisfactory sense
so far investigated. On hydrolysis the phosphatides yield phosphoric acid or glycerophosphoric acid, fatty acids, and basic bodies
such as choline and amino-ethyl alcohol
The
best
known phosphatides
Both
substance, kephalin.
(p. 184). are lecithin and the closely related these substances contain fatty acids
of the unsaturated series and are therefore very liable to oxidation. On this account their properties and solubilities soon alter on ex-
posure to light and air, so that their extraction and isolation in an unchanged state is attended with great difficulty.
Since lecithin yields a fatty acid, glycerol, phosphoric acid, and
choline on hydrolysis,
we may
provisionally write
its
structure:
CH
CO R
-
CHO CO R
CH
But
it is
2
phosphoric acid radical
choline radical
ineric forms,
obvious that glycerophosphoric acid namely an a and a p form.
may
exist in
two
iso-
HO
a
(J
H0\ = P O
O
CH 2
CH OH HO P = O
2
H0\
O
CHOH a' CH OH
2
CH
CH OH
2
(J
a form (unsym.)
form (sym.)
OILS, FATS,
AND WAXES
105
The a form
shown
contains an asymmetric carbon atom, and therefore should be capable of resolution. Willstatter and Ludecke* have
that the glycerophosphoric acid of lecithin is optically active. This shows that the a form is present, but it does not exclude
the possibility of the j8 form being present as well; indeed, Tutin and Hann f have adduced evidence that both forms are present. The problem of the constitution of lecithin is by no means settled. There is some evidence that two substances containing two different bases are present, and the nature of the union of these bases with a- and ^-glycerophosphoric acid is quite unsettled. The nature of the fatty acid has not been determined, and it would
appear that homologues of lecithin containing different fatty acids

exist.
In kephalin the base
is
amino-ethyl alcohoL
The Cerebrosides. These compounds contain no phorus. On hydrolysis they give galactose, a fatty acid, and a
phosbase
sphingosine. Up to the present only two cerebrosides have been described phrenosin and kerasin and both are obtained from
brain.
be identical except in so far as the former contains phrenosinic acid (C 25 50 O 3 ) and the The structure of sphingosine as latter, lignoceric acid (C 24 H 48 O 2 ).
to
These two compounds would appear
well as these two acids
is
unknown.
constitutional
RosenheimJ has suggested cerebrosides, but no finality has

REFERENCES.
formulae for these
yet been" reached.
The Chemistry of Plant Products, by Haas and Hill (London, 1922). The Fats, by J. B. Leathes: Monographs on Biochemistry (London,
Biochemie der Pflanzen, by F. Czapek, Erster Band (1922, Jena). Chemical Technology and Analysis of Oils, Fats, and Waxes, by Lewkowitsch (London, 1913).
Oils, Fats,
and Waxes, by Fryer and Weston, 2
vols.
(Cambridge, 1917).
Ber., 1904, 37, 3753.
f Trans., 1906, 89, 1749. J Biochem.J., 1916, 10, 142.
CHAPTER
The Terpenes and
The
VI
their Derivatives
terpenes embrace a large number of hydrocarbons of the empirical formula C5 8 and four main groups are recognized:
Sesquiterpenes, C H Polyterpenes, (C 5 H n
15
8)
Hemiterpenes, C 5 Terpenes proper,
C 10 H 16
24
.
.
terpenes proper and the sesquiterpenes form the most important constituents of the ethereal oils, and they are widely distributed in plants, especially in the coniferae and citrus
The
species.
O. Wallach belongs the credit of having elevated the methods of investigation of the terpenes to such a degree that the recognition and separation of the several terpene hydrocarbons have become
relatively
To
From
simple operations. the terpenes a large
number
of alcohols and ketones of the
general composition C 10 16 O, C 10 18 0, and C 10 20 O are derived. " These compounds are sometimes collectively termed camphors ",
since the commercially important, one of them.
common
or Japanese
camphor
is
study of the terpenes and their derivatives has attracted a large number of chemists, among whom Baeyer, Perkin junior, In Semmler, Wagner, and especially Wallach are noteworthy.
The
many
such as dipentene, terpinene, sylvestrene, &c., complete syntheses have been carried out, while in other cases, such as pinene, camphene, &c., at least a partial synthesis has been effected. The
cases,
isolation
usually much easier than that of the terpenes, since the former often crystallize well or
and purification of the camphors
is
THE TERPENES AND THEIR DERIVATIVES

form
characteristic crystalline derivatives.
107
Here
also the elucidation
of the constitution has been followed by numerous total syntheses, e.g. camphor and menthone, while other synthetic terpenes and
camphors have been obtained which have not yet been found
nature.
in
Of the numerous hydrocarbons of the formula C 5 8 isoprene stands in an especially close relationship to the terpenes. Isoprene occurs in the oil obtained by the dry distillation of caoutchouc.
,
Williams, Bouchardat, Tilden, and
more
:
recently Harries,
have
its
published
its
investigations constitutional formula,
concerning this hydrocarbon, while

:
CH 2 C(CH
3)
CH CH
2,
was established by
Of recent years isoprene has received consynthesis by Euler. siderable attention in connection with the problem of synthetic
rubber.*
With the exception of Properties of the Terpenes, C 10 H 16 when pure, are colourless, camphene, which is a solid, the terpenes, strongly refractive liquids which boil without decomposition. They have a pleasant odour, are volatile with steam, and many are optically
.
active.
terpenes polymerize very easily, and many, such as a-pinene and /?-phellandrene, are oxidized with resinification on exposure
The
terpenes into isomeric analogues. Nitrosyl chloride frequently gives well defined terpene nitrosochlorides, while many terpenes react with nitrogen peroxide to give
to the air.
Acids transform
many
nitrosates,
C 10H 16 (NO)O-NO 2 and with N 2 O 3 to give C 10 H 16 (NO)ONO, or pseudo-nitrosites, C 10 H 16 (NO)NO 2

,
nitrosites,
.
By
the
action of ozone the terpenes yield ozonides, while, with dilute potasAll these reactions have sium permanganate, they give glycols.
been extensively employed in the determination of the constitution

of the terpenes.
In most cases the terpenes and camphors are designated by names derived from the plants in which they were Since many first observed or which contain them most abundantly. terpenes, formerly considered as single substances, have been found to be mixtures, the terpenes isolated from them have been distinClassification,
guished from each other by prefixing Greek

y-terpinene.
letters, e.g. a-, /?-,
and
In this book some of the more important terpenes and the alcohols and ketones derived from them will be briefly considered in the
following groups:
*
Rubber, by B. D. Porritt (London, 1913)-
io8

A. Olefinic terpenes, or the terpenogen group. B. Monocyclic terpenes or menthadienes. C. Dicyclic terpenes:
1.
2.
3.
4.
The The The The
Sabinane Group. Carane Group. Pinane Group.
Camphane Group.
first
In accordance with a suggestion

terpenes
as
made by Wagner
may be
regarded as containing the same
the cyclic carbon skeleton
and Wagner designates hexahydrocymene as " the tetrahydrocymenes as menthenes ", and the ", " menthadienes ". In order to dihydrocymenes or terpenes as
"
/>-cymene
(i),
menthane
indicate the constitution of the dihydrocymenes the carbon atoms are numbered according to scheme (ii), whence it follows that A 1:4:
menthadiene * and
4 (S)-menthadiene would be represented

:
by formulae
3
(iii)
and
(iv) respectively:
C
c
CH 3
c
CH
c
<fH
H
c
)
c/cH
c
I
CH CH 3 CH 3
(i)
C
9
C 10
(ii)
CH CH, CH 3
(iii)
CH 3 CH
of this class are naturally able to combine with two molecules of halogen acid, halogen, &c.
Compounds
terpenes of the dicyclic group are distinguished from those of the monocyclic terpenes by the fact that they can only add two
univalent atoms or atomic groups. They therefore contain two Like the monocyclic terpenes, they are closely carbon rings.
related to />-cymene,
The
and can usually be converted into this comTheir dihydro compounds are derived from facility. hexahydrocymene either by the union of two carbon atoms in the w-position towards each other, by a diagonal linkage with the formation of a fused trimethylene and pentamethylene ring which
pound with
The position of the double linkages is indicated by the use of A in conjunction with the numbered position of the ten carbon atoms. The bracketed numbers indicate the second carbon attachment of the double bond outside the nucleus.

gives the sabinane group, or atom of the isopropyl group
109
by the union of the
tertiary carbon
is joined with a second carbon atom of the hexamethylene ring. According as this linkage occurs in the or p position we obtain the fundamental of o, y
hydrocarbons
the carane, pinane, and camphane groups:
CH,
CH,
I
CH-CH
CH,
CH r CH-
-CH,
/~tT
__ T /"ÎLI
yrL 2
V^H
'
.>
\^>
Vxxln
CH-C
C3 H
7
CH,
CH r CH
Carane
CH
CH
CH-CH
Pinane
CHj-CH-CH 2
Camphane
Sabinane
While these nuclear and bridge linkages are stable as regards the usual addition reactions, and are thus clearly distinguished from double linkages, they are broken with extraordinary facility by the action of heat and especially by hydra ting agents, giving rise to
derivatives of the monocyclic terpenes.
It follows that the
terpenes
one double bond only and may be described as sabinene, carene, pinene, and camphene. It is also evident that the possibilities of isomerism are more restricted than
will contain
derived from
them
in the case of the monocyclic terpenes.
THE OLEFINIC TERPENES AND THEIR DERIVATIVES

*
embrace a series of aliphatic compounds of the formulae C 10 H 16 C 10 H 10 O, and C 10 H 18 O, which were first described by Tiemann and Semmler. These
olefinic terpenes
The
and
their derivatives
,
open- chain terpenes bear a very close relationship to the cyclic terpenes and are easily transformed into them. The identification of these compounds as the principal odorous constituents of many essential oils has been made in comparatively
recent years. Beyond the observation of Oppenheim and PfafF in 1874 that the oil from Andropogon schoenanthus gives cymol
progress was made until 1890, when Schimmel's Berichte announced the fact that the aldehyde citral is the
on reduction,
principal
little
In the same year Dodge announced the presence of citronellal in citronella oil, while almost at the same time Semmler isolated geraniol from oil of geranium
oil.
odorous constituent of lemon
and made some progress
in the determination of its constitution.
no
Since this time the presence of the olefinic terpenes and their derivatives has been observed in a number of essential oils. The more
important compounds of this class are tabulated opposite. This tabulation shows that these compounds exhibit among themselves a certain similarity in structure. They contain ten carbon atoms, which are arranged in such a way that six of them form a straight chain, three of them form an unsaturated isopropyl group attached to one end of the chain, and the tenth forms a methyl group at the fourth carbon atom from the end of the chain. The grouping may therefore be considered as resembling that of a monocyclic terpene in which the ring has been ruptured. It has already been stated that Semmler * had observed the re-
cymene, and that by the action of potassium on geraniol or citral, jp-cymene had been obtained. hydrogen sulphate The relation of citral to p-cymene is made clear by the following
lationship of geraniol to
formulae:
CH CHO
Citral,
,CH 3
CH 3 C
*
CH - CH
/>-Cymene,
CH 3
-
CH C^
3
CH - CH
^C CH/
CH
Bertram and Walbaum f showed that by dehydration of geraniol, or still better linalol, dipentene and terpinene are formed, while Stephen J observed that by the action of formic acid on both geraniol and In these reactions linalol is probably linalol, terpineol is obtained. first transformed into the isomeric geraniol, and, by the removal and subsequent addition of water, ring formation occurs with the production of terpin, followed by that of dipentene and terpinene.
CH CH OH
2
CU^CH,
Geraniol
Terpin
CH - CH
^
CH
Cv
rûr L/ri2
xCH C(OH)(CH 3 )2
rîu ^rl
2
Terpineol
7.
Ber., 1890, 23, 1098, 2965, 3556; 1891, 24, 201, 682. prakt. Chem.y 1892, 45 [2], 590. J Ibid., 1898, 58 [2], 109; 60, 244.
no

number
of essential
oils.
Since this time the presence of the olefinic terpenes and their derivatives has been observed in a
The more
important compounds of this class are tabulated opposite. This tabulation shows that these compounds exhibit among themselves a certain similarity in structure. They contain ten carbon atoms, which are arranged in such a way that six of them form a straight chain, three of them form an unsaturated isopropyl group attached to one end of the chain, and the tenth forms a methyl group at the fourth carbon atom from the end of the chain. The grouping may therefore be considered as resembling that of a monocyclic terpene in which the ring has been ruptured. It has already been stated that Semmler * had observed the re-
cymene, and that by the action of potassium on geraniol or citral, p- cymene had been obtained. hydrogen sulphate The relation of citral to />-cymene is made clear by the following
lationship of geraniol to
formulae:
CH-CHO
Citral,
/CH 3
CH 3
C<^
i
CH - CH
p-Cymene,
CH 3
CH<^
CH
C\^
%C
CH - CH
CH
Bertram and Walbaum f showed that by dehydration of geraniol, or still better linalol, dipentene and terpinene are formed, while Stephen J observed that by the action of formic acid on both geraniol and In these reactions linalol is probably linalol, terpineol is obtained. first transformed into the isomeric geraniol, and, by the removal and addition of water, ring formation occurs with the prosubsequent duction of terpin, followed by that of dipentene and terpinene.
CH CH OH
-
CH1_CH
3) 2
CH -CH CH:C(CH
2 2
\CH-C(OH)(CH 3) CH 2~CH 2
Terpin
Geraniol
CH - CH
->
2
-
CH
C<^
NCH
2 2
C(OH)(CH 3 ) 2
CH - CH
Terpineol
Ber., 1890, 23, 1098, 2965, 3556; 1891, 24, 201, 682. prakt. Chern., 1892, 45 [2], 590. J Ibid., 1898, 58 [2], 109; 60, 244.
Name.
Probable Constitution.
Occurrence.
CH CH
Geraniol
CH
C CH CH 2 OH
:
and
nerol.
CH
CH 3
-
Geraniol in geranium oil from Andropogon schcenanthus. ,, ,, Oil of citronella from Andropogon nardus. German and Turkish rose oils, &c. Nerol in neroli and petit-grain oil.
CH CH 2 CH
and Citral neral.
II
C CH CHO
:
CH
3
Oil of lemon-grass from Andropogon citratus. Oils of lemon, Citrus limonum.
CH 3 CH
/ \
Eucalyptus staigeriana.
CH CH
II
CH, C(OH)
CH.
CH CH,
:
Linalol.
CH 3 CH
-
Oil of linaloe, oil of neroli. Oil of bergamot from Citrus Bergamia. Oil of lemon, petit-grain, spike lavender, ylatig-ylang, &c.
CH CH
li
CH
CH CH 2 CH,OH
.
I
Rhodinol.
Laevo form in geranium and rose
oil.
CH CH 3
3
CH CH, CH
li
CH CH
CH,
CHO
(?)
Rhodinal.
synthetic product.
CH
CH
CH, CH a CH 2
-
CH CH CPLOH
-
Citronellol.
v^-
CH,
Bulgarian and
German
rose
oil.
Oils of geranium
from Pelargonium
odoratissintum, &c.
CH
CH,
-
CH
Citronellal.
CH
CH
2 a
CH CH
-
CHO
Citronella
oil
CH
^
from Andropogon nardus.

oils.
oil, oil
Certain eucalyptus
/
CH,
CH
Lemon-grass
2
of mandarin orange,, &c.
[Facing p.
no

olefinic
in
Further examples of the formation of monocyclic terpenes from terpenes are afforded by citronellal and rhodinal, which, according to Tiemann and Schmidt, are transformed by acetic
anhydride into iso-pulegol and menthone respectively:
CH
/CH 2 -CHO
3
-CH< N
,CH a _^ prr rH / "* CH 2 -CH 2 -CH 2 -Cf ^"3-^H\

N/^LJ v^rls
CH - CH(OH) V
2
rH ^"
/
rûr Lxrl 2
r^nj >^rl 2
Citronellal
Iso-pulegol
CH -CHO
2
rt4
CH -CO
2
CH CH< \ / CH -CH
3
/CH = C^ /
2
->
CH
Nr'M Uhl3
CH<;
2
>CH CH<
2
CH ~CH
Menthone
Rhodinal
The
reverse of this process takes place
on exposing an aqueous
alcoholic solution of
opened and an
to bright sunlight, when the ring is unsaturated aldehyde, similar to citronellal but of
menthone
lower boiling-point, is obtained.* Before briefly describing the synthesis of the olefinic terpenes and their derivatives it is advisable to consider that of methylhep tenone, since the constitutions of many of these compounds as
well as their synthesis have been derived from this olefinic ketone.
Methylheptenone (CH 3 ) 2 C
,
CH CH 2 CH CO CH 3
2
v
was
first
obtained in small quantities from natural linaloa oil by Barbier and Bouveault,f while Tiemann J found that it was present in lemongrass oil to the extent of i to 3 per cent. Methylheptenone has been several methods, of which that of Barbier and Bousynthesized by veault may be described. In the first place 2-methyl-2 4-dibromobutane is condensed with the sodium derivative of acetylacetone.
:
This gives the unsaturated deketone (i) which can then be broken down by strong alkali into methylheptenone and acetic acid.
(CH 3 ) 2 CBr
CH +
2
/COCHa MaTH iNa
(CH a) 2 C _>
3
(CH 3 ) 2 C
CH
^^COCH
CH
|
I!
KOH CH
->
2
II
Br
CH CO CH
CH
CH CO CH
3
+CH COOK
3
2
2-Methyl 2:4dibromobutane
/>CH
L,ti 8 vû
(i)
+ NaBr + HBr
r.,
* Ciamician and Silber, Ber., 1907, 40, 2421. C. t Ber., 1899, 32, 830.
f C. r., 1895, 121, 168. 1896, 122, 393.
ii2

When
shaken with 75 per cent sulphuric acid, methylheptenone and gives dihydro-w-xylene.
loses water
/\ CH 3 - C CH
CHs
CH
CH
2
-HO
2
CH 3 C
/\
C
CH
O:C
The
CIi2 ' '/
CH CH
\/
H 113
in v>Jri3
preparation of several of the olefinic terpenes and their derivatives from methylheptenone may be illustrated by the fol-
lowing tabulation: Methyl -hep tenone *
Geranio Acid
IZn
'
andCH 2 10OOC 2 H 5
followed by dehydration
"v^
Reduction with Sodium and
Amyl
Alcohol
||
VRhodinic Acid
Reduction \viih
Sodium Amalgam
Rhodinol and Rhodinal
* *
Geraniol and Nerol (stereoisamers)

Linalol
It has already been shown reduced by sodium-amalgam in the presence of dilute acetic acid, geraniol and nerol are obtained.
Geraniol, Nerol, and Linalol.
that
when
citral in alcoholic solution is
is interesting to recall the fact that Bar bier's attempt to convert methylheptenone into dimethylheptenol, (CH 3) 2 C CH CH 2 CH 2 C(OH)(CH 3 ) 2 (C. r., 1899, 128, no), led to the discovery of the magnesium alkyl and aryl halides. Methylheptenone was allowed to react with magnesium and methyl iodide in the presence of dry ether, since Barbier had found that the zinc alkyls were unsuitable. This suggested that magnesium had reacted to form magnesium methyl-iodide, and the possibilities of this reaction were studied by Barbier's pupil, Victor Grignard. These organo-magnesium compounds are now generally designated Grignard Reagents, but would perhaps be more correctly termed Barbier- Grignard Reagents
:
* It
I)
r., 1896, 122, 398; Tiemann, Ber., 1898, 31, 325. Tiemann, loc. cit. Tiemann, loc. cit. Bouveault and Gourmand, C. r., 1904, 138, 1699. ** Tiemann, Ber., 1898, 31 2901
t Barbier and Bouveault, C.

J

These terpene-alcohols appear
to
113
be structurally identical, and are
* probably stereoisomerides of the formula
CH
(CH 3) 2 C
:
CH CH
CH
C CH CH 2OH
:
When
treated with acetic acid containing
to 2 per cent sulphuric
acid both give terpineol, but the reaction is much quicker in the case of nerol, from which it is concluded that the groups which unite to
form the terpineol ring are much

than in that of geraniol:
closer together in the case of nerol
H
:
CH OH
2
(CH 3 ) 2 C CH
CH - C - CH 3 HO CH - C - H (CH C CH CH CH - C - CH
-
CH
Geraniol
II
3) 2
Nerol
least
Linalol occurs in both dextro and laevo forms, and therefore at one asymmetric carbon atom is present in the molecule. This
facts are best explained
and other
on the assumption that
linalol
has
the formula:
OH
(CH 3 ) 2 C CH
:
CH
CH
C CH CH 2
:
CH
but this constitution has not yet been well established. Citronellal. The determination of the constitution of this aldehyde may be briefly considered in order to illustrate the diffiIn 1896 Tiemann culties attendant upon this type of investigation. and Schmidt f obtained acetone and j8~methyladipic acid by the oxidation of citronellal, and concluded quite legitimately from their
experimental results that the constitution of citronellal was correctly represented by the formula:
(CH 3 ) 2 C CH
:
CH
CH
2
CH(CH 3 )CH CHO

2
which on oxidation
3) 2
yields:
2 3
2
(CH CO + HOOC CH CH CH(CH )CH COOH

In 1901, however, Harries and Schauwecker J prepared the dimethylacetal of citronellal, which on oxidation with permanganate gave acetone and the half aldehyde of /J-methyladipic acid, whereas
further oxidation with chromic acid gave an oxydialdehyde and
*
Zeitschel, Ber., 1906, 39, 1780.
(D331)
f Ber., 1896, 29, 903; 1897, 30, 22, 33. J Ber., 1901, 34, 1498, 2981. 8
ii4
3 finally a keto-aldehyde, These results are best explained
CH CO-CH2 -CH
-CH 2 CH(CH3 )CH a CHO.
by the following formulae:
CH 3
\C CH CH CH CH CH CHO
2
2 3 2
CH
CH
*
> X
CH
|
C-CH 2 CH 2 -CH 2 CH CH 2 CH(OCH 3

-
)2
then in Tiemann and Schmidt's experiments the double bond moved from the ultimate to the penultimate carbon atom. Citral. In 1907 Harries and Himmelmann* obtained evidence to show that citral exists in two geometrically isomeric forms:
If this
is so,
HC CHO
-
CH C CH 3 OHC - C - H (CH C CH CH CH C - CH
(CH 3 ) 2 C
:
CH CH
Citral a.
3) 2
Citrai b.
The
preparation of a- and /Monone from citral will be described later. Rhodinol and Rhodinal. The constitution of these two compounds is by no means definitely settled as yet, and the literature
contains
many
contradictory statements.
fr.THE MONOCYCLIC TERPENES (C 10H 16 )

This terpene is known in three modifications, Tod-limonene, 7-limonene, and (d7)-limonene or dipentene. with pinene, dbefrolimonene is among the most widely gether It is present in lemon oil, oil of distributed terpenes. bergamot, of dill, and several other natural essential oils. L^ôlimonene oil occurs in oil of pine needles, oil of fir, and oil of peppermint. Dipentene, which may be obtained by mixing the two isomerides, or by racemization of either at 270, occurs naturally in oil of cinea and is also formed by heating pinene or camphene. Dipentene is thus in Swedish oil of turpentine, which has been prepared present by
distilling the natural
Limonene.
The
C 10H 16 Br4
product at a high temperature. limonenes combine with bromine to form tetrabromides,

,
which are stable
crystalline substances, while nitroso-
*Ber., 1907,40,2823.
115
chlorides of the general formula C 10 16 NOC1 are formed by the action of nitrosyl chloride. The nitrosochloride of the inactive
modification
is
converted into inactive carvoxime by the action of
alcoholic potash. Carvone* is a ketone which is readily converted into the isomeric carvacrol.f These results suggest that limonene contains a six-carbon ring to which paramethyl and isopropyl groups
are linked.
Inactive limonene has
now been
obtained synthetically
by a method which leaves no doubt as to its constitution. The Synthesis of Limonene, Terpineol together with terpin and limonene have been synthesized by Perkin jun. J with the aid of
the Barbier-Grignard reagent. The starting point which is obtained as follows: hydrobenzoic acid,
,
is
S-ketohexa-
2C 2 H 5 OOC
CH
CH
2I
+ Na C< X COOC H
2
2
p-Iodopropionic ester
C 2 H 5 OOC CH 2 CH 2 CN
H OOC CH CH COOC H
5 2 2 2
"
x
OC \ OC<
Y- Cyanopentan-ocye-tricarboxylic ester
HOOC-CH, -CH
HC1
COOH
COOH
/
rû CH
2
HOOC CH CH
2
Boil with acetic anhydride nnyuriue
->
and
distil
>CH COOFI
2
8-Ketohexahydrobenzoic acid
The
ester of this acid reacts with
ketonic
group being preferentially S-hydroxyhexahydro-p-toluic acid is obtained:
magnesium methyliodide, the attacked, and on hydrolysis
IMgO
CH -CH
2
HO
CH-COOC H
2 5
CH -CH
2
y yc<f CH 2 -CH 2 H,C
HC
3
CH -CH
2
J Trans., 1904, 85, 138, 416;
1906, 89, 1640; 1907, 91, 372.
OH
*
See p. 128.
C
t Carvacrol has the constitution:
CH
HC3
CH CH
n6
By
toluic acid is

the action of fuming hydrobromic acid, 8-bromohexahydro-/>formed which, on treatment with weak alkalies, gives
3-tetrahydro-/>-toluic acid:
CH - CH
CH 3
When
C^
CH
^>CH
2
COOH
the ester of this acid
is
treated with
is
magnesium methyliodide
the tertiary alcohol, terpineol,
obtained:
CH - CH
COOC H + 2MgCH 3 I
2
CH - CH
2
OMgl
- C CH ^)CH CH - CH 2
H,0
C(OH)(CH 3) 2
OC H 5
2
CH
Terpineol
is
Terpineol
transformed into <//-limonene (dipentene) by dehydrating agents, e.g. potassium hydrogen sulphate, and into terpin hydrate by shaking with dilute sulphuric acid, or directly from the
original cyclohexanone ester
by the action of excess of magnesium

2
methyliodide:
CH - CH
CH - CH
2
.OH
Terpineol
CH - CH
CH - CH
2
CH 2
CH - CH
2
CH 3
CH - CH
Terpin
^>CH-C(OH)(CH 3 ),
2
Dipentene
The
and
8,
alternative
method by which water may be eliminated from
terpineol,
namely between the groups attached to carbon atoms 4 would lead to the production of a terpene devoid of an asym-
metric carbon atom.

Terpinolene
117
CH - CH
//
CH S
__
\J
2
-CH
is
an
artificial inactive
It has
when
terpene first obtained by Wallach from pinene. not yet been observed in natural essential oils. It is produced terpin hydrate, terpineol, or cineol are boiled with dilute
sulphuric acid, and by heating pinene with concentrated sulphuric acid. With bromine, terpinolene forms a dibromide, C 10 16 Br 2 and a tetrabromide, C 10 16 Br4 from which it can be regenerated
in purity by reduction with zinc dust and alcohol.* Terpinolene is an unstable terpene, and is readily converted into terpinene by the action of dilute acids.
The Terpinene Group.

three terpenes:
This group embraces the following
CH
CH CH
CH 3 CH CH 3
-
CH 3 CH CH
-
CH CH
2
/\
2
CH CH
2
/\
c
CH CH
2 2
/\
2
CH CH
c
CH CH
CH
I
CH CH
CH
CH
a-Terpinene
y-Terpinene
p-Terpinene
Of
these terpinenes the a and y compounds have been found in essential oils, while the jS compound has hitherto only been obtained
synthetically.
Natural terpinene and the terpinene
artificially
pre-
pared from other terpenes or terpene alcohols represent a mixture of the a and y terpinenes, and the isolation of a pure a or y form has not yet been accomplished. Natural terpinene occurs in cardamom oil, coriander oil, and ajowan oil. It is formed when
dipentene, terpene, phellandrene, or cineol are boiled with dilute sulphuric acid and also when pinene is shaken with a little con-
centrated sulphuric acid. /3-terpinene was obtained
synthetically
by Wallach f
from
sabinaketone (p. 126) by condensation with bromacetic ester in the presence of zinc (Reformatsky's reaction). After hydrolysis, the
*
Ber., 1909, 42, 4644.
f Ann., 1907, 387, 68.
ii8

is
product
converted into an unsaturated acid by heating with acetic anhydride. On heating this unsaturated acid alone, it loses carbon dioxide and water and gives /?-terpinene:
HO CH COOC H
2 2
CH-COOH
HC(CH 3
)2
HC(CH 3
)2
HC(CH 3)
HC (CH
3) 2
Sabinaketone
(3-Terpinene
This method has been frequently used for the replacement of the oxygen of a cyclic ketonic group by the unsaturated side chain
(:
CH
2).
In 1904 Wallach* published the results which he had obtained in his exhaustive investigation of phellandrene obtained from water-fennel oil (Phellandrium aquaand pointed out that two isomeric phellandrenes are ticwri)
present in this
oil.
The Phellandrene Group.
Phellandrene
(z
:
p -Phellandrene
2
5-Dihydrocymene)
The
its
structure of the
:
synthesis from A that of jS-terpinene.
confirmed by Wallach f by 2-isopropylcyclohexanone after the manner of

j8
form was
later
Sylvestrene and Carvestrene. Sylvestrene has been found in Indian, Swedish, and Russian turpentine oil, and oil of pine It is dextrorotatory, and possesses a pleasant odour needles.
resembling that of lemons.
*
Ann., 1904, 336, 9.
\Ann. 1905, 340,

y
i;
343, 29.
119
Carvestrene is an artificial compound which was first obtained * by Baeyer by the distillation of vestrylamine hydrochloride.
C 10H 17 NH 2 HC1 - C 10H 16 +
NH C1
4
Both sylvestrene and carvestrene give a deep blue colour when dissolved in acetic anhydride and treated with concentrated sulphuric acid.
This property is not shown by any other terpene, and since sylvestrene and carvestrene are the only menthadienes of the meta series it is very probable that carvestrene is the inactive
form of
sylvestrene.
Carvestrene has been synthesized by Perkin junior and Tattersail, f by the action of magnesium methyliodide on the ester of
cyclohexanone-3-carboxylic acid in a similar manner to that of Later J the intermediate tetrahydro-w-toluic acid was dipentene. resolved and the dextrorotatory terpene prepared from it was
found to be identical in every respect with ^/-sylvestrene. Cyclohexanone-3-carboxylic acid was prepared by oxidizing the hexahydro derivative obtained by the reduction of w-hydroxybenzoic acid:
CH
CHOH
CH-COOH
CH-COOH
Synthetic Monocyclic Terpenes. The first complete synthesis of a monocyclic terpene was carried out by Baeyer in 1893, and although more convenient methods have been devised in recent years, yet on account of the richness of the field explored, his synthesis must be regarded as classical. In the presence of metallic sodium, two molecules of diethylsuccinate (i) condense to form
succino-succinic
ester.
ester
(ii)
diketohexamethylene
(iii) is
dicarboxylic
When the latter is treated with sodium ethoxide and isopropyl

formed which, on repetition
iodide a monoisopropyl derivative
of the process but using methyliodide in place of isopropyliodide, a methyl-iscpropyl derivative (iv). On treatment with congives centrated sulphuric acid methyl-isopropyl diketocyclohexane (v)
obtained, which may be reduced to the alcohol (vi). On bromination with strong hydrobromic acid a dibromo derivative (vii) is
is
Ber., 1894, 27, 1915, 3485;
t Trans.y 1907, 91, 480.
1896, 29, 2796. Proc. Chem. Soc., 1910, 26, 97. J
120
formed, from which a menthadiene of uncertain constitution is obtained on removing two molecules of hydrogen bromide by means of quinoline.
COOC H
2
COOCoHs
a
CO
2
CH
CH
CH CH COOC H
2
CH
C 2H 5 OOC
CH
CH CH
2
5
COOC H
(0
/ CO COOC H
2
(ii)
^ a TT CHg CH
s-i
/\
C0
*
"< >c
||
liii)
C/OOCxori5
->
2
^ 3 TT "<
f>t
/\ / CH CH> Cv
"
|
|
C0
X COOC
H5
C H OOC
2 5
C H OOC
5
(iv)
CO
CHOH
CBTRr
OCHCH CO
(v)
syntheses of limonene and carvestrene by Perkin junior have already been dealt with. These methods have been ex-
The
tended in several directions which

as follows.*
1
.
may be
briefly
summarized
the toluic acid by reduction to the hexahydro derivative and bromination. On removal of hydrogen bromide an aj8-tetra-
From
hydro toluic acid
is
obtained.
The
ester of the latter
is
treated with
magnesium methyliodide, and the resulting menthadiene contains

a conjugated double bond. By a similar process, but using the saturated hexahydro toluic acids, the corresponding menthanols and
menthenes have been obtained.

2.
From
the hydroxy toluic acid, which
is
reduced to the hexaacid.
hydro derivative and thence into the latter is then treated as above.
Synthesis of the Terpenes ", by Oil Record, 1912, 3, 149.
3. * "
bromohexahydro
The
From
the hydroxybenzoic acid by complete reduction and
W. H.
Perkin, The Perfumery and Essential
121
oxidation to the ketonic acid. Magnesium methyliodide attacks the ketonic group, and the methylhydroxy acid thus formed is converted into the
carvestrene).
4.
bromo
acid
and thence
to the unsaturated acid (c,f.
By the
action of sodamide
and carbon dioxide on the methyl-
cyclohexanone. resulting ketonic acid is then reduced to the hydroxyacid and thence through the bromo acid to the unsaturated acid.*
The
CH 2 CO M
.
.
MIJ
N^NH 2
_n +C0 2
CH 2 CO
.
.
CH.CIK 3
/ CH 2 CH 2
/CFU
CH,CH< 3
\ / CH2 CH 2
H J^ >CHCOOH CKLCEK
3
CH CHQH
2
> .
>CH-COOH
CH 2 CH 2
HBr
*
CH 2 CHBr / \ CH CH< >CH-COOH CH 2 CH2

cyclohexanone-2
:
sodium derivative of which gives methylcyclohexanone carboxylic acid on

5.
From
4-dicarboxylic
acid,
the
treatment with methyliodide:
CH
C 2 H.O-COC(Na) CH 2 25
I
C.H.OOC-C 26
CH 2
CH 2 CH 2
CH,
I
CH 2 CH 2
CH
CH-COOH
CH CH 2
2
The
reduced and the bromo acid prepared in the usual manner. Carvestrene has been synthesize^ in this way.f Hawarth and Fyfe \ have prepared menthadienes allied to the monocyclic terpenes by the application of the well-known method
ketonic group
is
for the conversion of nitrites into ketones
by the aid of the Barbier-
Grignard reagent.
*
t Trans., 1908, 29, 1876.
Tram., 1910, 97, 1756; 1911, 99, 526. J Trans., 1914, 105, 1659.
122
CH
i
:
CH(CH 3 )-CH a
Sod. cyanoacetate
CO
2
->
CH 2 CH
2
CH(CH 3)-CH
Heat
C.CH(CN)COOH
-*
CH
CH(CH 3)-CH
2
Methylcyclohexan 3 -one
/ CH \ / CH \
\ MgCH I / C-CH CN -> CH /

3 2
CH(CH 3)-CH,
\"
2
C-CH,COCH 3 ->
"
MgCH
3I
CH(CH 3 )-CH
2
CH
The
\ C-CH,>C(CH ),OH /
3
dehy-
CH(CH 3)-CH
dration/
-> CH,
\"
C-CH:C(CH 3
)2
trates
synthesis of j8-terpinene already referred to (p. 118) illusanother synthetic method which has been elaborated by
Perkin junior and Wallach.* Cycloketones are combined with abromopropionic ester in the presence of zinc (Reformatsky's reThe free acid on heating loses carbon dioxide and water, action).
giving an unsaturated
compound,
e.g.
CH3 CH<^\CO-^GH 3 CH/

N
/
\<f
f
^CH CB/
3
CH (CH 3 )COOH
)c:CHCH f
nitrosochloride of the latter gives the oxime on elimination of hydrogen chloride and on hydrolysis yields the ketone.
The
CH 3 CH/
\C-Q-C(CH 3):NOH->CH 3 CH/
\C-
CH 3 CH
are obtained on treating the with magnesium methyliodide. The Menthenes and their Derivatives. The monocyclic terpenes so far considered contain two double bonds, and are A number of monocyclic consequently termed menthadienes. terpenes of the general formula C 10 H 18 are known which contain one double bond and are consequently termed menthenes. The
latter
*
Trans., 1910, 97, 1429;
The menthanol and menthadiene
1911,99,118; Ann., 1910, 374, 198; 1911,379,131.
123
parent hydrocarbons are not very important, but a few of their derivatives merit consideration.
Pulegone, A-4 (8)-menthene-3-ketone

:
CH - CO
2
\C C(CH
:
3) 2
CH.2
is
the chief constituent of

isolated
oil
was
by Beckmann and ultimately synthesized by Tiemann and Schmidt in Semmler, 1896.* With hydroxylamine it forms both an oxime and an oxamino ketone, and Wallach has shown that this reaction is characteristic of When cyclic ketones when the double bond is in the side chain. the double bond is in the nucleus the so-called oxamino oximes are formed, in which one hydroxylamine molecule forms an additive compound at the double bond, and the other attaches itself to the
ketone group,
e.g.
of pennyroyal (Mentha pulegium). It and Pleissner in 1891, investigated by
HC
2
CH
CH 3 C
2
I
C
1
NOH
\/
CH CH
CH CH 2
3
\/
CHCH
An
oxamino oxime
On
*
f
reduction pulegone
is
converted into menthol, and on oxidabond moves with the formation
Ber., 1896,29, 913; 1897,30,22. By the action of hydroxylamine the double
of the oxime of isopulegone.
I2 4
tion into acetone and 3-methylcyclohexanone, further oxidation of
the latter giving j8-methyladipic acid:
CH
CH 3
i
CH CH 2
2
/\
2
CH
CH CO
C
CH CH2 CH C ^HOH
2
V CH
2
C!H
CH 3 CH
Menthol
CH
C!H
oxidation
CH2
2
CH
CH COOH
CH 2
3 -Methylcyclohexanone
V
COOH
acid
p-Methyladipic
+ CH COCH
3
with acetic anhydride it gives isooxidation of the latter isopulegone is obtained, which On pulegol. on treatment with baryta undergoes isomeric change to pulegone: *
citronellal is heated
When
CH CH
CH CH 3
CH CH
CH CH,
Menthone occurs in Japanese, American, and Russian peppermint oils. It is known in two opti-
Menthone and Menthol.
cally active modifications, of

*
which the
laevo
form may be obtained
Tiemann and Schmidt,
Ber., 1897, 30, 32.
125
by the oxidation of menthol with potassium dichromate and sulphuric acid below 50. Concentrated sulphuric acid converts laevomenthone into dextromenthone in the cold. * by Synthetic menthone was obtained by Kotz and Schwarz
distillation
of
the
calcium
salt
of
jS-methyl-a'-isopropylpimelic
acid:
CH 3
C!H
CH
CH
CH
2
CH
2
CH 2 CH COO CH COO-Ca
2
CH 2 CH
->
CH CH
2
CH 2 CO CH CH CH 3 CH 3
Menthone
-*
CH 2 CHOH CH CH
CH
CH
CH 3 CH 3
CH 3 CH 3
Menthol
Laevomenthol is the principal constituent of peppermint oil. A dextromenthol has been obtained by reducing the menthone from bucco oil. Several synthetic menthenols (menthols) have been
acids as synthesized by Perkin junior from the hexahydrotoluic On dehydration of laevomenthol a dextroalready indicated (p. 120).
menthene of the constitution shown below has been obtained, and this structure has been verified by its synthesis from i:4-methylcyclohexanone by Wallach.f
/ CH - CH \
3
CH - CH
2
CH
\ C /
CH< X
/CH 3 CH 3
C-
\,The Sabinane or Tanacetane Group .7 The closely related compounds of this group, the most important representative of
which is thujone or tanacetane, contain both a trimethylene and a pentamethylene ring, and can be converted into triSabinene and the methylene carboxylic acids by oxidation. contain the same carbon skeleton, and differ two thujenes must
*
Ann., 1907, 357, 206.
Ber ->
I9
6>
35 2 54>
126
only by the position of the double linkage since they all yield the same saturated dicyclic hydrocarbon C 10 18 sabinane or
thujane on gentle reduction.* Sabinene. The dextro form of this compound has been found With dry hydrochloric in Ceylon cardamom oil and majoram oil.
yields sabinene hydrochloride, but with moist acid terpinene dihydrochloride. With cold dilute sulphuric acid
acid
it
it it
gives
gives
terpinenol and
4-terpin, while on heating
it
gives terpinene: f
JHfCHj),
Sabinene
CH
CH,
OOH
Sabinene
hydrochloride dihydrochloride
On
is
first
oxidation with potassium permanganate sabinene glycol (ii) formed, which is then oxidized to sabineric acid (iii) and
(iv).
further to sabina ketone
CH,
COOH
C-OH
CO
CH(CH 3 ) 2
Sabinene
CH(CH 3 ) 2
111
CH(CH 3
iv
)2
On
treating this cyclic ketone with warm aqueous or alcoholic sulphuric acid the trimethylene ring is broken and 2-isopropylcyclo*
Tschugaeff and Formin, C. r., 1910, 151, 1058. t Wallach, Ann. 1907, 350, 165.
t

hexanone
(ii)
127
is
obtained.
Further disintegration leads to the

(i).
formation of a-tenacetone-dicarboxylic acid
COOH COOH HP
CH(CH 3 ) 2
Sabina Ketone
The Thujenes.
These terpenes
are obtained
from the ketone
thujone, which, according to Wallach, exists in isomeric forms. Thujone is found in thuja, wormwood, and sage oils and is laevo-
The dextro form is found in tansy oil and some wormwood oils. The oxime of thujone gives thujylamine, C 10 H 17 NH 2
rotatory.
on reduction, and the hydrochloride of this base yields thujene on distillation. An alternative method is due to Tschugaeff,* according to which thujone is reduced to thujyl alcohol and converted into its xanthicmethyl ester by treating the sodium compound of the alcohol with methyliodide and carbon disulphide. On dry distillation a thujene (]8) is obtained which is apparently not identical with that
obtained by the
first
method.
-
C 10 H 17
CS SCH 3 - C 10 H 18 + COS + CH 3 SH
Thujyl xanthic ester
CH(CH 3
a -Thujene
)2
CH(CH 3
P -Thujene
)2
Thujene combines with hydrogen chloride to give terpinene dihydrochloride, and is converted into terpineol on treatment with
dilute sulphuric acid.
*
J. Russ. Phys. Chem. Soc,> 1904, 36, 988.
28
THE CARANE GROUP

carone.
member of this group which we need consider is This terpene does not occur in nature, but has been obtained by the action of methylalcoholic potash on dihydrocarvone
The
only
hydrobromide:
CH3
CH 3
CO
CH,
CH
CH=
CH
CH
CH
CH,
CH
I
CHj CH
I
CH,
^C\CH
BrC(CH 3 ) 2
3
Dihydrocarvone
Carone
Dihydrocarvone is obtained by the action of mild reducing agents, such as zinc dust and alcohol, on carvone. Carvone is found as the dextro form in dill and carraway oil, and as the leevo form in spearmint and kuromoji oil, and has the constitution:
CH 3
C
CO CH
CH, v^ria 2 CH 2
CH
CH2
Carvone
Carone has an odour somewhat resembling camphor and peppermint. It gives caronic acid on oxidation, and the identity of this acid with dimethylcyclopropane-dicarboxylic acid has been established by its synthesis by Perkin junior and Thorpe.*
COOH
HOOC
Carone
- CH
CH
Caronic acid
* Trans., 1899, 75, 48.
THE PINANE GROUP
129
THE PINANE GROUP

The Pinenes.
oils,
Pinene
is
a very
common constituent of essential
and is the chief ingredient of the turpentine oils. Turpentine, the resinous juice exuding from various coniferae, consists of a solution of resins in turpentine oil. The oil is volatile in steam
while
the
resin
(colophany)
remains
behind.
The American
Algerian, and Greek turpentine oils contain chiefly dextropinene, while the French and Spanish oils contain the Icevo form. In most cases pinene is accompanied by small quantities of a closely related terpene of higher boiling-point. This is especially the case with the turpentine oils, and this related terpene is termed /?-pinene to distinguish it from the ordinary or a-pinene. The natural oil almost invariably contains (dl)-a- Pinene. traces of j8-pinene, which may be removed by making use of the
fact that a-pinene alone gives a nitrosochloride
with nitrosyl chloride.
nitrosochloride is then decomposed by aniline, or by boiling with sodium acetate and glacial acetic acid. Pinene combines with two atoms of chlorine or bromine, and therefore the pinene molecule contains one double bond. By the action of moist hydrogen halides, pinene is converted into dipentene dihydrohalides, while monohalogen hydrates are obtained with
it
The
perfectly
dry acid.
These, however,
like
the
halogen additive
ring, the hydrogen haloids having given rise to borneol derivatives. This easy transition of pinene into borneol and isoborneol has been utilized industrially
v
products, no longer contain the pinene
for the production of synthetic camphor from oil of turpentine. The oxidation products of pinene have been examined in detail by Baeyer, Tiemann, and Wagner, and it is to these investigators
of the structure of the pinene molecule. the action of moist oxygen Sobrero obtained pinol hydrate or By * sobrerol, C 10 16 (OH) 2 By means of permanganate solution Baeyer
that
we owe our knowledge
obtained a-pinonic acid, C 10 16 O 3 ,and pinoylformic acid, C 10 14 O5 , both of which are ketonic acids. As both acids yield the same
pinic acid, C 7 12 (COOH) 2 on further oxidation, Baeyer concluded that they contain respectively a methyl ketone, and an a3 ketonic acid, the oxidation of a-hydroxyCOOH, group. By
,
COCH
CO
pinic acid, obtained through the a-bromo acid, norpinic acid a derivative of cyclobutane is obtained, and this is the key to the problem of the structure of pinene. Like carone which gives caronic
*Ber., 1896, 29, 1907.
(D331)
130
acid, and therefore contains a cyclopropane nucleus, pinene must contain a bridged ring, of which one part consists of four carbon atoms.
C-CH,
COCH,
COCOOH
HOOC
HOOC
CM
Pinene
a-Pinonic acid
Pinoyl formic acid
COOH
HOOC
COOH v
CI
HOOC
Pinic acid
Norpinic acid
On heating with acids, a-pinonic acid and pinoyl-formic acid are transformed as follows:
COCH,,
COCH,
HOOC
CH
H2 C CH
a-Pinonic acid
J C-CH
CH
H'
3|
CH.
Methyl Ketone of Homoterpenylic lactone
QO-COOH
CO-COOH
HOOC
CH 3 CH
,CH 2
CH 3 CH 2
CHiC^
CH
Pinoyl formic acid
Homoterpenyl formic acid
COOH
OC
.
I
CH
C-CH,
CH3 9 OOH \>CH

H 2 CN
i
CH,
CH,
"CH
Homoterpenylic acid
Terpenylic acid
THE CAMPHANE GROUP
131
Simonsen * synthesized homoterpenylic, terpenylic, and terebic acids by the action of magnesium methyliodide on j8-acetyl-adipic, The j8-acetyl-glutaric, and /?-acetyl-succinic esters respectively. reactions are so similar that only one of them need be formulated:
C H OOC CH CH(COCH
2
3)
CH COOC H
2
2
Ethyl p-acetylglutarate
MgCH
->
3I
H OOC CH CH[C(CH
5
-
3) 2
OMgI]CH COOC 2H 5
2
C(CH 3) 2 - CH CH 2 COOC 2H 5
-
"^
O - CO - CH
Ethyl terpenylate
It
/?-Pinene is found together with a-pinene as already described. has also been observed in lemon oil, coriander oil, hyssop oil,
oil
and the
of Siberian pine needles. With hydrochloric acid it gives a mixture of bornyl chloride and dipentene dihydrochloride. On oxidation with potassium permanganate, j8-pinene glycol, nopinic
acid,
and a ketone, nopinone, are obtained: f
CH2 OH
s -,
COOH
OOH
r-'TtN. ^"^~T
CO
CH
'
C*\A***
.y\ CH
3
I
CH 2
CH 2
|
^CH
Nopinone
p-Pinene glycol
Nopinic acid
Nopinone has been used for the and camphor by Wallach.J
synthesis of j8-pinene, camphene,
2^THE CAMPHANE GROUP

By far the most important member of this group is the ketonic a substance which may exhibit manifold compound camphor
changes in a most interesting manner. The study of camphor is coeval with that of Camphor. organic chemistry itself, since it attracted the attention of such early
*
Trans., 1907, 91, 184.
f
Ann., 1907, 356, 227; 1909, 368, 9.

i.
t Ann., 1908, 363,
132

Dumas and
workers as
formula,
C 10 H 16 O. Camphor
Pelouze, who derived its correct molecular has been known from very early
times, and it was introduced into Europe as a medicinal agent by the Arabians before the sixth century. As early as 1675 Lemery observed the oxidation of camphor to camphoric acid by nitric acid,
and this reaction was correctly formulated by Malagati, Laurent, and Liebig.
C 10 H 16
= C H
10
16
great advance beyond this point was made by Bredt " in his paper on The Constitution of Camphoronic Acid ",* and the value of his deductions was soon afterwards enhanced by the
first
The
synthesis of camphoronic acid
by Perkin and Thorpe
in
1897^
prepared jS-hydroxytrimethyl glutaric ester by the action of zinc upon a mixture of acetoacetic ester and a-bromoisobutyric ester or
These authors
first
upon a mixture
of dimethylacetoacetic ester and
monobromacetic
(CH 3 ) 2 CBr
ester:
CO
CH 2
COOR
(CH 3 ) 2 C
|
CH 3
CO
|
CO^H^c
Br
C (OH)-CH 2
3
COOR CH
CH 2 /"
CH,
COOR
COOR
By
COOR
/3-Hydroxytrimethyl glutaric ester
replacing the hydroxyl group, first with chlorine and then by cyanogen, they obtained the ester of camphoronic nitrile, from
which the acid
itself
was produced on hydrolysis:
(CH 3) 2 C
C(CH 3) - CH 2
(CH 3 ) 2 C
C(CH 3 )
- CH
COOR CN
Camphoronic
nitrile
COOR
COOH COOH
Camphoronic acid
COOH
camphor by nitric acid, camphoric acid, and camphoronic acid may be obtained, and in camphanic acid, the paper already mentioned Bredt suggested the following relationship among these compounds and arrived at the correct constitutional
formula for camphor:
*
Ber., 1893, 26, 3049.
By
the oxidation of
f Trans., 1897, 71, 1169.
THE CAMPHANE GROUP

CH, - CHC(CH 3
)2
133
CH
CO
CH -CH
2
COOH
O
CH -C(OH)COOH
2
C(CH 3 ) 2
C(CH 3) 2
:H 2 -C-COOH
CH 2
C-
CH -C - COOH
2
CH 3
Camphor
CH 3
Camphoric
acid
CH 3
Camphanic
acid *
COOH CO COOH
COOH COOH
O
C0
CH,
C(CH 3) 2
C(CH 3) 2
CH 2 - C CH 3
COOH
-C-COOH
CH 3
(Hypothetical) a-Ketonic acid
Camphoronic acid
formula for camphor was accepted with some reserve at the time it has now been verified by synthesis. Komppa's Synthesis of Camphoric Acid.f Ethyloxalate
Although
this
were condensed by sodium ethoxide to give ethyldiketoapocamphorate (i), and a methyl group is introduced by the action of sodium and methyliodide, after which the diketocamphoric acid (ii) was reduced to the dihydroxy acid (iii). On boiling with hydriodic acid and red phosphorus the unsaturated With acid, dehydrocamphoric acid (iv) or (v), was obtained. hydrobromic acid, /8-bromocamphoric acid (vi) was formed, which on reduction with zinc dust and acetic acid gave r-camphoric acid (vii), which is identical with the racemic product obtained by the
jS/3-dimethylglutarate
and ethyl
oxidation of camphor.
COOR
-(-
H CH CO R
2
CO - CH CO R
-
CH
C CH 3
2
COOR
*
H CH CO R
Camphanic acid
is
CH C CH 3 CO - CH CO R
2
2C 2 H 5 OH
(i)
really the lactone of this
compound,
viz.
CH, -
C-
-COOH
C(CH 3 ),
CH - C
8
CO
CH 3
t Ber., 1903,
36, 4332; Ann., 1909, 368, 126; 1909, 370, 209.
134

/"U t_/rl
3
fix ^-rl
CH 3
2
CO - C - COOH CH -C-CH
3 3
HO-CH - C-CO H
CH 2 - C-< 2H C-CO
CO
CH
(ii)
CH 3 -C-CH a -C-CH - C- C0 H
3 2
CH 3 -C-CH 3 CH = C-CO H
2
(iii)
(iv)
CH 3
i.
or
2
CH
CH 3
2
C-CO
CH 2 - C-CO H
2
L
CH - CH-CO H
2
CHj'C'CHj
CH 3 -C-CH 3 CCH - CH-CO H

2 2
CHBr
- CH CO,H
(vi)
(v)
(vii)
synthesis of camphoric Perkin and Thorpe in 1906.*

alternate
An
acid
was described by
into
The Conversion
Camphoric
acid
of
Camphoric Acid
Camphor.
method. When it is reduced to campholide,f
converted into camphor by the following camphoric anhydride is treated with sodium amalgam
first
was
CH
CH
-C- -CO
3
CH 3 CH 2 - C - CH 2
CH 3 -C-CH 3 O / CH 2 - CH-CO
I
CH 3 .C-CH O CH - CH- CO
salt
Campholide, on treatment with potassium cyanide, gives a nitrile which, on hydrolysis, is converted into homocamphoric
acid,
CH CH, - C - COOK
3
I
CH 3 CH, - C - COOH
rr (~*TT tl3 v^'Lxrla
CH,
-in- CH CN
2
CH
-i,-
CHoCOOH
is
heating obtained:
*
On
the calcium or lead salt of this acid camphor
Trans., 1906, 89, 795. t Haller, Bull Soc. Chirn., 1896
[III],
15,7, 984; Forster, Trans., 1896, 69, 36.
THE CAMPHANE GROUP

CHa
Cri3
'35
CH - C - COO
2
I
CH 3 .C-CH 3 Ca CH - CH-CH 2 -COO

2
CH 3
CH - C
2
CO
Cri3
C/riQ
-i.Borneol occurs in nature in three
Borneol and Isoborneol.
CH.,
-C
C
CH
Borneol
CHOH
modifications, */-borneol in lyryobalanops camphora, a tree growing in Borneo and Sumatra, while /-borneol and inactive borneol are
present in the so-called baldrianic camphor. Borneol is obtained, together with traces of isoborneol, by the reduction of camphor with sodium and alcohol.* Isoborneol is probably stereoisomeric
with borneol, and
transformed into the latter by the action of sodium on a solution of borneol in benzene. Bornylene and Camphane. Borneol may be readily transformed into bornyl iodide, but this substance is more easily pre-
may be
pared by the action of hydriodic acid on pinene. When this iodide is treated with alcoholic potash at I7Q bornylene f is obtained while camphane J may be prepared by the reduction of bornyliodide with zinc dust and acetic acid:
CH 2
3
CH
CH -C-CH 3 CH 2
C
CHI
3
CH?
CH
Bornylene
CH
CH 3 -C-CH
CH 2 CH
CH 2
V~*
CH.
Bornyl Iodide
CH 3 -C-CH 3
CH 2
*
CH
CH 2
Camphane
Wallach, Ann., 1885, 230, 225. t Wagner, Ber., 1900 33, 2121. Aschan, Ber., 1900, 33, 1006.
136

Bornylene
is
remarkable on account of
its
On
oxidation with potassium permanganate, obtained.
pronounced volatility. camphoric acid is

It is
Camphene
is
the only natural solid terpene.
known
in
The dextro form has dextro, laevo, and inactive modifications. been found in ginger, rosemary, and spike oils, while the Icevo form occurs in citronella and valerian oils as well as in French and American
turpehtine. The structure of
camphene
is
is
not
known with
certainty,
but the
most probable formula
that of
Wagner.*
CH - CH 2
CH 3
C<T
CH 3
C =
:
A.
CH.2
Camphene
Fenchone occurs naturally in two stereoisomeric forms. Dextrofenchone was discovered in Wallach and Hartmann in fennel oil (Fceniculum vulgare) 1890 by while the laevo form was found in 1892, by Wallach, in oil of thuja. Fenchone resembles camphor in many of its properties, but it is a It is a ketone, and on reduction gives a secondary alcohol, liquid. fenchyl alcohol, C 10 H 1S O, from which the fenchenes, C 10 H 16 can be obtained on dehydration. The following constitutional formula for fenchone was put forward by Semmler and has recently been confirmed by the synthesis of this compound by Ruzika: f
y
,
Fenchone and the Fenchenes.
CH - CH - C(CH CH
2
2
8) 3
CH
When
J-fenchone
is
is
fenchyl alcohol
latter gives
reduced, a laevorotatory alcohol termed Dlobtained. With phosphorus pentachloride the
D/-fenchyl chloride, which is converted into Z)/-fenchene on treatment with aniline. When these reactions are conducted
without cooling ZW-fenchene

*
Ber., 1900, 33, 2124; see also
is
eventually obtained. J
t Ber., 1917, 50, 1362.
Semmler, Ber. r 1909, 42, 246, 962. J Wallach, Ann., 1898, 300, 294; 1901, 315, 283.
THE SESQUITERPENES AND POLYTERPENES
137
Komppa and Roschier later* proposed an alteration in the nomenclature of the fenchenes according to which Wallach's )/fenchene becomes /a-fenchene, and the Dd form becomes D/3Racemic a-fenchene has been synthesized by these fenchene.
More recently authors and the constitution (i) assigned to it. Roschier f claims to have established the constitution of j8-fenchene
by a study of its ozonization, and of the products subsequently obtained on hydrolysis.
CH - CH - CH
2 3
(CH 3 ) 2 C
CH .C-CH CH - CH - C CH
3 2
:
(i)
THE SESQUITERPENES AND POLYTERPENES

Although a number of sesquiterpenes have been known for a considerable time, we have as yet but very little knowledge of the carbon skeleton of any of these compounds. The following tabulation embraces the more important sesquiterpenes, and the reader desiring further information should consult the treatises enumerated
at the
end of
this chapter.
Sesquiterpene (C 15
2 4).
Occurrence.
Cadinene.
Oil of cade, cubeb, savin, cedar wood,
and camphor
Caryophyllene.
canellaalba.
oil.
oil, oil
Oil of cloves, copaiba balsam
of
Humulene.
Cedrene,and the alcohol cedrol,
Santalene, and the alcohol santalol,
Oil of hops.
Oil of cedar wood.
C 15 H 25 OH.
East Indian sandal- wood
oil.
Zingiberene.
Oil of ginger.
In addition a number of di-, tri-, and tetra-terpenes have been isolated, but little is known of their constitution.
*
Acad. Set. Fennicae, 1915 [A], 7,
i.
Loc.
cit.,
1919 [A], 10,
i.
138

The
them
and
resins are closely related to the terpenes and occur with in plants. The natural thick solutions in the essential oils are called balsams, whereas the true gum resins are amorphous
in
many
cases vitreous.
These products are of considerable
industrial value, especially as ingredients of varnishes, but still almost entirely ignorant of their constitution.
we
are

substances which impart to many plants a particular and often characteristic odour are almost infinite in variety, and comprise some of the most interesting compounds in the domain of
organic chemistry. others are aliphatic
The
Many
them possess a cyclic structure, while compounds which may be either saturated or
of
unsaturated; and they include representatives of such various groups as the hydrocarbons, alcohols, aldehydes, ketones, phenols, phenol
ethers, acids, esters, and lactones. Almost as soon as organic chemistry began to be seriously studied about a century ago, the esters of various acids with common alcohol
were obtained. Among these compounds the odours of several flowers and fruits were speedily recognized, and it was soon discovered that the odour of pine-apple is due to ethyl butyrate, that of the pear to amyl acetate, and that of the strawberry and raspberry to mixtures of several similar esters. The odour of crushed bitter almonds was found to be due to benzaldehyde, and as early as 1847 " " Collas introduced nitrobenzene or essence of mirbane as a
substitute for benzaldehyde. Even earlier than this Cahours, in 1844, found that methylsalicylate was the chief constituent of oil
of wintergreen, and soon afterwards the presence of salicylic aldehyde in the flowers of the meadowsweet and cinnamic aldehyde in
the barks of cinnamon and cassia was established. One of the earliest triumphs of synthetic organic chemistry was the synthesis of coumarin the lactone of o-hydroxy-cinnamic acid by Perkin in 1868, from sodium salicylamide and acetic anhydride.
the fragrant substance to which the perfume of the tonquin bean and woodruff are due, and it is said to be present in the artificial extract of new-mown hay.
is
Coumarin
In 1876 Tiemann and Haarmann synthesized vanillin, the sweetsmelling constituent of the vanilla pod. Vanillin is now obtained from eugenol, which is present in oil of cloves to the extent of about

80 per cent.
isoeugenol
is
139
When
eugenol
is
obtained, which gives
boiled with amylalcoholic potash, vanillin on oxidation:
CH-CH:CH 2
Eug-enol
Isoeug-enol
Vanillin
In 1888 Bauer discovered trinitro-^-butyltoluene, and this, as well as other strongly scented nitro compounds, has been used as artificial musk.
The
flowers of
may
or hawthorn are believed to contain anisic
aldehyde, and the latter has been prepared by the oxidation of anethole the chief constituent of anise oil.
CH
CH-.CH-CH 3
Anethole
3 J
Anisic Aldehyde
The odour
latter is
of heliotrope
is
said to be
prepared from and then oxidized:
saffrole,
which
to piperonal, and the is first converted into isosafrole
due
*"
H C
?
CHjCH'CH,
Safrole
Isosafrole
probably the chief constituent. ^-Phenylethylalcohol, obtained by the reduction of Phenylacetaldehyde phenylacetic acid, is also frequently present. an intense hyacinth-like odour and is used considerably possesses
Otto of roses
is
a mixture of which geraniol
is
in perfumery.
The methyl
ester of anthanilic acid
C 6 H/
is
X NH 2
(i) (2)
X COOH
present in neroli oil from orange flowers, ylang-ylang, &c., while jasmine contains indole in addition. Notwithstanding the fact that
scatole (p. 182) possesses a strong faecal odour, it is employed, as also indole, in the preparation of synthetic perfumes.
is
The
study of the odorous principle of the
violet,
commenced
140
in 1893, is one of the most interesting carried out in the realm of synthetic perfumes. These investigations chemists were unable to obtain sufficient material for their work from
by Tiemann and Kruger
the flowers, but as this characteristic fragrance is possessed by the dried root of iris (orris), the latter was used as the source of the oil
were made. To this substance, when the name irone, and a few years later ionone was purified, they gave introduced as a synthetic substitute. The latter is prepared from
on which
their experiments
citral (p. 114),
which undergoes the aldol condensation with acetone
in the presence of baryta to give pseudoionone:
(CH 3 )oC:CH-CH 2 -CH 2 C(CH 3 ):CH-CHO + CH 3 COCH 3 -> (CH 3) 2 C CH CH 2 CH 2 C(CH 3 ) CH CH

-
CH COCH 3
Pseudoionone
On
boiling with dilute sulphuric acid, a-
and /2-ionone are obtained:
CH CH 3
3
C-OH
H C
2
CH 2-CH:CH-COCH 3
C(OH)CH 3
H C
2
CH SCHv 6
3
CH-CH'.CH-COCH,
'C-CH 3
CH
a-Ionone
^* 1 2
/3-Ionone
a- Ionone possesses the light fragrance of the violet while the of the jS-isomer is much heavier.
odour
which consist
plants belonging to the Cruciferce yield volatile products to a large extent of sulphur compounds, and are known " by the generic name of mustard oils ". These oils do not generally pre-exist as such in the plant, but are formed by the action of a
Many
particular ferment or enzyme on a glucoside, and they consist as a rule of esters of isothiocyanic acid. typical example is that of
obtained from the black mustard, Brassica nigra and Brassica juncea, and which consists almost entirely of allyl isothiocyanate, CH 2 :CH- 2 -N:CS. It is produced by the action of the ferment
the
oil
CH
myrosin on the glucoside sinigrin (potassium myronate), when, besides

the volatile mustard
are formed:
oil,
141
dextrose and potassium hydrogen sulphate
C 10 H 16 NS 2O 9 K + H O - C 3H 5NCS + C 6 H 12 O 6 + KHSO 4
2
produced on a large scale synthetically by the action of allyl iodide on potassium thiocyanate in alcoholic solution, the heat employed in the operation causing the molecular transformation of the allyl thiocyanate first formed into the isothiooil is also
This mustard
cyanate.
Although the odorous principles of plants are frequently developed in some particular part or organ, such as the petals of the flower, they are sometimes found in both the flowers and fruit,
while in other cases they are contained chiefly in the foliage. The odorous principles are generally obtained by steam distillation, but
where the oil does not pre-exist in the plant, but is formed by the hydrolysis of a glucoside, as in the mustard oils, bitter almond oil, &c., a preliminary digestion with water is essential. Some of the essential oils which become impaired by heat, such as those from the orange, lemon, and bergamot, are obtained by exIn other cases the odour of the oil is so delicate that it pression. can only be preserved by extracting the materials with a volatile solvent or by maceration with a fixed solvent, such as an oil or fat.
in those cases
REFERENCES.
Die Terpene und Camphor, and Edition, by O. Wallach (Leipzig, 1914). Chemie der Alicyklischen Verbindungen, by O. Aschan (Brunswick, 1905)* Die Konstitution des Kamphers, by O. Aschan (Brunswick, 1905).
Brit. Assoc. Reports, 1900:
Camphor ", by A. Lapworth (London). The Chemical Synthesis of Vital Products, by R. Meldola (London,
Oils
"
The Chemistry of Essential (London, 1918).
and
Artificial Perfumes,
by E.
J.
Parry
CHAPTER
VII
The Amino Acids and

Introduction.
Polypeptides
Excluding mineral matter and fat, the dry material of animal organisms consists of a complex assortment of first, nitrogenous compounds termed proteins or proteids (TT/OCOTO? The same term is also applied to somewhat similar pre-eminent). compounds which occur in considerable quantities in all plants,
Since the proteins furnish the material especially in seeds or grain. in which the vital processes of growth, repair, and reproduction are These located, their study is of immense importance to physiology.
compounds
are usually colloidal
and non- volatile, and on
this
account
their study offers peculiar difficulties. All the proteins contain carbon,
hydrogen, nitrogen, and oxygen, while some contain phosphorus and sulphur in addition. It is doubtful if the molecular weight of any protein is known with certainty, and all that can be said is that the minimum value is probably 15,000, which is about four times as great as that of the most gigantic molecule which has yet been synthesized (p. 93). Some idea of the gigantic molecular dimensions of these compounds may be gathered from the statement that, assuming haemoglobin contains a single atom of iron in the molecule, the minimum molecular weight is about 16,600 (C 158 123 O 195 218 FeS 3 ). It is obvious that a slight error in the analytical results makes a very
great difference in the empirical formula. If a protein, for example casein, be completely hydrolyzed by boiling with concentrated hydrochloric acid, a clear dark-coloured
obtained which contains a number of products, the As of which has long taxed the chemist's ingenuity. separation early as 1820 Braconnot had obtained glycine and leu cine from gelatine, and in 1846 Liebig had obtained tyrosine from the decomsolution
is
position products of horn. At a later date Kossel and his collaborators examined the simpler proteins, such as the protamines, but progress was very slow until Fischer, in 1901, introduced new
142

methods
for the separation
143
and
identification of the products of
protein hydrolysis.
Isolation of the Amino Acids. The amino acids bear to the proteins a relationship recalling that of a hexose to a polysaccharose. The early attempts to explain the structure of the proteins were
hampered by experimental obstacles to the separation of the complex mixture of amino acids produced on hydrolysis. With the exception of tyrosine and cystine, which are sparingly soluble in water, the
major portion of the mixture remains as a syrup. Fischer made a practical advance of great importance as a result of his studies of the esters of the amino acids, substances which have the properties of aliphatic amines owing to the suppression of the carboxyl group
by
esterification.
For the separation of the amino acids, Fischer esterified the complex mixture, obtained on hydrolysis, with ethyl alcohol in the presence of hydrochloric acid, and after liberating the esters from their hydrochlorides by caustic soda at low temperatures or by sodium ethoxide, the esters were fractionated at 10 to 12 mm. and The esters of histidine and the diamino acids finally at 0*5 mm.* cannot be purified by distillation, while a few amino acids, e.g. tyrosine, require special methods for the liberation of their esters. More recently Dakin f has observed that certain amino acids can be extracted from water by but slightly miscible solvents, of which butyl alcohol now obtained as a by-product in the manufacture of acetone by the fermentation of cereals seems to be the most useful. After hydrolysis with sulphuric acid and neutralization
with baryta, the solution is concentrated in order to allow any The solution is then tyrosine, which may be present, to crystallize. extracted in a continuous apparatus at 60 to 80. Proline and the
feebly ionized monoamino acids are very easily extracted while the stronger acids and bases remain behind. By the application of this
method
to casein a
new hydroxyamino
acid, a-amino-/3-hydroxy-
2 )CH(OH) glutaric acid (/3-hydroxyglutamic acid, has been obtained in quantity exceeding 10 per cent. 2 COOH), Foreman J converts the mixture of amino acids into their dry
CH
HOOC CH(NH
lead salts and esterifies with absolute alcohol containing dry hydrochloric acid. The free hydrochloric acid is removed, partly by
reducing the liquid to half its bulk at 40 and 15 mm., and the remainder by the addition of absolute alcohol saturated with dry
* Ber. Ber. y 1902, 35, 2160. 9 1901, 34, 433; \ Biochem.jf., 1918, 12, 290. J Ibid., 1919, 13, 378.
144

gas.
ammonia
After removing the alcohol in vacuo, the ester hydro-
chlorides are dissolved in dry chloroform and the esters liberated by shaking with anhydrous barium oxide. In this way the usual
considerable loss of esters by hydrolysis
is
avoided.
Acids. The following table contains the principal amino acids which have been isolated from the
Classification of the
products of protein hydrolysis:
Amino
MONOBASIC MONOAMINO ACIDS
= aminoacetic acid, (NH )CHoCOOH +# = oc-aminopropionic acid, Alanine CH CH(NH )COOH Valine = a-aminoisovaleric acid, (CH CH CH(NH )COOH = a-aminoisobutylacetic acid, Leucine (CH CH CH CH(NH )COOH Isoleucine = a-amino-p-methylethylpropionic acid,
Glycine
2
3) 2
3) 2
(C 2H 5 )(CH 3 )CH
Caprine
oc-aminocaproic acid,
(CH 3 )(CH 2 )
CH(NH )COOH 3 CH(NH )COOH

2
DIAMINO ACIDS
Ornithine
aS-diaminovaleric acid,
Lysine
(H 2 N)CH 2
ocs-diaminocaproic acid,
CH
CH CH(NH )COOH
2
(H 2N)CH 2
Arginine
CH
CH
CIV CH(NH )COOH

2
-
a-amino-S-guanidovaleric acid,
(H 2 N) C
- NH CH
CH CH
2
CH(NH )COOH
2
NH
DIBASIC
Aspartic acid Glutamic acid
MONOAMINO ACIDS
2
= aminosuccinic acid, HOOC CH CH(NH )COOH = aminoglutaric acid, HOOC CH CH CH(NH )COOH
2
2 2 2
HYDROXY- AND THIO-AMINO ACIDS
CH (OH)CH(NH )COOH HOOC CH(NH CH(OH) CH COOH p-Hydroxyglutamic acid, C H 16 (OH) (NH COOH Diaminotrihydroxydodecanic acid,
Serine
a-amino-p-hydroxypropionic acid,
-
2)
11
2) 2
4-
denotes asymmetric carbon atom.

Cysteine Cystine
2
2
'45
= a-amino-p-thiolactic acid, CH (SH)CH(NH )COOH = disulphide of a-amino-(3-sulphydropropionic acid,

S S
CH CH(NH )COOH
2
2
CH CH(NH )COOH
2
2
AROMATIC AMINO ACIDS

Phenylalanine
==
a-amino-(3-phenylpropionic acid,
C 6 H 5 CH 2 CH(NH 2)COOH
Tyrosine
a-amino-p-hydroxyphenylpropionic acid,
HO
HETEROCYCLIC ACIDS
CH CH(NH )COOH
2
2
CH 2
H 2C CH-COOH
HO-HC,
.CH,
H C
2
^CH-COOH
NH
Proline
NH
Oxyproline
a-pyrolidine carboxylic acid
/3
hydroxypyrolidine
carboxylic acid
,C-CH a-CH(NH 2 )COOH
CH Histidine = ct-amino
propionic acid
NH
j3-iminazole-
Tryptophane
indolo o-amlnopropionic acid
with the exception of proline and oxy~ amino group in the a-position. proline, In the case of proline and oxyproline the carboxyl group is adjacent to the basic group of the ring. In all these acids the basic
It will
be observed
that,
all
these acids contain an
NH
is
amino group
group.
more
acids
Amino
or less neutralized by the adjacent carboxyl which contain an amino group in a non-
adjacent position to the carboxyl group will be described in a subse-
quent chapter
all
(p. 187).
The Resolution and
Identification of the
Amino
Acids.
more Nearly asymmetric carbon atoms. The early resolution of these acids had been limited by their amphoteric nature, and was easy only in the
the amino acids tabulated above contain one or
(D331)
10
146

is
case of aspartic acid, Piutti having shown in 1887 l ^ at asparagine resolved by simple crystallization from water.
suppressing the basic properties of the amino acids by benzoylating, formylating, or p-nitrobenzoylating the amino group, and
By
thus encouraging their capacity to form recrystallizable salts with the natural alkaloids, strychnine and brucine, Fischer and his collaborators succeeded in resolving the dl forms of many of the amino
acids.
became
In this manner optically active units were obtained which available as building materials for the construction of optically
active polypep tides.
acyl derivatives of the amino acids, in other derivatives depending on the reactivity of the
The above
common
with
amino group
with phenylcarbimide and benzene sulphonyl chloride, are useful for the identification as well as the isolation of their parent compounds, but the combination with j8-naphthalene-sulphonyl-chloride is probably the best of all. The resulting derivatives are formed in good
yield, are sparingly soluble,
and
crystallize well.
To
a minor ex-
tent, jS-naphthalene-sulphonyl-chloride
assumes a similar part to that
played by
phenylhydrazine in the sugar group.
MONOBASIC MONOAMINO ACIDS

glance at the tabulation on p. 164 will show that these acids form a large part of the products of hydrolysis of most proteins.
They
are
all
crystalline,
water-soluble, sweet- tasting
substances
which are almost insoluble in alcohol and ether. They have a neutral reaction to litmus, but form well-defined crystalline salts both with acids and bases. With the exception of glycine all these acids contain asymmetric carbon atoms, and one or other of the
active forms
present in protein hydrolysis products. The acids may be synthesized by a variety of methods of which the following are the more important.
is
(i)
By
the action of
3
ammonia on
->
the halogen fatty acids *: e.g.
CH CHBrCOOH
a-brompropionic acid
CH CH(NH )COOH
3
2
oc-aminopropionic acid
Fischer and Schmitzef have shown that good yields of halogen fatty acids are obtained by brominating the corresponding alkyl-
malonic acids and then converting the products into monobasic

acids
by
distillation.
Kolbe, Ann., 1860, 113, 220.
f Ber., 1906,
39, 351.

(2)
147
By
Strecker's method,
hyde
into the corresponding aminocyanhydrin, with

e.g.
which consists in converting an aldeammonia and
hydrocyanic acid, and hydrolyzing the product:
H-C
/H
->
H-C NH
/H
->
CH NH COOH
2
2
Formaldehyde
(3)
Glycine*
This method consists in combining potassium phthalimide with halogen fatty acid ester and hydrolyzing the product: e.g.
By
Gabriel's
method.f
/CCX C6H 4< X CCX>NK

Potassium phthalimide
C1CH 2 COOC,H 5
-
Monochloroacetic ester
C 6 H 4<
/ C H 4<
6
/ C0 \
>N CH 2 COOC 2H 5 + KC1

-
C0 \ >N CH
-
COOC H + H O
2
= CU
6
X COOH
+ CHoNH COOH + C H OH
2
Phthalic acid
Glycine
This reaction has met with very considerable application. (4) By the reduction of the oximes or phenylhydrazones of ketonic acids with sodium amalgam or aluminium amalgam: J e.g.
(C 2 H 5 )(CH 3 )CH
C COOC 2 H 5
NOH
sec.
Butyloximino acetic ester
(C 2 H 5 )(CH 3)CH
CH(NH )COOC H 5
2
Isoleucine
(5) By the method of Erlenmeyer junior. According to this method aldehydes or esters are condensed with hippuric acid, in the presence of acetic anhydride and sodium acetate, and the product is
subsequently reduced and hydrolyzed. Perkin reaction.

*
This
recalls the
well-known
Eschweiler, Ann., 1894, 278, 237. f Ber., 1889, 22, 426. t Tafel, Ber., 1886, 19, 2414; Bouveault, Bl. 1904 (3), 31, 1176; 1906 (3), 35, 966. Ann., 1893, 275, i 1899, 307, 70, 163.
t ;
148

/NHCOC H 5
6
C S H 6 CHO + H 2 C< X COOH

->
-V
C 6 H 5 CH C< X
:
COOH
2
C 6 H 5 CH 2 -CH<; X COOH
Glycine
/NHCOC H 5
6
->
C aH 6 CH 2CH(NH )COOH
Phenylalanine
sweet, KoX\a glue). Hippuric acid, the benzoyl derivative of glycine, was isolated from the urine of herbivorous animals by Rouelle as early as 1773. Glycine may be
(yXvicvs
obtained in relatively large quantity by the hydrolysis of glue or gelatine, and was obtained from this source by Braconnot in 1820.
Sarcosine and betai'ne
(p. 184).
may be
regarded as derivatives of glycine
In the synthesis of this acid by the Strecker method, a convenient modification * of the usual procedure consists in
Alanine.
ammonium
treating acetaldehyde with potassium cyanide in the presence of chloride. The acid may be resolved by fractional
crystallization of the brucine salt of its
with the aid of moulds. J
N-benzoyl derivative,! or Dextroalanine is one of the principal

the
products of the hydrolysis of fibroin Both active forms have a sweet taste.
main component
of silk.
form of this acid is very widely distributed in the animal kingdom, and is a substance of physiological imIt is found in the lymphatic glands, the spleen, and portance.
laevo
Leucine.
The
produced by the hydrolysis of haemoglobin, egg-albumin, and casein, from the last of which it is
It is
Its solution in hydrochloric acid is dextrorotatory, usually prepared. but a solution of the acid in water is laevorotatory. In contact
especially in the pancreas.
with Penicillium glaucum, a solution of ^/-leucine becomes laevorotatory,
owing
to the destruction of the
modification.
is
Isoleucine.
The
dextro form of this acid
obtained by the
hydrolysis of the proteins contained in beetroot sap, cereals, potaconsideration of the formula of isoleucine shows that toes, &c.
two dissimilar asymmetric carbon atoms are present in the molecule, and the following forms should therefore exist:
Dextro-, laevo-, and d7-isoleucine. Dextro-, laevo-, and rf/-alloisoleucine.
Delpine, J3/., 1903, 29, 1178, 1192. f Fischer, Ber., 1899, 32, 2454. J M'Kenzie, Harden, Trans. , 1903, 83 , 428; Ehrlich, Zentr., 1906, 2, 501. Ehrlich, Ber. 9 1907, 40, 2453.

Ehrlich * has
149
shown
that in alcoholic fermentation leucine
and
isoleucine give rise respectively to isoamyl alcohol and secondary butyl carbinol, which form the bulk of the fusel oil fraction. The
ammonia formed
(CH 3) 2 CH
2
in the reaction is assimilated

2 2
and removed.
Leucine
CH CH(NH )COOH + H O - (CH CH CH CH OH + NH 3 + CO

3) 2 2
2
Isoamylalcohol
(CH 3 )(C 2 H 5 )CH CH(NH 2 )COOH + H 2 O - (CH 3)(C 2 H 5 )CH Isoleucine
CH OH + NH 3 + CO
2
Secondary butylcarbinol
DlAMINO ACIDS
The diamino acids are strongly basic substances. They are almost invariably obtained among the hydrolytic products of the
proteins.
Ornithine.
Ornithine was obtained in 1877 by
Jaffe,
by the
hydrolysis of ornithuric acid, obtained from the excrement of birds fed on benzoic acid. Since on hydrolysis ornithuric acid yields two molecular proportions of benzoic acid to one of orni thine, its
constitution
is
represented as dibenzoyl orni thine:

(C 6 H 5 CONH) 2
C 4H COOH
7
Ornithine has been synthesized by several methods, of which the following are the most important. (i) By Fischer ,f using a combination of the phthalimide and
malonic ester condensations:
x co C 6 H/ >NK + BrCH 2 CH 2 CH 2 Br
C H 4<
>N CH
CH CH
2
Br
+ KBr
/ C0 \ CH< >N CH CH CH Br + NaCH(COOCoH ^ / X CO CH< >N CH CH CH CH(COOC H

-
5) 2
5) 2
Brominate,
hydrolyse, and heat
C 6 H 4<
>N CH 2 CH
f Ber.,
CH CHBrCOOH
-
Ber., 1907, 40, 1047.
1901, 34, 454; 1902, 35, 3772.
150

c
Ammonia
H </
CO
\N
CHo CH 2
.
CH 2 CE^NH^COOH
.CH .CH 2 .CH(NH 2)COOH
2
TT A i Hydrolysis
~*
^jj
yCOOH / + H N-CH N
COOH
(rf/)-a8-diaminovaleric acid (ornithine)
benzoyl piperidine is oxidized with potassium permanthe ring is opened and benzoyl Samino valeric acid is obganate tained. By the action of bromine and phosphorus on the latter a
(2)
When
derivative is obtained, gives monobenzoyl ornithine. into ornithine.*

i2
bromo
which on treatment with ammonia The latter on hydrolysis is converted
Cri2
>
C6 H 8
CO-NH[cH 2]cHBrCOOH
*-
CH CH 2
2
C6 H 5 CONH[CH ] 3 CH(NH )COOH - NH 2 [CH ] 3 CH(NH )COOH+ C H 5 COOH

2 2 2 2 6
(3) Sorensen's
condensed with potasployed by sium phthalimide to give phthaliminomalonic ester. The sodium compound of the latter is then condensed with y-bromopropylFischer.
is
method f is somewhat Bromomalonic ester
similar to that first
em-
phthalimide to give phthalimino-y-phthaliminopropylmalonic ester,
which on hydrolysis gives ornithine:
C 2H 5 O OC X C 2H 5O.OC
,OC X /OC X + Br[CH 2] 3 -N< 8H 4 CH-N<; >C >C 8H 4
^/
or
^/
C 2H 5 0-OC.
Lv,
2j3 i^
CÔ-OC^
/c \ X
/C 6 H 4
-*
[CH 2 ] 3 NH 2
N/ 1>\
\PH /^gtl.!
HOOC-HC<
NNH
Lysine. In 1889 Drechsel obtained lysine and a substance " " which he termed lysatinine by the hydrolysis of casein with hydrochloric acid. The latter was subsequently shown to be a mixture of lysine and arginine. Ornithine, lysine, and arginine may
* Fischer and Zemplin, Ber., 1909, 42, 1022.
f Zentr., 1903, 2, 34.
151
be precipitated from acid solution by phosphotungstic acid. This reagent also serves as a precipitant for the heterocyclic amino acids, but it does not precipitate the other amino acids derived from
protein.
and Weigert * synthesized butyronitrile and malonic ester as follows:

Fischer
this
acid
from y-chlor-
CN CH 2 CH CH 2 C1 + NaCH(COOC H ~> CN
2
.
5) 2
[CH 2] 3 CH(COOC 2H 6) 2
3
.
CH
CH(COOC H
2
5) 2
C 2H 5 ONO
CH CH
CH CH CN
2 2
NOH)COOC H 5 CH, CN
C(
2
Reduction
CH 2 CH(NH )COOH CH CH CH NH 2
.
Lysine has also been synthesized by von Braun.f For this purpose benzoylpiperidine is treated with phosphorus pentachloride, and gives the N-benzoyl derivative of the halogenated amine:
CH.
CH 2
H2
I-T
r*r Cf
^sr*T-T
^s
N-COC,HL
H 2 cl
^CH
x NH-CO-QKL
and the employed by Fischer and
acid,
'CH 2C1
The
latter is
transformed into the
nitrile
and the
succeeding steps are analogous to those Zemplen for the synthesis of ornithine:
C 6 H 5 CO NH[CH 2 5 CN
]
->
C 6 H 5 CO NH[CHJ 5 COOH
occurs
Arginine.
position
This
amino acid
among
the
products of a great number of proteins. It obtained from lupin seedlings by Schultze and Steiger in 1887. As much as 87 per cent has been found in the spermatazoa of
the salmon.
decomwas first
completely resistant to acids, but on hydrolysis by alkalies or the enzyme arginase it yields urea and ornithine:
It is
H 2N C NH [CH CH(NH )COOH + H O

-
2] 3
NH
*
- H N CO NH + H N
2
[CH 2] 3 CH(NH 2)COOH
Ber., 1902, 35, 3772.
t Ber., 1909, 42, 839.
152
Arginine was obtained synthetically by Schultze and Winterstein by the action of cyanamide on ornithine:
NH CN + H N[CH CH(NH )COOH NH = H N C NH

2
2] 3
[CH 2] 3 CH(NH 2 )COOH
has been suggested by Robinson that ornithine and lysine may play an important part in the phytochemical synthesis of some of the plant bases, and these theories will be discussed in the chapter
It
on the
alkaloids.
DIBASIC
MONOAMINO ACIDS
Aspartic Acid. Both aspartic and glutamic acids are strongly and form well defined metallic salts. They are still, however, The laevo form of aspartic sufficiently basic to combine with acids.
acidic
acid
frequently encountered among the hydrolytic products of proteins, but this acid is most conveniently prepared by the action
is
of hydrochloric acid on asparagine. Inactive aspartic acid has been obtained by the action of ammonia on fumaric acid, and the d acid by the action of ammonia on
/-bromosuccinic acid. Piutti f obtained aspartic acid by the action of hydroxylamine on oxalacetic ester and subsequent reduction of
the resulting isonitrososuccinic acid:
CO COOC H
2
I
HON C COOC H
: -
II 2
CH COOC H
2
~>
5
CH COOC 25 H
2 2
->
N CH COOCoH CH COOC H
|
many plants, especially asparagus and the shoots of beans, peas, and lupins, from which it is readily young extracted by water. It is noteworthy that when an aqueous solution
of equal quantities of d- and /-asparagine is evaporated a racemic compound is not formed, but the d and / forms crystallize out side
Laevoasparagine (NH 2 aspartic acid, occurs in
COCH CH(NH
2
)COOH),
the semi-amide of
by
side.
This acid is obtained to the extent of cent by the hydrolysis of the proteins from wheat. After 30 per hydrolysis with hydrochloric acid, glutamic acid is removed as its hydrochloride by saturation with hydrochloric acid gas.
*
Ber., 1899, 32, 3191.
f Gazz., 1887, 17, 519.
Glutamic Acid.

trosoglutaric acid.
153
Wolff* synthesized glutamic acid by the reduction of a-isoni-
HYDROXY- AND THIO-AMINO ACIDS

This hydroxyamino acid was obtained by Cramer as early as 1865 among the products resulting from the hydrolysis of silk with sulphuric acid. Since that time it has frequently been encountered among the hydrolytic products of the proteins. The natural form is laevorotatory.
Serine.
transformed into glyceric The folacid, while with hydriodic acid it is reduced to alanine. lowing are the more important methods by which the acid has been
it
When
treated with nitrous acid
is
synthesized. (1) Fischer and Leuchs f obtained a small yield of serine by the hydrolysis of the aminocyanhydrin of glycollic acid:
CH OH
2
CH OH
2
CH OH
2
C/ X
->
CHNH,
->
CHNH,
CN
COOH
Fischer and Jacobs J resolved the synthetic acid by the fractionation of the brucine or quinine salt of the ^-nitrobenzoyl
derivative.
condensed formic ester with hippuric ester in Erlenmeyer the presence of sodium ethoxide and reduced the resulting product with aluminium-mercury couple:
(2)
CO C H /NHCOC H 5 HCOOC H + H C< -> HO CH C X COOC H X COOC H 5 ~> CH OH CH(NH )COOH

6
Leuchs and Geiger synthesized the acid from ethoxyacetal by Strecker's method, subsequently removing the ethyl group with hydrobromic acid. Ethoxyacetal was prepared from chloracetal by the action of sodium ethoxide.
(3)
||
C1CH 2 CH(OC 2 H 5) 2
->
*
2
2
->
C H 5O CH 2 CHO
2
C H 5 O CH 2 CH(NH )COOH
->
HO CH CH(NH )COOH
2
-
Ann.y 1890, 260, 79. f Ber., 1902, 35, 3787; 1906, 39, 2942; 1907, 40, 1501. Ber. 1906, 39, 2644. Ber. y 1906, 39, 2948. Ber., 1902, 35, 3769. t
||
154
j3-Hydroxyglutamic Acid. As already mentioned, this acid was obtained by Dakin * by extraction of the hydrolytic products of
casein with butyl alcohol. More recently it has been identified among the hydrolytic products of glutenin and gliadin.f Its synthesis appears to have presented considerable difficulty, but was
eventually achieved from glutamic acid as follows. (i) was converted into a-uraminoglutaric acid (ii)
Glutamic acid
by the action
of potassium cyanate, and hydantoinpropionic acid (iii) obtained from the latter by warming with hydrochloric acid. On treatment with bromine in glacial acetic acid, hydantoin /3-bromopropionic acid
was formed, which, on boiling with water, gave hydantoinacrylic On prolonged boiling with barium hydroxide solution /?-hydroxy glutamic acid (vi) was obtained:
(iv)
acid (v).
COOH
COOH
2
CO - NH
CO - NH
CHNH CH CH COOH
2
2
CH NH CONH 2 CH 2
CH
2
CH - NH
CH CH
3
CH CH
NH
^>co
COOH
CO - NH
>CO
COOH
(iii)
COOH
(iv)
(i)
COOH
CH - NH
CH CH
II
COOH
(v)
CHNH CHOH CH COOH

2
(vi)
Cysteine and Cystine.
These two compounds embrace the
greater part of the sulphur obtained by the hydrolysis of the proteins. Cysteine is the sulphur analogue of serine, while cystine may be regarded as the disulphide. Cystine may be reduced to cysteine by
the action of zinc and dilute sulphuric acid, while the reverse change may be brought about by exposing an ammoniacal solution of cystine
to the atmosphere.
It
*
Cysteine
may be
readily prepared
from
hair.
has been obtained synthetically by Erlenmeyer
junior J as follows:
f Dakin, Biochem.J., 1919, 13, 398. Biochem.y., 1918, 12, 290. 1 Ann., 1904, 307, 236.
155
Ethylformylhippurate (i), obtained by the condensation of formic and hippuric esters, is reduced to the ester of benzoylserine (ii). By the action of phosphorus pentasulphide a thio derivative (iii) is obtained which on hydrolysis gives racemic cysteine (iv).
COOC H 5
2
COOC H
2
COOC H
2
6
COOH
6 2
C'NH'COC 6 H 5 -> CH-NH-COC H 5 -> CH-NH.COC H 5 -> CHNH
CHOH
(i)
CH OH
2
CHoSH
(iii)
CH SH
2
(ii)
(iv)
* Cysteine has been obtained from /-serine by converting it, with the aid of phosphorus pentachloride, into /?-chloro-a-aminopropionic acid and then treating the latter with barium hydrosulphide:
CH OH CH(NH )COOH -> CH C1- CH(NH )COOH ~> CH SH CH(NH )COOH

2
2
Cystine sometimes separates from urine as a sediment and is also a component of some gall-stones. Mercaptans, sulphides, and
substituted sulphuric acids are obtained by the decomposition of these sulphur compounds by living organisms.
THE AROMATIC AMINO ACIDS

Phenylalanine (a-amino-/?-phenylpropionic acid) was found Schultze f in plant seedlings and in, the products of hydrolysis by of seed proteins. Since that time it has been shown to be a constituent of
many
proteins.
first
This amino acid was
synthesized by Erlenmeyer and Lipp J

to phenylacetaldehyde:
by the application of the cyanhydrin reaction
C 6 H 5 CH 2 C/
Fischer
O
->
XH
C 6 H 5 CH 2 C
CN
->
C 6 H 6 CHoCH(NH )COOH
2
\H
synthesized the acid starting from benzylmalonic acid, which was obtained from benzylchloride and the sodium derivative
of malonic ester:
C 6 H 5 CH C1 + NaCH(COOC 2H 5) 2 -> C 6 H 6 CH 2 CH(COOC H 6) -> C 6 H 5 CH 2 CH(COOH) 2 -> C 6 H 6 CH 2 CBr(COOH) 2 -> C 6 H 6 CH 2 CHBrCOOH -> C H 6 CH 2 CH(NH )COOH
2 2 2
* Fischer
t Ber.,
J Ber.
and Raske, Ber., 1908, 41, 893. 1881, 14, 1785; Zeit.physiol. Chem., 1884, 9, 63. 1882, 15, 1006. Ber., 1900, 33, 2383; 1904, 37, 3064.
156
Fischer subsequently resolved the acid into its optical isomers. Sorensen * synthesized phenylalanine by the aid of the phthali-
mide
reaction:
CO
BrCH(COOC 2H 5) 2 -> C H 4<
6
CO
>N-CH(COOC 2 H 5 ) 2
CO
->
CO
Cell^
CO
CO CO
H p>N C(Na)(COOC 2 5 ) 2
CH H )>N C(CH 2 6 5 )(COOC 2 5 ) 2
2
->
C 6H 4
5
<^
CO C 6 H CH CH(NH )COOH + C H (COOH) + 2C H OH + CO

2
Wheeler and Hoffmann f condensed benzaldehyde with hydantoin (i) and the resulting benzylidene hydantoin (ii) on treatment with
hydriodic acid gave phenylalanine:
-
CH
|
OC< X NH - CO
(i)
>
HoN.CH-CH C /NH - C:CH-C H -> OC< X NH - CO COOH

6
"
H,
(ii)
by the reduction and hydrolysis of the product obtained by the condensation of benzaldehyde and diketopiperazine in the presence of sodium acetate and acetic
Sasaki J has obtained
it
More recently
anhydride:
CO - NH
CO - NH
->
C<^
NH - CO
^>CH 2
-
C 6 H CH
5
C<^
NH - CO
")C:CHC H
6
r>
2C 6 H 5 CH 2 CH(NH 2 )COOH
Tyrosine and dihydroxyphenylalanine were obtained in a similar way.
Tyrosine (j8-/>-hydroxyphenyl-a-aminopropionic acid) was obtained by Liebig in 1846 by heating cheese (rvpo$) with caustic It is the least soluble of the amino acids, and is therefore potash.
easily isolated
was
first
from the hydrolytic products of the proteins. It synthesized by Erlenmeyer and Lipp by nitrating phenylf
* Zeit. physiol. Chem., 1905, 44, 448.

J Ber.,
Amer. Chem. J., 1911, 45, 368.

Ann., 1883, 219, 161, 179.
1921, 54
[B], 163, 2056.
157
alanine, reducing the resulting para-nitro derivative, and then replacing the amino group by hydroxyl by means of nitrous acid:
C 6 H 6 CH 2 CH(NH )COOH -> O 2N C 6 H 4 CH 2 CH(NH )COOH -> H 2 N.C 6 H 4 CH 2 CH(NH 2)COOH -> HO.C H 4 -CH 2 -CH(NH )COOH
2 2 6 2
* obtained Erlenmeyer junior and Halsey tyrosine from the condensation product of ^-hydroxybenzaldehyde with hippuric acid in the presence of sodium acetate and acetic anhydride:
HO C H CHO + CH COOH HO C H CH C CO NH COC H N COC H HO C H CH C COOH HO CH CH, CH COOH -> NH CO C H NH CO C H HO-C H -CH .CH.COOH -> C H COOH + NH
6 4 2 4
:
fl
Wheeler and Hoffmann f condensed anisaldehyde with hydantoin and treated the resulting product with hydriodic acid. The latter brings about reduction and hydrolysis, and at the same time removes the methyl group from the methoxy group.
- C CH C H OCH oc X NH - CO
:
H N-CH-CH COOH
2
-C 6 H 4 OH
HETEROCYCLIC AMINO ACIDS

Proline (a-pyrrolidine carboxylic acid). This amino acid was discovered by Fischer in 1901 among the products of hydrolysis of casein. It has also been obtained by the hydrolysis of a number of proteins of vegetable origin, notably the prolamines, but it has
It is readily not yet been found to occur as such in any plant. soluble in alcohol, and can be partially separated from other amino
acids
by
this solvent.
The
of
racemic form was synthesized by Willstatter J by the action

acid:
ammonia on aS-dibromvaleric
CH
\
*
CH COOH + NH 3
= CH
\/
f
CH COOH +
zIIBr
Br
Br
NH
Amer. Ghent.}., ign, 45, 368.
Ber., 1897,30, 2981; Ann., 1899, 307, 138.
J Ber., 1900,33, 1162; Ann., 1902,326, 94, 104.
158

aS-dibromvaleric acid was prepared from trimethylene diester as follows:
2 )2
The
bromide and sodium malonic
Br.CH 2 -CH 2 -CH 2 .Br

Br2
+ NaCH(COOC H 5 HBr
Br[CH 2] 3 CHBrCOOH
->
Br[CH 2] 3 C.Br(COOC 2 H 5) 2 ->
Fischer and Zemplen,* and also Sorensen and Anderson,f have

also synthesized the acid by the application of the phthalimidemalonic ester method: Phthaliminomalonic ester and
trimethylene
dibromide are condensed malonic ester (i):
to
give
y - bromopropylphthalimino-
H O CO
6
CO CO
^>C 6
C 2 H 5 O- CO
^>CH-N^
H 4 + BrCH CH CH
2
Si
Br
H O CO
5
C 2 H 5 O.CO
CH CH, CH
2
Br
N(C 2 O 2}C 6 H 4
(i)
and the bromine atom replaced by hydroxyl by the action of alcoholic caustic soda, after which hydrochloric acid converts the product
a-amino-S-hydroxyvaleric acid (ii). with hydrochloric acid, ^/-proline is obtained
into
On
evaporation
C 2 H 5 OCO
XCH-CH-CH 2 OH
--
.CHjCHjCHOH
^N{C
}Ctf
HOOO-CH^'
Optically active proline was obtained synthetically as follows: J Nw-nitrobenzoylpiperidine (i) was oxidized to 8[-/n-nitrobenzoyl-
by the action of potassium permanganate. This product was then brominated, and the bromo derivative (iii) transformed into Nw-nitrobenzoylproline by the action of alkali:
amino]-valeric acid
(ii)
CH - CH - CH CH - N CH
2
2
->
2
CH - CH - CH CH - NH COOH
2 2 2 2
CO C H N0
6
COC H 4 N0
6
(i)
(ii)
* Ber. y 1909, 42, 1022.
f %** physiol. Chem., 1908, 56, 236.
J Ber., 1911,44, 1332.
THE AMINO ACIDS AND POLYPEPTIDES 159 CH - CH - CHBr CH - CH -CH COOH

a
2
CH - NH
>
COOH to. C H NO
6
CH,
-N
CO C H 4NO
6
(iii)
Nw-Nitrobenzoylproline.
optical isomerides by after which the active salts,
its
This compound was then resolved into

fractionally crystallizing
its
cinchonine
active proline
nitrobenzoylproline was converted into nitrobenzoic acid and the by the action of hydrochloric acid.
Hydroxyproline (/T-Hydroxypyrrolidine-a-carboxylic
acid).
This amino acid was discovered by Fischer among the products of

hydrolysis of gelatine. Its isolation presented considerable difficulty, but in recent years it has been obtained from several proteins. This amino acid contains two asymmetric carbon atoms, and all
four stereoisomeric forms have been recently obtained by Leuchs.*
were synthesized as follows: f S-chloro-yvalerolactone-a-carboxylic ester (i) was obtained by the condensation of epichlorhydrin with sodium malonic ester:
inactive forms
The two
CH
I
CHCNa)
I
COOC 2 H5
5
CICH 2-CH X
'''0+
COOC H
2
-^
CH 2
1
I
C1CH^CH~0--CO
(i)
After chlorination and saponification with concentrated hydrochloric acid, the lactone ring was opened by treatment with ammonia and the ammonium salt of hydroxyproline formed by immediate ring formation:
CH
I
CHC1
I
CH - NH - CH COONH 4
2
1
Cl
CH CH(OH) COONH
.
CH(OH)
is
CH 2
The
i
:
last stage
of this reaction
analogous to the reactions whereby
4-dihalogen paraffins are transformed by the action of primary amines in alcoholic solution into N-alkyl- and N-aryl-pyrrolidines,J
e.g.
CH -CH
2
2I
CH -CH
2
aC 6 H 6 NH 2
=
CH ~CH
2
C
2I
H NH
5
-HI
2 -CH 2 I
When
*
treated with methyliodide
and methylalcoholic potash,
Ber., 1919, 52 [B], 2086. f Ber., 1907, 40, 30. J Scholtz, Ber. 1899, 32, 848; V. Braun, Ber., 1911, 44, 1254.
t
160
hydroxyproline gives a mixture of two stereoisomeric oxyproline * (p. 216). dimethylbetaines (hydroxystachydrines)
HO CH
.
CH 2
2 3) 2
CH - N(CH
- CH
io
This inter-
Tryptophane (Indole-a-aminopropionic
esting
acid).
obtained in a pure crystalline condition > from casein, by Hopkins and Cole f in 1901. The natural form is
first
amino acid was
and it is present in nearly all proteins. It is, however, entirely absent from zein, the prolamine of maize, and it is also absent from gelatine. On fusion with potash it yields skatole and indole (p. 182). In the presence of putrefactive bacteria, indole acetic acid and indole propionic acid are formed in addition. Tryptophane has been obtained synthetically by Ellinger and Flamand J as follows: Indole-/?- aldehyde is condensed with hippuric acid in the presence of sodium acetate and acetic anhydride to give the lactone (i). On hydrolysis with boiling sodium hydroxide solution and subsequent reduction with sodium in alcohol, tryptolaevorotatory,
phane
is
obtained:
N\
CeH 4 \
CH 2 NHCOC 6 H 5 C - CHO /CH +
>
C 6I
NH
COOH
6 5
NH
(i)
2
CO-
C-CH:C-NHCOC H
C-CH -CH(NH )COOH

2
NH
COOH
NH
Indole-/?-aldehyde was obtained by the action of chloroform and caustic potash on indole (Reimer's reaction).
Histidine (a-amino-/?-iminazolepropionic acid). This amino acid was first discovered by Kossel among the decomposition of the protein sturine, which was obtained from the sperproducts matazoa of the sturgeon. From some proteins such as globin the yield may be as high as 10 per cent, and it is conveniently prepared
* Schultze, Trier, Zeit. physiol. Ghent., 1912, 79, 240; Kiing, ibid., 1913, 85, \ Journ. Physiol. 1901, 27, 418. 217. J Ber., 1907, 40, 3029; Zeit. physiol. Ghent., 1908, 55, 8. Zeit. physiol. Ghent., 1896, 23, 176.
,

salts it
161
from ox blood. When treated with alkaline solutions of diazonium forms a red-coloured product, and this is in accordance with its constitution as an iminazole derivative. * Knoop and Windaus observed that when histidine (i) is treated with nitrous acid, it gives a product (ii) which on reduction yields
/?-iminazolepropionic acid
(iii):
CH - NH
J
CH - NH
C
"*"
CH - NH
C
""*
^CH N
^CH N
CH 3 CH NH
2
CH 2
CH 2
COOH
(i)
CHOH COOH
(ii)
CH
COOH
(iii)
The same
of
authors have synthesized histidine by the combined action

acid:
ammonia and formaldehyde on glyoxylpropionic
CHO
NH
+
H +
O
~*
CH - NH CH
CO
NH,
3
N
CH 2 + 3H O
2
CH
COOH
The
by
its
COOH
constitutional formula of histidine has been fully confirmed
synthesis
to the first
by Pyman by two independent methods. According method, f citric acid is converted by well-known methods
successively into diaminoacetone:
CH COOH
2
|
H S0
2
CH -COOH
2
C(OH)COOH
->
CO
HN0
->
CH:NOH
2
CO
CH:NOH
CH NH 2
2
-*
CO
CH COOH
2
CH -COOH
2
CH NH 2
2
ring, which consists on an aminoketone with potassium thiocyanate and oxidizing the product with nitric acid, whereby the thiol group (SH) is removed, was next employed:
Gabriel's
method of synthesizing an iminazole
in acting
Beitr. z.
Chem. Phys.
u. Path., 1905, 7, 144.
t Pyman, Trans., 1911, 99, 672, 1392, 2172.

(D331)
ORGANIC CHEMICAL SYNTHESIS CH - NH CH - NH CH -NH -HC1

162
2 2
KCNS
>C-SH
-N
HNO
CO
N
CH NH
2
2
CH -NH
2
-HC1
CH .NH-CS-NH
2
product was then treated with nitrous acid, which replaces the amino group by hydroxyl, the hydroxyl substituted by chlorine, and the product condensed with sodium chloromalonic ester. The resulting product was hydrolyzed, carbon dioxide removed, and the chlorine atom replaced by an amino group:
The
CH - NH
>CH
-N
PCI,
CH - NH
(I
\CU
-N
2
C1
Nax
>C(COOC 2 H 5 ) 2
CH OH CH - NH
2
CH C1 CH - NH
N
CH C
2
-
>CH
-
N
CH CHC1 COOH
2
CH - NH CH /'
C1(COOC 2H 5 ) 2
CH CH(NH )COOH
-
The
racemic product thus obtained was resolved by the fractional
crystallization of its tartrate, when the laevo to be identical with the natural substance.
compound was found
According to the second method,* glyoxaline-4 (or 5)-formaldehyde is condensed with hippuric acid according to Erlenmeyer's method with the production of the lactone (i):
CH - NH
C C H 6 CONH
^
II
CHz
+ OHC-C
^)CH
HOOC
CH-N-COCH
CH CONH
5
C CH C II
: .
>
HOOC
CH - N CO CH 3
CH C
S
N
/
)CH
C CH :
o-oc
*
(i)
Pyman,
Trans,, 1916, 109, 186.
163
On boiling with dilute sodium carbonate the acetyl group is removed,

the oxazoline ring opened, and a-benzoylaminoglyoxaline-4 (or 5)On reduction, benzoylhistidine (iii) is acrylic acid (ii) obtained. obtained which gives racemic histidine on hydrolysis:
CH CO-NH
B
:
-
CH - NH CH CH C
(ii)
HOOC
X ^>C
CH - NH
)CH
2
C 8 H S CONH
CH-CH
-C
N
CH - NH
HOOC
(iii)
-*
HOOC CH(NH
The
Distribution of
2)
CH C
2
||
>CH N
in the Proteins.
Fol-
r-Histidine
Amino Acids
lowing the isolation and characterization of the various amino acids present in the proteins, chemists began to consider the losses of
in their separation, with a view to arriving results for the distribution of these acids in the quantitative various proteins. This line of inquiry has been vigorously pursued by Abderhalden, who has ascertained the component amino acids of
at
amino acids which occur
the albumins of egg, serum, and milk, as well as other proteins.
Osborne and his collaborators have investigated gliadin (from gluten of wheat and rye), hordein (from barley), zein (from maize), and several allied proteins.
In 1907 Fischer investigated the fibroin produced by silkworms and spiders, incidentally emphasizing the remarkable biological fact that there is only slight chemical difference between the synthetic products of two creatures whose diet is so vastly divergent. The
principal difference is the large proportion of glutamic acid which has been derived from ordinary silk, and the absence of serine. More recently Foreman * has applied his method for the isolation of the amino acids to caseinogen with even more satisfactory results.
The
attached tabulation illustrates a few of the results obtained

*
in this direction.
Biochem.y., 1919, 13, 378.
164

AMINO ACIDS
IN VARIOUS PROTEINS
THE POLYPEPTIDES
After his researches on the amino acids, commenced in 1899, had given some indication of the nature and variety of these chemical
units, Fischer next turned his attention to the artificial elaboration
of the protein molecules from their components. The amount of nitrogen liberated from the proteins by nitrous acid is small in comparison with the percentage of nitrogen in the original molecule.
This
fact, in conjunction with the early recognition of hippuric acid as benzoyl glycine, gave a clue as to the way in which the amino acids are linked together. to the number of amino acid According
groups present in the molecule, the synthetic products were termed

the dipeptide, glycylglycine, formed by the union of two molecules of glycine:
di-,
tri-,
&c., peptides.
The
simplest
is
NH CH COOH + NH CH COOH = NH CH CO-NHCH COOH + H O

2
Glycylglycine
Synthesis of the Polypeptides. As early as 1882, Curtius obtained two acids by the action of benzoyl chloride on the silver

salt of glycine.
165
One
of these
compounds had twice the molecular

to
2
weight expected, and was shown
be hippurylamidoacetic acid:
2
C 6 H CO
5
NH CH CO NH CH COOH
made
the
first
In 1904 the same chemist

to link together a series of
systematic attempt
amino acids
in chains.
For
this
purpose
glycine ester, quite free from its hydrochloride, was dissolved in dry ether and allowed to stand, when triglycylglycine ester (i) was
slowly deposited:
NH CHoCO[NHCH
2
CO] 2 NH
(i)
CH COOC H
2 2
The
e.g.
use of the azoimides effected a considerable improvement, benzoyl azoimide combines with glycine with the formation
of hippuric acid and the removal of hydrazoic acid (azoimide):
C 6 H 5 CO
N/
\N
+ HoN CH* COOH - C H CO NH CH COOH + HN

.
The
and combined with
ester of hippuric acid may in turn be converted into the azoimide a second molecule of glycine:
C 6 H 5 CO
NH CH CON + H N CH COOH - C H CONHCH CONH CH COOH + N H

2
In this way chains of different amino acids were obtained, but the method suffered from the drawback that the benzoyl group could not be eliminated without complete hydrolysis to the constituent
amino
acids.
The following methods, which were much more satisfactory.

i
.
devised by E. Fischer, are
The action of acids or
alkalies
upon derivatives of 2 5-diketo:
piperazine.
It is well
known
that
amino acid
esters are
changed by heat
into derivatives of 2.*5-diketopiperazine,
and these compounds yield
dipeptides on partial hydrolysis:
CH - CO
2
CO
CH
^>NH +
2
H O - H N-CH -CO-NH.CH -COOH

2
2
y. pr.
Chem. 1904
t
(2),
70, 57.
166
2. By the action of ammonia on the condensation product of the acid chlorides of halogen fatty acids and the amino acids or their esters.
This method makes possible

different
acid.
the
successive
introduction of
amino acid
The
radicles into a simple polypeptide or amino following synthesis of leucylglycylglycine through the
is
intermediate glycylglycine
quite straightforward:
2
2
CH
C1COC1
(+NH
3,
+ H N-CH -COOH -> CH C1CO-NH-CH COOH -> CH NH CONHCH COOH

2
2
3)
CH
CH
CHCH-CHoCHBrCOCl + HoN-CH 2 CO-NHCHoCOOH
CH CH CHBrCO NH CH CO NHCH COOH

2 2
2
>CH CHo CH(NH,)CO NHCHoCO NHCHoCOOH

.
-
the halogen acid chlorides of optically active acids, optically The method only allows of the active polypeptides are obtained.
By using
amide groups being introduced into the amino group of the acid, so that the chain can be lengthened only at this end.
3.
original
From
the acid chlorides of amino acids.
This complementary method arose as a result of the observation in 1904 that the chlorides of halogenated arylamino acids may be prepared by the action of phosphorus pentachloride on the acid
dissolved in acetyl chloride. These compounds react with the esters of amino acids and polypeptides, and after hydrolysis of the product
the halogen
is
replaced by ammonia.
In this way several higher
polypeptides have been prepared, e.g.
C 4 H 9 CHBrCONHCH 2 COCl
Bromisocapronylglycyl chloride
+ NH CH CONHCH COOC H
2
2 2 2
Glycylglycine ester.
->
->
C 4H 5 CHBrCONHCH 2 CONHCH 2 CONHCH 2 COOC 2 H 5 C 4 H 9 CH(NH 2 )CO[NHCH 2 CO] NH-CH 2 COOH

2
Leucyldiglycyl glycine
The
obtained by the action of thionyl chloride on the amino acids in which the amino group has been protected
acid chlorides
may be
carbethoxyglycyl chloride and glycine ester give carbethoxylglycylglycine ester, from which the
by carbomethoxylation
(p. 86), e.g.
167
amide can be obtained by hydrolysis; but the carbethoxyl group cannot be removed without complete hydrolysis of the molecule into
its
constituent units:
(C 2H 5 OOC)NH
CH COC1 + NH CH COOC H 5 -> (C H OOC) NH CH CONH CH COOC H 5

2
2 2
Carbethoxylglycylglycine ester
Although
acyl chlorides in acetyl chloride, and the consequent difficulty of separating them from solution without decomposition, presented a serious obstacle to its extension. This was overcome by preparing the acyl
this process is elastic, the solubility of
many such
amino acid hydrochlorides themselves. These the general formula [R- C- H(NH 3 C1)COC1], are chlorides, having also substituted ammonium chlorides, and are generally not readily
chlorides
of the
soluble in acetyl chloride. As they act smoothly on the esters of amino acids and polypeptides, the device has been a most fruitful one, and particularly useful in its application to the d- and /-amino
with consequent synthesis of optically active polypeptides. Straightforward as these reactions appear in description, they represent a very remarkable experimental feat, the rigid exclusion of water being necessary throughout.
acids,
The attached tabulation (p. 168) briefly illustrates the variety of polypeptides prepared by these reactions, but it only embraces a few of the numerous products obtained,*
The Relation of the Polypeptides to the Simpler Proteins.

It is generally believed that the amino acids are linked together in the protein molecules as in the polypeptides, i.e. the amino group of one molecule is linked to the carboxyl group of its neighbouring
amino acid
to
form long chains,
as for example:
NH CH
r
:
CO
1
NH CH CO
*
NH CH CO NH CH
r---J
COOH
----J
-I
r;
/ C^CH CH
3
CROftf
6_4_. i
,
<f
H2
<JH
COOK! j
Glycine
residue
Valyl residue
Tyrosine
residue
Aspartic
acid residue
obvious that the field of investigation is an extremely wide and an interesting calculation of the possibilities presenting one, themselves among the polypeptides has been made by Fischer.
It is
* For further examples see Emil Fischer's lecture (Ber., 1906, 39, 551).
68

>ME SOME POLYPEPTIDES SYNTHESIZED BY FISCHER'S METHODS
this estimate, the octadecapeptide has 816 possible while a polypeptide comprising 30 amino acids of which isomerides, 5 are glycine, 4 alanine, 3 leucine, 3 lysine, 2 tyrosine, 2 phenyl-
According to
alanine,
and 13 various other amino acids

.
has a
number
is
of possible
In these calculations isomerides reaching 1-28 X io 27 that the mechanism of linking the amino acid groups
that of
it is
assumed
from
limited to
arise
glycylglycine, and further complexity would
alternative linkages such as that of diketopiperazine. Moreover, hydroxyamino acids may participate in the linkages peculiar to esters and ethers.
far-reaching consequences of the methods provided to separate the components of an amino acid mixture have already been indicated, but the esters thus isolated were, until 1902, those
The
of amino acids only, unassociated with polypeptides. In that year Fischer and Bergell produced from silk fibroin, by successive hydro-
with hydrochloric acid, trypsin, and baryta, a dipeptide which appeared to be glycyl-^-alanine, although it could not be identified with the synthetic product; but in 1906 Fischer and Abderhalden obtained from the same source a methyldiketopiperazine, identical with that producible from glycine and d-alanine, thus indicating
lysis

that glycyW-alanine
fibroin.
is
169
Soon
after this the following
glycyW-tyrosine (silk (elastin), /-leucyW-glutamic acid
amongst the degradation products of silk polypep tides were recognized: fibroin), glycyl-/-leucine and ^-alanyl-/- leu cine
(gliadin), glycyW-alanyl-glycyl-
/-tyrosine (silk fibroin), and glycylproline anhydride (gelatine). As early as 1888 De Rey-Pailhade showed that extracts of yeast and many animal tissues are able to reduce sulphur to hydrogen Quite recently Hopkins has shown that this is due to sulphide. the presence of a dipeptide of cysteine and glutamic acid, which is " provisionally termed glutathione ". This compound is not affected
by proteolytic enzymes of the tissues, but is hydrolyzed by boiling acids to equivalent proportions of cystine and glutamic acid. Glutathione is an autoxidizable substance, and is of exceptional importance
in relation to the oxidation
in living cells.
and reduction processes which take place
In neutral or slightly alkaline solution it is oxidized spontaneously to the disulphide and acts as oxygen acceptor, while the oxidized form, on the other hand, acts as a hydrogen acceptor. This dipeptide is formed by the union of an amino group of one acid with a carboxyl group of the other, with elimination of water, but the exact allocation of the union is not yet known. *
Although the aggregate number of synthetic polypeptides must

exceed two hundred, the study of these compounds, demanding an experimental technique of the highest order, has served but partially to illuminate the gulf which still separates the chemist
from
his goal in the study of the proteins.
REFERENCES.
Untersuchungen
iiber
Aminosauren, Polypeptide und Proteine, by E.
Fischer, 1899-1906 (Springer, Berlin). The Chemical Constitution of the Proteins, Parts I and II, by R. H. Plimmer: Monographs on Biochemistry (Longmans), 1912. The Vegetable Proteins, by T. B. Osborne: Monographs on Bio-
chemistry (Longmans), 1909. The General Characters of the Proteins, by S. B. Schryver: Monographs on Biochemistry (Longmans), 1909.
* Biochem. For further information on the significance of J., 1921, 15, 286. this compound the reader should consult, Oxidations and Reductions in the Animal Body, by Dakin, 2nd Edition, London, 1922.
CHAPTER
Introduction and Scope.
organic bases
familiar
is
VIII
Some Simple Natural Organic

The
a matter of considerable difficulty.
Bases
classification of the natural
Many
of the
complex nitrogenous bases, now classified as alkaloids, were discovered long before organic chemistry had become a systematic science; indeed, as early as 1806 Sertiirner had discovered the basic nature of morphine, and in the next few years a large number of
plant bases, including narcotine, strychnine, brucine, caffeine, and
quinine, were isolated. These bases are almost insoluble in water and
extracted with the aid of immiscible solvents.
may be
readily
with their pronounced physiological
activity,
This fact, together enhanced the study
of the vegetable alkaloids. As a rule the animal bases are readily soluble in water, and cannot be conveniently extracted with immiscible solvents. As a conse-
quence of their isolation requiring a special technique, very few of the animal bases were isolated before 1890. The first great advance was made in 1885 by Brieger, who introduced precipitation methods whereby he isolated putrescene, cadaverine, and several other
putrefaction bases. In this book the natural organic bases will be considered in three chapters:
1.
Bases derived from amino acids and other simple natural
bases.
2.
3.
The pyrimidine and The alkaloids.
purine bases.
This
is
classification is largely one of convenience, and it should be remembered that no rigid classification of the natural organic bases
yet practicable.
Occurrence and Isolation of the Simple Natural Bases.

Having excluded the
alkaloids
and the pyrimidine and purine bases

170
SOME SIMPLE NATURAL ORGANIC BASES
171
from the scope of the present chapter, we may briefly consider the occurrence and isolation of the other natural bases.
stage of putrefaction is the hydrolysis of proteins into their constituent amino acids, but bacteria are able to break down
first
The
This degradation may take place in two ways: either an amino group may be eliminated (deaminization) or a carboxyl group may be removed (decarboxylation). In the first portion of this chapter the amines derived by the decarboxylation of monobasic amino acids will be dealt with. Decarboxylation may take place either by the simple removal of carbon dioxide, or the carboxyl group may be eliminated as formic acid, in which case
still
amino acids
further.
reduction must take place:
R-CH-NHJCOOIH
*L
I
> R-CH;NH+CO, * Z Z
* R-CH;NH,-l-H-COOH
RCH-NH,:COOH;
process applied to dibasic monoamino acids results in the production of co-amino acids, and as these substances still
The same
contain a carboxyl group they are only feeble bases. During the last few years almost all the amino acids have been converted into the corresponding bases either by bacteria or by chemical means.
has already been stated (p. 103) that when animal and vegetable tissues are extracted with ether, in addition to fats, oils, and cholesIt
terol, small quantities of certain
complex substances are extracted
which are termed lipins. Of these the best known arc lecithin and kephalin, which on hydrolysis give glycerol, fatty acids, and two amino alcohols, choline and amino-ethyl alcohol. Neurine and
trimethylamine are secondary decomposition products of choline. Creatine, creatinine, and other guanidine derivatives are other interesting animal bases, while the betai'nes may be regarded as
derived from the amino acids by methylation. It has already been pointed out that the majority of the bases dealt with in this chapter are soluble in water and are sparingly soluble in ether and chloroform. few monoamines like methyl-
but the majority must be isolated by methods. The preliminary purification of a tissue precipitation extract after removal of coagulable protein is best effected by lead In the former case the solution is first treated acetate or by tannin. by normal lead acetate, and then by the basic salt. After this treatvolatile in steam,
amine are
172
ment, which removes the proteins and the peptones, the solution is concentrated, when some bases, such as creatine, may separate. The most important precipitant is phosphotungstic acid in the presence of dilute sulphuric acid. Mercuric chloride and silver For the isolation of the indinitrate are occasionally employed. vidual bases it is necessary to prepare crystalline derivatives. For this
purpose the hydrochlorides, nitrates, picrates, platinichlorides, or auri chlorides may be prepared, or the mixture may be benzoylated.
SIMPLE MONOAM1NO BASES

Methylamine,
CH 3 NH
2,
the simplest aliphatic base, occurs in
Annual and Perennial Dog's Mercury (Mercurialis annua and M. It perennis) and in the root of the Sweet Flag (Acorus calamus). has been frequently encountered as a product of bacterial action, and may be derived from glycine by decarboxylation or, more probably, from choline.
Methylamine may be obtained synthetically by a simple reactions which need not be discussed here.
variety
of
Trimethylamine, (CH 3 ) 3 N,
Goosefoot
(Chenopodium
occurs in leaves of the Stinking Ash (Pyrus vulvarid), the Mountain
aucuparia), and in the flowers of the Hawthorn (Cratcegus cantha). It is of common occurrence in putrefaction products
Oxyaand is
derived from choline and similar quaternary bases. As early as 1855 Winckler observed the presence of trimethylamine in herring brine. Trimethylamine is usually prepared by the destructive distillation of
beet-sugar molasses, and in this case the parent substance is betai'ne. Hofmann's preparation of the methylamines by the action of
alcoholic
ammonia on methyliodide Isoamylamine, (CH 3 ) 2 CH
is
well known.
2
CH 2 CH NH
2,
is
probably
* and is certainly present in putrid meat.f present in fresh ergot In these cases it is probably derived from leu cine by decarboxylation,
and
it
may be prepared by
(CH 3 ) 2 (CH 3 ) 2
rapidly heating the latter.

-
Leucine CH CH CH(NH )COOH CH CH CH NH Isoamylamine

2
The isoamylamine
processes
is
obtained from ergot and during putrefaction mixed with 2-methylaminobutane, derived from probably
*
Barger and Dale, J. Physiol., 1909, 38, 343. t Barger and Walpole, ibid., 1908, 37, 343.
SIMPLE MONOAMINO BASES

isoleucine, while
also
173
normal amylamine, derived from norleucine, may
be present:
(C 2H 5 )(CH 3 )CH
(C H )(CH
2
6
-
CH(NH )COOH
2
Isoleucine
I
3)
CH CH (NH
2
2
2)
Methylaminobutane
Norleucine (caprine)
CH
CH
[CHo] 3
CH(NH )COOH
4
2 2
[CH CH NH
2] 3
Amylamine
,
/?-Phenylethylamine, C 6 H5 CH 2 CH 2 NH 2 isolated from putrid gelatine by Nencki in 1876, was one of the earliest putrefaction It is bases of which the composition was correctly determined.
derived by the decarboxylation of phenylalanine (p. 145). It is into note that phenylethylalcohol, C 6 5 2 2 OH, occurs teresting
H CH CH
in rose oil (p. 139).
Phenylethylamine
of benzylcyanide:
is easily
obtained synthetically by the reduction
C C H 5 CH 2 CN + aH 3 - C H 5 CH CH 2NH 2
6 2
but the
maximum yield
so far obtained does not exceed 50 per cent.*
p-Hydroxyphenylethylamine,
was
first
HO C H4 CH CH NH
6
2,
obtained by Schmitt and Nasse in 1865, by the decarboxylation of tyrosine (p. 145) by heat. It is the chief pressor constituent of putrid meat f and is present in extracts of ergot. J The following
are the
more important
synthetic
methods by which
this base
has
been prepared.
1.
The
reduction of ^-hydroxyphenylacetonitrile with sodium
and
alcohol:
HO C H CH CN + 4H - HO C H CH
6
CH NH
2
2.
From
the benzoyl derivative of jS-phenylethylamine by the

jj
following general reactions:

2
C 6 H 5 CH 2 CH NHCOC 6 H 5 -> NO 2 -C 6 H 4 .CH 2 *CH 2 .NH.COC 6 H 5 -> NH 2 C 6 H 4 CH 2 CH 2 NHCOC H 5 ~> HO-C 6 H 4 -CH 2 -CH 2 NH-CO-C 6 H 6 ~> HO-C H 4 -CH 2 -CH 2 -NH 2
-
Wohl and
Berthold, Ber., 1910, 43, 2175.
t Barger and Walpole, J. PhysioL, 1909, 38, 343. J Barger and Dale, ibid., 1909, 38, 67. Barger, Trans., 1909, 95, 1123. and Walpole, Trans., 1909, 95, 1720. Barger
||
174
3.

By
reduction of the condensation product of anisaldehyde with nitromethane. The />-methoxyphenylethylamine thus obtained is then boiled with hydriodic acid.*
CH O C H CHO + CH NO ~> CH O C H 4 CH CH NO -> CH O.C H .CH CH:NOH -> CH O-C H .CH -CH NH -> HO C H CH CH NH
3
6
This base produces physiological those produced by adrenaline, although
effects of the
same type
as
its activity is relatively
small.
{HO C 6 H4 CH 2 COOH).f
In the body
it is
partly converted into ^-hydroxyphenylacetic acid
number
of />-hydroxyphenylethylalkyl amines have been pre-
pared by Walpole and their physiological activity has been studied
by Dale.
Hordenine, p-HO C 6 H 4
CH CH N(CH 3
2
)2 ,
was obtained
from an infusion of barley germs by Leger.
The
base has only a
transitory existence during the germination of barley and has feeble Three syntheses of this base may be briefly depressor action. scribed.
1
.
Barger J obtained hordenine from /3-phenylethylalcohol by the
following general reactions:
C 6 H 6 CH -CH 2OH ->

2
C 6 H 5 CH 2 CH 2 C1 -> C 6 H 5 -CH 2 -CH 2 -N(CH 3 ) 2 -> N0 2 .C 6 H 4 -CH 2 -CH 2 N(CH 3 ) 2 -> NH 2 -C 6 H 4 -CH 2 .CH N(CH 3 ) 2 -> HO C 6 H 4 CH 2 CH N(CH 3 ) 2
2
to the base hordenine methyl ether, from which hordenine was tertiary obtained by boiling with hydriodic acid:
2.
Rosenmund methylated ^-methoxyphenylethylamine
CH O C H
3
6
CH
CH
->
3.
-> CH 3 O-C 6 H 4 .CH 2 -CH 2 .N.(CH 3 ) 2 HO-C 6 H 4 -CH 2 -CH 2 -N-(CH 3) 2

2
NH
quaternary hordenine methiodide, obtained by complete methylation of jp-hydroxyphenylethy-
By
||
distillation
in vacuo of
lamine:
HO.C 6 H 4 .CH 2 -CH -N(CH 3)I -> HO-C 6 H 4 -CH 2 .CH N(CH
2 2
3) 2
+ CH
3I
*
t
Rosenmund, Ber., 1909, 42, 4778. Ewins and Laidlow, J. PhysioL, 1910, 41, 78.
Ber., 1910, 43, 306.
||
J Trans., 1909, 95, 2193.
D. R.
P.,
233069
SIMPLE MONOAMINO BASES

Adrenaline
(epinephin),
175
HO
HO<^_J>~CH(OH)-CH NH CH
-
Although nothing is known of the nature of the parent substance from which adrenaline is derived, yet the base is obviously more
closely related to tyrosine than to
protein.
was
first
any other known constituent of The physiological importance of the supra-renal glands made clear by Addison in 1849, and in 1894 Oliver and
Schafer observed the remarkable rise of blood pressure caused by the injection of supra- renal extracts. Takamine isolated the active * principle of the glands in 1901, and Aldrich assigned to it the correct empirical formula in the same year. Natural adrenaline contains a methylamino group, and an alcoholic hydroxyl group, and on fusion with potash yields protocatechuic acid:
H(X
HO(
VCOOH
Pauly f showed that adrenaline contains an asymmetric carbon atom, and reduced the possible constitutional formulae to two:
OH
10H
OH
CHOH CH NHCH
2
CH-NH-CH
" 3
CH
(ii)
OII 2
(i)
Jowett J arrived
and favoured the first formula. The constitutional formula (i) of adrenaline was established by its and almost simultaneously by Dakin,|| and synthesis by Stolz
at similar results
the subsequent resolution of the synthetic product by Flacher,** the kevo form of which was completely identical with natural adrenaline.
Adrenaline has been synthesized by several methods, of which
the
first is
the most important.

,
* Amer.y.
Physiol, 1901, 5, 457. J Trans., 1904, 85, 192. 76 [B], 491, 498. 41 Proc. Roy. Soc., 1905,
Ber., 1903, 36, 2944.

Ber., 1904, 37, 4149. ** Zeit. physiol. Chem., 1908, 58, 581.
176
i.

Catechol
is
condensed with monochloracetic acid in the
presence of phosphorus oxychloride (or with chloracetyl chloride in the presence of aluminium chloride), and the resulting chloroacetocatechol (i) treated, in alcholic solution, at ordinary temperature^
with a concentrated aqueous solution of methylamine. The methylaminoacetocatechol (ii) so obtained is then reduced to racemic
adrenaline
(iii)
by means of aluminium amalgam, or
electrolytically.*
OH
ion
OH
OH
CO CH NHCH
2
OH
CH C1
2
CH NHCH
2
(i)
(ii)
(iii)
Protocatechic aldehyde is converted into the cyanhydrin (i), which, on reduction, gives 3 4-dihydroxyphenylethanolamine (ii). This base is about as active as adrenaline, and is known commer" arterenol ".f On methylation it is said to yield adrenaline. cially as
2.
:
(H0) 2 C 6 H 3
3.
CH(OH)CN ->
(HO) 2 C 6 H 3
CH(OH)CH 2NH
According to the method of Nagai,J diacetylprotocatechic aldehyde (i) is condensed with nitromethane, and the product (ii) is mixed with the calculated quantity of formaldehyde and reduced by zinc dust and acetic acid to give /?-hydroxy-/?-3
:
4-diacetoxy-
phenylethylmethylamine
(iii).
On
is
removing
the
acetyl
groups
from
this
compound, adrenaline
OCO-CH 3
r
1
obtained:
0-CO-CH 3
O-CO-CH,
CO CH 3
'
0-COCH 3 //
r
No.co.cH 3
CH(OH)CH NO
(ii)
CH(OH)CHNHCH 3
(iii)
CH(OH)-CH,NHH 2
Racemic adrenaline may be resolved into

the aid of rf-tartaric acid.
its
optical isomers with
^-adrenaline obtained as a byis then racemized product Lsevoadrenaline by means of acids. has many times the pressor effect of the dextro form. Several investigators, and have particularly Barger and Dale,
* D. R. P., 152814, 157300. f D. R. P., 193634. i yaps. Pat., 1918, 32440, 32441. J. Physiol, 1910, 41, 19; see also Tutin, Trans., 1910, 97, 2496.
The
DIAMINO BASES
177
prepared compounds analogous in chemical structure to adrenaline > and have examined their physiological action. The latter investigators have examined a large number of amines, and have shown that an action simulating that of adrenaline is not peculiar to this substance alone, but is possessed by a large series of amines, the The most active of simplest being primary aliphatic amines.
The presence of two the simpler bases is /?-phenylethylamine. in the 3:4 position of the nucleus increases the hydroxyl groups
effect,
which
chain.
is further intensified by a hydroxyl group in the side In short, the natural product seems to be the best adapted
for this special function.
DIAMINO BASES
Putrescine (tetramethylene
diamine,
Cadaverine (pentamethylene diamine, 2) 2 2] 5 historic interest, as they were among the earliest putrefaction bases to be isolated and characterized. They are, however, comparatively
NH [CH NH and NH [CH NH are of

2 21 4
2)
innocuous substances, having very slight physiological activity. Apart from the bacterial formation of putrescine and cadaverine, both bases have been isolated from ergot. Putrescine further occurs
in Thorn-apple (Datura),
and tetramethyl putrescine in a species of
Henbane (Hyoscyamus
muticus).
Both bases were prepared by Ladenburg in 1886, by reducing the necessary cyanides with sodium in hot alcohol.
Br-[CH 2] x Br
~>
CN-[CH 2] X CN ->
NH
-CH 2 [CH 2] X CH 2 NH 2
The origin who obtained
of both amines was definitely established by Ellinger,* putrescine by the action of putrefactive bacteria oa orni thine and similarly cadaverine from lysine:
NH

Ornithine
NH
[CH 2] 4
NH
Putrescine
NH

Lysine
NH
has
[CH 2] 6 NH 2
from
Cadaverine
Agmatine, guanidinobutylamine,
ergot,
been isolated
and
also obtained
under pressure.
(D331)
On
by heating herring spawn with dilute acid oxidation it yields guanidine and guanidino12
* Zeit. physiol. Chem., 1900, 29, 334.
178

it is
butyric acid, and

ation:
2
probably derived from arginine by decarboxyl-
NH C(:NH) NH [CH NH NH C(: NH) NH [CH CH(NH )COOH

2] 4
Agmatine
Arginine
2] 3
Kossel* has synthesized agmatine from cyanamide and tetramethylene

diamine:
NH CN + NH
2
[CH 2] 4NH 2
= NH
C[:NH]
NH
HETEROCYCLIC BASES
Glyoxaline, imidazole,
5
t
\"
II
CH
N/
CH
4 3
This compound may be regarded as the parent of several of the heterocyclic bases about to be described, and although it has not been directly obtained as a product of plant or animal metabolism, a short description of this compound appears to be advisable. Glyoxaline was obtained by Debus f as early as 1858 by the action of ammonia on glyoxal. During this reaction a portion of the is converted into formic acid and glyoxal formaldehyde, and the latter combines with ammonia and unchanged glyoxal to give glyoxaline:
CHO
+
NH
CH + CILO ||
Nil
\CH + 3 H
CH - N
CHO
NH
Glyoxaline may best be obtained by the action of ammonia on a mixture of formaldehyde and dinitrotartaric acid,J followed by elimination of carbon dioxide from the resulting glyoxaline dicarboxylic acid at 300.
In this reaction diketosuccinic acid
is
pre-
sumably formed:
HOOC-CO
NH
+
HOOC-C-NH
+ CH
2
->
HOOC-CO
NH
HOOC-C-N
^CH
HC-NH ^CH HC-N

I!
* Zeit. physiol. Chem., 1910, 68, 170. f Ann., 107, 204. J Maquenne, Ann. Chim., 1891, 24, 528; Fargher and Pyman, Trans., 1919, 115 f 217.
HETEROCYCLIC BASES
Glyoxaline forms
solution
reacts
thick,
179
colourless
silver
alkaline.
The
salt
prisms, and an aqueous is insoluble in water.
Ordinary reducing agents have no action on the base. With hydrogen peroxide, glyoxaline is oxidized to oxamide, while potassium permanganate gives formic acid. The glyoxaline nucleus has been the object of special study by Pyman and Fargher.* It is interesting to note that Windaus and Knoop f have obtained
4 (or 5)-methylglyoxaline by the action of zinc ammonium hydroxide on glucose and other monosaccharoses. In this reaction it is assumed that methylglyoxal and formaldehyde are formed as intermediate
products:
CFLCO
NH
NH
CH C - NH
3
CHO
The
formation
HC - N
derivatives
of glyoxaline
from
the
a-amino
derivatives of aldehydes, acetals, or ketones with the aid of the thiocyanates is a reaction of considerable importance. This reaction
was
discovered by Wohl and Marckwald, J and by the synthesis of 4 (or 5)-methylglyoxaline.

first
3
may be illustrated
CH CO
CH,NH 2
H CS
CH CO HUN
3
CH CO
3
HoN
"/^S
or
(i)
NH - C CH
-
/C
'
S S
'
'
CH
(iii)
t Ber.,
Trans., 1919, 115, 217, 1016; Fargher, T., 1920, 117, 668; 1905,88, 1166. % Ber., 1889, 22, 572, 1353-
1921, 119, 158.
i8o

is
Aminoacetone
condensed with potassium thiocyanate to give the On warming with hydrochloric or sul(i). On treatment phuric acid, mercaptoglyoxaline (ii) is obtained. with warm dilute nitric acid 4 (or 5)-methylglyoxaline (iv) is formed > This reaction possibly through the intermediate disulphide (iii). has been used extensively in the synthesis of glyoxaline derivatives.
substituted thiourea
N-alkyl- or aryl-glyoxalines are obtained when the alkyl- or arylisothiocyanates are used instead of potassium thiocyanate.
Histamine, 4-/3-aminoethylglyoxaline, jS-iminazoylethylamine. In 1910 Ackermann * obtained a large yield of this base by
the putrefaction of histidine (p. 160).
A little later Barger and and simultaneously Kutscher,J obtained the same base Dale,f The physiological activity of this base is very from ergot. pronounced, and in minute doses it produces chronic contraction
of the uterus.
Histamine was
first
obtained synthetically by Windaus and
Vogt. purpose glyoxaline-4-propionic ester (i) was converted into 4-/?-aminoethylglyoxaline (ii) by Curtius' method:
For
this
CH-NH N
II
CH-NH N in
Hydrazine
hydrate
CH-NH N CH
I!
I
CH
HNO.
CH
CH CH
CH,
CH,
B
OOC,H
r ONHNH,
ii
CO.N/*
CH-NH
1
CH-NH
C
Acids
k
C
CH,
-*
Alcohol
CH CH
CH
NH-COOC H
2
NH
(ii)
* Zeit. physiol. Chem., 1910, 65, 504. J Zeit. Physiol., 1910, 24, 163.
t Trans.,
1910, 97, 2592.
Ber., 1907,40, 3691.
BASES DERIVED FROM TRYPTOPHANE
181
This method is tedious and expensive, and a more satisfactory method was devised by Pyman.* For this purpose 4 (or 5)-chloromethylglyoxaline
(i)
is
converted into the corresponding cyanide

to histamine.
and reduced by sodium and alcohol
CH - NH
CH - NH
CH - NH
>CH N
CH
2
^
'
C1
(i)
>CH N CH CN
II
>CH N CH -CH NH
||
(ii)
the lower homologue of histamine, was synthesized from glyoxaline-4-acetic acid by a similar method to that which Windaus and Vogt employed for the synthesis of
4-j8-aminomethylglyoxaline
(i),
be obtained from diamino-acetone by means of the mercaptan reaction already described (p. i6i),f but the base is almost devoid of physiological action. Ewins J synthesized 4-methyl-j8-aminoethyglyoxaline (ii), and found it to be someStill more what less powerful than 4-^-aminoethylglyoxaline. have prepared 4-j8-methylaminorecently Fargher and Pyman but its physiological action is weak. cthylglyoxaline (iii),
histamine.
It
may
also
CH - NH
C(CH 3 )
N CH NH
2
2
2
NH
N
CH - NH
C
2
2
CH
CH
2
CH NH
(i)
CH NH-CH
(iii)
(ii)
BASES DERIVED
Indolethylamine
FROM TRYPTOPHANE
Tryptophane, un(3-j9-aminoethylindole). heat. like tyrosine, cannot be decarboxylated by Indolethylamine was obtained by Ewins and Laidlow both synthetically and by the action of putrefactive bacteria on tryptophane. The synthesis,
||
** was carried out along the lines subsequently described by Ewins of the well-known phenylhydrazone method for the synthesis of Indole derivatives. ff The requisite aldehyde could not be isolated
*
Trans., 1911,99,668. Trans., 1921, 119, 734.
f Ber.,
||
1911, 44, 1721.
Proc., 1910, 27, 343.
**
J Trans., 1911, 99, 2052. Trans., 1911, 99, 270.
ft Fischer, Ann., 1886, 236, 137.
182
in the free state, so the corresponding acetal was employed. Phenylhydrazine was condensed with y-aminobutyrylacetal in the presence of zinc chloride, and the base isolated as
its
picrate:
CH iCH-CH2NH 2
NH-NH2
OCH;CELNEL Z 2
NH +2C H OH
3
2
NH
Indolethylamine produces a transient stimulant effect upon the central nervous system, and acts as a direct stimulant on plain muscle.*
Scatole (/8-methylindole). Scatole was isolated from human It represents a further stage of putreby Brieger in 1877. factive decomposition in which decarboxylation and deaminization
faeces
are succeeded
by
partial oxidation of the side chain of tryptophane.
by Dunstan f and by Herter J from the wood of Celtis reticulosa, which grows in Java and Ceylon. Methylindole is readily obtained by the action of zinc chloride on the phenylhydrazone of propionaldehyde:
Scatole has been isolated
r
_
NH
CJH]CH S
CH
NH,
NH
or by the action of methyliodide on magnesium indolyliodide:
j|
NMgl
Magnesium
Indole.
N-CH,
NH
by the action of mag-
indolyliodide is readily obtained nesium alkyliodides on indole.
In the formation of indole complete oxidation of the side chain of the tryptophane molecule has occurred.
*
Laidlow, Biochem.J., 1911, 6, 141. J y. Biol. Chem.> 1909, 5, 489.

||
f Proc. Roy. Soc., 1889, 46, 211.

Fischer
i,
(loc. cit.).
Oddo, Gazz., 1911, 41,
229.
THE BETAINES
Indole was
either
first
183
obtained by Baeyer by distilling with zinc dust,
by with tin and hydrochloric acid. It is conveniently reducing indigo prepared by the reduction of indoxyl, obtained by heating indoxylic acid with sodium-amalgam or zinc dust.*
product
oxindole,
C H4
<^^ ^)CO,
or
the
obtained
C(OH)
C(OH)
CH
->
C 6H 4
<^
NH
^C-COOH
~+
C 6H 4
<^
yCH NH
C H4
6
\ /CH
Nil
Indoxylic acid
Indoxyl
Indole
distilling 0-nitro-
Baeyer and Emmerling f obtained indole by cinnamic acid with caustic potash and iron filings:
CH / NO
6
CH CHCOOH
:
CH
->
CH <^ yCH
4
C0 +
2
Oo
NH
o-Nitrocinnamic acid
Indole.
Indole
is
said to be obtained
when
of dichlorethylether and aniline
is distilled
the condensation product in steam.
CH C1-CHC1-O.CH CH +
2
2
2C 6 H 5 NH 2 ->
C 6 H N:CH.CH 2 .NH-C 6 H,
6
Dichlorethylether
CH -> C H <( >CH + NH 3

6
Ethylidene dianiline
NH
Indole
THE BETAINES
amino acids in which the nitrogen atom is directly attached to two methyl groups. They may be classified as a, j8, or y compounds according as they are derived from a, j8 or y amino acids. Willstatter J has made a detailed of the study betai'nes, and has shown that the a betai'nes and the isomeric esters
betai'nes are
3
The
of dimethylamino acids are interconvertible:
CH
I
N\
/CH
COOCH 3
^rla
^> <
c
I
_J
_ N CH \ CH )
i
X CH
^
3 3
This change only proceeds from left to right in the case of the betaines of j8 and y amino acids. The a betai'nes differ considerablj
*
Ber., 1904, 37, 1134.
f
Ber., 1869, 2, 680.
J Ber. y 1902, 35, 584.
184
in stability and are so unstable that they cannot be formed by the ordinary process of methylation e.g. aspartic acid, when treated
;
with methyliodide and fumaric acid.
alkali,
breaks
up
into trimethylamine
and
When the beta'ines
are dried above 100
their composition corre-
sponds to the cyclic anhydride structure. Many of the beta'ines crystallize with one molecule of water, and in this condition their
constitution
is
best expressed
by the open-chain formula.
CH - N(CH
2
|
|
3) 3
,
Betaine f trimethyglycine,
from Lycium barbarum
was
first
isolated
V./V-/
v-J
in 1863, It has been found in all species of Chenopodiaceae so far examined, including the sugar beet (Beta In the manuvulgaris), from which the compound derives its name.
and
facture of beet sugar most of the betaine remains in the molasses, " after desaccharification the final liquor, called Schlempe ", is
very rich in betaine. Betaine was first obtained synthetically by Liebrich by the action of monochloracetic acid on trimethylamine.
Cl
O
-> (CH 3 ) 3 N<^ ^>CO
2
<CH 3 ) 3 N + CH 2 C1COOH -* (CH 3 ) 3 N/
CH COOH
The same
CH 2
product was obtained by the methylation of glycine by Griess in 1875,

In a combined form, choline is probably present in every living cell. Choline enters into the composition of the phosphatides (p. ,104), and it may be considered as the fundamental unit or " *' of the phosphatides. Bausteine
Gholine (trimethyl
j8
hydroxyethyl
ammonium
hydroxide)
(CH 3) 3 :N/ X CH
/OH
2
CH OH
2
was discovered by Strecker in 1849. It is most readily obtained by hydrolyzing lecithin with baryta and subsequently precipitating the base with alcoholic platinic chloride.
choline has been effected in a variety of ways,
The synthesis of among which may be
mentioned:

i,.
185
in aqueous
The
action of trimethylamine
on ethylene oxide
solution (Wurtz, 1867):
(CH 3 ) 3
2.
N+
CH,
|
CH/
>0 + H O
a
(CH 3) 3 :N<; X
CH 2 CH OH
2
the action of trimethylamine on ethylene chlorhydrin, and subsequent decomposition of the chloride of the base with silver oxide *
By
(CH 3 ) 3 N
CH,Cl
CH OH 2
->
(CH 3) 3
:
/Cl
(CH 3) 3
N< CH CH OH X 2
2 2
/OH N/ X CH CH OH
2
According to Ewins,f acetyl choline

[(CH 3 ) 3 N(OH)
is
CH
CH
O CO CH ]
3
present in small quantity in some ergot extracts. The physiological action of a number of esters and ethers of choline has been
studied by Dale.
is prepared from kephalin (a phosfrom the brain) in a similar manner to that by which choline phatide It has been synthesized by Knorr by the is obtained from lecithin. action of ammonia on ethylene oxide:
Amino -ethyl Alcohol
NH +
3
CH. CH,OH >0 = CH NH CH/

i i
Neurine (vinyltrimethyl-ammonium hydroxide)

(CH 3) 3 N<"
:
:CH 2
occurs as a product of putrefaction and was isolated by Brieger in 1885 from putrid meat. Its structure is determined by its relation
to choline,
and by
bromide.
stances
The
yields
its synthesis from trimethylamine and ethylene condensation product obtained from these subneurine on treatment with moist silver oxide
(Hofmann, 1858):
/Br
(CHy^N/ x
Neurine
*
CH -CH
2
+ AgOH - (CH
2
/Br
3) 3
Br
;N<N
CH:CH 2
its
+ AgBr+ H O
2
a powerfully toxic compound, and in action resembles choline.

is
physiological
Renshaw,^. Amer. Ghent. Soc. 1910, 32,

t
128.
f Biochem.J., 1914, 8, 44.
i86
CREATINE AND SOME ALLIED SUBSTANCES

Creatine was first described by Chevreul in 1835, and was studied by Liebig in his classical investigation of the constituents of muscle juice. It is a constituent of all vertebrate muscle, and is
found in the juice of
hydrolysis with baryta
flesh to the extent of
it is
about 6 per cent. On converted into sarcosine (methylglycine)
and urea:
/-'ITT
C OOH
C(:NH)NH 2 +
Creatine
HO =
2
CH .NH-CH 3
2
!
COOH
Sarcosine
+ OC/ X
/NH 2
NH
Urea
In 1868 Volhard synthesized creatine by the action of cyanamide on

sarcosine in alcoholic solution at 100:
CH NH CH 3
2
.
COOH
of the urine of
+ CN-NH, =
CH, N< " X
/CH 3
C(:NH)NH 2
COOH
Creatinine is absent from muscle but is a normal constituent mammals. It may be obtained from creatine by the
action of heat or dehydrating agents:
CH
|
N/ X
C*TT 3
COOH
The
reaction
C(:NH)NH 2
CH N(CH CO
2
|
Creatine
3) 2) 2 ,
:
C NH
:
I
NH
alkalies.
Creatinine
creatine
may be reversed by the action of and Creatinine occur in cereals.
Both
Guanidine,
lings
HN
C/
/NH XNH
is
2
,
has been isolated from Vicia seed-
by Schultze.
It
most conveniently prepared by heating

2) 2
ammonium
thiocyanate:
aNH 4 SCN -* aCS(NH

More
->
NH C(NH
:
HCNS + H
Thiourea
Guanidine thiocyanate
Werner,* diamide and
recently guanidine thiocyanate has been obtained by in a 90 per cent yield, by heating a mixture of dicyano-
thiocyanate at 120. The first phase of probably the depolymerization of dicyanodiamide, the guanidine salt being formed by the union of cyanamide and
this reaction is
ammonium
ammonium
thiocyanate thus:
-
CN NH + NH HSCN = HN C(NH )HSCN

2
* Trans. , 1920, 117, 1133.
THE
(o-AMINO ACIDS
187
Guanidine is a very soluble, deliquescent, crystalline base which absorbs carbon dioxide freely, forming a carbonate.
Methylguanidine,
of muscle.
H N Cf N
2
*NH
NHCH 3
is
normal constituent
creatine, or
It may be obtained by the oxidation of from cyanamide and methylamine: synthetically
NH CN + NH CH
2
X - HN C< N
:
NH NHCH
2
Methylguanidine
Werner and
Bell * have prepared methylguanidine hydrochloride
by heating a mixture of dicyanodiamide and methylammonium chloride for three hours at 180.
THE co-AMINO ACIDS

which have been described in the previous chapter contain the amino group in the a position, and the basic ammo group is more or less neutralized by the presence of a carboxyl group attached to the same carbon atom, so that only the diamino acids are basic. When the amino group is not in the a position the basic character is more pronounced, and the so called co-amino acids are weak bases. These amino acids can be precipitated by phosphotungstic acid. The y, 8, and e amino acids are so weakly acidic that they do not form copper salts. The occurrence and synthesis of a few of these substances may be briefly considered.
acids
The monoamino
j8-Alanine, jS-aminopropionic acid, 2 -CH 2 -CH 2 *COOH. This substance was first obtained synthetically by Heintz in 1870
NH
by the action of ammonia on jS-iodopropionic acid. It may be obtained by the reduction of cyanacetic acid with zinc and
phuric acid.
It is best
alkali
2
also
sul-
prepared synthetically by the action of bromine and

reaction):
on succinimide (Hofmann's
CH - CCX >N-Br CH - CCK

I
CH
->
2
I
C(:NBr)OK
CH
|
COOK
:
CH N
a
CBr(OK)
CH NH
2
CH COOK
*
Trans., 1922, 122, 1793.
-*
CH COOK
2
i88
y-Amino-fl-butyric Acid, NH 2 CH 2 This acid is produced in putrefaction by the

-
Alanine was first isolated from Liebig's extract of meat by Since it is obtained from the meat base carnosine by Engeland. hydrolysis, it is doubtful if /?-alanine is present as such in muscle.
CH 2 CH COOH.
-
partial decarboxylation
of glutamic acid:
COOH CH(NH
2)
CH
CH COOH = NH CH
2 2
CH
CH COOH + CO
2
y-Amino-w-butyric acid has been synthesized from y-chlorobutyronitrile, C1CH 2 CH 2 CH 2 CN, by means of the phthalimide
reaction (p. 147).
It
may
also
be obtained by the oxidation of piperidine urethane
by
nitric acid;
\NH+ClCOOC2 Hg->/
''^N-COOCjH^NH-CHjCHfCHjf
COOH
3-Amino-w-valeric Acid, 2 (CH 2 )4 COOH. This acid was obtained by E. and H. Salkowski in 1883 from putrefied muscle and fibrin. During putrefaction it may be obtained by partial
deaminization of ornithine:*
NH
NH
+ zH - NH
(p. 157):
[CH 2] 3 CH 2 COOH
+ NH 3
or by the reduction of proline
CH
CH C CHCOOH + aH - NH
\/
[CH 2] 4 COOH
NH
obtained synthetically by hydrolysis of the oxidation product of benzoyl piperidine with potassium permanganate: f
It
first
was
OCH
N-CO-CA H R 5 6
COOH
2
6 g
* H.C'C 2
\cHjCH -NHCOC H
It
may
also
be obtained synthetically by a combination of the
phthalimide and malonic ester reactions. J /Mminazoylpropionic Acid. By the putrefaction of histi* Ackermann, Zeit. BioL, 1911,5?, 104; Neuberg, Biochem. t Schotten, Ber. 9 1884, 17, 2544; 1888, 21, 2240. j Gabriel, Ber. 1890, 23, 1767; 1891, 24, 1364.
y
Zeit.,
1911, 37, 490.
THE
co-AMINO ACIDS
189
dine hydrochloride a small quantity of this acid, together with much iminazoylethylamine, is obtained. The acid may be obtained synthetically
by the
action of
ammonia and formaldehyde on
/?-glyoxyl-
propionic acid:
HOOC CH CH CO
2
CHO
+ 2NH 3 + CHoO
HOOC
CHo CH 2 C
-
NH
CH~N
j8-Glyoxylpropionic acid with water.
acid
is
obtained
by
boiling
dibromlevulinic
Carnosine.
rise to jS-alanine
This is probably the base in muscle which gives on hydrolysis. Next to creatine it is the most
extract.
abundant base in meat
The
constitution
its
of carnosine as
by and Tutin *
:
established
synthesis from
j8-alanylhistidine histidine methyl ester
has
been
by Barger
NH-CH. >C CH CH COOCH + C1COCH CH NO CH = W

|
(3-Nitropropionyl chloride
->
NH-CH. >C CH CH COOH CH = NNH CO CH CH NH

|
REFERENCES.
The Simpler Natural Bases, by G. Barger: Monographs on Biochemistry (London, 1914). Biochemisches Handlexikon, Band 5, by Abderhalden (Berlin, 1911).
* Biochem. J. y 1918, 12, 402.
CHAPTER
IX
Bases
The Pyrimidine and Purine

Introduction.
alchemists were familiar with the peculiar concretionary conglomerates of urinary deposits known as urinary calculi, and it was from this source that Bergmann obtained uric
The
Almost contemporaneously, Scheele obtained the " which he termed lithic acid ", from human urine. acid, In 1838 Liebig and Wohler published the results of their investigation of uric acid in which they showed that it yields a large number of compounds which may be grouped together as derivatives of In view of the state of chemical theory alloxan and parabanic acid. at the time, these investigations must be regarded as classical. The study of these compounds was continued by Baeyer, and his results, published in 1863 and 1864, not on ty embraced the
acid in 1776.
same
synthesis of pseudo-uric acid, but also prepared the way for the subsequent discovery of the structure and synthesis of uric acid
and the
xanthine or purine bases. Emil Fischer published the results of his investigation of caffeine in 1882, and this work ultiallied
mately led to the synthesis of uric acid, several xanthine bases, and purine the parent substance of these compounds. With the modern development of biochemistry the pyrimidine and purine derivatives have acquired a new significance, and the
relation of the bases to these nucleic acids
and nucleoproteins may
be
briefly considered.
The Nucleoproteins and Nucleic Acids.
The
nucleo-
proteins are widely distributed in the animal and plant kingdoms, and are found in especially large amounts in glandular tissues such The nucleoproteins as those of the thymus, pancreas, and spleen.
are combinations of proteins with phosphorus-containing substances known as nucleic acids. Under the action of the gastric juice or of weak acids nucleoproteins lose a portion of their protein content,
and are transformed into a rather ill-defined class of substances known as nucleins which still possess some protein in combination
190
THE PYRIMIDINE AND PURINE BASES

with the nucleic acid molecule.
191
Through the action of pancreatic or further acid hydrolysis the remainder of the protein is split juice off and the nucleic acid set free.
Nucleoprotein
(gastric digestion)
Protein
Nuclein
(pancreatic digestion)
Protein
Nucleic acid
The
nucleic acids probably comprise but two substances
animal
is
is
nucleic acid and plant nucleic acid. Animal nucleic acid readily prepared from the thymus while plant nucleic acid
most
con-
Nucleic acids readily undergo veniently obtained from yeast. further hydrolysis by means of enzymes (" nucleases ") present in
most animal
tissues.
On
complete hydrolysis the nucleic acids yield
phosphoric acid, or carbohydrate derivative. The nucleic acids are not, however, simple substances whose molecules contain a single phosphoric acid,
purine and pyrimidine bases, and a carbohydrate
purine or pyrimidine group, and carbohydrate, but are apparently combinations of several radicles each of which contains these three compounds. Yeast nucleic acid is regarded as a combination of
four nucleotides in which two pyrimidine and two xanthine bases are present:
HO O=P O C H O C H ON
5 8
(guanine)
\ O==P
O C H 8O S C H N
6 6 4
(adenine)
O CH
6
C 4H4 C 4H
3
(cytosine)
0=P O C H HO
5
(uracil)
Yeast nucleic acid
simpler form of nucleic acid yields phosphoric acid, ribose, and guanine on hydrolysis, and has been termed guanylic acid. Inosinic acid is a similar compound which gives phosphoric acid, ribose, and
hypoxanthine on hydrolysis.
Levenne and Jacobs regard these
IQ2
substances as mononucleotides and represent them by the formulae:

N
(HO) 2P
O CH CH CHOH CHOH CH C H 4 ON
,
(guanine)
Guanylic acid
o
(HO) 2 P
O CH
CH CHOH CHOH CH C H ON 4
-
(hypoxanthine)
Inosinic acid
Under certain conditions partial hydrolysis may take place, in which case phosphoric acid is split off, and the compound of sugar and base For example, guanosin is which remains is called a nucleoside.
guanine-rf-riboside. Plant nucleic acid contains a pentose group, while animal nucleic acid contains a hexose. Both types contain the purine bases, adenine
and guanine, and the pyrimidine base cytosine. Uracil and thymine occur in plant and animal nucleic acid respectively. Nucleic acids from a variety of sources have been studied, but in no case have hydrolysis products other than those obtained by Kossel and his pupils from thymus and yeast nucleic acids been observed. These hydrolysis products may be tabulated:
HYDROLYSIS PRODUCTS OF NUCLEIC ACIDS
Origin. Laevulinic acid. Phosphoric acid.
Of Animal
Of Plant
.... .... .... .... .... ....
Origin.
(d-ribose). Phosphoric acid,
A Pentose
Guanine. Adenine. Cytosine or Uracil.
Guanine. Adenine. Cytosine or Uracil.
Thymine.
Thymine.
PYRIMIDINE COMPOUNDS
N = CH CH HC N - CH
I
I
1-6
25
I I
I
II
II
3-4
I
HN - CH H C CH II HN - CH
1
I
Pyrimidine (i.*3-diazine)
Pyrimidine hexahydride
HN - CO
OC
HN - CO
2
CH
HN - CO
Barbituric acid
(2H:6-Trioxopyrimidine hexahydride)
-c:r~~~ OC - C:NOH HN - CO
Violuric acid
(5-Oximino-2:4:6trioxopyrimidine hexahydride)
HN - CO IICHNH OC HN - CO
"
HN - CO
2
OC
C(OH) 2
HN - CO
Alloxan
(5-Dihydroxy-2:4:6trioxopyrimidine hexahydride)
Uramil
(5- Ami no- 2:4:6-11-10x0-
pyrimidine hexahydride)
PYRIMIDINE AND SOME OF ITS DERIVATIVES 193 HN - CO HN - CO HN - CO N = C NH 2
OC
CHOH
OC
CH
OC
C CH 3
OC
CH
HN - CO
Dialuric acid
(s-Hydroxy-a:4:6trioxopyrimidine hexahydride)
HN - CH
Uracil
(a:6-Dioxypyrimidine
tetrahydride)
HN - CH
Thymine
(s-Methyl-2:6:dioxypyrimidine tetrahydride)
HN - CH
Cytosine
(6-Amino-2-oxypyrimidine)
PYRIMIDINE AND SOME OF ITS DERIVATIVES

Before discussing the naturally occurring pyrimidine derivatives, pyrimidine itself and a few of its simpler derivatives may be considered on account of their relationship to the purine compounds. Pyrimidine (i:3-diazine), C 4 4 2 the parent substance of the
HN
pyrimidine bases, has not been found among the decomposition products of the nucleic acids. The constitutional formula of this base is shown in the tabulation on p. 192, as well as that of a number of bases which may be considered as derivatives of pyrimidine or
its fully
saturated hexahydride.
is
:
most conveniently prepared from barbituric acid as follows/* Barbituric acid is converted into 2 4 6-trichloropurine on treatment with phosphorus oxy chloride, and on reduction of this compound with zinc dust and hot water, pyrimidine is obtained:
Pyrimidine
:
NH - CO
CO
IICH
NI!
CC1
->
C1C
CH
CC1
II
->
NH - CO
Barbituric acid
N-
N - CH HC CH N = CH
II
II
Trichloropurine
Pyrimidine
Pyrimidine
to a
is
a colourless oil
which slowly
20 solution is neutral to litmus, and gives a white precipitate with mercuric chloride (C4 4 2 -f HgCl 2 ), a yellow compound with AuCl 3 ), and a picrate with picric acid gold chloride (C4 4 2
crystals, melting-point
mass of fibrous
crystallizes at zero Its aqueous to 22.
HN
).
HN + H4 N 2 + C 6 H3 N 3 (C 4
7
Barbituric Acid (malonyl
urea),
C 4 H4 N 2 O 3
was
first
obtained
by Baeyer during the course of his researches on the constitution It may be synthesized by the condensation of of uric acid.
Gabriel, Ber., 1900, 33, 3666; Emery, Ber., 1901, 34, 4180. (D331)
13
194
malonic acid and urea in the presence of phosphorus oxychloride: *
NH
CO
NH
HOOC CH + HOOC
NH - CO
2
- CO
2
CH
aH 2 O
NH - CO
Barbituric acid
note that Veronal, one of the most valuable
synthetic hypnotics,
prepared by of sodium ethoxide, or by the action of urea on diethylmalonyl

chloride:
closely related to barbituric acid, and may be combining diethylmalonic ester with urea in the presence
is
COOC H
2
NH
+ CO
CO - NH
(C 2 H 5 ) 2 C
(C 2 H 5 ) 2 C
CO + 2C H OH
2 5
COOC H
2
NH
CO - NH
Veronal
COC1
(C 2H 5 ) 2 C
NH
+ CO
CO - NH
(C 2 H 5 ) 2 C
CO +
2HC1
COC1
NH,
CO - NH
,
Violuric Acid (isonitrosobarbituric acid), C4 H3 N3 O4 may be conveniently obtained by the action of hydroxylamine on alloxan (p. 195), and also by the action of nitrous acid on barbituric acid. In the latter case the nitrous acid attacks the methylene group of
the barbituric acid molecule:
NH - CO
CO
CH
->
NH - CO
Barbituric acid
NH - CO CO C:NOH NH - CO
Violuric acid
Violuric acid and
its salts were extensively studied by Hantzsch the course of his researches on chromoisomerism. during
Uramil (amidomalonyl
urea),
C4 H 5 N3 O3 may
,
be obtained by
the reduction of violuric acid or by boiling thionuric acid with water. The latter was prepared from alloxan by Liebig and Wohler by the
action of
ammonium sulphite and

*
an excess of
9
ammonium
carbonate:
Grimaux, Bull. Soc. chim. 1876, 31, 146.
195
NH - CO
CO
i
NH -CO
+ NH HSO 3
4
NH - CO
2
C(OH) 2
I
-> CO
I
/NH
C<;
|
NH - CO
Alloxan
NH - CO
urea),
x so H
3
-> CO
I
CH-NH
I
NH - CO
Uramil
Thionuric acid
Alloxan (mesoxalyl
manner
C4 H4 O 5 N 2
acid,
is
readily obtained
it
by the
in this
action of strong nitric acid
on uric
and
was obtained
Its constitutional formula as early as 1817 by Brugnatelli. was determined by Baeyer, and it is one of the few organic compounds in which two hydroxyl groups are attached to the same carbon atom.
the action of strong reducing agents alloxan is converted into dialuric acid* (tartronyl ureide), while energetic oxidizing agents transform alloxan into parabanic acid,f probably according to the
By
following scheme:
NH - CO
O
C(OH> 2
NH ~*
/OH
C<
CO
COOH
NH - CO
_^ ""*
CO
NH - CO
Alloxan
NH - CO
:
NH - CO
Parabanic acid
Uracil
(2
6-dioxypyrimidine
by Behrend to a hypothetical substance, the derivatives of which he had obtained during the course of his researches on uric acid. Uracil itself was
(5-methyluracil).
The term
tetrahydride) uracil was applied
and Thy mine
obtained in 1900 by Ascoli J as a product of hydrolysis of yeast Since that time it has frequently been encountered nucleic acid. as a hydrolytic product of nucleic acid from various sources, especially
first
when
the latter
is
hydrolyzed by acids under pressure.
Under
these
circumstances
it is
probably formed by the hydrolysis of cytosine:

2
C 4H 3N 2 0(NH 2) + H
Cytosine
- C H N 0(OH) + NH
4
3 2
Uracil
obtained by the hydrolysis of the nucleic acid from the thymus gland by Kossel and Neumann in 1893, anc^ was soon afterwards obtained from nucleic acid from other sources.
first
Thymine was
obtained hydrouracil by the condensation of acrylic acid and urea, and by the action of bromine in glacial
*
Fischer and Roeder
Liebig and Wohler, Ann., 1838, 26, 276. Biltz, Heyn, and Bergius, Ann., 1916, 413, 68, 76. Ber.> 1901, 34, 3761. j J. physiol. Chem., 1900, 31, 162,
196
acetic acid uracil

on this compound a product was obtained which gave on heating with pyridine:
NH
NH
By
I
HOOC
CH
II
NH - CO
CH
I
NH - CO
2
NH - CO
CO +
2
CH -> CO
I
-> CO
NH - CH
II NH - CH
CHBr -> CO
2
IICH NH - CH
Uracil
(ii)
Hydrouracil
a series of similar reactions
thymine was obtained from methyl-
acrylic acid.
Wheeler and Merriam* found that the sodium derivative of

formylacetic ester
to
(i)
condenses with y-methylthiocarbamide f
form 2-methylthiol-4-oxypyrimidine (iii), from which easily formed by saponification with boiling mineral acid:
uracil is
CH(ONa)
NH
+ CH
3
N
->
2
CH
2
CH
I
CH
COOCoH 5
(i)
NH
(ii)
IICH + NaOH + C H OH HN CO
-
(iii)
NH - CH
->
CO
CH + CH SH
3
NH - CO
Uracil
In a similar way they obtained thymine by using formylpropionic ester in place of formylacetic ester, while acetoacetic ester gave
4-methyluracil,
and methylacetoacetic ester gave dirnethyluraciL Carboxyl derivatives have been prepared by replacing the hydroxyacrylic esters by ethoxylmethylene malonic ester or by formylsucA great variety of pyrimidine derivatives have been cinic ester.
obtained by means of these reactions. J Somewhat later Wheeler and Liddle
found that more
satis-
factory results could be obtained, in the preparation of uracil,
by
using thiocarbamide in place of y-methylthiocarbamide. intermediate 2-thiouracil is quantitatively converted into
The
uracil
when
boiled with an aqueous solution of chloracetic acid.

jf. y
In a
* Amer. Chem.
1903, 29, 480.
f 7-Thiocarbamides are obtained by the action of alkyl halides on thiourea. They are strongly basic and, as a rule, undergo condensations very readily. J For a list of researches on pyrimidine compounds down to 1908 see Amer. Chem. y., 1908, 40, 250. Since that time a large number of papers have appeared, Ibid., 1908, 40, 547. notably by Wheeler, Johnson, and Johns.

similar
for
197
way Wheeler and MacFarlane

in
substituted thiocarbamide
y-methylthiocarbamide thymine, and carried out the reaction in alcoholic solution. The intermediate 2-thiothymine was converted into thymine by boiling with a solution of monochloracetic acid
the preparation of
:
NH - CO
SC
NH - CO
CO
I
II! NH - CH
C-CH 3
i-CH 3
II
NH - CH
Thymine
2-Thiothymine
Uracil crystallizes from water in fine, colourless needles. With diazobenzene sulphonic acid it gives a red solution, while with bromine water and excess of baryta, a purple or violet coloured
and solution are obtained. Thymine crystallizes from water in colourless needles or rosettes which dissolve readily in hot water. With diazobenzene sulphonic
precipitate
acid
gives a more intense red colour than uracil, but it does not behave like uracil towards bromine water and baryta. Like uracil,
it
forming a compound which is precipitated by an excess of this reagent. Cytosine. This base was obtained in 1893 by Kossel and Neumann by the hydrolysis of thymus nucleic acid with 40 per cent sulphuric acid under pressure. The correct constitutional formula was assigned to this base by Kossel and Steudel in 1903.* Wheeler and Johnson f prepared 2-ethyl-thiol-6-chloropyrimidine
it
combines with
silver nitrate,
by ammonia and
dissolved
(ii)
by the action of phosphorus pentachloride on

(i).
6-oxypyrimidine
On
boiling
this
(iii)
substance with
2-ethyl-thiolalcoholic
in turn,
ammonia
the corresponding amide
was formed, which,
was converted
by saponification identical with cytosine:
into
2-oxy-6-aminopyrimidine,
NH - CO
C H S-C
2
5
N =
C 2 H 5 S-C
(ii)
C-C1
N = C-NH
->
CH -
CH
C 2H 6 S C
(iii)
CH
(i)
N = C-NH
->
OC
I
CH
II
NH-CH
*
Zeit physioL Chem., 1903, 38, 49.
Cytosine f Amer. Chem.J., 1903, 29, 505.
198
THE PURINE BASES

vO
\o
199
9
o Y M g a aj
2
vO
rt
Il3
as
S3
o 3
18
co
a'i
(J
as
o 6
O:
1
5
6
ON
N 2
8
3-Dime-
N2
8
7-Dimethyl-
ne
Guanine
H S
Theophylline
(i
thylxanthine),
H 7 C
Theobromine
xanthine),
H 7 C
Caffeine
N 2 O 3 H 8 C (i:
:7-Tri
10
methylxanthi
to
00
200
Cytosine crystallizes in colourless plates containing one molecule of water of crystallization, which it loses at 100. It forms salts
with acids and

acid.
it
is
converted into uracil on treatment with nitrous
With
dilute acidified solutions of potassium
bismuth iodide
It behaves like uracil gives a brick-red crystalline precipitate. towards diazobenzene sulphonic acid or bromine water and baryta,
Cytosine forms an easily crystallizable pier ate.
THE PURINE BASES

the table on pp, 198, 199 it is evident that the purine or xanthine bases may be regarded as derivatives of one parent sub" " stance to which the term purine (purum uricum) was applied Emil Fischer. Purine itself does not appear to be present in by
From
the living organism. Purine has been synthesized by Fischer.* For this purpose uric acid is heated with an excess of phosphorus oxy chloride at 160, when a crystalline compound, trichloropurine, is obtained. This
substance, by successive reduction with hydriodic acid and zinc dust, is converted into diiodopurine and thence into purine.
N = C-OH C NH HO C
N
C
Uric acid
N = C
^
C1C
C - NH
C
N
CI
Trichloropurine
N =
1C
C
C
NH N
N - CH NH HC C %CH ^ N N C
Purine
Diiodopurine
Isay f has carried out a direct synthesis of purine. The starting point is 4-methyluracil, which results from the hydrolysis of the
condensation product of urea and acetoacetic ester. On treatment with nitric acid a nitro group is introduced, and the methyl group is oxidized to carboxyl. On boiling this product 5-nitrouracil is
obtained:
Ber., 1899, 32, 493.
f Ber. 1906, 39, 280.

9
HN - CO
OC
THE PURINE BASES HN - CO

3
201
HN - CO
OC
C-NO 2
CH
OC
C-NO a
->
HN - C-CH
When
HN - C-COOH
5-Nitrouracil-4-carboxylic acid
HN - CH
s-Nitrouracil
4-MethyluraciI
heated with phosphorus oxychloride under pressure, 5-nitro(i), which with ammonia On reduction with gives 2-chloro-4-amino-5-nitropyrimidine (ii).
uracil yields 2:4-dichloro-5-nitropyrimidine
hydriodic acid, 4 is converted into
5-diaminopyrimidine its formyl derivative
(iii)
is
produced.
This
(iv),
which gives purine
when
heated at 210.
N = CH
C1C
IIC-NO
CC1
(i)
N = CH
2
-*>
C1C
II
IIC-NO
C-NH
(ii)
II
N = CH
2
->
HC
II C-NH
C-NH
(iii)
N = CH
HC
C-NH-CHO
The Constitution
of Uric Acid.
As
uric acid
is
found to
break up on oxidation into equimolecular proportions of alloxan and urea according to the equation
C 5 H 4 N4
its
+O +H
- C 4H N
2
+ CO(NH
Urea
2) 2
Uric acid
Alloxan
molecule presumably contains the nuclei of both these substances. Since all four hydrogen atoms of uric acid are replaceable by metals,
probable that these hydrogen atoms are linked to the nitrogen atoms as in the alloxan molecule. That this is actually the case is
it is
proved by the elimination of the whole of the nitrogen as trimethylamine when tetramethyluric acid is hydrolyzed with concentrated
hydrochloric acid at 70. Two formulae have been proposed which agree equally well with the above reactions, the first by Fittig* and the second by Medicus.f
*
Ber., 1878, 11, 1792.
f Ann. y 1875, 175, 236.
202
\ CO CO / HN - C NH
OC
I
I
ORGANIC CHEMICAL SYNTHESIS HN - C NH HN - CO

I
OC
IIC - NH
N
II
HN - C - NH
II
(i)
(ii)
Fittig's formula represents uric acid as a symmetrical arrangement of two condensed pyrimidine nuclei, while that of Medicus consists of a fused pyrimidine and glyoxaline (iminazole) nucleus. Now
Fischer prepared two monomethyluric acids, one of which gave methylalloxan and urea on oxidation, while the other gave alloxan and methylurea. This can only be accounted for by the grouping
proposed by Medicus, and

synthesis.
this
formula has been established by
Synthesis of Uric Acid. Following an observation of Strecker that uric acid could be hydrolyzed at high temperatures with the production of ammonia, carbon dioxide, and glycocoll,
Horbaczewski obtained uric acid by heating urea with glycocoll or with cyanacetic acid. The yield, however, was very small, and the
synthesis gives
little
information as to the structure of uric acid*
In 1888 Behrend and Roosen obtained uric acid by the condensation of isodialuric acid (prepared by a long and complicated process) with urea in the presence of strong sulphuric acid:
HN - CO
OC
I
C OH
NH
.
HN - CO
2
\^
2
OC
C |
NH
C0
HN - C OH
Isodialuric acid
NH
/ HN - C - NH
||
The most
satisfactory syntheses are those discovered
by Emil
Fischer and by
W.
Traube, and these may be
briefly described.
Emil Fischer's Synthesis* had correctly surmised the
early as 1838, Liebig and Wohler relation of uramil to uric acid; but
As
and cyanic acid were unsuccessful. By boiling uramil with a solution of potassium cyanate, Baeyer and Schlieper f obtained the potassium salt of pseudouric acid, but they were unable to dehydrate the resulting acid.
their attempts to unite uramil
*
Ber., 1897, 30, 559.
f Ann., 1863, 127,
3.
HN - CO
OC
2
THE PURINE BASES HN - CO

-
203
CHNH + KCNO = OC CH NH CONHK HN -CO HN - CO

Uramil
Potassium pseudourate
Fischer found that pseudouric acid may be dehydrated to uric by means of molten oxalic acid, or, more simply, by boiling with dilute mineral acids.
acid
HN -CO
OC
HN - CO
C - NH
CH - NH - CONH, _ OC
\ CQ + H
HN - CO
Pseudouric acid
HN - C - NH
Uric acid
This method has been applied by Fischer to the synthesis of various

alkyluric acids and, indirectly, to several of the xanthine bases.
Traube's Synthesis* Cyanacetylurea is first prepared by the condensation of cyanacetic acid or its ester and urea in the
W.
presence of phosphorus oxy chloride, and the product is then converted into 4-amino-2 : 6-dioxypyrimidine by the action of alkalies.
NH - CO
CO
CH 2
2
NH - CO
-*
CO
:
CH
:
NH
By
is
CN
NH - C NH
4-Amino-2 6-dioxypyrimidine
Cyanacetylurea
the action of nitrous acid the hydrogen of the methylene group replaced by an isonitroso group, and the latter on reduction is
transformed into an amino group:
NH - CO CO C:NOH NH - C NH
:
NH - CO
~>
CO
:
C NH 2
2
NH - C NH
:
4 5-Diamino-2 6-dioxypyrimidine
By
the action of chloroformic ester a urethane

is
the sodium derivative of the latter
obtained, and when heated, alcohol is eliminated

is
and sodium urate
is
formed.
Ber., 1900, 33, 1371, 3035.
204
NH - CO
CO
C N tNa)COOC H 5
2
II
NH - CO
_^
CO
C - N Na
II
NH - C NH
bases.
NH - C - NH
Sodium
urate
>
.
This method has been extended to embrace certain of the xanthine

In addition to Fischer's synthetic method, a number of methyluric acids* may be obtained by the direct methylation of uric acid.
For
this
purpose the
silver or lead salts of uric acid
may be
treated
with methyliodide, or they
may be obtained, more conveniently, by
the action of methylsulphate in the presence of dilute caustic soda.f The positions taken up by the methyl groups depend upon the
conditions of the experiment.
The Occurrence and Structure
of the
Purine Bases.
It
has already been pointed out that guanine and adenine are primary hydrolytic products of the nucleic acids, and it would appear that these two substances are the only purine bases obtained as primary
products.
Three other purine bases, hypoxanthine, xanthine, and uric acid, are formed from these by metabolic processes. With the exception of adenine, which was obtained from nucleic
acid
in 1886, all these bases have long been known. In addition, theobromine, which is a constituent of cocoa beans (Theo-
by Kossel
broma cacao), and caffeine, which occurs in small quantities in tea and coffee, were studied by Stenhouse as early as 1843.
The elucidation of the structure of the purine or xanthine bases almost entirely due to Emil Fischer, and the earlier work need not be discussed here. Fischer J made an elaborate study of the degradation products of the caffeine molecule, but as the constitution of this substance has since been established by its synthesis, the
is
story of this
work has
lost
some of its
earlier interest.
of caffeine into dimethylalloxan and methylurea indicates a structure similar to that of uric acid, and ultimately
The decomposition
the constitutional formula
observed that
oxidation,
shown on p. 199 was adopted. Fischer xanthine was converted into alloxan and urea on
and that theobromine was obtained by the action of methyliodide on the lead salt of xanthine, while caffeine resulted from the methylation of theobromine. The conversion of guanine
For the preparation and structure of several of the methyluric acids see E. Fischer (Ber. 1899, 32, 461). t Biltz and Damm, Ann., 1916, 413, 186. J Ann., 1882, 108, 141.
9
THE PURINE BASES

into xan thine,
205
first
by the
action of nitrous acid,
was
observed by
Strecker.
The Synthesis
of the Purine Bases.
The
synthesis of the
purine bases has attracted a number of chemists, but it will be sufficient to review briefly the methods adopted by Fischer and Traube.
Fischer's Methods.
From
purine bases and uric acid, it for the conversion of the latter into the former present themselves:
1.
the close relationship between the is evident that at least three methods
Reduction of uric acid to xan thine and subsequent methylMethylation of uric acid to monomethyluric acid, reduction
ation.
2.
to
further methylation. 3. Further methylation of uric acid to di- and tri-methyluric acids, and reduction of the products to the corresponding methyl-
me thylxan thine, and
xanthines.
A few examples of these methods may be briefly reviewed.

(a)
(i)
By
may
the direct methylation of uric acid, 3-methyluric acid be obtained, and this is converted into 3-methyl-8-chloroxan-
thine
(ii)
by the action of phosphorus oxy chloride.
The
latter
can
be methylated to give 8-chlorotheobromine (iii) or 8-chloroxanthine which are readily converted into theobromine and caffeine (iiifl),
respectively:
NH-CO II CO C-NH >CO CH,N C NH

I
NU-CO
CH N
'
II
^ CO C-NH >CC1
I
II
(i)
(ii)
js
^
3
I
CO NH-CO IIC-NCH II CO CO C-NCH >cci >cci CH N C N CH N C-N

CH_N
3
I
II
!l
(iii)
(iiia)
HN CO
OC
II
|
CH,N
3
C-NCH
II
OC
I
II
CO
g
II
CH N
3
C-N
>CH
CH N
3
C-NCH >CH C-N
Theobromine
Caffeine
2O6
(b) When heated with a mixture of phosphorus pentachloride and oxychloride, i 3-dimethyluric acid (i) yields 8-chlorotheophylline (ii), which on reduction is converted into theophylline (iii):
:
CH N-CO
S
CH N-CO
3
oi C- NH
OC C- NH
CH 3N-CO OC C-NH CN JST-C-N

(iii)
II
CH 3N-C-NH
(i)
CH 3N-C-N
(ii)
>
In addition to purine itself a number of the purine bases may be: obtained from trichloropurine by means of the following reactions:
N
1C
n
NH > OC C NH >CH >CH HN C N N C N

o
l
II
II C
CI
HN
HC1
I
CO
I
Di-iodopurine
Xanthine
C1C
II
C
II
NH
>CC1
*"
HC
||
C
||
N C N
NH >CH C N
CO
C
II
6>Amlao-2:8di.chloropuriae
Adenine
HN
NH;C
Alcoholic
CO
HI
II
HN
I
Ammonia
C NH NH-C >CC1 N C N
NH
>CH
Chloroguanine
Guanine
conversion of trichloropurine into purine has already been described (p. 200).
synthesis of uric acid starting from urea and cyanacetic acid has already been described. The sodium deriva-
The
Traube's Method.
The
THE PURINE BASES

tive of xanthine is obtained
:
207
:
when 4 5-diamino-2 6-dioxo-pyrimi-
dine
transformed into its formyl derivative, by means of formic acid, and the sodium derivative of the latter is heated:
(i) is
HN- CO
oi
P XTW C NH,
,
HN
HN i
CO
C NH CHO
I
HN
v
CO
CN(Na)CHO
2
OC
HN - C-NH
(i)
NH HN - CO
2
HN - C NH
OC
C - N Na
HN - C - N
When dimethylurea is used in place of urea, theophylline is CH 3N - CO CH 3N - CO OC C NH OC C - NH
2
obtained:
CH,N - C NH
This method
is
CH,N -
N
e.g.
/CH
monomethyl-
capable of considerable extension,
urea yields 3-methylxanthine, and guanidine gives guanine. When thiourea is employed and the sulphur ultimately removed with dilute
obtained, while adenine may be synthesized starting from thiourea and methylene cyanide:
nitric acid,
hypoxanthine
is
HN - CO
HS
C - NH,
HN - CO
I I
HN - CO
NH
HC
C C-
HS-C
NH
^>CH
N - C - NH
-C-N
:
-C -N
:
Hypoxanthine
NH
CN
*2
HN - C NH
_
SC
HN - C NH
HNO
2
CS +
2
CH 2
:
SC
C NOH
: :
Reduction
NH CN
HN - C NH HN - C NH N = C-NH N = C NH N = C NH rm C NH FAcid c SC S C NH Oxida- riQ C - NH ? / tion

2
2 2
HN
NH
HN
-N
^ CH
),CH
N
Adenine
-N
208
In addition to the foregoing methods Fischer and Ach * have shown that theophylline, xanthine, and several other purine bases may be obtained by the demethylation of caffeine. Before concluding our study of the purine derivatives it is advisable to
draw attention
to
been customary which condense
to the fact that in all these syntheses it has to start with pyrimidine derivatives or substances
form pyrimidine compounds at an early stage of the synthesis. In view of the suggestion of F. G, Hopkins f that the naturally occurring purine bases originate from histidine (p. 145), it is noteworthy that Fargher and PymanJ proposed to prepare
xanthine by the condensation of 4-amino-glyoxaline-5-carboxylic
acid,
HOOC C - NH
HN C-N
ii
>
elimination
with
cyanic
acid
and
subsequent
of
water.
The
attempted preparation of this glyoxaline derivative was not successful, but it should be remembered that the chemistry of the glyoxaline nucleus has only attracted considerable attention within the last
few years.
SYNTHETIC NUCLEOSIDES AND NUCLEOTIDES

has already been stated that the compound of sugar and base which remains when a nucleic acid is incompletely hydrolyzed is
It
termed a nucleoside.
Several such nucleosides
or purine gluco-
been synthesized by Emil purpose acetobromglucose or an allied compound is condensed with the silver salt of (p. 59) one of the purines in xylene solution. For example, the silver salt of theophylline and acetobromglucose give tetra-acetyl-theophyllineFor the removal of J-glucoside [C 7 H7 O 2 N 4 C6 H 7 O 6 (COCH3 )4 ].
have sides, as they may also be termed Fischer and his collaborators. For this
-
the acetyl groups, this substance, in methylalcoholic solution, is treated with ammonia at o, and the resulting compound crystallized from methylalcohol in vacuo. In this way theophylline- rf-glucoside,
probably having the formula

*
Ber., 1906, 39, 423.
f Trans., 1906, 109, 628.

Fischer and Helferich, Ber., 1914, 47, 210.
J Trans., 1919, 115, 217.
SYNTHETIC NUCLEOSIDES AND NUCLEOTIDES CH N - CO

3
209
CO C - N C H U O CH - C - N> CH N
.
II
is
obtained.
glucosides of hypoxanthine, xanthine, guanine, and adenine have been obtained indirectly from trichloropurine and dichlor-
The
adenine.
purpose it is better to use dichloradenine in place of trichloropurine, because in the subsequent removal of the acetyl groups ammonia reacts with the chlorine in the latter case. The preparation of adenine- ^-glucoside and hypoxanthine-</-glucothis
For
side
is
illustrated
by the equations:
N
rir CIC
==
CC1
N = C-NH
ism NH
n C
C
Aqueous ammonia
CIC
^.J,
J,
CC1
CC1
N
.,
Trichloropurine
Dichloradenine
c u Silver salt and

acetobromoglucose
N =
i
C
i
,-,,/,
CIC
C
(J,
NH N
CH
6
(COCH
3) 4
/'
CC1
-N
Dichloradenine-tetra-acetyl-cf-glucoside
N =
NH
I
C
I
C1C
NH N
C 6H n O 5
PH 4 I
-*
and
N = C NH HC C - N
| |
C 6 H n Os
-N
N-C-N
Adenine-rf-glucoside
Dichloradenine-rf-glucoside
HN0
N = C OH C N HC
II
It
>H N
C.H n O
Hypoxanthine-dT-glucoside
In a similar manner purine galactosides and rhamnosides have been

obtained.*
* Fischer and Fodor, Ber., 1914, 47, 1058; Fischer, Ber., 1914, 47, 1377(DS31)
14
210

The
synthesis of the nucleotides, necessitating of course the introduction of a phosphoric acid radicle, presented considerable
experimental difficulty. Success was eventually achieved by the use of phosphorus oxychloride. When this is condensed with
20 a theophylline-</-glucoside in pyridine solution at of theophylline-rf-glucoside phosphoric acid is obtained.*

[C 7 H 7 2 Purine
residue
good
yield
N C H O HPO
4
6
9 5
2]
2H 2 O
Glucose
residue
Phosphoric
acid residue
The
actual configuration of this
compound has not
yet been de-
termined.
which has been made in the problem of the synthesis of the nucleic acids, and to
results serve to illustrate the progress
These
show
that the achievement of this object will demand an experimental technique of the very highest order.
REFERENCES.
Nucleic Acids, Their Chemical Properties and Physiological Conduct, by W. Jones: Monographs on Biochemistry (London, 1913). Synthesen in der Puringruppe, by E. Fischer (Ber., 1899, 32, 436).
Vegetable Alkaloids,
by A.
*
Pictet, trans,
by H. Biddle (New York,
1904).
Fischer, Ber., 1914, 47, 3193.
CHAPTER X
The
Taken
designate
all
Alkaloids
in its etymological sense, the term alkaloid may serve to organic substances which possess basic properties,
but it is obviously impracticable to consider the many diverse types of organic bases as alkaloids. In recent years alkaloids have been
defined as those organic bases which contain a cyclic nitrogenous nucleus, and which are formed in the organism of the plant. Even this limited definition is too wide for our purpose, since it would
of the bases already dealt with, and in this book we shall consider the term alkaloid to cover those natural organic bases which may be regarded as derivatives of pyrrole, pyridine, tropane,
include
many
norharman, quinoline, isoquinoline, and phenanthrene.
CH
C-
"CH
3
CH,,
HC
NCH CH
HC
2
CHTropano
CH,
NH
Norharman
N
Quinoline
Isoqninoline
Phenanthrene
In 1806 Sertiirner, an apothecary of Hanover, obtained a basic crystalline body from opium, and thus had the honour of discovering the first vegetable base. In 1817 he published a second paper which " bore the title, Ueber das Morphium, eine neue salzfahige Grundlage und die Mekonsaure als Hauptbestandthiele des Opiums ", in which
211
212

definitely characterized
its
he
morphium
as a vegetable
"
alkali
"
and
behaviour with that of ammonia. This paper aroused compared considerable interest, and during the next twenty-five years many
more alkaloids were discovered. These vegetable bases were regarded as substituted ammonias by Liebig and Hofmann, while the latter considered most of them to be tertiary bases; but little further progress was made until the
discovery of pyridine, quinoline, and isoquinoline, and the recognition of these compounds as frequently forming the fundamental skeletons
of
many
of the alkaloid molecules.
coal tar a basic substance,
C9 H
In 1834 Runge obtained from " leucol ", and 7 N, which he termed
between 1846 and 1851 Anderson examined bone oil and isolated a homologous series of volatile bases from it, of which the first " member, of the formula C 5 H5 N, was termed pyridine ". Meanwhile Gerhardt, in 1842, had distilled quinine, cinchonine, and strychnine with solid caustic potash and had obtained an oil which " he termed quinoline ", and which Hofmann showed was identical " leucol ". with Runge's Subsequently several other alkaloids, such as nicotine, conine, piperine, &c., were converted into pyridine or one of its homologues by heating with zinc dust. In a similar way isoquinoline, which was discovered in coal tar by Hoogewerff and van Dorp in 1885, has been shown to be related to papaverine, narcotine, hydrastinine, and berberine. The subsequent progress in the isolation, investigation, and synthesis of the alkaloids has been very rapid, and before the individual
alkaloids are described a short sketch of the occurrence, isolation,
and general
lines of investigation of the alkaloids
may be
considered.
Occurrence of the Alkaloids.
The
alkaloids are not con-
fined to any special orders or parts of plants, but they are specially abundant in the families of Rubiacece, Solanacece, and Papaveracece r and rare in those of Labtatce and Rosacece. As a rule several closely
related alkaloids are present in the
opium
same plant, as, for example, more than twenty individual alkaloids have from which
been obtained. The alkaloids rarely exist in the plant in the free state, but are more frequently present as lactates, malates, citrates, or tannates, or combined with some other acid which is a peculiar
accompaniment of the alkaloid. Extraction of the Alkaloids. The extraction of alkaloids from plants, and their subsequent purification, are frequently operations of considerable difficulty, partly because in many cases two or more alkaloids occur together, and partly because soluble neutral and
THE ALKALOIDS
213
acidic substances, such as the glucosides, sugars, tannins, malic acid, &c., are present in large quantity. As a rule the alkaloids may be extracted by treating the macerated plant or vegetable product
with dilute acids, which convert the alkaloids into soluble salts. The filtered solution may then be treated with soda to liberate the alkaloids, which, being sparingly soluble, are usually precipitated and may be
separated by filtration; if not, the alkaline solution is extracted with ether, chloroform, &c. In a few cases, such as the extraction of nicotine from tobacco, water may be used as the extracting
solvent.
Many of the alkaloids give insoluble precipitates with a solution of tannic, picric, or phosphomolybdic acid, with platinic chloride, or with a solution of mercuric iodide in potassium iodide. These,
and several other reagents, are often used
isolation.
for their detection
and
Investigation of the Alkaloids. The alkaloids contain one or two atoms of nitrogen, rarely more, and are usually tertiary bases. The nitrogen is usually firmly fixed in the molecule, but it
can occasionally be removed as ammonia by the action of strong reducing agents. By the action of alkalies the nitrogen is sometimes removed as methylamine, indicating the attachment of a methyl
group
to the nitrogen
atom
in the molecule.
The
stability of the
atom is greatly diminished by making the element quinquevalent, and this property has been utilized by Hofmann for " exhaustive methylation ". breaking down the molecule by so-ca\led The application of this method to piperidine may be considered as an example. Piperidine is converted into the tertiary base (i), and this forms an additive compound with methyliodide, which gives dimethylpiperidinium hydroxide (ii) on treatment with silver oxide. The latter, on distillation, loses water and gives the unsaturated
cyclic nitrogen
open-chain base
(iii).
NCH
(i)
When this compound is again submitted to a similar series of reactions

and
distilled,
piperylene
(iv),
trimethylamine, and water are formed,
214
the reaction being analogous to the decomposition of tetraethylammonium hydroxide into triethylamine, ethylene, and water.
N(CH3 +H 2
)
CH
(C 2H 6 ) 4 N
OH
->
C 2H 4 +
(C 2
H N+HO
5) 3
The introduction of an acid radicle,

in place of a
e.g.
COOC 2H5
COC6 H 5
,,
hydrogen atom attached
the
readily oxidizable. of benzoylpiperidine (p. 151). in the case
compound
to a cyclic nitrogen atom, renders This has already been illustrated
Von Braun has employed phosphorus pentachloride for breaking down the cyclic structure of several alkaloids;* e.g. benzoylpiperidine
treated with phosphorus pentachloride gives a mixture of benzonitrile
and
5-dichloropentane:
C6 H CN
5
N-COCR H D
More
recently the
C1H 2 C
B
CH C1
2
same author has introduced cyanogen bromide for the same purpose, f When oxygen is present in the alkaloid it is usually in the form of hydroxyl or methoxyl, and occasionally as carboxyl or an ester
group.
remarkable fact that by far the greater number of more methoxyl groups (OCH3 ). The method employed for the estimation of these groups called the Zeisel method depends on the fact that all substances containing
It is a
alkaloids
contain one or
methoxyl groups are decomposed by hydriodic acid, yielding methyliodide and a hydroxy compound in accordance with the general
equation:
n(-OCH 3) + wHI = n(- OH) + nCH 3 I
and by estimating the methyliodide obtained (by conversion into silver iodide), the number of methoxyl groups can be determined, When hydrolysis can be effected it should precede any other process of decomposition. The action of alkalies, zinc dust, and
*
Ber., 1904, 37, 3588.
f Ber. 1916, 49, 2624.

%
215
other reducing agents often yield useful results, but the most valuable information is usually derived by regulated oxidation of the alkaloids*

following alkaloids may be considered as derivatives of pyrrole: hygrine, betonicine and turicine, and stachydrine. Hygrine is found to the extent of about 0*2 per cent in Peruvian cusco leaves, and was isolated from this source by Liebermann in
1889.
It is a liquid, and, like the majority of alkaloids, is laevorotatory.
It is ketonic
The
and a
tertiary base containing a
oxidation
it yields hygric acid, into carbon dioxide and N-methylpyrrolidine.
N-methyl group. On which on dry distillation decomposes
A possible
structure
of hygric acid
is
therefore
HC
2
CH
CH-COOH
HC
NCH
and
this structure
Hygric acid
has been established by
its
synthesis
ester,
2 5) 2]
by the action
of methylamine
on aS-dibromopropylmalonic
[CH 2 Br
by
Willstatter
CH
CH CBr(COOC H
2
and Ettlinger.*
Hygrine has been obtained synthetically by Hess f as follows: pyrrole magnesium bromide reacts with propylene oxide to give
hy droxypropylpyrrole
HC - CH HC
II II
H C - CHCH
2
\/
C-MgBr
\/
O
HC - CH OMgBr HC - C-CH -CH.CH

II
II
NH
HC - CH
->
\/
NH
OH
2
HC
C-CH -CH.CH 3
NH
Hydroxypropylpyrrole
reduction the corresponding pyrrolidine compound is obThe latter is then methylated by the action of formaldehyde, tained.
*
Ann., 1901, 326, 91.
On
t Ber., 1913, 46, 4104.
216

at the
which
same time
oxidizes the carbinol group to the ketone
and
gives y-hygrine:
H C - CH H C - CH CH NH
2
CH(OH) CH 3
+ CH O
2
Hydroxypropylpyrrolidine
H C - CH = H C CH CH COCH
2
2
2
\/
*
+HO
2
NCH
r-Hygrine
and Turicine are respectively the laevo and dextro varieties of a base of the formula C 7 H 13 O3 N. Both bases have been shown to occur in the Betony f (Betonia officinalis). Both these bases have been obtained by KiingJ by the methylation of
Betonicine
oxyproline (p. 145), so that they probably have the constitution:
HO-CH-CH
CH CH-CO
\/
N
3
O
3
CH CH
This formula has Deen recently confirmed by the work of Goodson and Clewer, who obtained 4-hydroxyhygric acid from the bark of Croton gubouga, and on methylation of the acid obtained a mixture of betonicine and turicine:
HO-CH-CH
2
-
CH CH COOH
N CH
4-Hydroxyhygric acid
Stachydrine, C7 H 13 O 2 N, occurs in the leaves of the orange tree and in the tubers of Stachys tuberifera, and was first isolated by von Planta in 1890. This compound is frequently classified as an alkaloid, but Schultze and Trier consider that the base is derived from proline (p. 145). On distillation Stachydrine yields the isomeric
||
* r
racemic. f Schultze and Trier, Zeit. physiol. Chem., 1912, 79, 235. Trans., 1919, 115, 923. J Ibid., 1913, 85, 217. Zeit. physiol. Chem., 1909, 59, 233. ||
THE PYRIDINE ALKALOIDS

methyl ester of hygric acid
is
(ii),
217
this ester
(iii)
transformed into stachydrine
and the methiodide of * (i) on hydrolysis:

ri2C
CH.2
CH-2
3
(i)
(ii)
(iii)

Trigonelline, piperine, conine, and nicotine as four of the simpler pyridine alkaloids.
may be
considered
from the seeds of fenugreek (Trigonella fcenum grcecum) by Jahns in 1885, and two years later he established its constitution by observing that when
Trigonelline,
C7 H7 O 2 N,
was
isolated
heated with hydrochloric acid to 270

acid.
*'
it is
converted into nicotinic
natural product was found to be identical with the " of nicotinic acid previously synthesized by methylbetai'ne
The
Hantzsch.f
CH
Trigonelline
Nicotinic acid
Betame
On
account of the presence of a betame ring, trigonelline may also be considered as a derivative of betame. Piperine occurs to the extent of 5 to 9 per cent in the dried fruits of black and white pepper (Piper nigruni), from which it was
by Oersted in 1819. It is a tasteless, colourless, weak On hydrolysis with base, and has no action on polarized light. alcoholic potash it is converted into piperidine and piperic acid:
first
isolated
C 17 H 19
N+H
= CaHuN + C H 10 O 4
12
Piperidine
Piperic acid
and as Riigheimer J showed that piperic chloride reacts with piperidine

* Trier, Zeit. physiol. Chem., 1910, 67, 324. t Ber., 1852, 15, 1390. f Ber., 1886, 19, 31.
218

may be
regarded as an amide of piperic
to give piperine, the alkaloid acid.
* Piperidine was obtained by Ladenburg by distilling the hydrochloride of pentamethylene-diamine, which in turn may be obtained
from trimethylene-dibromide:
CH
CH
CH 2
2
III
2
Br
CH CN
2
2
CH CH CH
by
CH NH
-
CH - CH
2
->
CH
->
->
Br
CH CN
2
CH
NH
IINH CH - CH
CH
2 2
Piperic acid was investigated
Fittig
and obtained synthetically
by Ladenburg and Scholtz.f
Piperonal condenses with acetaldehyde
in the presence of caustic soda solution to give piperonylacrolein, and this is converted into piperic acid by Perkin's reaction:
CHtCH-CHO
'WCH-CH-.CH-COOH
The complete
formula:
structure of piperine
is
therefore represented
by the
CH
a5;
Ô A
oc
CH
CH
CH
Cl JC CH:CH-CH'-CH-CO
Piperine
Conine, C 8 H 17 N, was first isolated as the free base from hemlock by Giesecke in 1827. Tli e hemlock (Conium maculatwri) contains three principal alkaloids, conine, conicei'ne, and conhydrine, together with smaller quantities of other bases. These alkaloids
are present in combination with malic and caffeic acids.
*
Ber., 1885, 18, 2956, 3100.
t Ber.,
Conine
1894, 27, 2958.
219
was examined by Liebig and Gerhardt, and the correct empirical formula derived by Hofmann in 1881. It is a volatile, oily base, and is extremely poisonous. Hofmann 's work had shown that in all probability conine was a-propylpiperidine. Ladenburg heated and obtained a mixture of bases, one of which pyridine propiodide appeared to be y-propylpyridine, since on oxidation it gave pyridiney-carboxylic acid. These bases were subsequently shown to be
isopropylidene
derivatives.
On
reduction
of
each
compound
with sodium and alcohol he obtained products which resembled In 1886 Ladenburg conine, but neither was identical with it. condensed picoline (a methylpyridine) with paracetaldehyde in sealed tubes with the aid of zinc chloride and obtained allylOn reduction with sodium and alcohol r-conine was pyridine. obtained. The base was resolved by crystallizing its acid tartrate, and the dextrorotatory form, on heating, was identical with conine. This alkaloid which had caused the death of the wisest of men was
the
first
to
succumb
to the synthetic skill of the chemist.
CH:CH-CH 3
N;
cu-Allyl pyiidine
H C\
2
CH-CH- CH- CH 3
Conine was subsequently synthesized by Engler and Bauer.*
By
distilling molecular equivalents of the calcium salts of propionic and picolinic acids they obtained a-ethylpyridyl-ketone, which on complete reduction gave r- conine.
^/ CO C H N
-
oc-Ethylpyridyl-
a-Ethylpyridyl-
r-Conine
ketone
alkamine
Ber., 1891, 24, 2530;
1894, 27, 1775.
22O

Nicotine.
This alkaloid was first isolated from the leaves of the tobacco plant by Posselt and Reimann in 1828. For a long time it was considered to be the only alkaloid present in tobacco, but more * and others have shown that several recently Pictet and Rotschy
closely
related alkaloids
are
present.
The
nicotine
content
of
tobacco varies from 0-6 to 10 per cent, and in general the better grades of tobacco contain the smaller amounts of the alkaloid. Nicotine is a diacid base, and since it forms two isomeric methiodides with methyliodide
it is
also a ditertiary base.
On
oxidation
is
with chromic acid, nicotinic acid (pyridine-j8-carboxylic acid) obtained, so that nicotine is a j8 derivative of pyridine.
N
put forward the correct constitutional formula for nicotine (jS-pyridyl-aPinner
first
CIL
CH,
N-methylpyrrolidine), and the correctness of his view was confirmed by the synthesis of
nicotine
NCH,
Nicotine
by
Pictet, Crepieux,
and Rotschy. f
The Synthesis
of Nicotine.
When
the mucate of jS-amido-
pyridine is submitted to dry distillation, N-jS-pyridylpyrrole (i) is obtained, the reaction being exactly analogous to the formation of pyrrole by the distillation of ammonium mucate:
CHOH CHOH COONH CHOH CHOH COONH

I
CH CH
:
~>
4
CH CH
:
NH + NH
aCO 2
passing the vapours of N-j8-pyridylpyrrole through a tube heated to a dull red heat, an intramolecular change takes place and *aj8-pyridylpyrrole is obtained (ii):
On
N
N
(0
Ber.,
1901,34,696.
t Ber., 1895, 28, 1904; 1904, 37, 2018.
THE TROPANE GROUP

The potassium
nicotyrine (iv)
salt of the latter reacts
221
with methyliodide to give

(iii),
the methiodide of
N-methyl-a/?-pyridylpyrrole on distillation over lime:
which gives
HC
C
CH
CH
3
H P-~9 H x\ I / \ C CH
HC-
NCH all!
"I
(iii)
N-CH
(iv)
The
selective reduction of the pyrrole nucleus could not be accomplished in one stage. The iodo derivative of nicotyrine on reduction
with tin and hydrochloric acid gives dihydronicotyrine, which may possibly have the structure (v). The perbromide of the latter then
The alkaloid was resolved yields /-nicotine on similar reduction. by the fractional crystallization of the tartrate, when the laevo form was found to be identical with the natural product, and much more
poisonous than the dextro form.
THE TROPANE GROUP

Several plants of the Solanaceae family are characterized by the presence in their tissues of some very poisonous alkaloids, which in
chemical properties and constitution closely resemble one These plants are the belladonna (Atropa belladonna), the henbane (Hyoscyamus niger), the common stramonium (Datura
their
another.
stramonium), and different species of the genus Scopolia. The bases which are present have been separated from each other with difficulty,
but the presence of the following alkaloids has been certainly established: atropine, hyoscyamine, pseudohyoscyamine, and hyoscine, which are all isomers of the formula C 17 H 33 NO 3 belladonnine,, C 17 21 2 and scopolamine (atroscine), C 17 21 NO 2 about which
;
H NO
little is
known.
seven alkaloids, atropine, hyoscyamine, and scopolamine are found in all the above plants, while belladonnine has only been found in the deadly nightshade (Atropa belladonna) up to the present.
Of these
Atropine was discovered in 1831 in the roots of the belladonna almost simultaneously by Mein and by Geiger and Hesse. Its chief use in medicine depends upon its action in dilating the pupil and paralysing the accommodation of the eye.
its Allies.
Atropine and
222

On
hydrolysis with acid or alkali
tropine.
it
yields
an acid
tropic acid
and a base
.
Tropic Acid.
acid was derived
These chemists used acetophenone as the starting point of the synthesis, but as the method has been superseded by more satisfactory methods in recent years we need not consider it in detail. M'Kenzie and Wood f convert acetophenone (i) into its cyanhydrin (ii), which on hydrolysis gives atrolactinic acid (iii), and this on distillation under reduced
in
by and Riigheimer by Ladenburg
correct constitutional formula for tropic Kraut, and a successful synthesis first achieved
The
1880.*
On treatment with ethereal hydropressure, atropic acid (iv). chloric acid the chloro acid (v) is obtained, which gives tropic acid (vi) on treatment with sodium carbonate solution:
CeH 5v
CH
>CO -> '
C 6H 5v /OH C 6 H 5x /OH -> >C< >C<
C 6 H 5X
->
3 (i)
CU/ \CN
(ii)
CH/ \COOH
(iii)
CUf
H
>C-COOH
(iv)
C 6H 5
C1CH 2
(v)
H
COOH
C6H5
HO-CHo COOH
(vi)
Tropine. Our knowledge of the constitution of tropine is chiefly due to the work of Ladenburg and Merling, and more recently
to the researches of Willstatter.
Tropine
is
a secondary alcohol
which on oxidation gives the ketone, tropinone. The relation between these compounds is made clear by their respective structural
formulae:
CH
- CH
NCH,
<?H,
CH,
CH-^CH
NCH, CO 3
CHOH
CH
2
CH
Tropine
CH
CH-f- CH 2
Tropinone
synthesis of tropinone by Willstatter J is classical on account of the richness of the field explored. By imaginary hydrolysis of the tropinone molecule at the dotted
lines,
The
succindialdehyde, methylamine, and acetone are obtained,

*
Ber., 1880, 13, 373, 2041. f Trans., 1919, 115, 828. J Ber., 1901,34, 129, 3^3; Ann., 1901, 317, 307, 1903,326,
i.
THE TROPANE GROUP

and Robinson * has succeeded
223
in obtaining tropinone by the condensation of these substances in aqueous solution. An improved yield was obtained when the calcium salt of acetone-dicarboxylic.
was employed instead of acetone. This synthesis is important not only on account of its simplicity, but also by reason of its bearing on Robinson's views on the phytochemical synthesis of the alkaloids.
acid
CH -CHO
2
CH - CHOH
2
CH COOCa'
2
+ NH CH 3
2 2 2
->
CH -CHO CH - CH - CH COOCa'
JL>VJLi3
+ CO CH - CHOH CH COOCa' CH - CH - CH
3
2 2 2 2
NCH
NCH, CO
2 HC1
\-s\~/
NCH CO
X^V^lJLjj 3
V^v-/
CH,
- CH - CH- COOCa'
CH - CH - CH
2
Since hyoscyamine and atropine are stereoisomeric they may be represented by the formula:
CH
CH
3
CH
CgHs
NCH CH-O.CO-CH CH OH CH - CH - CH
2
2
2
According to Gadamer f the tropine in both atropine and hyoscyamine is inactive, and the only difference between the two alkaloids lies in the fact that laevotropic acid is present in the molecule of
hyoscyamine.
The
alkaloids
relationship between tropinone
and several
closely allied
may be
briefly
summarized:
Electrolytic
reduction
Sodium and carbon dioxide
Tropine
With
<
Tropinone
j,
tropic acid
^^
t Arch.
d.
>
Tropine carboxylic acid
I Reduction
r-Ecgonine
4,
Atropine
Pseudotropine
^ Benzoylation
Tropacocaihe
r-Cocaihe
heated with sodium amyloxide it is converted into a tropine identical with the pseudotropine obtained by the
tropine
is
When
*
Tram., 1917, 111, 762.
Pharm., 1902, 239, 294.
224
hydrolysis of the coca alkaloid tropacocai'ne. Tropine and pseudo* have shown tropine are thus isomeric, and Barrowcliff and Tutin rtiat the isomerism is dependent on molecular i.e. it is
asymmetry,
cistrans isomerism.
Cocaine and some Synthetic Substitutes. Cocaine, along with several closely related alkaloids, occurs in coca leaves (Erythroxylon coca), from which it was first isolated by Neumann in 1860. It had long been known that the South American Indians were in
the habit of chewing these leaves as a stimulant. Cocaine is used in medicine usually in the form of its hydrochloride, as a rapid local
anaesthetic.
Cocaine is a tertiary base, and on hydrolysis benzoic acid, and methylalcohol:
it
yields ecgonine,
C 17 H 21 N0 4 + aH 2
The
= C H NO + C H O + CH OH
9
15
preparation of ecgonine from tropinone has already been tioned, and the relation of the former to cocaine is made clear
formulae,
men-
by the
CH - CH - CH COOH
2
NCH 3 CHOH CH - CH - CH
2
2
CH - CH - CH COOCH NCH CH O CO C H CH - CH - CH
2
Ecgonine
Cocaine
account of the fact that cocaine solutions become mouldy on long standing and decompose on boiling, various attempts have
On
been made to prepare suitable substitutes.

of pseudotropine
cocaine.
is
The
benzoyl derivative
known
and
anaesthetic, less toxic
as tropacocctine. It is a stronger local more resistant to micro-organisms than
In 1897 Merling obtained triacetonamine (i) by the condensation of three molecules of acetone with one of ammonia. It is a crystalline
with an ammoniacal and somewhat camphoraceous odour. On hydrolysis of the cyanhydrin, followed by benzoylation and methylation of the resulting acid, a-eucaine is obtained:
solid
(CH 3 ) 2 C
<*CH 3
COCH -* 2 NH * +
(CH 3) 2
II NH CO II C - CH
(i)
- CH
(CH 3) 2 C
II NCH
3
|
CH
/O-CO-C 6 H 5 C<
2
(CH 3 ) 2 C
|\X).OCH 3 CH
Trans., 1909, 95, 1966.
THE TROPANE GROUP

On
225
account of the irritant action of a-eucaine it has been largely Diacetonamine (i) is obtained by the superseded by fi-eucaine. condensation of two molecules of acetone and one of ammonia, and this on further condensation with acetaldehyde gives vinyldiacetamine (ii):
(CH 3 2C[0
)
H N!H+H;CH
2
I
C-CH _^ (CH NH. CO1^HsCHO (CH COCH

3 )2
3
I
3 2
C-CH
I
I
NH CO
2 (ii)
CH
(')
CH S -CH-CH
On
obtained.
reduction to the corresponding alcohol, two isomerides are The higher melting isomeride on benzoylation gives
p-eucaine:
(CH 3) 2 C
CH
NH CHO CO CH CH-CH
3 2
C 6H 5
p-Eucaine
Stovaine
operations.
is
a well-known local anaesthetic for
It is
minor surgical from dimethylaminoacetone as follows: prepared
CH
MgC H
2
Br
(CH 3 ) 2 NCH 2
C 6 H 5 COC1
2
CH
\ c</
OH \ p/ (CH NCH C H 0-COC H

CH
3
3) 2
HC1(CH 3 ) -N-CH 2
C 2H 5
Alypine is similar in constitution to stovaine and is frequently administered along with heroin (diacetyl-morphine), since it enhances the demulcent and sedative effects of the latter:
CH - N(CH C H C - O - COCH CH - N(CH

>
3 2
3) 2
Alypine
Anaesthesine, one of the simplest

(D331)
local anaesthetics, is
obtained
1501
226

ethyl-/>-nitrobenzoate with tin and hydrochloric acid. diethylamino derivative is known as novacame*
by reducing
Its
H2 N/
\COOC, H
N/
\COO
Novacame
Anaesthesine
THE POMEGRANATE ALKALOIDS

The
root bark of the pomegranate contains a
pelletierine
number of
alkaloids,
and theisomericôpelletierine, C 8 H 15 NO, C 9 H 15NO, and the two isomeric methylpelle/tfWflfopelletierine, C9 H17 NO, may be mentioned. Pseudoptlletierme is tierines, interesting because it resembles tropinone and gives rise to an eightcarbon ring on exhaustive methylation. It has been shown that this
amongst which
alkaloid
is
is
a higher
homologue of tropinone.
The
parent
compound
known
as granatinine:
CH - CH - CH CH - NCH CO CH - CH - CH
2
CH - CH - CH
2
NCH CH CH - CH - CH
CH
2
^-Pelletierine
Granatinine
NORHARMAN ALKALOIDS
Harmine and Harmaline. These two alkaloids, which have been the subject of much investigation during the last few years, occur together in the seeds of Peganum harmala. Their respective molecular formulae are C 13 H 12 ON 2 and C 13 H 14 ON 2 Since 1885 O. Fischer and his co-workers have published several papers dealing with harmine, but in view of the fact that the earlier constitutional formulae have been discredited, only the more recent work need be
.
considered.
In 1919 Perkin and Robinson f proposed the following formulae:

For the more recent study of the anaesthetic action of the tropine derivatives see von Braun and Miiller (Ber., 1918, 51, 741). t Trans., 1919, 115, 933.
*
NORHARMAN ALKALOIDS
CH
227
NH CH
Harmiae
CH
CH
NH
By
C-CH,
Harinaline
NH
CH-CH,
the elimination of the methyl, methoxyl, and methoxyl and methyl groups from the harmine molecule, norharmine, harman,
ind norharman or 4-carboline are formed respectively:
CH.O o
NH CH
Harman
Norharman
(4-carboline)
Norharman may
pounds, and
it
therefore be regarded as the parent of these comwill be observed that it contains a fused benzene-
pyrrole-pyridine nucleus.* Harman has been obtained by the oxidation of tryptophane (p. 145) by Hopkins and Cole,f and Spath J has shown that harman is identical with the alkaloid aribinc from
Aratiba rubra.
The
suggestion that harmine
is
a methyl-methoxy-4-carboline
,
has been more recently confirmed by Kermack, Perkin, and Robinson by its degradation to norharman by two separate methods, and the
" * Perkin and Robinson carboline (Trans., 1919, 115, 970) suggest the name for this structure, indicating an analogy both to carbazole and quinoline.
"
11
4JN
12
Thus harmine
is
ii-methoxy-3-methyl-4-carboline.
J
t,7. PhysioL, 1903, 29, 451.
Chem.
Zeit. y 1919, 43, 555.
Trans., 1921, 119, 1602.

(
331 )
15 a2
228
For this purpose i-methylindolesynthesis of the latter compound. acid (i) is converted by the condensation of its chloride 2-carboxylic
with amino-acetal into i-methylindole-2-carboxy-acetalylamide (ii), which, when treated with alcoholic hydrochloric acid, furnishes
5-keto-4-5-dihydroindole diazine (iii), from which norharman (N) is obtained by distillation with zinc dust:
CO-NH CH CH(OC2 H
2
5)
Norharman
also results
formaldehyde in
of the product:
from the condensation of tryptophane with the presence of sulphuric acid followed by oxidation
CfljCH (NH2)COOH
NH
NH CH
NH
THE ISOQUINOLINE ALKALOIDS

group comprise the opium alkaloids papaverine, laudanosine, narcotine, narceme, cryptopine, and protopine, together with the two alkaloids, hydrastine and berberine, which occur in the roots of golden seal (Hydrastis canadensis), and others of less importance. It should be noted that more than twenty alkaloids have been isolated from opium, and in addition the dried sap of the poppy contains resins, gums, sugars, fats, and protein matter. Of these alkaloids the following may be briefly considered: papaverine, laudanosine, and hydrastine. Papaverine. This alkaloid was first isolated from commercial
The
alkaloids of this

narcotine by
229
considerable
Merck in 1848, and number of chemists.

is
it
has attracted the attention of a

is
Papaverine
a tertiary base and
optically inactive.
On
treat-
ment with hydriodic acid it loses four methoxyl groups, while on fusion with caustic potash it gives two compounds, only one of which contains nitrogen. The compound containing nitrogen maybe oxidized to metahemipinic and cinchomeronic acids, which
prove that
it is
dimethoxy-isoquinoline:
CH 3 0/ CH 3 Ok
/S
VN X ;N
X
CH^/NcOOH
m-Hemipinic
acid
HOOCr^^N
Cinchomeronic
acid
Dimethoxyisoquinoline
The product
since
it
nitrogen is dimethyl-homocatechol, gives dimethyl-protocatechuic acid on oxidation:
containing no
COOH
OCH OCH 3
\yOCH
OCH 8
acid
Dimethylhomocatechol
Protocatechuic
Papaverine
is
represented by the formula,
CH Of CH 3
3
OCH OCH
3
Papaverine
and the correctness of
this structure has
been confirmed by the
complete synthesis by thesis may be briefly represented as follows:

* C.
r.,
Pictet
and Gams.*
The
steps in this syn-
1909, 149, 210; Ber., 1909, 42, 2943.
230

Vanillin
Veratrol
(CH 3 0)(OH)C
I
H 3 CHO
(CH 30) 2 C 6 H 4 I
Acetoveratrone
Methylvanillin
(CH 30) 2 C 6 H 3 CHO

I
Isoethoxy-mandelonitrile
(CH 3 0) 2 C 6H 3 CO
I
CH
Isonitroso-acetoveratrone
(CH 3O) 2 C 6H 3 CH(OH)CN

4
Homoprotocatechuic acid
(CH 3 O) 2 C 6 H 3 CO
*
CH NOH
:
(HO) 2 C.H 3
CH
I
COOH
Amino-acetoveratrone hydrochloride^ (CH 3 0) 2 -C 6 3 .CO-CH 2 -NH 2 HC1
Homoveratroyl chloride (CH 3 O) 2 C 6 H 3 CH 2 COCi
(CH 3 O) 2 C 6 H 3
Homoveratroyl-aminoacetoveratrone
CH
CO NH CH
4
CO C H (OCH
6 3
3) 2
(CH 3 0) 2 C 9 H 3
Honioveratroyl-hydroxy-homoveratryamine
CH
CO NH CH
I
CH(OH) C 6 H 3 (OCH 3) 2
.
(CH 3 O) 2C 6H 3
Papaverine
CH 2 C N CH CH
: :
CH
(OCH 3) 2
This alkaloid was first isolated by Hesse in The following 1871, and it has the empirical formula C 21 27 NO4 structural formula shows that it is closely related to papaverine:
Laudanosine.
CH
CH 3
OCH OCH
Laudanosine
and his co-workers have synthesized laudanosine by condensing homoveratrylamine with homoveratroyl chloride and then
Pictet
231
reducing the papaverine methochloride to methyltetrahydropapaverine. On resolution of the inactive synthetic alkaloid the dextro
be identical with the natural product. Hydrastine. The root of the golden seal (Hydrastis canaIt was densis) and the common barberry both contain hydrastine. first obtained in a condition by Perrius in 1862, and it has pure the empirical formula C 21 H 21 NO 6 On oxidation with potassium
to
.
form was found
permanganate in acid solution
it is
converted into meta-opianic acid
and hydrastinine,
C 21 H 21 NO + H 2
tf
+ O - C 10 H
10
+ C U H 13 NO
Opianic acid Hydrastinine
Opianic acid
constitution:
or
6-dimethoxy-o-phthalaldehydic acid
has
the
COOH
CH^f/^CHO
CHJ
Hydrastinine may be reduced to dihydrohydrastinine, C^H * by several methods, and Fritsch has synthesized this compound by the action of sulphuric acid on the condensation product of
piperonal and amino-acetal,
CH(OC 2 H 52
5}
CH(OC H 52
2 5)
CH
NH CHO
CH
CH
Methylene-
^N
dioxyisoquinoline
followed by the reduction of the methiodide of this compound,
CH,
CH
H,C<[
o^Y^l T
>"\/k
CH 2
Dihydrohydrastinine
NHCH CHO
Hydrastinine
According to Freund, dihydrohydrastinine may be converted into hydrastinine by oxidation with potassium dichromate and sulphuric
acid.
*
Ann., 1895, 286,
i.
232

More
recently hydrastinine has been synthesized Hydrastine has the constitution,
by Decker and
Becker.*
CH,
oX^V ^*
N-CH
HC
CH^.CO
Hydrastine

Alkaloids, Quinine and Cinchonine. Alcinchona bark has been used as the source of the febrifuge, though quinine, since the fifteenth century, yet the two alkaloids quinine and cinchonine were not definitely isolated until 1820, when Pelletier characterized both products. Several closely related alkaloids occur in cinchona bark, and the structure of the more important of them be represented by the formulae: may
The Cinchona
CH CH CH 2 CHR"
2
CH(OH)
R'
CH CH CH
2
N
Alkaloids.
Cinchonine and cinchonidine.
Hydrocinchonine and hydrocinchonidine.

Quinine and quinidine.
Ethylhydrocupreine and ethylhydrocupreidine.
*
Ann., 1913,395, 328.

the labours of
233
Our knowledge of the constitution of these alkaloids is due to many chemists, of whom Skraup, Koenigs, von Muller, and Rabe are the more important. None of these compounds has
yet been obtained synthetically.
Both cinchonine and quinine are ditertiary bases, and of the two oxygen atoms in quinine one is present as hydroxyl and the other
as methoxyl.
C oH 24 N 2 O 2
2
C 19 H 22 N 2 O
Cinchonine
Quinine
From
alkaloid
is
a study of the oxidation products it is evident that each divisible into two parts. On oxidation with chromic
acid, cinchonine
acid
and sulphuric
quinine gives quinic acid.

formulae,
These
yields cinchoninic acid and acids are represented by the
COOH
COOH
,OCH,
N
Cinchoninic acid
-N
Quinic acid
so that the second half
is
probably identical in both alkaloids,
CH
N
Cinchonine
15
(OH)N
N
Quinine
The
determination of the constitution of the second half has
proved a very difficult problem. Since methods are now available for dealing with each stage of the problem of the synthesis of these alkaloids, it is probable that both compounds will be obtained syn-
immediate future. These researches cannot be dealt with here, and the reader should consult the excellent summaries which have appeared from time to time in the Annual Reports of the Chemical Society. The therapeutic value of quinine is due to the fact that it appears to have a specific action in malaria. Many attempts have been
thetically in the
234

to
made
overcome the
for
bitter taste
and
to obtain
more
soluble salts
suitable
tannate has very little taste, while esterification of the hydroxyl group with chloroformic ester, or the conversion of quinine into saloquinine by means of
hypodermic
injection.
The
salicylic ester, results in the
production of tasteless derivatives.
The Strychnos Alkaloids, Strychnine and Brucine.

These two alkaloids are generally found together in several species of Strychnos, the most important sources being nux-vomica seeds and Ignatius beans. These alkaloids are even more complex than
quinine in structure, but Tafel and Leuchs have collected sufficient information to enable Perkin and Robinsonf to propose the following formula for strychnine:
CH CH CH
2
HC
Brucine
replacing
is
the
the dimethoxy derivative, the two methoxyl groups hydrogen atoms attached to the two asterisked
carbon atoms.

important alkaloids
This group includes at least four found in opium, namely morphine, codeine, pseudomorphine, and thebai'ne. We are still ignorant of the exact structure of any of these alkaloids, but a few of the numerous observations with regard to them may be briefly summarized. Morphine and Codeine have the empirical formulae C 17 H 19 NO3 and C 18 H 21 NO 3 respectively, indicating a difference of a methyl group between the two bases. The correctness of this view has been established by the conversion of morphine into codeine by
methylation.
The Morphine Group.
Morphine is a tertiary base and contains two hydroxyl groups, On distillaone of which is phenolic and the other alcoholic.
t
Trans., 1910, 97, 309.

tion over zinc dust
it
2 35
methylamine, and of the morphine molecule
gives phenanthrene, pyrrole, pyridine, triOur knowledge of the structure ammonia.

is
largely
due to the investigations of

provisional
Vongerichten, Knorr, and Pschorr. The following formula has been assigned to morphine by Pschorr:
CH
NCH,
CH
Morphine
is a non-poisonous compound which may from morphine by oxidation. Its structure is be readily prepared unknown. Thebaine was discovered in opium by Thiboumery in 1835. Our present knowledge of its structure is mainly due to Freund, and
Pseudomorphine
the following formulae
show
that
it is
related to
it
morphine in so
far
as both hydroxyl groups are methylated; but
contains two atoms
of hydrogen fewer than morphine:

(C 16
H ONCH
14
)(OH) 2 Morphine
3
(C 16 H 12 ONCH 3 )(OCH 3 ) 2 Thebaine

thebai'ne:
Pschorr f has suggested the following formula for
CH
OC
CH CH 2 CH a
NCH,
CH OC
3
Ber., 1907, 40, 1980.
Loc.
cit.
236

The
synthesis of substitutes for morphine, for use in medicine,
has not been very successful. Methyl- and ethyl-morphine have a more proJêen prepared, and the latter is stronger and exhibits Ethylmorphine dihydrochloride is longed action than codeine. known as dionine. The acyl derivatives, in which the phenolic
hydrogen atom
is
replaced
The
diacetyl derivative of
by an acyl group, resemble morphine. morphine is known as heroin.
THE PHYTOCHEMICAL SYNTHESIS OF THE ALKALOIDS*

The methods which have been employed in the laboratory for the synthesis of the alkaloids bear little or no analogy to those used by the plant, and more particularly is this the case with regard to the temperatures at which the reactions are conducted by the chemist
and the nature of the reagents employed.
Nevertheless
many
of
the reactions of organic chemistry, including condensation, hydrolysis, dehydration, polymerization, oxidation, and reduction, can take place under conditions of temperatures approaching those in the plant.
are the
Gadamer f suggests that the primary products of assimilation same for proteins and for alkaloids. When assimilation is
intense alkaloids are produced, but during periods of diminished assimilation the enzyme which synthesized proteins may break down
the alkaloids, the disintegration products of which the formation of proteins.

Pictet J imagines that alkaloids are
may be used
in
successive stages, involving (i)
produced in the plant in two the breakdown of complex nitro-
genous substances, such as protein or chlorophyll, with the production of relatively simple basic substances; (2) the condensation of these relatively simple substances with other compounds present in the plant, with the formation of the alkaloids. Among the com-
monest changes in the plant are the methylation of hydroxyl or amino groups by formaldehyde,
R OH + CH O = R OCH 3 + O R NH 2 + CH O - R NHCH 3 + O
2
2
the resulting methylated compounds being then able to undergo intramolecular transformation, by which the methyl group can
* See also Chapter
I.
r.>
f Ber. Deut. pharm. Ges., 1914, 24, 35.
1907,40,3771.
PHYTOCHEMICAL SYNTHESIS OF ALKALOIDS

methyl pyrrole,
237
enter the ring and so produce, for example, a pyridine ring from
CH
CH-CH
CH CH
II
II
CH-CH
~>
CH CH
-*
CH CH
II
II
CH CH
II
NH
Pyrrole
NCH
N
Pyridine
In support of these views, Pictet states that he was able to isolate a number of pyrrolidine bases by steam distillation of the leaves of
tobacco, carrot, parsley, and coco. These simple bases, which include pyrrolidine and methylpyrrolidine, he terms photo-alkaloids:
CH2 C
NH
Pyrrolidine
NCH
Methylpyrrolidine
Robinson's views,* which owe their inception to the simple synthesis of tropinone already described, differ fundamentally from those of Pictet. The amino acids and the carbohydrates are regarded as the most likely starting points for the majority of phytochemical
syntheses.
The
chief initial
compounds employed
are
ammonia,
formaldehyde, ornithine (p. 144), lysine (p. 144), and the degradation products of the carbohydrates. Citric acid is suggested as the
source of acetone residues which
acetone dicarboxylic acid.
supplies as its oxidation product, Further, a reactive acetone derivative
it
One or two in diacetylacetone or other polyketens.f of the applications of these suggestions may be briefly considered. It has already been noted (p. 216) that when formaldehyde is
may be found
employed for the methylation of amines, oxidation also takes place, amino alcohols yielding methylaminoketones. The reaction of formaldehyde and ornithine might therefore yield a carbinol amine
of the pyrrolidine series:
NH

Ornithine
2
+ CH O
2
= NH(CH )[CH CHO

3
2] 3
_
1
CH - CH(OH) CH 3 - CH CH
2
NH + C0
3
Trans., 1917, 111, 762, 876.
Collie, Trans., 1893, 63, 329;
1907,91, 1806,
2 38
Further oxidation accompanying methylation might attack both ends of the molecule to give succindialdehyde and methylamine:
NH

2
- OCH-CHo-CHo-CHO
+ aCH O - CH(OH) CH +aCH 3NH +C0 )>NCH 3 - CH(OH) CH

2
I
After condensation with acetone dicarboxylic acid and elimination of carbon dioxide, hygrine (i), cuschygrine (ii), and tropinone (p. 222) are obtained:
NCH 3
H2C
CH,
COOH
2
NCH 3 COOH
2 2
NCH3
COCH,
HG/\CHOH] +
NCH 3
I
CH^CO -CH^COOH
H.C/\ CH-CH-CO-CH COOH H.C/\ CH- CH

H 2C H 2C
CH
COOH
COOH
I
H 2C XXcHOH
|
NCH 3
2
f
]
+CH
CO-CH
4-
HOCH/\CH LV
2
pj
(0 NCH NCH 3 H,cX\CH-CH-CO-CHiHcX\CH 2 3

|
H 2C
(-L
'CH
(ii)
H c^"*'
i]
The may
condensation product which forms the source of these alkaloids also be the progenitor of nicotine by further condensation with
formaldehyde and ammonia. Similarly, by the extension of these simple reactions, Robinson is able to account for the formation of
the majority of the alkaloids, as well as for the frequent occurrence of several closely related alkaloids in the same plant.
REFERENCES.
The Plant Alkaloids, by T. A. Henry (Churchill, London, 1913). The Vegetable Alkaloids, by Ame Pictet, trans, by Biddle (Wiley,
New
York, 1904). Die Alkaloide, by Winterstein and Trier (Borntraeger, Berlin, 1910). Analytische Chemie der Alkaloide, by Bauer (Borntraeger, Berlin, 1921).
INDEX OF AUTHORS
Abderhalden, 163, 168.
Fischer, Emil,
acids, 142; glucosides, 67; nucleosides and nucleotides, 208; polypeptides, 164; purine compounds, 200; pyrimidine compounds, 190; tannins and depsides, 84; sugar researches, 42 et seq. Fischer, E., and Abderhalden, 168. and Ach, 208.
amino
Ackermann,
Aldrich, 175.
188.
glycerides, 97;
Anderson, 212. Armstrong, E. F., 48, 60, 74.

Asceli, 195. Aschan, 135. Auwers, 28.
Baeyer, i, 106, 119, 129, 183, 190, 193. Baly and Heilbron, 6, 9, n. Barbier, 112. Barbier and Bouveault, 1 1 1 . Barger, 172, 173, 176, 180, 189. Barrowcliff and Tutin, 224. Baudisch, 8. Bauer, 139. Becker, 232.
Behrend, 195.
Bell (see Werner), 187. 68, 78. Bertrand, 44. Biot, 42. Bourquelot, 69. Braconnot, 142, 148. Braun, v., 151, 214. Bredt, 132. Brieger, 170, 182. Butlerow, 42.
Bergmann,
Leuchs, 63. Schmitze, 146. Tafel, 44, 49. Zachs, 63. Zemplen, 158. Fischer, F., 95. Fischer, H., 21. Fittig, 142, 201. Flacher, 175. Flamand, 160. Flawitzki, 84. Foreman, 142, 163. Franck, TOO. Freund, 231. Fritsch, 231.
>
and and and and and and and and and and
Andrae, 62. Armstrong, 48.
Bergmann,
68.
Freudenberg, 90, 91, 92.

Helferich, 208.
Chevreul, 95. Ciamician and Silber,

Claisen, 23, 32. Clewer, 216. Cole, 1 60. Collas, 138.
Collie, 24.
1 1 1
Gabriel, 147, 193. Gadamer, 223, 236. Geiger, 221. Gerhardt, 212. Giesecke, 218. Goodson, 216.
Graebe, 25.
Grimaux, 44, 194. Grun, 96, 101.

Haller, 134. Hantzsch, 217. Harries, 107. Haworth, 70, 71, 72, 79, 121. and Hirst, 72.
Combes,
41.
Constein, 98. Cre"pieux, 220.
Cunningham,
78.
Dakin, 142, 154.

Dale, 172, 174, 176, 180.
Debus, 178.
Decker, 232.
Decker and v. Fellenberg, 39. Denham and Woodhouse, 79. Dodge, 109.
Heilbron, 6, 9, Herzig, 30. Hess, 78, 215.
n.
Hoesch, 89, 90.
Hofmann, 212, 213, 219. Hoogewerf and v. Dorp, 212.

Hopkins, 160, 169, 208. and Cole, 160. Horbaczewski, 202.
Dumas,
42.
Dunstan, 182.
Ehrlich, 148. Ellinger, 160. Engeland, 188.
Hudson,
44,
Erlenmeyer, senr., 2. Erlenmeyer, junr., 147, 154. Erlenmeyer and Lipp, 155, 156.
Everest, 37.
Irvine, 61, 66, 70, 79, 81, 97. Fyfe and Hogg, 58. and Hynd, 63. and Rose, 66. Isay, 200.
Ewart, 2. Ewins, 185. Ewins and Laidlow, 174, 181.

239
Jacobs. See Levenne. Jahns, 217.
240
Jdrgensen, 3. Jowett, 175.
Kelber, 100.

Reinke,
2.
Renshaw, 185. Robinson and Perkin, 39, 152, 223, 237. Rosenheim, 105.
Kermack, 227.
JKiliani, 42,
Rosenmund
174.
45. Kirchoff, 42. 86. Klepl,

179.
Rotschy, 220.
Rouelle. 148. Ruff, 46. Riigheimer, 222. Ruhemann, 27. Runge, 212. Ruzicka, 126.
Knoop and Windaus, 161,

Knorr, 235. Koenigs, 233. Kolbe, 24.
Komppa, 133. Kossel, 178, 197, 204, 205. Kostanecki, v., 25 et seq. Kotz and Swarz, 125. Kung, 216. Kuster, 21, Kutscher. 180.
Ladenburg, 177, 218, 219, 222.
Laidlow, 174, 181.
Salkowski, E. and H., 188.

Sal way, 100. Sasaki, 156.
Lapworth, 98. Lederhouse, 62. Leuchs, 63, 153. Levenne and Jacobs, 191.
Lewis, 84.
Liddle, 196.
Schmitt and Nasse, 173. Schryver, 2. Schultze, 151, 152, 155, 216. Semmler, 106, 109, no, 123, 126. Sertiirner, 211. Shibata, 41.
Simon, 59.
Simonis, 27.
Simonsen, 131. Skraup, 233.

Sorensen, 150, 158. Spoehr, 2, 5. Stenhouse, 25.
Stolz, 175. Strecker, 84, 147.
Liebermann, 215.
Liebig, 42, 142, 186, 190, 195, 202, 212, 219Liebrich, 184. Loew, 42. Ldwe, 84. Lowry, 60.
Tanret, ^9, 75Tattersall, 119, 120.

Thiele, 8. Tickle, 24. Tiemann, 109, in, 113, 123, 138, 140. Traube, 202, 203, 207. Trier, 216. Tschugaeff, 126, 127. Tutin, 189, 224.
Macbeth., 67.
Macdonald, 81. M'Kenzie and Wood, 222.
Maquenne,
178.
Marchlewski, 13, 19. Medicus, 201. Merck, 229.

Merling, 224. Michael, 67.
Ullmann, 24.
Moore,
7, 8, o.
Miiller, 28.
Wager, 3. Wagner, 106, 108, 135, 136,

Wallach, 106 et seq. Walpole, 172, 173, 174.
Nagai, 176. Nencki, 19.
Neuberg, 46, 102, 103, 189.
Neumann,
Oddo,
224. Nierenstein, 93.

182.
Warner, 3. Webster, 7,
9.
Weerman,
46.
Oliver and Schafer, 175.
Osborne, 163.
Pasteur, 55.
Pelletier, 13, 232.
Werner, and Bell, 187. Wheeler and Johnson, 264. and Liddle, 196. and Macfarland, 197. and Merriam, 196. Wiggers, 73.
Willstatter, anthocyanins, 33 et seq.\ assimilation, 3 et seq.; betaines, 183; cellulose, 78; chlorophyll, 13 et seq.; hygric acid, 215; proline, 157. Willstatter and Benz, 14.
1 86.
'
Perkin, A. G., ji, 32. Perkin, junr., W. H., 106, 115,122, 125, 128,138, 226, 227and Robinson, 226, 234. Robinson and Kermack, 227. and Tattersall, 119, 120. Piccard, 29. Pictet, 128, 134, 220, 230, 236. and Cre*pieux, 220. and Gams, 229. Piepenbring, 84. Piutti, 146, 152. Planta, v., and Schulze, 216. Posselt and Riemann, 220. Proctor, 84. Pschorr, 2J5.
and Everest, 22, 33. and M. Fischer 21. and Isler, 13. and Opp, 15. and Page, 20. and Stoll, 3,4, 5, 15, 55, and Utzinger, 15. and Zachmeister, 40. Windaus. 99, 100, 179, 180. and Knoop, 179. Wohl, 45, 173>
56.
Wonler, 190, 195, 202.
Purdie ana Irvine, 61.
Woodhouse,
Zeisel, 214.
79.
Pyman, 161, 181. and Fargher, 178,

Rabe, 233.
179, 181.
Zemplen. 158.
Zlokasoft, 24.
INDEX OF SUBJECTS
Acetobromoglucose, 59.
a-Acrose, 49.
)3-Acrose, 49. Adenine, 192, 199. Adrenalin, 175. /Etiophyllin, 17, 19.
Caryophyllin, 137.
Cellobiose, 72, 79. Cellulose, 77. Cerebrosides, 105. Cheiidonic acid, 23. Chinese tannin, 84. Chitose, 63.
/Etioporphyrin, 19.
Agmatin, 177.
Alanine, 144, 148, 187. Aldohexoses, 43 Aldopentoses, 53. Aldoses, 43. Alizarin yellow, 87. Alkaloids 211. Alkylglucosides, 43, 57. Allomerization, 18. Allose, 55. Alloxan, 192, 195, 201. Altrose, 55. Alypine, 225.
Chlorophyll, i, 13, 16. Chlorophyllide, 17. Chlorophyllin, 15. Cholesterol, 99. Choline, 184. Chrysin, 26, 29. Cinchonidine, 232. Cinchonine, 232.
Citral, no, 112, 114. Citronellal, in, 113.
Citronellol,
in,
56.
113.
Cocaine 223, 224. Codeine, 234.
Amino
acids, 142.
Co-enzyme,
Amino-ethyl-alcohol, 185.
Conine, 12, 219.

Creatine, 186. Creatinine, 186. Crystalline chlorophyll, 14. Cyanhydrin reaction, 45. Cysteine, 144, 154. Cystine, 145, 154. Cytosine, 192, 193, 197, 200.
Amorphous
Amygdalin,
chlorophyll, 14.
66.
Anaesthesine, 225.
Anethole, 139. AnisaldehycTe, 139. Anthocyanins, 33. Anthoxanthins, 22. Arabinose, 44, 45, 46. Arginine, 144, 151, 178.
Artificial glucosides, 64, 67.
Aspartic acid, 144, 152.

Aspergillus niger, 73. Assimilatory quotient, 5. Atropic acid, 223. Atropine, 221, 223-
Deaminization, 171. Decarboxylation, 171. Oelphinin, 39. Depsides, 84, 85. Dextrin, 77, 81.
Dialuric acid, 193, 195.
Diamino-caproic acid. See Lysine. Diamino-valeric acid. See Ornithine.

Didepsides, 85.
Digallic acid, 92.
Barbier-Grignard reagents, 112.

Barbituric acid, 192, 193. Benzoyl piperidine, 150. Benzylidine glucose, Si. Betaines, 183, 184, 217. Betonicine, 215. Bicyclic terpenes, 125. Borneol, 135. Bornylene, 135. Brucine, 234.
Dipentene, 144.
Disaccharoses, 43, 69.
Ecgonine, 223, 224. Emulsin, 57, 64.
Enzymes,
55, 65.
Cadaverine, 177. Cadinine, 137. Caffeine, 199, 204. Camphane, 100, 135. Camphene, 130. Camphorj 131. Camphoric acid, 132, 133. Cane-sugar, 70. Carane, 109, 128. Carnosine, 189. Carone, 128. Carotin, 14, 20.
241
Epiniphin. See Adrenalin. Eucaine, 303. Evernic acia, 124. Everninic acid, 89. Exhaustive methylation, 213.
Fenchene, 136. Fenchone, 136.

Fenton's reagent, 44. Fermentation, 56, 101. Flavone. 37.
Flavonol, 27.
Formaldehyde,
i,
Formhydroxamic
Formose, 42.
2 et seq. t 42, 236. acid, 8, 9.
242
Fucoxanthin, 20. Fusel oil, 149.
/3alactose, 44, 55 XJalangm, 26, 32. Gallotannin, oo. Gentianose, 75. Gentibiose, 74. Geranic acid, 112. Geraniol, up, 112.

Isoeugenol, 139. Isoleucine, 144, 147, 148, 173. Isopelletierine, 226. Isopulegol, 124. Isopulegone, 124. Isoquinoline alkaloids, 228. Isorhamnitin, 31.
Fructose, 44, 47, 50.
Japan camphor.
Kephalin, 185.
Lactose, 72.
See Camphor.
Kaempherol, 26, 32.
Glaucophyilin, 17. Glucoheptose, 45.
Gluconic acid, 45, 48, 50. Gluconic lactone, 40. Glucononose, 45.
Gluco-octpse, 45.
Laudanpsine, 230. Lecanpric acid, 89.

Lecithin, 104. Leucine, 144, 148, 172. Lichin products, 87. Limonine, 114. Liiialol, 112. Linamarin, 69. Lipase, 98. Lipins, 103. Luteolin, 26, 31. Lysine, 144, 150, 237.
Glucosamine, 62. Giucosazone, 47. Glucose, 44, 45, 49, 50. Glucose pentacetate, 59. Glucose phenylhydrazone, 47.
Glucosides, 64. Glucosone, 47.
Glutamic
acid, 144, 152.
Glutathione, 169. Glycerides, 95. Glycerose, 50, 56. Glycine, 144, i47 148. Glycocoll. See Glycine. Glycylalanine, 168. Glycylglycine, 168. Glyoxaline, n, 178. Grape-sugar. See Glucose.
Maltase, 64. Maltose, 57. 64.
Mannonic
acid, 45, 48, 50.
Manno-octose, 45.
IVfannose, 44, 45. Mannptriose, 75. Melecitose, 75. Melibiose, 73, 74. IVIenthadienes, 108. Menthenes, 122. Menthol, 123, 124.
Guanidine, 186. Guanine, 192. 199. Guanylic acid, 192. Gulose, 55.
Gums,
77.
Menthone, in. Methylamine, ii
172.
Hsematirtj 21.^
>
Haematimc acid, 21. Hsemin 20.

Haemocyanine, 14. Haemoglobin, 142. Harmalin, 226.
Methylanthranilate, 139. Methylenitan, 42. Methylglucosides, 43, 57.
Harman,
227.
Harmine, 226.
Helicin, 66.
Heptpses, 45. Heroin, 236. Hexoses, 53. Histamine, 180.

Histidine, 12, 145, 160. Homocamphoric acid, 134. Homoterpenyl -formic acid, 130. Homoterpenylic acid, 130. Hordenine, 174. Hydrastine, 231. Hydrastinine, 231. Hydrocinchonidine, 232. Hydrocinchonine, 232. Hydrouracil, 194. Hydroxyglutamic acid, 144, 154. Hydroxy-phenyl-ethyl-amine, 173. Hydrpxyproline, 145, 159. Hygric acid, 215. Hygrine, 215, 238. Hyoscine, 221. Hyoscyamine, 221. Hypoxanthine, 198. Idose. 55. Indian yellow, 25. Indican, 67. Indole, 139, 182. Inulin, 82. lonone, 140. I rone, 140. Isoamylamine, 172. Isoborneol, 135.
Methylguanidine, 187. Methylheptenone, in. Methylotannin, 91. Monocyclic terpcnes, 108, 119. Monoglycerides, 96. Monosaccharoses, 43. Morin, 26.
Morphine, 234. Mustard oils, 140.

Mutarptation, 59.
Myrosin, 140.
Nicotinic acid, 220. Nicotyrin, 221. Nitrpso terpenes, 108. Nopinone, 131. Norharman, 211, 227.
Natural glucosides, 64. Neurine, 18^.
Norpinic acid, 129, 130. Nucleic acids, 208.

Nucleosides, 208, 209. Nucleotides, 208, 209, 210.
Opium,
Oenin, 37. Olefinic terpenes, 108, 109. 21 1. Ornithine, 144, 149, 237. Orsellinic acid, 87.
Papaverine, 228. Pelargonidin, 39, 40.
Pelletierine, 226.
Penta-digalloyl-glucose, 92. Penta-gaTloyl-glucose, 91. Pentoses, 53. Perfumes, 138.
Phseophorbide, 16.
INDEX OF SUBJECTS
Phaeophorbin, 16. Yhellandrene, 118. Phenoftglucosides, 66. Phenyrafanine, 145, 148, 155.
Phenyl-ethyl-alcohol, 139, 173. Phenyl-ethylamine, 173. Phosphatides, 104. Photosynthesis, i. Phytol, 15. Phytosterol, 99. iPigments, natural, 13. Pinane, 109. Pinene, 129, 131.
2 43
Stachyose, 76. Starch, 77, 81.

Sterols, 99.
Stovaine, 225. Strychnine, 234. Sucrose, 70. Sylvestrene, 118.
Talose, 55.
Pinonic acid, 129, 130. Pinoyl formic acid, 129, 130.

Piperic acid, 218. Piperidine, 217. Piperine, 217. Polypeptides, 164. Polysaccharoses, 43, 77. Proline, 145, 157Proteins, ammo acids from, 142. Prulaurasine, 66, 69. Pulegone, 123. Purine, 198, 200, 201. Purine bases, 190, 205. Pyridinc alkaloids, 211, 212, 237. Pyrimidine bases, 190. Pyrocatechol tannins, 85. Py rones, 23. Pyrrole, 211, 237.
Tannins, 84. Terebic acid, 131. Terpenes, 106. Terpenylic acid, 130. Terpin, no, 116.
Terpineol, no, 116. Terpinolene, 117. Tetrasaccharoses, 76. Thcbaine, 235.
Theobromine,
Thujene, 127.
199, 204.
Thymine,
192, 193, 195, iQ7
Trehalose, 73. Trigonelline, 217,
Trimethylamine, 172.
Trimethylglycine, 184.
Tropane
alkaloids, 211.
Tropine, 222, 223. Tropinone, 223, 238. Tryptophane, 145, 160, 227. Turacine, 216. Turanose, 74.
Twitchell's reagent, 97.
Quercitin, 26, 30.
Quinic acid, 233. Quinine, 232.

Rafinose, 73, 74.
Uracil, 192, 193, 195, 196.
Uramil, 192, 194. Uric acid, 198, 201, 202.

Vanillin, 138, 139. Veronal, 194. Violuric acid, 192, 194.
Rhamnazin, 31, Rhamninose, 45.

Rhamnitin, 26, 31.
Rhamnoheptose, 45. Rhamnohexose, 45. Rhamno-octose, 45.

Rhodinal, in, 112, 114.
Waxes, 95, 99. Wintergreen oil, 138.

Xanthine, 24.
Sabina ketone, 118. Saoinane, 109. Sabinene, 126.

Salicin, 66.
Xanthone, 24.
Xanthophyll, 14, 20. Xylose, 44.
*
Sambunigrin, 66, 68.

Scatole, 139.
Zeisel's
method, 214.
56.
Sorbose bacterium, 44
Stachydrin, 216.
Zingiberine, 137.
Zymase,
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[<

OU_1 58459 >!J

^Manuals of Pure and ^Applied Chemistry

Natural Organic Products

of the Research Staff of Nobel Industries, Ltd.

BLACKIE AND SON LIMITED

LONDON; GLASGOW, BOMBAY

Printed and bound tn Great Britain

but partially surveyed.

which we know very

Wellcome Research Bureau,

which they have kindly placed Also, my thanks are due

clearly seen that chemical science contributes

to the health, comfort, luxury,

intellectual life of the

developments written by experts in the subjects with which they

Organic chemistry as a science

during ninety-six years!

the labours and discoveries

and elucidate her methods, are brought

THE PHOTOSYNTHESIS OF PLANT PRODUCTS

Compounds from Nitrates and Carbon Dioxide

CHLOROPHYLL AND OTHER NATURAL PIGMENTS

Chlorophyll-^ and Chlorophy 11-6

Action of Alkalies and Acids on Chlorophyll

7-Pyrone The Xanthones Flavones and Flavonols

THE ANTHOCYANIN PIGMENTS

Synthesis of Pelargonidin Origin of the Anthocyanins in Plants

.-.-...-..36 ........38 ._..-.. .40

Synthetic Preparation Synthesis of Glucose and Fructose Configuration of the Monosaccharoses

Pentoses and Hexoses

Fermentation of the Monosaccharoses

Methylglucosides Mutarotation and the Isomeric Forms of Glucose

..-.. -------------44 -------49 ------.53 ----.--....55 -------57

Methylated Sugars Glucosamines

DlSACCHAROSES Sucrose Maltose

Lactose Trehalose Melibiose

THE POLYSACCHAROSES The Celluloses

Cotton Cellulose Starches and Dextrins

Depsides Lichen Products Gallotannin

------.----84 ---------84 ......--.------------85 .--.--.----go

DEPSIDES, LICHEN PRODUCTS, AND TANNINS

Introduction and Classification

The Waxes The Sterols The Preparation

The The The

.-_--,_------------94 -------------------99 -----------99 -----------OILS, FATS,

ANIMAL AND VEGETABLE

of Fatty Acids from Hydrocarbons

OLEFINIC TERPENES AND THEIR DERIVATIVES

THE MONOCYCLIC TERPENES

The Terpinene Group The Phellandrene Group

-114 -115 -117 -117

Synthetic Monocyclic Terpenes The Menthenes and their Derivatives

THE DICYCLIC TERPENES

THE CARANE GROUP

THE CAMPHANE GROUP

Synthesis of Camphoric Acid Conversion of Camphoric Acid into

Borneol and Isoborneol

Bornylene and Camphane Fenchone and the Fenchenes