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Full text of "Chemical Synthesis"

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^Manuals of Pure and ^Applied 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.
A 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



In this work I have attempted to describe the more important
investigations which have been made by the organic chemist in
modern times in the domain of natural organic products. The
book covers only a limited field of organic chemistry, and even
this is but partially surveyed.

During recent years the study of natural organic products has
attracted chemists in increasing numbers. The results already
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.

On account of the nature of the subject-matter and the fact
that the book is intended 'for those who have a knowledge of organic
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, for information
which they have kindly placed at my disposal.

Also, my thanks are due to Professor R. M. Caven, the
general editor of the series, for many valuable suggestions,
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. HEPWORTH.

THE RESEARCH LABORATORIES, ARDEER,
March, 1924.



EDITOR'S NOTE



After many years of neglect chemistry is at length being recog-
nized in this country as one of the most important factors of modern
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, and intellectual life of the modern
citizen. It is a difficult task, nevertheless, to bring the latest achieve-
ments of chemistry within the reach of minds untutored in its first
principles; though this task should be attempted by those best
qualified to perform it.

The purpose 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
developments written by experts in the subjects with which they
deal.

Organic chemistry as a science is not yet one hundred years old;
it is still four years to the centenary of the synthesis of urea by
Wohler; yet how amazing has been the advance in our knowledge
during ninety-six years! Having 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
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. Of the labours and discoveries



vii



viii EDITOR'S NOTE

of these chemists, Dr. Hepworth gives an account in the present
volume. This account begins where Nature begins, with the photo-
synthesis of plant products; it continues with the study of chloro-
phyll and other natural pigments, and of the formation of carbo-
hydrates, tannins, oils, fats, and waxes. After notice of the terpenes,
and then of the amino acids and the natural bases which are elabo-
rated from these, the volume concludes with an account of the alka-
loids, and of recent research upon their synthesis. Thus the work
of Nature in the organic field, and the efforts of man to follow her
and elucidate her methods, are brought to view.

R. M. CAVEN.

ROYAL TECHNICAL COLLEGE, GLASGOW,
March, 1924.



CONTENTS



Page

INTRODUCTION -------- ..-xv

CHAPTER I
THE PHOTOSYNTHESIS OF PLANT PRODUCTS

Introduction - i

The Presence of Formaldehyde in the Plant and the Function of the

Chlorophyll z

Photocatalysis: the Synthesis of Formaldehyde from Carbon Dioxide and

Water 6

Photosynthesis of Nitrogen Compounds from Nitrates and Carbon Dioxide - 8

CHAPTER II

CHLOROPHYLL AND OTHER NATURAL PIGMENTS

CHLOROPHYLL - - - - -'3

Extraction of Plant Pigments 14

Amorphous and " Crystalline " Chlorophyll - - - - 14

Phytol 15

Chlorophyll-^ and Chlorophy 11-6 - v 16

Nomenclature - - - - - - - - - -16

Action of Alkalies and Acids on Chlorophyll - - - - 17

-^Etiophyllin and ^Etioporphyrin - - - - - - -19

Carotin, Xanthophyll, and Fucoxanthin ------ 20

Chlorophyll and Haemin 20

THE ANTHOXANTHINS 22

7-Pyrone .-.---.-.- 23
The Xanthones ----..----24
Flavones and Flavonols - - - - - - - - -26

THE ANTHOCYANIN PIGMENTS - - - 33

Introduction -..-.._..---.. 33

Extraction --- 34

Nomenclature - - - - - 35

Distribution .-.-...-..36

Salts of Benzopyroxonium ........38

Synthesis of Pelargonidin ._..-.. .40

Origin of the Anthocyanins in Plants 40

ix



x CONTENTS

CHAPTER III

THE CARBOHYDRATES

Page
Introduction - - - ' - - - - - - - -42

Classification ..-.. 43

THE MONOSACCHAROSES 44

Natural Sources ----- 5^.

Synthetic Preparation ---------44

Synthesis of Glucose and Fructose -------49

Configuration of the Monosaccharoses ------ 50

The Pentoses and Hexoses - - - - - - - .53

Enzymes ----.--....55

Fermentation of the Monosaccharoses ------ 56

Methylglucosides -57

Mutarotation and the Isomeric Forms of Glucose - - - - 59
Methylated Sugars - - - - - - - - -61

Glucosamines . - - -62

Giucal 63

Natural and Artificial Gluco sides -------64

Structure of the Glucosides - - - - - - - -65

Synthetic Glucosides ------- --67

THE DlSACCHAROSES ----------69

Sucrose -?o

Maltose -----------71

Cellobiose -----------72

Lactose -----------72

Trehalose - 73

Melibiose -----------73

THE TRISACCHAROSES 74

Raffinose -.--.------74

Gentianose -----------75

Melecitose -75

Mannotriose - - - -75

Rhamninose -----------76

TETRASACCHAROSES -- 76

Stachyose - 76

THE POLYSACCHAROSES ----77

The Celluloses ---------- 77

Cotton Cellulose ---- 78

Starches and Dextrins - - - - - - - - - 81

CHAPTER IV
THE DEPSIDES, LICHEN PRODUCTS, AND TANNINS

Introduction ------.----84

Classification of the Tannins ---------84

Isolation of the Tannins .... ..--.-- 85

The Depsides -----------85

Lichen Products 88

Gallotannin .--.--.----go



CONTENTS xi

CHAPTER V
ANIMAL AND VEGETABLE OILS, FATS, AND WAXES

Page

Introduction and Classification .-_--,_- 94
Occurrence ------------94

The Constitution and Synthesis of the Glycerides 95

Hydrolysis of the Oils and Fats -------- 9*7

The Waxes ------------99

The Sterols -----------99

The Preparation of Fatty Acids from Hydrocarbons - - - - 100

Fermentation Glycerol - - - - - - - - - 101

The Lipins ------------ 103

The Phosphatides - - - - - , - - - - -104

The Cerebrosides ----- 105



CHAPTER VI
THE TERPENES AND THEIR DERIVATIVES

Introduction - - - - - - - - - - - 106

Classification - - - - - - - - - - -107

THE OLEFINIC TERPENES AND THEIR DERIVATIVES - - 109

THE MONOCYCLIC TERPENES - 114

Limonene - - - - - - - - - -114

Synthesis of Limonene - - - - - - - -115

Terpinolene - - - - - - - - - - -117

The Terpinene Group - - - \- - - - - -117

The Phellandrene Group - - 118

Sylvestrene and Carvestrene - - - - - - - -118

Synthetic Monocyclic Terpenes - - - - - - -119

The Menthenes and their Derivatives - - - - - - 122

THE DICYCLIC TERPENES - - - -125

The Sabinane or Tanacetane Group 125

THE CARANE GROUP --- 128

THE PINANE GROUP 129

THE CAMPHANE GROUP - - - - - - - - -131

Synthesis of Camphoric Acid - - - - . - - - ~ *33

Conversion of Camphoric Acid into Camphor - - - - 1 34

Borneol and Isoborneol - - - - - - - - -135

Bornylene and Camphane - - - - - - - - 135

Fenchone and the Fenchenes - 136

SESQUITERPENES AND POLYTERPENES 137

NATURAL AND SYNTHETIC PERFUMES 138



xii CONTENTS

CHAPTER VII
THE AMINO ACIDS AND POLYPEPTIDES

Page
Introduction --------___ 142

Isolation of the Amino Acids - - - - - - - -143

Classification of the Amino Acids - - - - - - - -144

Resolution and Identification of the Amino Acids - - - - - 145

Synthesis of the Amino Acids -146

Monobasic Monamino Acids - - - - - - - - -146

Diamino Acids - - - - - - - - - - -149

Dibasic Monamino Acids - - - - - - - - -152

Hydroxy- and Thio-amino Acids - - - - - - - -153

Aromatic Amino Acids - - - - - - - - - -155

Heterocyclic Amino Acids 157

Distribution of the Amino Acids in the Proteins - - - - - 163

THE POLYPEPTIDES - - - - - - - - - -164

Synthesis of the Polypep tides 164

Relation of the Polypeptides to the Simpler Proteins - - - - 167

CHAPTER VIII

SOME SIMPLE NATURAL ORGANIC BASES

Introduction and Scope - - - - 170

Occurrence and Isolation - - - - - - - - -170

SIMPLE MONO AMINO BASES 172

Adrenaline ----------- 175

DIAMINO BASES ~ .. - - -177

HETEROCYLIC BASES - - - - - - - - - -17$

BASES DERIVED FROM TRYPTOPHANE - - l8l

THE BETA!NES - - - - - - 183

CHOLINE AND ALLIED BASES - - - - - - - - -184

CREATINE - 186

THE w- AMINO ACIDS 187

CHAPTER IX
PYRIMIDINE AND PURINE BASES

Introduction -... ...-..- 190

NucJeoproteins and Nucleic Acids 190

PYRIMIDINE AND SOME OF ITS DERIVATIVES 193

Uracil and Thymine - - 195

Cytosine . - - - 197



CONTENTS xiii

Page

THE PURINE BASES - - - - - - - - - -198

Purine ------------ 200

Uric Acid 201

Occurrence and Structure of the Purine Bases ----- 204
Synthesis of the Purine Bases -------- 205

SYNTHETIC NUCLEOSIDES AND NUCLEOTIDES 208

CHAPTER X
THE ALKALOIDS

Introduction - - - - - - - - - - -211

Occurrence ------------ 212

Extraction of the Alkaloids 212

Investigation of the Alkaloids 213

THE PYRROLE ALKALOIDS - - - - - - - - -215

Hygrine 215

Betonicine and Turicine 216

Stachydrine ----------- 216

THE PYRIDINE ALKALOIDS - - - 217

Trigonelline ----------- 217

Piperine ----------. 217

Conine ----- 218

Nicotine ----- 220

THE TROPANE GROUP ~ - - - - - - - -221

-Atropine and its Allies - - - - - - - - -221

Tropine 222

Cocaine and some Synthetic Substitutes ------ 224

^
THE POMEGRANATE ALKALOIDS -------- 226

THE NORHARMAN ALKALOIDS -- 226

Harmine and Harmaline -------- 226

THE ISOQUINOLINE ALKALOIDS 228

x/Papaverine 228

Laudanosine ----------- 230

Hydrastine - - - - - - - - - - -231

THE QUINOLINE ALKALOIDS - - - 232

The Cinchona Alkaloids Quinine and Cinchonine - 232

The Strychnos Alkaloids Strychnine and Brucine - 234

THE PHENANTHRENE ALKALOIDS 234

Morphine and Codeine -- 234

Thebaine ----------- 235

THE PHYTOCHEMICAL SYNTHESIS OF THE ALKALOIDS - 236

INDEX OF AUTHORS 239

INDEX OF SUBJECTS 241



TABLE OF ABBREVIATIONS EMPLOYED IN THE

REFERENCES



Abbreviated Title.
Absts.

Amer. Chem. J.
Amer. J. Physiol.
Ann.

Ann. Chim.
Arch. Pharm.
Ber.

Ber. Deut. hot. Ges.
Ber. Deut. pharm. Ges.
Biochem. J.
Biochem. Z.
Bull. Soc. chim.
Chem. Zeit.
Chim. et Ind.
C.r.

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. Chem. Soc.

y. Soc. Chem. Ind.

Proc.

Proc. Roy. Soc.

Site. Preuss. Akad. Wiss.

Berlin.
Trans.
Z. Biol.
Zentr.
Z. physiol. Chem.



Journal.

Abstracts in Journal of the Chemical Society, London.
American Chemical Journal.
American Journal of Physiology.
Justus Liebig's Annalen der Chemie.
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.
Chemiker Zeitung.
Chimie et Industrie.
Comptes rendus hebdomadaires des Stances de 1'Aca-

d&nie des Sciences.
Deutsches Reichs Patent.
Gazzetta chimica italiana.
Helvetica Chimica Acta.
Journal of the American Chemical Society.
Journal of Biological Chemistry.
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.
Proceedings of the Chemical Society, London.
Proceedings of the Royal Society.
Sitzungsberichte der Preussischen Akademie der Wis-

senschaften zu Berlin.

Transactions of the Chemical Society, London.
Zeitschrift fur Biologic.
Chemisches Zentralblatt.
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,
viz. mineral, vegetable, 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
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 it was performed under the influence
of a Vital Force.

It is easy to understand why in its early youth organic chemistry
was so closely connected with biology, for the materials which the
chemist was called upon to investigate were mostly products of
animal or vegetable origin. The isolation of urea from animal urine
by Rouelle, the recognition of uric acid, lactic acid, malic acid, and
glycerine 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 to yield up its treasure of chemical com-
pounds.

It is generally conceded that the doctrine of a special vital force
was discredited as an outcome of the synthesis of urea, from lead
cyanate and ammonium chloride, by Wohler in 1828;* and as, year by
year, new synthetic products were added to the list of organic com-
pounds, this last barrier, which separated organic from inorganic

* It 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.



xvi INTRODUCTION

chemistry, was swept away, and henceforth the former became the
chemistry of carbon compounds.

The subsequent development of organic chemistry cannot be
traced here, and it will be sufficient to say that, in the form in which
it exists to-day, organic chemistry may be deemed to have begun
with the work of Frankland at the middle of the nineteenth century.
Once the doctrine of the constancy of valency was accepted,
Couper, Crum Brown, and Kekul6 were 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 founda-
tions 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 number of natural
organic products enumerated in the text-books is indeed small in
comparison with the 150,000 carbon compounds of which organic
chemistry can boast to-day.

With the dawn of the twentieth century, more attention has
been paid to the chemistry of other vital 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 is due principally, but by no means exclusively, to
the pioneering researches of Emil Fischer; and the prospects which
have been opened out seem almost infinite in variety.

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
organic compounds, is now attracting chemists in increasing
numbers.

The investigation of plant pigments and especially chlorophyll
the plant pigment " par excellence " has been the subject of a
series of brilliant researches by Willstatter, and these studies have
led to the development of an extraordinary technique in the use of
solvents. 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 in-
vestigation of these compounds has proceeded very rapidly, princi-
pally owing to the classic researches of Emil Fischer. In spite of
the extensive results accomplished, we are still far from under-
standing all the chemical possibilities of even the monosaccharoses,
and the glucose molecule is now assuming a protean character
almost as wonderful as that of camphor. The recent work of Irvine
and his collaborators on the di- and poly-saccharoses, especially
cellulose, demands special consideration, and valuable results may
be expected from the new methods which are being employed.
The discovery of the methyl glucosides and acetobromoglucose may
be regarded as the cardinal points in the recent studies of the syn-
thetic glucosides. The remarkable achievements in the investigation
of gallotannin are almost unsurpassed in the realm of synthetic
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 enzymes has received considerable
attention, especially at the hands of J2. Fischer, H. E. and E. F.
Armstrong, Bayliss, and Bourquelot, and the value of these sub-
stances as the " chemical reagents " of the organism has been
repeatedly emphasized. The chemical investigation of these sub-
stances 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; and if this aim is eventually achieved, it may be safely
said that it will outweigh even the extraordinarily brilliant researches
which this chemist has already carried out.

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 pitfalls. Of the chemical constitution of the
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. No one imagines that in
the breakdown of the higher fatty acids all 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 living 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
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 to these classes are being isolated from
natural sources. 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
has been made, it cannot be said that a thoroughly successful pro-
duct has yet been prepared synthetically. Of the sesqui-terpenes
we know very little, while we are equally ignorant of the mechanism
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, by E. Fischer in
1901, led to numerous investigations of the nature of the amino
acids present therein. After the first decade, when the technique
had been worked out, investigators began to consider the losses
involved in the process of isolation, and more recently Dakin and
Foreman have introduced alternative methods for the isolation of
certain types of amino acids derived from the hydrolysis of proteins.
Fischer's investigations of many of the naturally occurring polypep-



INTRODUCTION xix

tides have been extended by a number of chemists, notably by
Abderhalden. Perhaps the most interesting polypeptide so far
discovered is 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
in the study of the proteins, vast regions still remain almost
untouched.

The classification of the natural organic bases is becoming an
increasingly difficult problem. The alkaloids, which were easily
isolated 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
interesting investigation of recent years being the classic study of
cryptopine and protopine by W. H. Perkin, jun., and that of harmine
and harmaline by the same author in collaboration with R. Robinson.
Each year brings forward new alkaloids for investigation, and the
field seems almost inexhaustible. Without doubt the most satis-
factory theory with regard to the phytochemical synthesis of the
alkaloids which has so far been put forward is that due to R. Robin-
son, and a consideration of his paper cannot fail to suggest numerous
problems which deserve the attention of the organic chemist. The
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 new bases which
may be regarded as derived from amino acids. 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-
tained in 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
valuable step towards the ultimate synthesis of the nucleic acids.



xx INTRODUCTION

It 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 limits
of temperature, there is just as much scope for endeavouring to
penetrate Nature's methods of synthesis as there was in the days
when it was believed that every organic compound required a vital
force for its elaboration.



ORGANIC
CHEMICAL SYNTHESIS



CHAPTER I
The Photosynthesis of Plant Products

Introduction. The processes by 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
long been recognized as the ultimate source of supply of that
element from which phyto-protoplasm is constructed, modern in-
vestigation has indicated that nitroger^ is not drawn by the plant
directly from the air, but is assimilatated in a combined state from
the soil by the roots, 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
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 2 + H 2 O = HCHO + O 2 ,

and that the resulting formaldehyde then polymerizes to give a
hexose (C 6 H 12 O 6 ) (p. 42). This plausible hypothesis has influ-
enced investigations on the synthetic aspects of carbon assimilation

* Ber., 1870,3,63.

, (D331) 1 1



2 ORGANIC CHEMICAL SYNTHESIS

to a remarkable extent, and for many years the question of the
presence of free formaldehyde in green leaves gave rise to the most
contradictory answers. This particular point has lost a good deal
of its original significance in view of the more recent results obtained,
especially by Willstatter, 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 inter-
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 in the plant is not surprising.

Robinson's views on the phytochemical synthesis of the alkaloids
will be dealt with in a later chapter (p. 237).

The Presence of Formaldehyde in the Plant and the
Function of the Chlorophyll. The presence of formaldehyde
in the plant was first reported by Reinke * in 1883. Since that
time many investigators have reported its presence, and these state-
ments have been taken as evidence of the truth of Baeyer's hypo-
thesis.

More 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
formaldehyde. The former investigator found that formaldehyde

* Ber. deut. hot. Gesells., 1883, 1, 406. t Proc. Roy. Soc., 1910, 82 B, 226.

t Ibid., 1908, 80 B, 30.



THE PHOTOSYNTHESIS OF PLANT PRODUCTS 3

is more abundant in chlorophyll films after exposure to bright
sunlight than when exposed to a dull light. When glass plates
covered with films of chlorophyll were kept in the dark no formalde-
hyde 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-
duced, and the presence of moist carbon dioxide increased the
quantity of formaldehyde very considerably. From these experi-
ments Schryver concluded that in the presence of sunlight, water,
and carbon dioxide, there is a continuous production of formaldehyde,
which is 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
regulated that at no time is a toxic quantity present.

Wager * has studied the decomposition of chlorophyll on ex-
posure 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 for-
maldehyde 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 formal-
dehyde was formed if pure chlorophyll, in colloidal solution, was
employed the colloidal solution being considered to approximate

* Proc. Roy. Soc., 1914, 87 B, 386. f Ibid., p. 378.

t Proc. Roy. Soc., 1916, 89 B, 342. Ber. t 1917, 50, 1791.



ORGANIC CHEMICAL SYNTHESIS



most closely to the condition of the chlorophyll in the chloroplast.
The formaldehyde described by earlier workers is attributed to the
oxidation of impurities accompanying the chlorophyll they em-
ployed. 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 -in vitro have
shown that carbon dioxide reacts with chlorophyll (i) in colloidal
solution to form a compound of the nature of a bicarbonate (ii).



R



N



N



H 2 o + co 2 = R <



0)






N



,o

'OH



:NH



It is 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. In this way a formaldehyde-peroxide
compound (iii) is assumed to be formed:



R




:NH



,O
^O



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



R






H



- N



*0









THE PHOTOSYNTHESIS OF PLANT PRODUCTS 5

No such peroxide (iii) has been observed when experiments are
carried out in vitro, but this is not considered surprising, " in view
of the essential difference between test-tube experiments and the
activity of the living cell ". The chloroplast will tolerate con-
centrations of carbon dioxide which decompose chlorophyll in
collbidal solution to phaeophytin, with precipitation of magnesium
carbonate, so that the chlorophyll in the chloroplast must be pro-
tected 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.

Spoehr * has shown that certain plant acids, especially dibasic
acids, readily undergo decomposition when exposed to ultra-violet
light in quartz vessels, with the formation of acetaldehyde and acetic
acid, and that the latter may undergo further decomposition, yield-
ing formaldehyde and formic acid.

The most satisfactory evidence that formaldehyde is the con-
necting link between carbon dioxide and the carbohydrates has been
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 ",
CO 2 /O 2 , is 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
temperature is 10 or 35, whether the atmosphere is rich in carbon
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 colour-
less part of the chloroplast, chlorophyll thus being the result of a
later synthetic stage. " The function of the chlorophyll may be
a protective one to the chloroplast when exposed to light, it may be
a light-screen as has been suggested by Pringsheim, or it may be
concerned in condensations and polymerizations subsequent to the
first act of synthesis with production of formaldehyde." J In this
connection it is noteworthy that in 1892 Molisch showed that

* Biochem. Zeitsch., 1913, 57, 95. t Ber., 191?, 50* 1777.

J Biochemistry, by B. Moore, p. 55.



6 ORGANIC CHEMICAL SYNTHESIS

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 deficiency, although iron is not a com-
ponent of the chlorophyll molecule. Green leaves etiolated by
darkness and then exposed to light regain their chlorophyll, which
is therefore itself a product arising from photosynthesis.

Photocatalysis : the Synthesis of Formaldehyde from
Carbon Dioxide and Water. It is a well established fact that
an aqueous solution of carbon dioxide is unable to absorb visible
light, but that it absorbs ultra-violet light of extremely short wave-
length. In order to gain the energy required for the first stage of
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
for the fact that the plant is able to accomplish this synthesis
in ordinary sunlight.

Baly and Heilbron * have suggested a theory which is based on
the quantitative study of the formation of hydrogen chloride from
hydrogen and chlorine, f It was found that the velocity of this
reaction is not proportional to the intensity of the light, but in-
creases 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 E is the amount of energy absorbed in activating the chlorine
molecule and K is the normal heat of formation of two molecules
of hydrogen chloride. The total energy E -)- K is radiated at
infra-red (heat) frequencies, which are characteristic of the hydrogen
molecule. It has been proved, however, that many of the infra-
red frequencies of a compound molecule are identical with those of
its component atoms, and consequently the molecules of hydrogen
chloride and chlorine have some infra-red frequencies in common.
Part of the energy E + K will therefore be reabsorbed by the
surrounding chlorine molecules, with the result that these become
partially or wholly activated. Baly and Heilbron consider that the
principle is applicable to all photochemical reactions, and may be
made use of in promoting a reaction when the reactant molecules

* Trans., 1921, 119, 1025. t Baly and Barker, Trans., 1921, 119, 653.



THE PHOTOSYNTHESIS OF PLANT PRODUCTS 7

are screened from the ultra-violet rays they normally require. For
this purpose the reactants are mixed with a " photocatalyst " (A),
which absorbs rays different from those characteristic of the re-
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 aqueous
solution of carbon dioxide gives no formaldehyde on exposure to
ultra-violet light, but that in the presence of certain inorganic
" catalysts ", e.g. colloidal ferric hydroxide, beryllium chloride,
&c., small quantities of formaldehyde are produced. Baly and
Heilbron have confirmed these experiments, and in addition have
observed that if a solution of carbon dioxide in water is agitated by
carbon dioxide during the exposure to ultra-violet light, distinct
traces of formaldehyde can soon be detected. These authors have
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 to formic acid.

2. 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 back of the vessel, where
the actinic intensity of the light is less.

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 is established:

Carbohydrate > Carbon Dioxide and Water

t 4

Formaldehyde .

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



8 ORGANIC CHEMICAL SYNTHESIS

must be used which has the same infra-red frequencies as carbon
dioxide; and malachite green, methyl orange, and />-nitroso-
dimethylaniline have been found to be suitable photocatalysts for
this reaction. A suitable photocatalyst for the second stage of the
reaction has not yet been found, but these authors suggest that
chlorophyll is an ideal photocatalyst for both stages of the synthesis.

The Photosynthesis of Nitrogen Compounds from
Nitrates and Carbon Dioxide. Potassium nitrate and possibly
ammonium salts are 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,
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 potas-
sium nitrite and methyl alcohol in aqueous solution to diffused day-
light and to ultra-violet light, and found that the methyl alcohol
became oxidized to formaldehyde at the expense of the nitrite, which
was reduced to hyponitrite, and the latter, at the moment of its
formation, reacted with the formaldehyde to form the potassium
salt of formhydroxamic acid (i):

KN0 2 + CH 8 OH - KNO + HCHO + HoO
KNO + HCHO - H C OH

N-OK

(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 re-
duction, green leaves check the accumulation of nitrite, thus indi-
cating 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.



THE PHOTOSYNTHESIS OF PLANT PRODUCTS 9

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.

More recently Baly, Heilbron, and Hudson f have investigated
the photosynthesis of nitrogen compounds from nitrates and carbon
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 H C OH, the activity being due to the
bivalent carbon atom. It is further assumed that the first product
of reaction is formhydroxamic acid (i), an atom of oxygen being
evolved which oxidizes a further quantity of formaldehyde to formic
acid. These changes may be represented by the following equations:

H - C - OH + O : NOK ~> H C OH -> H C OH

II I! +o

O : N - OK N OK

(i)

H. COOH



Under the conditions of the experiment, the potassium salt is com-
pletely hydrdlyzed to the free acid:

H - C - OH

II

N OH

and the latter compound readily loses oxygen with the formation of

a compound:

H - C - OH

NH
* Proc. Roy. Soc., 1919, 90 B, 158. f Trans., 1922, 121, 1078.



10



ORGANIC CHEMICAL SYNTHESIS



which may be regarded as a hydrate of hydrocyanic acid. With
formaldehyde the latter yields a labile ring compound (ii) which
undergoes rearrangement to give glycine (iii):

HO CH-CHOH CH 2 NHoCOOH

\/

NH (iii)

(ii)

Aqueous solutions of formhydroxamic acid prepared by the
action of ethyl formate on hydroxylamine in methyl alcoholic solu-
tion and formaldehyde were exposed to ultra-violet light, when a
reaction quickly ensued and a variety of products including methyl-
amine 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)-

In addition, it is 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
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

H-C-OH H-C-OH / \

I I H-C-OH HC-OH



H-C-OH



H-C-OH




NH



H-C-OH H-C-OH

(v)\

NH



By the condensation of two 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 N



H-C-OH H-C-OH
x <s

NH

(vi)




THE PHOTOSYNTHESIS OF PLANT PRODUCTS 11

Evidence of the formation of this substance, as well as histidine
(p. 145), has been adduced.

The authors summarize their views as follows:

Potassium nitrate Carbon dioxide and water

I 4,

Dtassium nitrite Activated formaldehyde

Formhydroxamic acid
Y



Nitrogen bases a-amino acids

_ __ i _ I
1 J"

Alkaloids and xanthine Substituted a-amino acids

bases J, (histidine, &c.)

Proteins

The readiness with which all these reactions take place is assumed
to be due to the cardinal fact that the various intermediate com-
pounds are produced in highly reactive phases.

Still more recently Baly, Heilbron, and Stern * have obtained a
number of naturally occurring nitrogen compounds photosyntheti-
cally 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
cases. 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 addi-
tion, nitric and probably nitrous acids are formed. This photosyn-
thesis is supposed to take place in two stages: first, the photosynthesis
of formaldehyde by the action of light on the carbonic acid,

H 2 CO 3 = H C OH + O 2 ;

and, secondly, the interaction of the activated formaldehyde and
ammonia, NHs + H . c . OH = CH 3 NH 2 + O.



The oxidation of the ammonia to nitric acid is said to be due to the

* Trans., 1923, 123, 185.



12 ORGANIC CHEMICAL SYNTHESIS

oxygen that is 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)
was qualitatively confirmed in every instance. Neither a- ami no
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

(London, 1922).

Biochemistry, by B. Moore (London, 1921).
Untersuchungen iiber die Assimilation der Kohlensanre, by R. Will-

statter and A. Stoll (1918).



CHAPTER II
Chlorophyll and other Natural Pigments

CHLOROPHYLL

Introduction. The role of chlorophyll in the realm of vital
synthesis has already been dealt with in the previous chapter. For
obvious reasons a correct knowledge of its constitution is of 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 progress.

In 1912 Willstatter and Isler * definitely showed that chlorophyll ,
as ordinarily obtained, and to which they had originally assigned the
formula C 55 H 72 O 6 N 4 Mg, is in reality a mixture of two substances,
and that two yellow pigments, carotin and xanthophyll, accompany
chlorophyll in the chloroplast of plants. A further pigment, fuco-
xanthin, has been isolated from brown algae.

The presence of magnesium in chlorophyll is remarkable, and at
once suggests other complex organic compounds containing traces

* Ann., 1912,390, 269.

13



14 ORGANIC CHEMICAL SYNTHESIS

of metallic elements. Of these the best known is haemoglobin,
the red colouring matter of blood, which contains iron, and yields
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
" crystalline chlorophyll " is obtained, whereas with ether an " amor-
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
green from the yellow pigments. The separation of carotin from
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
pigments in plants may be roughly summarized thus:



Green pigments JSH^Wt' ? pai ? per IO -

* fo tChlorophyll-&, f part per 1000.

Yellow pigments {Carotin, J part per 1000.

* B (Xanthophyll, J part per 1



1000.



The common Nettle (Urtica) is the plant which has most
frequently been used for the extraction of chlorophyll on a
large scale.

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 crypto-
gams and phanerogams. The formula suggested for this chlorophyll
was C 55 H 72 N 4 O 5 Mg, 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.



C 31 H 30 N 3 Mg-



= N

-io



COOCH 3
COOC 2 oH 3 9

Amorphous chlorophyll

Hydrolysis ~



+ 3 KOH -> C 31 H 30 N 3 Mg I _ COOK + CH 3 H + C 20 H 30 OH

I - COOK
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. Will-
statter and Stoll found that during the extraction with alcohol
an enzyme " chlorophyllase " is set free, and this brings about the
substitution. In other respects amorphous and crystalline chloro-
phyll are probably identical.

Phytol. According to the investigations of Willstatter,
Schuppli, and Mayer || phytol is a primary alcohol of the composition
C 20 H 39 OH. On oxidation with chromic acid a ketone, C 17 H 34 O,

* Willstatter and Oppe*, Ann., 1911, 378, i. f Ann., 1910, 378, 18.

t Willstatter and Utzinger, Ann., 1911, 382, 129.

Ann. 9 1910,378, 18. || Ann., 1919, 418, 121.



16 ORGANIC CHEMICAL SYNTHESIS

is obtained, from which it is concluded that phytol contains a double
bond between the a and j8 carbon atoms of the chain (i).

(W ()
C 16 H 31 C = C.CH 2 OH

C/O3 txH->

(i)

On further oxidation phytol gives phylenic acid and this acid forms
a lactone. Such behaviour is characteristic of acids containing
methyl groups in the a and j8 positions, and a double bond between
the a and j3 carbon atoms.

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
chlorophyll-0 and chlorophyll-6 by Willstatter in 1912.* Chloro-
phyll- a is a blue-black solid giving a green-blue solution in
organic solvents. Chlorophyll- b is a green-black solid giving
a green solution. The two chloroph)41s have much the same
solubility in the common organic solvents, but can be sepa-
rated by their different solubilities in methylalcohol. Both can
be obtained in microscopic crystals. These chlorophylls may
be written:

(C 32 H 30 ON 4 Mg) (COOCH 3 ) (COOC, H 39 ) Chlorophylls

(C 32 H 28 2 N 4 Mg) (COOCH 3 ) (COOC 20 H 39 ) 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 reverse change, i.e. the replacement of hydrogen
by magnesium, can be carried out by means of the Grignard re-
agent. J

When hydrolysis is allowed to proceed until the phytyl radicle
is removed, the monomethylester w r hich remains is called a phaeo-
phorbide;|| while the removal of the methyl radicle leaves a dibasic
acid phaeophorbin; e.g.

* Ann., 1912, 390, 269. t From Gr., #cu6s = dusky.

J Ann., 1913, 396, 180. From Gr., <t>vr6i> = a plant.

|| From Gr., <t>oppr) = food.



CHLOROPHYLL 17

COOCHg -Mg COOCH 3

[C 32 H 30 ON 4 Mg] -> [C 32 H 32 ON 4 ]

COOC 20 H 39 +H 2 COOC 20 H 39

Chlorophyll-a Phseophytin-a

(Phytyl phteophorbide)

. Hydrolysis COOCH 3 Hydrolysis COOH

-> [C 32 H 32 ON 4 ] -> [C 32 H 32 ON 4 ]

COOH COOH

Phaeophorbide-a Phaeophorbin-a

The chlorophyll derivatives may be classified in two main groups
according as they contain magnesium or are derived from the latter
by replacing the magnesium by hydrogen.

Magnesium Derivatives. Corresponding Hydrogen

Compounds.



g

Chlorophyll, MgR COOC 20 H 39 Phceophytin, H 2 R \ COOC, H 39

I "



fCOOCH 3 fCOOCH g

COOC 20 H 39 Phceophytin, H 2 R \ COOC,

I COOH I COOH"

Chlorophyllide, MgRJ^^SJ' Phaeophorbide, H 2 R

Chlorophyllin, MgR(COOH) 3 Phoeophorbin, H 2 R(COOH) 2

Glaucophyllin* or) M RH , COOfn Glaucoporphyrinf
Cyanophyllin, jMgKM^UUH) 2 of Cyanoporphyrin

Pyrophyllin, MgRH 2 (COOH) Pyroporphyrin, H,RH 2 (COOH)

^Etiophyllin, MgRH 3 ^tioporphyrin, H 2 RH 3

v

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, chloro-
}hyllin-tf, is produced. At 140 carbon dioxide is split off and
^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

If hot alkali is allowed to react with chlorophyll-a, an intra-
nolecular change occurs with the production of isochlorophyllin-<z,
someric with chlorophyllin-a. In this reaction the green colour

* From Gr., y\avKos bluish green. f From Gr., 7ro/?0tf/)eo$ = purple.

J Willstatter and Fritzsche, Ann., 1909, 371 , 33.

(D331) 2



i8 ORGANIC CHEMICAL SYNTHESIS

changes to a yellowish-brown but, after a few minutes, the original
green colour reappears. Willstatter * has suggested that this pheno-
menon 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:

y y

NH - CO



On hydrolysis the carboxyl y may enter into union with another
nitrogen group 8, or another carboxyl a may combine with nitrogen
y. The action of cold and hot alkali may be represented by the
scheme:

d y a

NH CO COOH

a 7 y

CO-O-C H NH CO




MgN 3 C 3l H 29 CO-OH

Chlorophyll! n - a
MgN 3 C 31 H 29 CO-OCH 3 ^ y ay

NH CO COOH
Chlorophyll - a III



MgN s 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 mole-
cule it can be seen that a very considerable number of lac tarns may
be formed. This type of rearrangement has been termed " allo-
merization " by Willstatter.

The further action of alkali, at higher temperatures, on chloro-
phyll-# results in the successive formation of cyanophyllin, ery-
throphyllin, and phyllophyllin, which are isomeric with glaucophyllin,
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 when heated with soda-lime are

* Ann., ign,382, 129.



PHAOPHYTIN-a



4

WITH ACIDS



STANDING IN
CHLOROPHYLL-a ALCOHOL ALLOM -CHLOROPHYLL-a



[3) (C0 8 C M H 3t ) WITH MgCH 3 I [C 31 H 29 N 3 M g ](NH-CO)(CO 2 CH 3 )(CO 2 C 2 oH39)

y y ft a.



n

I

a
o
r

METHYL-PHAOPHORBIDE-a ACID
[C M H 33 ON 4 ](CO 2 CH 3 ) (CO 2 CH 3 )



< PHAOPHORBIDE-a ACID

3 [C 32 H 32 ON 4 ](CO,CH 3 )(COOH) <



? METHYL-CHLOROPHYLLIDE-a
g [C 3 ,H 30 ON 4 Mg](C0 2 CH 3 ) (C0 2 CH 3 )

r , w



CHLOROPHYLLIDE-a

[C 32 H 30 ON 4 Mg](C0 2 CH 3 ) (C0 2 I



[C 31 H3oON 4 Mg](C0 2 CH 3 )(C0 2 C 20 H 39 )



PHYTOCHLORIN-e ACID ISOCHLOROPHYLLIN-a



CHLOROPHYLLIN-a ACID PHYTOCHLORIN, f and g



[C M H M ON 1 ](C0 1 H) 1



CYANOPORPHYIUN

[C,,H 3 ,N 4 ](CO,H) 2



[C 31 H M N 3 Mg](NH-CO) (COOH) a [C 31 H 29 N 3 Mg](NHCO) (COOH) 2

y a J3 y 8 y ft a



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



[C S2 H 32 ON,](C() 2 H) 2 | _



GLAUCOPORPHYLLIN



-I-

o p<?

"He



ERYTHROPHYRIN

3 [C 31 H M N 4 ](C0 2 H) t



ERYTHROPHYLLIN

[C M H M N.MgJ(C t U),



PHYLLOPORPHYRIN

[C 31 H M N,]{CO,H)



Ac it)



PHYLLOPHYLLIN



M^CHTl - [C^N.MgKCO.H)

#/$




SODA



LIME



RHODOPHYLLIN

[C 31 H 3a N 4 Mg](C0 2 H) 2



>



RHODOPORPHYLLIN

[C 31 H 34 N 1 ](C0 2 II) 2



PYRROPHYLLIN Ac_[ PYRRQPQRPHYLLIN

[C 3 iH M NJ(C0 2 H)



VETIOPHYLLi

[C 3l H M N 4 Mg]



AETIOPORPHYLLIN

[QiHagNJ




[Facing p. 18,



CHLOROPHYLL 19

converted into aetiophyllin, C 31 H 34 N 4 Mg, and astioporphyrin,
C 31 H 36 N 4 , respectively.

The table facing p. 18 summarizes the various decomposition
products of chlorophyll- a. Some of the intermediate products
formed by the decomposition of chlorophyll-a do not appear to be
fornfed when chlorophyll-6 is similarly treated.*

-^Etiophyllin and ^Etioporphyrin. The aetiophyllin mole-
cule contains no oxygen, so that the magnesium atom is probably
attached to nitrogen.

By the oxidation of phylloporphyrin, methyl-ethyl-maleinirnide
(i) and haematinic acid (ii) are formed. The structures of these
substances are known with certainty to be:

CH 3 C - C C 2 H 5 CH 3 C = C CH 2 CH 2 COOH

OC CO OC CO



NH NH

(0 (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 3 C - C C 2 H 5 CH 3 C - C C 2 H 5 CH 3 C - C - C 2 H 5

CH 3 C C-CH 3 CH 3 C CH HC C CH 3



NH NH NH

Phyllo-pyrrole Iso-hsemopyrrole 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 N



N N



' Willstatter, Ber., 1914, 47, 2854.



20 ORGANIC CHEMICAL SYNTHESIS

around which the methyl and ethyl groups are so disposed as
satisfactorily to account for the products obtained on oxidation and
reduction. In this way the following formulae are provisionally
given to aetioporphyrin and setiophyllin:

HC=CH



CH.-O-CH ,C C

ii >

C,H-C-C 0-CH
2 8



c

C-C-C.H.



G=OCII 3



CH 3




^Etioporphyrin ^tiophyllin

Carotin, C 40 H 56 , is an unsaturated hydrocarbon. It crystal-
lizes in lustrous rhombohedra which are orange-red by transmitted
and blue by reflected light. On exposure to the air it readily under-
goes oxidation and becomes bleached. Carotin also occurs in the
roots of carrot, and the colour of yellow or orange petals is not
infrequently due to it.

Xanthophyll, C 40 H 5G O 2 , forms yellow crystals with a blue
lustre. Like carotin, it undergoes bleaching on exposure to the air.
On reduction with magnesium powder and water xanthophyll is
converted into carotin.*

Fucoxanthin, C 40 H 54 O 6 , was first isolated from fresh brown
algae by Willstatter and Page.f Unlike carotin and xanthophyll,
which are neutral substances, fucoxanthin has basic properties, and
forms blue salts with mineral acids.

Chlorophyll and Haemin. Haemoglobin contains 0-47
per cent of iron and consists of a colourless protein named
globin, united to a coloured prosthetic or " non-protein " group.
Haemoglobin possesses the remarkable property of combining
with carbon monoxide and nitric oxide, and is most easily
oxidized to oxyhaemoglobin. When treated with weak acids,
oxy haemoglobin is easily resolved into globin and haematin. The
nature of the union between these two substances is quite
unknown.

* Ewart, Proc. Roy. Soc., 1915, 89 [B], i. f 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 haemo-
pyrrole. Willstatter and M. Fischer* treated haematoporphyrin
with alcoholic potash in the presence of pyridine and obtained
hsemoporphyrin, C 33 H 36 O 4 N 4 , which on distillation gave aetio-
phyllin. These observations are of special interest since they serve
to co-relate chlorophyll and haemin. Haemoporphyrin is a dicar-
boxylic acid of aetioporphyrin.

The oxidation products of haematin have been studied by
Kuster. f Two haematinic acids, which eventually proved to be
the anhydride and imide of carboxyethylmethylmaleic acid, were
obtained:

CH 3 C COOH CH 3 C - CO

H0 2 C CHo CHo - C COOH || / NH

HO 2 C-CH 2 .CH. 2 C - CO

Carboxyethylmethylmaleic acid Haematinic acid (i)

CH 3 C - CO CH, - C - CO



H0 2 C CH 2 - CH 2 . C - CO C 2 H 5 - C - CO

Haematinic Acid (ii) Methylethylmaleic anhydride

Both haematinic acids may be readily converted into methylethyl-
maleic 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 nitrogen to a carbon linking:



O C C C





> Zeil. Physiol. Chem., 1913, 87, 423. f Ann., 1906, 345, x.



22 ORGANIC CHEMICAL SYNTHESIS

The following tabulation briefly illustrates the relation of chloro-
phyll and its derivatives to those of haemin:

Chlorophyll Haemoglobin > Haematm

I

Chlorophyllin

A e t i o p or pby rin



Pyrrophyllin

i

AetiopJby'Uin



Haematoporphyrin




The following provisional formula which has been assigned to
haemin should be compared with that of aetiophyllin:



CH 3 .C



COOH.CH 2 .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
many plants. On account of their close relationship to the natural
blue colouring matters known as the anthocyanins (p. 33), Will-
statter and Everest* have proposed the adoption of the term
" anthoxanthins " to distinguish these yellow pigments.

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 pre-
paration 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 (ii) on treatment with fuming hydrochloric

acid:

CH - C(OH)CO 2 C 2 H 5 CH - C CO,H

/ / \

CO -> CO O



CH = C(OH)CO 2 C.,H 5
(i)



CH = C
(ii)



CO,H



and on heating this substance decarboxylation takes place, with the
successive formation of coumenic acid (iii) and y-pyrone (iv):

COOH



CH = C



CO



\



O



CH
CO



CH



CH = CH

(iii)



O

x /

CH = CH

(iv)



y-Pyrone is a colourless solid, and the basic properties of com-
pounds containing the y-pyrone nucleus are well marked. The
salts 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.

t Chelidonic acid (7-pyrone dicarboxylic acid) occurs in combination with the
alkaloid chelidonine in the root of the common celandine.



24 ORGANIC CHEMICAL SYNTHESIS

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 salts is due to
the oxygen atom (a) becoming quadrivalent when salt formation
occurs.

CH 3

C - CH

CO O(a)

\ /

C - CH

CH 3

(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 an-
hydride 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:

CO
HOOCX\

+ I I >-

X OH HO\X

O

Ullmann and Zlokasoff J obtained 0-phenoxybenzoic acid (i)
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 o

(i)

Xanthone crystallizes in long colourless needles, gives a blue
fluorescence in sulphuric acid, and readily forms oxonium salts.
By reduction under suitable conditions, xanthene (ii), xanthydrol
(iii), and dioxyxanthylene (iv) may be obtained.

* Trans., 1899, 75, 710. f Ann., 1860, 115, 197.

J Ber., 1905,38, 21 ii.




THE ANTHOXANTHINS 25

CHOH




(iii) (iv)

When 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
hindrance.

Indian Yellow or Piuri. This pigment is obtained by con-
centrating the urine of cows which have been fed upon mango leaves.
On account of its disagreeable smell it is seldom used as a dye-stuff.

The principal ingredient of this pigment is euxanthic acid
(C 19 H 18 O n ), which is present in the form of its magnesium or calcium
salt, for which Graebe * suggested the formula:

CO

HO C 6 H 3 <^>C 6 H 3 O CH(OH)[CH(OH)] 4 COOH
O

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 /\> H0 r

I + 1-2H.O +

X/OH H0\/

O

Euxanthone

Gentisin. This pigment is the yellow colouring matter of
Gentiana lutea, and its identity with 1:3: y-trihydroxyxanthone-
3-methylether has been established by v. Kostanecki.




)H

>*v >v >N

HOr




OCH,



* Ann., 1889, 254, 267. f Cf. Stenhouse, Ann., 1844, 51, 429.
J Ber., 1891, 24, 1894. Monats., 1891, 12, 207; 1895, 16, 919.



26



ORGANIC CHEMICAL SYNTHESIS



FLAVONE AND FLAVONAL PIGMENTS



Name.



Structural Formula.



Occurrence.



Chrysin



Quercetin



Rhamnetin



Morin



Luteolin



Galangin



Kaempferol



OH




HO



OH



CO



OH




Several varieties of
poplar, especially
Populus nigra, P.
pyramidalis.



Bark of Quercus
tinctorius, leaves
of horse chestnut,
hop, &c.



Dried berries of
Rhamnus cathar-
ticus, R. tinctoria.



Wood of Morus
tinctoria (yellow
wood).



Reseda luteola,
"weld"; Genista
tinctoria, " dyer's
broom ".



Galanga root.



Flowers of Del-
phinium consolida,
Prunus spinosa;
berries of Rham-
nus catharticus.



FLAVONE AND FLAVONAL PIGMENTS 27

The Flavones and Flavonols. Flavone has been obtained
in the free state in nature.* Many varieties of the primula possess
on their flower stalks, leaves, and seed capsules a characteristic dust
or meal. 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-ethoxyben-
zoate and acetophenone, in the presence of sodium, to give o-ethoxy-
benzoylacetophenone (i):



X\




cooc 2 H . r .,

-



(0

which, when digested with boiling hydriodic acid, yielded flavone.

CO CO

CO-CH 2






OH

N f HO

2. Ruhemann J employed esters of /? - hydroxyarylcinnamic
acids, which he prepared by the action of sodium phenolates on the
esters of propiolic acid, e.g.

C 6 H 5 C : C C0 2 C 2 H 5 + NaOC 6 H 5 = C 6 H 5 C(OC 6 H 5 ) : C(Na)CO 2 C 2 H 5

\

The esters were then converted into the corresponding acids and
chlorides, and the latter on treatment with aluminium chloride gave
the corresponding flavones:

HO CO CH CO

n / \CH

C 6 H 5 C-C 6 H 5 -> C 6 H 4 ||

\/ \ /C-C 6 H 5

o o

3. Simonis condensed benzoyl acetic ester and phenol in the
presence of phosphorus pentoxide:




CJETp-CO
2 5




f ^n. i i n

*" + C 2 H 5 OH + H 2 O



* Trans. , 1915, 107, 872. f ^^-, 1900, 33, 330.

J Ber., 1903, 36, 1913, 2188. Ber.> 1914, 47, 2229.




28 ORGANIC CHEMICAL SYNTHESIS

CO

Methylacetoacetic ester condenses in the
same way to give dimethyl-chromone:

o

It is interesting to note that if sulphuric acid is used in the con-
densation of phenols and j8-ketonic esters, the reaction takes a different
course and derivatives of a-pyrone (coumarin) are obtained.

Flavonol differs from flavone in the fact that it contains a
hydroxyl group in the y-pyrone ring in the place of the hydrogen
atom which is present in the case of flavone. Flavonol has been
obtained synthetically as follows:

i. Von Kostanecki and Szabranski* converted flavanone into
isonitroso flavanone (i) and thence into flavonol by the action of
dilute acids:

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:

O

CH 3 C 6 H 3 <^)CBrCHBrC 6 H 5

CO

CO

xOH Br / \C-OH

> CH 3 C a H 3 \ I > CH 3 -C 6 H 3 ||

X CO-C=C-C 6 H 5 \ /C-C 6 H 5

I o

OH

This is a general reaction and has been applied extensively.

On hydrolysis flavonol gives o-hydroxybenzoyl carbinol (ii)
and benzoic acid:

CO CO - C(OH)

/ \C-OH /

CTT II ,. /~i TT

6 rl 4 I) > <-6*~i4\

\ /C-C 6 H 5 X OH

O HO - C - C 6 H 5

* Ber. t 1904, 37, 2819. f ^^"- 1908, 41, 4233.



C 6 H 4



FLAVONE AND FLAVONAL PIGMENTS 29

CO - CH(OH) OH

+ C 6 H,COOH



OH CO C 6 H 5 CO CHoOH



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.

Chrysin (i : 3-dihydroxyflavone). This pigment was first
isolated from poplar buds, in which it is present to the extent of
about 0-25 per cent, by Piccard in 1873. For this purpose an alco-
holic 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
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 solu-
tion exhibit an intense yellow colour. It forms a diacetyl deri-
vative. On boiling with concentrated potassium hydroxide solu-
tion, chrysin gives phloroglucinol, benzoic acid, acetic acid, and a
little acetophenone:

C 15 H 10 4 + 3 H 2 O - C 6 H 6 O 3 + C 6 H 5 COOH + CH a COOH

The researches of v. Kostanecki indicated that chrysin was i : 3-
dihydroxyflavone, and this has been established by its synthesis by
Emilewicz, v. Kostanecki, and Tambor.* For this purpose phloro-
acetophenone-trimethyl-ether (i) is condensed with ethyl benzoate
in the presence of sodium to give 2:4: 6-trimethoxy-benzoyl-
acetophenone (ii):

OCH 3 OCH 3

X\_CO_CH 2

I ] - I I ' ^

CH 3 O\^/OCH 3 CH 3



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.




ORGANIC CHEMICAL SYNTHESIS



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
yields protocatechuic acid and phloroglucinol. When pentamethyl
quercetin is treated with alcoholic potash it gives methoxyfisetol-
dimethyl-ether (iii) and veratric acid (iv), which indicates that
quercetin is a derivative of flavonol: *



OCH 3 CO



COCH 3



CH 3




OCH L
OCH 3 ~



OCH 3

fV co:

k^kpH



CH 2 OCH 3



OCH,



+COOH



o>



CH,



111



iv



Quercetin has been synthesized from phloracetophenone dimethyl
ether and veratric aldehyde by v. Kostanecki, Lampe, and Tambor
as follows :f



{ / v

COCH:CH-< VOCH-
\ / a



OCH,



OCH



aCOCH 3
OH

Phloracetophenone
dimethyl-ether


f HCO-/ V
x O

Veratric
aldehyde



JI0




X)CI



OH



Hydroxytetramethoxy-benzal-
acetophenone



CH 3



CH 3 O



OCH,




HC1



CO-CH

CH-/ V-OCH 3 CH 3



OH



OCH



3 CO




C:NOH H 2 S0 4

CH-/ VoCH



^



3 CH 3



OCH,



CO




O



CH 2
CHQ



OCH,



CO




C-OH

c



O



* Herzig, Ber., 1909, 42, 155.

% This is analogous to the reaction:

CO CH



HC1 (Alcoholic)



Tetramethoxyflavone
t Ber. y 1904,37, 1402.

CO



OH CH-C.H.

6 o

w - Beazal-o-oxyacetophenoae



O

Flavanone




OCH 3
OCH 3



FLAVONE AND FLAVONAL PIGMENTS 31

OCR, _ OH CQ




O

Quercetin



The reduction of quercetin to cyanidin chloride will be dealt
with later (p. 37).

Rhamnetin (quercetin-3-methylether). Persian Berries the
seed-bearing fruit of various species of Rhamnus contain the
glucoside xanthorhamnin, which on hydrolysis gives a sugar and
the colouring matters rhamnetin, rhamnazin, and quercetin. Iso-
rhamnetin, which is a monomethylether of quercetin, occurs, together
with other products, in the common red clover.*




OH CO

vC-OH





-OH HOk A > < )OH CH 3
'OH V ^ OCH 3 ' 6

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 precipi-
tate with lead acetate.

Morin has been synthesized by v. Kostanecki, Larnpe, and
Tambor in a similar manner to quercetin. f

Luteolin is the main colouring matter of " weld "the dried
herbaceous plant known as Reseda luteola which is widely dis-
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 tetrahy-
droxyflavone, and this structure has been confirmed by its synthesis
by v. Kostanecki, Rozycki, and Tambor. For this purpose phlor-
acetophenone trimethyl-ether (i) is condensed with ethyl-veratrate

* Power and Salway, Trans., 1910, 97, 231. f Ber., 1906, 39, 625.



32 ORGANIC CHEMICAL SYNTHESIS

(ii) to give 2 14 : 6 : 3':4'-pentamethoxy-benzoyl-acetophenone (iii),
which on long digestion with concentrated hydriodic acid gives
luteolin:



OCH 3




H.OOC-/ )
8 \ /



0)




Galangin (dihydroxyflavonol) is obtained from galanga root
the rhizome of Alpinia officinarum. It has been obtained syn-
thetically by v. Kostanecki and Tambor in a similar manner to
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 Wilkin-
son, f

Von Kostanecki and Tambor J have obtained kaempferol syn-
thetically as follows: Hydroxy-4 : 6 : 4 / -trimethoxy chalkone (i), on
boiling with alcoholic sulphuric acid, gives i : 3 : 4 / -trimethoxy-
flavanone (ii):

OCH 3 OCH 3 CO




The latter on treatment with amyl nitrite and hydrochloric acid
yields isonitroso-i .'3 : 4-trimethoxyflavanone (iii), which on boiling
with ro-per-cent sulphuric acid gives 1:3: 4 / -trimethoxyflavonol

*Ber. 9 1901,34, 3723. t Trans. y 1902, 81, 585. J Ber. y 1904,3?, 792.

Chalkone or benzylidene acetophenone is readily prepared by the condensa-
tion 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 6 H 5 COCH : CHC 6 H 5 + H 2 O

(Claisen, Ber., 1887, 20, 257.)



THE ANTHOCYANIN PIGMENTS 33

(iv), and the latter on digestion with hydriodic acid yields kaemp-
ferol (v).

OCH 3 CO OCH 3 CO

,C:NOH /\/\C-OH

CH a o





THE ANTHOCYANIN PIGMENTS

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 is only within the last decade that the nature of the antho-
cyanins has been revealed.

The recognition of glucosides among the anthocyanins appears
to 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
led were inaccurate. In 1913 Willstatter began to publish, with
numerous collaborators, a series of investigations which have brought
this subject within the realm of synthetic chemistry. For the pur-
pose of distinguishing the glucosidic from the non-glucosidic pig-
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

* Ann., 1913, 401, 189.
(D331) 3



34 ORGANIC CHEMICAL SYNTHESIS

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 crystalline cyanine chloride. On hydrolysis, the sugar was
removed and crystalline cyanidine chloride was obtained.

Continuing these investigations, it soon became evident that the
almost infinite variety of colour and tint exhibited by flowers does
not imply the existence of an equally diverse series of plant-colouring
materials. It appears that only comparatively few basal colouring
materials are distributed throughout the flower kingdom, and from
these simple foundations the endless variety of floral shades and
colours is built up by slight alterations in structure.

The colouring matter of a large number of flowers has been
examined, and these investigations have now culminated in the
synthesis of pelargonidin by Willstatter. In the -early stages of the
investigation of the anthocyanins, the reduction of quercetin was
shown to produce cyanidin, and in this way the genetic re-
lationship 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
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 employed for the extraction vary according
to the plant which is used as a starting material, but the essential
part of the process is the formation of a sparingly soluble oxonium
salt. Water alone suffices in the case of the cornflower; hydro-
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 tempera-
ture and the dark red filtrate is precipitated with ether.

The investigation of the anthocyanins is rendered difficult by
the fact that they are not very stable substances. Aqueous or
alcoholic solutions of the pigments gradually lose their colour.
Decolorization can be delayed by the addition of salts such as sodium
chloride, and the addition of excess of mineral acid apparently stops
it completely.

Among the methods which have been employed for the purifica-
tion of the extracted pigments may be mentioned: precipitation and
crystallization of the chloride; purification by suitable reagents and



THE ANTHOCYANIN PIGMENTS 35

crystallization of the chloride; and separation as picrate and subse-
quent conversion into chloride.

The 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 anthocyanins, as glucosides, are readily soluble in
water, and as a rule in alcohol, but are insoluble in ether and chloro-
form. The glucosides are hydrolyzed by heating with dilute acids,
and the resulting anthocyanidin salts are insoluble in ether but are
generally soluble in water and in alcohol. With one exception, the
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 con-
verted 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
its basic properties to the fact that the oxygen atom may become
quadrivalent with the formation of oxonium salts. These salts may
be written (i) or (ii) according as we use the benzenoid or quinonoid
formula:

)H



c-CH





The y-pyrones may also be regarded as derivatives of y-pyrone
(iii), 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 ORGANIC CHEMICAL SYNTHESIS

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

CH CH





o

i

-- x

(Benzenoid) (i) (Orthoquinonoid) (ii)

The anthocyanidins are hydroxy or methoxy derivatives of
2-phenyl-benzopyroxonium salts; thus cyanidin chloride may be
written (iii) or (iv):

QH OH CH

PH ^f\ XV r.nu- QH






HO X/V/ C -\_/~ OH HO -XXXX C -^ > H
I

ci ci

(iii) (Orthoquinonoid) (iv) (Benzenoid)

It 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

OH




(0

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

Pelargonidin.

Pelargonin. Diglucoside of pelargonidin. Dahlia, scarlet geranium.

Callistephin. Monoglucoside of pelargonidin. Aster.

* The salts of 2-phenyl-benzopyroxonium have been also termed polyflavylium
salts or polyflavoxonium salts. In this way cyanidin chloride may also be desig-
nated as a pentahydroxy-flavoxonium chloride.

fHeilbron and Buck, Trans. , 1922, 121, 1198.



THE ANTHOCYANIN PIGMENTS

Cyanidin.



37



Cyanin.
Peonin.
Idaein.



Violanin.
Delphinin.

Oenin.



Diglucoside of cyanidin.
/Diglucoside of peonidin (mono-
\ ethyl ether of cyanidin).

Monogalactoside of cyanidin.

Delphinidin.

Rhamnoside of delphinidin.
/Diglucoside of delphinidin +-
( hydroxybenzoic acid.
| Monoglucoside of oenidin (del-
\ phinidin dimethyl ether).



Cornflower, dahlia.

Peony.

Fruit of cranberry.



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:

H OH

I 1LJ V

CO

,C-OH OH /X/ \C-OH OH



OH



HO





OH



[Intermediate product]



Cyanidin chloride



Cyanidin itself is insoluble in water, but readily soluble in
alcohol. With sodium carbonate it resembles cyanin in first be-
coming blue and then violet. Colourless modifications of both
cyanin and cyanidin are obtained by hydrolytic dissociation,
and the colour may be restored by concentration or the ad-
dition of acid.

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 ORGANIC CHEMICAL SYNTHESIS

one or other of the two forms depends on the condition of the solution.
OH



HO




o
6

Coloured (i)



H Cl
Colourless (ii)



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. This is in agreement
with formula (i), and this structure has been confirmed by its syn-
thesis.

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 benzoyla-
tion 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




Synthesis of Salts of Benzopyroxonium and its Deri-
vatives. The following are the more important methods by
which these compounds may be synthesized:



THE ANTHOCYANIN PIGMENTS 39

i . Decker and v. Fellenberg * obtained benzopyroxonium
chloride by the condensation of salicylaldehyde with acetaldehyde
in the presence of concentrated hydrochloric acid:

CHO CH 3 CH:CH

C 6 H 4 <( + I + HC1 = C 6 H 4 <^ I

OH CHO O : CH + 2H 2 O



The salt was analysed in the form of its double salts with ferric
chloride and gold chloride. In moist air the ferric chloride double
salt undergoes slow decomposition with the formation of cumarin,
probably according to the scheme:

CH : CH CH : CH



C.H



C 6 H



I
O : CH



O : CH

Cl OH

CH : CH CH : CH



-> C 6 H 4 <

Isomerization V Au rnu Oxidation



I

o-co



When acetaldehyde is replaced by acetone, salts of z-methyl-
benzopyroxonium are obtained, and it has been generally shown
that any compound containing the CH

CH 2 CO group may be used. In ^




this way co-ethoxy- and phenoxy- I I L / \
acetophenones have been converted ^^^T \ /
into compounds of the anthocyanidin
type.f

2. 2-Methyl-benzopyroxonium chloride has been obtained by
treating cumarin with magnesium methyl iodide in benzol solution:
PH'CH CHaMgI CH : CH



^ C 6 H 4 <

O-CO OMgl COCH 8

CH : CH



O : C-CH 3

i,

Ann., 1909, 364, 17. f Pra tt and Robinson, Trans., 1922, 121, 1577.



40 ORGANIC CHEMICAL SYNTHESIS

2-Phenyl-benzopyroxonium chloride has been obtained in a similar
manner, using magnesium phenyl bromide.

Synthesis of Pelargonidin, Pelargonidin has been syn-
thesized by Willstatter and Zachmeister * as follows: 2 : 4 : 6-tri-
hydroxybenzaldehyde (i) is condensed with sodium methoxyacetate,
in the presence of the corresponding anhydride, to give 5 : y-di-
methoxyacetyl-3-methoxycoumarin (ii), which on successive treat-
ment with caustic soda and diazomethane yields 3:5: y-trimethoxy-
coumarin (iii). This compound is then treated with magnesium
anisyl bromide and converted into the chloride of anisyl-trimethoxy-
benzopyroxonium (iv). On demethylation with hydriodic acid and
subsequent treatment with hydrochloric acid, pelargonidin chloride
is obtained.



OH CH 3 0-CH 2 CO-0 CH

-



A-



HI COCH




(0 i" ()

CH 3 CH CII S O CH HO CH

/\/\C-OCH




^okA/ 00 ^aovU^I) ^ vU c -O H

O O-C1 O-C.1

(* * * \ / * \

ll1 / ( 1V / 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.

We have already seen that the anthocyanidins have a structural
formula closely related to that of the flavones, and this fact in con-
junction with the production of cyanidin on the reduction of quercetin
has suggested that the anthocyanidins may be derived from the
flavones.

On 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, C 15 H 10 O 5 . . . . Luteolin, kaempferol, fisetin, C 15 H 10 O Q
Cyanidin, C 15 H 10 O 6 .... Quercetin, C 16 H 10 O 7
Delphinidin, C 15 H 10 O 7 .... Myricetin, C 15 H n O 8

* Sits. Preuss. Akad. Wiss. Berlin, 1914, 34, 886.



THE ANTHOCYANIN PIGMENTS 41

From this tabulation it is evident that the anthocyanidins contain
one atom of oxygen less 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 deter-
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
termed allocyanidin or " artificial an- OH OH

thocyanin ", but Willstatter has stated o=r /V/' / / \_ O H
that it is not a true anthocyanin pig- I | \ /

ment and he proposes for it an open S^/S^/C-OH
structural formula: 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 salts which appear to throw some
light 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 may be
used as an argument for the older oxidation hypothesis. It is quite
possible, however, that the two views may be reconciled on the
assumption that oxidation is needed in* the earlier stages of the
synthesis, and that only the final stage is one of reduction of flavone
derivatives to anthocyanin.

Finally, it should be remembered that the fact that small quanti-
ties of a natural anthocyanin pigment can be obtained artificially by
the reduction of a hydroxyflavonol, does not necessarily imply that
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. i J. Amer. Chem. Soc., 1919, 41, 208.



CHAPTER III
The Carbohydrates

Introduction* 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
laevulose by Berthelot. Kekule eventually applied the term dex-
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 aldo-
pentose (arabinose). Three hexobioses (sucrose, lactose, and maltose)
and one hexotriose (raffinose) were also known to be definite indi-
viduals. 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 con-
figurations. 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
by Irvine has opened the way to a multitude of contingent isomerides,
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.

Classification of the Carbohydrates, The carbohydrates
fall naturally into two classes, the sweet and crystalline compounds
termed sugars and the tasteless amorphous carbohydrates. Ac-
cording 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 H 12 O 6 ; the cane-sugar group,
embracing all the compounds of the formula C 12 H 2 2O n ; and the
amylose or starch group, which contained the amorphous, complex
carbohydrates of the general formuta (C 6 H 10 O 5 ) W . The three
principal groups of carbohydrates are now termed monosac-
charoses * (formerly glucose), disaccharoses (formerly the cane-
sugar group), and polysaccharoses (formerly the starches, &c.).

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 mono-
saccharoses 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 C 6 H 12 O 5 , so that the old term " carbohydrate " (hydrate
of carbon) is not now strictly applicable to all compounds classified
as carbohydrates.

* Fischer uses the suffix " ide " in place of " ose ", by analogy with the
glucosides.



44 ORGANIC CHEMICAL SYNTHESIS

THE MONOSACCHAROSES

Natural Sources. 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:

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.

MANNOSE. As condensation products, the mannans, in certain
mucilages, and in the cell walls of the endosperm of various seeds.
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 predominates.

2. Oxidizing Action by " Sorbose Bacterium". This
organism was discovered by Bertrand** and found to exert a selective
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. t 1887, 20, 3384.
Fischer and Tafel, Ber. y 1887, 20, 1088.
|| Fischer and Tafel, Ber., 1888, 21, 2634.
][ Grimaux, Contptes rendus, 1887, 104, 1276.
** Bertrand, Ann. Chint. Phys. y 1904, 8, 3, 181.



THE MONOSACCHAROSES



45



3. Aldol Condensation of the Lower Members in Alkaline
Solution. Dilute sodium hydroxide solution is usually used as
condensing agent, e.g. glycollic aldehyde polymerizes to erythrose:

CH 2 (OH)CHO + CH 2 (OH)CHO - CH 2 (OH) CH(OH; CH(OH) CHO

4, Conversion of a Lower to a Higher MonosaccRarose.
The Cyanhydrin Reaction. This reaction was discovered

by Kiliani in 1885 *, 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:

COOH



HO-
H-
HO
HO-



-H H

OH HCN.then HO

H Hydrolysis HO
of the Cyanhydrin



(


:HO

OT1


(

H"


:OOH

/^TT




U1J




"Uri






HCN,then H -




TT i i tjr*




nyuioiysis IJLW--
of the Cyanhydrin

TV/~\






nvj





CH 2 OH

Z-Gluconic acid



CH,OH



/-Arabinosc



CH a OH

/-Mannonic acid



A new asymmetric carbon atom is introduced in this reaction, and
consequently two products are formed.

This reaction opened the way to the artificial production of
/-glucose and /-mannose. The method was found to be capable of
wide extension, and is limited only by the diminishing amount of
material available for each succeeding step. The following series
were realized by Fischer: f



J-glucose
rf-mannose

^-"6^12^6

rhamnose -
C 6 H 12 O 5



f a-glucoheptose
\ (3-glucoheptose

mannoheptose

C 7 H 14 7

oc-rhamnohexose

C 7 H 14 6



/a-gluco-octose
(p-gluco-octose

rnanno-octose -

C 8 H 16 O 8
rhamnoheptose
C 8 H 16 O 7



" glucononose

mannononose

CoH 18 O 9
rharnno-octose



5. Conversion of a Higher to a Lower Monosaccha-
rose. The degradation of a sugar may be brought about in
four ways:

(a) WohVs method.^ This method may be illustrated by the
conversion of glucose into </-arabinose. In practice the oxime of

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



46 ORGANIC CHEMICAL SYNTHESIS

the monosaccharose is heated with acetic anhydride and a little zinc
chloride, when a vigorous reaction ensues and the pentacetate of
gluconic nitrile is formed. Hydrogen cyanide is then eliminated
by treatment with ammoniacal silver oxide.

CHO CH : NOH CN

CHOH CHOH CHOH CHO

(CHOH) 3 -> (CHOH) 3 -> (CHOH) 3 -> (CHOH) 3

CH 2 OH CH 2 OH CH 2 OH CH 2 OH

Glucose Glucose oxime Gluconic nitrile Arabinose

In this way glucose may be converted successively into arabinose,
erythrose, glycerose, and glycollic aldehyde.

(b) Ruff's method* In this method the calcium salt of the mono-
basic acid obtained from the higher monosaccharose is oxidized,
by means of Fenton's reagent, to the lower sugar.

C 6 H 12 6 -> C 6 H 12 7 + O -> C 5 H 10 O 5 + C0 2 + H 2 O
Glucose Gluconic acid Arabinose

(c) 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
into t/~arabinose and ultimately complete degradation to formaldehyde
achieved.

(d) Weermanri's method^ An alcoholic solution of gluconolactone
gives </-gluconamide on saturation with ammonia. When this is
treated with hypochlorous acid a 50 per cent yield of t/-arabinose is

produced.

HC1O H 2 O

-CH(OH)CONH 2 -> -CH(OH)N:CO -> - CHO + NH 3 + CO 2

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. This change may
be brought about with the aid of phenylhydrazine. The conversion
of glucose into fructose as carried out by Fischer may be considered.

* Ber., 1898, 31, 1573. t Biochem. Zeit., 1910, 24, 152.

%Absts.> 1915, 1, 387.



THE MONOSACCHAROSES 47

An excess of phenylhydrazine and glucose react with the formation
of glucosazone as follows:

CHO CH : N NHC 6 H 5

CHOH CHOH

(CHOH) 3 + C 6 H 5 NH-NH 2 "" (CHOH) 3 + C 6 H 5 NH NH 2

CH 2 OH CH 2 OH

Glucose Glucose phenylhydrazone *

CH : N-NHC 6 H 5

CO

-> | + C 6 H 5 NH 2

(CHOH) 3 + NH,

CH 2 OH

Intermediate product.

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

CH : N NHC 6 H 5 CHO

C : N NHC 8 H 5 Warm cone. HC1 CO
I -> |

(CHOH) 3 (CHOH) 3

CH 2 OH CH 2 OH

Glucosazonef Glucosone J

The osone on reduction of its 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:



CH : N NHC 6 H 5


CH 2 NH 2


CH 2 OH


I


|


|


C : N NHC 6 H 5


CO


CO


(CHOH) 3 ->


(CHOH) 3 ->


(CHOH)g


CH 2 OH


CH 2 OH


CH 2 OH


Glucosazone


Fructosamine


Fructose



* Fischer, Ber., 1887, 20, 821.
f Fischer, Ber., 1884, 17, 579. J Fischer, Ber., 1889, 22, 87.



48 ORGANIC CHEMICAL SYNTHESIS

It is interesting to note that Fischer has shown that the sugars
may be conveniently purified by preparing the pure phenylhydrazone
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
Polyhydroxy Acids. f The monocarboxylic acids, 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
gives gluconolactone. These lactones are crystalline compounds ^
which in aqueous solution pass into the corresponding acids, until
a condition of equilibrium is attained. Many of these lactones
may be reduced 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
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 to the alcohol, e.g. gluconic lac tone
gives glucose:

CO CHO

O (CHOH) 2 (CHOH) 2



H + H 2 = CHOH

CHOH CHOH



:H 2 OH CH 2 OH

Gluconic lactone Glucose

8. Interconversion of Isomeric Polyhydric Monocar-
boxylic Acids. J These acids undergo a very interesting change
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 trans-
formed into rf-mannonic acid, whereas d-mannonic acid under the
same conditions is partly converted into d-gluconic acid. The
asymmetric carbon group, to which the carboxylic group is directly
united, undergoes optical inversion. As the process is reversible
the original and newly formed products are usually present is

* Fischer and E. F. Armstrong, Ber. y 1902, 35, 3141.

t Fischer, Ber., 1890, 23, 930. J Fischer, ibid., 2611.



THE MONOSACCHAROSES 49

an equilibrium mixture. The reaction may be represented as
follows:

COOH COOH

H-C-OH HO-C-H



:HOH)* - (CHOH)*

CH 2 OH CH 2 OH

This method has proved of great value, not only for synthetic
purposes, but also as a means of ascertaining the configuration of
the monosaccharoses.

The Synthesis 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
summarized.

The earlier work, carried out by Butlerow and Loew, has already
been referred to. Fischer himself has stated that the directive in-
fluence on his 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 O 6 .
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
fructose 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
scheme illustrates the synthesis of some of these sugars.



(D331)



50 ORGANIC CHEMICAL SYNTHESIS

Acrolein dibromide Formaldehyde Glyeerose

I



^a-Acrose



a-Acrosazoue

i

a-Acrosoae



dl- Fructose



1- Fructose



dl-Marmitol



dl- Mannonic Acid
1 - Mannonic Acid d -Mannonic Acid

1 I N

1-Gluconic Acid 1-Mannose d-Mannose d-Glucomc Acid



1- Glucose



d-Glucosazone d- Glucose



d-Glucosone



d- Fructose



The Configuration of the Monosaccharoses. Before con-
sidering 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
two forms only. These may be represented thus:





These two arrangements are related as object and mirror image.
One may be designated as + or d y the other then becoming or /,

* As will be shown later, the formulae assigned to d- and /-glucose are chosen
arbitrarily. It is assumed that 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.



THE MONOSACCHAROSES



the choice being immaterial. If these two compounds are solids
the crystals of one are related to those of the other as object
to mirror image. Such crystals are said to be hemihedral or
enantiomorphous (Gr., eVai/r/o? = opposite), and the d and /
compounds are said to be enantiomorphously related to one
another.

If 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




H




COOH
1- Tartaric Acid



or by using projections of these models:
COOH COOH



COOH
Meso-Tartaric Acid



COOH



H-
HO-



H



COOH



H-



-H
-OH



H
H-



-OH
-OH



COOH



COOH



Mesotartaric acid is the simple optically inactive form. It is in-
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 d and / forms.

Thus it is evident that compounds like tartaric acid, which con-
tain two structurally identical asymmetric carbon groups, exist in
three optically isomeric forms which may be represented by the

signs , H f- , and ~| respectively. If, however, the two

asymmetric groups in this acid are made to have different structures,



52 ORGANIC CHEMICAL SYNTHESIS

as e.g. by reducing one of the COOH groups to CH 2 OH, the

configurations H and f- are no longer identical, so that four

optical isomerides are now possible, viz. , -j [-, H , and

K Of these four optical isomerides, the first two are enantio-
morphously 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-
cules of a tetrose, CH 2 OH CHOH CHOH CHO, or the corre-
sponding monocarboxylic acids, CH 2 OH CHOH CHOH COOH,
contain two dissimilar asymmetric carbon groups and would there-
fore exist in four optically active forms, and two of these (the h

and the + ) would give one and the same inactive dicarboxylic
acid. An extension of this reasoning to the pentoses shows that the
following tabulation represents the theoretical possibilities:

ASYMMETRIC
CARBON
ATOMS. OPTICAL ISOMERIDES.

Pentoses . . . 3 8, 4 pairs of enantiomorphously

related isomerides.

Corresponding monocar-
boxylic acid . . . . 3 8, 4 ,,

Corresponding dicarboxylic

acids . . . . 3 4,* 4 ,,

Hexoses . . . . 4 16, 8 ,,

Corresponding dicarboxylic

acids . . . . . . 4 10

Corresponding hexitols . . 4 10

Using the signs + and , as in the case of the tartaric acids r

* The molecules of a pentitol, CH 2 OH CHOH CHOH CHOH - CH 2 OH, and
those of the corresponding dicarboxylic acid, contain two asymmetric carbon groups
only, because the middle atom is combined with two structurally identical groups
[- CHOH-CH 2 OH or CHOH- COOH], and has therefore lost its asymmetry.
When the groups attached to i and 3 have the same configuration, + and + or
and , the compound is optically active (compare the tartaric acids). When
these two asymmetric groups have different configurations (one being + and the
other ), internal compensation ensues and the presence of the middle CHOH
group (2) renders possible the existence of two such internally compensated (in-
active) forms. There are thus four optically isomeric pentitols, of which two are
enantiomorphously related and optically active, and two are inactive by internal
compensation.



THE MONOSACCHAROSES



53



to distinguish any two enantiomorphously related groups, the con-
figurations of the aldopentoses and aldohexoses may be represented
thus:

Aldopentoses.



CH 2 OH
(X) CHOH
* CHOH
<Y) CHOH
CHO
Aldohexoses.



+



1



+ +



CHOH
CHOH + +

CHOH

<P) CHOH
CHO



+



^








+;-


-1- +


+ -k





+


+ +


1 ,


1


+ +


_! ~-


__


III IV


V VI


VII VIII


IX X


XI XII


XIII XIV


XV XV I



i II



The Pentoses and Hexoses. Laevoxylose under suitable
treatment gives one of the optically inactive pentitols and one of
the optically inactive trihydroxy-dicarboxylic acids, and therefore
must be represented by i, 2, 3, or 4, since these are the only con-
figurations 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
asymmetric carbon atom j8 is introduced. The configurations of
/-glucose and /-mannose must therefore be included in the series
IX to XVI.

* See p. 52.



54 ORGANIC CHEMICAL SYNTHESIS

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. (In the compounds
COOH + - + - COOH or CH 2 OH + - + - CH 2 OH, 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 regards that
particular asymmetric group directly united to the aldehyde group
(P) (P- 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).
This excludes IX or XVI, because a dicarboxylic acid or hexitol
having the corresponding configurations could not be produced
from two different aldohexoses. Laevoglucose must therefore be
either X or XV.

Since the signs + 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.

If XV is assigned to /-glucose, d-glucose becomes X, J-mannose
IX, /-mannose XVI, df-gulose V, /-gulose IV, while /-arabinose,
from which /-glucose and /-mannose are obtained, becomes 8,
d- arabinose 5, and /-xylose (from which /-gulose is derived) 2.

The optical relationships of the various members of the hexose
group are shown more fully by means of 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 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



55



CH



HO


-H HO


H HO


-H H


-OH HO-


-H HO


-H HO-


-H H-


, **
OH


HO


-H HO


-H HO


-H HO


-H H-


-OH HO-


-H H


-OH HO-


H


HO


-H HO


H H-


-OH H


-OH H-


-OH H


OH H


-OH H


-OH


HO


-H H-


-OH HO-


-H H


-OH- H


OH H


OH HO


-H HO-


H


CHO CHO CHO CHO C


:HO c


:HO c


:HO c


:HO


12345678


1- Allose 1- Altrose 1- Glucose 1- Gulose 1- Talose 1- Mannose 1- Galactose 1- Idose


C


HjjOH C


:H 2 OH C


:H 2 OH C


:iI 2 OH C


:H 2 OH C


;H 2 OH CF


[ 2 OH CH


OH


H


-OH H


-OH H


OH HO-


-H H-


OH H


-OH H-


-OH HO-


-H


H-


-OH H-


-OH H-


OH H-


-OH HO-


H H-


-OH HO-


-H H-


OH


H


-OH H-


-OH HO-


H HO-


H HO-


H HO-


-H HO-


H HO-


-H


H


-OH HO-


II H-


OH HO-


H HO-


H HO-


H H


-OH H-


OH


CHO CHO C


HO C


:HO c


MO C


:no c


HO C


HO


9 10 11 12 13 14 15 16


d- Allose d- Altrose d- Glucose d- Gulose d- Talose d- Mannose d- Galactoso cUJWos'e



Configurations of the Aldohexoses.



r v.



Enzymes. Before discussing the fermentation of the
saccharoses, it would be advisable to briefly consider the enzymes
(eVfJyUj; in yeast) -the lifeless products of the living cells which
directly induce these changes and act either in the presence or ab-
sence of the living organism.

Enzymes are substances of the utmost importance to all living
matter, and they may be regarded as the " chemical reagents " of
the organism. It has not been possible as yet to isolate an enzyme
in the pure state, and up to the present it has been impracticable to
do more than investigate the effects produced when mixtures con-
taining them are allowed to act upon substances of known composi-
tion. In many cases it is possible to obtain solid amorphous
preparations which furnish extremely active enzyme solutions
when dissolved in water. Unfortunately there is no definite
criterion of purity for these colloids, and the methods available
for their preparation are such as would not remove many known
impurities.

As a rule 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

* Ann., 1918, 416, 21.



56 ORGANIC CHEMICAL SYNTHESIS

for isolating and purifying enzymes so that the following points
may be settled: (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
questions definitely. As a preliminary study the case of horse-
radish peroxydase was chosen. Still more recently the same authors *
have devised an improved method of purification by means of
adsorption compounds with aluminium or ferric hydroxide, silicic
acid, kaolin, or talc. Similar methods have been applied to
invertase.f

Enzymes can act only within a limited range of temperature.
In general the enzymes of animal origin act best at 37, while
25 is a suitable temperature for those of vegetable origin.
With few exceptions enzymes can act only in neutral solution,
and a faintly acid medium is preferable to an alkaline one.
Many 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
which 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 in-
capable 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-
cillium, owing to the destruction of the dextrotartaric acid by the
fungus, and this device has been frequently employed for the resolu-
tion of inactive mixtures. Fischer has shown that this selective
action is exhibited by invertase and zymase in producing fermenta-
tion of carbohydrates. Of the aldohexoses only the three natural
sugars, c?-glucose, </-mannose, and rf-galactose are fermentable. The
tetroses, pentoses, heptoses, and octoses are not attacked by yeast,
while mannononose undergoes alcoholic fermentation and glycerose
* Ann., 1921,422,47. \Ann.> 1921, 425, i.



THE MONOSACCHAROSES 57

is 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 depends not only on
the structure but also 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 char-
acteristic 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 . . 165 .... +157

(3-Methyl glucoside . . 104 .... 33

The two products are regarded as stereoisomeric y or butylene
oxides, and have the following structural formulae:



H-C-OH

\

HO-C-H / HO-C-H



H-C-OH H-C-OH



CH 2 OH CH 2 OH

a - 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
alcohol and glucose. The action of enzymes towards them is
specific, for each form requires its own particular enzyme; thus,
a-methyl glucoside is hydrolyzed by maltase and jS-methyl glucoside
by emulsin.



$8 ORGANIC CHEMICAL SYNTHESIS

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
(C 7 H 14 O 6 ). 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
variety of glucose. It readily condenses with acetone, reduces
alkaline potassium permanganate, and unites with oxygen to give a
neutral product. When 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:

CH 2 (OCH 3 ) [CH OCH 3 ] 3 CHOH CH 2 OH.

On this basis an ethylene oxide structure must be assigned to the
new tetramethylglucose, and the new methylglucoside is a mixture
of stereoisomerides having the formulae:

CH 3 O -C-H H-C- OCH,





[CH OH] 3 [CHOH] 3

CHoOH CHoOH



The parent glucose has not yet been isolated in the free
state.

In addition to a- and j3-methyl glucosides, there are many other
derivatives of a- and jS-glucose. Under proper experimental con-
ditions all five hydroxyl groups in glucose become acetylated,
the a- or j8-pentacetate predominating according to the method
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 compounds is treated with
liquid hydrogen chloride or bromide, or, more easily, by the
action of a saturated solution of these two acids in acetic acid,
it is converted into the corresponding a- or jS-acetochloro- or
acetobromo-glucose:

* Trans., 1915, 107, 524.



THE MONOSACCHAROSES 59

AcO-CH Br-CH H-C-OAc H-CHBr



H-C-OA\


H- C-OAc\


H-C-OAc\


H-C-OAc\


1 O *"""


--- ^r I O S


1 -


> O


AcO-CH /


AcOCH / AcOCH /
\/[Ac=CH,CO-J\/


AcOCH /


HC


HC


HC


HC


1


1


1


I


H-C-OAc


H-C-OAc


H-C-OAc


H-C-OAc


1


1


1


1



CH 2 OAc CH 2 OAc CH 2 OAc CH 2 OAo

a Glucose pentacetate a Acetobromoglucose /3 Glucose pentacetate j8 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 deriva-
tives are known: a- and ^8-acetonitroglucose, a- and /?-acetomethyl-
glucoside, a- and /2-tetracetylglucose, and various methylglucoses
and methylglucosides.

Mutarotation: the Isomeric Forms of Glucose. The
gradual fall of optical rotation observed when a freshly prepared
solution of glucose is allowed to stand is known as mutarotation.
The change takes place very slowly when highly purified glucose
is 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 CH(OH) 2



HOH) 4 + H 2 -> [CHOH] 4
CH 2 OH CH 2 OH

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 + no to + 52-5
p-glucose, [a] D + 19 to + 52-5
y-glucose, [a] D + 52-5

Simon f compared the optical behaviour of a- and /J-glucose
* C. r. t 1895, 120, 1060. f C. r., 1901, 132, 487.



6o



ORGANIC CHEMICAL SYNTHESIS



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
1899, to be a process of reversible isomeric change and he subse-
quently concluded that Tanret's y-glucose is a mixture in which a-
and ^-glucose are present in equilibrium. Lowry f assumes that an
aldehyde or hydrate is an intermediate stage in the establishment of
equilibrium between the glucoses:



CH 2 OH



CH 2 OH



CH 2 OH



CHOH



+ H 9 0-
CH 2



CHOH

I

CHOH

H-C-OH

a - Form




CH(OH) 2



This explanation involves the opening of the ring, and an alter-
native 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 6 H 12 O fl







CHO




CHOH






H


C- OH


H-


C-OH




CHO

1


HO


C H


HO


C- H


)


(CHOH) 4

1


H


i. OH


H.


t




CH 2 OH


H


. c OH


H


C OH








CHoOH




CHoOH





(4)



(6)



* Trans., 1903, 85, 1306.



t Trans., iQ3> 85, 1314.



THE MONOSACCHAROSES 61

Position i 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
osazones. Our knowledge of the group in position 6 is restricted
to a few reactions such as oxidation to saccharic acid and the forma-
tion of dibromoderivatives. It is evident that the linkage of the
ring-forming oxygen atom in the molecule need not remain ex-
clusively in one position, but may connect different pairs of carbon
atoms, and thus all the groups from i to 6 must be regarded as
variables. For example:

Position i may possess either the a or (J configuration.
,, 2 may be involved in an ethylene-oxide ring.
,> 3 ,, a propylene-oxide ring.

,, 4 ,, ,, a butylene-oxide ring.

,, 5 ,, ,, an amylene-oxide ring.

,, 6 ,, ,, a hexylene-oxide ring.



It follows, therefore, that if we include an aldehydic variety, d-
glucose may react in any one of eleven forms or as a mixture of these
isomerides.

Methylated Sugars. The reactive properties of the hy-
droxyl 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
to enzymes.

In 1895, Fischer observed that sugars combine with one or two
molecules of acetone and also with benzaldehyde to form well-
defined isopropylidene and benzylidene compounds containing the
groups:



\*s V-J\ O

| >C(CH 3 ) 2 I

- C - / - C -



CH C 6 H 5



Since 1901, 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
all the hydroxyl positions of reducing sugars or into any hydroxyl
groups which remain unsubstituted in a sugar derivative. The
sequence of operations leading to a fully methylated glucose may be
expressed by the following scheme:



62



ORGANIC CHEMICAL SYNTHESIS



CH OH
CH-OH
CH-OH
CH

CHOH
CHoOH



, CH-

I CH-



CH OCH 3
OH



CH-OH



CH OCH 3

CH . OCH 3

O |
I CH-OCH,



CH OH
CH OCH 3



O



CH-



OH

^H 2 OH
Glucoside formation




CH OCH 3



:H OCH 3

^Hg OCHs
Methylation



CH

in-



OCH 3



CH OCH 3

Hydrolysis



The first stage is 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.
Acid hydrolysis eliminates the glucosidic alkyl group only, with the
result that a tetramethylglucose is produced. Extending these
principles, it is clear that if a sugar is substituted by any group or
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 com-
pounds crystallize readily 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
alkyl groups increase the solubility in organic solvents.

The Glucosamines. 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-
cule for one 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
derivative rather than a true sugar:

* Ber., 1903, 36, 2587.



THE MONOSACCHAROSES



HO-CH



HO CH - CHOH
CH CH



CHO



O



while Irvine and Hynd formulate chitose, with the aldehydic radical
present, as in the hexoses, in the butylene-oxide form:



O



CH 2 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 H



CH 2 OH


















H


1


I N


H-0
n



Fischer and Leuchs f have synthesized glucosamine from rf-arabinose
by the following reactions:



CH 2 OH



CH-OH



(

HO


:H 2 OH


C


:H 2 OH HO

HI \C\


H HO

H^ T T'^v


H
H


HO


H,


-HO


IICJ

H>te. TT


>'1"1O

/^\T T T T




,.-,.OTT


S* II 1 ""

y~V T T


OH H


OH


C

d-Arat


Ull

;HO

)inose




CH

a - Amir


on

CH(NH 2 )COOH CH(NH 2 )CHO
(!SrH 2 )CN a-Aniinog-luconic Glucosamine
log-luconic nitriie acic *



A 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 bio-
chemical interest attached to glucosamine as a connecting link be-
tween carbohydrates and amino acids.

Glucal. In 1913, Fischer obtained a strongly reducing com-
pound, C 6 H 10 O 4 , which he named glucal, by the reduction of

* Trans., 1912, 101, 1128. \Ber., 1903,86, 84.

J Ber., 1911, 44, 132. Sitz. Preuss. Akad. Wiss. Berlin, 1913, 311.



64 ORGANIC CHEMICAL SYNTHESIS

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 2 -CH(OH)-CH-CH(OH)-CH:CH

l o - 1

The Natural and Artificial Glucosides. The term gluco-
side is applied to a large number of 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
plants, but especially in the fruit, bark, and roots. The extraction
is usually effected either by water or alcohol. In the former case
it is first 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
bitter taste and laevorotary optical power. In chemical structure
they resemble the simple a- and /?-methylglucosides, and may there-
fore be represented by the general formula:

CHoOH CHOH - CH [CHOH] 2 - CH-O-R
i o !

where R is an organic radical.

The 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
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 these results it has been possible to draw conclusions as to
the configurations of some of the natural sugars and glucosides.
Maltose is an a-glucoside, for it is hydrolyzed by maltase and not by
emulsin. Emulsin brings about the hydrolysis of lactose, from which
it is evident that this sugar is related to the -glucosides. Alkyl

* Ber., 1920, 53 [B], 509.



THE MONOSACCHAROSES



glucosides derived from non-fermentable sugars are unattacked by
both maltase and emulsin.

The better known glucoside-splitting enzymes are shown in the
following table.

ENZYMES CAPABLE OF HYDROLYZING GLUCOSIDES



Enzyme.



Emulsin . .

Prunase . .
Amygdalase

Gaultherase
Tanriase

Rhamnase
Myrosin

Indigo ferment



Hydrolyses.



Many natural and syn-
thetic glucosides.
Prunasin
Amygdalin

Gaultherin
Tannins

Xanthorhamnin
Sinigrin

Indican



Products.



Glucose, d-mandelonitrile.
Glucose, e/-mandelonitrile

glucoside.

Methyl salicylate, glucose.
Gallic and ellagic acids, and

glucose.

Rhamnitin, rhamninose.
Allylthiocyanate, Potassium

hydrogen sulphate.
Indoxyl and glucose.



The 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
galactose, mannose, and fructose, are known. In the glucosides all
types of organic substances are united to glucose; for example,
alcohols, aldehydes, acids, phenols, &c. Avnumber of the better
known glucosides are given in the table on p. 66, and frequent refer-
ence will be made to some of these compounds throughout this book.

The Structure of the Glucosides. Three main points
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 may reasonably be concluded
that all glucosides hydrolyzed by it are derived from j8-glucose.

(D331) 5



66



ORGANIC CHEMICAL SYNTHESIS



Glucoside.



Products of Hydrolysis.



Arbutin

Phloridzin

Baptisin

Coniferin

Populin

Salicin



Amygdalin

Helicin

Linamarin

Prulaurasin

Sambunigrin

Gaultherin



Apiin

Isoquercitin

Xanthorhamnin



Sinigrin

Cyanin
Delphinin . .

Idaein



Phenols.

Glucose + hydroquinone.
Glucose + phloretin.
Rhamnose + baptigenin.

Alcohols.

Qlucose + coniferyl alcohol.
Glucose + saligenin + benzole acid.
Glucose + saligenin.

Aldehydes.

2 mols Glucose + J-mandelonitrile.
Glucose + salicylaldehyde.
Glucose + acetonecyanhydrin.
Glucose + racemic mandelonitrile.
Glucose + /-mandelonitrile.

Acids.
Glucose + methyl salicylate.

Oxyflavone Deriva lives .
Apiose + apigenin.
Glucose + quercetin.
2 mols Rhamnose + galactose + rhamnetin.

Mustard Oils.
Glucose + allyl isothiocyanate + KHSO 4 .

Anthocyanins .

2 mols Glucose + cyanidin.
2 mols Glucose + />-hydroxy benzoic acid + del-

phinidin.
Galactose + cyanidin.



The last point to be settled is the nature of the sugar residue. We
have seen that the simple sugars and their derivatives may exist in
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
process. Trustworthy information regarding the internal structure
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 be determined by such methods, when the
non-sugar residue is a substance containing several such groups.
Irvine and Rose * obtained a pentamethyl salicin by methylation

* Trans., 1906, 89, 814.



THE MONOSACCHAROSES 67

of the natural glucoside, and showed that the sugar in the parent
glucoside possessed a butylene- oxide linking. They supported
these observations by a synthesis of a pentamethyl salicin which
proved to be identical with that derived from the natural glucoside
by methylation.

More recently Macbeth and Pryde * have determined the struc-
ture 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
methylated, by the action of methyl iodide and dry silver oxide,
and the resulting tetramethylindican hydrolyzed to tetramethyl-
methylglucoside and indoxyl derivatives. On hydrolysis of the
former a crystalline tetramethylglucose was isolated which was
readily identified as the 2:3:5:6 or butylene oxide compound.
These results may be conveniently summarized:

Indican



I



Tetramethyl indican

_ ^ \ .

Tetramethyl methylglucoslde ladoxyl derivatives



1



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 struc-
ture is therefore established for the glucoside:

CHoOH CHOH CH - CHOH CHOH CH O C 8 H 6 N

I O - 1

and enzyme action and optical properties indicate that the compound
is a derivative of jS-glucose.

The Synthetic Glucosides. 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.

In 1879 Michael condensed crude acetochloroglucose with the
potassium salts of various phenols, and in this way prepared phenyl

* Trans., 1922, 122, 1660.



68 ORGANIC CHEMICAL SYNTHESIS

glucoside, helicin, salicin, and methylarbutin. A more satisfactory
method is to condense the non-saccharose constituent and aceto-
bromoglucose in the presence of silver oxide. By an extension of
this method purine glucosides (p. 208), terpene glucosides, and
cyanophoric glucosides have been synthesized. A new modification
of the glucoside synthesis consists in warming acetobromoglucose
with phenol in the presence of quinoline. During this process a
rearrangement takes place, and a mixture of a- and jS-phenol gluco-
sides is formed, which may be separated by crystallization from carbon
tetrachloride. This synthesis of a-glucosides is of considerable
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.

Amygdalin is 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 con-
stitution is not established with certainty, but in all probability it 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

\^ (Ag 2 0)



Ethyl d- and 1- tetra acetylglucosidomandelate
(CH 3 CO) 4 C 8 H 7 B -0-CH(C 6 H 5 )C0 2 C 2 H 8 )

\ (NH 8 )

d- and 1- mandelamide glucoside

C 6 H 115'- CH ( C 6 H 5> CONH 2

I (Crystallized from pyridine) I

1- Mandelamide glucoside d- Mandelamide glucoside

I r acetic anhydride and"! I

y L pyridine * w

1- Mandelamide glucoside tetra acetate d- Mandelamide glucoside tetraacetate



* Ber., 1917, 50, 1047.



THE DISACCHAROSES 69

(POCl,)
1- Mandelonitrile 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.

Finally it may be mentioned that Bourquelot has obtained
glucosides synthetically by means of enzymes. Whereas in dilute
aqueous solution the hydrolysis of j8-methyl glucoside by emulsin
is complete, hydrolysis is retarded by increasing amounts of methyl
alcohol until in the presence of a certain proportion of this alcohol
the enzyme is able to synthesize glucoside from glucose and the
alcohol. The reaction has been extended to other alcohols, the
enzyme being allowed to act on sugars dissolved in alcohols con-
taining varying amounts of water or acetone. In this way crystalline
glycol-, glycerol-, geranyl-, and cinnamyl-/?-glucosides have been
obtained by means of emulsin.

THE DISACCHAROSES

The 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,
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 the disaccharose reduces cupric salts, exhibits
mutarotation, and forms an osazone, e.g. maltose, lactose, and
melibiose, while in the latter case the sugar has no reducing pro-
perties, e.g. sucrose and trehalose.

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.



ORGANIC CHEMICAL SYNTHESIS



Irvine and his collaborators have employed five methylated
hexoses as reference compounds to determine the constitution of
the most important disaccharoses and polysaccharoses:



CHOH


CH OH


, CH OH CH 2 OCH 3


CH OCH 3


CH . OCH 3


CH-OCH 3 r-C-OH


> 1 <
CH OCH 3

CH


> I <
CH OCH 3

CH


> |
CH OCH 3

CH <


CH OCH 3
) CH-OCH 3


CH OCH 3


CHOH


CH OCH 3


CH OCH a


CH 2 OCH 3


CHOCH 3


CH 2 . OH


CH 2


2:3:s:6-Tetra- 2:3:6-Trimethyl-


2:3: s-Tri- Tetramethyl


methyl glucose or


glucose methyl-glucose Y-fr uctose


galactose







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 2 OH


CH 2 OH


CHOH
CH


, CH
CHOH


1 |




CHOH


CHOH


y


CHOH


4


\ / \




CH X


CH 2 OH


v_xjn. \j




(i)





CH 2 OH
CHOH

-C!H

CHOH



CH 2 OH

CHOH

CHOH







CHOH



o



CH
|
C - CH 2 OH



(ii)



This formula remained unchallenged until his isolation of y-
methylglucoside (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-
ponent is in the 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
tetramethylfructose. The methylated aldose proved to be the
tetramethylglucose of the butylene oxide type, while the ketose

* Trans. y 1916, 109, 1314.



THE DISACCHAROSES



displayed a rotatory power and reaction towards permanganate
which at once stamped it as being allied in structure to " y-glucose ".
The new provisional formula (ii) shows a butylene oxide aldose
coupled to an ethylene oxide ketose through their reducing
groups.

Maltose. Maltose is a reducing sugar which yields, on
hydrolysis with dilute acids or with maltase, two molecular pro-
portions of glucose. Consequently it is regarded as a biose having
the reducing group of one glucose molecule united through an
anhydride linking with a second glucose residue. The constitution
assigned to maltose by Fischer was:



CH
CHOH



CH 2
CHOH



CHOH

I


CH

1


CH
CHOH
CH 2 OH


CHOH
CHOH
CHOH



This structure has been confirmed by Haworth and Miss
Leitch.* Starting from the free sugar, methyl maltoside was pro-
duced by the regulated action of methyl sulphate and sodium
hydroxide, and the same reagents were then used to convert this
product into heptamethyl-methylmaltoside (i). On hydrolysis,
the tetramethylglucose (ii) and the trimethylglucose (iii) were
obtained.



H : OH



CHOCH 3
CHOCH 3
CH
CHOCH 3
CH 2 OCH 3



CH 2
CHOCH,



CH



O



CHOCH 3
CHOCH,
-CHOCH.
OHH



CHOH

CHOCH 3

|

1 CHOCH 3

UH +

CHOCH 3
CH 2 OCH 3



(i)



CH 2 OH
CHOCH 3
CH

CHOCH.,
O I

U:HOCH S
HOH



(iii)



* Trans., 1919, 115, 809.



72 ORGANIC CHEMICAL SYNTHESIS

Cellobiose. In the same paper the following formula was
suggested for cellobiose:

CH a OH



CH O CH


CHOH


-CH


3 1


1


CHOH

4 H c


CHOH
) |
CHOH


1


1


CHOH

I


CHOH


CH 2 OH



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. Lactose or milk sugar is present in the milk of all
mammalia, but 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
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
eight equivalents of acid, Haworth and Miss Leitch J have in-
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, when products were obtained
according to the following scheme:

Lactose > methyl lactoside > 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 73

Compound (A) was shown to be the butylene oxide form of tetra-
methyl galactose, while (B) was shown to be identical with the
trimethyl glucose isolated by Denham from methylated cellulose
(p. 79). From this evidence the following structural formula has
been assigned to lactose:



pt_r

VxJLJ.



CHOH CH
O I



CHOH



CHOH



CHOH

O I
CHOH

CHOH



[Galactose residue] [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
chlorophyll and do not elaborate starch. It is also found formed in
trehala manna, a cocoon formed by certain species of beetles on
several spiny plants native to Syria and Persia.

The 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,
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.

Melibiose has not been found naturally in the free state, but
is produced by the hydrolysis of raffinose:

C 18 H 32 16 + H 2 = C 6 H 12 + CnHwOu
Raffinose d-Fructose Melibiose

Melibiose is reduced by sodium amalgam to melibitol, which on
hydrolysis gives mannitol and ^/-galactose. It is hydrolyzed by
strong acids to ^/-glucose and ^-galactose. With emulsin the hydro-
lysis is slow, but melibiase, an enzyme found in bottom yeast, attacks
this disaccharose rapidly. It reduces Fehling's solution and forms
hydrazones and osazones.



74



ORGANIC CHEMICAL SYNTHESIS



Melibiose was the first disaccharose to be obtained synthetically.
It was prepared by Fischer and Armstrong * from acetochloro-
galactose and sodium glucosate, which condense to give melibiose
tetracetate. On hydrolysis with caustic soda, melibiose is obtained.



H

-d-



CH 2 OH
HO - C - H



H-d-O.
CH,CO O - C - H



+



- H






H



H C O COCH 3

CH 2 O COCH 3
Acetochlorogalactose

H



H - C - OH + C 2 H 5 ONa
HO - C - H



Glucose





A^x


vy ^Jni2


H -


<L


- O - CHCO 3 HO ~ C - H


3
CH 3 CO O -


<i.

P


- H

M


CTLT


Li
TJ P HI



NaCl + C 2 H 5 OH



H - C - O COCH 3
CH 2 - O COCH 3



O



HO-C - H



AH

Melibiose tetracetate

Turanose and Gentibiose are obtained by the hydrolysis of
the trisaccharoses, melecitose and gentianose, respectively.



THE TRISACCHAROSES

Raffinose, C 18 H 32 O 16 , is the best known and most widely
distributed trisaccharose. 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
(raffiner = to refine). It is most conveniently prepared from cotton-
seed meal by precipitation from an aqueous extract with calcium

* Ber., 1902, 35, 3144.



TRISACCHAROSES 75

oxide and subsequent decomposition of the calcium salt with
carbon dioxide.

Raffinose exhibits no reducing properties. On hydrolysis with
dilute acids it gives rf-fructose, (/-glucose, and df-galactose:

C 18 H 32 16 + 2H 2 = C 6 H 12 6 + C 6 H 12 6 + C 6 H 12 O 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
galactose and glucose. Invertase hydrolyzes raffinose to fructose and
melibiose, while emulsin breaks it down to sucrose and galactose.
From these observations the following formula may be constructed:

C 6 H U 5 - O - C 6 H 10 4 - O - C 6 H n 5

Fructose Glucose Galactose



Sucrose Melibiose

Gentianose was discovered by Meyer in 1882 in Gentian roots
(Gentiana luted), and is most conveniently prepared by extraction
of the dried roots with 95 per cent alcohol. Gentianose is a non-
reducing sugar which possesses a slightly sweet taste. On hydrolysis
it splits up into fructose 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).

CcH n 5 - O - C 6 H 10 4 - O - C 6 H n 5

Fructose Glucose Glucose

Sucrose Gentiobiose

Melecitose, or melezitose, was first observed by Bonastre in
1833 in the manna from the larch (Pinus larix). It is prepared from
Turkestan manna by extraction with warm water and crystallization
from methyl alcohol. It does not form osazones and is not a re-
ducing sugar.

On hydrolysis with dilute acids it gives glucose and turanose,
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
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
stachyose, and the separation of these sugars is tedious.

Mannotriose reduces Fehling's solution and forms a phenyl-



76 ORGANIC CHEMICAL SYNTHESIS

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 5 H 10 4 - O - C 6 H 10 4 - O - C 6 H n O 5

Glucose Galactose Galactose



Gluco-galactose Digalactose

Rhamninose, C 18 H 32 O 14 , along with rhamnetin, is a product
of the hydrolysis of the glucoside xanthorhamnetin, found in the
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. On hydrolysis with dilute acids it gives one molecule of
J-galactose and two molecules of rhamnose:

OHC C 5 H 1U 4 - O - C 6 H 10 3 - O - C 6 H n O 4
Galactose Rhamnose Rhamnose

TETRASACCHAROSES

Stachyose, lupeose, or mannotetrose, C 24 H 42 O 2 i, was dis-
covered by Planta in 1888 in the tubers of Stachys tubifera, in which
it is sometimes present to the extent of 70 per cent. Its occur-
rence in the manna of the ash has already been mentioned, and
it has also been found in the roots of various Labiatae.

It is not a reducing sugar. On hydrolysis with weak acids or
invertase it yields d- fructose and mannotriose:

C 24 H 42 O 2 i + H 2 O = C 6 H 12 O 6 + C 18 H 3 oO 16
Stachyose rf-Fructose Mannotriose

Stronger acids hydrolyze stachyose to the hexoses. According to
Bi6rry * the gastro-intestinal juice of Helix pomatia effects the
hydrolysis in the following stages:

(I) To rf-fructose and mannotriose.

(II) Mannotriose to */-galactose and a disaccharose.

(III) The disaccharose into galactose and glucose.

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 U O 5

Fructose Glucose Galactose Galactose

^ ^

-v .^^^

Mannotriose
* Biochem. Zeitsch., 1912, 44, 446.



THE POLYSACCHAROSES 77

THE POLYSACCHAROSES

The polysaccharoses are substances of high molecular weight,
and most of them are amorphous and insoluble in water. On hydro-
lysis they break down into sugars containing five or six carbon
atoms, and may therefore be regarded as anhydrides of these sub-
stances. Since we have no reliable knowledge of the molecular
weights of these compounds, their formulae are written (C 6 H 10 O 6 ) ;J
or (C 5 H 8 O 4 ) W , according as they give rise to hexoses or pentoses on
hydrolysis.

The polysaccharoses may be classified as follows:

1. Starches and dextrins, including glycogen, inulin, &c.

2. Gums, which comprise (a) natural gums and pentosans, and
(b) 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 com-
mercial points of view, and indeed, in spite of our limited know-
ledge, 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, it will be well to consider the
celluloses first of all.

The Celluloses. The term cellulose should be taken in
general to connote a group of substances rather than a single chemical
compound, and used in this generic sense we may classify the celluloses
as follows.

i. Normal or typical celluloses of the cotton type, e.g. the
cellulose obtained from cotton, flax, hemp, &c.



78 ORGANIC CHEMICAL SYNTHESIS

2. Compound celluloses of the wood cellulose, jute, and cereal
grass types. The natural celluloses occurring in jute, cereal straws,
esparto, &c., consist of some form of cellulose combined with a
non-cellulose constituent which may be either of the nature of lignin
(e.g. jute fibre), a pectic or gummy substance (e.g. flax), or a fatty sub-
stance (e.g. cork).

3. Hemi-, pseudo-, or reserve celluloses, 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
in the cell walls of the seeds of various plants, e.g. Soja hispida,
Cocos nucifera, beans, peas, &c.

Cotton Cellulose. The extensive study of the alkylated
sugars (p. 61), with which the names of Purdie, Irvine, and Haworth
are intimately connected, has opened out a hopeful method for the
determination of the constitution of the polysaccharoses. Now that
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 may be identified.

The original method, employing silver oxide and methyl iodide,
is not always successful owing to the experimental difficulties fre-
quently 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.

J Ber. t 1913, 46, 2401. Trans. , 1918, 113, 173.




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-trime-
thylglucose (i) was isolated.

-CH OH CH - O .......... (X)

CHOH

I
CHOH

CH
CHOH CH - O .......... (Y)

CH 2 OCH 3 CH 2 OH

(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
crystalline derivatives of glucose. The cellulose was treated with
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 2 OH

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.

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



8o ORGANIC CHEMICAL SYNTHESIS

More recently Irvine and Hirst * have shown that the cellulose
molecule is 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 i

containing ^

0-75 per cent a- and p-methylglucosides, 114-1 parts \

HC1) Glucose equivalent, 106 parts J 95 '5 P er cent

Denham and Woodhouse's work was 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
in place of 45-6 per cent required by the trimethyl derivative.
The material still preserved its fibrous nature, from which it was
concluded that no profound molecular change had taken place. The
trimethylcellulose was then submitted to simultaneous depoly-
merization, 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-
trimethyl methylglucoside only. On hydrolysis of the distilled
glucoside crystalline 2 : 3 : 6-trimethylglucose alone was obtained.
These reactions may be summarized:



Cotton cellulose

4

Trimethyl cellulose
i

2 ~> 3-> 6-Trimethyl methylglucoside



lulose ...... "j

i [yield 90 per cent.

J



^ I yield 89 per cent

2 "j 3"> 6-Trimethyl glucose . . . . J

The scheme affords a proof that all the glucose residues in cellulose
are identical in structure and have the hydroxyl groups 2, 3, and 6
unsubstituted. To satisfy this condition and to account for the
formation of cellobiose, it is necessary to include in the formula at
least two glucose residues (i). In view of the fact that the highest
yield of cellobiose so far obtained does not approach that theoretically

* 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

CHOH



Q



O



CHOH



CH - O - CH CHOH CHOH CH CH CH 2 OH
CH 2 OH ' O I



r

O



CH 2 OH

CH - O - CH - CH CHOH CHOH
CHOH
CHOH



CH CHOH CHOH CH

I O- 1

(ii)



. CH



O



CH - O
CH 2 OH



CH 2 OH



Starches and Dextrins. Starch is 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 vege-
table parts such as tubers, &c., and in the latex of certain plants.
It also occurs in green leaves, presumably as a temporary reserve
material.

The preparations, properties, and uses of starch need not be
dealt with here, and in spite of the amount of work which has been
devoted to the study of its chemical constitution our knowledge of
the nature of the starch molecule is very slight indeed.

Irvine and Macdonald f have shown that when starch is re-
peatedly methylated the reaction ceases when the methoxyl content
is 37 per cent. This value corresponds exactly with the theoretical
amount calculated on the basis that one hexose residue has acquired

* Irvine, .7. Soc. Chem. Ind. y 1922, 41 , 362 R.
t J. Soc. Chem. Ind. y 1922, 41, 362 R.

(D331) 6



82 ORGANIC CHEMICAL SYNTHESIS

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%)

~cr Y ^

Trimethyl: ^ Dimethyl- ^ Depolymerised

methyl glucoside methyl glucoside methylated starch

\ \

2. 3. 6. Trimethyl Dimethyl

glucose 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
properties resembles starch. It is derived from fructose, and until
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 constitu-
tion of these important natural compounds.



THE POLYSACCHAROSES 83



REFERENCES.



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, Hill (London,

1921).



CHAPTER IV

The Depsides, Lichen Products, and

Tannins

Introduction. In very early times 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 writers employ the term
" tannin " as the generic name for this widely disseminated group
of vegetable products, while others have unfortunately used it to
denote a particular substance better described as gallotannin.

Gallic acid was prepared by Scheele in 1786 by exposing nut
galls to the air, in a 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 investigations. In 1852 Strecker denoted gallotannin by the
formula C 27 H 22 O 17 , and considered 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
gallic acid with arsenious acid as digallic acid, and for a long time
afterwards gallotannin was assumed to be identical with digallic acid.
This erroneous view was finally shattered by Flawitzki, who, in 1895,
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,
Fischer not only synthesized compounds with tannin-like properties,
which he termed " Depsides " (Se^etv = to tan), but he also
synthesized two lichen products Lecanoric and Evernic acids.

Classification. Owing to our present incomplete knowledge
of the chemical constitution of the tannins, it is difficult to evolve a

84



DEPSIDES, LICHEN PRODUCTS, AND TANNINS 85

proper chemical classification of these substances. Proctor * classi-
fies 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.

2. Pyrocatechol Tannins, including all the pine barks,
acacias, 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 ".
The 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.
Some of the tannins in this class contain phloroglucinol as one of the
constituents of the molecule.

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 con-
centrated in vacuo.

In many cases it is preferable to employ an organic solvent for
extraction. Various mixtures of alcohol, water, and ether may be
used, but acetone is probably the best solvent. Ethyl acetate is
used extensively, but some tannin glucosides are insoluble in this
solvent. The method used by Fischer and Freudenburg for the
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.

HO-C 6 H 4 COOH + HOC 6 H 4 COOH - H 2 O+HO-C H 4 CO.O-C 6 H 4 COOH

Hydroxybenzoic'acid (a didepside)

This product may condense with another molecule of a phenol-
carboxylic acid to give a tridepside, HO- C 6 H 4 CO-O-C 6 H 4 CO-O-
C 6 H 4 COOH, and by an extension of this reaction tetradepsides may
be obtained. The nomenclature is, indeed, very similar to that
employed for the polysaccharoses and the polypeptides.

* Principles of Leather Manufacture, London, 1903. f Ann., 1910, 372, 35.



86 ORGANIC CHEMICAL SYNTHESIS

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 6 H 4 COOH + C1COOCH 3 - CH 3 CO 2 O C 6 H 4 COOH + HC1

In the case of those phenolic acids in which the hydroxyl group
is in the meta or para position to the carboxyl group, this reaction
may easily be brought about with the aid of caustic soda, but when
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.

-Hydroxybenzoic acid.f Salicylic acid.

w-Hydroxybenzoic acid. a- and (3-Hydroxynaphthoic acids.* *

Vanillic acid.J p-Resorcylic acid.

o-Cumaric 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
ester, the ^-methylcarbonato or carbomethoxy derivatives of /J-
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 solu-
tion of ammonia. In some cases a selective removal of a methyl-
carbonato group may be accomplished.

The substituted phenolic acids readily react with phosphorus
pentachloride to give acid chlorides in the usual way.

* Fischer had previously employed methylchloroformate for the protection of
the hydroxyl group in tyrosine, in the preparation of tyrosylglycine.

t Ber. 9 1908, 41, 2877. J Ann., 1910, 372, 47. Ber. 9 1909, 42, 226.

\\Ann., 1912,391,366. **Iter., 1913,46,2400.



DEPSIDES, LICHEN PRODUCTS, 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 6 H 4 COOH-> CH 3 .CO 2 -O-C 6 H 4 COOH - CH 3 CO 2 -O-C 6 H 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 3 CO 2 O C 6 H 4 COC1 + 2NH 2 CH 2 CO 2 C 2 H 6

- CH 3 CO 2 O C 6 H 4 CO NH - CH 2 CO 2 C 2 H 5 +HC1, NH 2 CH 2 COOC 2 H 6
-> HO C 6 H 4 CO NH - CH 2 COOH
/>-Hydroxyhippuric acid.

/>-Hydroxybenzophenone.f This was synthesized from
^>-hydroxybenzoic acid as follows:

C1CO 2 CH 3 PC1 5

HO-C 6 H 4 COOH -> CH 3 CO 2 OC 6 H 4 COOH -> CH 3 CO 2 -O-C 6 H 4 COC1

The acid chloride was then condensed with benzene by the usual
Friedel Craft reaction and the product hydrolyzed.

CH 3 C0 2 - O C 6 H 4 COC1 + C 6 H 6 -> CH 3 CO 2 O C 6 H 4 CO C 6 H 6
-> HO - C 6 H 4 CO C 6 H 5

In a similar way 2: 3: 4-trihydroxybenzophenone (alizarin yellow)
was obtained from pyrogallolcarboxylic acid.

Didepsides. The simplest didepside is obtained by the con-
densation of two molecules of ^-hydroxybenzoic acid J in cold alka-
line solution as follows:

CH 3 CO 2 O C 6 H 4 COC1 + NaO C 6 H 4 CO 2 Na

- CH 3 CO 2 O C 6 H 4 CO O C 6 H 4 CO 2 Na + NaCl

The product is then hydrolyzed with w-alkali at 20 to give the
didepside,

HO C 6 H 4 CO O C 6 H 4 COOH

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 is possible, viz. straight-chain
compounds of the type:

HO C 6 H 4 CO O-C 6 H 4 COOH

* Ber., 1908, 41, 2880. t Ber., 1909, 42, 1017. J Ber., 1909, 42, 216.



88



ORGANIC CHEMICAL SYNTHESIS



but with di- and tri-phenolcarboxylic acids several types are theo-
retically possible, e.g.

CH 3 CO 2 O C 6 H 4 COC1 H(X



CH 3 CO 2 O C 6 H 4 COC1



HO



C 6 H 3 COOH



HO
HO



\C 6 H 3 COOH
C 6 H 4 CO O x



Compounds of such types are not yet known with certainty.*

The following tabulation embraces the more important polydep-
sides prepared by these methods:



Didepsides.



Di-/>-hydroxybenzoic acid.f
Di-protocatechuic acid. J
w-Digallic acid.
Di-^S-resorcylic acid. J
Vanilloyl- vanillin. 1 1



Tridepsides.



Di-/>-hydroxybenzoyl-/>-
hydroxybenzoic acid. ||

Vanilloyl-/>-hydroxyben-
zoyl-/> - hydroxybenzoic
acid.ll



Tetrad epsides.



Tri-/>-hydroxybenzoyl-/>-
hydroxybenzoic acid.JI

Vanilloyl - di -p - hydroxy -
benzoyl - p - hydroxyben-
zoic acid.y



In 1918 Fischer prepared several depsides in which acetylation
of the phenolic hydroxyl groups had been used instead of carbo-
methoxylation.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.

Lichen Products. The only 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 from early times in medicine, dyeing, and as
food-stuffs. Two acids, lecanoric and evernic, which are found in
the varieties Roccela and Lecanora, and Evernia prunastris y have
been the subject of several investigations by Fischer and his col-
laborators. Orcinol (sym. methylresorcinol) is an important con-
stituent of " litmus " lichens.

Orsellinic Acid.** This acid has been synthesized from



.

* Ber. 9 1912, 45, 2712. t Ber. 9 1909, 42, 217. t Ann., 1911, 384, 238.

B*r., 1913, 46, 1124. \\Ann., 1910, 372, 63.

1 1 Ber., 1918, 51, 46; 1919, 52, 809. ** Ber., 1913, 46, 886.



DEPSIDES, LICHEN PRODUCTS, AND TANNINS 89

orcinol by Hoesch. Orcinol is converted into orcylaldehyde by
Gattermann's method, and, after protecting the two hydroxyl groups
by carbomethoxylation, is oxidized and subsequently hydrolyzed to
give orsellinic acid:

CHO CHO COOH

CH 3 /\OH CH 3 /\0-C0 2 CH 3 CH 3 /\OH






HC1,HCN

_ N/ \/ folio wed by

OH OH CH 3 CO 2 O NaQH OH

Orcinol Orcylaldehyde Orsellinic acid

Lecanoric Acid. This acid has long been known as an ester-
like anhydride of orsellinic acid. The acid has been studied and
synthesized by Fischer.* For this purpose orsellinic acid was
converted into its dimethylcarbonato derivative and thence into the
corresponding acid chloride.

COOH COOH COC1

CH,X\OH CH 3r X\0-CO 2 CH 3 CH 3 X\O-CO 2 CH 2

3 f I C1CO-CH- 3 f I 3 PC1, II 2 3



v





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
groups, it is evident that this synthesis alone does not establish the
structure of lecanoric acid. The authors have however synthesized
o-diorsellinic acid and found it to be different from lecanoric acid,
from which it is evident that in the above synthesis the acid chloride
condenses with the />-hydroxyl group of orsellinic acid, and the
constitutional formula of lecanoric acid thus becomes:

CO




OH

Lecanoric Acid

Everninic Acid. This acid, together with orsellinic acid, is
obtained by the hydrolysis of evernic acid with baryta. Everninic

* Ber. 9 1913, 46, 1138.




go ORGANIC CHEMICAL SYNTHESIS

acid has been synthesized from orcylaldehyde by Hoesch as follows:

CHO CHO CHO COOH

PH CH 3 /\OH CH 3 /\0-C0 2 CH 3 CH,/\OH
(CH 3 ) 2 SO, f 1 JC1C0 2 CH 3 I I ^ KMn0 4 I

and NaOH \/ >v/ and hydrolysis \S

OH OCH 3 OCH 3 OCH 3

Orcylaldehyde Everninaldehyde Everninic acid

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 tri-
methyl-lecanoric acid. Evernic acid must therefore be a mono-
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 / SOCH




3



Evernic acid

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 pre-
vailed 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 by the fol-
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.
On 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. They then expressed the opinion that the principal con-
stituent of tannin is not a glucoside, but a sugar ester comparable

* Ber., 1912, 45, 919,





DEPSIDES, LICHEN PRODUCTS, AND TANNINS 91

with pentabenzoylglucose, in which the acyl group is that of digallic
acid. Expressed by the formula

C 6 H 7 6 [C 6 H 2 (OH) 3 CO O 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 salt of gallotannin as a method of purification a method
originally recommended by Berzelius.

Pentagalloyl- glucose. Fischer and Freudenburg then turned
their attention to the synthesis of pentagalloyl-glucose. For this
purpose trimethylcarbonatogalloyl chloride was prepared from gallic
acid as follows:

COOH COOH coci

OC1CO.CH,
> 3
OH CH 3 C0 2 Ok yo.COL-CH, CHXO.Ok ^O-CO.CH,

-J 2 \ > ^/ r 23 32 \^ 2 3

OH O C0 2 CH 3 0-C0 2 -CH 3

This acid chloride was then condensed with glucose in chloroform
solution in the presence of quinoline to give penta (trimethylcarbonato-
galloyl) glucose, which on hydrolysis with alkali in aqueous acetone
gave pentagalloyl glucose. Both the a and ft forms were obtained
by fractional crystallization and, although not identical with gall-nut
tannin, closely resembled it in amorphism, taste, solubility, optical
activity, and feeble acidity. Moreover, the product precipitated
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
therefore contained no carboxyl or hydroxyl groups. On hydrolysis
it gave trimethylgallic acid and m-^>-dimethylgallic acid. Taking
this evidence, in addition to his earlier work, Fischer concluded that
gallotannin probably consists of a 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. y 1919, 52 [B], 829. f Ber., 1905, 38, 989.



92 ORGANIC CHEMICAL SYNTHESIS

trimethylgalloyl chloride with the m-/>-dimethyl ether of gallic acid
in the presence of alkali:

CH 3 O COOH CH 3 O COOH

'






CH 3 CK ,

CH 3 CH 3 O OCH 3 CH 3 6 CH 3 O~OCH 3

The chloride of this acid was then coupled with a- and /f-glucose
to give penta (pentamethyl-m-digalloyl) glucose which, from its
properties, appeared to be identical with methylotannin.

CHOR



'HOR CH 3 CO--



/ V>- --- ---- v _

/i -- ,

\CHOR R=CH 3 0<^ \CO-oY \



CH



CH 3 CH 3 OCH 3



HOR
CH 2 OR

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
principle of Chinese tannin. This was accomplished in 1918,
following the observation that the corresponding acetyl compounds
are superior to the methylcarbonato derivatives for depside pro-
duction. In making this advance, Fischer explained that the acety-
lated phenolcarboxylic acids would certainly have 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 pro-
ceeds quite smoothly.

The chloride of penta-acetyl-m-digallic acid is crystalline, and
with jS-glucose yields the compound:

C 6 H 7 6 [C 6 H 2 (0 COCH 3 ) 3 CO O C 6 H 2 (O CO CH 3 ) 2 - CO-] 6
This is then de-acetylated by cold aqueous caustic soda at zero,

r., 1918,51,45-



DEPSIDES, LICHEN PRODUCTS, AND TANNINS 93

giving penta (w-digalloyl) jS-glucose. The resemblance between
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 formula for
gallotannin, and suggested an alternative formula in 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
these criticisms. It 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
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
investigations Fischer synthesized hepta (tribenzoyl-galloyl) p-
iodophenylmaltosazone, a freak molecule of gigantic dimensions
(M.W. 4021), vastly exceeding that of any other synthetic product, f

Maltose > ^-iodophenylmaltosazone >
(-Iodophenylhydrazine) (tribenzoyl-galloyl chloride)

CH:N.NHC 6 H 4 I

C:N.NHC 6 H 4 I

CHOR

CHOR R R R R

| || || where R=-CO.C 6 H 2 (O'COC 6 H 5 ) 3

CHOR GO O O

I II II

CH0-CH- CH- CHCH- CH- CH



Hepta (tribenzoyl-galloyl) p-iodophenylmaltosazone [X^oH^OssNJ 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. f &&> I 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
oils, which are also termed " fixed " 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
consequently no glycerol can be obtained from them.

The manufacture of glycerol, soap, and candles from natural
fats, as well as the hardening of oils with the production of edible
and hydrogenated oils, are too well known to require elaboration
here.

During the Great War efforts were made to produce fatty acids
by the oxidation of suitable hydrocarbons, while in order to con-
serve glycerol supplies attempts were made to prepare edible fats
containing ethylene glycol and other polyhydric alcohols in place of
glycerol. Considerable success was also achieved in the preparation
of glycerol by the fermentation of sugar.

A very short account will be given of the chemistry of the lipins,
from which it will be seen that as yet we have very little knowledge
of the chemical constitution of these substances.

Occurrence. The oils, fats, and waxes are very widely
distributed in the vegetable kingdom, and they are found in especially

94



OILS, FATS, AND WAXES 95

large amounts in the reproductive bodies such as spores and seeds.
The commonest glycerides are those of oleic, palmitic, and stearic
acids, but the glycerides of many other acids such as, for instance,
Hnoleic and linolanic acids in linseed oil, erucic acid in colza and rape
oil, lauric acid in laural oil, myristic acid in oil of nutmeg, and
ricinoleic acid in castor oil are found in smaller quantities. The
majority of vegetable fats are liquid at ordinary temperatures, but
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
glycerides are esters of stearic, palmitic, and oleic acids. In certain
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
quantities, and those of the intermediate acids, caprylic, capric,
lauric, and myristic acids in traces.

The glycerides which occur in nature contain, in almost all cases,
three fatty acid radicles, and are thus triglycerides. These trigly-
cerides 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
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. A
perusal of the literature will show that many of these compounds
have been obtained. The method most commonly employed
for the preparation of monoglycerides depends either on the
action of glycerine chlorohydrins on the salts of fatty acids (i),
or on the esterification of the fatty acid with the chlorohydrin
and subsequent exchange of the halogen atoms for the hydroxyl
groups (ii).



9t> ORGANIC CHEMICAL SYNTHESIS

CH 2 C1 CH 2 O - CO R

(i) CHOH + AgOOC-R - CHOH
CH 2 OH CH 2 OH

CH 2 C1 CH 2 C1 CHoOH

(ii)CHCl -> CHC1 -> CHOH

CH 2 OH + HOOC-R CH 2 -O-CO-R CH 2 -O-CO-R

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 a-
monobenzoate is rapidly converted into a mixture of glycerol and
a dibenzoate when treated in ethereal solution with potassium
carbonate. The process is more conveniently followed with the
benzoyl derivatives of ethylene glycol in chloroform solution, whereby
it may be show r n that the change is balanced and attains an equili-
brium in the presence of the glycol and the mono- and di-benzoates.
Similarly, glycerol monoacetate is largely transformed into diacetin
and glycerol. The action of the potassium carbonate appears to be
definitely catalytic, since very small amounts of it suffice to accelerate
the change. The phenomena are very similar to those first observed
by Purdie,f who found that an exchange of alkyl radicals readily
took place between simple esters and alcohols in the presence of a
small amount of sodium alkyloxide. Grun J has shown that this
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 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 some of the triglycerides are known in more than
one form, as, for example, tristearin which exists in two forms,
melting-points 55 and 71 respectively. Grun prefers to regard
these as examples of co-ordination isomerism, but this hypothesis is
somewhat intangible.
* Ber., 1920, 53, 1589. f Trans., 1887, 53, 391. J Ber., 1921, 45 [B], 273, 290.



OILS, FATS, AND WAXES 97

This circumstance has rendered the synthesis of pure mono-
glycerides a matter of considerable difficulty. As initial material
for the synthesis of monoglycerides, Fischer, Bergmann, and Bar-
wind * adopted " acetone glycerol (i) (p. 61), the constitution of
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
a-monoglycerides. For example, stearyl chloride condenses with
isppropylidene glycerol in the presence of quinoline to give stearyl
isopropylidene glycerol (ii). On hydrolysis with semi-normal hydro-
chloric acid in the presence of ether, a-monostearin (iii) is obtained,

CH 2 OH C 17 H 35 COC1 CH 2 O - CO - C 17 H 35 CH 2 O CO C 17 H 3&

CUO. -> CH. -> CHOH

| >C(CH 3 ) 2 ! >0(CH 3 ) 2 |

CH 2 O/ CH/ CHoOH

(i) (ii) (iii)

Hydrolysis of the Oils and Fats. The glycerides are
hydrolyzed by superheated steam in a few hours, and more readily
in the presence of hydrochloric acid acting as a catalyst. Sulphuric
acid acts 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
oleic acid and adding strong sulphuric acid is used very extensively
for this purpose. The aromatic sulphonic acid is the catalyst, and
it acts more rapidly than sulphuric acid because it is soluble in fat,
fatty acid, and water. The addition of small quantities of lime or
magnesia accelerates the hydrolyzing action of steam, and if similar
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 2 O CO R CH 2 OH



CH O - CO - R + sCH 3 OH ^ sCH 3 O CO R -f CHOH

CH 2 O CO R CH 2 OH

* Ber. y 1920, 53 [B], 1589. f Trans., 1915, 107, 337.

( D 331 ) 7



98 ORGANIC CHEMICAL SYNTHESIS

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 quanti-
tatively 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. The maximum yield of glycerol is obtained
when the proportion is two molecules of fat to three of mannitol.
The nature of the fat thus obtained is 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
during germination. Lipase is not only able to hydrolyze fats, but
also many other esters, such as ethyl salicylate, ethyl acetate, and
ethyl carbonate. There appears to be a distinct difference between
the enzymes from different sources, and it has been stated that
lipase may be 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 syn-
thesizes fats is merely a question of conditions, mainly the presence
or absence of water. The glycerol extract of a fat-containing seed
which extract contains the lipase mixed with oleic acid will synthesize
a fat; while the addition of water results in the hydrolysis of this fat
into glycerol and fatty acid.

As early as 1855, Pelouze showed that oil seeds contain a sub-
stance which is capable of producing comparatively rapid hydrolysis
of the oils contained in the seeds; but little attention was paid to
this subject 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
considerably the hydrolysis of triglycerides, provided they be com-
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 gly-
cerides, 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

The Waxes. It has already been mentioned that the waxes
must be considered as esters formed by the combination of mono-
or di-hydric alcohols with higher fatty acids. The alcohols hitherto
identified in waxes belong both to the aliphatic and cyclic series,
the latter being represented by the sterols.

One of the best known vegetable waxes is carnauba wax from a
South American palm (Copernicia cerifera). It is a hard brittle com-
pound, the constitution of which is unknown. This wax contains
ceryl alcohol, C 26 H 53 OH, myriscyl alcohol, C 30 H 61 OH, and two
acids, cerotic acid, C 26 H 52 O 2 , and carnaubic acid, C 24 H 48 O 2 , together
with a hydroxy acid. Candelilla wax is obtained from the stem of
a leafless plant (Pedilanthus pavonis), growing chiefly in Mexico.
Its composition is unknown, but a hydrocarbon, hentriacontane,
C 30 H 62 , 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 impor-
tant 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, when saponification takes place
and the soap separates. The filtrate then contains glycerol and the
sterols. All animal fats contain cholesterol, while vegetable fats
contain either phytosterol itself or a closely allied substance belonging
to the group of sterols. Cholesterol is 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
bile, blood, brain, epidermis, in milk, and in the yolks of egg. It
may be conveniently prepared by evaporating to dryness the ethereal
extract of gall-stones.

Cholesterol, C 27 H 45 OH, has been the subject of prolonged
investigation especially by Windaus. Its constitution is as yet
unknown, but it appears to be a poly cyclic, hydroaromatic, secondary



ioo ORGANIC CHEMICAL SYNTHESIS

alcohol containing four reduced rings. Windaus * considers that
its constitution has been established to the extent indicated in the
expression:

(C 18 Hj



OTT

r



CH-OH CH

The term phytosterol was at one time employed to designate
a definite chemical individual of the formula C 27 H 45 OH, but is
now used as a generic term to include a number of substances having
certain properties in common. Windaus and Hauth f showed that
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 H 45 OH, and stigmasterol, C 30 H 47 OH an ob-
servation 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-
terol in crystalline form, melting-point, magnitude of optical rotation,
and chemical constitution, the latter being as yet unknown.

Other sterols which have been -described include, isocholesterol,
C 27 H 46 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,
in the presence of a catalyst. Thus, in the presence of manganese
compounds, C. Kelber converted a paraffin wax (m.p. 50), by
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 || used up to 5 per cent of various compounds



* Ber., 1919, 52 [B], 162. f #er., 1906, 39, 4378; 1907, 40, 3681.

I Trans., 1911, 99, 2154- &<*> 1920, 53 [B], 66, 1567.

|| Chem. Zeit.> 1920, 44, 309.



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. A 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 at 170 in
the presence of sodium carbonate, the mixture being stirred 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.

A. Grunf has studied these reactions in more detail, and has
shown 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 con-
tain 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
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 hydro-
carbons, but it indicates that the higher paraffins in nature probably
consist only to a small extent of normal hydrocarbons.

Fermentation Glycerol. As early as 1858 Pasteur observed
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. 9 *92O, 53 [B], 2128.

Helv. Chim. Acta, 1920, 3, 721.



102 ORGANIC CHEMICAL SYNTHESIS

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
described by K. Schweizer,* and by W. Constein and K. Ludecke,f
is the employment of sugar solutions containing large quantities of
sodium sulphite. Crude sugar, or even molasses, may be used, and
neither the race of yeast nor the temperature appears to have much
influence on the yield of glycerol. The monthly output in Germany
finally 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,
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, C 6 H 8 O 4 ,
which breaks down to two molecules of this keto-aldehyde, C 3 H 4 O 2 ,
one of which is reduced to glycerol, while the other is oxidized to
pyruvic acid:

CH 2 : C(OH)CHO + H 2 O H 2 CH 2 (OH) CH(OH) CH 2 OH

+ II = +

CH 2 : C(OH)CHO O CH 3 CO COOH

The pyruvic acid is decarboxylated by carboxylase to acetaldehyde,
CH 3 CO COOH - C0 2 + CH 3 CHO

and the latter is reduced to alcohol, while from a further molecule
of methylglyoxal, pyruvic acid is regenerated:

CHa-CO-CHO O CH 3 CO COOH

+ II = +

CH 3 CHO H 2 CH 3 CH 2 OH

Hence methylglyoxal and pyruvic acid would be intermediate
stages, and glycerol and acetaldehyde necessarily by-products. As
a matter of fact, the latter are always present during alcoholic fer-
mentation, and the circumstance that the only known form of methyl-
glyoxal does not ferment is not a fatal objection, since it is probably
the most stable of the many possible forms.

It was next found || that slightly alkaline salts do not suppress
the fermentation, but increase the yield of the by-products at the
expense of the main products; and then it was shown * * that by

* Helv. Chem. Ada, 1919, 2, 167. f Ber., 1919, 52 [B], 1385.

J Ibid.) 1677. 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 glycerol. Since the aldehyde-sulphite com-
pound dissociates, its yield, and that of the glycerol, should depend
on the concentration of the sodium sulphite employed, but not be
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 Sul- Acetaldehyde Glycerol

phite Used. Grammes. Grammes.



33 11*90

50 12-52

75



23*37
24-86
27-61
36-90



150 .... 18-65

The molecular ratio acetaldehyde : 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
glycerol. For a 100 per cent conversion, the fermentation would
have to proceed completely according to the equation:

C 6 H 12 O 6 + Na 2 SO 3 + H 2 O

= C 3 H 8 O 3 + CH 3 CH(OH)OSO 2 Na + 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 is much greater and the
yield of glycerol falls off considerably.

Still 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
(i) neutral fat and fatty acid; (2) substances having no relation to
the fats, such as cholesterol and certain pigments; (3) substances
containing fatty acids, nitrogen, and phosphorus, known as phos-

* 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 ORGANIC CHEMICAL SYNTHESIS

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
pure state, much confusion prevails regarding their number and
chemical properties. The term " lipoid " has been used in such a
vague and unsatisfactory sense sometimes even including the
neutral fats that it is better to consider the phosphatides and
cerebrosides together as lipins. The lipins can then be defined as
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
plastic consistence and have distinctly fat-like properties. They
occur abundantly in eggs, brain, heart, muscle, liver, and other
organs, and appear to be present in every animal and vegetable cell
so far investigated. On hydrolysis the phosphatides yield phos-
phoric acid or glycerophosphoric acid, fatty acids, and basic bodies
such as choline and amino-ethyl alcohol (p. 184).

The best known phosphatides are lecithin and the closely related
substance, kephalin. Both 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 2 CO R
CHO - CO R

CH 2 phosphoric acid radical choline radical

But it is obvious that glycerophosphoric acid may exist in two iso-
ineric forms, namely an a and a p form.

H0\

HO P = O

/ H0\

a CH 2 O CH 2 OH HO P = O

(J CHOH CH O

a' CH 2 OH CH 2 OH

a form (unsym.) (J form (sym.)



OILS, FATS, AND WAXES 105

The a form contains an asymmetric carbon atom, and therefore
should be capable of resolution. Willstatter and Ludecke* have
shown 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 phos-
phorus. On hydrolysis they give galactose, a fatty acid, and a base
sphingosine. Up to the present only two cerebrosides have been
described phrenosin and kerasin and both are obtained from
brain.

These two compounds would appear to be identical except in
so far as the former contains phrenosinic acid (C 25 H 50 O 3 ) and the
latter, lignoceric acid (C 24 H 48 O 2 ). The structure of sphingosine as
well as these two acids is unknown.

RosenheimJ has suggested constitutional formulae for these
cerebrosides, but no finality has yet been" reached.

REFERENCES.

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 Lewko-

witsch (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 VI
The Terpenes and their Derivatives

The terpenes embrace a large number of hydrocarbons of the
empirical formula C 5 H 8 , and four main groups are recognized:

Hemiterpenes, C 5 H 8 .
Terpenes proper, C 10 H 16 .
Sesquiterpenes, C 15 H 24 .
Polyterpenes, (C 5 H 8 ) n .

The 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
species.

To 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 simple operations.

From the terpenes a large number of alcohols and ketones of the
general composition C 10 H 16 O, C 10 H 18 0, and C 10 H 20 O are derived.
These compounds are sometimes collectively termed " camphors ",
since the commercially important, common or Japanese camphor is
one of them.

The study of the terpenes and their derivatives has attracted
a large number of chemists, among whom Baeyer, Perkin junior,
Semmler, Wagner, and especially Wallach are noteworthy. In
many cases, 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
isolation and purification of the camphors is usually much easier
than that of the terpenes, since the former often crystallize well or



THE TERPENES AND THEIR DERIVATIVES 107

form characteristic crystalline derivatives. 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 in
nature.

Of the numerous hydrocarbons of the formula C 5 H 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
published investigations concerning this hydrocarbon, while its
constitutional formula, CH 2 : C(CH 3 ) CH : CH 2 , was established by
its synthesis by Euler. Of recent years isoprene has received con-
siderable attention in connection with the problem of synthetic
rubber.*

Properties of the Terpenes, C 10 H 16 . With the exception of
camphene, which is a solid, the terpenes, when pure, are colourless,
strongly refractive liquids which boil without decomposition. They
have a pleasant odour, are volatile with steam, and many are optically
active.

The terpenes polymerize very easily, and many, such as a-pinene
and /?-phellandrene, are oxidized with resinification on exposure
to the air. Acids transform many terpenes into isomeric analogues.
Nitrosyl chloride frequently gives well defined terpene nitroso-
chlorides, while many terpenes react with nitrogen peroxide to give
nitrosates, C 10 H 16 (NO)O-NO 2 , and with N 2 O 3 to give nitrosites,
C 10 H 16 (NO)ONO, or pseudo-nitrosites, C 10 H 16 (NO)NO 2 . By the
action of ozone the terpenes yield ozonides, while, with dilute potas-
sium permanganate, they give glycols. All these reactions have
been extensively employed in the determination of the constitution
of the terpenes.

Classification, In most cases the terpenes and camphors are
designated by names derived from the plants in which they were
first observed or which contain them most abundantly. Since many
terpenes, formerly considered as single substances, have been found
to be mixtures, the terpenes isolated from them have been distin-
guished from each other by prefixing Greek letters, e.g. a-, /?-, and
y-terpinene.

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 ORGANIC CHEMICAL SYNTHESIS

A. Olefinic terpenes, or the terpenogen group.

B. Monocyclic terpenes or menthadienes.

C. Dicyclic terpenes:

1. The Sabinane Group.

2. The Carane Group.

3. The Pinane Group.

4. The Camphane Group.

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

<fH 3 C 7 CH 3 CH 3

c c c c

H 2 c/cH







c c c

) I I

CH C 8 CH

CH 3 CH 3 9 C C 10 CH, CH 3 CH 3 CH 3

(i) (ii) (iii)

Compounds of this class are naturally able to combine with two
molecules of halogen acid, halogen, &c.

The 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
carbon rings. Like the monocyclic terpenes, they are closely
related to />-cymene, and can usually be converted into this com-
pound with facility. Their dihydro compounds are derived from
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

* 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.



OLEFINIC TERPENES AND THEIR DERIVATIVES 109

gives the sabinane group, or by the union of the tertiary carbon
atom of the isopropyl group is joined with a second carbon atom
of the hexamethylene ring. According as this linkage occurs in the
o, m y or p position we obtain the fundamental hydrocarbons of
the carane, pinane, and camphane groups:



CH-CH CH,



CH-C



CH,



CH r CH-



CH,



-CH,



I
/~tT T __ T /"^ILI

yrL 2 V^H

/



.> \^> ' J Vxxln



CH, CH r CH CH CH CH-CH 2 CHj-CH-CH 2



C 3 H 7

Sabinane



Carane



Pinane



Camphane



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
derived from them will contain 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
in the case of the monocyclic terpenes.



THE OLEFINIC TERPENES AND * THEIR DERIVATIVES

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
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
on reduction, little progress was made until 1890, when Schim-
mel's Berichte announced the fact that the aldehyde citral is the
principal odorous constituent of lemon oil. 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
and made some progress in the determination of its constitution.



no ORGANIC CHEMICAL SYNTHESIS

Since this time the presence of the olefinic terpenes and their deri-
vatives 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 mono-
cyclic terpene in which the ring has been ruptured.

It has already been stated that Semmler * had observed the re-
lationship of geraniol to cymene, and that by the action of potassium
hydrogen sulphate on geraniol or citral, jp-cymene had been obtained.
The relation of citral to p-cymene is made clear by the following
formulae:

CH CHO ,CH 3

Citral, CH 3 * C



CH - CH CH 3

/>-Cymene, CH 3 C^ ^C - CH/

CH - CH CH



3



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
linalol, terpineol is obtained. In these reactions linalol is probably
first transformed into the isomeric geraniol, and, by the removal and
subsequent addition of water, ring formation occurs with the pro-
duction of terpin, followed by that of dipentene and terpinene.

CH CH 2 OH CU^CH,




Geraniol Terpin



CH - CH 2

^ CH 3 Cv xCH C(OH)(CH 3 )2

r^ur r^iu
L/ri2 ^rl 2

Terpineol

* Ber., 1890, 23, 1098, 2965, 3556; 1891, 24, 201, 682.
7. prakt. Chem.y 1892, 45 [2], 590. J Ibid., 1898, 58 [2], 109; 60, 244.



no ORGANIC CHEMICAL SYNTHESIS

Since this time the presence of the olefinic terpenes and their deri-
vatives 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 mono-
cyclic terpene in which the ring has been ruptured.

It has already been stated that Semmler * had observed the re-
lationship of geraniol to cymene, and that by the action of potassium
hydrogen sulphate on geraniol or citral, p- cymene had been obtained.
The relation of citral to />-cymene is made clear by the following
formulae:

CH-CHO /CH 3

Citral, CH 3 - C<^

i

CH - CH CH 3

p-Cymene, CH 3 C\^ %C CH<^

CH - CH CH 3

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
linalol, terpineol is obtained. In these reactions linalol is probably
first transformed into the isomeric geraniol, and, by the removal and
subsequent addition of water, ring formation occurs with the pro-
duction of terpin, followed by that of dipentene and terpinene.

CH - CH 2 OH CH 1_CH 2

\CH-C(OH)(CH 3 ) 2



CH 2 -CH 2 CH:C(CH 3 ) 2 CH 2 ~CH 2

Geraniol Terpin

CH - CH 2

-> CH 3 C<^ NCH - C(OH)(CH 3 ) 2

CH 2 - CH 2
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.



Geraniol
and nerol.



Citral and
neral.



Linalol.



Rhodinol.



Rhodinal.



Citronellol.



Citronellal.



Probable Constitution.



CH CH 2 CH 2 - C : CH - CH 2 OH



CH 3 CH 3

CH CH 2 - CH 2

II
C

/ \
CH 3 CH 3

CH CH 2 CH,

II
C

CH 3 X CH 3



C : CH CHO

I
CH 3



C(OH) CH : CH,
CH.



CH - CH 2 - CH 2 CH CH 2 . CH,OH

li I

C

CH 3 CH 3



CH CH, CH 2

li
C

CH 3 CH 3

CH, CH a - CH 2

v^-

CH 3 CH,

CH 2 - CH 2 - CH a

C

/ ^
CH, CH 2



CH CH 2 CHO

CH, (?)



- CH CH 2 - CPLOH
CH,



2 CH - CH 2 CHO
CH 3



Occurrence.



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.



Oil of lemon-grass from Andropogon citratus.
Oils of lemon, Citrus limonum.
Eucalyptus staigeriana.



Oil of linaloe, oil of neroli.

Oil of bergamot from Citrus Bergamia.

Oil of lemon, petit-grain, spike lavender, ylatig-ylang, &c.



Laevo form in geranium and rose oil.



A synthetic product.



Bulgarian and German rose oil.

Oils of geranium from Pelargonium odoratissintum, &c.



Citronella oil from Andropogon nardus.

Certain eucalyptus oils.

Lemon-grass oil, oil of mandarin orange,, &c.



[Facing p. no



OLEFINIC TERPENES AND THEIR DERIVATIVES in

Further examples of the formation of monocyclic terpenes from
olefinic 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 2 -CHO CH 2 - CH(OH) rH

CH 3 -CH< ,CH a _^ prr rH / V ^" 2

N CH 2 -CH 2 -CH 2 -Cf "* ^"3-^H\ /

N/^LJ r^nj r^ur

v^rls >^rl 2 Lxrl 2

Citronellal Iso-pulegol



CH 2 -CHO rt4 CH 2 -CO



/

CH 3 CH< /CH = C^ -> CH 3 CH<; >CH CH<



3 / = -> 3

\ / Nr'M

CH 2 -CH 2 Uhl3 CH 2 ~CH 2

Rhodinal Menthone

The reverse of this process takes place on exposing an aqueous
alcoholic solution of menthone to bright sunlight, when the ring is
opened and an unsaturated aldehyde, similar to citronellal but of
lower boiling-point, is obtained.*

Before briefly describing the synthesis of the olefinic terpenes
and their derivatives it is advisable to consider that of methyl-
hep 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 2 CO CH 3 , was first
obtained in small quantities from natural linaloa oil by Barbier and
Bouveault,f while Tiemann J found that v it was present in lemon-
grass oil to the extent of i to 3 per cent. Methylheptenone has been
synthesized by several methods, of which that of Barbier and Bou-
veault may be described. In the first place 2-methyl-2 : 4-dibromo-
butane 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 /COCHa (CH a ) 2 C (CH 3 ) 2 C

I MaTH I! II

CH 2 + iNa ^ _> CH KOH CH

| ^COCH 3 | -> | +CH 3 COOK

CH 2 Br CH 3 CO CH 2 CH 2

>CH CH 3 CO CH 2
2-Methyl 2:4- /

dibromobutane L,ti 8 v^u + NaBr

+ HBr

(i)

* Ciamician and Silber, Ber., 1907, 40, 2421. f C. r., 1895, 121, 168.
t Ber., 1899, 32, 830. C. r., 1896, 122, 393.



ii2 ORGANIC CHEMICAL SYNTHESIS

When shaken with 75 per cent sulphuric acid, methylheptenone
loses water and gives dihydro-w-xylene.

CH CH

/\ /\

CH 3 - C CH 2 - H 2 O CH 3 C CH 2



CHs CIi2



CH CH 2

'/ ' \/

O:C C

H in

113 v>Jri3

The preparation of several of the olefinic terpenes and their
derivatives from methylheptenone may be illustrated by the fol-
lowing tabulation:

Methyl -hep tenone *

IZn andCH 2 10OOC 2 H 5
followed by dehydration

Geranio Acid '

"v^

Reduction with Sodium and
Amyl Alcohol

VRhodinic Acid ||




Reduction \viih

Sodium Amalgam Rhodinol and Rhodinal * *



Geraniol and Nerol (stereoisamers)
Linalol



Geraniol, Nerol, and Linalol. It has already been shown
that when citral in alcoholic solution is reduced by sodium-amalgam
in the presence of dilute acetic acid, geraniol and nerol are obtained.

* It is interesting to recall the fact that Bar bier's attempt to convert methyl-
heptenone 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

t Barbier and Bouveault, C. r., 1896, 122, 398; Tiemann, Ber., 1898, 31, 325.

J Tiemann, loc. cit. Tiemann, loc. cit.
I) Bouveault and Gourmand, C. r., 1904, 138, 1699. ** Tiemann, Ber., 1898, 31 , 2901 .



OLEFINIC TERPENES AND THEIR DERIVATIVES 113

These terpene-alcohols appear to be structurally identical, and are
probably stereoisomerides of the formula *

CH 3

(CH 3 ) 2 C : CH CH 2 CH 2 C : CH CH 2 OH

When treated with acetic acid containing i 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 closer together in the case of nerol
than in that of geraniol: H C CH 2 OH

(CH 3 ) 2 C : CH - CH 2 CH 2 - C - CH 3 Geraniol

HO CH 2 - C - H

II
(CH 3 ) 2 C : CH - CH 2 CH 2 - C - CH 3 Nerol

Linalol occurs in both dextro and laevo forms, and therefore at
least one asymmetric carbon atom is present in the molecule. This
and other facts are best explained on the assumption that linalol has
the formula: OH

(CH 3 ) 2 C : CH CH 2 CH 2 C CH : CH 2

CH 3

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 diffi-
culties attendant upon this type of investigation. In 1896 Tiemann
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 2 CH 2 CH(CH 3 )CH 2 CHO

which on oxidation yields:

(CH 3 ) 2 CO + HOOC CH 2 CH 2 CH(CH 3 )CH 2 COOH

In 1901, however, Harries and Schauwecker J prepared the dimethyl-
acetal 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. f Ber., 1896, 29, 903; 1897, 30, 22, 33.

J Ber., 1901, 34, 1498, 2981.
(D331) 8



ii4 ORGANIC CHEMICAL SYNTHESIS

finally a keto-aldehyde, CH 3 CO-CH 2 -CH 2 -CH 2 CH(CH 3 )CH a CHO.
These results are best explained by the following formulae:



CH 3
\C CH 2 CH 2 CH 3 CH CH 2 CHO

CH 2 i

* CH 3
CH 3 |

> X C-CH 2 CH 2 -CH 2 CH - CH 2 CH(OCH 3 ) 2



If this is so, 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:

HC - CHO
(CH 3 ) 2 C : CH CH 2 CH 2 C CH 3 Citral a.

OHC - C - H
(CH 3 ) 2 C : CH - CH 2 CH 2 C - CH 3 Citrai b.

The preparation of a- and /Monone from citral will be described later.
Rhodinol and Rhodinal. The constitution of these two com-
pounds is by no means definitely settled as yet, and the literature
contains many contradictory statements.

fr.THE MONOCYCLIC TERPENES (C 10 H 16 )

Limonene. This terpene is known in three modifications,
d-limonene, 7-limonene, and (d7)-limonene or dipentene. To-
gether with pinene, dbefrolimonene is among the most widely
distributed terpenes. It is present in lemon oil, oil of bergamot,
oil of dill, and several other natural essential oils. L^^olimonene
occurs in oil of pine needles, oil of fir, and oil of peppermint. Dipen-
tene, 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
present in Swedish oil of turpentine, which has been prepared by
distilling the natural product at a high temperature.

The limonenes combine with bromine to form tetrabromides,
C 10 H 16 Br 4 , which are stable crystalline substances, while nitroso-

*Ber., 1907,40,2823.



THE MONOCYCLIC TERPENES 115

chlorides of the general formula C 10 H 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 is S-ketohexa-
hydrobenzoic acid, which is obtained as follows:



,
2C 2 H 5 OOC - CH 2 CH 2 I + Na 2 C<

X COOC 2 H 5
p-Iodopropionic ester

C 2 H 5 OOC CH 2 CH 2 CN

x

C 2 H 5 OOC CH 2 CH 2 COOC 2 H 5

Y- Cyanopentan-ocye-tricarboxylic ester

HOOC-CH, -CH 2 COOH

"



HC1



HOOC CH 2 CH 2 COOH



Boil with acetic anhydride /

-> OC< >CH COOFI



nnyuriue 2

OC \
and distil r^u

CH 2

8-Ketohexahydrobenzoic acid

The ester of this acid reacts with magnesium methyliodide, the
ketonic group being preferentially attacked, and on hydrolysis
S-hydroxyhexahydro-p-toluic acid is obtained:

IMgO CH 2 -CH 2 HO CH 2 -CH 2

yc<f y CH-COOC 2 H 5 ^ ^

H,C CH 2 -CH 2 H 3 C CH 2 -CH 2



J Trans., 1904, 85, 138, 416; 1906, 89, 1640; 1907, 91, 372.

OH

CH



* See p. 128. I

C



t Carvacrol has the constitution: H 3 C -

CH CH



n6



ORGANIC CHEMICAL SYNTHESIS



By the action of fuming hydrobromic acid, 8-bromohexahydro-/>-
toluic acid is formed which, on treatment with weak alkalies, gives
3-tetrahydro-/>-toluic acid:

CH - CH 2

CH 3 . C^ ^>CH COOH

CH 2



When the ester of this acid is treated with magnesium methyliodide
the tertiary alcohol, terpineol, is obtained:



CH - CH 2



COOC 2 H 5 + 2MgCH 3 I



CH - CH 2



OMgl



2 .

^)CH - C CH
CH 2 - CH 2



I
^
OC 2 H 5



H,0



C(OH)(CH 3 ) 2



CH 2



Terpineol



Terpineol is transformed into <//-limonene (dipentene) by dehy-
drating 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
methyliodide:

CH - CH 2 .OH



CH - CH 2



CH 2 - CH 2

Dipentene



CH 2 - CH 2

Terpineol



CH 2
CH 3



CH 2 - CH 2

^>CH-C(OH)(CH 3 ),
CH - CH 2
Terpin



The alternative method by which water may be eliminated from
terpineol, namely between the groups attached to carbon atoms 4
and 8, would lead to the production of a terpene devoid of an asym-
metric carbon atom.



THE MONOCYCLIC TERPENES 117

Terpinolene CH - CH 2 CH S

// \

\J __ ^

-CH 2



is an artificial inactive terpene first obtained by Wallach from pinene.
It has not yet been observed in natural essential oils. It is produced
when 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 H 16 Br 2 ,
and a tetrabromide, C 10 H 16 Br 4 , 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. This group embraces the following
three terpenes:

CH 3 CH CH 3 CH 3 CH - CH 3 CH 3 CH - CH 3



/\ /\ /\

CH 2 CH CH 2 CH CH 2 CH

CH 2 CH CH CH 2 CH 2 CH 2



c c

I I

CH 3 CH 3



CH 2



3 3 2

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 car-
damom 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 ORGANIC CHEMICAL SYNTHESIS

product is 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 2 COOC 2 H 5 CH-COOH






HC(CH 3 ) 2 HC(CH 3 ) 2 HC(CH 3 ) 2 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 ).

The Phellandrene Group. In 1904 Wallach* published
the results which he had obtained in his exhaustive investigation of
phellandrene obtained from water-fennel oil (Phellandrium aqua-
ticwri) and pointed out that two isomeric phellandrenes are
present in this oil.




2




Phellandrene p -Phellandrene
(z : 5-Dihydrocymene) 2

The structure of the j8 form was later confirmed by Wallach f by
its synthesis from A : 2-isopropylcyclohexanone after the manner of
that of jS-terpinene.

Sylvestrene and Carvestrene. Sylvestrene has been found
in Indian, Swedish, and Russian turpentine oil, and oil of pine
needles. It is dextrorotatory, and possesses a pleasant odour
resembling that of lemons.

* Ann., 1904, 336, 9. \Ann. y 1905, 340, i; 343, 29.



THE MONOCYCLIC TERPENES 119

Carvestrene is an artificial compound which was first obtained
by Baeyer * by the distillation of vestrylamine hydrochloride.

C 10 H 17 NH 2 HC1 - C 10 H 16 + NH 4 C1

Both sylvestrene and carvestrene give a deep blue colour when
dissolved in acetic anhydride and treated with concentrated sul-
phuric 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 Tatter-
sail, f by the action of magnesium methyliodide on the ester of
cyclohexanone-3-carboxylic acid in a similar manner to that of
dipentene. Later J the intermediate tetrahydro-w-toluic acid was
resolved and the dextrorotatory terpene prepared from it was
found to be identical in every respect with ^/-sylvestrene. Cyclo-
hexanone-3-carboxylic acid was prepared by oxidizing the hexahydro
derivative obtained by the reduction of w-hydroxybenzoic acid:

CH 2

CHOH





CH-COOH CH-COOH



Synthetic Monocyclic Terpenes. The first complete syn-
thesis 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 syn-
thesis must be regarded as classical. In the presence of metallic
sodium, two molecules of diethylsuccinate (i) condense to form
succino-succinic ester (ii) a diketohexamethylene dicarboxylic
ester. When the latter is treated with sodium ethoxide and isopropyl
iodide a monoisopropyl derivative (iii) is formed which, on repetition
of the process but using methyliodide in place of isopropyliodide,
gives a methyl-iscpropyl derivative (iv). On treatment with con-
centrated sulphuric acid methyl-isopropyl diketocyclohexane (v)
is obtained, which may be reduced to the alcohol (vi). On bromina-
tion with strong hydrobromic acid a dibromo derivative (vii) is

* Ber., 1894, 27, 1915, 3485; 1896, 29, 2796.
t Trans.y 1907, 91, 480. J Proc. Chem. Soc., 1910, 26, 97.



120 ORGANIC CHEMICAL SYNTHESIS

formed, from which a menthadiene of uncertain constitution is
obtained on removing two molecules of hydrogen bromide by means
of quinoline.

COOC 2 H 5 COOCoHs CO



CH 2 CH a CH 2 CH COOC 2 H 5

CH 2 CH 2 CH CH 2

C 2 H 5 OOC COOC 2 H 5 / CO

COOC 2 H 5

(0 (ii)

C0 C0

/\ /\ / CH

s-i TT CHg CH * C/OOCxori5 f>t TT CH> Cv

^ a "< || -> ^ 3 "< | " | X COOC 2 H 5

>c




C 2 H 5 OOC C 2 H 5 OOC

liii) (iv)

CO CHOH CBTRr

OCHCH

CO

(v)

The syntheses of limonene and carvestrene by Perkin junior
have already been dealt with. These methods have been ex-
tended in several directions which may be briefly summarized
as follows.*

1 . From the toluic acid by reduction to the hexahydro derivative
and bromination. On removal of hydrogen bromide an aj8-tetra-
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 hexa-
hydro derivative and thence into the bromohexahydro acid. The
latter is then treated as above.

3. From the hydroxybenzoic acid by complete reduction and

* " Synthesis of the Terpenes ", by W. H. Perkin, The Perfumery and Essential
Oil Record, 1912, 3, 149.



THE MONOCYCLIC TERPENES 121

oxidation to the ketonic acid. Magnesium methyliodide attacks
the ketonic group, and the methylhydroxy acid thus formed is con-
verted into the bromo acid and thence to the unsaturated acid (c,f.
carvestrene).

4. By the action of sodamide and carbon dioxide on the methyl-
cyclohexanone. The resulting ketonic acid is then reduced to the
hydroxyacid and thence through the bromo acid to the unsaturated
acid.*

CH 2 CO M MIJ _ n CH 2 CO H CH 2 CHQH
. . N^NH 2 +C0 2 . . J^ > .

CH.CIK /CFU CH,CH< >CHCOOH CKLCEK >CH-COOH

3 \ / 3 \ / 3 \ /

CH 2 CH 2 CH 2 CH 2 CH 2 CH 2

CH 2 CHBr

HBr / \

* CH CH< >CH-COOH



CH 2 CH 2



5. From cyclohexanone-2 : 4-dicarboxylic acid, the sodium
derivative of which gives methylcyclohexanone carboxylic acid on
treatment with methyliodide:

CH 3

I

C 2 H.O-COC(Na) CH 2 C.H.OOC-C CH



25 2 26 2






CH 2 CH 2 CH 2 CH 2

CH,

I
CH

CH-COOH
CH 2 CH 2

The ketonic group is 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
for the conversion of nitrites into ketones by the aid of the Barbier-
Grignard reagent.

* Tram., 1910, 97, 1756; 1911, 99, 526.
t Trans., 1908, 29, 1876. J Trans., 1914, 105, 1659.



122 ORGANIC CHEMICAL SYNTHESIS

CH(CH 3 )-CH a Sod. cyano- CH(CH 3 )-CH

/ \ acetate / \ Heat

CH 2 CO -> CH 2 C.CH(CN)COOH -*



CH 2 CH 2

i : Methylcyclohexan 3 -one

CH(CH 3 )-CH 2 CH(CH 3 )-CH,

/ \ MgCH 3 I / \" MgCH 3 I

CH 2 C-CH 2 CN -> CH 2 C-CH,COCH 3 ->

\ / "



CH(CH 3 )-CH dehy- CH(CH 3 )-CH

/ \ dration/ \

CH 2 C-CH,>C(CH 3 ),OH -> CH, C-CH:C(CH 3 ) 2

\ / \"

CH



The synthesis of j8-terpinene already referred to (p. 118) illus-
trates another synthetic method which has been elaborated by
Perkin junior and Wallach.* Cycloketones are combined with a-
bromopropionic ester in the presence of zinc (Reformatsky's re-
action). The free acid on heating loses carbon dioxide and water,
giving an unsaturated compound, e.g.

CH 3 CH<^\CO-^GH 3 CH/ \<f ^CH 3 CB/ )c:CHCH 3

N / ^ f X CH (CH 3 )COOH ^ f

The nitrosochloride of the latter gives the oxime on elimination of
hydrogen chloride and on hydrolysis yields the ketone.

CH 3 CH/ \C-Q-C(CH 3 ):NOH->CH 3 CH/ \C-
CH 3 CH

The menthanol and menthadiene are obtained on treating the
latter with magnesium methyliodide.

The Menthenes and their Derivatives. The monocyclic
terpenes so far considered contain two double bonds, and are
consequently termed menthadienes. A number of monocyclic
terpenes of the general formula C 10 H 18 are known which contain
one double bond and are consequently termed menthenes. The

* Trans., 1910, 97, 1429; 1911,99,118; Ann., 1910, 374, 198; 1911,379,131.




THE MONOCYCLIC TERPENES



123



parent hydrocarbons are not very important, but a few of their
derivatives merit consideration.

Pulegone, A-4 : (8)-menthene-3-ketone

CH 2 - CO

\C : C(CH 3 ) 2

CH.2



is the chief constituent of oil of pennyroyal (Mentha pulegium). It
was isolated by Beckmann and Pleissner in 1891, investigated by
Semmler, and ultimately synthesized by Tiemann and Schmidt in
1896.* With hydroxylamine it forms both an oxime and an oxamino
ketone, and Wallach has shown that this reaction is characteristic of
cyclic ketones when the double bond is in the side chain. When
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.



CH 3


CH 3

|


CH 3


CH

x\


CH


/\


/\
r^TU r*"Li

v_xJri2 V_x.Tl2

CH 2 CO


CH 2 C : NOH

\ /


/\

and | 2 | 2

CH 2 CO

\ /


C

II


\/
CH

I


\x

CH

1


C(CH 3 ) 2


C

/^


C . NHOH

/\


/ ^
CH 3 CH 2

Pulegone Isopulegone oxime t


CH 3 CH 3
Oxamino pulegone


CH

S\
CH 3 C CO




HO-NH
1 CH 2



H 2 C CH 2
\/
CH CH 3



CH 3 C C : NOH
I 1
CH 2 CH 2
\/
CHCH 3

An oxamino oxime



On reduction pulegone is converted into menthol, and on oxida-

* Ber., 1896,29, 913; 1897,30,22.

f By the action of hydroxylamine the double bond moves with the formation
of the oxime of isopulegone.



I2 4



ORGANIC CHEMICAL SYNTHESIS



tion into acetone and 3-methylcyclohexanone, further oxidation of
the latter giving j8-methyladipic acid:

CH 3 CH 3

i i

CH

/\
CH 2 CH 2



CH 2



CO



CH 2 CH2
CH 2 C



C

u



2 ^HOH

V
CH



C!H



CH 3 CH 3




Pulegone








CH 3






1






CH




Formic acid,


/\




or water


CH 2 CH




at 280


CH 2 CO



CH 3 CH 3
Menthol



CH 3

C!H



oxidation



CH 2

3 -Methylcyclohexanone

+
CH 3 COCH 3



CH2 CH a
CH 2 COOH

V COOH

p-Methyladipic
acid



When citronellal is heated with acetic anhydride it gives iso-
pulegol. On oxidation of the latter isopulegone is obtained, which
on treatment with baryta undergoes isomeric change to pulegone: *



CH CH 3



CH CH 3



CH CH a



CH CH,



CH 2 CHO


CH2 CH2
CH 2 CHOH


r^ur r^u
L/rl2 v^rlo

CH 2 CO

^ \ / -^


CH 2 CH 2
CH 2 CO


CH 2


CH

i


-^ \/ r

CH

i


C

II


/\
CH 3 CH2

Citronellal


C

r^u r^T-i
^rl 3 \^ri2

Isopulegol


C

/\
r^ur r^nr
Lxrl 3 Vxtl 2

Isopulegone


II
C

/\

f~*Tf f^TJ

^xJnL 3 v^ri2
Pulegone



Menthone and Menthol. Menthone occurs in Japanese,
American, and Russian peppermint oils. It is known in two opti-
cally active modifications, of which the laevo form may be obtained

* Tiemann and Schmidt, Ber., 1897, 30, 32.



THE DICYCLIC TERPENES 125

by the oxidation of menthol with potassium dichromate and sulphuric
acid below 50. Concentrated sulphuric acid converts laevomen-
thone into dextromenthone in the cold.

Synthetic menthone was obtained by Kotz and Schwarz * by
distillation of the calcium salt of jS-methyl-a'-isopropylpimelic

acid:

CH 3 CH 3 CH 3



C!H



CH CH



CH 2 CH 2 COO CH 2 CH 2 CH 2 CH 2

CH 2 COO-Ca -> CH 2 CO -* CH 2 CHOH



CH CH CH

CH CH CH



CH 3 CH 3 CH 3 CH 3 CH 3 CH 3

Menthone 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
synthesized by Perkin junior from the hexahydrotoluic acids as
already indicated (p. 120). On dehydration of laevomenthol a dextro-
menthene of the constitution shown below has been obtained, and
this structure has been verified by its synthesis from i:4-methyl-
cyclohexanone by Wallach.f

CH 2 - CH

/ \ /CH 3

CH 3 - CH C CH<

\ / X CH 3

CH 2



C- THE DICYCLIC TERPENES

\,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 tri-
methylene carboxylic acids by oxidation. Sabinene and the
two thujenes must contain the same carbon skeleton, and differ

* Ann., 1907, 357, 206. f Ber -> I 9 6 > 35 > 2 54-



126



ORGANIC CHEMICAL SYNTHESIS



only by the position of the double linkage since they all yield
the same saturated dicyclic hydrocarbon C 10 H 18 , sabinane or
thujane on gentle reduction.*

Sabinene. The dextro form of this compound has been found
in Ceylon cardamom oil and majoram oil. With dry hydrochloric
acid it yields sabinene hydrochloride, but with moist acid it gives
terpinene dihydrochloride. With cold dilute sulphuric acid it gives
terpinenol and i : 4-terpin, while on heating it gives terpinene: f




CH




JHfCHj),
Sabinene



OOH




CH,





C-Ci
CH(CH 3 ) 2


C-OH
CH(CH 3 ) 2


C-OH
CH(CH 3 ) 2


CH(CH 3 ) 2


Perpinene


i : 4-Terpin


Terpinenol


oc-Terpinene



Sabinene
hydrochloride dihydrochloride

On oxidation with potassium permanganate sabinene glycol (ii)
is first formed, which is then oxidized to sabineric acid (iii) and
further to sabina ketone (iv).



CH,




CH(CH 3 ) 2
Sabinene




COOH
C-OH



CO




C
CH(CH 3 ) 2




111



CH(CH 3 ) 2
iv



On treating this cyclic ketone with warm aqueous or alcoholic sul-
phuric acid the trimethylene ring is broken and 2-isopropylcyclo-

* Tschugaeff and Formin, C. r., 1910, 151, 1058.
t Wallach, Ann. t 1907, 350, 165.



THE DICYCLIC TERPENES 127

hexanone (ii) is obtained. Further disintegration leads to the
formation of a-tenacetone-dicarboxylic acid (i).

COOH
HP COOH




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-
rotatory. The dextro form is found in tansy oil and some worm-
wood oils. The oxime of thujone gives thujylamine, C 10 H 17 NH 2 ,
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 ) 2 CH(CH 3 ) 2

a -Thujene P -Thujene

Thujene combines with hydrogen chloride to give terpinene di-
hydrochloride, and is converted into terpineol on treatment with
dilute sulphuric acid.

* J. Russ. Phys. Chem. Soc,> 1904, 36, 988.



i 2 8 ORGANIC CHEMICAL SYNTHESIS

THE CARANE GROUP



The only member of this group which we need consider is
carone. This terpene does not occur in nature, but has been ob-
tained by the action of methylalcoholic potash on dihydrocarvone
hydrobromide:

CH 3 CH 3

CH CH CO CH CH

CH= CH - CH, CHj CH CH,

I I

^C\ BrC(CH 3 ) 2

CH, CH 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, CH 2



2 v^ria
CH



CH2

Carvone



Carone has an odour somewhat resembling camphor and pepper-
mint. It gives caronic acid on oxidation, and the identity of this
acid with dimethylcyclopropane-dicarboxylic acid has been estab-
lished by its synthesis by Perkin junior and Thorpe.*




COOH



HOOC - CH CH
Carone Caronic acid

* Trans., 1899, 75, 48.



THE PINANE GROUP 129

THE PINANE GROUP

The Pinenes. Pinene is a very common constituent of essential
oils, 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 y
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.

(dl)-a- Pinene. The natural oil almost invariably contains
traces of j8-pinene, which may be removed by making use of the
fact that a-pinene alone gives a nitrosochloride with nitrosyl chloride.
The nitrosochloride is then decomposed by aniline, or by boiling
it 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
perfectly dry acid. These, however, like the halogen additive
products, no longer contain the pinene ring, the hydrogen haloids
having given rise to borneol derivatives. v This easy transition of
pinene into borneol and isoborneol has been utilized industrially
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
that we owe our knowledge of the structure of the pinene molecule.
By the action of moist oxygen Sobrero obtained pinol hydrate or
sobrerol, C 10 H 16 (OH) 2 . By means of permanganate solution Baeyer *
obtained a-pinonic acid, C 10 H 16 O 3 ,and pinoylformic acid, C 10 H 14 O 5 ,
both of which are ketonic acids. As both acids yield the same
pinic acid, C 7 H 12 (COOH) 2 , on further oxidation, Baeyer concluded
that they contain respectively a methyl ketone, COCH 3 , and an a-
ketonic acid, CO COOH, group. By the oxidation of a-hydroxy-
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) 9



130



ORGANIC CHEMICAL SYNTHESIS



acid, and therefore contains a cyclopropane nucleus, pinene must con-
tain a bridged ring, of which one part consists of four carbon atoms.



C-CH,




COCH,



HOOC CM



Pinene




COCOOH



HOOC




a-Pinonic acid



COOH



HOOC C




Pinoyl formic acid

COOH
v

CI



HOOC




Pinic acid



Norpinic acid



On heating with acids, a-pinonic acid and pinoyl-formic acid
are transformed as follows:



COCH,,



HOOC CH




H 2 C



CH
a-Pinonic acid

QO-COOH
HOOC CH 3 CH

CHiC^

,CH 2



COCH,



J H ' i

C-CH 3 |



CH.



CH




Methyl Ketone of
Homoterpenylic lactone



CO-COOH
CH 3 CH 2



Pinoyl formic acid
COOH



OC



H



CH a



.



I
C-CH,



CH,



CH
Homoterpenyl formic acid



CH 3 9 OOH

\>CH
i

CH,



H 2 C N



Homoterpenylic acid



"CH
Terpenylic acid



THE CAMPHANE GROUP 131

Simonsen * synthesized homoterpenylic, terpenylic, and terebic
acids by the action of magnesium methyliodide on j8-acetyl-adipic,
j8-acetyl-glutaric, and /?-acetyl-succinic esters respectively. The
reactions are so similar that only one of them need be formulated:

C 2 H 5 OOC CH 2 CH(COCH 3 ) CH 2 COOC 2 H 5
Ethyl p-acetylglutarate

MgCH 3 I

-> C 2 H 5 OOC - CH 2 CH[C(CH 3 ) 2 OMgI]CH 2 COOC 2 H 5

C(CH 3 ) 2 - CH - CH 2 COOC 2 H 5

"^ O - CO - CH 2

Ethyl terpenylate

/?-Pinene is found together with a-pinene as already described.
It has also been observed in lemon oil, coriander oil, hyssop oil,
and the oil 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

CH 2 OH COOH

OOH CO

s r-'TtN. ' C*\A***

-- ^"^~- T CH




,

.y\

3 I CH 2 CH 2 |

^



CH 2

^CH
p-Pinene glycol Nopinic acid Nopinone

Nopinone has been used for the synthesis of j8-pinene, camphene,
and camphor by Wallach.J

2^THE CAMPHANE GROUP

By far the most important member of this group is the ketonic
compound camphor a substance which may exhibit manifold
changes in a most interesting manner.

Camphor. The study of camphor is coeval with that of
organic chemistry itself, since it attracted the attention of such early

* Trans., 1907, 91, 184. f Ann., 1907, 356, 227; 1909, 368, 9.
t Ann., 1908, 363, i.



132 ORGANIC CHEMICAL SYNTHESIS

workers as Dumas and Pelouze, who derived its correct molecular
formula, C 10 H 16 O. Camphor 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 ob-
served 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 + 3 = C 10 H 16 4

The first 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
synthesis of camphoronic acid by Perkin and Thorpe in 1897^
These authors first prepared jS-hydroxytrimethyl glutaric ester by
the action of zinc upon a mixture of acetoacetic ester and a-bromo-
isobutyric ester or upon a mixture of dimethylacetoacetic ester and
monobromacetic ester:

(CH 3 ) 2 CBr CO CH 2



COOR CH 3 CO^H^c - C (OH)-CH 2

COOR CH 3 COOR
(CH 3 ) 2 C - CO Br CH 2 /"

| | | / /3-Hydroxytrimethyl glutaric ester

COOR CH, COOR



By 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 2

COOR CN COOR COOH COOH COOH

Camphoronic nitrile Camphoronic acid

By the oxidation of camphor by nitric acid, camphoric acid,
camphanic acid, and camphoronic acid may be obtained, and in
the paper already mentioned Bredt suggested the following relation-
ship among these compounds and arrived at the correct constitutional
formula for camphor:

* Ber., 1893, 26, 3049. f Trans., 1897, 71, 1169.



CH, - CH-



THE CAMPHANE GROUP 133

CH 2 CH 2 -CH COOH CH 2 -C(OH)COOH



C(CH 3 ) 2



CH 2 - C-



CO



CH 3

Camphor



H 2 +



C(CH 3 ) 2
CH 2 -C - COOH

CH 3
Camphoric acid

COOH CO COOH

C(CH 3 ) 2 O

COOH



O



CH 2 - C

CH 3
(Hypothetical) a-Ketonic acid



C0



C(CH 3 ) 2
:H 2 -C-COOH

CH 3
Camphanic acid *

COOH COOH



C(CH 3 ) 2
-C-COOH



CH,

CH 3
Camphoronic acid



Although this 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
and ethyl jS/3-dimethylglutarate 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 diketo-
camphoric acid (ii) was reduced to the dihydroxy acid (iii). On
boiling with hydriodic acid and red phosphorus the unsaturated
acid, dehydrocamphoric acid (iv) or (v), was obtained. With
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
oxidation of camphor.



COOR H CH CO 2 R

-(- CH 3 C CH 3
COOR H CH CO 2 R



CO - CH - CO 2 R
CH C CH 3

CO - CH CO 2 R

(i)
* Camphanic acid is really the lactone of this compound, viz.



2C 2 H 5 OH



CH, - C-



-COOH



C(CH 3 ),
CH 8 - C CO

CH 3
t Ber., 1903, 36, 4332; Ann., 1909, 368, 126; 1909, 370, 209.



CH 3

- C-<



CO



(ii)



CH 3 -C-CH 3

-CH - C-

(iii)



C0 2 H



134 ORGANIC CHEMICAL SYNTHESIS

/"U fix

t_/rl 3 ^-rl 3

CO - C - COOH HO-CH - C-CO 2 H

CH 3 -C-CH 3 CH a -C-

CH i

(iv)

CH 3
CH 2 - C-CO 2 H

C-
CHBr - CH CO,H



CH 2 - C-CO 2 H

CH 3 -C-CH 3
CH = C-CO 2 H



or



CH 3

i.
L



CH - CH-CO 2 H
(v)



CH 3

2 C-CO 2 H

CHj'C'CHj



CH 3 -C-CH 3



(vi)



CH 2 - CH-CO 2 H
(vii)



An alternate synthesis of camphoric acid was described by
Perkin and Thorpe in 1906.*

The Conversion of Camphoric Acid into Camphor.

Camphoric acid was first converted into camphor by the following
method. When camphoric anhydride is treated with sodium amalgam
it is reduced to campholide,f



CH S



CH 3

-C-



-CO



CH



CH 3 .C-CH 3 O
- CH-



CO



CH 3
CH 2 - C - CH 2

CH 3 -C-CH 3 O

I /

CH 2 - CH-CO



Campholide, on treatment with potassium cyanide, gives a nitrile
salt which, on hydrolysis, is converted into homocamphoric
acid,

CH 3 CH 3

CH, - C - COOH



CH, - C - COOK



I



CH,



-in-



CH 2 CN



CH 5



rr A (~*TT
tl3 v^'Lxrla

-i,-



CHoCOOH



On heating the calcium or lead salt of this acid camphor is
obtained:

* Trans., 1906, 89, 795.

t Haller, Bull Soc. Chirn., 1896 [III], 15,7, 984; Forster, Trans., 1896, 69, 36.



THE CAMPHANE GROUP



'35



CHa Cri3
CH 2 - C - COO CH 2 - C CO

I \ -

CH 3 .C-CH 3 Ca

CH 2 - CH-CH 2 -COO

Borneol and Isoborneol. Borneol occurs in nature in three

CH 3



C/riQ * C Cri3

-i.-



CH., - C



C
C



CHOH



H

Borneol

modifications, */-borneol in lyryobalanops camphor a, 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 may be transformed into the latter by the action
of sodium on a solution of borneol in benzene.

Bornylene and Camphane. Borneol may be readily trans-
formed into bornyl iodide, but this substance is more easily pre-
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 C



CH



CH 3 -C-CH 3



CH 2 C CHI

CH 3 -C-CH 3

CH 2 CH CH 2

Bornyl Iodide



* Wallach, Ann., 1885, 230, 225.



CH ?



CH
Bornylene



CH



V~*

I



CH.



Aschan, Ber., 1900, 33, 1006.



CH 3 -C-CH 3



CH 2 CH CH 2

Camphane
t Wagner, Ber., 1900 33, 2121.



136 ORGANIC CHEMICAL SYNTHESIS

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

Camphene is the only natural solid terpene. It is known in
dextro, laevo, and inactive modifications. The dextro form has
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 not known with certainty, but the
most probable formula is that of Wagner.*



CH 2 - CH - C<T



A.



CH 3
CH 3



CH.2 C : =

Camphene

Fenchone and the Fenchenes. Fenchone occurs naturally
in two stereoisomeric forms. Dextrofenchone was discovered in
1890 by Wallach and Hartmann in fennel oil (Fceniculum vulgar e) y
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
liquid. It is a ketone, and on reduction gives a secondary alcohol,
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

CH 2 - CH - C(CH 8 ) 3
CH 2



CH 3

When J-fenchone is reduced, a laevorotatory alcohol termed Dl-
fenchyl alcohol is obtained. With phosphorus pentachloride the
latter gives D/-fenchyl chloride, which is converted into Z)/-fenchene
on treatment with aniline. When these reactions are conducted
without cooling ZW-fenchene is eventually obtained. J

* Ber., 1900, 33, 2124; see also Semmler, Ber. r 1909, 42, 246, 962.

t Ber., 1917, 50, 1362. 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/3-
fenchene. Racemic a-fenchene has been synthesized by these
authors and the constitution (i) assigned to it. More recently
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 2 - CH - CH 3
CH 3 .C-CH 3

CH 2 - CH - C : CH 2

(i)



(CH 3 ) 2 C



V^JLJL

1




CH 2




I 2 - CH -


:CH ;


(ii)





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 tabula-
tion 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 H 2 4).



Cadinene.
Caryophyllene.

Humulene.

Cedrene,and the alcohol cedrol,



Santalene, and the alcohol san-
talol, C 15 H 25 OH.

Zingiberene.



Occurrence.



Oil of cade, cubeb, savin, cedar wood,
and camphor oil.

Oil of cloves, copaiba balsam oil, oil of
canellaalba.

Oil of hops.

Oil of cedar wood.

East Indian sandal- wood oil.
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.



t Loc. cit., 1919 [A], 10, i.



138 ORGANIC CHEMICAL SYNTHESIS

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



NATURAL AND SYNTHETIC PERFUMES

The substances which impart to many plants a particular and
often characteristic odour are almost infinite in variety, and com-
prise some of the most interesting compounds in the domain of
organic chemistry. Many of them possess a cyclic structure, while
others are aliphatic compounds which may be either saturated or
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 dis-
covered 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 alde-
hyde 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.
Coumarin is 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.

In 1876 Tiemann and Haarmann synthesized vanillin, the sweet-
smelling constituent of the vanilla pod. Vanillin is now obtained
from eugenol, which is present in oil of cloves to the extent of about



NATURAL AND SYNTHETIC PERFUMES 139

80 per cent. When eugenol is boiled with amylalcoholic potash,
isoeugenol is obtained, which gives 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 ane-
thole the chief constituent of anise oil.




CH 3

J



CH-.CH-CH 3




Anethole Anisic Aldehyde

The odour of heliotrope is said to be due to piperonal, and the
latter is prepared from saffrole, which is first converted into isosafrole
and then oxidized:





*" H ? C

CHjCH'CH,

Safrole Isosafrole

Otto of roses is a mixture of which geraniol is probably the chief
constituent. ^-Phenylethylalcohol, obtained by the reduction of
phenylacetic acid, is also frequently present. Phenylacetaldehyde
possesses an intense hyacinth-like odour and is used considerably
in perfumery.

The methyl ester of anthanilic acid

X NH 2 (i)
C 6 H/

X COOH (2)

is 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 is
also indole, in the preparation of synthetic perfumes.

The study of the odorous principle of the violet, commenced



140 ORGANIC CHEMICAL SYNTHESIS

by Tiemann and Kruger in 1893, is one of the most interesting
investigations carried out in the realm of synthetic perfumes. These
chemists were unable to obtain sufficient material for their work from
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
on which their experiments were made. To this substance, when
purified, they gave the name irone, and a few years later ionone was
introduced as a synthetic substitute. The latter is prepared from
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 3 CH 3
C-OH
H 2 C CH 2 -CH:CH-COCH 3

H 2 C C(OH)CH 3

CH 3 CH-

v S 6




CH-CH'.CH-COCH,
'C-CH 3

CH ^* 1 2

a-Ionone /3-Ionone



a- Ionone possesses the light fragrance of the violet while the odour
of the jS-isomer is much heavier.

Many plants belonging to the Cruciferce yield volatile products
which consist 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
particular ferment or enzyme on a glucoside, and they consist as a
rule of esters of isothiocyanic acid. A typical example is that of
the oil obtained from the black mustard, Brassica nigra and Brassica
juncea, and which consists almost entirely of allyl isothiocyanate,
CH 2 :CH- CH 2 -N:CS. It is produced by the action of the ferment
myrosin on the glucoside sinigrin (potassium myronate), when, besides



NATURAL AND SYNTHETIC PERFUMES 141

the volatile mustard oil, dextrose and potassium hydrogen sulphate
are formed:

C 10 H 16 NS 2 O 9 K + H 2 O - C 3 H 5 NCS + C 6 H 12 O 6 + KHSO 4

This mustard oil is also 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 isothio-
cyanate.

Although the odorous principles of plants are frequently de-
veloped 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
in those cases 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 ex-
pression. In other cases the odour of the oil is so delicate that it
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.

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,



The Chemistry of Essential Oils and Artificial Perfumes, by E. J. Parry
(London, 1918).



CHAPTER VII
The Amino Acids and Polypeptides

Introduction. Excluding mineral matter and fat, the dry
material of animal organisms consists of a complex assortment of
nitrogenous compounds termed proteins or proteids (TT/OCOTO? = first,
pre-eminent). The same term is also applied to somewhat similar
compounds which occur in considerable quantities in all plants,
especially in seeds or grain. Since the proteins furnish the material
in which the vital processes of growth, repair, and reproduction are
located, their study is of immense importance to physiology. These
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, assum-
ing haemoglobin contains a single atom of iron in the molecule, the
minimum molecular weight is about 16,600 (C 158 H 123 O 195 N 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
solution is obtained which contains a number of products, the
separation of which has long taxed the chemist's ingenuity. As
early as 1820 Braconnot had obtained glycine and leu cine from
gelatine, and in 1846 Liebig had obtained tyrosine from the decom-
position products of horn. At a later date Kossel and his collabora-
tors examined the simpler proteins, such as the protamines, but
progress was very slow until Fischer, in 1901, introduced new

142



THE AMINO ACIDS AND POLYPEPTIDES 143

methods for the separation 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
finally at 0*5 mm.* The esters of histidine and the diamino acids
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 manu-
facture 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
tyrosine, which may be present, to crystallize. The solution is then
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-
glutaric acid (/3-hydroxyglutamic acid, HOOC CH(NH 2 )CH(OH)
CH 2 COOH), has been obtained in quantity exceeding 10 per cent.

Foreman J converts the mixture of amino acids into their dry
lead salts and esterifies with absolute alcohol containing dry hydro-
chloric 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. 9 1901, 34, 433; Ber. y 1902, 35, 2160. \ Biochem.jf., 1918, 12, 290.

J Ibid., 1919, 13, 378.



144 ORGANIC CHEMICAL SYNTHESIS

ammonia gas. 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.

Classification of the Amino Acids. The following table
contains the principal amino acids which have been isolated from the
products of protein hydrolysis:

MONOBASIC MONOAMINO ACIDS

Glycine = aminoacetic acid, (NH 2 )CHoCOOH

+ #
Alanine = oc-aminopropionic acid, CH 3 CH(NH 2 )COOH

Valine = a-aminoisovaleric acid, (CH 3 ) 2 CH CH(NH 2 )COOH

Leucine = a-aminoisobutylacetic acid, (CH 3 ) 2 CH CH 2 CH(NH 2 )COOH
Isoleucine = a-amino-p-methylethylpropionic acid,

(C 2 H 5 )(CH 3 )CH CH(NH 2 )COOH
Caprine = oc-aminocaproic acid, (CH 3 )(CH 2 ) 3 CH(NH 2 )COOH

DIAMINO ACIDS
Ornithine = aS-diaminovaleric acid,

(H 2 N)CH 2 CH 2 - CH 2 CH(NH 2 )COOH
Lysine = ocs-diaminocaproic acid,

(H 2 N)CH 2 CH 2 . CH 2 CIV CH(NH 2 )COOH
Arginine = a-amino-S-guanidovaleric acid,

(H 2 N) C - NH CH 2 CH 2 - CH 2 CH(NH 2 )COOH

NH
DIBASIC MONOAMINO ACIDS

Aspartic acid = aminosuccinic acid, HOOC CH 2 CH(NH 2 )COOH

Glutamic acid = aminoglutaric acid,

HOOC CH 2 CH 2 CH(NH 2 )COOH
HYDROXY- AND THIO-AMINO ACIDS

Serine = a-amino-p-hydroxypropionic acid, CH 2 (OH)CH(NH 2 )COOH
p-Hydroxyglutamic acid, HOOC - CH(NH 2 ) CH(OH) - CH 2 - COOH
Diaminotrihydroxydodecanic acid, C 11 H 16 (OH) 3 (NH 2 ) 2 COOH

4-
* C denotes asymmetric carbon atom.



THE AMINO ACIDS AND POLYPEPTIDES



'45



Cysteine = a-amino-p-thiolactic acid, CH 2 (SH)CH(NH 2 )COOH

Cystine = disulphide of a-amino-(3-sulphydropropionic acid,

S CH 2 CH(NH 2 )COOH



S CH 2 CH(NH 2 )COOH

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






CH 2 CH(NH 2 )COOH



H 2 C




CH 2
CH-COOH



HETEROCYCLIC ACIDS

HO-HC, .CH,



H 2 C




^CH-COOH



NH



NH



Proline = a-pyrolidine
carboxylic acid



Oxyproline = /3 - hydroxypyrolidine
carboxylic acid




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

N




CH



NH



Histidine = ct-amino j3-iminazole- Tryptophane = indolo o-amlnopropionic
propionic acid acid

It will be observed that, with the exception of proline and oxy~
proline, all these acids contain an amino group in the a-position.
In the case of proline and oxyproline the carboxyl group is adjacent
to the basic NH group of the ring. In all these acids the basic
amino group is more or less neutralized by the adjacent carboxyl
group. Amino acids which contain an amino group in a non-
adjacent position to the carboxyl group will be described in a subse-
quent chapter (p. 187).

The Resolution and Identification of the Amino Acids.
Nearly all the amino acids tabulated above contain one or more
asymmetric carbon atoms. The early resolution of these acids had
been limited by their amphoteric nature, and was easy only in the

(D331) 10



146 ORGANIC CHEMICAL SYNTHESIS



case of aspartic acid, Piutti having shown in 1887 l ^ at asparagine is
resolved by simple crystallization from water.

By suppressing the basic properties of the amino acids by ben-
zoylating, formylating, or p-nitrobenzoylating the amino group, and
thus encouraging their capacity to form recrystallizable salts with the
natural alkaloids, strychnine and brucine, Fischer and his collabo-
rators succeeded in resolving the dl forms of many of the amino
acids. In this manner optically active units were obtained which
became available as building materials for the construction of optically
active polypep tides.

The above acyl derivatives of the amino acids, in common with
other derivatives depending on the reactivity of the 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 pro-
bably 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

A 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 is present in protein hydrolysis products. The acids
may be synthesized by a variety of methods of which the following
are the more important.

(i) By the action of ammonia on the halogen fatty acids *: e.g.

CH 3 CHBrCOOH -> CH 3 CH(NH 2 )COOH

a-brompropionic acid 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.



THE AMINO ACIDS AND POLYPEPTIDES 147

(2) By Strecker's method, which consists in converting an alde-
hyde into the corresponding aminocyanhydrin, with ammonia and
hydrocyanic acid, and hydrolyzing the product: e.g.

/H /H

H-C -> H-C NH 2 -> CH 2 NH 2 COOH



Formaldehyde Glycine*

(3) By Gabriel's method.f This method consists in com-
bining potassium phthalimide with halogen fatty acid ester and
hydrolyzing the product: e.g.

/CCX
C 6 H 4 < >NK + C1CH 2 - COOC,H 5

X CCX
Potassium phthalimide Monochloroacetic ester

/ C0 \

C 6 H 4 < >N - CH 2 COOC 2 H 5 + KC1

/ C0 \

C 6 H 4 < >N - CH 2 COOC 2 H 5 + H 2 O



= C 6 U + CHoNH 2 COOH + C 2 H 5 OH

X COOH
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 2 )COOC 2 H 5
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. This recalls the well-known
Perkin reaction.

* Eschweiler, Ann., 1894, 278, 237. f Ber., 1889, 22, 426.

t Tafel, Ber., 1886, 19, 2414; Bouveault, Bl. t 1904 (3), 31, 1176; 1906 (3), 35,
966. Ann., 1893, 275, i ; 1899, 307, 70, 163.



148 ORGANIC CHEMICAL SYNTHESIS

/NHCOC 6 H 5 /

C S H 6 CHO + H 2 C< -V C 6 H 5 CH : C<

X COOH X COOH

/NHCOC 6 H 5

-> C 6 H 5 CH 2 -CH<; -> C a H 6 CH 2 CH(NH 2 )COOH

X COOH

Phenylalanine

Glycine (yXvicvs = 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
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 may be regarded as derivatives of glycine
(p. 184). ^

Alanine. In the synthesis of this acid by the Strecker method,
a convenient modification * of the usual procedure consists in
treating acetaldehyde with potassium cyanide in the presence of
ammonium chloride. The acid may be resolved by fractional
crystallization of the brucine salt of its N-benzoyl derivative,! or
with the aid of moulds. J Dextroalanine is one of the principal
products of the hydrolysis of fibroin the main component of silk.
Both active forms have a sweet taste.

Leucine. The laevo form of this acid is very widely distributed
in the animal kingdom, and is a substance of physiological im-
portance. It is found in the lymphatic glands, the spleen, and
especially in the pancreas. It is produced by the hydrolysis of
haemoglobin, egg-albumin, and casein, from the last of which it is
usually prepared. Its solution in hydrochloric acid is dextrorotatory,
but a solution of the acid in water is laevorotatory. In contact
with Penicillium glaucum, a solution of ^/-leucine becomes laevo-
rotatory, owing to the destruction of the d modification.

Isoleucine. The dextro form of this acid is obtained by the
hydrolysis of the proteins contained in beetroot sap, cereals, pota-
toes, &c. A consideration of the formula of isoleucine shows that
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.



THE AMINO ACIDS AND POLYPEPTIDES 149

Ehrlich * has 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 in the reaction is assimilated and removed.

(CH 3 ) 2 CH CH 2 CH(NH 2 )COOH + H 2 O

Leucine - (CH 3 ) 2 CH CH 2 CH 2 OH + NH 3 + CO 2

Isoamylalcohol
(CH 3 )(C 2 H 5 )CH CH(NH 2 )COOH + H 2 O

Isoleucine - (CH 3 )(C 2 H 5 )CH CH 2 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 4 H 7 COOH

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 2 - CH 2 CH 2 Br + KBr



/ C0 \

C 6 H 4 < >N - CH 2 CH 2 CH 2 Br + NaCH(COOCoH 5 ) 2

^ /



X CO

C 6 H 4 < >N CH 2 - CH 2 - CH 2 CH(COOC 2 H 5 ) 2



Brominate,
hydrolyse, and heat C 6 H 4 < >N CH 2 CH 2 - CH 2 - CHBrCOOH



Ber., 1907, 40, 1047. f Ber., 1901, 34, 454; 1902, 35, 3772.



150 ORGANIC CHEMICAL SYNTHESIS

CO
Ammonia c H </ \ N . CHo . CH 2 CH 2 CE^NH^COOH

-




TT A i yCOOH

Hydrolysis ^jj / + H 2 N-CH 2 .CH 2 .CH 2 .CH(NH 2 )COOH

~* N COOH

(rf/)-a8-diaminovaleric acid (ornithine)

(2) When benzoyl piperidine is oxidized with potassium perman-
ganate the ring is opened and benzoyl Samino valeric acid is ob-
tained. By the action of bromine and phosphorus on the latter a
bromo derivative is obtained, which on treatment with ammonia
gives monobenzoyl ornithine. The latter on hydrolysis is converted
into ornithine.*

i2 Cri2

> C 6 H 8 CO-NH[cH 2 ]cHBrCOOH - *-
CH 2 CH 2

C 6 H 5 CONH[CH 2 ] 3 CH(NH 2 )COOH

- NH 2 [CH 2 ] 3 CH(NH 2 )COOH+ C 6 H 5 COOH

(3) Sorensen's method f is somewhat similar to that first em-
ployed by Fischer. Bromomalonic ester is condensed with potas-
sium phthalimide to give phthaliminomalonic ester. The sodium
compound of the latter is then condensed with y-bromopropyl-
phthalimide to give phthalimino-y-phthaliminopropylmalonic ester,
which on hydrolysis gives ornithine:

C 2 H 5 O OC X /OC X ,OC X

CH-N<; >C 8 H 4 + Br[CH 2 ] 3 -N< >C 8 H 4
^/ ^/



C 2 H 5 O.OC

C



C 2 H 5 0-OC. Lv, 2j3 i^ x /C 6 H 4 [CH 2 ] 3 NH 2

/ c \ or -* HOOC-HC<

C^O-OC^ X N / \PH NNH 2

1>\ /^gtl.!



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.



THE AMINO ACIDS AND POLYPEPTIDES 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.

Fischer and Weigert * synthesized this acid from y-chlor-
butyronitrile and malonic ester as follows:

CN CH 2 CH 2 . CH 2 C1 + NaCH(COOC 2 H 5 ) 2

~> CN [CH 2 ] 3 CH(COOC 2 H 6 ) 2

CH 2 . CH(COOC 2 H 5 ) 2 C 2 H 5 ONO CH 3 . C( NOH)COOC 2 H 5

CH 2 CH 2 CN CH 2 CH, CN

Reduction CH 2 . CH(NH 2 )COOH

CH 2 CH 2 . CH 2 NH 2

Lysine has also been synthesized by von Braun.f For this pur-
pose benzoylpiperidine is treated with phosphorus pentachloride,
and gives the N-benzoyl derivative of the halogenated amine:

CH. CH 2

I-T r*r ^sr*T-T

H 2 Cf ^CH 2
H 2 cl 'CH 2 C1

^s x 2

N-COC,HL NH-CO-QKL




The latter is transformed into the nitrile and the acid, and the
succeeding steps are analogous to those employed by Fischer and
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

Arginine. This amino acid occurs among the decom-
position products of a great number of proteins. It was first
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.

It is completely resistant to acids, but on hydrolysis by alkalies
or the enzyme arginase it yields urea and ornithine:

H 2 N C NH - [CH 2 ] 3 CH(NH 2 )COOH + H 2 O

NH

- H 2 N CO NH 2 + H 2 N [CH 2 ] 3 CH(NH 2 )COOH

* Ber., 1902, 35, 3772. t Ber., 1909, 42, 839.



152 ORGANIC CHEMICAL SYNTHESIS

Arginine was obtained synthetically by Schultze and Winterstein
by the action of cyanamide on ornithine:

NH 2 CN + H 2 N[CH 2 ] 3 CH(NH 2 )COOH

NH

= H 2 N C NH [CH 2 ] 3 CH(NH 2 )COOH

It 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
on the alkaloids.

DIBASIC MONOAMINO ACIDS

Aspartic Acid. Both aspartic and glutamic acids are strongly
acidic and form well defined metallic salts. They are still, however,
sufficiently basic to combine with acids. The laevo form of aspartic
acid is frequently encountered among the hydrolytic products of
proteins, but this acid is most conveniently prepared by the action
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 2 H 5 HON : C - COOC 2 H 5 II 2 N CH COOCoH 5

I ~> I -> |

CH 2 COOC 2 H 5 CH 2 COOC 2 H 5 CH 2



25 2 COOC 2 H 5



Laevoasparagine (NH 2 COCH 2 CH(NH 2 )COOH), the semi-amide of
aspartic acid, occurs in many plants, especially asparagus and the
young shoots of beans, peas, and lupins, from which it is readily
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
by side.

Glutamic Acid. This acid is obtained to the extent of
30 per cent by the hydrolysis of the proteins from wheat. After
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.



THE AMINO ACIDS AND POLYPEPTIDES 153

Wolff* synthesized glutamic acid by the reduction of a-isoni-
trosoglutaric acid.



HYDROXY- AND THIO-AMINO ACIDS

Serine. 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.

When treated with nitrous acid it is transformed into glyceric
acid, while with hydriodic acid it is reduced to alanine. The fol-
lowing are the more important methods by which the acid has been
synthesized.

(1) Fischer and Leuchs f obtained a small yield of serine by the
hydrolysis of the aminocyanhydrin of glycollic acid:

CH 2 OH CH 2 OH CH 2 OH

C/ -> CHNH, -> CHNH,

X H | |

CN COOH

Fischer and Jacobs J resolved the synthetic acid by the frac-
tionation of the brucine or quinine salt of the ^-nitrobenzoyl
derivative.

(2) Erlenmeyer condensed formic ester with hippuric ester in
the presence of sodium ethoxide and reduced the resulting product
with aluminium-mercury couple:

CO C 6 H 5 /NHCOC 6 H 5



HCOOC 2 H 5 + H 2 C< -> HO CH : C

X COOC 2 H 5 X COOC 2 H 5

~> CH 2 OH CH(NH 2 )COOH

(3) 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.

C1CH 2 CH(OC 2 H 5 ) 2 -> C 2 H 5 O CH 2 CHO
-> C 2 H 5 O CH 2 CH(NH 2 )COOH -> HO CH 2 - CH(NH 2 )COOH

* Ann.y 1890, 260, 79. f Ber., 1902, 35, 3787; 1906, 39, 2942; 1907, 40, 1501.
t Ber. y 1906, 39, 2948. Ber., 1902, 35, 3769. || Ber. 9 1906, 39, 2644.



154



ORGANIC CHEMICAL SYNTHESIS



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 syn-
thesis appears to have presented considerable difficulty, but was
eventually achieved from glutamic acid as follows. Glutamic acid
(i) was converted into a-uraminoglutaric acid (ii) 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
(iv) was formed, which, on boiling with water, gave hydantoinacrylic
acid (v). On prolonged boiling with barium hydroxide solution
/?-hydroxy glutamic acid (vi) was obtained:
COOH COOH CO - NH CO - NH



CHNH 2

CH 2

CH 2

COOH
(i)



CH NH CONH 2

CH 2

CH 2

COOH



CO - NH



>CO



CH - NH

CH

II
CH

COOH

(v)



CH - NH

CH 3

CH 2

COOH

(iii)

COOH



CHNH 2

CHOH

CH 2

COOH

(vi)



CH



^>co

NH



CH 2

COOH

(iv)



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. Cysteine may be readily prepared from hair.
It has been obtained synthetically by Erlenmeyer junior J as follows:

* Biochem.y., 1918, 12, 290. f Dakin, Biochem.J., 1919, 13, 398.
1 Ann., 1904, 307, 236.



THE AMINO ACIDS AND POLYPEPTIDES 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 2 H 5 COOC 2 H 5 COOC 2 H 5 COOH

C'NH'COC 6 H 5 -> CH-NH-COC 6 H 5 -> CH-NH.COC 6 H 5 -> CHNH 2

CHOH CH 2 OH CHoSH CH 2 SH

(i) (ii) (iii) (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 2 OH CH(NH 2 )COOH -> CH 2 C1- CH(NH 2 )COOH
~> CH 2 SH CH(NH 2 )COOH

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
by Schultze f in plant seedlings and in, the products of hydrolysis
of seed proteins. Since that time it has been shown to be a con-
stituent of many proteins.

This amino acid was first synthesized by Erlenmeyer and Lipp J
by the application of the cyanhydrin reaction to phenylacetaldehyde:



O

C 6 H 5 CH 2 C/ -> C 6 H 5 CH 2 C CN -> C 6 H 6 CHoCH(NH 2 )COOH

XH \H

Fischer synthesized the acid starting from benzylmalonic acid,
which was obtained from benzylchloride and the sodium derivative
of malonic ester:

C 6 H 5 CH 2 C1 + NaCH(COOC 2 H 5 ) 2 -> C 6 H 6 CH 2 CH(COOC 2 H 6 ) 2
-> 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 2 )COOH

* Fischer and Raske, Ber., 1908, 41, 893.

t Ber., 1881, 14, 1785; Zeit.physiol. Chem., 1884, 9, 63.

J Ber. t 1882, 15, 1006. Ber., 1900, 33, 2383; 1904, 37, 3064.



156 ORGANIC CHEMICAL SYNTHESIS

Fischer subsequently resolved the acid into its optical isomers.
Sorensen * synthesized phenylalanine by the aid of the phthali-
mide reaction:

CO CO



BrCH(COOC 2 H 5 ) 2 -> C 6 H 4 < >N-CH(COOC 2 H 5 ) 2

CO CO

CO



-> Cell^ p>N C(Na)(COOC 2 H 5 ) 2

CO

CO
-> C 6 H 4 <^ )>N C(CH 2 C 6 H 5 )(COOC 2 H 5 ) 2

CO
- C 6 H 5 CH 2 CH(NH 2 )COOH + C 6 H 4 (COOH) 2 + 2C 2 H 6 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 2 /NH - C:CH-C 6 H 5 HoN.CH-CH 2 C 6 H,

OC< | > OC< I -> " 1

X NH - CO X NH - CO COOH

(i) (ii)

More recently Sasaki J has obtained it by the reduction and hydrolysis
of the product obtained by the condensation of benzaldehyde and
diketopiperazine in the presence of sodium acetate and acetic
anhydride:

CO - NH CO - NH

H 2 C<^ ^>CH 2 -> C 6 H 5 CH C<^ ")C:CHC 6 H r>

NH - CO NH - CO

- 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
potash. It is the least soluble of the amino acids, and is therefore
easily isolated from the hydrolytic products of the proteins. It
was first synthesized by Erlenmeyer and Lipp by nitrating phenyl-

* Zeit. physiol. Chem., 1905, 44, 448. f Amer. Chem. J., 1911, 45, 368.

J Ber., 1921, 54 [B], 163, 2056. Ann., 1883, 219, 161, 179.



THE AMINO ACIDS AND POLYPEPTIDES 157

alanine, reducing the resulting para-nitro derivative, and then re-
placing the amino group by hydroxyl by means of nitrous acid:

C 6 H 6 CH 2 CH(NH 2 )COOH -> O 2 N C 6 H 4 CH 2 CH(NH 2 )COOH
-> H 2 N.C 6 H 4 CH 2 CH(NH 2 )COOH -> HO.C 6 H 4 -CH 2 -CH(NH 2 )COOH

Erlenmeyer junior and Halsey * obtained tyrosine from the con-
densation product of ^-hydroxybenzaldehyde with hippuric acid
in the presence of sodium acetate and acetic anhydride:

HO C 6 H 4 CHO + CH 2 COOH HO C H 4 CH : C CO



NH COC 6 H 5 N COC 6 H 5

HO C 6 H 4 CH : C - COOH HO CH 4 - CH, CH - COOH

- I -> I

NH - CO C 6 H 5 NH CO C fl H 5

HO-C 6 H 4 -CH 2 .CH.COOH

-> | + C 6 H 5 COOH

NH 2

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 6 H 4 OCH 3 H 2 N-CH-CH 2 -C 6 H 4 OH



oc i

X NH - CO COOH



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
not yet been found to occur as such in any plant. It is readily
soluble in alcohol, and can be partially separated from other amino
acids by this solvent.

The racemic form was synthesized by Willstatter J by the action
of ammonia on aS-dibromvaleric acid:



CH 2 CH COOH + NH 3 = CH 2 CH COOH + zIIBr

\ \ \/

Br Br NH

* Ber., 1897,30, 2981; Ann., 1899, 307, 138. f Amer. Ghent.}., ign, 45, 368.
J Ber., 1900,33, 1162; Ann., 1902,326, 94, 104.



158 ORGANIC CHEMICAL SYNTHESIS

The aS-dibromvaleric acid was prepared from trimethylene di-
bromide and sodium malonic ester as follows:



Br.CH 2 -CH 2 -CH 2 .Br + NaCH(COOC 2 H 5 ) 2 -

Br 2 HBr

-> Br[CH 2 ] 3 C.Br(COOC 2 H 5 ) 2 -> Br[CH 2 ] 3 CHBrCOOH

Fischer and Zemplen,* and also Sorensen and Anderson,f have
also synthesized the acid by the application of the phthalimide-
malonic ester method: Phthaliminomalonic ester and trimethylene
dibromide are condensed to give y - bromopropylphthalimino-
malonic ester (i):

C 2 H 6 O CO CO

^>CH-N^ ^>C 6 H 4 + BrCH 2 CH Si CH 2 Br

C 2 H 5 O- CO CO

C 2 H 5 O CO CH 2 CH, CH 2 Br

X

C 2 H 5 O.CO N(C 2 O 2 }C 6 H 4

(i)

and the bromine atom replaced by hydroxyl by the action of alco-
holic caustic soda, after which hydrochloric acid converts the pro-
duct into a-amino-S-hydroxy valeric acid (ii). On evaporation
with hydrochloric acid, ^/-proline is obtained



CH-CH-CH 2 OH .CHjCHjCHOH

C X --

C 2 H 5 OCO ^N{C 2 2 }Ctf



HOOO-CH^'



Optically active proline was obtained synthetically as follows: J
Nw-nitrobenzoylpiperidine (i) was oxidized to 8[-/n-nitrobenzoyl-
amino]-valeric acid (ii) 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:
CH 2 - CH 2 - CH 2 CH 2 - CH 2 - CH 2

CH 2 - N - CH 2 -> CH 2 - NH COOH

CO C 6 H 4 N0 2 COC 6 H 4 N0 2

(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 a - CH 2 - CHBr CH 2 - CH 2 -CH COOH

>
CH - NH COOH CH, - N



to.



C 6 H 4 NO 2 CO C 6 H 4 NO 2

(iii) Nw-Nitrobenzoylproline.

This compound was then resolved into its optical isomerides by
fractionally crystallizing its cinchonine salts, after which the active
nitrobenzoylproline was converted into nitrobenzoic acid and the
active proline 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.*
The two inactive forms were synthesized as follows: f S-chloro-y-
valerolactone-a-carboxylic ester (i) was obtained by the condensa-
tion of epichlorhydrin with sodium malonic ester:



CH 2 , CHCNa) COOC 2 H 5 CH 2

I '''0+ I - ^ 1 I

CICH 2 -CH X COOC 2 H 5 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 2 - CHC1 CH 2 - NH - CH COONH 4

I I - 1 I

Cl CH 2 . CH(OH) COONH 4 CH(OH) - CH 2

The last stage of this reaction is analogous to the reactions whereby
i : 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 2 -CH 2 I CH 2 -CH 2



aC 6 H 6 NH 2 =



C 6 H 5 NH 2 -HI



H 2 -CH 2 I CH 2 ~CH 2 I

When treated with methyliodide and methylalcoholic potash,

* Ber., 1919, 52 [B], 2086. f Ber., 1907, 40, 30.
J Scholtz, Ber. t 1899, 32, 848; V. Braun, Ber., 1911, 44, 1254.



160 ORGANIC CHEMICAL SYNTHESIS

hydroxyproline gives a mixture of two stereoisomeric oxyproline
dimethylbetaines (hydroxystachydrines) * (p. 216).

HO . CH CH 2

CH 2 - N(CH 3 ) 2 - CH

io



Tryptophane (Indole-a-aminopropionic acid). This inter-
esting amino acid was first obtained in a pure crystalline condition >
from casein, by Hopkins and Cole f in 1901. The natural form is
laevorotatory, 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, trypto-
phane is obtained:

C - CHO CH 2 NHCOC 6 H 5

/ N\

CeH 4 \ /CH + > C 6 I

NH COOH NH CO-

(i)

C-CH:C-NHCOC 6 H 5 C-CH 2 -CH(NH 2 )COOH

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
products of the protein sturine, which was obtained from the sper-
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,
217. \ Journ. Physiol. , 1901, 27, 418.

J Ber., 1907, 40, 3029; Zeit. physiol. Ghent., 1908, 55, 8.
Zeit. physiol. Ghent., 1896, 23, 176.




THE AMINO ACIDS AND POLYPEPTIDES 161

from ox blood. When treated with alkaline solutions of diazonium
salts it 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 CH - NH CH - NH



^CH ^CH

J N C N C N

CH 3 "*" CH 2 ""* CH 2
CH NH 2 CHOH CH 2

COOH COOH COOH

(i) (ii) (iii)

The same authors have synthesized histidine by the combined action
of ammonia and formaldehyde on glyoxylpropionic acid:

CHO NH 3 H CH - NH



+ +

CO NH, O



CH



N



CH 3 ~* CH 2 + 3H 2 O



COOH COOH



The constitutional formula of histidine has been fully confirmed
by its synthesis by Pyman by two independent methods. According
to the first method, f citric acid is converted by well-known methods
successively into diaminoacetone:

CH 2 COOH CH 2 -COOH CH:NOH CH 2 NH 2

| H 2 S0 4 | HN0 2 | H 2 |

C(OH)COOH -> CO -> CO -* CO

CH 2 COOH CH 2 -COOH CH:NOH CH 2 NH 2

Gabriel's method of synthesizing an iminazole ring, which consists
in acting on an aminoketone with potassium thiocyanate and oxidizing
the product with nitric acid, whereby the thiol group (SH) is re-
moved, was next employed:

* Beitr. z. Chem. Phys. u. Path., 1905, 7, 144.

t Pyman, Trans., 1911, 99, 672, 1392, 2172.

(D331) H



162



ORGANIC CHEMICAL SYNTHESIS



CH 2 -NH 2 -HC1

CO
CH 2 -NH 2 -HC1



CH - NH



KCNS



>C-SH



-N



HNO 3



CH - NH



N



CH 2 .NH-CS-NH



CH 2 NH 2

The 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:

CH - NH CH - NH

>CH ^ (I \CU



PCI,



-N



C1



-N



Na x



>C(COOC 2 H 5 ) 2



CH 2 OH
CH - NH

>CH



N



CH 2 C1
CH - NH



N



CH - NH



/'
N



CH



CH 2 - C C1(COOC 2 H 5 ) 2 CH 2 - CHC1 COOH CH 2 - CH(NH 2 )COOH

The racemic product thus obtained was resolved by the fractional
crystallization of its tartrate, when the laevo compound was found
to be identical with the natural substance.

According to the second method,* glyoxaline-4 (or 5)-formalde-
hyde 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 ^)CH

^ CHz + OHC-C N



HOOC



CH 5 CONH



CH-N-COCH 3

II >
C : CH . C - N

HOOC

CH - N CO CH 3

)CH
/ C : CH - N

o-oc

(i)
* Pyman, Trans,, 1916, 109, 186.



CH S C : N



THE AMINO ACIDS AND POLYPEPTIDES 163

On boiling with dilute sodium carbonate the acetyl group is removed,
the oxazoline ring opened, and a-benzoylaminoglyoxaline-4 (or 5)-
acrylic acid (ii) obtained. On reduction, benzoylhistidine (iii) is
obtained which gives racemic histidine on hydrolysis:

CH - NH



CH B CO-NH



CH



^>C : CH - C N

HOOC X

(ii)



CH - NH



C 8 H S CONH



)CH



CH-CH 2 -C N

HOOC

(iii)

CH - NH

-* || >CH

HOOC CH(NH 2 ) - CH 2 C N

r-Histidine

The Distribution of Amino Acids in the Proteins. Fol-
lowing the isolation and characterization of the various amino acids
present in the proteins, chemists began to consider the losses of
amino acids which occur in their separation, with a view to arriving
at quantitative results for the distribution of these acids in the
various proteins. This line of inquiry has been vigorously pursued
by Abderhalden, who has ascertained the component amino acids of
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



ORGANIC CHEMICAL SYNTHESIS
AMINO ACIDS IN VARIOUS PROTEINS







.3*0




g





& .


G






*o-3 S








Jl4
















tt>




Protein.


3


jQ O rn


|1


.S s


S U 2


."2

CL!'O


"8*




c3


o c w

jS B bo





*


8> SS


fe


s






ffiQ


<


3


t3.S




E


Class of Protein.


Pro-
tamine.


Histone.


Albu-
mins.


Globu-
lin.


Phospho-
protein.


Sclero-
protein.


Chromo-
protein.


Glycine





+





3'8


O


35'2


O


Alanine


+


3-0


2'2


3*6


1-5


23-4


4-I9


Valine


4'3


I'D


2'5


+


7'2







Leucine, isoleucine




I7-5




20-9


9-4


1-8


30*0


Aspartic acid







2'2


4*^5


i '4





4*43


Glutamic acid





I'2


9'I


6-3




11*7




Serine


7-8









"5





0-56


Cystine










0-25


?





0-31


Lysine


O





3'7


i-o


6-0


5' 2


4-28


Arginine


87-4





4*9


11-7


3-8





5'4


Proline


II'O


4*5


3*5


4* 1


6-7


3'7




Hydroxyproline . .









2'O


0-3




1-04


Histidine


o





1-7


I-I


2-5





10-96


Tryptophane










+







+


Phenylalanine





5'


5-0


3* 1


3-2





4-24


Tyrosine








1-7


2-II


4'5


8-2




Total . .


110-5


34*7


47-2


64-54


64-1


89-2


70-81



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. According to the number of amino acid
groups present in the molecule, the synthetic products were termed
di-, tri-, &c., peptides. The simplest is the dipeptide, glycyl-
glycine, formed by the union of two molecules of glycine:

NH 2 CH 2 COOH + NH 2 CH 2 COOH = NH 2 CH 2 CO-NHCH 2 COOH + H 2 O

Glycylglycine

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



THE AMINO ACIDS AND POLYPEPTIDES 165

salt of glycine. One of these compounds had twice the molecular
weight expected, and was shown to be hippurylamidoacetic acid:

C 6 H 5 CO NH CH 2 CO NH CH 2 COOH

In 1904 the same chemist made the first systematic attempt *
to link together a series of 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 2 CHoCO[NHCH 2 CO] 2 NH CH 2 COOC 2 H 5

(i)

The use of the azoimides effected a considerable improvement,
e.g. benzoyl azoimide combines with glycine with the formation
of hippuric acid and the removal of hydrazoic acid (azoimide):

C 6 H 5 CO N/ 1 1 + HoN CH* - COOH
\N

- C 6 H 5 CO . NH CH a COOH + HN 3

The ester of hippuric acid may in turn be converted into the azoimide
and combined with a second molecule of glycine:

C 6 H 5 CO NH CH 2 CON 3 + H 2 N CH 2 COOH

- C 6 H 5 CONHCH 2 CONH CH a COOH + N 3 H

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 devised by E. Fischer, are
much more satisfactory.

i . 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 2 - CO

^>NH + H 2 O - H 2 N-CH 2 -CO-NH.CH 2 -COOH
CO CH 2

y. pr. Chem. t 1904 (2), 70, 57.



166 ORGANIC CHEMICAL SYNTHESIS

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 the successive introduction of
different amino acid radicles into a simple polypeptide or amino
acid. The following synthesis of leucylglycylglycine through the
intermediate glycylglycine is quite straightforward:

CH 2 C1COC1 + H 2 N-CH 2 -COOH -> CH 2 C1CO-NH-CH 2 COOH
(+NH 3 ) -> CH 2 NH 2 CONHCH 2 COOH

3 ,
CH-

CH CH 2 CHBrCO NH CH 2 CO NHCH 2 COOH



CH-CHoCHBrCOCl + HoN-CH 2 CO-NHCHoCOOH
CH



CH

>CH . CHo CH(NH,)CO NHCHoCO - NHCHoCOOH



By using the halogen acid chlorides of optically active acids, optically
active polypeptides are obtained. The method only allows of the
amide groups being introduced into the amino group of the original
acid, so that the chain can be lengthened only at this end.

3. 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 + NH 2 CH 2 CONHCH 2 COOC 2 H 5
Bromisocapronylglycyl chloride Glycylglycine ester.

-> C 4 H 5 CHBrCONHCH 2 CONHCH 2 CONHCH 2 COOC 2 H 5

-> C 4 H 9 CH(NH 2 )CO[NHCH 2 CO] 2 NH-CH 2 COOH

Leucyldiglycyl glycine

The acid chlorides may be obtained by the action of thionyl chloride
on the amino acids in which the amino group has been protected
by carbomethoxylation (p. 86), e.g. carbethoxyglycyl chloride and
glycine ester give carbethoxylglycylglycine ester, from which the



THE AMINO ACIDS AND POLYPEPTIDES 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 2 H 5 OOC)NH CH 2 COC1 + NH 2 CH 2 COOC 2 H 5

-> (C 2 H 5 OOC) - NH CH 2 CONH - CH 2 COOC 2 H 5
Carbethoxylglycylglycine ester

Although this process is elastic, the solubility of many such acyl
chlorides in acetyl chloride, and the consequent difficulty of sepa-
rating them from solution without decomposition, presented a serious
obstacle to its extension. This was overcome by preparing the acyl
chlorides of the amino acid hydrochlorides themselves. These
chlorides, having the general formula [R- C- H(NH 3 C1)COC1], are
also substituted ammonium chlorides, and are generally not readily
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
acids, 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.

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 CO NH CH CO NH CH CO NH CH COOH

r ----J 1 * -I r---J r- I

: / C ^ ! : <f H 2 : ; <JH 2 : ; H ;

! CH 3 CH 3 ! ! CROftf COOK!

u I 3 J t 6_4_. i , j

Valyl Tyrosine Aspartic Glycine

residue residue acid residue residue

It is obvious that the field of investigation is an extremely wide
one, and an interesting calculation of the possibilities presenting
themselves among the polypeptides has been made by Fischer.
* For further examples see Emil Fischer's lecture (Ber., 1906, 39, 551).



1 68



ORGANIC CHEMICAL SYNTHESIS



SOME



>ME POLYPEPTIDES SYNTHESIZED BY FISCHER'S
METHODS



By the Action of


On


Product.


Reference.


Hydrochloric
acid.


Glycine anhydride.


Glycylglycine.


Ber., 1901, 34, 2890.


Ammonia.


Chloracetylalanine .


Glycyl-rf/-alanine .


Ber., 1904,37, 2489.


Ammonia.


Brompropionyl-
glycine.


^//-Alanylglycine.


Ann., 1905,340, 130.


Ammonia.


J-Bromisocaproyl.
J-Alanine.


/-Leucyl.
{/-Alanine.


Ber., 1906, 39, 2916.


Phenylalanyl
chloride.


Glycine ester.


Phenylalanylgly-
cine.


Ber., 1905, 38, 2919.


d-Tryptophyl
chloride.


Glycine ester.


^-Tryptophylgly-
cine.


Ber., 1907, 40, 2741.


Ammonia.


Chloracetylglycyl-
glycine.


Diglycylglycine.


Ber., 1903, 36, 2983.
Ber., 1904, 37, 2500.


Liquid am-
monia.


Bromisocapronyl-
octaglycylglycine .


Leucyloctaglycyl-
glycine.


Ber., 1906, 39, 2906.



According to this estimate, the octadecapeptide has 816 possible
isomerides, while a polypeptide comprising 30 amino acids of which
5 are glycine, 4 alanine, 3 leucine, 3 lysine, 2 tyrosine, 2 phenyl-
alanine, and 13 various other amino acids has a number of possible
isomerides reaching 1-28 X io 27 . In these calculations it is assumed
that the mechanism of linking the amino acid groups is limited to
that of glycylglycine, and further complexity would arise from
alternative linkages such as that of diketopiperazine. Moreover,
hydroxyamino acids may participate in the linkages peculiar to esters
and ethers.

The 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
of amino acids only, unassociated with polypeptides. In that year
Fischer and Bergell produced from silk fibroin, by successive hydro-
lysis 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



THE AMINO ACIDS AND POLYPEPTIDES 169

that glycyW-alanine is amongst the degradation products of silk
fibroin. Soon after this the following polypep tides were recognized:
glycyW-tyrosine (silk fibroin), glycyl-/-leucine and ^-alanyl-/- leu cine
(elastin), /-leucyW-glutamic acid (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
sulphide. Quite recently Hopkins has shown that this is due to
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. Gluta-
thione is an autoxidizable substance, and is of exceptional importance
in relation to the oxidation and reduction processes which take place
in living cells. 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. J., 1921, 15, 286. For further information on the significance of
this compound the reader should consult, Oxidations and Reductions in the Animal
Body, by Dakin, 2nd Edition, London, 1922.



CHAPTER VIII
Some Simple Natural Organic Bases

Introduction and Scope. The classification of the natural
organic bases is a matter of considerable difficulty. Many of the
familiar 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 may be readily
extracted with the aid of immiscible solvents. This fact, together
with their pronounced physiological activity, 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. The pyrimidine and purine bases.

3. The alkaloids.

This classification is largely one of convenience, and it should be
remembered that no rigid classification of the natural organic bases
is 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.

The first stage of putrefaction is the hydrolysis of proteins into
their constituent amino acids, but bacteria are able to break down
amino acids still further. 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
reduction must take place:

R-CH-NHJCOOIH > R-CH;NH+CO,

*L I * Z Z



RCH-NH,:COOH; * R-CH;NH,-l-H-COOH



The same process applied to dibasic monoamino acids results
in the production of co-amino acids, and as these substances still
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.

It has already been stated (p. 103) that when animal and vegetable
tissues are extracted with ether, in addition to fats, oils, and choles-
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. A few monoamines like methyl-
amine are volatile in steam, but the majority must be isolated by
precipitation methods. The preliminary purification of a tissue
extract after removal of coagulable protein is best effected by lead
acetate or by tannin. In the former case the solution is first treated
by normal lead acetate, and then by the basic salt. After this treat-



172 ORGANIC CHEMICAL SYNTHESIS

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
nitrate are occasionally employed. For the isolation of the indi-
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.
perennis) and in the root of the Sweet Flag (Acorus calamus). It
has been frequently encountered as a product of bacterial action,
and may be derived from glycine by decarboxylation or, more prob-
ably, from choline.

Methylamine may be obtained synthetically by a variety of
simple reactions which need not be discussed here.

Trimethylamine, (CH 3 ) 3 N, occurs in leaves of the Stinking
Goosefoot (Chenopodium vulvarid), the Mountain Ash (Pyrus
aucuparia), and in the flowers of the Hawthorn (Cratcegus Oxya-
cantha). It is of common occurrence in putrefaction products and 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 is well known.

Isoamylamine, (CH 3 ) 2 CH CH 2 CH 2 NH 2 , is probably
present in fresh ergot * and is certainly present in putrid meat.f
In these cases it is probably derived from leu cine by decarboxylation,
and it may be prepared by rapidly heating the latter.

(CH 3 ) 2 CH CH 2 - CH(NH 2 )COOH Leucine
(CH 3 ) 2 CH CH 2 CH 2 NH 2 Isoamylamine

The isoamylamine obtained from ergot and during putrefaction
processes is probably mixed with 2-methylaminobutane, derived from

* Barger and Dale, J. Physiol., 1909, 38, 343.
t Barger and Walpole, ibid., 1908, 37, 343.



SIMPLE MONOAMINO BASES 173

isoleucine, while normal amylamine, derived from norleucine, may
also be present:

(C 2 H 5 )(CH 3 )CH - CH(NH 2 )COOH Isoleucine

I

(C 2 H 6 )(CH 3 ) CH CH 2 (NH 2 ) Methylaminobutane

CH 3 - [CHo] 3 CH(NH 2 )COOH Norleucine (caprine)

4
CH 3 [CH 2 ] 3 CH 2 NH 2 Amylamine

/?-Phenylethylamine, C 6 H 5 CH 2 CH 2 NH 2 , isolated from putrid
gelatine by Nencki in 1876, was one of the earliest putrefaction
bases of which the composition was correctly determined. It is
derived by the decarboxylation of phenylalanine (p. 145). It is in-
teresting to note that phenylethylalcohol, C 6 H 5 CH 2 CH 2 OH, occurs
in rose oil (p. 139).

Phenylethylamine is easily obtained synthetically by the reduction
of benzylcyanide:

C C H 5 CH 2 CN + aH 3 - C 6 H 5 CH 2 CH 2 NH 2

but the maximum yield so far obtained does not exceed 50 per cent.*
p-Hydroxyphenylethylamine, HO C 6 H 4 CH 2 CH 2 NH 2 ,
was first obtained by Schmitt and Nasse in 1865, by the decarboxyl-
ation 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 6 H 4 CH 2 CN + 4H - HO C 6 H 4 CH 2 CH 2 NH 2

2. From the benzoyl derivative of jS-phenylethylamine by the
following general reactions: jj

C 6 H 5 CH 2 CH 2 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 6 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.

|| Barger and Walpole, Trans., 1909, 95, 1720.



174 ORGANIC CHEMICAL SYNTHESIS

3. By reduction of the condensation product of anisaldehyde
with nitromethane. The />-methoxyphenylethylamine thus obtained
is then boiled with hydriodic acid.*

CH 3 O C 6 H 4 CHO + CH 3 NO 2 ~> CH 3 O C 6 H 4 CH : CH NO 2

-> CH 3 O.C 6 H 4 .CH 2 CH:NOH -> CH 3 O-C 6 H 4 .CH 2 -CH 2 NH 2

-> HO C 6 H 4 CH 2 CH 2 NH 2

This base produces physiological effects of the same type as
those produced by adrenaline, although its activity is relatively small.
In the body it is partly converted into ^-hydroxyphenylacetic acid
{HO C 6 H 4 CH 2 COOH).f

A 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 2 CH 2 N(CH 3 ) 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
pressor action. Three syntheses of this base may be briefly de-
scribed.

1 . Barger J obtained hordenine from /3-phenylethylalcohol by the
following general reactions:

C 6 H 6 CH 2 -CH 2 OH -> 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 2 N(CH 3 ) 2

-> HO C 6 H 4 CH 2 CH 2 N(CH 3 ) 2

2. Rosenmund methylated ^-methoxyphenylethylamine to the
tertiary base hordenine methyl ether, from which hordenine was
obtained by boiling with hydriodic acid:

CH 3 O C 6 H 4 CH 2 CH 2 NH 2 -> 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

3. By distillation in vacuo of quaternary hordenine methio-
dide, obtained by complete methylation of jp-hydroxyphenylethy-
lamine: ||

HO.C 6 H 4 .CH 2 -CH 2 -N(CH 3 )I -> HO-C 6 H 4 -CH 2 .CH 2 N(CH 3 ) 2 + CH 3 I

* Rosenmund, Ber., 1909, 42, 4778.

t Ewins and Laidlow, J. PhysioL, 1910, 41, 78.

J Trans., 1909, 95, 2193. Ber., 1910, 43, 306. || D. R. P., 233069



SIMPLE MONOAMINO BASES 175

Adrenaline (epinephin),

HO
HO<^_J>~CH(OH)-CH 2 NH - CH 3

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 any other known constituent of
protein. The physiological importance of the supra-renal glands
was first 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 proto-
catechuic acid:

H(X
HO( VCOOH




Pauly f showed that adrenaline contains an asymmetric carbon atom,
and reduced the possible constitutional formulae to two:

OH OH

10H





CHOH CH-NH-CH 3

CH 2 NHCH 3 CH 2 OII

(i) " (ii)

Jowett J arrived at similar results and favoured the first formula.
The constitutional formula (i) of adrenaline was established by its
synthesis by Stolz and almost simultaneously by Dakin,|| and
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. f Ber., 1903, 36, 2944.

J Trans., 1904, 85, 192. Ber., 1904, 37, 4149.

41 Proc. Roy. Soc., 1905, 76 [B], 491, 498. ** Zeit. physiol. Chem., 1908, 58, 581.



176 ORGANIC CHEMICAL SYNTHESIS

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 chloro-
acetocatechol (i) treated, in alcholic solution, at ordinary temperature^
with a concentrated aqueous solution of methylamine. The methyl-
aminoacetocatechol (ii) so obtained is then reduced to racemic
adrenaline (iii) by means of aluminium amalgam, or electrolytically.*
OH OH OH

ion OH






CO

CH 2 C1 CH 2 NHCH 3 CH 2 NHCH 3

(i) (ii) (iii)

2. 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-
cially as " arterenol ".f On methylation it is said to yield adrenaline.

(H0) 2 C 6 H 3 CH(OH)CN -> (HO) 2 C 6 H 3 CH(OH)CH 2 NH 2 .

3. 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 removing the acetyl groups
from this compound, adrenaline is obtained:

0-CO-CH 3 OCO-CH 3 0-COCH 3

O-CO-CH, r 1 CO ' CH 3 r // No.co.cH 3






CH(OH)CH NO CH(OH)CHNHCH CH(OH)-CH,NHH

(ii) (iii) 3 2

Racemic adrenaline may be resolved into its optical isomers with
the aid of rf-tartaric acid. The ^-adrenaline obtained as a by-
product is then racemized by means of acids. Lsevoadrenaline
has many times the pressor effect of the dextro form.

Several investigators, and particularly Barger and Dale, have

* 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.



DIAMINO BASES 177

prepared compounds analogous in chemical structure to adrenaline >
and have examined their physiological action. The latter investi-
gators 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
simplest being primary aliphatic amines. The most active of
the simpler bases is /?-phenylethylamine. The presence of two
hydroxyl groups in the 3:4 position of the nucleus increases the
effect, which is further intensified by a hydroxyl group in the side
chain. In short, the natural product seems to be the best adapted
for this special function.



DIAMINO BASES

Putrescine (tetramethylene diamine, NH 2 [CH 2 1 4 NH 2 ) and
Cadaverine (pentamethylene diamine, NH 2 [CH 2 ] 5 NH 2 ) are of
historic interest, as they were among the earliest putrefaction bases
to be isolated and characterized. They are, however, comparatively
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 2 -CH 2 [CH 2 ] X CH 2 NH 2

The origin of both amines was definitely established by Ellinger,*
who obtained putrescine by the action of putrefactive bacteria oa
orni thine and similarly cadaverine from lysine:

NH 2 - [CH 2 ] 3 CH(NH 2 )COOH NH 2 [CH 2 ] 4 NH 2

Ornithine Putrescine

NH 2 [CH 2 ] 4 CH(NH 2 )COOH NH 2 [CH 2 ] 6 NH 2

Lysine Cadaverine

Agmatine, guanidinobutylamine, has been isolated from
ergot, and also obtained by heating herring spawn with dilute acid
under pressure. On oxidation it yields guanidine and guanidino-

* Zeit. physiol. Chem., 1900, 29, 334.
(D331) 12



178 ORGANIC CHEMICAL SYNTHESIS

butyric acid, and it is probably derived from arginine by decarboxyl-
ation:

NH 2 C(:NH) NH - [CH 2 ] 4 NH 2 Agmatine

NH 2 C(: NH) . NH [CH 2 ] 3 CH(NH 2 )COOH Arginine

Kossel* has synthesized agmatine from cyanamide and tetramethylene
diamine:

NH 2 CN + NH 2 [CH 2 ] 4 NH 2 = NH 2 C[:NH] NH



HETEROCYCLIC BASES
Glyoxaline, imidazole,



II / CH

CH N



5 t

\"



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
glyoxal is converted into formic acid and formaldehyde, and the
latter combines with ammonia and unchanged glyoxal to give glyoxa-
line:

CHO NH 3 CH - Nil

j + + CILO - || \CH + 3 H 2

CHO NH 3 CH - N

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 dicar-
boxylic acid at 300. In this reaction diketosuccinic acid is pre-
sumably formed:

HOOC-CO NH 3 HOOC-C-NH HC-NH

+ + CH 2 -> ^CH - I! ^CH

HOOC-CO NH 3 HOOC-C-N HC-N

* 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 179

Glyoxaline forms thick, colourless prisms, and an aqueous
solution reacts alkaline. The silver salt is insoluble in water.
Ordinary reducing agents have no action on the base. With hydrogen
peroxide, glyoxaline is oxidized to oxamide, while potassium per-
manganate 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 2 CH 3 C - NH



CHO NH 3 HC - N

The formation of glyoxaline derivatives 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 first discovered by Wohl and Marckwald, J and may be illustrated
by the synthesis of 4 (or 5)-methylglyoxaline.



CH 3 CO CH 3 CO HUN CH 3 CO HoN

H ^ CS "/^S or

CH,NH 2

(i)




/ C ' S ' S ' C \
(iii)



NH - C - CH 3
N CH



* Trans., 1919, 115, 217, 1016; Fargher, T., 1920, 117, 668; 1921, 119, 158.
t Ber., 1905,88, 1166. % Ber., 1889, 22, 572, 1353-



i8o



ORGANIC CHEMICAL SYNTHESIS



Aminoacetone is condensed with potassium thiocyanate to give the
substituted thiourea (i). On warming with hydrochloric or sul-
phuric acid, mercaptoglyoxaline (ii) is obtained. On treatment
with warm dilute nitric acid 4 (or 5)-methylglyoxaline (iv) is formed >
possibly through the intermediate disulphide (iii). This reaction
has been used extensively in the synthesis of glyoxaline derivatives.
N-alkyl- or aryl-glyoxalines are obtained when the alkyl- or aryl-
isothiocyanates 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
Dale,f and simultaneously Kutscher,J obtained the same base
from ergot. The physiological activity of this base is very
pronounced, and in minute doses it produces chronic contraction
of the uterus.

Histamine was first obtained synthetically by Windaus and
Vogt. For this purpose glyoxaline-4-propionic ester (i) was
converted into 4-/?-aminoethylglyoxaline (ii) by Curtius' method:



CH-NH

II

N

C



CH 2

CH,



Hydrazine
hydrate



CH-NH

in



N



OOC,H B



CH 2
CH,

r



HNO.



CH-NH

I!

N



I

CH



ONHNH,



C

CH 2
CH 2

CO.N/*



Alcohol



CH-NH

1 k



C

CH,



CH 2
NH-COOC 2 H 6

* Zeit. physiol. Chem., 1910, 65, 504.
J Zeit. Physiol., 1910, 24, 163.



CH-NH

ii



C

Acids |

-* CH 2

CH 2

NH 2
(ii)

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)-chloro-
methylglyoxaline (i) is converted into the corresponding cyanide
and reduced by sodium and alcohol to histamine.

CH - NH CH - NH CH - NH

>CH II >CH || >CH



N ^ C N ^ C N



CH 2 C1 CH 2 CN CH 2 -CH 2 NH 2

(i) ' (ii)

4-j8-aminomethylglyoxaline (i), 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
histamine. It may also 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 synthe-
sized 4-methyl-j8-aminoethyglyoxaline (ii), and found it to be some-
what less powerful than 4-^-aminoethylglyoxaline. Still more
recently Fargher and Pyman have prepared 4-j8-methylamino-
cthylglyoxaline (iii), but its physiological action is weak.

CH - NH C(CH 3 ) - NH CH - NH



N C - N C - N



CH 2 NH 2 CH 2 CH 2



CH 2 NH 2 CH 2 NH-CH 3

(i) (ii) (iii)

BASES DERIVED FROM TRYPTOPHANE

Indolethylamine (3-j9-aminoethylindole). Tryptophane, un-
like tyrosine, cannot be decarboxylated by heat. Indolethylamine
was obtained by Ewins and Laidlow || both synthetically and by the
action of putrefactive bacteria on tryptophane. The synthesis,
subsequently described by Ewins ** was carried out along the lines
of the well-known phenylhydrazone method for the synthesis of
Indole derivatives. ff The requisite aldehyde could not be isolated

* Trans., 1911,99,668. f Ber., 1911, 44, 1721. J Trans., 1911, 99, 2052.
Trans., 1921, 119, 734. || Proc., 1910, 27, 343. ** Trans., 1911, 99, 270.

ft Fischer, Ann., 1886, 236, 137.



182



ORGANIC CHEMICAL SYNTHESIS



in the free state, so the corresponding acetal was employed. Phenyl-
hydrazine was condensed with y-aminobutyrylacetal in the presence
of zinc chloride, and the base isolated as its picrate:




CH i CH-CH 2 NH 2



NH-NH 2




OCH;CELNEL

2 Z



NH 3 +2C 2 H 5 OH



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
faeces by Brieger in 1877. It represents a further stage of putre-
factive decomposition in which decarboxylation and deaminization
are succeeded by partial oxidation of the side chain of tryptophane.
Scatole has been isolated 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:

r _ CJH]CH S



CH



NH,



NH



NH



or by the action of methyliodide on magnesium indolyliodide: j|




NMgl




N-CH,




NH



Magnesium indolyliodide is readily obtained by the action of mag-
nesium alkyliodides on indole.

Indole. In the formation of indole complete oxidation of the
side chain of the tryptophane molecule has occurred.

* Laidlow, Biochem.J., 1911, 6, 141. f Proc. Roy. Soc., 1889, 46, 211.
J y. Biol. Chem.> 1909, 5, 489. Fischer (loc. cit.).

|| Oddo, Gazz., 1911, 41, i, 229.



THE BETAINES 183

Indole was first obtained by Baeyer by distilling with zinc dust,
either oxindole, C H 4 <^^ 2 ^)CO, or the product obtained by

reducing indigo with tin and hydrochloric acid. It is conveniently
prepared by the reduction of indoxyl, obtained by heating indoxylic
acid with sodium-amalgam or zinc dust.*

C(OH) C(OH) CH

C 6 H 4 <^ ^C-COOH ~+ C 6 H 4 <^ yCH -> C 6 H 4 \ /CH

NH NH Nil

Indoxylic acid Indoxyl Indole

Baeyer and Emmerling f obtained indole by distilling 0-nitro-
cinnamic acid with caustic potash and iron filings:

CH : CHCOOH CH

C 6 H 4 / -> CH 4 <^ yCH { C0 2 + Oo

NO 2 NH

o-Nitrocinnamic acid Indole.

Indole is said to be obtained when the condensation product
of dichlorethylether and aniline is distilled in steam.



CH 2 C1-CHC1-O.CH 2 CH 3 + 2C 6 H 5 NH 2 -> C 6 H 6 N:CH.CH 2 .NH-C 6 H,

Dichlorethylether Ethylidene dianiline

CH

-> C 6 H 4 <( >CH + NH 3

NH

Indole

THE BETAINES

The betai'nes are 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 3
or y amino acids. Willstatter J has made a detailed study of the
betai'nes, and has shown that the a betai'nes and the isomeric esters
of dimethylamino acids are interconvertible:

/CH 3 X CH 3

CH 2 N\ ^> c _ N CH 3

I ^rla < I i \

COOCH 3 ( 1 _J ) ^ CH 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 ORGANIC CHEMICAL SYNTHESIS

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 alkali, breaks up into trimethylamine and
fumaric acid.

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 2 - N(CH 3 ) 3

Betaine f trimethyglycine, | | , was first isolated

V./V-/ v-J

from Lycium barbarum in 1863, It has been found in all species
of Chenopodiaceae so far examined, including the sugar beet (Beta
vulgaris), from which the compound derives its name. In the manu-
facture of beet sugar most of the betaine remains in the molasses,
and 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 + CH 2 C1COOH -* (CH 3 ) 3 N/ -> (CH 3 ) 3 N<^ ^>CO

CH 2 COOH CH 2

The same product was obtained by the methylation of glycine by
Griess in 1875,

CHOLINE AND ALLIED BASES

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
*' Bausteine " of the phosphatides.

Gholine (trimethyl - j8 - hydroxyethyl - ammonium hydroxide)

/OH
(CH 3 ) 3 :N/

X CH 2 CH 2 OH

was discovered by Strecker in 1849. It is most readily obtained
by hydrolyzing lecithin with baryta and subsequently precipi-
tating the base with alcoholic platinic chloride. The synthesis of
choline has been effected in a variety of ways, among which may be
mentioned:



CHOLINE AND ALLIED BASES 185

i,. The action of trimethylamine on ethylene oxide in aqueous
solution (Wurtz, 1867):
CH,



(CH 3 ) 3 N+ | >0 + H a O = (CH 3 ) 3 :N<;

CH/ X CH 2 CH 2 OH

2. By the action of trimethylamine on ethylene chlorhydrin,
and subsequent decomposition of the chloride of the base with silver
oxide : *

CH,Cl /Cl

(CH 3 ) 3 N + | -> (CH 3 ) 3 : N<

CH 2 OH X CH 2 CH 2 OH

/OH
- (CH 3 ) 3 : N/

X CH 2 CH 2 OH

According to Ewins,f acetyl choline

[(CH 3 ) 3 N(OH) CH 2 CH 2 O CO CH 3 ]

is present in small quantity in some ergot extracts. The physio-
logical action of a number of esters and ethers of choline has been
studied by Dale.

Amino -ethyl Alcohol is prepared from kephalin (a phos-
phatide from the brain) in a similar manner to that by which choline
is obtained from lecithin. It has been synthesized by Knorr by the
action of ammonia on ethylene oxide:

CH. CH,OH

NH 3 + i >0 = i

CH/ CH 2 NH 2

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 its synthesis from trimethylamine and ethylene
bromide. The condensation product obtained from these sub-
stances yields neurine on treatment with moist silver oxide
(Hofmann, 1858):

/Br /Br

(CHy^N/ + AgOH - (CH 3 ) 3 ;N< + AgBr+ H 2 O

x CH 2 -CH 2 Br N CH:CH 2

Neurine is a powerfully toxic compound, and in its physiological
action resembles choline.

* Renshaw,^. Amer. Ghent. Soc. t 1910, 32, 128. f Biochem.J., 1914, 8, 44.



i86 ORGANIC CHEMICAL SYNTHESIS

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 flesh to the extent of about 6 per cent. On
hydrolysis with baryta it is converted into sarcosine (methylglycine)
and urea:

/-'ITT



|
C



CH 2 .NH-CH 3 /NH 2

C(:NH)NH 2 + H 2 O = ! + OC/

OOH COOH X NH 2

Creatine Sarcosine Urea

In 1868 Volhard synthesized creatine by the action of cyanamide on
sarcosine in alcoholic solution at 100:

/CH 3

CH 2 . NH CH 3 CH, N<

| + CN-NH, = | " X C(:NH)NH 2

COOH COOH

Creatinine is absent from muscle but is a normal constituent
of the urine of mammals. It may be obtained from creatine by the
action of heat or dehydrating agents:

C*TT

CH 2 N/ 3 CH 2 N(CH 3 ) C : NH

| X C(:NH)NH 2 ~ | I

COOH CO - NH

Creatine Creatinine

The reaction may be reversed by the action of alkalies. Both
creatine and Creatinine occur in cereals.

/NH 2
Guanidine, HN : C/ , has been isolated from Vicia seed-

X NH 2

lings by Schultze. It is most conveniently prepared by heating
ammonium thiocyanate:

aNH 4 SCN -* aCS(NH 2 ) 2 -> NH : C(NH 2 ) 2 , HCNS + H 2 S
Thiourea Guanidine thiocyanate

More recently guanidine thiocyanate has been obtained by
Werner,* in a 90 per cent yield, by heating a mixture of dicyano-
diamide and ammonium thiocyanate at 120. The first phase of
this reaction is probably the depolymerization of dicyanodiamide,
the guanidine salt being formed by the union of cyanamide and
ammonium thiocyanate thus:

CN - NH 2 + NH 3 - HSCN = HN : C(NH 2 )HSCN
* 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.

*NH
Methylguanidine, H 2 N Cf , is a normal constituent

N NHCH 3

of muscle. It may be obtained by the oxidation of creatine, or
synthetically from cyanamide and methylamine:

X NH 2
NH 2 CN + NH 2 CH 3 - HN : C<

N NHCH 3
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

The monoamino 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.

j8-Alanine, jS-aminopropionic acid, NH 2 -CH 2 -CH 2 *COOH.
This substance was first obtained synthetically by Heintz in 1870
by the action of ammonia on jS-iodopropionic acid. It may also
be obtained by the reduction of cyanacetic acid with zinc and sul-
phuric acid.

It is best prepared synthetically by the action of bromine and
alkali on succinimide (Hofmann's reaction):

CH 2 - CCX CH 2 C(:NBr)OK

I >N-Br -> I

CH 2 - CCK CH 2 COOK

CH 2 N : CBr(OK) CH 2 NH 2

| -* I

CH a COOK CH 2 COOK

* Trans., 1922, 122, 1793.



i88 ORGANIC CHEMICAL SYNTHESIS

Alanine was first isolated from Liebig's extract of meat by
Engeland. Since it is obtained from the meat base carnosine by
hydrolysis, it is doubtful if /?-alanine is present as such in muscle.

y-Amino-fl-butyric Acid, NH 2 - CH 2 CH 2 - CH 2 COOH.
This acid is produced in putrefaction by the partial decarboxylation
of glutamic acid:

COOH CH(NH 2 ) - CH 2 CH 2 COOH

= NH 2 CH 2 CH 2 CH 2 COOH + CO 2

y-Amino-w-butyric acid has been synthesized from y-chloro-
butyronitrile, 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+ClCOOC 2 Hg->/ ''^N-COOCjH^NH-CHjCHfCHjf COOH

3-Amino-w-valeric Acid, NH 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 2 [CH 2 ] 3 CH(NH 2 )COOH + zH - NH 2 [CH 2 ] 3 CH 2 COOH + NH 3

or by the reduction of proline (p. 157):
CH 2

C



CH 2 CHCOOH + aH - NH 2 [CH 2 ] 4 COOH

\/
NH

It was first obtained synthetically by hydrolysis of the oxidation
product of benzoyl piperidine with potassium permanganate: f

OCH 2 COOH
N-CO-C A H R * H.C'C
6 5 2 \cHjCH 2 -NHCOC 6 H g

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. Zeit., 1911, 37, 490.
t Schotten, Ber. 9 1884, 17, 2544; 1888, 21, 2240.
j Gabriel, Ber. y 1890, 23, 1767; 1891, 24, 1364.



THE co-AMINO ACIDS 189

dine hydrochloride a small quantity of this acid, together with much
iminazoylethylamine, is obtained. The acid may be obtained syn-
thetically by the action of ammonia and formaldehyde on /?-glyoxyl-
propionic acid:

HOOC CH 2 CH 2 CO

| + 2NH 3 + CHoO

CHO

HOOC - CHo - CH 2 C NH



CH~N

j8-Glyoxylpropionic acid is obtained by boiling dibromlevulinic
acid with water.

Carnosine. This is probably the base in muscle which gives
rise to jS-alanine on hydrolysis. Next to creatine it is the most
abundant base in meat extract.

The constitution of carnosine as j8-alanylhistidine has been
established by its synthesis from histidine methyl ester by Barger
and Tutin : *



NH-CH. |

| >C - CH 2 - CH COOCH 3 + C1COCH 2 CH 2 NO 2

CH = W

(3-Nitropropionyl chloride

NH-CH.

-> | >C CH 2 - CH COOH
CH = N- I

NH - CO CH 2 CH 2 NH 2

REFERENCES.

The Simpler Natural Bases, by G. Barger: Monographs on Bio-
chemistry (London, 1914).

Biochemisches Handlexikon, Band 5, by Abderhalden (Berlin, 1911).
* Biochem. J. y 1918, 12, 402.



CHAPTER IX
The Pyrimidine and Purine Bases

Introduction. The 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
acid in 1776. Almost contemporaneously, Scheele obtained the
same acid, which he termed " lithic acid ", from human urine.

In 1838 Liebig and Wohler published the results of their investi-
gation of uric acid in which they showed that it yields a large number
of compounds which may be grouped together as derivatives of
alloxan and parabanic acid. In view of the state of chemical theory
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
synthesis of pseudo-uric acid, but also prepared the way for the
subsequent discovery of the structure and synthesis of uric acid
and the allied xanthine or purine bases. Emil Fischer published the
results of his investigation of caffeine in 1882, and this work ulti-
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
as those of the thymus, pancreas, and spleen. The nucleoproteins
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 191

with the nucleic acid molecule. Through the action of pancreatic
juice or further acid hydrolysis the remainder of the protein is split
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
nucleic acid and plant nucleic acid. Animal nucleic acid is most
readily prepared from the thymus while plant nucleic acid is con-
veniently obtained from yeast. Nucleic acids readily undergo
further hydrolysis by means of enzymes (" nucleases ") present in
most animal tissues. On complete hydrolysis the nucleic acids yield
phosphoric acid, purine and pyrimidine bases, and a carbohydrate
or carbohydrate derivative. The nucleic acids are not, however,
simple substances whose molecules contain a single phosphoric acid,
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 5 H 8 O a C 5 H 4 ON 5 (guanine)

\

O==P O C 6 H 8 O S C 6 H 4 N 5 (adenine)



O C 6 H 8 3 C 4 H 4 2 N 3 (cytosine)

0=P O C 5 H 8 3 C 4 H 3 2 N 2 (uracil)

HO

Yeast nucleic acid

A 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 ORGANIC CHEMICAL SYNTHESIS

substances as mononucleotides and represent them by the formulae:

N , o ,

(HO) 2 P O CH CH CHOH . CHOH CH C 5 H 4 ON 6 (guanine)

Guanylic acid

o

(HO) 2 P O CH 2 CH CHOH - CHOH CH C 5 H 4 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
which remains is called a nucleoside. For example, guanosin is
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

Of Animal Origin. Of Plant Origin.

Laevulinic acid. .... A Pentose (d-ribose).

Phosphoric acid. .... Phosphoric acid,

Guanine. .... Guanine.

Adenine. .... Adenine.

Cytosine or Uracil. .... Cytosine or Uracil.

Thymine. .... Thymine.

PYRIMIDINE COMPOUNDS

N = CH 1-6 HN - CH 2

I I I I 1 I
HC CH 25 H 2 C CH 2

II II I I II

N - CH 3-4 HN - CH 2

Pyrimidine (i.*3-diazine) Pyrimidine hexahydride

HN - CO HN - CO HN - CO HN - CO



I II I

-c:r~~~ "



OC CH 2 OC - C:NOH OC CHNH 2 OC C(OH) 2

HN - CO HN - CO HN - CO HN - CO

Barbituric acid Violuric acid Uramil Alloxan

(2H:6-Trioxopyrimi- (5-Oximino-2:4:6- (5- Ami no- 2:4:6-11-10x0- (5-Dihydroxy-2:4:6-

dine hexahydride) trioxopyrimidine pyrimidine hexahydride) trioxopyrimidine

hexahydride) 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 HN - CH HN - CH HN - CH

Dialuric acid Uracil Thymine Cytosine

(s-Hydroxy-a:4:6- (a:6-Dioxypyrimidine (s-Methyl-2:6:dioxy- (6-Amino-2-oxy-

trioxopyrimidine tetrahydride) pyrimidine pyrimidine)

hexahydride) tetrahydride)



PYRIMIDINE AND SOME OF ITS DERIVATIVES

Before discussing the naturally occurring pyrimidine derivatives,
pyrimidine itself and a few of its simpler derivatives may be con-
sidered on account of their relationship to the purine compounds.

Pyrimidine (i:3-diazine), C 4 H 4 N 2 , the parent substance of the
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.

Pyrimidine 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:

NH - CO N - CC1 N - CH

II I! II II II

CO CH 2 -> C1C CH -> HC CH

NH - CO N - CC1 N = CH

Barbituric acid Trichloropurine Pyrimidine

Pyrimidine is a colourless oil which slowly crystallizes at zero
to a mass of fibrous crystals, melting-point 20 to 22. Its aqueous
solution is neutral to litmus, and gives a white precipitate with
mercuric chloride (C 4 H 4 N 2 -f HgCl 2 ), a yellow compound with
gold chloride (C 4 H 4 N 2 + AuCl 3 ), and a picrate with picric acid
(C 4 H 4 N 2 + C 6 H 3 7 N 3 ).

Barbituric Acid (malonyl urea), C 4 H 4 N 2 O 3 , was first obtained
by Baeyer during the course of his researches on the constitution
of uric acid. It may be synthesized by the condensation of

* Gabriel, Ber., 1900, 33, 3666; Emery, Ber., 1901, 34, 4180.

(D331) 13



194 ORGANIC CHEMICAL SYNTHESIS

malonic acid and urea in the presence of phosphorus oxychloride: *
NH 2 HOOC NH - CO

CO + CH 2 - CO CH 2 + aH 2 O

NH 2 HOOC NH 2 - CO

Barbituric acid

It is interesting to note that Veronal, one of the most valuable
synthetic hypnotics, is closely related to barbituric acid, and may be
prepared by combining diethylmalonic ester with urea in the presence
of sodium ethoxide, or by the action of urea on diethylmalonyl
chloride:

COOC 2 H 5 NH 2 CO - NH

(C 2 H 5 ) 2 C + CO - (C 2 H 5 ) 2 C CO + 2C 2 H 5 OH

COOC 2 H 5 NH 2 CO - NH



Veronal
COC1 NH 2 CO - NH

(C 2 H 5 ) 2 C + CO = (C 2 H 5 ) 2 C CO + 2HC1

COC1 NH, CO - NH



Violuric Acid (isonitrosobarbituric acid), C 4 H 3 N 3 O 4 , 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 NH - CO

CO CH 2 -> CO C:NOH

NH - CO NH - CO

Barbituric acid Violuric acid

Violuric acid and its salts were extensively studied by Hantzsch
during the course of his researches on chromoisomerism.

Uramil (amidomalonyl urea), C 4 H 5 N 3 O 3 , 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 ammonium carbonate:

* Grimaux, Bull. Soc. chim. 9 1876, 31, 146.



PYRIMIDINE AND SOME OF ITS DERIVATIVES 195

NH - CO NH -CO NH - CO

I I I I /NH 2 | |

CO C(OH) 2 + NH 4 HSO 3 -> CO C<; -> CO CH-NH 2

i I I | x so 3 H I I

NH - CO NH - CO NH - CO

Alloxan Thionuric acid Uramil

Alloxan (mesoxalyl urea), C 4 H 4 O 5 N 2 , is readily obtained by the
action of strong nitric acid on uric acid, and it was obtained in this
manner as early as 1817 by Brugnatelli. Its constitutional formula
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.

By 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
following scheme:

/OH
NH - CO NH - C< NH - CO



O C(OH> 2 ~* CO



COOH _^ |
""* CO



NH - CO NH - CO NH - CO

Alloxan Parabanic acid

Uracil (2 : 6-dioxypyrimidine tetrahydride) and Thy mine
(5-methyluracil). The term uracil was applied 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
first obtained in 1900 by Ascoli J as a product of hydrolysis of yeast
nucleic acid. Since that time it has frequently been encountered
as a hydrolytic product of nucleic acid from various sources, especially
when the latter is hydrolyzed by acids under pressure. Under these
circumstances it is probably formed by the hydrolysis of cytosine:

C 4 H 3 N 2 0(NH 2 ) + H 2 - C 4 H 3 N 2 0(OH) + NH 3
Cytosine Uracil

Thymine was first 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.

Fischer and Roeder obtained hydrouracil by the condensation
of acrylic acid and urea, and by the action of bromine in glacial

* Liebig and Wohler, Ann., 1838, 26, 276.

t Biltz, Heyn, and Bergius, Ann., 1916, 413, 68, 76.

j J. physiol. Chem., 1900, 31, 162, Ber.> 1901, 34, 3761.



196 ORGANIC CHEMICAL SYNTHESIS

acetic acid on this compound a product was obtained which gave
uracil on heating with pyridine:

NH 2 HOOC NH - CO NH - CO NH - CO

CO + CH -> CO CH 2 -> CO CHBr -> CO CH

I II I I II II

NH 2 CH 2 NH - CH 2 NH - CH 2 NH - CH

Hydrouracil Uracil

By a series of similar reactions thymine was obtained from methyl-
acrylic acid.

Wheeler and Merriam* found that the sodium derivative of
formylacetic ester (i) condenses with y-methylthiocarbamide f (ii)
to form 2-methylthiol-4-oxypyrimidine (iii), from which uracil is
easily formed by saponification with boiling mineral acid:

CH(ONa) NH N CH

CH + CH 3 S C -> CH 2 S - C CH + NaOH + C 2 H 5 OH

I I II
COOCoH 5 NH 2 HN CO

(i) (ii) (iii)

NH - CH

-> CO CH + CH 3 SH

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 hydroxy-
acrylic esters by ethoxylmethylene malonic ester or by formylsuc-
cinic ester. A great variety of pyrimidine derivatives have been
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. The
intermediate 2-thiouracil is quantitatively converted into uracil
when boiled with an aqueous solution of chloracetic acid. In a

* Amer. Chem. jf. y 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,
notably by Wheeler, Johnson, and Johns. Ibid., 1908, 40, 547.



PYRIMIDINE AND SOME OF ITS DERIVATIVES 197

similar way Wheeler and MacFarlane substituted thiocarbamide
for y-methylthiocarbamide in the preparation of 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 :

NH - CO NH - CO

SC C-CH 3 - CO i-CH 3

II! I II

NH - CH NH - CH

2-Thiothymine Thymine

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
precipitate and solution are obtained.

Thymine crystallizes from water in colourless needles or rosettes
which dissolve readily in hot water. With diazobenzene sulphonic
acid it gives a more intense red colour than uracil, but it does not
behave like uracil towards bromine water and baryta. Like uracil,
it combines with silver nitrate, forming a compound which is preci-
pitated by ammonia and dissolved 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
(ii) by the action of phosphorus pentachloride on 2-ethyl-thiol-
6-oxypyrimidine (i). On boiling this substance with alcoholic
ammonia the corresponding amide (iii) was formed, which, in turn,
was converted by saponification into 2-oxy-6-aminopyrimidine,
identical with cytosine:

NH - CO N = C-C1 N = C-NH 2

C 2 H 5 S-C CH - C 2 H 5 S-C CH -> C 2 H 6 S C CH



(i) (ii) (iii)

N = C-NH 2

-> OC CH

I II
NH-CH

Cytosine
* Zeit physioL Chem., 1903, 38, 49. f Amer. Chem.J., 1903, 29, 505.



198



ORGANIC CHEMICAL SYNTHESIS







i


0)
I *




>Q
3


? -c^


|f>0?




58 *


*H^ a'^


*^*rt ^




w|c

1?H


P<*o b J?

li ol"
o >. 4 S H


^ 2




^


^rS *2~


ci'C^









a




1


W ffi







S




o




O


o ' o ' r


^


00


6 rt


U U ^ O w ti


J U U w


/\


j2^


I |


1


l^ C^


"S




r *-X r \ Hy


1


o


J2J O <5j2!O <H<H^ /-(

rcffi EO ffiffio as


\O IO ^-


2






CO |


OQ






<g H M


oPQ


I


1 .


g


.il
p


^a ^


|l
oo K


a


^


MH O

vO N ^


vfi, g










W 5? 1?

^ g-^Uo J

II *


B

i|


K M

KH 9 S/\H
X V s Y '
SI o

O /, r 1 , r


ffi

O

6

) 9 ^


2 ffi 2


1 O -"(J <>




*


II "


1 "







WTT /i >^ ^






I


^ ffi ^ 6
ffi


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ffi




s T ame and
Formula.


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5125 .S^,


14




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gaj IK


CE




J &


V~<r ^ p^ ^ x


H^ r ^




1


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M N


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THE PURINE BASES



199



\o






9



o Y M

g a aj

Il3



vO



vO



2

rt




as S3



O






o 3
18



a'i



co




(J



as
o i

6 O:



1



5



Guanine
C S H 6 ON 6



Theophylline
(i : 3-Dime-
thylxanthine),
C 7 H 8 2 N 4 .



Theobromine
3 : 7-Dimethyl-
xanthine),
C 7 H 8 2 N 4 .



ne



Caffeine
(i: 3 :7-Tri
methylxanthi
C 8 H 10 O 2 N



to



00



200 ORGANIC CHEMICAL SYNTHESIS

Cytosine crystallizes in colourless plates containing one molecule
of water of crystallization, which it loses at 100. It forms salts
with acids and is converted into uracil on treatment with nitrous
acid. With dilute acidified solutions of potassium bismuth iodide
it gives a brick-red crystalline precipitate. It behaves like uracil
towards diazobenzene sulphonic acid or bromine water and baryta,
Cytosine forms an easily crystallizable pier ate.



THE PURINE BASES

From 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
by Emil Fischer. Purine itself does not appear to be present in
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 N = C

HO C C NH ^ C1C C - NH



N C N N C N

Uric acid Trichloropurine

N = CI N - CH

1C C NH ^ HC C NH

%CH



^

N C N N C N

Diiodopurine Purine

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. 9 1906, 39, 280.



THE PURINE BASES 201

HN - CO HN - CO HN - CO

OC CH - OC C-NO a -> OC C-NO 2

HN - C-CH 3 HN - C-COOH HN - CH

4-MethyluraciI 5-Nitrouracil-4-carboxylic acid s-Nitrouracil

When heated with phosphorus oxychloride under pressure, 5-nitro-
uracil yields 2:4-dichloro-5-nitropyrimidine (i), which with ammonia
gives 2-chloro-4-amino-5-nitropyrimidine (ii). On reduction with
hydriodic acid, 4 : 5-diaminopyrimidine (iii) is produced. This
is converted into its formyl derivative (iv), which gives purine
when heated at 210.

N = CH N = CH N = CH

II II II

C1C C-NO 2 -*> C1C C-NO 2 -> HC C-NH 2



I



II II

CC1 N C-NH 2 N C-NH 2

(i) (ii) (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 N 4 3 + O + H 2 - C 4 H 2 N 2 4 + CO(NH 2 ) 2
Uric acid Alloxan Urea

its molecule presumably contains the nuclei of both these substances.
Since all four hydrogen atoms of uric acid are replaceable by metals,
it is probable that these hydrogen atoms are linked to the nitrogen
atoms as in the alloxan molecule. That this is actually the case is
proved by the elimination of the whole of the nitrogen as trimethyl-
amine 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 ORGANIC CHEMICAL SYNTHESIS

HN - C NH HN - CO

I \ I II

OC CO CO OC C - NH

I / I II N

HN - C NH II

HN - C - NH

(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 this formula has been established by
synthesis.

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 HN - CO

I I NH 2 | |

OC C OH . \^ ^ OC C - NH



NH 2 || / C0

HN - C OH HN - C - NH

Isodialuric acid



The most satisfactory syntheses are those discovered by Emil
Fischer and by W. Traube, and these may be briefly described.

Emil Fischer's Synthesis* As early as 1838, Liebig and Wohler
had correctly surmised the relation of uramil to uric acid; but
their attempts to unite uramil 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.

* Ber., 1897, 30, 559. f Ann., 1863, 127, 3.



THE PURINE BASES 203

HN - CO HN - CO

OC CHNH 2 + KCNO = OC CH - NH CONHK

HN -CO HN - CO

Uramil Potassium pseudourate

Fischer found that pseudouric acid may be dehydrated to uric
acid by means of molten oxalic acid, or, more simply, by boiling
with dilute mineral acids.

HN -CO HN - CO

OC CH - NH - CONH, _ OC C - NH

\ CQ + H 2



HN - CO HN - C - NH

Pseudouric acid Uric acid

This method has been applied by Fischer to the synthesis of various
alkyluric acids and, indirectly, to several of the xanthine bases.

W. Traube's Synthesis* Cyanacetylurea is first prepared by
the condensation of cyanacetic acid or its ester and urea in the
presence of phosphorus oxy chloride, and the product is then con-
verted into 4-amino-2 : 6-dioxypyrimidine by the action of alkalies.

NH - CO NH - CO

CO CH 2 -* CO CH 2

NH 2 CN NH - C : NH

Cyanacetylurea 4-Amino-2 : 6-dioxypyrimidine

By the action of nitrous acid the hydrogen of the methylene group
is replaced by an isonitroso group, and the latter on reduction is
transformed into an amino group:

NH - CO NH - CO

CO C:NOH ~> CO C NH 2



NH - C : NH NH - C NH 2

4 : 5-Diamino-2 : 6-dioxypyrimidine

By the action of chloroformic ester a urethane is obtained, and when
the sodium derivative of the latter is heated, alcohol is eliminated
and sodium urate is formed.

Ber., 1900, 33, 1371, 3035.



204 ORGANIC CHEMICAL SYNTHESIS

NH - CO NH - CO

CO C N tNa)COOC 2 H 5 _^ CO C - N . Na

II II >

NH - C NH 2 NH - C - NH

Sodium urate

This method has been extended to embrace certain of the xanthine
bases.

In addition to Fischer's synthetic method, a number of methyl-
uric 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 by Kossel in 1886, all these bases have long been known. In
addition, theobromine, which is a constituent of cocoa beans (Theo-
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
is almost entirely due to Emil Fischer, and the earlier work need not
be discussed here. Fischer J made an elaborate study of the de-
gradation products of the caffeine molecule, but as the constitution
of this substance has since been established by its synthesis, the
story of this work has lost some of its earlier interest.

The decomposition of caffeine into dimethylalloxan and methyl-
urea indicates a structure similar to that of uric acid, and ultimately
the constitutional formula shown on p. 199 was adopted. Fischer
observed that xanthine was converted into alloxan and urea on
oxidation, 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. 9 1899, 32, 461).

t Biltz and Damm, Ann., 1916, 413, 186. J Ann., 1882, 108, 141.



THE PURINE BASES 205

into xan thine, by the action of nitrous acid, was first 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 the close relationship between the
purine bases and uric acid, it is evident that at least three methods
for the conversion of the latter into the former present themselves:

1. Reduction of uric acid to xan thine and subsequent methyl-
ation.

2. Methylation of uric acid to monomethyluric acid, reduction
to me thylxan thine, and further methylation.

3. Further methylation of uric acid to di- and tri-methyluric
acids, and reduction of the products to the corresponding methyl-
xanthines.

A few examples of these methods may be briefly reviewed.

(a) By the direct methylation of uric acid, 3-methyluric acid
(i) may 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
(iiifl), which are readily converted into theobromine and caffeine
respectively:

NH-CO NU-CO

II II

CO C-NH ^ CO C-NH

I II >CO I >CC1

CH,N C NH CH N C N

(i) ' (ii) \

js ^

NH-CO CH_N CO

II II

CO C-NCH 3 CO C-NCH 3

I II >cci I !l >cci

CH 3 N C-N CH 3 N C N
(iii) (iiia)

\ I

HN CO CH,N CO

II II

OC C-NCH 3 OC C-NCH g

| II >CH I II >CH

CH 3 N C-N CH 3 N C-N

Theobromine Caffeine



2O6



ORGANIC CHEMICAL SYNTHESIS



(b) When heated with a mixture of phosphorus pentachloride
and oxychloride, i : 3-dimethyluric acid (i) yields 8-chlorotheophyl-
line (ii), which on reduction is converted into theophylline (iii):



CH S N-CO



oi



C-



NH



CH 3 N-CO
OC C-



NH



CH 3 N-CO
OC C-NH



CH 3 N-C-NH
(i)



CH 3 N-C-N
(ii)



CN



II >

JST-C-N



(iii)



In addition to purine itself a number of the purine bases may
be: obtained from trichloropurine by means of the following re-
actions:

N CI HN CO

II HC1 I I

1C C NH > OC C NH

n o >CH l II >CH

N C N HN C N

Di-iodopurine Xanthine




N==

C1C
I

N

Trichk


CC1

1

c* x


IH
>CC1

*

ine
^


aqueous


HN CO

1 1 m
r*lr* r* TsTTT i


HN-

HC

II

N-

Hyp

N=


-CO

CTSJTT


V *

C-*

wopur


KOH

%


\-xiLx ^ iNJn >
II II >CC1

N C N

Oxy2 : 8 dichloroporlne

N=C-NH 2
II HI


IN 11

II >CH

-C N

oxanthine
=C-NH 2



C1C C NH *" HC C NH
II II >CC1 || || >CH

N C N N C N

6>Amlao-2:8di.chloropuriae Adenine



HN CO



HI



HN CO



Alcoholic Ammonia



NH;C C NH NH-C C NH
I II >CC1 I II >CH

N C N N C N



Chloroguanine



Guanine



The conversion of trichloropurine into purine has already been
described (p. 200).

Traube's Method. The synthesis of uric acid starting from urea
and cyanacetic acid has already been described. The sodium deriva-



THE PURINE BASES



207



tive of xanthine is obtained when 4 : 5-diamino-2 : 6-dioxo-pyrimi-
dine (i) is transformed into its formyl derivative, by means of formic
acid, and the sodium derivative of the latter is heated:

HN- CO

oi



HN -



P , XTW

C NH,

C-NH 2
(i)



HN

i

HN -



CO HN

I I

C NH CHO v OC



NH 2



HN -



CO

CN(Na)CHO
C NH 2



HN - CO
OC C - N



Na



HN - C - N
When dimethylurea is used in place of urea, theophylline is obtained:



CH 3 N - CO
OC C NH 2



CH 3 N - CO
OC C - NH



CH,N - C NH



CH,N -



/

N



CH



This method is capable of considerable extension, e.g. monomethyl-
urea yields 3-methylxanthine, and guanidine gives guanine. When
thiourea is employed and the sulphur ultimately removed with dilute
nitric acid, hypoxanthine is obtained, while adenine may be syn-
thesized starting from thiourea and methylene cyanide:

HN - CO HN - CO HN - CO



HS



C - NH,



HS-C



I I



NH



C-



N - C - NH 2



- C - N



NH 2
CS +



CN



*2 _



HN - C : NH
SC CH 2 HNO 2



HC C - NH

^>CH

- C - N
Hypoxanthine

HN - C : NH

SC C : NOH Reduction



NH 2 CN HN - C : NH

N = C NH 2

S



N = C-NH 2
C NH 2 F ? rm / c SC C NH



HN



Acid

. NH 2 HN



HN - C : NH

N = C NH 2
Oxida- riQ



^
-N



CH



tion



C - NH



),CH



N
Adenine



- N



208 ORGANIC CHEMICAL SYNTHESIS

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 ad-
visable to draw attention to the fact that in all these syntheses it has
been customary to start with pyrimidine derivatives or substances
which condense to 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

ii >

H 2 N C - N

with cyanic acid and subsequent elimination 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

It has already been stated that the compound of sugar and base
which remains when a nucleic acid is incompletely hydrolyzed is
termed a nucleoside. Several such nucleosides or purine gluco-
sides, as they may also be termed have been synthesized by Emil
Fischer and his collaborators. For this purpose acetobromglucose
(p. 59) or an allied compound is condensed with the silver salt of
one of the purines in xylene solution. For example, the silver salt
of theophylline and acetobromglucose give tetra-acetyl-theophylline-
J-glucoside [C 7 H 7 O 2 N 4 - C 6 H 7 O 6 (COCH 3 ) 4 ]. For the removal of
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.

J Trans., 1919, 115, 217. Fischer and Helferich, Ber., 1914, 47, 210.



SYNTHETIC NUCLEOSIDES AND NUCLEOTIDES 209
CH 3 N - CO

CO C - N . C 6 H U O 5

II > CH
CH 3 N - C - N

is obtained.

The glucosides of hypoxanthine, xanthine, guanine, and adenine
have been obtained indirectly from trichloropurine and dichlor-
adenine. For this 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-</-gluco-
side is illustrated by the equations:

N == CC1 N = C-NH 2

rir n ism Aqueous ^.J, J,

CIC C NH ammonia CIC






CC1






CC1



N C N N C N

Trichloropurine Dichloradenine

c ., u N = C NH 2

Silver salt i i 2

and ,-,,/, (J,



CIC C N C 6 H 7 5 (COCH 3 ) 4



acetobromo-



glucose



/'
-N



CC1



Dichloradenine-tetra-acetyl-cf-glucoside



N = C NH 2 N = C NH 2

I I PH 4 I | |

NH 3 C1C C - N C 6 H n O 5 -* HC C - N C 6 H n O s

and



N C -N N - C - N

Dichloradenine-rf-glucoside Adenine-rf-glucoside

N = C . OH
HN0 2 HC C N . C.H n O

II > H
4 It N

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 ORGANIC CHEMICAL SYNTHESIS

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
theophylline-</-glucoside in pyridine solution at 20 a good yield
of theophylline-rf-glucoside phosphoric acid is obtained.*

[C 7 H 7 2 N 4 C 6 H 9 O 5 HPO 2 ] 2H 2 O
Purine Glucose Phosphoric
residue residue acid residue

The actual configuration of this compound has not yet been de-
termined.

These results serve to illustrate the progress which has been
made in the problem of the synthesis of the nucleic acids, and to
show that the achievement of this object will demand an experi-
mental 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 Alkaloids



Taken in its etymological sense, the term alkaloid may serve to
designate all 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
include many 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,
norharman, quinoline, isoquinoline, and phenanthrene.

CH



HC




H 2 C-



"CH CH,,



NCH 3 CH 2



H 2 C CH-



Tropano



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 ORGANIC CHEMICAL SYNTHESIS

he definitely characterized morphium as a vegetable " alkali " and
compared its behaviour with that of ammonia. This paper aroused
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. In 1834 Runge obtained from
coal tar a basic substance, C 9 H 7 N, which he termed " leucol ", and
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 H 5 N, was termed " pyridine ". Mean-
while 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
with Runge's " leucol ". 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 syn-
thesis 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 same plant, as, for example,
opium from which more than twenty individual alkaloids have
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 opera-
tions 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 extrac-
tion 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 for their detection and
isolation.

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
cyclic nitrogen atom is greatly diminished by making the element
quinquevalent, and this property has been utilized by Hofmann for
breaking down the molecule by so-ca\led " exhaustive methylation ".
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
open-chain base (iii).






NCH 3
(i)



When this compound is again submitted to a similar series of reactions
and distilled, piperylene (iv), trimethylamine, and water are formed,



214 ORGANIC CHEMICAL SYNTHESIS

the reaction being analogous to the decomposition of tetraethyl-
ammonium hydroxide into triethylamine, ethylene, and water.



N(CH 3 ) 3 +H 2
CH




(C 2 H 6 ) 4 N OH -> C 2 H 4 + (C 2 H 5 ) 3 N + H 2 O

The introduction of an acid radicle, e.g. COOC 2 H 5 , COC 6 H 5 ,,
in place of a hydrogen atom attached to a cyclic nitrogen atom, renders
the compound readily oxidizable. This has already been illustrated
in the case of benzoylpiperidine (p. 151).

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 benzo-
nitrile and i : 5-dichloropentane:



C 6 H 5 CN





C1H 2 C CH 2 C1
N-COC R H B

D



More recently the 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. It is a remarkable fact that by far the greater number of
alkaloids contain one or more methoxyl groups (OCH 3 ). The
method employed for the estimation of these groups called the
Zeisel method depends on the fact that all substances containing
methoxyl groups are decomposed by hydriodic acid, yielding methyl-
iodide 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.



THE PYRROLE ALKALOIDS 215

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

THE PYRROLE ALKALOIDS

The 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 and a tertiary base containing a N-methyl group. On
oxidation it yields hygric acid, which on dry distillation decomposes
into carbon dioxide and N-methylpyrrolidine. A possible structure
of hygric acid is therefore



H 2 C
H C



CH



CH-COOH



NCH 3



Hygric acid

and this structure has been established by its synthesis by the action
of methylamine on aS-dibromopropylmalonic ester,

[CH 2 Br - CH 2 - CH 2 CBr(COOC 2 H 5 ) 2 ]

by Willstatter 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 H 2 C - CHCH 3 HC - CH OMgBr

II II \/ II II I

HC C-MgBr + O - HC - C-CH 2 -CH.CH 3

\/ \/

NH NH

HC - CH OH
-> HC C-CH 2 -CH.CH 3



NH
Hydroxypropylpyrrole

On reduction the corresponding pyrrolidine compound is ob-
tained. The latter is then methylated by the action of formaldehyde,

* Ann., 1901, 326, 91. t Ber., 1913, 46, 4104.



216 ORGANIC CHEMICAL SYNTHESIS

which at the same time oxidizes the carbinol group to the ketone and
gives y-hygrine:

H 2 C - CH 2

H 2 C - CH CH 2 CH(OH) CH 3 + CH 2 O



NH

Hydroxypropylpyrrolidine

H 2 C - CH 2

= H 2 C CH CH 2 COCH 3 + H 2 O

\/
NCH

* r-Hygrine

Betonicine and Turicine are respectively the laevo and
dextro varieties of a base of the formula C 7 H 13 O 3 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
oxyproline (p. 145), so that they probably have the constitution:

HO-CH-CH 2

CH 2 CH-CO

\/ I

N O



CH 3 CH 3

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 2 CH COOH



N - CH 3
4-Hydroxyhygric acid

Stachydrine, C 7 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.
J Ibid., 1913, 85, 217. Trans., 1919, 115, 923.

|| Zeit. physiol. Chem., 1909, 59, 233.



THE PYRIDINE ALKALOIDS 217

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

CH.2 ri2C CH-2

3



H 2 C CH -


CO


H 2 C CH-COOCH 3


H 2 C CH-(


\x

N


.4 -


N


N-I

S\


CHs CHs

^




CH 3


/\

CH 3 CHa



(i) (ii) (iii)

THE PYRIDINE ALKALOIDS

Trigonelline, piperine, conine, and nicotine may be considered
as four of the simpler pyridine alkaloids.

Trigonelline, C 7 H 7 O 2 N, was isolated from the seeds of
fenugreek (Trigonella fcenum grcecum) by Jahns in 1885, and two
years later he established its constitution by observing that when
heated with hydrochloric acid to 270 it is converted into nicotinic
acid. The natural product was found to be identical with the
*' methylbetai'ne " of nicotinic acid previously synthesized by
Hantzsch.f




CH 3
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
first isolated by Oersted in 1819. It is a tasteless, colourless, weak
base, and has no action on polarized light. On hydrolysis with
alcoholic potash it is converted into piperidine and piperic acid:

C 17 H 19 3 N + H 2 = CaHuN + C 12 H 10 O 4

Piperidine Piperic acid

and as Riigheimer J showed that piperic chloride reacts with piperidine

* Trier, Zeit. physiol. Chem., 1910, 67, 324.

f Ber., 1886, 19, 31. t Ber., 1852, 15, 1390.



218 ORGANIC CHEMICAL SYNTHESIS

to give piperine, the alkaloid may be regarded as an amide of piperic
acid.

Piperidine was obtained by Ladenburg * by distilling the hydro-
chloride of pentamethylene-diamine, which in turn may be obtained
from trimethylene-dibromide:

CH 2 Br CH 2 CN CH 2 CH 2 - NH 2 CH 2 - CH 2

CH 2 -> CH 2 -> CH 2 -> CH 2 NH

III II

CH 2 Br CH 2 CN CH 2 CH 2 NH 2 CH 2 - CH 2

Piperic acid was investigated by 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 structure of piperine is therefore represented by the
formula:




CH



2




CH

a5; oc A CH

^O Cl JC CH:CH-CH'-CH-CO

CH

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. Conine

* Ber., 1885, 18, 2956, 3100. t Ber., 1894, 27, 2958.



THE PYRIDINE ALKALOIDS



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
pyridine propiodide and obtained a mixture of bases, one of which
appeared to be y-propylpyridine, since on oxidation it gave pyridine-
y-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
conine, but neither was identical with it. In 1886 Ladenburg
condensed picoline (a - methylpyridine) with paracetaldehyde in
sealed tubes with the aid of zinc chloride and obtained allyl-
pyridine. On reduction with sodium and alcohol r-conine was
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 2 C \ 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 com-
plete reduction gave r- conine.




^/ CO - C 2 H 5

N

oc-Ethylpyridyl-
ketone




a-Ethylpyridyl-
alkamine



r-Conine



Ber., 1891, 24, 2530; 1894, 27, 1775.



22O



ORGANIC CHEMICAL SYNTHESIS



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
recently Pictet and Rotschy * and others have shown that several
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 methio-
dides with methyliodide it is also a ditertiary base. On oxidation
with chromic acid, nicotinic acid (pyridine-j8-carboxylic acid) is
obtained, so that nicotine is a j8 derivative of pyridine.






N




Pinner first put forward the correct con-
stitutional formula for nicotine (jS-pyridyl-a-
N-methylpyrrolidine), and the correctness of
his view was confirmed by the synthesis of
nicotine by Pictet, Crepieux, and Rotschy. f




CIL



CH,



NCH,



Nicotine



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 4 CH : CH

I ~> I

CHOH CHOH - COONH 4 CH : CH



NH + NH 3



aCO 2



On 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):




N



N
(0

* Ber., 1901,34,696.




t Ber., 1895, 28, 1904; 1904, 37, 2018.



THE TROPANE GROUP 221

The potassium salt of the latter reacts with methyliodide to give
the methiodide of N-methyl-a/?-pyridylpyrrole (iii), which gives
nicotyrine (iv) on distillation over lime:

HC-



HC CH H P-~9 H

all! x\ I
C CH / \ C CH




NCH 3 ^ N-CH 3

"I

(iii) (iv)

The selective reduction of the pyrrole nucleus could not be accom-
plished 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
yields /-nicotine on similar reduction. The alkaloid was resolved
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
their chemical properties and constitution closely resemble one
another. These plants are the belladonna (Atropa belladonna), the
henbane (Hyoscyamus niger), the common stramonium (Datura
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 estab-
lished: atropine, hyoscyamine, pseudohyoscyamine, and hyoscine,
which are all isomers of the formula C 17 H 33 NO 3 ; belladonnine,,
C 17 H 21 NO 2 , and scopolamine (atroscine), C 17 H 21 NO 2 , about which
little is known.

Of these 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.

Atropine and its Allies. 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.



222 ORGANIC CHEMICAL SYNTHESIS

On hydrolysis with acid or alkali it yields an acid tropic acid
and a base tropine.

. Tropic Acid. The correct constitutional formula for tropic
acid was derived by Kraut, and a successful synthesis first achieved
by Ladenburg and Riigheimer in 1880.* 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
pressure, atropic acid (iv). On treatment with ethereal hydro-
chloric acid the chloro acid (v) is obtained, which gives tropic acid
(vi) on treatment with sodium carbonate solution:

CeH 5v C 6 H 5v /OH C 6 H 5x /OH C 6 H 5X

>CO -> >C< -> >C< -> >C-COOH

CH 3 ' CU/ \CN CH/ \COOH CUf

(i) (ii) (iii) (iv)

C 6 H 5 H C 6 H 5 H



C1CH 2 COOH HO-CHo COOH

(v) (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



2



<?H,



CH, CH-^CH



NCH, CHOH



NCH, CO



3



CH CH 2 CH 2 CH-f- CH 2

Tropine Tropinone

The 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, 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 223

and Robinson * has succeeded in obtaining tropinone by the con-
densation of these substances in aqueous solution. An improved
yield was obtained when the calcium salt of acetone-dicarboxylic.
acid 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.

CH 2 -CHO CH 2 - CHOH CH 2 COOCa'



NCH 3 + CO



+ NH 2 CH 3 ->

CH 2 -CHO CH 2 - CHOH CH 2 COOCa'

CH 2 - CH - CH COOCa' CH 2 - CH - CH 2

2 HC1



NCH, CO



CH,



JL>VJLi3 \-s\~/ X^V^lJLjj V^v-/

- CH - CH- COOCa' CH 2 - CH - CH



NCH 3 CO



Since hyoscyamine and atropine are stereoisomeric they may
be represented by the formula:

CH 2 CH CH 2 CgHs

NCH 3 CH-O.CO-CH

CH 2 - CH - CH 2 CH 2 OH

According to Gadamer f the tropine in both atropine and hyoscy-
amine 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 relationship between tropinone and several closely allied
alkaloids may be briefly summarized:

Electrolytic Sodium and

reduction carbon dioxide



Tropine < Tropinone > Tropine carboxylic acid



With tropic acid j, ^^ I Reduction

Atropine Pseudotropine r-Ecgonine

^ Benzoylation 4,

Tropacocaihe r-Cocaihe

When tropine is heated with sodium amyloxide it is converted
into a tropine identical with the pseudotropine obtained by the

* Tram., 1917, 111, 762. t Arch. d. Pharm., 1902, 239, 294.



224 ORGANIC CHEMICAL SYNTHESIS

hydrolysis of the coca alkaloid tropacocai'ne. Tropine and pseudo-
tropine are thus isomeric, and Barrowcliff and Tutin * have shown
rtiat the isomerism is dependent on molecular asymmetry, i.e. it is
cistrans isomerism.

Cocaine and some Synthetic Substitutes. Cocaine, along
with several closely related alkaloids, occurs in coca leaves (Ery-
throxylon 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 it yields ecgonine,
benzoic acid, and methylalcohol:

C 17 H 21 N0 4 + aH 2 = C 9 H 15 NO 3 + C 7 H 6 O 2 + CH 3 OH

The preparation of ecgonine from tropinone has already been men-
tioned, and the relation of the former to cocaine is made clear by the
formulae,

CH 2 - CH - CH COOH CH 2 - CH - CH COOCH 3

NCH 3 CHOH NCH 3 CH O - CO C 6 H 5

CH 2 - CH - CH 2 CH 2 - CH - CH 2

Ecgonine Cocaine

On account of the fact that cocaine solutions become mouldy
on long standing and decompose on boiling, various attempts have
been made to prepare suitable substitutes. The benzoyl derivative
of pseudotropine is known as tropacocctine. It is a stronger local
anaesthetic, less toxic and more resistant to micro-organisms than
cocaine.

In 1897 Merling obtained triacetonamine (i) by the condensation
of three molecules of acetone with one of ammonia. It is a crystalline
solid 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:

(CH 3 ) 2 C - CH 2 (CH 3 ) 2 C CH 2

<*CH COCH II II /O-CO-C 6 H 5

3 2 NH -* NH CO - NCH 3 C<

+ NH * II | |\X).OCH 3

(CH 3 ) 2 C - CH 2 (CH 3 ) 2 C CH 2

(i)
* Trans., 1909, 95, 1966.



THE TROPANE GROUP 225

On account of the irritant action of a-eucaine it has been largely
superseded by fi-eucaine. Diacetonamine (i) is obtained by the
condensation of two molecules of acetone and one of ammonia,
and this on further condensation with acetaldehyde gives vinyldia-
cetamine (ii):

(CH 3 ) 2 C[0 - j _^ (CH 3 ) 2 C-CH 1 ^ HsCHO (CH 3 ) 2 C-CH 3

H 2 N!H+H;CH 2 COCH 3 NH. CO NH CO

I ; I I I

CH 3 CH S -CH-CH 2

(') (ii)

On reduction to the corresponding alcohol, two isomerides are
obtained. The higher melting isomeride on benzoylation gives
p-eucaine:

(CH 3 ) 2 C CH 2

NH CHO CO C 6 H 5

CH 3 CH-CH 2
p-Eucaine

Stovaine is a well-known local anaesthetic for minor surgical
operations. It is prepared from dimethylaminoacetone as follows:

CH 3 CH 3 OH

MgC 2 H 5 Br \ p /



(CH 3 ) 2 NCH 2 (CH 3 ) 2 NCH 2 C 2 H 6

CH 3 0-COC 6 H 5
C 6 H 5 COC1 \ c< /

HC1(CH 3 ) 2 -N-CH 2 C 2 H 5

Alypine is similar in constitution to stovaine and is frequently
administered along with heroin (diacetyl-morphine), since it en-
hances the demulcent and sedative effects of the latter:

CH 2 - N(CH 3 > 2
C 2 H 5 C - O - COCH 5

CH 2 - N(CH 3 ) 2
Alypine

Anaesthesine, one of the simplest local anaesthetics, is obtained

(D331) 1501



226 ORGANIC CHEMICAL SYNTHESIS

by reducing ethyl-/>-nitrobenzoate with tin and hydrochloric acid.
Its diethylamino derivative is known as novacame*

H 2 N/ \COOC, H 5 H 2 N/ \COO

Anaesthesine Novacame



THE POMEGRANATE ALKALOIDS

The root bark of the pomegranate contains a number of alkaloids,
amongst which pelletierine and theisomeric^opelletierine, C 8 H 15 NO,
/tfWflfopelletierine, C 9 H 15 NO, and the two isomeric methylpelle-
tierines, C 9 H 17 NO, may be mentioned. Pseudoptlletierme is
interesting because it resembles tropinone and gives rise to an eight-
carbon ring on exhaustive methylation. It has been shown that this
alkaloid is a higher homologue of tropinone. The parent compound
is known as granatinine:

CH 2 - CH - CH 2 CH 2 - CH - CH 2

CH 2 - NCH 3 CO CH 2 NCH 3 CH 2

CH 2 - CH - CH 2 CH 2 - 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



227



CH 3




NH CH 3

Harmiae



CH



CH 3




NH C-CH,



NH CH-CH,



Harinaline



By 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 3

Harman




Norharman
(4-carboline)



Norharman may therefore be regarded as the parent of these com-
pounds, and it will be observed that it contains a fused benzene-
pyrrole-pyridine nucleus.* Harman has been obtained by the oxida-
tion 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 (Trans., 1919, 115, 970) suggest the name " carboline "
for this structure, indicating an analogy both to carbazole and quinoline.




11



4JN



12



Thus harmine is ii-methoxy-3-methyl-4-carboline.

t,7. PhysioL, 1903, 29, 451. J Chem. Zeit. y 1919, 43, 555.

Trans., 1921, 119, 1602.

( D 331 )



15 a2



228



ORGANIC CHEMICAL SYNTHESIS



synthesis of the latter compound. For this purpose i-methylindole-
2-carboxylic acid (i) is converted by the condensation of its chloride
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 2 CH(OC 2 H 5 )





Norharman also results from the condensation of tryptophane with
formaldehyde in the presence of sulphuric acid followed by oxidation
of the product:




NH




CfljCH (NH 2 )COOH



NH CH n



NH



THE ISOQUINOLINE ALKALOIDS

The alkaloids of this group comprise the opium alkaloids papa-
verine, 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 con-
sidered: papaverine, laudanosine, and hydrastine.

Papaverine. This alkaloid was first isolated from commercial



THE ISOQUINOLINE ALKALOIDS 229

narcotine by Merck in 1848, and it has attracted the attention of a
considerable number of chemists.

Papaverine is a tertiary base and is 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/ /S V X N CH^/NcOOH HOOCr^^N





CH 3 Ok X ;N

Dimethoxy- m-Hemipinic Cinchomeronic

isoquinoline acid acid

The product containing no nitrogen is dimethyl-homocatechol,
since it gives dimethyl-protocatechuic acid on oxidation:

COOH





OCH 3 \yOCH 3

OCH 3 OCH 8

Dimethyl- Protocatechuic
homocatechol acid



Papaverine is represented by the formula,

CH 3 Of
CH 3



OCH 3



OCH 3

Papaverine




and the correctness of this structure has been confirmed by the
complete synthesis by Pictet and Gams.* The steps in this syn-
thesis may be briefly represented as follows:

* C. r., 1909, 149, 210; Ber., 1909, 42, 2943.



230



ORGANIC CHEMICAL SYNTHESIS



Vanillin
(CH 3 0)(OH)C 6 H 3 CHO

I

Methylvanillin
(CH 3 0) 2 C 6 H 3 CHO

I

Isoethoxy-mandelonitrile
(CH 3 O) 2 C 6 H 3 CH(OH)CN

4

Homoprotocatechuic acid
(HO) 2 C.H 3 CH 2 COOH

I

Homoveratroyl chloride
(CH 3 O) 2 C 6 H 3 CH 2 COCi



Veratrol
(CH 3 0) 2 C 6 H 4

I

Acetoveratrone
(CH 3 0) 2 C 6 H 3 CO CH 3

I

Isonitroso-acetoveratrone
(CH 3 O) 2 C 6 H 3 CO CH : NOH

*

Amino-acetoveratrone hydrochloride^

(CH 3 0) 2 -C 6 H 3 .CO-CH 2 -NH 2 , HC1



Homoveratroyl-aminoacetoveratrone
(CH 3 O) 2 C 6 H 3 CH 2 CO NH CH 2 CO C 6 H 3 (OCH 3 ) 2

4

Honioveratroyl-hydroxy-homoveratryamine
(CH 3 0) 2 C 9 H 3 CH 2 CO NH CH 2 CH(OH) C 6 H 3 . (OCH 3 ) 2

I

Papaverine
(CH 3 O) 2 C 6 H 3 CH 2 C : N CH : CH CH 2 (OCH 3 ) 2



Laudanosine. This alkaloid was first isolated by Hesse in
1871, and it has the empirical formula C 21 H 27 NO 4 . The following
structural formula shows that it is closely related to papaverine:

CH



CH 3




OCH



OCH



Laudanosine



Pictet and his co-workers have synthesized laudanosine by con-
densing homoveratrylamine with homoveratroyl chloride and then



THE ISOQUINOLINE ALKALOIDS



231



reducing the papaverine methochloride to methyltetrahydropapa-
verine. On resolution of the inactive synthetic alkaloid the dextro
form was found to be identical with the natural product.

Hydrastine. The root of the golden seal (Hydrastis cana-
densis) and the common barberry both contain hydrastine. It was
first obtained in a pure condition by Perrius in 1862, and it has
the empirical formula C 21 H 21 NO 6 . On oxidation with potassium
permanganate in acid solution it is converted into meta-opianic acid
and hydrastinine,

C 21 H 21 NO tf + H 2 + O - C 10 H 10 5 + C U H 13 NO 3

Opianic acid Hydrastinine

Opianic acid or 5 : 6-dimethoxy-o-phthalaldehydic acid has the
constitution:

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 5 }



52



CH(OC 2 H 5 )



52



CH



NH



CHO




^N

CH CH

Methylene-
dioxyisoquinoline



followed by the reduction of the methiodide of this compound,



CH,




CH 2

o^Y^l

H,C<[ T



CH 2

Dihydrohydrastinine



>"\/k NHCH 3

CHO

Hydrastinine



According to Freund, dihydrohydrastinine may be converted into
hydrastinine by oxidation with potassium dichromate and sulphuric

acid.

* Ann., 1895, 286, i.



232 ORGANIC CHEMICAL SYNTHESIS

More recently hydrastinine has been synthesized by Decker and
Becker.* Hydrastine has the constitution,

CH,

oX^V ^* 2

N-CH

CH^.CO
HC





Hydrastine



THE QUINOLINE ALKALOIDS

The Cinchona Alkaloids, Quinine and Cinchonine. Al-
though cinchona bark has been used as the source of the febrifuge,
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
may be represented by the formulae:

CH

CH 2 CH 2 CHR"



R'




CH(OH) CH CH 2 CH 2

N



N



R'.


R


/


H


CH:


CH 2


H


CH 2


CH 3


OCH 3


CH:


CH 2


OC 2 H 8


CH 2


CH 3



Alkaloids.



Cinchonine and cinchonidine.
Hydrocinchonine and hydrocinchonidine.
Quinine and quinidine.
Ethylhydrocupreine and ethylhydrocupreidine.



* Ann., 1913,395, 328.



THE QUINOLINE ALKALOIDS 233

Our knowledge of the constitution of these alkaloids is due to
the labours of 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 2 oH 24 N 2 O 2 C 19 H 22 N 2 O

Quinine Cinchonine

From a study of the oxidation products it is evident that each
alkaloid is divisible into two parts. On oxidation with chromic
acid and sulphuric acid, cinchonine yields cinchoninic acid and
quinine gives quinic acid. These acids are represented by the
formulae,

COOH COOH



,OCH,





N -N

Cinchoninic acid Quinic acid

so that the second half is probably identical in both alkaloids,

CH 15 (OH)N





N N

Cinchonine 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-
thetically in the immediate future. These researches cannot be
dealt with here, and the reader should consult the excellent sum-
maries 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



234 ORGANIC CHEMICAL SYNTHESIS

made to overcome the bitter taste and to obtain more soluble salts
suitable for hypodermic injection. The tannate has very little
taste, while esterification of the hydroxyl group with chloroformic
ester, or the conversion of quinine into saloquinine by means of
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 follow-
ing formula for strychnine:

CH CH 2 CH



HC




Brucine is the dimethoxy derivative, the two methoxyl groups
replacing the hydrogen atoms attached to the two asterisked
carbon atoms.

THE PHENANTHRENE ALKALOIDS

The Morphine Group. This group includes at least four
important alkaloids 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 NO 3
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.

Morphine is a tertiary base and contains two hydroxyl groups,
one of which is phenolic and the other alcoholic. On distilla-

t Trans., 1910, 97, 309.



THE PHENANTHRENE ALKALOIDS



2 35



tion over zinc dust it gives phenanthrene, pyrrole, pyridine, tri-
methylamine, and ammonia. Our knowledge of the structure
of the morphine molecule is largely due to the investigations of
Vongerichten, Knorr, and Pschorr. The following provisional
formula has been assigned to morphine by Pschorr:



CH 2
NCH,




CH
Morphine



Pseudomorphine is a non-poisonous compound which may
be readily prepared from morphine by oxidation. Its structure is
unknown.

Thebaine was discovered in opium by Thiboumery in 1835.
Our present knowledge of its structure is mainly due to Freund, and
the following formulae show that it is related to morphine in so far
as both hydroxyl groups are methylated; but it contains two atoms
of hydrogen fewer than morphine:



(C 16 H 14 ONCH 3 )(OH) 2
Morphine



(C 16 H 12 ONCH 3 )(OCH 3 ) 2
Thebaine



Pschorr f has suggested the following formula for thebai'ne:



CH CH 2



CH 3 OC




CH a
NCH,



CH 3 OC



Ber., 1907, 40, 1980.



Loc. cit.



236 ORGANIC CHEMICAL SYNTHESIS

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

Gadamer f suggests that the primary products of assimilation
are the 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 may be used in
the formation of proteins.

Pictet J imagines that alkaloids are produced in the plant in two
successive stages, involving (i) the breakdown of complex nitro-
genous substances, such as protein or chlorophyll, with the pro-
duction 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 2 O = R OCH 3 + O
R NH 2 + CH 2 O - R NHCH 3 + O

the resulting methylated compounds being then able to undergo
intramolecular transformation, by which the methyl group can

* See also Chapter I. f Ber. Deut. pharm. Ges., 1914, 24, 35.

r.> 1907,40,3771.



PHYTOCHEMICAL SYNTHESIS OF ALKALOIDS 237

enter the ring and so produce, for example, a pyridine ring from
methyl pyrrole,

CH



CH-CH CH-CH CH CH

II II II II II I

CH CH ~> CH CH -* CH CH



NH NCH 3 N

Pyrrole 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 NCH 3

Pyrrolidine 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 it supplies as its oxidation product,
acetone dicarboxylic acid. Further, a reactive acetone derivative
may be found in diacetylacetone or other polyketens.f One or two
of the applications of these suggestions may be briefly considered.

It has already been noted (p. 216) that when formaldehyde is
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 2 - [CH 2 ] 3 CH(NH 2 )COOH + CH 2 O
Ornithine



= NH(CH 3 )[CH 2 ] 3 CHO



CH 2 - CH(OH)



CH



3



NH 3 + C0 2



_ CH 2 - CH 2
1 Trans., 1917, 111, 762, 876. f Collie, Trans., 1893, 63, 329; 1907,91, 1806,



2 3 8



ORGANIC CHEMICAL SYNTHESIS



Further oxidation accompanying methylation might attack both ends
of the molecule to give succindialdehyde and methylamine:



NH 2 [CH 2 ] 3 CH(NH 2 )COOH + aCH 2 O



- OCH-CHo-CHo-CHO



CH 2 - CH(OH)

I )>NCH 3

CH 2 - CH(OH)



+aCH 3 NH 2 +C0 2



After condensation with acetone dicarboxylic acid and elimination of
carbon dioxide, hygrine (i), cuschygrine (ii), and tropinone (p. 222)
are obtained:



NCH 3 COOH

HG/\CHOH]



H 2 C



H 2 C



+ CH^CO -CH^COOH 2
CH, H 2 C



NCH 3 COOH
H.C/\



CH-CH-CO-CH 2 COOH 2



NCH 3
H.C/\ CH- CH COCH,



H 2 C



CH



(0



NCH



H 2 C



NCH 3 COOH COOH NCH 3 NCH 3

XXcHOH I I HOCH/\CH 2 H,cX\CH-CH-CO-CHiHcX\CH 2

| I +CH 4 CO-CH 4- f ] LV | j 3 i]

pj (-L 'CH H c^"*'



2 2



(ii)



The condensation product which forms the source of these alkaloids
may 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.
Ackermann, 188.
Aldrich, 175.
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.

Bergmann, 68, 78.

Bertrand, 44.

Biot, 42.

Bourquelot, 69.

Braconnot, 142, 148.

Braun, v., 151, 214.

Bredt, 132.

Brieger, 170, 182.

Butlerow, 42.

Chevreul, 95.

Ciamician and Silber, 1 1 1 .

Claisen, 23, 32.

Clewer, 216.

Cole, 1 60.

Collas, 138.

Collie, 24.

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.

Dumas, 42.

Dunstan, 182.

Ehrlich, 148.

Ellinger, 160.

Engeland, 188.

Erlenmeyer, senr., 2.

Erlenmeyer, junr., 147, 154.

Erlenmeyer and Lipp, 155, 156.

Everest, 37.

Ewart, 2.

Ewins, 185.

Ewins and Laidlow, 174, 181.



Fischer, Emil, amino acids, 142; glucosides, 67;
glycerides, 97; 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.

and Andrae, 62.

and Armstrong, 48.

and Bergmann, 68.

and Freudenberg, 90, 91, 92.

and Helferich, 208.

and Leuchs, 63.

and Schmitze, 146.

and Tafel, 44, 49.

and Zachs, 63.

and 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.

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.
Heilbron, 6, 9, n.
Herzig, 30.
Hess, 78, 215.
Hoesch, 89, 90.
Hofmann, 212, 213, 219.
Hoogewerf and v. Dorp, 212.
Hopkins, 160, 169, 208.

and Cole, 160.
Horbaczewski, 202.
Hudson, 44,

Irvine, 61, 66, 70, 79, 81, 97.

Fyfe and Hogg, 58.

and Hynd, 63.

and Rose, 66.
Isay, 200.

Jacobs. See Levenne.
Jahns, 217.



239



240



ORGANIC CHEMICAL SYNTHESIS



Jdrgensen, 3.
Jowett, 175.

Kelber, 100.

Kermack, 227.

JKiliani, 42, 45.

Kirchoff, 42.

Klepl, 86.

Knoop and Windaus, 161, 179.

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.

Lapworth, 98.

Lederhouse, 62.

Leuchs, 63, 153.

Levenne and Jacobs, 191.

Lewis, 84.

Liddle, 196.

Liebermann, 215.

Liebig, 42, 142, 186, 190, 195, 202, 212, 219-

Liebrich, 184.

Loew, 42.

Ldwe, 84.

Lowry, 60.

Macbeth., 67.
Macdonald, 81.
M'Kenzie and Wood, 222.
Maquenne, 178.
Marchlewski, 13, 19.
Medicus, 201.
Merck, 229.
Merling, 224.
Michael, 67.
Moore, 7, 8, o.
Miiller, 28.

Nagai, 176.

Nencki, 19.

Neuberg, 46, 102, 103, 189.

Neumann, 224.

Nierenstein, 93.

Oddo, 182.

Oliver and Schafer, 175.

Osborne, 163.

Pasteur, 55.
Pelletier, 13, 232.
Perkin, A. G., ji, 32.

Perkin, junr., W. H., 106, 115,122, 125, 128,138,
226, 227-

and 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.

Purdie ana Irvine, 61.

Pyman, 161, 181.

and Fargher, 178, 179, 181.

Rabe, 233.



Reinke, 2.

Renshaw, 185.

Robinson and Perkin, 39, 152, 223, 237.

Rosenheim, 105.

Rosenmund 174.

Rotschy, 220.

Rouelle. 148.

Ruff, 46.

Riigheimer, 222.

Ruhemann, 27.

Runge, 212.

Ruzicka, 126.

Salkowski, E. and H., 188.

Sal way, 100.

Sasaki, 156.

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.

Tanret, ^9, 75-

Tattersall, 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.

Ullmann, 24.

Wager, 3.

Wagner, 106, 108, 135, 136,
Wallach, 106 et seq.
Walpole, 172, 173, 174.
Warner, 3.
Webster, 7, 9.
Weerman, 46.
Werner, 1 86.

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; chloro-
phyll, 13 et seq.; hygric acid, 215; proline, 157.

Willstatter and Benz, 14.

and Everest, 22, 33.

and M. Fischer > 21.

and Isler, 13.

and Opp, 15.

and Page, 20.

and Stoll, 3,4, 5, 15, 55, 56.

and Utzinger, 15.

and Zachmeister, 40.
Windaus. 99, 100, 179, 180.

and Knoop, 179.
Wohl, 45, 173-
Wonler, 190, 195, 202.
Woodhouse, 79.

Zeisel, 214.
Zemplen. 158.
Zlokasoft, 24.



INDEX OF SUBJECTS



Acetobromoglucose, 59.
a-Acrose, 49.
)3-Acrose, 49.
Adenine, 192, 199.
Adrenalin, 175.
/Etiophyllin, 17, 19.
/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.
Amino acids, 142.
Amino-ethyl-alcohol, 185.
Amorphous chlorophyll, 14.
Amygdalin, 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-

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.

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



Caryophyllin, 137.
Cellobiose, 72, 79.
Cellulose, 77.
Cerebrosides, 105.
Cheiidonic acid, 23.
Chinese tannin, 84.
Chitose, 63.
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, 113.
Cocaine 223, 224.
Codeine, 234.
Co-enzyme, 56.
Conine, 12, 219.
Creatine, 186.
Creatinine, 186.
Crystalline chlorophyll, 14.
Cyanhydrin reaction, 45.
Cysteine, 144, 154.
Cystine, 145, 154.
Cytosine, 192, 193, 197, 200.

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.
Dipentene, 144.
Disaccharoses, 43, 69.

Ecgonine, 223, 224.
Emulsin, 57, 64.
Enzymes, 55, 65.
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, 2 et seq. t 42, 236.

Formhydroxamic acid, 8, 9.

Formose, 42.



242



ORGANIC CHEMICAL SYNTHESIS



Fructose, 44, 47, 50.
Fucoxanthin, 20.
Fusel oil, 149.

/3alactose, 44, 55
XJalangm, 26, 32.
Gallotannin, oo.
Gentianose, 75.
Gentibiose, 74.
Geranic acid, 112.
Geraniol, up, 112.
Glaucophyilin, 17.
Glucoheptose, 45.
Gluconic acid, 45, 48, 50.
Gluconic lactone, 40.
Glucononose, 45.
Gluco-octpse, 45.
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.
Guanidine, 186.
Guanine, 192. 199.
Guanylic acid, 192.
Gulose, 55.
Gums, 77.

Hsematirtj 21.^

Haematimc acid, 21.

Hsemin > 20.

Haemocyanine, 14.

Haemoglobin, 142.

Harmalin, 226.

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.



Isoeugenol, 139.
Isoleucine, 144, 147, 148, 173.
Isopelletierine, 226.
Isopulegol, 124.
Isopulegone, 124.
Isoquinoline alkaloids, 228.
Isorhamnitin, 31.

Japan camphor. See Camphor.

Kaempherol, 26, 32.
Kephalin, 185.

Lactose, 72.
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.

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.
Menthone, in.
Methylamine, ii 172.
Methylanthranilate, 139.
Methylenitan, 42.
Methylglucosides, 43, 57.
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.

Natural glucosides, 64.
Neurine, 18^.
Nicotinic acid, 220.
Nicotyrin, 221.
Nitrpso terpenes, 108.
Nopinone, 131.
Norharman, 211, 227.
Norpinic acid, 129, 130.
Nucleic acids, 208.
Nucleosides, 208, 209.
Nucleotides, 208, 209, 210.

Oenin, 37.

Olefinic terpenes, 108, 109.

Opium, 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



2 43



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.
Pinonic acid, 129, 130.
Pinoyl formic acid, 129, 130.
Piperic acid, 218.
Piperidine, 217.
Piperine, 217.
Polypeptides, 164.
Polysaccharoses, 43, 77.
Proline, 145, 157-
Proteins, 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.

Quercitin, 26, 30.
Quinic acid, 233.
Quinine, 232.

Rafinose, 73, 74.
Rhamnazin, 31,
Rhamninose, 45.
Rhamnitin, 26, 31.
Rhamnoheptose, 45.
Rhamnohexose, 45.
Rhamno-octose, 45.
Rhodinal, in, 112, 114.

Sabina ketone, 118.
Saoinane, 109.
Sabinene, 126.
Salicin, 66.
Sambunigrin, 66, 68.
Scatole, 139.
Sorbose bacterium, 44
Stachydrin, 216.



Stachyose, 76.
Starch, 77, 81.
Sterols, 99.
Stovaine, 225.
Strychnine, 234.
Sucrose, 70.
Sylvestrene, 118.

Talose, 55.
Tannins, 84.
Terebic acid, 131.
Terpenes, 106.
Terpenylic acid, 130.
Terpin, no, 116.
Terpineol, no, 116.
Terpinolene, 117.
Tetrasaccharoses, 76.
Thcbaine, 235.
Theobromine, 199, 204.
Thujene, 127.

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.

Uracil, 192, 193, 195, 196.

Uramil, 192, 194.

Uric acid, 198, 201, 202.

Vanillin, 138, 139.
Veronal, 194.
Violuric acid, 192, 194.

Waxes, 95, 99.
Wintergreen oil, 138.

Xanthine, 24.
Xanthone, 24.
Xanthophyll, 14, 20.
Xylose, 44.

*

Zeisel's method, 214.
Zingiberine, 137.
Zymase, 56.



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