Chemical Basbvbms of Pharmacology an Introduction to Pharmacodynamics 1000160027 (1)

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THE CHEMICAL

BASIS OF PHARMACOLOGY

AN INTRODUCTION TO

PHARMACODYNAMICS BASED ON THE

STUDY OF THE CARBON COMPOUNDS

BY

FRANCIS FRANCIS, D.Sc., PH.D.

PROFESSOB OF CHEMISTRY, UKIVERSITY COLLEGE, BRISTOL

AND

J. M. FORTESCUE-BRICKDALE, M.A., M.D.(OxoN)

PHYSICIAN, BRISTOL ROYAL HOSPITAL FOR SICK CHILDREN

MEDICAL REGISTRAR, BRISTOL ROYAL INFIRMARY

DEMONSTRATOR OF PHYSIOLOGY, UNIVERSITY COLLEGE, BRISTOL

LONDON

EDWARD ARNOLD

1908

[AllMights Reserved]

' Did we know the mechanical affections of the particles of

rhubarb, hemlock, opium, and a man, as a watchmaker does

those of a watch, whereby it performs its operations, and of

a file, which by rubbing on them will alter the figure of any

of the wheels, we should be able to tell beforehand that

rhubarb will purge, hemlock Ml, and opium make a man

sleep; as well as a watchmaker can that a little piece of paper

laid on the balance will keep the watch from going till it be

removed; or that, some small part of it being rubbed by

a file, the machine would quite lose its motion and the watch

go no more.'

LOCKE, Human Understanding:

Book IV, chap, iii," 25.

359279

PREFACE:

IN writing the present volume the authors had no intention

of adding one more to the many existing textbooks, either of

Organic Chemistry or of Pharmacology. While they hope that

the purport of their work has been indicated succinctly but with

sufficient clearness in the title,they desire to say somewhat more

by way of preface which shall serve to introduce their readers

not to the subject but to the book.

Since the publication of Sir T. Lauder Brunton's Croonian

Lectures, which were delivered in 1889, no book has appeared

in the English language, so far as the authors are aware, dealing

with the relationshipsbetween the chemical structure and physio-logical

action of drugs ; though in the Textbook of Pharmacology

and Therapeutics (1901),edited by Dr. Hale White, there is a

short but admirable chapter on this subject by Dr. F. Gowland

Hopkins, F.R.S., of Cambridge.

It therefore seemed possiblethat some use might be found for

a book which should lay before English readers an outline of the

subject as at present understood. The book has been planned as

far as possible on chemical lines,as will be seen by a reference

to the headings of the chapters ; occasionally,however, it has

been found necessary to group together bodies which are of

similar physiological action but of no close chemical relationship,

as in chapters viii and xv. On the whole, however, the arrange-ment

of the subject-matter is on lines resembling those found in

works on organic chemistry, and so much of general chemical

theory has been introduced as will suffice to render this portion

of the subject clear to those who have not recently studied it.

The authors feel,indeed, that some modifications might be intro-duced

into the teaching of this subject to Medical Students,

vi PREFACE

which would enable them to realize its connexion with the

present day Pharmacology. It is,however, in the teachingof

Materia Medica that the authors would wish to see the most

radical changes introduced. This subject is placed before

Medical Students as if,on becoming qualified,their first dutywould be to go out and gathersimpleson the mountain-side ;

whereas in actual fact,what they have to do is to gauge the

relative merits or demerits of a host of syntheticremedies,the* literature ' of which is so plenteouslyshowered upon them as

soon as their names and addresses appear in the Medical Direc-tory.

The recognitionof crude drugsand the tests for purityin

preparedproductsare certainlyno longernecessary knowledge

for a doctor ; and of the numerous preparationswhich the student

commits wearilyto memory for examination purposes, only a

very small proportion are remembered and used in actual

practice.

It is hoped that in some small degreethe presentwork may

pointthe way to reform,and that meanwhile as an introduction

to a rational appreciationof one aspectof Pharmacology it may

be of use both to the student, and to the practitionerwho is

dailybrought in contact with the claims of new drugs,new

preparations,and new Trade-Names. The index will,it is

hoped,enable the book to be used to some extent as a work of

reference,in which may be found the prima facieevidence for

or againstclasses and individuals in the chemical materia

medica. Though clinical experienceis the only test of the

value of a drug,the probablephysiologicalaction may often be

fairlyaccuratelyestimated by a consideration of its chemical

structure ; and it seems highlyprobablethat a largenumber of

the syntheticremedies now on the market would never have

been introduced had medical men in generalbeen able to appre-ciate

how littlelikelihood there was of their provingsuperiorto

the older preparations.

To those who are engaged solelyin the study of organic

chemistry,it is hoped that this volume will serve as an intro-duction

to a particularlyfascinatingbranch of the applied

PREFACE vii

science. The authors would feel sincerelygratifiedshould their

work contribute,even to the smallest extent, towards the en-couragement

of the manufacture of synthetic drugs in this

country. This important industry,based as it is on the applica-tion

of such general scientific principlesas are discussed in the

present work, is dependent for its successful development on

economic and fiscal conditions ; it is to be hoped that the new

Excise regulationsas to the use of alcohol for manufacturing

purposes, and the recent alterations in the patent laws may

so favourably affect these conditions in Great Britain that it

may now be possible and profitableto produce synthetic drugs

at home on a scale largeenough to replacethe imported articles.

Whenever possible,the authors have consulted the original

papers dealing with the subjectin hand. They would here

express their indebtedness to the writings,among others, of

Lauder Brunton, Fraser, Crum Brown, Cash, Dunstan, Stock-man,

Dixon, Marshall, Schmiedeberg, Ehrlich, Emil Fischer,

Otto Fischer, Nencki, Einhorn, Loew, Hildebrandt, Hinsberg,

Heinz, Knorr and Filehne, I?aal, Baumann and Kast, v. Mer-

ing, Ladenberg, Sahli, Dujardin Beaumetz, .and Curci. Theywish particularly to acknowledge the assistance they have

received from the exhaustive treatise of S. Fraenkel, whose

Arzneimittelsyntheseillustrates the entire subjectwith a wealth

of example quiteunapproached in any other volume.

Finally, they would most sincerelythank their friend and

colleague,Dr. F. H. Edgeworth, Professor of Medicine at Uni-versity

College,Bristol,for much valuable advice and assistance

during the passage of the book through the press.

F. F.

J. M. F.-B.

UNIVEKSITY COLLEGE,

BKISTOL,

Jan. 1908,

CONTENTS

CHAPTER I

A. CHEMICAL INTRODUCTION

PAGES

Theory of Valency, Structural formulae, Isomerism, Inertia of Carbon

systems. Methods adopted for determination of constitutional

formulae.

V. ..... . . . f . .

1-13

B. GENERAL PHYSIOLOGICAL INTRODUCTION

Rational and Empiric methods of Therapeutics. Difficulties in

correlating chemical and physiological properties. Loew's theory of

poisons. General relationships between structure and action. Re-activity

of the drug and the bioplasm" . , . .

13-23

CHAPTER II

A. THE ALIPHATIC AND AROMATIC HYDROCARBONS

Their methods of preparation and properties. Methods used in the

synthesis of their derivatives. . . .... .

2^44

B. PHYSIOLOGICAL CHARACTERISTICS OF THE HYDROCARBONS

Effect on Physiological reactivity of the introduction of Methyl

or Ethyl groups, of un saturated condition of the molecule, and of

Isomeric and Stereoisomeric relationships, . . . .

45-54

CHAPTER III

CHANGES IN ORGANIC SUBSTANCES PRODUCED BY METABOLIC

PROCESSES

Syntheses " Sulphuric and Glycuronic acid derivatives, Compounds

of Amido-acetic acid, Urea. Sulphocyanides. Introduction of Acetyl

and Methyl radicals. Cystein derivatives. Processes of Oxidation

and Reduction 55-80

x CONTENTS

CHAPTER IV

THE ALCOHOLS AND THEIR DERIVATIVES

The Main Group of Anaesthetics and HypnoticsPAGES

I. General physiologicalaction of anaesthetics and hypnotics.Overton-MeyerTheory. Traube. Moore and Roaf on Chloroform.

Baglioni'stheory ["". . . .81-87

II. Methods of preparationand chemical and physiologicalpropertiesof the Alcohols. Esters of Halogen acids,Nitrous and Nitric,Sul-phurous

and Sulphuricacids. The Ethers. . . ,

' .'.

87-104

CHAPTER V

THE ALCOHOLS AND THEIR DERIVATIVES (CONTINUED)

The Oxidation productsof the Alcohols

The chemical and physiologicalcharacteristics of the Aldehydes,

Ketones, Sulphones,Acids. The derivatives of the Acids. Halogensubstitution products,Esters,Amides, Nitriles. Sulphurderivatives .

105-127

CHAPTER VI

AROMATIC HYDROXYL DERIVATIVES

Main Group of Aromatic Antiseptics

Chemical and physiologicalpropertiesof Phenols, Cresols,Di- and

Tri-oxybenzenes.Recent investigationsof the antisepticpower of

Phenol and itsderivatives,Creosote,Guaiacol,and their derivatives 128-148

CHAPTER VII

AROMATIC HYDROXYL DERIVATIVES (CONTINUED)

The Hydroxy Acids

Classification of Salicylicacid derivatives. Nencki's Salol Principle.Tannic and Gallic acids 149-160

CHAPTER VIII

ANTISEPTIC AND OTHER SUBSTANCES CONTAINING

IODINE AND SULPHUR

lodoform. Classificationof substances introduced in placeof lodoform

and the Alkali Iodides. Derivatives containingSulphur" Ichthyol 161-170

CONTENTS xi

CHAPTER IX

DERIVATIVES OP AMMONIA

The Main Group of SyntheticAntipyreticsPAGES

Chemical and physiologicalcharacter of Aliphaticand Aromatic

Amines. Aniline,Acetanilide and allied substances. Classification

and discussion ofâra-Amido-phenolderivatives ....171-197

CHAPTER X

THE MAIN GROUP OF SYNTHETIC ANTIPYRETICS (CONTINUED)

Hydrazineand its derivatives

Physiologicalaction of Phenylhydrazineand its derivatives. The

Pyrazolon group" Antipyrine,Pyramidon. General Summary of

Physiologicalcharacteristics of the Ammonia derivatives. .

198-212

CHAPTER XI

I. THE GROUP OF URETHANES, UREA AND UREIDES

Urethane. Hedonal. Hypnotics derived from Urea. Thio-urea.

Thiosinamine. Veronal hypnotics 213-220

II. THE PURINE GROUP AND PILOCARPINE

Diuretics and Cardiac tonics. Modification of substances of Xanthine

type. Diaphoretics.Pilocarpine 221-232

CHAPTER XII

THE ALKALOIDS

Chemical and physiologicalintroduction. Method of classification.

General principlesof Alkaloidal action. The Pyridinegroup" Coniine,

Nicotine,and allied substances 233-257

CHAPTER XIII

THE ALKALOIDS (CONTINUED)

Pyrrolidinegroup " Cocaine, Atropine, Hyoscyamine. Quinoline

group" Quinine,Cinchonine, and their substitutes. Strychnineand

Bmcine. .

258-283

xii CONTENTS

CHAPTER XIV

THE ALKALOIDS (CONTINUED)PAGES

iso-quinoline'group" Hydrastine, Cotarnine, Berberine. Morpholine (?)-

Phenanthrene group. Morphine, Codeine, and Opium Alkaloids "

Hordenine 284-303

CHAPTER XV

SYNTHETIC PRODUCTS WITH PHYSIOLOGICAL ACTION SIMILAR

TO COCAINE, ATROPINE, HYDRASTIS

Derivatives of Piperidine, Pyrrolidine, Amido- and Oxy-amido-

Benzoic acid, jpara-Amido-phenol, Guanidine, Tertiary Amyl-alcohol.

Halogen and other derivatives. Substitutes for Atropine and

Hydrastis,

304^319

CHAPTER XVI

THE GLUCOSIDES

Sinigrin, Sinalbin, Jalapin, Amygdalin, Coniferin, Phlorizin, Stro-

phanthin, Saponarin, "c. Purgatives derived from Anthraquinone.

320-330

CHAPTER XVII

DEPENDENCE OP TASTE AND ODOUR ON CHEMICAL CONSTITUTION."

ORGANIC DYES

I. Sternberg's views. Saccharin and its derivatives. Dulcin.

331-340

II. Odour. Physical and Chemical factors. Typical perfumes.

341-346

III. Organic dyes. Ehrlich's criticism of Loew's Theory of Poisons.

Picric acid, Aurantia, Chrysoidin, Bismarck brown, Methyl violet,

Methylene blue, Phosphine 347-355

APPENDIX. Curare action of Ammonium Bases, exceptions to general

rule. Action of Antipyrine derivatives. Hydroberberine. Influence of

Stereoisomerism on taste. Action of Rosaniline derivatives on Try-

panosomes 356-358

INDEX.

359-372

ERRATA

p. 4, line 3,for conine read coniine

p. 7, in formula for zso-butane omit Cl

line 18,for proteid read protein

p. 19, line 21, for central read cerebral

p. 21, line 6,for Kendrick read McKendrick

p. 27, line 7 from bottom, omit double

p. 39, in first formula for CH5 read CH3

p. 40, line 12 from bottom, for synthesis read syntheses

p. 42, line 11, for alkyl read halogen

p. 50, line 12 from bottom (acrolein),for CH : CH.COH read CH, : CH.COH

p. 52, in formula for bromtoluene/or- NO2 read CH3

p. 65, line 2, after to insert produce

CH" CH CH"CH

II I II II

p. 66, in first formula for CH C "c., read CH C "e.

Y Y

p. 71, line 18 from bottom, for CC13.CH2.CHO read CH3CHC1.CC13. CHO

p. 75, in formula for tyrosin/or OH2 read CH2

p. 77, formula for phenaceturic acid should be C6H5.CH2CO.NH.CH2.COOH

p. 79, line 10 from bottom, for CC13.CH2.CHO read CH3.CHC1.CC12CHO

line 6 from bottom, for /3-trichlorpropionicread trichlorbutyric

p. 90, in formula for ethyl nitrite for ON02 read ONO

p. 92, in formula for dimethyl-ethyl carbinol/or (C2H3) read (CH3)2

p. 104, line 9 from bottom, for (OC2H3)2 read (OCH3)a

p. 109, line 18,for CC13COH read CC1S.CH2OHline 21, for CC13

.CH2

.CHO read CH3CHC1CC12CHO

p. 112, last equation but one, for CaC03 read 2CaCO3

p. 113, second equation, add +H2O

p. 117, in formula for o-Xylene/or O read o

p. 119, last line,for acid read acids.

p. 123, last equation but one, for CH5COOC2H5 read CH8COOC3H5

p. 126, line 17,for Ferre read FerrS

in last formula C2H5 should in each case read CH3

p. 127, line 8,for alkyl read allyl

p. 131, line 2,for pinacol read guaiacol

line 9, in formula for hydroquinone/or C6H5 read C6H4

p. 142, first formula. C6H4.OCH3 should read C6H5OCH3

p. 144, in formula for p-acetamido-benzoyl -guaiacol for O.C6H4 read O.COC6H4

p. 149, line 14 from bottom, for C7H5 read C6H5

p. 156. The second resorcin derivative contains one molecule of resorcin and

two of salicylic acid and not as stated two molecules of resorcin and one of

salicylic acid.

(i)

(ii) ERRATA

p.174, sixth equation, add

+HaO after CH3NH2

p.181, formula for oxycarbanile should read C6H4

p.189, line 6 from bottom, for Propyl read Propionyl

p.200, last line, for ethyl ene-phenylhydrazine read ethylene-diphenylhydrazine

p.226, line 12, for Theophyllin and dioxypurin read Theophylline and dioxypurine

last formula, omit CH3 in position three

p.227, line 4 from bottom, for 1

:

6-dihydropurine read 6 dihydropurine

p.232, line 3, for glyoxolin read glyoxalin

p.308, in formula for triacetone-alkamine-carboxyl

p.

323, in formula for aceto-chlorhydrose/or (C3H30)4 read (CH80)4

THE

CHEMICAL BASIS OF PHARMACOLOGY

CHAPTEE I

A. CHEMICAL INTRODUCTION. Theory of Valency, Structural formulae,

Isomerism, Inertia of carbon systems. Methods adopted for determination

of constitutional formulae. B. GENERAL PHYSIOLOGICAL INTRODUCTION.

Rational and empiric methods of therapeutics. Difficulties in correlating

chemical and physiologicalproperties. Loew's theory of poisons. General

relationships between structure and action. Reactivity of the drug and the

bioplasm.

A. CHEMICAL INTRODUCTION.

Historical."

The commencement of a general Chemical Theory

was laid in 1811 by the enunciation of Avogadro's hypothesis,

which stated that equal volumes of gaseous substances, under

similar conditions of temperature and pressure, contain the same

number of molecules : and one of the most striking results of this

has been the rapid development of Organic Chemistry.

The synthesis of urea by Wohler, in 1828, was fatal to the

current theory of Vitalism, which supposed that organic substances

could alone be produced through the agency of life.

The researches of Berzelius, Liebig, Wohler, Gay Lussac,

Bunsen, and others, between 1830 and 1840, showed that many

atomic complexes could pass from compound to compound, behaving

in a manner similar to that of the individual atom. This theory of

Compound Radicals" groups of atoms which retained their existence

through various chemical changes "led to the realization of the

principlethat in organic reactions the rupture of the molecule

was always the least possible.

The investigationsof Laurent, Dumas, Gerhardt and Frankland,

between 1840 and 1860, led to the theory of valency, which has

played so important a part in the science of Organic Chemistry.

Theory of Valency. "The outcome of the molecular hypothesis

2 CHEMICAL INTRODUCTION

was the possibilityof assigningformulae to the followingsub-stances

:

Hydrochloricacid . . . .HC1

Water H2OAmmonia

.... ,. H3NMarsh gas . . . . . H4C

Since experiencehas shown that a singleatom of hydrogennevercombines with more than one atom of another element,it appears

that this substance possesses the facultyfor combination in as low

a degreeas any of the known elements ; a fact that is expressedin

the conceptionthat hydrogenhas only one power of combiningwith other atoms " one valency,graphicallyshown by one stroke.

Since oxygen combines with two atoms of hydrogenitsvalencyis

two, and for the same reason nitrogenis trivalent and carbon

tetravalent.

The examplesgiven are of course the simplestthat could be

taken,but they clearlyshow the varying powers of different

elements of unitingwith the same substance,hydrogen.Variation of Valency. " The questionif the valencyof an

element is constant or not, led to a long discussion. Kekule

and others regardedit as invariable as the atomic weightsthem-selves,

but the upholdersof this view were drawn into many

contradictions,of which the followingmay be taken as an example.Ammonia, NH3, combines with hydrochloricacid to form ammonium

chloride,NH4C1 ; since the valencyof hydrogenand chlorine are

the same, it follows that nitrogenfrom beingtrivalent in ammonia

has become pentavalentin ammonium chloride. Those who regarded

valencyas invariable had to look upon this latter substance as

a molecular compound of NH3 and HC1, and it was representedas

NH3 .HC1, and but littleattention was paidto the forcesthat kept

these halves together.Now various organicgroups may take the placeof hydrogenin

ammonia, it may be replaced,for instance,by the monovalent

radicals methyl (CH3)'or ethyl(C2H5)'.Now in the substance

triethylamine,N(C2H5)3,nitrogenis stilltrivalent,and the charac-teristic

propertiesof ammonia are stillpresent; it combines with

hydrochloricacid or methyl chloride,CH3 .Cl, and the resulting

compound N(C2H5)3CH3C1 should,accordingto the old hypothesisof the invariabilityof valency,be different from the substance

resultingfrom the addition of ethylchloride,C2H5C1,to methyl-

diethylamine,e.g. (CH3).N

. (C2H5)2. C2H6C1" but since these

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have been obtained byproceedingon such lineshave amply justifiedthe working hypothesis," for example,,the determination of the

structural formulae of indigoblue and eonrne, was soon followed bythe syntheticformation of these substances,and in the case of the

former,by itsproductionas an articleof commerce.

But the studyof OrganicChemistrycommences with the relativelysimpleinvestigationsof the changesproducedin hydrocarbons,the compoundsof carbon and hydrogen,by the entrance of certain

atoms or groups. Methane, CH4, on the replacementof one

hydrogenatom by chlorine givesmethylchloride,CH3C1,and the

characteristicsproducedby the entrance of the chlorine atom are

those that generallyfollow the replacementof hydrogenby that

element. When one hydrogen atom in water is replacedby an

organicradical such as methyl(CH3)',the simplestmember of the

group of alcoholsisproduced,CH3 .OH ; and again,the introduction

of the hydroxylgroup, (OH)',into methane,causes a number of

chemical,physical,and physiologicaldifferences,which are generallycharacteristicof the presence of that grouping.

The organicacids all contain the complex (COOH)', which

confers definite propertiesupon the hydrocarboninto which it

.enters.It isthe knowledgeof the characteristicsof such groups and

their combinations that is requiredto solve the difficultproblemof

determiningthe constitution of substances of unknown structure.

Isomerism. " But the questionis further complicatedby the

possibilityof differingarrangementsof the atoms in the molecule.

Supposingthe hydrocarbonethane,CH3 " CH3, isconsidered;itisat

once obvious that the hydrogenatoms are symmetricallyarrangedin the molecule,and that it is a matter of indifferencefor instance

which is replacedby the hydroxylgroup ; that is,OH.CH2 . CH3 is

clearlythe same as CH3 . CH2 .OH. Theoretically,then,the theory

of valencydemands that onlyone ethylalcohol should exist,and

onlyone isactuallyknown. But with the next higherhydrocarbon,

propane, CH3. CH2. CH3, the case is different;onlythe two end

methyl groups, and consequentlytheir hydrogenatoms, are sym-metrical,

but the hydrogenof the central CH2 group is different;

and consequentlythe theoryof valencypointsto the existence of

two alcoholsderivable from this substance,one OH. CH2.CH2.CH3,

and the other CH3. CH.OH.CH3. Now two are actuallyknown

normal- and eso-propylalcohol,and consequentlythistheorygivesthe

most satisfactoryexplanationof the existenceof two substances of the

empiricalformula C8H8O,havingthe same molecular magnitudeand

ISOMERISM 5

same vapour density,but differentchemical and physicalproperties.

These two bodies are said to be isomeric ; theydifferowing to the

different arrangement of the atoms in the molecule. This theoryof isomerism has played a most importantpart in Organic

Chemistry; the existence of such isomeric bodies was realizedabout

1823 and the explanationfollowed the introduction of the theoryof valencyin 1860. This theoryoffered a most satisfactoryin-terpretation

of observed phenomenauntil about 1876,when evidence

of its insufficiencyin certain cases began to accumulate. For

example,in the case of lactic acid it had been conclusivelyshown

that itsstructuralformula was representedby the followingscheme "

H

CH," C" OH

COOH

and yet three isomeric modifications were known, whose chemical

differenceswere sligtot,but whose physicaldifferenceswere consider-able.

One rotated the planeof polarizedlightto the right,the other

to the left,and the third had no action at all. Now the theoryof

valencycould offerno explanationfor the existence of such isomers,

and Le Bel and van 3i Hoff in 1877 broughtforward the hypothesis

that,were such systemsconsidered in three dimensions a satisfactory

explanationcould be obtained. The central carbon was regardedas

exertingitsvalencies in three dimensions towards the solid anglesof a regulartetrahedron,and when such a configurationis investi-gated,

it at once becomes evident that itisonlywhen four different

groups or atoms are attached to that carbon,that the existence of

two forms becomes possible,one the mirrored,non-superposable

imageof the other. If one form rotates the planeof polarizedlightto the right,the other will rotate it to the left. In the case of that

modification of lacticacid which has no action on polarizedlight,it

should be possibleto effecta resolution into itsactive components,and this was actuallycarried out. This theoryof the AsymmetricCarbon Atom, whose four valencies are saturated by differentgroups

or atoms, has received the fullestpossibleconfirmation,and it may

be stated that,with very few exceptions,the vast majorityof carbon

compounds,containingsuch groups, act on the planeof polarizedlight,and existin three or more opticallyisomeric forms,dependingon the number of such groups presentin the molecule. Further,no

case of an organicsubstance is known which rotates polarized


lightwhen in solution and does not contain one or more asym-metriccarbon atoms.

The example of tartaric acids is a classicalillustrationof the

manner in which this theoryhas been employed,for the older

theoryof isomerism was incapableof explainingthe existence of

dextro- and laevo-rot"toTytartaric,meso-tartaric and racemic acids,since it had been conclusivelyshown that all these forms are

identicaland representedby the formula

H

COOH" C" OH

COOH" C" OH

Now in this molecule there are two asymmetriccarbon atoms,and

it is clear that these may both rotate lightto the right,in the same

way as ^-lacticacid,and the mirrored image of this would rotate

lightto the left. Now supposingthat one rotates to the rightandthe other to the left,the net resultis an acid,i.e. meso-tartaric acid,which has no action on light,and which isfurther incapableof beingresolved into its active components,since it is intra-molecularlycompensated.Then the acid that is syntheticallyobtained in the

laboratory,by the employment of symmetricalforces,i.e. racemic

acid,would be a mixture of equalmolecules of dextro- and laevo-

rotatory,and hence have no action on light,but be capableof

being decomposedinto its active components. Pasteur had in-vestigated

this acid in 1853 and determined the methods that

could be employedfor this separation; but as this line of research

has, as yet,proved of but small value in the problemsto be

discussed,those desirous of obtainingfurther information on

the questionare referred to E. Werner, Lehrluch der Stereochemie,

or A. W. Stewart's Stereochemistry(Textbooksof PhysicalChemistryedited by Sir W. Ramsay),where the vast amount of work that

has been carried out on this theory,and its applicationto other

elements,is described.

That these investigationswill eventuallyplay an importantpartin the preparationof physiologicallyactive drugs is more than

likely.Several of the experimentsthat have been made with opticalisomerides will be described later,but the mere fact that penicillium

glaucumiscapableof destroyingone form in preferenceto another,

ISOMERISM 7

^-lactic,for instance,comparedwith /-lacticacid,is an indication

that molecules of one type have a closer connexion with the cells

of that particularform of life,than the other. Stillmore clearlyis this shown in the case of /-mandelic acid,which is broken down

bypenicilliumglaucumand bacterium termo,whereas the ^-modifica-tion

is similarlydecomposedby saccharomycesellipsoideus.Then.

J-asparagineis sweet, whereas the /-modification is not.

It will be readilyseen that considerations such as those justsketched further complicatethe problemof determiningthe con-stitution

of organicsubstances;as the molecular magnitudeincreases,so does the possiblenumber of isomers. Butane,C4H10"is the firstmember of the paraffinseries in which the possibilityof isomerism appears, e. g. ra-butane,CH34 CH2.CH2. CH3, and,

trimethylmethaneor ?"0*butane

CH3

CH3" C.H

But when the hydrocarbonC13H28 is considered,the possiblenumber is 802, and the difficultiesof assigningconstitutional

formulae to complexsubstances becomes at once apparent. Take

for example the proteitfXgroup; their molecular magnitude,comparedwith the majorityof organicsubstancesis enormous "

it is,perhaps,questionablewhether it is accuratelyknown for any

singlemember. Their decompositionproductsare numerous, and

certainlymany of these are simple,yet the ruptureof the molecule

has been so deep,that we are, up to the present,incapableof

piecingthem together,and in consequence are in ignoranceofthe structure of the originalsubstance. But E. Fischer's method

of dealingwith this problem,by the synthesesof the so-called

polypeptides,makes it appear quitelikelythat this extremelyimportantquestionmay be eventuallysolved. As far as can

be seen at present,there appears to be no limit to the possiblenumber of combinations and permutationsamong the relativelyfew elements found in organicsubstances;this is to be traced

firstlyto the fact that carbon possesses the peculiarpropertyof forming,with other carbon atoms,open and closed rings. This

tendencyto self-combination is much more marked in the case of

carbon,than in that of any other element : not onlyare molecules

known containingup to 30 carbon atoms linked to each other,


but this accumulation does not cause the slightestindication of

instability.And the other cause operatingis the resistancetowards

disruption,due to the peculiarpropertycarbon confers on molecules

into which it enters. Althoughnitro-glycerine,for instance,breaks

up with a largeevolution of heat,showingthat strongforces are

tendingto decomposeit,yet within fairlywide limits it is a

strikinglystable substance. It is due to this property,often

alluded to as the inertia of the carbon system,that isomerism is

observable among carbon compoundsto a very much greaterdegreethan in the case of any of the other elements,for it impliesthe

continued existence of the lessstableform " OrganicChemistryandnot Inorganicis the regionof isomerism. It is further in conse-quence

of this inertia,that OrganicChemistryis the regionof slow

reactions and consequentlyof measurements of velocity; and from

it follows the importantprinciplethat in determiningthe constitu-tion

of an organicsubstance the least possiblenumber of carbon

linkagesare broken in any reaction that it undergoes.

Determination of Constitutional formulae.

Before it is possibleto fullyinvestigateany organicsubstanceit is necessary either to obtain it pure or to be able to purifyone

or more of its derivatives. The usual criterion of purityin the

case of a solid is constancyand sharpnessof melting-pointon

recrystallizationfrom different solvents,and althoughthis is not

invariable,the exceptionsare but rarelymet with. The effectsof

even minute traces of impurityon the melting-pointare occasion-ally

very great,and may be comparedwith the differingphysiologicalreactions of,say, natural and artificialsalicylicacid,which onlydifferby the presence of minute traces of impurityin the latter

preparation.In this connexion it may be mentioned that the

great power of crystallizabilityof so many of the solid aromatic

substances has playeda very considerable partin the investigationof bodies belongingto that class.

In the case of liquids,constancyof boiling-pointis the most

importantcriterion; but again,constant boilingmixtures are not

uncommon, and if this be suspected,the best method is,ifpossible,to convert the liquidinto a solid derivative,and carry out the

investigationsupon this.

Althoughthese standards of purityare by no means allthat are

at the disposalof the Organicchemist,theyare the most importantand most generallyadopted.

CONSTITUTIONAL FORMULAE 9

But the methods available for obtainingthis purityare limited,and there are largegroups of substances which up to the presenthave resistedallattemptsat investigation,owing to the impossibilityof either purifyingthem or convertingthem into crystallizablederivatives.

It will be clear,from what has been previouslystated,that the

first factors necessary for the elucidation of the constitutional

formula will be the quantitativecompositionand molecular weightof the substance in question.It is not proposedto describe in

detail the methods employedfor the determination of either of

these constants ; the data for the firstare obtained by the completeoxidation of a known weight of the substance to itsfinal oxidation

products,water and carbon dioxide,the amount of the former beingdetermined byabsorptionby a known weightof calcium chloride ; of

the latterbyabsorptionin causticpotashsolution,and from the results

of this combustion the percentageamounts of carbon and hydrogenare calculated. If nitrogenispresent,the operationis carried out in

an atmosphereof carbon dioxide,and under these conditions free

nitrogenisevolved and itsvolume measured. Oxygenisalwaysdeter-mined

by difference,and other elements are estimated by specialmethods,of which a fullaccount isto be found in any of the textbooks

on OrganicChemistry. From the percentagecompositionthe least

ratio of the atoms presentis readilycalculated and the empiricalformula obtained. This may representthe true molecular weight,orthe lattermay be a simplemultipleof it. This magnitudemay be

determined from a knowledgeof the density,based on Avogadro'shypothesis,or by the determination of the loweringof the freezing-point or raisingof the boiling-pointof a pure solvent," the latter

methods possessinggreatimportancein the case of those substances

which cannot be volatilizedwithout decomposition.The molecular

weightmay also be determined,with a high degreeof probability,from purelychemical considerations,and the identityof the con-stants

obtained by both methods is of the greatestvalue to the

molecular hypothesis.Two cases will now be taken as illustrationsof what has been

previouslystated.I. On analysis,acetic acid givesthe followingresults:"

0 = 40-0%H= 6-6%O = 53-3 "/o


The simplestratio of the atoms presentisthen :

0-3?-"

H= = 6-6 or[CH20]

The empiricalformula for this substance is consequentlyCH2O,but since the densityis 30, the molecular weightis 60, and there-fore

the molecular formula is [CH2O]2 or C2H4O.2. This same

formula can be arrived at by purelychemical considerations such

as, for instance,the action of phosphoruspentachloride,whichresultsin the formation of a substance of the formula C2H3OC1.Since one of the generalreactions of this reagentis to replacethe

hydroxylgroup (OH) by chlorine,the deduction follows that the

simplestformula for acetic acid must be C2H3O .OH. The

questionthen arises as to the manner in which the atoms are

groupedin this molecule ; the action of phosphoruspentachloridehas

shown the presence of an hydroxylgroup (OH),and thisisalsoborne

out by the formation of a series of salts in which the hydrogenof

this groupingisreplaced; for instance,silveracetate,C2H3O . OAg.The next problemis the nature of the atomic arrangementof the

residue [C2H3O]',when the followingline of argument may be

employed. The acid chloride,acted upon by ammonia, gives

hydrochloricacid and an amide, a reaction representedby the

equation:[C2H30]'C1+ NH3 = HC1 + [C2H30]'NH2.

The amide thus obtained can be dehydratedby means of

phosphoruspentoxide,and a substance of the empiricaland

molecular formula C2H3N results:

[C2H3OyNH2-H20 = C2H3N.

The resultingderivative ismethylnitrileand may be synthesized

by the action of potassiumcyanideon methyliodide

CH3I + KCN = KI + CH3CN.

Since but one molecular structure is possiblefor methyliodide,it follows that C2H3N also contains this methyl group, which was

presentthroughoutthe seriesof reactionsand consequentlyin acetic

acid itself. Moreover,methyl nitrile,warmed with dilute acids,

passes back,by the absorptionof water,into acetic acid.



than the one previouslydiscussed,and here the theoryof valencyin the hands of Kekule gained one of its greatest victories.

Without going into details,the proofthat the hydrogenatoms

are of equalvalue has been shown on the followinggeneralargument.

Kepresentingthe molecule as

1 2345 6

C6 H H H H H H,

it has been provedthat if one of the hydrogenatoms be replacedby the radical (OH),say No. 1,the resultingcompoundphenol

1 23456

C6 (OH) H H H H H

is identicalwith those obtained by replacingeither 2,3, or 4 ; it

has been further provedthat with respectto positionnumbered 1,those numbered 2 and 6 are identical,and also 3 and 5. Conse-quently,

all the hydrogenatoms,and therefore the carbons to which

they are joined,are symmetricallyplacedtowards each other.

Kekule aptlyexpressedthis in the followingconstitutionalformula :

CH=CH

CH^ \CH

CH" CH

Here, the latent valencies,as they have been previouslytermed,are representedby double bonds, a point which will be dis-cussed

in a later chapter,and may for the presentbe disregarded.This structural arrangement,whilst clearlyshowingthe existence

of but one mono-substitution product,givesfurther a complete

explanationof the existence of three di-substitution derivatives,

alwaysprovided,of course, that isomerism is not possiblein the

substitutinggroup.Dichlorbenzene,for instance,existsin three isomericmodifications,

and representingthe benzene nucleus as a hexagon,the structural

formulae for these will be

-'Cl

(1) (2) 01 (3)

The firstis termed the ortho or 1 : 2-dichlorbenzene,the second

CONSTITUTIONAL FORMULAE 13

the meta or 1 : 3, and the fourth the para or 1:4, and since the

most extended observations have shown that in such cases never

more than three isomers are obtained,it follows that position1 : 2

must be the same as 1 : 6,and 1 : 3 as 1 : 5. Ladenburg,however,

subjectedthis to close investigationand conclusivelyprovedthat

such was the case.

The characteristicsof this closed-ringsystem are pronouncedand very differentfrom the open -chain hydrocarbons; the nucleus

has been shown to be present in so many aromatic oils and

resins that benzene and its derivatives are termed Aromatic,in distinction to the open-chainhydrocarbonswhich are called

Aliphatic.Now, more perhapsfor the sake of convenience than

anything else,since the number of benzene derivatives is so

enormous, these are usuallystudied separatelyfrom the aliphaticderivatives ; but as the number of substances of both seriesdescribed

in this work is but a mere fraction of those discussed in any of

the even moderatelysized textbooks on Chemistry,the hydro-carbonsand their derivatives,of both series,will be studied more

or less together,when it is hoped that a better grasp of their

similaritiesand many dissimilaritieswill be obtained.

Not onlyare such ring-shapedsubstances containingfrom three

to seven carbon atoms known, but many containingcarbon atoms

replacedby other elements have been isolated,and some of these

will be described in the followingchapters.

B. GENERAL PHYSIOLOGICAL INTRODUCTION.

Practical therapeuticsmay be deductive or inductive ; may, that

is to say, be based on some generalprincipleswhich in their turn

depend on the conceptionsheld as to diseased processes and the

pharmaco-dynamicsof certain substances,or they may be merelythe result of more or less discrete observations as to the curative

value of such substances in certain diseased conditions. The former

method is often spokenof as' rational',and the latteras

' empiric'.In one of his lectures on Pharmacologythe late Dr. Moxon, after

pointingout thisdistinction,warned his hearers against' reasoningsin medical therapeutics\ ' Inductions ' he continued,' are com-monly

in harmonywith the teachingsof Physiology,but I advise

you to hold them a good deal distinctfrom those teachings,and do

not be too readyto allow them to rest,even in appearance, on those

14 PHYSIOLOGICAL INTRODUCTION

teachings/ The lecture from which this passage is taken was

delivered in 1874, six years after the publicationof Crum Brown

and Fraser's work on the curariform action of the ammonium

bases,which appearedto be the beginningof a rational systemof

pharmacology.Physiologicalaction determined on generalprin-ciples

by a studyof chemical composition,an exact adaptationof

means to ends,and the disappearanceof empiricalmedicationseemed not impossibleachievements after a beginninghad once

been made by this importantand far-reachinggeneralization.Moxon, however, was a determined empiric,not owing to any

aversion to scientificmethod,but because he saw that our funda-mental

knowledgeof facts was not sufficientlylargeto supportanysuperstructureof a generalor theoretical character. Althoughremarkable advances in Pharmacologyhave been made duringthelast half century,the practicalpositionnow is not greatlychangedsince Moxon's lecture. Schmiedeberg,writingin 1902, said :

' The

relation of Therapeuticsto Pharmacologyis obvious,in so far as

the former is based on a scientificfoundation. This,however,is

very far from beingthe case. Everywhere,pristineempiricismis

master, entirelyunconfined by any scientificbarriers.' There are

not wanting, however,signsthat althoughempiricismmust for

many years longerdominate our treatment of diseased conditions,

yetthere is a growinginterestin the subjectof rationaltherapeutics,and a wider appreciationof the advantageswhich an extended

knowledge of the matter would ensure. Not only has a vast

amount of research been devoted to elucidatingsuch relationshipsas may exist between the chemical structure of a drug and its

physiologicalaction,but,in addition,some space is devoted to these

topicsin textbooks and in the medical press; moreover, there is

alreadya largeindustryestablished,though not indeed in this

country,which has for itsobjectthe productionof syntheticdrugs,the action of which is more or lessaccuratelypredictedfrom their

chemical constitution.

We may, therefore,allude to the obstacles which have preventeda stillgreaterexpansionof the domain of rationalism,and a more

completeabandonment of the therapyof empiricism.The difficulties

in correlatingchemical and physiologicalpropertiesfall into two

main divisions,the firsthas reference to the drug itself,and the

second to the organismon which itis intended to act.

Various physicalcharacteristics,such as solubilityand volatility,

markedlyinfluence and alter the action of a drug,and interfere

OBSTACLES TO RATIONALISM 15

with the developmentof its action. Upon these depend,in partat

least,speedof absorptionand excretion ; a decrease in the former or

an increase in the latter will generallymean a decrease in physio-logical

activity.The effect of solubilityis seen in the hypnoticschloralhydrateand sulphonal.The former is soluble and rapidly

absorbed,and consequentlyrapidlyproducesitsphysiologicaleffect;

the latter,owing to itsslightsolubility,isslowlyabsorbed and hence

the physiologicalaction isdelayed,but also prolonged,and drowsi-ness

may persistfor many hours after the administration of that

substance.

The physiologicalinactivityof the highermembers of many

homologousseries,such as the alcohols or acids,is attributable to

their insolubility,which renders them incapableof beingabsorbed.

The importantquestionof solubilityin fattysubstances will be

dealt with in the chapteron Narcotics.

The degreeof dissociationwhich a substance undergoeson solu-tion

in water can play an importantpart in its action on the

organism. But organicsubstances,with which alone this work

deals,are, with the exceptionof certain groups such as the acids,

generallyundissociated on solution. The case of the mercury salts

may, however,be givenas an illustrationof this phenomenon.Paul and Kroniginvestigatedthe disinfectant power of mercuric

chloride,HgCl2,bromide,HgBr2, and cyanide,Hg(CN)2,usingthe

spores of B. Anthracis,and found that in equimolecularsolutions

the chloride was the most powerfulantiseptic,then the bromide,and that the cyanidehad least action. This correspondsto the

degreeof dissociationwhich takes placein the three solutions. The

character of the metallic ion is,of course, of primaryimportance,assaltsof other bases which are stillmore dissociatedin solution have

not the same disinfectant action as those of mercury.An instructiveinsightinto the difficultiesof the problemisfurther

afforded by the researches of the same authors into the disinfectant

powers of a solution of perchlorideof mercury and common salt.

Many years ago, Bacelli,when advisingintravenous injectionsofmercurial saltsin cases of syphilis,employeda solution of the per-chloride

mixed with sodium chloride in the proportionof one to

three,which he stated was more effectivein actual practice.Pauland Kronig have shown that the actual process is as follows : "

A double salt(Na2HgCl4)is formed,which dissociatesinto positivesodium ions and negativecomplexions of mercury and chlorine.

The latterare inactive from an antisepticpointof view,but a cer-


tain amount of secondarydissociationof the complexnegativeion

occurs, resultingin the formation of the active mercury ions,thoughto a smaller extent than when an equimolecularsolution of mercuric

chloride alone is employed. The action is thus hindered,but in

practicethe increased solubilitywhich is obtained by the addition

of saltmore than counterbalances the decreased ionicdissociation.On

the other hand,salicylicacid,which is onlyvery slightlydissociated

on solution and consequentlyis a very weak acid,owes itsbactericidal

action to the entire molecule and not to the ions. Sodium salicylate,which is largelydissociated,when dissolved in water shows no

antisepticproperties.That the velocityof diffusionof a substance willplayan important

part in its physiologicalreactivityis clear,and to this factor may

be ascribed,for instance,the differences observed in the group of

digitalisglucosides.The most powerfulmember of this group is

digitoxin,a very insoluble crystallinesubstance. Cloetta has in-troduced

an amorphousand soluble form of digitoxinwhich has been

named digalen: following,in allprobability,on increased solubilitythere is increased diffusibility,and to this is attributed the absence

of digestivedisturbances when it is administered by the mouth.

Two further pointsmay be mentioned as of practicalimportance,which render the issues of pharmacologicalexperimentdifficulttodetermine. The firstof these is the erroneous impressionas to the

main action of a drugwhich may be producedby certain bye effects.

An extreme instance of this isalcohol,which iscommonly known as

a stimulant and is frequentlytaken to producea feelingof warmth,whereas its chief physiologicalactions are those of a narcotic and

antipyretic.The second isthe effectof dosage.Many bodies producevaried effectsaccordingto the doses in which theyare administered.

This,of course, does not dependon any real alteration in the physio-logicalcharacter of the drug,but is merelya matter of distribution.

A narcotic drug,for example,when givenin doses largeenoughto producesleep,may fail to exhibit certain secondaryactions

which are producedindependentlyof the effect on the central

nervous system. On the other hand, a substance with a specificaction on particularorgans, if given in toxic doses,may cause

generalsymptoms which entirelymask the particularand charac-teristic

effect.

Thus chloroform in narcotic doses causes a fall of temperature,which might be merelythe result of muscular relaxation coupledwith vasodilatation and increased heat loss. But it has been shown

LOEWS THEORY OF POISONS 17

that this fallof temperatureis partlydependenton a direct action

of the drug,which,apartfrom itsnarcotic powers, has an inhibitingeffecton oxidation processes. In this itdiffersfrom ether,thoughthere isalso a fall in temperatureduringether narcosis.

The main obstacle,however, to a rational appreciationof

pharmaceuticalactions lies in our ignoranceof the chemistryand

reactivityof the livingcells. To attemptto calculate the result

of a chemical interaction in which the constitution of only one

of the bodies concerned is known, is obviouslyan undertakingdestined to onlya partialmeasure of success : but this is what is

done when attemptsare made to set forth the chemical basis of

the action of drugs.Completeexplanations,in the proper sense of the word,are not

at presentpossible,but startingfrom the better-known factor,that is,the drug,it is possibleby introducingchemical variations

of a definitecharacter to modifythe pharmacologicalresults,andthus in some instances to gain an insightinto the chemical in-fluences

which can be broughtto bear on livingcells.We will now proceedto consider in detail the two variants

in any pharmacologicalprocess, namely (A) the cell protoplasm,and (B)the drug.(A)With respectto the protoplasm,the theoryof Oscar Loew is

of considerable interest. He divides the generalpoisonsinto1oxidizing/'catalytic/'salt-forming/and ' substituting/Thesein sufficientconcentration,act on alllivingprotoplasm,and dependfor their activityon the chemical character of the substances of

which livingcellsare composed.The specialpoisons,formingthe second main group, comprise

those which onlyact on certain classes of organisms.Under this

head are included the toxins,the antitoxins,and similar bodies,the action of which is specificfor certain kinds of protoplasm;the organicbases (includingthe alkaloids)which probablyact bydisturbingthe structuralcharacter of certain cells; and the indirect

poisonswhich make respirationimpossible,"c.

Now as regardsthe generalpoisons,the firstthree classes are

not importantfor our presentpurpose. The firstincludes bodies

such as ozone, peroxideof hydrogen,chromic acid,permanganates,hypochlorites,phosphorus,"c. Among the catalytic,i.e. those

which influence chemical action without undergoingany apparentchangethemselves,are the aliphaticnarcotics,which will be dealt

with later on in the present work. The third group owes its

c


existence to the amphotericcharacter of protein,and includes acids,the soluble bases such as alkalies and alkaline earths,and the

saltsof the heavymetals.

The fourth class includes a number of bodies which even in

extreme dilutions can react with aldehydesand amines,formingsubstitution products" whence the name. The more readilythis

reaction takes placethe more powerfulwill be the toxic effect.

Examplesmay be found,firstlyin hydrazineand phenylhydrazine,which most readilycombine with aldehydesand are consequently

powerfulpoisons; similarly,hydroxylamine,aniline and free

ammonia. Secondly,the phenolsand their derivatives,especiallythe amidophenols; and thirdly,prussicacid,sulphurettedhydrogen,and the acid sulphites" all substances capableof reactingwith

aldehydegroups.As a generalrule,primaryamines (notof the aliphaticseries)are

more reactive than secondary,and these more so than tertiary.

Pyridine,with a tertiarynitrogenatom, is much less toxic than

piperidine,which contains an NH group. Xanthine,with three

NH groups, is more toxic than theobromine with two such radicals.

Methyl aniline has a differentbut weaker action than aniline.

The amido group isreadilyattacked by nitrous or nitricacids,byaldehydes,ketones,"c.

Loew givesmany examplesselected from among those bodies

which are protoplasmicpoisons,and shows generallythat toxicityincreasesparipassu with reactivity.

Thus Loew explainsthe very various chemical structures of these

generalprotoplasmicpoisons,byshowingthat theywillallreact with

one or two very labile groups which he believes are presentin the

livingprotoplasmicmolecule,but undergo a chemical change and

become stable when the protoplasmdies. Consequently,these

generalpoisonshave no action on dead protein,so differingfrom

bodies likethe mineral acids,which are equallydestructive to living

or dead tissues.

Though considerations of this sort may helptowards elucidatingcertain generalreactions,theycompletelyfail to account for what

is generallyknown as the selective action of drugs.1 From our

presentpointof view,-itshould perhapsbe more correctlystated as

1 Drugs having a selective action are classed by Loew under 'special

poisons'. An important group among them, the Alkaloids,will be dealt

with in detail in a subsequentchapter,and Loew's theoryin generalwill

be criticized in the chapteron organicdyes.



the integrityof the proteinportion,concerning-which we can onlysaythat it is too labileto admit of examination in a livingcondition.1

(B) When we turn to the second factor in pharmacologicalreac-tions,

namely,the drugs,our survey of the subjectmay conveniently

be divided into two parts. In the first place,we may notice

certain generalitiesconnected with physiologicalactivitywhich

have been arrived at by the experimentalmethod, and then we

may go on to consider the theoretical views which have been

expressedas to the way in which drugs exhibit their particularactions in the animal body.

I. In correspondencewith their comparativelyslightchemical

reactivity,the aliphaticseriesof bodies do not on the whole possess

powerfulpharmacologicalactions. Brunton and Cash state that

the predominantfeature of the lower members of the fattyseriesis

their stimulant and anaesthetic action on the nerve centres (frogs).

Schmiedeberg collects in a generalclass the narcotics of the

aliphaticseries as (1)the Alcohol and Chloroform group. This

includes the gaseous and fluidhydrocarbons,the monatomic alcohols

and their ethers,ketones,aldehydes,and their halogenderivatives.

These are mainly characterized by their action on the cerebrum

producingnarcosis. They will be considered in detail in subsequent

chapters. (2)The Ammonia derivatives,on the other hand, are

characterized by a convulsant action on the cellsof the spinalcord.

When the triad nitrogen,by the addition of another alkyl

group is converted into pentadnitrogen,a remarkable change in

the physiologicalaction occurs, which was firstpointedout byCrum Brown and Eraser in 1868, subsequentlyconfirmed byBrunton and Cash, and very fullyillustratedby many observers.

All the quaternaryammonium bases have a curare-like action,

paralysingthe motor nerve endings.Numerous illustrationsof

this principlewill be found in the course of the presentwork.

II. The aromatic bodies being chemicallymore reactive are

physiologicallymore effective. Experimentswith frogs showed

that the members of the aromatic series,like the aliphatic,affect

the nervous system,but they appear to affect motor centres more

than sensory, so that instead of producinganaesthesia,like members

of fattyseries,theytend rather to giveriseto tremor,convulsions,

and paralysis(Brunton and Cash). The activityis,however,increased by the substitution of hydrogen. In this case, alterations

1 Pharmacologie,1902.

REACTIVITY OF THE DRUG 21

in physiologicalaction may be producednot onlyby alterationsin

the molecule as a whole, but by variations in the group which

substituteshydrogen. Examples of this will be considered in the

chapteron the Alkaloids,which are all heterocyclicbases with

various side chains. Especiallyimportantin this connexion is the

rule enunciated by^Kendrickand Dewar, that the introduction of

hydrogeninto the cyclicbases in all cases increases their physio-logicalaction,and thus their toxicity.

In a generalsense, also,Dujardin-Beaumetzand Bardel's con-ceptions

of the influence of various side groups on the benzene

compounds may be taken as accurate :"

(i)Those containinghydroxylare antiseptic,

(ii)Those containingan amido group or an acid amide are

hypnotic.

(iii)Those containingboth an amine group and an alkylgroupare analgesic.

These few generalrules will be found subjectto variation and

exception,due to one or more of those disturbingfactorswhich have

alreadybeen noted; but they show by their very existence that

within certain limits it ispossibleto modifythe physiologicalaction

of a drug at will in a givendirection. Other f rules ' of lessgeneralapplicabilitywill be noted under the various groups of compoundswhich will be discussed in subsequentchapters.

We have alreadydealt with the mechanism of interactionbetween

the livingcelland the drugfrom the pointof view of the cell,as far

as anythingcan be definitelystated about the matter ; a littlemore

may now be said regardingthe drug.The action of a drug appears to dependupon its possessing,firstly,

some group of atoms capableof exertinga specificeffect on the

cell,and secondly,another group or side chain capableof enteringinto some kind of chemico-physicalrelationshipwith certain cells,wherebythe firstis enabled to produceitsaction. This second is

commonly known as the anchoringgroup. The term 'chemico-

physical' was used advisedly,as it cannot be said to be definitelysettled whether a chemical reaction in the ordinarysense reallytakes place.P. Ehrlich has comparedthe reaction which is sup-posed

to take place with those postulatedby Witt for the

organicdyes. The dyeingpropertiesof a substance are dependenton the presence of certain atomic groupingswhich are termed

colour groups or chromophores.The entrance of the chromophoregroup into a molecule results in a derivative more or lesscoloured,


but lackingthe characteristicsof a dye,and it isonlywhen basic

or hydroxylradicals(auxochrome)are further introduced,that the

dyes result. For example,in azo-benzene C6H5 .N :N.C6H5 the

group N2 is the chromophore.The substance which is coloured (red)Witt termed the chromogene; it is not a dye,but becomes one on

the introduction of a basic group, e. g. C6H5 .N :N.C6H4(NH2).

Anthraquinone

is colourless(chromogene),but on the introduction of two hydroxyl

groups, the dye alizarinresults

Two groups are consequentlynecessary to confer on a substance

itsdyeingproperties; further,the colour itselfis dependenton the

number and nature of the " say " basic radicals; thus,amido-azo-

benzene,CgH5 .

N : N.C6H4(NH2), is yellow,the di-amido deri-vative

is orange, the tri-amido brown.

Many drugs can be extracted unchangedfrom the tissues,and

Ehrlich regardsthem as havingbeen withdrawn from solution and

existingthere in a state of,possibly,solid solution"in a corre-sponding

manner to a dye. A dye is also withdrawn from solution

by a cellular material,and Witt regardsit as forming a solid

solution from which it may be again withdrawn by the use of

a more powerfulsolvent. But it is much more probable,as Freud-

lich and Losev have shown,that since Henry'slaw does not hold for

dyestuffs,the phenomenonof dyeingis one of adsorption,and with

this may be compared the views expressedin the chapteronNarcotics as to the manner in which the drug enters the cell.

The non-toxicityof acidic substances is traced to the fact that

theyare no longercapableof beingabsorbed by the tissues. Ehrlich

has shown that those dyeswhich stain the brain tissue cease to do

so on conversion into sulphonicacids,as neurotropicsubstances

lose their characteristicson the entrance of such groups.

He also suggeststhat the analogybetween the physiologicalaction of substances and the theorythat has been sketched of the

dyes,may be of value in the syntheticproductionof drugs. Sub-stances

with the power of actingon definite cells may be found

(myotropic,neurotropic,"c.),and the character of their action

controlled by the introduction of groups (chromophore)of varied

pharmaco-dynamiceffect.

REACTIVITY OF THE DRUG 23

The selective action of a drug, which has already been referred

to from the opposite point of view, may in some instances be

explained by its solubilityin lipoidsubstances. This question will

be discussed in full in a later chapter (see p. 83).

This outline of the present position of the question as to the

relationshipsbetween chemistry and pharmaco-dynamics, will at least

show that, whereas in many instances and by many various ways

a close relationshipmay be shown to exist, there is as yet no

possibilityof the abandonment of empiricism in practicalmedicine.

Though much has been done much more remains, and though the

principlehas been demonstrated its limits are yet to be defined and

the details of its action delineated. Whether these details will be

rather of a chemical or physical character cannot at present be

stated. The various sciences are, after all, only aggregates of

convenience, and the boundaries which divide their territories

become less and less distinct the nearer we get to the actual nature

of things. The pharmacologist is merely concerned with the

correlation of the phenomena of physiology with those of the

intimate constitution of matter, whether that constitution be

determinable by physics or chemistry, or an indistinguishable

combination of both.

NOTE."

Ehrlich has always insisted on the differences which exist

between the action of a toxin and that of a drug the chemical formula

of which is known, and for some time was inclined to deny that it was

possible to suppose any similarity in the mechanism by which the toxin and

the drug are anchored to the cell.

Recently, however, he has somewhat modified his views in the matter and

now postulates groups or side-chains called chemio-receptors by which the

corresponding haptophoric groups of the drug are united to the cell body.

These chemio-receptors are supposed to differ from ordinary receptors in

being less intimately analogous to the nutritive apparatus of the cell,and

in being less capable of an independent existence ; hence they cannot be

thrown off as anti-bodies, nor are they increased in number when small

doses of a drug are administered over a long period of time.

CHAPTER II

A. THE A.LIPHATIC AND AROMATIC HYDROCARBONS. Their methods

of preparation and properties. Methods used in the synthesis of their

derivatives. B. PHYSIOLOGICAL CHARACTERISTICS OF THE HYDRO-CARBONS.

Effect on Physiological reactivityof the introduction of Methyl

and Ethyl groups, of unsaturated condition of the molecule, and of Isomeric

and Stereo-isomeric relationships.

A. ALIPHATIC AND AROMATIC HYDROCARBONS.

THE hydrocarbons are a number of compounds of carbon

and hydrogen which have been classified into various groups

owing to the striking differences that have been found to exist

between them.

Paraffin Hydrocarbons.

The simplestseries commences with methane, CH4, and related

to this, and possessing its general characteristics,are a large

number of what have been termed the methane or limit hydro-carbons,

or, owing to their great stability,the paraffins. Theyform what is termed an homologous series

" one in which each

member differs from the next by a constant quantity,viz. CH2.

Methane CH4

Ethane C0H, gases.

Propane C3H8

Butane C4H10 B. P. 1"

n. Hexane C6H14 B. p. 71"

Tetradecane C14H13 M. p. 5-5"

Di-myricyl C60H122 M. p. 102"

One general physical property of such a group is that as the

molecular magnitude increases the members of it pass from the

gaseous to the liquidphase, from liquidsof low boiling-pointto

those of high, or from liquidsof high boiling-pointto solids of

low melting-point as the case may be. This series only contains

singly linked carbon atoms, and since the limit of saturation by

PARAFFIN HYDROCARBONS 25

hydrogen has been reached,they are frequentlycalled the limit

hydrocarbons.Isomerism first appears in butane,C4H10,and the

theoryof valencysatisfactorilyaccounts for the existence of two

substances of that formula,having the same vapour densityandmolecular weight,but differingphysicaland chemical properties,viz.,w-butane,CH3 . CH2 . CH2 . CH3, and iw-butane,

CH3

CH" C.H

The n- or normal derivations are those consistingof a chain of

carbon atoms,whilst the iso- have a branched structure. But since

this latternomenclature may not be sufficientlyprecise,such hydro-carbons

may be regardedas derivativesof methane ; thus,w0-butane

may be termed tri-methyl-methane.This is,perhaps,clearer in the

case of pentane. ^-Pentane is CH3 . CH2 . CH2 . CH2 . CH3, two

2"0-pentanesexist; if the first

CH3

CH3" C" CH3

CH"

is termed tetra-methyl-methane,and the second ethyl-di-methyl-

C2H5

CH3" C.H

CH,

methane, their respectivestructures are at once evident.

Occurrence in Nature. Many of these hydrocarbonsoccurin nature. Methane, or marsh gas, formed by the decayof organicsubstances,is found in the coal measures, and in regionslikeBaku in the Caucasus,and in the petroleumdistrictsof America.

Largedepositsof petroleum,consistingof mixtures of members of

this series,are found in America, Russia,Alsace and Hanover.

That from America consistsalmost exclusivelyof normal paraffins.The fractions boilingbetween 50"-60" consist chieflyof pen-tane

and hexane,between 70"-80" hexane and heptane,between

90"-120" heptaneand octane. Refined petroleumor kerosene boils

26 ALIPHATIC AND AROMATIC HYDROCARBONS

at 150"-300". The solid high-boilingparaffinsare more abundant

in the petroleumfrom Baku than in that from America, and are

also obtained by the distillationof the tar from turf, lignite,and

bituminous shales.

Paraffins that liquefyreadilyand fuse between 30" and 40",are

known as vaselines and employedas salves.

Properties. All the members of this group are insoluble in

water ; the lower are soluble in alcohol and ether,but the solubilitydiminishes as the molecular weight increases. They are charac-terized

by their great stabilityand consequentslightreactivity.Fuming nitric or even chromic acid does not affectthem in the cold,and on heatingthe action is but slow. Chlorine and bromine giveriseto substitution products,a characteristic propertyof the satu-rated

hydrocarbons.Methane, for instance,givesfirstlymethylchloride,CH3C1, then CH2C12,CHC13, and finallyCC14,in which

all the hydrogenatoms have been replacedby chlorine;in such

reactions,for every atom of chlorine that enters the molecule an

atom of hydrogen is removed in the form of hydrochloricacid,

e.g. CH4 + C12= HC1 + CH3C1, and so on.

Olefines.

The next group of hydrocarbonscontains two hydrogenatoms less

than those justconsidered,and forms an homologousseries,with

physicalpropertiessimilar to the paraffins.When the structure of,

say, the simplestmember, ethylene,is considered,it is seen that

apparentlycarbon isactingas a trivalent element,thus CH2 . CH2.But all the members of this series,quiteunlike the paraffins,are

very reactive and possess the followingproperties: They absorb

a molecule of chlorine,bromine,and iodine,without the formation

of the correspondinghalogenhydride.In a similar manner, mole-cules

of hydrogen or the haloid acids are readilyadded, and

these reactions usuallytake placewith considerable ease. The

explanationthat is offered of these phenomena is the assumptionthat the fourth valencies of each carbon atom mutuallysaturateeach other,graphicallydescribed by a double bond,e. g. H2C = CH2,or CH2:CH2 and the substance is said to be unsaturated. The

reactions alluded to beingexpressedby the followingequations:"

CH2 : CH2 + C12= CH2C1 . CH2C1.

CH2:CH2+H2=CH3.CH3.CH2 : CH2 + HI = CH3 . CH2I.



The reaction with the halogensis similar,chlorine for instance

givesdichlorethyleneand then tetrachlorethane,

CH CHC1 CHCL

CH CHC1 CHC12Tetrachlorethane.

Acetyleneand many of its derivatives are characterized by the

formation of solid silverand copper compounds, which when dry are

extremelyexplosive.These may be employedfor the detection and

isolation of the acetylenes,since on treatment with hydrochloricacid the pure hydrocarbonis liberated. Acetyleneitself is at

present preparedin large quantityby the action of water on

calcium carbide and is used for illuminatingpurposes.

Benzene hydrocarbons.

The last seriesof hydrocarbonsmay be regardedas derived from

the simplestmember, benzene,by means of the replacementof one or

more of the hydrogenatoms by the residues of the aliphaticseries.The constitutional formula assignedto the parenthydrocarbonbyKekule,viz.

is in agreement with most of itspropertiesand those of its deriva-tives,

as previouslyindicated. But when the nature of the alternate

double and single bonds is investigatedit becomes at once

apparent that phenomena of a different order appear with the

formation of this closed-ringsystem. In this case, the double bond

bears no similarityto that previouslydiscussed. For instance,the

action of chlorine on benzene givesrise to substitution productssuch as C6H6C1 or C6H4C12, and not to addition derivatives,as

might have been expectedhad the unsaturated nature of the mole-cule

been akin to that of ethylene.Moreover, had this double

union been analogousto that previouslydiscussed,the compounds1 : 2 and 1 : 6 should be different,whereas they are identical,e. g.

Cl Cl

I

= Cl" "'

CH CH2.

BENZENE HYDROCARBONS 29

for,in the firstcase, between the two carbon atoms carrying-thechlorine atoms there exists one of these double bonds,which is

absent in the second. In a correspondingcase in the open-chain

ethylenederivatives,these two chlorine substitution productswouldhave been different,i.e. isomeric.

It may be put in a different way as follows : There is but

littledifference between the two hydrocarbonsrc-hexane,

CH3 . CH2 . CH2 . CH2 . CH2 . CH3,

and hexamethylene,or, hexahydrobenzene,

xCH2 "

CH2" CH

Further,the unsaturated ethylenederivative

CH3 . CH2 . CH2 .CH : CH . CH3

has the same generalcharacteristicsas tetrahydrobenzene,

/CH2 " CH.

CH2" "CHCH2" CH/

that is,the behaviour of the two towards the halogens,halogen

hydrides,"c.,is similar to that previouslydescribed. Then with

the di-ethylene,CH3 .

CH : CH.CH : CH

. CH3 ,

and dihydrobenzene,CH2-CH

CH2" CH

XCH=

much about the same relationshipholds true,both have the generalpropertiesof di-ethylenederivatives. But when the third double

linkageis introduced and dihydrobenzenebecomes benzene,these

generalpropertiesdisappearand are replacedby entirelydifferentcharacteristics. The entrance of the radical of this hydrocarbon,termed phenyl,into various molecules,results in changesin the

physical,chemical and physiologicalpropertiesof quitea different

order from those producedby the correspondingentrance of aliphaticradicals: as a result appear what are termed the negativecharac-teristics

of the benzene nucleus,phenomena which will be studied

in detail,in relation to physiologicallyactive substances,in the

followingchapter.


Sources. Not onlybenzene but numerous other derivatives are

obtained by the dry distillationof coal. They are presentin coal

tar,which is producedin enormous quantitiesin the manufacture of

coal gas. Among the homologuesfound are toluene or methylbenzene, C6H6.CH3, the three dimethylbenzenes or xylenes,C6H4(CH3)2and the three trimethylbenzenes,C6H3(CH3)3.Among the higherboilingfractions of coal tar,many more

highly condensed aromatic hydrocarbonsare found; of these,naphthalene,C10H8,and anthracene,C14H10,are the onlytwo that

will be discussed. The former shows great similarityto benzene,from which it differsby C4H2. Its deportmentis satisfactorilyexplainedby the constitutional formula suggestedby Erlenmeyer,

It consists of two benzene nuclei,having in common two carbon

atoms occupyingthe ortho position.Anthracene is the parenthydrocarbonof a series of vegetable

compoundsof which the most importantis the dye alizarine. The

followingformula expresses itsrelationshipto benzene and itsvarious

syntheses,

/CH\XCH\/CH\CH C C C

I IICH C

CH

A,,

Oxidation and Reduction. The chiefcharacteristicof the benzene

hydrocarbonsisthe greatstabilityof the ringcomplex; in the vast

majorityof reactions undergoneby its derivatives the nucleus itself

is not destroyed.This feature distinguishesthe aromatic substances

from the derivatives of the methane and other open-chainseries.As a very generalrule,oxidation or reduction can be carried

on without tearingthis ring asunder. In the former process the

benzene homologueshave their side chains oxidized to (COOH)which occupiesthe positionof the substitutinggroup. This con-

OXIDATION AND REDUCTION 31

sequentlyaffords a method of distinguishingbetween isomeric

derivatives. Thus the three xylenes,

C6H4"Ji{J"l:2,1:3 and 1:4,

are isomeric with ethylbenzene,C6H5 . C2H5; on oxidation,1 : 2-

xylenegivesphthalicacid,

,COOHl : 2"

the meta isomer givesthe corresponding1 : 3 di-carboxylicacid,and the para, 1 : 4 di-carboxylicor terephthalicacid ; on the other

hand, ethylbenzene givesbenzoic acid C6H5 .COOH. Of the

three di-carboxylicacids mentioned above,onlythe ortho givesan

anhydride,

r IT /C0\0V^tfXl iX /î/^" S^J

this beingdue to the proximityof the two reactinggroups.Similar peculiaritiesto this will be noticed among a large

number of ortho substituted benzene derivatives,so much so that

the interaction of two such groups with each other,or with

another substance to form a closed chain,can be generallytaken

as a proofthat theyoccupy adjacentpositions(i.e. ortho)in the

nucleus.

The reduction of benzene is much more difficultthan that of

the unsaturated open-chainhydrocarbons.Benzene itself,heated

to a hightemperaturewith hydriodicacid,giveshexamethylene,

/CH2" CH2XCH2" "CH2.

\CH2" CH/

Salicylicacid reduced by sodium in amyl alcohol solution givesfl-pimelicacid,

COOH COOH

CH C.OH CH2

CH CH CH.

/Lg

CH;

NCH,Such a breakdown of the benzene nucleus,as in this latter

case, resultingin the final substance possessingthe same carbon


content as the original,is,relativelyspeaking,extremelyrare.Powerful oxidizingagents,of course, effectcompletedecomposition,the invariable rule in carbonaceous compounds; but in those cases

where the nucleus itselfis attacked,the resultingderivative has

generallya less carbon content than that of the benzene derivative

experimentedupon.

GENERAL METHODS USED IN THE PREPARATION OF THE

HYDROCARBONS.

Since the hydrocarbonsare the parentsubstances of all other

organicbodies,their synthesesare of especialinterest,and althoughthe methods that may be used for their preparationare many, the

followingare the more important.A few,such as acetylene,canbe obtained by the direct union of their elements,but the majorityare formed by the union of simplerhydrocarbonnuclei.

1. Hydrocarbons of the Paraffin and Benzene series can be

obtained by heatinga mixture of the sodium salt of the acid with

caustic soda.

CH8!COONa + NaOjH = Na2CO3Sodic acetate. Methane.

C6H5:COONa4-NaOjH= Na2CO3 + C6H6Sodium benzoate. Benzene.

2. The Wiirtz synthesisconsists in actingupon the iodo or

bromo derivatives of the hydrocarbons,in etherial solution,with

metallic sodium

C2H5jI+ Na2 + IjC2H6= 2NaI + C2H5 . C2H5

Ethyl iodide. w-Butane.

As a rule,the iodine derivatives react best,and the reaction pro-ceeds

better with primaryhalogenderivatives (i.e. those containingthe. CH2X group)than with secondary(:CHX), and seldom with

tertiary(jC" X).Mixtures of halogenderivatives may also be employed,i.e.

CH3 . CH2:I+ Na2 + I;CHa . CH2 . CH2 . CH3 =

M-Iodo-butane.

2NaI + CH3.CH2.CH2.CH2.CH2.CH3w-Hexane.

SYNTHESIS OF HYDROCARBONS 33

Fittigfurther showed that a similar reaction could be employedfor the preparationof Benzene homologues.

C6H6jBr+ Na2 + IiC2H5 = NaBr + Nal -f C6H5 . C2H5Brom-benzene. Ethyl-benzene.

C6H5jBr+ Na + BriC6H5= 2NaBr + C6H5 . C6H5

Diphenyl.

It may also be employed for the preparationof Ethylene

derivatives,

CH2 : CH . CHa|I+ Na + IjCH8 = CH2 : CH. CH2. CH3 + 2NaI

Allyliodide. a-Butylene.

CH2:CH.CH2iI + Na + IjCH2.CH:CH2 =

2NaI + CH2 : CH.CH2 . CH2 .CH : CH2

DiaUyl.

Acetylene can also be obtained by actingon chloroform with

sodium,or more convenientlyon bromof orm with finelydivided silver.

CH

CH;CL + 6Na + ClJCH = 6NaCl + II

CH

The reaction has been further extended to the preparationof

closed-ringhydrocarbons,termed the Cyclo-paraffins,which will not

be further described,owing to the fact that theyare of relativelyslightimportanceas regardsthe questionsto be discussed in this

work. Two examplesmay be given.

"H2!Br! + Na2 = 2NaBr + CH,

HJBrTrimethyleneorCyelo-propane.

CH2 . CH2 . CH2;Br CH2 .CH9 . CH2

i + Na2 = 2NaBr+ I I

H2 . CH2 . CH2jBr CH2 . CH2 . CH2

Hexamethylene or

Cyclo-hexaneorHexahydro-benzene.

The "Wiirtzsynthesisis consequentlyof very wide applicability,but isof the greatestimportancein the preparationof the highermembers of the saturated hydrocarbons.As regardsthe formation

of benzene homologues,ithas been largelyreplacedby the Friedel

D


and Crafts' method, which will be described later. Further,it will

be seen that this syntheticprocess constitutes an excellent means

of determiningthe constitution of the hydrocarbons.

3. Unsaturated hydrocarbonsof the ethyleneand acetyleneseries,as well as benzene homologuescontainingunsaturated carbon

systemssubstituted in the nucleus,can readilybe obtained by the

action of an alcoholicsolution of potashon the correspondingbrom-derivative.

Ethylene.

CHJHi !

Ethylbromide.

Fhenyl-ethylene.

C6H5CHBr.CH3 + KOH = C6H5CH : CH2 + KBr + H2OBrom-ethylbenzene. Styrol.

or for acetyleneand itsderivatives :

Acetylene.

CH2Br CH

| + 2KOH = 2KBr + 2H2O + III

CH2Br CH

Ethylenedibromide.

Di-phenyl-acetylene.

C6H6CHBr.CHBrC6H5 + 2KOH = 2KBr + 2H2OStilbene bromide.

+ C6H6C;C.C6H5Tolan.

The reaction with alcoholic potashis of great value for the

preparation,not onlyof such types of hydrocarbonsas those men-tioned,

but also for unsaturated derivatives of the most varied

nature.

As regardsthe preparationof ethylene, the removal of the

elements of hydrobromicacid,or generallyof the halogenhydrides,is often very similar to that of the elements of water. This hydro-carbon

can be easilyobtained by the dehydrationof ethylalcohol

by means of sulphuricacid.

CHJH "": CH0

AHJ IIC

+H20H2


36 DERIVATIVES OF ALIPHATIC HYDROCARBONS

will be taken as illustrations of the value of such derivatives in

syntheticaliphaticchemistry.

A. Syntheses of Aliphatic Derivatives from the Alcohols or

Acetic Acid.

i. On oxidation alcohols containinga primary group, i.e.

" CH2. OH pass to aldehydesand then acids.

CH3OH -" H.COH -" H.COOH

Formaldehyde. Formic acid.

CH3.CH2OH -" CH3.COH -" CH3.COOH

Acetaldehyde. Acetic acid.

ii.Acetic acid acted upon by phosphorustri- or penta-chloridegivesacetylchloride.

CH3.COOH + PC15 = HC1 + POC13+ CH3CO.C1.

The resultingsubstance is extremelyreactive,and is used for the

purpose of introducingthe acetylgroup (CH3CO)' into a largenumber of bodies,e. g.

= HC1+CH3CO.OC2H5Ethylacetate.

= HC1 + CH3CO.NHC2H5

Ethylamine. Ethylacetamide.

CeHsNHiHj = HC1 + C6H6NH. COCH3

Aniline. Acetanilide or Antifebrin.

iii.Calcium acetate distilledwith calcium formate givesacet-

aldehyde.

(CH3COO)2Ca+ (H.COO)2Ca = 2CH3. CHO + 2CaCO3

iv. Calcium acetate distilledalone,or with the calcium salts of

other organicacids exceptformic,givesrise to the group of bodies

called ketones,substances used in the preparationof the sulphonals.

CH3

CO(CH3COO)2Ca = CaC03

CH,L3

Dimethyl ketone

or acetone.

SYNTHESIS OF ALIPHATIC DERIVATIVES 37

CH3

or (CH3COO)2Ca+ (C2H5.COO)2Ca = 2CaCO3 + CO

Calcium propionate.

Methyl-ethylketone.

v. Chloral and chloroform are both obtained from ethylalcohol,

althoughthe latter may also be formed from acetone,a substance

obtained in considerable quantityin the destructive distillation

of wood.

B. Syntheses from the Halogen derivatives of the Hydro-carbons-

i. Ethyl iodide treated with silver hydrateor dilute aqueous

potashpasses over to ethylalcohol.

C2H6:Ij+jA"OH= C2H6OH + AgI

ii.Acted upon by potassiumcyanide,ethylnitrileresults.

CaH6|Ij"+iK|CN= C2H6CN + KI

This reaction is of considerable importance,since by means of it

the lengthof the carbon chain can be increased,moreover the result-ing

substance is capableof undergoingseveral importantchanges.On saponification,i.e. treatment with dilute potashor acids,the

nitrilesabsorb water and become acids.

C2H6CN + 2H20 = C2H5COOH + NH3

Propionicacid.

That is,startingwith ethyliodide,CgH5I,a substance containingtwo carbon atoms,propionicacid,containingthree,is obtained.

On reduction,the nitriles become amines,thus

CTT /T\T " oTJ C" TI r^TI ATTI"J[j.el/l" T "wHn = VyollrVyXlolN Xln." O " ^ O A "

Now one of the generalpropertiesof primaryamines,or those

containingthe " CH2NH2 group, is their decompositionby nitrous

acid with the formation of alcohols,e. g.

C2H5.CH2.NH2+ HN02 = C2H5.CH2OH + H2O + N2.

Consequently,startingwith ethylalcohol,the next highermemberof the series,propylicalcohol,and so on, may be synthesizedby such

reactions.

38 DERIVATIVES OF ALIPHATIC HYDROCARBONS

iii.Acted upon by ammonia in alcoholic solution,ethyliodide

givesrise to a mixture of the substituted ammonias.

C2H5NH2

Ethylamine.

= HI + (C2H5)2NH

Diethylamine.

C2H6;Ij+jH;N(C2H6)2= HI + (C2H5)3NTriethylamine.

and (C2H5)3N+ C2H5I = (C2H5)4N.ITetraethyl-ammonium-iodide.

iv. Ethyliodide readilyacts on finelydivided zinc or magnesium,formingthe metallo-organicderivatives. These are a particularlyreactive group of substances,and may be employedin a varietyof

syntheses.The magnesium derivatives have,for the last six years,

replacedthe spontaneouslyinflammable zinc compounds.With ethyliodide the followingreaction takes placein etherial

solution :"

C2H6

and the resultingcompound may be employedfor many syntheses,for example,for those of the secondaryand tertiaryalcohols.

Magnesium ethyliodide reacts with aldehydessuch as acetalde-

hyde,CH3CHO, and ketones,such as acetone,CH3.CO.CH3,accordingto the followingreaction :"

*= CH3.CH/"gI

vC2H5 \U"ii,

and CH3.CO.CH3 + MgLC2H5 =

'j**l xyjJij

C

ICH3

CH3

and the resultingcompounds are decomposedby water and dilute

acids yieldingsecondaryalcohols from the aldehyde,and tertiaryfrom the ketones.

Methyl-ethyl-carbinol.

SYNTHESIS OF ALIPHATIC DERIVATIVES 39

CH3 CH

CH6 CH3Dimethyl-ethyl-carbinol.

They can also be employedfor the synthesisof saturated and

unsaturated hydrocarbons,ethers,ketones,aldehydes,carboxylicacids,phenols,thiophenols,"c.

v. Symmetricalderivatives of ethane are usuallypreparedfrom

ethylenedibromideCH2Br

CH2Br

a substance which can be easilyobtained by passingethylene

CH2

CH,L2

into bromine. This unsaturated hydrocarbonresults from the

dehydrationof ethylalcohol by means of sulphuricacid.

CH2;H j CH2 Br CH2Br

CH2jOH; *CH2 Br CH2Br

The bromide obtained by this reaction undergoesthe same

generalreactions as those previouslydescribed,e. g.

CH2BrJ ^

CH2OH COOH

I AgOH I Oxidation .

CH2Br CH2OH COOH

Glycol. Oxalic acid.

CH2Br CH2CN CH2.COOHI

z KCN I" Sapomfication

CH0.CH2Br CH2CN CH2 .COOH

Succinic acid.

The various syntheticreactions which can be carried out by means

of acetoacetic ester or malonic ester will be found described in any

textbook,but sufficientexampleshave been givento show clearlythat it is not the paraffinsthemselves but their more reactive

oxidation productsor halogenderivatives which are employedin

the preparationof members of the aliphaticseries.

40 DERIVATIVES OF AROMATIC HYDROCARBONS

OUTLINE OF METHODS EMPLOYED IN THE SYNTHESES OF

DERIVATIVES OF AROMATIC HYDROCARBONS.

The readiness with which the aromatic hydrocarbonstake partin the most varied reactions sharplydistinguishesthem from the

other group, and their reactivityis such that they constitute the

practicalfoundation for the synthesesof the aromatic derivatives.

The rapidand brilliant developmentof the chemistryof this group

is largelydue to the fact that the parenthydrocarbonsare easilyaccessible in largeamounts. They are presentin coal-tar,in the

tar from peat,and in smaller quantitiesin that from wood and

bitumenous shales,and also in some varietiesof petroleum.Acted upon by nitric or sulphuricacids,the hydrocarbonsof

this seriesreadilypass into nitro or sulphonicacid derivatives,and

from these,but more especiallythe first,a largeseries of substances

can be formed.

A. Nitrobenzene,C6H5NO2, an example of the class of nitro

derivatives,is formed quantitativelyby actingon benzene with a

mixture of nitricand sulphuricacid.

C6H6;H + "OH!N02= C6H5NO2 + H2O

By this means one group is very readilyintroduced into the nucleus,

a second with more difficulty,and up to the presentit has not been

found possibleto introduce more than three. Now nitrobenzene

can be easilyreduced to aniline,C6H5NH2, by means of tin and

hydrochloricacid or other similar reducingagents. This substance,which is the phenylderivative of ammonia, lends itselfparticularly

readilyto a most varied series of synthesis.On solution in acids

and treatment with nitrous acid at a low temperaturethe diazo

substances are formed,e. g.

^NC6H6NH2.HC1 + HN02 = C6H6-N +2H2O

Cl

Diazobenzene chloride,producedin this reaction,is an explosivebody,but its isolation is unnecessary since the followingreactions

are all carried out in solution.

i. On boilingwith strong alcohol the hydrocarbonsresult.

C6H6.N2.C1 + C2H6OH = C6H6 + N2 + HC1 + CH3CHO

ii. Acted upon by cuprous bromide,chloride,or iodide,the cor-responding

halogenderivatives are formed.

C.H..N..C1 -" C6H6C1+N2

SYNTHESIS OF AROMATIC DERIVATIVES 41

iii. On boilingwith water the diazo group is replacedby

hydroxyl.C6H5.N2.C1+ H20 = C6H6OH + HC1 + N2

Phenol.

iv. If the diazo salt is acted upon by a solution of copper

sulphatemixed with potassiumcyanide,the nitrilesare formed.

C6H6.N2.CN -* C6H6CN + N2Benzonitrile.

v. On reduction phenylhydrazineis formed. This substance

is one of the most reactive among the aromatic derivatives,and will

be described later.

C6H6 . N2 .Cl + 4H = C6H6NH - NH2 .

HC1

Phenylhydrazinehydrochloride.

vi. Acted upon by aniline,the diazoamido derivativesresult.

C6H5 .

N :N.p + H!NHC6H6 = C6H5 .

N : N.NHC6H5 + HC1

Diazoamido-benzene.

The resultingsubstance on standingin presence of an acid under-goes

intramolecular change and becomes ^-amidoazo-benzene,the

simplestrepresentativeof the azo dyes.

C6H5 .N : N.NHC6H6 -" C6H6 .

N : N" "

j"amidoazo-benzene.

B. The ease with which the sulphonicacids are produceddis-tinguishes

the aromatic hydrocarbonsfrom the aliphatic.These

substances are readilyobtained by heatingthe former with concen-trated

or fuming sulphuric; it has not been found possibleby this

means to introduce more than three of these sulphogroups.

C6HjH + OH;.SO2OH = C6H5SO2OH + H2OBenzene sulphonicacid.

The resultingderivatives or their sodium salts possess a high

degreeof solubilityin water, and consequentlythe introduction of

the sulphogroup is of the greatestvalue when such a propertyis

desirable,as, for instance,in many of the organicdyes.The two followingreactions are characteristic of the sulphonic

acids.

i. When fused with potash,phenolsare formed,a reaction used

in the technical preparationof resorcinoland other phenols.

C6H5;S02OK+ KiOH = C6H6OH + K2SOS


ii. Distilled with potassiumcyanidethe nitrilesare formed.

CgHgjSO^ + KjCN = C6H5CN + K2S03

C. The third method used for the preparationof the aromatic

derivativesdependsupon the characteristic behaviour of the benzene

homologueson oxidation. Toluene,C6H5CH3, for instance,givesbenzoic acid,C6H5COOH, and,generallyspeaking,on oxidation the

side-chains are replacedby carboxylgroups, whilst the nucleus

remains untouched. As previouslymentioned,many of the homo-logues

are found in coal-tar,or may be synthesizedby the reactions

described ; the most importantof these syntheseswas originatedbyMM. Friedel and Crafts. When the alkylderivatives of the aliphatic

hydrocarbons,preferablythe chlorides,are dissolved in benzene and

treated with aluminium chloride,hydrochloricacid is evolved and

the aliphaticradical is linked on to the benzene nucleus,e. g.

(i)CH.P + HjC.H, = HC1 + C6H6CH3

or 6CH3C1 + C6H6 = 6HC1 + Ce(CH3)6Hexamethyl benzene,

or (ii)CHp3 + 3H:C6H5 = 3HC1 + CH(C6H5)3Triphenylmethane.

or (iii)C6H5 . CHjCl+ H!C6H6 = HC1 + C6H5 . CH2 . C6H5

Diphenyl methane.

A similar reaction also takes placebetween benzoylchloride and

benzene with the formation of diphenylketone.

(iv)C6H5CO!CiTfi;C6H5= HC1 + C6H5.CO.C6H5

Diphenylketone or

Benzophenone.

and between carbonylchloride and benzene with formation of

benzoylchloride.

(v)C6HjH + CijCOCl= C6H5COC1 + HC1

The reaction is of very considerable importance,but will onlytake

placeprovidedthe chlorine atom is attached to aliphaticresidues or

in the side-chain of a benzene derivative,such,for instance,as (iii)

or (iv)above. Phenylchloride,C6H5C1,for example,cannot replace

methyl chloride in reaction (i).The part playedby aluminium

chlorideprobablyconsists in the formation of double compoundssuch

as C6H5A12C15,which with methylchloride,for instance,regenerate

A12C16and givetoluene,C6H5 . CH3. But besides bringingabout



and the alcohol behaves on oxidation in a preciselysimilar manner

to ethylalcohol,

C6H5CH2OH -" C6H6CHO -^ C6H5COOH

Benzaldehyde. Benzole acid.

ii.With potassiumcyanidebenzylcyanideis formed.

C6H6CH2;C + K!CN = KCN + C6H5CH2CN

This nitrilefurther behaves like ethylnitrile,and on saponifica-tion givesthe correspondingacid,phenylacetic,C6H5CH2 . COOH,and on reduction the amine C6H6CH2.CH2NH2 .

iii. On treatment with ammonia or primary and secondaryamines the correspondingsubstituted amines result,

C6H6CH2;C1 + H;NH2 = C6H5CH2NH2

or C6H6CH2:C1+ H!NHC6H5 = C6H6CH2NHC6H5 + HC1.

Now none of the above reactions take placewith chlortoluene,

C"H*"CH3When the chlorine atom, or, generallyspeaking,the halogen,is attached directlyto the nucleus it is so tightlyheld that the re-actions

which are employed in the formation of derivatives of the

open-chainhydrocarbonsare no longeravailable for the preparation

of the correspondingbenzene derivatives. Chlortoluene on oxidation

giveschlorobenzoic acid

/en

and this substance can pass through a number of changes,in all of

which the chlorine atom remains attached to the nucleus. It isonlywhen the so-called negativecharacteristics of the benzene ringhave

been depressed,as, for instance,by the introduction of nitro groups,

that the reactivityof the chlorine atom appears. So much so may

this be the case that in picrylchloride,C6H2 (NO2)3C1,for instance,where there is an accumulation of three such groups, the chlorine

shows much about the same power of takingpartin reactions as the

very reactive benzoylchloride previouslyalluded to.

PHYSIOLOGICAL CHARACTERISTICS 45

B. GENERAL PHYSIOLOGICAL CHARACTERISTICS

OF THE HYDROCARBONS.

The aliphatichydrocarbonsare on the whole less active physio-logicallythan those of the aromatic series. The lower members of

the marsh-gasseriesproducesleep,and, if inhaled,eventuallycausedeath by asphyxia.The toxic propertiesof this series increase as

the carbon atoms become more numerous. Hexane is activelyin-toxicant,

producinga long stageof excitement,followed by deepanaesthesia. Octane,which is contained in the commercial ligroineand in crude petroleum,producesa similaranaesthesia ; in addition,there is a tendencyto vomiting(Versmann). The unsaturated

hydrocarbons,ethylene,propylene,and butylenehave very similar

action ; amylenehas propertiesresemblingthose of chloroform,but

is not so safe. Acetylene(oneper cent, in air)producesnarcosiswith failure of heart and respiration.Lauder Brunton has pointedout that the characteristicaction of these aliphatichydrocarbonsis on the nerve centres,tendingto produceat first excitement

and then narcosis; they act on the sensory side ; the aromatic

hydrocarbons,on the other hand,act mainlyon the motor side,pro-ducing

convulsions and paralysis.1Benzene givesrise to slightparesisof the voluntarymuscles,but its principalaction is on the

higher cerebral centres, producinglethargyand somnolence.

Later,a kind of f intention tremor 'occurs in the voluntarymuscles.

Diphenyl,C6H5 . C6H5,however,ispracticallyinert,and this remark-able

diminution in physiologicalactivityextends to many of its

compounds.Naphthalene,which is lesstoxic than benzene,slows the respira-tion

; small doses raisethe blood pressure, whereas largedoses depressit. It decreases nitrogenousmetabolism,and has an antipyreticaction ; it has more narcotic action than phenol.

The hetero-cycliccompoundspyrrol,furfurane, and thiophenetoa certain extent resemble benzene in their physiologicalaction.

CH=CH"v" AA vy AAV

Pyrrol I ;"NH is more toxic thanr"TT ntr/CH=

Pyridine CH N and

\CH=CH/1 The solid or liquidnonvolatile hydrocarbonsare without physiological

action,and pass through the body unaltered. Hence the uselessness of

petroleumemulsion as a food-stuff or as a drug.

46 PHYSIOLOGICAL CHARACTERISTICS

PiperidineCH2"2~2"NH far more so than pyridine.

The physiologicalreaction of these reduced derivatives decreases

with the size of the chain,thus pyrollidine

CH2 " CH2\NHI

C H2" CH/

is less active than piperidine.The various substitution productsof the hydrocarbonswill be

dealt with in the subsequentchapters,but some generalremarks on

alkylgroups, as theyaffect physiologicalaction,may convenientlybe made here.

i. The physiologicalaction of an aliphaticcarbon system is

generallyincreased by the entrance of alkylgroups ; this is also

observed in the aromatic series when the magnitudeof the side-

chain is increased by the addition of such groups. But with the

increase in molecular weightthere generallyfollows a decrease in

solubility,volatility,"c.,and consequentlythere comes a periodin

an homologousserieswhen physiologicalreactivitybeginsto decrease

owing to lessened absorptionby the organism. This is illustrated

in the case of the simplealcohols,where the lower members show

increasingreactivityas the series is ascended,whereas the highermembers are quiteinert substances.

ii.In the cycliccompounds the replacementof the hydrogenatoms of the ringby alkylgroups causes a considerable changein

physiologicalaction,not always,however,in the same direction.

In the case of benzene,toluene,xyleneand mesitylenethe effectof

increasingthe number of methylgroups is to cause a diminution of

activity,and to some extent a qualitativemodification.

In anilineand thiophene,on the other hand,considerablyincreased

toxicityresults from substitutingthe hydrogenof the nucleus by

alkylgroups ; in phenolthe antisepticpower is increased,whilst

the toxic action is diminished by such substitution,as in

1 : 3-Cresol3

iii.In the pyridinehomologuesthe intensityof the action is in-creased

by the entrance of alkylgroups. Pyridinehas the leastphysio-logicalaction ; picoline(methylpyridine)is stronger,dimethyl

pyridinemore so, whereas collidine (trimethylpyridine)is about

six times,and parvuline(tetramethylpyridine)nearlyeighttimes as

OF THE HYDROCARBONS 47

powerfulas the parentsubstance. The entrance of the alkylgroupdoes not lead to a change in the degreeof their activityas drugs,but alters their specificeffect so that the physiologicalreaction of the

resultingderivatives resembles that of the natural alkaloids.

iv. The replacementof the hydroxylhydrogen atom in the

alcohols is followed by a very considerable rise in volatilityand an

increase of stabilitytowards oxidizingagents. The hypnoticethyl

alcohol,C2H5OH, for example,passes to the anaesthetic substance

ether,C2H5.O.C2H5.The inert glycerolbecomes the narcotic

glycerin-etherCH," O" CH,

CH O" CH

CH2" O" CH2

In the aromatic seriesthe antisepticphenol,C6H5OH becomes the

inert phenetol,C6H6OC2H5. In pyrocatechin

p TT /OH , 9"6n4\OH -1

the replacementof one or both of the phenolichydrogen atoms

resultsin substances of less toxic nature. But on the other hand

a similar replacementin the case of resorcin

C6H4(OH)21:3 giving1:3 C61

resultsin an increase of toxicity.In the case of 1 : 4-amido-phenol

/OH

a decrease in toxicityfollows the replacementof the phenolic

hydrogenby either the methylor ethylradical.

v. If the hydrogenatoms in ammonia are successivelyreplaced

by alkylgroups, the resultingprimary,secondary,and tertiaryamines show diminishingphysiologicalreaction,the specialconvul-

sant effect of ammonia beinglost. But as the tertiaryamines pass

over to the ammonium compounds a great increase in toxicity

occurs, and theyapproachin their action many of the alkaloids.

When the hydrogen atoms of the NH2 group in aniline are

replacedby alkylgroups the physiologicalaction of the resultingsubstances correspondsto that of the aliphaticamines,and the con-

vulsant action is depressed.But, on the other hand, as previously


remarked,the introduction of alkylsinto the nucleus of aniline

increases its convulsant action.

The narcotic amides of the aromatic series,such as benzamide,

C6H6CONH2, and salicylamide,

i . oX

losethis action on the replacementof the amido hydrogenatoms,and

the resultingsubstances in largedoses are convulsants,like ammonia

and strychnine.vi. The imido hydrogensin xanthine may be substituted by

methyl,and the resultingcompounds,mono-, di-,and tri-methyl-xanthine show a physiologicalreactivitywhich varies considerablyfrom that of the parent substance. The most strikingdifference is

in the action on the cardiac muscle,which developsin proportiontothe number of methylgroups.

vii. It is of course only to be expectedthat in those cases

where the replacementof a hydrogenatom by alkylgroups entirelyalters the chemical nature of the resultingsubstance,that a corre-sponding

changein physiologicalcharacteristicswill appear. For

example,the replacementof the carboxylichydrogenof the organicacids leads to the productionof bodies entirelywithout acid pro-perties

(esters),and with altered physiologicalaction; thus the

toxic oxalicacid givesriseto the narcotic diethyloxalate. Similarlysalicylicacid givesthe less toxic methyl ester (oilof wintergreen).The changeproducedin the acidic or toxic substance phenolon con-version

into its inert ethers has been previouslymentioned. On the

other hand,physiologicalactivity,which had been hindered by the

presence of the carboxylradical,may again be brought out bythe replacementof the hydrogenatom, as is seen in the case of

cocaine. Somewhat similar is the alteration producedin the

chemicallyreactive imido derivatives by substitution of the

hydrogen atom, resultingin the formation of more stable sub-stances.

This may cause the appearance of physiologicalpropertieswhich are absent in the parentsubstance ; thus l-phenyl-3-methylpyrazolon(p.204),containingan NH group, is entirelywantingin the characteristic antipyreticpropertiesof antipyrine,whichcontains an N.CH3 group; or it may result in a decrease of

toxicity,as in case of 1-hydroxy-tetra-hydroquinoline;this sub-stance

(oritsmethylester)possesses marked antipyreticproperties,but is a protoplasmicpoison,and hence cannot be used as a drug.

OF THE HYDROCARBONS 49

Fischer and Filehne ascribed the toxic secondaryeffectsto the

presence of the reactive imido group, and theyfound,as expected,that on convertingthis into 1-hydroxy-tetrahydro-w-ethylquinoline,and so increasingthe stability,theyobtained a derivative with far

less toxic action,introduced into pharmacyin 1883 under the name

of Kairine.

CH2

:H

1-Hydroxy-tetrahydro- 1-Hydroxy-tetrahydro-quinoline. n-ethylquinoline(kairine).

"Differences between the Methyl and Ethyl Groups.

The ethylgroup appears to have a certain affinityfor the central

nervous system,as many substances containingthis radical have

pronouncedhypnoticpropertieswhich are entirelywantingin the

correspondingmethylderivatives. This is strikinglyshown in the

group of sulphones,whose hypnoticpropertiesappear to be solelydetermined by the presence of the ethylgroup, since the methylderivatives are quiteinert. 1 :2-amidophenolhas no hypnoticproperties,but when the hydrogenatom of eitherthe hydroxylor the

amido group is replacedby methyl,derivatives with slightnarcotic

power result,thus

and

have slightnarcotic properties,but the triethylderivative on the

other hand

OCH

has pronounced action. In this connexion itis interestingto note

Ehrlich and Michaelis's observation that certain dyescontaininganamido group in which both hydrogenatoms have been replacedbyethyl,thus

-N"c:2;'***"

E


are capableof stainingnerve structure,whereas the correspondingdimethylcompounds

\CHS

do not possess thisproperty.It has been observed that dulcin

has an extremelysweet taste,whereas the correspondingmethylderivative isentirelywantingin this property.

Unsatnrated Substances.

An importantfactor in the physiologicalaction of organicsub-stances

is the presence in the molecule of un saturated or doublyunsaturated carbon systems. The apparentlylow valencyshown

by carbon in various series of compounds has previouslybeen

discussed,and the difference in the significanceof the double bond

in open and closed chain derivatives described (pp.26,28).Generallyspeaking,open-chainderivativescontainingunsaturated

carbon atoms are more toxic than the correspondingsaturated bodies.

Thus allylalcohol,CH2 : CH.CH2OH, is fiftytimes more toxic than

fl-propylalcohol,CH3. CH2. CH2OH. Acrolein,CH : CH.COH,

and croton-aldehyde,CH3 .CH : CH.COH, are more toxic than the

correspondingsaturatedaldehydes.On the other hand,allylamine,CH2 : CH.CH?NH2, is without

physiologicalaction,but vinylamine,CH3 .

CH : CHNH2, is very

toxic. Generallyspeaking,the group (C : CH.NHg)" appears

to be especiallyactive in this respect.With these examplesmay be comparedsafrol

/CH2 .CH : CH2 1

C6H3^-O\nTT 3

3\0"CH* 4

the most toxic of all the etherialoils,and the "much less poisonousisosafrol

"V/J.JL

Q"CH:CH.CH3

CH2

The doublyunsaturated di-iodo-acetylene,CI jCI, is stated to

be one of the most toxic bodies known.



the primaryand secondaryalcohols may be compared. Here the

isomeric secondaryhave greaternarcotic and toxic characteristics

than the primaryalcohols. The differingtoxicityof allylamineand its isomer vinylaminehas alreadybeen mentioned. In the

aromatic series the isomeric ortho,meta, and para substitution

productsoften vary considerablyin their therapeuticor toxic

capacity,but there is no generalrule as to which of the three will

be more and which least active.

Bokorny found that 1 : 4 compounds were generallymore toxic

for the lower plantsand animals,thus

1 : 4-nitrophenol,C6H4 ,1 :4-nitrotoluene,

1 :4-bromtoluene,

are all more toxic than their isomeric 1 : 2 or 1 : 3 derivatives. On

the other hand, 1 :2-nitrobenzaldehydeis more toxic than the 1 :4

derivative,and salicylicacid

n TI /OH

is the only one of the three isomeric oxybenzoicacids which is

therapeuticallyactive.

Gibbs showed that the toxic dose per kilo weightof the dioxy-benzenes was

.06 gm. in the case of 1 : 2 C6H4"^**,-1 gm. with 1 : 4 C6

/OTTand in the case of resorcin,1 : 31C6H4/Qjj,1-0 gm.

The three isomeric amido-toluenes showed very similar physio-logicalaction. Injectedinto the jugularvein of a dog the follow-ing

amounts representedthe toxic doses per kilo weight:

1 :2-toluidine,C6H4"3 = .208 gm.,

1:3= -125 gm., 1 : 4 = -10 gm.

Occasionally,unlike the precedingcase of the toluidines,there is

an alteration in specificaction dependenton the relativepositionofthe substitutinggroups in benzene. The three cresols

are an exampleof this. They stimulate the vagus centre,causingheart failure,and also act peripherallyon the nerve endingsand

ISOMEBISM 53

are vasomotor poisons.All three cresols act equallyon the peri-pheralnerve endings,but ortho- and para-cresol,especiallythe former,

are much more powerfulvagus stimulants,whereas ortho- and meta-

cresol act more markedly on the vasomotor system. Numerous

other instances will be found in the subsequentchapters.

Stereochemical relationships.

Pasteur in 1860 described the connexion between chemical con-figuration

of molecules and their action on ferments,and showed

that while certain moulds were capableof breakingdown dextro-

rotatorytartaric acid,they had no action on the foeiw-rotatoryacid. Emil Fischer described many sugars which react towards

ferments in a similar manner, one opticalisomer beingattacked byan enzyme, the other not. He thoughtthat the explanationofthe phenomenon ' probablylies in the structure of the enzyme

. .

.for doubtless the enzymes are opticallyactive and consequently

possess an asymmetricstructure'. This led to the view that the

molecular configurationof the enzyme and of the fermentable sugar

are complementary,so that ' the one may be said to fitthe other as

a key fitsa lock '. But it must be remembered that we are in a state

of profoundignoranceas to the configurationof the enzymes. As

regardsthe animal organism,Brion found that laevo- and meso-

tartaric acids were oxidized to an almost equalextent and that dextro-

tartaric was attacked to a much less extent than either,whereas

racemic acid was least oxidized of all these stereochemical isomers.

These examples are sufficient to indicate that there is an

unquestionableinterdependencebetween the stereochemical con-figuration

of the molecule and physiologicalaction.

That the configurationof the molecule has an influence upon the

sense of taste is illustratedin the case of fetfro-asparagine,which

is sweet, whilst the laevo-rot"torymodification is not; dextro-

glutaminicacid is sweet,whereas the laevo acid is tasteless.

The influence of configurationon the toxicityof isomers has been

observed in some cases, thus the local anaesthetic action of dexlro-

cocaine on the tongue is strongerand sets in more rapidlythan that

of the laevo modification,althoughthe effect is not so lasting.Mayor states that laevo-nicotme is twice as toxic as the dextro

derivative. Atropinehas a more powerfulstimulatingactionon the spinalcentres than hyoscyamine. But one of the

most interestingobservations was that made originallyby Crum


Brown and Fraser, who showed thatmany alkaloids, when acted

upon by alkyl iodides, gained acurare-like action (paralysis of ends

of motor nervesof muscles) without losing their individual charac-teristics.

In all thesecases

the conversion of nitrogen from the tri-

to the quinquevalent conditionoccurs (see pp.

2 and 20). That this

newcharacteristic is dependent on

thespace

relations of the molecule

is clearly shown by the investigation of analogous substances, and

of changes in bodies not containing nitrogen. Thus it has been

shown that phosphorus, arsenic, and antimony derivatives lose

their physiological characteristicson being converted, by the

action of alkyl iodides, into salts of the phosphonium, arsonium,

and stibonium bases, whichpossess strong curare-like action.

This clearly indicates that the change in physiological action

is not merely dependent onthe

passageof trivalent atoms to

quinquevalent, but ratheron

the change in stereochemical configura-tion

; " on a change froma plane to

atridimensional arrangement of

the atoms. This is stillmore clearly shown in Curci and KunkePs

observation that the change of the inert dimethyl-sulphide, (CH3)2S,

to trimethyl-sulphine-hydroxide, (CH3)3S .OH, also results in the

appearanceof the

curarecharacter. Now, in the

caseof sulphur,

adivalent element, the configuration of the sulphide must be plane,

but with theappearance

of two extra valencies in the second

derivative the configuration changes to the solid, asshown by the

fact that such substancesmay

exist in optically active forms.

CHAPTEE III

CHANGES IN ORGANIC SUBSTANCES PRODUCED BY

METABOLIC PROCESSES

Syntheses " Sulphuric and Glycuronic acid derivatives*Compounds of

Amidoacetic acid, Urea. Sulphocyanides. Introduction of Acetyl and

Methyl radicals. Cysteinderivatives. Processes of Oxidation and Reduction.

THE investigationswhich have been made on the changesproducedin organic substances by their passage through the organism have

led to the generalizationthat such changesalwaystend to the forma-tion

of less toxic bodies. From the pointof view of the synthetic

preparationof drugs,it is most important to observe that these

modifications generallylead to the productionof derivatives with

more acidic properties" or, in other words, the introduction of

acid groups tends to lower the toxicityof an organicsubstance.

If the course of a drugthroughthe system is followed,it isfound

that no reaction takes placein the mouth, but in the stomach the

hydrochloricacid presentmay cause an increase in the solubilityof

basic substances,and also cause the breakdown of such derivatives

as the anilides into aromatic amines and acids,and the absorptionof basic substances will consequentlystart from this region.The

pepsinpresenthas littleif any action. In the intestines the alkali

presentmay cause an increase in the solubilityof organicacids,orthe decompositionof their metallic salts,but a much more impor-tant

action is that of the pancreaticjuiceand bile which bringabout the saponification,not only of the fats,but of such esters

as salol,givingphenoland salicylicacid. Nencki was the first

to realize the value of this fact,and his so-called c salol principle',founded upon this,will be described in detail later on.

But it is in the tissues or blood that the more profoundchangesof oxidation and reduction take place. Besides these two main

alterations,various syntheticprocesses are also carried out,all tend-ing,

as previouslymentioned,towards a reduction in the toxicity

56 METABOLIC PROCESSES

of the originalsubstance. The latter processes will be described

first,thoughit generallyhappens that theyfollow those of oxidation

or reduction before the final elimination of the substance in the urine.

A. SYNTHETIC PROCESSES.

Of these the most importantthat take placeare with sulphuricand glycuronicacids or amidoacetic acid. Next in importanceis

the formation of urea derivatives and sulphocyanides,and, less

seldom met with,the introduction of acetylor methyl groups and

the productionof cysteinderivatives. Although this does not

exhaust the various reactions which have been described,it includes

all the more important,and in the discussion of these only a few

typicalexamplesof each will be given.It does not often happen that a particularsubstance is excreted

entirelyin any one form, as for instance as a sulphonicester ; it

may be found chieflyin that form,but also partiallyas a glycuronicacid derivative,or even partiallyunchanged,this may depend on

dosage or other factors quiteunknown. Consequently,in the

various reactions discussed,it must be understood that the elimina-tion

of the substance in questionchieflyoccurs by means of the

synthesisunder which it is described,but that at the same time

others may take place,which,judgingfrom the relative amounts

in the urine,are of lesserimportance.

I. Sulphonic Esters.

The sulphuricacid requiredfor the productionof these sub-stances

must be formed by the oxidation of albuminous bodies

containingsulphur,and in this connexion it may be mentioned

that etherialhydrogensulphatesin the urine are generallyincreasedin conditions interferingwith the normal performanceof the

hepaticfunctions. The etherial sulphatesnormallyfound in the

urine representonlyone-thirteenth of the totalsulphates.Thoughpartiallyderived from tissues,the greaterpart are due to proteindecompositionin the intestine,hence their increase in conditions

of intestinal putrefactionand obstruction. When decompositionof proteinmatter within the organismis takingplaceon a largescale,as e. g. in foul empyemata, or gangrene of internal organs,

a similar increase in etherial sulphatesin the urine is noted.

Indican (indoxylpotassiumsulphate),which occurs in small

amounts in normal urine,is increased under like conditions.

FORMATION OF SULPHONIC ESTERS 57

Aromatic substances containinghydroxyl,(OH), in the nucleus

are generallyfound combined with sulphuricacid as alkali salts in

the urine,synthesiswith glycuronicacid also takingplace.Phenol, C6H6 . OH, for instance (besidesundergoingfurther

oxidation to dioxybenzenes),is found as phenylsulphuricacid,the followingreaction takingplace:"

C6H5OiH + OH;SO2 .OH = H2O + C6H6 . O.SO2 .

OH.

The free acid itself is unknown, since on liberation from its

salts by stronghydrochloricacid,it immediatelybreaks down into

sulphuricacid and phenol. Such substances,althoughstable in

aqueous or alkaline solutions,are readilydecomposedby mineral

acids.

The toxicityof phenolhas consequentlybeen diminished by this

synthesis,and it was onlyto be expectedthat sodium or potassiumphenylsulphateshould be non- toxic substances. Further than this

the introduction of the sulphonicacid groupinginto the ringitself,givingriseto phenolsulphonicacid

prr/OH

producesa substance which isequallyinnocuous.If the hydroxylderivative itself is non-toxic,owing to the

presence of some groupingin the ring,then it passes unchangedthroughthe organism; an exampleof this ishomogentisinicacid

OH 1

3\CH2.COOH5whereas the correspondinggentisinicacid,

/OH 1

C6H/OH 4

\COOH 5

which is toxic,is partiallyeliminated as the non-toxic sulphuricacid derivative. Similarlythe highlypoisonoushydroquinone

r " /OH ,.C6H4\,OH

leaves the systemin the form of itssulphonicester.Many of the aromatic ketones are oxidized to acids in the body,

but when they contain a hydroxylgroup, and the possibilityof

combination with sulphuricor glycuronicacids appears, then these


lattersynthesestake placeto the exclusion of the former. Aceto-

phenone,C6H5 . CO.CH8, for instance,is oxidized to benzoic acid,

C6H,COOH, but

i

Paeonol C6H3^-CO.CEL 2

\0,CH3'5OH

GallacetophenoneC6H

cO.CH3 4

(OH 1

and ResacetophenoneC6HJOH 3

(CO.CHg4

are found in the urine as their sulphuricand glycuronicacidderivatives.

The entrance of an acid group into the nucleus of the phenolscauses the loss of this power of unitingwith sulphuricacid,for

instance,salicylicacid

p TT /OH 1

2

and also the 1 :4 isomer (bothmuch less toxic than phenol)are not

eliminated as esters,but behave like benzoic acid. When the acid

character is lost,however,either by conversion into an ester such as

r n /OH 1

^6il4\coO.CH32

or an amide

PIT /OH 1

these bodies regaintheir characteristicsand are found as sulphuricderivatives (Baumann and Herter); the introduction of more

hydroxylgroups into the ring causes the reappearance of this

synthesis,as in the previouslymentioned case of gentisinicacid or

protocatechuicacid,

fCOOH 1

C6HJOH 3

(OH 4

also vanillicacid,(COOH 1

C6H3 OCH, a6 3lOH 3

4



and then the primaryalcohol group presentis oxidized,with the

resultthat glycuronicacid derivatives finallyappear. As regardsthe nature of the resultingcompounds,theyappear to be (atall

events in the case of aliphaticsubstances),very analogousto the

glucosides.Taking chloral as an example,it is found that it is

reduced in the body and eliminated as urochloralic acid,a synthesiswhich may probablybe representedby the scheme

1. CCL, .CHO + H2 = CC13. CH2 .

OH

Chloral. Trichlorethylalcohol.

2. COOH COOH

CH.OH CH.OH

CH.OH CH.OH

CH.OH + CC13 -" CH.OH

CHOH CH2 CH.OH

I I I /OHCHO OH CH"

Glycuronicacid.

COOH

!HOH

\O.CH2.CC12

H2O + CHOH

O

!HOH

[^-O.CH2.CC13Urochloralic acid.

It appears, however,that a differenttype of combination can take

place; thus Y. Kotake 1 has shown that rabbits dosed with vanillin

eliminate in the urine a glycuronicacid derivativeof vanillicacid,the

first reaction consistingin the oxidation of the aldehyde,which

1 Zeit.f.physiol.Chem.,45, 320.

GLYCURONIC ACID DERIVATIVES 61

then condenses with glycuronicacid without the elimination of

water,

1. fCHO 1 fCOOH 1

C6H3 O.CH33 C6H3 O.CH8 3

(OH 4 (OH 4

Vanillin. Vanillic acid.

2. COOH COOH

I (COOH |(CHOH)4 + C6H3 O.CH3 =(CHOH)4I (OH | OH

"bHO CH" cCOOH

IO.CH3Blum has shown that thymolbehaves in a similar manner,

C3H,.CH3.C6H3OH+ CeH1007= C3H7.CH3.C6H3O.C6H11O7and Fenivessythat carbostyrilalso unites with glycuronicacidwithout the elimination of water,

(C6H4)C3H2N.OH+ C6H1007= (C6H2).C3H2N.O.C6HnO7.There does not seem to be any sharpline of demarcation drawn

between these two groups by any of the investigatorsof these

glycuronicderivatives. In but relativelyfew cases have they been

isolated in a state of purity,the statement usuallymet with beingthat such and such a substance is eliminated conjugatedwith

glycuronicacid.It ispossiblethat hydroxyderivatives of the aliphaticserieswhich

combine with this acid do so in a similar manner to trichlorethyl-alcohol,i.e. form true glucosides; such are bromal and butylchloral,which are firstlyreduced to the correspondingalcohol ; the

secondaryalcohols and,to a much less extent,the primary(exceptmethyland ethyl,which are readilyoxidized),and alsoalcoholsof highmolecular weight;some polyhydricalcohols,such as propyleneglycol,but not glycerol1 ; many aliphaticketones,such as dichloracetone,which are firstlyreduced to their secondaryalcohols. Acetoacetic

ester is firstlyoxidized to carbon dioxide and acetone,and this

latter reduced to secondarypropylalcohol; it is then eliminated as

itsglycuronicacid derivative. Finallycome tertiaryalcohols,suchas tertiarybutyl,tertiaryamyl,and pinacone.

On the other hand some aromatic hydroxylderivatives may form

addition productssimilar to those producedwith vanillic acid or

1 Otto Neubauer,Chem. Centr.,1901,ii.314,from Arch. Exp. Path. Pharm.,

46, 133-54.


thymol,but no definitestatement can be made, since condensation

with elimination of water is stated to take placein the following

cases. Lesnik l found that both a- and /3-naphtholoccurred in

the urine as such derivatives

C10H7OH+C6H100, = C10H7.O.C6H906+ H20.Pellacani 2,confirmed by Bonanni 3,found a similar productin the

case of borneol and menthol,

C10H17OH+ C6H1007= C10H17.O.C6H906+ H20and

CIOH19OH+ C6H1007= C]0H19O.C6H906+ H20.

Schmiedebergand Meyer 4 found that camphorwas firstlyoxidized

to campherol,C10H160 -* C10H15O.OH

and then eliminated as a condensation productwith glycuronicacid,

C10H15O.OH+ C6H1007 = C10H1?O.O.C6H906+ H20.Other investigatorshave noticed reactions correspondingto the

latter in case of carvon, pinene,phellandrene,and sabinene.

Salkowski and Neuberg have recentlyshown that the synthetical

phenylglycuronicacid meltingat 150",and of composition

C6H6O.C6H906is identical with the acid excreted in the urine of a sheepdosed

with phenol.An interestingsynthesisis that undergoneby phenetol,

C6H6OC2H?,which isfirstlyoxidized and then eliminated with glycuronicacid

as the so-calledchinaethonic acid,

C6H5OC2H6 -" 1:4C6

6 c

Another method by means of which the toxicityof a substance

is lowered consists in the addition of water ; Fromm and Hilde-

brandt5 have shown that thujon is converted in the body to

thujonhydrateand then eliminated as a glycuronicderivative,

O.C10H16+ H20 = O.C10H17OHand

O.CIOH17OH+ C6H1007= O.C10HI7O.C6H906.

1 Schmiedeberg,Arch., 24, 167.

2 Arch.f.Exp. Path. u. Pharm., 17, 369.

8 Hoffmeister, Beitragz. Chem. PhysioL,I,304.4 Zeit.f.physlol.Chem., 3, 422.

6 Zeit. f.physiol.Chem.,33, 579.

DERIVATIVES OF AMIDOACETIC ACID 63

III. Derivatives of Amidoacetic acid.

Amidoacetic acid,glycocollor glycineis the simplestamido

acid,and may be obtained syntheticallyby warming monochlor-

acetic acid with dryammonium carbonate.

COOH.CH2jCl + HJNH2 = COOH.CH2.NH2

It is soluble in water,possesses a sweet taste,and was shown byNencki and Schultzens1 to giverise to urea when administered in

food (seep. 74).The fact that glycineand other amino acids giverise to urea

if introduced with food or intravenously,and the fact of their

appearance in the urine in acute yellowatrophy of the liver

(whereurea elimination is decreased correspondingly),are taken

as indicatingthe positionof those bodies as intermediaries between

proteinand urea. This may or may not be true,but if true,some

synthesismust precedethe formation of urea, as the amino acids

contain lessN than C, which is the reverse of what occurs in urea.

The combination of glycineand benzoic acid takes placein the

kidneysubstance,at any rate partially.Minced kidneysubstance

can effect this synthesis,and blood containingbenzoic acid,ifpassedthroughthe livingkidney,is found afterwards to contain hippuricacid.

This typicalsynthesis,the firstof itskind which was discovered,is illustratedby benzoic acid,which forms hippuricacid,

COOH COOH

I.....

ICH2.NH|H + HOjOC.C6H5 = H2O + CH2" NH.CO.C6H5Amidoacetic acid. Hippuricacid.

A similar reaction takes placewith any benzene derivative which,if oxidized in the body,givesriseto this acid or itsderivatives,such,for instance,as toluene,ethylor propylbenzene,xylene(firstlyoxidized to

mesitylene(firstlyoxidized to mesitylenicacid),;?-nitrotoluene,/3-bromtoluene,and in the case of dogsallthe nitrobenzaldehydes.

Salicylic,^?-oxybenzoic,nitrobenzoic,chlor and brombenzoic acids,anisic,a- and /3-naphthoic,toluic,mesitylenicand cuminic acids all

1 Zeit.f.BioL,8, 124,1872.


form derivatives analogousto hippuricacid. In this connexion it

may be mentioned that whereas phenylpropionicacid

C6H5CH2.CH2.COOH

is oxidized in the body to benzoic acid and eliminated as hippuricacid,phenylacetic acid,C6H5CH2. COOH, forms phenylaceturic

acid,C6H5CH2 . CO.NH.CH2COOH ; but this questionwill be

further discussed under the generalheadingof oxidation processes.

The a-carboxylicacid of thiophene,andthe correspondingaldehydeafter oxidation in the organism,behave in a similar manner to

benzoic acid.

a-methylpyridineisfirstlyoxidized to the a-carboxylicacid and

then eliminated as a glycocollderivative.

IV. Urea Derivatives.

The mode of formation of these derivatives isby no means clear;

they may be formed outside the body by the action of cyanicacid on primaryor secondaryamines.

C2H5.NH2 + CONH = C2H6.NH.CO.NH2

Cyanic acid. Ethyl urea.

and it may be that a reaction somewhat analagousto this takes

placein the animal organism.Taurin

CH2NH2

!H2. SO.OH

is eliminated as taurocarbamic acid

CH2.NH.CO.NH2!CH2 . SO2OH

Amido-benzoic and amido-salicylicacids similarlyform urea

derivatives,

and CLHL^-OH/COOH

^NH.CO.NH2,

Schmiedebergnoticed small quantitiesof ethylurea

C2H6.NH.CO.NH2

in the urine after dosingwith ethylaminecarbonate.

Many derivatives appear in the urine as salts of urea. Sieber

FORMATION OF SULPHOCYANIDES 65

and others found that the nitrobenzaldehydesare firstlyoxidized to

their correspondingacids,then combine with glycocollto nitro-

hippuricacids,and that these latter substances then formed salts

with urea.

V. Formation of Sulphocyauides.

Pascheles1 showed that some proteinscontainingeasilysplit-off sulphurcould convert potassiumcyanideinto sulphocyanide,KCNS, at the temperatureof the room, and it is probablethat the

formation in the animal organism of sulphocyanidesfrom the

organicnitrilesmay be ascribed to a similar reaction. With the

exceptionof methylnitrile,CH3CN, the homologuesof this seriesare

very poisonous,and in theirpassage throughthe bodyare converted

into the much lesstoxic sulphocyanides.It is interestingto note

that Nencki2 states that the stomach under normal conditions

contains a minute amount of free sulphocyanicacid. Gscheidlen

found it constantlyin human urine,and the potassiumsalt occurs

normallyin saliva,probablyas an excretoryproduct.

VI. Introduction of the Acetyl Radical.

One of the most interestingexamplesof the introduction of an

acetylgroup in the passage of an organicsubstance throughthe

body was observed by R. Cohn 3,who found that rabbits treated

with 0z-nitrobenzaldehydeconverted this into ^-acetylamido-benzoic acid.

The firstchangeconsistsin the oxidation of the aldehydegroupto the acid,

n PTT/COOHH C

The second,the reduction of nitrobenzoic acid to amidobenzoic,

PI TT/COOH

"TT OTT ri i n TJ yCOOHC"H"N02 +6 = 2H*0 + C"H"NH2

and thirdly,the syntheticformation of the acetylderivative,

COOH CH3 .COOH

|.

=C6H4/ +H20;H;+ COOH; \NH.CO.CHNH;

1 Arch.f.exp. Paihol. u. Pharm.,34, 281.2 Ber.,28, 1318.8 Zeit. physiol.Chem.,18, 133-6.

9


VII. Reactions with Acetic Acid.

Jaffe and Colin l found that furfurol,the aldehydeof furfuran,is partlyoxidized in the organismto the correspondingacid,and

then eliminated as a glycocollderivative,but to a smaller extent it

undergoescondensation with acetic acid to furfuracrylicacid,

CH" CH CH" CH

II I II IICH C.CH:0 + H2!CHCOOH = H20 + CH C.CH : CH.COOH

v vwhich is then eliminated as a derivative of amidoacetic acid,

C4H3O.CH : CH.COOH + H2N.CH2 .COOH

= H2O + C4H3O.CH : CH.CO.NH.CH2COOH

VIII. Introduction of the Methyl Radical.

His2 found that pyridineis eliminated in the urine as methyl-pyridyl-ammoniumhydroxide,and this observation was confirmed

by R. Cohn 3; it is one of the most interestingchangesin animal

chemistry.CH CH

CHlH

Hoffmeister states that an animal dosed with tellurium or

tellurium compounds eliminates tellurium dimethide,Te (CH3)2.

In this connexion it isinterestingto notice that accordingto the

observations of Albanese, Gottlieb,Kriiger,and Schmidt the

methylatedxanthines are deprivedof one or more of their methyl

groups on passingthroughthe organism.

IX. Formation of Cystin Derivatives.

Baumann showed that cystin,one of the primarydissociation

productsof proteins,found in urine in cases of cystinuria,is the

disulphideof cystein,which he formulated

\3H1 Per.,20, 2311. a Archw exp. Path. Pharm., 22.3 Zeit. physiol.Chem.,18, 112-30.


68 OXIDATION PROCESSES

Then in complexcompounds containingoxygen further oxidation

alwaystakes placeat the most highlyoxidized placein the mole-cule,

providedthe carbon at that pointis linked to hydrogen.Thus ethylalcohol,CH3 . CH2OH, is oxidized to acetaldehyde,

CH3.CHO, and this further to acetic acid,CH3 .

COOH ; and

"-oxypropylaldehyde,CH3 . CHOH.CH2 . CHO, is converted into

0-oxybutyricacid,CH3 . CHOH.CH2. COOH, since the aldehyde

group (CHO)'is the most highlyoxidized system in the molecule.

It is a very generalrule that a carhon atom cannot be linked to

more than one hydroxylgroup, and when attempts are made to

introduce more, i.e. on further oxidation,water is splitoff,and the

followinggeneralreactions take place,dependingupon the number

of hydrogenatoms attached to the oxidized carbon :"

CHOH H

Oxidized.

O -"

CH

CEL ==H90+

CH3Propylalcohol.

or O,

CH

CHO

CH2

CH,

Butyricaldehyde.

=H0+

C HSCH

Butyricacid.

The aldehydesare consequentlythe intermediate,and the organicacids the finalproductsin the oxidation of alcohols containingthe

primarygroup X" CH2OH. With secondaryalcohols,i.e. those

containingthe

group, a similar reaction takes place,and on further oxidation theyyieldketones,

CH

A":CH

OH

CH

CH,

CO

CH,

Acetone or

dimethylketone.

SELECTIVE OXIDATION 69

With tertiaryalcohols,such as (CH3)3.C.OH,not containinghydrogenlinked on to the alreadyoxidized carbon atom, further

oxidation is not so easy, and energeticreagents are necessary,

when the molecule breaks down into substances of smaller carbon

content.

3. CH3 CH3.

Oxidation.

CH3" C.OiH -* CH3.COAcetone. ~H2O[~2 ~|

[H.COOHj

Although the above may be taken as a short summary of the

effects of oxidation on aliphaticsubstances (thearomatic will be

discussed later),yet the nature of the actual oxidation processes

which have been observed to take placeon the passage of organic

substances throughthe animal organism are of a different order

from those carried out in the laboratory.Such changesare characterized by a strikingselectiveoxidizing

action ; thus an animal capableof completelybreakingdown many

hundred grainsof sugar to its end productsin twenty-fourhours

is incapableof similarlytreatingsay a few grainsof sodium

formate,which to the extent of 50-70 per cent, of the dose taken

is eliminated unchangedin the urine. Further than this,of these

two changesthe latter is much more readilycarried out in the

laboratorythan the former. Then dextrose and laevulose are

completelydecomposed by the body cells,but the sexvalent

alcohol mannite passes throughwith very littlechange. In this

case the replacementof a " CH2OH group by C HO or

HOH by C=O

I I

has been sufficientto bringabout completeoxidation.

Even stereochemical isomerides are differentlyacted upon ; thus,

in alcaptonuria,naturallyoccurringphenylalanin,

C6H6 . CH2 . CHNH2 . COOH,

is almost quantitativelyoxidized to homogentisinicacid,

C6H3(OH)2.CH2.COOH,

whereas the racemised form is onlyoxidized to the extent of 50 per

cent. Then m- and /-tartaricacids are much more completely


broken down by the organism than are ^#^0-tartaric and racemic

acids,and this latter acid is not decomposedinto its opticalisomer-

ides. In this connexion it may be mentioned that Chabrie' found

that /-tartaricis more toxic than the dextro form, and both of these

more than racemic acid ; for instance,the followingamounts produce

the same action : 34-26 gms. I,104-24 gms. d, and 165-25 gms.

racemic acid.

The few examplesgivenclearlyshow the characteristic selective

action of the tissues,oxidizingsome substances completely,reject-ingothers with but slightchemical or physicaldifferences.

Our ignoranceof the manner in which the actual process of

oxidation takes placeis readilyrealized when it is remembered that

no singlecase is known of the completeoxidation of an organicsubstance in aqueous solution by the oxygen of the air. Nencki

attemptedto determine,without success, the extent of the oxidation

of sugar and albumen on exposure in alkaline solutions to the air

at a temperatureof 36" C. ; the amount was extremelysmall.

The problem is further complicatedby the observation that in

some cases the oxidizingaction may be depressed,in others in-creased,

by the simultaneous dosage with other substances ; thus

Nencki and Sieber * found that while the body of a healthymancould form -82 gm. of phenolfrom 2 gms. of benzene,under normal

conditions this amount dropped to -33 gm. if 2 gms. of alcohol

per kilo, body weight were simultaneouslyadministered. Pfliiger,Poehl, and others have shown that under other conditions the

oxidizingaction of the animal organism may be increased.

It is not proposedto discuss the various hypothesesthat have

been brought forward in this connexion. Traube assumed the

existence of oxidizingenzymes, afterwards shown to be presentin

the lungs, kidney, muscles, "c., by Schmiedeberg,Salkowski,

Jaquet,"c., but their action appears to be very limited,quitein-sufficient

to account for the varietyof known oxidation processes,

althoughin all probabilitythey play some partin these changes.The suggestionthat in some way or other the oxygen is activated

in the body is difficult to follow ; itis more probablethat,as Pfliigerhas suggested,it is not the oxygen that is activated,but that the

activityis a function of proteinsof the livingprotoplasm.

1 Pflug.Arch., 31, 319.

OXIDATION OF ALIPHATIC SUBSTANCES 71

(a). OXIDATION OF ALIPHATIC SUBSTANCES.

Hydrocarbons. The oxidation of the hydrocarbonsof the ali-phatic

series on their passage throughthe organismhas not yetbeen observed,and as may be gatheredfrom the previousremarksis hardlyto be expected.It follows that if the petroleumemulsionshave any therapeuticvalue,it cannot dependon any analogyto cod

liveroil,which is readilyutilizedby the organism,i.e.broken down

to its end oxidation products.In fact these bodies taken by the

mouth are completelyeliminated in an unchangedcondition in the

faeces.

Primaryalcohols are oxidized,either completelyor, in some cases,

to the correspondingacid,but,as might be expected,the unstable

intermediate aldehydesare never found in the body; if producedatalltheyare but transitoryproductsto the higherstageof oxidation.

Formaldehyde,a saturated solution of which is termed formalin,

probablyowes its remarkable antisepticpropertiesto the ease with

which it abstracts oxygen and becomes formic acid,a process

which causes the breakdown of organicmatter.

Combinations of formaldehydewith indifferent organicbodies,such as milk and sugar are free from toxic effects,1and on beingintro-duced

into the animal system it is found that one-quarterpassesdirectlyinto the urine,one-tenth combines with ammonia, givinghexamethylenetetramine,but the largestpart is found as formic

acid.

On the other hand, chloral,CC13 . CHO, and butyl chloral,

CC13. CH2 .CHO, are not oxidized to their correspondingacids,

but reduced to alcohols and eliminated,as previouslymentioned,as compoundsof glycuronicacid.

The animal organismappears to exercise a greaterpower of

oxidizingethyl,propyl,or butyl groups than it possesses over

methyl; thus methylalcohol,or its esters,and methylamineor

methyl nitrile,giveformic acid,whereas ethylalcohol or ethyl-amine are completelybroken down, and the highernitriles,whichare much more toxic than methylnitrile,are converted into sulpho-cyanides.As regardsthe secondaryalcohols,Albertoni has shown

that isopropylalcohol,CH3. CHOH.CH3, is partlyoxidized to

acetone,CH3. CO.CH3, and partlyunchanged.The tertiaryalcohols,such as amyl alcohol or trimethylcarbinol,

1 J. Jacobsen,Chem. Cent. Blatt.,8, 693, 1906.


more difficultto oxidize than either primary or secondary,passthroughthe body unchanged. The replacementof hydrogenbychlorine causes an increase in the stabilityof the alcohols towards

oxidizingagents; thus trichlorethylalcohol,CC13. CH2OH, and

trichlorbutylalcohol,CC13" CH2 . CH2OH, pass unchanged throughthe animal organism,and are eliminated as glycuronicderivatives.A correspondingprotectionis noticed in the case of the organicacids,whereas acetic acid,CH3 .

COOH, is readilyoxidized ; trichloracetic

acid or trichlorbutyricacid are onlypartiallydecomposed.A similar protectionagainstthe oxidizingaction of the organism

is noticed in the case of the sulphonicacid group ; both ethylsulphate,1

02OH

and sulphoaceticacid,

CHKcOOH

passingthroughthe body unchanged.As regardsthe polyhydricalcohols,glycerol,

CH0OH

CHOH

la2OH

is readilyoxidized,but mannite,

CH..OH

(CHOH)4

CH2OH

onlypartially,whereas the sugars,

CHOHCH2OH

4and

(c

JHO

CO

c:

xtrose.

Laevulose.

Dextrose. CHOHCH

are of course completelybroken down.

1 Salkowski,Pflug.Arch.,5, 357.

OXIDATION OF ALIPHATIC SUBSTANCES 73

Passingto the final oxidation productsof the primaryalcohols,i.e. the group of acids,their completebreakdown into carbon-

dioxide and water is as a rule effected with greaterdifficultythan

that of the alcohols or aldehydes,yet in the animal organismthis

process takes placewith greatease. With the exceptionof formic

acid,the fattyacids are easilyoxidized,and as their molecular

magnitude increases and stearic,CH3(CH2)16.COOH, palmitic,

CH3(CH2)U .COOH, and the unsaturated oleic,

C8H7 .

CH : CH(CH2)7 .COOH,

acids are reached,these in the form of their glycerolesters con-stitute

the importantgroup of food-stuffs,the fats.

Oxy-acids,such as glycolicacid,CH2OH.COOH, /9-oxybutyric,

CH3CHOH.CH2. COOH,1 lacticacid,

/OH\COCHg.CH

are easilyoxidized,but in phosphoruspoisoningand in several

pathologicalconditions this latter acid appears in the urine. In

this connexion 0-oxybutyricacid,CH3. CHOH.CH2. COOH (anditsoxidation productacetoaceticacid,CH3 . CO.CH2 . COOH), may

be mentioned ; as is well known these occur in diabetes.

Conflictingstatements are met with as regardsoxalicacid ; some

state that it passes unchangedinto the urine,whilst Marfori found

that a considerable amount was fullyoxidized,and that the same

process takes placewith sodium oxalate,of which 30 per cent, of

the amount taken reappears in the urine. Faust found that the

whole of this acid injectedinto a dog could be recovered from the

urine. Malonic acid, CH2(COOH)2, is largelydestroyed,onlytraces passingthroughunchanged;tartronicacid,CHOH(COOH)2,is completelybroken down, and so are succinic,

CH2.COOH

CH2.COOH

and, to a very largeextent,tartaricacid (seep. 70),

CH.OH.COOH

CH.i.OH.COOH

1 G. Satta,Beitr. Chem. PhysiolPath.,6, 1-26,1904.


and malic acid,

CH.OH.COOH

CH2.COOH

Only very small amounts of glutaricacid,

,.COOH

escape oxidation.

Amido acids givenin moderate amounts are completelybroken

down,the nitrogenappearingas urea. Glycocoll,CH2. NH2 .COOH,

and leucin,CH3 . (CH2)3.CHNH2 . COOH, even in largeamounts,

never appear in the urine,whereas alanin,CH3.CHNH2. COOH,

asparticacid,CH.NH2.COOH

to2.COOH

and glutaminicacid,JHNH2.COOH

.COOH

are partiallyoxidized,and partiallypass through the organismunchanged.1

Wohlgemuth 2 has found that rabbits fed with racemised tyrosin,leucin,asparticacid,and glutaminicacid oxidized the opticalisomeride occurringnormallyin the body,whilst the other was

partiallyor completelyexcreted in the urine. Thus ^-tyrosinisthe form in which this substance occurs normallyin animals,and

when the racemised form is given,d- is destroyedand /- found in

the urine.

The acid amides,with exceptionof acetamide,CH3 . CONH2, and

oxamide,

CONH2

CONH2

which are but partiallyoxidized,are as completelybroken down as

their correspondingacids. The nitrilesof the acetic acid series,formed by the dehydrationof the correspondingammonium

salt,e.g.CH3.COONH4-2H2O = CH3CN,

1 Stolte,Hofmeister'sBeitr"ge,5, 15,1903.2 Ber.,38, 2064,1905.



Accordingto Juvalta \ phthalicacid and also phthalimide,2

/COOH 1 . o and C /C*

a U

are broken down, in the case of the former substance to the extent

of over 57 per cent, of the amount given. Pribram 3 states that

phthalicacid is excreted quantitativelyin the rabbit.

Methyl quinolineis stated by Rudolf Cohn to be almost com-pletely

oxidized in the body,and the same author showed that 1 : 2-

nitrobenzaldehydeto a largeextent underwent the same fate,and

that onlysmall amounts were oxidized to the corresponding1 : 2-

nitrobenzoic acid.

Benzene itselfis oxidized to phenol,and also 1 :4- and 1 :2-dioxy-benzene,but the oxidation does not go further,since 1 :2-dioxy-benzene is eliminated unchanged. Naphthaleneis eliminated as a

glycuronicderivative in a similar manner to the jS-oxyderivatives

(/3-naphthol).The homologous benzenes undergo similar changes to those

previouslymentioned (p.30),the side-chains beingoxidized and

replacedby COOH. Thus toluene,C6H5CH3 ,givesbenzoic acid,

xylene,C.H""J;g",givestoluic aeid,C6H4"

and mesitylene,C6H3(CH3)3 1:3:5, gives mesitylenicacid,

C6H3(CH3)2COOH. Ethylbenzene,C6H6 . CH2 . CH3 ,is also oxi-dized

to benzoic acid. Propyl benzene,C6H5 . CH2 . CH2 . CH3 ,

behaves similarly,givingrise to the same acid,althoughisopropylbenzene,C6H5 .

CH (CH3)2,is oxidized in the ringto a phenol-likederivative. This may be comparedwith the behaviour of cymene,

L3

which Zieglershowed gave cumic acid,

Now when the hydrocarbonis treated with powerfuloxidizing

agents,such as dilute nitricacid or chromic acid,the propylgroup is

firstattacked,giving

1 Juvalta,Zeit.f.physiol.Chem., 13, 26.8 Koehne, Chem. Centr.,2, 296, 1894.8 Chem. Centr.,2, 668,1904.

OXIDATION OF AROMATIC SUBSTANCES 77

but when a mild agent,such as caustic soda and oxygen (air),is

employed,the methylgroup is oxidized.

1 : 2-Nitrotoluene,

P w /N"2

is oxidized to the alcohol

/-I TT/NO0

and eliminated as a glycuronicacid derivative.

Generallyspeaking,such radicals as CH3, CH2 . OH, CHO,and CH2 . NH2, attached to the benzene nucleus,are oxidized to

" COOH * and eliminated as hippuricacid (p.63).Phenylpropionicacid,

C6H5.CH2.CH2.COOH,and cinnamic acid,CH5CH : CH.COOH, are converted into benzoic

acid,but phenylaceticacid,C6H5 . CH2 .COOH, givesphenaceturic

acid,C6H5CH2. CONH.CO.NH2, and mandelic acid,2

C6H5'CH\COOH,passes throughthe organismunchanged,whereas phenylamidoaceticacid,

C6H6.

CHH giyesCeH

Now since phenylpropionicacid givesbenzoic acid,it cannot pass

throughthe stage of phenylacetic acid,and consequentlyKnoopconsidersthat the oxidation of that acid can onlytake placein the

P position.As previouslymentioned,ethylbenzene,C6H5 . CH2 . CH3,(p.76)givesbenzoic acid,and itisprobablethat the CH2 group is

attacked first,and not the methyl; this is borne out by the fact

that acetophenone,C6H6COCH3, also givesbenzoic acid. Other

acidsinvestigatedby Knoop containingmore than two carbon atoms

in the side-chaindid not givebenzoic acid. An analogousoxidationof hydrogenin the /?positionis seen in the formation of /?-oxy-butyricacid,CH3. CH.OH.CH2. COOH, and the further oxidation

products,acetoacetic acid,CH3. CO.CH2. COOH, and acetone,

CH3.CO.CH3, in diabetes.

1 Knoop, Hofmeister'sBeitrSge,6, 150,1904.* Schotten,Zeit.f.physiol.Chem.,8, 68,1884.


In many cases oxidation in the nucleus takes placeprovidedthatthe hydrogenin the 1 : 4 positionto the group alreadypresent isnot itselfsubstituted. Thus aniline,C6H5NH2, is partiallyoxidizedto 1 :4-amidophenol,

OH

K. Klingenbergshowed that diphenyl,

f^ TTVyfi"l,

C

givesthe sulphuricester of 1 :4-oxydiphenyl,

.OH 1:4

H6

Phenylmethane gives1 :4-oxyphenylmethane,and a similar typeof action isnoticed with chlor-,brom-,and iodo-benzene,which givesrise to cysteinderivatives,in which the H atom in the 1 : 4 positionto the halogenatom has been attacked (seep. 66). On the other

hand,

C6H4NH2 1 : 4 C6H4Br 1 : 4

Benzidine,| 1:4 Dibromdiphenyl,IC6H4NH2 1 : 4 C6H4Br 1 : 4

are not oxidized by the animal organism. Nolting,who examined

a largenumber of cases, states that the hydrogenof the benzene

nucleus is onlyreplacedby hydroxyl(OH) in the para positionto

the substitutinggroup, and should this positionbe occupiedsuch

a type of oxidation does not take place.From a physiologicalpointof view the oxidation of indol,

in the organismis of considerable importance.When this substance

(whichhas distinct but not very marked toxic properties)is formed

in the intestineas the result of putrefaction,or is introduced experi-mentally,absorptionrapidlytakes place; and itundergoesoxidation,

most probablyin the cellsof the liver,to indoxyl,

C(OH)

C.H/VH,NH

REDUCTION 79

which is eliminated as the potassiumsulphuricester

C(O.S02OK)CH/NcH

NH

This ester is known as urine indican,owing to the fact that it was

supposedto be identical with the indican of plants,which isnot the

case ; this derivative on further oxidation givesindigoblue,which

producesa characteristiccolour in the urine.

C(OS02OK) CO CO

f)f~^ TT / xv.f^TT i (\ f^ TT / NO " C^t \.O TT i V~U^!f\ÛgllÂ "^"1 TU2 = ^6114\/^' ' \ y/^/6Ji4+ J^*loU4

NH NH NH

Indigoblue.

C. REDUCTION.

The direct reduction of the oxidized derivatives of the aliphaticand aromatic series,such as alcohols,acids,phenols,ketones,back

to the hydrocarbonsfrom which they are derived is by no means

an easy matter,and powerfulreagentsare required,and it is not to

be expectedthat such changes should occur during the passage of

these derivatives throughthe animal organism.The cases of substances undergoinga process of reduction on their

passage through the organismare, relativelyto oxidation,very rare.

One of the most interestingis that of chloral,CC13CHO, and butyl-chloral,CC13 . CH2 . CHO, which are reduced to their correspondingalcohols and eliminated as compounds of glycuronicacid (seep. 60),this process beingmuch more difficultto accomplishin the laboratorythan the oppositeone of oxidation to the correspondingacids trichlor-

acetic and j8-trichlorpropionic.In the aromatic seriesthe easilyreduced quinoneundergoesthis

changein the organism,and is eliminated as hydroquinone.Other examplesof reduction are met with in the case of some

nitro compounds. Thus Eric Meyer has shown that nitrobenzene

is partiallyconverted into 1 :4-amidophenol,

/OH


but chiefly eliminated unchanged. Similarly 1 : 3- and 1 : 4-nitro-

phenol,

give some of their corresponding amido derivatives. The case of

nitrobenzaldehyde has been previously alluded to (p. 65).

G. Hoppe-Seyler has shown that 1 : 2-nitrophenylpropiolic acid,

r H 2

ê^XC : C.COOH,

is eliminated as the potassium salt of the conjugated sulphuric ester

of indoxyl. This change probably takes place in the following

manner : "

1. C ! C.COOH Reduction5jT"H

C6H4/-" C6H4" "C.COOH

\

2. C" OH C" OH

NH NH

Indoxyl.

3. C" OH HjO.SO2OH C" O.SO2OH

+ = C6H4"(\CHH NH

Indoxyl-sulphate.

Many organic dyes, such as alizarin blueor indophenol blue

lose their colour while in the cells and fluids of the body, but

regain it on exposure to air.

CHAPTER IV

THE ALCOHOLS AND THEIR DERIVATIVES. THE MAIN GROUP OF

ANAESTHETICS AND HYPNOTICS. I. General physiologicalaction of

anaesthetics and hypnotics. Overton-Meyertheory. Traube. Moore and

Roaf on Chloroform. Baglioni'stheory.II. Method of preparationand chemical and physiologicalpropertiesof

the Alcohols. Esters of Halogen acids,Nitrous and Nitric,Sulphurousand

Sulphuricacids. The Ethers.

I. GENERAL OUTLINES OF THE PHYSIOLOGY OF

HYPNOTIC AND ANAESTHETIC DRUGS.

THE distinction between the pharmacologicalgroups of anaes-thetics

and narcotics is importantin practice,but does not depend

upon differences in physiologicalaction or chemical constitution.

For the productionof generalanaesthesia,volatilebodies,which are

rapidlyabsorbed and excreted,are most suitable,whereas lessvolatile

liquidor solid substances,whose activityis only graduallysetfree in the organism,can more convenientlybe employedfor pro-ducing

hypnosis.The latter condition can of course be producedby small doses of a bodylikechloroform,but the method of adminis-tration

is inconvenient,and the resultingsleeprapidlypasses away.

On the other hand,largedoses of a narcotic like chloral hydrate

may producecompletesurgicalanaesthesia ; indeed this body was

used intravenouslyfor a short time in the middle of last century,and major operationsperformedunder its influence. The dis-advantage

of such a procedureis that the dosagehas to be too

highfor the completesafetyof the patient.The physiologicalaction of the entire group of aliphaticnarcotics

is first on the highercentres of the cerebrum,then on the lower

centres of the medulla and cord. Eventuallythe reflexes are

G

82 THE ALCOHOLS AND THEIR DERIVATIVES

completelyabolished,and this constitutes an importantdistinctionbetween this group and the alkaloidal narcotics of which the chief

representativeis morphine. In largedoses this substance increases

reflexirritability,and in small doses does not depressit.

The aliphaticnarcotics belongto several chemical groups, the

chief beingthe alcohols,aldehydes,ketones,and their derivatives.

Though it appears doubtful whether methane itself is narcotic,ethane and acetyleneare direct narcotics. Those which belongtothe alcohol group owe their specificaction to the hydrocarbonradicals,not to the hydroxyl.When the latter are increased the

narcotic action is diminished ; but the hydroxylradicals may be

anchoringgroups. As a rule ethylcompounds are more powerfullyhypnoticthan methyl,especiallywhen occurringin bodies which

offer some resistance to oxidative processes.

The entrance of carboxylappears to stop all narcotic effects,though the esters containingan alkylgroup in placeof the hydro-gen

of the carboxylradical are active. Thus urethane,

/2J"*-5^

owes its activityto the ethylgroup. The higherthe molecular

weight of the alcoholic group the more powerfulis the hypnoticaction.

Thus hedonal,

CO^?%T /CH0

is much more powerfulthan urethane. The aldehydesand ketones

are not as a rule convenient narcotics,as they cause a marked

preliminarystageof excitement.

Many of the aldehydederivatives,unsubstituted by halogens,areonly feeblynarcotic,the parent substances being often irritant.

The ketones themselves have not yieldedany bodies of great prac-tical

importance,althoughamong their derivatives are the valuable

sulphones.The introduction of a halogen,especiallychlorine,greatlyen-hances

the narcotic power, but these compounds have the great

disadvantageof being respiratoryand cardiac depressants.Theother halogenelements have a stillmore deleteriouseffect.

There remain for consideration several pointsof a theoretical


84 THEORIES OF HYPNOSIS

Liminal Value. Distribution.o

Coefficient g^Trional -0018

. . . . .446

Tetronal. .

-0013....

4-04

SulphonalButylchloralhydrateBromal hydrate .

Chloral hydrate .

Ethyl methane.

Methyl methane.

Monacetin. ,

Diacetin.

Triacetin. .

Chloralamide"

Chlorhydrin .

Dichlorhydrin .

"006. . . . .

Ml

"002 L59

"002. . . . .

-66

"02 -22

"04 .14

"4 .04

"05 06

"015 -23

"01 -3

"04

"04

"002

In the sulphonederivatives it was found that those most soluble

in fat were also those that showed greatestphysiologicalactivity,whereas in thisseriesBaumann and Kast had traced this activityto

the presence of ethylgroups.Action. Distribution Coefficient.

Dimethyl-sulphomethane very slight -106

Dimethyl-sulphoethane slight "151

Sulphonal marked 1-115

Trional more marked 4 46

Tetronal more marked 4-04

Mansfield has recentlyshown that some narcotics have more

powerfulaction when givento starved animals than is the case when

the animals are well fed. This,he suggests,may be due to the fact

that in the latter the tissue fats absorb some of the narcotic and

render it incapableof actingon the central nervous system.

The Overton-Meyertheorythen,based on the above observations,is that indifferentsubstances gainaccess to the cellsof the central

nervous systemowing to their solubilityin the celllipoidsin which

these cellsare particularlyrich,and that gradationsin narcotic power

are due to the presence of groups which increase the partitionco-efficient,

i.e. which render the derivatives more soluble in such fattysubstances. The theoryonlyexplainsthe presence of the active

substance in the cell,and when this has been effected we are in

completeignoranceof the next phase,althoughit is fairlyobvious

that there will be greatdifferencesbetween inert substances,of the

nature of ether or chloroform,and bodies which are chemicallyactive,such as aniline. The Overton hypothesisfurther would lead

to the suppositionthat cells rich in lipoidsubstance should show a

preferentialabsorption; that this isnot alwaysthe case is seen in the

THEORIES OF HYPNOSIS 85

fact that the aliphaticnarcotics do not attack the peripheralnervous

system,which contains a largeamount of such bodies. Further,

Cushny has pointedout that many benzene derivatives have a highdistribution coefficient,thoughwithout narcotic action.

J. Traube differs from Overton in his views as to the manner in

which the substance enters the cell,and considers that it is not the

content of lipoidwhich determines the sequence or the amount of

osmosis. He ascribesthe direction and velocityof osmosis to the

differenceof the surface tensions,as he does not hold the prevailingviews as to the nature of osmotic pressure. Rapidpenetrationinto

the cellsseems to be the most essential condition for enablinganarcotic substance to exercise its paralysingand other effects on

the interiorof certain cells,and 'we have found that a near relation

exists between osmotic velocityand surface tension,and therefore

we can expectthat surface tension and narcotic power run parallel'.This he finds is reallythe case, even when most varied types of

narcotics are compared. Traube considers that when the drug has

thus gainedentrance to the cellit may exercise its narcotic power

in proportionto its solubilityin the cell lipoids.Moore and Roaf have recentlypromulgatedthe theorythat

anaesthetic substances form unstable compounds with the cell pro-teins,

which onlylast so long as sufficient partialpressure of the

gas in the tissue fluids is maintained. Beginningwith solutions

of blood serum and haemoglobin,and continuingtheirinvestigationswith extracts of livingtissues (brain,heart,lungs,"c.),theyshowed that at higherpressures chloroform and other anaesthetics

did not obey the ordinarylaws of solution,althoughtheir curves,

examined in the lightof the phaserule,exclude the hypothesisofthe formation of chemical compounds. Other anaesthetic substances

varied in the degreeto which this took place,but no variation in

kind was found among them.

It appears quitepossiblethat adsorptionconstitutes the mechan-ism

by which substances of narcotic nature are taken up in the

cells. Moore and Roaf s vapour pressure curves for chloroform and

serum have the characteristic form of adsorptioncurves. Gibbs

has shown that the further the surface tension of a liquidis

depressedby the dissolved substance,the greaterwill be its adsorp-tion;it is moreover a generalprinciplethat chemical action is

proportionalto concentration ; the latter will be greatestwhen

solubilityand, hence,distribution ratio are greatest.It seems to

the presentwriters that these generalprinciplesinclude the essential

86 THEORIES OF HYPNOSIS

basis of the previoushypotheses.The substance enters the cell

by adsorption,and the magnitude of its effect depends on its

concentration.

What next takes placeis pure conjecture,but in the case of some

substances a parallelmay be drawn with the so-called catalyticreactions. Bredighas shown that the rate of decompositionof

solutions of hydrogenperoxideby colloidalplatinumis roughlypro-portional

to the concentration of the latter substance ; the action is

hindered,that is ' poisoned',by the presence of traces of carbon-

monoxide (almostwithout exceptionblood poisonsact similarly),but on itsremoval the decompositionproceedsas before. Now the

conversion of the total platinuminto a compound by the ' toxic '

substance is out of the question,owing to the extreme disparityof

the amounts of the two substances. Thus, approximately,in a TV

normal solution of hydrogenperoxidecontainingT^J^ colloidal

Nplatinuman amount of carbon monoxide = -^

" " " "is sufficient

10,000,000

to stopthe action. If this iscomparedto the action of chloroform,for

instance,it will be seen that after adsorptionhas taken placeits

further action may be comparedto that of carbon monoxide in

the examplegivenabove.

Strychninealso playsa correspondingr61e,bringingabout re-actions

out of all proportionto the quantityemployed.It is generallysupposedthat the reaction broughtabout by col-loidal

platinumtakes placein the adsorbed layeron the surface of

the platinumparticles; the poisonswill also be absorbed,and either

by further chemical action or purelyphysicalmeans coat and,hence,isolatethe active surface with an inert layer. The correspondingpicturewill be life processes takingplacethroughthe agency of

similar colloidal substances. The actions may be depressed,as the

oxidation processes appear to be by the administration of ether or

chloroform,or the velocitywith which they are takingplacemaybe enormouslyincreased,as perhapsmay be the case with strychnine.Baglionihas formulated a theoryof narcosis based on observa-tions

on the various groups of benzene phenolderivatives. One of

these groups, containingacetanilide,phenylhydrazine,benzylalcohol,benzaldehyde,acetophenone,benzoic acid,and salicylicacid,pro-duces

paralysingeffectsonly,without convulsions. The amount of

paralysisproducedvaries inverselyas to the amount of oxygen presentin the side-chain. Thus benzylalcoholis a powerfulparalysingagent; benzaldehydeis less powerful,and benzoic acid least. He

ALIPHATIC ALCOHOLS 87

thus concludes that narcotic effect also dependson the power to

withdraw oxygen from the cinogen'compounds in the central

nervous system; that is,that narcosis isa reducingprocess. Depriva-tionof oxygen, as by breathingCO2,or inertgases, such as hydrogen,

givesrise to a series of symptoms correspondingto chloroform

narcosis. Herter has shown,by means of methyleneblue injections,that chloroform,ether and chloralhydrate(aslikewise low tempera-tures)

markedlydimmish the oxidizingcapacityof the tissues.

II. THE ALCOHOLS OF THE ALIPHATIC SERIES.

The group of alcohols may be regardedas derived from water bythe replacementof one hydrogenatom by an hydrocarbonradical ;

theyconsequentlycontain the so-called hydroxylgroup, and their

propertiesdepend,to a very largeextent,upon the nature of the

hydrocarboncomplexto which this isjoined.The primarycontain the group :CH2OH, the secondary:CH.OH,

and in the tertiaryalcohols the hydroxylgroup is linked on to a

carbon carryingno hydrogen atoms, e. g. (CH3)3C.OH. As

previouslymentioned (p.68),the nature of theiroxidation products,

among the most importantof the aliphaticderivatives,isdependent

upon the presence of these groupings.Thus a primaryalcohol,such

as ethylalcohol,CH8.CH2OH, givesrise firstlyto an aldehyde,

acetaldehyde,CH3 . CHO, which passes, on further oxidation,to an

acid,aceticacid,CH3COOH. On the other hand a secondary,such as

CH3 CH3

*"0-propylalcohol,CH.OH givesa ketone,CO acetone,

CH3 CH3

whereas a tertiaryalcohol on similar treatment breaks down, givingketones or acids of smaller carbon content,e. g.

CH3 CH3

CH3.C.OH -* CH3.CO,

CH3 CO2,H2O

Those alcohols which contain the radical of the aromatic hydro-carbonsattached to hydroxyl,such,for example,as phenol,C6H5.OH,

show such strikingdifferencesboth chemicallyand physiologicallyto

the aliphaticderivatives that theywill be described separately.

88 PREPARATION OF THE ALCOHOLS

Methyl alcohol,CH3 . OH, the simplestmember of the series,is

one o" the productsof the dry distillation of wood. Ethylalcohol,

C2H5OH, isobtained by the fermentation of sugar, and,as previouslymentioned (p.36),is one of the chiefstarting-pointsfor the prepara-tion

of the aliphaticderivatives. The various specialmethods which

can be employedfor the synthesisof members of this group will not

be described ; they are to be found in any textbook on organicchemistry,but the followingthree generalmethods of preparationare important.

General Methods of Preparation.

1. The monohalogenderivatives of the paraffins,and especiallythe iodides,are readilyconverted into alcohols,in many cases bysimplyheatingwith water to a temperatureof 100"-120" ; thus

C2H5I+ H2O = HI + C2H6.OH. But since the reaction is re-

versible,e.g. C2H5OH + HI = H2O + C2H5I, it may not take

placeto any greatextent,a state of equilibriumbeingmore or less

rapidlyattained. In consequence, as a very generalrule,a base is

requiredto combine with the liberated acid; thus with silver

hydratethe reaction may take placeat the ordinarytemperature,whereas with lead oxide boilingis generallynecessary.

In other cases the previousformation of the ester may be desir-able;

thisis obtained by the interactionofthe halogenderivativewitheither silveror sodium acetate,and on decompositionof the resultingsubstance with potashor soda the alcohol is readilyobtained,e. g.

A. CH2Br CH2.(OOC.CH3)I +2CH3.COOAg = | + 2AgBrCH2Br CH2.(OOC.CH3)

Ethylenedibromide.

B. CH2.(OOC.CH3) CH2 .OH

+ 2KOH = 2CH3COOK + |

H2.(OOC.CH3) CH2.OH

Glycol.

2. Another generalmethod consists in decomposingthe esters of

sulphuricacid with water. These esters may be readilyobtained

by treatingthe hydrocarbonsof the ethyleneseries with concen-trated

sulphuricacid,e. g.

A. CH2 OH /O.C2H6|| +S02/ = SO/CH0 \OH \\OH

Ethylene. Ethyl-sulphuricacid.

PROPERTIES OP THE ALCOHOLS 89

B. /".CSH5 OH

SO/ + H20 = SO/ + C2H5.OH.\OH \OH

The esters which are formed by treatment of the unsaturated

hydrocarbonswith sulphuricacid contain the acid radical attached

to the carbon which carriesthe least number of hydrogenatoms.

Thus CH2 CH3 CH3

CH givesCH" O.SO2OH and consequentlyCH.OH| the alcohol

'

|CH3 CH3 CH3

and CH3 CH3\/CH3

CH2 gives C\ and consequentlythe alcohol

/ XO.S02OH (CH3)3.C.OH.CH3 CH3

3. Derivatives of ammonia containingthe amido group .NH2are all decomposedby nitrous acid in aqueous solution and the

group replacedby hydroxyl,e. g.

C2H5NH2 + HN02 = C2H6OH + N2 + H20Ethylamine.

CH3.CO.NH2 + HNO2 = CH3.CO.OH + N2 + H2OAcetamide. Acetic acid.

.O

Y:

.2 .

CO/ + 2HN02 =CO/ (C02+ H20)+ 2N2 + 2H2O

X XNOH

Urea. Carbonic acid.

General Properties.

The alcohols are neutral colourless compounds,and the lower

members of paraffinserieshave a characteristicburningtaste and

smell,and their solubilityin water decreases as the carbon content

increases. Thus methyl,ethyl,and propylalcohols are miscible

with water in all proportions.Primary n- butylalcohol is soluble

in twelve partsof water. Those containing4-11 carbon atoms are

oilsimmiscible with water,and the highermembers are solids.

Isomerism is first observed in the alcohols of the limit hydro-carbonsin the case of those derived from propane, CH3. CH2. CH3,

which givesriseto a primaryCH3 . CH2 . CH2OH and a secondary

90 THE POLYHYDEIC ALCOHOLS

CH3. CHOH.CH3 called wo-propylalcohol,easilydistinguishedbytheir oxidation products.

The chemical characteristicsof the group dependessentiallyon

the presence of the hydroxylgroup. Sodium and potassiumreplacethe hydrogenof this radical,e. g. C2H5 . ONa, givingrise to sub-stances

called alcoholates ; these are readilydecomposedby water,

are employedin many syntheticprocesses, form valuable condensing

agents,and may be used for the purpose of reducingnitro com-pounds

of the aromatic series to the correspondingazoxyderivatives.

When acted upon by acids or acid chlorides the alcoholsreadily

yieldthe esters,e. g.

C2H5OH + HC1= H20 + C2H5C1

C2H6OH + HN02 = H20 + C2H5 . ONO2

Ethyl nitrite.

C2H5OH + H2S04 = H20 + C2H5O.S02OHEthyl sulphate.

C2H5OH + CH3COOH= H2O + CH3COOC2H5Ethyl acetate.

C2H6OH + PC15 = HC1+POC13 + C2H6C1

C2H6OH + C6H5COC1 = HCl-{-C6H5COOC2H5Ethyl benzoate.

On dehydration,by sulphuricacid or zinc chloride,the alcohols

are converted into unsaturated hydrocarbons,e. g.

CH2;H CH2= H.O+ I

CH2;OH CH2

Polyhydric Alcohols.

Besides containingone hydrogenatom replacedby hydroxyl,the

hydrocarbonsmay have more, but it has been previouslypointed

out that,as a very generalrule,one carbon atom cannot carry more

than one hydroxylgroup. Attempts to obtain CH3.CH(OH)2 bythe action of silver hydrate,for instance,on CH3 . CHC12 alwayslead to the dehydrationproductof the unknown alcohol,i.e.the

aldehyde,

CHS.CH"JJJ= H20 + CH3CHO


92 PHYSIOLOGICAL PROPERTIES OF THE ALCOHOLS

may result,an effect unseen when glycerolis injectedintravenously.Death may occur after toxic doses by respiratoryfailure.

Further,the aldehydesand ketones,with theirmarked physiologicalreactivity,become the inert sugars.

Caffeine loses its characteristicphysiologicalreaction,and it is

possiblethat in this case, as with the others,this decrease in

reactivitymay be ascribed to the dropin stabilitytowards oxidizingprocesses, which follows the entrance of the hydroxylgrouping.

The alcohols act on the central nervous system,in particularonthe cerebrum,the intensityof their actions dependingupon the

number of carbon atoms present,and increasingas the homologousseries is ascended,althoughto some extent methyl alcohol is an

exception.

Thus,in the case of rabbits :"

Methylalcohol,CH3OH, 6-12 gms. without action.

Ethyl " C2H5OH, 7 gms. drunkenness,12 gms. sleep.rc-Propyl

" C3H7OH, 12 gms. producesleepin 5 minutes

and death in 5 hours.

fl-Butyl" C4H9OH, 3 gms. producedrunkenness,7 gms.

sleepand death.

iso-Amyl-" (CH3)2CH.CH2OH, 2 gms. producedrowsiness.The primaryalcohols are less narcotic than the secondary,and

these lessthan the tertiary.Thus :"

J*0-propylalcohol,CH3 . CHOH.CH3, 2 gms. producedrowsi-ness.

Methyl-ethylcarbinol,CH3 . CHOH.C2H6, 2 gms. producedrowsiness.

Diethyl " C2H5.CHOH.C2H5, 2 gms. producesleep.

In the case of the tertiaryalcohols the action dependson the

nature of the alkylradicals attached to the carbon atom carryingthe hydroxylgroup. If that radical is methyl the reaction is

relativelyweak, but if ethylthe physiologicalreaction is largelyincreased (seep. 49),the increase varyingwith the number of such

groups present,thus :"

Trimethylcarbinol,(CH^C.OH, 4 gms. producesleep.

Dimethyl-ethylcarbinol,""ffl\C.OH, 2|ms'Pr,od,uce8 to

C2H5 J 9 hours' sleep.Triethylcarbinol,(C2H5)3C.OH,1 gm. produces10 to 12

hours' sleep.(Comparethe substituted urea derivatives,p. 216.)

ESTERS OF INORGANIC ACIDS 93

A similar characteristicis noticed in the pinacones,substituted

derivatives of the physiologicallyinactive diprimaryalcohol glycol

CH2OH

CH2OHthus :"

(CH3)2.C.OHMethyl pinacone, 10 gms. producesleep.

(CH3)2.C.OH

3\f"lOTTTV/I- it. i "1.1 " C9H,/ -

'

2 gms. producesleep.Methyl-ethylpmacone, ^ I |lightônvulsions.*

L

(C2H5)2.C.OHVery insoluble. 1-5 gms.

Ethylpinacone, | producedeeperand longer(C2H5)2.C.OH sleep.3 gms. produce

sleepafter 2 hours.

Owing to the above observations Mering introduced amylene

hydrate,

CH3)CH3 C.OH,

3

CH

in 1887 as a hypnotic.It is obtained from the unsaturated

hydrocarbonamylene,by the generalmethod previouslydescribed,i.e.throughthe agency of amylsulphuricester. It has the hypnotic

propertiesof an alcohol,but is also liableto producesymptoms of

intoxication with nausea and headache. It is said to be a diuretic-

It influencesthe heart and respirationlike other amyl compounds.

DERIVATIVES OF THE ALCOHOLS.

A. THE ESTERS.

I. Aliphatic Esters of the Halogen Acids.

The esters are a group of substances in which the hydrogenatomof the acids is replacedby an organicradical; theyconsequentlybelongto two groups, (1)those obtained from the inorganicacids,and (2)those derived from the organicacids (seep. 122).

The former onlywill be discussed at this point,and the latter in

connexion with the organicacids themselves. If the halogenacids,

hydrochloric,hydrobromicand hydriodicbe considered,it will be

seen that on replacingthe hydrogenby the radicalsof the paraffins,

94 PREPARATION AND PROPERTIES OF THE ESTERS

this group of substances results,thus HC1 givesCH3.C1 or C2H5C1,"c. From another pointof view these derivatives may be looked

upon as the halogensubstitution productsof the limit hydrocarbons,thus CH4 acted upon by chlorine givesCH3C1,

CH4 + C12 = HC1 + CH3C1.

But as the alcohols are invariablyused in their preparationthe

former view may be adopted,and the two reactions compared

+ HCl=NaCl + HO

General methods of preparation.

1. The interaction of the alcohols and hydrochloricor hydro-bromic acid is reversible and is not complete unless one of

the substances formed is removed from the sphereof reaction.

Thus in the case of methyl or ethylalcohol,zinc chloride or

sulphuricacid may be employedto remove the water formed. But

with the higheralcohols unsaturated hydrocarbonsmay be firstlyformed,and these add on the halogenacid in such a manner that

isomers of the desired esters are obtained. Further,hydriodicacid,

especiallywhen in excess, is capableof reducingthe iodides.

2. The phosphorushalogenderivatives readilyreact with the

alcohols,givingrise to substances of this class,

PBr3+ 3C2H6OH = 3C2H6Br + H3PO3Phosphorustribromide.

PI3+ 3C2H5OH = 3C2H6I+ H3PO3

Phosphorustri-iodide.

phosphoruspentachlorideeasilygivesthe correspondingchloride.

General Properties.

The esters of the halogenacids are etherial,pleasant-smellingliquids,almost insoluble in water. The lower members are gases

at ordinarytemperatures,e.g. methylchloride,ethylchloride,and

methyl bromide. The chlorides boil 20"-28" lower than the

bromides,and these 28"-34" lower than the correspondingiodides.

Their stabilitydecreases from the chlorides to the iodides,and

consequentlytheir reactivityincreases in the same direction. Theyare well adapted,especiallythe iodides,to the most varied series of

syntheticreactions,many of which have been previouslydescribed

(p.37).

PHYSIOLOGICAL PROPERTIES 95

General Physiological characteristics following entrance

of Chlorine.

The entrance of chlorine into aliphaticcompounds increases their

depressanteffect on the heart,and as a very generalrule in-creases

their narcotic action. Their toxic action appears to stand

in direct relationshipto their narcotic properties,and the latter to

increase with the amount of chlorine present. Thus methylchloride,

CH3C1, is less toxic than methylenechloride,CH2C12, and this less

than chloroform,CHC13 ; the fullychlorinated methane derivative

carbon tetrachloride,CC14;acts much more slowlyand persistentlythan chloroform,and is usuallystated to be a more powerfulheart

depressant,althoughCushny describes it as onlyhalf as powerful as

chloroform. Considerable interest consequentlylies in the investi-gation

of the results followingthe entrance of chlorine into a

substance which acts as a heart stimulant. Thus caffeine has

a stimulant action on the central nervous system and is a diuretic.

In moderate doses it also stimulates the heart,an effect which can

be producedby the local applicationof solutions of caffeine to the

frog'sheart. Chlorcaffeine is a much feebler cardiac stimulant ; the

other actions of caffeine,however, are stillpresent(Pickering).Then glycerinis physiologicallyinert,but the chlorhydrinshave

narcotic action and produceparalysisand dilation of the vessels.

Monochlorhydrin,CH2OH.CHOH.CH2C1, is the least and trichlor-

hydrin,CH2C1.CHC1.CH2C1, the most toxic.

The increase in narcotic propertiesfollowingthe entrance of

chlorine,led to the introduction of trichlorisopropylalcohol Isopral,

CC13. CHOH.CH3, by Impens in 1903. This substance may be

formed by the action of methyl magnesium iodide (Grignard'sreagent,see p. 38) on chloral and the decompositionof the resultingsubstance by water,

A. CH3 . Mg.I + CC13CHO = CC13 .

CÔMgl\CH3

/K V

J3. CC13. C^-OMgl+ H20 = Mgl .

OH + CC1S.C^-OHbut its action on the heart is more powerfulthan chloral,and

consequentlyit cannot be givenin heart disease.

Similarlytrichlorbutylalcohol,

96 ESTERS OF HYDROCHLORIC ACID

Chloretone has been introduced as an antiseptic,anaesthetic,and

hypnotic.It is also known as aneson or anesin (aone per cent,

solution of acetone chloroform).It is not a very toxic substance,the

dose being "3 to 1-5 gm.; the solutions have a local anaesthetic

action. It apparentlydoes not differ in its physiologicalactionfrom other chlorine narcotics.

The above givesa generalindication of the physiologicalresults

followingthe introduction of chlorine into organicsubstances ; the

effect of the entrance of this member of the halogenseries,as well

as bromine and iodine,into other groups, such as the aldehydesand

acids,will be described after the discussion of those derivatives.

Esters of Hydrochloric Acid.

Ethyl chloride,C2H5C1,and ethylbromide have been employedas generalanaesthetics ; a mixture of these and methylchloride is

known as somnoform. Webster (BiochemicalJournal,June, 1906)investigatedthese drugs,and also ethyliodide,which,owing to its

unpleasanttaste and itsvolatility,isunsuitable for clinicalpurposes.There is apparentlyno difference in the physiologicalaction of

these drugs beyond what may be attributed to their varyingvolatility.With largedoses respirationceases some time before

the heart. Blood pressure after a short preliminaryrise is con-siderably

depressed,this beingdue to the depressantaction on the

cardiac pump. No action on the vagus endingswas demonstrated,

though Cole (B.M.J.,1903, i, p. 1421) found that the vagus

terminations were paralysed.Somnoform appears especiallyliableto cause respiratoryfailure.

Ethylchloride is twice as soluble in blood as in water, and experi-mentswith dogs showed that its vapour has a paralyticaction on

the heart muscle but that nineteen times as much is requiredto

producethe same effectas chloroform.

Chloroform,CHC13, is obtained by the action of bleachingpowderon dilute alcohol or acetone ; the reaction commences in the case

of alcohol at 45" C.,and the chloroform formed is distilled off,washed with water, treated with concentrated sulphuricacid to

destroyother chlorinated derivatives such as those of ethane,and

rectified. In all probabilityalcohol is firstlyoxidized to chloral,

CClgCHO, which,in the presence of calcium hydrate,is converted

into chloroform. In the case of acetone,the intermediate productis probablyCC13. CO.CH3, which then breaks down into chloroform


and acetic acid. A much purer preparationmay be obtained by the

action of alkalis on chloral. It is onlyslightlysoluble in water,

1 litre of saturated solution at ordinarytemperaturescontainingabout 7 gms. of chloroform. The pure preparationis not very

stable,breakingdown into the very toxic phosgene,COC12,hydro-chloricacid and chlorine ; the officialpreparation,which is much

more stable,contains a trace of ethylalcohol,or when made from

acetone a small quantityof that substance; both these in the

amounts presentare physiologicallyinert,and there is no reason

why chloroform preparedfrom ethylalcohol should in any way be

preferredto that obtained from acetone.

Breteau and P. Woog have found that chloroform may be keptin ordinaryglassbottles in diffused daylightwithout suffering

decomposition,if any of the followingsubstances are added in

proportionof 2-4 partsper 1,000:" Oil of turpentine,pure sperma-ceti,

menthol geraniol,menthol salicylate,and thymol.The theories as to the narcotic or anaesthetic propertiesof chloro-form

have been discussed in the generalintroduction to the narcotic

compounds. The symptoms known asf delayedchloroform poison-ing

',which include a remarkable fattyinfiltrationof the liver and

are not infrequentlyfatal,are in realitythose of an acid intoxication.

They are occasionallymet with after other anaesthetics. Diminished

oxidation processes characterize the action of allthe halogennarcotics;it is supposedthat the imperfectoxidation of the body fats givesrise to acids of the fattyseries,and hence the productionof these

symptoms. The action does not apparentlydependon the narcosis,but is a specialpropertyof this class of drugs.

Carbon tetrachloride,CC14,which was originallyinvestigatedbySimpson and others in the earlydaysof anaesthesia,was made the

subjectof more recent experimentby Marshall,who found that the

differences in action between this body and chloroform were mainlydue to its physicalcharacters. It is,however,more toxic and more

irritatingto the mucous membrane of the trachea and bronchi.

Recentlyit has been employed by hairdressers to clean the hair,and a case of accidental poisoningowing to the inhalation of the

vapour has been reported(Lancet,1907, i.1725). This case was

apparentlyserious,and very nearlyhad a fatal termination.

Dichlorethane,CH3 . CHC12, the symmetricalderivative ethylenedichloride,CH2C1.CH2C1,and trichlorethane or methylchloroform,CH3 " CC13,have all a very similar action to chloroform.

98 ESTERS OF HYDROBROMIC ACID

Esters of Hydrobromic Acid.

The lower alkylbromides have a similar action to the chlorides ;

thus methyl bromide,CH3Br, and ethylbromide,C2H5Br, have

anaesthetic properties,and are only slightlytoxic,but the latter

substance producesirritation of the respiratorypassages to a greaterextent than the correspondingchlorine derivative. The narcosis

producedby ethylbromide differs from that of chloroform,since it

sets in more rapidly,but also ceases more quickly.This is in agree-ment

with Schleich's theory,accordingto which narcosis is deeperand lasts longer,the higher the boiling-pointof the anaesthetic

(boiling-pointof ethylbromide = 38",chloroform = 61").

Bromoform, CHBr3, has a narcotic action,and was firstused in

1889 by Stepp in whooping-coughof children,and also in cases of

asthma. It is preparedfrom either alcohol or acetone in a very

similar manner to chloroform.

In ethylenedibromide,C2H4Br2,the toxicityincreases; the

anaesthetic action is slight,and it tends to cause paralysisof the

extremities and stoppage of the heart. It is stated to have a

peculiaraction on the respiratorycentre,diminishingthe desire to

breathe,and it has consequentlybeen suggestedthat it might be

of advantagein asthma.

The bromine derivatives being less stable than the chlorine

decomposemore rapidly,and many attemptshave been made to

employsuch compoundsin placeof potassiumbromide in epilepsy,with the hope of avoidingthe depressanteffectsof this salt. Up

to the present,however,no substitute has been found ; thus hexa-

methylene^tetramine-brommethylate(bromalin),(CH2)6N4.CH3Br,has not the desired effect; the sedative action is much lessthan that

of potassiumbromide,as are also the unpleasantafter-effects.

Tribromhydrin,C3H6Br9,has no advantageover bromide; itreacts

very similarlyto the correspondingtrichlorhydrin.It is also an

intestinalirritant.

Bromipin is a compound of bromine with sesame oil (seealso

lodipin),which liberatesthe element slowlyin the organism.The disadvantageof the organicbromine preparationsin the

treatment of epilepsyis that,althougha considerable amount of

bromine may be administered,it is presentin such a form that onlysmall quantitiesare set free in the body at a time ; consequently,when it is desirable to producea rapideffectthese preparationsareuseless.


100 ESTERS OF THE NITROGEN ACIDS

II. Esters of Nitrous and Nitric Acid.

The nitrous acid esters may be obtained by the action of nitrous

acid on the alcohols,e. g.

C2H50;H + 6H;NO = C2H5O.NO + H2O.

They are liquidswith characteristic smell,and are readilydecom-posed

by alkalisinto the correspondingalcohol and alkaline nitrite.

They are isomeric with the nitro paraffins,e. g. nitroethane,

C2H6NO2, but these on reduction yieldamines,C2H5NH2, whereas

the correspondingnitrous ethylester is saponified,yieldingethyl

alcohol,C2H5OH.The esters of nitric acid result from the interaction of alcohols

and nitricacid,e. g.

C2H50:H + OH:N02 = H20 + C2H5O.N02.

They are pleasant-smellingliquids,explodingwhen rapidlyheated,and easilysaponifiedby alkalis,givingalcohol and alkaline nitrate.

Physiological Properties.

As a generalrule,the entrance of the nitro or nitroso group into

a molecule increases its toxicity,irrespectiveof the manner in which

the linkageis effected; whether throughoxygen as in the esters,

or direct to carbon as in nitroso and nitro paraffins.The nitrous esters of the fattyseries do not act on the vaso-

motor centre but directlyon the vessels,causingpowerfulexpansion.Cash and Dunstan investigatedcarefully-preparedspecimensof

nitrous esters. They found that,as regardsthe principaleffect,i.e.reduction of blood pressure, the activityof various nitrites took the

followingorder when equalvolumes were administered to animals

by inhalation: " (1) Secondary propyl,(2) tertiarybutyl,(3)secondarybutyl,(4)w0-butyl(nearlyequal),(5)tertiaryamyl,

(6)a-amyl,(7)/9-amyl(nearlyequal),(8)methyl,(9)butyl,(10)

ethyl,(11)propyl. This order is somewhat modified when the

nitritesare givenby intra-vascular injections.When the duration

of subnormal pressure is considered,the order is nearlythe reverse

of that givenabove ; the effectof methylnitritebeingthe last,and

secondarypropylone of the firstto disappear.In some animals toxic effectsin the tissueshave been observed,but

in man death occurs owing to blood changes,methaemoglobinand

nitricoxide haemoglobinbeingformed.

PHYSIOLOGICAL PROPERTIES \ ; :. 101

Divergentviews have been held as to the chemical action of the

nitrites on the tissue cells; Loew considers that a combination

occurs with the amide group of the proteinmolecule ; Marshall,

Haldane,and others consider that the nitrous acid esters act directly.Binz considers that nitric oxide is formed ; a small portionisexcreted unchangedin the urine.

Bradburyinvestigated:

Methyl nitrate CH,

Ethylenedinitrate CHS

ON02

ON00

Nitroglycerin

Erythroltetranitrate

Mannitol hexanitrate

EL.O.NO,

CH2O.N02

CHO. N02

H2O.N02

CH2ON02

(CH.O.NO^

CH2ON02

CH2ON02

fCH.(CH.ON02)4

CH, ONO,

Erythroltetranitrateis lesspowerfulthan amyl nitrile or nitro-

glycerin,but its effects are more prolonged; mannitol hexanitrate

is not nearlyso powerful,but its action may be more prolonged.Its main advantageis its comparativelylow cost.

Marshall found mannitol pentanitrateintermediate in action

between the two.

Nitroglycerinis practicallyabsorbed into the blood unchanged,hence itspowerfuland prolongedaction (Brunton).

Nitro Paraffins. When the nitro group is linked directlyto

carbon,as for instance the nitro paraffins,an entirelydifferent

physiologicalreaction appears. Nitro ethane,C2H5NO2, for instance,

althougha toxic substance,has no action at all on the blood vessels,

and, like nitromethane,CH3NO2, causes death in relativelysmalldoses.

Nitro Derivatives of Aromatic Series. The introduction of the

nitro group into the aromatic series(p.40)also raisesthe toxicity

102 ESTERS OF THE SULPHUR ACIDS

in the resultingsubstance. Thus nitrobenzene producestremors

and increased reflexes,and eventuallycoma.

Nitrothiopheneacts in a preciselysimilar manner to nitrobenzene.

Nitronaphtholis toxic in small doses,either givenby the mouth

or subcutaneously.On the other hand ^"-nitrotoluene,

is almost non-toxic.

Nitroglycerin,hydroxylamine,and nitrobenzene act chieflyon the

central nervous system ; the action on the blood is secondary. The

chief toxic action of dinitrobenzene is on the red blood cells.

The entrance of a negativegroup causes a decrease or entire loss

of toxic properties,as, for instance,in the case of nitrobenzoic

acids or nitrobenzaldehydes,which are converted into acids (p.77)in the body.

III. Esters of Sulphurous and Sulphuric Acids.

When silver sulphiteis acted upon by ethyliodide,the ethylesterof sulphurousacid results,

Ag.S02OAg + 2C2H5l = 2AgI + C2H5.S02OC2H6.

Such esters may be regardedas the derivatives of unsymmetrical

sulphurousacid ; they are decomposedby potashwith the formation

of ethylsulphonicacid,

C2H5SO2OC2H5 + H2O = C2H6SO2OH + C2H5OH.

In the aromatic series the correspondingsulphonicacids are of very

much greater importance,and are formed by the direct action of

sulphuricacid upon the benzene derivatives,

C6H6;H + OHjSO2OH = H2O + C6H5.SO2OH.

This method of introducingthe sulphonicacid group can be used

with a very largenumber of substituted aromatic derivatives,and

givesrise to a group of substances soluble in water or whose sodium

salt is soluble in that liquid,a factor of importancein the dyeindustry.

The interaction of sulphuricacid and the alcohols givesrise to

esters which are much less stable than the sulphonicacids. Ethylalcohol givesthe ethylester of sulphuricacid

THE ETHERS 103

Phenol givesthe ester

Unlike the previouslymentioned derivatives,the hydrocarbon

radical is attached to oxygen, and in consequence they are readily

decomposedby alkalis,regeneratingacid and alcohol.

The introduction of these acidic groupingsinto organicsubstances

results in a great drop in pharmacologicalactivity,thus the toxic

phenolgivesthe inert phenolsulphonicacid,

OH

or the equallyinert phenylsulphuricester (seep. 56),

OC6H,OH

The hypnoticpropertiesof morphia are modified and considerablyweakened in its sulphuricester.

Phenyl-dimethyl-pyrazolis toxic,whereas its sulphonicacid

derivative given in doses of 5-6 gms. to rabbits producesno effect.

Dinitro-naphtholis toxic in small doses,whereas its sulphonicacid is inert.

It is interestingto note in this connexion Ehrlich's observation

that basic dyesstain the cortical nerve cells,whereas their sulphonicacids do not.

B. THE ETHERS.

The ethers are derivatives of the alcohols in which the hydrogenof the hydroxylgroup is replacedby alkyls,or they may be re-garded

as derivatives of water in which both hydrogen atoms have

been replacedby similar or dissimilar groups ; they are consequentlyclassifiedas simple,such as ethylether,C2H6 . 0.C2H6 ; or mixed,

such as methylethylether,CH3 . 0.C2H5.1. Their most importantmethod of preparationconsists in the

interaction of sulphuricacid and the alcohols. Thus

A. S"

The ethylester of

sulphuricacid.

104 PHYSIOLOGICAL PROPERTIES OF THE ETHERS

or at this stagea different alcohol may be allowed to react with the

sulphuricester and a mixed ether obtained thus

5 + CH3OH = SO

The ethers are volatile,neutral liquids,only slightlysoluble in

water. The lowest members are gases, the next liquids,and the

highestsolids ; their boiling-pointsare much lower than those of

the correspondingalcohols. From a chemical standpointthey show

but slightreactivity,since all the hydrogen atoms are attached to

carbon. Although not easilyattacked by oxidizingagents,they

yield,when oxidized,the same productsas their corresponding

alcohols.


The replacementof hydrogen in the hydroxyl group of the

alcohols results in the formation of substances much more stable

towards the oxidation processes of the body. The lower volatile

members of the series are more used as anaesthetics than hypnotics.

Dimethyl ether,(CH3)2O,acts very like nitrous oxide,producinga

rapidand transient anaesthesia.

The anaesthetic propertiesof diethylether,(C2H5)2O,are well

known. Its action is discussed in the generalintroduction to the

narcotic bodies.

The mixed aliphaticethers have not been investigated,and it

would be of considerable interest to find out whether methyl ethyl

ether,CH3 .

O. C2H6, which in the pure state boils at 11" C.,has

any advantagesover ordinarydiethylether.As the molecular magnitude of the ethers increases,their physio-logical

reaction becomes less.

Methylal,CH2(OC2H3)2,producesanaesthesia slowly;the action

is prolongedand deepbut somewhat uncertain,and patientsquicklybecome accustomed to it.

Acetal,CH3CH(OC2H5)2, is also an uncertain hypnotic,and pro-duces

unpleasantcardiac symptoms and considerable excitement.

The mixed aromatic aliphaticethers,such for instance as phene-tol,C6H0 . 0.C2H5, are not comparable to the simple aliphaticethers,and the derivative mentioned is entirelywithout anaesthetic

action.

CHAPTEE V

THE ALCOHOLS AND THEIR DERIVATIVES (continued).The chemical

and physiologicalcharacteristics of the Aldehydes, Ketones, Sulphones,Acids. The derivatives of the Acids. Halogen substitution products,

Esters,Amides, Nitriles. Sulphur derivatives.

THE OXIDATION PRODUCTS OF THE ALCOHOLS.

I. THE ALDEHYDES.

THE aldehydesare the first oxidation productsof the primaryalcohols,and contain the group (CHO)' linked on to an organicradical.

They may be obtained :"

1. By the oxidation of the primaryalcohol,which readilytakes

placeon warming them with potassiumbichromate and sulphuric

acid,

CH.CHOH -"

or C6H6CH2OH -" C6H5.CHOBenzyl alcohol. Benzaldehyde.

2. Aldehydesof both aliphaticand aromatic seriesare obtained bythe distillationof the lime salts of the respectiveacids with calcium

formate,

(CH3COO)2Ca + (H.COO)2Ca = 2CaCO3 + 2CH3COH

or (C6H5COO)2Ca+ (H.COO)2Ca = 2CaCO3 + 2C6H6COH.

3. Aldehydesof the aromatic series are obtained by the action of

chromylchloride,CrO2Cl2,upon the homologous benzenes. Thus

toluene givesfirstlya brown addition product,C6H5CH3 . (CrO2Cl2)2,which is decomposedinto benzaldehyde,C6H6 . CHO, by the action

of water.

The aldehydesexhibit the usual physicalpropertiesof an homolo-gous

series: the lower are volatileliquidssoluble in water, but as

the molecular magnitudeincreases,their solubilityin that medium

becomes lessand eventuallynil,and at the same time theydecompose

106 ALIPHATIC AND AROMATIC ALDEHYDES

on distillationat ordinarypressures. In chemical respectstheyare

neutral substances characterized by their great reactivity.Theyreadilypass to carboxylicacids,and in consequence are powerfulre-ducing

agents" the aliphaticto a greaterextent than the aromatic :

CH3.CHO + O = CH3COOH

C6H6CHO + 0 = C6H5COOH.

The majorityof the aliphaticaldehydesare converted into resins

by the alkalis,but those of the aromatic seriesgiverise to a mixture

of acid and alcohol,e.g.

2C6H5CHO + KOH = C6H5COOK + C6H5CH2OH.

On reduction theyyieldprimaryalcohols :

R.CHO + 2H = R.CH2OH.

Under ordinarycircumstances theydo not unite with water,but

many of their halogensubstitution productsyieldreadily-decom-posable

hydrates;e.g. chloral,CC13.CHO, giveschloral hydrate,

CC13. CH"^They unite with prussicacid,formingthe nitrilesof the hydroxy

acids,e.g.

CHXHO + HCN =

Nitrile of lactic acid.

Nitrileof mandelic acid.

Similarlytheycombine with sodium bisulphite,formingcrystal-linederivatives that may be employedfor their purification"

With ammonia the aliphaticaldehydesalso form compoundswhich

may be similarlyemployedfor their purification,

CH3CHO + NHa = CH3.

but with the aromatic amines a more complicatedreaction occurs.

Aldehydes of both series combine with phenylhydrazineandhydroxylamine,

K.CHO + H2N.NHC6H6 = E.CH :N.NHC6H5 + H2Oor ECHO + H2N.OH = RCH : N.OH + H2O.


108 THE ALDEHYDES

antisepticof sufficientstrengthcan be employedin this manner

without producingtoxic symptoms. Experimentsad hoc by one

of the presentwriters will be found in the Guy'sHospitalReports,vol. Iviii. Recently,formic acid and the formates have been

credited with tonic properties,but the clinical evidence is as yetmeagre.

The formylcompoundof urea, CO(N : CH2)2,which slowlybreaksoff formaldehydeand possesses no smell,has been introduced.

Compounds have also been formed between formaldehydeand the

antisepticgroup of phenols,such as eugenol,thymol,and iodo

thymol; these readilybreak down into their components,and a

combined action of antisepticsubstances is obtained.

When ammonia acts on formaldehyde,hexamethylenetetramineresults. This also in allprobabilityliberatesformaldehydein the

body,and to this may be ascribed its value as a urinaryantiseptic;

it limits suppurationanywherealong the urinarytract from the

kidneysto the orificeof the urethra,and on this account is the best

urinaryantisepticwe possess. It goes by a number of trade names,

namely,urotropine, aminoform, formin, cystamine, cystogen,

metramine, uretone, urisol, and vesaloine.

Paraldehyde,a polymericform of acetaldehyde,has the dis-advantage

of a very unpleasantodour and taste. It acts first on

the highercerebral centres and then on other partsof the central

nervous system,finallyproducingspinalanaesthesia and death. It

has no depressantaction on the heart (cf.chloral),and it may be

givenfor long periodswith safety.Its main disadvantageis its

irritant action on the gastricmucosa. It has antisepticpowers,like acetaldehyde,and can be combined with starch,dextrine,"c.,to form antisepticapplications.

Physiological Characteristics of Halogen Substitution

Products of the Aldehydes.

The entrance of -chlorineinto acetaldehydewith the formation of

trichloracetaldehydeor chloral,CC13. CHO, causes a largeincreasein narcotic power, but the simultaneous action of the halogenis

observed,viz.,depressionof cardiac and respiratorycentres.That the action of chloral is due to both halogen and

aldehydegroups is seen by the fact that on oxidation to trichlor-

acetic acid,CC13. COOH, the physiologicalreaction disappears,

whereas on reduction to trichlorethylalcohol,CC13. CH2OH, a sub-stance

with narcotic propertiesisobtained,althoughthese are much

HALOGEN DERIVATIVES OF THE ALDEHYDES 109

lesspowerfulthan those of the originalchloral. The action of the

chlorine may be traced by comparingchloral with paraldehyde,

since the latter has no depressantaction on cardiac and respiratory

activity,and indeed is said to act as a mild cardiac tonic.

Chloral,CC13CHO, was discovered in 1832 by Liebig,and is

obtained by the action of chlorine upon alcohol;the reaction is

complicated,and will be found discussed in works on organic

chemistry. It is an oily,pungent-smellingliquid,which poly-merizes

on keeping. Unlike acetaldehydeit combines with water,

forminga crystallinederivative,

CCl3CH""gchloral hydrate,a substance which,contraryto the generalrule,contains two hydroxylgroups linked into one carbon atom. It

readilyyieldschloroform with even dilute solutions of alkali,

CCl3.CHO + KOH = CHCl3 + H.COOK,and it was this that led

Liebreich in 1869 to try its hypnoticaction,%sinceit might be

supposedthat this decompositionwould take placein the body;it was, however,shown later that chloral is reduced to trichlorethylalcohol,CC13COH, and is eliminated as a derivative of this sub-stance

and glycuronicacid (seep. 60); consequentlythe old idea

of itsphysiologicalreaction had to be abandoned.

Butylchloral,CC13. CH2 . CHO, has a more powerfulaction than

chloral,but the effectspass off more rapidly.Butylchloral hydrateis said not to depressthe heart,but this is by no means certain.

There is no explanationfor its specificeffect on the fifth nerve.

Trigemin is a compound of butylchloral hydrateand pyramidon.The correspondingbrom and iodo substitution productsof

acetaldehydeshow very considerablydiminished hypnoticaction.

Bromal, CBr3 . CH(OH)2, in animals causes irritationof the

respiratorypassages, and in largerdoses dyspnoeaand cyanosis;stilllargerdoses produceanaesthesia but not hypnosis.

lodal,CI3.CH(OH)2. The replacementof bromine by iodine

appears to increase the action upon peripheralnerve-endingsand

muscles,but the substance has only slighthypnoticproperties.The mono-iodo derivative CH2I.CH(OH)2 has not such a powerfulaction as chloral,but has a strongdepressantaction on the heart.

Owing to the reactivityof the aldehydegroupingin chloral it is

possibleto modifythe substance in various directions;up to the

presentit has been found that all those derivatives which easilysplitoff chloral in the organismshow the ordinarychloral reaction,

110 HALOGEN DERIVATIVES OF THE ALDEHYDES

whereas the more stable either do not possess hypnoticpropertiesor are toxic substances. Combinations with other hypnoticshave

not givenany very striking-results,thus chloral alcoholate,

CC1*-CH\OC2H6)formed by the addition of chloral and alcohol has no advantages

over the hydrateitself.

Dormiol, introduced by Fuchs,and formed by the union of chloral

and amyl alcohol,

yCHg .OH

CCL.CHO + OH-C"-CH3 = CCL

.CH"n p/

\r if u " -

25

is not very stable,being easilybroken down, probablyeven bysolution in water,into its constituents. It has a penetratingsmelland taste,and its action is not reliable.

Chloral urethane (ural,soninal),

CC13-^\NH.COOC2H6,was preparedin the hopethat the hypnoticeffectsof ethylurethane

might be added on to that of chloral. An apparentlyidentical

body is known as nralinm. The hypnoticeffect wears off before the

toxic,and in animals paralysisof the hindquartersaccompaniesthe

sleepinduced by the drug. Diarrhoea,diuresis,salivation,itching,and disturbances of respirationare producedby largedoses.

Similarly,chloral was combined with acetone, which has a slightnarcotic action,but the resultingsubstance,chloral acetone,

CC13. CHOH.CH2 . CO.CH3 ,

possesses but littlenarcotic action,and in the organismis dehy-dratedwith formation of CC13.CH : CH.CO.CH3. On the other

hand the correspondingaromatic derivative chloral acetophenone,

CC13.CH.OH.CH2. CO.C6H5 (thecombination with acetophenone,

a powerfulhypnotic),has not the slightesthypnoticaction,but

like the previouscompound it is eliminated as

CC13.CH: CH.CO.C6H5.

Then, in another direction,Mering and Zuntz introduced the

compoundof formamide and chloral,chloral formamide, or chloral

amide. This is formed by the direct union of the two,

CCL.CHO + H.CONHo =

ALDEHYDE DERIVATIVES 111

a reaction which does not take placewith the unsubstituted

acetaldehyde.This derivative has a slightlybitter taste,less

harmful action than chloral,but on the other hand much less

hypnoticpower. Since urochloralicacid is found in the urine,its

action probablydependson its slow decompositionin the organisminto chloral itself.

Chloral ammonia,

CC1'CH "vNTH2,was intended to combine the hypnoticaction of chloral hydratewith the stimulant action of ammonia on the heart and respiration.

The condensation productsof chloral with various aldoximes and

ketoximes have givenproductsof no pharmacologicalvalue. These

derivatives,formed accordingto the generalreaction

E : N.OH + CC13.

CHO = C.C13

are but slightlysoluble in water.

The productsresultingfrom the condensation of chloral with

various sugars have been investigatedby Hauriot and Eichet,andothers.

Milk-sugarchloralidehas no narcotic action,but producesepilep-tiform fitswith bronchorrhoea and asphyxia.

Chloral (freefrom water)and glucoseare combined as chloralose,

C8HnCl3O6. It is a somewhat rapidhypnotic,but is less easilytoleratedthan chloral hydrate.It may producerestlessness,diplopia,tremors,and haemoglobinuria.Its main toxic action is on the re-spiratory

centre. Eichet says itacts on the grey matter of the cortex

cerebri,the cord beingunaffected. The uncertain results are said

to be due to the formation of a second compound, parachloralose,which is toxic without beinghypnotic.

Arabino-chloralose is easilysoluble in water,producesno stageof excitement,and has a minimum lethal dose equalto twice that

of chloralose. It is,however,a much less powerfulhypnotic.A second compound,pararabino-chloralose,is onlyslightlysoluble.The pentosecompounds are probablyless active and less toxic

owing to their greaterstabilityin the body.When chloral reacts with antipyrineseveral substances result"

hypnal,C13H15N2O3C13,meltingat 67"-68",and chloralantipyrin,C13H13C13N2O2,formed at a highertemperatureand possessingnophysiologicalreaction. Hypnal has a similar toxic and hypnoticaction to chloral hydrate.The toxic dose is the same, so that the

112 THE KETONES

presence of antipyrinheightensthe toxicityof the chloral. It is

used as an analgesicas well as a hypnotic.The various condensation productsof choral with aromatic

hypnotics,investigatedby Tappeiner,have littleor no physio-logicalreaction.

II. THE KETONES.

The ketones are a group of substances closelyrelated to the

aldehydes,both contain the carboxylgroup linked,in the case of

the former compounds,to alkylgroup, but in the case of aldehydesto an alkylgroup and hydrogen.

CH3 CH3

CO Dimethylketone, CO Acetaldehyde.

The relationshipswill be noticed in their more importantmethodsof preparationand generalreactions. They may be divided into

two classes,in a similar manner to the ethers : Simple,such as

acetone,CH3 . CO.CH3 ; and Mixed, such as methylethylketone,CH3.CO.C2H5.They are formed by the oxidation of secondaryalcohols,

CH3.CHOH.CH3 -" CH3.CO.CH3

Iso-propylalcohol.

C6H5 . CHOH.CH3 -" C6H5.CO.CH3Phenylmethyl carbinol. Acetophenone.

or by the distillationof the lime-saltof the correspondingacid,

(CH3COO)2Ca = CaC03 + CH3COCH3

(C6H5COO)2Ca = CaCO3 + C6H5.CO.C6H5

whereas the mixed ketones are obtained from the lime-salt of two

acids,

(CH3COO)2Ca + (C2H3COO)2Ca = 2CH3. CO.C2H5+ CaCO3

(C6H6COO)2Ca+ (CH3COO),Ca = 2C6H6COCH3 + 2CaCO3.

The ketones are neutral bodies,and the lower members of the

series are volatile etherial-smellingliquids.They are much less

readilyoxidized than the aldehydes,and unlike that group of

substances do not polymerize.


Their reactionswith hydroxylamine,phenylhydrazine,and prussic

acid resemble very closelythose of the previousgroup,

(CH3)2CO+ H2N.NHC6H5 = (CH3)2C:N.NHC6H5 + H2O

C6H6CO.CH3+ H2N.OH = C6H5 . C(N.OH).CH3

CH3.CO.CH3 + HCN =

Those containinga methylgroup react with sodium bisulphite,

formingcrystallinederivatives which may be employedfor puri-fication

owing to the ease with which they are obtained,and

then decomposedby acids or alkalis with the recovery of the

ketone.

CH3.CO.CH3 + NaHS03 =

and

Physiological Characteristics.

The ketones in generalphysiologicalaction closelyresemble the

alcohols,they giverise to narcosis and loweringof the blood

pressure. Acetone,CH3 . CO.CH3, producesintoxicationand sleep,but is lesspowerfulthan ether or chloroform and less toxic than

ethylalcohol. The hypnoticproperties,traceableto the ethylgroups,are clearlyseen in diethylketone,C2H6.CO . C2H6 (Propion),which

was introduced as a hypnoticand anaesthetic,but its solubilityin

water is not great,and this,combined with an unpleasanttaste,renders it of littleuse.

Similar hypnoticpropertiesare noticed in dipropylketone,but as the molecular magnitudeincreases the solubilityin water

decreases,and the higherketones are not likelyto be of any

pharmacologicalvalue.

The diminution in physiologicalaction which accompaniestheintroduction of hydroxylgroups is observed in the case of the

inert ketoses (ketonesugars)justas it isin that of the aldehydes.The stabilityof the ketonic acidsdependson the relativepositions

of the ketonic and carboxylgroupings.Thus acetoacetic ester,

CH3CO.CH2.COOH, is very unstable,readilybreakingdowninto acetone.

Levulinic acid,CH3COCH2CH2 . COOH, on the other hand,is

more stable,and at the same time much more toxic.

i

114 THE SULPHONALS

Ketones,both simpleand mixed,aliphaticand aromatic,are ob-served

to possess hypnoticproperties.Benzophenone,C6H5 . COC6H5,

has a slightaction but much less than the aliphaticderivatives.

In the mixed aromatic and aliphaticketones the action depends

largelyon the nature of the latter radical. Thus acetophenone,

C6H5CO.CH3 (Hypnone),has a marked hypnoticaction.

The attemptswhich have been made to increase the solubilityof

acetophenoneby the introduction of the amido group or its substi-tuted

derivatives have not led to substances of practicalimportance.

Phenylethylketone,C6H5COC2H6, has a more powerfulaction

than acetophenone.

DERIVATIVES OF THE KETONES.

SULPHONALS.

When water is withdrawn from a mixture of alcohol and alde-hyde,

the acetalsresult,

CH3CHO + 2C2H5OH = CH3CH(OC2H5)2+ H2O,

but a correspondingreaction does not take placewith the ketones.

The correspondingsulphurderivatives,however, are known, and

are obtained by the action of a dehydratingagent,such as hydro-chloricacid on a mixture of ketone and thioalcohol,

CH3 ..., CH3I..--'TT^Q/^ TT I C C* TI....- Jl:bU2"l5 | yD.U2H5

co+ ; = H2o + c"I'...... HiSC2H6 IXS.C2H5

Acetone. Ethyl mercaptan. Acetone-ethylmercaptol.

The resultingsubstances are liquidswith an unpleasantsmell,and are

readilyoxidized by potassiumpermanganateto a group of substances

called sulphones,CH3 CH3

SC2H5 |yS02C2H5+04 = C"

S.C2H5 IXS02C2H5CH3 CH3

Acetone-diethylsulphone.

Many of these derivatives,investigatedby Baumann and Kast,have valuable hypnoticproperties.


116 PHYSIOLOGICAL PROPERTIES OF SULPHONES

C2H5\p /SO2C2H5 (Trional)has a more powerful and pro-

CH3/ \SO2C2H5 longedaction than sulphonal.

(Tetronal)ismuch less soluble than the other

/^2TT5compounds and has the most powerfuloô-tl/r

, .. .. " ,i ,, , ,6 hypnoticaction of all the sulphones.

The intensityof the action of these sulphonesis consequently

dependent on the number of ethyl groups they contain : this,

apparently,is only true for dogs. Clinically,the distinction does

not hold good.

Sulphonaland trional are only slightlysoluble in water, and

hence are but slowlyabsorbed ; consequently,their action tends to

be undulyprolonged; also the use of these substances,if continued

for a long time, may bring about destructive action on the red

blood corpusclesand consequenthaematoporphyrinuria.To increase the solubilityof these derivatives,attempts have

been made to producepharmacologicallyactive amido substitution

products,but so far without success..

As regardsthe metabolic changesof the sulphones,the interest-ing

observation has been made that those which are most stable

outside the body are physiologicallyreactive,and are to a greateror

less extent broken down by the organism,whereas those that are

least stable are inert,and pass through unchanged. Thus, of the

previouslymentioned substances,ethylene-diethylsulphone,methy-

lene-diethylsulphone(easilydecomposedby alcoholic potash),methy-

lene-dimethylsulphone,ethylidene-dimethylsulphone are found

unaltered in the urine; whereas sulphonal,f reversed ' sulphonal,

trional,and tetronal (substancesunacted upon by acids and alkalis,

and most oxidizingand reducingagents)are to a varyingextent

decomposed.It is,however,true that sulphonals,which are but slightlystable,

and hence readilydecomposed in the body, may have no hypnoticaction. Thus the diethylsulphonepreparedfrom acetoacetic ester,

CH3 . C(S02C2H6)2. CH2 . COOC2H5,

has no hypnoticaction,although no trace of it can be found in the

urine,and the same is true of its ethylderivative,

CH8. C(S02C2H6)2. CH(C2H6).COOC2H5)

in spiteof the number of ethylgroups.

THE ACIDS 117

III. THE ACIDS.

The organicacids are characterized by the presence of the so-

called carboxylgroup .COOH and their basicitydetermined by the

number of these present. The acids of the paraffinseries are

termed fatty,owing to the occurrence of their highermembers

in the natural fats; these substances,on boilingwith alkalis,

giverise to glycerinand the correspondingalkali salts" soaps;

and hence the process of convertingan ester into an acid and

alcohol has been termed saponification.

Methods of Preparation.

The most importantgeneralmethods of preparationare :"

1. The oxidation of the primaryalcohols and aldehydes,

CH3.CH2OH -+ CH3.COOHCHo.CHO -" CH3COOH

o o

and in the aromatic series,

C6H5CH2OH -* C6H5COOH

C6H5COH -*" C6H5COOH.

2. The addition of water to the nitriles,often carried out bytreatment with 50 per cent, sulphuricacid and water. Or the

reaction may be effectedby means of alkalis,

CH3CN + 2H20 + HC1 = CH3COOH + NH4C1

. C6H5CN + 2H20 + HC1 = C6H5COOH + NH4C1

CH3.CH2CN + H2O + KOH = CH3CH2COOK + NH3

3. The aromatic monocarboxylicacids are readilyobtained from

the benzene homologuesby oxidation (seep. 42) (othermethodswill be mentioned later),

C6H5CH3 + 3O = C6H5COOH + H2OToluene.

O.C6H4(CH3)2 _" C6H4(COOH)2o-Xylene. Phthalic acid.

The lower members of the fattyseries are soluble in water,but

this propertyrapidlydecreases with increasingmolecular weight.The lower may be distilledwithout change,but the highermem-bers

are decomposed.As the molecular magnitude increases the

aciditydiminishes.The aromatic acids are found (partlyin the free state)in many

118 THE ACIDS

balsams and resins,and in the animal organism; theyresult from

the decompositionof albuminous substances,and are crystallinesolids

which generallysublime undecomposed,and are onlysoluble with

difficultyin water.


The entrance of the acidic carboxylgroup into the members of

the limit hydrocarbons,resultingin the formation of the acids,

givesriseto a class of substances with but slighttoxic action. The

first member, formic acid,is exceptional,as it is in most of its

chemical characteristics. Thus, unlike acetic acid,it is a powerful

reducingagent, to which,probably,its antisepticaction may be

partlyascribed,and, unlike the other members of the series,it forms

no acid chloride,and its nitrile,prussicacid,(HCN), has acidic pro-perties

; it is,further,a much more powerfulacid than acetic.

Of the fattyseries,formic acid has the most powerfulantiseptic

properties,acetic less,propionicacid least;on the other hand,the

correspondingaction of the benzene substituted acids increases with

increase of molecular weight. Thus phenylaceticacid,

C6H5CH2COOH,is lesspowerfulthan phenylpropionic,C6H5.CH2.CH2.COOH, and

this less than phenylbutyricacid,C6H5CH2 . CH2 . CH2 .COOH.

Formic acid is much more toxic than the other members of

the series,except butyricacid, which has also slightnarcotic

properties.The introduction of the hydroxylgroup into butyricacid,resulting

in the formation of /8-oxybutyricacid,CH3.CHOH.CH2.COOH,givesrise to a substance which exists in three opticalisomerides,ascribed to the presence of an asymmetriccarbon atom marked with

a star ; the inactive acid has no physiologicalaction,but the other

modifications produceacid intoxication similar to that seen in diabetic

coma.

In a very similar manner intraperitonealinjectionsof the various

opticalmodifications of tartaric acid show that the laevo-rotatoryacid is the most toxic,the dextro acid about one-half,whereas racemic

acid is not more than one-quarteras toxic as the laevo form.

With the dibasic acids the simplest,oxalic,

COOH

COOH,


is toxic,but the toxicityvery rapidlydecreases as the carboxyl

groups are separated,

CH2.COOH;XXij malonicacid, succmic acid,

CH2 .

COOH

CH2COOH

H2 glutaricacid.

COOHCH0.L2

In the unsaturated acids,

COOH.C.H H.C.COOH

fumaric, and maleic,H.C.COOH H.C.COOH

the difference due to structural form is very marked. Fodera

showed that the former was non-toxic,whereas the latter was

poisonousfor higheranimals.

The acids of the fattyseries,probablyowing to the presence of

the carboxylgroup, do not show narcotic properties,or do not show

them to any marked extent. Butyricacid has a slightaction which

may be traced to the ethylgroup, C2H6 .CH.COOH ; it is more

marked in dimethyl-aceticacid,

and stillmore in dimethylethylaceticacid,

CEU

CH3 C.COOH,C2H6)

of which 3-5 gms. producesleepand 4-5 sleepand death (rabbits).The introduction of the carboxyl group into aromatic sub-stances

is of great pharmacologicalimportance,since a drop in

toxicityresults. Thus benzene may not be taken in doses of

more than 2 to 8 gms. per day,whereas benzoic acid,C6H5COOH,is very much less toxic,and may be taken in doses of 12 to 16 gms.

Naphthalenein largedoses is toxic ; its carboxylicacid has no physio-logicalreaction. Not more than 1 to 2 gms. of phenol can be

administered,but 1 : 3- and 1 :4-hydroxybenzoicacid,

120 RADICALS OF THE ACIDS

have no action,and salicylicacid,the 1 : 2 derivative,may be givenin doses twice to three times as great as those of phenolwithout toxic

symptoms appearing.The toxic aniline becomes the inert ^-amido

benzoic acid,

C6H4\COOH,

by the introduction of the carboxylgroup into the nucleus. The

replacementof hydrogenin the methylgroup in phenacetin,

with the formation of

p TT /OC2H5C6M4\NH.CO.CH2.COOH

bringsabout the loss of its toxic and therapeuticproperties.

Allusion may be made here to the introduction of the acid radical

of either series into physiologicallyactive basic bodies. The radical

of acetic acid,or acetyl,(CH3CO)',of lactic acid,or lactyl,

benzoic acid, or benzoyl,(C6H5.CO)',salicylicacid,or salicyl,

"c.,can readilyreplacethe hydrogenof the amido or imido group

throughthe interaction of the acid itself or the correspondingacid

chloride with the base in question(seepp. 36, 43).The resultingsubstances are of greatimportancein the synthetic

preparationof drugs; from a chemical standpointsuch derivatives

are more stable,and lessreadilyoxidized than the bases from which

theyare obtained. The lactylsubstitution productsare more soluble

than the acetyl,and the salicylleast ; and the latter are broken

down with such difficultyby the organismthat,as a generalrule,

they do not possess physiologicalaction. The pharmacologicalreaction of this group of substances is that of the base from which

they are obtained.

The action of the benzoylresidue when introduced into the

alkaloidsis remarkable ; thus ecgonine-methyl-ester(seep. 259) has

no anaestheticaction,but itsbenzoylderivative,i.e. cocaine,possessesmost powerfulproperties.

HALOGEN DERIVATIVES OF ALIPHATIC ACIDS 121

The toxicityof aconitine stands in intimate relationshipto the

benzoyland acetylgroups presentin that alkaloid ; when these are

eliminated the resultingsubstance has no action. Even splittingoff the acetylresidue causes a drop in toxicity,and the loss of

the stimulatingaction,shown by aconitine,on the respiratorycentres.

DERIVATIVES OF THE ORGANIC ACIDS.

A. Halogen Substitution Products.

The halogenderivatives of the fattyacids may be obtained,like

the parent acids,by the oxidation of chlorinated alcohols or

aldehydes,CC13.CHO -* CC13.COOH

Chloral. Trichloracetic acid.

or by the direct substitution of the hydrogenof the hydrocarbonresidue by halogens.

These derivatives have more pronouncedacidicpropertiesthan the

acids from which theyare derived,otherwise theyshow very similar

characteristics.

Physiological Action.

The replacementof hydrogenby the halogens,as previouslynoticed in other cases, causes an increase in narcotic action;thus

sodium acetate is quiteinert,but sodium monochlor acetate,

CH2Cl.COONa, has pronounced narcotic properties;the further

replacementof hydrogen,instead of increasingthis characteristic,bringsabout a diminution. Dichloracetic acid has less action

than the mono derivative,whereas trichloraceticacid,CC13. COOH,has very slight,if any, correspondingphysiologicalreaction. In this

case the difference in the action may be ascribed to the varyingstabilityof the substances. Monochloracetic is easilydecomposedon heating,even at body temperature; trichloris most stable,anddichloraceticof intermediate stability.It ispossiblethat the narcotic

action of the firsttwo acids is due to the liberation of hydrochloricacid in the cerebral cortex,since in animals rendered drowsybythese

acids the symptoms are diminished by the injectionof sodium

carbonate into the vessels. Also,trichloraceticacid does not giverise to hydrochloricacid on decomposition,but to chloroform,and,as alreadystated,has no narcotic action.

122 ESTERS OF ORGANIC ACIDS

In the other substituted acids the introduction of chlorine some-times

lessens the narcotic action,thus sodium butyrateis more

powerfulthan sodium trichlorbutyrate.Crotonic acid is twice as

powerfulan hypnoticas the monochlor derivative.

The replacementof hydrogen in acetic acid by bromine and

iodine also results in substances with narcotic action,monoiodo

acetic acid having less action than the correspondingbrominederivative.

Monobrom- and to a very much less extent monochlor-acetic

acid producemuscular rigidityin frogs.

B. The Esters.

The esters of the organicacids resemble very closelythose of the

mineral acids previouslydescribed (p.93),and are obtained byanalogousmethods; the most importantbeingthe interaction of

an acid and alcohol,e. g.

CH3COOiH + OH:C2H6 = H2O + CH3COOC2H5Ethyl acetate.

As this reaction is reversible (ethylacetate is decomposedbywater with the reformation of alcohol or acid),it is carried out in

the presence of hydrochloricor sulphuricacids,or the volatileester

is removed as it is formed.

The esters of the fattyacids are neutral,volatile,pleasant-smel-lingliquids,generallyinsoluble in water. They are preparedin

largequantitiesfor the artificialproductionof fruit essences ; the

acetic ester of amyl-alcohol,CHgCOO.CgHjj,in dilute solution is

used as pear oil; the octylester has the odour of oranges ; the isoamylester of propionicacid smells like pineapple.

When heated with water, or more rapidlyand completelywithsolutions of the alkalis,they are decomposedinto alcohol and

acid,

CH3.COOC2H5 + KOH = CH3COOK + C2H5OH.

Physiological Characteristics.

The loss of the acidicpropertiesof the acids by the replacementof the hydroxylhydrogenby alkylgroups producesin the esters

pharmacologicalpropertiescloselyresemblingthose of the alcohols.

Ethylformate,H.COOC2H5, producesirritationof the throat and


124 PHYSIOLOGICAL PROPERTIES OF THE AMIDES

salts of the originalacids or into ammonia and the acids them-selves,

CH3CONH2 + H2O = CH3COONH4

or CH3CONH2 + KOH = CH3COOK + NH3.


Formamide and acetamide produceconvulsions similar to those

set up by picrotoxin; propionamidehas less action,and butyl-amide stillless; the action of the last-named only occurs through

decompositionand the liberation of ammonia. On the other hand,

butylamidehas a most powerfulnarcotic action,and this propertydecreases in the seriestillit disappearsentirelyin the case of form-

amide. Lactamide and /2-oxybutylamidehave the same action as

propionamide.The aromatic amides have narcotic properties; this is seen in the

case of benzamide,C6H5CONH2, althoughlargedoses are necessary,

and also in the followingsubstances :"

jt?-methylbenzamide,

the amide of anisicacid,

H

Phenylacetamide,C6H5CH2CONH2, is a weaker hypnoticthan

benzamide. Amidoacetamide,NH2 . CH2CONH2, has no action,but

itsbenzoylderivative,the amide of hippuricacid,

C6H6CO.NH.CH2CONH2,has slightnarcotic properties.

The amide of cinnamic acid,C6H5CH :CH.CONH2, has strong

hypnoticproperties.When the hydrogenatoms of the amido group in benzamide are

replacedby methylor ethylgroups, the narcotic action isdepressed,and the resultingsubstance producessymptoms similar to those of

ammonia and strychnine.This may be observed in the followingseries :"

C6H6CONH2 C6H5CONH.CH3Methyl benzamide.

C6H6CONH.C2H6 C6H5CON(CH3)2Ethyl benzamide. Dimethyl benzamide.

THE NITRILES 125

Urea is the diamide of carbonic acid,

nn/OH "/NH,CU\OH -"

(seep. 216),and it is interestingto note, in connexion with the

narcotic propertiesof benzamide,that benzoylurea,

CO/NHCOC6H5CO\NH2

does not show any similar physiologicalreaction.

D. The Nitrites.

The nitrilesresultfrom the dehydrationof the acid amides,e. g.

;;= CH3CN,

and on the absorptionof water pass back into the amides,and then

into the acids themselves or their ammonium salts,

CH3CN + H20 = CH3CONH2

CH3CONH2 + H2O = CH3COONH4.

They are obtained by the action of dehydratingsubstances on the

acid amides,or by the action of an alcoholic solution of potassium

cyanideon an alkylderivative of the aliphaticseries,

C2H5I+ KCN = C2H5CN + KI.

Another method of preparationconsistsin the distillationof the

potassiumalkylsulphateswith potassiumcyanide,

+ C2H6CN

C6H5SO2OK + KCN = K2SO3 + C6H6CN,

The nitrilesare liquidsusuallyinsoluble in water,possessingan

agreeableetherialsmell and distillingwithout decomposition.


The nitrileof formic acid,or prussicacid,HCN, differsfrom

itshomologuesby itsgreattoxicity.Methylnitrile,CH3CN, is,for

instance,much less poisonous; but,on the other hand,the isomeric

methylcarbylamine,CH3NC, is extremelytoxic,more so it is said

than prussicacid,and it seems, therefore,quitelikelythat prussicacid itself has the constitution HNC, in which nitrogenis

quinquevalent.

126 PHYSIOLOGICAL PROPERTIES OF THE NITRILES

Bunge found that the nitrile of oxalic acid,i.e. cyanogen,

CN

CN

has one-fourth the toxicityof prussicacid.The toxicityof the nitrilesof the fattyseries increases with the

increase of molecular weight; thus Verbruggefound for rabbits :"

Acetonitrile -13 gm. per kilo bodyweightPropionitrile -065

" " "

Butyronitrile-010" " "

Isobutyronitrile-009 " " "

Isovaleronitrile -045" " "

The introduction of the carboxylgroup into acetonitrilelowers

the toxicity,thus cyaneticacid = 2-0 gms., the ethylester,however

= 1-5 gm.

In the aromatic series,benzonitrile is less poisonous,the toxic

dose being"20 gm., for 0-tolylnitrileit is -60 gm., and for naph-thonitrile 1-0 gm. The introduction of the phenylresidue into

acetonitrileraises the toxicity,which,in this case, = -05 gm.

Barthe and Ferre investigatedthe three substances,

CH2.COOC2H5

CN fH\COOCH3 I/CN\COOCH3

CH2COOC2H5

formed by insertingfirst one (CH2COOCH3)' group in cyan-

aceticmethylester,and then a second similar group. The firsthad

the most energeticphysiologicalreaction,and was most similar to

cyanogen; then came the second,and the third showed no toxic

action.

SULPHUR DERIVATIVES.

When oxygen in the alcohols is replacedby sulphur,resultingin

the formation of the mercaptans,such as methylmercaptan,CH3SH,an increase in toxicityis observed,althoughthese derivatives have

lessphysiologicalaction than sulphurettedhydrogen,SH2. Theyact mainly on the central nervous system,causingparalysisand

convulsions,and finallydeath from respiratoryfailure. The mer-captans

are characterized by their strong odour,which increases

with the molecular weight.

SULPHUR DERIVATIVES 127

The further replacement of the hydrogen atom by an alkyl group

results in sulphides,the analogues of the ethers. Methyl sulphide,

CH3.S.CH3, produces paralysisof central origin; ethyl sulphide

is physiologicallyinactive and has not the powerful odour of the

mercaptans ; consequently, the physiologicalreactivityof sulphur-etted

hydrogen is still further depressed by the replacement of both

hydrogen atoms by alkyl groups.

Of the latter derivatives the unsaturated alkyl sulphide,

C3H5\ciC3H5/S"

has been used for cholera, and in solution in oil for subcutaneous

injectionsin cases of tuberculosis.

In the aldehydes the replacement of oxygen by sulphur is followed

by a rise in toxic properties.

Paraldehyde, for example, does not act upon the heart, whereas

trithioaldehyde,also possessing hypnotic properties,is a powerfulheart poison.

Patty acids in which sulphur replacesone or two atoms of oxygen

are non-toxic.

Carbon bisulphide is a powerful poison, acting mainly on the

central nervous system. Workers in caoutchouc factories occasion-ally

develop toxic phenomena " headache, giddiness, deafness,

amaurosis, and occasionallyparaplegia. Its direct action appears

to be narcotic.

The xanthates, e. g.

cs/"$H"\SNa

(substances which are easily decomposed into alcohol and carbon

disulphide),have similar physiological action to CS2; a generalnarcosis can be produced in man by these bodies. Their alkaline

salts are antiseptics.

[Note." Other sulphur compounds will be discussed in connexion

with the corresponding oxygen derivatives.]

CHAPTER VI

AROMATIC HYDKOXYL DERIVATIVES. " Main Group of Aromatic Anti-septics.

" Chemical and physiologicalpropertiesof Phenols,Cresols,Di- and

Tri-oxybenzenes.Recent investigationsof the antisepticpower of Phenol

and its derivatives Creosote,Guaiacol,and their derivatives.

I. MONO-, DI-, AND TRI-OXYBENZENES.

THE substitution of hydrogenin the aromatic nucleus by hydroxyl

givesrise to the phenols,a group of substances which correspondtothe tertiaryalcohols of the fattyseries,since they do not yieldacid

or ketones on oxidation. Like the alcohols they are distinguishedas mono-, di-,"c.,accordingto the number of hydrogen atoms

replacedby the hydroxylgroup.

Methods of Preparation.

1. They may be obtained,as previouslyindicated (p.41)by the

decompositionof the diazo salts,especiallythe sulphates,with

boilingwater,

C6H5 .N : N.HS04 + H2O = C6H5OH + N2 + H2SO4

2. They also result from the fusion of the sulphonicacids with

sodium or potassiumhydrate,

C6H5.SO2ONa + NaOH = Na2SO3+ C6H6OH

General Properties.

The phenols,in contrast to the alcohols,have stronglymarked

acidic properties,which are enhanced by the entrance of more

negativegroups into the nucleus. Thus phenol readilygivessodium phenate,C6H6ONa, when treated with caustic soda,but is

PROPERTIES OF THE PHENOLS 129

incapableof decomposing"sodium carbonate with the formation of

that salt. On the other hand nitro-phenol,

and picricacid,

C6H2\OHare sufficientlypowerfulto liberate carbon dioxide from the carbo-nate

with the formation of the correspondingphenates.The presence of the hydroxylgroup in the benzene nucleus

renders more easy the replacementof other hydrogenatoms bychlorine,bromine,or nitro groups.

The hydrogenof the hydroxylgroup is readilyreplacedby alcohol

or acid radicals. Thus sodium phenate,treatedwith methylor ethyliodide,givesrise to anisol,C6H5OCH3, or phenetol,C6H5OC2H5;these derivativesare very stable and are not decomposedby potash.

The acid esters result from (1)the interaction of phenolor the

phenateswith the acid chlorides.

C6H5ONa + CH3COCl = NaCl-f C6H5O.(CH3CO),or (2)digestingthe phenolsand acids with phosphorusoxychlorideor pentachloride.

(3)In the polyhydricphenolsall the hydroxylhydrogenatoms

may be replacedby acetylgroups, by heatingwith aceticanhydrideand sodium acetate.

The acid esters resultingfrom these reactions are readilydecom-posed

into their componentsby alkalis,thus phenylacetate,

C6H5O.OCCH3 + KOH = C6H5OH + CH3COOK.

Nencki,in 1886, was the firstto realize the importanceof this

group of substances for pharmacology,since by their formation

both the phenolsand acids with which theyare combined losetheir

caustic properties,and the resultingderivatives are slowlybrokendown onlyon reachingthe intestinalcanal,where the physiologicalaction of their componentscomes into play.

This method of treatingphenolicsubstances is generallytermedNencki's Salol Principle, since salol,C6H6O.(OC.C6H4. OH), was

the firstof these derivativesintroduced.

The acidic nature of the phenolscan also be eliminated by the

correspondingformation of carbonates,etherial carbonates,or amides.

Carbonates are formed by the agency of phosgene,

(i)C6H5ONa + Cl.COCl = C6H5O.COCl + NaCl

and (ii)C6H5O.COC1 + H2O = C6H5O.COOH + HCL

1C

130 AEOMATIC HYDROXYL DERIVATIVES

When ammonia is broughtinto playat the second phaseof the

reaction,the amides result,

C6H5O.COC1 + NH3 = C6H5O.CONH2 + HC1,

or such derivatives may be obtained directlyby the action of

urea chloride on the phenolsor their salts,

C6H5OH + C1.CONH2 = HC1 + C6H6O.CONH2.

The substances of this group are generallysolids and are soluble in

water.

Chlorformic ester givesriseto the correspondingesters,

C6H6ONa + Cl.COOC2H5 = Nad + C6H5O.COOC2H5 ;

bodies of this type are usuallyliquids,insoluble in water.

The sulphuricesters of phenolhave previouslybeen mentioned

(p.102).Homologous Phenols.

The three cresols0, m, p

L3

are found in coal-tar and beechwood-tar,thymol,

OH.1

C6H3 CH3 .3

C3H7 .6

in oilof thyme. Carvacrol,

(OH .1

CeH8JCH, .2

(C3H7.5

in the oil of certain varietiesof satureja.These substituted phenolscannot be oxidized to theircorrespondingacids by means of chromic

acid,unless the hydrogenof the hydroxylgroup is replacedby alkyl

or acid radicals.

Folyhydric Phenols.

Several representativesof the dihydricphenols,

are found in plantsor may be obtained as decompositionproductsof plantsubstances.

Pyrocatechol,

p IT /OH -i.

o

u" * ' '


132 AROMATIC HYDROXYL DERIVATIVES

Phenol itselfor the oil of cloves is frequentlyused for the same

purpose. The antipyreticaction of the benzene ring,which is not

lostin the phenolseries,cannot be utilized for obvious reasons.

The action on the spinalcord decreases with the number of

hydroxyls,but in other respectsthe toxicityis increased. Thus

phenol and the dioxybenzenesproducespasms in frogs,whereas

trioxybenzene(1:2:3)onlyproducesshivering; on the other hand,the animal becomes more comatose and atoxic than with resordin.

Binet holds that the toxic symptoms (collapseand convulsions)ofthe phenolsare traceable to the benzene nucleus,but are modified

by the introduction of OH or acylgroups. The antagonisticaction of these is seen in

OCH3 OCH3

MkTi / \nLi

, guaiacol| | ,and veratrol[

Vwhich show a progressivedecrease in toxicity.The carboxylgroupalso modifies the toxicity; gallicacid,

COOH

producesno shivering,and is a much less powerfulblood poisonthan pyrogallol.The lower phenolsare protoplasmicpoisons,causingcoagulation,but this propertyis lostin the highermembers

of the series,e.g. phloroglucin,OH

The toxic propertiesof the phenolsare depressedby the replace-mentof hydrogenatoms in the nucleus by alkylgroups, whereas

the antisepticcharacteristics are increased. This alteration,how-ever,

is more marked with 1 : 3-cresolthan with the others ; recent

investigationshave shown that the toxicityof 1 : 2-cresol liesvery

near that of phenol,whereas 1 : 4-cresol is greater. As regards

antisepticpropertiesthe 1 : 3 derivative is more powerfulthan the

1 :4, and ortho cresolis the weakest of the three.

CRESOL ANTISEPTICS 133

Koch and Lubbert have drawn attention to the greatvalue of

thymol,OH 1

CTT I /"^TT Q

6J131 U"13 o

| /^1 TT /?

VV^g-tl- D

as an antiseptic.The homologousphenols,however,are much lesssoluble in water

than phenolitself,and various methods have been tried by which

to modifythis factor. The majorityof these have been based on

the use of different solvents,the solution,for instance,of these

derivatives in various fats,or in solutions of different salts,such as

caustic soda,soaps, or calcium hydrate.Metakalin, for instance,is a solidcompoundof pure w-cresol and

potassiumcresotinate,

fCH3

ICOOK,

in a sodium soap, and itcontains the leasttoxic but most powerfully

antisepticof the three cresols.

Lysol is oil of tar mixed with linseed or a fattyoil,and com-pletely

saponifiedwith potashin the presence of alcohol. It is not

so irritatingor so toxic as carbolic,and may vary in antiseptic

strengthowing to varyingproportionsof the differentcresols.

Creolin is an emulsion of cresols in resin soap, and is destroyed

by mineral acids,caustic alkalis,and sodium chloride. It contains

varyingamounts of the differentcresols.

Cyllin, an improvedpreparationof creolin,has a bactericidal

power sixteen times that of pure phenol(Rideal)when tested with

B. Typhosus" f medicinal' cyllinwas used. Klein finds it thirtytimes as strongwhen tested with B. pestis.

Jonesen1 experimentedwith dogsin nitrogenousequilibrium,ob-serving

the effects of cresolson their outputof nitrogen,ammonia,and indigo.The cresol was entirelyeliminated by the urine,nonewas ever found in the faeces. Duringthe periodsin which cresolwas

giventhe ammonia decreased,owingto the conjugationof the H2SO4with cresol. The effect on indigovaried with the different isomers,the greatestaugmentationoccurred with ortho-,and the least with

flzefo-cresol,the para derivative beingintermediate. The cresolsare

also to a smaller extent conjugatedwith glycuronicacid,the amount

1 Biochem. Zeitschr.,vol.i,fasc. 5 and 6,pp. 399-407, 1907.


beinggreaterthe more toxic the cresol. The total amount recover-able

from the urine also varied directlywith the toxicity.Withmeta-cresol it was 46-5 per cent.,with 0rô-cresol 30-35 per cent.,

and with _para-cresolit fellto 27 per cent, of the amount ingested.These phenomena, as also the toxicity,may of course be merelythe results of variations in the rapidityof absorption.

Bechhold and Ehrlich1 have recentlyinvestigatedvarious

phenolderivatives,and have shown" 1. that the entrance of chlorine

or bromine into the nucleus of phenolcauses an increase in anti-septic

power. In the followingcomparisonsan amount of phenolequalto 1,000 gm. molecules was taken,and againstit were com-pared

the quantitiesof various substances,also in gm. molecules,

necessary to preventthe growth of certain bacteria in a givenfluid.

Phenol 1000 DiphtheriabacillusTrichlor

""40

Tribrom"

"22

Tetrachlor"

16" "

Pentachlor"

7" "

Pentabrom"

2" "

In the last case, for instance,one gm. molecule of pentabromphenolhas the same action in preventingthe growth of diphtheriabacillus as 500 gm. molecules of phenol.

2. The entrance of alkylgroups into the nucleus of phenol,aspreviouslymentioned,increases its antisepticvalue,and a similar

increase was noticed in the case of the halogenderivatives ; thus

Phenol = 1000 DiphtheriabacillusTetrachlor

"= 16

" "

CeBr4"(oH3Tetrabr"m-0-cresol = -9" "

jy " 9"^~

a= "'"

)" "

" " ft P' " 3) JJ

Tetrabrom phenol = "22" "

Dibrom-jo-xylenol= 3-9

Tribrom-^-xylenol= "L3

Dibrompseudocumin ol= 6-5"

1 Hoppe-Seyler'sZeit.fur.Phys. Chem.,47, 173,1906.

ANTISEPTIC VALUES 135

That is,tribrom-w-xylenolis twentytimes as active as tribrom-

phenol. Tetrabrom-0-cresol is about sixteen times as active as

tetrachlor-phenol.This brominated cresolis but very slightlytoxic ;

a one per cent, solution killsdiphtheriabacillus in less than two

minutes,whereas a correspondingone per cent, phenolsolution

requiresmore than ten. Further,the same strengthsolution kills

bacilluscoliin less than fiveminutes,whereas phenolrequiressixty.3. The combination of two phenol nuclei,as, for example,

jo-dihydroxy-diphenyl,C6H4.OH

C6H4.OH,

or the derivatives of diphenylmethane,such as those givenin the

followingtable,as well as their chlorinated derivatives,are more

powerfulthan phenol.

Phenol = 1000 Diphtheriabacillus

jo-dioxy-diphenyl,

OH.C6H4.C6H4.OH = 47

Tetrachlor phenol =16,, "

Tetrachlor-0-diphenyl,

OH.C6H2C12. C6H2C12.

OH = -7

Tetrabrom-0-diphenyl,

OH.C6H2Br2.C6H2Br2OH= -4

Tetrabrom-^-dioxy-diphenylmethane,

CH2(C6H2Br2OH)2= 1-8

H exabrom-j^-dioxy-diphenylmethane,

CH2(C6HBr3OH)2 = "14

H exabrom-jt?-dioxy-dipheny1 carbinol,

CH.OH.(C6HBr3OH)2 = -6

4. The combination of two phenolgroups by means of CO or SO2decreases the antisepticpower.

Phenol = 1000 Diphtheriabacillus

Tetrabrom-dioxy-diphenyl-methane =1-8" "

Tetrabrom-dioxy-benzophenone,OH.C6H2Br2.CO.C6H2Br2OH ="177

Tetrabrom-dioxy-diphenyl-sulphone,OH.C6H2Br2.S02.C6H2Br2OH = "34


5. The entrance of the acid grouping(COOH) depressesthe

antisepticpower of the phenols.Phenol = 1000 Diphtheriabacillus

Tetrachlor phenol, C6H.C14.OH = 16" "

Tetrachlor-^-oxybenzoicacid,\TT

= 683" "

= "40Tricolor phenol, C6H2C13.

OH

Trichlor-phenoxy-aceticacid,

Tribrom phenol

Tribrom-phenoxy-aceticacid,

= "740

= 22

= 49"

As regardsthe relative toxicityof the halogenderivatives of

phenol,it is found that the entrance of a bromine atom reduces the

convulsant action,so characteristicof phenolitself,and also lowers

the toxicity,but the further introduction causes a rise in this

characteristic,and tribrom or trichlor phenolare about equalto

phenolitself,whereas tetra and pentahalogenderivatives are more

powerful; the latter in fact may be regardedas very toxic sub-stances.

All the solutions were made up with the same amount of alkali,viz. 100 c.c. solution contained 6-5 c.c. of normal caustic soda. It

was observed that the toxicityof phenoland "?-cresolwas depressedin such solutions.

BACTERICIDAL VALUES 137

The followingsubstances were also investigated:"

(a)Tetrabrom-hydroquinone-phthalein.

B. DipUJieriae.Antiseptic1 in 80,000 (comparedwith 1 in 200,000

HgCl2). Bactericidal l"/osolution,more than 2 less than 6

minutes ; -5" solution,10 minutes (comparedwith l"/ooHgCl2less than 1 minute).

B. Typkosus.1 in 400, no antisepticaction.

B. Pyocyaneus.No bactericidalaction. 3 "/oin 60 minutes (com-paredwith 5"/00HgCl2 in lessthan 15 minutes).

Animal Experiments.

Guinea-pigs,weight 250-370 gms. 1 "/osolution : 3 c.c. sub-

cutaneouslyand 5-7 c.c. by oesophagealtube " no action; 3 c.c.

intraperitoneallycaused death (peritonitis).

(b)Tetrabrom-hydroquinoiie-phthaleiii-oxinie.

B. Liphtheriae.Antiseptic1 in 80,000; bactericidal 1 "/ooin more

than 15 minutes.

B. Typhosus.No antisepticor bactericidalaction in 1 in 200.

M. Gonorrhoeas. Antisepticand bactericidalin 1 in 1,600.

Animal Êxperiments.

Guinea-pigsj

250-510 gms. weight. l"/osolutions: subcu-

taneously3 c.c. were painful; no other effect. 1 c.c. intraperi-toneally,no action. Repeated doses 16 c.c. by oesophageal

tube produced traces of albumin in urine,but no other

action.

(c)Hexabrom-dioxyphenyl-carbinol.

E. Diphtkeriae.Antisepticand bactericidal in 1 in 320,000solution.

IB.Pseudodiphtheriae.Antiseptic1 in 128,000.StreptococcusPyog. Antiseptic1 in 5,000.B. Coli. Antiseptic1 in 80.

B. Pyocyaneus.Antiseptic1 in 400.

B. Coli. Bactericidal 3 "/ solution in over 60 minutes./ O

Staphylococci.Bactericidal 1 "/osolution from 30 to 60 minutes.

B. Pyocyaneus.5 "/osolution "inNaOH from 15 to 30 minutes.

Meat could not be sterilizedwith 1 in 200, nor serum with

1 in 100,nor milk with 1 in 1,000.


Animal Experiments.

White mouse, weight 15 gms. 1 "/osolution -8 c.c. intraperi-toneallykilled in 30 minutes. Rabbit,2,100 gms., 45 c.c. of

1-5 "/osolution intravenouslywas fatal. Guinea-pigsweighing300 gms. showed only transient paralysisof hind limbs when

1 c.c. of a 3 "/osolution was injectedintracardially.Others weigh-ing500 to 620 gms. took 25 c.c. of a 1 "/0solution per os. Most of

the bromine derivative was excreted in the faeces in 7 days.Man. 10 c.c. of 1 "/osolution per os producedno illeffects. The

taste is unpleasantand burning.Rabbits,guinea-pigs,and mice infected with various organisms

were giventhis solution in various ways (intravenously,"c.)but

without any effect.

(d)Hexabroin-dioxyphenyl-methoxy-methaiie.

3. Diphtheriae.Antiseptic1 in 200,000 to 1 in 640,000 ; bac-tericidal

1 in 320,000.B. Pyocyaneus.Antiseptic1 in 400.

Animal Experiments.

White mice, about 15 gms. weight. 1 "/osolution,-8 c.c. fatal

subcutaneously.Local necrosis. Sublethal doses had no effect on

animals infected with trypanosomiasis.

(e)Tetrachlor-ortho-diphenol and tetrabrom-ortho-diphenol.

B. Diphtheriae.Antiseptic1 in 200,000 to 1 in 640,000; bac-tericidal

1 "/oin less than 2 minutes.

B. Coli. Bactericidal 1 "/o,5 to 30 minutes.

Animal Experiments.

The bromide only was used. -3 gms. in 10 c.c. was fatal for

guinea-pigssubcutaneously.-1 c.c. of 1 % solution intraperitone-

allyand -25 c.c. subcutaneouslywas fatal for white mice. No

effect was producedon infected animals by injectionswith sub-

lethal doses.

(f) Tetrabrom-ortho-cresol.

B. Diphtheriae.Antiseptic1 in 200,000-160,000; bactericidal

1 in 320,000.B. Coli. Bactericidal l"/osolution in lessthan 5 minutes.



This derivative,like the previousone, is decomposedinto its

constituents in the small intestine by the pancreaticjuiceand

bacteria.

Epicarin, introduced in 1899, /3-oxynaphthol-0-oxy-;?2-toluicacid,

HO.C10H6[-CH2-C6H3"g"OH]is obtained by the action of chlormethylsalicylicacid on /3-naphtholdissolved in acetic acid,

/COOK "COOH

C6H3ÔH = C6H/ OH

\CH2C1+ C10H7OH \CH2" C10H6.

OH + HC1.

It has powerfulacid properties,and forms salts soluble in water. It

is a powerfuland non-irritatingantiseptic,and is mainly excreted

unchanged. It has been used as an antiparasiticfor the skin.

/3-naphthylaminesulphonicacid,

-OH

JS02OH,

very readilycombines with nitrites,formingthe innocuous diazo

compound. It has thus been employed in cases of poisoningbynitrites,and also to preventthe urine becomingalkaline in diseases

of the bladder.

The action of the halogenderivatives of naphtholhas not been

investigated.

POLYHYDRIC PHENOLS.

I. A. Dioxybenzenes.

Accordingto Frankel,the toxicityand the antisepticactionincreases with the number of hydrogen atoms in the benzene

nucleus replacedby hydroxylgroups. On the other hand,Schmiede-

bergstates that one of the dioxybenzenes,i.e. resorcin,

C6H4"(oH1 : 3,

is less toxic,and has lessantisepticpower than phenol.The trioxyderivative,pyrogallol,C6H3(OH)3, however, is certainlymorepoisonousthan resorcin. Of the three isomeric dioxybenzenes,the 1 : 2 derivative,pyrocatechin,is the most toxic,then the 1 : 4

hydroquinone,whilst resorcin,the 1:3 derivative,is the least

poisonous,and consequentlythe onlyisomer employedin medicine.

It isformed by fusingany of the disulphonicacids with caustic soda,

CREOSOTE AND GUAIACOL 141

which means that an intramolecular changetakes placewith the

1 : 4 and 1 : 2-sulphonates,and that 1 : 3-dioxybenzeneis the most

stable of the three isomers at the temperaturesrequisitefor such

reactions.

The monoacetylderivative

1:3 C6H4"(o.COCH3goes by the name of Euresol.

B. Etherial Derivatives of Dioxybenzenes.

Creosote from beechwood-tar consists chieflyof a mixture of

phenol,cresols,guaiacol,

and itshomologues,creosol,

C,H,"CH,)"g"H"Owing to the presence of phenols,the action of creosote is very

similar to that of phenolitself. It has antisepticproperties,but is

toxic and has caustic action. The latterdependson the presence of

the free hydroxylgrouping,and many derivatives have been intro-duced,

based on the salol principle,in order to overcome this

objectionablecharacteristic.The esters which have been preparedfor this purpose all break

down into their componentsin the intestine.

Creosote carbonate,for instance,like creosote itself" a mixture

of several substances " is obtained by the action of carbonylchloride

on an alkaline solution of creosote. The formation of the ester of

carbonic acid by this means producesa very greatdrop in toxicityand the lossof the caustic action of the originalmixture.

Other esters of creosote have been preparedand introduced into

medicine,but these have been all replacedby what is supposedto

be the most powerfulphysiologicalagent presentin the mixture,viz. guaiacol,or its derivatives. It is probable,though,that the

methylester of homobrenzcatechin,

/CH3C6H3\-OCH3

\OH

which ispresentin creosote,may be an importantconstituent,since,

judgingfrom what has been previouslystated,its toxicityshouldbe less,but itsantisepticvalue greater,than that of guaiacol,which

has no methylgroup substituted in the nucleus. This homologueis


difficultto isolate from the mixture,and has not yet been intro-duced

into pharmacology.Gnaiacol is obtained from anisol by nitration,and reduction of

resulting1 : 2-nitro anisol to the amido derivative j this is then

diazotized and boiled with water.

C6H4.OCH3 -* C6

PH/N:N.OH n.o PTTOH

"-6n4 ^4 \OCH3

It is a toxic substance,and irritatesthe gastricmucosa. Its sub-cutaneous

use is dangerous,owing to the collapseand cardiac

depressionit may produce.In toxic doses it producesexcitation,followed by paralysisof the central nervous system,the former

symptoms beingless marked in the higheranimals. It is less toxic

and more powerfullyantisepticthan phenol.

Inorganic Acid Esters of Guaiacol.

A. 1. Guaiacol carbonate or Duotal,

y v^vyga.I4. OCH3\O.C6H4 . OCH3

results from the interaction of carbonylchloride and the sodium

salt of guaiacol.T

+COC12 = 2NaCl + CO(OC6H4.OCH3)2

In this reaction guaiacolmay be replacedby a largenumber of

hydroxyl derivatives,such, for instance,as menthol, eugenol,

carvacrol,"c.

Creosotal (creosotecarbonate)and Duotal are both insoluble,and

therefore tasteless. The former is a yellowalmost odourless liquidmiscible with alcohol and oils,and the latter a white crystalline

powder slightlysoluble in oil and glycerin.2. Mixed carbonates of aromatic and aliphaticradicals may be

obtained by the action of chloroformic esters on sodium guaiacolor

other alliedsubstances,such as eugenol,creosol,and carvacrol,

Ethyl-guaiacolcarbonate,

or generally

X.ONa + Cl.COOR =

ESTERS OF GUAIACOL 143

The resultingderivatives,in distinction to the carbonate,are

liquids,and on this groundare suitable for injection,but have little

practicalimportance.3. Carbamic esters of guaiacoland allied substances can be

obtained by the interaction of urea chloride and the phenolor its

sodium salt.

.CONH2= NaC1 + CO"\O.cX

. OCH3Instead of guaiacol,the followinghydroxylderivatives have been

employed:" Menthol,carvacrol,eugenol,thymol,geraniol,"c.

B. Phosphateof guaiacolor Phosphatol, PO(OC6H4 . OCH3)3,was intended to combine the action of phosphoruswith that of

the cresolin cases of tuberculosis.

C. Phosphiteof guaiacol(Guaiacophosphal)is obtained by the

action of phosphorustrichlorideon the sodium salt,

= 3NaCl + P(O.C6H4.OCH3)3.

It is a crystallinepowder,and, in distinction to the phosphateand

carbonate,is soluble in fattyoils. Under the name Phosphotal is

sold a mixture of the phosphorousethers of the creosote phenols(neutralphosphites)containing90 per cent, creosote and 9 per cent.

P0Oo.

It is not caustic and is much less toxic than creosote./ o

D. Mixed sulphuricesters of phenolsand aliphaticradicalshavebeen obtained by the action of ethylchlorsulphuricacid upon alkaline

solutions of guaiacol.

The various phenolicsubstances previouslymentioned may be used

in placeof guaiacol,and the ethylgroup can be replacedby methyl,butyl,"c.

Organic Acid Esters of Guaiacol.

Various aliphaticacid esters of guaiacoland similar phenols,orof the mixture creosote,have been prepared.They are formed byheatinga mixture of the acid,phenol,and a dehydratingagent,such as phosphorustrichloride,to a temperatureof 135". Thus in

the case of oleicacid,

CH3 . (CH2)7. CH : CH(CH2)6. CH2CO|OH;

= HaO + 0^X0(0! H (Guaiacololeate),

this ester isliquidand insolublein water.


The valerianic ester or Geosote,

1 - 9. C TT^""^

is also a liquidinsoluble in water,onlyslightlysoluble in dilute

acids and alkalies,and soluble in largequantitiesof alcohol,ether,

chloroform,"c. It has an oilycharacter and a penetratingaromatic

odour. Eosote is a similar preparation,said to be lesspure.

Further descriptionof this group is unnecessary, and it is hardly

likelythat derivatives of pharmacologicalvalue greaterthan the

carbonate can be found in this class.

In a similar manner, aromatic acid esters have been preparedand

investigated.Thus the benzoic acid ester of guaiacolor Benzosol,

has been introduced,but this substance is decomposedwith rather

more difficultythan the carbonate,and its product,benzoic acid,is

of littlepharmacologicalvalue,exceptpossiblyas an expectorantand urinarydisinfectant.

The salicylicacid ester or Guaiacolsalol,

r TT /OCH3L6H4\o.OC.C6H4OH,

like the previousderivative,is a solidwith low melting-point,which

breaks down in the small intestine into guaiacoland the antiseptic

salicylicacid,but againthis decompositiondoes not take placeat all

readily,and in order to decrease the stabilityof these aromatic

esters an amido group has been introduced into the 1 : 4 positionin

the benzoylradical" /?-acetamido-benzoyl-guaiacol,

p TT /OCHgTa *\Q.C"H4. NH(COCH3).

This substance may be obtained by the action of 1 : 4-nitrobenzoylchloride on sodium guaiacol.

C.H/S"1+ C,H /"1H*= NaCl + C6H4"PCH"

The resultingsubstance is then reduced,and the acetylgroupintroduced in the ordinaryway.Although this derivative is decomposedwith greaterease than

the benzoic acid ester,it is improbablethat its value can be greaterthan others previouslymentioned.

GUAIACOL DERIVATIVES 145

Attempts to increase Solubility of Guaiacol.

A. Einhorn and Hiitz have introduced the hydrochloricacid salt

of diethyl-glycocoll-guaiacol,or Guaiasanol,

CH3.COCH2N(C2H5)2. HC1.

This may be obtained by the action of diethylamineon the

chloracetylderivative of guaiacol,

CH3 " TT /OCH,

-OCH3".COCH2N(C2H5)2.

This substance is soluble in water,precipitatedas an oilybase bycarbonates,and is broken down in the intestinein the usual way.Its antisepticaction is equalto that of boracic acid,it is slightlyanaesthetic and very slightlytoxic. Three grams subcutaneouslyin

rabbits producedno symptoms.B. The simplestmethod of increasingsolubilityis to form the

sulphonicacids,whose sodium or potassiumsalts are soluble in

water. This has been carried out with guaiacol,althoughtheresultingcompound is no exceptionto the generalrule that such

derivativeshave lessphysiologicalaction than the parentsubstance.1 : 2-guaiacolsulphonateof potash,or Thiocol,

X)CH3C6H /OH *

\S02OK

was introduced by C. Schwarz in 1898, and may be obtained bythe sulphonationof guaiacolat a temperaturebelow 80" C. The

introduction of the sulphonicgroup results in a completeloss of

the characteristictaste and smell of guaiacol,and a loweringofantisepticpower. As might be expectedfrom the presence of theacid grouping,it passes unchangedthroughthe body.

The 1 : 4-sulphonicacid of guaiacolresultswhen the sulphonationis carried out at highertemperatures,but thisderivativeand itssalts

have no pharmacologicalvalue owing to their objectionableaction

on the stomach.

The process of sulphonationcan clearlybe carried out with a largenumber of phenolsubstances,or with such mixtures as creosote,butin all cases the resultingsubstances will have lessantisepticpower.

L


Snlphosote and Sirolin are preparationsof thiocol combined

with flavouring1agents.C. It has been found that the glycerinester of guaiacol,or

Guaiamar,

/OCH8

is soluble in water ; it may be obtained by the action of monochlor-

hydrin on sodium guaiacol,or by treatingthe phenoland glycerinwith a dehydratingsubstance. It is decomposed in the body like

the other esters,but its bitter aromatic taste appears to be againstits use as a guaiacolsubstitute.

D. The introduction of the carboxylgroup into the nucleus of

guaiacol,givingrise to the acid

/OCH3C6H /OH '

\COOH

results in a substance with less antisepticpower and no greatadvantageover the phenolitself owing to its slightsolubility.

E. By the action of monochloracetic acid on 1 : 2-dioxybenzenein presence of an alkali,there results brenzcatechin-monoacetic

acid,

C6H/"Na+ Cl.CH2COOH = CJT/O.CH.COOH

L2X

This substance goes by the name of Guaiacetin; it is soluble in

water and almost tasteless. It is similar to guaiacolin the toxic

symptoms it produces.

GENERAL REMARKS ON CREOSOTE DERIVATIVES.

The only active constituent of creosote which has been at all

widelyemployedis guaiacol,C6H4 . OCH3 .

OH. Other bodies have,

however, been isolated,such as creosol,the monomethyl ether of

homopyrocatechin./CH,

C6H3fOCH3\OH

which has been previouslymentioned.

Veratrol,the dimethylether C6H4(OCH3)2, though less toxic

is more irritatingto the gastricmucosa than guaiacol.The corre-sponding

monoethylether



Another derivative of pyrogallol is

Galla-acetophenone,or

methyl-keto-trioxybenzene, CH3

.

CO.C6H2(OH)3; it is obtained by

heating pyrogallic acid, acetic acid, and

a

dehydrating agent such

as

zinc chloride. It has powerful antiseptic properties, and is less

toxic than pyrogallol. It does not stain linen, but is notsuch

an

active local application for psoriasis.

CHAPTER VII

AROMATIC HYDROXYL DERIVATIVES (CONTINUED). The HydroxyAcids. " Classificationof Salicylicacid derivatives. Nencki's Salol Principle.Tannic and Gallic Acids.

HYDROXYBENZOIC ACIDS.

IT has been previouslyremarked that the pharmacologicalreaction

of benzene is very considerablydiminished by the introduction of

the carboxylgroup, and the resultingbenzoic acid,C6H5COOH,

may be given in largedoses without much physiologicalresult.

On the other hand, the phenylsubstitution productsof the aliphatic

acids,such as phenylacetic,C6H5 . CH2COOH, phenylpropionic,

C6H5CH2 . CH2 . COOH, and phenylbutyricacid,

C6H5CH2 . CH2 . CH2 . COOH,

show antisepticpower strongerthan phenoland increasingwithincrease of molecular magnitude.

The unsaturated cinnamic acid,C7H5CH : CH.COOH, in the

form of its sodium salt,the so-called Hetol, was introduced byLanderer in 1892. It may be obtained by the condensation of

benzaldehydeand acetic acid (Perkin'ssynthesis),

C6H5CHJO+ H2]CH.COOH = H2O + C6H5CH : CH.COOH.

It causes a considerable leucocytosisin experimentalanimals

(rabbits),and also in man. It was thus thought that valuable

results might be obtained in tuberculous disease by increasing

phagocytosis.The clinicalresults have not been altogethersatis-factory,

and the treatment has never been at all generallyadopted,at any rate in this country; of 903 cases collectedfrom the literature

41 per cent, died or were unaffected.

Based on the salol principlea largenumber of esters of this acid

have been introduced into pharmacology. Thus the 1 : 3-cresol

ester,Hetocresol, C6H6CH :CH.CO.OC6H4.CH3,is an insoluble

150 THE AROMATIC HYDROXY-ACIDS

powder intended for use as a local applicationto tuberculous

sinuses,"c.

The guaiacolester,Styracol, C6H5CH : CH.CO.OC6H4.OCH3,istasteless,and issaid to liberate85 per cent, of guaiacolin the body.It is intended as a substitute for that drug,and to combine the

supposedadvantagesof cinnamic acid.

Physiological Effects produced by Entrance of the Carboxyl

Radical into the Nucleus of Phenol.

When a carboxylgroup is introduced into the phenolnucleus,the

physiologicalreaction of the resultingsubstance dependson the

relative positionsof the two substituents ; in all three isomers,however,a very greatdropin toxicityis noticed.

When the two groups are next to each other,i.e.1 :2-oxybenzoicor salicylicacid,

^

j"COOH

L-OH

the resultingsubstance has antisepticpropertiescloselyallied to

phenol,and at the same time other characteristics appear which are

barelynoticeable,if at all,in the hydroxylsubstance itself. Thus

salicylicacid has an antipyreticaction,and more particularlya

specificaction in rheumatism. On the other hand, both 1 : 3-oxy-benzoic acid,

COOH

and the 1 : 4 derivative,COOH

have entirelylostallthe physiologicalcharacteristicsof phenol,andhave neither the antisepticnor the therapeuticaction of salicylicacid,the ortho derivative.


When the hydrogenatom of the hydroxylgroup is replacedbymethyl,

the physiologicalaction of the 1 : 2 derivative is very much weaker

than salicylicacid itself,it has onlyslightantisepticand antipyreticaction,and,in the case of animals,is onlytoxic in largedoses. The

corresponding1 : 4 derivative,anisic acid,has no pharmacologicalreaction at all,and passes unchangedthroughthe organism.

Whereas the introduction of a methyl group into the nucleus of

phenoltends to lower the toxicity,whilst raisingthe antiseptic

power, the result in the case of salicylicacid is as follows: "

OM0-homosalicylicacid (/3-cresotinicacid)1

LoC WV^V^JiJt *W

\GH3 6

is physiologicallythe most reactive,and in relativelysmall doses

producesa paralysisof the muscles of the heart,/?ara-homo-

salicylic(a-cresotinicacid)X)H 1

C6H3^-COOH 2

\CH3 4

has lessreaction than salicylicitself,whereas wfo-homosalicylic

OH 1

C6H3;"COOH 2

\CH3 3

producesno pharmacologicalreaction.The oxynaphthoicacids have a similaraction to salicylicacid,but

though more powerfultheyare also caustic,and in doses of 1"5 gm.

producefatal resultsin rabbits.

A. SALICYLIC ACID AND ITS DERIVATIVES.

Salicylicacid occurs in the free state in buds of Spiraeaulmaria,and as methyl ester in oil of Gaultheria procumbens(oilof winter-

green).It may be preparedby the action of carbon dioxide on sodium

phenateat a temperatureof 180"-220",

2C6H6ONa + C02 = C6H4

152 SALICYLIC ACID

This reaction may be modified by saturatingsodium phenatewith carbon dioxide under pressure, when sodium phenylcarbonate

results,

C.H.ON. + CO, = CO"(""aH

This substance,heated to 120"-130" under pressure, undergoesintramolecular changeto sodium salicylate,

ro/CU\ONa

r " /OHOaH. ^^xcOONa.

Salicylicacid has a sweet,acid taste,and in this form onlyhas

antisepticaction. Its sodium salt is a crystallinepowder with an

unpleasant,sweet taste ; itisdecomposedby mineral acids,and hence

also in the stomach,with the liberationof the free acid.

Both salicylicacid and its sodium salt have objectionable

secondaryactions" deafness,tinnitus aurium,headache,delirium,

haematuria,albuminuria,$c.

In order to overcome these objectionablepropertiesa largevarietyof salicylicacid derivatives have been preparedand many intro-duced

into pharmacy. Nencki was the firstto lead the way into

this new field of pharmacodynamics,and to combine together,in

the form of esters,two physiologicallyreactive components. He

found that,in spiteof the toxicityof these components,the slow

breakdown of the esters in the organism led to derivatives

of relativelyslighttoxicity.Such esters,generallypossess-ing

hardly any taste and no caustic action,pass unchangedthroughthe stomach,and are decomposedin the duodenum by the

action of alkali and enzymes. The acid formed by this saponifica-tion is neutralized by the alkali,and the physiologicalaction of the

phenol,which is slowlyand continuouslyliberated,commences byreabsorptionfrom that region. From this pointof view the so-

called ' salol principle' has been alreadyalluded to in the previous

pages on phenolicsubstances and their derivatives.

If it is desired to obtain only the pharmacologicalreaction of

the acid,then clearlyit must be combined with an hydroxylde-rivative

which itself possesses little or no physiologicalactivity;that is,preferablyan aliphaticalcohol or an allied substance.

Salicylicacid,owing to the presence of the hydroxylas well as

the carboxylgroups, can playthe partof both phenoland acid,and

the derivatives employedin medicine may be classifiedas follows :"

CLASSIFICATION OF DERIVATIVES 153

I. Those formed by replacementof hydrogenatom of carboxyl

group, substances of generalformula

i . o n TT/OH

These are further subdivided accordingto the nature of the radical

R, viz. : (a)Those in which R isof an aliphaticnature,i.e. physio-logicallyinactive,and (b)those in which the radical isof a phenolic,

and,hence,antisepticnature.

II. Those derivatives formed by replacinghydrogenof the

hydroxylgroup, of generalformula

ij,

n n TT /DA.

X cannot be the radical of aliphaticalcohols for reasons previously

given(p.151),but must be of a type which will be easilybrokendown in the organismwith the liberationof free salicylicacid.

III. Derivatives in which both hydrogen atoms have been

replaced,T /OX

Subdivided in this manner, it will be noticed that Class I (a)andClass II contain closelyallied substances,i.e. derivatives whose

physiologicalaction is very similar to salicylicacid itself.

Class I (a).Methylsalicylate,

(oilof wintergreen),can be giveninternallyas an emulsion or in

milk in 10-20 minim doses. It is very active,has not the un-pleasant

sweet taste of sodium salicylate,but isoften very irritatingto the stomach. Appliedexternally,it is useful in acute muscular

rheumatism.

Ethylsalicylate,H

was investigatedowing to the fact that ethylderivatives are often

less harmful than the correspondingmethyl.Accordingto Hough-ton, itis onlyhalf as toxic as the previouslymentioned substance.

154 SALICYLIC ACID DERIVATIVES

The monoglycerinester of salicylicacid,Glycosal,

/OH

is obtained by the action of condensingagents,such as 60 per

cent, sulphuricacid on a mixture of salicylicacid and glycerin.The triglycerinester has also been investigated,but is found to be

reabsorbed to nothinglike the same extent as the mono derivative,of which about 96 per cent, undergoesthat process.

It is a crystallinepowder,slightlysoluble in water, more so in

alcohol and glycerin.It possesses no odour,and is intended for

internal and external use. Externallyit is not irritating,and is

fairlyrapidlyabsorbed,appearingin the urine about six hours

after a solution in alcohol has been paintedon the skin.

The methoxymethylester of salicylicacid,Mesotan,

OH

was introduced by Floret in 1902, and is obtained by the action of

chlormethylether on sodium salicylate,

.CH2 . O.CH3

= NaCl + C6H4

It is unstable,and very readilybreaks down in presence of water

into formaldehyde,a reaction probablyexpressedby the followingreaction :"

6H4\COO.CH2 . O.CH3 + H20

It is used as a localapplicationto painfuljointsin acute rheumatism

and similar conditions. It has been observed to producedermatitis,and should therefore be employedin weak dilutions,and in media

not easilyabsorbed,e. g. vaseline or olive oil. The preparationis

unstable.

Acetol-salicylicester,Salacetol,

C6H4/OH

\COO.CH2 . CO.CH3,



In placeof phenol,the followingand many other similar hydroxylsubstances may be combined with salicylicacid throughthe agency

of phosphorusoxy-chloride:"

1. a- and /3-naphthol. * " ^6^4\COOC H

2. 1 : 2-,1 : 3-, 1 : 4-cresol . . C6H4"gJoc3 Thymol . . , , C"H"COO.C10H134. One molecule of resorcin giving C6H4"^"QQQ jj QH

6

or the correspondingmethoxy p " /OHderivatives

.

,

"

,.^n4\COO.C6H4OCH

5. Guaiacol. . C6

6. The mixture of phenolscalled creosote.

7. l:4-nitrophenol . . .C

8. Gaultheriaoil. . .

9. GaUicacid. . . " C6

In placeof salicylicacid,the inert anisic acid,

may be used to carry physiologicallyactive phenolsin the form of

their respectiveesters. Thus the anisic acid derivatives,among

others,of the followinghave been prepared:"

2. Guaiacolv . . , C,

3- Creoso1.....

c

and salicylicacid has been replacedby the homosalicylicacids.

The above examplesshow the largenumber of permutationsandcombinations which can be made between acids and hydroxyl-con-tainingsubstances ; theyare all decomposedlike salol,for example,and substances with novel pharmacologicalaction cannot be looked

SALOL GROUP 157

for in this group. One may have an advantageover another as

regardstaste or solubilityor the ease with which it breaks up in the

duodenum and so allows its physiologicalreaction to appear. It

will be evident that there are possibilitiesenough to enable fresh

derivatives of this type to be continuallyplacedon the market,

althoughthe probabilityof these possessingadvantagesover the

older preparationsis but slight.An exampleisgivenby Frankel of the manner in which a drug

may be introduced,althoughitsconstitution would indicate at once

that it is valueless. Thus 1 :2-methoxyor ethoxybenzoicacid on

nitration givesa 5-nitro derivative,

/COOH 1

C6H/O.CH3 2

\N02 5

This was reduced and converted into the correspondingacetylderivative by means of aceticanhydride,

/COOHC6H/OCH3

\NH(COCH3).

Now such a substance would neither have the phenacetinreaction,owing to the presence of the carboxylgroup, nor the physiologicalaction of salicylicacid,since it does not contain the free hydroxylgroup.

In this group of salicylicaeid derivatives salicyl-acetyl-/?-amido-phenolether,or Salophen,

C6H4"(cOO.C6H4. NH(COCH3),

may be mentioned; it can be obtained by the reduction of the

p-nitrophenolester of salicylicacid,followed by the conversion

of the amido substance into its acetylderivative. It is almost

insoluble in water, and has no taste or smell,and is of small

toxicity,but on decompositionin the organismitgivesrise to 1 : 4-

acetylamidophenol,

a substance possessingbut very slightantisepticaction,and more

nearlyrelated,in itsphysiologicalaction,to the anilineantipyreticsthan to phenol. It is unaffected by pepsin,but decomposedin thesmall intestine. Its antipyreticaction is feeble,but it may be

employedfor the salicylaction in acute rheumatism.


Class II.

Acetyl-salicylicacid,or Aspirin,

"(CH3CO)

was introduced by Dreser in 1899 as a substitute for salicylicacid.It is obtained by the action of acetic anhydrideor acetylchlorideon salicylicacid at high temperatures.It is largelyused instead

of sodium salicylatein acute rheumatism. It is thought to be

better toleratedbythe stomach,and onlyrarelygivesriseto unpleasantsymptoms. Erythema and pruritushave occasionallybeen observed.

Salicyl-aceticacid,).CHCOOH

is obtained by actingupon the sodium salt of the anilide,

".NHC6H5,

with the sodium salt of chloracetic acid :"

/ONa + Cl.CH2COONa_ n w /O-CHaCpONa NftC1

On heatingwith alkalis this is decomposed:"

^T O.TT+NaOH

.CHCOONa, p "+CH

Class III.

Acetylsalicylicmethylester,Methyl rhodin,

0(COCH3)

is a colourlesscrystallinesubstance,not affectedby dilute acids,and

consequentlyundecomposedin the stomach. It is stated to be

better adaptedfor patientswith enfeebled digestionthan sodium

salicylate.Benzosalin is the methylester of benzoylsalicylicacid,

(COC6H5)

it is not decomposedtillit reaches the small intestine,and does not

splitoff phenol,but,beyondthis,it appears to possess no particularadvantagesover other salicylcompounds.

TANNIC ACID 159

B. TANNIC ACID AND ITS DERIVATIVES.

The tannic acids,or tannins,occur widelydistributed in the

vegetablekingdom. They are soluble in water, and form com-pounds

with gelatinand with animal hides,and are consequently

employed in the manufacture of leather. They also precipitate

proteinsolutions. Some appear to be glucosidesof gallicacid,

(OH)3 . C6H2 . COOH, and,on boilingwith dilute acids,givegrape

sugar and gallicacid ; others contain phloroglucinin placeof sugar.

Pure tannic acid,however,appears to be a digallicacid,since on

warming with dilute acids or alkalisit givesriseto that acid alone.

Like salicylicacid,it has antisepticproperties; its main propertyis due to its local action on protoplasm,and is known as

' astrin-

gency '. It appears in the urine partlyas gallicacid and pyrogallol;in some cases, apparently,some tannic acid is passedunchanged,in

others as a sulphuricester. But tannic acid has two characteristics

which stand in the way of its employment as an intestinal dis-infectant.

Firstly,it possesses an objectionabletaste,and,secondly,it loses its antisepticpropertyin the stomach,owing to its com-bining

with proteinbodies in its contents or mucous membrane.

Consequently,it is necessary to obtain derivatives which can pass

unchangedthroughthat organ, but willbe decomposed,likesalol,in

the duodenum. For this purpose various acetylderivatives have

been investigated,and it has been found that the triacetyltannic

acid and those substances containingmore acetylgroups are not

decomposedby the intestinal juice,and consequentlyhave not

the requiredaction.When tannic acid is treated with a mixture of acetic acid and

aceticanhydride,however,a mixture of mono- and di-acetyltannic

acid results,which H. Meyer and F. Miiller introduced into phar-macyin 1894 under the name of Taxmigen, C14H8(COCH3)2O9.

This body is insoluble in water,and consequentlytasteless. It is

dissolved by alkalis and precipitatedby acids. At body tempera-tureit forms a stickymass in presence of water, but it can be

obtained in tablets which obviate this disadvantage.Both this

and the next mentioned body appear in the urine as gallicacid.In another direction tannic acid derivatives have been obtained

by combination with albuminous substances. Gottlieb and others

precipitatedegg albumen with the acid,but the resultingcompoundisdecomposedin the stomach. If,however,it is heated for 6-10

hours at 110" C.,itlosesthis property,and is not broken down into

160 TANNIC ACID DERIVATIVES

its constituents until it reaches the duodenum. This preparation

goes by the name of Taxmalbin; it contains 50 per cent, of tannin.

A similar preparationis named Hoiithin. Other preparationsof

this type can be obtained by precipitatinggelatinesolutions with

tannic acid (Tannocol),or with casein (Tannocase).These bodies

fulfiltheir purpose, but consideringwhat their purpose was, it seems

not a littlecurious that they should be seriouslyrecommended in

diseased conditions of the lower bowel to be givenper rectum.

The combination of an antisepticsubstance,formaldehyde,with

tannic acid ismethyleneditannic acid,or Tannoforin,

'\CUH909

obtained by the action of hydrochloricacid on a solution of form-aldehyde

and tannic acid,or by heatingthe components under

pressure.

It is onlyslightlysoluble in water,soluble in alcohol,and devoid

of odour. It appears to be mainlyuseful as an external application.Tannic acid has also been combined with hexamethylenetetramine,

and the resultingsubstance is termed Tannopin or Tannon,

(CH2)6N4(C14HM09)3)but this body will not liberate so much formaldehyde,and conse-quently

will not have so powerfulan antisepticaction as the direct

compound of tannin and formalin. It is only broken down

in alkaline solutions,and is intended for use as a urinarydisinfectant.

Tannal is a tannate of aluminium, it is insoluble in water,and

has the formula A12(OH)4(CMH9O9)2+ IOH2O.

NOTE. "With regardto the clinicalvalue of these two classes of

derivatives,it may be remarked that sodium salicylatewill probablybe found quiteas efficaciousand suitable as any of the newer pro-ducts

in the very largemajorityof cases. When this body is not

well tolerated by the stomach,that is if nausea or vomitingoccurs,salicin,the glucoside(seep. 322),may be tried or acetylsalicylicacid. General toxic symptoms are met by either diminishingthe

dose or by givingsome preparationwhich is less rapidlyand com-pletely

absorbed or contains a smaller proportionof the active

principle.As to the tannic acid substitutes those combined with proteinin

some form or other appear to be the most scientificallyjustifiable.

CHAPTEE VIII

ANTISEPTIC AND OTHER SUBSTANCES CONTAINING IODINE AND

SULPHUR." lodoform. Classification of substances introduced in placeof

lodofonn and the Alkali iodides. Derivatives containingSulphur" Ichthyol.

ANTISEPTICS CONTAINING IODINE.

I. lodoform and Substances of Allied Physiological Action.

IODOFORM, CHI3, was the firstsolid antisepticintroduced into

pharmacy. It may be obtained by the action of iodine,in the

presence of the alkalis,on a largenumber of aliphaticderivatives,such as ethylalcohol,acetone,acetaldehyde,"c. It is generallypreparedby addingiodine to a warm solution of either soda or

potashin dilute alcohol or acetone ; the iodoform formed separatesout and is filteredoff. The solution contains alkaline iodides and

iodates; on the addition of a further quantityof alcohol(oracetone)and the passage of a slow stream of chlorine throughthe solution

(resultingin the liberation of free iodine),a further quantityofiodoform separatesout.

It may also be obtained by the electrolysisof a solution of alcohol

(oracetone)containingpotassiumiodide,whilst a slow stream of

carbon dioxide is beingpassedthroughit.It is unnecessary to describe the characteristicpropertiesof this

well-known substance. As such,it is not an antiseptic,and its

action dependson the liberation of free iodine by the action of the

secretions of the wound upon which or in which it is used. Owingto itsphysicalcharacteristics(itmelts at 120" and volatilizesreadilyat medium temperatures)it cannot be sterilizedby heat.

lodoform possesses two greatdisadvantages" firstly,its objec-tionablesmell,and,secondly,the fact that it may be absorbed from

wounds and consequentlygive rise to toxic symptoms. Various

attemptshave been made to overcome these objectionsto its use, and

three classes of compounds have been producedas substitutes :"

A. Unstable compounds or mixtures of iodoform with various

substances tendingto destroyor lessen its smell.

M

162 ANTISEPTICS CONTAINING IODINE

B. Insoluble and unstable iodine derivatives.

C. Derivatives of totallydifferent type to iodoform itself,but

which,like it,liberate iodine and consequentlyhave a similar

physiologicalaction.

Class A.

To this group belongsiodoformin, (CH2)6N4.CHI3,an addition

productof hexamethylenetetramine and iodoform,but this com-pound

has alwaysa slightsmell of the latter substance,owing to

the ease with which it is broken down into its constituents bymoisture. It contains 75 per cent, iodoform.

lodoformal, althoughnot a derivative of iodoform,may be men-tioned

in this place.It is the hydriodideof hexamethylene,and is

said to possess higherantisepticpower than iodoform. Its action

probablydepends on its dissociation into hexamethyleneand

hydriodicacid,this latter substance being readilydecomposed,

givingfree iodine.

Various tannic acid and albuminous preparationsof iodoform

have been put on the market, such for instance as iodoformogen,

an almost odourless compound with albumen, which may be

sterilizedat 100" and is stated not to give rise to iodine-eczema

as readilyas does iodoform itself. But many substances of this typeare merelymixtures,and will not further be described.

Class B.

Various unstable compoundsof iodine and albumen or glutinoussubstances have been introduced. That which goes by the name of

lodolene is an iodo derivative of albumen. It is a yellowpowderinsoluble in the ordinarysolvents.

lodyloform is a preparationof iodine and a glutinoussubstance;it is a yellowish-brownodourless powderinsoluble in water and con-taining

10 per cent, of iodine. Sperlingstates that it is equivalentto iodoform in disinfectingpower, but is less efficacious in the

treatment of wounds.

lodeigon and peptoiodeigon are compoundsof iodine with pro-tein

; the former is insoluble in water,the lattersoluble.

Class C.

It is necessary that an iodoform substitute should be an insoluble

solid,possessingantisepticproperties,but have no smell and only

slighttoxicity.Since the characteristicaction of iodoform is due



Belongingto a different class from the previouscompoundsis

tetra-iodo-pyrrolor lodol,I.C" C.I

It is obtained by the action of iodine on alkaline solutions of pyrrol,or by firstlyobtainingtetrachlorpyrrolby the action of chlorine on

pyrrol,and then decomposingthis derivative with potassiumiodide,

1. C4H4 .NH + 8C1 = 4HC1 + C4C14. NH

2. C4C14.

NH + 4KI = 4KC1 + C4I4.NH.

lodol.

The physiologicalaction of iodol,which is a tastelessand odour-less

powder,is very similar to that of iodoform,but it adheres better

to the epidermisand the surface of wounds. It has alsobeen used as

a substitute for potassiumiodide,as one-half of the iodine reappears

in the urine,showingthat it is broken up in the body.

II. Iodine-containing Antiseptics not liberating that

element in the organism.

The followingderivatives owe their increased antisepticpower to

the replacementof hydrogenby iodine,but,unlike the previouslymentioned substances,iodine is not liberated.

Quinoline,as well as 1-oxyquinoline,has marked antipyreticand

antisepticproperties,and the latter characteristicis increased bythe replacementof hydrogenby iodine. Based on this,the follow-ing

two compoundshave been introduced into pharmacy:"

SO2OH

Quinoline-l-oxy-2-iodo-4-sulphonicacid or Loretin,

I'

OH

This is obtained from 1-oxyquinolineby the action of cold fumingsulphuricacid ; the sodium salt of the resultingsulphonicacid is

then treated with iodine. It is a yellow,tasteless,insoluble powder,

SOZOIODOL DERIVATIVES 165

and when mixed with sodium bicarbonate goes by the name of

Griserin, It is used in tuberculosis and other infectious diseases.

Cl

l-oxy-2-iodo-4-chlor-quinolineor vioform,

was introduced in 1900 by E. Tavel and Tomarkim.

1-oxyquinolineis chlorinated,and the resultingsubstance acted

upon by iodine in potassiumiodide solution. It is a greyish-yellowtastelesspowder,insoluble in water,and without smell ; it may be

sterilizedby heatingto 100",at highertemperaturesdecompositionsets in. It is stated to have a more powerfulaction than iodoform.

The iodine derivatives of 1 : 4-phenolsulphonicacid were investi-gated

by Ostermayerin 1880, and introduced under the name

of Sozoiodol preparations.When phenolis acted upon by warm

sulphuricacid the chief productis /(-phenolsulphuricacid,

I

)2OH.

When a solution of the potassiumsalt of this acid is treated with

chloride of iodine,the di-iodide of ô-phenolsulphonateof potashis

formed,

The free acid may be obtained by the action of sulphuricacid upon

the barium salt; it goes by the name of Sozoiodolic acid,

H

and is soluble in water and alcohol.

The sodium salt is more soluble in water than the potassium;with the exceptionof the mercury compound all the salts are more

or less soluble in that medium.

The sozoiodol preparationspass unchangedthroughthe organism,and it is difficultto imaginethat theypossess any pronouncedaction.

Phenol has antisepticproperties,but the introduction of the sul-phonic

group results,as is the invariable rule,in a decrease in

physiologicalcharacteristics;and althoughthe introduction of

iodine atoms into the molecule of this substance tends to raise the


antisepticpower, it cannot do so to any greatextent in a substance

possessingsuch powerfulacid propertiesas phenolsulphuricacid.Frankel remarks that it isonlythe zinc and mercury saltswhich are

of value,and in all probabilitythese owe their reactivitynot to the

acid (sozoiodol),radical,but to the metallic ion.

lodo-anisol,n TT X)CH3

was introduced in 1904, and is obtained from the 1 :4-iodanisol,

cwj00*by the action of chlorine,which givesriseto

On treatment with caustic alkali this iodochloride givesiodoso-

anisol,

and when this is boiled with water the followingdecompositiontakes place:"

2p TT /OCH3 r R /OCH3 , p TT /OCH3_ .

s

It is an explosivesubstance,onlyslightlysoluble in cold water,and

is used mixed with an equalquantityof calcium phosphate,or made

into a pastewith glycerin.It behaves like a superoxide,and to

this may possiblybe ascribed its action ; if this is the case it may

be compared to benzoylperoxide(C6H5CO)2. 02,which has also

been recommended as a useful antiseptic; it may be appliedlocallyas a powder,and does not giveriseto symptoms of irritation owingto its mild anaesthetic effect.

Losophane is a tri-iododerivative of 1 :3-cresol,

It contains 80 per cent, iodine. It is a crystallinepowdersolublein alcohol,oil,"fec.,and has been used in parasiticskin diseases. It

is,however,too irritantto be of much value.

Nosophen is tetra-iodo phenolphthalein.It is insoluble in water

and only slightlysoluble in alcohol. It has a slightodour like

that of iodine,of which it contains 60 per cent. It is used as

a dustingpowder. Internally,it is said to pass throughthe system

SUBSTITUTES FOR ALKALI IODIDES 167

unchanged. Antiosin is its sodium salt and Eudoxiii its bismuth

salt. The former is soluble in water,and is a non-toxic external

antiseptic;the latter is insoluble,and intended for use in putre-factiveconditions of the gastro-intestinaltract.

The proportionof iodine in various preparationsis shown in the

followingtable,modified from one givenin Martindale and West-

cott'sextra Pharmacopoeia(10thedition):"

Iodine easilyliberated.

per cent.

lodoform 96-6

lodol 90-0

Aristol 50-0

Europhen 28-5

Iodine not liberated.

per cent.

Losophen 80-0

Di-iodo salicylicacid 66-67

lodo salicylicacid 50-0

Pass unchanged throughanimal organism.

per cent.

Sozoiodol 50-0

ORGANIC SUBSTANCES INTRODUCED IN PLACE OF

THE ALKALI IODIDES.

The objectionable,and occasionallyvery inconvenient,character,

isticsof potassiumiodide have led to the investigationof many non-

toxiciodine-containingorganicsubstances. It is clearthat to bringabout the same physiologicalreaction as the alkaline iodides,these

organicderivatives must be decomposedin the body,and that con-sequently

the onlydifferencebetween them will be that,instead of

the rapidabsorptionof the former,a slower process will take place,

dependenton their stability,or the ease with which the organicderivative is broken down in the system.

On lines similar to those previouslyindicated with other bodies,iodine has been combined with proteinmatter, and one of such

bodies"

lodalbin, contains 21-5 per cent, of that element. It passes un-changed

throughthe stomach,and is decomposedin the intestinal

canal ; the reabsorptionof iodine commences from that region.lodipin is a preparationformed by the addition of iodine to un-

saturated oils; of the latter,oilof sesame is said to be the best,onaccount of the ease with which it is digestedand its freedom from

taste. Two varieties of this preparationare on the market,one

containing10 per cent, iodine and suitable for internal administra-tion,

and the other 24 per cent, speciallyuseful for injections.It appears to be a most reliable substitute for potassiumiodide,

and is most useful for subcutaneous injections,in which case iodine

is onlyslowlyexcreted by the urine.

168 ANTISEPTICS CONTAINING SULPHUR

Accordingto Lesser,patientsmay be accustomed to the use of

iodides by means of subcutaneous injectionsof this derivative.

Experimentshave shown that iodipin,when subcutaneouslyin-jected,

remains for a long time at the seat of injection,and only

slowlybecomes absorbed by the tissues in the form of potassiumiodide. Its diffusion throughoutthe bodyis shown by the fact that

iodine was detected in the epithelialscales of a syphilideduringthe administration of the drug.

lothion is di-iodo-hydroxy-propane,CH2I.CHI.CH2OH, and

though it cannot be used internallyor hypodermically,it is in-tended

as a substitute for potassiumiodide,the method of adminis-tration

beingby inunction.

SUBSTANCES CONTAINING SULPHUR.

Sulphuritself,thoughan inert body,is,like iodoform,capableof

producingantisepticeffects when ib is broughtin contact with fresh

tissues. It has been employedinstead of iodoform in surgery for

packingsuppuratingcavities and forother purposes ; the tissuesround

are blackened and sloughaway, and a strongsmell of sulphuretted

hydrogen is observed,which would indicate a reducingprocess.Lane,who was the firstto employit in this way in 1893,thinks the

action isdue to the formation of sulphurousacid,which is sub-sequently

oxidized to sulphuricacid. A powerfulreaction appears

to take place,and,as a rule,it is unsafe and unnecessary to leave

the sulphurin contact with the tissues for more than 24 hours.1

Organicsulphurderivatives in which sulphuris in the divalent

and hence unoxidized condition have mild antisepticaction,com-bined

with the propertyof promotingthe formation of granulationtissue,and consequentlymany attemptshave been made to arrive

at substances which might have a correspondingaction to iodoform,but so far without any marked success.

Thus thio-resorcin,C6H4O2S2,obtained by the action of sulphuron a solution of resorcin in potash,cannot be employedowing to

the cutaneous irritation which it produces.

Sulphaminol, OH

preparedfrom oxy-diphenyl-amine,has not provedof value.

A combined sulphurand iodine derivative is the ethyliodide1 Med. Chi. Trans.,vol. 78.

ICHTHYOL 169

addition compound of allylurea (seethiosinamine,p. 218) which

goes by the name of Tiodine,

CS\NH2C2H6I.This is a crystallinesubstance soluble in water in all proportions,and readilyabsorbed by the organismwhen taken by the mouth or

hypodermically.In therapeuticdoses it is said to be absolutelynon-toxic.

ICHTHYOL.

The most commonly employedorganicsulphurcompound is per-haps

that known as ichthyol,whose chemical constitution has not

yet been determined. It is a bituminous product containingabout 15 per cent, of sulphur.Ordinarymedicinal ichthyolis

sulphoichthyolateof ammonia, but correspondingpreparationsof

lithium,sodium and zinc are manufactured. Owing to the un-pleasant

smell and taste of ichthyol,numerous modifications of the

originalsubstances have been prepared.Desichthyol is prepared

by the action of superheatedsteam on ichthyol,and is tasteless.

A combination with albumin,Ichthalbin, is insoluble,and conse-quently

has neither taste nor odour.

Ichthoform is preparedby the action of formaldehyde,and

though tasteless,is only very slightlysoluble in alkaline fluids,

so that internallyits action is slow.

Various salts of the sulphonicacid have been introduced,such

as : Perrichthyol,the iron derivative,and Ichthargan, the silver

salt. Anytols are compoundsof phenolswith anytin, the ammonia

salt of a hydrocarbonsulphonate,obtained with ichthyoland con-taining

33 per cent, of ichthyolsulphonicacid.Various bodies have also been preparedwhich closelyresemble

ichthyol.Thiol is a mixture of sulphonizedhydrocarbons,and is

obtained by heatinggas oil with sulphur.Tumenol and petro-

snlphol are similar preparations.Blubber and lanolin have also

been combined with sulphur; and lysol,when treated with sulphur,becomes converted into a dark brown mass, soluble in water,and

showing some of the propertiesof ichthyol.All these bodies of

unknown constitution are empiricalimitations of the natural pro-duct,

which is also of unknown chemical constitution ; but,besides

these,a largenumber of pure chemical substances have been sug-gested

as likelyto have the same therapeuticvalue as ichthyolwithout its aesthetic disadvantages.Alkyl sulphides,disulpho-

170 SUBSTANCES CONTAINING SULPHUR

cyanide of potassium, alkyl-thio-urea, thio-dinaphthyol- oxide, thio-

biazol derivatives, and various other sulphur compounds have all

been tried and found wanting.

Frankel has formulated the essential points onwhich he considers

the therapeutic efficacy of ichthyol depends. Theseare :

"

1. The sulphur must be present inan

unoxidized form, firmly

combined in the molecule, and not in the form ofan easily

separated sulphydrilgroup.

2. The compound must be unsaturated.

3. The compound must be cyclic in character.

Frankel suggests that these conditionsare

best satisfied by taking

as abasis thiophene,

CH" CH

II II

CH CH

Y

certain derivatives of whichare

stated to correspond veryclosely to

ichthyol in their pharmacological properties.


172 DERIVATIVES OF AMMONIA

They are characterized by their propertyof unitingwith alkylhalogenderivatives,wherebythe trivalent nitrogenpasses over to

the pentavalentcondition (seep. 2). The resultingsubstances

may be regardedas ammonium haloids in which the hydrogenatoms are replacedby the alkylgroup,

NH3 + HI = NH4I; (CH3)3N+ CH3I = (CH8)4N.IAmmonium Tetra-methyl

iodide. ammonium iodide.

General Methods employed in the preparation of the Amines.

1. Primary amines may be obtained by the reduction of the

nitriles,in alcoholic solution,by means of sodium.

CH3CN +4H = CH3.CH2.NH2Methyl nitrile. Ethylamine.

C6H6CN +4H = C6H5CH2.NH2.Benzonitrile. Benzylamine.

2. The action of ammonia in alcoholic solution on the halogen

derivatives of the aliphatic series givesrise to a mixture of

primary,secondary,and tertiaryamines,and also of the quaternaryammonium salts,and the isolation of any singleproductis an

operationwhich will be found described in the textbooks. The

method is chieflyused for the preparationof tertiaryamines " those

most easilyisolated" but for the productionof primaryor secondarythe formation of other productsis to be avoided; in the former

case, instead of ammonia, one of its derivatives,phthalimide,is best

employed.Phthalimide readilygivesa potassiumderivative,which easily

interacts with ethyliodide,for example,givingthe corresponding

ethylphthalimide,

This substance is then decomposedby means of stronghydro-chloricacid or alkali,givingphthalicacid and the corresponding

primary amine,

For the preparationof secondaryamines the followingindirect

method can be used.

PREPARATION OF THE AMINES 173

When aniline,C6H6NH2 ,istreated with ethyliodide,for instance,

the tertiaryamine, C6H6N(C2H5)2,diethylanilineis the product

most easilyisolated. This substance givesa nitroso-derivative on

treatment with nitrous acid,

_

jMiitroso-dietliylaniline.

This,on heatingwith potash,forms nitroso-phenoland Diethyl-

amine,

In the case of the halogen derivatives of the aromatic series,

no reaction with ammonia, similar to that justdescribed,takes

place.It is onlywhen such a substituent as the nitro group has

replaceda hydrogenatom in the nucleus in the o and p positionto the halogen,that the characteristic propertyof the benzene

complexisweakened,and ammonia iscapableof interacting.When

three such groups are present,as for instance in picrylchloride,

-N02N02N02Cl

the reactivityof the chlorine atom is greatlyincreased,and ammonia

very readilygivesriseto the correspondingamine.

(N02)3NH2

In the aromatic series,the true analoguesof the aliphaticamines

are those derivativescontainingthe amido group in the side-chain,

benzylamine,C6H5 . CH2NH2, for instance. This substance,how-ever,

may be obtained by the action of ammonia on the correspondinghalogenderivative,C6H6CH2C1,that is by a reaction analogoustothat which takes placewith the aliphatichalogensubstitution

products.3. Amido compounds result from the reduction of the nitro

derivatives of either aliphaticor aromatic series. But this method

of preparationis entirelyconfined to the latterhydrocarbons,owingto the ease with which the nitro substitutionproductsof this series

are obtained. Nitro-benzene,for instance,is reduced to aniline on

a commercial scale by means of iron and hydrochloricacid"

C6H6NO2 + 6H = C6H5NH2 + 2H2O.


Secondaryamines of the aromatic series may be obtained from

the acetylderivatives of the primary. Thus aniline heated with

acetic acid givesacetanilide,

C6H5NHiH| + CH3COiOHi = H2O + C6H5NH(COCH3),

and when this substance is acted upon by sodium in an indifferent

solvent,such as toluene,the correspondingsodium derivative is

obtained,

C6H6NH(COCH3) + Na = H + CeH6N"^CH3 *

This readilyreacts with an aliphatichalogenderivative givingthe correspondingalkyl-acetanilide,which on treatment with potashis broken down into the secondaryamine and aceticacid,

t;w^îi.C6H6N"(^H+KOH = C6H5NHC2H5 + CH3COOK

Ethylaniline.

4. Acid amides of the aliphaticseries on treatment with bromine

or potashgive amines containingone lesscarbon atom. The first

phaseof the reaction consistsin the formation of bromamides,

CH3CONH2 + Br2+ KOH = CH3CONHBr + KBr + H2O

These derivatives are then further broken down into amines,

CH3CONHBr + 3KOH = KBr + K2CO3 + CH3NH2Methylamine.

This method is applicableto the amides of the fattyseriesup to

those containingfive carbon atoms.

In the aromatic series this reaction is used for the commercial

productionof anthranilic acid,and has been one of the chief factors

in the success of the indigosynthesis.

Mon-amide of phthalicacid.

.

""

... rw/CONHBrin. C"H4\COOK

Anthranilic acid.

PROPERTIES OF THE AMINES 175

General Properties of the Ammonia Derivatives.

The lower members of the aliphatic amines are gases with

ammoniacal odour,and are readilysoluble in water; the highermembers are liquidsalso soluble,and it is onlyin the case of those

with high molecular magnitudethat the solubilityin this liquidbecomes slight.They are strongerbases than ammonia,the basicityincreasingin proportionto the number of alkylgroups replacinghydrogenatoms of the originalammonia.

On the other hand,in the case of aromatic amines,this propertyis powerfullydepressed,aniline is a weak base; diphenylamine,(C6H5)2NH, stillweaker; and in triphenylamine,(C6H5)3N,thischaracteristichas entirelydisappeared.The entrance of halogenatoms or nitro groups into the nucleus of aniline further depressesitsalreadyslightbasic properties.

The aromatic amines are colourless liquidsor solids,having a

peculiarand characteristicsmell ; unlike the aliphatictheyhave no

alkaline reaction,and are onlyslightlysoluble in water.

The reactivityof primaryand secondaryamines of both series,as comparedwith the tertiary,is dependenton the ease with which

the hydrogenatoms of the originalammonia are replaced.In the

aromatic series,unlike the aliphatic,the hydrogenatoms in the

primaryand secondaryamines may be replacedby potassium.Primary and Secondary Amines of both series behave in a

characteristicmanner with nitrous acid. Primary amines of the

fattyseriesyieldalcohols,

C2H6NH2+ HN02 = C2H5OH + H2O + N2.In the aromatic series,the importantdi-azo reaction takes place(seep. 41).

The Secondary Amines of both seriesgivenitrosamines,i. (C2H5)2NH+ HN02 = H20 + (C2H6)2NO

Diethyl-nitrosamine.

ii. C6H5NH.CH3 + HN02= H20 + C6H6

Nitrosamine of methyl aniline.

The nitrosamines of the aromatic seriesundergoan interestingintramolecular change,on treatingtheir alcoholic solution with

hydrochloricacid,when jo-nitrosoderivatives are obtained.

_" NO.C6H4.NHCH3.#-nitroso-inethylaniline.


The Tertiary Amines of the Aliphatic Series either do not

Teact at all with nitrous acid,or are completelydecomposed; whereas

in the aromatic series,the hydrogenatom in the 1 : 4 positioninthe ringis attacked,with the formation of jt?-nitrosoderivatives.

(CH3)2N.C6H5+HN02 = (CH3)2N.C6H4.NO + H20.

jp-nitroso-dimethylaniline.

The aliphaticamines are of littleif any physiologicalimportance,and in consequence the followingstatements and reactions will onlyapplyto the amines of the aromatic series.

Both aniline and ^-amidophenol,

are very sensitive to oxidizingagents,but their stabilitycan be

very largelyincreased by their conversion into a group of deriva-tives

called the Anilides. These may be obtained by the action of

the acid,or acid chloride or anhydride,on the amine (seep. 120).

: = C6H5NH.COCH3Acetanilide.

C6H5NH|Hj + CH3CO:Clf= C6H5NH.COCH3 + HC1

or C6H6NHjHi + C^COps = C6H5NH.COC6H5 + HC1

Benzanilide.

It is possibleby this means to introduce a varietyof different

radicals in placeof the hydrogenof either primaryor secondaryamines.

The acid anilides are very stable derivatives,theycan often be

distilledwithout change,and also directlynitrated or sulphonated.They are characterized by their greatpower of crystallization,and

consequentlyserve as a means of detectingmany of the aromatic

The introduction of the acidicgrouping,as mightbe expected,de-presses

the basiccharacteristics,methylacetamide,CH3NH.COCH3,is onlyslightlybasic,the hydrochlorideof acetanilide is decom-posed

by water. Modified characteristicssimilar to this are observed

on the entrance of acidic groupingsinto basic substances. Thus

the powerful base methylamine,CH3NH2, becomes glycocol,COOH.CH2 . NH2, on the replacementof hydrogenby the acidic

COOH group; in this substance both the basic propertiesof the

NH2 group and the characteristicsof the COOH are very consider-

PHYSIOLOGICAL PROPERTIES OF THE AMINES 177

ablymodified. Phenol,C6H5OH, has powerfulacidic properties,and forms saltsby the replacementof the hydroxylhydrogenatom ;

jo-amidophenol,~)H

by the entrance of the NH2 group, has entirelylostthis salt-forming

power, the alreadyslightbasic propertiesof aniline being still

further depressed.The anilidesare broken down into theircomponentson treatment

with alkalis or heatingwith mineral acids,and the physiologicalreaction of these derivatives is due to this decompositiontaking

placein the organism.

General Physiological Properties.

The physiologicaleffectfollowingthe entrance of the ammonia

residue is dependent,firstlyand chiefly,on the nature of the

nucleus into which it enters,and secondlyon the reactivityofthe nitrogencomplex;thirdlya curious variation of physiologicalreactivityis noticed when trivalent derivatives pass over into

those of the ammonium type.Ammonia itself,and its salts,are remarkable in differingfrom

the caustic alkalis,which are in combination depressant,whereasammonia is a stimulant.

Intravenouslyinjected,ammonia producestetanic convulsions,

partlycerebraland partlyspinalin origin; the convulsions are not so

markedlyreflexin character as those producedby strychnine.The

irritabilityof the spinalreflexes is,however,increased. It also

quickensthe heart and respiration: the latter action isprobablydueto stimulation of the centre in the medulla. The rise of blood

pressure, which almost immediatelyfollows the preliminaryfall,isnot due to central action,but appears to be partly,at least,a conse-quence

of the increased cardiac action. The main differencebetween

the action of ammonia and strychnineis due to the rapidparalysisof the motor nerve endingsby the former,which preventsthe

superventionof tetanus.

When the hydrogenatoms are replacedbyradicalsof the aliphatichydrocarbonsthese characteristics disappear,and the resultingprimary,secondary,and tertiaryamines irritatethe mucous mem-brane,

but otherwise have slight,if any, physiologicalreaction.

Further,the replacementof two hydrogen atoms by amido

groups, e. g. in tetramethylenediamine,NH^CH^NHg, or penta-N


methylenediamine,NH2 . CH2 . (CH^ . NH2, givesrise to similarlyinactive substances.

When the amido group replaceshydroxylin the aliphaticacids,

resultingin the formation of bodies of the nature of acetamide,

CH3CONH2, itisagainfound that pharmacologicallyinactive bodies

result. If the amido group replaceshydrogen in the aliphaticnucleus of these acids,the result is similar. NH2. CH2. COOH,

amido acetic,NH2 . CH2 . CH2 . COOH, /3-amidopropionicacids,

"c.,are inert,but unlike acetamide these are broken down in the

organism,as previouslydescribed (p.74).

Betaine,trimethylglycocol,COO

is physiologicallyinactive,and itshydrochloride,under the name of

Acidol, has been introduced as a solid substitute for hydrochloricacid ; it is very readilysoluble in water, and contains 23-78 per cent.

acid,which is slowlysplitoff in the stomach.

When the amido group replacesa hydrogenatom in the benzene

nucleus,substances of the nature of aniline result,and a com-pletely

new and valuable set of pharmacologicalpropertiesappear ;

this observation has formed the basis for the synthesisof a large

group of so-called 'antipyretics',which will be described later.

The entrance of a second amido group into the aromatic nucleus

givesrise to powerfullytoxic substances unlike the corresponding

aliphaticdiamines.The passage of a primary aromatic amine to a secondaryis

followed by a correspondingalteration in physiologicalproperties.

Methyl,ethyl,and amyl anilineare less toxic than aniline,and have

lostthe power which that substance possesses of producingmuscular

spasms, but,on the other hand,they bringabout the paralysisof

the peripheralendingsof the motor nerves, in a somewhat similar

manner to the alkylalkaloids,althoughwithout the curare action

of the quinquevalentnitrogenderivatives. (Compare action of

antifebrin and exalgin.)The presence of an imido group may result in an increase of

toxicity,most probablydue to increase of reactivity.Thus,guanidin

is a powerfulpoison.Xanthine,with three imido groups, is,accordingto Eilehne,more toxic than theobromine with one, and this more



greatresistanceto decompositionin the organism,with the result

that they are usuallycompletely,or almost completely,inactive

physiologically.But it must be remembered that whereas the

aliphaticradicals,with exceptionof perhapslactic and citricacids,have no pharmacologicalaction,some of the aromatic acids have

a considerable effect,such,for instance,as salicylic(p.151).

Consequently,if such an acid is one of the decompositionproductsof the acyl-nitrogenderivative,its action will appear togetherwith

that of the basic residue.

B. Hydrogen of Hydroxyl Group by Acid Radicals.

Whereas the replacementof hydrogenof the amido group by acid

radicals bringsabout a decrease in toxicity,a different action is

noticed when the hydrogenof an hydroxylgroup is similarlydis-placed.

In this case an increase in toxic propertiesis noticed.

Ecgoninemethyl ester,C10H16NO2. OH, has no local anaesthetic

action ; by the replacementof the hydroxylhydrogenby benzoyl,cocaine results,C10H16NO2. 0.COC6H5, a powerfullocalanaesthetic.

Benzoyllupinineis much more toxic than lupinine.

C10H18N.O.CO.C6H6 C10H18N.OHBenzoyl-lupinine. Lupinine.

Mono-acetylmorphine,diacetylmorphine (Heroine),benzoylmorphine,and dibenzoylmorphine have a similar physiologicalaction to codeine (methylmorphine),but are far more toxic. The

depressanteffecton the spinalcord,and especiallyon the respiratory

centre,is much greaterthan that of morphine. Compared with

codeine,one-tenth of the dose will producea similar narcotic effect.

Veratrine may be splitup by the action of an alkali into cevine

and tiglinicacid,

C32H4,N09+ H20 = C,H,Oi+ CfrH41^0,Veratrine. Tiglinicacid. Cevine.

Cevine has the same physiologicalaction as veratrine,but its

toxicity,owing to the absence of the substituted acid group, is ten

times less.

The increase in toxicityproducedby the introduction of the acid

group does not dependon the physiologicalaction of that group in

itself,but upon its power of coveringcertain ( anchoring'

groups in

the molecule,so that the latter,beingmore generallyresistant,can

producea specificaction (i.e. on the central or peripheralnervous

DERIVATIVES OF AROMATIC AMINES 181

system).The acid radical may also form an anchoring'group itself

for the productionof a specialphysiologicalresponse.

ANILINE DERIVATIVES.

The discoveryof Calm and Hepp that aniline (oracetanilide)is

a powerfulantipyretic,and also possesses antineuralgicproperties,togetherwith the low priceof this substance,has led to the pro-duction

of a largenumber of itsderivatives.

Aniline and its salts have a powerfulantipyreticaction,like

phenol,and it producesspasmodicmuscular contractions of central

origin,as does ammonia. The main toxic symptoms are weakness,

dizziness,cyanosis,and finallycollapse,with or without vomitingdue to direct irritationof the gastricmucosa.

Aniline also breaks up the red blood cells,liberatingthe

haemoglobin.Toxic symptoms of a similar nature but lesspronouncedcharacter

are observed among workers in the dyeingindustry,in which aniline

oil is used.1 Aniline was at one time employed as a remedy for

phthisisand other forms of tuberculous disease,the vapour beinginhaled in combination with certain aromatic antiseptics.Likemost schemes for internal antisepsis,however,this failed when

put to a practicaltest; the tubercle bacilli in the blood-stream

remained unaffected,whereas the patientsexhibited symptoms of

poisoningdue to the presence of the drug.It was onlyto be expectedthat when the reactive amido group is

rendered more stable by replacinghydrogenwith the acetylgroup,the resultingacetanilide(antifebrin)should be a far less toxic

substance.

Antifebrin, C6H6NH(COCH3), shows the same generalreaction

as aniline. It reduces fever,has similar antineuralgicproperties,and a similar thoughlessmarked action on the red blood corpuscles;but the effect,dependentas it is on the decompositionof the anilide

in the organism,is not producedso rapidlyas by the free base. No

effect on nitrogenousmetabolism occurs with therapeuticdoses.In pyrexiaa slightdiminution may occur.

Acetanilide is oxidized in the body to jt?-aminophenoland is

excreted in the urine partlyas oxycarbanile,

1 Dearden,British Medical Association Meeting,1902.

182 DERIVATIVES OF AROMATIC AMINES

/?-acetyl-aminophenol,and /"-aminophenol.The latter is further

changed by combination with sulphuricand glycuronicacids.These changes in structure diminish the toxicityof aniline or

acetanilide,but do not destroyentirelytheir antipyreticaction.

The most varied acid radicals have been introduced in placeofthe acetytgroup in acetanilide,but without the productionof sub-stances

with any novel physiologicalreaction ; since this factor is

unquestionablya function of the decompositionof these derivatives

into aniline,this was hardlyto be expected. It is onlywhen the

enteringgroup has physiologicalcharacteristics of its own that

these may appear simultaneouslywith those of aniline.

Among substances of this type are the following:"

1. Formanilide,C6H5NH(OCH), formed by rapidlyheatingoxalic acid and aniline,or treatinganiline with formic acid. It

has powerfulantipyreticand analgesicproperties,and acts as a

local anaesthetic,but is much more toxic than acetanilide,this

being undoubtedlydue to the fact that it is much more easilydecomposedby dilute acids.

2. Benzanilide,C6H5NH(COC6H5), is onlybroken down by the

organismwith difficulty,and consequentlylargerdoses are requiredthan in the case of acetanilide.

3. Salicylanilide,C6H5NH(COC6H4 . OH), and anisanilide,

C6H5NH(COC6H4 . OCH3), like most derivatives of this type,are.

onlybroken down by the organismwith such difficultythat their

physiologicalreaction is but slight.Attempts to increase the solubilityof acetanilide by the forma-tion

of such substances as acetanilidoacetic acid and formanilido-

acetic acid,by the action of chloraceticacid on acetanilide or form-

anilide,"

+ C1.CH2 .COOH = HC1 + C6H4]

when R = (COCH3)'or (CHO)',gave negativeresults,since these

substances,havinglost their basic characteristicsand become acidsr

obeythe generalrule that such derivatives therebylosetheir physio-logicalproperties.Formanilidoacetic acid,however,owing to its

instability,is about as toxic as formanilide. For similar reasons,

Cosparin,

p " /NHCOCH3^"n*\ SO2ONa

the jp-sulphonateof acetanilide,obtained by the action of aceticacid


on sulphanilicacid,

should have no physiologicalimportance,since its action can onlydependon its decompositioninto the inert sulphanilicacid.

In order to increase the solubilityof acetanilide and phenacetin,derivativeswere obtained containingthe sulphonicgroup in placeof

the hydrogenof the methane radical ; these were preparedfirstlybydehydratingthe aniline salt of monochloracetic acid by means of

phosphoruspentoxide,

CH2C1.COO(C6H5NH3)-H20 = CH2C1.CO.NHC6H6,and then heatingthis latter substance in aqueous solution with

sodium sulphite"

C6H5NH.(COCH2C1)+ Na2S03= NaCl + C6H5NH.(CO.CH2.SO2ONa)

The resultingsubstances are much more soluble than acetanilide or

phenacetin,and,if their action is similar,which is stated to be the

case, theymust be broken down in the organism,the acidic group-ing

not beingsufficientlystable for them to obeythe generalrule.Another method of modifyingthe action of aniline,that is of

making it more stable,consists in convertingit into a urethane

derivative by the action of chlorformic ester"

C6H6NHiH+ CljCOOC2H6= HC1 + C6H5NH.COOC2H6Phenyl urethane.

The resultingsubstance,termed Enphorin, is much less toxic

than aniline. Physiologicallyits action resembles that of acet-anilide

rather than that of urethane. It depressesthe temperature,and has considerable analgesicproperties.Large doses weaken the

pulseand respiration.It has also a bactericidal action,and has

been employed to check suppuration.It is not of value as a

hypnoticlike other urethane derivatives (hedonal,"c.). It does

not lead to the formation of methaemoglobin.In largedoses itacts

like a urethane derivative,paralysingthe central nervous system;

the effect is very similar to the pareticaction of alcohol. In

moderate doses it is said to decrease metabolic processes, but its

antipyreticaction is similar to that of the other bodies of this group,

beingdue to the dilatation of the cutaneous vessels. It increases

the conjugatedsulphatesin the urine,and is partlyexcreted as

oxyphenylurethane,an indication consequentlythat this derivative

is lesstoxic than euphorinitself(seep. 196).

184 DERIVATIVES OF /-AMIDO-PHENOL

Whereas Exalgin(methylacetanilide)has powerfullytoxic pro-perties,

the correspondingMethyleupliorin,

is an almost indifferentsubstance.

When aniline is converted into the secondaryamine, methyl-aniline,C6H5NHCH3, a substance is obtained which paralysesthe

motor nerve endings. Exalgin, which is the acetylderivative of

this,

has a somewhat similar action to acetanilide,but a powerfullytoxic secondaryreaction,producingepilepticconvulsions and profusesalivation. Death results from respiratoryfailure. The convulsions

can be stoppedby the induction of anaesthesia,and are probably

partlycerebral and partlyspinal.Smaller (non-toxic)doses pro-duce

in mammals lethargyand a fallof arterialpressure.

Finally,the replacementof aniline by any of the toluidines has

no advantages,since they act on the red blood corpuscles,forming

methaemoglobinin a similar manner to aniline itself.

On injectioninto the jugularvein of a dog the lethal dose of

these bases per kilo,weighthas been found to be : orô-toluidine

"208 gm., 1 : 3-toluidine -125 gm., 1 : 4-toluidine -1 gm.

But when converted into their acetylderivatives a considerable

difference is noticed ; both 1 : 3 and 1:4 are non -toxic,and this

characteristicis onlynoticed with the 1 : 2 substance. Then it is

only the 1 : 3 derivative that has antipyreticproperties,and Bar-

barini states that it is less toxic and has a stronger action than

antifebrin.

Aniline and ^-toluidine depressthe respiratorycapacitymorethan either the o- or /-derivative; further,the former substances

depressthe temperatureto a greaterextent than the latter.

DERIVATIVES OF /-AMIDO-PHENOL, C6H4" 1:4.*

On their passage through the organism,aniline,acetanilide,or

generallyspeaking,any of the physiologicallyactive derivatives of

1 1 :2-amido phenol,unlike the 1 : 4 derivative,is inactive,but when the

hydroxyl hydrogen atom is replaced by alkyl radicals,bodies possessingnarcotic propertiesresult ; the 1 : 2 and 1 : 3 present no pharmacologicaladvantage,and are both more toxic than the para derivative.


these substances,are partiallyconverted in ^-amido-phenol,which

is eliminated as a sulphonateor as a compound of glycuronicacid.

Since observations have shown that such changesalwaystend to

the productionof less toxic derivatives,it was but natural to in-vestigate

the therapeuticvalue of this substituted aniline. The

chemical nature of this substance,and the modifications of the

characteristics of each substituent by their simultaneous presence

in the molecule,have alreadybeen described : the pharmacological

propertiesare those to be expected,viz.energeticantipyreticaction,but much lesstoxicityand haemolyticaction than isshown by aniline.

The whole group of physiologicallyactive derivatives of aniline or

jo-amido-phenolare broken down in the organismwith the produc-tionof this latter substance,and the indophenolreaction in the

urine may be taken as a test for their reactivity.

Trenpeland Hinsberghave stated that the ' antipyreticaction

of aniline and ^-amido-phenolderivatives appears to be, within

certain limits,proportionalor nearlyproportionalto the amount of

aniline or /"-amido-phenolor phenetidinformed in the organism'.

On the other hand, if these substances are not formed (i.e. if no

indophenolreaction with the urine occurs),then the preparationis

not physiologicallyactive.

Thus,

Methacetin,C Phenacetin,C

/OC1 TTand acetamidophenol-propyl-ether,C6H4\\rTjn

are readilydecomposedin the organism,giving/"-amido-phenol,and

show physiologicalcharacteristicssimilar to those derivatives of

phenacetin,

in which R = CH3, C2H6,C3H7,or wo-propylgroups. But ethyl-acetamido phenol,

H

which is not decomposed,has no antipyreticor other action.

It will be readilyseen that the generalphysiologicalreaction of

the whole of the /?-amido-phenolderivatives will be that of the free

base itself,or of itsethoxyor methoxysubstitutionproduct,and that

186 DERIVATIVES OF J9-AMIDO-PHENOL

added to this reaction will be that of the radical attached to thei

amido group ; in the case of acid derivatives of the aliphaticseries,for example,this would be nil.

In the case of //-amido-phenol,two different classes of modifica-tions

can be carried out; either the hydrogen of the hydroxyl

group can be replacedby radicals,or the hydrogenatoms of the

amido group can be similarlydisplaced.The replacementof H in the NH2 group by acetyl,givingacet-

amido-phenol,

results in the productionof a substance with powerfulantipyretic,antineuralgic,and possiblyslightnarcotic properties,but of much

lower toxicitythan the originalsubstance. The further replace-mentof the hydrogenof the hydroxylgroup by methyl,

r w /OCH3C6U4\NHCOCH3

(methacetin),causes an increase in both the former propertiesand

a decrease in the action on the blood ; replacedby ethyl,

r TT /OC2H(

(phenacetin),the narcotic action is increased,and a further diminu-tion

in the formation of methaemoglobinis noticed. The maximum

antipyreticand antineuralgicaction is found in the case of methyl,but lesser toxicityin case of ethyl. The antipyreticaction di-minishes

with the increasingmolecular magnitude of the group

replacingH of the hydroxyl. In one direction,then,the possiblevariations as regardsalkylgroups replacingthat hydrogenatom is

limited to either methylor ethyl.In phenacetinthe hydrogenatom R,

ft "

,COCH3,

may be replacedby acid groups, which will be discussed later,or byradicals of the aliphatichydrocarbons.The entrance of methylcauses an increase in the narcotic and also in the antineuralgicproperties,but the substance has onlya slightantipyreticpower.Replacedby ethyl,a similar decrease in toxicity,increase in

narcotic,and decrease in antipyreticpropertiesare noticed.


188 DERIVATIVES OF ^-AMIDO-PHENOL

As the preparationof p-mtro phenolin a state of purityis by no

means easy ; the method of preparationis modified. jo-Phenetidin

is diazotized and treated with a phenoland sodium carbonate,

OC2H5 r n /OC2H5 p H /OC2H52-

: N.C6H4 .OH

and the resulting-compound is readilyconverted into the di-ethoxyderivative

: N.C6H4 . OC2H5,

which, on reduction,givestwo molecules of phenetidin"

Half of the yieldis then converted into phenacetiriby means of

acetic acid,and the other half againused for the preparationof

a fresh quantityof phenetidin.Physiologicallythe toxic effect of this substance is not great.

DujardinBeaumetz gave 2-5 grams to a rabbit weighing2"26 kilo-grams

without any toxic effect,and 2 grams have been givenfor

every kilogrambody-weightin other animals. Large doses producethe characteristic aniline action on the red corpuscles,the blood

becomes thick and purple,and finallyshows the spectrum of meth-

haemoglobin.The darkeningof the urine also takes place,and

occasionallya reducingsubstance appears. The ' antipyreticaction '

is thus explainedby Schmiedeberg.In the firstplace,metabolism

experimentshave shown that the nitrogenexcretion is increased

with small doses,and onlydecreased with largeones ; thus a direct

decrease in nitrogenousmetabolism cannot be the cause of the fall

in temperature.Now, if animals in which the temperaturehas been

raised by puncture of the corpus striatum are givenmoderate doses

of phenacetinor one of its congeners, or even small doses of

morphine (-01"02 grams, J"| grain),a fall of temperatureis

observed after one or two hours,which,however, is onlytemporary.If this experiment,however,is performed,and the animal placedin

an incubator at 31-32" C.,no fall of temperaturetakes place; thus,

the fall of temperaturemust be induced by increased heat-loss,and

not by diminished heat production.Large doses of these drugs,

however, paralysethe centre for heat production.The heat-loss is shown by plethysmographicexperimentsto be

due to dilatation of the cutaneous vessels,with a correspondingcontraction of the internal arterioles.


The characteristicanalgesicaction of phenacetinis mainlydue

to its effect on the sensory tracts in the cord.

Phenacetin is,however, onlyslightlysoluble in water,and con-sequently

is onlyslowlyabsorbed. Many attemptshave been made

to increase the solubilitywithout so diminishingthe stabilityof

the substance as to cause its decompositionor rapiddecomposition

by a 2 per cent, solution of hydrochloricacid,whereby the toxic

hydrochlorideof phenetidinwould be formed in the stomach. For

this purpose various acid radicals have been introduced into the

basic NH2 group, and the followingexamples,which are classified

accordingto the typeof chemical modification,show that (1)onlyin

some cases has the desired result followed;(2)the substances de-scribed

illustratethe modifications in the physiologicalreaction which

can be obtained by such variations of the molecular structure ; (3)no substance has been obtained,by such modifications,with any

novel pharmacologicalproperties,nor of course was this likely,if the action of these derivatives actuallydepends,as it most pro-bably

does,on their decompositioninto one and the same substance,

jo-amido-phenolor its ethylether.

Class I.

1. Formyl-phenetidin,

formed byactingwith formic acid and sodium formate on phenetidin,has an action entirelydifferentfrom that of the other derivatives of

this substance. The antipyreticeffect almost entirelydisappears,and is replacedby a powerfullydepressantaction on the cells of

the spinalcord. It is,in fact,a physiologicalantagonistto strych-nine,but unfortunatelyit has no therapeuticvalue in checking

convulsions caused by disease.

2. Propyl-phenetidm,

r IT /OC2H5^M4\NH.(COCH2.CH3)

termed Triphenin by Mering,has similar propertiesto phenacetin,but its slightsolubilityresults in slow absorption,and consequentmild physiologicalreactivity.

3. Lactyl-phenetidin,

5

(Lactophenin),is obtained by heatingthe lactic acid salt of the

190 DERIVATIVES OF jo-AMIDO-PHENOL

base to 130"-180",or by heatinglacticanhydrideor lactic ester

with the base to this temperature;or it may be obtained byreplacingthe halogen in a-brompropionyl-phenetidinby OH,

throughthe agency of aqueous sodium acetate. Its action appears

to be identicalwith that of phenacetin,but it is more soluble; the

narcotic action is well marked, though the antipyreticaction is

slighter.It is mainlyvaluable as an antineuralgic.In rabbits its

effectcloselyresembles that producedby chloral hydrate,the animal

remainingunconscious and motionless,and irresponsiveto painfulreflexes,though the respirationand circulation are not affected

(Schmiedeberg).It is more liable than phenacetinto lead to the

formation of the toxic hydrochlorideof phenetidinin the stomach.

4. jo-Ethoxyphenyl-succinimide(Pyrantin)

is obtained by the action of succinic anhydrideon the base.

The sodium salt is soluble in water. It is an uncertain antipyreticand analgesic,but is said to have no toxic action on haemoglobin.

5. Diacet-phenetidin)C2H

CfiH44

was thoughtlikely,on theoreticalgrounds,to prove a more powerful

antipyreticthan phenacetin,but in actual practicethis was not

established. It is very unstable.

6. Salicyl-phenetidin

TT /OCH

(Salophenor Saliphenin),like the majorityof such derivatives,is

onlybroken down in the organismwith difficulty.It was origi-nallyintroduced to replacesalol,in order to avoid the formation of

phenolin the organism. It is unaffected by the gastricjuice,but

decomposedby the pancreatic.It is slightlyantipyretic,but

appears mainlyactive as to the salicylportionof the molecule. It

is mostlyexcreted unchangedin the urine. No increase in the

conjugatedsulphatesoccurs. Quinic acid producesa similarlyinert compound with phenetidin.


7. Amygdophenin,

C6H4\NH2CO.CH(OH).C6H5,is obtained by heating/^zra-phenetidinwith mandelic acid at

130"-170" C. The mandelic acid diminishes the toxicityandthe antipyreticaction by diminishingthe solubilityand rapidityof absorption.

Class II.

A. Attempts to increase the solubilityof phenacetinby the

ordinarymethods employed in organicchemistry,that is by the

introduction of a (COOH) or (SO2OH) group into the nucleus,were unlikelyto lead to the desired result,since Nencki had shown

that such changestend to destroyphysiologicalactivity.Thus,both the soluble phenacetinsulphonicacid,

C6H3f-NH.COCH3\S02OH

and phenacetincarboxylicacid,

0"H5C6H3f-NH.COCH3

\COOH

preparedin Schering'slaboratory,are but very slightlyreactive.Fhesin, the sodium salt of the former acid,

XOC2H5C6H/NHCOCH3

\S02ONais a light-brownpowder,soluble in water,with a slightlyastringentsalt taste. It is employedin doses of 15-30 grains,and apparentlypossesses analgesicand antipyreticaction.

On the other hand, the introduction of a second amido groupinto the nucleus,affordinganother possibilityfor the preparationof soluble derivatives,is not feasible,since it results in a largeincrease in toxicity.

B. The replacementof hydrogenin the amido group by acid

radicalshas led to the preparationof several substances of greatersolubilitythan phenacetin.But it was hardlyto be expectedthat,if the stabilityof the body were such as to allow of itsdecompo-sition,

giving-amido-phenolin the organism,there should be any


considerable decrease in toxicity; if,on the other hand,the stabilitywas great,then the presence of acid groups might be expectedto

giveriseto substances with littleif any physiologicalactivity.1. The citricacid derivatives of phenetidinare :"

i. CH2COOH

C.OH.COOH Apolysin,ICH2 . CO-NH.C6H4. OC2H5

ii. CH2 . CO.NH.C6H4 . OC2H5

C.OH.COOH

CH2 . CO.NH.C6H4 . OC2H5.

Apolysiu is soluble in about 80 partsof cold water, and freelyin hot water, alcohol,and glycerin.It has been used in migraine,but is said by some observers to have neither the analgesicnor the

antipyreticpropertiesof phenacetin.It is,like lactophenin,easily

decomposedby the hydrochloricacid in the stomach,givingrise to

the toxic phenetidinsalt ; this producesboth local and general

symptoms. If injectedsubcutaneouslyno decompositionoccurs,and the substance passes unchanged into the urine; its onlyphysiologicalaction then is due to the acid radicals.

CH2 . CO.NH.C6H4OC2H5

/^tr"?he?\C.OH.CO.NH.C6H4OC2H5(Citrophenm),,

CH2.CO.NH.C6H4.OC2H5

is soluble in 40 partsof water,and has a pleasanttaste. Its action

resembles that of phenacetin.The formula givenabove was that

givenby Boos ; Hildebrand,however, states that it is merelythe

citrate of phenetidin; its action physiologicallyis similar to that of

a salt of phenetidin,and not to that of a true substitution product.Chemicallyit givesa red coloration with perchlorideof iron,which

apolysindoes not. It is a blood poisonlike the other phenetidinsalts.

2. Schmidt preparedethoxy-succinanilicacid,

.CO.CH2.CH2.CO.OH,


and ethoxytartranilicacid,

r " /OC2H5C6H4\NH.CO.CHOH.CH.OH.COOH,

but owingto the introduction of the acid group, these bodies have

no antipyreticaction.

3. In a similar manner ethoxyphenyl-glycin,

".CH2.COOH,has been found to possess no pharmacologicalvalue.

4. Fheiiosal,

"C0H,

D.CH2.O.C6H4.COOH,

obtained by heatingsalicylaceticacid with phenetidinto 120 ",is

a white crystallinepowder,soluble with difficultyin water,alcohol,and ether. It has a bitter acrid taste,and has been employedforits antipyreticand analgesicqualities,which, however,are but

slight.

Class III.

Schmidt and Majert,in order to increase the solubilityof phe-nacetin,preparedamido-phenacetin(glycocoll,-phenetidin,Ph.enocoll),

OC0He

by the action of ammonia on bromacetylphenetidin.The

hydrochlorideis soluble in 16 partsof water, forminga solution

of bitter,salinetaste. It has the usual phenacetin-likeaction,and

a few authors state that it is an antiperiodic.This is not, how-ever,

generallyaccepted.It appears to have some antisepticpro-perties,

as it has been employed externallyas a substitute for

iodoform.

Phenocoll hydrochloride,owing to its solubility,is more rapidlyabsorbed,and consequentlyacts more quicklythan phenacetin.Itis said to be more powerfullyanalgesic,and to be an efficientsubsti-tute

for salicylatesas an antipyreticin acute rheumatism. It may

cause collapseand cyanosis.Mosse considers it of value in septicinfectionsonly. It israpidlyexcreted by the kidneys,so that its

action is but transitory.

Salocoll, itssalicylicacid compound,is the onlysaltof phenocollwhich is insolublein water. Its action resembles that of the parentsubstances.

o

194 DERIVATIVES OF jo-AMIDO-PHENOL

Class IV.

Various condensation productsof phenetidinwith aldehydesandketones have been preparedand investigated.

1. Salicyl-phenetidin

"C2H5: CH.C6H4 .

OH

(Malakin),is preparedby the action of salicylaldehydedirect or in

alcoholic solution on phenetidin.It is almost insoluble in water,

and onlyslightlysoluble in alcohol. As an antipyretic,itsaction is

said to be slow,but itis a useful analgesic.The dose is 8-25 grains.Its insolubilityinterfereswith itsphysiologicalaction.

2. Methyl-benzylidene-phenetidin,

obtained by the action of acetophenoneon phenetidin.The citric

acid salt of this derivative goes by the name of Malarin. The

originalsubstance is practicallyinsoluble in water,but freelysolublein hot alcohol. It has a bitter taste,and is employedas an anti-pyretic

and analgesicin doses of 7 grainsseveral times daily.Ithas considerable action in these directions,but is of littlevalue as a

hypnoticas it is markedlytoxic,and its action is too precipitate.3. Vanillin-phenetidin,

^6"4\N . CH.C6H3

preparedby the action of phenetidinon vanillin,is antipyreticand antiseptic,and also contracts the blood vessels. It is,however,too expensiveto be of practicalvalue as a substituteforphenacetin.

Various js?-amido-phenolderivatives of substituted vanillins have

been investigated.Vanillinethylcarbonate,preparedby the action

of chlorformic ester on an alcoholic solution of vanillin in presence

of potassiumhydrate,yCOH 1

C6H3"-OCH3 3

\O.COOC2H54or phenacetyl-vanillin,

3

\O.CH2.COOC6H6,

may replacevanillinin these reactions.



nacetin,which is then converted into acetamido phenol. It is said to

be of value in rheumatism and neuralgia,but the antipyreticand

narcotic actions are very slight,decompositionwithin the organism

takingplaceslowly.5. j9-Acetamidophenoxylacetamide

.CH.CONH

is obtained by the action of monochlor-aeetamide on acet-^?-amido

phenolin presence of the calculated amount of alcoholic potash.

The correspondinglactylderivative is obtained in a similar manner

from lactyl-/?-amido-phenol.It has marked antipyreticaction.

Class VI.

On its passage through the organism,phenyl urethane,

C6H5NH.COOC2H5 (Euphorin),is partiallyconverted into p-oxy-

phenylurethane,and, on the same principlesas those previously

mentioned,this substance and many of its derivatives have been

introduced into pharmacology.1. ^-oxyphenylurethane,

OH

It ispracticallynon-toxic,but may produceslightrigors.2. Acetyl-/"-oxyphenylurethane (Neurodin),

/OHCH/ /COCH/C

XN^C

The toxic effects are still further reduced by the entrance of

the acetylgroup, as are also the antipyreticand analgesicactions.

It is very insoluble in cold water,and its antipyreticaction,though

rapid,is somewhat uncertain.

3. p-ethoxyphenylurethane,

.COOC2H6"

althoughnot free from toxic effects,has a much more certain action

in loweringthe temperature than those derivatives previouslymentioned.


4. The acetyl derivative of this substance,

/oc2H6C6H/ /COCH3

is named Thermodin. Its antipyretic effect is said to be gradual,

and toxic symptoms have not been observed. It isvery insoluble except

in acid media, and should therefore be administered combined with

acetic acid andsyrup, or in some similar

way.It is a mild diuretic,

but is said to have no depressant action on the heart or respiration

in medicinal doses. It is also claimed that it destroys the plas-

modium malariae.

Various derivatives of the oxyphenyl urethane series have been

prepared by Merck; one group may

be obtained by passing carbonyl

chloride into a solution of /?-oxyphenyl urethane or acid derivatives

of ^-phenetidin inpresence

of alkali; the reaction which takes

place maybe represented by the following equation : "

r H/OH

a. rnnrn/"-C6H4

"

NHCOR9TTP1C"H"\NH.COB + C]2 = \0.cX

"

NH.COR+ 2H

R= OC2H5

,OC3H7 j CH3

,C2H5 ; C6H5.

If the reaction is carried out in alcoholic solution in presence of

sodium alcoholate, mixed carbonates are formed. The reactionmay

be expressed in the following manner : "

OIH ! ) !

C6H4"( +;CliCOJCl:

XNH.COR

-

9TTP1 _i_ P1 + C

E = OC2H5, OC3H7; CH3) C2H6J C6HS.

On varying the alcohol,the groups methyl or propyl replace ethyl

in the above derivatives.

CHAPTEE X

THE MAIN GROUP OF SYNTHETIC ANTIPYRETICS (CONTINUED)."

Hydrazine and its derivatives. " Physiologicalaction of Phenylhydrazineand

its derivatives. The Pyrazolon group " Antipyrine,Pyramidon. General

Summary of Physiologicalcharacteristics of the Ammonia derivatives.

II. DERIVATIVES OF PHENYLHYDRAZINE.

LIKE ammonia, hydrazine,NH2 " NH2, is a strongbase and an

extremelytoxic substance ; its most importantderivative is phenyl-hydrazine,C6H6NH " NH2, a body which is largelyemployedin

syntheticchemistry,

Preparation and Properties.

Phenyl-hydrazinemay be obtained by the reduction of the diazo-

benzene salts,C6H5N :N.C1,throughthe agency of acid sulphitesof

the alkalies on the yellowpotassiumsalt of diazobenzene sulphonic

acid,wherebycolourlesspotassiumbenzenehydrazinesulphonateis

formed directly,

C6H6N : N.S02OK + KHS03+H20= C6H6NH.NH.SO2OK + KHSO4.

When the resultingsulphonateis heated with hydrochloricacid,

phenylhydrazinehydrochlorideis formed "

C6H6NH.NH.SO2OK + HC1 + H2O= C6H5NH.NH2 .

HC1 + KHSO4.

A somewhat simplermethod for the preparationof phenyl-hydrazineconsists in the reduction of diazobenzene chloride by

stannous chloride,

C6H5N :N.Cl + 2SnCl2+ 4HCl = C6H6NH.NH.HCl + 2SnCl4.

The double salt of phenylhydrazinehydrochlorideand stannic

chloride separatesout, is decomposedby potash,and the solution

extracted with ether ; the free base may then be purifiedby distil-lation

in vacua.

Phenylhydrazineis a stronglybasic substance,more readily


oxidized than aniline; it reduces Fehling'ssolution,and is a most

importantreagentfor the identificationof (i)aldehydesand (ii)ketones,with which itundergoesthe followinggeneralreactions :"

i. CH3 CH3

2;N.NHPh = H2O + CH : N.NHPh1

Acetaldehyde.

C6H5CHp + H2jN.NHPh = H2O + C6H6CH : N.NHPh

Benzaldehyde.

ii. CH3 CH3

CjO + H2;N.NHPh = H20 + C : N.NHPh

CH3 CH3

CH3 CH3

= H9O + C : N.NHPh

The developmentof the chemistryof the carbohydratesby Emil

Fischer was largelybased upon reactions similar to these,since that

group is entirelycomposedof ketonic or aldehydicalcohols.There are few classesof organicsubstances which lend themselves

more readilyto the synthesisof ringsystemscontainingnitrogenthan do phenylhydrazineand its derivatives. From the phar-macological

pointof view,the pyrazolonderivatives,among which

isantipyrine,are by far the most important,and will be described

later.


The reactivityof phenylhydrazinewith aldehydesand ketones,

togetherwith its powerfulreducingaction,giveit very pronouncedtoxic properties.

Like hydroxylamine,NH2OH, hydrazineitself,and to a lesser

extent aniline,itbringsabout destruction of the red blood corpusclesand decompositionof the haemoglobin,besidesbeinga powerfulpro-toplasmic

poison.The brown pigmentformed in the blood appears to

be partlymethaemoglobinand partlya substance derived from phenyl-hydrazineitself (Hoppe-Seyler).Death takes placefrom general

paralysisof cerebral origin,accompaniedby convulsions. The admini-

1 The radical Phenyl,C6H6,may be written Ph,Methyl Me, and EthylEt.

200 DERIVATIVES OF PHENYLHYDRAZINE

stration of phenylhydrazineisfollowed by the appearance of allantoin

in the urine. The various attemptswhich have been made to reduce

the toxicity,or rather to bring about a more protractedphenyl-hydrazinereaction in the organism,follow very closelythose

employedin the case of aniline.

By a completelycorrespondingreaction,the stabilityof the base

can be increased by the replacementof the amido hydrogenatom bythe acetylgroup, but the resultingsubstance,acetylphenyl-hydra-zine, C6H5NH" NH(COCH3) (Hydracetin),is stillcapableof

reducingFehling'ssolution,althoughto a less extent than the

originalsubstance. Intense depressionand collapse,marked fall

of temperature,haemoglobinuria,and diminution of the amount of

urine excreted,follow even on small doses. Medicinally,only"2 gram (3 grains)is the maximum dose,so that had it been

possibleto employ it,it would have been much cheaper than

antipyrine.The intense stainingof the tissues after death is evidence of the

extent to which haemoglobinis broken up by this substance. It

has been employed,like pyrogallicacid,in the treatment of

psoriasis,but practicallyis too toxic even for external application.1

Diacetylphenylhydrazine,C6H5NH" N (COCH3)2,is less toxic,but has a cumulative action as a haemic poison.Thus,though a

powerfulantipyretic,it is not possibleto employit therapeutically.In this connexion itmay be mentioned that a-j5-diacetylphenyl-hydrazine,

XCOCH3C6H6 .

N/- _NH(COCH3),

obtained by the interaction of sodium phenylhydrazine,ether,and

acetylchloride,does not appear to have been tried,althoughfrom

the fact that it is capableof reducingFehling'ssolution,its action

is not likelyto differ much from that of the above-mentioned bodies.

In a very similar manner the amido hydrogenatom has been

replacedby the radical benzoyl,but the resultingbenzoylphenyl-hydrazine,C6H5NH" NH(COC6H5), acts on the blood in doses

that have no action on the central nervous system.This is also true of ethylene-phenylhydrazine,

/NH2 /NH2C6H6.N^C2H4-N.C6H6

1 Berl. Klin. Woch., 1899.


and its succinylderivative

/NH(CO.C2H4COOH) /NH(COC2H4 . COOH)C6H6.N^-C2H4- -N.C,H5

The relative toxicityof phenylhydrazineis lowered by the re-placement

of hydrogen by alkylor acid groups, but the presence of

both,as in the case of acetyl-methyl- or ethyl-phenylhydrazine,

does not decrease the generalaction on the blood,althoughthe lower-ing

of toxicityis sufficientlymarked, and it might be worth while

to investigatethe physiologicalreactivityof dimethylacetylphenyl-hydrazine,

which is a more stable substance.

In the hope of loweringthe toxicityattempts have been made to

introduce the phenylhydrazineradical into substances containingthe acidic (COOH) group. Thus laevulinic acid,

CH3.CO.CH2.CH2.COOH,

reacts with the base,in the form of its acetate in aqueous solution,in the generalmanner previouslydescribed,yieldingthe hydrazone

CH3.C.CH2.CH2.COOH

N.NH.C6H5

This body has been termed Antithermin. Laevulinic acid itself

is toxic,and itscompound, though activelyantipyretic,too poisonousfor generaluse ; it is also liable to cause gastricirritation.

Based on the same idea,the substance Orthin

,NH.NH2 1

C6H/OH 2

\COOH 5

has been introduced. The presence of the acid grouping againlowers the toxicity,but the substance is unreliable as an antipyreticand producesundesirable by-effects.Attempts to modify the action of phenylhydrazineby the intro-duction

of the salicylresidue into a-phenylmethylhydrazine

202 PYRAZOLON DERIVATIVES

(whichis somewhat less toxic than the unsubstituted base),bymeans of salicylaldehyde,result in the formation of the hydrazone

C6H5 .

N^^-N : CH.C6H4 .

OH

known as Agathin, a tasteless,odourless body insoluble in water.

But this substance shows its antineuralgicaction onlyin doses of

4-6 gms. (3i~3iss),a fact which bears out the generalobservation

that salicylderivatives of this type are onlydecomposedwith such

difficultyby the organismthat they are unsuitable as antipyreticsand antineuralgics.It may produceviolent headache.1

It will be seen from the above that it has not been found possibleto eliminate the powerfulaction which phenylhydrazinehas on the

red blood corpuscles,and it does not seem likelythat any of the

methods described can be so modified as to yieldsubstances of the

slightestpharmacologicalvalue.

III. PYRAZOLON DERIVATIVES OF THE

TYPE OF ANTIPYRINE.

1. Phenyl-3-methylpyrazolon,the firstderivative of this group,

was obtained by Knorr, in 1883,throughthe interaction of phenyl-hydrazineand acetoacetic ester. The formation of pyrazolonis a

generalone, and other /3-ketonicacid esters react in a similar manner.

As the formation of antipyrinewill be easier to follow if the

enolic formula 2 for acetoacetic ester is employed,

CH3.C(OH) = CH.COOC2H5,

this explanationof the reaction will be adoptedalthoughits

accuracy is perhapsquestionable.The first phase of the reaction consists in the formation of a

hydrazone"

i. CH3 CH3

C.JOH+HJNH" NHC6H5 c" NH" NHC6H5

COOC2H5 COOC2H5

1 Pharm. Journ., vol. xxiii,p. 86.

2 Acetoacetic ester reacts under certain conditions as if its constitution

were expressedby the formula CH3 .CO.CH2

. COOC2H6 ; under others, by

the formula CH3 . C(OH) : CH.COOC2H5. Such a substance istermed ' Tauto-

meric ' and the firstis called the * Keto ' and the second the ' Enol ' form.


204 PHYSIOLOGICAL PROPERTIES OF ANTIPYRINE

Many modifications of this synthesishave been made since its

discovery,and will be found in the largertextbooks on organicchemistry.

Physiological Properties of Antipyrine and its derivatives.

It is interestingto note that the characteristicantipyrinepro-perties

are entirelyabsent in l-phenyl-3-methylpyrazolon,

CH"

CO-N.C6H6,

and it is onlywhen the imido hydrogenatom isreplacedby methyl,that these appear : -

CH3

N.CH3IICH

io_:'6AJ-5 *

With Antipyrine (Phenazone)the paralysingaction on the motor

centres in the mid brain is not well marked. It is not narcotic,but

in largedoses it producesdestruction of haemoglobin,collapse,and

convulsions. The latter are well marked in frogswith doses of

from 50-60 mgm. It has the greatadvantageof easy solubilityin

water. Its antipyreticaction is not due to any influence on the

oxygen capacityof the blood. Sweating,as acceleratingheat-loss,also has but a small share,for the fall of temperatureproducedby

antipyrineoccurs when sweatinghas been preventedby belladonna.

It does not act,however,when the higherpartsof the brain are cut

off by section throughthe cord or throughthe crus cerebri. In

fever experimentallyproducedby damage to the corpus striatum

antipyrineproducesa fall of temperature.Most probablythis effectis due to the dilatation of the cutaneous

vessels and a consequentincrease of heat-loss.

In some animals (includingman) the thermotaxic centre is so

stimulated by this process that heat productionis forthwith in-creased

as a compensatorymeasure. In man, also,there is a decrease

in the respiratoryactivity.

ANTIPYRINE DERIVATIVES 205

Nitrogenousmetabolism,which is practicallyuninfluenced in

health,is decreased in pyrexialconditions when this drug is ad-ministered.

This is not a direct action,but is dependentmerelyonthe antipyreticeffect of the drug,which cannot influence the

increased nitrogenwaste due to toxic processes.

As an analgesic,it is largelyused,and the number of cases in

which bad by-effectshave occurred does not appear to be great.When firstintroduced,Se"e gave 15 grainsevery hour up to 50

or 100 grains,but it is not now givenin these largedoses. In

cases in which unpleasantsymptoms (collapse,oedema,rashes,"c.)have appeared,these have not alwaysbeen the result of largedoses.Guttmann reportsa case in which a man took 15 grainsof anti-

pyrinein fivedays,which produceda condition closelyresemblingcholera,except that diarrhoea was not present,and there was a

duskyrash on the abdomen.

Antipyrineis found in the urine to some extent unchanged,but

chieflyas a glycuronicacid derivative;most probablyoxidation,with the formation of oxyantipyrine,precedesthis synthesis.

When j"-tolylhydrazine

is employed in the pyrazolonsynthesis,instead of the phenylderivative,Tolylpyrine

CH3

-N.CH3

CH

CO" N,r.C6H4.CH3is obtained. It is more irritatingthan antipyrine,and affects

the circulationunfavourably,while its analgesicaction is not so

pronounced.The salicylicacid saltsof both antipyrineand tolylpyrinehave been

introduced under the names of Salipyrine and Tolysal. These are

obtained by meltingtogetherthe constituents on the water bath ;the resultingderivativescontain a free carboxylgroup, and from

them a series of salts may be obtained. They are readilydecom-posed

into their constituents by hydrochloricacid,and their

1 Pharm. Journ.,vol. xxiii.p. 605.

206 ANTIPYRINE DERIVATIVES

physiologicalreaction correspondsto that of a mixture of anti-

pyrineand salicylicacid.Several derivatives of this type have been introduced into

pharmacology,for example:"Tussol is the mandelic acid (C6H6CH.OH.COOH) salt of anti-

pyrine.It has been givenas a remedy for whooping cough in

doses of 15-30 cgms. per diem for children under one year, and more

proportionatelyto age for older children. There is no evidence

that it is superiorto antipyrine,which is well toleratedby children.

Hypnal, or Hypnol, is a compound of chloralhydrateand anti-

pyrine.It is said to be more soporificand to have less action on

the circulation than chloral,but its generaltoxicityis higher.Bichloral-antipyrineis still more toxic,and has no advantagesover chloral or hypnal.1

Anilopyrine (Acetanilideand antipyrine)is a soluble white

powder,but apparentlyhas no particularadvantageover a mixture

of the two bodies which has longbeen a favourite prescriptionfor

neuralgiaand headaches of various sorts.

Bodies of this type,owing to the ease with which they are

decomposed,can onlyact as mixtures,and it is consequentlyfruit-less

to search for substances with new physiologicalreactions

amongst derivatives of such a nature.

Fyramidon, or 4-dimethylamido-antipyrine,is the only anti-pyrine

derivative which has provedof value. It is obtained by the

followingreactions :"

1. When nitrous acid acts on a solution of antipyrinehydro-chloride,nitroso-antipyrineis obtained "

CH3 CH3

H

A-K+ HN09 =

C N.CEU C N.CH3

NO" Ci

CO" N.C.H. C(JO-N.C.H,2. This on reduction givesamido antipyrine,

GEL

NH2" C

.CH3

CO-N.C6H61 Pharm. Journ.,vol. xxi,p. 161.


which is isolated by means of its benzylidenederivative,and on

methylationgivesPyramidon "

CH3

C N.CH,

*

(CH3)2N.C

CO" N.V V

Pyramidonis a solid which dissolvesin water,givingan alkaline

solution,and is a more powerfulbase than antipyrine.The dose is

about one-third that usuallygivenin the case of the latter drug.It has no irritant effect on the stomach,and may also be prescribedin nephritisand heart disease,as its effect on the circulation is

but slight.It is not a blood poison.It has been used on the

continent both as an antipyreticand an analgesic,but in this

country its use is mainly as a drug of the latter class. It is

excreted in the urine partlyunchanged,partlyas glycuronicacid,and partlyas uramino-antipyrine"

CHQ

NH,.CO.NH" C

N.CH3

-N.C6H5After the exhibitionof pyramidona derivativeoccasionallyappears

in the urine which,on standing,becomes oxidized and producesthered colouringmatter,rubazonic acid.

It has been suggestedthat pyramidonshould not be giventodiabetics,as, contraryto the generalrun of antipyrinederivatives,it

increasesnitrogenousmetabolism.

GENERAL SUMMARY OF THE PHYSIOLOGICAL

CHARACTERISTICS OF THE AMMONIA DERIVATIVES.

The three substances,antifebrin,phenacetin,and antipyrine(phenazone)may be taken as representativeof the entire seriesof

syntheticantipyreticswhich have justbeen described. They are

not onlychemicallyrepresentativebodies,but therapeuticallytheyare probablymore valuable than all the other members of the

classes to which theybelongput together.From the pharmaco-logicalpointof view theymay be considered as true antipyretics;

208 PHYSIOLOGICAL PROPERTIES

that is to say, they so influence the thermotaxic centre that it

causes a generalcutaneous vaso-dilatation to take placeduringpyrexia,thus producingincreased heat-lossand a fallin temperature.That they are not mere generalvaso-dilatorsis shown by the fact

that the deepvesselsare not affected. This,a centralaction,is very

different physiologicallyfrom the effectproducedby the external

applicationof cold,when heat-loss is increased,but the thermo-taxic

centre is uninfluenced. In health,the thermotaxic centre

maintains a certain fairlyconstant ratio between heat-productionand heat-loss ; in pyrexiathis ratio is altered,and increased heat-

productiondoes not lead to a sufficientincrease in heat-loss;the

true antipyreticsso influence or sensitize the thermotaxic centre

that the ratio tends to return to normal. This may or may not be

a valuable measure therapeutically; at presentthe tendencyis to

consider it disadvantageousto reduce the temperature in this way,

and the antipyreticdrugsare mainlyused for other purposes.

The antipyreticaction is a function of the benzene nucleus,for

it is shared by such varied derivatives as phenol,pyrocatechin,

salicylacid,aniline and its derivatives,phenylhydrazine,and the

ajomatic semi-carbazides R.NH.NH.CO.NH2. Phenyl-azo-imide,

also acts as an antipyreticand analgesicin mammals. Moreover,

other ringformations,such as pyridineand quinoline,have the same

physiologicalaction.

On the other hand,allringcompoundsare not active antipyretics.The ethylester of a-naphthylazoacetoaceticacid,

P TT "M " "NT PTT010H7JN *

a-acetone-naphthalideand phenanthren,are examplesof inactive

substances with ringstructures.The side-chains in the above-mentioned compoundsvary so much

that it is clear that no importancecan be attached to them as anti-pyretic

agents. Their function is possiblyto enable the molecule to

anchor itselfto the cells in the central nervous system,and for this

purpose the basic chains are more suitablethan the acid. Aniline is

a more powerfulantipyreticthan phenol,but less powerfulthan

phenylhydrazine; the latter owes its physiologicalactivitypartlyto its chemical instability.

The second therapeuticaction of these bodies,which, as has

OF AMMONIA DERIVATIVES 209

previouslybeen noted is at presentthe most generallyemployed,isthe analgesicand slightlyhypnoticpowers which they possess.

This is not solelydue to the benzene ring,but is apparentlytheresult of two factors,eitherjointlyor separately.One factor is the

presence of the ketonic group, such as CH3 .CO.NH.R. Ethyl-

ketone,acetophenone,and other ketones are hypnotics.The second

factor is the ethoxygroup, which apparentlyaccounts for the

hypnoticeffectin some of the jo-amino-phenolderivatives,whilst in

lactopheninand some other bodies both these factors are united.

The two main groups may now be considered in detail,as they

presentdifferentpointsof interestcorrespondingto their chemical

structure.

The group of which antipyrineand pyramidonare typesowes its

antipyreticpropertiesto the ring formation,which contains a

nitrogenelement. The monomethylpyrazolon

CH3

C NH

H

CO" N.-C6H5

is not antipyretic;in antipyrineitselfthe second methylgroupreplacingthe hydrogenof the imido radical apparentlythereforeacts as an anchoringgroup.

The phenylradical apparentlyintensifiesthe action ; some anti-pyretic

effect can be obtained without it; in view,however,of the

known antipyreticeffectof benzene,the pyrazolonringmight be

regarded as intensifyingthis by the substitution of one of the

hydrogenatoms. The introduction of the basic group (inpyra-midon)increases the reaction. w0-Pyrazolonderivatives are toxic,but not antipyretic.

The anilineand /?0ra-amino-phenolderivatives can be considered

together,as the action dependson the liberationof the latterin the

organism.Acetyl-^-amino-acetophenone,

p w /COCH3^^XNHCOCH,,

has no antipyreticaction,because the para group, COCH^ preventsthe formation of C6H4OH.NH2. These bodies may be regardedasdesignedto producea slow and gradualaniline or jt?-amino-phenol


reaction; theyare, as it were, methods ofdosage.This beingso, itis

obvious that those compoundsfrom which the parent substance is

slowlyevolved will be little toxic and also less efficientas anti-pyretics,

whereas the powerfulantipyreticswillalwaysbe dangerousin practice.

The toxic propertiesof these substances may be specifiedas(1)a generalaction on the central nervous system,and (2)a specialaction on the blood (disintegrationof the red cells and formation

of methaemoglobin).The generaltoxic action is practicallythe

same for aniline and phenol,and differs in degreeonlyowing to the

fact that primary amines are more active physiologicallythan

alcohols. There is,however,no generalagreement in the relative

toxicityof the two series of compounds,though as a generalrule

those which contain but one side-chain are the most toxic. The

lengthof the side-chains also has a certain influence,

The followingtable is givenby Frankel :"

The action as blood poisonsis dependenton the presence of the

basic group ; hence phenylhydrazineis more active than aniline in

this respect;ammonia and, still more, hydroxylamineand hydra-zine producethe same effect. The substitution of the two hydrogenatoms of the base does not necessarilymodifythis action.

Exalgin,

.W"CO"IL.



out physiological action; the substitution o" the hydrogen of the

hydroxyl group by an aliphatic acid produces too unstablea com-pound,

with toxic action. If the second hydrogen atom of the basic

residue in phenacetin is replaced by an alkyl group anarcosis

similar to that produced by alcoholoccurs; an

acidgroup

in

this place isso easily detached that it has

no physiological

importance.

Compounds derived from ortho-or wtfta-phenetidin are too toxic

for practical purposes.

CHAPTEE XI

I. THE GROUP or URETHANES, UREA AND UREIDES. " Urethane.

Hedonal. Hypnotics derived from Urea. Thio-urea. Thiosinamine.

Veronal hypnotics.

II. THE PURINE GROUP AND PILOCARFINE." Diuretics and Cardiac

tonics. Modification of substances of Xanthine type. Diaphoretics. Pilo-

carpine.

I. THE GROUP OF URETHANES, UREA, AND THE

UREIDES.

CARBONIC acid forms amides, which are in all respectsanalogous

to those of a dibasic acid,thus-"

yOTT x"WH" /~N"TTr*c\/ C*C\s 2 C*C\s 2

"\OH J\OH \OC2H{

Carbonic acid. Carbamic acid. Urethane. Urea.

A. Carbamic acid is unknown in the free state,but its ammonium

salt,

C(.ONH4,

is present in commercial ammonium carbonate. This substance is

toxic,probably owing to its very labile character,and produces

symptoms similar to those caused by ammonia. But its esters,the

urethanes, are much more stable and consequentlyless toxic ; they

possess, moreover, hypnotic propertiesdepending upon the nature

of the organicradical replacingthe hydroxylhydrogen.

A. The Urethanes.

The urethanes are obtained by the action of ammonia or the

substituted ammonias, on the esters of chlor-carbonic acid1 :

Phenyl urethane,

or Euphorin.

1 This method of introducing the (COOC2H6) radical into basic or other sub-stances,

with the resulting depression of toxicity,is one often employed

(p. 130).

214 THE URETHANES

and by the action of heat on a mixture of urea nitrate and the

correspondingalcohol,

Methyl-propyl-carbinol. Methy-propyl-c'inol-ure thane. Hedonal.


Binet has found that the physiologicalreactivityof these deriva-tives

increases accordingto the magnitudeof the alcohol radical.

The introduction of the acetylgroup lowers the toxicitywithout

otherwise alteringthe physiologicalaction. In the case of warm-blooded

animals, the relative toxicityof these substances is as

follows :"

H.COCH3 when R = CH3 1

O.R"

R = C2H5 1-5

pn /NH2 when X = CH3 ...2

LU\O.X"

X = C2H5 . .

4

in spiteof the presence of an amido group, has no depressanteffect

on the respiratorycentre ; on the contrary,it has some stimulant

action,but onlyin doses which exceed those giventherapeutically.It has no action on blood pressure or on the pulserate,and is

markedly diuretic,like all the urea derivatives. Its hypnoticaction israpid,but not sufficientlypowerfulfor use in cases where

there is any pain or distress. Even in largedoses it does not

appear in the urine,but is apparentlyconverted into urea. Small

doses are said to decrease nitrogenousmetabolism,whereas largedoses have a contraryeffect.

Di-urethane,NH(COOC2H5)2, is a more powerfulnarcotic,owingto the presence of a second alkylradical.

acts similarlyto urethane,beingnarcotic and powerfullydiuretic.The dose is double that of chloral. It has been employedas

a preliminaryto generalanaesthesia with chloroform ; its absorp-tionis slow,and it must be given at least an hour before the

DERIVATIVES OF UREA 215

anaesthetic. There are, however, other more serious objectionsto

its practicalemployment in this manner.

B. Urea and its Derivatives.

Urea,nn/NH2

was firstsynthesizedbyWohler in 1828 from ammonium w0-cyanate,which undergoesan intra-molecular transpositionon the evaporationof its aqueous solution

"

CO:N.NH4 -"

It is found in various animal fluids,chieflyin the urine of mammals,and may be separatedas the somewhat insoluble nitrate.

It may also be preparedby the followingsyntheticprocesses :"

Urethane.

2.

Diethyl-carbonate.

3. COôcH + 3NH3 =

Chlorformic ester.

Urea crystallizesin longneedles,or rhombic prisms,which have

a coolingtaste. It is soluble in 1 part cold water, 5 of alcohol,but almost insoluble in ether. It is decomposedby nitrous acid,asare allsubstances containingthe amido group.

The Alkyl Ureas may be preparedby reactions similar to those

employedin the case of urea itself,

1. Mono-alkylureas.

Urethane. Ethyl-amine. Ethyl urea.

2. Di-alkylureas.A. Unsymmetrical.

Diethyl-amine. a-Diethylurea.


B. Symmetrical.

-

ro/^^Q^s4. P TT OTT

. û"^NHC2H5+L2H6oidS. Diethylurea.

Chlorformic ester.

3. Tetra-alkylurea.

Tetra-ethylurea.

The alkylureas are crystallinesubstances,with the exceptionof

the tetra substitution derivatives,and show the same characteristic

reactions and propertiesas urea itself,and,like it,form salts with

one equivalentof acid.


Urea has but slighttoxic propertiesfor animals or higherplants.It has no action at all on the lower plants.Its chief effect in the

animal body is to producediuresis,and it also has a very slightnarcotic action. Toxic doses (injectionsof Tj^ the total body-weight in rabbits)producespasms and opisthotonos.Ammoniais not set free in the blood.

When the hydrogenof the amido group is replaced,it is found

that the simplealkylureas have no narcotic action;with those

containingtertiaryalkyl groups the generalcharacteristic is

observed (seep. 92),viz.that a tertiarysystem containingmethylgroups, such as

/CH3" C^-CH,

\CH3is less reactive than those containingethyl,such as

/C2H6 /C2H5" C^-CH3 tertiarybutylor tertiaryheptyl," C"-C2H6

\CH3 \C2H6

(a) CO^5 3-4 gms. without action.

3 gms. producedrowsiness,but no sleep.(b) COrVr^ Vv* Inactive ethylaminebases are apparentlyset

25 free in the body.

OP UREA DERIVATIVES 217

producesleep-

NH2This is more active than amylene hy-

r/"3 drate as a hypnotic; but sleepoccurs

(d) CCK \CH later,"winl?tothefactthattllisderiva-^ 2 6 tive,which is not easilysoluble,takes

longerto decompose.

passes into the urine

(e) C0" \C H^changed. It is very stable,

_

rvQjj2\ 5

Q uand has no physiologicalaction.

1 gm. producessleepafter 2 hours,

Precede(ity a Periodof intoxication.

Urea Derivative containing Bromine.

The a-monobronW*0-valerylurea has been introduced by Saam

under the name of Bromnral "

\NH.CO.CHBr.CH.(CH3)2.

It is not easilysoluble in .cold,but dissolves readilyin hot water,

ether,alcohol,and weak alkalies;Saam thinks that the narcotic

action of this drug depends upon three factors. The main hypnoticis the M0-propylradical in the valerianic acid,but its action is

intensified,firstlyby the presence of the urea grouping, and

secondlyby the bromine atom. The correspondingchlorine com-pound

is but slightlyhypnotic,the iodine compound is inactive.

The lethal dose for rabbits beginsat 1 gm. per kilo, body-weight;in dogs, "5 gm. per kilo, produced toxic effects,mainly on the

respiration,while larger doses produced death from respiratoryfailure,the heart remaining unaffected. The hypnotic action is

mild,and is interfered with by the presence of pain,cough,or active

delirium.

218 SULPHUR DERIVATIVES OF UREA

Sulphur Derivatives of Urea.

Thio-urea or sulphocarbamine,NH

is obtained by heatingammonium thio-cyanateto 170"-180" C.

/NT ITpa .

AT XTTT~ P^5/ X

2S, N.NH4 ^NH*

Many of its reactions indicate a constitution expressedby the

formula "

HN."

It causes slowingof the pulseand respiration,and bringsabout

generalparalysisof central origin,cardiac failure,and death in

convulsions.

Allyl-thio-urea (

Phenyl-thio-ureaC

Ethyl.thio.ureaCS^fa

Acetyl-thio-ureaC

are activelytoxic,as are also compounds in which both ammo

groups are substituted with different radicals,e.g.

AH i t i j-t.'r\o/^ HC-Jtlo

*

Allyl-phenyl-thio-urea vN"HC H

Methyl-ethyl-thio-urea

The symmetricalcompounds,however, like urea itself,and

dimethylor diphenylurea have only very slightphysiologicalaction.

Of these bodies,allyl-thio-urea,or Thiosinamine, is the onlyone of pharmacologicalimportance.In toxic doses it producesnarcosis,death occurringwith oedema of the lungsand hydrothorax.

Very small doses excite the central nervous system,largerdoses

depressit. Thiosinamine appears to have a characteristicaction

on organizedscar tissue. When injectedsubcutaneouslyit causes

absorptionand softeningof cicatricialbands and adhesions. This

action,however,does not appear to be constant.


220 UREIDES

and the correspondingdipropyl-malonyl-urea"

NH" CO

XN H" CO

They state that of the series investigatedfthe three mentioned

stand out prominently in point of hypnotic action. . .

and

experiments have shown that diethyl-acetyl-ureais about equal in

hypnotic power to sulphonal,that dipropyl-malonyl-ureais about

four times as powerful, but not infrequentlyhas a remarkably pro-longed

after-effect. Diethyl-malonyl-urea stands midway between

these two, and hence surpasses in intensityof action all the hitherto

employed hypnotics. Inasmuch as it has advantages with regard

to taste and solubility,it would appear to be the most valuable of

these new derivatives for therapeuticpurposes/This substance,which goes by the name of Veronal, is stated to

be a prompt hypnotic,and it may be mentioned that the effective

dose of veronal costs less than that of Trional, or any other hypnotic

excepting chloral hydrate.Veronal may be obtained by the condensation of diethylmalonic

acid with urea in presence of sodium ethylate,

sHINEL

CO;OC2H6 HiNH

Veronal is also a diuretic,but it has no irritant action on the

kidneys. It does not influence the blood pressure or depress the

heart. It has no action on the gastro-intestinalmucosa. It is said

to dimmish nitrogenous metabolism. The toxicityis low, 9 gms.

(135 grains) having been taken in a singledose without serious

results; "/ gm. per kilogram body-weight can be given to animals

before a direct toxic action occurs.

PURINE AND ITS DERIVATIVES 221

II. THE PURINE GROUP.

The compoundsof this group are allderived from the substance

purine"N=CH

C" NHCH

This complexis found in a largenumber of the productsof animal

and plantlife,namely,uric acid,xanthine,guanine,theobromine

(foundin cocoa beans),caffeine,"c.Their nomenclature isbased on the scheme

6

1 N " C

1 I 7

2C 5C" NvLi /C8

3 N" 6" N/4 9

thus : NH" CO CH3 .N" CO

60 C" NHV CO C" N"

"CO

XJH,

[__C" NH' CH3.N" C" N'

Uric acid or Caffeine or

2:6: 8-triketo-purine. 1:3:7-trimethyl-2:6-diketo-purine,

NH" CO

CH3

CO

i-LN"Theobromine or

8 :7-dimethyl-2:6-diketo-purine.

The systematicinvestigationof this group was carried out byEmil Fischer and his students,and the followingsynthesisof uric

acid will givesome idea of the generalmethod adopted.1. Malonic acid condenses with urea in presence of phosphorus

oxychlorideto givemalonyl-urea,or barbituric acid,

NHjH OHiCO NH" CO

CO +. CH2 = CO CH2+2H20

NH;H OHiCO NH" CO

222 SYNTHESIS OF URIC ACID

2. Malonyl-ureais converted into an wo-nitroso derivative bymeans of nitrous acid"

NH" CO

CO C : N.OH

NH" CO

3. Reduced with hydriodicacid this substance givesthe corre-sponding

amido derivative

NH" CO

CO CH,NH2

NH" CO

4. This amido-barbituric acid givespseudo-uricacid on treatment

with potassiumcyanate"

NH" CO NH" CO

CO CH.NH2 + CO:NH = CO CH" NHCO" NH2

NH" CO NH" CO

5. Pseudo-uric acid treated with dilute mineral acids loses water

and givesuric acid "

NH" CO NH" CO

CO C" NH CO = CO C" NHVI II ! I II "co+H2o

NH" C" JOH HjNH NH" C" NIT

Purine itselfmay be isolated by the reduction of 2 : 6 : 8-trichlor-

purine,obtained by the action of phosphorusoxychlorideon

potassiumurate "

N=C.OH N=C.C1

I /H ||OH.C C" N"f +POCL = Cl" C C" NH

II II "C.OH || ||N-C" W N" C "

N=CH

on reduction -" CH C " NHv

II II "C.HN_c W

SYNTHESIS OF THEOPHYLLINE 223

Theophylline, which Kossel found in tea,may be synthesized

from dimethyl-ureain a manner very similar to the above: "

1. CH3" N;H OHjCO CH3-N" CO

CO + CH2 = 2H20+ COCH2

CH3 .NjH OHiCO CH3" N" CO

2. CH3-N-CO CH3.N" CO

CO CH2 + HN02 = CO C : N.OH + H2O

CH3.N" CO CH3.N" CO

3. CH3" N" CO CH3" N" CO

COC:N.OH + 4H -" CO CHNH2

CH3 .N-CO CH3" N" CO

This derivative CH3" N" CO

acted upon with

CO:NH = CO CH" NH" CO" NH2

CH3 " N" CO

l:3-dimethyl-pseudo-uricacid.

4. CH8" N" CO CH8.N" CO

CO C" NH " CO = H20+ CO C" NH

"N" C.|OH HNH CH.N"C"

q " JL 1 V-/ XN XI

1 :3-Dimethyluric acid,or1 :3-Dimethyl-2:6 :9-triketo-

purine.

5. When thisuric acid derivativeis treated with chloride of phos-phorus,and the resultingsubstance reduced,theophyllineis formed.

CH3" N" CO CH3" N" CO

CO C" NHv P5"ls CO C" NH

CH8 .N" C" NH CH3

CH" N" CO

reduced

x"CO I || "CC1' CH" N-(

.NH

I IICH3

Theophylline,or

1 :3-dimethyl-2:6-diketo-purine.

^\J V^.l"XJ.v

I II "H.N"C

.

N^

224 PILOCARPINE

Pilocarpine has been introduced into this group, althoughit doesnot contain the purinecomplex. Like theobromine,theophylline,and caffeine,it contains a glyoxalinring. Jaborandi leaves contain

three alkaloids,pilocarpine,pilocarpidineand jaborine,and the

most recent researches pointthe followingconstitutional formula

for the firstsubstance :"

C2H6" CH" CH-CH2 CH

the presence of the glyoxalinring being shown by the many

relationshipspilocarpinebears to the methylglyoxalinderivatives.

Physiological Reactions of Purine Derivatives.

Purine itself

N=CH

HC C" NH

H

acts on the cerebrum like the ammonium salts,and has a tendencyto produceconvulsions. It also producesrigidityof the muscles.

These actions it transmits to its derivatives,caffeine and theo-

bromine.

A. Oxy-derivatives.

6-Oxy-purineNH" CO

CH C" NHV

JUL_N"CH(Hy poxanthine, Sarcine),has a power of producingtetanic spasms,but no rigidity;in dogs,it is said to be largelyoxidized into

allantoine,HN" CH" NH

oi CO

"CO NH,

OXY-PURINE DERIVATIVES 225

This substance,however, is stated by Baldi to increase the

excitabilityof the spinalcord,and to producemuscular rigidityin frogs.Walker Hall injectedrabbits dailyfor two months with

small doses,and found degenerativechangesin the liver cells and

alterations in the bone marrow.

In man, hypoxanthineis excreted mainlyas uric acid. It is said

to act in about six hours,producingincreased reflex irritabilityand spontaneous spasms, and then generaltonic contractions.

50-100 mgms. constitute a fatal dose for dogs.

8-Oxypurineproducesno tetanus,but only muscular rigidity.Its action is but feeble.

B. Alkyl and Oxyalkyl Derivatives.

To pass on to the correspondingmethyl derivatives,7-methyl-

purineacts more powerfullyon the muscles than purine,but is

nevertheless a weak poison. 1 gram subcutaneouslyhas no action

on dogs.1 : 7-Dimethyl-6-oxypurineis a tetanizingagent,and also pro-duces

rigidityin frogs,but acts less powerfullythan caffeine.

7 :9-Dimethyl-8-oxypurineproducesboth muscular rigidityandtonic convulsions similarlyto the previouscompound, and the

differences between the two monoxypurines,from which they are

derived,are probablydue merelyto differencesin rate of absorption.

C. Dioxy Derivatives.

6 :8-Dioxypurineis too insoluble to have any marked action,but is said to have some action on the central nervous system.

Xanthine, 2 : 6-dioxy-purine,

HN" CO

OC C" NHV

U\r"TiJ"^riW

has no marked diuretic action,but may producehaematuria. It

has the same action on muscle and spinalcord as 8-oxypurine.

D. Dioxy-alkyl Derivatives.

The two monomethyl-xanthinesact similarlyto caffeine and

theobromine,both on the muscles and on the nervous system,but

are more powerfultonic convulsants.

226 XANTHINE DERIVATIVES

Heteroxanthine (7-methyl-xanthine)has more paralysingaction

on the cord than 3-methyl-xanthine,and isgenerallymore powerful,

though it does not raise the reflex excitabilityso much. The

3-methyl-xanthineis a diuretic for dogs.Theobr online, 3 7-dimethyl-2: 6-dioxypurine,

HN" CO CH3

OC C" N\I II "CH,

H3C.N" C" W

is a very powerfuldiuretic. Its action on the activityand

irritabilityof muscle resembles that of caffeine,but it has no vaso-constrictor

action. In toxic doses itproducesmore rigidity,but not

such severe convulsions as caffeine. Like xanthine,it has a direct

coagulatingaction on muscular protoplasm,but unlike xanthine

it has no action on the heart.

Theophyllin (1: 3-dimethyl-2: 6-dioxypurin),known also by its

trade name Theocine,

3

CO C"

CH3N" CO

-NH

||CH3.N" C-

is a more powerfuldiuretic;it has no action on the heart or central

nervous system,but acts more markedlyon muscle than theobro-

mine. Its diuretic effect is said not to last so long as that of

theobromine. In two cases it producedgastrichaemorrhageanddeath ; this was also observed experimentallyin animals.

Paraxanthine (1:7-dimethyl-2:6-dioxypurine),

CH3" N

has a yet more powerfuldiuretic action,and also producesmoremuscular rigidityand paralysisthan either of the other two

dimethyldioxypurines.


223 XANTHINE DERIVATIVES

1:3: 9-Trimethyl-xanthine,

CH3 .N" CO

CO C-N,

I II "CH,CH3.N" C" W

CH3is much less active than caffeine; it producesthe same muscular

rigidity,but more paralysisand lessconvulsions.

l:3:7:"-Tetramethyl-xanthineis very similar in its action to

caffeine.

Two methyl compounds of the insoluble 6 :8-dioxypurineareknown, namely i$0-caffeme or l:7:9-trimethyl-6:8-dioxypurine,which has a much slighteraction than caffeine,and 7 :8-dimethyl-6:8-dioxypurihe,which acts very slightlyalso,in a similar manner

to theophylline.

E. Trioxy Derivatives.

The next oxypurineis 2 :.6:8-trioxypurine,or uric acid, which is

inactive. But 1 :3 :7 :9-tetra-methyluric acid isactive,and producesmuscular rigidity,paralysis,and tetanic convulsions.

MODIFICATIONS OF SUBSTANCES OF XANTHINE

TYPE.

Theobromine is a powerfuldiuretic,but its practicalvalue is

much diminished by the fact that it is onlyabsorbed with difficulty.The formation of double salts which are easilysoluble is achieved

by means of the combination of this purinebase with an alkali,thus :"

Dinretin is a compound of sodium theobromine with sodium

salicylatecontaining50 per cent, theobromine. The salicylatetakes

no partin the physiologicaleffect.

Uropherin is a similar compound,lithium beingsubstituted for

sodium. This may possiblymake the absorptionsomewhat more

rapid,but otherwise has no advantage,as lithium is not inert and

might even produceundesirable by-effects.

Aguriii is sodium theobromine combined with sodium acetate.

Theobromine salicylate is an acid salt,and is also soluble

in water.

XANTHINE DERIVATIVES 229

Tlieocine sodium acetate is said to be somewhat safer than

theocine,which has occasionallyproducedseriousby-effects.It is

a very powerfuldiuretic.The attempts to producecaffeine derivatives of practicalvalue

have not been successful.

Sympherol is a sulphuricacid compoundof caffeine,

CH3, N" CO

CH3Jo.SO2OH.

CH3. N" C" 1

Its salts are easilysoluble,but with the disappearanceof the action

on the central nervous system the diuretic action vanishes also ;

moreover, theyhave a very bitter taste and are not stable.

Chloral and caffeinehave been combined in the hope of neutra-lizing

the stimulatingaction of the latter,but the drugso producedhas no diuretic action and merelybehaves like chloral hydrate.

Ethoxycaffeine,

CH3*-N" CO

CO C" NxI II "C.OC,H5,

CH3.N" C" W

is diuretic,but also narcotic.

Methoxycaffeineis inactive.

Theacyl-amino-caffeinesaresaid to be powerfuldiureticswithout

any action on the central nervous system.

GENERAL REVIEW OF PURINE DERIVATIVES.

The introduction of methyl groups increases both the diuretic

effect of the purinesand also their action on voluntarymuscle,whereas it decreases the action on the central nervous system and

the generaltoxic effect. The introduction of oxygen alters the

relativeintensityof the various actions,but in no regularmanner.The influence of a CO group seems to vary accordingas it is

placedbetween NCH3 or NH groups. As a generalrule itproducesa reduction in toxicity,but on the other hand guanineis less toxic

than xanthine,thoughcontainingone CO group less"

230 REVIEW OF PURINE DERIVATIVES

HN" CO

H2N.C C" NHv

|| || ^CH (Guanine)N" C W

The introduction of a hydroxylgroup into the caffeine molecule

reduces it to a physiologicallyinactive body,probablyowing to the

fact that it is thus converted into a substance which is easilydecomposed in the organism. The formation of an ether with

methyl or ethylproducesa compound which at firstgivesriseto no

symptoms exceptthose of a generalintoxication. Subsequently,

however, a rigidityresemblingthat producedby caffeine occurs.

The action on the blood pressure is less marked than that of caffeine,but does not differ from it in quality.Medium doses in man are

distinctlynarcotic,but diuresisonlyoccurs with fatal doses.

Caffeine-methyl-hydroxide,which is practicallynon-toxic,

CH3.N-" CO

i CH3

CH3.uu

/\CH3OH

has no diuretic action,nor has caffeidine,

CH3NH" CO

i-i|| "CH

[_C_NCH3NH-

a decompositionproductof caffeine,though this in largedoses

producesmuscular rigidityand paralysisof central origin.The diuretic action is,however,not attributable to the largerbut

to the smaller of the two ringsof which the purinebodies are

formed, and the same is true of the action on the muscles and

central nervous system.The pyrimidinecompoundsare derived from a nucleus formulated

thus :"

N=CH

HCH

UH

PILOCARPINE 231

1 :3-dimethyl-4:5-diamino-2 :6-dioxypyrimidine,

CH3.N" CO

OC C" NH2

CH3.N" C" NH2

isinactive until the second (imidazol)ringis formed by linkingthe

two nitrogensystemsby the (CH) group, thus "

when theophyllineresults.

The introduction of chlorine,likethat of hydroxyl,diminishes the

action of caffeine,but the cyanogen group intensifiesit.

PILOCARPINE.

The imidazol or glyoxalinring,

CH-NHv

II "CH,CH W

is common to the purinebodies and to pilocarpine;for which

reason the latterbody is described here.

This alkaloid,CnH16N2O2,giveson oxidation homopilopicacid,a substance representedin allprobabilityby the structuralformula "

C2H6.CH" CH.CH2COOH

CO CH0

YIt is thoughtto act as a haptophoregroup. If the lactone structure

of this derivative is destroyedby means of alkalis,the resultingsubstance,

C2H6 .CH CH2 . CH2COOH

COOH CH2OH

is physiologicallyinert (Marshall).This seems generallytrue of

232 PILOCARPINE

bodies with similar constitution. The alkaloid in all probabilityhas a constitution expressed by the formula

"

CH3

C2H5" CH" CH" CH0C Ns

CO CH0

Y

The part played by the glyoxolin portion in producing the

characteristic effects of pilocarpinehas not been determined.

Filocarpine acts mainly in stimulating the nerve endings to

secreting glands of all kinds. On the vagus fibres to the heart

it acts in exactly the same way as electrical stimulation, through

the 'nerve endings '. It stimulates all unstriped muscle in the same

way, and lastlyit acts on the post-ganglionic nerve fibres of the

oculomotor nerve to the iris,producing myosis. It is thus the

physiologicalantagonist of atropine.

It will thus be seen that,physiologically,pilocarpineacts very

similarlyto muscarine,

and in a less accurate sense it resembles nicotine. Older determina-tions

of the constitution of the alkaloid endeavoured to connect it

with these two bodies, but recent investigationshave shown that

pilocarpinedoes not contain a pyridine nucleus.

Isopilocarpine is isomeric with pilocarpineand acts in the same

way. It is six times weaker in efficient doses and at least twenty

times weaker in large doses (Marshall).

Pilocarpidine, which differs from pilocarpinein possessing one

CH3 group less,is still weaker than pilocarpine.

Jaborine is apparently a condensation product of two molecules

of pilocarpine. It possesses an atropine-likeaction.

CHAPTER XII

THE ALKALOIDS. Chemical and physiological introduction. Method

of classification. General principlesof Alkaloidal action. The Pyridine

group " Coniine, Nicotine, and allied substances.

THE ALKALOIDS.

THE vegetable alkaloids are a group of substances,nearly all

tertiaryamines, which are speciallyabundant in the dicotyledons.It is seldom that one alkaloid only is present,as a rule there are

many, and they generallyoccur combined with the so-called plantacids

" citric,malic,and tannic,althougha considerable number are

found associated with peculiaracids; the quinine alkaloids,for

instance,with quinicacid,the opium group with meconic acid,and the

aconitine with aconitic acid. The discoveryof pyridinein 1846 byAnderson and of quinolinein the previousyear by Runge, togetherwith the elucidation of the constitution of these substances,was the

firstgreat step in the investigationof the alkaloids. Gerhardt had

found in 1842 that strychnine,cinconine,and quinine heated with

potash gave quinoline,whereas nicotine,coniine,brucine,and others

heated with zinc dust gave either pyridineor its homologues. The

alkaloids,then, appear to be derived from pyridineand quinolinein

the same way that the aromatic substances are derived from benzene.

With the exceptionof pilocarpine,caffeine,and theobromine, which

have been described under the purinederivatives,this class of organic

derivatives may be defined as productsof plant life derived from

those two substances or from nuclei closelyrelated to them.

Before discussingthe physiologicalpropertiesof the group, a

short account of the chemistryof these ring complexes will be

given.

I. PYRIDINE AND PIPERIDINE.

Pyridine,C6H6N, and many of its homologues can be obtained

from bone oil,and are also found in coal tar.

Pyridine itself shows great stabilitytowards oxidizingagents,but its homologues behave in a similar manner to those of benzene,

being converted on oxidation into acids which still contain the

pyridinenucleus.

234 SYNTHESIS OF PYRIDINE

As in the case of the aromatic derivatives,this behaviour is

assumed to be due to the presence of a six-membered ringcontain-ing

one nitrogenatom"

CH

'Hor, as it will be written in the

followingpagesCHk X!H

The formation of pyridinefrom pentamethylenediamineby heat-ing

the hydrochloride,and the oxidation of the resultingpiperidineis in agreementwith this conception:"

xCH2.CH2.NH;H1. CH2" ! +HC1

XCH2.CH3.JNH2

2.

One method used in the syntheticformation of pyridinederiva-tives

is due to Hantzch, and consists in the condensation of

/3-ketocompounds (suchas acetoacetic ester)with aldehydesand

ammonia.

An exampleof this condensation is seen in the followingforma-tion

of dihydro-collidine-dicarboxylicester by the interaction of

acetaldehyde,ammonia, and acetoacetic ester "

CH3

CH

A- H20C2H6OOC.CiH HiC.COOCoH;."j;"i H:u.uuuu2"i5 /\

II II_^

CÔOC.G/ ^C.COOC.H

C-H3.G :O.CH"

/^TT p"l Jo C*TI

NOH OH;/ cu3.c\yo.ciisi rr NH

,2 -+ 2H00

""NH"

On oxidation,the dihydroderivative yieldsthe corresponding

pyridinesubstitution product,which on saponificationgivesthe


236 SYNTHESIS OF CCXNIINE

Reducingagents convert pyridineor its derivatives into hexa-

hydro-pyrjdineor piperidine,

CH

CH /\CH2or

HH NH

Piperidinehas an odour of pepper and occurs as a salt of pipericacid in pepper (piperine).

Coniine,a-propyl-piperidine,

H,.CH9.CH,

H

found in hemlock seeds,was the firstalkaloid to be synthesized.Startingfrom pyridine,this was carried out in the followingmanner :"

1. Pyridineacted upon by methyliodide givesan iodomethylate,

and when this substance is heated to 300" C. it undergoesan intra-molecular

change,characteristic of this type of derivative,and

givesa-methyl-pyridine,

2. a-Methyl-pyridinecondenses at high temperaturewith par-

aldehyde,forminga-allyl-pyridme"

CH:CH.CH3.+ 0;CH.CH =

3. a-Allyl-pyridineon reduction givesa-propyl-piperidine,but

the resultingsubstance is opticallyinactive,whereas coniine is

dextro-rotatory.When the syntheticsubstance iscrystallizedwith

dextro-t"rtaric acid, atfr0-coniine-tartrateseparatesout first;and

if this is decomposedwith potash,eoniine,identical with the

natural product,is formed.

PYRROL AND ITS DERIVATIVES 237

II. PYRROL AND PYRROLIDINE.

Pyrrol,C4H6N, is a feeblybasic body found in coal tar and

bone oil,containinga four-membered carbon chain united by the

imide group ; its structure is representedby the formula"

CH" CH

II IICH CH

r v "'.;;:On reduction with hydriodicacid and phosphorus,it givestetra-

hydropyrrolor pyrrolidine,CH0" CH2,

CH2 CH,

or

YHH

This substance is a much strongerbase than pyrrol,and may be

obtained from penta-methylene-diamineby heating its hydro-chloride (ina similar manner to piperidine)"

CH2" CH

/CH2CH2.NHiH I ICH2/ " + HC1 = NH4C1 + CH2 CH2

2\CH2.;NH2" \V/NH

From ft-methyl-pyrrolidinea largenumber of different alkaloids

of the atropine-cocainegroup are derived. They are substitution

productsof a combined piperidineand pyrrolidinenucleus "

CH2 CH CH2

PyrrolidineN.CH3 PiperidineCH2

CH2 -CH -CH2

Ecgonine,for instance,which is formed by the action of con-centrated

mineral acids or barytawater,on cocaine,has the follow-ing

constitutional formula :"

CH2" CH CH.COOH

N.CH0 CH.OH

JH CII2

238 SYNTHESIS OF QUINOLINE

III. QUINOLINE.

The quinolinebases occur with pyridinein bone oil,and their

method of synthesisand decompositionall pointto the constitu-tional

formula "

CH CH

or

H

That is,a combination of benzene and pyridinenuclei. This is

well shown, for instance,in its synthesisfrom (A) 0-toluidine and

glyoxal,(B)or the productionof a-methyl-quinolinefrom 0-amido-

benzaldehydeand acetone :"

H:TT /"VOTI /^TTf ^ f

:rl0 \J:U"1 \^JnL

A.

One generalmethod for the formation of quinolineand its

derivatives,substituted in the benzene nucleus,is due to Skraup,and consistsin heatinganiline,glycerin,and sulphuricacid with

some oxidizingagent,such as arsenic acid or nitrobenzene. In all

probabilityacrolein is formed by the dehydrationof glycerin;this combines with aniline,forming acrolein-aniline,which is

then oxidized to quinoline:"

1. CH2OH

CHOH - 2H2O

CH0OH

CH2

= CH

CHO

2. C6H6N[H2"+6jHC.CH: CH2 = H20 + C6H6N : CH.CH : CH2

PROPERTIES OF QUINOLINE

N N

239

The three replaceablehydrogenatoms in the pyridinenucleus of

quinolineare designatedby a, /3,y, those of the benzene nucleus

with 1,2, 3,4.

4 y

a

Another method consistsin numberingthe former Py 1,2,3 and

the latter B 1-4.

4 3

The quinolinebases are liquidspossessinga penetratingodour,and,like the pyridines,are tertiarybases. They are but slightlyattacked by nitric or chromic acids,but are oxidized by potassiumpermanganate to a-#-pyridine-dicarboxylicacids,the benzene

nucleus beingdestroyed:"

On reduction with zinc and hydrochloricacid,the pyridinenucleustakes up four hydrogenatoms, givingtetra-hydro-quinoline,

CH,

or

[H NH

A considerable changein chemical characteristics follows this

reduction,since the resultingsubstance behaves like a secondaryfattyamine attached to an aromatic nucleus.

240 ISO-QUINOLINE

IV. ISO-QUINOLINE.

2*0-Quinoline,C9H7N, is similar to quinoline,with which it is

isomeric;it occurs with it in the crude material obtained from

coal tar. On oxidation it yields/3-y-pyridine-dicarboxylicacid,and

for this reason and others the followingformula has been assignedto it:"

CH COOH

OxidationOOH

On reduction,itgivesa powerfulbase,tetra-hydro-w0-quinoline.

IV (A). QUINAZOLINE DERIVATIVES.

Quinazoline may be regardedas quinoline,in which a (CH) group

is replacedby a second nitrogenatom in the 1 : 3 positionto the

one alreadypresent.N N

CH

H

Quinoline. Quinazoline.

The dihydro derivative of this substance is of interest,and, on

account of its relationshipto quinoline,will be alluded to in this

place,although,as far as is known, the quinazolinenucleus does

not appear in any of the alkaloids.

When o-nitro-benzylchlorideis acted upon by aniline the follow-ing

reaction takes place:"

,N02+ C6H5NH2 = HC1 + C6H4"(

XCH0.H0C1 NHC6H5

The resultingsubstance readilygivesa formylderivative when

acted upon by formic acid.

NO, CHO

H2.N.C6H,

QUINAZOLINE DERIVATIVES 241

On reduction the formyl compound givesphenyl-dihydro-quina-

zoline"

NO CHO' " '

CHiO!"X1 ^-^0 ^~* 1JLV/ I

,H4" I -* C.H/'\CH2-N.C6H5 \

CH2-N.C6H6

N=CH

This derivative o" dihydro-quinazolinewas expectedto possess anti-pyretic

properties,but was found to have only slighttoxic action

and to give rise to a subjectivefeelingof hunger. It was intro-duced

into pharmacy,either as a free base or as the hydrochloride,under the name of Orexine, but owing to the objectionabletaste of

these substances theyhave been replacedby the tannate, a chalky,

white,odourless and tasteless powder,readilysoluble in dilute hydro-chloricacid and hence also in the gastricjuice,but,like the base

itself,insoluble in water.

It is said to aid digestionand to increase the secretion of hydro-chloricacid in the stomach ; it has,however, in some cases proved

too irritatingto the gastricmucosa, and unless well diluted may

producevomiting.

Diphenyl-dihydro-quinazoline

!H2

has no action,whereas the methyl derivative

/Wen,

is a very toxic substance.

242 MORPHOLINE AND PHENANTHRENE

V. MORPHOLINE AND PHENANTHRENE.

A. Knorr designatedas morpholinethe base whose constitutional

formula isrepresentedas follows :"

O

This compound is extremelyinteresting,owing to its relationshipto the opium alkaloids. The objectionsto the old method of

preparationfrom diethanol-amine and sulphuricacid are the diffi-culties

experiencedin obtainingthe amine and also its highprice.

In 1901, however,Marckwald and Chain found that it could be

easilyobtained by the followingreactions :"

. CH2 . OC10H7+ 2KOH

o-Toluene sulpha- Brom-ethyl-j3-naphthylmide. ether.

= C6H4\S02N(CH2. CH2 . OC10H7)2+ 2KBr + 2H2O

2. This derivative is quantitativelydecomposedby mineral acids

into toluene,sulphuricacid,/3-naphthol,and morpholine.

. N(CH2 . CH2 . OC10H7)2+ 3H2O

B. Phenanthrene,C14H10,occurs, togetherwith anthracene,in

coal-tar,and its constitutional formula isrepresentedas follows :"

Owing to its intimate connexion with the opium alkaloids,the

studyof its derivatives has received considerable attention duringthe last few years.

Pschorr and his students have devised new methods for its

synthesis;Werner and Schmidt have investigatedthe sulphonicacids and their decompositionproducts,the nitro and amido com-pounds,

and also the derivatives of phenanthraquinone.


244 CLASSIFICATION OF ALKALOIDS

chemical standpointinto five or six groups, accordingto the

character of the nitrogen-bearingringfrom which theyare derived,and the various members of the different groups exhibit a certain

rough resemblance to each other in their physiologicalaction.The groups, the parentsubstances of which have been previouslydescribed,are :"

I. The Pyridine group, containingconiine,nicotine.II. The Fyrrolidine group, containingcocaine,atropine,

hyoscyamine.III. The Quinoline group, containingquinine,cinchonine,

strychnine,brucine.IV. The /w-Quinolinegroup, containinghydrastine,narcotine,

cotarnine,berberine.V. The Morpholine (?)-Phenanthrenegroup, containingthe

opiumalkaloids,morphine,codeine,thebaine.In the firstgroup are contained substances which act mainlyon

the peripheralnervous system,thoughcentral effects are also to be

obtained.

In the second group certain somewhat specializedactions are

observed,mainly on sensory nerve endings,but here also largedoses have an effect on the central nervous system,especiallythe

highercerebralcentres.The third group contains substances powerfullytoxic for living

protoplasm;they have a certain preferentialaction on the nerve

cellsin the spinalcord,which is more marked in some members of

the group than others;they have very little,if any peripheralaction.

In the fourth group are a number of bodies which do not entirelydifferin their action from those of the third and fifthgroups ; theyhave a central action mainly on the medulla,but to some extent

are also muscle poisons.In the fifth group central action againpredominates,and in man

this action is especiallynoticeable,owing to the high degree of

developmentwhich the cerebral centres attain. The members of

this group have also an action on the cord resemblingthat of some

members of the fourth group.

The productionof a largenumber of artificialalkaloids,differingin various directions from those natural alkaloids the chemical

constitution of which is determined,has thrown considerable light

on various factors in the physiologicalaction of these bodies. Thus

the positionof the substitutinggroups may be altered;their

THE NUCLEUS AND THE SUBSTITUTING GROUPS 245

constitutionvaried in many ways, or theymay be removed altogether.As a rule,the main physiologicalaction of an alkaloid can onlybealtered or destroyedby profoundalterations in the atom-groupswhich constitute the central ringor ' nucleus ' of the molecule. The

functions of the substituents appear to be mostly'haptophore';that is,theyenable the central groups to combine with the proto-plasm

of certaincellsand thus to producetheir proper effect.If theyare removed or so modified as to entirelydestroytheir haptophoric

power, the pharmacologicalaction of the drug will be correspond-inglyaltered. But on replacingor restoringthe haptophoricgroup,

the originalcharacteristicswill return,as the central nucleus has

remained allthe while intact. Thus the phenol-hydroxylgroup in

morphineseems necessary for the manifestation of the narcotic action,forif the hydrogenis replacedby acid or alkylradicals this effect

can no longerbe obtained (p.293); on the other hand, the well-

known physiologicaldifferencesbetween morphineand apomorphineare due to correspondinglyradical changesin the central partof

the molecule (p.301).If the side-chain is extended to a greatextent,the physiological

action of the ringmay be lost,and the effect of the alkylportionofthe molecule become preponderatinglyobvious. An exampleof this

may be found (p.251)in the pyridinecompounds.An example,too, of the effect of alkylsubstituents is well seen

in the a-keto-piperidineseries(or 0-oximes).a-Oxy-a-pipecoline

CH3-C

is more active than piperidon"

CH2

CH/NCH,

/?-methyl-hexanone-w0-oximeis five times as active as the

a compound (experimentson mice).

246 EFFECT OF SUBSTITUTING GROUPS

Trimethyl-heptanone-w0-oxime

CH3 0" " CHn " C-Ho\

I "onxr ntr "VTTJ/

CHS

CHo" CH " NH'

CH

is much more toxic than hexanone-M0-oxime,and acts more power

fullyon the motor nerve endings.The two isomers of methyl-propyl-heptanone-^0-oxime,namely,

0.tL"" vyJtl" C/Hgv CH2 " {-'H " ^"H2\I "CO and I "COCH2" CH" NHX CH2" CH" NHX

C3H7 CH3

act very similarlyto one another,and differ from the parent base

in producingless convulsive effectand more narcosis ; theyare also

more powerfulin the paralyticaction on the motor nerve endings.

Trimethyl-z"0-propyl-piperidon

CH

CH3" CH/\CH2 or CH3" CH/\CH" CH3

CH"" CHV /TO CHA/COTH NH

is ten times as poisonousas piperidon;the alkylgroups suppress

the convulsive action and accentuate the paralyzingaction on the

motor nerve endings,which is not very marked even with fatal

doses of the parentsubstance.

Certain pointsas to the structure of the central ringare also of

importance. If the ring itselfis broken,the physiologicalactionis lost. Examples of this may be seen in 5-amido-valerianic acid,which by the loss of water givespiperidon

CH2 CH

= H2O +

CH

NHiH NH

OPEN AND CLOSED RINGS 247

and "S-y-Amido-butyricacid and a-pyrrolidon,

GEL ,CH2 CH,. jCH2= H20 +

cni colon cu^ycoNHJH NH

The two bodies in which the ringis not closed,are without any

marked action,whereas the closed-ringderivatives formed from

them by loss of the elements of water act like strychnine(or

perhapspicrotoxin).Similarly,pentamethylene-diamine

rH/CH2.CH2.NH2CU2\CH2.CH2.NH2

is not toxic,whereas the closed-chain derivative,piperidine,formed

from itby loss of ammonia (seep. 234),has a definitetoxic action.

Metanicotine,which has onlyone-tenth the toxic power of nicotine,

may also be cited as an example(p.256).The number of groups in the ringinfluences the activityof the

compound,but does not produceany alterationin kind. Piperidine,a six-membered ring,is more toxic than pyrollidinewith five. The

positionof the N atom in the double benzene-pyridineringdoes not

appear to be of importance,thus quinolineand ^0-quinolineare

physiologicallyidentical.

On the other hand, the replacementof a CH group in benzene

by nitrogencauses a marked difference in the action of the

resultingcompound and its derivatives. Thus bases derived from

the benzene ringalone,aniline for example,are characterized bytheir power of reducingthe body temperatureand breakingupthe red blood cells,whereas pyridinehas neither antisepticnor

antipyreticpower. The condensation of a benzene and pyridinering (quinoline)results in powerfullytoxic and antisepticbodies,but the double benzene nuclei,diphenyl,phenanthrene,and naph-thalene,

have no antipyreticderivatives. The condensation of two

ringsof the pyridineseries(dipyridine,parapicoline,"c.)givesriseto bodies resemblingin their action the natural alkaloids,to which

theyare chemicallyrelated.

Some idea of the variations in action which are conditioned bychanges in ring-structuremay be gainedfrom a study of the

artificialringcompounds" the cyclicisoximes,such as piperidon,

248 ISO-OXIMES AND CYCLIC-KETONES

ketones,such as cyclohexanone,and imines,piperidine.The first

all contain the group (CO.NH) in the ring;they are the least

toxic of the three series,and have least paralysingaction on the

motor nerve endingsand the central nervous system. They are

characterized by producingpicrotoxin-likeconvulsions,i.e. convul-sions

dependent on excitation of bulbar and possiblycortical

centres,unaccompaniedby increased reflexirritability.The lower

members of the series are the least active,in the highermembers

the picrotoxineffectsare most marked.

CH,

CH,

CH,

CH

CO

NH

Pyrrolidon.

CH2" CH,

CH2 CH5

CH0 CO

NH

Hexanonisoxim e.

The ketones, CH2

CH/\CH2cnlJCHCH2^CH

more toxic,producemore paralysisof central origin,but no con-vulsions

; the imines are the most toxicof all,and have most action on

the motor nerve endings.In all three series the largerringsarethe more active.

The variation in the selectiveaction of these compounds neces-sarily

impliesvariation in the protoplasmof the differentstructures

in the body on which theyact,a matter which has alreadybeenconsidered (p.19). From this pointof view the alkaloids may be

regardedas a number of keys,each of which will fit into certain

protoplasmiclocks,but it must also be admitted that the locks are

often very bad ones, as in many instances differentlyshapedkeyswill turn them. Thus, in general,chloroform,morphine,quinine,

THE PYRIDINE GROUP 249

and aconitine,lower the body temperature,whilst strychnine,nicotine,picrotoxin,caffeine,and cocaine raise it

" a very miscel-laneous

list from the structural point of view"

and later on

abundant exampleswill be seen under such well-defined actions as

local anaesthesia and mydriasis(p.260).The alkaloids are classedby Loew as specialpoisons,that is,those

which do not in sufficientlystrongdilution invariablydestroyproto-plasm.

They act onlyon certain kinds of protoplasm,e. g. that of

the central nervous system,but do not damage other kinds (seep. 17).The toxic action is merelyan exaggerationof the pharmacologicalaction of the alkaloids when used as drugs,the dosagebeing so

regulatedthat stimulation and not destruction is producedin the

cell bodies. It may, of course, happenthat with smaller doses the

toxic action of the drug entirelydisappears,owing to the dilution

being too great to affect those structures on the disturbance of

which the fatal issue depends. For instance,quinine,when givenin largeenough doses to destroythe malarial parasite,does not

necessarilyproduceits specificeffecton the cerebrum.

We shall now proceedto consider the various alkaloids of which

the chemical structure isknown, adoptingthe classificationpreviouslymentioned. For practicalconvenience,the opium alkaloids which

belongchemicallyto two groups have been considered together.Hordenine is separatelydescribed (seep. 303).

In order not to interruptundulythe arrangementof the alkaloids

on a chemical basis,a chapterhas been added in which the various

syntheticsubstitution productsrecentlyintroduced into practicearedescribed. These,thoughpharmacologicallysimilar to the alkaloids

theyare intended to replace,are often very different chemically,andhence it was thoughtadvisable to deal with them separatelyin a

chaptersupplementaryto the systematicaccount of the alkaloidal

I. THE PYRIDINE GROUP.

The principalalkaloids to be considered in this group are coniine

and its stereoisomer,methylconiine,conhydrineand its isomer

pseudo-conhydrine(derivedfrom hemlock),nicotine and nicoteine

(fromtobacco),and piperine(fromblack pepper).Physiologicallyand chemicallythese bodies vary considerablyin

complexity,and it will be well to beginwith the simplest,namelythat substance formingthe chemical basis of that group, pyridine.

250 PYRIDINE GROUP

This,containingas itdoes one atom of tertiarynitrogenin the ring,is very inactivej

CH

CH/NCH

CH

hydration,which resultsin the formation of an imide group, producesthe much more active body,piperidine,

ca

C]

Pyridine, which is a liquidwith a powerfuland distinctiveodour,if inhaled,stimulates the fifth,nerve and producesdyspnoea,thenslow,shallow breathing,and eventuallysleep.In very largedosesit paralysesthe sensorium,producingcompleteanaesthesia and

abolition of reflexes,smaller doses may inhibit respiration;onstimulation of the vagus centre in dogs breathingstopsin expira-tion.

Small doses act on the heart,increasingthe force and slowingthe rhythm of the beat ; largedoses paralysethe muscle,causinga fallof blood pressure, and finallystopthe heart altogether.Dosesof 1 gram (15minims)per diem produceno symptoms.

Piperidine,and also pyrollidine,which is formulated "

CH," CH0

H, H.or

and cyclohexamethylene-imine

CH0" CH

CH,

H

have much the same action,producingin cold-blooded animals


252 CONIINE

Couiine ispropyl-piperidine"

)" CH2.CH2.CH," 2. o

IH

It is more powerfulstill,though similar in its action to piperi-dine. It acts probablymainlyon motor nerve endings,producingmuscular paralysis.It also raises the blood pressure, by local action

on the peripheralvessels,and slows the pulseby action on the

vagus centre or terminations;there is also slightquickeningof

respiration,followed by retardation,an effect probablypartlycentral and partlyperipheral.e"0-Propyl-piperidinehas a similar

action to coniine,but it has onlyone-third of the toxicityof that

substance.

iso-Coniine apparentlyacts like coniine.

^-Methyl-coniine "

CH,.CH0.CH,

The imide hydrogenof coniine in this compound is now replacedbya methyl group; no great physiologicalchange,however,occurs.

Dimethyl-coniineis much less toxic. The muscular spasms occur-ring

after coniine poisoningare said by some authors to be absent

after methyl-coniine,which also acts more specificallyon the spinalcord. Its fatal dose is one-third less than that of coniine.

Conhydrine

NH

and its isomer,pseudo-conhydrine,act lesspowerfullythan coniine,

the proportionaldoses being-03,*2,and over -3 grams per kilogram

body-weightin guinea-pigs(Findlay).A series of bodies known as Coniceines, having two atoms of

hydrogenlessthan coniine,are of interest,as they are thoughtto

illustratethe action of the double bond (seep. 50).

THE CONICEINES 253

y-Coniceine

CH2

CH/NcCH

" CH2 . CH2 . CH3

is said to be seventeen times more toxic than coniine ; and a-coni-

ceine,the constitution of which is uncertain,is also more toxic ; it

may be a stereo-isomer of "$-and e-coniceine. 5-Coniceine,which

may be formulated "

CH

CH/TSCH.

CHA UCH.CH2 . CH2. CH3

is less active,owing possiblyto the presence of a tertiarynitrogenatom.

/3-Coniceine,which has probablythe structural formula "

CH

H

is less toxic than a-coniceine. The latter is more toxic than coniine.

Pipecolineand ethyl-piperidinehave been previouslymentioned

(seep. 251). The piperidinehomologuesof the compositionC7H15N,that is di-methylpiperidineand ethyl-piperidine,are termed

lupetidines,whereas the methyl-ethylderivatives are called copelli-dines. These substances are formed by the reduction of the corre-sponding

homologouspyridineswith sodium and alcohol.

The toxicityof these compounds increases approximatelyin

geometricalprogression,as their molecular weight increases in

arithmetical progression.This holds good,however,only up to

the iso-butyland hexylderivatives,which both show a marked

decrease in toxicity.The proportionsare 1:2:4:8:5:4.

Lupetidine(a-a'-dimethyl-piperidine)acts like curare ; it has no

specialcardiac action,but paralysesrespiration.It has a toxic

254 PIPERIDINE HOMOLOGUES

action on the red blood cells,producingvacuolation;the central

nervous systemis slightlyaffected,and there is some local anaes-thetic

action.

/?-Ethyl-piperidine(/3-lupetidine)producessalivation and tetanic

convulsions. It is not so toxic as j3-propyl-piperidine,which it

otherwise resembles ; the latter,again,is not so toxic as coniine.

Propyl-lupetidine,the most powerfulpoisonof this series,in addi-tion

to its action on the motor nerve endings,has a marked effect

on the central nervous system,but does not damage the red blood

cellsso much as the other members of the series.

w0-Butyl-lupetidineparalysesthe heart and has a true narcotic

action; it also paralysesthe motor nerve endings. In hexyl-lupetidinethis effectis but slightlyobserved.

Copellidine

an,

is twice as toxic as lupetidine,and acts principallyon the motor

nerve endings.

Piperylalkin,

Pipecolylalkin,

H

and methyl-pipecolylalkin,

" CH2.CH2.OH

CH2.CH2OH

-CH2 . CH2OH

r.CH3

have been physiologicallyinvestigated.The first two produceparalysisof central origin,the last appears to be innocuous.

From a consideration of these compounds it will be seen that not

onlythe size but also the positionof the side-chain in relation to

NICOTINE 255

the N in the ringmay influencephysiologicalaction" asymmetrical

compoundsdo not behave quitesimilarlyto the symmetrical.As

a rule,too, though not always,the alkaloids in which the sub-

stituents are attached to nitrogenare more active than those in

which the groups are linked to carbon.

Stilbazoline

IH

has littlepower of excitingconvulsions,but is powerfullypara-lysing.

The fatal dose is about three times as largeas that of

coniine.

Piperine, which has a structural formula representedby

CO" CH,

N" CO.CH : CH.CH

acts similarlyto piperidine,but has less action in contractingthe

peripheralarterioles. This appears to be due to the attachment of

the acid radical to the nitrogeninstead of one of the carbon atoms

in the ring.Nicotine has a somewhat more complicatedmolecular structure,

and in all probabilityis a-pyridyl-/3-tetrahydro-#-methyl-pyrrol;it may be representedby the followingformula :"

CH3

N

CH2

On oxidation it givesriseto /3-pyridine-carboxylicacid,

COOH

256 NICOTINE DERIVATIVES

and is consequentlya /3-derivativeof pyridine;startingfrom

/?-amido-pyridine,Pictet and Crepieuxhave synthesizeda base

showingall the propertiesof the natural alkaloid.

The action of nicotine closelyresembles that of coniine,but it is

more powerful.If givenin doses not largeenough to be immedi-ately

fatal,nicotine causes clonic and tonic convulsions of central

origin,stimulation of the respiratorycentre,a rise followed by a fall

of arterialblood pressure, and finallyextreme depressionof the whole

central nervous system,which ends in death. Nerve cells in the

peripheralgangliaare paralysed,hence after preliminarystimulationthere is diminution in the secretoryactivityof glands. Small doses

slow the heart,largerdoses render its action rapidand irregular.This is partlyvagaland partlydue to direct action on the muscu-lature.

The action on the blood vessels is peripheral,and differs

from that of adrenalin in that it lasts for a shorter time,and is

followed by a periodof vaso-dilatation.

Nicoteiue

CH,

has a similar but more powerfulaction than nicotine,apparentlytraceable to the presence of the double bond,whereas oxynicotine,

obtained by the action of hydrogen peroxideon nicotine,is

weaker. Its constitution is that of an aldehyde,and in its forma-tion

the pyrrolidineringis probablybroken "

CH3

NH

CH/ CHO

TI

CH CH,

Metanicotine, which acts like nicotine,is much weaker. A dose

nine times as largeis requiredto producethe toxic symptoms, and

is onlyfatal in double the time. The constitution of metanicotine

is representedby the formula"

NICOTINE DERIVATIVES 257

NH.CH3

and it is consequently methyl-/3-pyridyl-"$-butyl-amine. Thus in

these two compounds the original physiological action remains,

though the pyrrolidine ring is destroyed. This shows that the

ring formation is not essential for the production of the pyrrolidine

action.

The physiological effects of all these bodiesare very similar, from

pyridine onwards, but they differ markedly in degree. The most

curious point of difference is that pyridine itself lowers the arterial

pressure by weakening the heart, whereas all the rest, whichare

hydrated bodies, raise the arterialpressure by constricting the

smaller arteries. The marked action which nicotine has in this

respect maybe due not only to the

presenceof the pyrrolidine

ring, but also tosome synergetic action from the pyridine, which is

latent in that compound and requires thepresence

of extra hydrogen

atoms, orof

somesubstituent

group to give it actuality.

CHAPTER XIII

THE ALKALOIDS (CONTINUED)." Pyrrolidinegroup " Cocaine,Atropine,Hyoscyamine. Quinolinegroup " Quinine,Cinchonine, and their substitutes.

Strychnineand Brucine.

II. THE PYRROLIDINE GROUP.

The constitution of Cocaine is expressedby the formula "

CH2" CH CH.COOCH3

N.CH3 CH.O(C6H6CO)

CH2" CH CH2

and is thus benzoyl-ecgonine-methyl-ester,the two hydrogenatomsin the carboxyland hydroxylgroups having been replacedbymethyland benzoylrespectively.

The chief physiologicalpropertiesof cocaine are :"

1. It stimulates the vaso-motor centre and partiallyparalysesthe vagus. It also acts slightlyas a stimulant to the accelerator

nerves to the heart. For these reasons the blood pressure is raised.

2. Its action on the cerebral and spino-medullarycentres is at

firstexcitant and then profoundlydepressant.It thus causes death

by convulsions or paralysisof the respiratorycentre.3. It causes peculiar' foam-like ' degenerationand vacuolation of

the liver cells,which Ehrlich says is quitecharacteristicin mice.

4. It raisesthe body temperature.6. It dilatesthe pupil.6. It increases power of muscular work.

7. It produceslocalanaesthesia.Cocaine thus differs remarkablyfrom its immediate chemical

predecessor,ecgonine,in its physiologicalaction.This substance

CH2" CH CH.COOH

N.CHQ CH.OH

CHQ" CH- CH2


260 PHYSIOLOGICAL ACTION

both o" which are correlated to the chemical structure of the

molecule. The remaininggroups will now be considered.

4. Elevation of Temperature.This is quitea marked property,and the onlysubstance which exhibits it in a more powerfulmanneris/3-tetrahydro-naphthylamine"

CH,

H.NH2

It appears that its physiologicaleffect is not onlysimilar but due

to the same process in the body,namely,increased heat productionby central stimulation. It does not occur in animals under the

influence of chloral.

.5. MydriaticAction. This action is due to a stimulatingeffect

on the motor nerves to the dilatorfibres of the iris,and thus cannot

be abolished by muscarine. Its exact relationto the chemical struc-ture

of the molecule of cocaine is not known, but it appears to

be derived from the ecgoninering,which, though not generally

mydriatic,causes some dilatation of the pupilin cats. The benzoyl

group is essential for the appearance of this action. It is probablydependenton the structural arrangement,which isassociated with the

riseof temperature,as j3-tetrahydro-naphthylamineis also mydriatic.6. The effect on muscular action which has been attributed,

apparentlywith accuracy, to cocaine,has not been shown to dependon any specialchemical groups contained in the molecule. It may,

perhaps,be attributed partlyto the true stimulant action of cocaine

on the.central nervous system,which is accompaniedby a d.ecrease.

in nitrogenouselimination. A diminution in the oxidizingr"mflflgff*i

injhebodyis said to follow on the administrM" att|hfldm^y.7. By far the most importantphysiologicalattribute of cocaine

from a practicalpointof view is its power of producinglocal

analgesiaand anaesthesia. Not onlypain but all sensations are

affected ; for instance,taste is abolished when cocaine is appliedto

the mucous membrane of the mouth,and heat and cold cannot be felt.

The local anaesthetic action of cocaine dependspartlyon the

structure of the ecgoninenucleus,and partlyon the presence and

relative positionsof the two substitutinggroups.The ecgoninenucleus is possiblythe least importantfactor in the

productionof anaesthesia,as it has been found that many other

OF COCAINE 261

substances,providedtheypossess similar substituents,can producethis effect. Various theories have been put forward to explainthe

part playedby the ecgoninering,several of which have subse-quently

been disproved.The most strikingfeature of ecgonineis

its arrangement in a double ring,and this suggesteditself as

a causal factor in the physiologicalaction of cocaine. However,

a substance,w-methyl-benzoyl-oxy-tetramethyl-piperidin-carboxyl-methyl-ester,is a local anaesthetic,though containingbut a single

ring"

CH2" CH - CH.COOCH3 CH3" C(CH3)" CH2

N.CH3 CH.O(C6H5CO) N.CH3

"CH -- CH2 CH3" C(CH3)" CH2

Cocaine. w-Methyl-benzoyl,"c.

In fact,it has been found that a largenumber of substances,such as phenol,/?0ra-chlorphenol,picricacid,salicyl-methyl-ester,

phenacetin,"c., have anaesthetic or analgesicproperties.The

simplestbody producingthese effects is the methyl ester of

benzoic acid,C5H4COOCH3. The (N.CH3)group may be replacedby (NH),the resultingproductbeingnor-^-ecgonine"

CH2" CH" CH.COOH

NH CH.OH

CH2" CH" CH2

This, when benzoyland methyl groups are introduced,as in

ordinarycocaine,producesnor-cocaine,a powerfulanaesthetic,buttoo toxic for practicalpurposes " the toxicityprobablybeingdue to

the presence of the imide group (NH)".That the ecgoninering has its influence on the anaesthetic

propertiesof cocaine seems to be shown by the fact that certain

alterations,not affectingthe substitutinggroups, may be accompaniedby alterationsin the anaesthetic potencyof cocaine. Thus its con-version

into a quaternarybase by the addition of methyl-iodidedestroysthe distinctivecocaine action,and substitutes a curare-like

one in its place.07^/"0-Chlor-cocame and #^fa-nitro-cocaine have only slight

anaesthetic properties; weta-oxy-cocainehas no anaesthetic action,but is slightlytoxic,and in largedoses producesdegenerationof

the livercells. The flâ-amido compound producesneither anaes-

262 COCAINE DERIVATIVES

thesia nor destruction of liver cells. The latter propertycan,however, be restored by introducingbenzoylor acetylinto the

amido group, and a powerfullyanaesthetic body is producedby this

means. By the action of chlorformic ester on the amido derivative,cocaine-urethane is produced,a strong anaesthetic,actingon the

livercharacteristically,and givingriseto toxic symptoms "

CH2" CH CH.COOCH3

N.CH3 CH.O(C6H6CO)

(COOC2H5)NH" CH"

CH CH2Cocaine urethane.

The (CH3.COO) group isessentialto the action of cocaine,as acti-vating

the inhibitorycarboxylgroup. It may be replacedby other

acyls.Thus coca-ethyline,containingthe (C2H5COO) group, coca-

propyline(C3H7COO), coca-ô-butyrine,"c.,have been prepared,but have no advantagesover cocaine in practice.

Benzoyl-ecgonine,benzoyl-nor-ecgonine,and ecgonineitself,have no anaesthetic action.

By the abstraction of water an anhydrideof ecgoninecan be

formed,CH9" CH CH.COOH

I IN.CH3 CH

CH2" CH CH

which,like ecgonine,has no anaesthetic action. Its ester is also

inactive"

CH0" CH CH.COOCH3I IN.CH3 CH

r*TT f^TT^Jlo " v^Xl- -CH

In the firstcase the inactivitymay be explainedby the presence

of the carboxylgroup. In the second case this explanationcannot

hold good,and recourse must be had to the essential change in the

ecgoninering,and possiblyto the presence of the double bond.

The (CH3.COO) group has also been thoughtto exercisea specificstrengtheningeffect on the physiologicalaction. This view may

TROPINONE DERIVATIVE 263

be supportedby the fact that laevo-rofatorybenzoyl-ecgonine-nitrile,thoughanaesthetic,is comparativelyweak in itsaction "

CH2" CH CH.CN

N.CHQ CH.O(C6H5CO)I

CH0" CH- jaAs againstthis are the facts that the benzoylester of pseudo-

tropine,CH2" CH -CEL

N.CH3

-G

H.CH

CH*" CH

which contains no (CH3COO) group, isa powerfulanaesthetic(thoughtropine-benzoyl-esteris a weak one),while the methylatedbenzoylester of a-cocaine (an isomeric bodyobtained from tropinone)has

no anaesthetic action.

CH2" CH- -CO

CH2

N.CH3

CH,," CH C"(CNCH0

HCN

CH2" CH - CH2Tropinone.

N.CHfl

CH2" CH - CH2

Tropinone-cyanhydrine.

CH2" CH-

ICH2

N.CH,

COOH

ca

TI

N.CH,

CH2" CH CH2a-Ecgonine. a-Cocaine.

It would be safer,therefore,to attribute the weakeningof the

physiologicalaction of the nitrileof laevo-rotaiorybenzoyl-ecgonineto some actual antagonisticeffect of the (CN)Xgroup, similar to

that of the originalcarboxyl.The importanceof the benzoylgroup is shown by the fact that

in its absence no anaesthetic effect occurs, and moreover many

substances containingit,such as benzoyl-tropine,the benzoylderivatives of morphine,hydro-cotarnine,quinine,and cinchonine

264 ANAESTHIOPHORE GROUP

are local anaesthetics. In the ecgoninederivatives it cannot act

without simultaneous replacementof the carboxylby a COOR

group, and the presence of these two groups alone in such a simplesubstance as benzoic methyl-ester,C6H5COOCH3, is sufficientto

producelocal anaesthesia.

In accordance with the nomenclature of the theoryof dye-stuffs,it is called by Erhlich the ' anaesthiophore'

group, while the

(N.CH3)group he calls ' auxotox ' (seep. 22).The former cannot be

replacedby any acid of the aliphaticseries;and if replacedbyanother aromatic acid,the anaesthetic effects are either abolished

or much diminished.

Phenylacetyl(C6H5CH2CO) ecgoninehas a slightanaesthetic

action.

Again, atropinehas slightanaesthetic properties.This is a

compound of tropeinewith tropicacid "

Homatropine,in which tropicacid is replacedby mandelic acid,

C6H6.CH"g"OHjhas more anaesthetic action.

Benzoyltropine,where benzoic acid,C6H6COOH, replacesthe

tropicacid,is a powerfullocal anaesthetic.

Cocaine existsnaturallyas a Zaevo-rotaiorybody.A dextro-rotatorycocaine can be prepared which only differs from the ordinarycocaine in producinga more rapidand intense anaesthesia,and one

which passes off in a shorter time.

The generalconclusions to be drawn from the observations on

the relation between the chemical constitution and physiologicalaction of cocaine are :"

(1)The action on the central nervous system(includingthe vaso-

motor effect)are due to the j^rrolidinering from which cocaine is

originallyderived.

(2) The peculiaraction on the liver is a specialattribute of

ecgonine,and is partlydependenton the presence of tertiarynitrogen.

(3)The elevation of temperatureand the peculiareffect on

muscular energy cannot be traced to any specialchemical factors.

(4) The mydriaticeffect also is not yet accounted for in the

chemical structure.

ATROPINE 265

(5)The anaesthetic effect is largelydependenton the presence

of the alkyland benzoylradicals,,but is also due to the ecgonine

ring,as this cannot be materiallyaltered without destroyingor

diminishingthis action. Of all these factors the presence of the

benzoylgroup appears to be the most important,as numerous other

compoundscontainingthis radical exhibit a similarpharmacologicaleffect.

ATROPINE.

The chemical similaritybetween atropineand cocaine is accom-panied

by a physiologicalsimilaritywhich is no less remarkable.

Both are esters combined with bases which differfrom one another

merelyin respectof one carboxylgroup "

CH2" CH CH2 CH2" CH CH.COOH

N.CHQ CH.OHCH." N.CH, CH.OH

" CH- CH,CH2" CH CH2Tropine. Ecgonine.

Atropineis the ester of tropineand tropicacid,the latter bodycontaininga benzylnucleus and an asymmetriccarbon atom- "

C6H5-CH\COOHTropicacid.

Thus atropine is"

CH2" CH CH2

N .CH3

H2" CH - CH2The physiologicalaction of atropineis complicated;its effects

on the organismdependlargelyon dosage,and divergentviews

are stillheld on the details of its mode of action. Atropineacts

firstlyon the central nervous system,producing(inlargetoxic

doses)delirium,followed by profounddepression.In small medi-cinal

doses its action on the cerebrum is generallynot noticeable.

Toxic doses also raise the temperature,sometimes to a very con-siderable

extent. Its peripheralaction paralysesthe terminations

of the nerves to secretoryglandsand unstripedmuscle (includingthe sphincteriridisin mammals); it has some action on sensory

nerve endings,but on the nerves supplyingstripedmuscle it has

practicallyno action. It also paralysesthe vagus terminations to

266 ATROPINE AND COCAINE

the heart. The comparisonbetween atropineand cocaine maythus be set forth in tabular form :"

Atropine. Cocaine.

Cerebral and ((largedoses) deliriant deliriant

medullary j(smallerdoses)no sedative effect sedative

centres ( (finalaction)profounddepression profounddepressionCardiac Jvagus depressant depressantterminations 3

Temperature raised raised

Bloodvessels contracted (central) contracted (central)(riseof blood pressure) (riseof blood pressure)

Eye powerfulmydriatic lesspowerfulmydriaticSensorynerves slight local anaes- powerful local anaes-thetic

thetic

Nerves to un- paralysed no action

stripedmuscle

Nerves to no action,except in very large no action,exceptwhenstripedmuscle doses,when they are paralysed locallyapplied

( by largedoses, possibly increases

Muscle } unstripedmuscle paralysed power of action in

j by small," "

stimulated stripedmusclef striped muscle, unaffected

to o'secreting " paralysed j "lands,when secre-

{ tion is paralysedLiver no specialaction specificdegeneration

(mice)

When these actions are analysed,the first fact which is broughtout is that the generaltoxic action of atropineand cocaine is some-what

similar. The excitation,followed by depressionof the cerebral

and medullarycentres,the rise of blood pressure and temperature,and the inhibitoryaction on the vagus terminations seem common

characteristicsof the two drugs. The mydriaticand local anaes-thetic

actions differ mainlyin degree.The action of atropineon unstripedmuscle is to a certain extent

analogousto the action of cocaine on stripedmuscle. Very small

doses of atropinestimulate involuntarymuscle fibres and increase

their conductingpower: cocaine taken internallyhas probablyastimulatingeffect on voluntarymuscle, and here the dose which

actuallyreaches the muscle must be very small.

The main differencesare, then,the characteristicaction of atropineon the nerves to unstripedmuscle and secretingglands(thoughcocaine is said to act on these glandswhen locallyapplied),and the


268 LADENBURG'S GENERALIZATION

in this,as in toxic doses it causes mydriasisin cats. But it is onlywhen tropineis combined with certain aromatic acids that the full

effect is obtained. These aromatic acids all resemble one another

in containingalcoholic hydroxyl. Thus the combinations with

//""ITT/~\TT

tropicacid (formingat r opine); C6H

mandelic acid (forminghomatr opine),

and atrolactinicacid C6H5C"-CH3\COOH

are allmydriatic,whilst those containingeither(1)no aromatic acid,likelactyl-,acetyl-,or succinyl-tropeine,or (2)ah aromatic acid with-out

hydroxyl,like cinnamic acid,C6H5CH :CH.COOH, or (3)an aro-matic

acid with hydroxylof the phenoltype,likesalicyl-tropeine,

CH2" CH -- CH2

N.CH3 CH.O(CO.C6H4. OH)

CH2" CH - CH2

are without mydriaticaction.The influence of an aromatic acid containingalcoholic hydroxyl

in callingforth mydriaticpropertiesin the base is not confined to

the derivatives of tropine,but also occurs in such allied substances

as ra-methyl-triacetone-alkamme1 and #-methyl-vinyl-diacetone-alkamine,of which the mandelic acid esters are mydriatic,but onlyin one stereo-isomericform.

The principlethus illustrated,which is known as' Ladenburg's

generalization'',may thus be expressed:"

' Those tropeinesonlyare

possessedof mydriaticaction which are combined with an acid side-

chain possessinga benzene ringand an aliphatichydroxyl/Marshall,Jowett and Hann, and Jowett and Pyman2 have

shown that this generalizationis not absolute. Thus terebyltropeine(infollowingformulae R = tropineradical),

(CH3)2:C"CH.CO.R

C CH0

1 The hydrochloridehas been introduced into medicine as euphthalmine(seepp. 306,316). 2 Tram. Chem. Soc.,1900,1906 and 1907.

MYDRIATIC ACTION 269

which contains neither a benzene ringnor aliphatichydroxyl,is

distinctlymydriatic,thoughits action is much weaker than that o"

atropine.Phthalide-carboxyl-tropeine,

aCKCO.Rc"which is similar to homatropine,

apTT/OHC\CO.R

has also marked mydriaticaction. On the other hand,the lactone

of 0-carboxyphenyl-glyceryl-tropeine,

/\ pTT/OHf \"( H",E

IJ" COO

which contains a benzene group and alcoholic hydroxyl,is onlyfeeblymydriatic; intravenous injectionsare moderatelyactive,but

not direct instillationsinto the conjunctiva.The relativepositionof the benzoyland nitrogengroups appears

to be of importance.Tropine,like ecgonine,is a combination or

condensation of two rings,a pyrrolidineand piperidine.It is to

the latterthat the side-chains are attached :"

CH2" CH2 CH2 CH2 CH," CH CH,

N.N.CH2 N.CH3 CH2 N.CH3 CH.OR

2" CH2 CH2 CH2 CH2 "

CH C.

n-Methylpyrollidine. n-Methylpiperidine.

The radical R is in the para or y positionrelativelyto the nitrogen,and this is also the case with the alkamines havingmydriaticaction,thus :"

(CH3)2: C CH2

N.CH3 CH.OR

(CH3)2:C- -CH2

The mydriaticeffectwhich is thus broughtinto action by the

presence of certain side-chains is a propertyinherent in the parent

270 MYDBIATIC ACTION

substance. Stereo-isomers are found to behave differentlyinthis respect.Tropineexists,as has alreadybeen noted,in two

such forms. The second,pseudo-tropine,forms with mandelic

acid an isomer of homatropinewhich has no mydriaticaction.

Moreover,the addition of methyl bromide to the nitrogengroupenfeebles the physiologicalaction *

:"

CH CH CH

fITT XT/-"* Pl_/Jig IN "",jj

^"

PITT rrrr pvy J10 v" XI v""H2

It must be remarked that,physiologically,the effectof atropineon the eye differs somewhat from that of cocaine. The effect

of cocaine is to stimulate the dilator fibressuppliedby the sym-pathetic,and onlypartiallyto paralysethe sphincterfibres from

the oculo-motor nerve. There is no action on the ciliarymuscle

or on the lightreflex. Atropine,on the other hand, certainlyparalysesthe sphincternerve fibresand the circularmuscle fibresof

the iristhemselves ; it also abolishes the reaction for accommodation

and lightby paralysisof the nerve terminations in the ciliarymuscle. Whether it also stimulates the sympatheticnerve fibres is

a disputedpoint,and the experimentalevidence has been variouslyinterpreted.It seems more in consonance with the generalphysio-logical

action of atropineto suppose that it has no excitinginfluence

on the terminations of the dilator nerve.

The mydriaticaction of atropineis clearlyonlypartof itsgeneralaction on the nerves to unstripedmuscle,and on the unstripedmusclefibresthemselves;and though direct evidence as to the chemical

factors producingthe well-known action of atropineon the intes-tine,

bladder,"c.,is not forthcoming,there is no reason to suppose

that these factors are other than those which produceits effectsonthe eye. Its action on secreto-motor nerves is known to be distinct

from the central action which raises the blood pressure. As, like

the other peripheraleffects of atropine,the secreto-inhibitoryaction

is antagonizedby pilocarpine,it may perhapsbe assumed to rest on

a similar constitutionalbasis.

Atropineis opticallyinactive ; hyoscyamine, its isomer,exists in

two forms,dextro- and laevo-Yotatory.It is possiblethat the tropinenucleus in the isomers hyoscyamineand atropineis opticallyinactive,

1 This substance,like homatropine,acts more rapidlyand for a shorter

time. This is due to more rapidabsorptionand excretion.

THE QUINOLINE GROUP 271

and that the isomerism of these substances dependsonly on the

activityor inactivityof the tropicacid radical present; it has been

suggestedthat in the livingplantonlydextro- and fotfvo-hyoscyamine

occur, but that on dryingthese combine to givethe inactive atropine.Considerable differences are observed in the physiologicalaction of

these opticalisomers. In respectof the excitant action on the

spinalcord :"

d-Hyoscyamineis strongest; then atropine; then ^-hyoscyamine.On the other hand,in respectof the action on the iris,secreting

glands,and the vagus, the order is:"

(1) -Hyoscyamine; (2)atropine; (3) -hyoscyamine.The conclusion is that the action of atropinedependson its con-taining

the two, /- and ^-hyoscyamine,each of which exerts its

specificphysiologicalaction.

(ii)Paralysis of sensory nerve endings. This is not so marked

a propertyof atropineas of cocaine. Benzoyltropine,which onlydiffersfrom cocaine in the absence of the COOCH3 group, is a local

anaesthetic,thoughnot so powerfulas cocaine. Its isomer,benzoyl

pseudo-tropine(tropo-cocaine),is a more powerfullocal anaesthetic

than cocaine. Aliphaticesters of tropinehave no anaesthetic

properties.Thus in atropine,as in the substances which have been

enumerated when dealingwith cocaine,the benzoylgroup seems to

be of greatimportancein callingout the anaesthetic power of the

III. THE QUINOLINE GROUP.

The alkaloids belongingto this group form the chief active

principlesof cinchona and nux vomica. The parent substance,quinoline

has an action which somewhat resembles that of quinine,as it is

an antisepticand antipyretic.It cannot,however,be used thera-

peutically,as itprovokesvomiting,and even in small doses is liable

to producecollapse,respiratorydisturbances,and oedema of the

lungs.

Qninoline has a marked antisepticaction;it also affects the

272 QUINOLINE DERIVATIVES

metabolic cellprocesses so that the intake of oxygen is decreased,and

the amount of energy producedis diminished; thus the heat

productionis lowered.

Compared with quinine,however,it is a feeble antipyretic,with

littleaction on the malarial parasite; in pneumonia it completelyfailed to reduce the temperature(Brieger).

"6-1-0 gram producesparalysisof voluntarymuscles and loss of

reflexes in rabbits,and is eventuallyfatal. Quinoline is not ex-creted

as such,but appears in the urine in the form of a body

precipitableby bromine,stated by Donart to be carboxypyridine.The action of hydrogenwhen added to the quinolinemolecule is

the same as was noted with pyridine.Tetrahydro-^-oxy-quinolinekills rabbits in two hours in doses of

"6 gram ; a similar dose of jo-oxy-quinolinehas hardlyany effect.

^0-Quinoline,quinoline,and pyridinepresentsome remarkable

analogies.The first two are not only similar in physiologicalaction,but identicallyactingcompounds may be derived from

either,an importantpracticalpointowing to the expensivenessof

the first-named body. Hydrationhas a similar intensifyingeffect

on allthree.

Decahydro-quinoline,

CH0 CH CH2

CH2CH0 CH

H2

is a powerfulblood poison,even in small doses. Generally,quino-lineand pyridineact more powerfullyon the central nervous

system,and on the heart,whereas decahydro-quinolineand piperi-dine have a more rapidlydestructive effect on the red blood cells.

Hexahydro-quinoline,an intermediatelyplacedbody,more closelyresembles the non-hydratedbase. It has marked action on the

heart and nervous system,and less on the blood.

As a rule,the quinquevalentnitrogenderivatives of quinolineand

w0-quinolinedo not show a curare-likeaction,thus contrastingwith

the correspondinganiline derivatives,and the bodies obtained from

the natural alkaloids. The methyl iodides of both quinolineand

^0-quinoline,oxyethyl-quinoline-ammoniumchloride and diquino-

line-dimethyl-sulphate,

QUINOLINE DERIVATIVES 273

Quinotoxine

CH3 SO4H CH3 S04H

(abodycontainingtwo quinquevalentnitrogenatoms)are exceptions,and allact like curare.

Quinaldine (a-methyl-quinoline),

lepidine(y-methyl-quinoline),

a-y-dimethyl-quinoline,

l-tolu-quinoline,

and 3-tolu-quinoline

have been investigatedby Stockman,who finds that the physio-logicalactivityas regardsthe nervous systemvaries inverselywith

the number of substituted methyl groups, but that the relative

positionsof the methyland nitrogenare not of any importance.T

274 KAIROLINE

The introduction of methoxylin the para positionin the benzene

nucleus weakens the antipyreticaction of quinoline.

jo-Methoxy-quinoiine,or j"-quinanisol,

on reduction becomes Thalline,

CH

H

which has no specificaction in malaria,is a powerfulanti-pyretic

and is also very activelydestructive to the red blood cells.

It produces,moreover, necrosis of the renal papillae,as do tetra-

hydro-quinoline,or ô-thalline,awa-thalline,acetyl-thalline,and its

urea and thio-urea compounds.The introduction of an acid or alkylradical into the NH group of

tetrahydro-quinolinedoes not affect the physiologicalaction.

The presence of OH groups in the benzene nucleus of the reduced

quinolinecompoundshas the generaleffectof acceleratingthe anti-pyretic

action and also of renderingit more transitory,possibly

owing to more rapidabsorptionand elimination. Two substances

illustratethese points:"

Eairolin A, or w-ethyl-tetrahydro-quinoline,

and Kairoliu B, or ft-methyl-tetrahydro-quinoline


276 CONSTITUTION OF QUININE AND CINCHONINE

poisonsthe cellsof the nervous system,and the effectsof quinineon the specialsenses must probablybe attributed to a direct

action on the sensory epithelium.General metabolism iscertainlydepressed,as might be expectedfrom a protoplasmicpoison.There is also diminished heat productionand probablyincreasedheat loss.

Quinine, C20H24N2O2,and Cinchonine, C19H22N2O,differ chemi-cally

in that a hydrogenatom in cinchonine is replacedin quinineby oxymethyl; physiologically,quinineis much the more active.

Both consist of two parts,a quinolinering,the existence of which

has longbeen established,and a residual part,the constitution of

which is stilla matter of discussion.

Skraup givesthe followingformulae :"

CH CH

1\CH.CH: CHCH/T\CH.CH: CH2 CH/1\CH

I |

HO.ct"H*ICH HO.cl CHJcHLoipon-anteil',or

HO.c CHcH resid"l portion

oCinchonine. I

OCH3

Quinine.

Cinchonine is more toxic than cinchonidine,its

isomer,and than the two oxycinchoninesof Hesse and Langlois.

The methylgroup, however, which constitutes the chemical differ-ence,

does not in itselfseem to producethe typicalquinineeffect;it may be replacedby ethyl,propyl,or amyl,with an intensification

rather than a diminution of physiologicalaction.

Cupreine, an alkaloid found in an allied speciesof plant,the

remijia,has considerable resemblance to quinineand cinchonine,

Cupreine,C19H20N2.(OH)2,Cinchonine,C19H21N2. OH,

Quinine,C19H20N2. OH.OCH3,

quininebeing methyl-cupreine.1Cupreineis less active physio-logicallyeven than cinchonine,and only half as toxic as

1 Schmiedeberg.

CINCHOTOXINE 277

quinine,but its alkylsubstitution productsare active,as are the

homologousquininebodies. It thus appears that the alkylgroupsmerelyact as a protectiveto the hydroxyl,and the fact that the

higheralkylsare more active than methylmay be explainedby the

relative difficultywith which the latter is oxidized.

It is thoughtthat in the organismpart of the cinchonine is

oxidized to cupreine,the introduction of OH in the para position

beinga usual form of oxidation in the body,and that thus the typical

quinineaction is produced.The largenessof the dose of cinchonine

necessary to producea marked effect is thoughtto be due to the

small amount of cupreineformed. The artificialremoval of CH3from quininedoes not result in cupreine,but in an isomeric body,

apoquinine,though converselyit is possibleto producequininefrom cupreine.The small amount in which the latter substance

occurs in nature preventsthis beinga practicallyvaluable procedure.It is not,however,now thoughtthat the specificquinineaction

is due to the quinolineportion,but to the residual portionof the

molecule,the so-called ' Loipon-Anteil'

; and in this portioncertain

groups are considered to be the principalfactors. It is possible,for

instance,to convert the C.OH group in cinchonine into CO, this

results in the formation of an NH group and the ruptureof the

ringcomplex. The productis known as cinchotoxine,and is

entirelywithout the physiologicalaction of quinine; it is very much

more toxic,and somewhat resembles digitoxin"

CH

H2C/1\CH.CH:CH2dig

HOC

CH2. C9H6NCinchonine.

CH

HoCX \CH.CH:CH2UrL '

0:C

-CH2.C9H6NCinchotoxine.

But it cannot be decided whether the characteristic effects of

quinineare lost owingto the breakingof the ringor the appearance

of the ketone group in placeof the alcoholichydroxyl.The vinylgroup is not apparentlyof importancein determining

the generaltoxicity,but it is remarkable that quinineis the onlyantipyreticdrug containinga side-chain with a double bond.

278 ANTIPYRETIC ACTION OF QUININE

S. Frankel has synthesizeda body (acetylamino-safrol)resemblingphenacetin,but containingan allylgroup, but thoughit appearedto reduce the temperaturein experimentalanimals,it had no action

resemblingthat of quininein malaria.

It must be remembered that the so-calledantipyreticaction of

quinineis to a largeextent due to its toxic action on lower organ-isms,such as the plasmodiummalariae. It is this action really

which placesit at the head of the list of antipyretics.It has,however,been shown experimentallyto possess a slightpower of

reducingtemperature,apartfrom any paraciticidalaction. This is

most probablya resultof diminishingheat productiondue to a generalinhibition of proteinmetabolism ; in other words,by a toxic action

on livingprotoplasm.It is,however,probablethat the double bond is associated here

as elsewhere with considerable physiologicalactivity.The bodyknown as quitenine,in which vinylis replacedby carboxyl,

C18H21N202"CH :CH2 Oxidation C18H21N2O2"COOH

Quinine. Quitenine.

has very littleaction as a protoplasmicpoison,but whether this

is due to the presence of carboxyl,the absence of vinyl,or both,cannot be decided.1

It is clear,however,that the residualportionof the quininemole-cule

is the one on which its physiologicalaction depends,and that

the quinolineportionmerely acts as a link which enables it to

exert its specificaction;in the quinolineportionthe presence of

oxymethylin the para positionis also essential.

Quinidine isa d#ztfr0-rotatoryquinine,with a similaraction physio-logically.It is also,however,narcotic. The numerous isomers of

cinchonine produceconvulsions.

Hydroquinine,in which hydrogenis introduced into the quinolinering,is a very poisonousbody,producingparalysisand inhibitingrespirationin quitesmall doses. Half a gram subcutaneouslyhasbeen fatal to an animal.

Desoxy-quinine,a substance which differsfrom quininein con-taining

no hydroxylin the residual portion,givesall the reactions

1 Hunt, however, has shown that quininederivatives in which the vinylgroup has been altered to .CH2.CH3,.CHOH.CH3, .CHC1.CH3,have the

same toxic action as the parent substance on infusoria (Archiv.Internat.de Pharmacodyn. Bd. 12. 1904).

QUININE SUBSTITUTES 279

of quinine.A correspondingsubstance can be formed from cin-

chonine.

These bodies are ten times more toxic than their precursors.

CH CH

CH/^CH.CH: CH2 CH2/1\^CH.CH: CH2

CH(CHJCH, CH! CH2

NNK

CH2 . C9H5N.OCH3 CH2 . C9H6 .N

DesOXy-quinine. Desoxy-cinchonine.

SUBSTITUTES INTENDED TO REPLACE QUININE.

Apart from the occurrence of the toxic symptoms known as

' cinchonism ',which the administration of quininemay produce,this

drughas two specialdrawbacks in practice,itsintenselybittertaste

and its relativelyinsoluble character. Hence a number of salts of

quinineand other compoundshave been introduced,on the one hand

with a view of abolishingthe taste,and on the other of increasingthe solubilityof the drug. As a matter of fact these two aims are

not compatiblewith one another. The onlyquininecompoundswhich are tasteless are the insoluble ones. In the soluble salts of

these compounds the characteristic bitter taste is restored. For

convenience,therefore,quininesubstitutes will be divided into two

classes,the insoluble ones intended for oral administration,and the

soluble ones suitable for hypodermicor intravenous injection.

I. Insoluble in Water.

Among the ordinarysalts,the tannate,an amorphous powderobtained by actingon the sulphatewith a tannic acid solution,is

practicallytasteless. It is,however,uncertain in its action,and

is firstbroken down in the small intestine. Esters formed from the

hydroxylgroup in the residual portionhave also been produced.Euquinine is the propionicacid ester of quinine,is practicallytasteless,and is said not to irritate the stomach. A carbonic acid

ester of diquinineis known as Aristoquin. This body is soluble in

dilute acids,so that itdissolvesin the stomach;itisnot reprecipitatedin the intestine*

C,H.COO.OC1,H11N,0

Euqumme. Aristoquin,

280 QUININE SUBSTITUTES

Aristoquinis not so rapidlyexcreted as the hydrochlorideof

quinine,and its toxicityfor man is stated to be lower.

Saloquinine is the salicylicacid ester "

20H23N20

It is said to be less active therapeutically,and to show un-pleasant

by-effectsmore frequently.The dosagemust, of course, be

double that of ordinaryquinine. A salicylateof saloquininehas

also been produced,which is insoluble,and is intended to combine

the advantagesof salicylatesand quininewithout their bitter taste.

These two compounds are soluble in dilute acids,and are conse-quently

decomposed in the stomach.

An t"0-valerylester of quininehas also been synthesized,but is

not on the market. It is similar to the salicylcompound.

Quinaphthol is /3-naphthol-a-monosulphateof quinine" -

(C10H6. OH.S03H) . C20HMN202

and is a yellowpowder,containingabout 42 per cent, quinine,veryslightlysoluble in hot water and alcohol. It is decomposedin the

intestine,and is primarilyintended as an intestinal antiseptic.

Quinaphenin is quinine-phenetidin-carboxylicacid "

It is a white,very insoluble powder. Therapeuticallyit has no

advantage,beyond that of tastelessness,over a mixture of the two

bodies.

II. Soluble in Water.

Besides the ordinarysalts of quinine,some of which are suffi-ciently

soluble for hypodermic injection,two bodies have been

introduced for this purpose, namely, Quiuopyrine and Quinine

Hydrochloro-Carbamide. The first of these is a compound of

quininehydrochloride,and antipyrine,and is a white powder easilysoluble in water. It is unsuitable for internal administration,owingto its toxicity.The second is a compound of urea with quinineand hydrochloricacid,soluble in one partof water. Its disadvantageis that it contains very littlequinine.

STRYCHNINE 281

STRYCHNINE AND BRUCINE.

Our knowledgeof the chemical structure of these two bodies is

very imperfect.But littleis known as to the nature of the carbon

ringsof which theyare constructed,or as to the partsplayedby the

oxygen and nitrogen. It appears probablethat one nitrogenis

situated in a reduced quinolineor indol ring,and that its basic

character is modified by the presence of a carboxylgroup. The

formula for strychninewill be representedthus :"

(C20H220)CO

The physiologicalaction of strychnine is mainlyon the cellsof

the spinalcord,wherebythe resistance to the translation of slight

sensory stimuli into reflected muscular action is removed. The

evidence pointsto some structure between the anterior motor cells

and the terminations of the sensory nerve fibres in the cord.

Schafer has described intermediate cells in the posteriorhornswhich link the pyramidaltract with the lower motor neurons, and

which are intimatelyconnected with the sensory nerve endingsin

the posteriorhorns. Its action on the medulla may be said roughlyto correspondto that on the cord,while,with regard to the

cerebrum,the specialsenses appear to be rendered more acute,

thoughthere is no evidence to show how this takes place.Lightand

tactile impressions,the most easilytested,have been shown to be

improvedby small doses. The remainingactions of strychnine,

though importanttherapeutically,are not of much theoretical

interest,as theydependeither upon the central action (e.g. vagus

and vaso-constrictor effects),or on the convulsions (increasedforma-tion

of carbon dioxide,and increased heat production).Of more

interest,from the presentpointof view,isthe action of strychnineonlower forms of life.The higheranimals,owingto the preponderatingeffect of strychnineon the nervous system,show none of its action

as a protoplasmicpoison.But on protozoaitsaction is very similar

to that of quinine,to which it is chemicallyrelated,and it is

possiblethat its effects on higherinvertebrates (e.g.Ascaris)aremainlydue to its toxic action on protoplasm.1

1 Shrieder explainsthe resistance of some ascarides to strychnineas due

to their closingtheir mouths when placedin a solution of the drug,which

can thus act onlythroughthe skin.

282 STRYCHNINE DERIVATIVES

Piperidon,

NH

which is a-keto-piperidine,is stated by some authoritiesto have the

same action on the spinalcord as strychnine.Its activitydepends,as previouslystated (seep. 246),on the closure of the ring; at any

rate,fl-amino-valerianicacid,in which earboxylis of course present,has no action.

The questionwhether the action of strychnineon the spinalcord

dependsupon the presence of the piperidongroup

NH

is complicatedby the presence of the second oxygen atom in the

strychninemolecule. Briefly,it may be said that the characteristic

action dependson the presence of loth oxygen atoms ; removal of

either lessens the activity,removal of both destroysit.

Thus Desoxystryclinine AJ

is more bitterthan strychninebut less toxic.

Dihydrostrychnoline "j

has no action on the cord.

Strychnidine

(C20H22OCH2

is bitter,and physiologicallystands between strychnineand desoxystrychnine.

Strychnoline

is inactive.

Electrolyticreduction of strychninegivesrise to two bodies

(Tafel),


CHAPTEE XIV

THE ALKALOIDS (CONTINUED). "so-quinolinegroup " Hydrastine,

Cotarnine, Berberine. Morpholine (?)-Phenanthrenegroup " Morphine,Codeine, and Opium Alkaloids. Hordenine.

IV. ô-QUINOLINE GROUP.

IN this group are contained a number of alkaloids,the therapeuticeffectsof which differconsiderably,in degreeif not in kind. Some

of them are derived from Opium,viz, Papaverine,

Narcotine,Narceine ;

others from HydrastisCannadensis,viz.Hydrastine,

Berberine.

The latter planthas been extensivelyused in order to arrest

haemorrhage,owing to its action as a vaso-constrictor,and it has

also been employedin placeof ergotto stimulate uterine contrac-tions.

It has thus very littlein common with opium from the

therapeuticpointof view,and it is a curious fact that its alkaloidal

principlesshould be so closelyrelated chemicallyto some of those

found in the last-named plant.

Hydrastine * C21H21NOg,has the formula "

CH2

and differs from narcotine in possessingone methoxylgroup less.

Its physiologicalaction is stilla matter of some doubt,especiallyas

regardsits direct action on the muscular walls of the smaller blood-vessels

and the uterus. In toxic doses it has an action resembling

HYDRASTINE AND HYDRASTININE 285

that of strychnine,but itis also a directmuscle poisonand a gastro-intestinalirritant. In moderate doses,it stimulates and then

paralysesthe centres in the medulla and cord,and,after possiblya short stageof excitation,depressesboth voluntaryand involuntarymuscle. Many authors assert that it has a direct ecbolic action.

In medicine its main value lies in its action on the medullarycentres,wherebythe vagus, vaso-constrictor,and respiratorycentres

are stimulated,and the blood pressure rises. Its action on involun-tary

muscle,however,causes cardiac weakness,and the rise is not

maintained for long.Theoretically,its strychnine-likeaction is interesting,the latter

alkaloid belongingto a group which ischemicallyso closelyrelated

(quinoline).When hydrastineis decomposed,water is taken up, and two

bodies,hydrastinineand opianicacid,are produced.

C21H21N06+ H20 = CIOHM06 + CnH:3NOsHydrastine. Opianicacid. Hydrastinine.

Opianicacid has the constitutional formula

CHO

Similarly,narcotine yieldsopianicacid and cotarnine.

C22H27N07+ H20 = C10H1006+ C12H16N04Narcotine. Cotarnine.

Hydrastinineand cotarnine have very similar constitutions-

CH2 CH,

CR

H.CH3:HO

Hydrastinine. Cotarnine.

The positionof dioxymethylene-and methoxy-groupsare not

known with certainty.The aldehydegroup CHO, in the formula for hydrastinine,best

explainsits physiologicalcharacters,most alkaloidal vaso-con-

strictorshavingthis group (cf.yohimbine,which,however,has but

a slighteffecton the arterioles).

286 HYDRASTININE

The action of hydrastinine differsmarkedlyfrom that of its

parent substance. It has no convulsant action,"and it does not

weaken the heart ; on the other hand, it is a depressantof the

cerebral cortical cells. Its action on the uterine muscle is not

certain,nor is it yet decided whether it has any direct effect on

the arterial walls. Its power of raisingthe blood pressure is more

sustained owing to cardiac stimulation. It is also a mydriatic.Death occurs owing to respiratoryfailure. The action of hydrastineon the blood pressure may be regardedas partof its strychnine-likeproperties.Hydrastinine,on the other hand, has a more specialized

power, and heightensthe contractilityof the cardiac muscle. The

same effect,namely,a rise in blood pressure, is thus producedbya somewhat different means in the two bodies,and is moreover

much more marked in hydrastinine.Accordingto the aldehydeformula,it contains the group " NH.CH3. It is thus a secondaryamine, and contains a hydrogen atom replaceableby methyl.A pentavalentbody of this kind,trimethyl-hydrastylammonium

chloride,has been prepared. It has but littlevaso-constrictor

action ; itproducesa generalparalysis,with an initialriseof blood

pressure followed by a fall. Death occurs, as with curare, from

paralysisof the respiratorymuscles (peripheral).An oxidation product,hydrastininicacid,

CO.NH.CH3

isphysiologicallyinactive.

Opianic acid CHO

0kJoOCH

has slightnarcotic properties.It is almost inactive in the case of

warm-blooded animals,but in the case of cold-blooded animals it

producesnarcosis,paralysisof centralorigin,and very slightmuscularcontractions. Its combination with the hydrastininemolecule seems

to producea diminution of physiologicalactivity,as well as certain

marked alterationsin the latterwhich have alreadybeen noted.

Narcotine, Cot ar nine, and Hydrocotarnine resemble other

alkaloids of the morphinegroup ; they may be considered here in

COTAKNINE 287

their relation to hydrastinine.Two o" the salts of cotarnine have

recentlybeen introduced into medicine,the hydrochloride,known as

' Stypticin ', and the phthalate,'Styptol'. These trade names

indicate the use for which theyare intended,but it isprobablethat

that result is producedby these drugs in a somewhat different

manner. Cotarnine hydrochloride,which retains slightlythe nar-cotic

propertiesof narcotine,has no vaso-constrictor action,nor

does it increase the coagulabilityof the blood. Its effect as a

stypticis thoughtto be due to its slowingthe respiratorymove-ments,

whereby the blood stream is somewhat retarded and the

formation of a clot favoured. The phthalicacid compound has

also a distinct sedative effect,followed,if largedoses are given,byconvulsions,paralysis,and death. It has no action on the heart,but death occurs from respiratoryfailure. It is said to induce

uterine contractions. It appears to have some direct action in

checkingcapillarybleeding,for it is not a vaso-constrictor. This

action is,at any rate,in partdue to the phthalicacid,

PTT/COOH ,"

U^*\COOB

as neutral phthalateof ammonium acts similarlybut not so

powerfully.Narcotine and hydrastine,with their various derivatives and

compounds,act on the whole in very similar manner, and the

secondaryproductscorrespondfairlycloselywith one another. The

main pointsof difference are that all narcotine derivatives tend to

reproducethe narcotine action of the originalsubstance,while the

productsformed from hydrastineact most markedly on the

arteriolesand the blood pressure.

Methyl-narcotimideis a marked local anaesthetic ; the amide is

uncertain in itsaction on man, sometimes resemblingmorphineandsometimes codeine.

Methyl-hydrastamideis a vaso-dilator,and has been unsuccess-fully

tried as an emmenagogue.

Berberine, C20H17NO4,the remainingalkaloid of hydrastis,has

very littleaction in the amount in which it is presentin the drug.20 grams (300 grains)have failed to produceany symptoms in

man. It is said to be completelydecomposedin the body,thus

differingfrom hydrastine,which is excreted unchanged in the

urine. Its constitution is expressed,in all probability,by the

formula "

288 MORPHOLINE (P)-PHENANTHRENE GROUP

OCH3

Large doses lower the blood pressure, raise the body temperature,increase peristalsis,and finallyproducegeneralparalysisof central

origin.As a constituent of hydrastiscanadensis,it probablyacts

onlyas af bitter '.

Hydro-berberine,which contains four atoms more of hydrogen,is a vaso-constrictor,raisingthe blood pressure by its action on the

centre in the medulla. It also producesconvulsions of spinal

originbefore the final paralysis.The generalchange in physio-logicalaction producedby the addition of hydrogenis thus well

illustrated. Berberilic acid,

CH 0"C"H2' CO-NH-CH2 " CH2 . C6H2"(")"CH2COOH COOH

like the correspondingoxidation productof hydrastine,is physio-logicallyinactive.

V. MOEPHOLINE(?)-PHENANTHRENE GROUP.

Alkaloids of Opium.

Opium is said to contain no lessthan twenty-onealkaloids,besides

five non-basic substances,some of which are physiologicallyactive.

Besides these there are numerous alkaloidal bodies which have been

artificiallyproducedfrom the opium bases,and of these a few are of

pharmacologicalimportance.Chemically,the opium alkaloids fall into two main groups, the

w0-quinolinegroup and the phenanthrenegroup. Physiologicallyalso,two main groups may be described,namely,those with the

physiologicalattributes of morphineand those resemblingthebaine.

Unfortunatelythese two groups do not correspondin the very

OPIUM ALKALOIDS 289

least; both morphineand thebaine,for instance,belongchemicallyto the phenanthrenegroup.

Before consideringthe compositionand propertiesof these bodies

in detail,a few generalobservations may be made. Chemically,the

questionof the structure of morphinecannot be regardedas settled,

as neither of the suggestedformulae is in consonance with all the

facts. Physiologically,much attention must be givento the details

of any experimentson the action of these bases in the organism.The discordant resultswhich have occasionallybeen obtained make

it clear that much dependsboth on the size of the dose of any givenalkaloid,and the speciesof animal employedin the experiment.For

instance,originallyC. Bernard described morphineas soporificand

thebaine as tetanizing,and the other alkaloids have been classed as

belongingto one or other of these groups. As a matter of fact,

however,careful experimentwith graduateddoses has shown that

all the opium alkaloids possess both actions,but that they are

developedin very different proportions.Thus though Bernard's

classificationis very convenient and marks the main action of these

bodies,it must be remembered that intermediarysubstances occur,

and that in no substance is either the soporificor the tetanizingaction entirelyabsent.

With regardto the various artificialproductswhich have been

constructed from morphine,it will be found that in generalthey

only differ from that substance physiologicallyin a qualitative

manner, so longas onlythe circumferential portionsof the molecule

are altered. If,however,the intimate structure is broken down,

productswill result differingentirelyin their pharmacologicalproperties(cf.apomorphine).

The principalalkaloids belongingto the phenanthrenegroupare: "

Morphine,Codeine,Thebaine.

Those of the w-quinolinegroup are :"

Papaverine,Narcotine,

Narceine,

Laudanosine,

Laudanine,

Cotarnine,

Hydro-cotarnine.

290 MORPHINE

Of these,narcotine,cotarnine and hydro-cotarninehave alreadybeen partiallyconsidered in connexion with the zso-quinolinegroup.

They will,however,be brieflydealt with in this section in so far

as their pharmacologyconnects them with the opium alkaloids.

Morphine, C17H19NO3.

Knorr's formula for morphineis based on its apparent originfrom two bodies,phenanthreneand morpholine,justas cocaine and

atropineoriginatein a double-ringtropine.Phenanthrene is representedby the formula

8

9 10

The numbers indicate the method of nomenclature of its derivatives.

For dogs this substance is inert,and after oxidation is eliminated

as a compound of glycuronicacid. This reaction,however,appearsnot to be universal,as in some animals it has a narcotic effect. If,however, one or more hydroxylgroups are introduced,e. g. 2, 3,and 9-phenanthrol,substances are obtained producingsevere tetanic

convulsions in warm-blooded animals. Phenanthrene- 9-carboxylicacid,4-methoxy-phenanthrene-9-carboxylicacid,and phenanthrene-3-sulphonicacid have a similar action. The introduction of more

oxymethyl or acetylgroups, however,has the effect of lesseningboth the toxicityand the tetanizingaction. It does not appear

that any phenanthrenederivatives as yetknown have any narcotic

effect,thoughone compound of phenanthrene-quinone,

CO CO

namely 2-brom-phenanthrene-l-sulphonicacid,is said to have a

morphine-likeaction on the respiratorycentre.

Morphine is supposedto be a derivative of tetrahydro-dioxy-phenanthrene,to which the morpholinecomplex is united. Knorr

assignedto the alkaloid the structural formula"


292 NAPHTHALAN-MORPHOLINE

and codeine in itschemical relationshipsthan any of the synthetic

morpholinebases. It is a combination of tetrahydro-naphthalene,

and morpholine,

O

N

H

and has the formula "

S. Frankel throws doubts on the resemblance between the physio-logicalaction of this substance and that of morphineon man, but

Leubuscher l states that it is very close.

Vahlen,on the assumptionthat the phenanthrenenucleus was

the more importantportionof the morphinemolecule,synthesizedan amido-oxy-phenanthrene,to the hydrochlorideof which he gave

the name Morpbigeuiu "

Many derivatives of this body were obtained which acted like

morphinephysiologically,but chemicallytheywere not pure. One,

however,called

1 AnnaUn, 307, 172,1899.

THE PHENOLIC HYDROXYL 293

Epiosin

N N.CH,

was said to have analgesicand slightnarcotic action,and to

produceconvulsions,thus resemblingcodeine. It did not,however,slow the pulse,whereas it did raise the blood pressure, thus differ-ing

from morphine. There were also greatquantitativedifferences,"12 gm. correspondingto about -3gm. dionine. Pschorr,however,holds that all this work is at fault,and states that the originalsubstance was not morphigeninbut a nitrogen-freephenanthrenederivative.

It is to the presence of the phenolichydroxylgroup that mor-phine

owes its acid properties.The hydrogenmay be replacedby an alkylgroup, or an acid radical. If this is done,a remark-able

change in the physiologicalaction takes place,and the

characteristic narcotic effect is either much diminished or en-tirely

lost. The narcotic effect of morphine on man is much

more marked than on the lower animals,owing to the more com-plex

developmentof the highestnervous centres,and its toxic

effect is also,for similar reasons, far greater. The diminution of

this action,and the increase in tetanizingpower which accompanies

any substitution of the hydrogen of the phenolichydroxylbyanother group, is due to a destruction of the ' anchoring' group for

narcosis and not to the introduction of any new factor. That this

is so may be seen from the facts that (1)any substitution productshows the same physiologicaleffect,those compounded with in-organic

acids are, however,rather more easilydissociated in the

organism; (2)a dimorphine,in which two morphinemolecules are

united by an ethyleneresidue,e. g.

Ethylene-dimorphine,

CHN0

is without narcotic effect.

Of the numerous substances,both natural and artificial,more or

less resemblingmorphine in action,it will only be necessary to

mention a few which eitherillustratea pharmaco-dynamicprinciple,or have been actuallyused in medicine.

294 CODEINE AND DIONINE

Codeine, C17H18NO2. OCH3.

This is the methylether of morphinein which the hydrogenofthe phenol-hydroxylgroup has been replacedby methyl,and the

constitutional formula for this alkaloid is consequentlydependenton that of morphine. It was obtained in 1881 by Grimaux by the

action of methyl-iodideand an alkali on morphine,

CH3O\ /O" CH2'

^N" CH2Alcohol hydroxyl.

CH3

Owing to its small toxicityin man and its sedative action on the

respiratorymucosa, it is largelyemployedin therapeutics.Experi-mentally,it stands midway between morphine and thebaine. It is

much more toxic for animals than morphine. Metabolic processes

seem to be less influenced,and constipationis not so marked.

Codeine is incapableof forming an ether correspondingto the

morphinetherof morphine,in which linkagetakes placethrough

phenolichydroxyl,as the distinctivemethyl group would in that

case be lost.

Acetyl codeine

O" CH2

(CH3CO)CK"

"

"

XN-CH2

CH,

has been prepared,but is practicallyuseless,as it does not affect

respirationand causes extreme reflexirritability(Dreser).

Dionine C,H5 . Ox /O" CH2"C14H10"|

HO/ \N" CH2

CH3

is the hydrochlorideof ethylmorphine,and differs somewhat

markedlyfrom the numerous morphinesubstitution productswhichhave been constructed and tested physiologically.In the firstplaceit is very easilysoluble in water, and is therefore suitable for

hypodermicinjection,and in the second placeit is fathermorepowerfulin its action than the correspondingmethyl derivative

(codeine).In this it illustrates a generalpracticalrule,ethylic

HEROINE 295

compoundsbeing-usuallymore effectivephysiologicallythan those

of methyl. Higher homologuesand substitutions with aromatic

radicals act less powerfullythan codeine and dionine.

Dionine has also analgesicproperties,and has been employedin

ophthalmicpractice.It is not a localanaesthetic,and occasionallysets up some irritationof the conjunctivawith considerable chemosis

(Hinshelwood).

Heroine.

This is a diacetylcompound, both the alcoholic and phenolichydroxylgroups beingsubstituted. It is thus a diacetic ester of

morphine"

CH3CO.(X /O" CH2/C14H10\ I

CH,CO.(X XN" CH9

CH3

Its action on the respirationis in some way selective,and is said

to be more sedative than that of morphine. It is,at any rate,

more powerfulthan codeine. The frequencyof the respirationis

diminished,and cough is checked. It has no marked anaesthetic

action,but is generallysoporific.Harnack,who objectedto its use

therapeutically,owing to itstoxic properties,remarked that acetylsubstitution productsof hetero-cycliccompoundsusuallymanifested

high toxicity.This,however,is not exactlytrue,and the fact

seems to be that the acetylgroup renders a substance more toxic

when it replaceshydroxylhydrogen,and lesstoxic when it replacesamide hydrogen(S.Frankel).Examplesmay be found in atropine,

scopolamine,and homatropine,which are more toxic than tropine,and cocaine,which againis more toxic than ecgonine.The best

example,however,may be found in aconitine,where the substitu-tion

of acetylfor the hydroxylgroup converts an almost inert bodyinto a powerfulpoison,while the introduction of two more acetyl

groups has no effect exceptto slightlydecrease the toxicity(Cashand Dunstan). Heroine is largelyused owing to itsspecificaction

on the respiratorycentre. The minimal fatal dose for rabbits is

said to be a littlelargerthan that of codeine (-1gram per kilo,

body-weight),but the minimal effective dose in practiceis onlyone-tenth that of codeine. The hydrochlorideis usuallyprescribed

owing to its solubility.The mono-acetylcompoundis not employed,it is more like morphinein its action,havingless tendencyto pro-

296 MORPHINE AND CODEINE DERIVATIVES

duce tetanic convulsions,greaterhypnoticpower, and less toxicitythan heroine. It has,however,no specialaction on the respiratory

organs.

Benzoyl morphine "

C6H5CO.O

" CH2

CH3

The action of this compound is very similar to that of codeine,and thus illustrates the rule that the substitution productsof mor-phine

owe their physiologicalaction to the fact that the anchoring

group for the narcotic effectis partlycovered,and that the group

introduced for this purpose is of comparativelysmall importance.

Practically,however,benzoylmorphine,which has been introduced

into pharmacyunder the name of Peronine, has the disadvantageof being less soluble than either heroine or dionine,and also of

possessinga burningtaste.

Less Important Artificial Derivatives.

Morpho-chinoline ether

OC9H6NV /O" CH,

N-CH

CH

is interesting,though of no practicalvalue. It has the main

characteristicsof codeine,causingspasm, especiallyof the respira-torymuscles,and a rise of blood pressure. It acts throughthe

centres in the medulla.

Chlorine and bromine have been substituted for various hydroxyland hydrogen atoms, with the generalresult of destroyingthenarcotic effect.

The chloride of codeine

CHO /O" CH

|N-CH

is a powerfulmuscle poison,in addition to possessinga generalcodeine-like action. This is supposedto be due to the halogen,

METHO-CODEINE AND wo-MORPHINE 297

which is known as a muscle poison(asfor examplein CHC13),but

it is curious that morphinetrichloride,

Cl X)-CHC1(?)"C14H10"I

CK XN" CH2ICH3

which contains three chlorine atoms is onlya slightmuscle poison.Metho-codeine "

/O CH2CH0(X / C

HCK N CH2

C H3

The ring-structure in this compound is broken,with a consequent

change in the physiologicalaction. There are no narcotic and

tetanizingactions,but onlymuscle poisoningand slightdepressionof the cord. There is some blood changealso,so that the urine

becomes deepgreen. It thus clearlyresembles apomorphine,exceptthat it producesno vomiting;it was formerlyconsidered to be

identicalin compositionwith that body.It has no action on the pupils,but depressesthe respiratory

centres like morphine; unlike that drug it increases the blood

pressure, and frequencyof the heart. Its stereo-isomer has a similar

action.

^-Morphine is a substance obtained,togetherwith small

quantitiesof an isomeric derivative /3-/s0-morphine,by the action

of water on brom-morphine. The followingformula has been

suggested:"

" CH2" CH2

N.CH3

The corresponding2"0-codeinehas also been prepared,but neither

of these derivatives has any narcotic action,even when givenin

gram doses. If the constitutional formula givenabove is correct,

the failurein physiologicalaction may be attributed to the changein positionof the morpholinering,which is there representedasattached to one benzene nucleus only.Compounds of morphineand codeine,in which the nitrogenis

298 THEBAINE

quinquevalent,have been investigated.They are the so-called

brommethylatesand have the formulae"

ca CH.(X

HO

)

CH

'"\iCH, Bi

"CH,

CH,

Physiologically,theyare characterized by a greatdiminution of

toxicity,due to their rapidand completeelimination in the urine.

In cats the tetanizingaction is especiallydiminished.

Thebaine, C19H21NO3.This substance,a possiblestructural formula for which is written

below,is not only physiologicallydifferent from morphine,as it

producespracticallyno narcosis and is an active tetanizingagent,but differs also chemicallyin beingderived from a dihydrophenan-threne,instead of a tetrahydrophenanthrene,and in havingboth its

hydroxylhydrogensreplacedby methylgroups.

CH2" CH2" N.CH3

O.CH O.CH,

The fact that it does not producea morphineeffect is probablyowing to the absence of an

' anchoring'OH group, as well as to

differences in the number of hydrogenatoms combined with the

phenanthrenering.

By the action of dilute HC1, a substance known as thebenine can

be produced,which has a generalparalysingaction. Its structure

may possiblybe representedas follows :"

CH2 CH2\

OCH " NH.CH, \0

CH

* The positionof these hydrogen atoms is not certain.


300 NARCOTINE AND COTARNINE

has practicallyno narcotic action,as the OH group is absent,which

serves as an anchoringgroup to the cells of the cerebrum. The

anchoringgroup for the spinalcord (tetanizing)has not been

identified.

Laudanine, C20H25NO4,which also occurs in two stereo-isomers,has a constitution similar to that of laudanosine,but contains onlythree methoxygroups, and one hydroxyl,in placeof the four methoxy

groups contained in that alkaloid. The racemic form can be

converted into racemic laudanosine. It should be less powerfula poisonthan laudanosine,owing to the fact that it has one less

methoxy group.

Narcotine, C22H23NO7, closelyresembles hydrastine(p.284)in its chemical structure,it is methoxy-hydrastine"

O.CH,

Its action resembles that of morphine,but is much feebler;it

producesa short periodof slightexaltation of sensibility,and a

littleshivering,and then loss of sensation,intoxication,and paralysis.Some loss of sensibilityin the eyes and of the nerves to electrical

stimulation occurs. The soporificaction predominates.It is said

that in cats tetanic convulsions precedethe stageof narcosis (Mohr),while in man therapeuticdoses are onlyused as an antipyretic.Itis also stated to be aphrodisiac.

Cotarnine is a decompositionproductof narcotine,and its con-stitution

is most probablyrepresentedby the formula"

H.CH,

O.CH,

The other productis the non-nitrogenousopianicacid,C10H10O5

(p.286). It has a slightparalysingaction on motor nerves, but

not more than other members of the group. Hydro-cotarnine,which contains two less atoms of hydrogen than cotarnine,acts

APOMORPHINE AND APOCODEINE 301

similarlyto codeine,but is less toxic. It is,however,more toxic

than morphine.Narceine, the constitution of which is very probablyrepresented

by the formula written below, since it may be obtained by the

action of potashon the iodomethylateof narcotine,is said to be

inactive in doses of 1 gram or more (Mohr). It is a tertiarybase,and a substituted phenyl-benzylketone.

O.CH

A sodium compound of narceine combined with sodium salicylatehas been introduced into pharmacyunder the name of Antispasxuiu.

Its action resembles that of morphine,but is fortyto fiftytimes

weaker.

Narceine-phenyl-hydrazoneis said to produceconvulsions and

respiratoryparalysisin doses of "! gram per kilo, body-weight.

Narceine-ethyl-hydrochloridehas recentlybeen introduced,under

the name of Narcyl, as a remedy for irritablecough. The medi-cinal

dose is -06 gram.

Apomorphine and Apocodeine.

Dehydratingagents act on morphine in two ways, either byproducingcondensation products" trimorphineand tetramorphine,"c.,or by simplyabstractingone molecule of water, givingrise to

apomorphine, C17H19NO3" H2O = C17H17NO2.This substance can

be shown to contain (1)two free hydroxylgroups, and (2)tertiarynitrogenin ringformation ; accordingto Pschorr,it is a derivative

of phenanthrene-quinoline"

CH2 N.CH3

H

302 APOMORPHINE AND APOCODEINE

The positionof the hydroxylin the ring-is,however,conjectural.

Physiologically,apomorphineis marked by slightnarcotic action,but by a considerable degreeof excitorypower, followed by paralysisof the spinalcord and medulla. The emetic action of morphineis

immenselyincreased. It will be noted that the constitution givenabove for apomorphinedoes not resemble that of morphineat all

closely.The phenanthreneringis indeed represented,but not the

morpholine.Hence Pschorr has suggestedan alternative structure

for morphine,the so-called ' pyridine' formula "

This arrangement,however, does not explaincertain chemical

reactions,e.g. the splittingoff of morphol and morphenolfrom

morphine.It will be seen that,whatever the real structure of morphinemay

be,apomorphineis not derived from it solelyby the abstraction of

water, but that its productionalso involves profoundalterations in

the ringsystems to which the physiologicaldifferences must be

attributed.

The methylbromideof apomorphine(Euporphin)is a lesspower-ful

emetic,and has less action on the heart. The removal of the

elements of water from codeine givesrise to a substance (apocodeine)having similar physiologicalreactions,though not so powerful.Its constitution is not definitelyknown, as it has been found

impossibleto prove the presence of one free OH group, which byanalogyit should contain.

Apocodeiue has been shown by Dixon to exert a nicotine-like

action on nerve cells,and this fact suggeststhat the purgativeaction of opiumalkaloidsvaries directlywith their paralysingaction

on the sympatheticganglia. Larger doses paralysemotor nerve

endings" firstthose of skeletalmuscles and then those of the arterial

walls;laterthose of intestineand bladder,and the acceleratorfibresto

HOKDENINE 303

the heartare

affected. Owing- to its actionon the ganglionic

nerve cells, he has suggested itsuse as a hypodermic purgative.

Addendum to Alkaloids.

Hordenine,1 C10H15ON, isan

alkaloidal body obtained by E. Leger

from malt. It isa

colourless crystalline substance, dissolving readily

in alcohol, chloroform, orether

; Leger 2 has suggested for it the

following formula:

"

1 :4 C6

It formsa

number of salts whichare readily soluble in water, and

whose pharmacological action has been investigated by Camus.3

The sulphate is notvery toxic, the minimum lethal dose for

a dog being -3 gm. perkilo intravenously. After small doses the

vagusis stimulated, and the heart beats

more slowly and vigorously;

larger doses paralyse thevagus

centre. A rise of bloodpressure

and acceleration of the pulse rate followson the administration of

1gram per kilo, to a dog or

rabbitper os.

Whena

fatal dose is

given death occursfrom respiratory failure. The action of this

body therefore closely resembles that of phenol itself.

1 Comp. Eend., 1906, 142, 108. " ""., 1906, 143, 234.

3 ib., 1906, 142, 110.

CHAPTER XV

SYNTHETIC PRODUCTS WITH PHYSIOLOGICAL ACTION SIMILAR TO

COCAINE, ATROPINE, HYDRASTIS." Derivatives of Piperidine,Pyrrolidine,Amido- and Oxy-amido-benzoicacid,j9ara-Amido-phenol,Guanidine, TertiaryAmyl-alcohol. Halogen and other derivatives. Substitutes for Atropine,Hydrastis.

A LAftGE number of syntheticproductshave recentlybeen intro-duced,

the physiologicalaction of which resembles that of various

natural alkaloids. Structurallythey often closelyresemble the

bodies they are intended to replace,and in some cases they have

certain pharmacologicaladvantagesas regardstoxicity,rapidityof

action,"c. For convenience they will here be grouped accordingto the alkaloid they are intended to replace,i.e. accordingto their

physiologicalproperties.The various salts of quinineand other

bodies introduced as improvementson quininehave alreadybeen

described,as these are not true substitutes but merelymodificationsof the originalalkaloid.

I. SUBSTITUTES FOR COCAINE.

A. Derivatives of Piperidine and Pyrrolidine.

A group of bodies has been introduced as cocaine substitutes,the

studyof which admirablyillustratesthe relationshipbetween physio-logicalaction and chemical structure,namely,those derived from

diacetone-amine,triacetone-amine,and their correspondingalcohols.The firsttwo of these are formed by the action of ammonia on

acetone :"

CH3 CH3

AoiH, CH,

diacetone-amine.

SYNTHESIS OF TBIACETONE-AMINE 305

(*) CH3 CO

T / \riTJCH3 CO + 2NH3 =

(CH3)+

C\JC(CH3)2NH

triacetone-amine.

Diacetone-amine,on heatingwith acetone,givestriacetone-amine"

CO CO

CH/\CH3 CH/\CH2

NH2 NH

Aldehydereacts in a similarmanner, and by this means a seriesof

bases similar to triacetone-amine may be synthesized.Thus acet-

aldehydegivesthe so-calledvinyl-diacetoner-amine"

CO CO

CH,/\CH3 CHj/NcH,,+ COH.CHq= +H2"

(CHÔv 3(CH3)2CVCH(CH3)NH2 KH

By the action of methylamineand ethylamineon acetone,alkylderivativesof diacetone-amine are formed.

Triacetone-amine

CH3

" C -CH3" C - CH2I INH CO

CH3" C - CH

CH3has a powerfulcurare-likeaction; itsreduced derivativealkamine

CH3

/~1TT /-I fVTTvyXljj Vy " " ^stt.^

NH CH.OH

CH3" C CH2

CH,

306 COMPARISON OF ECGONINE "TRIACETONE-AMINE

and the compoundsderived therefrom manifest a similar action;the introduction of a carboxylgroup

CH,

CH3" C CH2

CH3" C CH

c

abolishes this action altogetherbut producesa substance which is

more powerfullytoxic.A comparisonof the structure of the methyl derivative of tri-

acetone-alkamine with that of tropineand ecgoninereveals a re-markable

similarity,so that it was possiblefor Merlingto predictthe physiologicalaction of the derivatives of methyl-triacetone-alkamine by a knowledgeof those of the correspondingecgonine

compounds.

L3

Triacetone-methyl-alkamine.

CH2" CH CH.COOH CH2" CH CH2

N.CH3 CH.OH N.CH3 CH.OH

CH2" CH CH2 CH2" CH CH2

Ecgonine. Tropine.

If a carboxylgroup isintroduced into the firstof these derivatives,

a body is producedresemblingecgoninestillmore closely,the main

differencesbeingthat the carboxylstands in a different relation to

the nitrogen,and the second ringis not closed :"


308 DERIVATIVES OF TRIACETONE-AMINE

in normal saline at body temperature,(2)mixing some adrenalin

solution with the localanaesthetic.

The benzoylgroup in eucaine cannot be replacedby acetylwith-out

loss of anaesthetic action (asis the case with cocaine),but other

aromatic radicals may replacethe benzoyland leave the localanaes-thetic

action intact. The amygdalicacid derivative,however,is an

exception.The derivatives of triacetone-alkamine behave similarlyto those

of the carboxylderivative,thoughneither of the parentsubstances

has any local anaesthetic power. The alkylgroup in eucaine

which replacesthe carboxylichydrogenis not of physiologicalimportance,thus forming a contrast to cocaine.

Benzoyl-triaeetone-alkamine-carboxylis a local anaesthetic "

CH3

CH3" C - CH2

NH*cooH

CH3" C CH2

"H,

Triacetone-amine, and triaceton^-alkamine

CH3 CH3

CH3" C CH2 CH3" C CH2

NH CO NH CH.OH

CH3" C CH2 CH3" C CH2

CH3 CH3produceonly slightlocal irritation,whereas triacetone-alkamine-

carboxyl

CH3

CH3" C CH2

NH 0/OHI\COOH

""

C C HoCH3-

CH3

PYRROLIDINE DERIVATIVES 309

is a powerfullocalirritant. The carboxylgroup seems therefore to

be responsiblefor this effect,which may be much modified byesterification. These esters are, however,two or three times more

toxic than the bodies from which they are derived; thus the

derivative producedby the substitution of cinnamylfor benzoylin a-eucaine " the methyl-esterof cinnamyl-#-methyl-triacetone-alkamine-carboxyl" is three times more toxic than the corresponding

cinnamyl-w-methyl-triacetone-alkamine.The latter and the corre-sponding

methane compound are among the leasttoxic bodies of the

series; the phenyland amygdyl derivatives are the most toxic. The

alkylderivatives (ethyland methyl),thoughmuch more toxic than

the mother substances,are less so than the aromatic substitution

products.A lower homologue of benzoyl-triacetone-alkamine,benzoyl-

/S-hydroxy-tetramethyl-pyrrolidinehas a powerfullocalanaesthetic

action,and is lesstoxic than jS-eucaine"

CH3

CH8" C CH2

NH

CH3" C CH.O.COCflH6

CH3

The mandelic acid ester

H.O.CO.(CHOH)C6Hf

has a slighteraction on the pupilthan euphthalmine,which it

closelyresembles. In fact,a completeseries of derivatives can be

obtained from the pyrrolidinebase correspondingphysiologicallyto those from pyridine,thus illustratingthe close relationshipbetween these two bodies.

The generalaction of the bodies of the eucaine group, when given

310 OXY-AMIDO-BENZOIC ACIDS

in largerdoses than those necessary to producethe therapeuticeffect,is paralysisof the central nervous system after a more or

less marked periodof excitation. Those which contain carboxyl(eitherwith or without the ester group)produceincrease in reflexes,excitement,generaltonic and clonic convulsions,and finallypara-lysis.

The peripheralnervous systemis unaffected.

In the bodies without a carboxylgroup the excitement is of

shorter duration,the generalparalysisappears earlier,and is more

complete.The motor nerve endingsare acted on as in the case of

curare, and largerdoses paralysethe vagus. Generallyspeaking,the two classes are typifiedby the toxic symptoms of a-eucaine and

/3-eucainerespectively.

B. Derivatives of Ainido and Oxyamido Benzoic Acid.

Another seriesof localanaesthetics has been introduced,of which

orthoform is typical.Einhorn and Heintz found that the benzoylesters of oxy-amido-benzoicacid possessedanaesthetic properties,and on the analogyof cocaine thoughtthat,if the benzoylgroupwere removed,the anaesthetic action would disappear.This,how-ever,

was found not to be the case, and by replacingthe benzoyl

group more intenselypowerfulsubstances were in some instances

produced.Many of these compounds,however,are irritatingor painfulon

injection,and some have but a slightanaesthetic effect.

The methylester of 0-amino-#"-oxybenzoicacid

H2

producesan anaesthesia which is hardlyperceptible,but the methylester ofjo-amido-w-oxybenzoicacid

is well known as the local anaesthetic Orthoform. This body

being very slightlysoluble is also but feeblytoxic. It is,

however, only active when directlyappliedto the nerve endings,and is useless when appliedto the unbroken skin or mucous mem-brane.

Its soluble hydrochlorideis not available in practice,owingto the pain producedby its injection.Orthoform has also been

observed to give rise to severe dermatitis of an erythematous,

ORTHOFORM-NEU 311

pustular,or even gangrenous type. It is also somewhat expensive(rathermore so than morphinehydrochloride).

Orthoform-nen (the new orthoform),the methyl ester of

j0-hydroxy-7"-amido-benzoicacid,

is much cheaper,and equallyactive physiologically,but exceptfor this it appears to have the same disadvantagesas orthoform.

Its hydrochlorideis soluble,but irritant. It may be obtained from

79-oxy-benzoicacid,a substance which results from the action of

carbon-dioxide on potassiumphenateat a temperatureof 200-220 "C.

When this acid is acted upon by dilute nitric acid,#z-nitro-oxy-benzoic acid results,which is then converted into its methyl ester

and reduced :"

COOH COOH COOCH8 COOCH3

OH

OH

A very largenumber of bodies have been preparedwhich re-semble

orthoform,but onlya few are of any practicaluse. It has been

found generallythat those containinga hydroxylgroup in the

benzene nucleus,either free or substituted,are all irritant;those

which do not exhibit this structure are unirritating.In order to obtain a soluble compound, Einhorn prepared

glycocollderivatives of the amido and carboxy-amidoacids of this

series. These compoundsprovedto have anaesthetic properties,but

differed from the mother-substance in being stronglybasic and

easilysoluble in water. Their anaesthetic powers do not in any

way correspondquantitativelyto the substances from which theyare

derived.

Nirvanine isthe methylester of diethyl-glycocoll-7"-amido-0-oxy-benzoic acid"

OH

NH.COCH2N(C2H5)2

312 ANAESTHESIN AND NOVOCAIN

It is less toxic than orthoform,and has also an antisepticaction.It is very soluble in water. It has no action on the unbroken skin ;

injectionsproducepainand localoedema,and it is far too irritatingfor ophthalmicwork.

The ethylester of 7?-amino-benzoicacid is a local anaesthetic,and is known as Anaesthesin,

It is obtained by the seriesof reactions formulated as follows :"

C6H6CH3Toluene. NO2 NO2

2?-nitrotoluene. ^-nitro-benzoicacid.

COOC2H5 reduced ,COOC2H5

ethylester of

#-nitro-benzoicacid*

Its action is similar to that of orthoform.

Novocain is the hydrochlorideof the diethyl-amino-ethynolester

ofjt?-amido-benzoicacid"

COO.C2H4N(C2H6)2. HC1

It is said to be non-irritant even in strongsolutions. It is soluble

in one part of water, and the solution may be boiled without

decomposition.Its toxicityis slight.The substances above enumerated,with the possibleexceptionof

novocain,are obviouslyunsuitable for producingsurgicalanaes-thesia.

They have,however,been employedwith varyingsuccessto allaygastricpain,due either to an organiclesionor to functional

derangement.Anaesthesin has also been employedto allayvomiting,when due

to causes within the stomach,but seeingthat in most of these cases

the vomitingserves to remove an irritant and nocuous substance,

the fieldof utilityfor the drug in this direction appears to be some-what

limited. As illustratingthe purelylocal action of anaes-

thesin on the gastricmucosa, it is found that it will counteract the

effectsof tartar emetic,but not those of apomorphine(Reiss).

HOLOCAINE 313

C. Derivatives of jo-Amido Phenol.

The anilinederivatives,thoughmainlyused as generalanalgesics,have a slightlocalanaesthetic action,and in some this propertyis

sufficientlymarked to givethem a practicalvalue.

Phenetidin,OC2H5

when combined with a second ring,givesrise to the compoundknown as Holocaine.

Holocaiue, the condensation productof ^-phenetidineand phen-

acetin,

+ CH3.CjOjNH.C6H4.OC2H6

= OC2H6")"-N;C.NH,C6H4OC2H5CH3

as employedin practice,is the hydrochlorideofjo-diethoxy-ethenyl-diphenylamine"

CH8C"^\

It is more toxic than cocaine,but it producesa rapidanaesthesia.It keepswell,but has the disadvantageof beingonly slightlysoluble. In toxic doses it producesgeneralconvulsions. Its prac-tical

applicationhas been limited to ophthalmicoperations; two or

three dropsof a 1 per cent, solution produceanaesthesia within

one minute,and two or three instillationsat intervals of five

minutes will render the eye anaestheticfor about fortyminutes.Numerous similar compoundshave been tried experimentally,

but are found to have no advantageover holocaine. They are, all

of them, also antiseptics.It appears that in this seriesthe ortho

and para compoundshave equalphysiologicalproperties.

314 STOVAINE AND ALYPIN

D. Gnanidine Derivatives.

The guanidinecompounds,of which a largenumber have been

tested,are lesstoxic than cocaine ; theyact more promptlyand for

a longertime,and their solutions are stable. They are, however,

irritating;and the solution of the most powerfulof the series is

decomposedby light.This body,known as Acoine, is the hydro-chloride of di^-anisykmonophenetyl-guanidine,

OCH3.HC1

OCH3

E. Derivatives of Tertiary Amyl Alcohol.

A group representedby stovaine and alypinmay be regardedas derivatives of dimethyl-ethyl-carbinol"

CH3

C2H5" C" OH

CH3

Stovaine :" Alypin:"

CH3 CH2.N(CH3)2

C2H6" C" O.COC6H5 C2H5" C" O.COC6H5

CH2.N(CH3)2. HC1 CH2 . N(CH3)2 .

HC1

or, dimethyl-amino-benzoyl- or, tetra-methyl-diamiuo-benzoyl-dimethyl-ethyl-carbinol. ethyl-dimethyl-carbinol.

Stovaine differsfrom cocaine in many importantpoints; whilst it

is about as powerfulin anaesthetic action it is onlyhalf as toxic ; it

is a vaso-dilator,not a vaso-constrictor,and has a toxic effect on the

heart. It has an acid reaction to litmus paper, and is decomposedin the presence of alkalis. It appears to be unsuitable for instilla-tion

into the conjunctiva,but may be usefullyemployedfor infil-tration

anaesthesia. As much as 20 grainshave frequentlybeen


316 EUPHTHALMINE

(Heliotropin),C6H3.(CHO).(OCH2O).1:3:4, are less pronouncedlocal anaesthetics.

II. SUBSTITUTES FOE ATROPINE.

Not onlycan bodies havinga physiologicalresemblance to cocaine

be derived from triacetone alkamine (seep. 306),but by alteringtheside-chain a mydriaticsubstance similar in constitution and action

to atropinemay be obtained. Atropine,it will be remembered,isthe ester of tropicacid and tropine;homatropinethe ester with

mandelic acid. The mandelic acid ester of methyl-triacetonealkamine ismydriatic"

CH"

It will be noted that the hydroxylis in the para positionas regardsthe nitrogen,as in tropine.Vinyl-diacetone-alkamine,

may be treated in a similar manner with like results. Two stereo-

isomeric "-methyl-vinyl-diacetone-alkaminesexist,owing to the

presence of an asymmetriccarbon atom in the ring,marked with

an asterisk on the above formula.

The a-mandelic acid derivative is not mydriatic;justas the

mandelic acid ester of i|r-tropine,isomeric with homatropine,is

inactive ; the hydrochlorideof the ^-esteris known as Euphthal-

xnine. It is easilysoluble in water, and has no anaesthetic

properties.

ADRENALIN 317

Euphthalmineresembles atropinein checkingthe secretion of

the gastricmucosa, and in counteractingthe effectsof pilocarpineand eserine. In toxic doses it causes in frogsparesis,convulsions,

dyspnoea,and death from cardiac failure. It differsfrom atropinein its retardingaction on the pulserate,due to its action on the

vagus centre and the cardiac muscle.

Emnydrine is atropinemethyl-nitrate,and is similar in itsaction

to the methylbromide ; itproducesa mydriasisof a somewhat en-during

nature,and is thus not a suitablesubstitutefor homatropine.Mydriasine is the trade name for a preparationof the methylbro-mide;

the propertiesof thisbodyhave alreadybeen described (p.270).The correspondingmandelic acid ester of pyrrolidinemerely

destroysthe reactivityof the sphincteriridisto light;that of

/S-hydroxy^tetramethyl-pyrrolidine

CH3

CH3" C CH2

NH

CH3" C CHOH

CHfl

is similar to euphthalminephysiologically,but is weaker in mydri-atic and toxic action,

III. SUBSTITUTES FOB HYDRASTIS.

The most importantbody recentlyintroduced into medicine is

the extract preparedfrom the supra-renalglands,and known as Adre-nalin,

supra- renalin,epinephrin,hemisine,"c. The chemical consti-tution

of this body is not absolutelydecided,but the balance of

evidence isin favour of the formula

CH.OH.CH2 . NHCH3

Its action physiologicallyis chieflyon unstripedmuscle,which it

causes to contract by direct stimulation. Thus Elliott has shown

that after the dilatorpupillaemuscle has been entirelyseparated

318 ADRENALIN DERIVATIVES

from its nervous connexions for some months it will contract on

the applicationof adrenalin more rapidlyand completelythan an

iriswhose nervous supplyis intact. It does not act,however,on

plainmuscle which is not normallyinnervated by the sympathetic,and thus is without action on the muscles of the bronchioles,and

the pulmonaryand cerebral blood-vessels. A dose of ""$mgm. intra-venously

injectedin rabbits doubles the generalarterial blood

pressure, and less than one-millionth of a gram givesa distinct

action. In addition to its specificaction on unstripedmuscle sup-plied

by the sympathetic,adrenalin has certain toxic actions. The

NH.CH8 groupingis resistant in the body,and suggestsa proto-plasmic

poison. As a matter of fact,it producesglycosuriaand

inflammatorychangesin the liver and kidneys. It appears also to

have a speciallytoxic action on the cardiac muscle of dogs(Elliott).Death may occur from largedoses,with symptoms of collapse,

coma, and paralysisof the central nervous system without any

increase in blood pressure.

Catechol,n TT /OH ,

. 0

the parent-substancefrom which adrenalin is chemicallyderived,in

doses of about 2 mgms. per kilogrambody-weightproducesan

appreciableriseof arterial pressure, and this is also the case with

many of its simplerchemical derivatives;for instance,pyrocate-chuic aldehyde,chloracetyl-pyrocatechin,"c. Replacementof the

phenolichydroxyl-hydrogenrenders these bodies inactive.

Adrenalone is a ketone obtained by the oxidation of the opticallyactive tribenzene-sulphonederivative of adrenalin. An opticallyinactive product,which otherwise is apparentlyidentical with the

correspondingderivative of the ketone,has been synthesizedby the

action of methylamine,CH3NH2, on

/OH .....1

C6H /OH.....

2

\CO.CH2C1 .4

(a derivative which has much the same physiologicalactivityas

catechol).

CO.CH2C1 Cp.CH, . NHCH3

+ CH3NH2 =

H

OH

ADRENALONE 319

The syntheticketone on reduction givesthe correspondingalcohol,

/CHOH.CH2NHCH3C6H3"-OH

\OH

which producesas greata physiologicalreaction as adrenalin,althoughit is not identical with the natural product,differingchieflyin its

opticalinactivity.The ketone itselfhas a vaso-constrictor action,but is hardlymore powerfulthan some of the simplerpyrocatechinderivatives mentioned above.

From syntheticadrenalone a largenumber of bodies have been

preparedwhich may be groupedinto the followingclasses l:"

I. C6H3(OH)2 . CO.CH2NH2.II. Derivatives of the type C6H8(OH)2.CO.CH2NHR.

(a)Where R is in an aliphaticgroup, e. g. methyl,ethyl,

amyl,and heptyl.

(b)Where R is a mixed group, e. g. benzyl.

(c)Where R is purelyaromatic,e. g. phenyl,tolyl,naphthyl.III. Derivatives of the type C6H3(OH)2.CO.CH2.NR2, e.g.

dimethyl,diamyl.IV. Derivatives of the ammonium type

C6H3(OH)2. CO.CH2 . NR3OH,e. g. salts of trimethyl,dimethyl-phenyl,"c.

Physiologically,Classes I and II (a)all produce a marked rise

in arterial pressure in doses of about 1 mgm. per kilogrambody-

weight,their reduction bases actingsimilarlyto adrenalin. Sub-stances

in Class II (b)act similarlybut less powerfully,and approxi-mateto those in Class II (c)which cause a fall of pressure followed

by a slightrise. Their reduction productsin some cases cause a

marked rise of pressure, but on the whole they are not so active as

those of the first two groups. Class III is less active than

Class II (a),but the reduction productsare very powerful. Class IV

is apparentlyless active,but only a few members have been tested.

Nicotine,coniine,and other bodies which have a vaso-constrictor

action have been dealt with in their placeamong the alkaloids,and

therefore need not be further noticed here; they cannot, more-over,

from a practicalstandpoint,be considered as substitutes for

hydrastis.

1 H. D. Dalkin,Journ. PhysioL,xxxii,May, 1905.

CHAPTER XVI

THE GLUCOSIDES, " Sinigrin,Sinalbin,Jalapin,Amygdalin, Coniferin,

Phlorizin,Strophanthin,Saponarin,"c. Purgativesderived from Anthra-

quinone.

THE GLUCOSIDES.

THE Glncosides are a class of vegetablesubstances which on

hydrolysisgive rise to various aromatic derivatives and sugars "

chieflyglucose,but often rhamnose or pentose,and occasionallyto a mixture of several sugars.

The name indicates botanical rather than pharmacologicalorchemical relationships.The common chemical characteristic,the

carbohydratenucleus,is probablyof great importancein plantphysiology,beingthe nutritive portionof the molecule ; the residual

portionis also of importance,and isprobablynot a mere excretion,as was at one time thought. From the pharmacologicalpointof

view,the carbohydratenucleus appears to increase but not to deter-mine

the activityof these bodies. The one exceptionto the rule

that the glucosideis more active than its non-carbohydratemoietyis,accordingto Frankel,eonsolidine,a glucosideobtained from

burrage.This body producesparalysisof central origin,and its

decompositionproduct,consolein,is three times more toxic. A num-ber

of glucosidescan be preparedartificially,though few of these are

of pharmacologicalimportance.Van Rijnl classifiesthe naturallyoccurringglucosidesaccordingto the plantsfrom which they are

derived. He remarks that,in the presentstate of our knowledgeof the structure of these bodies,a completechemical classification

is not possible;but even were the structure of all glucosidesaccuratelyknown, a botanical classificationwould stillstand,as, in

general,plantsof alliedspeciescontain similar chemical components.For the presentpurpose, however,a chemical classification will

be found more convenient. As with the alkaloids,so with the

glucosides,onlya few out of a largenumber of natural productsare used in medicine,and still fewer have had their chemical

structure determined. These may be classified,as was suggested

1 Die Glykoside,1900.

GLUCOSIDES OBTAINED FROM PEPPER 321

by Umney, accordingto the chemical character of the non-glucoseportionof the molecule. He divided them into four groups, as

ethylene,benzene,styrolene,and anthracene derivatives,and,as far

as possible,this classificationwill be followed. Some glucosides,not in Umney's originallist,have been added to his groups, of

which the last is the most interestingfrom a pharmacologicalpointof view.

It will be seen that very little,if anything,is known in this

group of the interdependenceof constitution and physiologicalaction.

Class I.

The ethylenederivatives include a number of bodies derived from

mustard and tropaeolumseeds,characterized by their sharpburningtaste,and allalliedto,or derived from,mustard oil.

Sinigrin, C10H16NS2KO94-H2O, isthe glucosideof black pepper,and is also found in horse-radish root. It is the potassiumsaltof myronic acid,and probablyhas the followingconstitutionalformula "

O.S02OK

S.C6HU05IIN.C3H6

On decompositionit givesrise to allyl-mustardoil,C3H6N : C : S,

glucose,and potassiumbisulphate.Sinalbin, C30H42N2S2O15,the correspondingglucosidederived

from white pepper is

O" SO2OC16H24O6

S.C6HU06

N.CH2.C6H4.OHWhen decomposed,it givessinalbin-mustard oil,C7H7O.N:C:S,glucose,and the sulphuricacid ester of sinapin.

Sinapinis a compound of choline and sinapinicacid"

OH

CH30/\OCH3O]

/fJH \ " ^1

!H:CH" CO.C2H4(3

322 SALICIN AND HELICIN

Glycotropaeolin,which has not yet been isolated,is the originof

benzoyl-mustardoiland benzoyl-cyanide,in the seeds of Tropaeolummajus. Experimentson its aqueous solution,and the investigationof itsderivatives,suggestthe constitutional formula "

O~SO2OK

C.S.(.C6Hn06-f-aAq

N.CH2C6H5

Jalapin(Scammonin),C34H56O16,theactiveprincipleof Scammony(Convolvulusscammonia),is a glucoside,splittingup when heated

with dilute acids into glucoseand jalapinolicacid,to which Kramer

assignsthe constitution"

"CHCH.OH .(C10H20)COOH

This acid has the same compositionas the substance obtained

from ipomoein(theglucosidefrom Ipomoeapanduratus)by heatingit with dilute acids,when decompositioninto sugar, "-methyl-crotonic acid (?),and ipomeolicacid,C16H32O3,takes place.

Class II.

The benzene group contains bodies allied to Salicin, C13H18O7,a glucosidewhich is decomposedby dilute acids into glucoseand

saligenin"

^

CHoOH

Ganltherin, C14H18O8,the glucosidefrom Gaultkeria procumbent,

givessalicylicacid methylester and glucose,when decomposedbydilute acids.

Helicin, C13H16O7,is the correspondingaldehydeto salicin"

"C6HU06

It exists also in an amorphousform (wo-helicin),which givesno

aldehydereactions.Michael obtained this glucosidesyntheticallyby the action of an


324 AESCULIN

the B. Tuberculosis,mainly as a stimulant to the activityof the

cells of the host.

Amygdalin, contained in almonds and many other plants(primus,

pyrus, mespilus,"c.),is a derivative of the nitrileof mandelic acid,

and the sugar is probablymaltose,or a similar di-glucose,whichdoes not contain a free aldehydegroup, since amygdalinhas no

action of Fehling'ssolution.Its physiologicalaction dependson itsdecompositionin the small

intestine,with liberation of HCN.

C20H27NOn+ 2H20 = 2C6H1206+ C6H5CHO + HCN

Benzaldehyde. Prussic acid.

Class III.

With few exceptionsthis group does not contain bodies of any

greatphysiologicalinterest.

Styroleneis phenyl-ethylene,C6H5CH : CH2.Aesculin, C16H16O9,a glucosideobtained from the horse-chestnut

and other plants,gives,when treated with dilute acids,glucose,and

aesculetin,a bodywhich is isomeric with daphnetin(fromDaphneMezereum);the constitution of these substances is probablyex-pressed

by the formulae "

OH

CO HOj/No- CO

" CH:CH -~ CH:CH

Aesculetin. Daphnetin.

Both are dioxy-coumarin.A tincture of the horse-chestnut has

been prescribedas an emmenagogue. The dried bark of DaphneMezereum is a gastricstimulant,and externallya rubefacient,but

this action isprobablydue to the volatile oil,and not to the glucoside.The aqueous solution of aesculin has a marked blue fluorescence,which can be seen in the urine fifteen minutes after hypodermicinjection.It has been used in lupusas an auxiliaryto the Finsen

lighttreatment,apparentlyits value is due to the fluorescence.

Coniferin, C16H22O8,has the structural formula"

/CH : CH.CH2OH 1

CH-O.CHO5 35

4

PHLORIZIN 325

Derivatives of it are (i)gluco-vanillin,

/CHO 1

C6H3Ô.C6Hn063

\OCH3 4

obtained by the careful oxidation of coniferin,and (ii)glucovanillieacid,

L3

obtained by oxidation of coniferin by means of potassiumperman-ganate.

The former is a convulsant poisonfor some animals,but

10-15 grams have no action on man.

Hesperidin occurs in resinous varietiesof cifrus,on heatingwithdilute sulphuricacid givesrhamnose,glucose,and hesperetin:"

C50H60027+ 3H20 = C6H1406+ 2 C6H12O6+ 2 C16HUO6Rhamnoee. Glucose. Hesperetin.

Hesperetinhas probablythe followingconstitution :"

,CH : CH.COO.C6H3(OH)2

\OCH3In the alkaloid the hydrogenatoms of the hydroxylgroups are

joinedto rhamnose and glucose.Fhlorizin is the onlyglucosideof this group which is interesting

from a physiologicalstandpoint.Its action is well known, and is

shared in a lessdegreeby phloretin,the body formed when glucosehas been splitoff.

Phloretin has a constitution expressedby the formula "

OH

CO"

C

This is based on itsdecompositionby potashinto phloroglucinand

phloretinicacid "

i " 4, r IT^"14CH(CH3).COOH

In its chemical reactionsphloretinis similar to Cotoin, a glucosideobtained from coto bark (speciesundetermined),which has a specialaction on the intestinalvessels. These are dilated,and thus absorp-tion

is favoured. It has no astringentor antisepticaction,but is

326 STROPHANTHIN

largelyused in anti-diarrhoeic mixtures in the form of a tincture.

The sugar-freenucleus is stated to have the constitution (Schmiede-berg)"

/(OH),C6H2fCO.C6H5

\OCH3Fortoin is methylenedicotoin,CH2(C14HnO4)2; it has not the

bitter taste of cotoin,is more powerfulin action,and is also

bactericidal(Pharm.J.,i.1900,p. 531).Several substances have been described under the name of

Strophanthin ; two of these are crystallineglucosidesobtainedfrom StrophantkusKombe,and the other an amorphouspreparationfrom Strophanthushispidus.Arnaud, and later Kohn and Kulisch,isolated a substance of the composition,C31H48O12,from S. Kom.be.

This glucosidehas a bitter taste,and itsaqueous solution is opticallyinactive. On hydrolysisit yieldsstrophanthidin,and a sugar or

mixture of sugars whose compositionhas not been determined.

Strophanthidin,C19H28O4,or C28H40O6,althougha very hygroscopicsubstance is not soluble in water.

Merck's preparation,which is termed ^-strophanthin,was isolated

from Strophanthusgrainsby Thorns. The formula C30H46O12. 9 H2Ohas been assignedto it ; Schedel showed its value in conditions of

cardiac weakness. The amorphousstrophanthinobtained from the

seeds of Strophanthnshispidus,is givenin much smaller doses than

the previousderivative,but whether it is more powerfulin itsaction,

or has more toxic properties,has not yetbeen decided.

In these groups must also be included Iridin, C24H25O13,a gluco-sidewith a complexstructure,obtained from the Irisflorentinaand

Iris versicolor.

It breaks down primarilyon saponificationinto glucoseand

irigenine,C18H16O8. This latter body yieldsiretol (oxymethyl-

phloroglucin),OH

OH

formic acid,and iridinicacid,OH

CH

on heatingwith concentrated solution of potash.

SAPONABIN 327

Iridin is a cholagoguepurgative.Saponarin, a glucosidefound in Saponariaofficinalis,and other

plantsmay probablybe classed here. With iodine this derivative

givesriseto the blue colour characteristicof starch,and hence was

formerlyregardedas an amorphousvarietyof that substance.

Barger,who has recentlyinvestigatedthis substance,found on

hydrolysisthat it yieldedglucose,a body named saponaretin,and

another identical with vitexin,a colouringmatter obtained byPerkin from the decompositionof the glucosideof Titex littoralif,and supposedto have a constitution representedby the formula "

H H" C6H4.OH 1:4

Saponaretinmay be identicalwith homovitexin (Perkin).Scoparinmay be methoxy-vitexin.Bhamnetin, the decompositionproductof the glucosidesof

various speciesof Ehamnus, includingR. Purshiana,is stated to

have the followingconstitution :"

O

CH,O

It also is a colouringmatter,like Quercitrin C21H22O12,which,on

hydrolysis,givesrise to quercetinand the carbohydraterhamnose.

QuercetinO OH

is found combined and free in many varietiesof plants,such as the

leaves and flowers of the horse-chestnut,and the berries of Hippo-

phoearhamnoides. Perkin and Hummel found an identicalpigmentin onion rinds. Rhamnetin is mono-diethyl-quercetin,Fisetin

(fromEhus Cotinus)is mono-oxy-quercetin,and a pigmentin the

328 ANTHRAQUINONE

leaves and stems of some speciesof tamaris is a methyl ether of

quercetin"

Chrysin, O

which has three atoms of oxygen less,can be decomposedinto

phloroglucin,benzoic acid,and acetic acid,justas quercetinyieldsphloroglucin,protocatechuicacid,and glycolicacid.

Class IV.

This group contains a number of purgativebodies derived from

anthraquinone"CO

Chrysophauic acid, dioxy-methyl-anthraquinone,

["CeHaOCeH3"HOH'

is a purgativeprinciplepresentin rhubarb. As a glucoside,it

occurs as chrysophan,which has not yet been isolated in the same

plant.Increase in the hydroxylgroups producesincreased purga-tive

action,as in Emodin, trioxy-methyl-anthraquinone"

ca

OH/"

xcox : NOH

(Theorientation of these derivatives is not certain.)An identicalemodin occurs in rhubarb,and combined with rham-

nose as a glucosidein frangulabark (Buckthorn); the form obtained

from aloes differs slightly.1The oxidation productof emodin,

aloechrysin,is intermediate physiologicallybetween emodin and

chrysophanicacid.

1 There are fifteen theoreticallypossibleisomers.

DERIVATIVES 329

Whereas the oxygen appears to increase the intensityof the

action,and its positionis also of importance,the methyl group

appears to be of littleimportance.Vieth,from the syntheticside,

arrangedthe followingtable.The numbers in the formula show the positionof the substituting

groups :"

8 CO 1

O 4

Most active,Anthrapurpurin,l:2:7-trioxy-anthraquinone.\ as strong,Flavopurpurin,1:2:6 " "

J as strong,Anthragallol, 1:2:3" "

| as strong,Purpur-oxy-anthin,l:3-dioxy-anthraquinone.Y1 as strong,Alizarin(Bordeaux),1:2:3: 4-tetraoxy-anthraquinone.""$as strong,Purpurin,l:2:4-trioxy-anthraquinone.A number of productssuch as rufigallicacid (hexa-oxy-anthra-

quinone),acetyl-rufigallic-tetramethylether,ordinaryalizarin,nitro-

purpurin,and cyaninare inactive. Some of the active bodies contain

a methylgroup and some do not.

The purgativepropertieshave been variouslyattributed to the

anthracene group, to the ketonic groups in anthraquinone,and to

the latter in the presence of hydroxyland aliphaticside-chains.The greateractivityof the natural glucosidesas purgatives,when

comparedwith their hydrolyticdecompositionproducts,is due to the

fact that the latter are too rapidlyabsorbed from the intestine,and

thus lose their laxative effect.

A number of syntheticbodies have been preparedfrom anthracene

" startingfrom aloin,which has the formula C17H18O7+ 1"H2O,and contains several hydroxylgroups; these have been variouslycombined in order to producebodies which,while possessingthe

purgativeaction,have not the bitter taste of the parentsubstance.The compoundsshould also be more stable and thus more active

for reasons alreadynoted.The methyleneradical may replacetwo hydrogen atoms of

hydroxylgroups, and tribromaloin,C17H15Br3O7,and triacetyl-aloin,C17H16(C2H3O)3O7,have been preparedand found to be active.

The last named is also tasteless.

Fnrgatin or Fnrgatol is a diacetate of anthrapurpurin(1:2:7-

330 SAPONINS

trioxy-anthraquinone),a mild laxative. Marshall states that it

irritates the kidneys, and causes pain in the back; the urine is

stained red (Dixon).

Exodine is apparently diacetyl-rufigallic-tetramethyl-ether(rufi-

gallic acid is l:2:3:5:6:7-hexaoxy-anthraquinone); its action is

mild. The hexamethyl ether of rufigallicacid has purgative pro-perties,

but these are not possessedby acetyl-rufigallicacid,the penta-

methyl ether, or the diacetyl-tetramethylether of this anthraquinone

derivative.

[Purgen, not belonging to this group, is phenol-phthalein,and is

not absorbed to any considerable extent.]

Saponins.

A series of glucosidicbodies,of which the empiricalformulae alone

are known, are of great importance from the pharmacological point

of view, as among them are many drugs frequentlyused in practice.

These are the saponins, bodies which, for the most part, have the

characteristic property of producing a frothy solution with water,

and corresponding,with some exceptions,to the general formula

CnH2n_8O10.

Various groups have been constructed, according to the number

of carbon atoms, but a definite correspondence between these groups

and specialpharmacological propertieshas not been made out. The

bodies produced by hydrolysis(sapogenins)are usually inert.

Some confusion exists as to the terms employed. Schmiedebergcalls the entire class Sapotoxins, and the hydrolyticdecomposition

products Saponins. Van Rijn calls the entire class Saponins,apply-ingthe term Sapotoxin to some individual members of Robert's

first group. W. E. Dixon notes that the term Sapotoxins should

be applied to the 'more active ' members of the group,

( but is used

somewhat loosely'.

Senegin, quillaia,sapotoxin, saponin, digitonin,quillaiacacid,

polygallicacid, sarsa-saponin,and smilax-saponin are among the

more important members of the group.


332 DEPENDENCE OF TASTE ON CONSTITUTION

owing to the fact that the body in solution is applieddirectlytothe nerve terminations,chemical structure becomes of greatimport-ance;

and this is also true in the case of smell,where the end

organs are directlystimulated by the contact of emanations "of

bodies not in solution,but in a gaseous form, as shown by the

careful researches of Aitken.

Thus the process by which the end organs of taste and smell are

stimulated is more nearlyanalogousto the process by which a

thread (oran animal cell)takes up a dye-stuffthan that by which

the retina records the impressionsof various kinds of light.Our presentknowledgeof the subjectof intra-molecular vibra-tions

is so slightthat nothingmore than the mere suggestioncanbe thrown out that the stimulus in the case of taste and smell is

likewise due to some type of vibratorymovement, transmitted

directly,not indirectly,to the sensitiveend organs by the sapidorodorous substance. Several facts in the generalrelationshipswhich have been shown to exist between chemical structure and

taste are at any rate consonant with such a view.

In MendeleefFs periodicclassificationof the elements it will be

noticed that those possessinga sweet taste are mostlyfound in the

third (boron,aluminium,scandium, yttrium,lanthanum) and

fourth (lead,cerium)groups. It is interestingto note that

beryllium,which occurs in the second group, but which shows

such marked resemblance to the third,should also possess a sweet

taste. On the other hand,the bitter elements are found mainlyinthe second group (magnesium,zinc,cadmium, mercury); while

sulphurin the sixth group often givesrise to bitter compounds,and chlorine in the seventh group to sweet ones.

The characteristictaste of acids and bases dependsupon their

dissociation,the hydrogen ion giving rise to the acid and the

hydroxylto the alkaline taste ; consequentlythe strongerthe acid

(thatis,the greaterthe degreeof dissociation)the more pronouncedis the acidic taste. A similar relationshipholds good with the

alkalis. Organic acids consequentlylose their taste on conversion

into esters.

The remainingfacts concerningthe relationshipsbetween taste

and smell and chemical constitution are too disjointedfor anythinglike systematicarrangement.They will therefore be groupedunder

a few main headings,which,while not showing any mutual inter-dependence,

will enable the experimentalevidence to be presentedin a more orderlymanner.

HYDROXYL DERIVATIVES 333

Among organiccompounds,substances with very low or with

very highmolecular weightare usuallytasteless.

1. Sternberg1has pointedout that among organicsubstances

a certain ( harmony'

or equilibriumis necessary in order to producea sweet taste ; if this is much disturbed,the sweet taste is lost.

The alkyland hydroxylgroups must be equalin number, or the

former onlyexceed the latter by one. Thus

OH

inCH2OH X| OH.CHf NC

-in,CHOH inosite,glycerin'

--

"HX

"H

,!H

OH.CHk JCH.OHCH,

"

CH'

methylglucoside,I and rhamnose,(CHOH).(CHOH),

JHO

[2OHare all sweet; so are the di-saccharides,but the tri- and poly-saccharides are tasteless.

But methylrhamnoside

CH3

(CHOH)3

I

CH"OCH3is bitter,and the ethylderivative stillmore so "

CH3

(CHOH)3

in

1 Geschmack und Geruch,Dr. Wilhelm Sternberg,and many papers.

334 INFLUENCE OF THE PHENYL RADICAL

2. In the aliphaticseriesthe polyhydricalcohols,oxy-aldehydes,and oxy-ketonesare characterized by their sweet taste. In the

series from ethylalcohol to mannite,C6H8(OH)6, the taste increases

in proportionto the number of hydroxylgroups. Grape sugar,

CH2OH(CHOH)4 . CHO, containingan aldehydegroup, is sweeter

than mannite. Slightalterations in the compositionof the sugars

completelyalter their taste,and the condensation productsof the

sugars with ketones are all bitter. The replacementof hydroxylhydrogenby acid radicals converts the sugars into bittersubstances,and further replacementproducestasteless derivatives. Although

grape sugar is sweet, glycuronicacid,COOH. (CHOH)4 . CHO,

has the characteristicacid taste.

3. The nitro group does not appear to influence taste in one

direction or another. Amyl nitrite and similar compounds,nitro-benzene,

l:2-nitro-phenolare sweet. Trinitro-phenol(picricacid)and dinitro-monochlor-phenolare bitter. Nitro-dichlor-phenolis

tasteless.

4. Another fact,connected most probablywith molecular equili-brium,is the passage of a sweet substance into a bitter by the

replacementof positivealkylgroups by negativephenylradicals,thus: "

Sweet. Bitter.

(1) CH3.CHOH.CH2OH1 :2-Dioxy-propane.

(2)CH3.CHOH.CHOH.CH2OH1:2: 3-Trioxy-butaue.

(3)CH2OH.(CHOH)3.CH.CH.OCH3

0

Methyl-glucoside.

C6H5.CHOH.CH2OH

Phenyl-glycol.

C6H6 . CHOH.CHOH.CH2OH

a-phenyl-glycerol.

CH2OH.(CHOH)3 . CH.CH.O.CH2C6H6

0

B enzyl-glucoside .

Possiblyit is the presence of aromatic radicals in the natural

glucosideswhich accounts in a similar way for their bitter taste.

The introduction of -CH2OH or chlorine or bromine into the

aromatic nucleus of phenyl-glucosidedoes not diminish the bitter

taste,thus :"

phenyl-glucoside,

salicin,

mono-chlor salicin,

C6HU06 O.C6H5)

C6HU06.O.C6H4.CH2OH

n TT r\ r\ n TT /CHoOri

:2,

INFLUENCE OF AMIDO GROUPS 335

are bitter,but benzoyl-salicin(populin),

C6Hn06 .

0. C6H4 . CH20(COC4H6))

is sweet,and the introduction of a second benzoylgroup givesriseto a tastelessbody.

Tetra-acetyl-chlor-salicin

C6H7(COCH3)405. 0.C6H3"ÔHis also tasteless,and so ishelicin,the aldehydeof salicin,

C6HU06-O.C6H4.CHO.

5. Hydrocarbons,either of aliphaticor aromatic series,are usuallytasteless. The introduction of oxygen or nitrogen,however,or of

both, under definite conditions may cause the appearance of a

substance possessingthis quality.Sternberghence calls them

' Sapiphore' groups.

Positive and negativeradicalsmust be combined in order to pro-duce

the effect,negativehydroxylswith positivealkyls,and positiveamido groups with negativecarboxyls.Thus when NH2 and

COOH groups occur in close proximityin a molecule (i.e. the

a position)the effect is more pronouncedthan when they are

separatedby carbon atoms (/3and y positions); a-amido-carboxylicacids of the aliphaticseries,for instance,are sweet,but /3-amido-valerianic acid is only slightlyso, and has a bitter after-taste,whereas y-amido-butyricacid has lost the sweet taste. a-Amido-

"-oxy-propionicacid,

CH3.CH.OH.CH,Hj ;

and a-amido-/3-oxy-valerianicacid,

CH3 . CH2 . CHOH.CH"^^Hare quitesweet,whereas a-oxy-jS-amido-propionic,

CH3.CHNH2.CH"g"?oHjis not. In this connexion it is interestingto note that a-pyrroli-dine carboxylicacid

CH2" CH2

CH0 CH.

has also a sweet taste.

.COOH

NH

336 INFLUENCE OF AMIDO GROUPS

In the aromatic series this does not always hold good, the

negativephenylnucleus playingan importantpart,as mentioned

previouslyin the case of phenyl-glycerin.Thus phenyl-amido-acetic acid,

is tasteless,but a-amido-)3-phenyl-propionicacid is sweet " "

When the substituents (NH2 and COOH) are in the ring,Stern-

berg compares the ortho derivatives to the a-aliphaticsubstances.Thus

1 . 9

is sweet,whereasNH

,

is tasteless. Further,l:2-amido salicylicacid is slightlysweet,whereas the 1:3 and 1:4 amido acids are tasteless.

The ortho sulphonatedderivative of benzoic acid,

has the characteristicacid taste ; the sulphamide,S0NH2

is tasteless,but the correspondinginner anhydride,0-anhydrosulph-amine-benzoic acid,

has an intenselysweet taste,and has been introduced under the

name of Saccharin. It is obtained from toluene by firstlysulpho-nating at 100" C., which givesthe best yieldof l:2-toluene-

sulphonicacid,

then convertingthe resultingsubstance into the sulphochloridebymeans of phosphoruspentachloride,and this into the amide,

S0NH

through the agency of ammonia. o-Tolyl-sulphamideis then

oxidized by potassiumpermanganate,and if the solution is keptalkaline the potassiumsalt of "?-sulphamine-benzoicacid,

SACCHARIN 337

0NH2

is formed,but when the free acid is liberatedby means of a mineral

acid,dehydrationoccurs and saccharin results"

.S02NH;H /SO2VC6H/ J = H20 + C6H4" "NH

\CO;OH \CO/

Up to 1891 the commercial saccharin usuallycontained 40 per cent.

of the tasteless1 :4 derivative. One method of separationis based

on the differing-solubilityof these substances in xylene,saccharin

being-soluble,but the other insoluble.

Saccharin passes unchangedthroughthe organism; the sodium

salt goes by the name of Crystallose, the ammonium is termed

Sncramine.

Saccharin stillretains itssweet taste when a hydrogenatom of

nucleus isreplacedby NH2 "

but a correspondingreplacementby a nitro group givesrise to

a substance with bitter taste.

The replacementof the imide hydrogenby the ethylgroup

resultsin a tastelesssubstance.

6. Salicylicacid is sweet,and itsamide,

i . o n TI""H

is tasteless;but although0z*oxybenzoicacid is also sweet, its

amide,

is bitter; itsdehydrationproduct,however,the nitrile

is sweet. Among the nitro derivatives of ^-oxybenzoiconlyone, viz.

H 1

C6H -,

\COOH 3

338 DIBASIC ACIDS

is sweet,the others are tasteless ; all the dinitro-w-oxybenzoicacids

are also tasteless,but the trinitro acid is bitter.

The dioxybenzoicacids are tasteless.

7. The presence of two carboxylgroups in the molecule and the

effectof NH2 groups on taste isillustratedby the followingfacts :"

Malonic acid,CH2(COOH)2, and succinic acid

CH2.COOH

CH2.COOH

have the ordinaryacid taste ; methyl-amido-malonicacid

CHNH2.COOH

CH0.

is sour, and so isasparticacid"

I

m

COOH

Diamido-succinic acid,

CH.NH2.COOH

CH.NH2.COOH

a substance which isonlyvery slightlysolublein water,istasteless.

Dextro-glutaminicacid

PTT/CH2.COOHn2\CH.NH2.COOH

is sweet,and so is the amide of asparticacid,i.e. dextro-asparagin,

CH.NH2.COOH

CH2.CONH2

Imido^succinic-ethylester

CH.COOH

I "HCH.COOC2H6

is bitter,whereas itsamide

CH.CONH2

I "HCH.COOC2H5

is sweet.

8. The effects of stereochemical influences upon the sense of

taste have been previouslymentioned (seep. 53). This influence

is but slight,or at all events has so far onlybeen noticed in a few


340 CYCLIC CONSTITUTION AND TASTE

CQ /NH.C6H4 . OC2H5 1 : 4 ro/NH.C6H4 . OC2H5J\NH2 J\NH.C6H4.OC2H5

1 : 4-phenetolcarbamide (Duloin). Di-_p-phenetolcarbamide.Sweet. Tasteless.

Dulcin, or Sucrol, breaks down in the organism,givingrise to

the toxic substance phenetidin,

consequentlyits physiologicalaction is similar to that of the phena-cetin derivatives.

11. The conversion of chain into cyclicderivatives also affects

taste. Thus :

y-amido-butyricacid,NH2 . CH2 . CH2. CH2 . COOH, is tasteless,

pyrrolidonI I is bitter,frH- -CO

CH2 . CH2 . CH2 . CH2 .

COOH

5-amido-valerianicacid I is tasteless,

NH2

.

C H2oxy-piperidon| | is bitter.

NH - CO

Sarcosin I is slightlysweet,CJOOH

whereas its anhydrideCH3

CH2" N" CO

is bitter.

CO " N" CH2

CH3

N(CH3)3.CH(C2H6).COOHTrimethyl-amido-butyricacid | is sweet,

OH

the anhydridebitter.

Sternbergascribes the bitter taste of the alkaloids to their cyclicconstitution.

ODOUR AND CHEMICAL CONSTITUTION 341

II. ODOUR.

Our knowledgeof the correlation of odour and structure has

been mainlyacquiredfor the purpose of producingsyntheticper-fumes,

an industrylargelycarried on in Germany and France. In

the short sketch which follows the authors are mainlyindebted to

the works of Georg Cohn1 and Zwaardemaker 2,the former from

the chemical,and the latterfrom the physiologicalside.

The most necessary condition for the productionof an odorous

substance is volatility,since it is found that bodies of low volatility" generallyassociated with high molecular weight" have no effect

on the olfactoryorgans. But the molecular magnitudemust fall

within certain limits ; frequentlythose with low molecular weight" such as the volatile aldehydesof the aliphaticseries" have

unpleasantodours,whereas the highermembers have none at all;

between these limits lie citraland citronellal(p.344),which are

typicalscents,and the aromatic aldehydes,of highermolecular

weight,which also have pleasantodours.Some importancemust also be ascribed to the concentration of

the odorous substance and most probablyto the nature of the

solvent. Such substances as vanillin,piperonal,cumarin,and ionone,

have a very differentodour when in strongsolution to that wiiich

they possess when much diluted. The natural essentialoilsused

in perfumeryowe their pleasantodour to several constituents,and

small variation in the concentration of one may bringabout greatalterationsin the odour of the oilitself. It isgenerallystated that

artificialbenzaldehydecannot be used for the more expensivevarietiesof scent,owing to the impossibilityof freeingit from minute traces

of impurities.Phenylaceticacid and /2-naphthylaminehave no odour

in the crystallinecondition,but smell disagreeablywhen in solution.

This property has been compared to the variation in colour

sometimes observed when a soliddye-stuffis dissolved in water,and

a further similarityhas been noted between the way in which odours

adhere to certain bodies like paper, woven materials,,"c.,and the

process of dyeing.1. The chemical constitution of a substance is clearlyof primary

importancein determiningits odour,but at presentlittleis known

of the generalcorrelationbetween these two. Followingthe analogywith the dyes,certain ' Osmophore' groups have been described,such

1 Die Riechstoffe,1904. * Physiologicdes Geruchs,1895.

342 OSMOPHOKE GROUPS

as hydroxyl(OH), aldehyde(CHO), ketone (.CO.),ether (.O.),nitrile (CN), nitro (NO2),azoimide (N3),which may condition

odour in various bodies previouslyodourless,and such groups may

obviouslygiverise to substances of pleasantor unpleasantodour.

But a classificationon the basis o" the osmophoresisimpossiblein the

presentstate of our knowledge.Equallyimpossibleis a classification

based on the character of the odour,as there are no words in any

languageby which odours may be described,the onlyterms in use

beingthose which pointa similarityto some other odour,such as

f camphoraceous',' vinous ',"c.

2. Two or more osmophoregroups may be presentin the same

body,or one may often replaceanother without materiallyalteringthe odour; thus benzaldehyde,nitrobenzene,benzonitrile,phenyl-azoimide,have all a very similar smell. The introduction of several

substituent groups, however,leadingto an increase in the molecular

weight,may account for the observed diminution in the intensityofthe odour of the resultingderivative.

3. Homologousderivatives usuallyhave a similar smell ; this is

noticed in the case of the methyland ethylesters of salicylicacid,or the methyland ethylethers of /3-naphthol,or the correspondingdi-derivativesof hydroquinone.

But the ethylgroup in the esters and ethers may lead to a

strikingdiminution in the odour,whereas the methyl derivatives

are scented (comparep. 49). Thus the ethylester of anthranilicacid,

1;2C"H4"(co6c2H5,has only a slightsmell ; the M0-butylester has none, but the

methylester has the odour of orange blossoms.

In the aromatic series the entrance of a methyl group into the

ringdoes not cause much alterationin the odour ; thus nitro-benzene

and nitro-toluene are very similar,and methyl-vanillin,methyl-cumarin,smell very likethe substances from which theyare derived.

Radicals rich in carbon have a considerable influence on odour,asillustratedin the table on the next page.

The amyl radical appears to have a specialfunction,as it pro-duces

a uniform odour in the bodies into which it is introduced,

e. g. amyl-alcohol,amyl-methyl-ketone,amyl-and diamyl-aniline.4. The halogensonlyinfluence odour when introduced into the

side-chains,and not when substituted in the nucleus of aromatic

derivatives;thus brom-jtf-naphthol-methyl-etherand the chlori-nated

benzaldebydeshave a similar smell to the parentsubstances.

INFLUENCE OF NITROGEN RADICALS 343

5. Phenols and phenolethers have characteristic odours,andthose with olefine substituents,especiallythe allylor propenylgroups, are found in several volatile oils. The carboxylgroupdestroysthe odour of alcoholicand phenolicsubstances.

6. Nitrogen-containingradicals playan importantpartin deter-mining

odour,and for this purpose the nitro group is of more

importancethan the nitrile.

Phthalide has no smell.

CH

C6H4"CO

"0

""0-propyl-phthalide,

CH.CH(CH8)2

CO

wo-propylidene-phthalide,

C:C(OH3)2

CH.C4H9

butyl-phthalide,C6H4"(CO

all smell of celery.

Fhenyl-acetylene has

an unpleasantsmell.

C6H5.C;CH

:4-tolyl-acetylene,CH3. C6H4 .C |CH,

1 :4-ethyl-phenyl-acetylene,

C/2-H-5" Cg.H4.0

i OH,

both smell of anise.

1 :4-w0-propyl-phenyl-acetylene,(CH3)2CH.C6H4.C;CH,

*-trimethyl-phenyl-acetylene,

(CH3)3C6H2.C;CH,have a pleasantetherialsmell.

""0-Nitrilesgenerallyhave extremelydisagreeableodours. The

higherhomologuesof trinitro-benzene smell of musk. Methyl-benzoate has the characteristic slightsmell of so many of the

aromatic esters,whereas the 1 :4-amido derivative smells of orange

blossom. In the series of nitro derivatives smellingof musk a

nitro group may be replacedby the azoimide without alteringthe

odour of the originalsubstance.

344 PERFUMES

7. It is among the higheralcohols and ketones,and especiallythe

aldehydes,that the majorityof substances used in perfumeryis to

be found. The followinglist contains a few typicalexamplesofeach class. The isolation and identification of such substances

from the essential oils and their artificial production,or the

synthesisof closelyallied derivatives,has been developedwith

great success during the last twenty-fiveyears, and has resulted

in an industryof considerable importance:"

Alcohols :

1. Linalool.

odour resembles that of mayflower

/OH(CH3)2. C : CH.CH2 . CH2 . C^-CH:CH2

\CH32. Citronellol

" " "roses

(CH3)2. C : CH.CH2 . CH2 . CH(CH3).CH2 . CH2OH3. Geraniol

.... " " "roses

(CH3)2.C : CH.CH2 . CH2 . C(CH3) : CH.CH2OH

4. Among ring structures are found borneol,menthol, terpineol

(lilacodour).

These alcohols " and so far onlythose with more than eightcarbon

atoms have been found in volatile oils" may be converted into

esters (seep. 122) and variations in odour obtained. Thus the

linalool and geraniolesters of acetic acid have an odour of oil

of bergamot. The esters of borneol all possess an odour similar to

the acetate,the intensityof which diminishes with an increase in

the molecular weightof the acid. The acetate of ^-borneol ispresentin oil of hemlock,valerian,kesso,"c.

Aldehydes :

1. Citral or geranial . . .odour resembles that of lemons

(CH3)2C:CH.CH2 . CH2 . C(CH3): CH.CHO

2. Cinnamic aldehyde " " "cinnamon

C6H6CH: CH.CHO

3. Vanillin" " "

vanilla

/CHO 1

C6H /OCH3 8

4. Piperonal " " "heliotrope

!HO 1

3

PERFUMES 345

Ketones :

1. Methyl-ethyl-acetone. .odour resembles that of peppermint

2. Various derivatives of cyclo-hexanone,e.g. pulegone "

3. Camphor,fenchone,carvone (odourof caraway)4. lonone

. . .odour resembles that of fresh violets

5. Various substitutionproductsof acetophenone,C6H5.CO.CH3.

Phenols and Phenol-ethers :

1. Carvacrol.

odour resembles that of thyme

/OH 1

C6H/CH3 3

\C3H762. Thymol

"

/OH 1

CTJ s r" TJ O6"13^-U3"17 A

\"H3 5

3. 0-naphthol-methylether. . "

C10H7.O.CH34. Safrol

5. Eugenol

L3\ '

\CH2.CH;CH2 4

/OH l"C.HQ^-0

" thyme

oilof neroli

oilof sassafras

oilof cloves

H

OCH, 2

4

8. Isomeric relationshipsnaturallyplay an importantpart in

conditioningodour,as theydo with regardto other physicalcharac-teristics

of organiccompounds, Thus ô-vanillin is scentless,and

in the artificialmusks " e. g. in trinitro-i/r-butyl-ethyl-benzol,

and in many similar derivatives havingthe same odour,the three

346 INFLUENCE OF ISOMERIC RELATIONSHIPS

nitro groups must be symmetricallyplaced,otherwise this charac-teristic

is lost.

The 1:2 and 1:4 (butseldom the 1:3) positionsin the benzene

nucleus are substituted in many of the artificial scents. Thus

1 :4-methoxy-acetophenone,CH3 . CO.C6H4 . OCH3, has a pleasant

smell; the 1:3 isomer is without scent. l:2-amido-acetophenone,

1: 2-amido-benzaldehyde,

JHO

and 1 :2-nitro-phenolhave strongodours,whereas the corresponding1:3 and 1:4 derivatives have none. In this connexion it may be

mentioned that although salicyl(orthoderivative)and anis-alde-

hydes (para)both occur in nature, neither the corresponding0z-oxy-benzaldehydenor its derivatives are found.

9. Reduction may alter a scent,but does not render it disagree-able,

as seen in the followingcases. Cinnamic aldehyde,

C6H5CH:CH.CHO,

smells of cinnamon. The reduced derivative,C6H5 . CH2 . CH2 .CHO,

has a most characteristic odour of lilacand jasmine. Coumarin

o"

co

has the odour of woodruff,also noticeable in melilotin"

/O -CO

CflH4

10. Unsatnrated substances generallyhave powerful odours.

Triply-linkedcarbon systems are frequentlyassociated with un-pleasant

odours,thus phenyl-propiol-aldehyde,C6H6C " C.CHO, and

1 :2-nitro-phenyl-acetylene,NO2 . C6H4 .

C |CH, are most disagree-able.This may be contrasted with the effect of the double bond,

which usuallygivesrise to bodies with pleasantsmells; compare

styrene,C6H6CH:CH2, which is found in storax oil,and various

other instance* which have been previouslygiven.


348 CRITICISM OF LOEWS THEORY

by methylradicals,the colour passes from red to violet-red,and in

hexa-methylrosaniline becomes violet-blue. The replacementof hydrogenatoms by ethylor phenylgroups intensifiesthis effect.

Hexa-ethylrosaniline is violet with a blue nuance, and the tri-

phenylsubstitution productis blue.Allusion has alreadybeen inade (p.22)to the auxochrome groups

described by Witt. These are of two kinds,basic and acid,so that

from each chromogentwo series of analogousdyesmay often be

obtained,thus :"

Acid Dyes.

Auxochrome (OH).

Oxy-azo-benzene.Bioxy-azo-benzene.

Rosolic acid.

Thionol.

Aposafranone,

Basic Dyes.

Auxochrome (NH2).

Amido-azo-benzene.

Diamido-azo-benzene.

Rosaniline.

Thionol ine.

Aposafranine.

The introduction of more than one acid or basic auxochrome

group will,to some extent,tend to deepenthe intensityof the

colour.

Largelyon the groundsof his observations on the action of dye-stuffs Ehrlich has criticizedthe ' substitution '

theoryof Loew, to

which allusion has been made in an earlier chapter(p.17). The

evidence he has collected on this pointmay be summarized as

follows 1:" In some basic dyesthe amido group, or groups, undergo

interaction with substances containingaldehyderadicals,and a

changeof colour isproduced.Thus red fuchsin becomes violet when

treated with an aldehyde.Now, in the case of the substituting

poisons,Loew supposedthat an interaction took placebetween

these and amido or aldehydegroups presentin the livingproto-plasm.But Ehrlich has never been able to observe that colour

changesof the type mentioned occur in the body,either with this

basic dye which reacts with aldehydegroups, or with certain other

dyes(e.g.Kehrmann's azonium base obtained from safranine)which

interact with substances containingamido groups, causingchar-acteristic

changesof colour.

Other bodies,such as anilinand benzaldehyde,which very readilycondense to benzylidene-anilin,have also been employed,but no

derivative of either anilin and an aldehyde-containingsubstance,or

1 Studies in Immunity, 1906,jchap.xxxiv.

EHRLICH'S HYPOTHESES 349

of benzaldehydeand an amido group, has ever been extracted

from the tissues.

Ehrlich has also employedthe aromatic dyes to elucidate the

distribution of poisonsand drugs in the animal body,or, in other

words, to throw lighton the selective action of cells. Thus he

shows that the brown stainingwith ;?0ra-phenylene-diainme,which

is most marked round the central tendon of the diaphragm,and the

muscles of the eye, larynx,,and tongue,is due to the more copiousblood supplyof these muscles,that is,to the presence of an abun-dance

of oxygen. Similarly,in these situations the motor nerve

endingswere more intenselystained with methyleneblue.

From observations of this character Ehrlich deduces the hypothesisthat the various cellsof the body take up different chemical sub-stances

in a greateror less degreeaccordingto their 'chemical

environment '

:" absence or presence of oxygen, alkaline or acid re-action,

"c. Thus a nerve ending,if in a neutral or acid environ-ment,

will take up the dyealizarin,but when the surroundingreac-tion

is alkaline it is stained by quitda differentsubstance,namely,methyleneblue.

It is possibleto modify the distribution of a dye-stuffby the

addition of other substances ; thus the stainingof the nerve endings

by means of methyleneblue,which occurs intra vitam,may be

preventedby the addition of the soluble acid dye called orange

green. The latter,that is,has a strongeraffinityfor the methyleneblue than the nerve endingspossess. On this principleis com-pounded

the well-known l Triacid ' stain.

The introduction of a second body may also render a dye active

in the tissues; thus Bismarck brown does not stain peripheralnerve

endings(e.g. taste buds)in the frog,but the addition of methyleneblue causes the nerve endingsto take a double colour. In perma-nent

preparationsthe blue quicklyfades,and the brown stain onlyremains. Ehrlich believes that this principleunderlies many of the

'abnormal actions of drugs,especiallyin inherited or acquiredhyper-sensitiveness'.

Besides these somewhat theoretical results,observations on the

physiologicalaction of the organicdye-stuffshave also,of recent

years, begun to lead to results of practicalvalue;and it is quitepossiblethat importantdevelopmentsin therapeuticsmay result

from a further studyof these derivatives. Many possess a remark-able

bactericidalaction,but it has not as yet provedpossibleto

employ them againstordinarybacterial infections. The parasitic

350 PICRIC ACID

trypanosomeshave,however,been shown to be markedlyinfluencedboth in experimentalanimals and in man by treatment with certain

dye-stuffs,such as malachite green G (seep. 354),and trypan red

(seep. 352). These bodies are thoughtto act by favouringthe

developmentof immunizingsubstances within the organism.Malachite green has also been employedby F. Loeffler for

separatingcoloniesof B. coli and B. typhiabdominalis ; the growthof the former organism was preventedby an admixture of this dyewith the culture medium, the colonies of the latter remainingunaffected.

Class I.

NITKO DERIVATIVES OF THE PHENOLS.

Picric Acid, C6H2(NO2)3OH,and Dinitro-cresol"

CH3

OH

The introduction of the nitro group into phenolicsubstances in-creases

the antisepticand toxic action. Both are powerfulblood

poisons,renal irritants,and respiratorydepressants,especiallythe

latter,possiblyowing to its greatersolubility.The group of

naphtholnitro-derivativesincludes Martius yellow,OH

which is similar in its action to dinitro-cresol. The introduction

of a sulphonicgrouping,resultingin the formation of dinitro-

l-naphthol-7-sulphonicacid,

OH

SO2OH

naphtholyellowS, has the usual effectof destroyingthe toxicity.

AZO-DYES 351

Anrantia or Kaiser Yellow is the ammonium or sodium salt of

hexa-nitro-diphenylamine,

NH/C6H2(N03)3H\C6H2(N03)3

and is stated to have toxic properties.

Class II.

Azo- DYES.

The azo-dyesare a class of substances which contain as chromo-

phore the group .N:N. As previouslymentioned, azo-benzene

itself,C6H5.N:N.C6H6, althoughpossessinga red colour,is not

a dye-stuff; by the entrance of auxochrome groups, such as hydroxyland amido, the colouringpower appears, and the shade is modified.

The simplestazo-dyes,like most simpledyes,are yellow,and their

tint is dependentfirstlyon the nature of the auxochrome group, and

secondlyon that of the carbon complex. They may be made to pass

throughred to violet,and in some cases to brown. Blue azo-dyeshave so far only been obtained from those substances containingseveral azo-groups in the molecule. Those containingthe benzene

nucleus are yellow,orange or brown ; those containingthe naph-thalene,red ; by the entrance of several of the latter nuclei,violet-

blue or black dyes are produced.As a generalrule their technical preparationis extremelyeasy.Aniline,for instance,is diazotized in the usual way, and when

the solution is added to an alkaline solution of the phenol or its

sulphonate,oxy-azo-benzeneor Tropaeolin ,Y. is formed "

1. C6H5NH2 -" C6H6N:NC1.2. C6H6N : N.C1 + C6H5ONa = NaCl + C6H5N : N.C6H4OH.

In this reaction phenolmay be replacedby resorcin,a- or /3-naph-

thol,their various sulphonates,or salicylicacid. Sulphanilicacid

and benzidine

C6H4NH2

may be used in placeof aniline,and consequentlya largenumber

of dye-stuffscan be obtained.

The combination of diazo bodies with amines,as a rule,is not

so easy. Some, such as 1 :3-phenylene-diamine,

352 AZO-DYES

combine directlyin neutral aqueous solution;thus chrysoidinis

obtained by mixing equivalentsolutions of diazo-benzene chloride

and l:3-phenylene-diamine,

C6H5.N : N.C1 + C.H4 = C6H5N :N.C3H+ HC1.

But in other cases, as with diphenylamine,solution in methylatedspiritsand treatment with a strongsolution of the diazo derivative

is requisite.The azo-dyes,containinga sulphonicacid group, are, as might

be expected,but slightlytoxic substances,1and are used for

colouringwines (Rougesoluble,Bordeaux B, Ponceau R, Orange 1,

Jaune solide).Those without such groups have also,as a rule,but

slightpoisonousproperties.

Chrysoidin C6H5 .

N :N.C6H3 .HC1

producesslightalbuminuria and a marked reduction of body-weight.In very dilute solution it agglutinatescholera and other vibrios.

It has antisepticproperties,but no specificaction.

Bismarck brown C.

has toxic properties.OH

Sudani CH.N:N" /" ~\65

oproducesslightalbuminuria,but the m-mtro compoundis non-toxic.

N02

"OH_N .-N" /" "\

oTrypan Bed is a benzidine dye obtained from benzidine-mono-

sulphonicacid by diazotization and combination with the sodium

salt of the disulphonicacid of /3-naphthylamine.It has the follow-ing

constitutional formula : "

1 For toxicityof dye-stuffs,see G. M. Meyer, American Chem.Soc.. vol. 29,p. 892, 1907.

AZO-DYES 353

O2ONa

N : N" C6H3" C6H4" N : N-

SO2ONa NH2 SO2ONa NH2 SO2ONa

8O2ONa SO2ONaEhrlich and Shiga experimentedwith this substance on mice

infected with trypanosomiasis.1 per cent, solutions were injectedsubcutaneouslyin doses of -5 to 1-0 c.c. This had a very marked

though temporary destructive action on the parasites,which the

observers attributed to a specialeffect on the body of the host,

leadingto the productionof parasiticidalsubstances. Animals

aftercure were protectedto a greatextent againsta second infection.

Trypan Blue (preparedby Nicolle and Mesnil),thoughdifferingin chemical constitution,has an action similar to that of trypan red

on the trypanosomes; Ehrlich states that strainsrendered resistant to

the one are alsoimmune to the other,thoughtheymay be destroyedby fuchsin or by the use of atoxyl(the sodium salt of para

amido-phenyl-arsenicacid).Thus in Ehrlich's words l this specificresistanceconstitutesa cribrum therapeuticumor therapeuticsieve,bywhich any new remedyof this typemay be classified.He possesses

a strain of trypanosomeswhich are resistantto all these pharmaco-dynamicagents; and thus,if a mouse infected with this strain is

cured by any new drug,the latter cannot belongto one of these

Ponceau 4 G.B. C6H5.N:N

Di-phenylamineorange

is non-toxic.

BO2ONa

C6H 1:4

N:N.C6H4.NH.C6H5

producesalbuminuria,but otherwise has onlyslighttoxic action ;

on the other hand its isomer Metanil yellow

/SCXONaC6H4" 1:3

XN:N.C6H4.NH.C6H5is toxic for dogsin doses of 20 gms. after 4 days.This is probablydue to the presence of free diphenylamine.

1 Harben Lecture,1907,Lancet,ii,1907,p. 351.

A a

354 DI- AND TRI-PHENYL-METHANE DYES

Class III.

Di- AND TKI-PHENYL-METHANE DYES.

Among the diphenyl-methanedyes is Fyoktanin, in its pure

state termed Auramin O (mixedwith dextrin it goes by the name

of Auramin I,II,III).It isthe hydrochlorideof imido-tetramethyl-

diamido-diphenylmethane "

(CH8)2N.CeH4. C.C6H4N(CH3)2HC1

NH

Brilliant Green, also known as malachite green G, and diamond

green G, or ethylgreen, is the sulphateof tetraethyl-di-jtjara-amido-

triphenyl-carbidride,

'6AJ^

It has alreadybeen mentioned,owing to the fact that ithas been

employedby Wendelstadt to destroythe trypanosomesof tse-tse

flydisease.

Methyl Violet is a mixture of the hydrochloridesof the hexa-

methyl-pararosaniline,

and penta-methyl-benzyl-pararosaniline; it is a strongerantisepticthan the yellowpyoktaninand relativelyless toxic. It has been

used locallyfor inoperablecancer.A largenumber of similar derivatives have been studied and

found to have antisepticproperties,which differ but slightlyfromthose of the parentdyes.

Rosaniline or Fnchsin has a constitution expressedby the

followingformula "

NH2.C2H4XNH2\rH)CH/^s/

7?-Fuchsinor jt^zra-Magenta (pararosaniline)does not contain a

methyl group.

The antisepticpowers of these bodies have never been shown to

be in direct relation with their stainingproperties,but appear to

dependentirelyon the presence of the aromatic nuclei.

Eosin, the alkali salt of tetrabromfluorescein,has been shown by

Noguchi to have the power of neutralizingcertain toxins occurring


APPENDIX

PAGE 20. The followingtable,showing the curare-like action of

various ammonium bases,has been modified from one given byH. Hildebrandt and Loos. In place of the minimum dose of each

substance capable of producing complete paralysisper kilo, body-weight, curarine has been taken as unity and proportionalvaluesassignedto the others.

The minimum dose of curarine is "008 m. gm.

Curarine. . . ... .

/.

1

1. Methyl-strychninesulphate . . .V '" 100

Methyl ester of strychnine-iodoaceticacid " .187

Ethyl-strychninesulphate. . . . . .312

2. Benzyl-atropinebromide . . ."""

.. .75

3. Benzyl-brucinebromide . . " .*"" "

. .187

Methyl-brucineiodide . " . " " *312

4. Methyl cinchonine sulphate .....312

Methyl ester of cinchonine-iodoacetic acid. *

375

Amyl-cinchonine iodide. . " . . "

625

5. Tetra-methyl-ammonium iodide. . . .

625

6. Benzyl-nicotineiodide . " . . . .3750

Methyl-nicotinesulphate .-

. /..-.*. * * . .12500

Ethyl-nicotineiodide. .

*''

'

. .^

; .18750

7. Benzyl-tropineiodide . . . ."""".

.7500

Methyl ester of tropine-iodoaceticacid . . .12500

PAGE 54. There are a certain number of ammonium bases which

do not produce a curare-like effect. Thus Fraser and Crum Brown

showed that when the methyl and halogen groups were attached to

the nitrogenin the pyrrolidinering of nicotine there was no curare

action ; this appeared,however, when the nitrogen in the pyridinering was made quinquevalent. Loos showed many years ago that

the intensityof the curare-like action depended largelyon the nature

of the added alkyl groups. Thus ethyl strychninesulphate,ethylnicotine sulphate,and amyl cinchonine sulphateare respectivelylessactive than the correspondingmethyl-sulphates.The chlormethylateof papaverine(Pohl)and the correspondingderivatives of cotarnine and

hydrastinine(Fiihner)have no action whatever. The variety of

halogen makes no difference to the productionof the curare effect,

but considerable differences are noted if oxygen takes the place of

the halogen element (Hildebrandt).

PAGE 64. Hildebrandt states that whereas o-oxybenzoic acid

(salicylicacid)leaves the body conjugated with glycine,the para

APPENDIX 357

compound is eliminated as a glycuronicacid derivative (Zeitschr.physiol.chem. 1904,Bd. xliii).

PAGE 207. Kobert has investigatedvarious substances of the

antipyrinetype with the followingresults : "

3-Antipyrineaccordingto Michaelis is constituted as follows "

CO" N.CH,

CH

CH3.C N.C6H6

It is a more active poison than the ordinary5-antipyrine; this is

apparentlydirectlytraceable to the different way in which the car-

bonyl group is linked in the two substances.

On the other hand iso-antipyrine,formulated by Michaelis

C6H5.C N.CH3

.CHa

is less toxic than 3-antipyrine,but more so than ordinaryantipyrine;whereas pyramidon has a more powerfulaction than antipyrine,3-pyramidon

CO" N.CH3

(CH3)2N.C

CH3.C N.C6H5

has a slighteraction,and, further,is much less toxic than the parentsubstance,3-antipyrine; that is to say, the entrance of the N(CH3)2group into ordinaryantipyrineincreases the action,whereas a decrease

follows its introduction into 3-antipyrineor into tso-antipyrine.

PAGE 272. Ftihner has recentlyshown that quinolineis oxidized

in the body to jpara-oxy-quinoline,thus exactlyresemblinganiline.

PAGE 288. Hydroberberineis the stereo-isomer of canadine,an

alkaloid occurringin very small quantitiesin Hydrastiscanadensis ;

corydaline,from Corydaliscava, is structurallyvery similar to the

methyl substitution product of hydroberberine(F. Meyer), and is

physiologicallyinactive. The correspondingethylderivative slows

the respirationand pulse rate,but has no influence on the blood

pressure (Meyer and Heinz).

358 APPENDIX

PAGE 338. Further examples of the influence of stereo-chemical

differenceson

taste are: (1) leucin, the Zaew-rotatory variety of which

is bitter, whilst the dextro-rotatory variety is sweet (E. Fischer and

Warburg) ; (2) tryptophane, which when occurring in the body is

almost tasteless, whereas the artificially prepared substance is sweet

(Ellinger).

PAGE 346. Perkin has shown that closure ofan aromatic ring does

not necessarily produce anyalteration in the odour of a substance.

He instances the aliphatic terpineol"

CH3.O "CH.C-CH3

\CH" CH \O

-

CH

H3C" CH/

and the corresponding cyclic body

xjCH-

CH2\ /C

"CH.C"-

H

PAGE 352. Ehrlich x has investigated various substituted rosanilines

with regard to their action on trypanosomes.

There isa decreased activity in the di- and tri-oxy derivatives of

malachite green and in orô-oxy-hexamethyl-rosaniline ; onthe other

hand, trimethoxy-pararosaniline is a more powerful trypanocide than

theoxy

derivatives of malachitegreen or methyl violet.

The introduction of carboxyl radicals hasa

muchmore

marked

effect in diminishing the action;

thus chrome- violet, chrome-blue and

azo-green arealmost inactive.

1 Berl. Klin. Wochenschr. Nos. 9-12, 1907.

INDEX

Abrastol, 139.

Acetal, physiologicalaction of,104.

Acetaldehyde, preparationof,36.

Acetamide, 124.

Acetamide and oxamide, partialoxi-dation

in body of,74.

Acetamido-phenol -benzoate,195.

Acetanilide,181.Acetic acid,determination of constitu-tional

formula, 10 ; preparation of,117 ; reactions with, in body, 66.

Acetoacetic acid,113.

Acetone, 112, 113.

diethyl-sulphone,114.Acetoneamine derivatives,comparison

with ecgonine,306.

Acetophenone, 114.

Acetyl chloride,reactions of,36.

Acetyl-codeine,294.

Acetylene, chemical properties,27 ;

metallic derivatives of,28 ; physio-logicalaction of,45 ; preparationof,

33, 34.

" di-iodo-,50.

Acetyl-pyrogallol,147." radical,120 ; introduction of,dur-ing

passage of substances throughbody, 65.

Acetyl-salicyclicacid,158.

Acid-amides,physiologicalpropertiesof, 124, 178 ; preparation and pro-perties,

123.

Acid radicals,introduction of, into

basic substances,120.

Acid, salicylic,dissociation of,16.Acidol, 178.

Acids,amido-, taste of,335." aromatic, physiologicalaction,119,

120 ; syntheseswith glycinein body,63.

" halogen substitution products of

aliphatic,121, 122.

" hydroxy aromatic, 149.

" physiological effect following re-placement

of H in COOH group,4o"

" physiologicalpropertiesof the,118;preparation and properties of, 117,118.

Acoine, 314.

Aconitic acid,51.

Aconitinc, 121.

Acrolein,50.

Adrenalin, 317.

Adrenalone, 318.

" derivatives,319.Aescnlin, 324.

Agathin, 202.

Ag-urin, 228.

Aitken, on smell,332.Alcaptonuria, 75.

Alcohols,aliphatic,classification,87.Alcohols and derivatives,81 ; taste of,

334.

Alcohols,chemical characteristics,90 ;

comparison of physiologicalactionof primary, 92 ; comparison of

primary and secondary,52 ; compari-sonof physiologicalaction of primary,

secondary, and tertiary,92; effect

on physiologicalaction of replace-mentof hydrogen of OH group, 47 ;

generalmethods of preparation,88 ;

generalphysiologicalproperties,91 ;

general properties,89 ; polyhydric,90 ; secondary and tertiaryprepar-ation

of, 89 ; used in perfumery,344.

Aldehydes, action of sodium bi-sul-

phite on, 106.

" aromatic, physiologicalaction,107 ;

halogen substitution products of ali-phatic,

108 ; physiologicalaction of,107 ; polymerization of, 107 ; pre-paration

of, 105 ; propertiesof,104,105 ; used in perfumery, 344.

Aliphaticalcohols,classification,87.

Aliphatic and aromatic derivatives,subdivisions,13.

Aliphatic and aromatic series,relative

pharmacological action,20.

Aliphaticderivatives,generalmethodsof synthesis,35 ; synthesis from

acetic acid,36 ; synthesis from alco-hols,

36 ; synthesis from halogenderivatives,37.

Aliphatic dibasic acids,taste of, 338.

Aliphatic hydrocarbons, 24 ; physio-logicalcharacteristics,45.

Alkali - iodides, organic substitutes,167.

Alkaloids,233 ; action of substitutinggroups, 245 ; alkyl substituents,action of, 245 ; bitter taste of,340 ;

360 INDEX

classification of,244 ; curare action of

quinquevalent nitrogen derivatives,54 ; generalphysiologicalcharacter-istics,

243 ; Loew's specialpoisons,249 ; opium, 288 ; opium, containingtso-quinoline ring, 299 ; pyridinegroup of, 249.

Alkyl and oxy-alkylderivatives of uric

acid,225." ureas, preparationof,215.Allyl-alcohol,50." sulphide,127." thiourea,218." trimethyl ammonium hydrate,51.Allylamine,50.Aloin, 329.

Alypin, 314.

Ami do-ace tamide, 124.

Amido-acetic acid, derivatives of,formed in body, 63.

" (glycine),formation of derivatives

in body with :" benzoic acid, 63 ;

jp-brom-benzene, 63 ; chlorbenzoic

acid,63 ; cuminic acids,63 ; mesity-lenic acid,63 ; naphthoic acids,63 ;nitrobenzoic acid, 63 ; p-nitro-tolu-ene, 63 ; phenyl acetic acid, 64 ;

salicylicacid,63 ; xylene, 63.

" syntheseswith, in body, 56.

Amido-acids, aliphatic,taste of, 335 ;

aromatic,taste of,336 ; oxidation of,in body, 74 ; 7 taste of,340.

Amido-benzoic acid,formation of urea

derivative in body, 64.

a-Amido-cinnamic acid, oxidation of,in body, 75.

Amido-dibasic acids,taste of,338.

p-Amido-phenol, derivatives of, 184 ;

types of derivatives,186.

Amido-salicylicacid,formation of urea

derivative in body, 64.

Amido-valerianic acid,taste of,335.

Amines, action of nitrous acid on,89.

" aliphatic,physiologicalaction of,47.

" aromatic,preparationof,173,174.

" classification,171 ; effect producedby entrance of acidic groups, 176,177 ; generalmethods of preparation,172 ; physiologicalpropertiesof,177 ;

preparation of, 37, 38; primary,171 ; primary,secondary,and tertiaryreactions of,175 ; propertiesof,175 ;

tertiary,171.

Aminoform, 108.*

Ammonia, derivatives of, 171 ; sum-mary

of physiological action of,207.

" physiologicalpropertiesof,177.Ammonium bases, curareform action,

U, 20.

Ammonium compounds, quaternary,physiologicalaction of,179.

Amyffdalin, 324.

Amyg-dophenin, 191.

Amyl-acetate,122.

" alcohol, derivatives with local

anaesthetic action,314." nitrite,100." radical,influence on odour, 342.

Amylene hydrate, 93.

Anaesthesin, 312.

Anaesthetic action of benzoic acid

derivatives,310." power of glycocoll derivatives of

benzoic acids,311.Anaesthetics and hypnotics, distinc-tion

between, 81; main group of,81.

Anesin, 96.

Aneson, 96, 315.

Anil ides,physiologicalaction of,179 ;

preparation of, 176 ; stabilityof,176.

Aniline and phenol derivatives,com-parison

of physiologicalaction of,210.

" and thiophene,increased toxicityonintroduction of alkyls,46.

" methyl and ethyl, physiologicalpropertiesof,178.

Aniline,derivatives,181.physiologicalaction of,181.

primary and secondary deriva-tives,

47.

Anilopyrine, 206.

Anisanilide,182.Anisol, 129.

Annidalin, 163.

Anthracene, 30.

Anthraquinone derivatives,329 ; pur-gatives,328.

Antifebrin, 181.

Antiosin, 167.

Antipyretics,main group of synthetic,171.

Antipyrine, 48, 2O4.

" chloral,111." physiologicalaction of, 204, 205,

209.

" preparationof,202." salicylicacid salts of,205.

Antiseptics,aromatic, 128.

" containingiodine,161 : comparisonof,167.

Antispasmin, 301.

Antithermin, 201.

Anytin, 169.

Anytols, 169.

Apocodeiue, 301, 302.

Apolysin, 192.

Apomorphine, 301.

Arabino-chloralose,111.

INDEX 361

Arbuttn, S23.

Aristol, 163.

Aristoquin, 279, 280.

Aromatic acids,physiologicalaction of,119, 120.

" antiseptics,128." derivatives,action of nitric and sul-phuric

acid on, 40 ; outline of syn-theticmethods for preparation of,

40 ; oxidation of in organism, 75.

" esters of halogen acids,99." halogen derivatives, preparation

from diazo-compounds, 40 ; stabilityof,99.

" hydrocarbons, preparation from

diazo-derivatives,40." hydroxy acids,149." hydroxyl derivatives,128." ketones,preparationof,42." nitro derivatives, 101." substances oxidized in body :" ani-line,

78 ; benzene,76; benzidine,78;cymene, 76; di-phenyl, 78; ethyl-benzene,76; indol,78; naphthalene,76 ; nitro-toluene, 77 ; phenyl-methane, 78 ; phenyl-propionicacid,77 ; propyl-benzene, 76 ; toluene,76.

" substances,physiologicalaction fol-lowing

introduction of COOH group,119.

Arsonium bases,physiologicalaction,54.

Asaprol, 139.

Asparagine,dextro,and toevo,differencein taste,53.

Aspirin, 158.

Asymmetric carbon atom, theory of,5.

Atropine, 264 ; central actions of,267 ;

comparison with cocaine,266 ; con-stitution

of,265 ; effect on eye com-pared

with cocaine, 270 ; mydriaticaction,270 ; paralysisof nerve end-ings

to involuntary muscle, 267 ;

paralysisof sensory nerve endingscaused by, 271 ; physiologicalactiondependent on two opticalisomers,271 ; physiologicalaction of, 265 ;

substitutes,316.Auramin O, 354.

Aurantia, 351.

Auxochrome groups of Witt,348.Avogadro's hypothesis,1.Azo-dyes,351.

" physiologicalaction of,352.

Bactericidal action of dyes,349.Baglioni,theory of narcosis,86.Bauman and Kast on sulphonals,114,

115.

Bechhold and Ehrlich,antisepticvalueof phenols, 134.

Benzaldehyde, preparationof,105.

Benzamide, 124.

Benzanilide,182.Benzene, determination of constitu-tional

formula,,11,12.

Benzene-derivatives,comparison of

toxicity of isomers, 52; different

types of,43.Benzene homologues,oxidation of,30 ;

reduction of, 31 ; physiologicalac-tion,

46 ; preparation of, 33 ; syn-thesis

of,42.Benzene hydrocarbons, 28; nature of

double bonds in,28, 29.

Benzene nucleus, negative character-istics

of,29.

Benzene, physiologicalaction of, 45 ;

sources of, 30 ; stabilityof ringcomplex, 30.

Benzene sulphonic acids,preparationof,41.

Benzenes, di-oxy,taste of,339.

Benzidine, not oxidized in body, 78 ;value in dye industry,351.

Benzoic acid, 149 ; derivatives,withlocal anaesthetic action,310.

Benzo-naphthol,139.Benzonitrile,126.Benzophenone, 114.

Benzosal, 144.

Benzosalin, 158.

Benzoyl-arbutin,323.Benzoyl-lupinene,180.Benzoyl-morphine,296.Benzoyl radical,120.

Benzoyl-salicin,taste of,335.Benzylamine, 173.

Benzyl chloride andchlortoluene,com-parison,

43.

Berberlne, 287.

Betaine, 178.

Betol, 139.

Bile,action of,55.B ism ark brown, 352.

Bisulphide of carbon, 127.

Bokorny, comparison of toxicity of

benzene isomers,52.Borneol, glycuronic acid derivatives

of,62.

Bredig on colloidal solutions,86.Brilliant green, 354.

Brom-acetic acid,122.Bromal, 109.

Bromalin, 98.

Brom-benzene,99.Bromine, derivatives of urea, 217.

Bromine, organic preparationsof,forepilepsy,98.

Bromipin, 98.

Broxnoform, 98.

Bromural, 217.

Brucine, 281.

362 INDEX

Brunton and Cash, ammonium com-pounds,

20.

Butyl-amide, 124.

Butyl-chloral,109." reduction of, in body,79.

tso-Butyl-o-cresol,163.Butyric acid,119.

Butyronitrile,126.

Caffeine, 227.

Caffeine,effect of introduction of (OH)group, 92.

Cahn and Hepp, aniline derivatives,181.

Camphor, glycuronic acid derivatives

of,62.Carbamic esters of guaiacol,143.

Carbon-bisulphide,127.

Carbon, tendency to self-combination,7.

Carbon tetrachloride,97.Carbonic acid,ammonia derivatives of,

213.

Carbostyril,synthesiswith glycuronicacid,61.

Carvacrol,130.Cash and Dunstan, on nitrous esters.

100.

Catalyticpoisons,17.

Catechol,causing rise of arterial pres-sure,318.

Cellotropin, 323.

Cells,selective action of, 19 ; stainingreactions,19.

Cevine, decomposition product of

veratrine,180.Chain into cyclicderivatives,effect on

taste,340.1 Chemical Environment,' Ehrlich's

views, 349.

Chloracetic acids,physiological pro-perties

of,121.Chloral, 108, 109.

Chloral-acetophenone,110.

Chloral-alcoholate,110.

Chloral-amide, 110.

Chloral-ammonia, 111.

Chloral-antipyrine,111.Chloral -formamide, 110.

Chloral,formation of urochloralic acid

in body, 60 ; reduction of,in body, 79.

Chloral-hydrate,106." production of surgicalanaesthesia,

81.

Chloral -urethane,110.Chloralose, 111.

Chlorbenzene, 99.

Chlor-caffeine,physiologicalaction of,95.

Chloretone, 96, 315.

Chlorides of carbon, physiologicalaction of, 95.

Chlorinated phenols,antisepticactionof,134.

Chlorine,physiologicalcharacteristicsfollowingentrance of,95.

Chloroform, 96,97.Chloroform acetone, 315.

Chloroform, 'delayed poisoning,'97;fall of temperature after narcotic

doses,16.Chlor-toluene and benzylchloride,

comparison, 43.

Choline,51.Chromium oxychloride,preparationof

aromatic aldehyde, 105.

Chrysin, 328.

Chrysoidin,352.Chrysophanic acid, 328.

Cinchona alkaloids,271.Cinchonine, oxidation of in organism.

277.

Cinchonine and quinine, 276.

Cinchotoxine,277.Cinnamic acid,51, 149; oxidation in

body, 77.

Citral,344.Citric acid derivatives of phenetidin,

192.

Citronellol,344.

Citrophen, 192.

Coca-ethyline,262.

Coca-propyline,262.

Cocaine, 120, 180, 258.

o-Cocaine,263.

Cocaine, action of (CH3COO) group,262 ; action of (C6H,COO) group,263 :

' anaesthiophore '

group, 264 ;

classification of physiologicalaction,258 ; comparison with atropine, 266 ;

derivatives,261 ; dextro,laevo,differ-ence

in action of,53 ; elevation of

temperature effect,260 ; mydriaticaction of,260 ; production of local

anaesthesia,260 ; relations between

physiologicalaction and constitu-tion,

264 ; substitutes for,304.

Cocaine-urethane,262.Codeine, 294.

" acetyl derivative of,294 ; chloride

of,296.Colloidal solutions,86.

Compound radicals,theory of,1.Conhydrine, 252.

Coniceines,252.Coniferin, 324.

Coniine, 252.

tso-Coniine,252.Coniine derivatives,252.

Coniine,synthesis of,236.Constitutional formulae, factors re-quired,

9 ; acetic acid,10 ; benzene,11.

Copellidine,254.


364 INDEX

Eosin, 354.

Eosote, 144.

Epicarin, 140.

Epiosin, 293.

Erythrol tetranitrate,101.Esters, general methods of prepara-tion,

90,94,122 ; generalproperties,94 ; physiologicalproperties,122,123.

" of halogen acids,93." of hydriodicacid,99." of hydrobromic acid,98." of hydrochloricacid, 96.

" of inorganicacids,93-103." of nitrous and nitric acids,100." of salicylicacid,odour of,342." of sulphurous and sulphuric acids,

102.

" used in perfumery, 344.

Ethers, formation from alcohols re-sulting

in lessened toxicity,47 ;

physiologicalaction of,103 ; prepara-tionand propertiesof,103, 104.

Ethoxy-caffeine,229.p-Ethoxy-phenyl-succinimide,190.Ethyl acetate,122, 123.

Ethyl alcohol,preparationof,88.

Ethylainine,decomposition by nitrous

acid,89.

Ethyl-benzamide,124.Ethyl bromide, 98.

Ethyl chloride,96.Ethyl ester of tyrosin,123.Ethyl-formate,122.Ethyl-guaiacolcarbonate,142.Ethyl iodide,99.

Ethyl mercaptan, 114.

Ethyl and methyl groups, physiologicaldifferences,49.

Ethyl -salicylate,153.

Ethylene, physiologicalaction of,45.Ethylene dibromide, 98.

Ethylene-diethyl-sulphone,115.Ethylene-dimorphine, 293.

Ethylene hydrocarbons, preparationof,33, 34.

Ethylidene-dimethyl-sulphone,115.Eucaine, A and B (a and "),307.Eudoxin, 167.

Eugallol, 147.

Eugenol, 131.

" use in perfumery,345.Enmydrine, 317.

Euphorin, 183, 196,213.Euphtfcalmine, 316.

Euporphin, 302.

Eupyrin, 195.

Euquinine, 279.

Euresol, 141.

Enropnen, 163.

Exalgin, 184, 210.

Ezodine, 330.

Ferrichthyol, 169.

Fischer and Filehne on Kairine,49.Fisetin, 327.

Formaldehyde, 71.

" compounds of,107, 108.

Formalin, 71.

Formamide, 124.

Formamint, 107.

Formanilide, 182.

Formic acid,antisepticproperties,118.

Forxnin, 108.

Formyl-phenetidin, 189.

Formyl-urea, 108.

Fortoin, 326.

Fraser and Crum Brown, ammonium

compounds, 20.

Freundlich and Losev, Theory of dye-ing,22.

Friedel and Craft's synthesis,42.

Fuchsin, 354.

Fumaric acid,119.Furfurane, physiologicalaction of,45.

Furfurol,synthesiswith acetic acid in

body, 66.

Gallacetophenone,58, 148.

Gallic acid,132, 159.

Gaultherin, 322.

Gentisinic acid,57.Geosote, 144.

Geraniol,344.

Glucosides,320." classification,320; taste of, 333,

334.

Glutaminic acid,dextro and laevo,differ-ence

in taste,53.Glutaric acid,119.

Glycine,derivatives of,formed in body,63.

Glycocoll, derivatives of amido and

oxy-amido benzoic acids,311.

" derivatives of,formed in body, 63.

Glycocoll-phenetidin,193.

Glycol,preparationof,88.

Qlycosal, 154.

Glycuronic acid derivatives,59.

Glycuronic acid,derivatives of,formedin body :" borneol,62 ; camphor, 62 ;

choral,60 ; dichloracetone, 61 ; men-thol,

62 ; naphthol, 62 ; pinacone,61 ; pinene, 62 ; phellandrene, 62 ;

phenetol,62 ; primary alcohols,61 ;

sabinene,62 ; thujon, 62 ; vanillin,61.

substances causing appearance

of in urine, 59; substances which

form derivatives with,61 ; syntheseswith, in body, 56.

Griserin, 165.

Guaiacetin, 146.

Guaiacol, 142.

" attempts to increase solubilityof,

INDEX 365

145; carbamic esters of,143; inor-ganic

esters of,142,143 ; oleate,143 ;

organic esters of, 143 ; sulphonatesof,145.

Guaiacolsalol, 144.

Gnaiacophosphal, 143.

Guaiamar, 146.

Ouaiasanol, 145.

Guanidine, 178.

Halogen acids,aromatic esters of,99.

Halogen derivatives of aromatic series,stabilityof,178.

Halogens, influence on odour,342.Hedonal, 82, 214.

Helicin, 322.

Heptane, 25.

Heroine, 180, 295.

Hesperidin, 325.

Heteroxanthine, 226.

Hetocresol, 150.

Hetol, 149.

Hexamethylene-tetramine,108." and iodoform, 162.

" tannic acid, derivatives of,160.

Hexane, 25,45.Hinsberg and Trenpel on aniline deri-vatives,

185.

Hippuric acid,formation of in body,63.Holocaine, 313.

Homatropine, 264,268.

Homogentisinic acid,57.Homologous derivatives,smell of,342.HontMn, 160.

Hordenine, 303.

Hydracetin, 200.

Hydrastine, 284.

Hydrastinine,285, 286.

Hydrastininicacid,286.Hydriodic acid,esters of,99.Hydrobromic acid,esters of,98.Hydrocarbons,aliphatic,24.Hydrocarbons,aliphaticaromatic taste

of, 335 ; aliphatic not oxidized inthe body, 71 ; benzene, 28 ; benzene,sources of,30 ; methods of prepara-tion,

32 ; paraffins,24 ; paraffins,pre-parationof,32 ;physiologicalcharac-teristics,45.

Hydrochloric acid,esters of,98.Hydrocotarnine, 286.

Hydroquinine, 278.

Hydroquinone, 57, 131,140." taste of,339.Hydroxy acids,aromatic,149.Hydroxy-benzoic acids,119, 120.

Hydroxy-propane,iodine derivatives.168.

Hydroxyl derivatives,aromatic, 128.Hydroxy lamine, action on aldehyde,

106.

Ryoscyamine, 270.

Hypnal, 111,206.Hypnone, 114.

Hypnosis, theory of Overton and

Meyer, 83, 84 ; views on, 85,86.Hypnotic action of ureides,219, 220.

Hypnotics and anaesthetics,distinc-tion

between, 81; main group of,81.

Ichthalbin, 169.

Ichtharsan, 169.

Ichthoform, 169.

Ichthyol, 169." efficacydependent on several fac-tors,

170.

Imido acids,taste of,338.

Imido-derivatives,effect of replacingH of NH group by alkyls,48.

Indican,urine,79.Indol,oxidation in body, 78.

Indophenol reaction,with aniline de-rivatives,185.

Inertia of carbon systems, 8.

Intestines,action of alkali in, 55.

lodal,109.

Zodalbin, 167.

lodeig-on, 162.Iodide of tso-butyl-o-cresol,163.

Iodides,organicsubstitutes,167.Iodine antiseptics,comparison of,167.Iodine, containing antiseptics,161 ;

entrance into aliphaticand aromatic

substances,163.Zodipin, 167.

Xodo-auisol, 166.

lodo-compounds,aromatic,99.Iodoform, 99, 161, 162.Iodoform,classes of substitutes,161,

162.

lodoformal, 162.

lodoformin, 162.

lodoformog-en, 162.

lodol, 164.

Zodolene, 162.

lodyloform, 162.

lonone, 345.

lothion, 168.

Iridin, 326.

Irigenin,326.Isomeric relationships,influence on

sense of smell, 345.Isomerism, 4, 5.

" interdependence of physiologicalaction,51.

Iso-oximes,cyclicketones,246,248.Iso-pilocarpine,232.

Isopral, 95.

iso-quinoline,constitution of,240.

Jaborine, 232.

Jalapin, 322.

366 INDEX

Kairine,49, 275.

Kairolin A, B, 274.

Kaiser yellow,351.

Ketones, aromatic, oxidation of, in

body, 57 ; preparation of,42 ; classi-fication

and preparation,112 ; cylic,246, 248 ; preparation of, 86, 37 ;

properties of, 112; reaction with

phenyl-hydrazine,"c.,112; used in

perfumery, 345.

Ketonic acids,stabilityof,113.Robert's paradox, 19.

Lactamide,124.Lactic acid,appearance in urine,73.Lactophenin, 189.

Lactylamido-phenol-ethyl-carbonate,195.

Lactyl-phenetidin,189.

Lactyl radical,120.

Lactyl-tropeine,267.

Ladenbui-g'sgeneralizationon mydri-atic action,268.

Laudanine, 300.

Landanosine, 299.

Lenigallol, 147.

Lepidine, 273.' Leuco ' compounds, 347.

Levulinic acid,113.Liminal values,83, 84.

Linalool,344.

Lipoid substances,solubilityof nar-cotics

in, 83.Loew's ' substitution ' theory,criticism

by Ehrlich,348 ; theory of poisons,17.

Loretin, 164.

Losophane, 166.

Lupetidines,253,254.

Lupinene, 180.

Lysol, 133.

Lysol,sulphur preparation,169.

Magnesium, organic derivatives,38 ;

synthesiswith, 38.

Malachite green, 354 ; action on bacte-ria,

350.

Malakin, 194.

Malarin, 194.

Maleic acid,119.Malonic acid,119.Mannitol hexanitrate,101.Marsh gas, physiologicalaction of,45.Martius's yellow,350.Mercaptans, 126.

Mercapturic acids, formation of, in

body, 67.

Mercury, bromide, chloride,cyanide,15.

Mercury salts,double compounds of,15, 16.

Merling,physiologicalaction of ace-

tone-amine derivatives,306.Mesotan, 154.

Metabolic changes of sulphonals,116.Metabolic processes, 55.

Metakalin, 133.

Metanicotine,256.Metanil yellow, 353.

Methacetin, 185.

Methane, preparationof,32.

Metho-codeine, 297.

Methylacetate,123.

Methyl alcohol,preparationof,88.Methyl and ethyl groups, physiologicaldifferences,49.

Methyl-benzamide, 124.

Methylbromide,98.Methyl-chloroform, 97.

Methyl-coniine,252.Methylecgonine, 120.

Methyl-ethyl-ether,probable value of,104.

Methylenphorin, 184.

Methyl group, introduction of, duringpassage of substances through body,66.

Methyl-keto trioxybenzene,148.Methyl nitrile,125, 126.Methyl rhodin, 158.

Methyl salicylate,153.Methyl sulphide,127.

Methyl violet,354.

Methylal, physiological action of,104.

Methylene blue, 355.

Methylene diethyl-sulphone,115.

Metramine, 108.

Mikrocidine, 139.

Molecular magnitude, determination

of,9.Moore and Eoaf, hypothesis on action

of anaesthetic substances, 85 ; on

chloroform,85.

Morphenol, 291.

Morphigenin, 292.

Morphine, 290.

" benzoyl derivative, 296 ; constitu-tion

of, 291; derivatives of, 293;

di-acetylderivative,295 ; ethyl deri-vative,

294 ;* pyridine,'formula for,

302.

tso-Morphine,297.

Morphol, 291.

Morpholine and phenanthrene, 242.

Morpholine-phenanthrene alkaloids,288.

Morpho-quinoline ether,296.

Morphothebaine, 299.

Musk, artificial,345.

Mydriasine, 317.

Mydriatic action,Ladenburg's general-ization,268.

INDEX 367

Naphthalan-morpholine,291.Naphthalene, 30.

" oxidation of,in body, 76 ; physio-logicalaction of,45.

Naphthol, a- and 0-, glycuronicacidderivatives of,62.

Naphthol-sulphonic acid,139.

Naphthols, 139.

Naphthylamine-sulphonicacid,140.Narceine, 301.

Narcotic action,enhanced by entrance

of chlorine into molecule,82." of alcohols, aldehydes, ketones,

82.

Narcotic effects,depressedby carboxyl

group, 82.

Narcotic propertiesof sulphones,115,116.

Narcotics, aliphatic,groups of, 82;physiologicalaction of,81.

JTarcotine, 286,300.

JTarcyl, 301.

Nencki, salol principle,55, 129; sul-

phocyanic acid in stomach, 65.

Neurine, 51.

Nenrodin, 196.

Nicoteine, 256.

Nicotine, 255.

Nicotine, difference between dextro and

laevo,53.

Nirvanine, 311.

Nitriles,aromatic,126." aromatic, preparationof,41, 42.

" formation of sulphocyanides in

body, 65.

" of fattyseries,toxicityof,126." odour of, 343 ; physiologicalpro-perties,

125, 126 ; preparation of,37, 125; reactions of,37, 125.

t'so-Nitriles,odour of,343.

Nitrites,chemical action on tissue

cells,101.

Nitrobenzaldehyde,oxidation in body,63.

rn-Nitrobenzaldehyde,changes of, in

body, 65.

Nitrobenzene,reduction of,in body, 79.

Nitro-compounds, aromatic, reduction

of,173.Nitro-derivatives, aromatic series,physiologicalaction,101, 102.

" odour of,342.

Nitro-glycerine,101,102.

Nitro-group,influence on taste,334.

Nitro-naphthol, physiological action

of,102.Nitre-paraffins,101.

Nitro-phenol,129.

Nitro-phenols,reduction of,by organ-ism,80.

Nitro-phenyl-propiolicacid,reduction

of,by organism, 80.

Nitro-thiophene,physiologicalactionof,102.

Nitro-toluene,oxidation in body, 77.

Nitrogen, influence on odour, 343.

Nitrous and nitric acid,esters of,100 ;

physiologicalaction of,100.

Ndlting, on oxidation processes in

body, 78.

Nosophen, 166.

Novocain, 312.

Nux vomica, 271.

Octane, 25.

" physiologicalaction of,45.

Odour, 341.

" dependence on physical factors,341.

Oil of Wintergreen, 153.

Olefines,chemical propertiesof,26.

Opianic acid,physiologicalpropertiesof,286.

Opium alkaloids,288; classification,289 ; containing tso-quinolinering,299.

Opticalisomers,5.

Opticallyactive tartaric acids,6.

Orcin, 131.

Orcinol,taste of,339.Orexine, 241.

Organic dyes,347.

Orthin, 201.

Orthoform, 310.

Orthoform-neu, 311.

'Osmophore* groups, 341, 342;

presence of several in molecule,342.

Overton, Meyer and,theory of hypno-sis,83,84.

Oxalic acid,oxidation in body of, 73 ;

toxicityof,118.Oxalic and succinic acids, synthesis

from ethylene,39.

Oxidation,differences between methyland ethyl groups, 71 ; general pro-cess

of,67,68,69.

" in organism, theories of,70." of aromatic derivatives in body, 75.

" of aromatic substances, Nolting'srule,78.

" of stereochemical isomerides,69." processes in the body taking place

with :" Alanin, 74 ; alcohols,71 ;

aliphaticacids,73; aliphaticsub-stances,

71 ; amido-acids, 74 ; dex-trose,

69 ; esters,71 ; formaldehyde,71; formate of soda,69; glutaricacid,74 ; glycerol,72 ; glycolicacid,73 ;

hydrocarbons, 71; malic acid,74;malonic acid, 73 ; mannite, 69, 72 ;

methyl alcohol,71 ; methylainine,71 ; nitriles, 71 ; oxalic acid, 73 ;

oxy -acids,73 ; oxy-butyricacid,73 ;

368 INDEX

phenylalanine, 69 ; secondary alco-hols,

71 ; succinic acid, 73 ; sugars,69, 72 ; tartaric acid,69,70,73 ; tar-

tronic acid, 73; tertiaryalcohols,71.

Oxidation,selective,69,70.

Oxidizingpoisons,17.

Oxy -benzenes,comparison of toxicity,52 ; preparation and properties,128.

Oxybenzoic acids,150.

Oxybutyric acid,118.

Oxycarbanil,181.

Oxyphenacetin-salicylate,195.

Paeonol, 58.

Pancreatic juice,action of,55.

Papaverine, 299.

Parabino-chloralose, 111.

Paraffin hydrocarbons, 24 ; preparationof,32.

Paraffins, chemical properties,26;isomerism in the, 25 ; nitro-com-

pounds of, 101 ; occurrence in

nature, 25; physical propertiesof,24.

Paraldehyde^lOS.Pararosaniline, 347.

Paraxanthine, 226.

Pasteur, chemical configuration and

ferments,53.Penicillium glaucum, action on lactic

acid,7 ; on mandelic acid, 7.

Pentamethylene-diamine, 247.

Pentane, 25.

Pepper, glucosidesof,321.Peptoiodeiffon, 162.

Peronine, 296.

Petroleum emulsion, 45.

Petrosnlphol, 169.

Pharmacology, relation to therapeutics,14.

Phenacetin, 186, 187, 188.

Phenacetin, attempts to increase solu-bility

of, 191 ; theory of physio-logicalaction,211.

Phenanthrene and morpholine, 242.

Phenetidin, derivatives, 189, 190;derivatives with local anaesthetic

action, 313, 314 ; ortho and meta

derivatives,212.

Phenetol, 129.

" comparison with aliphaticethers,104 ; formation of chinaethonic

acid from, in body, 62.

Phenocoll, 193.

Phenol and aniline derivatives, com-parison

of physiologicalaction of,210.

Phenol and phenol-ethersused in per-fumery,345.

Phenol, changes of,in body, 57 ; de-rivatives

with local anaesthetic

action, 313.Phenol esters,129.

Phenolphthalein,tetra-iodo,166.Phenols and phenol ethers, character-istic

odour of,343.

Phenols,antisepticvalues,and generalconclusions, 139 ; elimination of

acidic nature of, 129, 130; homo-logous,

130 ; introduction of COOH

group into, 150; local anaesthetic

action of, 315; physiologicalactionof,131,132; polyhydric, 130; pre-paration

of,128; preparation from

diazo-compounds, 41 ; propertiesof,129.

Phenol-sulphonic acid,57.

Phenosal, 193.

Phenylacetamide, 124.

Phenyl acetate,129.

Phenyl-acetic acid, antiseptic pro-perties

of,118." synthesis with glyciiiein body,

64 ; with a-methyl-pyridine,64.Phenylacetylene and its derivatives,

odour of,343.

Phenylalanin, oxidation of, in body,75.

Phenyl-azoimide,208.

Phenyl-ethyl-ketone,114.

Phenyl-ethylene, glucosides derived

from, 324.

" (styrol),preparationof,34.

Phenylhydrazine, action on aldehydes,106 ; action on ketones,113 ; deriva-tives

of,200. 201,202 ; physiologicalaction of, 199 ; preparation of,41,198; reactions of, 199.

Phenyl-methane, 183.

" derivatives,196.Phenyl-propionicacid,oxidation of,in

body, 64.

Phenyl radical,effect on taste,334.

Phesiii, 191.

Philadelphiayellow, 355.

Fhloretin, 325.

Pnlorizin, 325.

Phloroglucin,physiologicalaction of,132 ; taste of,339.

Phosphate and phosphite of guaiacol,143.

Phosphatol, 143.

Phospliine, 355.

Phosphonium bases, physiologicalaction, 54.

Phosphotal, 143.

Phthalic acid, oxidation of,in body,76 ; preparationof,117.

Phthalide and its derivatives,odour

of,343.

Phtlialimide,in preparation of am-

INDEX 369

ines, 172; oxidation in the body,76.

Picric acid,129,350.

Picrylchloride,173.

Pilocarpidine,232.

Pilocarpine, 231,232." constitution of,224.Pinacol,131.Pinacones,physiologicalaction of,93.

Pipecolylalkin,254.

Piperidine,physiologicalaction of,46,25O.

Piperidon,245." derivatives,246.

Piperine, 255.

Piperonal,use in perfumery, 344.

Piperylalkin,254.Poisons, 'catalytic,'17 ; Loew's theory,17, 348; 'oxidizing,'17; special,18; 'substituting/17, 348.

Polygallicacid,330.

Polyhydric phenols,130.

Polymerizationof aldehydes,107.

Ponceau, 4 G. B., 353.

Popnlin, 323.

Populin,taste of,335.Primary amines, 171.

Propion, 113.

Propionamide, 124.

Propionitrile,126.Propyl-phenetidin,189.Propyl, n- and iso-,physiologicalaction

of,92.

Protein, occurrence of tyrosin and

phenylalanin in, 75.

Proteins,difficultyin determinationof composition, 7.

Protocatechuic acid,58.Protoplasm,Loew's theory,17.Prussic acid,125.

Pseudo-tropine,270." benzoyl ester,263.

Psoriasis,148.Purgatin, 329.

Pnrgatol, 329.

Purg-en, 330.

Purification of organic compounds, 8 ;methods used,8.

Purine derivatives,general review of,229.

" group, 221." nomenclature, 221.

Purine, physiologicalaction of,224 ;

synthesisof,222.Pyoktanin, 354.

Pyramidon, 206.

Pyrantin, 190.

Pyrazolon derivatives,202.Pyridine, action of oxidizing agents

on, 235; action of reducingagents on,236 ; and piperidine,233 ; changesof,duringpassage through body,66 ;

comparison with quinoline, "c.,272 ; derivatives, differences in

physiologicalaction,257 ; group of

alkaloids,249 ; homologues, physio-logicalaction,46,251,253 ; physio-logicalaction of,45, 25O ; synthesis

of,234.Pyrocatechol,130, 140.Pyrogallicacid, 131, 140, 147 ; taste

of,339.

Pyrroland pyrrolidine,constitution of,237.

" physiologicalaction of,45." tetra-iodo-,164.

Pyrrolidinealkaloids,258.

Pyrrolidon,248.

Quaternary ammonium compounds,physiologicalaction of, 179.

Quercetin, 327.

Quillaia,330.

Quillaiacacid,330.Quinaldine, 273.

p-Quinanisol,274.Quinaphenin, 280.

Quinaphthol, 280.

Quinazolinederivatives,240.Quinidine,278.

Quinine,action of vinylradical,277,278.Quinine and cinchonine, 276.

Quinine-hydrochloro-carbamide,280.

Quinine, insoluble derivatives of,279 ;' Loipon-Anteil,'277;soluble deriva-tives

of,280 ; substitutes,279.Quinoline, action of oxidizing agents

on, 239 : action of reducing agentson, 239 ; alkaloids,271 ; antiseptics,164,165 ; comparison with quinine,272 ; homologues,273 ; 1-hydroxy-tetra-hydro-,48 ; tso-quinoline,pyri-dine, comparison of,272 ; methyl-,oxidation of in body, 76 ; 1-oxy-2-iodo-4-chlor,165 ; l-oxy-2-iodo-4-sulphonic acid, 164 ; physiologicalaction, 272 ; reduced derivatives,272 ; synthesisof,238 ; tetrahydro-w-ethyl-,274 ; tetrahydro-"-methyl,274.

tso-Quinoline-alkaloids,284; classifica-tion,

289 ; nucleus,opium alkaloids,299.

Quinopyrine, 280.

Quitenine,278.

Racemic acid,6; Pasteur's investiga-tionson, 6.

Reduction,influence on sense of smell,346 ; processes takingplacein body,

Resacetophenone, 58.Resorcinol,131, 140.

Resorcin,thio-,168.

Bb

370 INDEX

Rhamnetin, 327.

Khamnose, methyl-, taste of,333.Bhodin, methyl-, 158.

Roaf and Moore, anaesthetic substances,85.

Rosaniline,354." its derivatives,347.

Saccharin, 336.

" derivatives,336,337.

Safrol,345.

"toxic propertiesof,50 ; iso-,50.

Salacetol, 154.

Salen, 155.

Salicin, 322.

Salicyl-acetyl-p -amidophenol ether,157.

Salicylanilide,182.Salicyl-phenetidin,190, 194.

Salicylradical, 120.

Salicylicacid,120, 150, 152.acetol ester of, 154 ; acetyl de-rivative,

158; classification of deriva-tives,

153 ; derivatives,151; deriva-tives

based on salol principle,156;derivatives, taste of, 337 ; dissocia-tion

of, 16; glycerin ester, 154;

methoxy-methyl ester of,154; pre-paration

of, 151 ; reduction of, to

pimelic acid,31 ; salts of antipyrine,205.

Saliphenin, 190.

Ealipyrine, 205.

Salocoll, 193.

Salol, 155.

Salol group, 156, 157.

" principle, 55, 152 ; derivatives

synthesizedon, 156.

" substances of type of,156.

Salophen, 157, 190.

Saloquinine, 280.1 Sapiphore

'

groups of Sternberg,335.

Saponaretin,327.

Saponarin, 327.

Saponification,55.

Saponins, 330.

Sapotoxines,330.

Sarsa-saponin,330.Saturated and unsaturated derivatives,

26.

Scaxu.zn.onin, 322.

Schmiedeberg, classification of nar-cotics,

"c.,20 ; relation of therapeu-ticsto pharmacology, 14.

Scoparin,327.Secondary amines,171.

Senegin, 330.

Senses of taste and smell,331.Sesame oil,iodine preparationof,167.Sinalbin, 321.

Sinapin, 321.

Sinig-iin, 321.

Sirolin, 146.

Smilax-saponin,330.Snake venoms, action of eosin on

355.

Solubilityand volatilityin relation to

physiologicalaction,14,15, 46.

Somnal, 110.

Somnoform, 96.

Sozoiodol, preparations,164, 165.

Sozoiodolic acid, 165.

Stereochemical influences on sense of

taste,338." relationshipsand physiologicalac-tion,

53.

Stereo -isomerism, 5.

Sternberg on taste,333.

Stilbazoline, 255.

Stibonium bases,physiologicalaction,54.

Stockman, physiological action of

quinoline derivatives,273.Stomach, action of hydrochloric acid

in, 55 ; presence of sulphocyanicacidin,65.

Stovaine, 314.

Strophanthin, 326.Structural formulae,3 ; determination

of,3.Strychnidine, 282.

Strychnine, 281, 283.

Stypticin, 287.

Styptol, 287.

Styracol, 150.

Styrolene,324.Substituted ureas, preparationof,215.Substitutingpoisons,17.Succinie acid,119.Succinic and oxalic acids, synthesis

from ethylene,39.Sucramine, 337.

Sncrol, 340.

Sudan 1,352.Sulphaminol, 168.

Sulphocyanides,formation of in body,65.

Sulphonal, 115,116.

Sulphonals,preparation of,114.Sulphones and sulphonals,distribution

co-efficient of,84.Sulphonic acid group, influence on

physiologicalaction,103 ; protectionagainstoxidation in organism, 72.

Sulphonic esters, formation in the

body with :" Gallacetophenone,58 ;

gentisinicacid, 57 ; homogentisinicacid,57 ; hydroquinone, 57 ; paeonol,58 ; phenol, 57 ; vanillic acid,58 ;iso-vanillic acid,58; veratric acid,59.

Sulphosote, 146.

Sulphur, antiseptics containing,186 ;

derivatives,126 " derivatives of urea,218.


372 INDEX

Urea, derivatives containing bromine,217 ; derivatives, taste of,339.

" formation of derivatives in bodywith :" Taurine, 64 ; amido-benzoic

acid, 64 ; amido-salicylicacid, 64 ;

ethylamine-carbonate,64." preparation of, 215 ; quinine de-rivatives

of,280." ureides,and urethanes, 213.

Ureas substituted,physiologicalaction

of, 216; sulphur derivatives,218;synthesisof,1.

Ureides,classification of,219.

Urethane, 214.

Urethane, phenyl, 183 ; derivatives of,196.

Urethanes, preparationof,213." urea, and ureides,213.

Uretone, 108.

Uric acid,alkyland oxy-alkyl deriva-tives,

225 ; dioxy derivatives,225 ;

synthesis,221, 222.

Urine indican,79,

TJrisol, 108.

Uropherin, 228.

Urotropixi, 108.

Valency, theory of, 1, 2j variation

of,2.

Valeronitrile,126.Vanillic acid,58.iso-Vanillic acid, 50.

Vanillin,piperonal,"c., odour of,de-pending

on concentration,341.

Vanillin,phenetidin,194." use in perfumery, 344.

Vaselines, 26.

Velocityof reactions,8.Veratric acid, 59.

Veratrine,decomposition products of,180.

Veratrol,146.

Veronal, 220.

Vesaloine, 108.

Vinylamine, toxic propertiesof,50.Vinyl-diacetone-amine,305.

Vioform, 165.

Volatilityand solubilityin relation to

physiologicalaction,14,15,46.

Wintersrreen oil, 153.

Witt, theory of dyes, 22.

Wurtz, synthesisof hydrocarbons, 32.

Xanthates,127.Xan thine, 225.

Xanthine derivatives,225, 226.

" effect of NH groups, 178.

" mono-, di-,and tri-methylderiva-tives,

physiologicalaction of,48." tri- and tetra-methyl derivatives,

228.

Xanthines, methylated, action of

organism on, 66.

YohimMne, 285.

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Chemical Basbvbms of Pharmacology an Introduction to Pharmacodynamics 1000160027 (1)