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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 of^ara-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
4 CHEMICAL INTRODUCTION
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
6 CHEMICAL INTRODUCTION
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,
8 CHEMICAL INTRODUCTION
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
10 CHEMICAL INTRODUCTION
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.
12 CHEMICAL INTRODUCTION
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-
16 PHYSIOLOGICAL INTRODUCTION
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
18 PHYSIOLOGICAL INTRODUCTION
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.
20 PHYSIOLOGICAL INTRODUCTION
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,
22 PHYSIOLOGICAL INTRODUCTION
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.
28 ALIPHATIC AND AROMATIC HYDROCARBONS
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.
30 ALIPHATIC AND AROMATIC HYDROCARBONS
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 /^i/^" 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
32 ALIPHATIC AND AROMATIC HYDROCARBONS
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
34 ALIPHATIC AND AROMATIC HYDROCARBONS
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
42 DERIVATIVES OF AROMATIC HYDROCARBONS
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
44 DERIVATIVES OF AROMATIC HYDROCARBONS
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
48 PHYSIOLOGICAL CHARACTERISTICS
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
50 PHYSIOLOGICAL CHARACTERISTICS
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.
52 PHYSIOLOGICAL CHARACTERISTICS
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
54 PHYSIOLOGICAL CHARACTERISTICS
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
58 METABOLIC PROCESSES
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
60 METABOLIC PROCESSES
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.
62 METABOLIC PROCESSES
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.
64 METABOLIC PROCESSES
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
66 METABOLIC PROCESSES
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
70 METABOLIC PROCESSES
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.
72 METABOLIC PROCESSES
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.
74 METABOLIC PROCESSES
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.
76 METABOLIC PROCESSES
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.
78 METABOLIC PROCESSES
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\^Ugll^A "^"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
80 METABOLIC PROCESSES
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
^e^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 |light^onvulsions.*
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 .
C^OMgl\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
PHYSIOLOGICAL PROPERTIES 97
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.
Physiological Properties.
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.
PHYSIOLOGICAL PROPERTIES 113
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 powerfulo^o-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.
Physiological Properties.
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,
PHYSIOLOGICAL PROPERTIES 119
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.
Physiological Properties.
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.
Physiological Properties.
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.
134 AROMATIC HYDROXYL DERIVATIVES
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 0r^o-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
136 AROMATIC HYDROXYL DERIVATIVES
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 ^Experiments.
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.
138 AROMATIC HYDROXYL DERIVATIVES
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.
140 AROMATIC HYDROXYL DERIVATIVES
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
C6H3^OH = 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
142 AROMATIC HYDROXYL DERIVATIVES
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.
144 AROMATIC HYDROXYL DERIVATIVES
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
146 AROMATIC HYDROXYL DERIVATIVES
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
148 AROMATIC HYDROXYL DERIVATIVES
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.
PHYSIOLOGICAL PROPERTIES 151
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,
156 SALICYLIC ACID DERIVATIVES
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.
158 SALICYLIC ACID DERIVATIVES
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
164 ANTISEPTICS CONTAINING IODINE
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 ^o-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
166 ANTISEPTICS CONTAINING IODINE
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.
174 DERIVATIVES OF AMMONIA
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^^ii.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.
176 DERIVATIVES OF AMMONIA
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
178 DERIVATIVES OF AMMONIA
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
180 DERIVATIVES OF AMMONIA
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
PHYSIOLOGICAL PROPERTIES 183
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 : or^o-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.
PHYSIOLOGICAL PROPERTIES 185
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.
PHYSIOLOGICAL PROPERTIES 189
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.
PHYSIOLOGICAL PROPERTIES 191
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
192 DERIVATIVES OF ^-AMIDO-PHENOL
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,
PHYSIOLOGICAL PROPERTIES 193
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.
196 DERIVATIVES OF ^-AMIDO-PHENOL
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.
PHYSIOLOGICAL PROPERTIES 197
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
PHYSIOLOGICAL PROPERTIES 199
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.
Physiological Properties.
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.
PHYSIOLOGICAL PROPERTIES 201
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.
PHYSIOLOGICAL PROPERTIES 207
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
210 PHYSIOLOGICAL PROPERTIES
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.
212 PHYSIOLOGICAL PROPERTIES
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.
Physiological Properties.
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. CO^ocH + 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.
216 PHYSIOLOGICAL PROPERTIES
B. Symmetrical.
-
ro/^^Q^s4. P TT OTT
. ^u"^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.
Physiological Properties.
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_^
C^OOC.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 fl^a-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-^o-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 ^o-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. ^o-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"
(CH^Ov 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
C6H3^O.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"^OHis 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 ^o-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 or^o-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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