Skip to main content

Full text of "The chemical basis of pharmacology; an introduction to pharmacodynamics based on the study of the carbon compounds"

See other formats 


.J.^"^"^^-. 


Department 

of 

Pharmacology 

Univ/^r&ity 

Tor^to 


THE  CHEMICAL 
BASIS  OF  PHAEMACOLOGY 

AN  INTRODUCTION  TO 
PHARMACODYNAMICS  BASED  ON  THE 
STUDY  OF  THE  CARBON  COMPOUNDS 

BY 

FRANCIS  FRANCIS,  D.Sc,  Ph.D. 

PROFESSOR  OF  CHEMISTRY,  UNIVERSITY  COLLEGE,  BRISTOL 

J?MrFORTESCUE-BIlICKDALE,  M.A.,  M.D.(Oxo^ 

PHYSICIAN,    BRISTOL  ROYAL  HOSPITAL  FOR   SICK   CHILDREN 

MEDICAL   REGISTRAR,    BRISTOL   ROYAL   INFIRMARY 

DEMONSTRATOR   OF   PHYSIOLOGY,    UNIVERSITY   COLLEGE,    BRISTOL 


LONDON 
EDWARD   ARNOLD 

1908 

[All  Bights  Beserved] 


Digitized  by  the  Internet  Arciiive 

in  2007  with  funding  from 

IVIicrosoft  Corporation 


http://www.archive.org/details/chemicalbasisofpOOfranuoft 


'  Bid  we  Jcnow  the  mechanical  affections  of  the  particles  of 
rhubarb,  hemlocJc,  opium,  and  a  man,  as  a  watchmaJcer  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  tvill  purge,  hemlock  hill,  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. 


t^REFACE 

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  relationships  between  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  possible  that  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  teaching  of 
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  duty 
would  be  to  go  out  and  gather  simples  on  the  mountain-side ; 
whereas  in  actual  fact,  what  they  have  to  do  is  to  gauge  the 
relative  merits  or  demerits  of  a  host  of  synthetic  remedies,  the 
*  literature '  of  which  is  so  plenteously  showered  upon  them  as 
Boon  as  their  names  and  addresses  appear  in  the  Medical  Direc- 
tory. The  recognition  of  crude  drugs  and  the  tests  for  purity  in 
prepared  products  are  certainly  no  longer  necessary  knowledge 
for  a  doctor ;  and  of  the  numerous  preparations  which  the  student 
commits  wearily  to  memory  for  examination  purposes,  only  a 
very  small  proportion  are  remembered  and  used  in  actual 
practice. 

It  is  hoped  that  in  some  small  degree  the  present  work  may 
point  the  way  to  reform,  and  that  meanwhile  as  an  introduction 
to  a  rational  appreciation  of  one  aspect  of  Pharmacology  it  may 
be  of  use  both  to  the  student,  and  to  the  practitioner  who  is 
daily  brought  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  facie  evidence  for 
or  against  classes  and  individuals  in  the  chemical  materia 
medica.  Though  clinical  experience  is  the  only  test  of  the 
value  of  a  drug,  the  probable  physiological  action  may  often  be 
fairly  accurately  estimated  by  a  consideration  of  its  chemical 
structure ;  and  it  seems  highly  probable  that  a  large  number  of 
the  synthetic  remedies  now  on  the  market  would  never  have 
been  introduced  had  medical  men  in  general  been  able  to  appre- 
ciate how  little  likelihood  there  was  of  their  proving  superior  to 
the  older  preparations. 

To  those  who  are  engaged  solely  in  the  study  of  organic 
chemistry,  it  is  hoped  that  this  volume  will  serve  as  an  intro- 
duction to   a   particularly  fascinating  branch   of  the  applied 


PREFACE  vii 

science.  The  authors  would  feel  sincerely  gratified  should  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  principles  as  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  regulations  as  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  profitable  to  produce  synthetic  drugs 
at  home  on  a  scale  large  enough  to  replace  the  imported  articles. 
Whenever  possible,  the  authors  have  consulted  the  original 
papers  dealing  with  the  subject  in  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,  Paal,  Baumann  and  Kast,  v.  Mer- 
ing,  Ladenberg,  Sahli,  Dujardin  Beaumetz,  and  Curci.  They 
wish  particularly  to  acknowledge  the  assistance  they  have 
received  from  the  exhaustive  treatise  of  S.  Fraenkel,  whose 
Arzneimittelsynthese  illustrates  the  entire  subject  with  a  wealth 
of  example  quite  unapproached  in  any  other  volume. 

Finally,  they  would  most  sincerely  thank  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. 
University  College, 
Beistol, 

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 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 24-44 

B.    Physiological  Characteristics  op  the  Hydrocarbons 

Effect  on  Physiological  reactivity  of  the  introduction  of  Methyl 
or  Ethyl  groups,  of  unsaturated  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  Hypnotics 

PAGES 

I.  General  physiological  action  of  anaesthetics  and  hypnotics. 
Overton-Meyer  Theory.  Traube.  Moore  and  Roaf  on  Chloroform. 
Baglioni's  theory 81-87 

II.  Methods  of  preparation  and  chemical  and  physiological  properties 
of  the  Alcohols.  Esters  of  Halogen  acids,  Nitrous  and  Nitric,  Sul- 
phurous and  Sulphuric  acids.    The  Ethers 87-104 

CHAPTER  V 

The  Alcohols  and  their  derivatives  (continued) 

The  Oxidation  products  of  the  Alcohols 

The  chemical  and  physiological  characteristics  of  the  Aldehydes, 
Ketones,  Sulphones,  Acids.  The  derivatives  of  the  Acids.  Halogen 
substitution  products,  Esters,  Amides,  Nitriles.     Sulphur  derivatives  . 

105-127 

CHAPTER  VI 

Aromatic  Hydroxyl  derivatives 

Main  Group  of  Aromatic  Antiseptics 

Chemical  and  physiological  properties  of  Phenols,  Cresols,  Di-  and 
Tri-oxybenzenes.  Recent  investigations  of  the  antiseptic  power  of 
Phenol  and  its  derivatives,  Creosote,  Guaiacol,  and  their  derivatives  128-148 

CHAPTER  VII 

Aromatic  Hydroxyl  derivatives  (continued) 

The  Hydroxy  Acids 

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

CHAPTER  VIII 

Antiseptic  and  other  substances  containing 
Iodine  and  Sulphur 

Iodoform.  Classification  of  substances  introduced  in  place  of  Iodoform 
and  the  Alkali  Iodides.   Derivatives  containing  Sulphur— Ichthyol  161-170 


CONTENTS  xi 

CHAPTER  IX 

Derivatives  of  Ammonia 
The  Main  Group  of  Synthetic  Antipyretics 

PAGES 

Chemical  and  physiological  character  of  Aliphatic  and  Aromatic 
Amines.  Aniline,  Acetanilide  and  allied  substances.  Classification 
and  discussion  of  2>a^a-Amido-phenol  derivatives    ....     171-197 

CHAPTER   X 

The  Main  Group  of  Synthetic  Antipyretics  (continued) 

Hydrazine  and  its  derivatives 

Physiological  action  of  Phenylhydrazine  and  its  derivatives.  The 
Pyrazolon  group— Antipyrine,  Pyramidon.  General  Summary  of 
Physiological  characteristics  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  physiological  introduction.  Method  of  classification. 
General  principles  of  Alkaloidal  action.  The  Pyridine  group— Coniine, 
Nicotine,  and  allied  substances 233-257 


CHAPTER  XIII 

The  Alkaloids  (continued) 

Pyrrolidine  group  —  Cocaine,  Atropine,  Hyoscyamine.  Quinoline 
group— Quinine,  Cinchonine,  and  their  substitutes.  Strychnine  and 
Brucine 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  of  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 


I 

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  physiological  properties.  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  o£  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 
principle  that  in  organic  reactions  the  rupture  of  the  molecule 
was  always  the  least  possible. 

The  investigations  of  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 

B 


2  CHEMICAL  INTRODUCTION 

'was  the  possibility  of  assigning  formulae  to  the  following  sub- 
stances : 

Hydrochloric  acid .         .         .         •         HCl 

Water HgO 

Ammonia H3N 

Marsh  gas H^C 

Since  experience  has  shown  that  a  single  atom  of  hydrogen  never 
combines  with  more  than  one  atom  of  another  element^  it  appears 
that  this  substance  possesses  the  faculty  for  combination  in  as  low 
a  degree  as  any  of  the  known  elements ;  a  fact  that  is  expressed  in 
the  conception  that  hydrogen  has  only  one  power  of  combining 
with  other  atoms— one  valency,  graphically  shown  by  one  stroke. 
Since  oxygen  combines  with  two  atoms  of  hydrogen  its  valency  is 
two,  and  for  the  same  reason  nitrogen  is  trivalent  and  carbon 
tetravalent. 

The  examples  given  are  of  course  the  simplest  that  could  be 
taken,  but  they  clearly  show  the  varying  powers  of  different 
elements  of  uniting  with  the  same  substance,  hydrogen. 

Variation  of  Valency. — The  question  if  the  valency  of  an 
element  is  constant  or  not,  led  to  a  long  discussion.  Kekule 
and  others  regarded  it  as  invariable  as  the  atomic  weights  them- 
selves, but  the  upholders  of  this  view  were  drawn  into  many 
contradictions,  of  which  the  following  may  be  taken  as  an  example. 
Ammonia,  NHg,  combines  with  hydrochloric  acid  to  form  ammonium 
chloride,  NH^Cl ;  since  the  valency  of  hydrogen  and  chlorine  are 
the  same,  it  follows  that  nitrogen  from  being  trivalent  in  ammonia 
has  become  pentavalent  in  ammonium  chloride.  Those  who  regarded 
valency  as  invariable  had  to  look  upon  this  latter  substance  as 
a  molecular  compound  of  NHg  and  HCl,  and  it  was  represented  as 
NH3 .  HCl,  and  but  little  attention  was  paid  to  the  forces  that  kept 
these  halves  together. 

Now  various  organic  groups  may  take  the  place  of.  hydrogen  in 
ammonia,  it  may  be  replaced,  for  instance,  by  the  monovalent 
radicals  methyl  (CH3)'  or  ethyl  (CgH^y.  Now  ii>  the  substance 
triethylamine,  N(C2H5)3,  nitrogen  is  still  trivalent,  and  the  charac- 
teristic properties  of  ammonia  are  still  present ;  it  combines  with 
hydrochloric  acid  or  methyl  chloride,  CH3 .  CI,  and  the  resulting 
compound  N(C2H5)3CH3C1  should,  according  to  the  old  hypothesis 
of  the  invariability  of  valency,  be  different  from  the  substance 
resulting  from  the  addition  of  ethyl  chloride,  CgH^Cl,  to  methyl- 
diethylamine,   e.g.   (CH3) .  N  .  (C2H5)2 .  CgHgCl— but   since  these 


VARIATION   OF  VALENCY  8 

two  bodies  are  identical,  it  is  a  clear  proof  that  the  valency  of 
nitrogen  can  vary,  that  it  is  three  in  the  case  of  ammonia  or  the 
substituted  ammonias,  and  five  in  the  case  of  ammonium  chloride 
or  its  substituted  derivatives.  When  it  is  remembered  that  our 
mode  of  regarding  valency  is  entirely  empirical,  it  may  be  said  that 
two  valencies  are  latent  in  the  former  case,  and  that  under  suitable 
conditions  these  appear  and  are  capable  of  binding  together  other 
atoms.  In  the  case  of  carbon,  the  essential  constituent  of  organic 
substances,  the  valency  is  taken  as  four,  for  in  those  compounds  in 
which  it  is  apparently  less,  such  striking  and  characteristic  pro- 
perties appear,  that  latent  valencies  are  presumed  to  be  present. 
These  cases  will  be  discussed  later. 

Structural  Formulae. — The  direct  outcome  of  this  theory  of 
valency  was  the  building  up  of  structural  formulae  for  various  com- 
pounds, relative  pictures,  it  must  be  remembered,  of  the  groupings 
of  the  atoms  in  the  molecule.  If  water  is  represented  as  H — O — H, 
then  potash  is  K — O — H,  methane 

H 

H— C— H 

I 
H 


and  methylic  alcohol 


H 
H— C— O— H 


J. 


The  somewhat  empirical  method  by  which  these  formulae  are  de- 
duced is  of  the  greatest  importance,  and  one  of  the  chief  problems  in 
organic  chemistry  is  to  determine  this  structural  arrangement  of 
the  atoms  in  the  molecule,  and  the  relationship  between  this  structure 
and  the  chemical  and  physical  properties  of  the  compound.  Two 
general  methods  are  employed,  viz.  the  synthetic  and  analytical, 
but  in  the  case  of  molecules  containing  few  atoms,  the  determina- 
tion of  the  constitution  may  be  made  on  the  basis  of  the  valency 
of  the  elements  concerned;  this  treatment  is,  however,  neces- 
sarily limited  and  is  only  applicable,  with  any  degree  of  accuracy, 
to  molecules  built  up  of  atoms  of  low  valency.  The  synthetic 
building  up  of  the  substance  from  constituents  of  known  structural 
formulae,  or  the  analytical  breaking  down  of  the  body  into  simpler 
molecules,  generally  gives  the  desired  data,  and  the  results  that 

B  2, 


4  CHEMICAL  INTRODUCTION 

have  been  obtained  by  proceeding  on  such  lines  have  amply  justified 
the  working  hypothesis, — for  example,  the  determination  of  the 
structural  formulae  of  indigo  blue  and  conine,  was  soon  followed  by 
the  synthetic  formation  of  these  substances,  and  in  the  case  of  the 
former,  by  its  production  as  an  article  of  commerce. 

But  the  study  of  Organic  Chemistry  commences  with  the  relatively 
simple  investigations  of  the  changes  produced  in  hydrocarbons, 
the  compounds  of  carbon  and  hydrogen,  by  the  entrance  of  certain 
atoms  or  groups.  Methane,  CH^,  on  the  replacement  of  one 
hydrogen  atom  by  chlorine  gives  methyl  chloride,  CH3CI,  and  the 
characteristics  produced  by  the  entrance  of  the  chlorine  atom  are 
those  that  generally  follow  the  replacement  of  hydrogen  by  that 
element.  When  one  hydrogen  atom  in  water  is  replaced  by  an 
organic  radical  such  as  methyl  (CHg)',  the  simplest  member  of  the 
group  of  alcohols  is  produced,  CHg .  OH ;  and  again,  the  introduction 
of  the  hydroxyl  group,  (OH)',  into  methane,  causes  a  number  of 
chemical,  physical,  and  physiological  differences,  which  are  generally 
characteristic  of  the  presence  of  that  grouping. 

The  organic  acids  all  contain  the  complex  (CO OH)',  which 
confers  definite  properties  upon  the  hydrocarbon  into  which  it 
enters.  It  is  the  knowledge  of  the  characteristics  of  such  groups  and 
their  combinations  that  is  required  to  solve  the  difiicult  problem  of 
determining  the  constitution  of  substances  of  unknown  structure. 

Isomerism. — But  the  question  is  further  complicated  by  the 
possibility  of  differing  arrangements  of  the  atoms  in  the  molecule. 
Supposing  the  hydrocarbon  ethane,  CHg — CHg,  is  considered ;  it  is  at 
once  obvious  that  the  hydrogen  atoms  are  symmetrically  arranged 
in  the  molecule,  and  that  it  is  a  matter  of  indifference  for  instance 
which  is  replaced  by  the  hydroxyl  group ;  that  is,  OH.CHg .  CHg  is 
clearly  the  same  as  CHg .  CHg .  OH.  Theoretically,  then,  the  theory 
of  valency  demands  that  only  one  ethyl  alcohol  should  exist,  and 
only  one  is  actually  known.  But  with  the  next  higher  hydrocarbon, 
propane,  CHg.  CHg.  CHg,  the  case  is  different;  only  the  two  end 
methyl  groups,  and  consequently  their  hydrogen  atoms,  are  sym- 
metrical, but  the  hydrogen  of  the  central  CHg  group  is  different; 
and  consequently  the  theory  of  valency  points  to  the  existence  of 
two  alcohols  derivable  from  this  substance,  one  OH .  CHg.  CHg.  CHg, 
and  the  other  CHg.  CH.OH. CHg.  Now  two  are  actually  known 
normal-  and  2>o-propyl  alcohol,  and  consequently  this  theory  gives  the 
most  satisfactory  explanation  of  the  existence  of  two  substances  of  the 
empirical  formula  CjHgO,  having  the  same  molecular  magnitude  and 


ISOMERISM  5 

same  vapour  density,  but  different  chemical  and  physical  properties. 
These  two  bodies  are  said  to  be  isomeric ;  they  differ  owing  to  the 
different  arrangement  of  the  atoms  in  the  molecule.  This  theory 
of  isomerism  has  played  a  most  important  part  in  Organic 
Chemistry ;  the  existence  of  such  isomeric  bodies  was  realized  about 
1823  and  the  explanation  followed  the  introduction  of  the  theory 
of  valency  in  1860.  This  theory  offered  a  most  satisfactory  in- 
terpretation of  observed  phenomena  until  about  1876_,  when  evidence 
of  its  insufficiency  in  certain  cases  began  to  accumulate.  For 
example,  in  the  case  of  lactic  acid  it  had  been  conclusively  shown 
that  its  structural  formula  was  represented  by  the  following  scheme — 

H 
CH3— C— OH 

COOH 

and  yet  three  isomeric  modifications  were  known,  whose  chemical 
differences  were  slight,  but  whose  physical  differences  were  consider- 
able. One  rotated  the  plane  of  polarized  light  to  the  right,  the  other 
to  the  left,  and  the  third  had  no  action  at  all.  Now  the  theory  of 
valency  could  offer  no  explanation  for  the  existence  of  such  isomers, 
and  Le  Bel  and  van  't  Hoff  in  1877  brought  forward  the  hypothesis 
that,  were  such  systems  considered  in  three  dimensions  a  satisfactory 
explanation  could  be  obtained.  The  central  carbon  was  regarded  as 
exerting  its  valencies  in  three  dimensions  towards  the  solid  angles 
of  a  regular  tetrahedron,  and  when  such  a  configuration  is  investi- 
gated, it  at  once  becomes  evident  that  it  is  only  when  four  different 
groups  or  atoms  are  attached  to  that  carbon,  that  the  existence  of 
two  forms  becomes  possible,  one  the  mirrored,  non-superposable 
image  of  the  other.  If  one  form  rotates  the  plane  of  polarized  light 
to  the  right,  the  other  will  rotate  it  to  the  left.  In  the  case  of  that 
modification  of  lactic  acid  which  has  no  action  on  polarized  light,  it 
should  be  possible  to  effect  a  resolution  into  its  active  components, 
and  this  was  actually  carried  out.  This  theory  of  the  Asymmetric 
Carbon  Atom,  whose  four  valencies  are  saturated  by  different  groups 
or  atoms,  has  received  the  fullest  possible  confirmation,  and  it  may 
be  stated  that,  with  very  few  exceptions,  the  vast  majority  of  carbon 
compounds,  containing  such  groups,  act  on  the  plane  of  polarized 
light,  and  exist  in  three  or  more  optically  isomeric  forms,  depending 
on  the  number  of  such  groups  present  in  the  molecule.  Further,  no 
case  of  an  organic   substance  is  known  which  rotates  polarized 


6  CHEMICAL  INTRODUCTION 

light  when  in  solution  and  does  not  contain  one  or  more  asym- 
metric carbon  atoms. 

The  example  of  tartaric  acids  is  a  classical  illustration  of  the 
manner  in  which  this  theory  has  been  employed,  for  the  older 
theory  of  isomerism  was  incapable  of  explaining  the  existence  of 
dextro'  and  /o^tJO-rotatory  tartaric,  meso-tartaric  and  racemic  acids, 
since  it  had  been  conclusively  shown  that  all  these  forms  are 
identical  and  represented  by  the  formula 

H 

COOH— C— OH 

I 
COOH~C— OH 


A 


Now  in  this  molecule  there  are  two  asymmetric  carbon  atoms,  and 
it  is  clear  that  these  may  both  rotate  light  to  the  right,  in  the  same 
way  as  ^-lactic  acid,  and  the  mirrored  image  of  this  would  rotate 
light  to  the  left.  Now  supposing  that  one  rotates  to  the  right  and 
the  other  to  the  left,  the  net  result  is  an  acid,  i.  e.  meso-tartaric  acid, 
which  has  no  action  on  light,  and  which  is  further  incapable  of  being 
resolved  into  its  active  components,  since  it  is  intra-molecularly 
compensated.  Then  the  acid  that  is  synthetically  obtained  in  the 
laboratory,  by  the  employment  of  symmetrical  forces,  i.  e.  racemic 
acid,  would  be  a  mixture  of  equal  molecules  of  dextro-  and  laevo" 
rotatory,  and  hence  have  no  action  on  light,  but  be  capable  of 
being  decomposed  into  its  active  components.  Pasteur  had  in- 
vestigated this  acid  in  1853  and  determined  the  methods  that 
could  be  employed  for  this  separation ;  but  as  this  line  of  research 
has,  as  yet,  proved  of  but  small  value  in  the  problems  to  be 
discussed,  those  desirous  of  obtaining  further  information  on 
the  question  are  referred  to  E.  Werner,  Lehrhuch  der  Stereochemiej 
or  A.  W.  Stewart^s  8tereocJiemistry  (Textbooks  of  Physical  Chemistry 
edited  by  Sir  W.  Ramsay),  where  the  vast  amount  of  work  that 
has  been  carried  out  on  this  theory,  and  its  application  to  other 
elements,  is  described. 

That  these  investigations  will  eventually  play  an  important  part 
in  the  preparation  of  physiologically  active  drugs  is  more  than 
likely.  Several  of  the  experiments  that  have  been  made  with  optical 
isomerides  will  be  described  later,  but  the  mere  fact  that  penicillium 
glmicum  is  capable  of  destroying  one  form  in  preference  to  another, 


ISOMERISM  7 

</-lactic,  for  instance,  compared  with  /-lactic  acid,  is  an  indication 
that  molecules  of  one  type  have  a  closer  connexion  with  the  cells 
of  that  particular  form  of  life,  than  the  other.  Still  more  clearly 
is  this  shown  in  the  case  of  /-mandelic  acid,  which  is  broken  down 
by  penicillium  glaucum  and  bacterium  termo,  whereas  the  ^-modifica- 
tion is  similarly  decomposed  by  saccharomyces  ellipsoideus.  Then 
^-asparagine  is  sweet,  whereas  the  /-modification  is  not. 

It  will  be  readily  seen  that  considerations  such  as  those  just 
sketched  further  complicate  the  problem  of  determining  the  con- 
stitution of  organic  substances;  as  the  molecular  magnitude 
increases,  so  does  the  possible  number  of  isomers.  Butane,  C^Hjq, 
is  the  first  member  of  the  parafiin  series  in  which  the  possibility 
of  isomerism  appears,  e.g.  ?i-butane,  CH3.  CH^.CHg. CHg,  and, 
trimethylmethane  or  «>o-butane 

CH3 

CH3— C.H 

I 
CH3CI 

But  when  the  hydrocarbon  CjgHgg  is  considered,  the  possible 
number  is  802,  and  the  difiiculties  of  assigning  constitutional 
formulae  to  complex  substances  becomes  at  once  apparent.  Take 
for  example  the  proteid  group;  their  molecular  magnitude, 
compared  with  the  majority  of  organic  substances,  is  enormous — 
it  is,  perhaps,  questionable  whether  it  is  accurately  known  for  any 
single  member.  Their  decomposition  products  are  numerous,  and 
certainly  many  of  these  are  simple,  yet  the  rupture  of  the  molecule 
has  been  so  deep,  that  we  are,  up  to  the  present,  incapable  of 
piecing  them  together,  and  in  consequence  are  in  ignorance  of 
the  structure  of  the  original  substance.  But  E.  Fischer's  method 
of  dealing  with  this  problem,  by  the  syntheses  of  the  so-called 
polypeptides,  makes  it  appear  quite  likely  that  this  extremely 
important  question  may  be  eventually  solved.  As  far  as  can 
be  seen  at  present,  there  appears  to  be  no  limit  to  the  possible 
number  of  combinations  and  permutations  among  the  relatively 
few  elements  found  in  organic  substances;  this  is  to  be  traced 
firstly  to  the  fact  that  carbon  possesses  the  peculiar  property 
of  forming,  with  other  carbon  atoms,  open  and  closed  rings.  This 
tendency  to  self-combination  is  much  more  marked  in  the  case  of 
carbon,  than  in  that  of  any  other  element :  not  only  are  molecules 
known  containing  up  to  30  carbon  atoms  linked  to  each  other, 


8  CHEMICAL  INTRODUCTION 

but  this  accumulation  does  not  cause  the  slightest  indication  o£ 
instability.  And  the  other  cause  operating  is  the  resistance  towards 
disruption,  due  to  the  peculiar  property  carbon  confers  on  molecules 
into  which  it  enters.  Although  nitro-glycerine,  for  instance,  breaks 
up  with  a  large  evolution  of  heat,  showing  that  strong  forces  are 
tending  to  decompose  it,  yet  within  fairly  wide  limits  it  is  a 
strikingly  stable  substance.  It  is  due  to  this  property,  often 
alluded  to  as  the  inertia  of  the  carbon  system,  that  isomerism  is 
observable  among  carbon  compounds  to  a  very  much  greater  degree 
than  in  the  case  of  any  of  the  other  elements,  for  it  implies  the 
continued  existence  of  the  less  stable  form — Organic  Chemistry  and 
not  Inorganic  is  the  region  of  isomerism.  It  is  further  in  conse- 
quence of  this  inertia,  that  Organic  Chemistry  is  the  region  of  slow 
reactions  and  consequently  of  measurements  of  velocity ;  and  from 
it  follows  the  important  principle  that  in  determining  the  constitu- 
tion of  an  organic  substance  the  least  possible  number  of  carbon 
linkages  are  broken  in  any  reaction  that  it  undergoes. 

Determination  of  Constitutional  formulae. 

Before  it  is  possible  to  fully  investigate  any  organic  substance 
it  is  necessary  either  to  obtain  it  pure  or  to  be  able  to  purify  one 
or  more  of  its  derivatives.  The  usual  criterion  of  purity  in  the 
case  of  a  solid  is  constancy  and  sharpness  of  melting-point  on 
recrystallization  from  different  solvents,  and  although  this  is  not 
invariable,  the  exceptions  are  but  rarely  met  with.  The  effects  of 
even  minute  traces  of  impurity  on  the  melting-point  are  occasion- 
ally very  great,  and  may  be  compared  with  the  differing  physiological 
reactions  of,  say,  natural  and  artificial  salicylic  acid,  which  only 
differ  by  the  presence  of  minute  traces  of  impurity  in  the  latter 
preparation.  In  this  connexion  it  may  be  mentioned  that  the 
great  power  of  crystallizability  of  so  many  of  the  solid  aromatic 
substances  has  played  a  very  considerable  part  in  the  investigation 
of  bodies  belonging  to  that  elass. 

In  the  case  of  liquids,  constancy  of  boiling-point  is  the  most 
important  criterion ;  but  again,  constant  boiling  mixtures  are  not 
uncommon,  and  if  this  be  suspected,  the  best  method  is,  if  possible, 
to  convert  the  liquid  into  a  solid  derivative,  and  carry  out  the 
investigations  upon  this. 

Although  these  standards  of  purity  are  by  no  means  all  that  are 
at  the  disposal  of  the  Organic  chemist,  they  are  the  most  important 
and  most  generally  adopted. 


CONSTITUTIONAL  FORMULAE  9 

But  the  methods  available  for  obtaining  this  purity  are  limited, 
and  there  are  large  groups  of  substances  which  up  to  the  present 
have  resisted  all  attempts  at  investigation,  owing  to  the  impossibility 
of  either  purifying  them  or  converting  them  into  crystallizable 
derivatives. 

It  will  be  clear,  from  what  has  been  previously  stated,  that  the 
first  factors  necessary  for  the  elucidation  of  the  constitutional 
formula  will  be  the  quantitative  composition  and  molecular  weight 
of  the  substance  in  question.  It  is  not  proposed  to  describe  in 
detail  the  methods  employed  for  the  determination  of  either  of 
these  constants ;  the  data  for  the  first  are  obtained  by  the  complete 
oxidation  of  a  known  weight  of  the  substance  to  its  final  oxidation 
products,  water  and  carbon  dioxide,  the  amount  of  the  former  being 
determined  by  absorption  by  a  known  weight  of  calcium  chloride  ;  of 
the  latter  by  absorption  in  caustic  potash  solution,  and  from  the  results 
of  this  combustion  the  percentage  amounts  of  carbon  and  hydrogen 
are  calculated.  If  nitrogen  is  present,  the  operation  is  carried  out  in 
an  atmosphere  of  carbon  dioxide,  and  under  these  conditions  free 
nitrogen  is  evolved  and  its  volume  measured.  Oxygen  is  always  deter- 
mined by  difference,  and  other  elements  are  estimated  by  special 
methods,  of  which  a  full  account  is  to  be  found  in  any  of  the  textbooks 
on  Organic  Chemistry.  From  the  percentage  composition  the  least 
ratio  of  the  atoms  present  is  readily  calculated  and  the  empirical 
formula  obtained.  This  may  represent  the  true  molecular  weight,  or 
the  latter  may  be  a  simple  multiple  of  it.  This  magnitude  may  be 
determined  from  a  knowledge  of  the  density,  based  on  Avogadro^s 
hypothesis,  or  by  the  determination  of  the  lowering  of  the  freezing- 
point  or  raising  of  the  boiling-point  of  a  pure  solvent, — the  latter 
methods  possessing  great  importance  in  the  case  of  those  substances 
which  cannot  be  volatilized  without  decomposition.  The  molecular 
weight  may  also  be  determined,  with  a  high  degree  of  probability, 
from  purely  chemical  considerations,  and  the  identity  of  the  con- 
stants obtained  by  both  methods  is  of  the  greatest  value  to  the 
molecular  hypothesis. 

Two  cases  will  now  be  taken  as  illustrations  of  what  has  been 
previously  stated. 

I.  On  analysis,  acetic  acid  gives  the  following  results  : — 

c  =  40-0  y 

H=    6.6% 
O  =  533  % 


10  CHEMICAL  INTRODUCTION 

The  simplest  ratio  of  the  atoms  present  is  then : 

H=    ^  =  6-6         or[CH20] 

r.      53-3      „  ^ 
0  =  ^=3.3 

The  empirical  formula  for  this  substance  is  consequently  CHgO, 
but  since  the  density  is  30,  the  molecular  weight  is  60,  and  there- 
fore the  molecular  formula  is  [CH20]2  or  C2H4O2.  This  same 
formula  can  be  arrived  at  by  purely  chemical  considerations  such 
as,  for  instance,  the  action  of  phosphorus  pentachloride,  which 
results  in  the  formation  of  a  substance  of  the  formula  C2H3OCI. 
Since  one  of  the  general  reactions  of  this  reagent  is  to  replace  the 
hydroxy  1  group  (OH)  by  chlorine,  the  deduction  follows  that  the 
simplest  formula  for  acetic  acid  must  be  CgHgO .  OH.  The 
question  then  arises  as  to  the  manner  in  which  the  atoms  are 
grouped  in  this  molecule ;  the  action  of  phosphorus  pentachloride  has 
shown  the  presence  of  an  hydroxy  1  group  (OH),  and  this  is  also  borne 
out  by  the  formation  of  a  series  of  salts  in  which  the  hydrogen  of 
this  grouping  is  replaced ;  for  instance,  silver  acetate,  CyHgO .  OAg. 
The  next  problem  is  the  nature  of  the  atomic  arrangement  of  the 
residue  [CgHgO]',  when  the  following  line  of  argument  may  be 
employed.  The  acid  chloride,  acted  upon  by  ammonia,  gives 
hydrochloric  acid  and  an  amide,  a  reaction  represented  by  the 
equation  ; 

[C^UfiYCl  +  NH3  =  HCl  +  [CgHgOj'NHg. 

The  amide  thus  obtained  can  be  dehydrated  by  means  of 
phosphorus  pentoxide,  and  a  substance  of  the  empirical  and 
molecular  formula  CgHgN  results : 

[CgHgOl'NHa-  H2O  =  C2H3N. 

The  resulting  derivative  is  methyl  nitrile  and  may  be  synthesized 
by  the  action  of  potassium  cyanide  on  methyl  iodide 

CH3I  +  KCN  =  KI  +  CH3CN. 

Since  but  one  molecular  structure  is  possible  for  methyl  iodide, 
it  follows  that  C2H3N  also  contains  this  methyl  group,  which  was 
present  throughout  the  series  of  reactions  and  consequently  in  acetic 
acid  itself.  Moreover,  methyl  nitrile,  warmed  with  dilute  acids, 
passes  back,  by  the  absorption  of  water,  into  acetic  acid. 


CONSTITUTIONAL  FORMULAE  11 

The  presence  o£  two  groupings  (CHg)  and  (OH)  in  the  acid 
have  now  been  proved,  and  since  the  synthetic  formation  of  methyl 
nitrile  indicates  that  the  second  carbon  atom  is  directly  attached 
to  the  first,  the  constitutional  formula  for  acetic  acid  is 

[By  the  replacement  of  the  OH  group  by  chlorine,  the  reactive 
acid  chloride  results : 

CH3.C<0 

The  amide  has  the  formula 

iO 


CH,.C 


NiH^ 


and  the  process  of  dehydration  is  indicated  by  the  dotted  line. 
The  reabsorption  of  water  by  the  nitrile,  CH3 .  CN  +  HgO  = 


'XNHg 
and  this +  H20  = 


CH3.C<(^, 

CHg.C^Q-^JJ^ 


Ammonium  acetate.] 
It  may  be  further  noted  that  all  the  reactions  described  point 
to  the  molecular  formula  of  the  acid  as  CgH^Og  and  not  CHfi, 

11.  The  analysis  of  benzene  gave  the  following  data  : 

C  =  92-3  % 

H=  v^vy, 

the  simplest  ratio  of  atoms  present  is 

tt  ^r[CH] 

H  =  Y"  =^-^ 

The  empirical  formula  is  therefore  CH,  but  since  the  density 
is  39  the  molecular  weight  is  78,  and  consequently  the  molecular 
formula  CgHg.  But  when  benzene  is  acted  upon  by  chlorine  the 
simplest  derivative  that  can  be  obtained  is  CgHgCl,  and  remem- 
bering that  hydrogen  and  chlorine  are  of  equal  valency,  it  follows, 
from  this  absolutely  different  line  of  reasoning,  that  CgHg  again 
represents  the  molecular  formula  of  this  body.  The  determination 
of  the  atomic  arrangement  in  this   case   is  much  more  complex 


12  CHEMICAL  INTRODUCTION 

than  the  one  previously  discussed,  and  here  the  theory  of  valency 
in  the  hands  of  Kekule  gained  one  of  its  greatest  victories. 
Without  going  into  details,  the  proof  that  the  hydrogen  atoms 
are  of  equal  value  has  been  shown  on  the  following  general 
argument. 

Representing  the  molecule  as 

1      2    3    4    5     6 

Cg  H  H  H  H  H  H, 

it  has  been  proved  that  if  one  of  the  hydrogen  atoms  be  replaced 
by  the  radical  (OH),  say  No.  1,  the  resulting  compound  phenol 

1        2     3    4    5     6 

CeCOH)  HHH  H  H 

is  identical  with  those  obtained  by  replacing  either  2,  3,  or  4 ;  it 
has  been  further  proved  that  with  respect  to  position  numbered  1, 
those  numbered  2  and  6  are  identical,  and  also  3  and  5.  Conse- 
quently, all  the  hydrogen  atoms,  and  therefore  the  carbons  to  which 
they  are  joined,  are  symmetrically  placed  towards  each  other. 
Kekule  aptly  expressed  this  in  the  following  constitutional  formula : 

CH=CH 

CH^  \CH 

CH— CH 

Here,  the  latent  valencies,  as  they  have  been  previously  termed, 
are  represented  by  double  bonds,  a  point  which  will  be  dis- 
cussed in  a  later  chapter,  and  may  for  the  present  be  disregarded. 
This  structural  arrangement,  whilst  clearly  showing  the  existence 
of  but  one  mono-substitution  product,  gives  further  a  complete 
explanation  of  the  existence  of  three  di-substitution  derivatives, 
always  provided,  of  course,  that  isomerism  is  not  possible  in  the 
substituting  group. 

Dichlorbenzene,  for  instance,  exists  in  three  isomeric  modifications, 
and  representing  the  benzene  nucleus  as  a  hexagon,  the  structural 
formulae  for  these  will  be 


Cl 

Aci 

Cl 

X 

a 

(1) 

The  first  is  termed  the  ortho 

(2) 
or  1 :  2-dichlor 

benz 

(3) 

ene,  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  position  1  :  2 
must  be  the  same  as  1  : 6,  and  1  :  3  as  1 : 5.  Ladenburg,  however, 
subjected  this  to  close  investigation  and  conclusively  proved  that 
such  was  the  case. 

The  characteristics  of  this  closed-ring  system  are  pronounced 
and  very  different  from  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-chain  hydrocarbons  which  are  called 
Aliphatic.  Now,  more  perhaps  for  the  sake  of  convenience  than 
anything  else,  since  the  number  of  benzene  derivatives  is  so 
enormous,  these  are  usually  studied  separately  from  the  aliphatic 
derivatives  ;  but  as  the  number  of  substances  of  both  series  described 
in  this  work  is  but  a  mere  fraction  of  those  discussed  in  any  of 
the  even  moderately  sized  textbooks  on  Chemistiy,  the  hydro- 
carbons and  their  derivatives,  of  both  series,  will  be  studied  more 
or  less  together,  when  it  is  hoped  that  a  better  grasp  of  their 
similarities  and  many  dissimilarities  will  be  obtained. 

Not  only  are  such  ring-shaped  substances  containing  from  three 
to  seven  carbon  atoms  known,  but  many  containing  carbon  atoms 
replaced  by  other  elements  have  been  isolated,  and  some  of  these 
will  be  described  in  the  following  chapters. 


B.     GENERAL  PHYSIOLOGICAL  INTRODUCTION. 

Practical  therapeutics  may  be  deductive  or  inductive ;  may,  that 
is  to  say,  be  based  on  some  general  principles  which  in  their  turn 
depend  on  the  conceptions  held  as  to  diseased  processes  and  the 
pharmaco-dynamics  of  certain  substances,  or  they  may  be  merely 
the  result  of  more  or  less  discrete  observations  as  to  the  curative 
value  of  such  substances  in  certain  diseased  conditions.  The  former 
method  is  often  spoken  of  as  ^  rational ',  and  the  latter  as '  empiric  \ 
In  one  of  his  lectures  on  Pharmacology  the  late  Dr.  Moxon,  after 
pointing  out  this  distinction,  warned  his  hearers  against  ^  reasonings 
in  medical  therapeutics  \  ^  Inductions  '  he  continued,  '  are  com- 
monly in  harmony  with  the  teachings  of  Physiology,  but  I  advise 
you  to  hold  them  a  good  deal  distinct  from  those  teachings,  and  do 
not  be  too  ready  to  allow  them  to  rest,  even  in  appearance,  on  those 


14  PHYSIOLOGICAL   INTRODUCTION 

teachings/  The  lecture  from  which  this  passage  is  taken  was 
dehvered  in  1874,  six  years  after  the  publication  of  Crum  Brown 
and  Fraser's  work  on  the  curariform  action  of  the  ammonium 
bases,  which  appeared  to  be  the  beginning  of  a  rational  system  of 
pharmacology.  Physiological  action  determined  on  general  prin- 
ciples by  a  study  of  chemical  composition,  an  exact  adaptation  of 
means  to  ends,  and  the  disappearance  of  empirical  medication 
seemed  not  impossible  achievements  after  a  beginning  had  once 
been  made  by  this  important  and  far-reaching  generalization. 
Moxon,  however,  was  a  determined  empiric,  not  owing  to  any 
aversion  to  scientific  method,  but  because  he  saw  that  our  funda- 
mental knowledge  of  facts  was  not  sufficiently  large  to  support  any 
superstructure  of  a  general  or  theoretical  character.  Although 
remarkable  advances  in  Pharmacology  have  been  made  during  the 
last  half  century,  the  practical  position  now  is  not  greatly  changed 
since  Moxon's  lecture.  Schmiedeberg,  writing  in  1902,  said:  'The 
relation  of  Therapeutics  to  Pharmacology  is  obvious,  in  so  far  as 
the  former  is  based  on  a  scientific  foundation.  This,  however,  is 
very  far  from  being  the  case.  Everywhere,  pristine  empiricism  is 
master,  entirely  unconfined  by  any  scientific  barriers/  There  are 
not  wanting,  however,  signs  that  although  empiricism  must  for 
many  years  longer  dominate  our  treatment  of  diseased  conditions, 
yet  there  is  a  growing  interest  in  the  subject  of  rational  therapeutics, 
and  a  wider  appreciation  of  the  advantages  which  an  extended 
knowledge  of  the  matter  would  ensure.  Not  only  has  a  vast 
amount  of  research  been  devoted  to  elucidating  such  relationships 
as  may  exist  between  the  chemical  structure  of  a  drug  and  its 
physiological  action,  but,  in  addition,  some  space  is  devoted  to  these 
topics  in  textbooks  and  in  the  medical  press;  moreover,  there  is 
already  a  large  industry  established,  though  not  indeed  in  this 
country,  which  has  for  its  object  the  production  of  synthetic  drugs, 
the  action  of  which  is  more  or  less  accurately  predicted  from  their 
chemical  constitution. 

We  may,  therefore,  allude  to  the  obstacles  which  have  prevented 
a  still  greater  expansion  of  the  domain  of  rationalism,  and  a  more 
complete  abandonment  of  the  therapy  of  empiricism.  The  difficulties 
in  correlating  chemical  and  physiological  properties  fall  into  two 
main  divisions,  the  first  has  reference  to  the  drug  itself,  and  the 
second  to  the  organism  on  which  it  is  intended  to  act. 

Various  physical  characteristics,  such  as  solubility  and  volatility, 
markedly  influence  and  alter  the  action  of  a  drug,  and  interfere 


OBSTACLES  TO  RATIONALISM  15 

with  the  development  of  its  action.  Upon  these  depend,  in  part  at 
least,  speed  of  absorption  and  excretion ;  a  decrease  in  the  former  or 
an  increase  in  the  latter  will  generally  mean  a  decrease  in  physio- 
logical activity.  The  effect  of  solubility  is  seen  in  the  hypnotics 
chloral  hydrate  and  sulphonal.  The  former  is  soluble  and  rapidly 
absorbed,  and  consequently  rapidly  produces  its  physiological  effect  ; 
the  latter,  owing  to  its  slight  solubility,  is  slowly  absorbed  and  hence 
the  physiological  action  is  delayed,  but  also  prolonged,  and  drowsi- 
ness may  persist  for  many  hours  after  the  administration  of  that 
substance. 

The  physiological  inactivity  of  the  higher  members  of  many 
homologous  series,  such  as  the  alcohols  or  acids,  is  attributable  to 
their  insolubility,  which  renders  them  incapable  of  being  absorbed. 

The  important  question  of  solubility  in  fatty  substances  will  be 
dealt  with  in  the  chapter  on  Narcotics. 

The  degree  of  dissociation  which  a  substance  undergoes  on  solu- 
tion in  water  can  play  an  important  part  in  its  action  on  the 
organism.  But  organic  substances,  with  which  alone  this  work 
deals,  are,  with  the  exception  of  certain  groups  such  as  the  acids, 
generally  undissociated  on  solution.  The  case  of  the  mercury  salts 
may,  however,  be  given  as  an  illustration  of  this  phenomenon. 

Paul  and  Kronig  investigated  the  disinfectant  power  of  mercuric 
chloride,  HgClg,  bromide,  HgBrg,  and  cyanide,  Hg(CN)2,  using  the 
spores  of  B .  Anthracis,  and  found  that  in  equimolecular  solutions 
the  chloride  was  the  most  powerful  antiseptic,  then  the  bromide, 
and  that  the  cyanide  had  least  action.  This  corresponds  to  the 
degree  of  dissociation  which  takes  place  in  the  three  solutions.  The 
character  of  the  metallic  ion  is,  of  course,  of  primary  importance,  as 
salts  of  other  bases  which  are  still  more  dissociated  in  solution  have 
not  the  same  disinfectant  action  as  those  of  mercury. 

An  instructive  insight  into  the  difficulties  of  the  problem  is  further 
afforded  by  the  researches  of  the  same  authors  into  the  disinfectant 
powers  of  a  solution  of  perchloride  of  mercury  and  common  salt. 
Many  years  ago,  Bacelli,  when  advising  intravenous  injections  of 
mercurial  salts  in  cases  of  syphilis,  employed  a  solution  of  the  per- 
chloride mixed  with  sodium  chloride  in  the  proportion  of  one  to 
three,  which  he  stated  was  more  effective  in  actual  practice.  Paul 
and  Kronig  have  shown  that  the  actual  process  is  as  follows  : — 
A  double  salt  (NagHgClJ  is  formed,  which  dissociates  into  positive 
sodium  ions  and  negative  complex  ions  of  mercury  and  chlorine. 
The  latter  are  inactive  from  an  antiseptic  point  of  view,  but  a  cer- 


16  PHYSIOLOGICAL   INTRODUCTION 

tain  amount  of  secondary  dissociation  of  the  complex  negative  ion 
occurs,  resulting  in  the  formation  of  the  active  mercury  ions,  though 
to  a  smaller  extent  than  when  an  equimolecular  solution  of  mercuric 
chloride  alone  is  employed.  The  action  is  thus  hindered,  but  in 
practice  the  increased  solubility  which  is  obtained  by  the  addition 
of  salt  more  than  counterbalances  the  decreased  ionic  dissociation.  On 
the  other  hand,  salicylic  acid,  which  is  only  very  slightly  dissociated 
on  solution  and  consequently  is  a  very  weak  acid,  owes  its  bactericidal 
action  to  the  entire  molecule  and  not  to  the  ions.  Sodium  salicylate, 
which  is  largely  dissociated,  when  dissolved  in  water  shows  no 
antiseptic  properties. 

That  the  velocity  of  diffusion  of  a  substance  will  play  an  impoi-tant 
part  in  its  physiological  reactivity  is  clear,  and  to  this  factor  may 
be  ascribed,  for  instance,  the  differences  observed  in  the  group  of 
digitalis  glucosides.  The  most  powerful  member  of  this  group  is 
digitoxin,  a  very  insoluble  crystalline  substance.  Cloetta  has  in- 
troduced an  amorphous  and  soluble  form  of  digitoxin  which  has  been 
named  digalen :  following,  in  all  probability,  on  increased  solubility 
there  is  increased  diffusibility,  and  to  this  is  attributed  the  absence 
of  digestive  disturbances  when  it  is  administered  by  the  mouth. 

Two  further  points  may  be  mentioned  as  of  practical  importance, 
which  render  the  issues  of  pharmacological  experiment  difficult  to 
determine.  The  first  of  these  is  the  erroneous  impression  as  to  the 
main  action  of  a  drug  which  may  be  produced  by  certain  bye  effects. 
An  extreme  instance  of  this  is  alcohol,  which  is  commonly  known  as 
a  stimulant  and  is  frequently  taken  to  produce  a  feeling  of  warmth, 
whereas  its  chief  physiological  actions  are  those  of  a  narcotic  and 
antipyretic.  The  second  is  the  effect  of  dosage.  Many  bodies  produce 
varied  effects  according  to  the  doses  in  which  they  are  administered. 
This,  of  course,  does  not  depend  on  any  real  alteration  in  the  physio- 
logical character  of  the  drug,  but  is  merely  a  matter  of  distribution. 
A  narcotic  drug,  for  example,  when  given  in  doses  large  enough 
to  produce  sleep,  may  fail  to  exhibit  certain  secondary  actions 
which  are  produced  independently  of  the  effect  on  the  central 
nervous  system.  On  the  other  hand,  a  substance  with  a  specific 
action  on  particular  organs,  if  given  in  toxic  doses,  may  cause 
general  symptoms  which  entirely  mask  the  particular  and  charac- 
teristic effect. 

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


LOEWS   THEORY   OF   POISONS  17 

that  this  fall  of  temperature  is  partly  dependent  on  a  direct  action 
of  the  drug",  which,  apart  from  its  narcotic  powers,  has  an  inhibiting- 
effect  on  oxidation  processes.  In  this  it  differs  from  ether,  though 
there  is  also  a  fall  in  temperature  during  ether  narcosis. 

The  main  obstacle,  however,  to  a  rational  appreciation  of 
pharmaceutical  actions  lies  in  our  ignorance  of  the  chemistry  and 
reactivity  of  the  living  cells.  To  attempt  to  calculate  the  result 
of  a  chemical  interaction  in  which  the  constitution  of  only  one 
of  the  bodies  concerned  is  known,  is  obviously  an  undertaking 
destined  to  only  a  partial  measure  of  success :  but  this  is  what  is 
done  when  attempts  are  made  to  set  forth  the  chemical  basis  of 
the  action  of  drugs. 

Complete  explanations,  in  the  proper  sense  of  the  word,  are  not 
at  present  possible,  but  starting  from  the  better-known  factor, 
that  is,  the  drug,  it  is  possible  by  introducing  chemical  variations 
of  a  definite  character  to  modify  the  pharmacological  results,  and 
thus  in  some  instances  to  gain  an  insight  into  the  chemical  in- 
fluences which  can  be  brought  to  bear  on  living  cells. 

We  will  now  proceed  to  consider  in  detail  the  two  variants 
in  any  pharmacological  process,  namely  (A)  the  cell  protoplasm, 
and  (B)  the  drug. 

(A)  With  respect  to  the  protoplasm,  the  theory  of  Oscar  Loew  is 
of  considerable  interest.  He  divides  the  general  poisons  into 
'oxidizing,^  ^catalytic,'  'salt-forming,*  and  ^substituting.'  These 
in  sufficient  concentration,  act  on  all  living  protoplasm,  and  depend 
for  their  activity  on  the  chemical  character  of  the  substances  of 
which  living  cells  are  composed. 

The  special  poisons,  forming  the  second  main  group,  comprise 
those  which  only  act  on  certain  classes  of  organisms.  Under  this 
head  are  included  the  toxins,  the  antitoxins,  and  similar  bodies, 
the  action  of  which  is  specific  for  certain  kinds  of  protoplasm ; 
the  organic  bases  (including  the  alkaloids)  which  probably  act  by 
disturbing  the  structural  character  of  certain  cells ;  and  the  indirect 
poisons  which  make  respiration  impossible,  &c. 

Now  as  regards  the  general  poisons,  the  first  three  classes  are 
not  important  for  our  present  purpose.  The  first  includes  bodies 
such  as  ozone,  peroxide  of  hydrogen,  chromic  acid,  permanganates, 
hypochlorites,  phosphorus,  &c.  Among  the  catalytic,  i.  e.  those 
which  influence  chemical  action  without  undergoing  any  apparent 
change  themselves,  are  the  aliphatic  narcotics,  which  will  be  dealt 
with  later  on  in   the   present  work.     The  third  group  owes  its 

0 


18  PHYSIOLOGICAL  INTRODUCTION 

existence  to  the  amphoteric  character  of  protein,  and  includes  acids, 
the  soluble  bases  such  as  alkalies  and  alkaline  earths^  and  the 
salts  of  the  heavy  metals. 

The  fourth  class  includes  a  number  of  bodies  which  even  in 
extreme  dilutions  can  react  with  aldehydes  and  amines,  forming* 
substitution  products — whence  the  name.  The  more  readily  this 
reaction  takes  place  the  more  powerful  will  be  the  toxic  eJffect. 
Examples  may  be  found,  firstly  in  hydrazine  and  phenylhydrazine, 
which  most  readily  combine  with  aldehydes  and  are  consequently 
powerful  poisons ;  similarly,  hydroxylamine,  aniline  and  free 
ammonia.  Secondly,  the  phenols  and  their  derivatives,  especially 
the  amidophenols ;  and  thirdly,  prussic  acid,  sulphuretted  hydrogen, 
and  the  acid  sulphites — all  substances  capable  of  reacting  with 
aldehyde  groups. 

As  a  general  rule,  primary  amines  (not  of  the  aliphatic  series)  are 
more  reactive  than  secondary,  and  these  more  so  than  tertiary. 
Pyridine,  with  a  tertiary  nitrogen  atom,  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  different  but  weaker  action  than  aniline. 

The  amido  group  is  readily  attacked  by  nitrous  or  nitric  acids,  by 
aldehydes,  ketones,  &c. 

Loew  gives  many  examples  selected  from  among  those  bodies 
which  are  protoplasmic  poisons,  and  shows  generally  that  toxicity 
inereases  pari  passu  with  reactivity. 

Thus  Loew  explains  the  very  various  chemical  structures  of  these 
general  protoplasmic  poisons,  by  showing  that  they  will  all  react  with 
one  or  two  very  labile  groups  which  he  believes  are  present  in  the 
living  protoplasmic  molecule,  but  undergo  a  chemical  change  and 
become  stable  when  the  protoplasm  dies.  Consequently,  these 
general  poisons  have  no  action  on  dead  protein,  so  differing  from 
bodies  like  the  mineral  acids,  which  are  equally  destructive  to  living 
or  dead  tissues. 

Though  considerations  of  this  sort  may  help  towards  elucidating 
certain  general  reactions,  they  completely  fail  to  account  for  what 
is  generally  known  as  the  selective  action  of  drugs.  ^  From  our 
present  point  of  view,  it  should  perhaps  be  more  correctly  stated  as 

*  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  subsequent  chapter,  and  Loew's  theory  in  general  will 
be  criticized  in  the  chapter  on  organic  dyes. 


SELECTIVE  POWER  OF  CELLS        19 

the  selective  action  of  cells.  The  most  specialized  poisons — such  as 
cocaine  or  strychnine — are  capable  o£  reacting*  with  a  great  number 
of  different  sorts  of  cells,  but  within  the  body  certain  cells  appear 
more  and  others  less  susceptible,  and  hence  the  special  train  of 
symptoms,  for  example,  which  follows  the  introduction  into  the 
body  of  the  various  alkaloids. 

That  the  structure  of  the  cytoplasm  varies  is  seen  by  reference  to 
many  histological  observations.  The  well-known  differences  in 
staining-reaction  of  different  kinds  of  cells  and  in  different  parts  of 
the  same  cell  are  examples  in  point.  Thus,  methylene-blue  stains 
axis  cylinders,  the  spiral  fibres  in  ganglion  cells  and  the  sensory  nerve 
endings,  whereas  the  straight  processes  of  the  cells  are  unstained, 
and,  as  a  rule,  the  motor  nerve  endings.  Neither  fuchsin,  methyl- 
violet,  nor  safranin  stains  the  axis  cylinders. 

The  toxic  proteins  or  toxins  very  closely  resemble  the  alkaloids 
in  their  manner  of  action  on  the  body  cells  and  it  is  there- 
fore, perhaps,  hardly  remarkable  that  the  well-known  side-chain 
theory  of  Ehrlich  should  be  applied  to  both  these  groups.  Thus  the 
anterior  cornual  cells  in  the  cord  may  be  supposed  to  possess  certain 
side-chains  which  render  them  specially  capable  of  uniting  with 
strychnine,  and  those  of  the  central  cortex  similar  side-chains  ready 
to  unite  with  morphine.^  Robert's  paradox,  that  the  more  powerful 
the  drug  and  the  more  marked  its  effects,  the  less  is  any  chemical 
change  to  be  detected  in  its  passage  through  the  body,  is  pro- 
bably more  apparent  than  real.  It  is  true  that,  whereas  certain 
substances  which  are  hardly  toxic  at  all  are  completely  decomposed, 
others,  with  minute  lethal  doses,  can  be  recovered  unchanged  in 
the  urine.  There  is  not  wanting,  however,  an  increasing  amount  of 
evidence  that  in  reality  minute  quantities  of  such  bodies  as  the 
alkaloids  are  retained  in  the  body,  and  probably  take  part  in  some 
chemical  reaction  which  may  or  may  not  be  of  a  catalytic  nature. 
Thus  atropine  is  said  to  be  oxidized  in  the  body  to  the  extent  of 
two-thirds  of  the  dose  given. 

It  is  necessary,  as  Schmiedeberg  points  out,  to  extend  to  the 
word  '  chemical  ■*  a  very  wide  significance.  It  must,  in  fact, 
include  all  those  changes  which  are  commonly  called  physico- 
chemical;  the  cell  itself,  containing  protein,  lecithin,  salts,  water, 
&c.,  may  be  looked  upon  as  a  physico-chemical  combination  in 
a  state  of  equilibrium,  upon  which  depends  its  vital  activity.  The 
most  characteristic  properties  of  the  cell  are  those  which  depend  on 
^  See  note  at  end  of  chapter. 
C  2 


20  PHYSIOLOGICAL  INTRODUCTION 

the  integrity  of  the  protein  portion,  concerning  which  we  can  only  say 
that  it  is  too  labile  to  admit  o£  examination  in  a  living  condition.^ 

(B)  When  we  turn  to  the  second  factor  in  pharmacological  reac- 
tions, namely,  the  drugs,  our  survey  of  the  subject  may  conveniently 
be  divided  into  two  parts.  In  the  first  place,  we  may  notice 
certain  generalities  connected  with  physiological  activity  which 
have  been  arrived  at  by  the  experimental  method,  and  then  we 
may  go  on  to  consider  the  theoretical  views  which  have  been 
expressed  as  to  the  way  in  which  drugs  exhibit  their  particular 
actions  in  the  animal  body. 

I.  In  correspondence  with  their  comparatively  slight  chemical 
reactivity,  the  aliphatic  series  of  bodies  do  not  on  the  whole  possess 
powerful  pharmacological  actions.  Brunton  and  Cash  state  that 
the  predominant  feature  of  the  lower  members  of  the  fatty  series  is 
their  stimulant  and  anaesthetic  action  on  the  nerve  centres  (frogs). 
Schmiedeberg  collects  in  a  general  class  the  narcotics  of  the 
aliphatic  series  as  (1)  the  Alcohol  and  Chloroform  group.  This 
includes  the  gaseous  and  fluid  hydrocarbons,  the  monatomic  alcohols 
and  their  ethers,  ketones,  aldehydes,  and  their  halogen  derivatives. 
These  are  mainly  characterized  by  their  action  on  the  cerebrum 
producing  narcosis.  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  cells  of  the  spinal  cord. 
When  the  triad  nitrogen,  by  the  addition  of  another  alkyl 
group  is  converted  into  pentad  nitrogen,  a  remarkable  change  in 
the  physiological  action  occurs,  which  was  first  pointed  out  by 
Crum  Brown  and  Fraser  in  1868,  subsequently  confirmed  by 
Brunton  and  Cash,  and  very  fully  illustrated  by  many  observers. 
All  the  quaternary  ammonium  bases  have  a  curare-like  action, 
paralysing  the  motor  nerve  endings.  Numerous  illustrations  of 
this  principle  will  be  found  in  the  course  of  the  present  work. 

II.  The  aromatic  bodies  being  chemically  more  reactive  are 
physiologically  more  effective.  Experiments  with  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  producing  anaesthesia,  like  members 
of  fatty  series,  they  tend  rather  to  give  rise  to  tremor,  convulsions, 
and  paralysis  (Brunton  and  Cash).  The  activity  is,  however, 
increased  by  the  substitution  of  hydrogen.     In  this  case,  alterations 

*  Fhat'macologie,  1902. 


REACTIVITY   OF  THE   DRUG  21 

in  physiological  action  may  be  produced  not  only  by  alterations  in 
the  molecule  as  a  whole^  but  by  variations  in  the  group  which 
substitutes  hydrogen.  Examples  of  this  will  be  considered  in  the 
chapter  on  the  Alkaloids,  which  are  all  heterocyclic  bases  with 
various  side  chains.  Especially  important  in  this  connexion  is  the 
rule  enunciated  by  Kendrick  and  Dewar,  that  the  introduction  o£ 
hydrogen  into  the  cyclic  bases  in  all  cases  increases  their  physio- 
logical action,  and  thus  their  toxicity. 

In  a  general  sense,  also,  Dujardin-Beaumetz  and  BardeFs  con- 
ceptions of  the  influence  of  various  side  groups  on  the  benzene 
compounds  may  be  taken  as  accurate  : — 

(i)  Those  containing  hydroxyl  are  antiseptic, 
(ii)  Those  containing  an  amido   group   or  an   acid   amide  are 
hypnotic. 

(iii)  Those  containing  both  an  amine  group  and  an  alkyl  group 
are  analgesic. 

These  few  general  rules  will  be  found  subject  to  variation  and 
exception,  due  to  one  or  more  of  those  disturbing  factors  which  have 
already  been  noted;  but  they  show  by  their  very  existence  that 
within  certain  limits  it  is  possible  to  modify  the  physiological  action 
of  a  drug  at  will  in  a  given  direction.  Other  ^  rules '  of  less  general 
applicability  will  be  noted  under  the  various  groups  of  compounds 
which  will  be  discussed  in  subsequent  chapters. 

We  have  already  dealt  with  the  mechanism  of  interaction  between 
the  living  cell  and  the  drug  from  the  point  of  view  of  the  cell,  as  far 
as  anything  can  be  definitely  stated  about  the  matter;  a  little  more 
may  now  be  said  regarding  the  drug. 

The  action  of  a  drug  appears  to  depend  upon  its  possessing,  firstly, 
some  group  of  atoms  capable  of  exerting  a  specific  effect  on  the 
cell,  and  secondly,  another  group  or  side  chain  capable  of  entering 
into  some  kind  of  chemico-physical  relationship  with  certain  cells, 
whereby  the  first  is  enabled  to  produce  its  action.  This  second  is 
commonly  known  as  the  anchoring  group.  The  term  'chemico- 
physical  ''  was  used  advisedly,  as  it  cannot  be  said  to  be  definitely 
settled  whether  a  chemical  reaction  in  the  ordinary  sense  really 
takes  place.  P.  Ehrlich  has  compared  the  reaction  which  is  sup- 
posed to  take  place  with  those  postulated  by  Witt  for  the 
organic  dyes.  The  dyeing  properties  of  a  substance  are  dependent 
on  the  presence  of  certain  atomic  groupings  which  are  termed 
colour  groups  or  chromophores.  The  entrance  of  the  chromophore 
group  into  a  molecule  results  in  a  derivative  more  or  less  coloured, 


22  PHYSIOLOGICAL  INTRODUCTION 

but  lacking  the  characteristics  of  a  dye,  and  it  is  only  when  basic 
or  hydroxyl  radicals  (auxochrome)  are  further  introduced,  that  the 
dyes  result.  For  example,  in  azo-benzene  CgHg .  N  :  N.CgHg  the 
group  Ng  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.  CgHg .  N :  N.CgH4(NH2). 
Anthraquinone 

is  colourless  (chromogene),  but  on  the  introduction  of  two  hydroxyl 
groups,  the  dye  aHzarin  results 

CeH4<cC>C6H.(OH),. 

Two  groups  are  consequently  necessary  to  confer  on  a  substance 
its  dyeing  properties  j  further,  the  colour  itself  is  dependent  on  the 
number  and  nature  of  the — say — basic  radicals ;  thus,  amido-azo- 
benzene,  CgH^ .  N  :  N.CgH4(NH2),  is  yellow,  the  di-amido  deri- 
vative is  orange,  the  tri-amido  brown. 

Many  drugs  can  be  extracted  unchanged  from  the  tissues,  and 
Ehrlich  regards  them  as  having  been  withdrawn  from  solution  and 
existing  there  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  regards  it  as  forming  a  solid 
solution  from  which  it  may  be  again  withdrawn  by  the  use  of 
a  more  powerful  solvent.  But  it  is  much  more  probable,  as  Freud- 
lich  and  Losev  have  shown,  that  since  Henry's  law  does  not  hold  for 
dyestuffs,  the  phenomenon  of  dyeing  is  one  of  adsorption,  and  with 
this  may  be  compared  the  views  expressed  in  the  chapter  on 
Narcotics  as  to  the  manner  in  which  the  drug  enters  the  cell. 

The  non-toxicity  of  acidic  substances  is  traced  to  the  fact  that 
they  are  no  longer  capable  of  being  absorbed  by  the  tissues.  Ehrlich 
has  shown  that  those  dyes  which  stain  the  brain  tissue  cease  to  do 
so  on  conversion  into  sulphonic  acids,  as  neurotropic  substances 
lose  their  characteristics  on  the  entrance  of  such  groups. 

He  also  suggests  that  the  analogy  between  the  physiological 
action  of  substances  and  the  theory  that  has  been  sketched  of  the 
dyes,  may  be  of  value  in  the  synthetic  production  of  drugs.  Sub- 
stances with  the  power  of  acting  on  definite  cells  may  be  found 
(myotropic,  neurotropic,  &c.),  and  the  character  of  their  action 
controlled  by  the  introduction  of  groups  (chromophore)  of  varied 
pharmaco-dynamic  effect. 


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  solubility  in  lipoid  substances.  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 
relationships  between  chemistry  and  pharmaco-dynamics,  will  at  least 
show  that,  whereas  in  many  instances  and  by  many  various  ways 
a  close  relationship  may  be  shown  to  exist,  there  is  as  yet  no 
possibility  of  the  abandonment  of  empiricism  in  practical  medicine. 
Though  much  has  been  done  much  more  remains,  and  though  the 
principle  has  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-recepfors  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. 


CHAPTEK  II 

A.  The  Aliphatic  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  reactivity  of  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  simplest  series  commences  with  methane,  CH^,  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.  They 
form  what  is  termed  an  homologous  series — one  in  which  each 
member  differs  from  the  next  by  a  constant  quantity,  viz.  CHg. 

Methane       CH^ 

Ethane         CgHg 


Propane        CgHg 

Butane         C^H^q     b.  p.  1* 


n.  Hexane    CgH^^     b.  p.  71° 
Tetradecane  Cj^Hjg    m.  p.  5-5' 


Di-myricyl  C^^B.^^^  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  liquid  phase,  from  liquids  of  low  boiling-point  to 
those  of  high,  or  from  liquids  of  high  boiling-point  to  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  frequently  called  the  limit 
hydrocarbons.  Isomerism  first  appears  in  butane,  C^Hjq,  and  the 
theory  of  valency  satisfactorily  accounts  for  the  existence  of  two 
substances  of  that  formula,  having  the  same  vapour  density  and 
molecular  weight,  but  differing  physical  and  chemical  properties, 
viz.,  w-butane,  CHg .  CHg .  CH2 .  CH3,  and  iw-butane, 

I 

CH3— C .  H 

I 
CH3 

The  n-  or  normal  derivations  are  those  consisting  of  a  chain  of 
carbon  atoms,  whilst  the  iso-  have  a  branched  structure.  But  since 
this  latter  nomenclature  may  not  be  sufficiently  precise,  such  hydro- 
carbons may  be  regarded  as  derivatives  of  methane  ;  thus,  iso-butane 
may  be  termed  tri-methyl-methane.  This  is,  perhaps,  clearer  in  the 
case  of  pentane.  w-Pentane  is  CHg.  CHg.  CHg.  CHg.  CHg,  two 
i^o-pentanes  exist;  if  the  first 

CH3 

I 

CH„— C— CH3 

I 
CH3 

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

C2H5 

CH,— C .  H 

I 
CH3 

methane,  their  respective  structures  are  at  once  evident. 

Occurrence  in  Nature.  Many  of  these  hydrocarbons  occur 
in  nature.  Methane,  or  marsh  gas,  formed  by  the  decay  of  organic 
substances,  is  found  in  the  coal  measures,  and  in  regions  like 
Baku  in  the  Caucasus,  and  in  the  petroleum  districts  of  America. 
Large  deposits  of  petroleum,  consisting  of  mixtures  of  members  of 
this  series,  are  found  in  America,  Russia,  Alsace  and  Hanover. 
That  from  America  consists  almost  exclusively  of  normal  paraffins. 
The  fractions  boiling  between  50°-60°  consist  chiefly  of  pen- 
tane and  hexane,  between  70°-80°  hexane  and  heptane,  between 
90°-120°  heptane  and  octane.     Refined  petroleum  or  kerosene  boils 


26     ALIPHATIC  AND  AROMATIC  HYDROCARBONS 

at  150°-300°.  The  solid  high-boiling  paraffins  are  more  abundant 
in  the  petroleum  from  Baku  than  in  that  from  America,  and  are 
also  obtained  by  the  distillation  of  the  tar  from  turf,  lignite,  and 
bituminous  shales. 

Paraffins  that  liquefy  readily  and  fuse  between  30°  and  40°,  are 
known  as  vaselines  and  employed  as  salves. 

Properties.  All  the  members  of  this  group  are  insoluble  in 
water ;  the  lower  are  soluble  in  alcohol  and  ether,  but  the  solubility 
diminishes  as  the  molecular  weight  increases.  They  are  charac- 
terized by  their  great  stability  and  consequent  slight  reactivity. 
Fuming  nitric  or  even  chromic  acid  does  not  affect  them  in  the  cold, 
and  on  heating  the  action  is  but  slow.  Chlorine  and  bromine  give 
rise  to  substitution  products,  a  characteristic  property  of  the  satu- 
rated hydrocarbons.  Methane,  for  instance,  gives  firstly  methyl 
chloride,  CH3CI,  then  CH^Clg,  CHCI3,  and  finally  CCI4,  in  which 
all  the  hydrogen  atoms  have  been  replaced  by  chlorine;  in  such 
reactions,  for  every  atom  of  chlorine  that  enters  the  molecule  an 
atom  of  hydrogen  is  removed  in  the  form  of  hydrochloric  acid, 
e.g.   CH4  +  Cl2  =  HCl  +  CH3Cl,  and  so  on. 

Olefines. 

The  next  group  of  hydrocarbons  contains  two  hydrogen  atoms  less 
than  those  just  considered,  and  forms  an  homologous  series,  with 
physical  properties  similar  to  the  paraffins.  When  the  structure  of, 
say,  the  simplest  member,  ethylene,  is  considered,  it  is  seen  that 
apparently  carbon  is  acting  as  a  trivalent  element,  thus  CHg.  CHg. 
But  all  the  members  of  this  series,  quite  unlike  the  paraffins,  are 
very  reactive  and  possess  the  following  properties  :  They  absorb 
a  molecule  of  chlorine,  bromine,  and  iodine,  without  the  formation 
of  the  corresponding  halogen  hydride.  In  a  similar  manner,  mole- 
cules of  hydrogen  or  the  haloid  acids  are  readily  added,  and 
these  reactions  usually  take  place  with  considerable  ease.  The 
explanation  that  is  offered  of  these  phenomena  is  the  assumption 
that  the  fourth  valencies  of  each  carbon  atom  mutually  saturate 
each  other,  graphically  described  by  a  double  bond,  e.  g.  HgC  =  CHg, 
or  CHgiCHg  and  the  substance  is  said  to  be  unsaturated.  The 
reactions  alluded  to  being  expressed  by  the  following  equations  : — 

CH2 :  CH2  +  CI2  =  CH2CI .  CH2CI. 
CHg  I  CHg  +  Hg  =  CHg .  CHg. 
CH2 :  CH„  +  HI  =  CH, .  CH  J. 


OLEFINES  27 

The  chief  characteristic,  then,  of  the  define  hydrocarbons  is  the 
ease  with  which  they  become  saturated,  i.  e.  pass  back  into  the  limit 
hydrocarbons  or  their  derivatives.  The  graphic  mode  of  representa- 
tion must  not  be  understood  to  mean  a  more  stable  state  of  union 
of  the  two  halves  of  the  molecule;  it  is  rather  the  contrary,  such 
a  state  of  combination  generally  indicating  less  stability,  since  it  is 
at  that  point  that  the  molecule  is  first  attacked  by  reagents.  It 
will  further  be  noticed,  in  the  following  chapters,  that  this  state  of 
combination  usually  confers  a  rise  in  toxicity,  above  that  of  the 
corresponding  saturated  substance ;  this  certainly  depends  on  the 
much  greater  chemical  reactivity  of  such  groupings. 

The  members  of  this  series  are  absorbed  by  sulphuric  acid, 
ethylene  giving  ethylsulphuric  acid, 

CH2  /OH  /O.C2H5 

II     +S0,/       =so/ 

CH2  ^OH  \0H 

and  through  the  agency  of  this  substance  alcohol  and  ethers  may  be 
obtained  by  the  action  of  water  or  alcohol,  e.g. 

/OC^Hg    OHiH  /OH 

SO/      +  =    so/        +CAOH 

^OH  ^OH 

Ethyl  alcohol, 
and 

yOiC^Hg       C^H^OH  /OH 

SO/     •  +  =  SO/         +C2H,.0.CA 

^OH  ^OH 

Ethyl  ether. 

Acetylenes. 

In  this  homologous  series,  the  first  member,  acetylene,  is  the  most 
important;  it  contains  two  hydrogen  atoms  less  than  ethylene,  and 
for  reasons  similar  to  those  previously  mentioned  the  existence  of 
three  double  bonds  is  postulated,  and  the  substance  said  to  be 
doubly  unsaturated,  e.g.  HC  i  CH.  The  reactivity  of  members  of 
this  group  is  quite  similar  to  that  of  the  previous.  They  absorb 
one  molecule  of  hydrogen,  giving  ethylenes,  e.  g — 

CH:CH  +  H2=  CH2:CH2 

which  then  absorb  a  second,  passing  over  to  paraffins,  e.  g. 

CH2 1  CHg  +  Hg  =  CH3 .  CHg . 


28     ALIPHATIC  AND  AROMATIC  HYDROCARBONS 

The  reaction  with  the  halogens  is  similar,  chlorine  for  instance 
gives  dichlorethylene  and  then  tetrachlorethane, 

CH  CHCl  CHCI2 

III     +01^=  II        +Cl2->   I 
CH  CHCl  CHCI2 

Tetrachlorethane. 

Acetylene  and  many  of  its  derivatives  are  characterized  by  the 
formation  of  solid  silver  and  copper  compounds,  which  when  dry  are 
extremely  explosive.  These  may  be  employed  for  the  detection  and 
isolation  of  the  acetylenes,  since  on  treatment  with  hydrochloric 
acid  the  pure  hydrocarbon  is  liberated.  Acetylene  itself  is  at 
present  prepared  in  large  quantity  by  the  action  of  water  on 
calcium  carbide  and  is  used  for  illuminating  purposes. 


Benzene  hydrocarbons. 

The  last  series  of  hydrocarbons  may  be  regarded  as  derived  from 
the  simplest  member,  benzene,  by  means  of  the  replacement  of  one  or 
more  of  the  hydrogen  atoms  by  the  residues  of  the  aliphatic  series. 
The  constitutional  formula  assigned  to  the  parent  hydrocarbon  by 
Kekule,  viz. 

/CH=CHv 
»       CH<^  >CH 

^CH— CH^ 

is  in  agreement  with  most  of  its  properties  and  those  of  its  deriva- 
tives, as  previously  indicated.  But  when  the  nature  of  the  alternate 
double  and  single  bonds  is  investigated  it  becomes  at  once 
apparent  that  phenomena  of  a  different  order  appear  with  the 
formation  of  this  closed-ring  system.  In  this  case,  the  double  bond 
bears  no  similarity  to  that  previously  discussed.  For  instance,  the 
action  of  chlorine  on  benzene  gives  rise  to  substitution  products 
such  as  CgHgCl  or  CgH^Clg,  and  not  to  addition  derivatives,  as 
might  have  been  expected  had  the  unsaturated  nature  of  the  mole- 
cule been  akin  to  that  of  ethylene.  Moreover,  had  this  double 
union  been  analogous  to  that  previously  discussed,  the  compounds 
1 ;  2  and  1 :  6  should  be  different,  whereas  they  are  identical,  e.  g. 

01  CI 

I 

—CI     =    CI— rT^ 


V 


BENZENE   HYDROCARBONS  29 

for,  in  the  first  case,  between  the  two  carbon  atoms  cariying  the 
chlorine  atoms  there  exists  one  o£  these  double  bonds,  which  is 
absent  in  the  second.  In  a  corresponding  case  in  the  open-chain 
ethylene  derivatives,  these  two  chlorine  substitution  products  would 
have  been  different,  i.  e.  isomeric. 

It   may  be    put   in   a  different  way  as   follows  :    There  is  but 
little  difference  between  the  two  hydrocarbons  ?i-hexane, 

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

and  hexamethylene,  or,  hexahydrobenzene, 

/CH2 — CHgx 
CH,<  >CH,. 

^CH^— CH/ 

Further,  the  unsaturated  ethylene  derivative 

CH3 .  CH2 .  CH2 .  CH :  CH .  CH3 

has  the  same  general  characteristics  as  tetrahydrobenzene. 


/CH,- 


-CH 


CHA  >CH 

that  is,  the  behaviour  of  the  two  towards  the  halogens,  halogen 
hydrides,  &c.,  is  similar  to  that  previously  described.  Then  with 
the  di-ethylene, 


CHg.CHiCH.CHrCH.CHa, 


and  dihydrobenzene. 


.CH2— CH. 


cr/  \ch 

\CH  =  CfEl/ 


much  about  the  same  relationship  holds  true,  both  have  the  general 
properties  of  di-ethylene  derivatives.  But  when  the  third  double 
linkage  is  introduced  and  dihydrobenzene  becomes  benzene,  these 
general  properties  disappear  and  are  replaced  by  entirely  different 
characteristics.  The  entrance  of  the  radical  of  this  hydrocarbon, 
termed  phenyl,  into  various  molecules,  results  in  changes  in  the 
physical,  chemical  and  physiological  properties  of  quite  a  different 
order  from  those  produced  by  the  corresponding  entrance  of  aliphatic 
radicals :  as  a  result  appear  what  are  termed  the  negative  charac- 
teristics of  the  benzene  nucleus,  phenomena  which  will  be  studied 
in  detail,  in  relation  to  physiologically  active  substances,  in  the 
following  chapter. 


80     ALIPHATIC  AND  AROMATIC  HYDROCARBONS 

Sources.  Not  only  benzene  but  niimerouB  other  derivatives  are 
obtained  by  tlje  dry  diHtillation  of  coal.  They  are  present  in  coal 
tar,  wWu'h  is  pnxhieed  in  enormous  quantities  in  the  manufacture  of 
coal  truH.  Anionjr  the  homologues  found  are  toluene  or  methyl 
b(»nzene,  C',,!!;., .  ('Tfy,  the  three  dimethyl  benzenes  or  xylenes, 
C^U^{VA\,^),^  and  the  three  trimethyl  benzenes,  CqH3(CH3)3. 

Anu)nf»f  the  higher  boiling  fractions  of  coal  tar,  many  more 
highly  condensed  aromatic  hydrocarbons  are  found;  of  these, 
naphthalene,  Cj^Hg,  and  anthracene,  Cj^Hj^,  are  the  only  two  that 
will  be  discussed.  The  former  shows  great  similarity  to  benzene, 
from  which  it  differs  by  C^H.^.  Its  deportment  is  satisfactorily 
explained  by  the  constitutional  formula  suggested  by  Erlenmeyer, 

CH    CH 

ch/\c/\ch 

II 

chI^/CvJch 

CH    CH 

It  consists  of  two  benzene  nuclei,  having  in  common  two  carbon 
atoms  occupying  the  ortho  position. 

Anlhr:i(«Mii'  is  iho  jKntMii  liydrocarbon  of  a  series  of  vegetable 
compounds  ol"  whicb  llit>  ui.>^l  iinjmrtant  is  the  dye  alizarine.  The 
following  formula  cxpn^^sos  its  nhitionship  to  benzene  and  its  various 
Kvnil»(>sos, 


CH       C 

Vh/\ch/\:h^ 


cu      cu 

C  CH 


Oxidation  and  Reduction.  The  chief  characteristic  of  the  benzene 

h\(]ro(:iih(>tis  is  \\\c  r:vc:\\  slaMUfv  of  <he  ring  complex ;  in  the  vast 
uKii>Mii\  ,^t'  i-(';uiion^  uiul(M-LriM\i'  by  its  derivatives  the  nucleus  itself 
is  uo{  Acs\vo\cd.      riiis  l\>:iturt  ilistinguishes  the  aromatic  substances 

\\o\\\  tlu'  tliMiN  ;iliv(>s  of  tlii^  nuMb:nu^  niul  oihcv  iipon-cluiin  scM-ios. 
As  a  vtMv  mMn'ial  iul(\  t^xiihit  iiMi  or  rtHliu'tuui  can  lu'  larriinl 
on  without  tearing  this  vluix  nsmuU  r.  In  the  former  jv  en  i  ss  the 
b(^n-*Mu^  homologaes  \\'.\\c  \\\c\v  s'ulc  Av.un^  oxidized  to  (COOH) 
whuh  oocapies  the  posuion  ol'  the  sul>siituiing  gwup.     This  con- 


OXIDATION   AND   REDUCTION  31 

sequently   affords   a   method   of  distinguishing   between   isomeric 
derivatives.     Thus  the  three  xylenes, 


^«^*\CH    1:2>  l:3andl  :4, 


are  isomeric  with  ethyl  benzene,  C^Hg .  C^H.^;  on  oxidation,  1  :  2- 
xylene  gives  phthalic  acid, 

p  „  /COOH  ,  .  2 

the  meta  isomer  gives  the  corresponding  1  :  3  di-carboxylic  acid, 
and  the  para,  1  :  4  di-carboxylic  or  terephthalic  acid ;  on  the  other 
hand,  ethyl  benzene  gives  benzoic  acid  CgH^ .  COOH.  Of  the 
three  di-carboxylic  acids  mentioned  above,  only  the  ortho  gives  an 
anhydride, 

C  H  /'C^\o 

this  being  due  to  the  proximity  of  the  two  reacting  groups. 

Similar  peculiarities  to  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  generally  taken 
as  a  proof  that  they  occupy  adjacent  positions  (i.  e.  ortho)  in  the 
nucleus. 

The  reduction  of  benzene  is  much  more  difficult  than  that  of 
the  unsaturated  open-chain  hydrocarbons.  Benzene  itself,  heated 
to  a  high  temperature  with  hydriodic  acid,  gives  hexamethylene, 

.CHg— CHgv 

CH/  >CH,. 

\CH2— CH/ 

Salicylic  acid  reduced  by  sodium  in  amyl  alcohol  solution  gives 
«-pimelic  acid, 

COOH  COOH 

I  I 

CH      C.OH  CH.         COOH 

II  I  -     I  I 

CH        CH  CHa         CH, 

\CH^  ^Ch/     ' 

Such  a  breakdown  of  the  benzene  nucleus,  as  in  this  latter 
case,  resulting  in  the  final   substance  possessing  the  same  carbon 


32     ALIPHATIC  AND  AROMATIC  HYDROCARBONS 

content  as  the  original,  is,  relatively  speaking,  extremely  rare. 
Powerful  oxidizing  agents,  o£  course,  effect  complete  decomposition, 
the  invariable  rule  in  carbonaceous  compounds ;  but  in  those  cases 
where  the  nucleus  itself  is  attacked,  the  resulting  derivative  has 
generally  a  less  carbon  content  than  that  of  the  benzene  derivative 
experimented  upon. 


General  Methods  used  in  the  Preparation  of  the 
Hydrocarbons. 

Since  the  hydrocarbons  are  the  parent  substances  of  all  other 
organic  bodies,  their  syntheses  are  of  especial  interest,  and  although 
the  methods  that  may  be  used  for  their  preparation  are  many,  the 
following  are  the  more  important.  A  few,  such  as  acetylene,  can 
be  obtained  by  the  direct  union  of  their  elements,  but  the  majority 
are  formed  by  the  union  of  simpler  hydrocarbon  nuclei. 

I.  Hydrocarbons  of  the  FarafiBlu  and  Benzene  series  can  be 
obtained  by  heating  a  mixture  of  the  sodium  salt  of  the  acid  with 
caustic  soda. 

CH3;C00Na  +  NaOjH  =  Na.COg  +  CH^ 

Sodic  acetate.  Methane. 

CgH^iCOONa  +  NaOiH  =  NaaCOg  +  CgHg 

Sodium  benzoate.  Benzene. 


2.  The  Wiirtz  synthesis  consists  in  acting  upon  the  iodo  or 
bromo  derivatives  of  the  hydrocarbons,  in  etherial  solution,  with 
metallic  sodium 

C,H  JI  +  Na,  + 1  C,H.  =  2NaI  +  C,H, .  C,H 


'2'"^ 5:^  ^■^""'2 


2xj.g  —  ^^^cA.  -r  ^2"5  •  ^2^-^5 


Ethyl  iodide.  w-Butane. 

As  a  rule,  the  iodine  derivatives  react  best,  and  the  reaction  pro- 
ceeds better  with  primary  halogen  derivatives  (i.  e.  those  containing 
the.  CHgX  group)  than  with  secondary  (:  CHX),  and  seldom  with 
tertiary  (:  C— X). 

Mixtures  of  halogen  derivatives  may  also  be  employed,  i.  e. 

CH. .  CH,;I  +  Na,  +  liCH, .  CH, .  CH, .  CH 


.2:-   .    -^"g 


w-Iodo-butane. 

2NaI  +  CH3.CH2.CH2.CH2.CH2.CH3 

«-Hexane. 


SYNTHESIS  OF  HYDROCARBONS       33 

Fittig  further  showed  that  a  similar  reaction  could  be  employed 
for  the  preparation  of  Benzene  homologues. 

CeHgiBr  +  Naa  +  IjCaHs  =  NaBr  +  NaT  +  CgHg .  CgH^ 

Brom-benzene.  Ethyl -benzene. 

CsHglBr  +  Nag  +  BriCeHg  =  2NaBr  +  CgH, .  CgHg 

Diphenyl. 

It   may  also   be   employed   for    the   preparation   of    Ethylene 
derivatives, 

CHg :  CH  .  CHgjI  +  Na  +  IjCHg  =  CH2 :  CH  .  CHg .  CH3  +  2NaI 

Allyl  iodide.  a-Butylene. 

CH^iCH.CH^jI  +  Na  +  IiCHg.CHrCH^  = 

2NaI  +  CH2 :  CH.CH^ .  CH^ .  CH  :  CR^ 

Diallyl. 

Acetylene  can  also  be  obtained  by  acting  on  chloroform  with 
sodium,  or  more  conveniently  on  bromof  orm  with  finely  divided  silver. 

CH 


CH:Cl,  +  6Na  +  Cl,:CH  =  6NaCl+  „ 


Jh 


The  reaction  has  been  further  extended  to  the  preparation  of 
closed-ring  hydrocarbons,  termed  the  CyclQ-parafi5.nSy  which  will  not 
be  further  described,  owing  to  the  fact  that  they  are  of  relatively 
slight  importance  as  regards  the  questions  to  be  discussed  in  this 
work.     Two  examples  may  be  given. 


<CH2:Br  yCHg 

-fNa.  =  2NaBr+CH2<  | 
CHjBr  ^CH^ 

Trimethylene  or 
Cyclo-propane. 

CH2 .  CH2 .  CH^iBr  CH, .  CH, .  CH^ 

+  Na2  =  2NaBr+  |     "  ^     | 

H^.CH^.CH^iBr  CH^.CH^.CHa 

Hexamethylene  or 

Cyclo-hexane  or 

Hexahydro-benzene. 


i 


The  Wiirtz  synthesis  is  consequently  of  very  wide  applicability, 
but  is  of  the  greatest  importance  in  the  preparation  of  the  higher 
members  of  the  saturated  hydrocarbons.  As  regards  the  formation 
of  benzene  homologues,  it  has  been  largely  replaced  by  the  Friedel 


34    ALIPHATIC  AND  AROMATIC  HYDROCARBONS 

and  Crafts'  method,  which  will  be  described  later.  Further,  it  will 
be  seen  that  this  synthetic  process  constitutes  an  excellent  means 
of  determining  the  constitution  of  the  hydrocarbons. 

3.  Unsaturated  hydrocarbons  of  the  ethylene  and  acetylene  series, 
as  well  as  benzene  homologues  containing  unsaturated  carbon 
systems  substituted  in  the  nucleus,  can  readily  be  obtained  by  the 
action  of  an  alcoholic  solution  of  potash  on  the  corresponding  brom- 
derivative. 


Ethylene. 


CH^jH: 


CHgiBr* 


CH^ 


iOH:  =  KBr+H20  + 

CH^ 

Ethylbromide. 

Phenyl-ethylene. 

CgHgCHBr.CHa  +  KOH  =  CgH^CH  :  CHg  +  KBr  +  H^O 

Brom-etliylbenzene.  Styrol, 

or  for  acetylene  and  its  derivatives : 

Acetylene. 

CH^Br  CH 

I  +2K0H  =  2KBr  +  2H20+  ||| 

CH^Br  CH 

Ethylene  dibromide. 

JDi-phenyl-acetylene. 

C6H,CHBr.CHBrC,H5  +  2KOH  =  2KBr  +  2H,0 

Stilbene  bromide. 

+   CgHgC    i    C.CgHg 

Tolan. 

The  reaction  with  alcoholic  potash  is  of  great  value  for  the 
preparation,  not  only  of  such  types  of  hydrocarbons  as  those  men- 
tioned, but  also  for  unsaturated  derivatives  of  the  most  varied 
nature. 

As  regards  the  preparation  of  ethylene,  the  removal  of  the 
elements  of  hydrobromic  acid,  or  generally  of  the  halogen  hydrides, 
is  often  very  similar  to  that  of  the  elements  of  water.  This  hydro- 
carbon can  be  easily  obtained  by  the  dehydration  of  ethyl  alcohol 
by  means  of  sulphuric  acid. 

fit   :  CH2 

I    ^     II      +H,0 

oh;         cHo 


CH^ 


CH^: 


SYNTHESIS  OF  ALIPHATIC  DERIVATIVES        35 

This  method  is  usually  adopted  for  its  preparation,  and,  generally 
speakings  is  the  most  convenient  for  the  formation  of  all  hydro- 
carbons of  this  series. 


Outline  of  the  Methods  employed  in  the  Synthesis 
OF  Derivatives  of  the  Aliphatic  Hydrocarbons. 

Theoretically  the  hydrocarbons  may  be  looked  upon  as  the  start- 
ing-point for  the  preparation  of  organic  substances.  Practically, 
however,  this  only  applies  to  the  aromatic  series  and  not  to  the 
aliphatic.  In  this  latter,  the  hydrocarbons  themselves  are,  from 
a  synthetic  point  of  view,  of  little  or  no  value.  The  great  stability 
of  the  paraffins,  or,  in  other  words,  their  slight  reactivity,  has  already 
been  alluded  to ;  they  are  attacked  by  the  halogens  with  the  forma- 
tion of  the  corresponding  halogen  derivatives,  and  these  are  very 
reactive  and  of  the  greatest  value  in  synthetic  work.  But  the 
difficulty  of  limiting  such  a  reaction,  that  is,  of  converting  say 
methane,  CH^,  into  monochlor  methane,  CH3CI,  and  not  at  the  same 
time  into  CHgClg  or  CHCI3  or  CCl^,  together  with  certain  practical 
objections,  renders  this  operation  by  no  means  an  easy  one  to  carry 
out.  The  halogen  derivatives  are  much  more  readily  obtained  from 
the  alcohols,  and  consequently  it  is  this  class  of  aliphatic  substances 
which  is  of  importance  in  synthetic  work.  Methyl  and  ethyl  alcohols 
are  readily  obtained  in  quantity,  the  former  by  the  dry  distillation 
of  wood,  and  the  latter  by  the  fermentation  of  sugar.  Among  the 
products  of  the  first  process  is  acetic  acid,  which  may  further  be 
prepared  by  the  oxidation  of  ethyl  alcohol,  and  from  this  oxidation 
product  of  the  hydrocarbons  another  large  and  important  series  of 
derivatives  can  be  obtained. 

When  the  alcohols  are  acted  upon  by  the  halogen  acids,  they 
easily  give  their  corresponding  halogen  derivatives,  thus  ethyl 
alcohol  gives  either  ethyl  chloride,  bromide,  or  iodide,  and  of  these 
three  the  first  is  the  most  and  the  last  the  least  stable,  or  in  other 
words,  ethyl  iodide  is  more  reactive  than  the  bromide,  and  the 
bromide  more  reactive  than  the  chloride.  This  variation  in  stability 
is  exactly  what  might  have  been  expected,  since  hydrochloric  acid, 
HCl,  is  more  stable  than  hydrobromic,  HBr,  and  this  more  so  than 
hydriodic  acid,  and  the  organic  derivatives  mentioned  may  be 
looked  upon  as  the  organic  salts  of  these  acids. 

In  the  following  examples  ethyl  alcohol  or  ethyl  iodide  or  bromide 

D  2, 


36    DERIVATIVES  OF  ALIPHATIC  HYDROCARBONS 

will  be  taken  as  illustrations  of  the  value  of  such  derivatives  in 
synthetic  aliphatic  chemistry. 

A.  Syntheses  of  Aliphatic  Derivatives  &om  the  Alcohols  or 

Acetic  Acid. 

i.   On   oxidation    alcohols    containing    a    primary   group,   i.  e. 
- — CHg.  OH  pass  to  aldehydes  and  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  phosphorus  tri-  or  penta-chloride 
gives  acetyl  chloride. 

CH3.COOH+PCI5  =  HCI  +  POCI3  +  CH3CO.CI. 

The  resulting  substance  is  extremely  reactive,  and  is  used  for  the 
purpose  of  introducing  the  acetyl  group  (CH3CO)'  into  a  large 
number  of  bodies,  e.  g. 


CH3CO;Cli  +  C2H50:Hi   =  HCI  +  CH3CO.OC2H5 

Ethylacetate. 


CH3COiCli  +  C2H5NH;H;   =   HCl  +  CHgCO.NHC.H 


Ethylamine.  Ethylacetamide. 

CH3COPi  +  C6H5NH:Hj  =   HCl  +  C^H^NH.  COCH3 

Aniline.  Acetanilide  or  Antifebrin. 

iii.  Calcium  acetate  distilled  with  calcium  formate  gives  acet- 
aldehyde. 

(CH3COO)2Ca  +  (H.COO)2Ca  =  2CH3.  CHO  +  2CaC03 

iv.  Calcium  acetate  distilled  alone,  or  with  the  calcium  salts  of 
other  organic  acids  except  formic,  gives  rise  to  the  group  of  bodies 
called  ketones,  substances  used  in  the  preparation  of  the  sulphonals. 

CH, 

I 
(CH3COO)2Ca  =  CaC03  +  C0 

CH3 

Dimethyl  ketone 
or  acetone. 


SYNTHESIS  OF  ALIPHATIC  DERIVATIVES         37 

CH3 

or        (CH3COO),Ca  +  (C2H5.COO)2Ca  =  2CaC03  +  CO 

Calcium  propionate.  | 

Methyl- ethyl 
ketone. 

V.  Chloral  and  chloroform  are  both  obtained  from  ethyl  alcohol, 

although  the  latter  may  also  be  formed  from  acetone,  a  substance 

obtained  in   considerable   quantity   in  the  destructive  distillation 

of  wood. 

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

i.  Ethyl  iodide  treated  with  silver  hydrate  or  dilute  aqueous 
potash  passes  over  to  ethyl  alcohol. 

CgHsilj  +  jAgvOH  =  CgHgOH  +  Agl 

ii.  Acted  upon  by  potassium  cyanide,  ethyl  nitrile  results. 

C2H5iIi  +  jKiCN  =  C2H5CN  +  KI 

This  reaction  is  of  considerable  importance,  since  by  means  of  it 
the  length  of  the  carbon  chain  can  be  increased,  moreover  the  result- 
ing substance  is  capable  of  undergoing  several  important  changes. 
On  saponification,  i.  e.  treatment  with  dilute  potash  or  acids,  the 
nitriles  absorb  water  and  become  acids. 

C2H6CN  +  2H2O  =   C2H5COOH  +  NH3 

Propionic  acid. 

That  is,  starting  with  ethyl  iodide,  CgH^I,  a  substance  containing 
two  carbon  atoms,  propionic  acid,  containing  three,  is  obtained. 
On  reduction,  the  nitriles  become  amines,  thus 

C,H5CN  +  2H,  =  C,H,CH,NH,. 

Now  one  of  the  general  properties  of  primary  amines,  or  those 
containing  the  — CHgNHg  group,  is  their  decomposition  by  nitrous 
acid  with  the  formation  of  alcohols,  e.  g. 

C2H5.CH,.NH2  +  HN02  =  C2H5.CH2OH  +  H2O  +  N2. 

Consequently,  starting  with  ethyl  alcohol,  the  next  higher  member 
of  the  series,  propylic  alcohol,  and  so  on,  may  be  synthesized  by  such 
reactions. 


38   DERIVATIVES  OF  ALIPHATIC  HYDROCARBONS 

iii.  Acted  upon  by  ammonia  in  alcoholic  solution,  ethyl  iodide 
gives  rise  to  a  mixture  of  the  substituted  ammonias. 

CgHjL  +  i  HiNH^  =  HI  +  C2H5NH2 

Ethylamine. 

C^H^Ji  +  iHiNHCgHs  =  HI  +  (C2H5)2NH 

Diethylamine. 

C,H,;l(+:HiN(C,H,),  =  HI  +  (C,H,)3N 

Triethylamine. 

and  (C,H,)3N  +  C,H,I  =  (C,H,),N.I 

Tetraethyl-ammonium-iodide. 

iv.  Ethyl  iodide  readily  acts  on  finely  divided  zinc  or  magnesium, 
forming  the  metallo-organic  derivatives.  These  are  a  particularly 
reactive  group  of  substances,  and  may  be  employed  in  a  variety  of 
syntheses.  The  magnesium  derivatives  have,  for  the  last  six  years, 
replaced  the  spontaneously  inflammable  zinc  compounds. 

With  ethyl  iodide  the  following  reaction  takes  place  in  etherial 
solution : — 

C,H,I  +  Mg  =  Mg/c,H, 

and  the  resulting  compound  may  be  employed  for  many  syntheses, 
for  example,  for  those  of  the  secondary  and  tertiary  alcohols. 

Magnesium  ethyl  iodide  reacts  with  aldehydes  such  as  acetalde- 
hyde,  CH3CHO,  and  ketones,  such  as  acetone,  CH3 .  CO.CH3, 
according  to  the  following  reaction : — 

CH3 .  COH  +  Mg<I  ^H^  =  CH3 .  CH<gMgI 

CH3 
and  CHj.CO.CHa  +  Mgl.CjHs  =  C^^^^^ 

CH3 

and  the  resulting  compounds  are  decomposed  by  water  and  dilute 
acids  yielding  secondary  alcohols  from  the  aldehyde,  and  tertiary 
from  the  ketones. 

1.    CH3CH<0^^I  +  H,0  =  CH3.CH<OH^  +  Mg4jj 

Methyl-ethyl-carbinol. 


SYNTHESIS  OF  ALIPHATIC  DERIVATIVES        39 

CHg  ClHg 

CH5  CH3 

Dimethyl-ethyl-carbinol. 
They  can  also  be  employed  for  the  synthesis  of  saturated  and 
unsaturated   hydrocarbons,   ethers,  ketones,  aldehydes,  carboxylic 
acids,  phenols,  thiophenols,  &c. 

V.  Symmetrical  derivatives  of  ethane  are  usually  prepared  from 
ethylene  dibromide 

CH^Br 

I 
CHgBr 

a  substance  which  can  be  easily  obtained  by  passing  ethylene 

CH, 

li 

into  bromine.     This  unsaturated  hydrocarbon   results  from  the 
dehydration  of  ethyl  alcohol  by  means  of  sulphuric  acid. 


CH^jH   j 

CH2 

Br 

->ll 

+ 

1 

CHjOHi 

CH2 

Br 

CHaBr 


CHgBr 


The  bromide  obtained  by  this  reaction  undergoes  the  same 
general  reactions  as  those  previously  described,  e.  g. 

CHaBr   ^  ^„  CH^OH   ^  .,  ^.       COOH 
I      2        AgOH    I      2  Oxidation     1 

CHgBr     "^     CH2OH        "^        COOH 

Glycol.  Oxalic  acid. 

CHoBr  ^^^,    CHgCN    ^        .^    ^.       CH^.COOH 
j      2        e:CN      I     2  Saponification      .      ^ 

CHgBr     "^    CHgCN  "^  CHg.COOH 

Succinic  acid. 

The  various  synthetic  reactions  which  can  be  carried  out  by  means 
of  acetoacetic  ester  or  malonic  ester  will  be  found  described  in  any 
textbook,  but  sufficient  examples  have  been  given  to  show  clearly 
that  it  is  not  the  paraffins  themselves  but  their  more  reactive 
oxidation  products  or  halogen  derivatives  which  are  employed  in 
the  preparation  of  members  of  the  aliphatic  series. 


40    DERIVATIVES  OF  AROMATIC  HYDROCARBONS 
Outline  of  Methods  employed  in  the  Syntheses  of 

DERIVATIVES    OF   ArOMATIC    HYDROCARBONS. 

The  readiness  with  which  the  aromatic  hydrocarbons  take  part 
in  the  most  varied  reactions  sharply  distinguishes  them  from  the 
other  group,  and  their  reactivity  is  such  that  they  constitute  the 
practical  foundation  for  the  syntheses  of  the  aromatic  derivatives. 
The  rapid  and  brilliant  development  of  the  chemistry  of  this  group 
is  largely  due  to  the  fact  that  the  parent  hydrocarbons  are  easily 
accessible  in  large  amounts.  They  are  present  in  coal-tar,  in  the 
tar  from  peat,  and  in  smaller  quantities  in  that  from  wood  and 
bitumenous  shales,  and  also  in  some  varieties  of  petroleum. 

Acted  upon  by  nitric  or  sulphuric  acids,  the  hydrocarbons  of 
this  series  readily  pass  into  nitro  or  sulphonic  acid  derivatives,  and 
from  these,  but  more  especially  the  first,  a  large  series  of  substances 
can  be  formed. 

A.  Nitrobenzene,  CgHgNOg,  an  example  of  the  class  of  nitro 
derivatives,  is  formed  quantitatively  by  acting  on  benzene  with  a 
mixture  of  nitric  and  sulphuric  acid. 

CeHsiH  +  OHiNOg  =  CeH^NOg  +  HgO 
By  this  means  one  group  is  very  readily  introduced  into  the  nucleus, 
a  second  with  more  difficulty,  and  up  to  the  present  it  has  not  been 
found  possible  to  introduce  more  than  three.  Now  nitrobenzene 
can  be  easily  reduced  to  aniline,  CgH^NHg,  by  means  of  tin  and 
hydrochloric  acid  or  other  similar  reducing  agents.  This  substance, 
which  is  the  phenyl  derivative  of  ammonia,  lends  itself  particularly 
readily  to  a  most  varied  series  of  synthesis.  On  solution  in  acids 
and  treatment  with  nitrous  acid  at  a  low  temperature  the  diazo 
substances  are  formed,  e.  g. 

CjHjNH^.HCl  +  HNOa  =   CeH^-N^     +211  fi 

Diazobenzene  chloride,  produced  in  this  reaction,  is  an  explosive 
body,  but  its  isolation  is  unnecessary  since  the  following  reactions 
are  all  carried  out  in  solution. 

i.  On  boiling  with  strong  alcohol  the  hydrocarbons  result. 

CeHg.Ng.Cl  +  CgHgOH  =  CgHg  +  Ng+HCl+CHaCHO 

ii.  Acted  upon  by  cuprous  bromide,  chloride,  or  iodide,  the  cor- 
responding halogen  derivatives  are  formed. 

C^H^.N^.d    -*    CeH.Cl  +  N^ 


SYNTHESIS  OF  AROMATIC  DERIVATIVES  41 

iii.  On  boiling-  with  water  the  diazo  group  is  replaced  by 
hydroxyl. 

CeH,.N2.Cl  +  H,0  =  CeH^OH  +  HCl  +  N^ 

Phenol, 
iv.    If   the   diazo   salt  is  acted  upon  by  a  solution  of   copper 
sulphate  mixed  with  potassium  cyanide,  the  nitriles  are  formed. 
C,H5.N,.CN    -*    C,H,CN  +  N3 
Benzonitrile. 
V.    On  reduction  phenyl  hydrazine  is  formed.     This  substance 
is  one  of  the  most  reactive  among  the  aromatic  derivatives,  and  will 
be  described  later. 

C6H5.N2.CI  +  4H  =  CeHgNH-NHg.HCl 

Phenylhydrazine  hydrochloride, 
vi.  Acted  upon  by  aniline,  the  diazoamido  derivatives  result. 

CgHg .  N :  N.lCi  +  HiNHCgHg  =  C.U, .  N  :  N.NHCgHs  +  HCl 

Diazoamido-benzene. 
The  resulting  substance  on  standing  in  presence  of  an  acid  under- 
goes intramolecular  change  and  becomes  />-amidoazo-benzene,  the 
simplest  representative  of  the  azo  dyes. 

C,H, .  N  :  N.NHCeH^      ->      C,H, .  N  :  N-<^        ^-NH, 

jp-amidoazo-benzene. 

B.  The  ease  with  which  the  sulphonic  acids  are  produced  dis- 
tinguishes the  aromatic  hydrocarbons  from  the  aliphatic.  These 
substances  are  readily  obtained  by  heating  the  former  with  concen- 
trated or  fuming  sulphuric ;  it  has  not  been  found  possible  by  this 
means  to  introduce  more  than  three  of  these  sulpho  groups. 

CgHsjH  +  OHj.SOgOH  =  CeHgSOgOH  +  Hp 

Benzene  sulphonic  acid. 

The  resulting  derivatives  or  their  sodium  salts  possess  a  high 
degree  of  solubility  in  water,  and  consequently  the  introduction  of 
the  sulpho  group  is  of  the  greatest  value  when  such  a  property  is 
desirable,  as,  for  instance,  in  many  of  the  organic  dyes. 

The  two  following  reactions  are  characteristic  of  the  sulphonic 
acids. 

i.  When  fused  with  potash,  phenols  are  formed,  a  reaction  used 
in  the  technical  preparation  of  resorcinol  and  other  phenols. 

CeHglSOgOK  +  KiOH  =  C6H5OH  +  K2SO3 


42    DERIVATIVES  OF  AROMATIC  HYDROCARBONS 

ii.  Distilled  with  potassium  cyanide  the  nitriles  are  formed. 
CgHsiSO^OK  +  KiCN  =  C.H^CN  +  KgSOg 

C.  The  third  method  used  for  the  preparation  of  the  aromatic 
derivatives  depends  upon  the  characteristic  behaviour  of  the  benzene 
homologues  on  oxidation.  Toluene,  CgHgCHg,  for  instance,  gives 
benzoic  acid,  CgHgCOOH,  and,  generally  speaking,  on  oxidation  the 
side-chains  are  replaced  by  carboxyl  groups,  whilst  the  nucleus 
remains  untouched.  As  previously  mentioned,  many  of  the  homo- 
logues are  found  in  coal-tar,  or  may  be  synthesized  by  the  reactions 
described ;  the  most  important  of  these  syntheses  was  originated  by 
MM.  Eriedel  and  Crafts.  "When  the  alkyl  derivatives  of  the  aliphatic 
hydrocarbons,  preferably  the  chlorides,  are  dissolved  in  benzene  and 
treated  with  aluminium  chloride,  hydrochloric  acid  is  evolved  and 
the  aliphatic  radical  is  linked  on  to  the  benzene  nucleus,  e.  g. 

(i)  CHgiCiTHiCgHs  =  HC1  + CgHgCHg 

or  6CH3CI  +  CgHg  =  6HC1  +  Cg(CH3)6 

Hexamethyl  benzene, 
or        (ii)  CHpg  +  SHiCgHs  =  3HCl  +  CH(CgH5)3 

Triphenyl  methane, 
or      (iii)  CgHg .  CHgfCl  +  ifflCgHg  =  HCl  +  CgH^ .  CHg .  C^Hg 

Diphenyl  methane. 

A  similar  reaction  also  takes  place  between  benzoyl  chloride  and 
benzene  with  the  formation  of  diphenyl  ketone. 

(iv)  C6H5CO:cr+ HiCgHg  =  HCl  +  CgHg.CO.CgHg 

Diphenyl  ketone  or 
Benzophenone. 

and  between  carbonyl  chloride  and  benzene  with  formation  of 
benzoyl  chloride. 

(v)  CgHjHTCliCOCl  =  CgHgCOCl  +  HCl 

The  reaction  is  of  very  considerable  importance,  but  will  only  take 
place  provided  the  chlorine  atom  is  attached  to  aliphatic  residues  or 
in  the  side-chain  of  a  benzene  derivative,  such,  for  instance,  as  (iii) 
or  (iv)  above.  Phenyl  chloride,  CgHgCl,  for  example,  cannot  replace 
methyl  chloride  in  reaction  (i).  The  part  played  by  aluminium 
chloride  probably  consists  in  the  formation  of  double  compounds  such 
as  CgHgAlgClg,  which  with  methyl  chloride,  for  instance,  regenerate 
AlgClg  and  give  toluene,  CgHg .  CH3.     But  besides  bringing  about 


TYPES  OF  AROMATIC  DERIVATIVES  43 

synthesis  of  this  type,  aluminium  chloride  can  also,  under  suitable 
conditions,  cause  the  breakdown  of  the  benzene  homologue  into 
benzene ;  thus  if  hexamethyl  benzene,  Cg(CH3)g,is  treated  with  this 
reagent  and  a  current  of  hydrochloric  acid  conducted  through  the 
liquid  the  methyl  groups  are  broken  off  as  methyl  chloride,  and 
CgH(CH3)5,  then  0^112(0113)4,  &c.,  and  finally  benzene  itself  results. 
The  oxidation  of  toluene  gives  rise  to  benzoic  acid,  OgH^OOOH, 
and  when  this  substance  is  acted  upon  by  phosphorus  pentachloride, 
benzoyl  chloride,  OgHgOOOl,  is  formed.  The  reactivity  of  this 
substance  may  be  compared  to  that  of  acetyl  chloride,  previously 
described,  and  it  is  employed  for  very  similar  purposes,  that  is,  to 
introduce  the  benzoyl  group  (OgH^OO)'  into  a  variety  of  com- 
poundsj  e.  g. 

(i)  OgHgNHiHi  +  OgHgCOiCJ:  =  HOI  +  OgH5NH(OOOgH5) 

Benzanilide. 

(ii)  CeH,N(CH3);H:  +  C,H,COiCl;  =  HCl  +  CeH^N/gg^^jj^ 

Methyl-benzanilide. 
(iii)  OgHsOiHi  +  OgHsOOlCij  =  HOl  +  OgHgOOOOgHg 

Phenyl-benzoate. 

The  benzene  derivatives  can  belong  to  two  distinct  types,  firstly, 
those  in  which  the  hydrogen  of  the  benzene  nucleus  is  substituted. 
These  are  obtained  by  the  general  methods  described,  and  show  the 
properties  of  the  true  aromatic  derivatives.  The  second  class  is 
produced  by  the  substitution  of  the  hydrogen  atom  or  atoms  in  the 
side-chain,  that  is,  in  the  aliphatic  portion  of  the  molecule;  these 
are  obtained  by  similar  methods  to  those  described  in  the  preparation 
of  the  paraffin  derivatives,  and,  like  these,  have  corresponding  pro- 
perties. If  toluene  is  taken  as  an  example;  when  chlorinated  at 
a  high  temperature  benzyl  chloride,  OgH^OHgOl,  is  obtained,  but  if 
this  process  takes  place  in  the  cold,  chlortoluene 

n  XT  //CJH3 

^6^4\C1 

results.  These  two  substances  are  of  course  isomeric,  but  the  first 
shows  the  properties  of  the  aliphatic  halogen  derivatives,  the  second 
those  of  the  aromatic. 

Benzyl  chloride  gives  the  following  reactions  : — 

i.  With  silver  hydrate  it  gives  the  corresponding  alcohol, 

OeHsOHap  +  AgfOH  =  0gH50H2OH  + AgOl 

Benzyl  alcohol. 


44    DERIVATIVES  OF  AROMATIC  HYDROCARBONS 

and  the  alcohol  behaves  on  oxidation  in  a  precisely  similar  manner 
to  ethyl  alcohol, 

CgHgCHgOH    -»     CgHgCHO    -^    CgH^COOH 

Benzaldehyde.  Benzoic  acid. 

ii.  With  potassium  cyanide  benzyl  cyanide  is  formed. 

CgHgCHgiCi  +  KjCN  =  KCN  +  CgHsCH^CN 

This  nitrile  further  behaves  like  ethyl  nitrile,  and  on  saponifica- 
tion gives  the  corresponding  acid,  phenyl  acetic,  CgH5CH2 .  COOH, 
and  on  reduction  the  amine  CgHgCHg.CHgNHg  • 

iii.  On  treatment  with  ammonia  or  primary  and  secondary 
amines  the  corresponding  substituted  amines  result. 


CeHgCHgiCl-f  HiNHg  =  CgHgCHgNH^  +  HCl 
or        CeHsCH^jCl  +  HiNHCeHs  =  CgHgCHgNHCeHs  +  HCl. 

Now  none  of  the  above  reactions  take  place  with  chlortoluene, 


When  the  chlorine  atom,  or,  generally  speaking,  the  halogen, 
is  attached  directly  to  the  nucleus  it  is  so  tightly  held  that  the  re- 
actions which  are  employed  in  the  formation  of  derivatives  of  the 
open-chain  hydrocarbons  are  no  longer  available  for  the  preparation 
of  the  corresponding  benzene  derivatives.  Chlortoluene  on  oxidation 
gives  chlorobenzoic  acid 

p    TT    /CI 

and  this  substance  can  pass  through  a  number  of  changes,  in  all  of 
which  the  chlorine  atom  remains  attached  to  the  nucleus.  It  is  only 
when  the  so-called  negative  characteristics  of  the  benzene  ring  have 
been  depressed,  as,  for  instance,  by  the  introduction  of  nitro  groups, 
that  the  reactivity  of  the  chlorine  atom  appears.  So  much  so  may 
this  be  the  case  that  in  picryl  chloride,  CgHg  (N02)3C1,  for  instance, 
where  there  is  an  accumulation  of  three  such  groups,  the  chlorine 
shows  much  about  the  same  power  of  taking  part  in  reactions  as  the 
very  reactive  benzoyl  chloride  previously  alluded  to. 


PHYSIOLOGICAL  CHARACTERISTICS  45 


B.    GENERAL    PHYSIOLOGICAL     CHARACTERISTICS 
OF    THE    HYDROCARBONS. 

The  aliphatic  hydrocarbons  are  on  the  whole  less  active  physio- 
logically than  those  of  the  aromatic  series.  The  lower  members  of 
the  marsh-gas  series  produce  sleep,  and,  if  inhaled,  eventually  cause 
death  by  asphyxia.  The  toxic  properties  of  this  series  increase  as 
the  carbon  atoms  become  more  numerous.  Hexane  is  actively  in- 
toxicant, producing  a  long  stage  of  excitement,  followed  by  deep 
anaesthesia.  Octane,  which  is  contained  in  the  commercial  ligroine 
and  in  crude  petroleum,  produces  a  similar  anaesthesia ;  in  addition, 
there  is  a  tendency  to  vomiting  (Yersmann).  The  unsaturated 
hydrocarbons,  ethylene,  propylene,  and  butylene  have  very  similar 
action ;  amylene  has  properties  resembling  those  of  chloroform,  but 
is  not  so  safe.  Acetylene  (one  per  cent,  in  air)  produces  narcosis 
with  failure  of  heart  and  respiration.  Lauder  Brunton  has  pointed 
out  that  the  characteristic  action  of  these  aliphatic  hydrocarbons 
is  on  the  nerve  centres,  tending  to  produce  at  first  excitement 
and  then  narcosis ;  they  act  on  the  sensory  side  ;  the  aromatic 
hydrocarbons,  on  the  other  hand,  act  mainly  on  the  motor  side,  pro- 
ducing convulsions  and  paralysis.^  Benzene  gives  rise  to  slight 
paresis  of  the  voluntary  muscles,  but  its  principal  action  is  on  the 
higher  cerebral  centres,  producing  lethargy  and  somnolence. 
Later,  a  kind  of  '  intention  tremor '  occurs  in  the  voluntary  muscles. 
Diphenyl,  CgHg .  CgHg,  however,  is  practically  inert,  and  this  remark- 
able diminution  in  physiological  activity  extends  to  many  of  its 
compounds. 

Naphthalene,  which  is  less  toxic  than  benzene,  slows  the  respira- 
tion ;  small  doses  raise  the  blood  pressure,  whereas  large  doses  depress 
it.  It  decreases  nitrogenous  metabolism,  and  has  an  antipyretic 
action ;  it  has  more  narcotic  action  than  phenol. 

The  hetero-cyclic  compounds  pyrrol,  furfurane,  and  thiophene  to 
a  certain  extent  resemble  benzene  in  their  physiological  action. 
CH=CHv 
Pyrrol    \  >NH     is  more  toxic  than 

CH=CH'^ 

/CH-CH\ 
Pyridine     CH  N     and 

\CH=CH/ 

^  The  solid  or  liquid  nonvolatile  hydrocarbons  are  without  physiological 
action,  and  pass  through  the  body  unaltered.  Hence  the  uselessness  of 
petroleum  emulsion  as  a  food-stuff  or  as  a  drug. 


46  PHYSIOLOGICAL  CHARACTERISTICS 

Piperidine     CH2<^pTT^~rH  /-^^   ^^^  more  so  than  pyridine. 

The  physiological  reaction  of  these  reduced  derivatives  decreases 
with  the  size  of  the  chain,  thus  pyrollidine 

CHg — CH^v 
I  >NH 

CHg — CHg 

is  less  active  than  piperidine. 

The  various  substitution  products  of  the  hydrocarbons  will  be 
dealt  with  in  the  subsequent  chapters,  but  some  general  remarks  on 
alkyl  groups,  as  they  affect  physiological  action,  may  conveniently 
be  made  here. 

i.  The  physiological  action  of  an  aliphatic  carbon  system  is 
generally  increased  by  the  entrance  of  alkyl  groups ;  this  is  also 
observed  in  the  aromatic  series  when  the  magnitude  of  the  side- 
chain  is  increased  by  the  addition  of  such  groups.  But  with  the 
increase  in  molecular  weight  there  generally  follows  a  decrease  in 
solubility,  volatility,  &c.,  and  consequently  there  comes  a  period  in 
an  homologous  series  when  physiological  reactivity  begins  to  decrease 
owing  to  lessened  absorption  by  the  organism.  This  is  illustrated 
in  the  case  of  the  simple  alcohols,  where  the  lower  members  show 
increasing  reactivity  as  the  series  is  ascended,  whereas  the  higher 
members  are  quite  inert  substances. 

ii.  In  the  cyclic  compounds  the  replacement  of  the  hydrogen 
atoms  of  the  ring  by  alkyl  groups  causes  a  considerable  change  in 
physiological  action,  not  always,  however,  in  the  same  direction. 
In  the  case  of  benzene,  toluene,  xylene  and  mesitylene  the  effect  of 
increasing  the  number  of  methyl  groups  is  to  cause  a  diminution  of 
activity,  and  to  some  extent  a  qualitative  modification. 

In  aniline  and  thiophene,  on  the  other  hand,  considerably  increased 
toxicity  results  from  substituting  the  hydrogen  of  the  nucleus  by 
alkyl  groups ;  in  phenol  the  antiseptic  power  is  increased,  whilst 
the  toxic  action  is  diminished  by  such  substitution,  as  in 

1  :  3-Cresol .  CeH4<(^][j[ 

iii.  In  the  pyridine  homologues  the  intensity  of  the  action  is  in- 
creased by  the  entrance  of  alkyl  groups.  Pyridine  has  the  least  physio- 
logical action ;  picoline  (methyl  pyridine)  is  stronger,  dimethyl 
pyridine  more  so,  whereas  collidine  (trimethyl  pyridine)  is  about 
six  times,  and  parvuline  (tetramethyl  pyridine)  nearly  eight  times  as 


OF  THE  HYDROCARBONS  47 

powerful  as  the  parent  substance.  The  entrance  of  the  alkyl  group 
does  not  lead  to  a  change  in  the  degree  of  their  activity  as  drugs, 
but  alters  their  specific  effect  so  that  the  physiological  reaction  of  the 
resulting  derivatives  resembles  that  of  the  natural  alkaloids. 

iv.  The  replacement  of  the  hydroxyl  hydrogen  atom  in  the 
alcohols  is  followed  by  a  very  considerable  rise  in  volatility  and  an 
increase  of  stability  towards  oxidizing  agents.  The  hypnotic  ethyl 
alcohol,  CgHgOH,  for  example,  passes  to  the  anaesthetic  substance 
ether,  CgH^.O.CgHg.  The  inert  glycerol  becomes  the  narcotic 
glycerin-ether 

CH2— O— CHo 


i 


I 
H  — O— CH 

I  I 

CH2— O— CH, 


In  the  aromatic  series  the  antiseptic  phenol,  CgH^OH  becomes  the 
inert  phenetol,  CgHgOCgH^.     In  pyrocatechin 

CeHi^oH^'^ 

the  replacement  of  one  or  both  of  the  phenolic  hydrogen  atoms 
results  in  substances  of  less  toxic  nature.  But  on  the  other  hand 
a  similar  replacement  in  the  case  of  resorcin 

CeH,(OH),  1  :3  giving  1:3  CeH,<(°g}j3 

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

^e^^XNHg 

a  decrease  in  toxicity  follows  the  replacement  of  the  phenolic 
hydrogen  by  either  the  methyl  or  ethyl  radical. 

V.  If  the  hydrogen  atoms  in  ammonia  are  successively  replaced 
by  alkyl  groups,  the  resulting  primary,  secondary,  and  tertiary 
amines  show  diminishing  physiological  reaction,  the  special  convul- 
sant  effect  of  ammonia  being  lost.  But  as  the  tertiary  amines  pass 
over  to  the  ammonium  compounds  a  great  increase  in  toxicity 
occurs,  and  they  approach  in  their  action  many  of  the  alkaloids. 

When  the  hydrogen  atoms  of  the  NHg  group  in  aniline  are 
replaced  by  alkyl  groups  the  physiological  action  of  the  resulting 
substances  corresponds  to  that  of  the  aliphatic  amines,  and  the  ccn- 
vulsant  action  is  depressed.    But,  on  the  other  hand,  as  previously 


48  PHYSIOLOGICAL  CHARACTERISTICS 

remarked,  the  introduction  of  alkyls  into  the  nucleus  o£  aniline 
increases  its  convulsant  action. 

The  narcotic  amides  of  the  aromatic  series,  such  as  benzamide, 
CgHgCONHg,  and  salicylamide, 

^6H4\cONH2  ^  •  ^ 

lose  this  action  on  the  replacement  of  the  amido  hydrogen  atoms,  and 
the  resulting  substances  in  large  doses  are  convulsants,  like  ammonia 
and  strychnine. 

vi.  The  imido  hydrogens  in  xanthine  may  be  substituted  by 
methyl,  and  the  resulting  compounds,  mono-,  di-,  and  tri-methyl- 
xanthine  show  a  physiological  reactivity  which  varies  considerably 
from  that  of  the  parent  substance.  The  most  striking  difference  is 
in  the  action  on  the  cardiac  muscle,  which  develops  in  proportion  to 
the  number  of  methyl  groups. 

vii.  It  is  of  course  only  to  be  expected  that  in  those  cases 
where  the  replacement  of  a  hydrogen  atom  by  alkyl  groups  entirely 
alters  the  chemical  nature  of  the  resulting  substance,  that  a  corre- 
sponding change  in  physiological  characteristics  will  appear.  For 
example,  the  replacement  of  the  carboxylic  hydrogen  of  the  organic 
acids  leads  to  the  production  of  bodies  entirely  without  acid  pro- 
perties (esters),  and  with  altered  physiological  action;  thus  the 
toxic  oxalic  acid  gives  rise  to  the  narcotic  diethyl  oxalate.  Similarly 
salicylic  acid  gives  the  less  toxic  methyl  ester  (oil  of  wintergreen). 
The  change  produced  in  the  acidic  or  toxic  substance  phenol  on  con- 
version into  its  inert  ethers  has  been  previously  mentioned.  On  the 
other  hand,  physiological  activity,  which  had  been  hindered  by  the 
presence  of  the  carboxyl  radical,  may  again  be  brought  out  by 
the  replacement  of  the  hydrogen  atom,  as  is  seen  in  the  case  of 
cocaine.  Somewhat  similar  is  the  alteration  produced  in  the 
chemically  reactive  imido  derivatives  by  substitution  of  the 
hydrogen  atom,  resulting  in  the  formation  of  more  stable  sub- 
stances. This  may  cause  the  appearance  of  physiological  properties 
which  are  absent  in  the  parent  substance ;  thus  l-phenyl-3-methyl 
pyrazolon  (p.  204),  containing  an  NH  group,  is  entirely  wanting 
in  the  characteristic  antipyretic  properties  of  antipyrine,  which 
contains  an  N.CH3  group;  or  it  may  result  in  a  decrease  of 
toxicity,  as  in  case  of  1-hydroxy-tetra-hydro  quinoline;  this  sub- 
stance (or  its  methyl  ester)  possesses  marked  antipyretic  properties, 
but  is  a  protoplasmic  poison,  and  hence  cannot  be  used  as  a  drug. 


OF  THE  HYDROCARBONS 


49 


Fischer  and  Filehne  ascribed  the  toxic  secondary  effects  to  the 
presence  of  the  reactive  imido  group,  and  they  found,  as  expected, 
that  on  converting  this  into  l-hydroxy-tetrahydro-«-ethylquinoline, 
and  so  increasing  the  stability,  they  obtained  a  derivative  with  far 
less  toxic  action,  introduced  into  pharmacy  in  1883  under  the  name 
of  Kairine, 


CH2 
/V^CH. 


I      NH 
OH 

1-Hydroxy-tetrahydro- 
quinoline. 


CH. 


/\/\ 


W 


CH. 


/CH, 


OH 


C2H5 


1-Hydroxy-tetrahydro- 
n-ethylquinoline  {kairine). 


Differences  between  the  Methyl  and  Ethyl  Groups. 

The  ethyl  group  appears  to  have  a  certain  affinity  for  the  central 
nervous  system,  as  many  substances  containing  this  radical  have 
pronounced  hypnotic  properties  which  are  entirely  wanting  in  the 
corresponding  methyl  derivatives.  This  is  strikingly  shown  in  the 
group  of  sulphones,  whose  hypnotic  properties  appear  to  be  solely 
determined  by  the  presence  of  the  ethyl  group,  since  the  methyl 
derivatives  are  quite  inert.  1 : 2-amidophenol  has  no  hypnotic 
properties,  but  when  the  hydrogen  atom  of  either  the  hydroxyl  or  the 
amido  group  is  replaced  by  methyl,  derivatives  with  slight  narcotic 
power  result,  thus 


and 


^6^4<(nh.ch,^  •  ^ 


P     XT     /^OCHg 

^6^^\N(CH3)2 


have  slight  narcotic  properties,  but  the  triethyl  derivative  on  the 
other  hand 

C  H  /^^2^5 
^e*l*\N(C,H,), 

has  pronounced  action.  In  this  connexion  it  is  interesting  to  note 
Ehrlich  and  Michaelis^s  observation  that  certain  dyes  containing  an 
amido  group  in  which  both  hydrogen  atoms  have  been  replaced  by 
ethyl,  thus 


50  PHYSIOLOGICAL   CHARACTERISTICS 

are  capable  of  staining  nerve  structure,  whereas  the  corresponding 
dimethyl  compounds 

"^\CH3 
do  not  possess  this  property.     It  has  been  observed  that  dulcin 

P     XT     /^OCgHg 

^6^4\NH.CONH2 

has  an  extremely  sweet  taste,  whereas  the  corresponding  methyl 
derivative  is  entirely  wanting  in  this  property. 

XJnsatnrated  Substances. 

An  important  factor  in  the  physiological  action  of  organic  sub- 
stances is  the  presence  in  the  molecule  of  unsaturated  or  doubly 
unsaturated  carbon  systems.  The  apparently  low  valency  shown 
by  carbon  in  various  series  of  compounds  has  previously  been 
discussed,  and  the  difference  in  the  significance  of  the  double  bond 
in  open  and  closed  chain  derivatives  described  (pp.  26,  28). 

Generally  speaking,  open-chain  derivatives  containing  unsaturated 
carbon  atoms  are  more  toxic  than  the  corresponding  saturated  bodies. 
Thus  allyl  alcohol,  CHg :  CH.CHgOH,  is  fifty  times  more  toxic  than 
^-propyl  alcohol,  CH3  .  CHg.  CHgOH.  Acrolein,  CHrCH.COH, 
and  croton-aldehyde,  CH3 .  CH  :  CH.COH,  are  more  toxic  than  the 
corresponding  saturated  aldehydes. 

On  the  other  hand,  allylamine,  CHg :  CH.CHgNHg,  is  without 
physiological  action,  but  vinylamine,  CHg.  CH  :  CHNHg,  is  very 
toxic.  Generally  speaking,  the  group  (C :  CH.NHg)''  appears 
to  be  especially  active  in  this  respect. 

With  these  examples  may  be  compared  safrol 

/CH2 .  CH  :  CH2  1 

the  most  toxic  of  all  the  etherial  oils,  and  the  much  less  poisonous 
isosafrol 

/CH.-CH.CHg  1 

The  doubly  unsaturated  di-iodo-acetylene,  CI  J  CI,  is  stated  to 
be  one  of  the  most  toxic  bodies  known. 


UNSATURATED   SUBSTANCES  51 

Choline 

(CH3)3:N<gg^-CH.OH 

is  but  slightly  toxic,  whereas  its  dehydration  product  neurine 
(CH3)3:N<g5  =  CH, 

is  extremely  toxic,  and  this  characteristic  is  still  more  pronounced 
in  the  doubly  unsaturated  compound 

On  the  other  hand,  allyl-trimethyl  ammonium  hydrate 
(CH3)3!N<CH,.CH:CH, 

a  homologue  o£  neurine,  is  only  slightly  toxic.  This  substance  is 
a  derivative  of  the  physiologically  inactive  allyl-amine 

H^N.CHg.CHiCHg. 

NujQerous  other  instances  occur,  but  need  not  be  quoted.  Sufficient 
examples  have  been  given  to  show  that  though  as  a  rule  the  un- 
saturated compounds  are  more  toxic  than  the  saturated,  yet  this  is 
not  invariably  the  case.  To  the  exceptions  already  mentioned 
may  be  added  the  inert  cinnamic,  CgHgCH ;  CH.COOH,  and 
aconitic  acids 

CH.COOH 

I.COOH 


Hg.COOH. 

It  is  however  highly  probable  that  in  both  these  cases  the  presence 
of  the  carboxyl  group  has  been  sufficient  to  depress  physiological 
reactivity. 

Isomerism. 

The  structural  arrangement  of  the  atoms  in  the  molecules  of 
isomeric  bodies  plays  such  an  important  part  in  their  physiological 
action,  and  is  described  in  such  detail  throughout  this  work,  that 
only  a  few  points  will  be  mentioned  here. 

As  typical  of  the  interdependence  of  physiological  action  and 
molecular  structure  among  the  aliphatic  series  such  compounds  as 

E  2 


52  PHYSIOLOGICAL   CHARACTERISTICS 

the  primary  and  secondary  alcohols  may  be  compared.  Here  the 
isomeric  secondary  have  greater  narcotic  and  toxic  characteristics 
than  the  primary  alcohols.  The  differing  toxicity  of  allylamine 
and  its  isomer  vinylamine  has  already  been  mentioned.  In  the 
aromatic  series  the  isomeric  ortho,  meta,  and  para  substitution 
products  often  vary  considerably  in  their  therapeutic  or  toxic 
capacity,  but  there  is  no  general  rule  as  to  which  of  the  three  will 
be  more  and  which  least  active. 

Bokorny  found  that  1 : 4  compounds  were  generally  more  toxic 
for  the  lower  plants  and  animals,  thus 

1 : 4-nitrophenol,   CgH4<^-vTQ  ,      1 : 4-nitrotoluene,  ^e^i^^nu^  y 

1  r4-bromtoluene,  CgH^Z-n    ^ 

are  all  more  toxic  than  their  isomeric  1 : 2  or  1 : 3  derivatives.  On 
the  other  hand,  1 : 2-nitrobenzaldehyde  is  more  toxic  than  the  1 : 4 
derivative,  and  salicylic  acid 

^6^4\COOH  ^  -^ 

is  the  only  one  of  the  three  isomeric  oxybenzoic  acids  which  is 
therapeutically  active. 

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

•06  gm.  in  the  case  of  1 :  2  CeHy^^,  -1  gm.  with  1 : 4  C6H4<^q^, 

and  in  the  case  of  resorcin,  1 :  3'  CgH^<^QTT,  1*0  gm. 

The  three  isomeric  amido-toluenes  showed  very  similar  physio- 
logical action.  Injected  into  the  jugular  vein  of  a  dog  the  follow- 
ing amounts  represented  the  toxic  doses  per  kilo  weight : 

1 :2-toluidine,  CgH^/™^  =  .gos  gm., 

1:3=  -125  gm.,     1  :  4  =  -10  gm. 
Occasionally,  unlike  the  preceding  case  of  the  toluidines,  there  is 
an  alteration  in  specific  action  dependent  on  the  relative  position  of 
the  substituting  groups  in  benzene.     The  three  cresols 

are  an  example  of  this.  They  stimulate  the  vagus  centre,  causing 
heart  failure,  and  also  act  peripherally  on  the  nerve  endings  and 


ISOMERISM  53 

are  vasomotor  poisons.  All  three  cresols  act  equally  on  tlie  peri- 
pheral nerve  endings,  but  ortho-  and  para-eresol,  especially  the  forme  r, 
are  much  more  powerful  vagus  stimulants,  whereas  ortho-  and  meta- 
cresol  act  more  markedly  on  the  vasomotor  system.  Numerous 
other  instances  will  be  found  in  the  subse€[uent  chapters. 

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  capable  of  breaking  down  dextro- 
rotatory  tartaric  acid,  they  had  no  action  on  the  laevo-voia>toTy 
acid.  Emil  Fischer  described  many  sugars  which  react  towards 
ferments  in  a  similar  manner,  one  optical  isomer  being  attacked  by 
an  enzyme,  the  other  not.  He  thought  that  the  explanation  of 
the  phenomenon  ^probably  lies  in  the  structure  of  the  enzyme 
.  .  .  for  doubtless  the  enzymes  are  optically  active  and  consequently 
possess  an  asymmetric  structure  ^  This  led  to  the  view  that  the 
molecular  configuration  of  the  enzyme  and  of  the  fermentable  sugar 
are  complementary,  so  that  '  the  one  may  be  said  to  fit  the  other  as 
a  key  fits  a  lock '.  But  it  must  be  remembered  that  we  are  in  a  state 
of  profound  ignorance  as  to  the  configuration  of  the  enzymes.  As 
regards  the  animal  organism,  Brion  found  that  laevo-  and  meso- 
tartaric  acids  were  oxidized  to  an  almost  equal  extent  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  sufiicient  to  indicate  that  there  is  an 
unquestionable  interdependence  between  the  stereochemical  con- 
figuration of  the  molecule  and  physiological  action. 

That  the  configuration  of  the  molecule  has  an  influence  upon  the 
sense  of  taste  is  illustrated  in  the  case  of  ^e^^ro-asparagine,  which 
is  sweet,  whilst  the  laevo-voidutorj  modification  is  not;  dextro- 
glutaminic  acid  is  sweet,  whereas  the  laevo  acid  is  tasteless. 

The  influence  of  configuration  on  the  toxicity  of  isomers  has  been 
observed  in  some  cases,  thus  the  local  anaesthetic  action  of  dextro- 
cocaine  on  the  tongue  is  stronger  and  sets  in  more  rapidly  than  that 
of  the  laevo  modification,  although  the  effect  is  not  so  lasting. 
Mayor  states  that  /«^i?o-nicotine  is  twice  as  toxic  as  the  dextro 
derivative.  Atropine  has  a  more  powerful  stimulating  action 
on  the  spinal  centres  than  hyoscyamine.  But  one  of  the 
most  interesting  observations  was  that  made  originally  by  Crum 


54  PHYSIOLOGICAL   CHARACTERISTICS 

Brown  and  Eraser,  who  showed  that  many  alkaloids,  when  acted 
upon  by  alkyl  iodides,  gained  a  curare-like  action  (paralysis  of  ends 
of  motor  nerves  of  muscles)  without  losing  their  individual  charac- 
teristics. In  all  these  cases  the  conversion  of  nitrogen  from  the  tri- 
to  the  quinquevalent  condition  occurs  (see  pp.  2  and  20).  That  this 
new  characteristic  is  dependent  on  the  space  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  characteristics  on  being  converted,  by  the 
action  of  alkyl  iodides,  into  salts  of  the  phosphonium,  arsonium, 
and  stibonium  bases,  which  possess  strong  curare-like  action. 
This  clearly  indicates  that  the  change  in  physiological  action 
is  not  merely  dependent  on  the  passage  of  trivalent  atoms  to 
quinquevalent,  but  rather  on  the  change  in  stereochemical  configura- 
tion ; — on  a  change  from  a  plane  to  a  tridimensional  arrangement  of 
the  atoms.  This  is  still  more  clearly  shown  in  Curci  and  KunkeFs 
observation  that  the  change  of  the  inert  dimethyl-sulphide,  (CH3)2S, 
to  trimethyl-sulphine-hydroxide,  (CH3)3S  .OH,  also  results  in  the 
appearance  of  the  curare  character.  Now,  in  the  case  of  sulphur, 
a  divalent  element,  the  configuration  of  the  sulphide  must  be  plane, 
but  with  the  appearance  of  two  extra  valencies  in  the  second 
derivative  the  configuration  changes  to  the  solid,  as  shown  by  the 
fact  that  such  substances  may  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.  Cystein  derivatives.  Processes  of  Oxidation  and  Reduction. 

The  investigations  which  have  been  made  on  the  changes  produced 
in  organic  substances  by  their  passage  through  the  organism  have 
led  to  the  generalization  that  such  changes  always  tend  to  the  forma- 
tion of  less  toxic  bodies.  From  the  point  of  view  of  the  synthetic 
preparation  of  drugs,  it  is  most  important  to  observe  that  these 
modifications  generally  lead  to  the  production  of  derivatives  with 
more  acidic  properties — or,  in  other  words,  the  introduction  of 
acid  groups  tends  to  lower  the  toxicity  of  an  organic  substance. 

If  the  course  of  a  drug  through  the  system  is  followed,  it  is  found 
that  no  reaction  takes  place  in  the  mouth,  but  in  the  stomach  the 
hydrochloric  acid  present  may  cause  an  increase  in  the  solubility  of 
basic  substances,  and  also  cause  the  breakdown  of  such  derivatives 
as  the  anilides  into  aromatic  amines  and  acids,  and  the  absorption 
of  basic  substances  will  consequently  start  from  this  region.  The 
pepsin  present  has  little  if  any  action.  In  the  intestines  the  alkali 
present  may  cause  an  increase  in  the  solubility  of  organic  acids,  or 
the  decomposition  of  their  metallic  salts,  but  a  much  more  impor- 
tant action  is  that  of  the  pancreatic  juice  and  bile  which  bring 
about  the  saponification,  not  only  of  the  fats,  but  of  such  esters 
as  salol,  giving  phenol  and  salicylic  acid.  Nencki  was  the  first 
to  realize  the  value  of  this  fact,  and  his  so-called  '  salol  principle ', 
founded  upon  this,  will  be  described  in  detail  later  on. 

But  it  is  in  the  tissues  or  blood  that  the  more  profound  changes 
of  oxidation  and  reduction  take  place.  Besides  these  two  main 
alterations,  various  synthetic  processes  are  also  carried  out,  all  tend- 
ing, as  previously  mentioned,  towards  a  reduction  in  the  toxicity 


56  METABOLIC  PROCESSES 

of  the  original  substance.  The  latter  processes  will  be  described 
first,  though  it  generally  happens  that  they  follow  those  of  oxidation 
or  reduction  before  the  final  elimination  of  the  substance  in  the  urine. 


A.     SYNTHETIC  PROCESSES. 

Of  these  the  most  important  that  take  place  are  with  sulphuric 
and  glycuronic  acids  or  amidoacetic  acid.  Next  in  importance  is 
the  formation  of  urea  derivatives  and  sulphocyanides,  and,  less 
seldom  met  with,  the  introduction  of  acetyl  or  methyl  groups  and 
the  production  of  cystein  derivatives.  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 
typical  examples  of  each  will  be  given. 

It  does  not  often  happen  that  a  particular  substance  is  excreted 
entirely  in  any  one  form,  as  for  instance  as  a  sulphonic  ester ;  it 
may  be  found  chiefly  in  that  form,  but  also  partially  as  a  glycuronic 
acid  derivative,  or  even  partially  unchanged,  this  may  depend  on 
dosage  or  other  factors  quite  unknown.  Consequently,  in  the 
various  reactions  discussed,  it  must  be  understood  that  the  elimina- 
tion of  the  substance  in  question  chiefly  occurs  by  means  of  the 
synthesis  under  which  it  is  described,  but  that  at  the  same  time 
others  may  take  place,  which,  judging  from  the  relative  amounts 
in  the  urine,  are  of  lesser  importance. 

Z.     Snl|>honic  Esters. 

The  sulphuric  acid  required  for  the  production  of  these  sub- 
stances must  be  formed  by  the  oxidation  of  albuminous  bodies 
containing  sulphur,  and  in  this  connexion  it  may  be  mentioned 
that  etherial  hydrogen  sulphates  in  the  urine  are  generally  increased 
in  conditions  interfering  with  the  normal  performance  of  the 
hepatic  functions.  The  etherial  sulphates  normally  found  in  the 
urine  represent  only  one-thirteenth  of  the  total  sulphates.  Though 
partially  derived  from  tissues,  the  greater  part  are  due  to  protein 
decomposition  in  the  intestine,  hence  their  increase  in  conditions 
of  intestinal  putrefaction  and  obstruction.  When  decomposition 
of  protein  matter  within  the  organism  is  taking  place  on  a  large 
scale,  as  e.g.  in  foul  empyemata,  or  gangrene  of  internal  organs, 
a  similar  increase  in  etherial  sulphates  in  the  urine  is  noted. 

Indican  (indoxyl  potassium  sulphate),  which  occurs  in  small 
amounts  in  normal  urine,  is  increased  under  like  conditions. 


FORMATION   OF   SULPHONIC   ESTERS  57 

Aromatic  substances  containing  hydroxy!,  (OH),  in  tlie  nucleus 
are  generally  found  combined  with  sulphuric  acid  as  alkali  salts  in 
the  urine,  synthesis  with  glycuronic  acid  also  taking  place. 

Phenol,  CgHg .  OH,  for  instance  (besides  undergoing  further 
oxidation  to  dioxybenzenes),  is  found  as  phenyl  sulphuric  acid, 
the  following  reaction  taking  place  : — 

CgHgOiH  +  OHISO2 .  OH  =  H^O  +  C,U, .  O.SO^ .  OH. 

The  free  acid  itself  is  unknown,  since  on  liberation  from  its 
salts  by  strong  hydrochloric  acid,  it  immediately  breaks  down  into 
sulphuric  acid  and  phenol.  Such  substances,  although  stable  in 
aqueous  or  alkaline  solutions,  ar^  readily  decomposed  by  mineral 
acids. 

The  toxicity  of  phenol  has  consequently  been  diminished  by  this 
synthesis,  and  it  was  only  to  be  expected  that  sodium  or  potassium 
phenyl  sulphate  should  be  non-toxic  substances.  Further  than  this 
the  introduction  of  the  sulphonic  acid  grouping  into  the  ring  itself, 
giving  rise  to  phenol  sulphonic  acid 

^e^^XSOgOH 

produces  a  substance  which  is  equally  innocuous. 

If  the  hydroxyl  derivative  itself  is  non-toxic,  owing  to  the 
presence  of  some  grouping  in  the  ring,  then  it  passes  unchanged 
through  the  organism ;  an  example  of  this  is  homogentisinic  acid 

/OH  1 

CgHg^OH  4 

\CH2.COOH  5 

whereas  the  corresponding  gentisinic  acid, 

/OH         1 
aH,^-OH        4 


\C00H  5 


which  is  toxic,  is  partially  eliminated  as  the  non-toxic  sulphuric 
acid  derivative.     Similarly  the  highly  poisonous  hydroquinone 

^e^^XOH  ^  ''  ^ 

leaves  the  system  in  the  form  of  its  sulphonic  ester. 

Many  of  the  aromatic  ketones  are  oxidized  to  acids  in  the  body, 
but  when  they  contain  a  hydroxyl  group,  and  the  possibility  of 
combination  with  sulphuric  or  glycuronic  acids  appears,  then  these 


Gallacetopbenone   CgHg- 


58  METABOLIC  PROCESSES 

latter  syntheses  take  place  to  the  exclusion  of  the  former.  Aceto- 
phenone,  CgHg .  CO.CH3,  for  instance,  is  oxidized  to  benzoic  acid, 
CeH.COOH,  but 

.OH  1 

Paeonol   CgHgf-CO.CHg  2 

\O.CH3     5 

rOH  1 

OH  2 

OH  3 

ICO.CH3  4 

[OH         1 
and  Resacetophenone    CgHgJOH  3 

(CO.CH3  4 

are  found  in  the  urine  as  their  sulphuric  and  glycuronic  acid 
derivatives. 

The  entrance  of  an  acid  group  into  the  nucleus  of  the  phenols 
causes  the  loss  of  this  power  of  uniting  with  sulphuric  acid,  for 
instance,  salicylic  acid 

p  „  /OR        1 

^6^4\cOOH  2 

and  also  the  1 :4  isomer  (both  much  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 


or  an  amide 


C6H,< 


COO.CH3  2 


OH  1 

2 


^6^4\co.NH<,  2 


these  bodies  regain  their  characteristics  and  are  found  as  sulphuric 
derivatives  (Baumann  and  Herter);  the  introduction  of  more 
hydroxyl  groups  into  the  ring  causes  the  reappearance  of  this 
synthesis,  as  in  the  previously  mentioned  case  of  gentisinic  acid  or 
protocatechuic  acid. 


also  vanillic  acid. 


fCOOH  1 
CgH3  OH        3 

OH        4 


^6^31 


fCOOH  1 
OCH3    3 

OH        4 


FORMATION  OF  GLYCURONIC  DERIVATIVES    59 

and  isovanillic — 

fCOOH 

3 


'6^3  i 


COOH  1 

an  J  OH 


But  veratric  acid 


[oCHg    4 
fCOOH  1 


CgHg^O.CH 


.   3 
O.CH,   4 


passes  througli  the  body  unchanged,  since  it  contains  no  free 
hydroxyl  groups,  and  consequently  cannot  undergo  the  sulphuric 
or  glycuronic  acid  syntheses.  In  this  connexion  it  may  be  pointed 
out  that  a  methoxy  group  (O.CH3)',  replacing  hydrogen  of  the 
benzene  nucleus,  is  much  more  resistant  towards  the  oxidizing 
influences  of  the  body  than  is  a  similarly  situated  methyl  group 
(see  p.  76). 


II.    Glycuronic  Acid  Derivatives. 

Glycuronic  acid,  COH  (CH.0H)4C00H,  may  be  obtained  by  the 
reduction  of  saccharic  acid,  C00H.(CH.0H)4.C00H,  and  is  a 
syrup  which  rapidly  passes  into  its  lactone  on  warming;  nothing 
certain  is  known  of  its  origin  in  the  body. 

Glycuronic  acid  appears  in  the  urine  in  poisoning  by 


Phosphoric  acid. 

Phosphorus. 

Lactic  acid. 

Hydrochloric  acid. 

Strychnine. 

Curare. 

Arsenic. 

Butyl  chloral  hydrate. 

Morphine. 

Prussic  acid. 

Chloroform. 

Turpentine. 


Antipyrin. 

Pyramidon. 

^-naphthol. 

Sandal- wood  oiL 

Chinosol. 

Chloral  hydrate. 

Resorcin. 

Acetanilide. 

Phenetidin. 

Menthol. 

BorneoL 

Camphor. 


It  is  usually  found  in  diabetic  urine,  and  is  thought  by  some  to 
be  a  preliminary  derivative  of  sugar,  the  oxidation  of  which  is  in 
that  disease  carried  so  far  and  no  further. 

In  the  various  syntheses  which  take  place  in  the  animal  organism 
it  is  probable  that  combination  with  grape  sugar  takes  place  first. 


60 


METABOLIC   PROCESSES 


and  then  the  primary  alcohol  group  present  is  oxidized^  with  the 
result  that  glycuronic  acid  derivatives  finally  appear.  As  regards 
the  nature  of  the  resulting  compounds,  they  appear  to  be  (at  all 
events  in  the  case  of  aliphatic  substances),  very  analogous  to  the 
glucosides.  Taking  chloral  as  an  example,  it  is  found  that  it  is 
reduced  in  the  body  and  eliminated  as  urochloralic  acid,  a  synthesis 
which  may  probably  be  represented  by  the  scheme 

1.  CCI3 .  CHO  +  Hg  =  CCI3 .  CH2 .  OH 

Chloral.  Trichlorethyl  alcohol. 


COOH 

I 
CH.OH 


CH.OH 
CH.OH  +  CCl 


COOH 

I 
CH.OH 

I 
CH.OH 

CH.OH 


CHOH   CH2 

CHO     OH 

Glycuronic  acid. 


CH.OH 
I     /OH 


^^\O.CH.,.CCl 


H,0  +  CHOH 


CH^O.CHg.CCl, 

Urochloralic  acid. 


It  appears,  however,  that  a  different  type  of  combination  can  take 
place ;  thus  Y.  Kotake  ^  has  shown  that  rabbits  dosed  with  vanillin 
eliminate  in  the  urine  a  glycuronic  acid  derivative  of  vanillic  acid,  the 
first  reaction  consisting  in  the  oxidation  of  the  aldehyde,  which 


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


GLYCURONIC  ACID  DERIVATIVES  61 

then  condenses  with  glycuronic  acid  without  the  elimination  of 
water, 

1.  fCHO     1  (COOH  1 
C,H3  O.CH33             CeH3  O.CH3    3 

(oh       4  (OH         4 

Vanillin.  Vanillic  acid. 

2.  COOH  COOH 
I                          fCOOH         I 

(CHOH)4  +  C.H3  O.CH3  =  (CHOH), 
I  [oH  I       .OH 

CHO  CH<(3^^jjCC00H 

io.CH. 

Blum  has  shown  that  thymol  behaves  in  a  similar  manner, 

CsH^.CHg.CgHgOH  +  CgHioO^  =  CgH^.CHg.CgHgO.CgH^iO^ 

and  Fenivessy  that  carbostyril  also  unites  with  glycuronic  acid 

without  the  elimination  of  water, 

(C,H,)C3H,N.0H  +  C,HiA  =  (CeH,).C3H,N.0.C,H„0,. 

There  does  not  seem  to  be  any  sharp  line  of  demarcation  drawn 
between  these  two  groups  by  any  of  the  investigators  of  these 
glycuronic  derivatives.  In  but  relatively  few  cases  have  they  been 
isolated  in  a  state  of  purity,  the  statement  usually  met  with  being 
that  such  and  such  a  substance  is  eliminated  conjugated  with 
glycuronic  acid. 

It  is  possible  that  hydroxy  derivatives  of  the  aliphatic  series  which 
combine  with  this  acid  do  so  in  a  similar  manner  to  trichlorethyl- 
alcohol,  i.  e.  form  true  glucosides ;  such  are  bromal  and  butyl 
chloral,  which  are  firstly  reduced  to  the  corresponding  alcohol;  the 
secondary  alcohols  and,  to  a  much  less  extent,  the  primary  (except 
methyl  and  ethyl,  which  are  readily  oxidized),  and  also  alcohols  of  high 
molecular  weight;  some  polyhydric  alcohols, such  as  propylene  glycol, 
but  not  glycerol  ^ ;  many  aliphatic  ketones,  such  as  dichloracetone, 
which  are  firstly  reduced  to  their  secondary  alcohols.  Acetoacetic 
ester  is  firstly  oxidized  to  carbon  dioxide  and  acetone,  and  this 
latter  reduced  to  secondary  propylalcohol ;  it  is  then  eliminated  as 
its  glycuronic  acid  derivative.  Finally  come  tertiary  alcohols,  such 
as  tertiary  butyl,  tertiary  amyl,  and  pinacone. 

On  the  other  hand  some  aromatic  hydroxyl  derivatives  may  form 
addition  products  similar  to  those  produced  with  vanillic  acid  or 

*  Otto  Neubauer,  Chem.  Centr.,  1901,  ii.  314,  from  Arch.  Exp.  Path.  Phamt., 
46,  133-54. 


62  METABOLIC  PROCESSES 

thymol,  but  no  definite  statement  can  be  made,  since  condensation 
with  elimination  of  water  is  stated  to  take  place  in  the  following 
cases.  Lesnik^  found  that  both  a-  and  /3-naphthol  occurred  in 
the  urine  as  such  derivatives 

C,„H,OH  +  CeH,<,0,  =  C,„H,.O.CeH,0,  +  H,0. 
Pellacani  2,  confirmed  by  Bonanni  ^^  found  a  similar  product  in  the 
case  of  borneol  and  menthol, 

C,„H„OH  +  C,HjA  =  C„H„.O.C,HA+H,0 
and 

C.„H„OH  +  C,HiA  =  Cj„H„O.CeHsOe  +  H,0. 

Schmiedeberg  and  Meyer  *  found  that  camphor  was  firstly  oxidized 
to  campherol, 

Ci„H,,0    -*    C,„H,,O.OH 
and  then  eliminated  as  a  condensation  product  with  glycuronic  acid, 

CioH,,O.OH  +  CeH,A  =  C.oH.^O.O.CeH^Oe  +  Hp. 
Other  investigators  have  noticed  reactions  corresponding  to   the 
latter    in    case    of    carvon,   pinene,    phellandrene,   and   sabinene. 
Salkowski  and  Neuberg  have  recently  shown  that  the  synthetical 
phenylglycuronic  acid  melting  at  150°,  and  of  composition 

C,H,O.CeHA 
is  identical  with  the  acid  excreted  in  the  urine  of  a  sheep  dosed 
with  phenol. 

An  interesting  synthesis  is  that  undergone  by  phenetol, 
CgHgOCgHg, 
which  is  firstly  oxidized  and  then  eliminated  with,  glycuronic  acid 
as  the  so-called  chinaethonic  acid, 

CgHgOCgHg    ->    1 ;  4  CqH.^<^q^  jj  +  CgHioO^ 

Another  method  by  means  of  which  the  toxicity  of  a  substance 
is  lowered  consists  in  the  addition  of  water;  Fromm  and  Hilde- 
brandt^  have  shown  that  thujon  is  converted  in  the  body  to 
thujonhydrate  and  then  eliminated  as  a  glycuronic  derivative, 

O.C,oH,6  +  H20  =  O.C,oHi,OH 
and 

O.C,,H,,OH  +  CeH,A  =  O.C,oHi,O.CeHA. 

^  Schmiedeberg,  Arch.,  24,  167. 

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

'  Hoffmeister,  Beitrag  z.  Chem.  Physiol,  1,  304. 

*  Zeit.f.physiol.  Chem.,  3,  422.  ^  Zeit.  f.  phi/siol.  Chem.,  33,  579. 


DERIVATIVES   OF  AMIDOACETIC  ACID         63 

III.    Derivatives  of  Amidoacetic  acid. 

Amidoacetic  acid,  glycocoll  or  glycine  is  the  simplest  amido 
acid,  and  may  be  obtained  synthetically  by  warming  monochlor- 
acetic  acid  with  dry  ammonium  carbonate. 

COOH.CHgiiCiTHJNHg  =  COOH.CH^.NH^  +  HCl 

It  is  soluble  in  water,  possesses  a  sweet  taste,  and  was  shown  by 
Nencki  and  Schultzens^  to  give  rise  to  urea  when  administered  in 
food  (see  p.  74). 

The  fact  that  glycine  and  other  amino  acids  give  rise  to  urea 
if  introduced  with  food  or  intravenously,  and  the  fact  of  their 
appearance  in  the  urine  in  acute  yellow  atrophy  of  the  liver 
(where  urea  elimination  is  decreased  correspondingly),  are  taken 
as  indicating  the  position  of  those  bodies  as  intermediaries  between 
protein  and  urea.  This  may  or  may  not  be  true,  but  if  true,  some 
synthesis  must  precede  the  formation  of  urea,  as  the  amino  acids 
contain  less  N  than  C,  which  is  the  reverse  of  what  occurs  in  urea. 

The  combination  of  glycine  and  benzoic  acid  takes  place  in  the 
kidney  substance,  at  any  rate  partially.  Minced  kidney  substance 
can  effect  this  synthesis,  and  blood  containing  benzoic  acid,  if  passed 
through  the  living  kidney,  is  found  afterwards  to  contain  hippuric 
acid. 

This  typical  synthesis,  the  first  of  its  kind  which  was  discovered, 
is  illustrated  by  benzoic  acid,  which  forms  hippuric  acid, 

COOH  COOH 


CHg.NHjH  +  HOiOC.CgHs  =  H^O  +  CHa— NH.CO.CgHg 

Amidoacetic  acid.  Hippuric  acid. 

A  similar  reaction  takes  place  with  any  benzene  derivative  which, 
if  oxidized  in  the  body,  gives  rise  to  this  acid  or  its  derivatives,  such, 
for  instance,  as  toluene^  ethyl  or  propyl  benzene,  xylene  (firstly 
oxidized  to 


CeH4< 


CH,     ), 


.COOH 

mesitylene   (firstly  oxidized  to  mesitylenic   acid),  /j-nitrotoluene, 
/3-bromtoluene,  and  in  the  case  of  dogs  all  the  nitrobenzaldehydes. 

Salicylicj^-oxybenzoic,  nitrobenzoic,  chlor  and  brombenzoic  acids, 
anisic,  a-  and  /3-naphthoic,  toluic,  mesitylenic  and  cuminic  acids  all 

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


64  METABOLIC    PROCESSES 

form  derivatives  analogous  to  hippuric  acid.  In  this  connexion  it 
may  be  mentioned  that  whereas  phenyl  propionic  acid 

CeH^CHg.CHg.COOH 

is  oxidized  in  the  body  to  benzoic  acid  and  eliminated  as  hippuric 
acid,  phenyl  acetic  acid,  CgH^CHg.  COOH,  forms  phenyl  aceturic 
acid,  CgHgCHg .  CO.NH.CH2COOH ;  but  this  question  will  be 
further  discussed  under  the  general  heading  of  oxidation  processes. 

The  a-carboxylic  acid  of  thiophene,and  the  corresponding  aldehyde 
after  oxidation  in  the  organism,  behave  in  a  similar  manner  to 
benzoic  acid. 

a-methyl  pyridine  is  firstly  oxidized  to  the  a-carboxylic  acid  and 
then  eliminated  as  a  glycocoU  derivative. 

IV.     Urea  Derivatives. 

The  mode  of  formation  of  these  derivatives  is  by  no  means  clear ; 
they  may  be  formed  outside  the  body  by  the  action  of  cyanic 
acid  on  primary  or  secondary  amines. 

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

Cyanic  acid.  Ethyl  urea. 

and  it  may  be  that  a  reaction  somewhat  analagous  to  this  takes 

place  in  the  animal  organism. 

Taurin 

CH2NH2 

I 
CH2 .  SO.OH 

is  eliminated  as  taurocarbamic  acid 

CH2.NH.CO.NH2 
I 
CH2 .  SO2OH 

Amido-benzoic  and  amido-salicylic  acids  similarly  form  urea 
derivatives, 

p  TT  /COOH  /COOH 

^6"4\nH.CO.NH2        and     CgHa^OH 

\NH.CO.NH2. 

Schmiedeberg  noticed  small  quantities  of  ethyl  urea 

C2H5.NH.CO.NH2 

in  the  urine  after  dosing  with  ethylamine  carbonate. 

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


FORMATION  OF  SULPHOCYANIDES  65 

and  others  found  that  the  nitrobenzaldehydes  are  firstly  oxidized  to 
their  corresponding  acids,  then  combine  with  glycocoU  to  nitro- 
hippuric  acids,  and  that  these  latter  substances  then  formed  salts 
with  urea. 

V.     Formation  of  Sulphocyauides. 

Pascheles^  showed  that  some  proteins  containing  easily  split- 
off  sulphur  could  convert  potassium  cyanide  into  sulphocyanide, 
KCNS,  at  the  temperature  of  the  room,  and  it  is  probable  that  the 
formation  in  the  animal  organism  of  sulphocyauides  from  the 
organic  nitriles  may  be  ascribed  to  a  similar  reaction.  With  the 
exception  of  methyl  nitrile,  CHgCN,  the  homologues  of  this  series  are 
very  poisonous,  and  in  their  passage  through  the  body  are  converted 
into  the  much  less  toxic  sulphocyauides.  It  is  interesting  to  note 
that  Nencki^  states  that  the  stomach  under  normal  conditions 
contains  a  minute  amount  of  free  sulphocyanic  acid.  Gscheidlen 
found  it  constantly  in  human  urine,  and  the  potassium  salt  occurs 
normally  in  saliva,  probably  as  an  excretory  product. 

VI.     Introduction  of  the  Acetyl  Radical. 

One  of  the  most  interesting  examples  of  the  introduction  of  an 
acetyl  group  in  the  passage  of  an  organic  substance  through  the 
body  was  observed  by  R.  Cohn  ^,  who  found  that  rabbits  treated 
with  ?;2-nitrobenzaldehyde  converted  this  into  ???-acetylamido- 
benzoic  acid. 

The  first  change  consists  in  the  oxidation  of  the  aldehyde  group 
to  the  acid, 

pxT/COH,^  __   p„/COOH 

The  second,  the  reduction  of  jiitrobenz(;>k)  acid  to  amidobenzoic, 

and  thirdly,  the  synthetic  formation  of  the  acetyl  derivative, 

/COOH     CH3  /COOH 

CeH/        I      =CeH/  +H,0 

\NH;Hi  +  COiOHi  \NH.CO.CH, 


^  Arch.f.  exp.  Pathol,  u.  Fharm.,  34,  281. 

»  Ber.,  28,  1318. 

»  Zeit.  physiol.  Chem.,  18,  133-6. 


66  METABOLIC  PROCESSES 

VII.    Reactions  with  Acetic  Acid. 

Jaff6  and  Colin  ^  found  that  f urfurol,  the  aldehyde  of  f urfuran, 
is  partly  oxidized  in  the  organism  to  the  corresponding  acid,  and 
then  eliminated  as  a  glycocoU  derivative,  but  to  a  smaller  extent  it 
undergoes  condensation  with  acetic  acid  to  furfuracrylic  acid, 
CH— CH  CH— CH 

II  I II         II 

CH     C.CH:0  +  H2;CHCOOH  =  H20  +  CH     C.CH :  CH.COOH 

\/ 
O 

which  is  then  eliminated  as  a  derivative  o£  amidoacetic  acid, 
C4H3O.CH  :  CH.COOH  +  H2N.CH2 .  COOH 

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

VIII.     Introduction  of  the  Methyl  Radical. 

His  2  found  that  pyridine  is  eliminated  in  the  urine  as  methyl- 
pyridyl-ammonium  hydroxide,  and  this  observation  was  confirmed 
by  R.  Cohn  ^  ;  it  is  one  of  the  most  interesting  changes  in  animal 
chemistry. 

CH  CH 

ch/\ch         ch/\ch 


Y 


CH\  JCH     CH 


CH 


N 

CH3  OH 

Hoffmeister  states  that  an  animal  dosed  with  tellurium  or 
tellurium  compounds  eliminates  tellurium  dimethide,  Te  (CH3)2 . 

In  this  connexion  it  is  interesting  to  notice  that  according  to  the 
observations  of  Albanese,  Gottlieb,  Kriiger,  and  Schmidt  the 
methylated  xanthines  are  deprived  of  one  or  more  of  their  methyl 
groups  on  passing  through  the  organism. 

IX.     Formation  of  Cystin  Derivatives. 

Baumann  showed  that  cystin,  one  of  the  primary  dissociation 
products  of  proteins,  found  in  urine  in  cases  of  cystinuria,  is  the 
disulphide  of  cystein,  which  he  formulated 

/NH^ 
CHg.CeCOOH 
\SH 
^  Ber.,  20,  2311.  «  Archiv  exp.  Path,  Pharm.,  22. 

'  Zeit.physiol.  Chem.y  18,  112-30. 


FORMATION   OF   CYSTIN   DERIVATIVES  67 

but  C.  Neuberg-  and  Friedmann  proved  later  that  the  amido  and 
(SH)  groups  were  attached  to  different  carbon  atoms, 

SH.CHg .  CH.NH2COOH. 

When  dogs  are  treated  with  either  chlor-  or  brom-benzene  the  mer- 
capturic  acids  formed  are  derived  from  the  same  cystein  which  is 
found  in  protein- cystin.  In  the  urine  these  compounds  are  com- 
bined with  a  strong  laevo-rotatory^  monobasic  acid,  and  when 
decomposed  with  mineral  acids  give  chlor-  or  brom-phenyl-mercap- 
turic  acid,  substances  of  the  following  constitution : — 

NH.COCH3 

/ \  ' 

X-<^        ^_S.CH— (iH~COOH 

1 : 4  chlor-  or  brom-phenyl-mercapturic  acid. 

These  may  be  synthesized  by  heating  brom-phenyl-cystein  dissolved 
in  benzene  with  acetic  anhydride. 

B.    OXIDATION. 

By  oxidation  is  meant  not  only  the  combination  of  oxygen  with 
a  compound,  but  also  the  splitting  off  of  hydrogen,  or  its  replace- 
ment by  oxygen. 

The  final  oxidation  products  of  carbonaceous  compounds  are 
carbon  dioxide  and  water,  and  if  nitrogen  is  present  this  may 
appear  in  the  free  state ;  the  term  combustion  is  usually  employed 
to  such  a  complete  breakdown. 

The  change  of  food-stuffs  in  the  body  is  very  similar;  carbon 
dioxide  is  the  end  oxidation  product  of  the  carbon,  but  the  nitrogen 
appears  mainly  as  uric  acid  or  urea. 

In  organic  compounds  the  introduction  of  oxygen  is  almost  in- 
variably accompanied  by  an  increase  in  the  velocity  of  reaction, 
and  the  ^ inertia^  of  the  carbon  complex,  previously  mentioned,  is 
largely  diminished,  the  more  so  as  the  accumulation  of  oxygen 
increases. 

When  once  partial  oxidation  of  the  hydrocarbon  has  set  in,  the 
further  replacement  of  hydrogen  by  oxygen  becomes  easier  and 
easier.  Thus  methane,  CH^,  is  only  oxidized  with  considerable 
difficulty.  Methyl  alcohol,  CH3.  OH,  is  readily  oxidized  to  form- 
aldehyde, H.COH,  and  this  passes  even  on  exposure  to  the  air  to 
formic  acid,  H.COOH.  Formaldehyde  abstracts  oxygen  from 
silver  oxide,  formic  acid  from  the  more   stable  mercuric  oxide. 

p  % 


68  OXIDATION  PROCESSES 

Then  in  complex  compounds  containing  oxygen  further  oxidatioi 
always  takes  place  at  the  most  highly  oxidized  place  in  the  mole 
cule,  provided  the  carbon  at  that  point  is  linked  to  hydrogen. 

Thus  ethyl  alcohol,  CHg.CHgOH,  is  oxidized  to  acetaldehyde 
CH3.CHO,  and  this  further  to  acetic  acid,  CHg.  COOH  ;  an( 
/3-oxypropyl  aldehyde,  CH3  .  CHOH.CHg .  CHO,  is  converted  int< 
/S-oxybutyric  acid,  CH3 .  CHOH.CH^.  COOH,  since  the  aldehydi 
group  (CHO)'  is  the  most  highly  oxidized  system  in  the  molecule. 

It  is  a  very  general  rule  that  a  carbon  atom  cannot  be  linked  t( 
more  than  one  hydroxyl  group,  and  when  attempts  are  made  t( 
introduce  more,,  i.  e.  on  further  oxidation,  water  is  split  off,  and  th( 
following  general  reactions  take  place,  depending  upon  the  numbe] 
of  hydrogen  atoms  attached  to  the  oxidized  carbon  : — 

/0;H 
1.         CH2OH  CH<^OH  ^^^ 

I  Oxidized.  |  I 

CHg        O     ->  CH.  =H20+    CH. 

I  I     '  '  \     ' 

CH3  CH3  CH3 

Propyl  alcohol.  Butyric  aldehyde, 

or  0>X  yOH 

C^OiH 


COOH 


chI9h  :.h,o+  ch, 


i 


'2 


H,  ^^3 


Butyric  acid. 
The  aldehydes  are  consequently  the  intermediate,  and  the  organic 
acids  the  final  products  in  the  oxidation  of  alcohols  containing  tht 
primary  group  X— CHgOH.     With  secondary  alcohols,  i.  e.  thos( 
containing  the 

I^CH.OH 

group,  a  similar  reaction  takes  place,  and  on  further  oxidation  the;^ 
yield  ketones, 

2.               CH3  CH3  CH3 

JL  0      l/OiH  I 

CH.OH  _X    C<bH  =  H„0  +  CO 

I                        I     • I 

6H3  CH3  CH3 

Acetone  or 
dimethyl  ketone. 


SELECTIVE  OXIDATION 


With  tertiary  alcohols,  such  as  (0113)3.  C.OH,  ^^^  containing 
hydrogen  linked  on  to  the  already  oxidized  carbon  atom,  further 
oxidation  is  not  so  easy,  and  energetic  reagents  are  necessary, 
when  the  molecule  breaks  down  into  substances  of  smaller  carbon 
content. 


3.  CH3  CHg 

I      .    Oxidation. 


CH3— C.OiH    ->       CH3.CO 


I  Acetone.    fHgO 


[h.coohJ      '<5^2^+^o, 


Although  the  above  may  be  taken  as  a  short  summary  of  the 
effects  of  oxidation  on  aliphatic  substances  (the  aromatic  will  be 
discussed  later),  yet  the  nature  of  the  actual  oxidation  processes 
which  have  been  observed  to  take  place  on  the  passage  of  organic 
substances  through  the  animal  organism  are  of  a  different  order 
from  those  carried  out  in  the  laboratory. 

Such  changes  are  characterized  by  a  striking  selective  oxidizing 
action ;  thus  an  animal  capable  of  completely  breaking  down  many 
hundred  grains  of  sugar  to  its  end  products  in  twenty-four  hours 
is  incapable  of  similarly  treating  say  a  few  grains  of  sodium 
formate,  which  to  the  extent  of  50-70  per  cent,  of  the  dose  taken 
is  eliminated  unchanged  in  the  urine.  Further  than  this,  of  these 
two  changes  the  latter  is  much  more  readily  carried  out  in  the 
laboratory  than  the  former.  Then  dextrose  and  laevulose  are 
completely  decomposed  by  the  body  cells,  but  the  sexvalent 
alcohol  mannite  passes  through  with  very  little  change.  In  this 
case  the  replacement  of  a  — CHgOH  group  by  CHO  or 


i 


HOH  by  0=0 


has  been  sufficient  to  bring  about  complete  oxidation. 

Even  stereochemical  isomerides  are  differently  acted  upon ;  thus, 
in  alcaptonuria,  naturally  occurring  phenylalanin, 

C5H5 .  CH2 .  CHNH2 .  COOH, 

is  almost  quantitatively  oxidized  to  homogentisinic  acid, 

C6H3(OH)2.CH2.COOH, 

whereas  the  racemised  form  is  only  oxidized  to  the  extent  of  50  per 
cent.     Then  m-  and  /-tartaric  acids  are  much  more   completely 


70  METABOLIC  PROCESSES 

broken  down  by  tbe  organism  than  are  ^^a^^ro-tartaric  and  racemic 
acids,  and  this  latter  acid  is  not  decomposed  into  its  optical  isomer- 
ides.  In  this  connexion  it  may  be  mentioned  that  Chabri^  found 
that  /-tartaric  is  more  toxic  than  the  dextro  form,  and  both  of  these 
more  than  racemic  acid ;  for  instance,  the  following  amounts  produce 
the  same  action :  34-26  gms.  Ij  104-24  gms.  d,  and  165-25  gms. 
racemic  acid. 

The  few  examples  given  clearly  show  the  characteristic  selective 
action  of  the  tissues,  oxidizing  some  substances  completely,  reject- 
ing others  with  but  slight  chemical  or  physical  differences. 

Our  ignorance  of  the  manner  in  which  the  actual  process  of 
oxidation  takes  place  is  readily  realized  when  it  is  remembered  that 
no  single  case  is  known  of  the  complete  oxidation  of  an  organic 
substance  in  aqueous  solution  by  the  oxygen  of  the  air.  Nencki 
attempted  to  determine,  without  success,  the  extent  of  the  oxidation 
of  sugar  and  albumen  on  exposure  in  alkaline  solutions  to  the  air 
at  a  temperature  of  36°  C. ;  the  amount  was  extremely  small. 

The  problem  is  further  complicated  by  the  observation  that  in 
some  cases  the  oxidizing  action  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  healthy  man 
could  form  -82  gm.  of  phenol  from  2  gms.  of  benzene,  under  normal 
conditions  this  amount  dropped  to  -33  gm.  if  2  gms.  of  alcohol 
per  kilo,  body  weight  were  simultaneously  administered.  Pfliiger, 
Poehl,  and  others  have  shown  that  under  other  conditions  the 
oxidizing  action  of  the  animal  organism  may  be  increased. 

It  is  not  proposed  to  discuss  the  various  hypotheses  that  have 
been  brought  forward  in  this  connexion.  Traube  assumed  the 
existence  of  oxidizing  enzymes,  afterwards  shown  to  be  present  in 
the  lungs,  kidney,  muscles,  &c.,  by  Schmiedeberg,  Salkowski, 
Jaquet,  &c.,  but  their  action  appears  to  be  very  limited,  quite  in- 
sufficient to  account  for  the  variety  of  known  oxidation  processes, 
although  in  all  probability  they  play  some  part  in  these  changes. 

The  suggestion  that  in  some  way  or  other  the  oxygen  is  activated 
in  the  body  is  difficult  to  follow ;  it  is  more  probable  that,  as  Pfliiger 
has  suggested,  it  is  not  the  oxygen  that  is  activated,  but  that  the 
activity  is  a  function  of  proteins  of  the  living  protoplasm. 

1  PJlug.  Arch.,  31,  319. 


OXIDATION   OF   ALIPHATIC   SUBSTANCES       71 


(a).     OXIDATION   OF   ALIPHATIC    SUBSTANCES. 

Hydrocarbons.  The  oxidation  of  the  hydrocarbons  o£  the  ali- 
phatic series  on  their  passage  through  the  organism  has  not  yet 
been  observed,  and  as  may  be  gathered  from  the  previous  remarks 
is  hardly  to  be  expected.  It  follows  that  if  the  petroleum  emulsions 
have  any  therapeutic  value,  it  cannot  depend  on  any  analogy  to  cod 
liver  oil,  which  is  readily  utilized  by  the  organism,  i.e.  broken  down 
to  its  end  oxidation  products.  In  fact  these  bodies  taken  by  the 
mouth  are  completely  eliminated  in  an  unchanged  condition  in  the 


Primary  alcohols  are  oxidized,  either  completely  or,  in  some  cases, 
to  the  corresponding  acid,  but,  as  might  be  expected,  the  unstable 
intermediate  aldehydes  are  never  found  in  the  body ;  if  produced  at 
all  they  are  but  transitory  products  to  the  higher  stage  of  oxidation. 
Formaldehyde,  a  saturated  solution  of  which  is  termed  formalin^ 
probably  owes  its  remarkable  antiseptic  properties  to  the  ease  with 
which  it  abstracts  oxygen  and  becomes  formic  acid,  a  process 
which  causes  the  breakdown  of  organic  matter. 

Combinations  of  formaldehyde  with  indifferent  organic  bodies, 
such  as  milk  and  sugar  are  free  from  toxic  effects,^  and  on  being  intro- 
duced into  the  animal  system  it  is  found  that  one-quarter  passes 
directly  into  the  urine,  one-tenth  combines  with,  ammonia,  giving 
hexamethylene  tetramine,  but  the  largest  part  is  found  as  formic 
acid. 

On  the  other  hand,  chloral,  CCI3 .  CHO,  and  butyl  chloral, 
CCI3.CH2.  CHO,  are  not  oxidized  to  their  corresponding  acids, 
but  reduced  to  alcohols  and  eliminated,  as  previously  mentioned, 
as  compounds  of  glycuronic  acid. 

The  animal  organism  appears  to  exercise  a  greater  power  of 
oxidizing  ethyl,  propyl,  or  butyl  groups  than  it  possesses  over 
methyl;  thus  methyl  alcohol,  or  its  esters,  and  methylamine  or 
methyl  nitrile,  give  formic  acid,  whereas  ethyl  alcohol  or  ethyl- 
amine  are  completely  broken  down,  and  the  higher  nitriles,  which 
are  much  more  toxic  than  methyl  nitrile,  are  converted  into  sulpho- 
cyanides.  As  regards  the  secondary  alcohols,  Albertoni  has  shown 
that  isopropyl  alcohol,  CHg.  CHOH.CH3,  is  partly  oxidized  to 
acetone,  CH3 .  CO.CH3,  and  partly  unchanged. 

The  tertiary  alcohols,  such  as  amyl  alcohol  or  trimethyl  carbinol, 

1  J.  Jacobsen,  Chem,  Cent.  Blatt.,  8,  693, 1906. 


72  METABOLIC  PROCESSES 

more  difficult  to  oxidize  than  either  primary  or  secondary,  pass 
through  the  body  unchanged.  The  replacement  of  hydrogen  by 
chlorine  causes  an  increase  in  the  stability  of  the  alcohols  towards 
oxidizing  agents;  thus  trichlorethyl  alcohol,  CClg.CHgOH,  and 
trichlorbutyl  alcohol,  CCI3  •  CHg .  CHgOH,  pass  unchanged  through 
the  animal  organism,  and  are  eliminated  as  glycuronic  derivatives. 
A  corresponding  protection  is  noticed  in  the  case  of  the  organic  acids, 
whereas  acetic  acid,  CHg .  COOH,  is  readily  oxidized ;  trichloracetic 
acid  or  trichlorbutyric  acid  are  only  partially  decomposed. 

A  similar  protection  against  the  oxidizing  action  of  the  organism 
is  noticed  in  the  case  of  the  sulphonic  acid  group ;  both  ethyl 
sulphate,^ 


and  sulphoacetic  acid, 


'^\0H 
^^2\coOH 


passing  through  the  body  unchanged. 

As  regards  the  polyhydric  alcohols,  glycerol, 

CHoOH 


CHOH 
,0H 


CH. 


is  readily  oxidized,  but  mannite, 

CHgOH 

(CHOH)^ 

CH2OH 
only  partially,  whereas  the  sugars, 


CH2OH 


CH2OH 


^^____.  .    (CHOH)^ 


(CHOH)^    and      | 
C 

in 


CHO 


CO 

Dextrose.  CHgOH 

Laevulose. 
are  of  course  completely  broken  down. 

^  Salkowski,  Tflug.  Arch.^  5,  357. 


OXIDATION   OF  ALIPHATIC    SUBSTANCES       73 

Passing  to  the  final  oxidation  products  of  the  primary  alcohols, 
i.e.  the  group  of  acids,  their  complete  breakdown  into  carbon- 
dioxide  and  water  is  as  a  rule  effected  with  greater  difficulty  than 
that  of  the  alcohols  or  aldehydes,  yet  in  the  animal  organism  this 
process  takes  place  with  great  ease.  With  the  exception  of  formic 
acid,  the  fatty  acids  are  easily  oxidized,  and  as  their  molecular 
magnitude  increases  and  stearic,  CH3(CH2)i6.  COOH,  palmitic, 
CIIq(C}I.J^^  .  COOH,  and  the  unsaturated  oleic, 

CgH^.  CH  :  CH(CH2)7 .  COOH, 

acids  are  reached,  these  in  the  form  of  their  glycerol  esters  con- 
stitute the  important  group  of  food-stuffs,  the  fats. 

Oxy-acids,  such  as  glycolic  acid,  CHgOH.COOH,  /3-oxybutyric, 
CH3CHOH.CH2.  COOH,i  lactic  acid, 

CH3.CH<(^QQjj 

are  easily  oxidized,  but  in  phosphorus  poisoning  and  in  several 
pathological  conditions  this  latter  acid  appears  in  the  urine.  In 
this  connexion  )S-oxybutyric  acid,  CH3.  CHOH.CHg.  COOH  (and 
its  oxidation  product  acetoacetic  acid,  CHg .  CO.CHg .  COOH),  may 
be  mentioned ;  as  is  well  known  these  occur  in  diabetes. 

Conflicting  statements  are  met  with  as  regards  oxalic  acid  ;  some 
state  that  it  passes  unchanged  into  the  urine,  whilst  Marfori  found 
that  a  considerable  amount  was  fully  oxidized,  and  that  the  same 
process  takes  place  with  sodium  oxalate,  of  which  30  per  cent,  of 
the  amount  taken  reappears  in  the  urine.  Faust  found  that  the 
whole  of  this  acid  injected  into  a  dog  could  be  recovered  from  the 
urine.  Malonic  acid,  CH2(COOH)2,  is  largely  destroyed,  only 
traces  passing  through  unchanged;  tartronic  acid,  CH0H(C00H)2, 
is  completely  broken  down,  and  so  are  succinic, 

CHg.  COOH 


k 


!H2.C00H 

and,  to  a  very  large  extent,  tartaric  acid  (see  p.  70), 

CH.OH.COOH 

CH.OH.COOH 

^  G.  Satta,  Beitr.  Chem.  Physiol.  Path.,  6,  1-26,  1904. 


74  METABOLIC  PROCESSES 

and  malic  acid, 

CH.OH.COOH 

CH2.COOH 

Only  very  small  amounts  of  glutaric  acid, 

p„  /CH2.COOH 
^^2\CH2.COOH 

escape  oxidation. 

Amido  acids  given  in  moderate  amounts  are  completely  broken 
down,  the  nitrogen  appearing  as  urea.  GlycocoU,  CHg .  NHg .  COOH, 
and  leucin,  CH3 .  (CHgjg.CHNHg.  COOH,  even  in  large  amounts, 
never  appear  in  the  urine,  whereas  alanin,  CHg.CHNHg.  COOH, 

aspartic  acid, 

CH.NH^.COOH 


h 


H2.COOH 


and  glutaminic  acid, 

CHNHg.COOH 
.CHo.COOH 


CH^ 


are  partially  oxidized,  and  partially  pass  through  the  organism 
unchanged.^ 

Wohlgemuth  ^  has  found  that  rabbits  fed  with  racemised  tyrosin, 
leucin,  aspartic  acid,  and  glutaminic  acid  oxidized  the  optical 
isomeride  occurring  normally  in  the  body,  whilst  the  other  was 
partially  or  completely  excreted  in  the  urine.  Thus  J-tyrosin  is 
the  form  in  which  this  substance  occurs  normally  in  animals,  and 
when  the  racemised  form  is  given,  d-  is  destroyed  and  I-  found  in 
the  urine. 

The  acid  amides,  with  exception  of  acetamide,  CH3 .  CONHg,  and 

oxamide, 

CONH2 

I 
CONH2 

which  are  but  partially  oxidized,  are  as  completely  broken  down  as 
their  corresponding  acids.  The  nitriles  of  the  acetic  acid  series, 
formed  by  the  dehydration  of  the  corresponding  ammonium 
salt,  e.g. 

CH3.COONH4-2H2O     =      CHgCN, 

*  Stolte,  Hofmeister^s  Beitrdge,  5,  15,  1903. 
2  Ber.,  38,  2064,  1905. 


OXIDATION  OF  AROMATIC   SUBSTANCES        75 

which  are  fairly  readily  converted  back  into  the  acids  by  the  action 
of  dilute  acids  or  alkalis,  e.  g. 

CH3CN  +  2H2O  =  CH3COONH4 

are  not,  with  the  exception  of  the  lowest  member  CH3CN,  decom- 
posed in  this  manner  on  their  passage  through  the  organism,  but, 
as  previously  mentioned,  are  converted  into  sulphocyanides  (see 
p.  65).  Methyl  nitrile,  which  is  the  least  toxic  member  of  the 
group,  is  oxidized  to  formic  acid,  but  with  the  higher  homologues 
no  organic  acid  is  formed. 


(b).    OXIDATION   OF   AROMATIC  SUBSTANCES. 

As  regards  the  members  of  this  series,  the  breakdown  of  the 
benzene  nucleus  itself  is  only  of  the  rarest  occurrence,  the  changes 
which  are  effected  on  the  passage  of  aromatic  substances  through  the 
organism  being  confined  to  alterations  in  the  substituting  groups  or 
replacement  of  hydrogen  atoms  in  the  benzene  ring. 

Phenylalanin,  C^U, .  CH^ .  CH.NHg .  COOH,  tyrosin, 

pxr/OH 

^6^4\oH2 .  CH.NH2 .  COOH 
and  a-amido  cinnamic  acid, 

CgH, .  CH  :  CH<((,Q^jj 

occupy  a  unique  position  among  the  aromatic  derivatives,  since  they 
are  almost  completely  oxidized  in  the  body,  whereas  phenyl  pro- 
pionic, CgHgCHg .  CHg .  COOH,  and  cinnamic  acids, 

CgHgCH  :  CH.COOH, 

are  changed  into  benzoic.  So  far  as  is  known,  only  two  cyclic 
compounds  of  the  benzene  series  occur  in  combination  in  the 
protein  molecule,  viz.  tyrosin  and  phenylalanin,  and  it  is  interest- 
ing to  observe  that  these  are  among  the  very  few  substances 
known  which  are  completely  oxidized  by  the  animal  organism. 

In  this  connexion  it  is  interesting  to  note  that  in  alcaptonuria, 
phenylalanin,  tyrosin,  and  a-phenyl  propionic  acid  give  rise  to 
homogentisinic  acid,^  and  that  the  naturally  occurring  optically 
active  phenylalanin  is  converted  almost  quantitatively,  whereas  the 
racemised  form  is  only  changed  to  the  extent  of  50  per  cent. 

^  Neubauer,  Falta,  Zeit.f.  physiol.  Chem.,  42,  81,  1904. 


76  METABOLIC  PROCESSES 

According  to  Juvalta  ^,  phthalic  acid  and  also  phthalimide,^ 
C,H /COOH  1^3^^^  C,H /CO^NH, 

are  broken  down,  in  the  case  of  the  former  substance  to  the  extent 
of  over  57  per  cent,  of  the  amount  given.  Pribram  ^  states  that 
phthalic  acid  is  excreted  quantitatively  in  the  rabbit. 

Methyl  quinoline  is  stated  by  Rudolf  Cohn  to  be  almost  com- 
pletely oxidized  in  the  body,  and  the  same  author  showed  that  1 : 2- 
nitrobenzaldehyde  to  a  large  extent  underwent  the  same  fate,  and 
that  only  small  amounts  were  oxidized  to  the  corresponding  1  : 2- 
nitrobenzoic  acid. 

Benzene  itself  is  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.  Naphthalene  is  eliminated  as  a 
glycuronic  derivative  in  a  similar  manner  to  the  )3-oxy  derivatives 
(/3-naphthol). 

The  homologous  benzenes  undergo  similar  changes  to  those 
previously  mentioned  (p.  30),  the  side-chains  being  oxidized  and 
replaced  by  COOH.     Thus  toluene,  CgH^CHg ,  gives  benzoic  acid, 

yCH  yCH 

xylene,  CqH.^<^^j^^,  gives  toluic  acid,  C6H4<^^q^jj 

and  mesitylene,  CgH3(C  113)3  1  •  3  :  5,  gives  mesitylenic  acid, 
C6H3(CH3)2COOH.  Ethyl  benzene,  C^R, .  CH2 .  CH3 ,  is  also  oxi- 
dized to  benzoic  acid.  Propyl  benzene,  CgHg.  CHg.  CHg  .  CH3, 
behaves  similarly,  giving  rise  to  the  same  acid,  although  isopropyl 
benzene,  CgHg .  CH  (CH3)2,  is  oxidized  in  the  ring  to  a  phenol-like 
derivative.    This  may  be  compared  with  the  behaviour  of  cymene, 

which  Ziegler  showed  gave  cumic  acid, 

C  H  /^^(^^'i)2  1 . 4 

Now  when  the  hydrocarbon  is  treated  with  powerful  oxidizing 
agents,  such  as  dilute  nitric  acid  or  chromic  acid,  the  propyl  group  is 
first  attacked,  giving 

^  Juvalta,  Zeit.f.  physiol.  Chem.,  13,  26. 
«  Koehne,  Chem.  Centr.,  2,  296,  1894. 
'  Chem.  Centr.,  2,  668,  1904. 


OXIDATION   OF   AROMATIC   SUBSTANCES        111 
P„  /COOH,  ... 

but  when  a  mild  agent,  such  as  caustic  soda  and  oxygen  (air),  is 
employed,  the  methyl  group  is  oxidized. 
1 ;  2-Nitrotoluene, 


is  oxidized  to  the  alcohol 


p    TT    /NOg 

'-6«4\CH20H 


and  eliminated  as  a  glycuronic  acid  derivative. 

Generally  speaking,  such  radicals  as  CHg,  CHg  .  OH,  CHO, 
and  CHg .  NHg,  attached  to  the  benzene  nucleus,  are  oxidized  to 
— COOH  ^  and  eliminated  as  hippuric  acid  (p.  63). 

Phenyl  propionic  acid, 

CgHg.CH^.  CHg.  COOH, 

and  cinnamic  acid,  CH^CH  :  CH.COOH,  are  converted  into  benzoic 
acid,  but  phenyl  acetic  acid,  CgHg .  CHg .  COOH,  gives  phenaceturic 
acid,  CgHgCHg .  CONH.CO.NHg,  and  mandelic  acid,^ 

CeHg.CH^^^QQjj^ 

passes  through  the  organism  unchanged,  whereas  phenylamido 
acetic  acid, 

C,H,.CH<gH^jj  gives  C ^  .  CH<OH^jj 

Now  since  phenyl  propionic  acid  gives  benzoic  acid,  it  cannot  pass 
through  the  stage  of  phenyl  acetic  acid,  and  consequently  Knoop 
considers  that  the  oxidation  of  that  acid  can  only  take  place  in  the 
/3  position.  As  previously  mentioned,  ethyl  benzene,  CgHg .  CHg .  CH3, 
(p.  76)  gives  benzoic  acid,  and  it  is  probable  that  the  CHg  group  is 
attacked  first,  and  not  the  methyl ;  this  is  borne  out  by  the  fact 
that  acetophenone,  CgH^COCHg,  also  gives  benzoic  acid.  Other 
acids  investigated  by  Knoop  containing  more  than  two  carbon  atoms 
in  the  side-chain  did  not  give  benzoic  acid.  An  analogous  oxidation 
of  hydrogen  in  the  ^position  is  seen  in  the  formation  of  )S-oxy- 
butyricacid,  CHg.  CH.OH.CHg.  COOH,  and  the  further  oxidation 
products,  acetoacetic  acid,  CHg.  CO.CHg.  COOH,  and  acetone, 
CHg.  CO.CHg,  in  diabetes. 

^  Knoop,  Hofmetster's  Beitrage,  6,  150,  1904. 
^  Schotten,  Zeit.  f.  phi/siol.  Chem.,  8,  68,  1884. 


78  METABOLIC  PROCESSES 

In  many  cases  oxidation  in  the  nucleus  takes  place  provided  that 
the  hydrogen  in  the  1 : 4  position  to  the  group  already  present  is 
not  itself  substituted.  Thus  aniline,  C^HgNHg,  is  partially  oxidized 
to  1 : 4-amidophenol, 

OH 
.NH. 


K.  Klingenberg  showed  that  diphenyl. 


^6^5 


i 


6^5 

gives  the  sulphuric  ester  of  1 : 4-oxydiphenyl, 

C6H,.0H1:4 

CeHs 

Phenyl  methane  gives  1 : 4-oxyphenyl  methane,  and  a  similar  type 
of  action  is  noticed  with  chlor-,  brom-_,  and  iodo-benzene,  which  gives 
rise  to  cystein  derivatives,  in  which  the  H  atom  in  the  1  : 4  position 
to  the  halogen  atom  has  been  attacked  (see  p.  66).  On  the  other 
hand, 

CgH^NHg  1:4  CgH^Br  1  : 4 

Benzidine,  |  1:4  Dibromdiphenyl,  | 

CgH^NHg  1 : 4  C^H^Br  1 :  4 

are  not  oxidized  by  the  animal  organism.  Nolting,  who  examined 
a  large  number  of  cases,  states  that  the  hydrogen  of  the  benzene 
nucleus  is  only  replaced  by  hydroxyl  (OH)  in  the  para  position  to 
the  substituting  group,  and  should  this  position  be  occupied  such 
a  type  of  oxidation  does  not  take  place. 

From  a  physiological  point  of  view  the  oxidation  of  indol, 

C6H4<^-^jj^CH, 

in  the  organism  is  of  considerable  importance.  When  this  substance 
(which  has  distinct  but  not  very  marked  toxic  properties)  is  formed 
in  the  intestine  as  the  result  of  putrefaction,  or  is  introduced  experi- 
mentally, absorption  rapidly  takes  place ;  and  it  undergoes  oxidation, 
most  probably  in  the  cells  of  the  liver,  to  indoxyl, 

C(OH) 
C,H,/^CH, 
NH 


REDUCTION  79 

which  is  eliminated  as  the  potassium  sulphuric  ester 

C(0.S02QK) 


This  ester  is  known  as  urine  indican,  owing  to  the  fact  that  it  was 
supposed  to  be  identical  with  the  indican  of  plants,  which  is  not  the 
case ;  this  derivative  on  further  oxidation  gives  indigo  blue,  which 
produces  a  characteristic  colour  in  the  urine. 

C(0S020K)  CO  CO 

2CeH,<^CH  +  O2     =  CeH,<^C  :  C<^CeH,  +  KHSO, 

NH  NH        NH 

Indigo  blue. 


C.    REDUCTION. 

The  direct  reduction  of  the  oxidized  derivatives  of  the  aliphatic 
and  aromatic  series,  such  as  alcohols,  acids,  phenols,  ketones,  back 
to  the  hydrocarbons  from  which  they  are  derived  is  by  no  means 
an  easy  matter,  and  powerful  reagents  are  required,  and  it  is  not  to 
be  expected  that  such  changes  should  occur  during  the  passage  of 
these  derivatives  through  the  animal  organism. 

The  cases  of  substances  undergoing  a  process  of  reduction  on  their 
passage  through  the  organism  are,  relatively  to  oxidation,  very  rare. 
One  of  the  most  interesting  is  that  of  chloral,  CCI3CHO,  and  butyl- 
chloral,  CCI3 .  CHg .  CHO,  which  are  reduced  to  their  corresponding 
alcohols  and  eliminated  as  compounds  of  glycuronic  acid  (see  p.  60), 
this  process  being  much  more  difficult  to  accomplish  in  the  laboratory 
than  the  opposite  one  of  oxidation  to  the  corresponding  acids  trichlor- 
acetic and  /3-trichlorpropionic. 

In  the  aromatic  series  the  easily  reduced  quinone  undergoes  this 
change  in  the  organism,  and  is  eliminated  as  hydroquinone. 

Other  examples  of  reduction  are  met  with  in  the  case  of  some 
nitro  compounds.  Thus  Eric  Meyer  has  shown  that  nitrobenzene 
is  partially  converted  into  1 : 4-amidophenol, 

ptt/OH 
^6^*\NH2, 


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, 

^6^i\C  :  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  Reduction  S"^^ 
CeHZ                            -^       CgHX   >C.COOH 

\no,  ^ 

2.  C— OH  C— OH 
C6H4<^C.:COO:H  =  C02  +  C6H4<^CH 

NH  NH 

Indoxyl. 

3.  C-jOH      HjO.SO^OH  C— O.SO^OH 

CeH,<0>CH+ =     CeH,<(^CH 

NH  NH 

Indoxyl-sulphate. 

Many  organic  dyes,  such  as  alizarin  blue  or  indophenol  blue 
lose  their  colour  while  in  the  cells  and  fluids  of  the  body,  but 
regain  it  on  exposure  to  air. 

4 


CHAPTEE    IV 

The  Alcohols  and  their  Derivatives.  The  Main  Group  of 
Anaesthetics  and  Hypnotics.  I.  General  physiological  action  of 
anaesthetics  and  hypnotics.  Overton-Meyer  theory.  Traube.  Moore  and 
Roaf  on  Chloroform.    Baglioni's  theory. 

II.  Method  of  preparation  and  chemical  and  physiological  properties  of 
the  Alcohols.  Esters  of  Halogen  acids,  Nitrous  and  Nitric,  Sulphurous  and 
Sulphuric  acids.    The  Ethers. 

I.     GENERAL   OUTLINES   OF  THE   PHYSIOLOGY  OF 
HYPNOTIC  AND   ANAESTHETIC   DRUGS. 

The  distinction  between  the  pharmacological  groups  of  anaes- 
thetics and  narcotics  is  important  in  practice^  but  does  not  depend 
upon  differences  in  physiological  action  or  chemical  constitution. 
For  the  production  o£  general  anaesthesia,  volatile  bodies^  which  are 
rapidly  absorbed  and  excreted,  are  most  suitable,  whereas  less  volatile 
liquid  or  solid  substances,  whose  activity  is  only  gradually  set 
free  in  the  organism,  can  more  conveniently  be  employed  for  pro- 
ducing hypnosis.  The  latter  condition  can  of  course  be  produced 
by  small  doses  of  a  body  like  chloroform,  but  the  method  of  adminis- 
tration is  inconvenient,  and  the  resulting  sleep  rapidly  passes  away. 
On  the  other  hand,  large  doses  of  a  narcotic  like  chloral  hydrate 
may  produce  complete  surgical  anaesthesia ;  indeed  this  body  was 
used  intravenously  for  a  short  time  in  the  middle  of  last  century, 
and  major  operations  performed  under  its  influence.  The  dis- 
advantage of  such  a  procedure  is  that  the  dosage  has  to  be  too 
high  for  the  complete  safety  of  the  patient. 

The  physiological  action  of  the  entire  group  of  aliphatic  narcotics 
is  first  on  the  higher  centres  of  the  cerebrum,  then  on  the  lower 
centres   of    the  medulla  and  cord.     Eventually  the   reflexes    are 

G 


82     THE   ALCOHOLS   AND   THEIR  DERIVATIVES 

completely  abolished^  and  this  constitutes  an  important  distinction 
between  this  group  and  the  alkaloidal  narcotics  of  which  the  chief 
representative  is  morphine.  In  large  doses  this  substance  increases 
reflex  irritability,  and  in  small  doses  does  not  depress  it. 

The  aliphatic  narcotics  belong  to  several  chemical  groups,  the 
chief  being  the  alcohols,  aldehydes,  ketones,  and  their  derivatives. 

Though  it  appears  doubtful  whether  methane  itself  is  narcotic, 
ethane  and  acetylene  are  direct  narcotics.  Those  which  belong  to 
the  alcohol  group  owe  their  specific  action  to  the  hydrocarbon 
radicals,  not  to  the  hydroxyl.  When  the  latter  are  increased  the 
narcotic  action  is  diminished ;  but  the  hydroxyl  radicals  may  be 
anchoring  groups.  As  a  rule  ethyl  compounds  are  more  powerfully 
hypnotic  than  methyl,  especially  when  occurring  in  bodies  which 
offer  some  resistance  to  oxidative  processes. 

The  entrance  of  carboxyl  appears  to  stop  all  narcotic  effects, 
though  the  esters  containing  an  alkyl  group  in  place  of  the  hydro- 
gen of  the  carboxyl  radical  are  active.     Thus  urethane. 


C0<^ 


NH2 
OC,H„ 


owes  its  activity  to  the  ethyl  group.  The  higher  the  molecular 
weight  of  the  alcoholic  group  the  more  powerful  is  the  hypnotic 
action. 

Thus  hedoual, 

is  much  more  powerful  than  urethane.  The  aldehydes  and  ketones 
are  not  as  a  rule  convenient  narcotics,  as  they  cause  a  marked 
preliminary  stage  of  excitement. 

Many  of  the  aldehyde  derivatives,  unsubstituted  by  halogens,  are 
only  feebly  narcotic,  the  parent  substances  being  often  irritant. 
The  ketones  themselves  have  not  yielded  any  bodies  of  great  prac- 
tical importance,  although  among  their  derivatives  are  the  valuable 
sulphones. 

The  introduction  of  a  halogen,  especially  chlorine,  greatly  en- 
hances the  narcotic  power,  but  these  compounds  have  the  great 
disadvantage  of  being  respiratory  and  cardiac  depressants.  The 
other  halogen  elements  have  a  still  more  deleterious  effect. 

There   remain  for  consideration  several  points  of  a  theoretical 


THEORIES   OF   HYPNOSIS  83 

character  as  to  the  general  processes  which  underlie  the  production 
of  narcosis. 

1.  The  researches  o£  Overton  showed  the  velocity  with  which 
substances  diffuse  into  the  protoplasm ;  these  are  divided  into  four 
groups,  the  first  diffuse  rapidly,  the  second  less,  the  third  least,  and 
the  fourth  group  contains  those  bodies  for  which  the  cells  are  com- 
pletely impermeable. 

Class  I.  Univalent  alcohols,  aldehydes,  ketones,  aldoximes,  and 
ketoximes,  nitro-alkyl  and  cyanides,  neutral  esters  of 
the  inorganic  and  many  organic  acids,  aniline,  pyri- 
dine, and  the  majority  of  the  free  alkaloids. 

Class  II.  The  divalent  alcohols  and  amides  of  mono-carboxylic 
acids. 

Class  III.  Glycerol,  urea,  the  hexoses  and  amido-acids  are  only 
very  slightly  diffusable. 

Class  IV.  Salts  of  strong  inorganic  acids,  inorganic  acids  and 
bases. 

The  permeability  increases  in  homologous  series,  and  by  the 
replacement  of  hydrogen  by  methyl  or  methyl  by  ethyl,  &e. 

Now,  as  a  very  general  rule,  the  rapidity  of  diffusion  into  mem- 
branes depends  upon  the  solubility  of  substances  in  such  bodies  as 
fats,  cholesterin,  and  lecithin,  and  Overton  has  brought  forward  the 
hypothesis  that  the  magnitude  of  the  distribution  coefficient  be- 
tween fat  and  water  determines  the  velocity  of  osmosis.  Both 
Overton  and  Hans  Meyer  draw  attention  to  the  fact  that  as  a  rule 
narcotics,  anaesthetics,  and  antipyretics  are  substances  which  diffuse 
rapidly,  and  they  consequently  conclude  that  the  narcotic  value  of 
a  drug  ■  depends  'principally  on  its  solubility  in  lipoid  substances. 
Although  narcotics  are  all  more  or  less  soluble  in  water,  there 
is  no  direct  relationship  between  this  solubility  and  narcotic 
power.  Meyer  tabulated  the  aliphatic  narcotics  according  to  the 
smallest  molecular  concentration  which  produced  definite  physio- 
logical effect,  the  values  being  expressed  as  fractions  of  the  normal 
solution  (1  gm.  molecule  per  litre),  and  termed  '^liminal  values  ■*. 

If  these  are  compared  with  the  '  distribution  coefficient  ^,  i.  e. 
the  ratio  of  the  solubility  in  fats  Sp  to  their  solubility  in  water  Sw, 
it  is  found  that  the  liminal  values  are  smallest  when  the  distribu- 
tion coefficient  is  high — the  most  powerful  narcotics  are  those 
which  are  most  soluble  in  oil  or  fat  and  least  soluble  in  water. 


84 


THEORIES   OF    HYPNOSIS 


Tjiminal  Value. 

Distribution. 

CoeflScient  g- 

Trional  .... 

.    .0018 446 

Tetronal 

.    .0013 

.     4.04 

Sulphonal 

.      .006 

.      Ml 

Butylchloral  hydrate    . 

.002 

1.59 

Bromal  hydrate     . 

.002 

.66 

Chloral  hydrate     . 

.02 

.22 

Ethyl  methane     . 

.04 

.14 

Methyl  methane  . 

4 

.04 

Monacetin     .... 

.05 

•06 

Diacetin       .... 

•015 

.23 

Triacetin      .... 

.01 

•3 

Chloralamide 

.04 

Chlorhydrin 

•04 

Dichlorhydrin 

.002 

In  the  sulphone  derivatives  it  was  found  that  those  most  soluble 
in  fat  were  also  those  that  showed  greatest  physiological  activity, 
whereas  in  this  series  Baumann  and  Kast  had  traced  this  activity  to 
the  presence  of  ethyl  groups. 

Action.  Distribution  Coefficient, 

very  slight  .106 

slight  .151 

marked  1-115 

more  marked  4  46 

more  marked  4-04 


Dimethyl-sulpho  methane 

Dimethyl-sulpho  ethane 

Sulphonal 

Trional 

Tetronal 


Mansfield  has  recently  shown  that  some  narcotics  have  more 
powerful  action  when  given  to  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  tiss2ie  fats  absorb  some  of  the  narcotic  and 
render  it  incapable  of  acting  on  the  central  nervous  system. 

The  Overton-Meyer  theory  then,  based  on  the  above  observations, 
is  that  indifferent  substances  gain  access  to  the  cells  of  the  central 
nervous  system  owing  to  their  solubility  in  the  cell  lipoids  in  which 
these  cells  are  particularly  rich,  and  that  gradations  in  narcotic  power 
are  due  to  the  presence  of  groups  which  increase  the  partition  co- 
efficient, i.  e.  which  render  the  derivatives  more  soluble  in  such  fatty 
substances.  The  theory  only  explains  the  presence  of  the  active 
substance  in  the  cell,  and  when  this  has  been  effected  we  are  in 
complete  ignorance  of  the  next  phase,  although  it  is  fairly  obvious 
that  there  will  be  great  differences  between  inert  substances,  of  the 
nature  of  ether  or  chloroform,  and  bodies  which  are  chemically 
active,  such  as  aniline.  The  Overton  hypothesis  further  would  lead 
to  the  supposition  that  cells  rich  in  lipoid  substance  should  show  a 
preferential  absorption ;  that  this  is  not  always  the  case  is  seen  in  the 


THEORIES    OF   HYPNOSIS  85 

fact  that  the  aliphatic  narcotics  do  not  attack  the  peripheral  nervous 
system,  which  contains  a  large  amount  of  such  bodies.  Further, 
Cushny  has  pointed  out  that  many  benzene  derivatives  have  a  high 
distribution  coefficient,  though  without  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  lipoid  which  determines  the  sequence  or  the  amount  of 
osmosis.  He  ascribes  the  direction  and  velocity  of  osmosis  to  the 
difference  of  the  surface  tensions,  as  he  does  not  hold  the  prevailing 
views  as  to  the  nature  of  osmotic  pressure.  Rapid  penetration  into 
the  cells  seems  to  be  the  most  essential  condition  for  enabling  a 
narcotic  substance  to  exercise  its  paralysing  and  other  effects  on 
the  interior  of  certain  cells,  and  ^  we  have  found  that  a  near  relation 
exists  between  osmotic  velocity  and  surface  tension,  and  therefore 
we  can  expect  that  surface  tension  and  narcotic  power  run  parallel'. 
This  he  finds  is  really  the  case,  even  when  most  varied  types  of 
narcotics  are  compared.  Traube  considers  that  when  the  drug  has 
thus  gained  entrance  to  the  cell  it  may  exercise  its  narcotic  power 
in  proportion  to  its  solubility  in  the  cell  lipoids. 

Moore  and  Roaf  have  recently  promulgated  the  theory  that 
anaesthetic  substances  form  unstable  compounds  with  the  cell  pro- 
teins, which  only  last  so  long  as  sufficient  partial  pressure  of  the 
gas  in  the  tissue  fluids  is  maintained.  Beginning  with  solutions 
of  blood  serum  and  haemoglobin,  and  continuing  their  investigations 
with  extracts  of  living  tissues  (brain,  heart,  lungs,  &c.),  they 
showed  that  at  higher  pressures  chloroform  and  other  anaesthetics 
did  not  obey  the  ordinary  laws  of  solution,  although  their  curves, 
examined  in  the  light  of  the  phase  rule,  exclude  the  hypothesis  of 
the  formation  of  chemical  compounds.  Other  anaesthetic  substances 
varied  in  the  degree  to  which  this  took  place,  but  no  variation  in 
kind  was  found  among  them. 

It  appears  quite  possible  that  adsorption  constitutes  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  adsorption  curves.  Gibbs 
has  shown  that  the  further  the  surface  tension  of  a  liquid  is 
depressed  by  the  dissolved  substance,  the  greater  will  be  its  adsorp- 
tion; it  is  moreover  a  general  principle  that  chemical  action  is 
proportional  to  concentration ;  the  latter  will  be  greatest  when 
solubility  and,  hence,  distribution  ratio  are  greatest.  It  seems  to 
the  present  writers  that  these  general  principles  include  the  essential 


86  THEORIES   OF   HYPNOSIS 

basis  o£  the  previous  hypotheses.  The  substance  enters  the  cell 
by  adsorption,  and  the  magnitude  of  its  effect  depends  on  its 
concentration. 

What  next  takes  place  is  pure  conjecture,  but  in  the  case  of  some 
substances  a  parallel  may  be  drawn  with  the  so-called  catalytic 
reactions.  Bredig  has  shown  that  the  rate  of  decomposition  of 
solutions  of  hydrogen  peroxide  by  colloidal  platinum  is  roughly  pro- 
portional to  the  concentration  of  the  latter  substance ;  the  action  is 
hindered,  that  is  '  poisoned ',  by  the  presence  of  traces  of  carbon- 
monoxide  (almost  without  exception  blood  poisons  act  similarly), 
but  on  its  removal  the  decomposition  proceeds  as  before.  Now  the 
conversion  of  the  total  platinum  into  a  compound  by  the  ^ toxic' 
substance  is  out  of  the  question,  owing  to  the  extreme  disparity  of 
the  amounts  of  the  two  substances.  Thus,  approximately,  in  a  y\ 
normal  solution  of  hydrogen  peroxide  containing  x^J^^  colloidal 

N 
platinum  an  amount  of  carbon  monoxide  =  -,  ^  _  _  ^  ^  _  _  is  sufficient 

10,000,000 

to  stop  the  action.  If  this  is  compared  to  the  action  of  chloroform,  for 

instance,  it  wiU  be  seen  that  after  adsorption  has  taken  place  its 

further  action  may  be  compared  to  that  of  carbon  monoxide  in 

the  example  given  above. 

Strychnine  also  plays  a  corresponding  r61e,  bringing  about  re- 
actions out  of  all  proportion  to  the  quantity  employed. 

It  is  generally  supposed  that  the  reaction  brought  about  by  col- 
loidal platinum  takes  place  in  the  adsorbed  layer  on  the  surface  of 
the  platinum  particles ;  the  poisons  will  also  be  absorbed,  and  either 
by  further  chemical  action  or  purely  physical  means  coat  and,  hence, 
isolate  the  active  surface  with  an  inert  layer.  The  corresponding 
picture  will  be  life  processes  taking  place  through  the  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  velocity  with  which  they  are  taking  place  may 
be  enormously  increased,  as  perhaps  may  be  the  case  with  strychnine. 

Baglioni  has  formulated  a  theory  of  narcosis  based  on  observa- 
tions on  the  various  groups  of  benzene  phenol  derivatives.  One  of 
these  groups,  containing  acetanilide,  phenylhydrazine,  benzylalcohol, 
benzaldehyde,  acetophenone,  benzoic  acid,  and  salicylic  acid,  pro- 
duces paralysing  effects  only,  without  convulsions.  The  amount  of 
paralysis  produced  varies  inversely  as  to  the  amount  of  oxygen  present 
in  the  side-chain.  Thus  benzylalcohol  is  a  powerful  paralysing 
agent  j  benzaldehyde  is  less  powerful^  and  benzoic  acid  least.     He 


ALIPHATIC  ALCOHOLS  87 

thus  concludes  that  narcotic  effect  also  depends  on  the  power  to 
withdraw  oxygen  from  the  ^inogen"*  compounds  in  the  central 
nervous  system ;  that  is,  that  narcosis  is  a  reducing  process.  Depriva- 
tion of  oxygen,  as  by  breathing  COg,  or  inert  gases,  such  as  hydrogen, 
gives  rise  to  a  series  of  symptoms  corresponding  to  chloroform 
narcosis.  Herter  has  shown,  by  means  of  methylene  blue  injections, 
that  chloroform,  ether  and  chloralhydrate  (as  likewise  low  tempera- 
tures) markedly  diminish  the  oxidizing  capacity  of  the  tissues. 

II.    THE  ALCOHOLS   OF  THE  ALIPHATIC   SERIES. 

The  group  of  alcohols  may  be  regarded  as  derived  from  water  by 
the  replacement  of  on6  hydrogen  atom  by  an  hydrocarbon  radical ; 
they  consequently  contain  the  so-called  hydroxyl  group,  and  their 
properties  depend,  to  a  very  large  extent,  upon  the  nature  of  the 
hydrocarbon  complex  to  which  this  is  joined. 

The  primary  contain  the  group  rCHgOH,  the  secondary  :CH.OH, 
and  in  the  tertiary  alcohols  the  hydroxyl  group  is  linked  on  to  a 
carbon  carrying  no  hydrogen  atoms,  e.g.  (CH3)3C.OH.  As 
previously  mentioned  (p.  68),  the  nature  of  their  oxidation  products, 
among  the  most  important  of  the  aliphatic  derivatives,  is  dependent 
upon  the  presence  of  these  groupings.  Thus  a  primary  alcohol,  such 
as  ethyl  alcohol,  CHg.CHgOH,  gives  rise  firstly  to  an  aldehyde, 
acetaldehyde,  CH3 ,  CHO,  which  passes,  on  further  oxidation,  to  an 
acid,  acetic  acid,  CH3COOH.  On  the  other  hand  a  secondary,  such  as 

C/Hq  CHo 

I      .  I 

2>c>-propyl  alcohol,  CH.OH  gives  a  ketone,  CO  acetone, 

CH3  CH3 

whereas  a  tertiary  alcohol  on  similar  treatment  breaks  down,  giving 
ketones  or  acids  of  smaller  carbon  content,  e.  g. 

CH3  CHg 

CH3.C.OH         ->  CH3.CO, 


A 


H3  CO,,  H,0 


Those  alcohols  which  contain  the  radical  of  the  aromatic  hydro- 
carbons attached  to  hydroxyl,  such,  for  example,  as  phenol,  CgHg.OH, 
show  such  striking  differences  both  chemically  and  physiologically  to 
the  aliphatic  derivatives  that  they  will  be  described  separately. 


88  PREPARATION  OF  THE  ALCOHOLS 

Methyl  alcohol,  CHg .  OH,  the  simplest  member  o£  the  series,  is 
one  of  the  products  of  the  dry  distillation  of  wood.  Ethyl  alcohol, 
CgHgOH,  is  obtained  by  the  fermentation  of  sugar,  and,  as  previously 
mentioned  (p.  36),  is  one  of  the  chief  starting-points  for  the  prepara- 
tion of  the  aliphatic  derivatives.  The  various  special  methods  which 
can  be  employed  for  the  synthesis  of  members  of  this  group  will  not 
be  described ;  they  are  to  be  found  in  any  textbook  on  organic 
chemistry,  but  the  following  three  general  methods  of  preparation 
are  important. 

General  Methods  of  Preparation. 

1.  The  monohalogen  derivatives  of  the  paraffins,  and  especially 
the  iodides,  are  readily  converted  into  alcohols,  in  many  cases  by 
simply  heating  with  water  to  a  temperature  of  100°-120° ;  thus 
CgHgl  +  HgO  =  HI  +  CgHg .OH.  But  since  the  reaction  is  re- 
versible, e.g.  CgHgOH-t-HI  =  HgO  +  CgHgl,  it  may  not  take 
place  to  any  great  extent,  a  state  of  equilibrium  being  more  or  less 
rapidly  attained.  In  consequence,  as  a  very  general  rule,  a  base  is 
required  to  combine  with  the  liberated  acid;  thus  with  silver 
hydrate  the  reaction  may  take  place  at  the  ordinary  temperature, 
whereas  with  lead  oxide  boiling  is  generally  necessary. 

In  other  cases  the  previous  formation  of  the  ester  may  be  desir- 
able; this  is  obtained  by  the  interaction  of  the  halogen  derivative  with 
either  silver  or  sodium  acetate,  and  on  decomposition  of  the  resulting 
substance  with  potash  or  soda  the  alcohol  is  readily  obtained,  e.  g. 

A.  CHgBr  CH2.(OOC.CH3) 

I  +2CH3.COOAg=   I  +2AgBr 

CH^Br  CH^-COOCCHg) 

Ethylene  dibromide. 

B.  CH2.(OOC.CH3)  CHg .  OH 
I                         +2K0H  =  2CH3COOK+  I 
CH2.(OOC.CH3)                                            CH2.OH 

Glycol. 

2.  Another  general  method  consists  in  decomposing  the  esters  of 
sulphuric  acid  with  water.  These  esters  may  be  readily  obtained 
by  treating  the  hydrocarbons  of  the  ethylene  series  with  concen- 
trated sulphuric  acid,  e.  g. 

A.        CH2  OH  .O.C2H5 

II    +so/      =so/ 

CH2  \0H  \0H 

Ethylene.  Ethyl-sulphuric  acid. 


PROPERTIES    OF   THE   ALCOHOLS  89 

B.  /O.C2H5  .OH 

S02<  +H2O  =  S02<  +C2H5.OH. 

\0H  \0H 

The  esters  which  are  formed  by  treatment  of  the  unsaturated 
hydrocarbons  with  sulphuric  acid  contain  the  acid  radical  attached 
to  the  carbon  which  carries  the  least  number  of  hydrogen  atoms. 

Thus  CH,  CH3  CH3 

II  !  I 

CH   gives  CH— O.SO2OH  and  consequently    CH.OH 

I  I  the  alcohol  | 

CHg  CH3  CH3 

and  CH3  CH3 

\  \  yCHg 

C  :  CHg  gives     C^  and  consequently  the  alcohol 

/  /  MSO^OH  (CH3)3.C.OH. 

CH3  ,    CHg 

3.  Derivatives  of  ammonia  containing  the  amido  group  .NHg 
are  all  decomposed  by  nitrous  acid  in  aqueous  solution  and  the 
group  replaced  by  hydroxyl^  e.  g. 

C2H5NH2  +  HNO2  =  C^H.OH  +  Ng  +  HgO 

Ethylamine. 

CH3.CO.NH2  +  HNO2  =  CH3.CO.OH  +  N2  +  H2O 

Acetamide.  Acetic  acid. 

.NH2  /OH 

C0<         +  3HNO2  =  C0<        (CO2  +  H2O)  +  2N2  +  2H2O 
\NH2  ^OH 

Urea.  Carbonic  acid. 


General    Properties. 

The  alcohols  are  neutral  colourless  compounds^  and  the  lower 
members  of  paraffin  series  have  a  characteristic  burning  taste  and 
smelly  and  their  solubility  in  water  decreases  as  the  carbon  content 
increases.  Thus  methyl,  ethyl,  and  propyl  alcohols  are  miscible 
with  water  in  all  proportions.  Primary  ?i-butyl  alcohol  is  soluble 
in  twelve  parts  of  water.  Those  containing  4-11  carbon  atoms  are 
oils  immiscible  with  water,  and  the  higher  members  are  solids. 

Isomerism  is  first  observed  in  the  alcohols  of  the  limit  hydro- 
carbons in  the  case  of  those  derived  from  propane,  CHg .  CHg .  CH3, 
which  gives  rise  to  a  primary  CH3 .  CHg .  CHgOH  and  a  secondary 


90        THE  POLYHYDRIC  ALCOHOLS 

CH3 .  CHOH.CH3  called  i.!?o-propyl  alcohol,  easily  distinguished  by 
their  oxidation  products. 

The  chemical  characteristics  of  the  group  depend  essentially  on 
the  presence  of  the  hydroxyl  group.  Sodium  and  potassium  replace 
the  hydrogen  of  this  radical,  e.  g.  CgHg .  ONa,  giving  rise  to  sub- 
stances called  alcoholates ;  these  are  readily  decomposed  by  water, 
are  employed  in  many  synthetic  processes,  form  valuable  condensing 
agents,  and  may  be  used  for  the  purpose  of  reducing  nitro  com- 
pounds of  the  aromatic  series  to  the  corresponding  azoxy 
derivatives. 

When  acted  upon  by  acids  or  acid  chlorides  the  alcohols  readily 
yield  the  esters,  e.  g. 

C2H50H  +  HC1=  H2O  +  C2H5CI 

C2H5OH  +  HNO2  =  H2O  +  C2H5 .  ONO2 

Ethyl  nitrite. 

C2H,OH  +  H2S04=  H2O  +  C2H5O.SO2OH 

Ethyl  sulphate. 

CgHgOH  +  CHgCOOHcr  H^O  +  CHgCOOC.Hg 

Ethyl  acetate. 
C2H50H  +  PCl5=    HCI  +  POCI3  +  C2H5CI 

C2H5OH    +    C6H5COCI       =         HCl+CgHgCOOCgHg 

Ethyl  benzoate. 

On  dehydration,  by  sulphuric  acid  or  zinc  chloride,  the  alcohols 
are  converted  into  unsaturated  hydrocarbons,  e.  g. 

CH2iH  CH2 

=  H2O+  II 
HJOH  CH. 


i 


Polyhydric  Alcohols. 

Besides  containing  one  hydrogen  atom  replaced  by  hydroxyl,  the 
hydrocarbons  may  have  more,  but  it  has  been  previously  pointed 
out  that,  as  a  very  general  rule,  one  carbon  atom  cannot  carry  more 
than  one  hydroxyl  group.  Attempts  to  obtain  CH3 .  CH(0H)2  by 
the  action  of  silver  hydrate,  for  instance,  on  CHg .  CHCI2  always 
lead  to  the  dehydration  product  of  the  unknown  alcohol,  i.e.  the 
aldehyde, 

CH3.CH<^Pj^  =  H2O  +  CH3CHO 


PHYSIOLOGICAL  PROPERTIES  OF  THE  ALCOHOLS  91 

and  in  a  similar  manner  CH3 .  CClg .  CH3  does  not  yield 

/OH 
CH3 .  Cf  CH3 
'      \0H 

but  the  dehydration  derivative  CH3 .  CO.CH3  dimethylketone  or 
acetone.     Consequently  the  simplest  dihydric  alcohol  is  glycol, 

CHgOH 


i 


HoOH 


which  may  be  obtained  by  reactions  similar  to  those  previously 
described.  With  the  entrance  of  a  second  hydroxyl  group  the 
solubility  in  water  increases,  but  that  in  alcohol  and  ether  decreases. 
At  the  same  time  the  physiological  activities  decrease  and  almost 
entirely  disappear  in  the  case  of  the  trihydric  derivative  glycerol, 

CH.OH 

I 
CHOH 

I 
CH2OH 

a  substance  obtained  by  the  saponification  of  fats  in  the  soap 
industry. 

These  polyhydric  alcohols  show  the  same  general  chemical  charac- 
teristics as  the  simpler  ones  previously  described.  As  the  number 
of  hydroxyl  groups  increases  so  does  the  sweet  taste;  this  property, 
not  apparent  in  ethyl  alcohol,  CHgCHgOH,  is  noticed  in  glycol, 
CHgOH.CHgOH,  and  increases  in  glycerol  and  those  pentahydric 
alcohols,  such  as  mannitol,  which  are  so  closely  related  to  the  sugars, 
themselves  pentahydroxy-aldehydes  or  ketones. 

Physiological  characteristics. 

The  entrance  of  the  hydroxyl  radical  (OH)  into  aliphatic  sub- 
stances results  in  a  decrease  in  their  physiological  reaction,  a  decrease 
which  is  still  more  marked  as  the  number  of  such  groups  increases. 

Thus  the  narcotic  ethyl  alcohol,  CH3 .  CHgOH,  passes  to  the  inactive 
glycol,  CH2OH.CH2OH,  and  propyl  alcohol,  CH3 .  CH^XH^OH,  to 
the  almost  inert  substance  glycerol,  CHgOH.CHOH.CHaOH. 
Glycerol  is  not  absolutely  without  physiological  action.  In  large 
doses  it  may  produce  restlessness  and  tremors,  or  even  tetanic 
spasm.     If  given  by  the  mouth  or  subcutaneously  haemoglobinuria 


92  PHYSIOLOGICAL  PROPERTIES  OF  THE  ALCOHOLS 

may  result,  an  effect  unseen  when  glycerol  is  injected  intravenously. 
Death  may  occur  after  toxic  doses  by  respiratory  failure. 

Further,  the  aldehydes  and  ketones,  with  their  marked  physiological 
reactivity,  become  the  inert  sugars. 

Caffeine  loses  its  characteristic  physiological  reaction,  and  it  is 
possible  that  in  this  case,  as  with  the  others,  this  decrease  in 
reactivity  may  be  ascribed  to  the  drop  in  stability  towards  oxidizing 
processes,  which  follows  the  entrance  of  the  hydroxyl  grouping. 

The  alcohols  act  on  the  central  nervous  system,  in  particular  on 
the  cerebrum,  the  intensity  of  their  actions  depending  upon  the 
number  of  carbon  atoms  present,  and  increasing  as  the  homologous 
series  is  ascended,  although  to  some  extent  methyl  alcohol  is  an 
exception. 

Thus,  in  the  case  of  rabbits  : — 

Methyl  alcohol,  CH3OH,    6-12  gms.  without  action. 

Ethyl         „       CgHgOH,  7  gms.  drunkenness,  12  gms.  sleep. 

n-Vro-pjl   „       C3H7OH,  12  gms.  produce  sleep  in  5  minutes 

and  death  in  5  hours. 
n-Bntjl    „       C4H9OH,  3  gms.  produce  drunkenness,  7  gms. 

sleep  and  death. 
iso-Amjl-  „      (CH3)2CH.CH20H,  2  gms.  produce  drowsiness. 
The  primary  alcohols  are  less  narcotic  than  the  secondary,  and 
these  less  than  the  tertiary.     Thus  : — 

J^o-propyl  alcohol,  CHg .  CHOH.CH3,  2  gms.  produce  drowsi- 
ness. 
Methyl-ethyl  carbinol,   CHg .  CHOH.CgH^,   2  gms.   produce 

drowsiness. 
Diethyl  „         CgH^.  CHOH.CgHg,  2  gms.    produce 

sleep. 
In  the  case  of  the  tertiary  alcohols  the  action  depends  on  the 
nature  of  the  alkyl  radicals  attached  to  the  carbon  atom  carrying 
the  hydroxyl  group.  If  that  radical  is  methyl  the  reaction  is 
relatively  weak,  but  if  ethyl  the  physiological  reaction  is  largely 
increased  (see  p.  49),  the  increase  varying  with  the  number  of  such 
groups  present,  thus  : — 

Trimethyl  carbinol,  (CH3)3C.OH,  4  gms.  produce  sleep. 

Dimethyl-ethyl  earbinol,  g A)  }  c.OH,    'iZl^^^^i'  "^ 
Triethyl  carbinol,  (C2H5)3C.OH,    I  gm.   produces  10  to    12 

hours'  sleep. 
(Compare  the  substituted  urea  derivatives,  p.  216.) 


ESTERS   OF  INORGANIC  ACIDS  93 

A  similar  characteristic  is  noticed  in  the  pinacones,  substituted 
derivatives  of  the  physiologically  inactive  diprimary  alcohol  glycol 

CH2OH 


I 


H2OH 


thus : — 

(CH3),.C.0H 
Methyl  pinacone,  |  10  gms.  produce  sleep. 

(CH3),.C.0H 


CH 
CgHg/'y^^'^  2   gms.   produce   sleep. 


3\C.0H 


Methyl-ethylpinacone,     c^hH  ^„  ^  ll^it  ^nTul^io;: 


CoH 


.OH 


'2-' 

(C2H5)2.C.OH    Very  insoluble.      1-5    gms. 
Ethyl  pinacone,  |  produce  deeper  and  longer 

(C2H5)2.C.OH        sleep.     3     gms.    produce 
sleep  after  2  hours. 

Owing  to  the  above  observations  Mering  introduced  amylene 
hydrate, 

CH3  ] 

CH3    C.OH, 

in  1887  as  a  hypnotic.  It  is  obtained  from  the  unsaturated 
hydrocarbon  amylene,  by  the  general  method  previously  described, 
i.e.  through  the  agency  of  amylsulphuric  ester.  It  has  the  hypnotic 
properties  of  an  alcohol,  but  is  also  liable  to  produce  symptoms  of 
intoxication  with  nausea  and  headache.  It  is  said  to  be  a  diuretic* 
It  influences  the  heart  and  respiration  like  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  hydrogen  atom 
of  the  acids  is  replaced  by  an  organic  radical ;  they  consequently 
belong  to  two  groups,  (1)  those  obtained  from  the  inorganic  acids, 
and  (2)  those  derived  from  the  organic  acids  (see  p.  122). 

The  former  only  will  be  discussed  at  this  point,  and  the  latter  in 
connexion  with  the  organic  acids  themselves.  If  the  halogen  acids, 
hydrochloric,  hydrobromic  and  hydriodic  be  considered,  it  will  be 
seen  that  on  replacing  the  hydrogen  by  the  radicals  of  the  paraffins^ 


94  PREPARATION  AND  PROPERTIES  OF  THE  ESTERS 

this  group  of  substances  results,  thus  HCl  gives  CH3.CI  or  CgHgCl, 
&c.  From  another  point  o£  view  these  derivatives  may  be  looked 
upon  as  the  halogen  substitution  products  of  the  limit  hydrocarbons, 
thus  CH4  acted  upon  by  chlorine  gives  CH3CI, 

CH4  +  CI2  =  HCI  +  CH3CI. 

But  as  the  alcohols  are  invariably  used  in  their  preparation  the 
former  view  may  be  adopted,  and  the  two  reactions  compared 

NaOH  +  HCl=NaCl  +  H20  i  CHgOH  +  HCl^CHgCl  +  Hp. 

General  methods  of  preparation. 

1.  The  interaction  of  the  alcohols  and  hydrochloric  or  hydro- 
bromic  acid  is  reversible  and  is  not  complete  unless  one  of 
the  substances  formed  is  removed  from  the  sphere  of  reaction. 
Thus  in  the  case  of  methyl  or  ethyl  alcohol,  zinc  chloride  or 
sulphuric  acid  may  be  employed  to  remove  the  water  formed.  But 
with  the  higher  alcohols  unsaturated  hydrocarbons  may  be  firstly 
formed,  and  these  add  on  the  halogen  acid  in  such  a  manner  that 
isomers  of  the  desired  esters  are  obtained.  Further,  hydriodic  acid, 
especially  when  in  excess,  is  capable  of  reducing  the  iodides. 

2.  The  phosphorus  halogen  derivatives  readily  react  with  the 
alcohols,  giving  rise  to  substances  of  this  class, 

PBr3  +  3C2H50H  =  3C2H5Br  +  H3P03 

Phosphorus  tribromide. 

PI3  +  3C2H5OH  =  3C2H5I  +  H3PO3 

Phosphorus  tri-iodide. 
phosphorus  pentachloride  easily  gives  the  corresponding  chloride. 

General  Properties. 

The  esters  of  the  halogen  acids  are  etherial,  pleasant-smelling 
liquids,  almost  insoluble  in  water.  The  lower  members  are  gases 
at  ordinary  temperatures,  e.g.  methyl  chloride,  ethyl  chloride,  and 
methyl  bromide.  The  chlorides  boil  20°-28°  lower  than  the 
bromides,  and  these  28°-34°  lower  than  the  corresponding  iodides. 
Their  stability  decreases  from  the  chlorides  to  the  iodides,  and 
consequently  their  reactivity  increases  in  the  same  direction.  They 
are  well  adapted,  especially  the  iodides,  to  the  most  varied  series  of 
synthetic  reactions,  many  of  which  have  been  previously  described 
(p.  37). 


PHYSIOLOGICAL  PROPERTIES  95 

General  Physiological  characteristics  following  entrance 
of  Chlorine. 

The  entrance  of  chlorine  into  aliphatic  compounds  increases  their 
depressant  effect  on  the  heart,  and  as  a  very  general  rule  in- 
creases their  narcotic  action.  Their  toxic  action  appears  to  stand 
in  direct  relationship  to  their  narcotic  properties,  and  the  latter  to 
increase  with  the  amount  of  chlorine  present.  Thus  methyl  chloride, 
CH3CI,  is  less  toxic  than  methylene  chloride,  CHgClg,  and  this  less 
than  chloroform,  CHCI3 ;  the  fully  chlorinated  methane  derivative 
carbon  tetrachloride,  CCI4;  acts  much  more  slowly  and  persistently 
than  chloroform,  and  is  usually  stated  to  be  a  more  powerful  heart 
depressant,  although  Cushny  describes  it  as  only  half  as  powerful  as 
chloroform.  Considerable  interest  consequently  lies  in  the  investi- 
gation of  the  results  following  the  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  produced  by  the  local  application  of  solutions  of  caffeine  to  the 
f rog''s  heart.  Chlorcaffeine  is  a  much  feebler  cardiac  stimulant ;  the 
other  actions  of  caffeine,  however,  are  still  present  (Pickering). 

Then  glycerin  is  physiologically  inert,  but  the  chlorhydrins  have 
narcotic  action  and  produce  paralysis  and  dilation  of  the  vessels. 
Monochlorhydrin,  CHgOH.CHOH.CHgCl,  is  the  least  and  trichlor- 
hydrin,  CHgCLCHCl.CH^Cl,  the  most  toxic. 

The  increase  in  narcotic  properties  following  the  entrance  of 
chlorine,  led  to  the  introduction  of  trichlorisopropyl  alcohol  Isopral, 
CCI3.CHOH.CH3,  bylmpens  in  1903.  This  substance  may  be 
formed  by  the  action  of  methyl  magnesium  iodide  (Grignard's 
reagent,  see  p.  38)  on  chloral  and  the  decomposition  of  the  resulting 
substance  by  water, 

/H 

A.  CH3 .  Mg.I  +  CCI3CHO  =  CCI3 .  C(-OMgI 

NCH, 

B.  CCI3 .  C^OMgl  +  H2O  =  Mgl .  OH  +  CCIo-C^OH 

\CH3  \CH3 

but  its  action   on  the  heart  is  more  powerful  than  chloral,  and 
consequently  it  cannot  be  given  in  heart  disease. 
Similarly  trichlorbutyl  alcohol, 


^^?Cl!>-0H  +  4H,0 


96  ESTERS   OF   HYDROCHLORIC   ACID 

Chloretone  has  been  introduced  as  an  antiseptic,  anaesthetic,  and 
hypnotic.  It  is  also  known  as  anesou  or  anesiu  (a  one  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  apparently  does  not  differ  in  its  physiological  action 
from  other  chlorine  narcotics. 

The  above  gives  a  general  indication  of  the  physiological  results 
following  the  introduction  of  chlorine  into  organic  substances ;  the 
effect  of  the  entrance  of  this  member  of  the  halogen  series,  as  well 
as  bromine  and  iodine,  into  other  groups,  such  as  the  aldehydes  and 
acids,  will  be  described  after  the  discussion  of  those  derivatives. 

Esters  of  Hydrochloric  Acid. 

Ethyl  chloride,  CgH^Cl,  and  ethyl  bromide  have  been  employed 
as  general  anaesthetics ;  a  mixture  of  these  and  methyl  chloride  is 
known  as  somuoform.  Webster  [Biochemical  Journal,  June,  1906) 
investigated  these  drugs,  and  also  ethyl  iodide,  which,  owing  to  its 
unpleasant  taste  and  its  volatility,  is  unsuitable  for  clinical  purposes. 
There  is  apparently  no  difference  in  the  physiological  action  of 
these  drugs  beyond  what  may  be  attributed  to  their  varying 
volatility.  With  large  doses  respiration  ceases  some  time  before 
the  heart.  Blood  pressure  after  a  short  preliminary  rise  is  con- 
siderably depressed,  this  being  due  to  the  depressant  action  on  the 
cardiac  pump.  No  action  on  the  vagus  endings  was  demonstrated, 
though  Cole  {B.M.J.,  1903,  i,  p.  1421)  found  that  the  vagus 
terminations  were  paralysed.  Somnoform  appears  especially  liable 
to  cause  respiratory  failure. 

Ethyl  chloride  is  twice  as  soluble  in  blood  as  in  water,  and  experi- 
ments with  dogs  showed  that  its  vapour  has  a  paralytic  action  on 
the  heart  muscle  but  that  nineteen  times  as  much  is  required  to 
produce  the  same  effect  as  chloroform. 

Chloroform,  CHCI3,  is  obtained  by  the  action  of  bleaching  powder 
on  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  sulphuric  acid  to 
destroy  other  chlorinated  derivatives  such  as  those  of  ethane,  and 
rectified.  In  all  probability  alcohol  is  firstly  oxidized  to  chloral, 
CCI3CHO,  which,  in  the  presence  of  calcium  hydrate,  is  converted 
into  chloroform.  In  the  case  of  acetone,  the  intermediate  product 
is  probably  CCJgV.CO.CHg,  which  then  breaks  down  into  chloroform 


PHYSIOLOGICAL  PROPERTIES  97 

and  acetic  acid.  A  much  purer  preparation  may  be  obtained  by  the 
action  of  alkalis  on  chloral.  It  is  only  slightly  soluble  in  water, 
1  litre  of  saturated  solution  at  ordinary  temperatures  containing 
about  7  gms.  of  chloroform.  The  pure  preparation  is  not  very 
stable,  breaking  down  into  the  very  toxic  phosgene,  COClg,  hydro- 
chloric acid  and  chlorine ;  the  official  preparation,  which  is  much 
more  stable,  contains  a  trace  of  ethyl  alcohol,  or  when  made  from 
acetone  a  small  quantity  of  that  substance;  both  these  in  the 
amounts  present  are  physiologically  inert,  and  there  is  no  reason 
why  chloroform  prepared  from  ethyl  alcohol  should  in  any  way  be 
preferred  to  that  obtained  from  acetone. 

Breteau  and  P.  Woog  have  found  that  chloroform  may  be  kept 
in  ordinary  glass  bottles  in  diffused  daylight  without  suffering 
decomposition,  if  any  of  the  following  substances  are  added  in 
proportion  of  2-4  parts  per  1,000 : — Oil  of  turpentine,  pure  sperma- 
ceti, menthol  geraniol,  menthol  salicylate,  and  thymol. 

The  theories  as  to  the  narcotic  or  anaesthetic  properties  of  chloro- 
form have  been  discussed  in  the  general  introduction  to  the  narcotic 
compounds.  The  symptoms  known  as  '  delayed  chloroform  poison- 
ing 'j  which  include  a  remarkable  fatty  infiltration  of  the  liver  and 
are  not  infrequently  fatal,  are  in  reality  those  of  an  acid  intoxication. 
They  are  occasionally  met  with  after  other  anaesthetics.  Diminished 
oxidation  processes  characterize  the  action  of  all  the  halogen  narcotics ; 
it  is  supposed  that  the  imperfect  oxidation  of  the  body  fats  gives 
rise  to  acids  of  the  fatty  series,  and  hence  the  production  of  these 
symptoms.  The  action  does  not  apparently  depend  on  the  narcosis, 
but  is  a  special  property  of  this  class  of  drugs. 

Carbon  tetrachloride,  CCl^^  which  was  originally  investigated  by 
Simpson  and  others  in  the  early  days  of  anaesthesia,  was  made  the 
subject  of  more  recent  experiment  by  Marshall,  who  found  that  the 
differences  in  action  between  this  body  and  chloroform  were  mainly 
due  to  its  physical  characters.  It  is,  however,  more  toxic  and  more 
irritating  to  the  mucous  membrane  of  the  trachea  and  bronchi. 
Recently  it  has  been  employed  by  hairdressers  to  clean  the  hair, 
and  a  case  of  accidental  poisoning  owing  to  the  inhalation  of  the 
vapour  has  been  reported  (Lancet,  1907,  i.  1725).  This  case  was 
apparently  serious,  and  very  nearly  had  a  fatal  termination. 

Dichlorethane,  CHg .  CHClg,  the  symmetrical  derivative  ethylene 
dichloride,  CH2CI.CH2CI,  and  trichlorethane  fcr  Mt^f'^tmoiorm, 
CH3  •  CCI3,  have  all  a  very  similar  action  A  chloroforof 

J   Pharmacology 


98  ESTERS   OF  HYDROBROMIC  ACID 

Esters   of  Hydrobromic   Acid. 

The  lower  alkyl  bromides  have  a  similar  action  to  the  chlorides ; 
thus  methyl  bromide,  CHgBr,  and  ethyl  bromide,  CgH^Br,  have 
anaesthetic  properties,  and  are  only  slightly  toxic,  but  the  latter 
substance  produces  irritation  of  the  respiratory  passages  to  a  greater 
extent  than  the  corresponding  chlorine  derivative.  The  narcosis 
produced  by  ethyl  bromide  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,  according  to  which  narcosis  is  deeper 
and  lasts  longer,  the  higher  the  boiling-point  of  the  anaesthetic 
(boiling-point  of  ethyl  bromide  =  38°,  chloroform  =  61°). 

Bromoform,  CHBrg,  has  a  narcotic  action,  and  was  first  used  in 
1889  by  Stepp  in  whooping-cough  of  children,  and  also  in  cases  of 
asthma.  It  is  prepared  from  either  alcohol  or  acetone  in  a  very 
similar  manner  to  chloroform. 

In  ethylene  dibromide,  CgH^Brg,  the  toxicity  increases;  the 
anaesthetic  action  is  slight,  and  it  tends  to  cause  paralysis  of  the 
extremities  and  stoppage  of  the  heart.  It  is  stated  to  have  a 
peculiar  action  on  the  respiratory  centre,  diminishing  the  desire  to 
breathe,  and  it  has  consequently  been  suggested  that  it  might  be 
of  advantage  in  asthma. 

The  bromine  derivatives  being  less  stable  than  the  chlorine 
decompose  more  rapidly,  and  many  attempts  have  been  made  to 
employ  such  compounds  in  place  of  potassium  bromide  in  epilepsy, 
with  the  hope  of  avoiding  the  depressant  effects  of  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  less  than  that 
of  potassium  bromide,  as  are  also  the  unpleasant  after-effects. 

Tribromhydrin,  CgHgBrg,  has  no  advantage  over  bromide;  it  reacts 
very  similarly  to  the  corresponding  trichlorhydrin.  It  is  also  an 
intestinal  irritant. 

Bromipin  is  a  compound  of  bromine  with  sesame  oil  (see  also 
lodipin),  which  liberates  the  element  slowly  in  the  organism. 

The  disadvantage  of  the  organic  bromine  preparations  in  the 
treatment  of  epilepsy  is  that,  although  a  considerable  amount  of 
bromine  may  be  administered,  it  is  present  in  such  a  form  that  only 
small  quantities  are  set  free  in  the  body  at  a  time;  consequently, 
when  it  is  desirable  to  produce  a  rapid  effect  these  preparations  are 


PHYSIOLOGICAL   PROPERTIES  99 

Esters   of  Hydriodic   Acid. 

In  the  iodine  derivatives  the  antiseptic  properties  are  much  more 
marked  than  in  the  others,  and  an  increase  in  toxicity  is  observed. 
Ethyl  iodide,  CgH^I,  acts  like  chloroform,  but  anaesthesia  comes  on 
slowly  and  is  more  permanent.  It  may  be  used  to  relieve  spasms 
of  the  respiratory  passages. 

Iodoform,  CHI3,  possesses  narcotic  and  hypnotic  properties,  but  is 
chiefly  characterized  by  its  extraordinary  antiseptic  power.  Partly 
for  this  reason,  but  mainly  because  the  majority  of  the  iodine  deriva- 
tives employed  in  medicine  are  allied  to  the  aromatic  phenols,  they 
will  be  discussed  later  (see  Chap.  VIII). 

Aromatic   Esters   of  Halogen   Acids. 

The  hydrogen  atoms  in  the  benzene  nucleus  are  more  readily 
replaced  by  chlorine  and  bromine  than  the  hydrogen  of  the  paraffins. 
An  important  method  used  in  their  preparation  consists  in  the 
decomposition  of  the  diazo  derivatives  (p.  41)  by  means  of  the 
haloid  acid ;  e.  g. 

CeHgNiN.OSOgH  +  HI  =  CgH^I  +  Na  +  H^SO^, 

and  by  the  action  of  heat  upon  the  cuprous  salt  addition  product, 
CeH^NrN.Cl.CugClg  =  C6H5CI  +  N2  +  CU2CI2. 

The  benzene  halogen  derivatives  have  a  slight  odour,  are  in- 
soluble in  water,  volatilize  without  decomposition,  and  are  very 
stable.  Unlike  the  aliphatic  substitution  products,  they  are  unacted 
upon  by  the  alkalis,  ammonia,  potassium  cyanide,  &c. 

Corresponding  to  their  stability  it  is  found  that  the  halogen  is 
not  split  off  in  the  organism,  and  that  they  do  not  show  hypnotic 
properties.  With  the  entrance  of  chlorine  the  antiseptic  properties 
increase  (see  later). 

Chlorbenzene  acts  on  the  spinal  cord  to  a  greater  extent  than 
benzene. 

The  action  of  brombenzene  is  more  powerful,  and 

is  very  toxic ;  the  entrance  of  bromine  into  the  molecule  of  benzene 
does  not  bring  about  narcotic  properties. 

The  aromatic  iodo  compounds  are  more  toxic  than  those  not 
containing  that  halogen. 

Ha 


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. 


CgHgOiH  +  OHINO  =  CjjH5O.NO  +  H2O. 

They  are  liquids  with  characteristic  smell,  and  are  readily  decom- 
posed by  alkalis  into  the  corresponding  alcohol  and  alkaline  nitrite. 
They  are  isomeric  with  the  nitro  paraffins,  e.  g,  nitroethane, 
CgHgNOg,  but  these  on  reduction  yield  amines,  CgHgNHg,  whereas 
the  corresponding  nitrous  ethyl  ester  is  saponified,  yielding  ethyl 
alcohol,  C2H5OH. 

The  esters  of  nitric  acid  result  from  the  interaction  of  alcohols 
and  nitric  acid,  e.  g. 

C^HsOiH  +  OHiNOa  =  H2O  +  C2H5O.NO2. 

They  are  pleasant-smelling  liquids,  exploding  when  rapidly  heated, 
and  easily  saponified  by  alkalis,  giving  alcohol  and  alkaline  nitrate. 

Physiological   FropertieSr 

As  a  general  rule,  the  entrance  of  the  nitro  or  nitroso  group  into 
a  molecule  increases  its  toxicity,  irrespective  of  the  manner  in  which 
the  linkage  is  effected ;  whether  through  oxygen  as  in  the  esters, 
or  direct  to  carbon  as  in  nitroso  and  nitro  paraffins. 

The  nitrous  esters  of  the  fatty  series  do  not  act  on  the  vaso- 
motor centre  but  directly  on  the  vessels,  causing  powerful  expansion. 

Cash  and  Dunstan  investigated  carefully-prepared  specimens  of 
nitrous  esters.  They  found  that,  as  regards  the  principal  effect,  i.  e. 
reduction  of  blood  pressure,  the  activity  of  various  nitrites  took  the 
following  order  when  equal  volumes  were  administered  to  animals 
by  inhalation: — (1)  Secondary  propyl,  (2)  tertiary  butyl,  (3) 
secondary  butyl,  (4)  iso-huijl  (nearly  equal),  (5)  tertiary  amyl, 
(6)  a-amyl,  (7)  /3-amyl  (nearly  equal),  (8)  methyl,  (9)  butyl,  (10) 
ethyl,  (11)  propyl.  This  order  is  somewhat  modified  when  the 
nitrites  are  given  by  intra-vascular  injections.  When  the  duration 
of  subnormal  pressure  is  considered,  the  order  is  nearly  the  reverse 
of  that  given  above ;  the  effect  of  methyl  nitrite  being  the  last,  and 
secondary  propyl  one  of  the  first  to  disappear. 

In  some  animals  toxic  effects  in  the  tissues  have  been  observed,  but 
in  man  death  occurs  owing  to  blood  changes,  methaemoglobin  and 
nitric  oxide  haemoglobin  being  formed. 


PHYSIOLOGICAL  PROPERTIES 


101 


Divergent  views  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  protein  molecule ;  Marshall, 
Haldane,  and  others  consider  that  the  nitrous  acid  esters  act  directly. 
Binz  considers  that  nitric  oxide  is  formed ;  a  small  portion  is 
excreted  unchanged  in  the  urine. 

Bradbury  investigated : 

Methyl  nitrate  CH3  .  ONOg 


Ethylene  dinitrate 


CH2 .  ONO2 


Nitroglycerin 


Erythrol  tetranitrate 


Mannitol  hexanitrate 


CH2.O.NO2 
CH2O.NO2 


HO.NO, 


H2O.NO2 
CH2ONO2 


(CH.O.N02)2 

CH2ONOJ, 
CH2ONO2 

I 
{CH.ON02)4 


CH2ONO2 

Erythrol  tetranitrate  is  less  powerful  than  amyl  nitrile  or  nitro- 
glycerin, but  its  effects  are  more  prolonged ;  mannitol  hexanitrate 
is  not  nearly  so  powerful,  but  its  action  may  be  more  prolonged. 
Its  main  advantage  is  its  comparatively  low  cost. 

Marshall  found  mannitol  pentanitrate  intermediate  in  action 
between  the  two. 

Nitroglycerin  is  practically  absorbed  into  the  blood  unchanged, 
hence  its  powerful  and  prolonged  action  (Brunton). 

Nitro  Fara£B.us.  When  the  nitro  group  is  linked  directly  to 
carbon,  as  for  instance  the  nitro  paraffins,  an  entirely  different 
physiological  reaction  appears.  Nitro  ethane,  CgHgNOg,  for  instance, 
although  a  toxic  substance,  has  no  action  at  all  on  the  blood  vessels, 
and,  like  nitromethane,  CH3NO2,  causes  death  in  relatively  small 
doses. 

Nitro  Derivatives  of  Aromatic  Series.  The  introduction  of  the 
nitro  group  into  the  aromatic  series  (p.  40)  also  raises  the  toxicity 


102  ESTERS   OF  THE   SULPHUR  ACIDS 

in  the  resulting  substance.  Thus  nitrobenzene  produces  tremors 
and  increased  reflexes,  and  eventually  coma. 

Nitrothiophene  acts  in  a  precisely  similar  manner  to  nitrobenzene. 

Nitronaphthol  is  toxic  in  small  doses,  either  given  by  the  mouth 
or  subcutaneously.     On  the  other  hand  jo-nitrotoluene, 


/( 


CH, 


is  almost  non-toxic. 

Nitroglycerin,  hydroxylamine,  and  nitrobenzene  act  chiefly  on  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  negative  group  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.  17) 
in  the  body. 

III.    Esters   of  Snlphnrous   and   Sulplinric   Acids. 

When  silver  sulphite  is  acted  upon  by  ethyliodide,  the  ethyl  ester 
of  sulphurous  acid  results, 

Ag.SO.OAg  +  2C2H5I  =  2AgI  +  C^Hj .  SO.OC.H,. 

Such  esters  may  be  regarded  as  the  derivatives  of  unsymmetrical 
sulphurous  acid ;  they  are  decomposed  by  potash  with  the  formation 
of  ethyl  sulphonic  acid, 

CaHgSOgOC^H^  +  H.O  ==:  CgHsSO^OH  +  C^H^OH. 

In  the  aromatic  series  the  corresponding  sulphonic  acids  are  of  very 
much  greater  importance,  and  are  formed  by  the  direct  action  of 
sulphuric  acid  upon  the  benzene  derivatives, 

CeHglH  +  bHiSOpH  =  H20  +  C6H5.SO,OH. 

This  method  of  introducing  the  sulphonic  acid  group  can  be  used 
with  a  very  large  number  of  substituted  aromatic  derivatives,  and 
gives  rise  to  a  group  of  substances  soluble  in  water  or  whose  sodium 
salt  is  soluble  in  that  liquid,  a  factor  of  importance  in  the  dye 
industry. 

The  interaction  of  sulphuric  acid  and  the  alcohols  gives  rise  to 
esters  which  are  much  less  stable  than  the  sulphonic  acids.  Ethyl 
alcohol  gives  the  ethyl  ester  of  sulphuric  acid 

SO<ggH, 


THE   ETHERS  103 

Phenol  gives  the  ester 

^^2\0H 

Unlike  the  previously  mentioned  derivatives,  the  hydrocarbon 
radical  is  attached  to  oxygen,  and  in  consequence  they  are  readily 
decomposed  by  alkalis,  regenerating  acid  and  alcohol. 

The  introduction  of  these  acidic  groupings  into  organic  substances 
results  in  a  great  drop  in  pharmacological  activity,  thus  the  toxic 
phenol  gives  the  inert  phenol  sulphonic  acid, 

or  the  equally  inert  phenyl  sulphuric  ester  (see  p.  56), 


SO,<(J^^''^' 


'2\0H 


The  hypnotic  properties  of  morphia  are  modified  and  considerably 
weakened  in  its  sulphuric  ester. 

Phenyl- dimethyl-pyrazol  is  toxic,  whereas  its  sulphonic  acid 
derivative  given  in  doses  of  5-6  gms.  to  rabbits  produces  no  effect. 

Dinitro-naphthol  is  toxic  in  small  doses,  whereas  its  sulphonic 
acid  is  inert. 

It  is  interesting  to  note  in  this  connexion  Ehrlich's  observation 
that  basic  dyes  stain  the  cortical  nerve  cells,  whereas  their  sulphonic 
acids  do  not* 

B.    THE  ETHERS. 

The  ethers  are  derivatives  of  the  alcohols  in  which  the  hydrogen 
of  the  hydroxyl  group  is  replaced  by  alkyls,  or  they  may  be  re- 
garded as  derivatives  of  water  in  which  both  hydrogen  atoms  have 
been  replaced  by  similar  or  dissimilar  groups  ;  they  are  consequently 
classified  as  simple,  such  as  ethyl  ether,  CgHg .  O.CgHg ;  or  mixed, 
such  as  methyl  ethyl  ether,  CHg .  O.CgHg. 

1.  Their  most  important  method  of  preparation  consists  in  the 
interaction  of  sulphuric  acid  and  the  alcohols.     Thus 

The  ethyl  ester  of 
sulphuric  acid. 


104  PHYSIOLOGICAL  PROPERTIES  OF  THE  ETHERS 

or  at  this  stage  a  different  alcohol  may  be  allowed  to  react  with  the 
sulphuric  ester  and  a  mixed  ether  obtained  thus 

S0/ggA  +  CH30H  =  S0/g}{  +  C,H,.0.CH3. 

The  ethers  are  volatile^  neutral  liquids,  only  slightly  soluble  in 
water.  The  lowest  members  are  gases,  the  next  liquids,  and  the 
highest  solids ;  their  boiling-points  are  much  lower  than  those  of 
the  corresponding  alcohols.  From  a  chemical  standpoint  they  show 
but  slight  reactivity,  since  all  the  hydrogen  atoms  are  attached  to 
carbon.  Although  not  easily  attacked  by  oxidizing  agents,  they 
yield,  when  oxidized,  the  same  products  as  their  corresponding 
alcohols. 

Physiological   Properties. 

The  replacement  of  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,  (CHg)20,  acts  very  like  nitrous  oxide,  producing  a 
rapid  and  transient  anaesthesia. 

The  anaesthetic  properties  of  diethyl  ether,  (C2H5)20,  are  well 
known.  Its  action  is  discussed  in  the  general  introduction  to  the 
narcotic  bodies. 

The  mixed  aliphatic  ethers  have  not  been  investigated,  and  it 
would  be  of  considerable  interest  to  find  out  whether  methyl  ethyl 
ether,  CHg.O.CgH^,  which  in  the  pure  state  boils  at  11° C,  has 
any  advantages  over  ordinary  diethyl  ether. 

As  the  molecular  magnitude  of  the  ethers  increases,  their  physio- 
logical reaction  becomes  less. 

Methylal,  CH2(OC2H3)2,  produces  anaesthesia  slowly;  the  action 
is  prolonged  and  deep  but  somewhat  uncertain,  and  patients  quickly 
become  accustomed  to  it. 

Acetal,  CH3CH(OC2H5)2,  is  also  an  uncertain  hypnotic,  and  pro- 
duces unpleasant  cardiac  symptoms  and  considerable  excitement. 

The  mixed  aromatic  aliphatic  ethers,  such  for  instance  as  phene- 
'^^>  C6H3.O.C2H5,  are  not  comparable  to  the  simple  aliphatic 
ethers,  and  the  derivative  mentioned  is  entirely  without  anaesthetic 
action. 


CHAPTER  V 

The  Alcohols  and  their  Derivatives  (continued).  The  chemical 
and  physiological  characteristics  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. 
L  THE  ALDEHYDES. 

The  aldehydes  are  the  first  oxidation  products  of  the  primary 
alcohols^  and  contain  the  group  (CHO)'  linked  on  to  an  organic 
radical. 

They  may  be  obtained  : — 

1.  By  the  oxidation  of  the  primary  alcohol,  which  readily  takes 
place  on  warming  them  with  potassium  bichromate  and  sulphuric 
acid, 

CH3.CH2OH    -^    CHg.C^g 

or  CgHgCHpH    ->    CgHg.CHO 

Benzyl  alcohol.  Benzaldehyde. 

2.  Aldehydes  of  both  aliphatic  and  aromatic  series  are  obtained  by 
the  distillation  of  the  lime  salts  of  the  respective  acids  with  calcium 
formate, 

(CH3COO)2Ca  +  (H.COO)2Ca  =  2CaC03  +  2CH3COH 

or    (CeH5COO)2Ca  +  (H.COO),Ca  =  2CaC03  +  2C6H5COH. 

3.  Aldehydes  of  the  aromatic  series  are  obtained  by  the  action  of 
chromyl  chloride,  CrOgClg,  upon  the  homologous  benzenes.  Thus 
toluene  gives  firstly  a  brown  addition  product,  CgH5CH3 .  (Cr02Cl2)2, 
which  is  decomposed  into  benzaldehyde,  CgH^ .  CHO,  by  the  action 
of  water. 

The  aldehydes  exhibit  the  usual  physical  properties  of  an  homolo- 
gous series  :  the  lower  are  volatile  liquids  soluble  in  water,  but  as 
the  molecular  magnitude  increases,  their  solubility  in  that  medium 
becomes  less  and  eventually  nil,  and  at  the  same  time  they  decompose 


106     ALIPHATIC  AND  AROMATIC  ALDEHYDES 

on  distillation  at  ordinary  pressures.  In  chemical  respects  they  are 
neutral  substances  characterized  by  their  great  reactivity.  They 
readily  pass  to  carboxylic  acids,  and  in  consequence  are  powerful  re- 
ducing agents — the  aliphatic  to  a  greater  extent  than  the  aromatic  : 

CH3.CHO  +  O  =  CH3COOH 
CeHgCHO  +  O  =  CeHgCOOH. 

The  majority  of  the  aliphatic  aldehydes  are  converted  into  resins 
by  the  alkalis,  but  those  of  the  aromatic  series  give  rise  to  a  mixture 
of  acid  and  alcohol,  e.g. 

SCgH^CHO  +  KOH  =  CeH^COOK  +  CeHsCH^OH. 
On  reduction  they  yield  primary  alcohols  : 

R.CH0  +  2H  =  KCHgOH. 
Under  ordinary  circumstances  they  do  not  unite  with  water,  but 
many  of  their  halogen  substitution  products  yield  readily-decom- 
posable hydrates;  e.g.  chloral,  CCI3.  CHO,  gives  chloral  hydrate, 

CCI3 .  CH<^Qjj 

They  unite  with  prussic  acid,  forming  the  nitriles  of  the  hydroxy 
acids,  e.g. 

CH3CH0-hHCN  =  CH3.CH<:^^^ 

Nitrile  of  lactic  acid. 
CeH,CHO  +  HCN  =  CeH^.CH^gJJ 

Nitrile  of  mandelic  acid. 

Similarly  they  combine  with  sodium  bisulphite,  forming  crystal- 
line derivatives  that  may  be  employed  for  their  purification — 

CH3CH0  +  S0<gNa  =  CH3.CH<OHo^^ 

With  ammonia  the  aliphatic  aldehydes  also  form  compounds  which 
may  be  similarly  employed  for  their  purification, 

CH,CHO  +  NH3  =  CH, .  CH/g^ 

but  with  the  aromatic  amines  a  more  complicated  reaction  occurs. 
Aldehydes  of  both  series  combine  with  phenylhydrazine  and 
hydroxylamine, 

R.CHO  +  H^N .  NHC^H^  =  E.CH  :  N.NHCgH^  +  Hfi 
OP  ECHO  +  H2N.OH  =  RCH  :  N.OH  +  Hp. 


PHYSIOLOGICAL  PROPERTIES  ItTT 

The  lower  members  o£  the  aliphatic  series  readily  polymerize, 
formic  aldehyde,  for  instance,  changes  slowly  at  20°,  but  rapidly 
at  ordinary  temperatures,  to  trioxymethylene,  (H.CH0)3.  Small 
quantities  of  acids  convert  acetaldehyde,  CH3CHO,  at  ordinary 
temperatures  into  paraldehyde,  (CHgCHOjg,  but  if  the  temperature 
be  kept  low  metaldehyde,  (CHaCHOjg,  is  formed. 

The  aromatic  aldehydes  are  distinguished  from  those  of  the  other 
series  by  not  undergoing  such  molecular  condensations,  i.e.  by  not 
polymerizing. 

Physiological  Characteristics. 

The  physiological  characteristics  of  the  alkyl  group,  observed  in 
this  class  of  derivatives,  are  probably  more  marked  owing  to  the 
great  chemical  reactivity  of  the  CHO  group.  In  formaldehyde,  the 
effect  on  the  tissues  and  cells  as  well  as  its  great  antiseptic 
properties  are  prominent  characteristics.  But  in  acetaldehyde, 
CH3CHO,  the  anaesthetic  properties  are  more  marked,  and  still 
more  pronounced  in  its  polymeric  form  paraldehyde,  which  is  not  so 
toxic  as  metaldehyde. 

The  entrance  of  hydroxyl  groups  into  the  aldehyde  molecule 
depresses  their  physiological  reactivity,  and  the  aldose  sugars^  for 
instance,  show  no  trace  of  narcotic  properties. 

The  aromatic  aldehydes  are  only  slightly  toxic,  owing  to  the  ease 
with  which  they  are  oxidized,  and  their  physiological  properties  are 
practically  those  of  the  corresponding  aromatic  acid. 

The  strong  antiseptic  action  and  hardening  effects  of  formalde- 
hyde on  the  tissues  are  closely  related  to  its  exceptional  reactivity. 
Owing  to  this  reactivity  various  compounds  can  be  obtained,  and  it 
is  necessary  from  a  physiological  standpoint  that  these  should  slowly 
break  down  with  the  liberation  of  formaldehyde. 

Such  substances  are  the  compounds  resulting  from  the  interac- 
tion of  formaldehyde  and  gelatine,  starch,  dextrine,  and  milk-sugar. 
They  are  for  the  most  part  very  mild  antiseptics. 

Formaldehyde  is  not  usually  given  internally.  Recently,  tablets 
known  as  formamint  have  been  introduced,  in  which  the  formic 
aldehyde  is  combined  with  milk-sugar,  and  liberated  on  solution. 
They  are  intended  for  the  treatment  of  septic  conditions  in  the 
mouth  and  fauces.  Maguire,  in  1900,  described  a  method  of 
injecting  a  1  in  2,000  solution  of  formic  aldehyde  into  the  median 
basilic  vein  for  the  disinfection  of  the  lungs  in  phthisis,  but 
although  he  reported  good  results  there  is  no  evidence  that  an 


108  THE  ALDEHYDES 

antiseptic  of  sufficient  strength  can  be  employed  in  this  manner 
without  producing  toxic  symptoms.  Experiments  ad  hoc  by  one 
of  the  present  writers  will  be  found  in  the  Guy^s  Hospital  'Reports, 
vol.  Iviii.  Recently^  formic  acid  and  the  formates  have  been 
credited  with  tonic  properties,  but  the  clinical  evidence  is  as  yet 
meagre. 

The  formyl  compound  of  urea,  CO(N  :  CH2)2,  which  slowly  breaks 
off  formaldehyde  and  possesses  no  smell,  has  been  introduced. 

Compounds  have  also  been  formed  between  formaldehyde  and  the 
antiseptic  group  of  phenols,  such  as  eugenol,  thymol,  and  iodo 
thymol;  these  readily  break  down  into  their  components,  and  a 
combined  action  of  antiseptic  substances  is  obtained. 

When  ammonia  acts  on  formaldehyde,  hexamethylene  tetramine 
results.  This  also  in  all  probability  liberates  formaldehyde  in  the 
body,  and  to  this  may  be  ascribed  its  value  as  a  urinary  antiseptic ; 
it  limits  suppuration  anywhere  along  the  urinary  tract  from  the 
kidneys  to  the  orifice  of  the  urethra,  and  on  this  account  is  the  best 
urinary  antiseptic  we  possess.  It  goes  by  a  number  of  trade  names, 
namely,  urotropine,  aminofonu,  forxnin,  cystamine,  cystogen, 
metramine,  nretone,  iirisol,  and  vesaloine. 

Paraldehyde,  a  polymeric  form  of  acetaldehyde,  has  the  dis- 
advantage of  a  very  unpleasant  odour  and  taste.  It  acts  first  on 
the  higher  cerebral  centres  and  then  on  other  parts  of  the  central 
nervous  system,  finally  producing  spinal  anaesthesia  and  death.  It 
has  no  depressant  action  on  the  heart  (cf.  chloral),  and  it  may  be 
given  for  long  periods  with  safety.  Its  main  disadvantage  is  its 
irritant  action  on  the  gastric  mucosa.  It  has  antiseptic  powers, 
like  acetaldehyde,  and  can  be  ^combined  with  starch,  dextrine,  &c., 
to  form  antiseptic  applications. 

Physiological  Characteristics  of  Halogen  Substitution 
Frodncts  of  the  Aldehydes. 

The  entrance  of  chlorine  into  acetaldehyde  with  the  formation  of 
trichloracetaldehyde  or  chloral,  CCI3 .  CHO,  causes  a  large  increase 
in  narcotic  power,  but  the  simultaneous  action  of  the  halogen  is 
observed,  viz.,  depression  of  cardiac  and  respiratory  centres. 

That  the  action  of  chloral  is  due  to  both  halogen  and 
aldehyde  groups  is  seen  by  the  fact  that  on  oxidation  to  trichlor- 
acetic acid,  CCI3 .  COOH,  the  physiological  reaction  disappears, 
whereas  on  reduction  to  trichlorethyl  alcohol,  CCI3 .  CHgOH,  a  sub- 
stance with  narcotic  properties  is  obtained,  although  these  are  much 


HALOGEN  DERIVATIVES  OF  THE  ALDEHYDES  109 

less  powerful  than  those  of  the  original  chloral.  The  action  of  the 
chlorine  may  be  traced  by  comparing  chloral  with  paraldehyde, 
since  the  latter  has  no  depressant  action  on  cardiac  and  respiratory 
activity,  and  indeed  is  said  to  act  as  a  mild  cardiac  tonic. 

Chloral,  CCI3CHO,  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-smelling  liquid,  which  poly- 
merizes on  keeping.  Unlike  acetaldehyde  it  combines  with  water, 
forming  a  crystalline  derivative, 

CCl3CH<(^Qjj 

chloral  hydrate,  a  substance  which,  contrary  to  the  general  rule, 
contains  two  hydroxyl  groups  linked  into  one  carbon  atom.  It 
readily  yields  chloroform  with  even  dilute  solutions  of  alkali, 
CCl3.CHO  +  KOH  =  CHCl3  + H.COOK,  and  it  was  this  that  led 
Liebreich  in  1869  to  try  its  hypnotic  action,  since  it  might  be 
supposed  that  this  decomposition  would  take  place  in  the  body; 
it  was,  however,  shown  later  that  chloral  is  reduced  to  trichlorethyl 
alcohol,  CCI3COH,  and  is  eliminated  as  a  derivative  of  this  sub- 
stance and  glycuronic  acid  (see  p.  60) ;  consequently  the  old  idea 
of  its  physiological  reaction  had  to  be  abandoned. 

Butyl  chloral,  CCI3 .  CHg .  CHO,  has  a  more  powerful  action  than 
chloral,  but  the  effects  pass  off  more  rapidly.  Butyl  chloral  hydrate 
is  said  not  to  depress  the  heart,  but  this  is  by  no  means  certain. 
There  is  no  explanation  for  its  specific  effect  on  the  fifth  nerve. 
Trigemin  is  a  compound  of  butyl  chloral  hydrate  and  pyramidon. 

The  corresponding  brom  and  iodo  substitution  products  of 
acetaldehyde  show  very  considerably  diminished  hypnotic  action. 

Bromal,  CBr3 .  CH(0H)2,  in  animals  causes  irritation  of  the 
respiratory  passages,  and  in  larger  doses  dyspnoea  and  cyanosis; 
still  larger  doses  produce  anaesthesia  but  not  hypnosis. 

lodal,  Cl3.CH(0H)2.  The  replacement  of  bromine  by  iodine 
appears  to  increase  the  action  upon  peripheral  nerve-endings  and 
muscles,  but  the  substance  has  only  slight  hypnotic  properties. 
The  mono-iodo  derivative  CH2l.CH(OH)2  has  not  such  a  powerful 
action  as  chloral,  but  has  a  strong  depressant  action  on  the  heart. 

Owing  to  the  reactivity  of  the  aldehyde  grouping  in  chloral  it  is 
possible  to  modify  the  substance  in  various  directions;  up  to  the 
present  it  has  been  found  that  all  those  derivatives  which  easily 
split  off  chloral  in  the  organism  show  the  ordinary  chloral  reaction. 


110   HALOGEN  DERIVATIVES  OF  THE  ALDEHYDES 

whereas  the  more  stable  either  do  not  possess  hypnotic  properties 
or  are  toxic  substances.  Combinations  with  other  hypnotics  have 
not  given  any  very  striking  results,  thus  chloral  alcoholate, 

formed  by  the  addition  of  chloral  and  alcohol  has  no  advantages 
over  the  hydrate  itself. 

Dormiol,  introduced  by  Euchs,  and  formed  by  the  union  of  chloral 
and  amyl  alcohol, 

.CH,  ,0H 


\aH 


CCI3 .  CHO  +  OH-C^CHg  =  CCI3 .  CH<(q_ 


\C„H 


2"5 

is  not  very  stable,  being  easily  broken  down,  probably  even  by 
solution  in  water,  into  its  constituents.     It  has  a  penetrating  smell 
and  taste,  and  its  action  is  not  reliable. 
Chloral  urethane  (ural,  somnal), 

CCI3 .  CH^-jj^  jj^QQ^^jj^^ 

was  prepared  in  the  hope  that  the  hypnotic  effects  of  ethyl  urethane 
might  be  added  on  to  that  of  chloral.  An  apparently  identical 
body  is  known  as  uralinm.  The  hypnotic  effect  wears  off  before  the 
toxic,  and  in  animals  paralysis  of  the  hindquarters  accompanies  the 
sleep  induced  by  the  drug.  Diarrhoea,  diuresis,  salivation,  itching, 
and  disturbances  of  respiration  are  produced  by  large  doses. 

Similarly,  chloral  was  combined  with  acetone,  which  has  a  slight 
narcotic  action,  but  the  resulting  substance,  chloral  acetone, 

CCI3 .  CHOH.CH2 .  CO.CH3 , 

possesses  but  little  narcotic  action,  and  in  the  organism  is  dehy- 
drated with  formation  of  CC13.  CH  :  CH.CO.CH3.  On  the  other 
hand  the  corresponding  aromatic  derivative  chloral  acetophenone, 
CCI3.  CH.OH.CHg.  CO.CgHg  (the  combination  with  acetophenone, 
a  powerful  hypnotic),  has  not  the  slightest  hypnotic  action,  but 
like  the  previous  compound  it  is  eliminated  as 
CCI3.CH:  CH.CO.CgHg. 
Then,  in  another  direction,  Mering  and  Zuntz  introduced  the 
compound  of  f  ormamide  and  chloral,  chloral  formamidei  or  chloral 
amide.     This  is  formed  by  the  direct  union  of  the  two, 

CClg.CHO  +  H.CONH^  =  CCI3 .  CH<J|  q^.jj 


ALDEHYDE   DERIVATIVES  111 

a  reaction  which  does  not  take  place  with  the  unsubstituted 
acetaldehyde.  This  derivative  has  a  slightly  bitter  taste,  less 
harmful  action  than  chloral,  but  on  the  other  hand  much  less 
hypnotic  power.  Since  urochloralic  acid  is  found  in  the  urine,  its 
action  probably  depends  on  its  slow  decomposition  in  the  organism 
into  chloral  itself. 
Chloral  ammonia, 

CCl3.CH<(-^jj^^ 

was  intended  to  combine  the  hypnotic  action  of  chloral  hydrate 
with  the  stimulant  action  of  ammonia  on  the  heart  and  respiration. 
The  condensation  products  of  chloral  with  various  aldoximes  and 
ketoximes  have  given  products  of  no  pharmacological  value.  These 
derivatives,  formed  according  to  the  general  reaction 

R  :  N.OH  +  CCI3 .  CHO  =  C.CI3 .  CH<^q^  .  ^ 

are  but  slightly  soluble  in  water. 

The  products  resulting  from  the  condensation  of  chloral  with 
various  sugars  have  been  investigated  by  Hauriot  and  Richet,  and 
others. 

Milk-sugar  chloralide  has  no  narcotic  action,  but  produces  epilep- 
tiform fits  with  bronchorrhoea  and  asphyxia. 

Chloral  (free  from  water)  and  glucose  are  combined  as  chloralose, 
CgHjjClgOg.  It  is  a  somewhat  rapid  hypnotic,  but  is  less  easily 
tolerated  than  chloral  hydrate.  It  may  produce  restlessness,  diplopia, 
tremors,  and  haemoglobinuria.  Its  main  toxic  action  is  on  the  re- 
spiratory centre.  Richet  says  it  acts  on  the  grey  matter  of  the  cortex 
cerebri,  the  cord  being  unaffected.  The  uncertain  results  are  said 
to  be  due  to  the  formation  of  a  second  compound,  parachloralose, 
which  is  toxic  without  being  hypnotic. 

Arabino-chloralose  is  easily  soluble  in  water,  produces  no  stage 
of  excitement,  and  has  a  minimum  lethal  dose  equal  to  twice  that 
of  chloralose.  It  is,  however,  a  much  less  powerful  hypnotic. 
A  second  compound,  pararabino- chloralose,  is  only  slightly  soluble. 
The  pentose  compounds  are  probably  less  active  and  less  toxic 
owing  to  their  greater  stability  in  the  body. 

When  chloral  reacts  with  antipyrine  several  substances  result — 
hypnal,  CjgHjgNgOgClg,  melting  at  67^-6^°,  and  chloralantipyrin, 
CjgHjgClgNgOg,  formed  at  a  higher  temperature  and  possessing  no 
physiological  reaction.  Hypnal  has  a  similar  toxic  and  hypnotic 
action  to  chloral  hydrate.     The  toxic  dose  is  the  same,  so  that  the 


112  THE  KETONES 

presence  of  antipyrin  heightens  the  toxicity  o£  the  chloral.     It  is 
used  as  an  analgesic  as  well  as  a  hypnotic. 

The  various  condensation  products  of  choral  with  aromatic 
hypnotics,  investigated  by  Tappeiner,  have  little  or  no  physio- 
logical reaction. 

11.    THE  KETONES. 

The  ketones  are  a  group  of  substances  closely  related  to  the 
aldehydes,  both  contain  the  carboxyl  group  linked,  in  the  case  of 
the  former  compounds,  to  alkyl  group,  but  in  the  case  of  aldehydes 
to  an  alkyl  group  and  hydrogen. 


CH,  CH 


CO      Dimethyl  ketone,    CO      Acetaldehyde. 
H,  H 


i 


The  relationships  will  be  noticed  in  their  more  important  methods 
of  preparation  and  general  reactions.  They  may  be  divided  into 
two  classes,  in  a  similar  manner  to  the  ethers :  Simple,  such  as 
acetone,  CH3.CO.CH3j  and  Mixed,  such  as  methyl  ethyl  ketone, 
CH3.CO.C2H,. 

They  are  formed  by  the  oxidation  of  secondary  alcohols, 

CH3.CHOH.CH3    ->     CH3.CO.CH3 

Jso-propyl  alcohol. 

CgHg    .    CHOH.CH3  -^  C6H5.CO.CH3 

Phenylmethyl  carbinol.  Acetophenone. 

or  by  the  distillation  of  the  lime-salt  of  the  corresponding  acid, 

(CH3COO)2Ca  =  CaCOg  +  CHgCOCHg 
(CfiHgCOOjaCa  =  CaCOg  +  CgH^.CO.CeHg 

whereas  the  mixed  ketones  are  obtained  from  the  lime-salt  of  two 
acids, 

(CH3COO)2Ca  +  (C2H3COO)2Ca  =  2CH3 .  CO.CoH^  +  CaC03 
(C6H5COO)2Ca  +  (CH3COO),Ca  =  2C6H5COCH3  +  2CaC03. 

The  ketones  are  neutral  bodies,  and  the  lower  members  of  the 
series  are  volatile  etherial-smelling  liquids.  They  are  much  less 
readily  oxidized  than  the  aldehydes,  and  unlike  that  group  of 
substances  do  not  polymerize. 


PHYSIOLOGICAL  PROPERTIES  113 

Their  reactions  with  hydroxylamine,  phenylhydrazine,  and  prussic 
acid  resemble  very  closely  those  of  the  previous  group, 

(CH3)2CO  +  H2N.NHCeH5  =  (^3)20  :  N.NHC.H,  +  Hp 

CeHgCO.CHg+H^N.OH  =  C^H,  .  C(N.0H).CH3 

.OH 
CH,.C0.CH3  +  HCN  =  CH3C^CH3 

Those  containing  a  methyl  group  react  with  sodium  bisulphite, 
forming  crystalline  derivatives  which  may  be  employed  for  puri- 
fication owing  to  the  ease  with  which  they  are  obtained,  and 
then  decomposed  by  acids  or  alkalis  with  the  recovery  of  the 
ketone. 

CH3.CO.CH3  +  NaHS03  =  (011^2^(^25,0^ 
and      (CH3)2C^gQp-^^_^  -^^Qjj  ^  (CH3)2CO  +  Na^SOg  +  Rfi, 


Physiological  Characteristics. 

The  ketones  in  general  physiological  action  closely  resemble  the 
alcohols,  they  give  rise  to  narcosis  and  lowering  of  the  blood 
pressure.  Acetone,  CH3 .  CO.CH3,  produces  intoxication  and  sleep, 
but  is  less  powerful  than  ether  or  chloroform  and  less  toxic  than 
ethyl  alcohol.  The  hypnotic  properties,  traceable  to  the  ethyl  groups, 
are  clearly  seen  in  diethyl  ketone,  CgH^.CO  .  CgHg  (Propion),  which 
was  introduced  as  a  hypnotic  and  anaesthetic,  but  its  solubility  in 
water  is  not  great,  and  this,  combined  with  an  unpleasant  taste, 
renders  it  of  little  use. 

Similar  hypnotic  properties  are  noticed  in  dipropyl  ketone, 
but  as  the  molecular  magnitude  increases  the  solubility  in  water 
decreases,  and  the  higher  ketones  are  not  likely  to  be  of  any 
pharmacological  value. 

The  diminution  in  physiological  action  which  accompanies  the 
introduction  of  hydroxyl  groups  is  observed  in  the  case  of  the 
inert  ketoses  (ketone  sugars)  just  as  it  is  in  that  of  the  aldehydes. 

The  stability  of  the  ketonic  acids  depends  on  the  relative  positions 
of  the  ketonic  and  carboxyl  groupings.  Thus  acetoacetic  ester, 
CH3CO.CH2 .  COOH,  is  very  unstable,  readily  breaking  down 
into  acetone. 

Levulinic  acid,  CHgCOCHgCHg .  COOH,  on  the  other  hand,  is 
more  stable,  and  at  the  same  time  much  more  toxic. 

I 


114  THE  SULPHONALS 

Ketones,  both  simple  and  mixed,  aliphatic  and  aromatic,  are  ob- 
served to  possess  hypnotic  properties.  Benzophenone,  CgHg .  COCgHg , 
has  a  slight  action  but  much  less  than  the  aliphatic  derivatives. 
In  the  mixed  aromatic  and  aliphatic  ketones  the  action  depends 
largely  on  the  nature  of  the  latter  radical.  Thus  acetophenone, 
CgHgCO.CHg  (Hypnone),  has  a  marked  hypnotic  action. 

The  attempts  which  have  been  made  to  increase  the  solubility  of 
acetophenone  by  the  introduction  of  the  amido  group  or  its  substi- 
tuted derivatives  have  not  led  to  substances  of  practical  importance. 

Phenyl  ethyl  ketone,  CgHgCOCgHg,  has  a  more  powerful  action 
than  acetophenone. 

DERIVATIVES    OF  THE   KETONES. 
SULPHONALS. 

When  water  is  withdrawn  from  a  mixture  of  alcohol  and  alde- 
hyde, the  acetals  result, 

CH3CHO  +  2C2H5OH  =  CH3CH(OC2H5)2  +  H20, 

but  a  corresponding  reaction  does  not  take  place  with  the  ketones. 
The  corresponding  sulphur  derivatives,  however,  are  known,  and 
are  obtained  by  the  action  of  a  dehydrating  agent,  such  as  hydro- 


chloric  acid 

on  a  mixture  of  ketone  and  thioalcohol, 

CH3 

c6+ 

I--.... 
CH3 

=  H,0 
HiSC^Hj 

CH3 

/S.C2H5 

+  c<( 

CH3 

Acetone. 

Ethyl  mercaptan. 

Acetone-ethyl 
mercaptol. 

The  resulting  substances  are  liquids  with  an  unpleasant  smell,  and  are 
readily  oxidized  by  potassium  permanganate  to  a  group  of  substances 
called  sulphones, 

CH3  CH3 

i    .SC^H,  lySOAHs 

C<(  +04  =  C< 

nS.C.H^  t^SOAH, 

CH3  CH3 

Acetone-diethyl  sulphone. 

Many  of  these  derivatives,  investigated  by  Baumann  and  Kast, 
have  valuable  hypnotic  properties. 


PHYSIOLOGICAL  PROPERTIES  115 

They  found  the  disulphones  containing  sulpho  groups  joined  to 
separate  carbon  atoms,  for  instance,  ethylene-diethyl  sulphone, 


CH2.SOAH5 

Ho.  SOoCoH, 


i 


■5 

had  no  physiological  reaction.  Also,  that  disulphones  derived 
from  methane  were  without  action,  as,  for  instance,  methylene- 
dimethyl  sulphone, 

^"^^^sO^CHg 
or  methylene-diethyl  sulphone, 

^^2\sOAH5 
When  hydrogen  in  the  original  methane  of  the  methylene-dimethyl 
sulphones    was    substituted    by    methyl    again,   inert    substances 
resulted, 

^^^•^^XSO^CHg      ^"^       CHg/'^XSO^CHg 

Ethylidene-dimethyl  sulphone. 

But  with  the  entrance  of  ethyl  groups  narcotic  properties  followed ; 
thus 

CgHg  .  CH<(^oq2       3  Jias  a,  slight  narcotic  action ; 

^TT^\C<^oQ^pTT^  has  a  slight  narcotic  action; 

C2H5\p/^S02CH3    is  isomeric  with,  and  has  precisely  the  same 
^2^6^   \SO2CH3    action  as,  sulphonal. 

And  precisely  corresponding  physiological  reactions  are  observed 
in  the  derivatives  of  methylene-diethyl  sulphone ;  thus 


CH3  .  CH<^oQ^p^TT^     has  a  similar  action  to  sulphonal. 

<SO  O  TT 
SO^r^H^     produces  sleep  and  has  toxic  properties. 


'2^2"5 
'SO2C2H. 
>2C2H5 

(Sulphonal)  in  small  doses  is  excreted  un- 
CH3\p//S02C2H5   changed  in  urine  and  produces  sleep ;  in  large 
CH3/'   \SO2C2H5   doses  it  produces  inco-ordination,  and  a  con- 
dition resembling  drunkenness. 

I  2 


116  PHYSIOLOGICAL  PROPERTIES  OF  SULPHONES 

C2H5\p /SOgCgHg  (Trional)    has  a   more   powerful   and   pro- 
CH3X    xSOgCgHg  longed  action  than  sulphonal. 

(Tetronal)  is  much  less  soluble  than  the  other 
p2    sXc/      2   2    5  compounds    and    has    the     most    powerful 
^    ^  2  2    5  hypnotic  action  of  all  the  sulphones. 

The  intensity  of  the  action  of  these  sulphones  is  consequently- 
dependent  on  the  number  of  ethyl  groups  they  contain :  this, 
apparently,  is  only  true  for  dogs.  Clinically,  the  distinction  does 
not  hold  good. 

Sulphonal  and  trional  are  only  slightly  soluble  in  water,  and 
hence  are  but  slowly  absorbed ;  consequently,  their  action  tends  to 
be  unduly  prolonged  ;  also  the  use  of  these  substances,  if  continued 
for  a  long  time,  may  bring  about  destructive  action  on  the  red 
blood  corpuscles  and  consequent  haematoporphyrinuria. 

To  increase  the  solubility  of  these  derivatives,  attempts  have 
been  made  to  produce  pharmacologically  active  amido  substitution 
products,  but  so  far  without  success. 

As  regards  the  metabolic  changes  of  the  sulphones,  the  interest- 
ing observation  has  been  made  that  those  which  are  most  stable 
outside  the  body  are  physiologically  reactive,  and  are  to  a  greater  or 
less  extent  broken  down  by  the  organism,  whereas  those  that  are 
least  stable  are  inert,  and  pass  through  unchanged.  Thus,  of  the 
previously  mentioned  substances,  ethylene-diethyl  sulphone,  methy- 
lene-diethyl sulphone  (easily  decomposed  by  alcoholic  potash),  methy- 
lene-dimethyl  sulphone,  ethylidene-dimethyl  sulphone  are  found 
unaltered  in  the  urine;  whereas  sulphonal,  'reversed^  sulphonal, 
trional,  and  tetronal  (substances  unacted  upon  by  acids  and  alkalis, 
and  most  oxidizing  and  reducing  agents)  are  to  a  varying  extent 
decomposed. 

It  is,  however,  true  that  sulphonals,  which  are  but  slightly  stable, 
and  hence  readily  decomposed  in  the  body,  may  have  no  hypnotic 
action.    Thus  the  diethyl  sulphone  prepared  from  acetoacetic  ester, 

CH3 .  C(SO,C,H,), .  CH, .  COOC^H^, 

has  no  hypnotic  action,  although  no  trace  of  it  can  be  found  in  the 
urine,  and  the  same  is  true  of  its  ethyl  derivative, 

CH3.  C(SO,C,H,), .  CH(C,H,).C00C2H,, 

in  spite  of  the  number  of  ethyl  groups. 


1 


THE  ACIDS  117 

III.     THE  ACIDS. 

The  organic  acids  are  characterized  by  the  presence  of  the  so- 
called  carboxyl  group  .COOH  and  their  basicity  determined  by  the 
number  of  these  present.  The  acids  of  the  paraffin  series  are 
termed  fatty,  owing  to  the  occurrence  of  their  higher  members 
in  the  natural  fats;  these  substances,  on  boiling  with  alkalis, 
give  rise  to  glycerin  and  the  corresponding  alkali  salts — soaps ; 
and  hence  the  process  of  converting  an  ester  into  an  acid  and 
alcohol  has  been  termed  saponification. 

Methods    of  Preparation. 

The  most  important  general  methods  of  preparation  are  : — 
1.  The  oxidation  of  the  primary  alcohols  and  aldehydes^ 


CH3 .  CH^OH 

->     CH3.COOH 

CH3.CHO 

->     CH3COOH 

and  in  the  aromatic  series, 

CeH,CH,OH 

-*     CeH^COOH 

CeH.COH 

->     CgHgCOOH. 

2.  The  addition  of  water  to  the  nitriles,  often  carried  out  by 
treatment  with  50  per  cent,  sulphuric  acid  and  water.  Or  the 
reaction  may  be  effected  by  means  of  alkalis, 

CH3CN  +  2H2O  +  HCI  =  CHgCOOH  +  NH^Cl 
CgH^CN  +  SHp  +  HCl  =  CeH^COOH  +  NH^Cl 
CH3.CH2CN  +  H2O  +  KOH  =  CH3CH2CGOK  +  NH3 

3.  The  aromatic  monocarboxylic  acids  are  readily  obtained  from 
the  benzene  homologues  by  oxidation  (see  p.  42)  (other  methods 
will  be  mentioned  later), 

C6H5CH3  +  3O  =  CgHsCOOH  +  HgO 

Toluene. 

O.C,H,(CH3),    _*    C,H,(C00H)2 

0-Xylene.  PhthaUc  acid. 

The  lower  members  of  the  fatty  series  are  soluble  in  water,  but 
this  property  rapidly  decreases  with  increasing  molecular  weight. 
The  lower  may  be  distilled  without  change,  but  the  higher  mem- 
bers are  decomposed.  As  the  molecular  magnitude  increases  the 
acidity  diminishes. 

The  aromatic  acids  are  found  (partly  in  the  free  state)  in  many 


118  THE  ACIDS 

balsams  and  resins,  and  in  the  animal  organism ;  they  result  from 
the  decomposition  o£  albuminous  substances,  and  are  crystalline  solids 
which  generally  sublime  undecomposed,  and  are  only  soluble  with 
difficulty  in  water. 

Physiological  Properties. 

The  entrance  o£  the  acidic  carboxyl  group  into  the  members  of 
the  limit  hydrocarbons,  resulting  in  the  formation  of  the  acids, 
gives  rise  to  a  class  of  substances  with  but  slight  toxic  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 
reducing  agent,  to  which,  probably,  its  antiseptic  action  may  be 
partly  ascribed,  and,  unlike  the  other  members  of  the  series,  it  forms 
no  acid  chloride,  and  its  nitrile,  prussic  acid,  (HCN),  has  acidic  pro- 
perties ;  it  is,  further,  a  much  more  powerful  acid  than  acetic. 

Of  the  fatty  series,  formic  acid  has  the  most  powerful  antiseptic 
properties,  acetic  less,  propionic  acid  least;  on  the  other  hand,  the 
corresponding  action  of  the  benzene  substituted  acids  increases  with 
increase  of  molecular  weight.     Thus  phenylacetic  acid, 

CgHsCH^COOH, 
is  less  powerful  than  phenylpropionic,  CgHg.CHg.CHg.COOH,  and 
this  less  than  phenylbutyric  acid,  CgH^CHg .  CU^ .  CHg .  COOH. 

Formic  acid  is  much  more  toxic  than  the  other  members  of 
the  series,  except  butyric  acid,  which  has  also  slight  narcotic 
properties. 

The  introduction  of  the  hydroxyl  group  into  butyric  acid,  resulting 
in  the  formation  of  /S-oxybutyric  acid,  CHg.CHOH.CHg.COOH, 
gives  rise  to  a  substance  which  exists  in  three  optical  isomerides, 
ascribed  to  the  presence  of  an  asymmetric  carbon  atom  marked  with 
a  star ;  the  inactive  acid  has  no  physiological  action,  but  the  other 
modifications  produce  acid  intoxication  similar  to  that  seen  in  diabetic 
coma. 

In  a  very  similar  manner  intraperitoneal  injections  of  the  various 
optical  modifications  of  tartaric  acid  show  that  the  laevo-Yot&tory 
acid  is  the  most  toxic,  the  decctro  acid  about  one-half,  whereas  racemic 
acid  is  not  more  than  one-quarter  as  toxic  as  the  laevo  form. 

With  the  dibasic  acids  the  simplest,  oxalic, 

COOH 

I 
COOH, 


PHYSIOLOGICAL  PEOPERTIES  119 

is  toxic,  but  the  toxicity  very  rapidly  decreases  as  the  carboxyl 

groups  are  separated, 

CH^.COOH 

CH„<ri/-iXxj  malonic  acid,  I  succinic  acid, 

2\LOOH  ^jj^    (.QQjj 

glutaric  acid. 


CHgCOOH 


CH. 


CHo .  COOH 


In  the  unsaturated  acids, 

COOH.C.H  H.C.COOH 

fumaric,  11  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 
poisonous  for  higher  animals. 

The  acids  of  the  fatty  series,  probably  owing  to  the  presence  of 
the  carboxyl  group,  do  not  show  narcotic  properties,  or  do  not  show 
them  to  any  marked  extent.  Butyric  acid  has  a  slight  action  which 
may  be  traced  to  the  ethyl  group,  CgHg .  CH.COOH ;  it  is  more 
marked  in  dimethyl-acetic  acid, 

^^3^CH.C00H, 

and  still  more  in  dimethylethylacetic  acid, 

CH3) 

CH3  C.COOH, 

of  which  3-5  gms.  produce  sleep  and  4-5  sleep  and  death  (rabbits). 

The  introduction  of  the  carboxyl  group  into  aromatic  sub- 
stances is  of  great  pharmacological  importance,  since  a  drop  in 
toxicity  results.  Thus  benzene  may  not  be  taken  in  doses  of 
more  than  2  to  8  gms.  per  day,  whereas  benzoic  acid,  CgHgCOOH, 
is  very  much  less  toxic,  and  may  be  taken  in  doses  of  12  to  16  gms. 
Naphthalene  in  large  doses  is  toxic ;  its  carboxylic  acid  has  no  physio- 
logical reaction.  Not  more  than  1  to  2  gms.  of  phenol  can  be 
administered,  but  1 : 3-  and  1 : 4-hydroxybenzoic  acid, 

PTT  /OH 
^6^*\C00H, 


120  EADICALS  OF  THE  ACIDS 

have  no  action,  and  salicylic  acid,  the  1 : 2  derivative,  may  be  given 
in  doses  twice  to  three  times  as  great  as  those  of  phenol  without  toxic 
symptoms  appearing.  The  toxic  aniline  becomes  the  inert  wz-amido 
benzoic  acid, 

^6^4\C00H, 

by  the  introduction  of  the  carboxyl  group  into  the  nucleus.  The 
replacement  of  hydrogen  in  the  methyl  group  in  phenacetin, 

^e^^XNH.COCHg  ^'^' 
with  the  formation  of 

^6^4\NH.CO.CH2.  COOH 

brings  about  the  loss  of  its  toxic  and  therapeutic  properties. 

Allusion  may  be  made  here  to  the  iutrodnction  of  the  acid  radical 
of  either  series  into  physiologically  active  basic  bodies.  The  radical 
of  acetic  acid,  or  acetyl,  (CH3CO)',  of  lactic  acid,  or  lactyl, 

(CH3 .  CH<^^Q  J) 

benzoic  acid,   or  benzoyl,  (CgH^ .  CO/,  salicylic  acid,  or   salicyl, 

(CgH^^^^Q  y, 

&c.,  can  readily  replace  the  hydrogen  of  the  amido  or  imido  group 
through  the  interaction  of  the  acid  itself  or  the  corresponding  acid 
chloride  with  the  base  in  question  (see  pp.  36,  43). 

The  resulting  substances  are  of  great  importance  in  the  synthetic 
preparation  of  drugs ;  from  a  chemical  standpoint  such  derivatives 
are  more  stable,  and  less  readily  oxidized  than  the  bases  from  which 
they  are  obtained.  The  lactyl  substitution  products  are  more  soluble 
than  the  acetyl,  and  the  salicyl  least ;  and  the  latter  are  broken 
down  with  such  difficulty  by  the  organism  that,  as  a  general  rule, 
they  do  not  possess  physiological  action.  The  pharmacological 
reaction  of  this  group  of  substances  is  that  of  the  base  from  which 
they  are  obtained. 

The  action  of  the  benzoyl  residue  when  introduced  into  the 
alkaloids  is  remarkable ;  thus  ecgonine-methyl-ester  (see  p.  259)  has 
no  anaesthetic  action,  but  its  benzoyl  derivative,  i.  e.  cocaine,  possesses 
most  powerful  properties. 


HALOGEN  DERIVATIVES  OF  ALIPHATIC  ACIDS  121 

The  toxicity  of  aconitine  stands  in  intimate  relationship  to  the 
benzoyl  and  acetyl  groups  present  in  that  alkaloid ;  when  these  are 
eliminated  the  resulting  substance  has  no  action.  Even  splitting 
off  the  acetyl  residue  causes  a  drop  in  toxicity,  and  the  loss  of 
the  stimulating  action,  shown  by  aconitine,  on  the  respiratory 
centres. 


DERIVATIVES   OF  THE   ORGANIC  ACIDS. 

A.     Halogen   Substitution   Products. 

The  halogen  derivatives  of  the  fatty  acids  may  be  obtained,  like 
the  parent  acids,  by  the  oxidation  of  chlorinated  alcohols  or 
aldehydes, 

CCI3.CHO     -^     CCI3.COOH 

Chloral.  Trichloracetic  acid. 

or  by  the  direct  substitution  of  the  hydrogen  of  the  hydrocarbon 
residue  by  halogens. 

These  derivatives  have  more  pronounced  acidic  properties  than  the 
acids  from  which  they  are  derived,  otherwise  they  show  very  similar 
characteristics. 

Fhysiologfical   Action. 

The  replacement  of  hydrogen  by  the  halogens,  as  previously 
noticed  in  other  cases,  causes  an  increase  in  narcotic  action;  thus 
sodium  acetate  is  quite  inert,  but  sodium  monochlor  acetate, 
CHgCl.COONa,  has  pronounced  narcotic  properties;  the  further 
replacement  of  hydrogen,  instead  of  increasing  this  characteristic, 
brings  about  a  diminution.  Dichloracetic  acid  has  less  action 
than  the  mono  derivative,  whereas  trichloracetic  acid,  CCI3 .  COOH, 
has  very  slight,  if  any,  corresponding  physiological  reaction.  In  this 
case  the  difference  in  the  action  may  be  ascribed  to  the  varying 
stability  of  the  substances.  Monochloracetic  is  easily  decomposed 
on  heating,  even  at  body  temperature ;  trichlor  is  most  stable,  and 
dichloracetic  of  intermediate  stability.  It  is  possible  that  the  narcotic 
action  of  the  first  two  acids  is  due  to  the  liberation  of  hydrochloric 
acid  in  the  cerebral  cortex,  since  in  animals  rendered  drowsy  by  these 
acids  the  symptoms  are  diminished  by  the  injection  of  sodium 
carbonate  into  the  vessels.  Also,  trichloracetic  acid  does  not  give 
rise  to  hydrochloric  acid  on  decomposition,  but  to  chloroform,  and, 
as  already  stated,  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  butyrate  is  more 
powerful  than  sodium  trichlorbutyrate.  Crotonic  acid  is  twice  as 
powerful  an  hypnotic  as  the  monochlor  derivative. 

The  replacement  of  hydrogen  in  acetic  acid  by  bromine  and 
iodine  also  results  in  substances  with  narcotic  action,  monoiodo 
acetic  acid  having  less  action  than  the  corresponding  bromine 
derivative. 

Monobrom-  and  to  a  very  much  less  extent  monochlor-acetic 
acid  produce  muscular  rigidity  in  frogs. 

B.     The  Esters. 

The  esters  of  the  organic  acids  resemble  very  closely  those  of  the 
mineral  acids  previously  described  (p.  93),  and  are  obtained  by 
analogous  methods;  the  most  important  being  the  interaction  of 
an  acid  and  alcohol,  e.  g. 


CHsCOOjH  +  OH:C2H5  =  Rfi  +  CHgCOOC^H^ 

Ethyl  acetate. 

As  this  reaction  is  reversible  (ethyl  acetate  is  decomposed  by 
water  with  the  reformation  of  alcohol  or  acid),  it  is  carried  out  in 
the  presence  of  hydrochloric  or  sulphuric  acids,  or  the  volatile  ester 
is  removed  as  it  is  formed. 

The  esters  of  the  fatty  acids  are  neutral,  volatile,  pleasant-smel- 
ling liquids,  generally  insoluble  in  water.  They  are  prepared  in 
large  quantities  for  the  artificial  production  of  fruit  essences ;  the 
acetic  ester  of  amyl-alcohol,  CHgCOO-CgHj^,  in  dilute  solution  is 
used  as  pear  oil ;  the  octyl  ester  has  the  odour  of  oranges ;  the  isoamyl 
ester  of  propionic  acid  smells  like  pineapple. 

When  heated  with  water,  or  more  rapidly  and  completely  with 
solutions  of  the  alkalis,  they  are  decomposed  into  alcohol  and 
acid, 

CHg  .  COOC2H5  +  KOH  =  CH3COOK  +  C2H5OH. 

Physiological  Characteristics. 

The  loss  of  the  acidic  properties  of  the  acids  by  the  replacement 
of  the  hydroxyl  hydrogen  by  alkyl  groups  produces  in  the  esters 
pharmacological  properties  closely  resembling  those  of  the  alcohols. 

Ethyl  formate,  H.COOCgH^,  produces  irritation  of  the  throat  and 


THE  ACID  AMIDES  123 

air  passages,  muscular  excitement,  stupor  but  not  sleep,  and 
vomiting". 

Methyl  acetate,  CH3 .  COOCH3,  produces  deep  stupor;  its  anaes- 
thetic action  is  uncertain ;  there  is  no  muscular  excitement. 

Ethyl  acetate,  CH3 .  COOCgHg,  acts  in  a  very  similar  manner  to 
ether,  but  the  action  is  much  slower. 

The  acetates  of  the  higher  fatty  radicals  have  a  slower  and  more 
prolonged  action. 

The  loss  of  acidic  properties,  through  the  formation  of  esters,  may 
result  in  bringing  out  the  main  physiological  action  of  the  molecule. 

Thus  tyrosin, 

^  „  /OH 
i'"^6^4\cH2 .  CH(NH2).C00H, 

is  non-toxic,  but  its  ethyl  ester, 

^   p    TT   /OH 

^'"^e^A^CR^ .  CH(NH2).COOC2H5, 

is  a  powerful  poison  (dogs). 


C.     Acid  Amides. 

The  acid  amides  are  derived  from  the  acids  by  the  replacement  of 
hydroxy]  by  the  amido  group, 

CH3.CO.OH     -^     CH3CO.NH2. 

They  may  be  obtained  by  the  distillation  of  the  ammonium  salts  of 
the  acids, 

CH3CO:0;NH2iH2|  =  Hp  +  CHgCONH^, 

or  by  the  action  of  the  acid  chloride  upon  ammonia, 

CH3COCI  +  NH3  =  HCI  +  CH3CONH2 
CeH^COCl  +  NHg  =  HCl  +  CgH^CONHg, 
or  by  the  action  of  ammonia  upon  the  esters, 

CH5COOC2H5  +  NH3  =  CH3CONH2  +  C2H5OH 
C6H5COOC2H5  +  NH3  =  C^HsCONH^  +  C^H^OH. 
The  amides  are  usually  solid  crystalline  bodies;  the  lower 
members  of  the  fatty  series  are  soluble  in  water,  those  of  the  aromatic 
in  boiling  water.  The  introduction  of  the  acidic  group  into 
ammonia  results  in  a  very  considerable  drop  in  basicity.  The 
aliphatic  amides  unite  with  acids  to  form  salts,  but  these  are  un- 
stable substances. 

The  amides  readily  absorb  water  and  pass  into  the  ammonium 


124  PHYSIOLOGICAL  PROPERTIES  OF  THE  AMIDES 

salts  of  the  original  acids  or  into  ammonia  and  the  acids  them- 

SPI  VPS 

CH3CONH2+H20  =  CH3COONH4 

or    .  CH3CONH2  +  KOH  =  CHgCOOK  +  NHg. 

Physiological  Properties. 

Formamide  and  acetamide  produce  convulsions  similar  to  those 
set  up  by  picrotoxin ;  propionamide  has  less  action,  and  butyl- 
amide  still  less ;  the  action  of  the  last-named  only  occurs  through 
decomposition  and  the  liberation  of  ammonia.  On  the  other  hand, 
butylamide  has  a  most  powerful  narcotic  action,  and  this  property 
decreases  in  the  series  till  it  disappears  entirely  in  the  case  of  form- 
amide.  Lactamide  and  /S-oxybutylamide  have  the  same  action  as 
propionamide. 

The  aromatic  amides  have  narcotic  properties ;  this  is  seen  in  the 
case  of  benzamide,  CgH^CONHg,  although  large  doses  are  necessary, 
and  also  in  the  following  substances  : — 

<pTT 
CONH 

the  amide  of  anisic  acid, 

oca 


^6H4<(cONH2,       -^  •  ^"^e^^^CONH 


3 

2> 

/OH  1  .0  o  XT  yOCoH. 


Phenylacetamide,  CgH^CHgCONHg,  is  a  weaker  hypnotic  than 
benzamide.  Amidoacetamide,  NHg .  CHgCONHg,  has  no  action,  but 
its  benzoyl  derivative,  the  amide  of  hippuric  acid, 

C^H5CO.NH.CH2CONH2, 

has  slight  narcotic  properties. 

The  amide  of  cinnamic  acid,  C^HgCH :  CH.CONHg,  has  strong 
hypnotic  properties. 

When  the  hydrogen  atoms  of  the  amido  group  in  benzamide  are 
replaced  by  methyl  or  ethyl  groups,  the  narcotic  action  is  depressed, 
and  the  resulting  substance  produces  symptoms  similar  to  those  of 
ammonia  and  strychnine.  This  may  be  observed  in  the  following 
series : — 

CeH^CONHg  CeH5CONH.CH3 

Methyl  benzamide. 
CeH,C0NH.C,H3  CeH,C0N(CH3), 

Ethyl  benzamide.  Dimethyl  benzamide. 


THE  NITRILES  125 

Urea  is  the  diamide  of  carbonic  acid, 


co<gg 


(see  p.  216),  and  it  is  interesting  to  note,  in  connexion  with  the 
narcotic  properties  of  benzamide,  that  benzoyl  urea, 

does  not  show  any  similar  physiological  reaction. 

D.    The  Nitriles. 

The  nitriles  result  from  the  dehydration  of  the  acid  amides,  e.  g. 

cH3ciO:Niia:2i  =  CH3CN, 

and  on  the  absorption  of  water  pass  back  into  the  amides,  and  then 
into  the  acids  themselves  or  their  ammonium  salts, 

CH3CN  +  HgO  =  CH3CONH2 

CH3CONH2  +  H2O  =  CH3COONH4. 

They  are  obtained  by  the  action  of  dehydrating  substances  on  the 
acid  amides,  or  by  the  action  of  an  alcoholic  solution  of  potassium 
cyanide  on  an  alkyl  derivative  of  the  aliphatic  series, 

C2H5I  +  KCN  =  C2H5CN  +  KL 

Another  method  of  preparation  consists  in  the  distillation  of  the 
potassium  alkyl  sulphates  with  potassium  cyanide, 

CeHgSOgOK  +  KCN  =  K^SOg  +  CeH^CN, 

The  nitriles  are  liquids  usually  insoluble  in  water,  possessing  an 
agreeable  etherial  smell  and  distilling  without  decomposition. 

Physiological  Properties. 

The  nitrile  of  formic  acid,  or  prussic  acid,  HCN,  differs  from 
its  homologues  by  its  great  toxicity.  Methyl  nitrile,  CH3CN,  is,  for 
instance,  much  less  poisonous ;  but,  on  the  other  hand,  the  isomeric 
methyl  carbylamine,  CH3NC,  is  extremely  toxic,  more  so  it  is  said 
than  prussic  acid,  and  it  seems,  therefore,  quite  likely  that  prussic 
acid  itself  has  the  constitution  HNC,  in  which  nitrogen  is 
quinquevalent. 


126  PHYSIOLOGICAL  PROPERTIES  OF  THE  NITRILES 

Bunge  found  that  the   nitrile   of  oxalic   acid,  i.  e.    cyanogen, 

CN 

I 
CN 

has  one-fourth  the  toxicity  of  prussic  acid. 

The  toxicity  of  the  nitriles  of  the  fatty  series  increases  with  the 
increase  of  molecular  weight ;  thus  Verbrugge  found  for  rabbits  : — 

Acetonitrile  '13  gm.  per  kilo  body  weight 

Propionitrile  -065         „  „  ^, 

Butyronitrile  -010         „  „  ,, 

Isobutyronitrile  -009        „  ,,  „ 

Isovaleronitrile  -045        „  j,  j, 

The  introduction  of  the  carboxyl  group  into  acetonitrile  lowers 
the  toxicity,  thus  cyanetic  acid  =  2-0  gms.,  the  ethyl  ester,  however 
=  1-5  gm. 

In  the  aromatic  series,  benzonitrile  is  less  poisonous,  the  toxic 
dose  being  -20  gm.,  for  o-tolylnitrile  it  is  '60  gm.,  and  for  naph- 
thonitrile  1-0  gm.  The  introduction  of  the  phenyl  residue  into 
acetonitrile  raises  the  toxicity,  which,  in  this  case,  =-05  gm. 

Barthe  and  Ferre  investigated  the  three  substances, 


CH.<; 


p„/CN  CH^.COOC.H, 

CN  y^XCOOCHg  '/CN 

COOCH3  iH,C00CH3  |\C00CH3 

CH2COOC2H5 


formed  by  inserting  first  one  (CH2COOCH3)'  group  in  cyan- 
acetic  methyl  ester,  and  then  a  second  similar  group.  The  first  had 
the  most  energetic  physiological  reaction,  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  replaced  by  sulphur,  resulting  in 
the  formation  of  the  mercaptans,  such  as  methylmercaptan,  CHgSH, 
an  increase  in  toxicity  is  observed,  although  these  derivatives  have 
less  physiological  action  than  sulphuretted  hydrogen,  SHg.  They 
act  mainly  on  the  central  nervous  system,  causing  paralysis  and 
convulsions,  and  finally  death  from  respiratory  failure.  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  paralysis  of  central  origin;  ethyl  sulphide 
is  physiologically  inactive  and  has  not  the  powerful  odour  of  the 
mercaptans ;  consequently,  the  physiological  reactivity  of  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, 


an 


s-> 


has  been  used  for  cholera,  and  in  solution  in  oil  for  subcutaneous 
injections  in  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  powerful 
heart  poison. 

Fatty  acids  in  which  sulphur  replaces  one  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  occasionally  paraplegia.  Its  direct  action  appears 
to  be  narcotic. 

The  xanthates,  e.  g. 

CS/^^^Hg 
^^\SNa 

(substances  which  are  easily  decomposed  into  alcohol  and  carbon 
disulphide),  have  similar  physiological  action  to  CSg;  a  general 
narcosis  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.] 


CHAPTEE  VI 

Aromatic  Hydeoxyl  Derivatives. — Main  Group  of  Aromatic  Anti- 
septics.— Chemical  and  physiological  properties  of  Phenols,  Cresols,  Di-  and 
Tri-oxybenzenes.  Recent  investigations  of  the  antiseptic  power  of  Phenol 
and  its  derivatives  Creosote,  Guaiacol,  and  their  derivatives. 

I.     MONO-,  DI-,  AND  TRI-OXYBENZENES. 

The  substitution  of  hydrogen  in  the  aromatic  nucleus  by  hydroxyl 
gives  rise  to  the  phenols,  a  group  of  substances  which  correspond  to 
the  tertiary  alcohols  of  the  fatty  series,  since  they  do  not  yield  acid 
or  ketones  on  oxidation.  Like  the  alcohols  they  are  distinguished 
as  mono-,  di-,  &c.,  according  to  the  number  of  hydrogen  atoms 
replaced  by  the  hydroxyl  group. 


Methods  of  Preparation. 

1.  They  may  be  obtained,  as  previously  indicated  (p.  41)  by  the 
decomposition  of  the  diazo  salts,  especially  the  sulphates,  with 
boiling  water, 

C^U, .  N  :  N.HSO^-f-  H,0  =  C.UfiR  +  N^-l-  H^SO, 

2.  They  also  result  from  the  fusion  of  the  sulphonic  acids  with 
sodium  or  potassium  hydrate, 

CgH^.SO^ONa  +  NaOH  =  Na^SOg  +  CgHsOH 
^6^<S0,0Na  +  ^^^^H  =  2Na,S03-i-CeH/g}J 


General  Properties. 

The  phenols,  in  contrast  to  the  alcohols,  have  strongly  marked 
acidic  properties,  which  are  enhanced  by  the  entrance  of  more 
negative  groups  into  the  nucleus.  Thus  phenol  readily  gives 
sodium  phenate,  CgHgONa^  when  treated  with  caustic  soda,  but  is 


PROPERTIES   OF  THE  PHENOLS  129 

incapable  of  decomposing  sodium  carbonate  with  the  formation  of 
that  salt.     On  the  other  hand  nitro-phenol, 

pxr/OH 
^6^<N02 

and  picric  acid, 

an 


2\0H 

are  sufficiently  powerful  to  liberate  carbon  dioxide  from  the  carbo- 
nate with  the  formation  of  the  corresponding  phenates. 

The  presence  of  the  hydroxyl  group  in  the  benzene  nucleus 
renders  more  easy  the  replacement  of  other  hydrogen  atoms  by 
chlorine,  bromine,  or  nitro  groups. 

The  hydrogen  of  the  hydroxyl  group  is  readily  replaced  by  alcohol 
or  acid  radicals.  Thus  sodium  phenate,  treated  with  methyl  or  ethyl 
iodide,  gives  rise  to  anisol,  CgHgOCHg,  or  phenetol,  CgH^OCgHg; 
these  derivatives  are  very  stable  and  are  not  decomposed  by  potash. 

The  acid  esters  result  from  (1)  the  interaction  of  phenol  or  the 
phenates  with  the  acid  chlorides. 

CgH^ONa-f  CH3COCI  =  NaCl+C6Hp.(CH3CO), 
or  (2)  digesting  the  phenols  and  acids  with  phosphorus  oxychloride 
or  pentachloride. 

(3)  In  the  polyhydric  phenols  all  the  hydroxyl  hydrogen  atoms 
may  be  replaced  by  acetyl  groups,  by  heating  with  acetic  anhydride 
and  sodium  acetate. 

The  acid  esters  resulting  from  these  reactions  are  readily  decom- 
posed into  their  components  by  alkalis,  thus  phenyl  acetate, 
CeHgO.OCCHg  +  KOH  =  CgHpH  +  CH3COOK. 
Nencki,  in  1886,  was  the  first  to  realize  the  importance  of  this 
group  of  substances  for  pharmacology,  since  by  their  formation 
both  the  phenols  and  acids  with  which  they  are  combined  lose  their 
caustic  properties,  and  the  resulting  derivatives  are  slowly  broken 
down  only  on  reaching  the  intestinal  canal,  where  the  physiological 
action  of  their  components  comes  into  play. 

This  method  of  treating  phenolic  substances  is  generally  termed 
Nencki's  Salol  Principle,  since  salol,  CgH50.(OC.CgH4 .  OH),  was 
the  first  of  these  derivatives  introduced. 

The  acidic  nature  of  the  phenols  can  also  be  eliminated  by  the 
corresponding  formation  of  carbonates,  etherial  carbonates,  or  amides. 
Carbonates  are  formed  by  the  agency  of  phosgene, 

(i)  CgHsONa  +  CLCOCl  =  CgHgO.COCl  +  NaCl 
and        (ii)  CgHgO.COCl  +  HaO    =  CgHgO.COOH  +  HCL 


130         AROMATIC   HYDROXYL  DERIVATIVES 

When  ammonia  is  brought  into  play  at  the  second  phase  of  the 
reaction^  the  amides  result, 

CeHgO.COCl  +  NHg  =  CgHgO.CONHg  +  HCl, 

or  such  derivatives  may  be  obtained  directly  by  the  action  of 
urea  chloride  on  the  phenols  or  their  salts, 

CgHpH  +  ClCONHg  =  HCl  +  CeHgO.CONHg. 

The  substances  of  this  group  are  generally  solids  and  are  soluble  in 
water. 

Chlorformic  ester  gives  rise  to  the  corresponding  esters, 

C6H50Na  +  Cl.COOC2H5  =  NaCl  +  CeHgO.COOCaHg ; 

bodies  of  this  type  are  usually  liquids,  insoluble  in  water. 

The  sulphuric  esters  of  phenol  have  previously  been  mentioned 
(p.  102). 

Homologons  Phenols. 

The  three  cresols  o,  m,  p 

prr/OH 

are  found  in  coal-tar  and  beechwood-tar,  thymol, 

|0H     .  I 

(C3H,  .  6 
in  oil  of  thyme.     Carvacrol, 

rOH     .  1 

CA  CH3    .  2 

(C3H,  .  5 

in  the  oil  of  certain  varieties  of  satureja.  These  substituted  phenols 
cannot  be  oxidized  to  their  corresponding  acids  by  means  of  chromic 
acid,  unless  the  hydrogen  of  the  hydroxyl  group  is  replaced  by  alkyl 
or  acid  radicals. 

Folyhydric  Phenols. 

Several  representatives  of  the  dihydric  phenols, 

are  found  in  plants  or  may  be  obtained  as  decomposition  products 
of  plant  substances. 
Pyrocatechol, 


PHYSIOLOGICAL  PROPERTIES  131 

may   be   obtained  by  the  distillation  of  catecbin,  and  by  fusing 
many  resins  with  potash.     Its  monomethyl  ether,  pinacol, 

^6^4\OCH3, 

occurs  in  creosote  from  beechwood-tar,  a  homologue,  eugenol, 

(C3H,     1 

CeH3  OH       4 

(OCH3  3 

occurs  in  oil  from  Eugenia  caryophyllata,  &c. 

Resorcinol,  CgH4(OH)2 1 : 3,  is  the  most  important  member  of  the 
group,  and  may  be  obtained  from  asafoetida,  galbanum,  and  other 
resins  by  heating  them  with  potash.     Its  methyl  homologue,  orcin, 


CgHg 


CH3      1 

OH    3 
OH    5 


is  found  in  many  lichens. 

Hydroquinone^  CgHg(0H)2l  :4,  is  so  called  on  account  of  the  ease 
with  which  it  may  be  obtained  by  the  reduction  of  quinone. 

Pyrogallic  acid,  CgH3(OH)3 1 : 2  : 3,  is  the  best  known  member  of 
the  trihydric  phenols,  its  dimethyl  ether  is  found  in  beech  wood 
creosote.  It  is  less  stable  than  the  dioxy  and  still  less  than 
monoxybenzenes,  it  readily  reduces  salts  of  silver,  mercury,  and  gold, 
with  the  formation  of  the  metals  and  the  complete  breakdown  of 
the  ring  nucleus  into  acetic  and  oxalic  acids. 


Fhysiological  Properties  of  the  Phenols. 

The  entrance  of  the  hydroxyl  group  into  benzene,  with  the 
formation  of  phenol,  causes  a  great  increase  in  antiseptic  and  toxic 
properties.  Phenol  and  its  homologues  in  large  doses  produce  con- 
vulsions of  spinal  origin,  an  action  which  is  not  so  marked  in  the 
higher  members  of  the  series.  The  introduction  of  long  aliphatic 
side-chains,  or  of  several  alkyl  groups  hinders  this  action.  The 
phenols  also  act  on  nerve  endings.  Large  doses  paralyse  motor 
nerve  endings,  while  small  doses  have  a  marked  local  anaesthetic 
action.  The  old-fashioned  remedy  for  an  aching  tooth  is  to  fill 
the  cavity  with  a  clove,  which  owes  its  anaesthetic  properties  to 
eugenol. 

K  2 


132         AROMATIC   HYDROXYL  DERIVATIVES 

Phenol  itself  or  the  oil  of  cloves  is  frequently  used  for  the  same 
purpose.  The  antipyretic  action  of  the  benzene  ring,  which  is  not 
lost  in  the  phenol  series,  cannot  be  utilized  for  obvious  reasons. 

The  action  on  the  spinal  cord  decreases  with  the  number  of 
hydroxyls,  but  in  other  respects  the  toxicity  is  increased.  Thus 
phenol  and  the  dioxybenzenes  produce  spasms  in  frogs,  whereas 
trioxybenzene  (1:2:3)  only  produces  shivering;  on  the  other  hand, 
the  animal  becomes  more  comatose  and  atoxic  than  with  resorcin. 
Binet  holds  that  the  toxic  symptoms  (collapse  and  convulsions)  of 
the  phenols  are  traceable  to  the  benzene  nucleus,  but  are  modified 
by  the  introduction  of  OH  or  acyl  groups.  The  antagonistic 
action  of  these  is  seen  in 

OCHo  OCH3 


Pyrocatechin  ,  guaiacol 


/\ 


°^,andveratrolf     ^^^^ 


which  show  a  progressive  decrease  in  toxicity.    The  carboxyl  group 
also  modifies  the  toxicity ;  gallic  acid, 

COOH 


OHWOH 
OH 

produces  no  shivering,  and  is  a  much  less  powerful  blood  poison 
than  pyrogallol.  The  lower  phenols  are  protoplasmic  poisons, 
causing  coagulation,  but  this  property  is  lost  in  the  higher  members 
of  the  series,  e.g.  phloroglucin, 

OH 


OH 


OH. 


The  toxic  properties  of  the  phenols  are  depressed  by  the  replace- 
ment of  hydrogen  atoms  in  the  nucleus  by  alkyl  groups,  whereas 
the  antiseptic  characteristics  are  increased.  This  alteration,  how- 
ever, is  more  marked  with  1 : 3-cresol  than  with  the  others ;  recent 
investigations  have  shown  that  the  toxicity  of  1 : 2-cresol  lies  very 
near  that  of  phenol,  whereas  1  : 4-cresol  is  greater.  As  regards 
antiseptic  properties  the  1 : 3  derivative  is  more  powerful  than  the 
1 : 4,  and  ortho  cresol  is  the  weakest  of  the  three. 


CRESOL   ANTISEPTICS  133 

Koch  and  Lubbert  have  drawn  attention  to  the  great  value  of 
thymol, 

fOH       I 


CgHg- 


CH3     3 


C3H,    6 
as  an  antiseptic. 

The  homologous  phenols,  however,  are  much  less  soluble  in  water 
than  phenol  itself,  and  various  methods  have  been  tried  by  which 
to  modify  this  factor.  The  majority  of  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  solid  compound  of  pure  «2-cresol  and 
potassium  cresotinate, 

CH, 


CfiHg 


3 

OH 
COOK 


in  a  sodium  soap,  and  it  contains  the  least  toxic  but  most  powerfully 
antiseptic  of  the  three  cresols. 

Lysol  is  oil  of  tar  mixed  with  linseed  or  a  fatty  oil,  and  com- 
pletely saponified  with  potash  in  the  presence  of  alcohol.  It  is  not 
so  irritating  or  so  toxic  as  carbolic,  and  may  vary  in  antiseptic 
strength  owing  to  varying  proportions  of  the  different  cresols. 

Creolin  is  an  emulsion  of  cresols  in  resin  soap,  and  is  destroyed 
by  mineral  acids,  caustic  alkalis,  and  sodium  chloride.  It  contains 
varying  amounts  of  the  different  cresols. 

Cylliu,  an  improved  preparation  of  creolin,  has  a  bactericidal 
power  sixteen  times  that  of  pure  phenol  (Rideal)  when  tested  with 
B.  Typhosus — ^  medicinal '  cyllin  was  used.  Klein  finds  it  thirty 
times  as  strong  when  tested  with  B.  pestis. 

Jonesen^  experimented  with  dogs  in  nitrogenous  equilibrium,  ob- 
serving the  effects  of  cresols  on  their  output  of  nitrogen,  ammonia, 
and  indigo.  The  cresol  was  entirely  eliminated  by  the  urine,  none 
was  ever  found  in  the  faeces.  During  the  periods  in  which  cresol  was 
given  the  ammonia  decreased,  owing  to  the  conjugation  of  the  HgSO^ 
with  cresol.  The  eft'ect  on  indigo  varied  with  the  different  isomers, 
the  greatest  augmentation  occurred  with  ortko-,  and  the  least  with 
meta-cresol,  the  para  derivative  being  intermediate.  The  cresols  are 
also  to  a  smaller  extent  conjugated  with  glycuronic  acid,  the  amount 

*  Bioehem.  Zeitschr.,  vol.  i,  fasc.  5  and  6,  pp.  399-407,  1907. 


134 


AKOMATIC   HYDROXYL  DERIVATIVES 


being  greater  the  more  toxic  the  cresol.  The  total  amount  recover- 
able from  the  urine  also  varied  directly  with  the  toxicity.  With 
mefa-cresol  it  was  46-5  per  cent.,  with  ortko-cresol  30-35  per  cent., 
and  with  jpara-ciesol  it  fell  to  27  per  cent,  of  the  amount  ingested. 
These  phenomena,  as  also  the  toxicity,  may  of  course  be  merely 
the  results  of  variations  in  the  rapidity  of  absorption. 

Bechhold  and  Ehrlich^  have  recently  investigated  various 
phenol  derivatives,  and  have  shown — 1.  that  the  entrance  of  chlorine 
or  bromine  into  the  nucleus  of  phenol  causes  an  increase  in  anti- 
septic power.  In  the  following  comparisons  an  amount  of  phenol 
equal  to  1,000  gm.  molecules  was  taken,  and  against  it  were  com- 
pared the  quantities  of  various  substances,  also  in  gm.  molecules, 
necessary  to  prevent  the  growth  of  certain  bacteria  in  a  given  fluid. 


Phenol 


1000 

Diphtheria  bacillus 

>40 

>i              >i 

>22 

a                  a 

16 

>3                       » 

7 

»>                  >y 

2 

a                 yi 

Trichlor 

Tribrom 

Tetrachlor 

Pentachlor 

Pentabrom 


In  the  last  case,  for  instance,  one  gm.  molecule  of  pentabrom 
phenol  has  the  same  action  in  preventing  the  growth  of  diphtheria 
bacillus  as  500  gm.  molecules  of  phenol. 

2.  The  entrance  of  alkyl  groups  into  the  nucleus  of  phenol,  as 
previously  mentioned,  increases  its  antiseptic  value,  and  a  similar 
increase  was  noticed  in  the  case  of  the  halogen  derivatives ;  thus 


Phenol      = 


Tetrachlor 


1000    Diphtheria  bac 
16 


CH 


CgBr^/QjjS  Tetrabrom-o-cresol        =         -9 


„  m- 

yy    V- 


=  2-2 

=  1-1 

=  >22 

=  3-9 


Tetrabrom  phenol 
C6HBr2<((™3)2  Dibrom-i?-xylenol 

C6Br3<^^Q^3)2  Tribrom-»z-xylenol     =    <1.3 

Cg(CH3)3<^^A  Dibrompseudocuminol=      6*5 

»  Hoppe-Seyler's  Zeit.fur,  Fhys.  Chem.,  47, 173, 1906. 


llus 


ANTISEPTIC   VALUES  135 

That  is,  tribrom-»z-xylenol  is  twenty  times  as  active  as  tribrom- 
phenol.  Tetrabrom-o-cresol  is  about  sixteen  times  as  active  as 
tetracblor-phenol.  This  brominated  cresol  is  but  very  slightly  toxic ; 
a  one  per  cent,  solution  kills  diphtheria  bacillus  in  less  than  two 
minutes,  whereas  a  corresponding  one  per  cent,  phenol  solution 
requires  more  than  ten.  Further,  the  same  strength  solution  kills 
bacillus  coli  in  less  than  five  minutes,  whereas  phenol  requires  sixty. 

3.  The  combination  of  two  phenol  nuclei,  as,  for  example, 
jo-dihydroxy-diphenyl, 

an,.  OH 
I 

CeH,.OH, 

or  the  derivatives  of  diphenyl  methane,  such  as  those  given  in  the 
following  table,  as  well  as  their  chlorinated  derivatives,  are  more 
powerful  than  phenol. 


Phenol  =    1000 

Diphtheria  bacillus 

^-dioxy-diphenyl, 

OH.CeH^.CeH^.OH  =      47 

5J                          }f 

Tetrachlor  phenol                                 =       16 

3J                        }J 

Tetrachlor-o-diphenyl, 

OH.CeH^Cl^.CgH^Cla.OH  =        -7 

a                  >J 

Tetrabrom-o-diphenyl, 

OH.C,H,Br, .  C,H,Br,OH  =       -4 
Tetrabrom-jt?-dioxy-diphenyl  methane, 

CH,(C,H,Br,OH),  =      1.8 
Hexabrom-jo-dioxy-diphenyl  methane, 

CH,(C,HBr30H),  =  <1.4 
Hexabrom-jo-dioxy-diphenyl  carbinol, 

CH.OH.(C6HBr30H)2  =        -6 

4.  The  combination  of  two  phenol  groups  by  means  of  CO  or  SO2 
decreases  the  antiseptic  power. 

Phenol  =  1000     Diphtheria  bacillus 
Tetrabrom-dio3cy-diphenyl-methane  =1-8  „  „ 

Tetrabrom-dioxy-benzophenone, 

OH.CgH^Brg .  CO.CgHaBrpH    =  >177 
Tetrabrom-dioxy-diphenyl-sulphone, 

OH.CeH^Br^.SOg.CgH^Br^OH  =     <34 


136 


AROMATIC  HYDROXYL  DERIVATIVES 


5.  The  entrance  of  the  acid  grouping   (COOH)  depresses  the 
antiseptic  power  of  the  phenols. 

Phenol  =  1000     Diphtheria  bacillus 
Tetrachlor  phenol,  CgH.Cl^ .OH      =       16  „ 

Tetrachlor-m-oxybenzoic  acid, 

^6^^4\cOOH  ~     ^^^  '^  '' 

Trichlor  phenol,  CeHgClg .  OH  =    >40  „  „ 

Trichlor-phenoxy-acetic  acid, 
'OH 


^6^^KCH2C00H 
Tribrom  phenol 

Tribrom-phenoxy-acetic  acid, 
OH 


>740 
22 


CeHBrg^^jj^^^QQjj  -    490  „  „ 

As  regards  the  relative  toxicity  of  the  halogen  derivatives  of 
phenol,  it  is  found  that  the  entrance  of  a  bromine  atom  reduces  the 
convulsant  action,  so  characteristic  of  phenol  itself,  and  also  lowers 
the  toxicity,  but  the  further  introduction  causes  a  rise  in  this 
characteristic,  and  tribrom  or  trichlor  phenol  are  about  equal  to 
phenol  itself,  whereas  tetra  and  penta  halogen  derivatives  are  more 
powerful ;  the  latter  in  fact  may  be  regarded  as  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  toxicity  of  phenol  and  o-cresol  was  depressed 
in  such  solutions. 


Toxic  dose  for  white  mice  1000 

gms.  m  we 

ight 

in  alkali  solution 

without 

of  6-5  c.c.  NaOH  in 

alkali 

100  c.c.  solution. 

gms. 

gms. 

Phenol 

.25 

.20 

immediate  spasms. 

Monobrom-phenol 

.35 



"                 yi 

Trichlor 

•24 

— 

spasms  after  a  few 
minutes. 

Tribrom           „ 

.28 

— 

spasms  after  a  few 
minutes. 

Tetrachlor 

.12 

— 

slight       spasms 
shortly  before  death. 

Pentachlor      „ 

•056 

— 

no  spasms. 

o-cresol 

.41 

.32 

immediate  spasms- 

Tetrabrom-o-cresol 

.44 

no  spasms. 

BACTERICIDAL  VALUES  137 

The  following-  substances  were  also  investigated  : — 
(a)  Tetrabrom-Iiydroqtiinone-phthalein. 

B,  Biphtheriae.  Antiseptic  1  in  80,000  (compared  with  1  in  200,000 
HgClg).  Bactericidal  1°/^  solution,  more  than  2  less  than  6 
minutes ;  -5°/,  solution,  10  minutes  (compared  with  1°/^^  HgClg 
less  than  1  minute). 

B.  Typhosus.     1  in  400,  no  antiseptic  action. 

B.  Byocyaneus.  No  bactericidal  action.  3  °/^  in  60  minutes  (com- 
pared with  5°/,^  HgClg  in  less  than  15  minutes). 

Animal  Experiments, 

Guinea-pigs,  weight  250-370  gms.  1  y^  solution :  3  c.c.  sub- 
cutaneously  and  5-7 c.c.  by  oesophageal  tube — no  action;  3 c.c. 
intraperitoneally  caused  death  (peritonitis). 

(b)  Tetrabrom-hydroquinone-phthalein-oxime. 

B.  Biphtheriae,    Antiseptic  1  in  80,000 ;  bactericidal  1  y^^  in  more 

than  15  minutes. 
B.  Typhosus,     No  antiseptic  or  bactericidal  action  in  1  in  200. 
M.  Gonorrhoeae.     Antiseptic  and  bactericidal  in  1  in  1,600. 

Animal  Experiments. 

Guinea-pigs  J  250-510  gms.  weight,  ly  solutions:  subcu- 
taneously  3 c.c.  were  painful;  no  other  effect.  Ic.c.  intraperi- 
toneally, no  action.  Repeated  doses  16  c.c.  by  oesophageal 
tube  produced  traces  of  albumin  in  urine,  but  no  other 
action. 

(c)  Hezabrom-dioxsrplienyl-carbiuol. 

B.   Biphtheriae,     Antiseptic    and    bactericidal    in   1   in  320,000 

solution. 
B,  Bse%idodiphtheriae,     Antiseptic  1  in  128,000. 
Streptococcus  Pyog.     Antiseptic  1  in  5,000. 
B,  Coli.    Antiseptic  1  in  80. 
B.  Pyocyaneus.     Antiseptic  1  in  400. 
B,  Coli.     Bactericidal  3  °/  solution  in  over  60  minutes. 
Staphylococci.     Bactericidal  1  y  solution  from  30  to  60  minutes. 
B,  Pyocyaneus,     5  y  solution  in  NaOH  from  15  to  30  minutes. 

Meat  could  not  be  sterilized  with  1  in  200,  nor  serum  with 

1  in  100,  nor  milk  with  1  in  1,000. 


138         AKOMATIC   HYDHOXYL   DERIVATIVES 

Animal  Experiments. 

White  mouse,  weight  15  gms.  1  °/^  solution  -8  c.c.  intraperi- 
toneally  killed  in  30  minutes.  Rabbit,  2_,100  gms.,  45  c.c.  of 
1-5  y^  solution  intravenously  was  fatal.  Guinea-pigs  weighing 
300  gms.  showed  only  transient  paralysis  of  hind  limbs  when 
1  c.c.  of  a  3  "/^  solution  was  injected  intracardially.  Others  weigh- 
ing 500  to  620  gms.  took  25  c.c.  of  a  1  %  solution  per  os.  Most  of 
the  bromine  derivative  was  excreted  in  the  faeces  in  7  days. 

Ma?i.  10  c.c.  of  1  y^  solution  jo<?/  os  produced  no  ill  effects.  The 
taste  is  unpleasant  and  burning. 

Rabbits,  guinea-pigs,  and  mice  infected  with  various  organisms 
were  given  this  solution  in  various  ways  (intravenously,  &c.)  but 
without  any  effect. 

(d)  Hexabrom-dioz3rplienyl-xiiethoxy-methane, 

B.  BiphtTieriae,     Antiseptic  1  in  200,000  to  1  in  640,000;    bac- 
tericidal 1  in  320,000. 
B.  Pyocyaneus,     Antiseptic  1  in  400. 

Animal  Experiments. 

White  mice,  about  15  gms.  weight.  1  y^  solution,  '8  c.c.  fatal 
subcutaneously.  Local  necrosis.  Sublethal  doses  had  no  effect  on 
animals  infected  with  trypanosomiasis. 

(e)  Tetrachlor-ortho-dipheuol  and  tetrabrom-ortho-dipheuol. 

B.  JDlphtheriae.     Antiseptic  1  in  200,000  to  1  in  640,000;    bac- 
tericidal 1  y^  in  less  than  2  minutes. 
B.  Coli.     Bactericidal  1  y^,  5  to  30  minutes. 

Animal  Experiments, 

The  bromide  only  was  used.  -3  gms.  in  10  c.c.  was  fatal  for 
guinea-pigs  subcutaneously.  -1  c.c.  of  1  °/^  solution  intraperitone- 
ally  and  -25  c.c.  subcutaneously  was  fatal  for  white  mice.  No 
effect  was  produced  on  infected  animals  by  injections  with  sub- 
lethal doses. 

(f)    Tetrabrom-ortho-cresol. 

B,  BipUheriae.    Antiseptic   1   in   200,000-160,000;    bactericidal 

1  in  320,000. 
B.  Coli.    Bactericidal  ly^  solution  in  less  than  5  minutes. 


NAPHTHOL   DERIVATIVES  139 

Animal  Experiments. 

Gtiinea-joigs  treated  with  1  gm.  in  16'5  c.c.  water  with  addition  of 
caustic  soda  gradually  lost  weight  and  died  after  28  days.  Cause  not 
obvious.  For  white  mice  the  fatal  dose  subcutaneously  was  '44  gm. 
per  1,000  gm.  body- weight.  Sublethal  doses  had  no  effect  on  mice 
infected  with  streptococci. 

The  general  conclusion  from  these  experiments  was  that^ 
though  some  of  these  bodies  were  powerful  disinfectants,  none  of 
them  were  more  damaging  to  bacteria  than  to  the  animal  body 
when  used  as  internal  disinfectants.  Similar  conclusions  were 
arrived  at  by  one  of  the  present  writers  ^  with  regard  to  perchloride 
of  mercury_,  oxycyanide  of  mercury,  formic  aldehyde,  chinosol, 
protargol,  and  sodium  taurocholate,  and  by  Dr.  W.  V.  Shaw  ^  for 
formalin,  guaiacol  and  chinosol. 

The  introduction  of  hydroxyl  into  the  nucleus  of  naphthalene 
gives  rise  to  two  isomeric  substances 
OH 

/\^-0H 

a-Naphthol  I    and /S-Naphthol  ^     ^^ 


\/\y 

Both  of  these  derivatives  are  more  powerful  antiseptics  than 
phenol;  the  a  derivative  is  more  toxic  than  the  other,  and  in  conse- 
quence is  not  employed  in  medicine.  Owing  to  its  slight  solubility, 
/3-naphthol  is  only  used  in  dermatology ;  its  sodium  salt,  which  is 
much  more  soluble  in  water,  goes  by  the  name  of  Mikrocidine.  In 
order  to  increase  the  solubility,  the  /3-naphthol  sulphonic  acid  was 
investigated,  but  it  was  found  that  the  introduction  of  the  acid 
group  had  considerably  lowered  the  antiseptic  action.  These  de- 
rivatives go  by  the  name  of  Asaprol  or  Abrastol,  and  are  the 
potassium  or  calcium  salts  of  /3-naphthol-a-sulphonic  acid.  To 
lessen  the  caustic  action  and  diminish  the  toxicity,  )3-naphthol  was 
converted  into  acid  esters  according  to  the  salol  principle.  Thus 
Betol  is  the  salicylic  ester,  CjqH^O  .  (OC.CgH^OH),  and  benzo- 
naphthol,  introduced  by  Yvon  and  Berliez  in  1891,  the  benzoic 
acid  ester,  which  is  formed  by  the  action  of  benzoyl  chloride  on 
/3-naphthol, 

CjoH^ .  OH  -}-  CgHgCOCl  =  HCl  +  Q^^11^0,{C0C^}l^y 

*  Guy's  Hospital  Reports,  vol.  Iviii. 
^  Journal  of  Hygiene,  April,  1903. 


140         AROMATIC   HYDROXYL  DERIVATIVES 

This  derivative,  like  the  previous  one,  is  decomposed  into  its 
constituents  in  the  small  intestine  by  the  pancreatic  juice  and 
bacteria. 

Epicarin,  introduced  in  1899,  j8-oxynaphthol-(?-oxy-;?z-toluic  acid, 

HO.CjoHe  [^— CH2— C6H3<^Qjj       J 

is  obtained  by  the  action  of  chlormethylsalicylic  acid  on  )S-naphthol 
dissolved  in  acetic  acid, 

/COOH  .COOH 

aH.^OH  =    CfiHo^OH 

\CH2Cl  +  CioH^OH  XCH^-CioHg .  OH  +  HCl. 

It  has  powerful  acid  properties,  and  forms  salts  soluble  in  water.    It 
is  a  powerful  and  non-irritating>  antiseptic,  and  is  mainly  excreted 
unchanged.    It  has  been  used  as  an  antiparasitic  for  the  skin. 
/S-naphthylamine  sulphonic  acid, 

^o^exso^OH, 
very  readily  combines  with  nitrites,  forming  the  innocuous  diazo 
compound.    It  has  thus  been  employed  in  cases  of  poisoning  by 
nitrites,  and  also  to  prevent  the  urine  becoming  alkaline  in  diseases 
of  the  bladder. 

The  action  of  the  halogen  derivatives  of  naphthol  has  not  been 
investigated. 

POLYHYDRIC  PHENOLS. 

I.    A.  Dioxybenzenes. 

According  to  Frankel,  the  toxicity  and  the  antiseptic  action 
increases  with  the  number  of  hydrogen  atoms  in  the  benzene 
nucleus  replaced  by  hydroxyl  groups.  On  the  other  hand,  Schmiede- 
berg  states  that  one  of  the  dioxybenzenes,  i.  e.  resorcin, 

^«^4\0H  ^  '^' 

is  less  toxic,  and  has  less  antiseptic  power  than  phenol.  The  trioxy 
derivative,  pyrogallol,  CgH3(OH)3,  however,  is  certainly  more 
poisonous  than  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  consequently  the  only  isomer  employed  in  medicine. 
It  is  formed  by  fusing  any  of  the  disulphonic  acids  with  caustic  soda, 


CREOSOTE  AND   GUAIACOL  141 

which  means  that  an  intramolecular  change  takes  place  with  the 
1 ;  4  and  1 : 2-sulphonates,  and  that  1 : 3-dioxybenzene  is  the  most 
stable  of  the  three  isomers  at  the  temperatures  requisite  for  such 
reactions. 

The  monoacetyl  derivative 

goes  by  the  name  of  Euresol. 

B.     Etherial   Derivatives   of  Dioxybenzenes. 

Creosote  from  beechwood-tar  consists  chiefly  of  a  mixture  of 
phenol,  cresolsj  guaiacol, 

l:aC,H,<gCH3 

and  its  homologues_,  creosol, 

C,H3(CH3)<g^H3 

Owing  to  the  presence  of  phenols,  the  action  of  creosote  is  very 
similar  to  that  of  phenol  itself.  It  has  antiseptic  properties,  but  is 
toxic  and  has  caustic  action.  The  latter  depends  on  the  presence  of 
the  free  hydroxyl  grouping,  and  many  derivatives  have  been  intro- 
duced, based  on  the  salol  principle,  in  order  to  overcome  this 
objectionable  characteristic. 

The  esters  which  have  been  prepared  for  this  purpose  all  break 
down  into  their  components  in  the  intestine. 

Creosote  carbonate,  for  instance,  like  creosote  itself — a  mixture 
of  several  substances — is  obtained  by  the  action  of  carbonyl  chloride 
on  an  alkaline  solution  of  creosote.  The  formation  of  the  ester  of 
carbonic  acid  by  this  means  produces  a  very  great  drop  in  toxicity 
and  the  loss  of  the  caustic  action  of  the  original  mixture. 

Other  esters  of  creosote  have  been  prepared  and  introduced  into 
medicine,  but  these  have  been  all  replaced  by  what  is  supposed  to 
be  the  most  powerful  physiological  agent  present  in  the  mixture, 
viz.  guaiacol,  or  its  derivatives.  It  is  probable,  though,  that  the 
methyl  ester  of  homobrenzcatechin, 

CfiXloX—OCxlq 

'    '\0H  ' 
which  is  present  in  creosote,  may  be  an  important  constituent,  since, 
judging  from  what  has  been  previously  stated,  its  toxicity  should 
be  less,  but  its  antiseptic  value  greater,  than  that  of  guaiacol,  which 
has  no  methyl  group  substituted  in  the  nucleus.    This  homologue  is 


142         AROMATIC   HYDROXYL   DERIVATIVES 

difficult  to  isolate  from  the  mixture,  and  has  not  yet  been  intro- 
duced into  pharmacology. 

Gnaiacol  is  obtained  from  anisol  by  nitration,  and  reduction  of 
resulting  1 : 2-nitro  anisol  to  the  amido  derivative ;  this  is  then 
diazotized  and  boiled  with  water. 

CgH^.OCHg    -^    ^6^^<^och^    -^    ^6H4<(oCH3 

^6^4\oCH3  ^  •  '^  ^6^4  \OCH3 

It  is  a  toxic  substance^  and  irritates  the  gastric  mucosa.  Its  sub- 
cutaneous use  is  dangerous,  owing  to  the  collapse  and  cardiac 
depression  it  may  produce.  In  toxic  doses  it  produces  excitation, 
followed  by  paralysis  of  the  central  nervous  system,  the  former 
symptoms  being  less  marked  in  the  higher  animals.  It  is  less  toxic 
and  more  powerfully  antiseptic  than  phenol. 

Inorganic   Acid   Esters   of  Gnaiacol. 
A.   1.    Gnaiacol  carbonate  or  Duotal, 


OC6H4.OCH3 
OCH, 


'^XO.CgH 


results  from  the  interaction  of  carbonyl  chloride  and  the  sodium 
salt  of  gnaiacol. 

2C6H4<^^^^3  +  COCI2  =  2NaCl  +  C0{0C,1I^ .  OCHg)^ 

In  this  reaction  gnaiacol  may  be  replaced  by  a  large  number  of 
hydroxyl  derivatives,  such,  for  instance,  as  menthol,  eugenol, 
carvacrol,  &c. 

Creosote!  (creosote  carbonate)  and  Dnotal  are  both  insoluble,  and 
therefore  tasteless.  The  former  is  a  yellow  almost  odourless  liquid 
miscible  with  alcohol  and  oils,  and  the  latter  a  white  crystalline 
powder  slightly  soluble  in  oil  and  glycerin. 

2.  Mixed  carbonates  of  aromatic  and  aliphatic  radicals  may  be 
obtained  by  the  action  of  chloroformic  esters  on  sodium  guaiacol  or 
other  allied  substances,  such  as  eugenol,  creosol,  and  carvacrol, 

^e^^^ONa  +  CLCOOC^H^  "  ^^^^^^^'^XO.CeH^.  OCH3 

Ethyl-guaiacol  carbonate. 
or  generally 

X.ONa  +  Cl.COOR  =  NaCl  +  CO<^Q| 


ESTERS   OF   GUAIACOL  143 

The  resulting  derivatives,  in  distinction  to  the  carbonate,  are 
liquids,  and  on  this  ground  are  suitable  for  injection,  but  have  little 
practical  importance. 

3.  Carbamic  esters  of  guaiacol  and  allied  substances  can  be 
obtained  by  the  interaction  of  urea  chloride  and  the  phenol  or  its 
sodium  salt. 

^e^KoNa  +  CI.CONH2  =  ^^^^  +  ^^<\0.CX  •  OCH3 

Instead  of  guaiacol,  the  following  hydroxyl  derivatives  have  been 
employed : — Menthol,  carvacrol,  eugenol,  thymol,  geraniol,  &c. 

B.  Phosphate  of  guaiacol  or  Phosphatol,  PO(OC6H4 .  OCH3)3, 
was  intended  to  combine  the  action  of  phosphorus  with  that  of 
the  cresol  in  cases  of  tuberculosis. 

C.  Phosphite  of  guaiacol  (Guaiacophosphal)  is  obtained  by  the 
action  of  phosphorus  trichloride  on  the  sodium  salt, 

PCI3  +  3C,H,<ggj2  =  3NaCl  +  P(O.C,H, .  OCH3)3. 

It  is  a  crystalline  powder,  and,  in  distinction  to  the  phosphate  and 
carbonate,  is  soluble  in  fatty  oils.  Under  the  name  Phosphotal  is 
sold  a  mixture  of  the  phosphorous  ethers  of  the  creosote  phenols 
(neutral  phosphites)  containing  90  per  cent,  creosote  and  9  per  cent. 
P2O3 .     It  is  not  caustic  and  is  much  less  toxic  than  creosote. 

J).  Mixed  sulphuric  esters  of  phenols  and  aliphatic  radicals  have 
been  obtained  by  the  action  of  ethylchlorsulphuric  acid  upon  alkaline 
solutions  of  guaiacol. 

S0,<gCA^C,H/0CH3  =  NaCl  +  SO,<OCA  ^^^^ 

The  various  phenolic  substances  previously  mentioned  may  be  used 
in  place  of  guaiacol,  and  the  ethyl  group  can  be  replaced  by  methyl, 
butyl,  &c. 

Organic  Acid  Esters  of  Guaiacol. 

Various  aliphatic  acid  esters  of  guaiacol  and  similar  phenols,  or 
of  the  mixture  creosote,  have  been  prepared.  They  are  formed  by 
heating  a  mixture  of  the  acid,  phenol,  and  a  dehydrating  agent, 
such  as  phosphorus  trichloride,  to  a  temperature  of  135°.  Thus  in 
the  case  of  oleic  acid, 

CH3 .  (CH,), .  CH  :  CH(CH,)e .  CH^COpHj  +  CeH4<^^™3 

=  H2O  +  CgH^^Q  QQ^Q  jj  \  (Guaiacol  oleate), 
this  ester  is  liquid  and  insoluble  in  water. 


144         AROMATIC   HYDROXYL  DERIVATIVES 

The  valerianic  ester  or  Geosote, 

1:2  ^6H4<(o.coC4H9 

is  also  a  liquid  insoluble  in  water,  only  slightly  soluble  in  dilute 
acids  and  alkalies,  and  soluble  in  large  quantities  of  alcohol,  ether, 
chloroform,  &c.  It  has  an  oily  character  and  a  penetrating  aromatic 
odour.     Eosote  is  a  similar  preparation,  said  to  be  less  pure. 

Further  description  of  this  group  is  unnecessary,  and  it  is  hardly 
likely  that  derivatives  of  pharmacological  value  greater  than  the 
carbonate  can  be  found  in  this  class. 

In  a  similar  manner,  aromatic  acid  esters  have  been  prepared  and 
investigated.     Thus  the  benzoic  acid  ester  of  guaiacol  or  Benzosol, 

r  XT  /OCH3 

has  been  introduced,  but  this  substance  is  decomposed  with  rather 
more  difficulty  than  the  carbonate,  and  its  product,  benzoic  acid,  is 
of  little  pharmacological  value,  except  possibly  as  an  expectorant 
and  urinary  disinfectant. 

The  salicylic  acid  ester  or  Gnaiacolsalol, 

'OCH3 

.OCCgH^OH, 

like  the  previous  derivative,  is  a  solid  with  low  melting-point,  which 
breaks  down  in  the  small  intestine  into  guaiacol  and  the  antiseptic 
salicylic  acid,  but  again  this  decomposition  does  not  take  place  at  all 
readily,  and  in  order  to  decrease  the  stability  of  these  aromatic 
esters  an  amido  group  has  been  introduced  into  the  1  : 4  position  in 
the  benzoyl  radical — ^^-acetamido-benzoyl-guaiacol, 

p  „  /OCH3 

""e^^XCCgH^ .  NH(C0CH3). 

This  substance  may  be  obtained  by  the  action  of  1 :  4-nitrobenzoyl 
chloride  on  sodium  guaiacol. 

CeH<?&i  +  C,H/g-Cf  3  =  NaCl+C,H/OCH'c,H,NO, 

The  resulting  substance  is  then  reduced,  and  the  acetyl  group 
introduced  in  the  ordinary  way. 

Although  this  derivative  is  decomposed  with  greater  ease  than 
the  benzoic  acid  ester,  it  is  improbable  that  its  value  can  be  greater 
than  others  previously  mentioned. 


^6H4<(o.( 


GUAIACOL  DERIVATIVES  145 

Attempts  to  increase  Solubility  of  Gnaiacol. 

A.  Einhorn  and  Hiitz  have  introduced  the  hydrochloric  acid  salt 
of  diethyl-glycocoU-guaiacol,  or  Gnaiasauol, 

This  may  be  obtained  by  the  action  of  diethylamine  on  the 
chloracetyl  derivative  of  guaiacol^ 

r  jj  //^^Ho  p  TT  yOCHg 

^^4\0Na  +  CH2Cl.C0Cl  ^6^4\O.COCH2Cl  +  NH(C2H5)2 

->    ^6W4\o.COCH2N(C2H5)2. 

This  substance  is  soluble  in-  water,  precipitated  as  an  oily  base  by 
carbonates,  and  is  broken  down  in  the  intestine  in  the  usual  way. 
Its  antiseptic  action  is  equal  to  that  of  boracic  acid,  it  is  slightly 
anaesthetic  and  very  slightly  toxic.  Three  grams  subcutaneously  in 
rabbits  produced  no  symptoms. 

B.  The  simplest  method  of  increasing  solubility  is  to  form  the 
sulphonic  acids,  whose  sodium  or  potassium  salts  are  soluble  in 
water.  This  has  been  carried  out  with  guaiacol,  although  the 
resulting  compound  is  no  exception  to  the  general  rule  that  such 
derivatives  have  less  physiological  action  than  the  parent  substance, 

1 :  2-guaiacolsulphonate  of  potash,  or  Thiocol, 


yOCHg 
CeHs^OH 

\SO,OK 


was  introduced  by  C.  Schwarz  in  1898,  and  may  be  obtained  by 
the  sulphonation  of  guaiacol  at  a  temperature  below  80°  C.  The 
introduction  of  the  sulphonic  group  results  in  a  complete  loss  of 
the  characteristic  taste  and  smell  of  guaiacol,  and  a  lowering  of 
antiseptic  power.  As  might  be  expected  from  the  presence  of  the 
acid  grouping,  it  passes  unchanged  through  the  body. 

The  1 : 4-sulphonic  acid  of  guaiacol  results  when  the  sulphonation 
is  carried  out  at  higher  temperatures,  but  this  derivative  and  its  salts 
have  no  pharmacological  value  owing  to  their  objectionable  action 
on  the  stomach. 

The  process  of  sulphonation  can  clearly  be  carried  out  with  a  large 
number  of  phenol  substances,  or  with  such  mixtures  as  creosote,  but 
in  all  cases  the  resulting  substances  will  have  less  antiseptic  power. 


146         AROMATIC   HYDROXYL  DERIVATIVES 

Snlphosote  and  Sirolin  are  preparations  of  thiocol  combined 
with  flavouring  agents. 

C.  It  has  been  found  that  the  glycerin   ester  of  guaiacol,  or 
Gnaiamaor, 

(.JJ/OCH3 

is  soluble  in  water ;  it  may  be  obtained  by  the  action  of  monochlor- 
hydrin  on  sodium  guaiacol,  or  by  treating  the  phenol  and  glycerin 
with  a  dehydrating  substance.  It  is  decomposed  in  the  body  like 
the  other  esters,  but  its  bitter  aromatic  taste  appears  to  be  against 
its  use  as  a  guaiacol  substitute. 

D.  The  introduction  of  the  carboxyl  group  into  the  nucleus  of 
guaiacol,  giving  rise  to  the  acid 


Cr/qh"^ 


C6H4<o3^  +  Cl.CH,COOH  =  C,H,<Jj^"2> 


'"^\c6oH 

results  in  a  substance  with  less  antiseptic  power  and  no  great 
advantage  over  the  phenol  itself  owing  to  its  slight  solubility. 

E.  By  the  action  of  monochloracetic  acid  on  1 : 2-dioxybenzene 
in  presence  of  an  alkali^  there  results  brenzcatechin-monoacetic 
acid, 

CH^COOH 
.OH 

This  substance  goes  by  the  name  of  Gnaiacetin ;  it  is  soluble  in 
water  and  almost  tasteless.  It  is  similar  to  guaiacol  in  the  toxic 
symptoms  it  produces. 

GENERAL  REMARKS    ON  CREOSOTE    DERIVATIVES. 

The  only  active  constituent  of  creosote  which  has  been  at  all 
widely  employed  is  guaiacol,  CgH^ .  OCH3 .  OH.  Other  bodies  have, 
however,  been  isolated,  such  as  creosol,  the  monomethyl  ether  of 
homopyroeatechin, 

/CH3 
C6H3^0CH3 
^OH 

which  has  been  previously  mentioned.  S 

Veratrol,  the  dimethyl  ether  CgH4(OCH3)2,  though  less  toxic 
is  more  irritating  to  the  gastric  mucosa  than  guaiacol.  The  corre- 
sponding monoethyl  ether 

C  H  /^^2^5 


REMARKS   ON   CREOSOTE   DERIVATIVES       147 

is    much   more    expensive    and    appears   to   have   no   therapeutic 
advantages. 

Of  the  numerous  guaiacol  derivatives  none  fulfil  all  the  con- 
ditions at  which  the  pharmacologists  aimed.  The  desideratum  is 
a  guaiacol  which  shall  be  easily  soluble  in  water,  tasteless,  and 
non-irritating.  The  solubility  cannot  be  combined  with  absence 
of  taste.  The  only  substance  which  appears  to  combine  these 
characters  is  thiocol,  the  etherial  sulphate  of  guaiacol  and  potassium. 
This,  however,  is  the  form  in  which  guaiacol  is  ordinarily  excreted, 
hence  it  is  not  remarkable  that  it  passes  unchanged  through  the 
body.  Thus  it  cannot  liberate  guaiacol  or  exert  any  antiseptic 
action.  It  does  not  appear  that  any  guaiacol  derivative  which  is 
not  broken  up  in  the  body  with  the  liberation  of  guaiacol  can  exert 
any  antiseptic  action.  Knapp  and  Suter  investigated  several  com- 
pounds, taking  as  an  index  the  amount  of  sulphonic  acid  esters 
excreted.  Guaiacol  cinnamic  acid  ester  liberated  84'94  per  cent., 
guaiacol  carbonate  50  per  cent.;  guaiacol  glyceric  ether,  which  is 
antiseptic  in  itself,  is  mainly  absorbed  as  such,  very  little  appearing 
in  the  urine  as  the  sulphur  compound.  The  synthesis  of  other 
bodies  with  guaiacol  may  or  may  not  be  an  advantage ;  probably 
it  is  the  guaiacol  itself  which  is  the  important  factor  in  all  these 
cases.  Thus  in  the  cinnamic  acid  compound  it  is  more  than  doubt- 
ful whether  this  combination  has  any  real  advantage  beyond  that 
which  it  obtains  from  the  facility  with  which  guaiacol  is  liberated 
in  the  body. 

II.     Trioxybeuzenes. 

Pyrogallol,  CgH3(OH)3 1:2:3,  is  the  only  trioxy  derivative 
employed  in  medicine,  it  has  antiseptic  properties  and  is  mainly 
employed  as  an  application  for  psoriasis.  It  is  a  very  toxic  body, 
causing  the  usual  symptoms  of  poisoning  by  phenols  if  it  is  absorbed 
to  any  extent.  It  is  partly  excreted  as  a  sulphonic  acid  ester  in 
the  urine. 

Engallol,  monacetyl  pyrogallol,  CgH3(OH)20.COCH3,  is  very 
similar  in  its  action  to  pyrogallol,  but  the  toxicity  is  said  to  be 
decreased. 

Lenigallol  is  triacetyl  pyrogallol,  CgH3(0. 000113)3 ;  it  is  non-toxic 
and  non-irritant,  owing  to  the  replacement  of  the  three  hydroxy! 
hydrogen  atoms  by  acetyl  groups.  Its  action  on  the  skin  is  very 
much  less  powerful,  owing  to  the  slow  formation  of  pyrogallol; 
it  is  thus  unsuited  to  cases  where  a  rapid  reducing  agent  is  required. 

I*  Z 


148         AROMATIC  HYDROXYL  DERIVATIVES 

Another  derivative  of  pyrogallol  is  Galla-acetophenone,  or 
methyl-keto-trioxybenzenej  CHg  .  CO.CgH2(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  not  such  an 
active  local  application  for  psoriasis. 


CHAPTER  VII 

Aromatic  Hydroxyl  Derivatives  (continued).  The  Hydroxy 
Acids. — Classification  of  Salicylic  acid  derivatives.  Nencki's  Salol  Principle. 
Tannic  and  Gallic  Acids. 

HYDROXYBENZOIC  ACIDS. 

It  has  been  previously  remarked  that  the  pharmacolog-ical  reaction 
of  benzene  is  very  considerably  diminished  by  the  introduction  of 
the  carboxyl  group,  and  the  resulting  benzoic  acid,  C^HgCOOH, 
may  be  given  in  large  doses  without  much  physiological  result. 
On  the  other  hand,  the  phenyl  substitution  products  of  the  aliphatic 
acids,  such  as  phenyl  acetic,  CgH^ .  CHgCOOH,  phenyl  propionic, 
CeHgCHg .  CHg .  COOH,  and  phenyl  butyric  acid, 

CeH^CHa .  CHg .  CHg .  COOH, 

show  antiseptic  power  stronger  than  phenol  and  increasing  with 
increase  of  molecular  magnitude. 

The  unsaturated  cinnamic  acid,  C7H5CH  :  CH.COOH,  in  the 
form  of  its  sodium  salt,  the  so-called  Ketol,  was  introduced  by 
Landerer  in  1892.  It  may  be  obtained  by  the  condensation  of 
benzaldehyde  and  acetic  acid  (Perkin^s  synthesis), 

CeHgCHiO  +  HgiCH.COOH  =  HgO  +  CgHgCH  :  CH.COOH. 

It  causes  a  considerable  leucocytosis  in  experimental  animals 
(rabbits),  and  also  in  man.  It  was  thus  thought  that  valuable 
results  might  be  obtained  in  tuberculous  disease  by  increasing 
phagocytosis.  The  clinical  results  have  not  been  altogether  satis- 
factory, and  the  treatment  has  never  been  at  all  generally  adopted, 
at  any  rate  in  this  country  j  of  903  cases  collected  from  the  literature 
41  per  cent,  died  or  were  unaffected. 

Based  on  the  salol  principle  a  large  number  of  esters  of  this  acid 
have  been  introduced  into  pharmacology.  Thus  the  1 ;  3-cresol 
ester,  Hetocresol,  CgHgCH  ;  CH.CO.OCgH^ .  CH3,  is  an  insoluble 


150 


THE  AROMATIC   HYDROXY-ACIDS 


powder    intended    for  use  as   a   local   application  to  tuberculous 
sinuses,  &c. 

The  guaiacol  ester,  Styracol,  CeHgCH  :  CH.CO.OCeH^.OCHg, 
is  tasteless,  and  is  said  to  liberate  85  per  cent.  o£  guaiacol  in  the  body. 
It  is  intended  as  a  substitute  for  that  drug,  and  to  combine  the 
supposed  advantages  of  cinnamic  acid. 


Fhysiologfical  Effects  produced  by  Entrance  of  the  Carbozyl 
Radical  into  the  Nucleus  of  Phenol. 

When  a  carboxyl  group  is  introduced  into  the  phenol  nucleus,  the 
physiological  reaction  of  the  resulting  substance  depends  on  the 
relative  positions  of  the  two  substituents ;  in  all  three  isomers, 
however,  a  very  great  drop  in  toxicity  is  noticed. 

When  the  two  groups  are  next  to  each  other,  i.e.  1 : 2-oxybenzoic 
or  salicylic  acid, 

/\— COOH 


OH 


the  resulting  substance  has  antiseptic  properties  closely  allied  to 
phenol,  and  at  the  same  time  other  characteristics  appear  which  are 
barely  noticeable,  if  at  all,  in  the  hydroxyl  substance  itself.  Thus 
salicylic  acid  has  an  antipyretic  action,  and  more  particularly  a 
specific  action  in  rheumatism.  On  the  other  hand,  both  1 :  3-oxy- 
benzoic  acid, 

COOH 


and  the  1 : 4  derivative. 


I— OH 


COOH 


OH 

have  entirely  lost  all  the  physiological  characteristics  of  phenol,  and 
have  neither  the  antiseptic  nor  the  therapeutic  action  of  salicylic 
acid,  the  ortho  derivative. 


PHYSIOLOGICAL  PROPERTIES  151 

When  the  hydrogen  atom  of  the  hydroxyl  group  is  replaced  by 
methyl^ 

(.JJ/OCH3 
^6^4\cOOH, 

the  physiological  action  of  the  1 1, 2  derivative  is  very  much  weaker 
than  salicylic  acid  itself,  it  has  only  slight  antiseptic  and  antipyretic 
action,  and,  in  the  case  of  animals,  is  only  toxic  in  large  doses.  The 
corresponding  1 : 4  derivative,  anisic  acid,  has  no  pharmacological 
reaction  at  all,  and  passes  unchanged  through  the  organism. 

Whereas  the  introduction  of  a  methyl  group  into  the  nucleus  of 
phenol  tends  to  lower  the  toxicity,  whilst  raising  the  antiseptic 
power,  the  result  in  the  case  of  salicylic  acid  is  aa  follows: — 
OrMo-homosalicylic  acid  ()S-cresotinic  acid) 

/OH         1 

aHs^COOH  2 

'    '\CH3       6 

is  physiologically  the  most  reactive,  and  in  relatively  small  doses 
produces  a  paralysis  of  the  muscles  of  the  heart,  paraAxoiao- 
salicylic  (a-cresotinic  acid) 

.OH        1 

CeHg^COOH  2 

'    '\CH3       4 

has  less  reaction  than  salicylic  itself,  whereas  ??2^^a-homosaIicylic 

>0H        1 

aHg^COOH  2 

\CH3       3 

produces  no  pharmacological  reaction. 

The  oxynaphthoic  acids  have  a  similar  action  to  salicylic  acid,  but 
though  more  powerful  they  are  also  caustic,  and  in  doses  of  1«5  gm. 
produce  fatal  results  in  rabbits. 


A.    SALICYLIC  ACID  AND  ITS   DERIVATIVES. 

Salicylic  acid  occurs  in  the  free  state  in  buds  of  Spiraea  ulmariay 
and  as  methyl  ester  in  oil  of  Gaultheria  procumhens  (oil  of  winter- 
green). 

It  may  be  prepared  by  the  action  of  carbon  dioxide  on  sodium 
phenate  at  a  temperature  of  180''-220°, 

2CeH,0Na  +  C0,  =  C^H./g^^^^  +  C^H^OH. 


152  SALICYLIC  ACID 

This  reaction  may  be  modified  by  saturating  sodium  pbenate 
with  carbon  dioxide  under  pressure,  when  sodium  phenyl  carbonate 
results, 

CeH,ONa+CO,  =  CO<^g^Jj^ 

This   substance,   heated  to  120**-130°   under   pressure,  undergoes 
intramolecular  change  to  sodium  salicylate, 


C0< 


ONa        _^     p  TT  /OH 
OC«H,  ^6^*\C00Na. 


Salicylic  acid  has  a  sweet,  acid  taste,  and  in  this  form  only  has 
antiseptic  action.  Its  sodium  salt  is  a  crystalline  powder  with  an 
unpleasant,  sweet  taste  ;  it  is  decomposed  by  mineral  acids,  and  hence 
also  in  the  stomach,  with  the  liberation  of  the  free  acid. 

Both  salicylic  acid  and  its  sodium  salt  have  objectionable 
secondary  actions — deafness,  tinnitus  aurium,  headache,  delirium, 
haematuria,  albuminuria,  &c. 

In  order  to  overcome  these  objectionable  properties  a  large  variety 
of  salicylic  acid  derivatives  have  been  prepared  and  many  intro- 
duced into  pharmacy.  Nencki  was  the  first  to  lead  the  way  into 
this  new  field  of  pharmacodynamics,  and  to  combine  together,  in 
the  form  of  esters,  two  physiologically  reactive  components.  He 
found  that,  in  spite  of  the  toxicity  of  these  components,  the  slow 
breakdown  of  the  esters  in  the  organism  led  to  derivatives 
of  relatively  slight  toxicity.  Such  esters,  generally  possess- 
ing hardly  any  taste  and  no  caustic  action,  pass  unchanged 
through  the  stomach,  and  are  decomposed  in  the  duodenum  by  the 
action  of  alkali  and  enzymes.  The  acid  formed  by  this  saponifica- 
tion is  neutralized  by  the  alkali,  and  the  physiological  action  of  the 
phenol,  which  is  slowly  and  continuously  liberated,  commences  by 
reabsorption  from  that  region.  From  this  point  of  view  the  so- 
called  '  salol  principle '  has  been  already  alluded  to  in  the  previous 
pages  on  phenolic  substances  and  their  derivatives. 

If  it  is  desired  to  obtain  only  the  pharmacological  reaction  of 
the  acid,  then  clearly  it  must  be  combined  with  an  hydroxyl  de- 
rivative which  itself  possesses  little  or  no  physiological  activity; 
that  is,  preferably  an  aliphatic  alcohol  or  an  allied  substance. 

Salicylic  acid,  owing  to  the  presence  of  the  hydroxyl  as  well  as 
the  carboxyl  groups,  can  play  the  part  of  both  phenol  and  acid,  and 
the  derivatives  employed  in  medicine  may  be  classified  as  follows : — 


CLASSIFICATION  OF  DERIVATIVES  153 

I.  Those  formed  by  replacement  of  hydrogen  atom  of  carboxyl 
group,  substances  of  general  formula 


^•^^6^4\COOR 


These  are  further  subdivided  according  to  the  nature  of  the  radical 
R,  viz. :  (a)  Those  in  which  R  is  of  an  aliphatic  nature,  i.  e.  physio- 
logically inactive,  and  (b)  those  in  which  the  radical  is  of  a  phenolic, 
and,  hence,  antiseptic  nature. 

II.  Those   derivatives   formed   by   replacing  hydrogen   of    the 
hydroxyl  group,  of  general  formula 


:2CeH,<; 


OX 
COOH 


X  cannot  be  the  radical  of  aliphatic  alcohols  for  reasons  previously 
given  (p.  151),  but  must  be  of  a  type  which  will  be  easily  broken 
down  in  the  organism  with  the  liberation  of  free  salicylic  acid. 

III.  Derivatives  in  which  both  hydrogen    atoms    have    been 
replaced. 

Subdivided  in  this  manner,  it  wiU  be  noticed  that  Class  I  (a)  and 
Class  II  contain  closely  allied  substances,  i.  e.  derivatives  whose 
physiological  action  is  very  similar  to  salicylic  acid  itself. 


Methyl  salicylate. 


Class  I  (a), 

pxr/OH 
^6^4\COOCH3, 


(oil  of  wintergreen),  can  be  given  internally  as  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  is  often  very  irritating 
to  the  stomach.  Applied  externally,  it  is  useful  in  acute  muscular 
rheumatism. 

Ethyl  salicylate, 

p  XT  /OH 

^6J^4\COOC2H5, 

was  investigated  owing  to  the  fact  that  ethyl  derivatives  are  often 
less  harmful  than  the  corresponding  methyl.  According  to  Hough- 
ton, it  is  only  half  as  toxic  as  the  previously  mentioned  substance. 


154  SALICYLIC  ACID   DERIVATIVES 

The  monoglycerin  ester  of  salicylic  acid,  Glycosal, 

^«***\COO.C3H5(OH)2, 

is  obtained  by  the  action  of  condensing  agents,  such  as  60  per 
cent,  sulphuric  acid  on  a  mixture  of  salicylic  acid  and  glycerin. 
The  triglycerin  ester  has  also  been  investigated,  but  is  found  to  be 
reabsorbed  to  nothing  like  the  same  extent  as  the  mono  derivative, 
of  which  about  96  per  cent,  undergoes  that  process. 

It  is  a  crystalline  powder,  slightly  soluble  in  water,  more  so  in 
alcohol  and  glycerin.  It  possesses  no  odour,  and  is  intended  for 
internal  and  external  use.  Externally  it  is  not  irritating,  and  is 
fairly  rapidly  absorbed,  appearing  in  the  urine  about  six  hours 
after  a  solution  in  alcohol  has  been  painted  on  the  skin. 

The  methoxymethyl  ester  of  salicylic  acid,  Mesotan, 


C6H4< 


OH 
COO.CH2.O.CH3, 


was  introduced  by  Floret  in  1902,  and  is  obtained  by  the  action  of 
chlormethyl  ether  on  sodium  salicylate, 


C6H,< 


OH 

COONa  +  CLCHg-aCHg 

=  NaCl  +  C6H4<(^^QQ^^jj     Q^^jj 


It  is  unstable,  and  very  readily  breaks  down  in  presence  of  water 
into  formaldehyde,  a  reaction  probably  expressed  by  the  following 
reaction : — 

^  6^4\cOO.CH2  •  O.CH3  +  H2O 

=  CeH4<(^  Jq  jj  +  H.CHO  +  CH3OH. 

It  is  used  as  a  local  application  to  painful  joints  in  acute  rheumatism 
and  similar  conditions.  It  has  been  observed  to  produce  dermatitis, 
and  should  therefore  be  employed  in  weak  dilutions,  and  in  media 
not  easily  absorbed,  e.  g.  vaseline  or  olive  oil  The  preparation  is 
unstable. 

Acetol-salicylic  ester,  Salacetol, 


CfiH^^ 


/OR 

\COO.CH2 .  CO.CH3, 


THE   SALOL   GROUP  155 

is  obtained  by  the  action  of  cbloracetone  on  sodium  salicylate, 
'OH 


CeH,<; 


COONa  +  ^^-^^^.CO.CHg 


_  NaCl  +  C6H,>^^QQ^^jj  ^^Q^^jj 


Like  the  previous  compound,  it  is  very  readily  saponified,  so  much 
so  that  the  secondary  action  of  salicylic  acid  may  appear  almost  as 
quickly  as  in  the  case  of  the  free  acid  itself. 

Salen  is  a  mixture  of  methyl  and  ethyl  glycolic  acid  esters  of 
salicylic  acid, 

^e^^\COOClIfiOOCU^     and     C6H4<^^qq^jj^(.qq(x^jj^ 

These  substances  are  crystalline,  and  have  melting-points  between 
28°-29°  C.  and  38°-39°  C.  respectively.  When  mixed,  however,  they 
liquefy,  and  do  not  become  solid  till  raised  to  a  temperature  of 
S'^-IO"  C.  The  mixture  is  soluble  in  alcohol,  castor  oil,  or  a  mixture 
of  olive  oil  and  chloroform.  It  is  inodorous,  and  is  intended  to. 
replace  oil  of  wintergreen  as  a  local  application. 

Class  I  (b). 

One  of  the  simplest  representatives  of  this  group  is  the  phenyl 
ester  of  salicylic  acid,  or  Salol, 

'OH 


flK 


COO.CeHg. 

It  results  on  heating  the  acid  itself  to  200-220"  with  the 
elimination  of  water  and  carbon  dioxide, 

or  it  may  be  obtained  by  the  action  of  phosphorus  oxychloride  on 
a  mixture  of  salicylic  acid  and  phenol, 

^e^^xcOOiH  +  OHjCeHg  "  ^2^  +  ^^^^xcOOCeH^. 

Both  the  toxicity  and  the  intestinal  antiseptic  action  of  salol  are 
due  to  the  phenol  group.  The  sodium  salicylate  is  not  antiseptic 
(p.  16),  and  is  much  less  toxic  than  phenol.  The  salol  compounds 
are  unsuited  for  wound  dressings,  as  they  are  only  split  up  with 
difficulty  by  the  body  fluids.  When  the  specific  action  of  the 
salicylate  is  required,  a  compound  which  on  decomposition  yields 
some  indifferent  body  should  be  employed^ 


4.  One  molecule  of  resorcin  giving    ^e^ixcOO  C  H     OH 


156  SALICYLIC  ACID  DERIVATIVES 

In  place  of  phenol,  the  following  and  many  other  similar  hydroxyl 
substances  may  be  combined  with  salicylic  acid  through  the  agency 
of  phosphorus  oxy-chloride : — 

1.  a-  and  jS-naphthol  .         .         .     ^6^4x^000  H 

2.  l:2.,l:3.,l:4.cresol   .        .     ^e^,<(cOOC,}I,.ClI, 

3    Thymol ^e^KcOO.C,,U^ 

'OH 

rvr..  p„/O.COCeH,.OH 

^^^       '>  ''  "  ^e^^XO.COCgH^OH 

or  the  corresponding  methoxy     p,  tt  yOH 

derivatives  .         .        .     ^e^^^COO.CeH^OCHg 

5.  Guaiacol  .         .         .         .     CeH4<^(3()^^jj^Q^jj^ 

6.  The  mixture  of  phenols  called  creosote. 

7.  l:4-nitrophenol      .        .        .    C6H4<(gQo.CeH, .  NO^ 

8.  Gaultheria  oil  ...     CeH,<(^()Q  ^.^jj^^^^^^^jj^ 

9.  GaUic  acid      ....    ^6H4<(co.O.OC.C6H2(OH)3 
In  place  of  salicylic  acid,  the  inert  anisic  acid, 

^6H4<^COOH  ^ '  ^' 

may  be  used  to  carry  physiologically  active  phenols  in  the  form  of 
their  respective  esters.  Thus  the  anisic  acid  derivatives,  among 
others,  of  the  following  have  been  prepared  : — 

2.  Guaiacol  ....     C,H,<0gg3^^^^  OCH3 

and  salicylic  acid  has  been  replaced  by  the  homosalicylic  acids. 

The  above  examples  show  the  large  number  of  permutations  and 
combinations  which  can  be  made  between  acids  and  hydroxyl-con- 
taining  substances ;  they  are  all  decomposed  like  salol,  for  example, 
and  substances  with  novel  pharmacological  action  cannot  be  looked 


SALOL   GROUP  157 

for  in  this  group.  One  may  have  an  advantage  over  another  as 
regards  taste  or  solubility  or  the  ease  with  which  it  breaks  up  in  the 
duodenum  and  so  allows  its  physiological  reaction  to  appear.  It 
will  be  evident  that  there  are  possibilities  enough  to  enable  fresh 
derivatives  of  this  type  to  be  continually  placed  on  the  market, 
although  the  probability  of  these  possessing  advantages  over  the 
older  preparations  is  but  slight. 

An  example  is  given  by  Frankel  of  the  manner  in  which  a  drug 
may  be  introduced,  although  its  constitution  would  indicate  at  once 
that  it  is  valueless.  Thus  1 : 2-methoxy  or  ethoxybenzoic  acid  on 
nitration  gives  a  5-nitro  derivative, 

/COOH  1 

'    '\nO,  "  5 
This  was  reduced  and  converted  into  the  corresponding  acetyl 
derivative  by  means  of  acetic  anhydride, 

.COOH 

\NH(C0CH3); 
Now  such  a  substance  would  neither  have  the  phenacetin  reaction, 
owing  to  the  presence  of  the  carboxyl  group,  nor  the  physiological 
action  of  salicylic  acid,  since  it  does  not  contain  the  free  hydroxyl 
group. 

In  this  group  of  salicylic  acid  derivatives  salicyl-acetyl-jo-amido- 
phenol  ether,  or  Salophexir 

'OH 
.COO.C6H4.NH(COCH3), 

may  be  mentioned;  it  can  be  obtained  by  the  reduction  of  the 
/?-nitrophenol  ester  of  salicylic  acid,  followed  by  the  conversion 
of  the  amido  substance  into  its  acetyl  derivative.  It  is  almost 
insoluble  in  water,  and  has  no  taste  or  smell,  and  is  of  small 
toxicity,  but  on  decomposition  in  the  organism  it  gives  rise  to  1:4- 
acetylamido  phenol, 

a  substance  possessing  but  very  slight  antiseptic  action,  and  more 
nearly  related,  in  its  physiological  action,  to  the  aniline  antipyretics 
than  to  phenol.  It  is  unaffected  by  pepsin,  but  decomposed  in  the 
small  intestine.  Its  antipyretic  action  is  feeble,  but  it  may  be 
employed  for  the  salicyl  action  in  acute  rheumatism. 


C6H4\( 


158  SALICYLIC   ACID  DERIVATIVES 

Class  II. 
Acetyl-salicylic  aeid^  or  Aspirin, 

was  introduced  by  Dreser  in  1899  as  a  substitute  for  salicylic  acid. 
It  is  obtained  by  the  action  o£  acetic  anhydride  or  acetyl  chloride 
on  salicylic  acid  at  high  temperatures.  It  is  largely  used  instead 
of  sodium  salicylate  in  acute  rheumatism.  It  is  thought  to  be 
better  tolerated  by  the  stomach,  and  only  rarely  gives  rise  to  unpleasant 
symptoms.  Erythema  and  pruritus  have  occasionally  been  observed. 
Salicyl-acetic  acid, 

p  „  /O.CHgCOOH 

^6^4\C00H 

is  obtained  by  acting  upon  the  sodium  salt  of  the  anilide, 
pTT /ONa 

^6^4<\CO.NHC6H5, 

with  the  sodium  salt  of  chloracetic  acid : — 

p  jr  /ONa  4-  Cl.CHoCOONa       ^  „  yO.CH2COONa  ^  ^^  p, 
^6^4\cONHC6H5  -  ^6^4\C0NHC6H5     +^^^^' 

On  heating  with  alkalis  this  is  decomposed : — 


^e^Ko 


w.CH2C00Na^T.x  p.TT 


O.CHoCOONa 


=  ^6H4<^coONa  "^  ^^eHs-NH^ . 


Class  III. 

Acetyl  salicylic  methyl  ester,  Methyl  rhodin, 
p„/0(C0CH3) 

^6^4\COOCH3 

is  a  colourless  crystalline  substance,  not  affected  by  dilute  acids,  and 
consequently  undecomposed  in  the  stomach.  It  is  stated  to  be 
better  adapted  for  patients  with  enfeebled  digestion  than  sodium 
salicylate. 

Benzosalin  is  the  methyl  ester  of  benzoyl  salicylic  acid. 


^e^i'Co 


(COC.H,) 
COO.CH, 


it  is  not  decomposed  till  it  reaches  the  small  intestine,  and  does  not 
split  off  phenol,  but,  beyond  this,  it  appears  to  possess  no  particular 
advantages  over  other  salicyl  compounds. 


TANNIC   ACID  159 

B.     TANNIC   ACID  AND  ITS  DERIVATIVES. 

The  tannic  acids,  or  tannins,  occur  widely  distributed  in  the 
vegetable  kingdom.  They  are  soluble  in  water,  and  form  com- 
pounds with  gelatin  and  with  animal  hides,  and  are  consequently 
employed  in  the  manufacture  of  leather.  They  also  precipitate 
protein  solutions.  Some  appear  to  be  glucosides  of  gallic  acid, 
(0H)3 .  CgHg .  COOH,  and,  on  boiling  with  dilute  acids,  give  grape 
sugar  and  gallic  acid ;  others  contain  phloroglucin  in  place  of  sugar. 
Pure  tannic  acid,  however,  appears  to  be  a  digallic  acid,  since  on 
warming  with  dilute  acids  or  alkalis  it  gives  rise  to  that  acid  alone. 

Like  salicylic  acid,  it  has  antiseptic  properties ;  its  main  property 
is  due  to  its  local  action  on  protoplasm,  and  is  known  as  'astrin- 
gency  \  It  appears  in  the  urine  partly  as  gallic  acid  and  pyrogallol ; 
in  some  cases,  apparently,  some  tannic  acid  is  passed  unchanged,  in 
others  as  a  sulphuric  ester.  But  tannic  acid  has  two  characteristics 
which  stand  in  the  way  of  its  employment  as  an  intestinal  dis- 
infectant. Firstly,  it  possesses  an  objectionable  taste,  and,  secondly, 
it  loses  its  antiseptic  property  in  the  stomach,  owing  to  its  com- 
bining with  protein  bodies  in  its  contents  or  mucous  membrane. 
Consequently,  it  is  necessary  to  obtain  derivatives  which  can  pass 
unchanged  through  that  organ,  but  will  be  decomposed,  like  salol,  in 
the  duodenum.  For  this  purpose  various  acetyl  derivatives  have 
been  investigated,  and  it  has  been  found  that  the  triacetyl  tannic 
acid  and  those  substances  containing  more  acetyl  groups  are  not 
decomposed  by  the  intestinal  juice,  and  consequently  have  not 
the  required  action. 

When  tannic  acid  is  treated  with  a  mixture  of  acetic  acid  and 
acetic  anhydride,  however,  a  mixture  of  mono-  and  di-acetyl  tannic 
acid  results,  which  H.  Meyer  and  F.  Miiller  introduced  into  phar- 
macy in  1894  under  the  name  of  Tannigen,  Ci4H8(COC  113)209. 
This  body  is  insoluble  in  water,  and  consequently  tasteless.  It  is 
dissolved  by  alkalis  and  precipitated  by  acids.  At  body  tempera- 
ture it  forms  a  sticky  mass  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  gallic  acid. 

In  another  direction  tannic  acid  derivatives  have  been  obtained 
by  combination  with  albuminous  substances.  Gottlieb  and  others 
precipitated  Qgg  albumen  with  the  acid,  but  the  resulting  compound 
is  decomposed  in  the  stomach.  If,  however,  it  is  heated  for  6-10 
hours  at  110°  C,  it  loses  this  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  Tannalbin ;  it  contains  50  per  cent,  of  tannin. 
A  similar  preparation  is  named  Houthin.  Other  preparations  of 
this  type  can  be  obtained  by  precipitating  gelatine  solutions  with 
tannic  acid  (Tauuocol);  or  with  casein  (Taunocase).  These  bodies 
fulfil  their  purpose,  but  considering  what  their  purpose  was,  it  seems 
not  a  little  curious  that  they  should  be  seriously  recommended  in 
diseased  conditions  of  the  lower  bowel  to  be  given  jper  rectum. 

The  combination  of  an  antiseptic  substance,  formaldehyde,  with 
tannic  acid  is  methylene  ditannic  acid,  or  Tanuoform, 

obtained  by  the  action  of  hydrochloric  acid  on  a  solution  of  form- 
aldehyde and  tannic  acid,  or  by  heating  the  components  under 
pressure. 

It  is  only  slightly  soluble  in  water,  soluble  in  alcohol,  and  devoid 
of  odour.    It  appears  to  be  mainly  useful  as  an  external  application. 

Tannic  acid  has  also  been  combined  with  hexamethylene  tetramine, 
and  the  resulting  substance  is  termed  Tanuopin  or  Tannon, 

(CH,),N,(ChH,„0,)3, 
but  this  body  will  not  liberate  so  much  formaldehyde,  and  conse- 
quently will  not  have  so  powerful  an  antiseptic  action  as  the  direct 
compound  of  tannin  and  formalin.  It  is  only  broken  down 
in  alkaline  solutions,  and  is  intended  for  use  as  a  urinary 
disinfectant. 

Tannal  is  a  tannate  of  aluminium,  it  is  insoluble  in  water,  and 
has  the  formula  Al2(OH)4(Ci4H909)2  +  IOH20. 

Note. — With  regard  to  the  clinical  value  of  these  two  classes  of 
derivatives,  it  may  be  remarked  that  sodium  salicylate  will  probably 
be  found  quite  as  efficacfous  and  suitable  as  any  of  the  newer  pro- 
ducts in  the  very  large  majority  of  cases.  When  this  body  is  not 
well  tolerated  by  the  stomach,  that  is  if  nausea  or  vomiting  occurs, 
salicin,  the  glucoside  (see  p.  322),  may  be  tried  or  acetyl  salicylic 
acid.  General  toxic  symptoms  are  met  by  either  diminishing  the 
dose  or  by  giving  some  preparation  which  is  less  rapidly  and  com- 
pletely absorbed  or  contains  a  smaller  proportion  of  the  active 
principle. 

As  to  the  tannic  acid  substitutes  those  combined  with  protein  in 
some  form  or  other  appear  to  be  the  most  scientifically  justifiable. 


CHAPTER  Vin 

Antiseptic    and    other    substances    containing    Iodine    and 

Sulphur.— Iodoform.      Classification  of  substances  introduced  in  place  of 
Iodoform  and  the  Alkali  iodides.   Derivatives  containing  Sulphur — Ichthyol. 

ANTISEPTICS   CONTAINING  IODINE. 

I.     Iodoform  and  Substances  of  Allied  Physiological  Action. 

Iodoform,  CHI3,  was  the  first  solid  antiseptic  introduced  into 
pharmacy.  It  may  be  obtained  by  the  action  of  iodine,  in  the 
presence  o£  the  alkalis,  on  a  large  number  of  aliphatic  derivatives, 
such  as  ethyl  alcohol,  acetone,  acetaldehyde,  &c.  It  is  generally 
prepared  by  adding  iodine  to  a  warm  solution  of  either  soda  or 
potash  in  dilute  alcohol  or  acetone ;  the  iodoform  formed  separates 
out  and  is  filtered  off.  The  solution  contains  alkaline  iodides  and 
iodates ;  on  the  addition  of  a  further  quantity  of  alcohol  (or  acetone) 
and  the  passage  of  a  slow  stream  of  chlorine  through  the  solution 
(resulting  in  the  liberation  of  free  iodine),  a  further  quantity  of 
iodoform  separates  out. 

It  may  also  be  obtained  by  the  electrolysis  of  a  solution  of  alcohol 
(or  acetone)  containing  potassium  iodide,  whilst  a  slow  stream  of 
carbon  dioxide  is  being  passed  through  it. 

It  is  unnecessary  to  describe  the  characteristic  properties  of  this 
well-known  substance.  As  such,  it  is  not  an  antiseptic,  and  its 
action  depends  on  the  liberation  of  free  iodine  by  the  action  of  the 
secretions  of  the  wound  upon  whicb  or  in  which  it  is  used.  Owing 
to  its  physical  characteristics  (it  melts  at  120°  and  volatilizes  readily 
at  medium  temperatures)  it  cannot  be  sterilized  by  heat. 

Iodoform  possesses  two  great  disadvantages — firstly,  its  objec- 
tionable smell,  and,  secondly,  the  fact  that  it  may  be  absorbed  from 
wounds  and  consequently  give  rise  to  toxic  symptoms.  Various 
attempts  have  been  made  to  overcome  these  objections  to  its  use,  and 
three  classes  of  compounds  have  been  produced  as  substitutes  : — 

A.  Unstable  compounds  or  mixtures  of  iodoform  with  various 
substances  tending  to  destroy  or  lessen  its  smell. 


162  ANTISEPTICS   CONTAINING  IODINE 

B,  Insoluble  and  unstable  iodine  derivatives. 

C.  Derivatives  of  totally  different  type  to  iodoform  itself^,  but 

which,  like  it,  liberate  iodine  and  consequently  have  a  similar 
physiological  action. 

Class  A. 

To  this  group  belongs  iodoformin,  (CH2)6N4  .CHI3,  an  addition 
product  of  hexamethylene  tetramine  and  iodoform,  but  this  com- 
pound has  always  a  slight  smell  of  the  latter  substance,  owing  to 
the  ease  with  which  it  is  broken  down  into  its  constituents  by 
moisture.    It  contains  75  per  cent,  iodoform. 

lodoformal,  although  not  a  derivative  of  iodoform,  may  be  men- 
tioned in  this  place.  It  is  the  hydriodide  of  hexamethylene,  and  is 
said  to  possess  higher  antiseptic  power  than  iodoform.  Its  action 
probably  depends  on  its  dissociation  into  hexamethylene  and 
hydriodic  acid,  this  latter  substance  being  readily  decomposed, 
giving  free  iodine. 

Various  tannic  acid  and  albuminous  preparations  of  iodoform 
have  been  put  on  the  market,  such  for  instance  as  iodoformogen, 
an  almost  odourless  compound  with  albumen,  which  may  be 
sterilized  at  100°  and  is  stated  not  to  give  rise  to  iodine-eczema 
as  readily  as  does  iodoform  itself.  But  many  substances  of  this  type 
are  merely  mixtures,  and  will  not  further  be  described. 

Class  B. 

Various  unstable  compounds  of  iodine  and  albumen  or  glutinous 
substances  have  been  introduced.  That  which  goes  by  the  name  of 
lodolene  is  an  iodo  derivative  of  albumen.  It  is  a  yellow  powder 
insoluble  in  the  ordinary  solvents. 

lodyloform  is  a  preparation  of  iodine  and  a  glutinous  substance; 
it  is  a  yellowish-brown  odourless  powder  insoluble  in  water  and  con- 
taining 10  per  cent,  of  iodine.  Sperling  states  that  it  is  equivalent 
to  iodoform  in  disinfecting  power,  but  is  less  efficacious  in  the 
treatment  of  wounds. 

lodeigon  and  peptoiodeigon  are  compounds  of  iodine  with  pro- 
tein ;  the  former  is  insoluble  in  water,  the  latter  soluble. 

Class  C. 

It  is  necessary  that  an  iodoform  substitute  should  be  an  insoluble 
solid,  possessing  antiseptic  properties,  but  have  no  smell  and  only 
slight  toxicity.     Since  the  characteristic  action  of  iodoform  is  due 


IODOFORM   SUBSTITUTES  163 

to  the  liberation  of  iodine,  this  property  has  been  retained  in 
all  the  substances  hitherto  introduced  to  supersede  it.  In  fact  the 
aim  of  the  manufacturers  has  been  to  produce  easily  decomposed 
iodine  derivatives,  and,  so  far,  no  other  element  or  radical  has  been 
found  that  will  satisfactorily  replace  iodine,  although  attempts 
have  been  made  with  sulphur,  which  will  be  described  later. 

The  entrance  of  iodine  into  aliphatic  and  aromatic  substances  is 
generally  followed  by  a  rise  in  antiseptic  power,  but  derivatives  of 
the  first  type  are  usually  sufficiently  stable  to  resist  decomposition 
by  the  wound  secretions.  It  was  but  natural  that  the  antiseptic 
phenols  should  be  investigated  in  the  hope  of  obtaining  suitable 
substitutes,  but  again,  when  the  hydrogen  of  the  nucleus  is  replaced 
by  iodine,  the  stability  of  the  resulting  iodo-phenols  is  too  great, 
and  although  they  possess  powerful  antiseptic  properties,  they  can 
in  no  sense  of  the  word  be  regarded  as  iodoform  substitutes.  On 
the  other  hand,  those  phenolic  derivatives  in  which  the  hydrogen 
of  the  hydroxyl  group  is  replaced  by  iodine  are  readily  decomposed 
with  the  liberation  of  the  halogen,  and  have  consequently  been 
introduced  into  pharmacy.  Of  these  the  two  following  are  the 
most  important : — 


Di-i*o-butyl-o-cresol  iodide  or  Enrophen, 


C6H2\-CH3 

.OH 
CgHoc— CH, 


/^o-butyl-d-cresol  is  obtained  by  the  action  of  condensing  agents 
on  a  mixture  of  o-cresol  and  iso-hutjl  alcohol ;  when  iodine  acts  on 
an  alkaline  solution  of  this  substance  europhen  results.  It  is  a 
yellow,  light  powder,  keeps  well  when  dry,  and  in  contact  with 
moisture  slowly  gives  off  free  iodine.  It  is  said  to  be  valuable  for 
syphilitic  cases. 

/C3H7 

Di-thymol-di-iodide,  Aristol,  or  Annidalin, 

^6H2^CH3 
\C3H, 

was  introduced  by  Eichkoff  in  1890,  and  may  be  obtained  by  the 
action  of  iodine  on  an  alkaline  solution  of  thymol.  It  is  a  brick-red 
powder,  insoluble  in  water,  and  is  said  to  be  a  useful  application  for 
wounds. 

M  2, 


164  ANTISEPTICS   CONTAINING  IODINE 

Belonging  to  a  different  class  from  the  previous  compounds  is 

tetra-iodo-pyrrol  or  lodol, 

I.C— C.I 

II      II 
I.C     C.I 

\/ 

NH 

It  is  obtained  by  the  action  of  iodine  on  alkaline  solutions  of  pyrrol, 
or  by  firstly  obtaining  tetrachlorpyrrol  by  the  action  of  chlorine  on 
pyrrol^  and  then  decomposing  this  derivative  with  potassium  iodide, 

1.  C4H4 .  NH  +  8C1  =  4HC1  +  C4CI4 .  NH 

2.  C4CI4  .  NH  +  4KI  =  4KC1  +  CJ^ .  NH. 

lodoL 

The  physiological  action  of  iodol,  which  is  a  tasteless  and  odour- 
less powder,  is  very  similar  to  that  of  iodoform,  but  it  adheres  better 
to  the  epidermis  and  the  surface  of  wounds.  It  has  also  been  used  as 
a  substitute  for  potassium  iodide,  as  one-half  of  the  iodine  reappears 
in  the  urine,  showing  that  it  is  broken  up  in  the  body. 


II,    Iodine-containing  Antiseptics  not  liberating  that 
element  in  the  organism. 

The  following  derivatives  owe  their  increased  antiseptic  power  to 
the  replacement  of  hydrogen  by  iodine,  but,  unlike  the  previously 
mentioned  substances,  iodine  is  not  liberated. 

Quinoline,  as  well  as  1-oxyquinoline,  has  marked  antipyretic  and 
antiseptic  properties,  and  the  latter  characteristic  is  increased  by 
the  replacement  of  hydrogen  by  iodine.  Based  on  this,  the  follow- 
ing two  compounds  have  been  introduced  into  pharmacy : — 

SO2OH 
I 

Quinoline- l-oxy-2-iodo-4-sulphonic  acid  or  Loretin, 

OHN 

This  is  obtained  from  1-oxyquinoline  by  the  action  of  cold  fuming 
sulphuric  acid ;  the  sodium  salt  of  the  resulting  sulphonic  acid  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 
Griseriu,     It  is  used  in  tuberculosis  and  other  infectious  diseases. 

CI 
l-oxy-2-iodo-4-chlor-quinoline  or  vioform, 


OH  N 


was  introduced  in  1900  by  E.  Tavel  and  Tomarkim. 

1-oxyquinoline  is  chlorinated,  and  the  resulting  substance  acted 
upon  by  iodine  in  potassium  iodide  solution.  It  is  a  greyish-yellow 
tasteless  powder,  insoluble  in  water,  and  without  smell ;  it  may  be 
sterilized  by  heating  to  100°,  at  higher  temperatures  decomposition 
sets  in.     It  is  stated  to  have  a  more  powerful  action  than  iodoform. 

The  iodine  derivatives  of  1 : 4-phenol  sulphonic  acid  were  investi- 
gated by  Ostermayer  in  1880,  and  introduced  under  the  name 
of  Sozoiodol  preparations.  When  phenol  is  acted  upon  by  warm 
sulphuric  acid  the  chief  product  is  ;?-phenol  sulphuric  acid, 

prr/OH 

When  a  solution  of  the  potassium  salt  of  this  acid  is  treated  with 
chloride  of  iodine,  the  di-iodide  of  /(-phenol  sulphonate  of  potash  is 
formed, 

C6H4<(sQpK  +  2ICl  =  C6H2T2<(g^^Qg-+2HCl. 

The  free  acid  may  be  obtained  by  the  action  of  sulphuric  acid  upon 
the  barium  salt ;  it  goes  by  the  name  of  Sozoiodolic  acid, 

OH 


^6H2T2\SO  OH  ^  ^^20* 


and  is  soluble  in  water  and  alcohol. 

The  sodium  salt  is  more  soluble  in  water  than  the  potassium; 
with  the  exception  of  the  mercury  compound  all  the  salts  are  more 
or  less  soluble  in  that  medium. 

The  sozoiodol  preparations  pass  unchanged  through  the  organism, 
and  it  is  difficult  to  imagine  that  they  possess  any  pronounced  action. 
Phenol  has  antiseptic  properties,  but  the  introduction  of  the  sul- 
phonic group  results,  as  is  the  invariable  rule,  in  a  decrease  in 
physiological  characteristics;  and  although  the  introduction  of 
iodine  atoms  into  the  molecule  of  this  substance  tends  to  raise  the 


166  ANTISEPTICS   CONTAINING  IODINE 

antiseptic  power,  it  cannot  do  so  to  any  great  extent  in  a  substance 
possessing  such  powerful  acid  properties  as  phenol  sulphuric  acid. 
Frankel  remarks  that  it  is  only  the  zinc  and  mercury  salts  which  are 
of  value,  and  in  all  probability  these  owe  their  reactivity  not  to  the 
acid  (sozoiodol),  radical,  but  to  the  metallic  ion. 
lodo-anisol,  ri  tj  /OCHo 

was  introduced  in  1904,  and  is  obtained  from  the  1 : 4-iodanisol, 

CeH,<0CH3 

by  the  action  of  chlorine^  which  gives  rise  to 

p  „  /OCH3 

On  treatment  with  caustic  alkali  this  iodochloride  gives  iodoso- 
anisol, 

and  when  this  is  boiled  with  water  the  following  decomposition 
takes  place : — 

2CeH,<JCH3  ^  c,H,<OCH3  +  c,H/gCH3 

It  is  an  explosive  substance,  only  slightly  soluble  in  cold  water,  and 
is  used  mixed  with  an  equal  quantity  of  calcium  phosphate,  or  made 
into  a  paste  with  glycerin.  It  behaves  like  a  superoxide,  and  to 
this  may  possibly  be  ascribed  its  action ;  if  this  is  the  case  it  may 
be  compared  to  benzoyl  peroxide  (CgHgCO)^ .  Og,  which  has  also 
been  recommended  as  a  useful  antiseptic ;  it  may  be  applied  locally 
as  a  powder,  and  does  not  give  rise  to  symptoms  of  irritation  owing 
to  its  mild  anaesthetic  effect. 

Losophaue  is  a  tri-iodo  derivative  of  1 : 3-cresol, 

It  contains  80  per  cent,  iodine.  It  is  a  crystalline  powder  soluble 
in  alcohol,  oil,  &c.,  and  has  been  used  in  parasitic  skin  diseases.  It 
is,  however,  too  irritant  to  be  of  much  value. 

Nosophen  is  tetra-iodo  phenolphthalein.  It  is  insoluble  in  water 
and  only  slightly  soluble  in  alcohol.  It  has  a  slight  odour  like 
that  of  iodine,  of  which  it  contains  60  per  cent.  It  is  used  as 
a  dusting  powder.    Internally,  it  is  said  to  pass  through  the  system 


SUBSTITUTES  FOR  ALKALI  IODIDES 


167 


unchanged.  Antiosin  is  its  sodium  salt  and  Endozin  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- 
factive conditions  of  the  gastro-intestinal  tract. 

The  proportion  of  iodine  in  various  preparations  is  shown  in  the 
following  table,  modified  from  one  given  in  Martindale  and  West- 
cott^s  extra  Pharmacopoeia  (10th  edition) : — 


Iodine  easily  liberated. 


Iodoform 
lodol 
Aristol 
Europhen 


per  cent. 
96.6 
90-0 
50-0 

28-5 


Iodine  not  liberated. 

per  cent. 
Losophen  80'0 

Di-iodo  salicylic 

acid  66-67 

lodo  salicylic  acid  50-0 


Pass  unchanged  through 
animal  organism. 


Sozoiodol 


per  cent. 
50-0 


ORGANIC  SUBSTANCES  INTRODUCED  IN  PLACE  OF 
THE  ALKALI  IODIDES. 

The  objectionable,  and  occasionally  very  inconvenient,  character- 
istics of  potassium  iodide  have  led  to  the  investigation  of  many  non- 
toxic iodine-containing  organic  substances.  It  is  clear  that  to  bring 
about  the  same  physiological  reaction  as  the  alkaline  iodides,  these 
organic  derivatives  must  be  decomposed  in  the  body,  and  that  con- 
sequently the  only  difference  between  them  will  be  that,  instead  of 
the  rapid  absorption  of  the  former,  a  slower  process  will  take  place, 
dependent  on  their  stability,  or  the  ease  with  which  the  organic 
derivative  is  broken  down  in  the  system. 

On  lines  similar  to  those  previously  indicated  with  other  bodies, 
iodine  has  been  combined  with  protein  matter,  and  one  of  such 
bodies — 

lodalbin,  contains  21-5  per  cent,  of  that  element.  It  passes  un- 
changed through  the  stomach,  and  is  decomposed  in  the  intestinal 
canal ;  the  reabsorption  of  iodine  commences  from  that  region. 

lodipin  is  a  preparation  formed  by  the  addition  of  iodine  to  un- 
saturated oils ;  of  the  latter,  oil  of  sesame  is  said  to  be  the  best,  on 
account  of  the  ease  with  which  it  is  digested  and  its  freedom  from 
taste.  Two  varieties  of  this  preparation  are  on  the  market,  one 
containing  10  per  cent,  iodine  and  suitable  for  internal  administra- 
tion, and  the  other  24  per  cent,  specially  useful  for  injections. 

It  appears  to  be  a  most  reliable  substitute  for  potassium  iodide, 
and  is  most  useful  for  subcutaneous  injections,  in  which  case  iodine 
is  only  slowly  excreted  by  the  urine. 


168         ANTISEPTICS   CONTAINING   SULPHUR 

According  to  Lesser,  patients  may  be  accustomed  to  the  use  of 
iodides  by  means  o£  subcutaneous  injections  of  this  derivative. 

Experiments  have  shown  that  iodipin,  when  subcutaneously  in- 
jected, remains  for  a  long  time  at  the  seat  of  injection,  and  only 
slowly  becomes  absorbed  by  the  tissues  in  the  form  of  potassium 
iodide.  Its  diffusion  throughout  the  body  is  shown  by  the  fact  that 
iodine  was  detected  in  the  epithelial  scales  of  a  syphilide  during 
the  administration  of  the  drug. 

lothion  is  di-iodo-hydroxy-propane,  CHgl.CHI.CHgOH,  and 
though  it  cannot  be  used  internally  or  hypodermically,  it  is  in- 
tended as  a  substitute  for  potassium  iodide,  the  method  of  adminis- 
tration being  by  inunction. 

SUBSTANCES   CONTAINING   SULPHUR. 

Sulphur  itself,  though  an  inert  body,  is,  like  iodoform,  capable  of 
producing  antiseptic  effects  when  it  is  brought  in  contact  with  fresh 
tissues.  It  has  been  employed  instead  of  iodoform  in  surgery  for 
packing  suppurating  cavities  and  forother  purposes ;  the  tissues  round 
are  blackened  and  slough  away,  and  a  strong  smell  of  sulphuretted 
hydrogen  is  observed,  which  would  indicate  a  reducing  process. 
Lane,  who  was  the  first  to  employ  it  in  this  way  in  1893,  thinks  the 
action  is  due  to  the  formation  of  sulphurous  acid,  which  is  sub- 
sequently oxidized  to  sulphuric  acid.  A  powerful  reaction  appears 
to  take  place,  and,  as  a  rule,  it  is  unsafe  and  unnecessary  to  leave 
the  sulphur  in  contact  with  the  tissues  for  more  than  24  hours.  ^ 

Organic  sulphur  derivatives  in  which  sulphur  is  in  the  divalent 
and  hence  unoxidized  condition  have  mild  antiseptic  action,  com- 
bined with  the  property  of  promoting  the  formation  of  granulation 
tissue,  and  consequently  many  attempts  have  been  made  to  arrive 
at  substances  which  might  have  a  corresponding  action  to  iodoform, 
but  so  far  without  any  marked  success. 

Thus  thio-resorcin,  CgH^OgSg,  obtained  by  the  action  of  sulphur 
on  a  solution  of  resorcin  in  potash,  cannot  be  employed  owing  to 
the  cutaneous  irritation  which  it  produces. 


Sulphamiuol,  OH 


/\ 


\/ 


NH— 


— S,— 


/\ 


\/ 


prepared  from  oxy-diphenyl-amine,  has  not  proved  of  value. 

A  combined  sulphur  and  iodine  derivative  is  the  ethyl  iodide 
1  Med.  Chi,  Trans.,  vol.  78. 


ICHTHYOL  169 

addition  compound  o£  allyl  urea  (see  thiosinamine,  p.  218)  which 
goes  by  the  name  of  Tiodine, 


/NHC3H, 
\NH,aHJ. 


This  is  a  crystalline  substance  soluble  in  water  in  all  proportions, 
and  readily  absorbed  by  the  organism  when  taken  by  the  mouth  or 
hypodermically.  In  therapeutic  doses  it  is  said  to  be  absolutely 
non-toxic. 

ICHTHYOL. 

The  most  commonly  employed  organic  sulphur  compound  is  per- 
haps that  known  as  ichthyol,  whose  chemical  constitution  has  not 
yet  been  determined.  It  is  a  bituminous  product  containing 
about  15  per  cent,  of  sulphur.  Ordinary  medicinal  ichthyol  is 
sulphoichthyolate  of  ammonia,  but  corresponding  preparations  of 
lithium,  sodium  and  zinc  are  manufactured.  Owing  to  the  un- 
pleasant smell  and  taste  of  ichthyol,  numerous  modifications  of  the 
original  substances  have  been  prepared.  Desichthyol  is  prepared 
by  the  action  of  superheated  steam  on  ichthyol,  and  is  tasteless. 
A  combination  with  albumin,  Ichthalbin,  is  insoluble,  and  conse- 
quently has  neither  taste  nor  odour. 

Ichthoform  is  prepared  by  the  action  of  formaldehyde,  and 
though  tasteless,  is  only  very  slightly  soluble  in  alkaline  fluids, 
so  that  internally  its  action  is  slow. 

Various  salts  of  the  sulphonic  acid  have  been  introduced,  such 
as :  Perrichthyol,  the  iron  derivative,  and  Ichthargan,  the  silver 
salt.  Anytols  are  compounds  of  phenols  with  anytin,  the  ammonia 
salt  of  a  hydrocarbon  sulphonate,  obtained  with  ichthyol  and  con- 
taining 33  per  cent,  of  ichthyol  sulphonic  acid. 

Various  bodies  have  also  been  prepared  which  closely  resemble 
ichthyol.  Thiol  is  a  mixture  of  sulphonized  hydrocarbons,  and  is 
obtained  by  heating  gas  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  properties  of  ichthyol.  All  these  bodies  of 
unknown  constitution  are  empirical  imitations  of  the  natural  pro- 
duct, which  is  also  of  unknown  chemical  constitution ;  but,  besides 
these,  a  large  number  of  pure  chemical  substances  have  been  sug- 
gested as  likely  to  have  the  same  therapeutic  value  as  ichthyol 
without   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  on  which  he  considers 
the  therapeutic  efficacy  of  ichthyol  depends.     These  are  : — 

1.  The  sulphur  must  be  present  in  an  unoxidized  form,  firmly 

combined  in  the  molecule,  and  not  in  the  form  of  an  easily 
separated  sulphydril  group. 

2.  The  compound  must  be  unsaturated. 

3.  The  compound  must  be  cyclic  in  character. 

Frankel  suggests  that  these  conditions  are  best  satisfied  by  taking 
as  a  basis  thiophene, 

CH— CH 

II         II 
CH    CH 


Y 


certain  derivatives  of  which  are  stated  to  correspond  very  closely  to 
ichthyol  in  their  pharmacological  properties. 


CHAPTEE  IX 

Deeivatives  of  Ammonia.— T/je  Mam  Group  of  St/nthetic  Antipyretics. — 
Chemical  and  physiological  character  of  Aliphatic  and  Aromatic  Amines. 
Aniline,  Acetanilide,  and  allied  substances.  Classification  and  discussion  of 
l?ara-Amido-phenol  derivatives. 

DERIVATIVES  OF  AMMONIA. 


I.    THE  AMINES. 

The  Organic  Amines  may  be  regarded  as  derivatives  o£  ammonia, 
NH3,  in  which  the  hydrogen  atom  or  atoms  have  been  replaced  by 
alkyl  groups;  they  are  distinguished  as  primary,  secondary,  or 
tertiary,  according  to  the  actual  number  of  atoms  so  replaced. 
Thus:- 


CH3NH, 

Methyl  amine. 
Primary. 


NH 


CH, 

ch: 

Di-methyl  amine. 
Secondary. 


CH, 

CHl  VN 


CH, 

Tri-methyl  amine. 
Tertiary. 

The  Primary  Amines  are  consequently  substances  in  which  the 
hydrogen  atom  of  any  hydrocarbon,  aliphatic  or  aromatic,  has  been 
replaced  by  the  Amido  (NHg)  group.  Several  such  radicals  can 
replace  hydrogen  atoms  in  the  same  molecule,  and  give  rise  to 
primary  mon-amines,  di-amines,  &c. : — 


or 


CH. 


CH3 

Ethane. 

Benzene. 


CH3 

I 
CH2NH2 

Ethyl  amine. 

C,H,NH, 

Aniline. 


CH^NH. 


CH2NH2 

Ethylene  di-amine. 

C  H  /^^^2 


Phenylene  di-amine. 

The  Secondary  Amines  are  compounds  containing  the  so-called 
Imido  group  (NH). 

The  Tertiary  Amines,  less  reactive  than  the  others,  have  all  the 
hydrogen  atoms  of  the  original  ammonia  replaced  by  alkyl  groups. 


172  DERIVATIVES   OF  AMMONIA 

They  are  characterized  by  their  property  of  uniting  with  alkyl 
halogen  derivatives^  whereby  the  trivalent  nitrogen  passes  over  to 
the  pentavalent  condition  (see  p.  2).  The  resulting  substances 
may  be  regarded  as  ammonium  haloids  in  which  the  hydrogen 
atoms  are  replaced  by  the  alkyl  group, 

NH3  +  HI  =  NHJ;  (CH3)3N  +  CH3l  =  (CH3)4N.I 

Ammonium  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 .  NH2 

Methyl  nitrile.  Ethylamine. 

CeHgCN   +4H  =  CgHgCHg.NHg. 

Benzonitrile.  Benzylamine. 

2.  The  action  of  ammonia  in  alcoholic  solution  on  the  halogen 
derivatives  of  the  aliphatic  series  gives  rise  to  a  mixture  of 
primary,  secondary,  and  tertiary  amines,  and  also  of  the  quaternary 
ammonium  salts,  and  the  isolation  of  any  single  product  is  an 
operation  which  will  be  found  described  in  the  textbooks.  The 
method  is  chiefly  used  for  the  preparation  of  tertiary  amines — those 
most  easily  isolated — but  for  the  production  of  primary  or  secondary 
the  formation  of  other  products  is  to  be  avoided;  in  the  former 
case,  instead  of  ammonia,  one  of  its  derivatives,  phthalimide,  is  best 
employed. 

Phthalimide  readily  gives  a  potassium  derivative,  which  easily 
interacts  with  ethyl  iodide,  for  example,  giving  the  corresponding 
ethyl  phthalimide. 

This  substance  is  then  decomposed  by  means  of  strong  hydro- 
chloric acid  or  alkali,  giving  phthalic  acid  and  the  corresponding 
primary  amine, 

C6H4<cS>-C2H3  +  2H,0  =  CeH,<^ggg  +  C,H,NH,. 

For  the  preparation  of  secondary  amines  the  following  indirect 
method  can  be  used. 


PREPARATION   OF   THE   AMINES  173 

When  aniline,  CgH^NHg,  is  treated  with  ethyl  iodide,  for  instance, 
the  tertiary  amine,  CgH5N(C2H5)2,  diethylaniline  is  the  product 
most  easily  isolated.  This  substance  gives  a  nitroso-derivative  on 
treatment  with  nitrous  acid, 

C,H,N(C,H,),+  HNO,  =  H,0  +  NO-<^ )>-N(C,H,), 

^-nitroso-diethyl  aniline. 
This,  on  heating  with  potash,  forms  nitroso-phenol  and  Diethyl- 
amine, 

In  the  case  of  the  halogen  derivatives  of  the  aromatic  series, 

no  reaction  with  ammonia,  similar  to  that  just  described,  takes 
place.  It  is  only  when  such  a  substituent  as  the  nitro  group  has 
replaced  a  hydrogen  atom  in  the  nucleus  in  the  0  and  p  position 
to  the  halogen,  that  the  characteristic  property  of  the  benzene 
complex  is  weakened,  and  ammonia  is  capable  of  interacting.  When 
three  such  groups  are  present,  as  for  instance  in  picryl  chloride, 

.NO2 

C  H    P^2 
^6^2  i  NO. 

I  CI 

the  reactivity  of  the  chlorine  atom  is  greatly  increased,  and  ammonia 
very  readily  gives  rise  to  the  corresponding  amine. 

C  H  I  ^^^2)3 

^6^2  1  NH2 

In  the  aromatic  series,  the  true  analogues  of  the  aliphatic  amines 
are  those  derivatives  containing  the  amido  group  in  the  side-chain, 
benzylamine,  CgHg  .  CHgNHg,  for  instance.  This  substance,  how- 
ever, may  be  obtained  by  the  action  of  ammonia  on  the  corresponding 
halogen  derivative,  CgHgCHgCl,  that  is  by  a  reaction  analogous  to 
that  which  takes  place  with  the  aliphatic  halogen  substitution 
products. 

3.  Amido  compounds  result  from  the  reduction  of  the  nitro 
derivatives  of  either  aliphatic  or  aromatic  series.  But  this  method 
of  preparation  is  entirely  confined  to  the  latter  hydrocarbons,  owing 
to  the  ease  with  which  the  nitro  substitution  products  of  this  series 
are  obtained.  Nitro-benzene,  for  instance,  is  reduced  to  aniline  on 
a  commercial  scale  by  means  of  iron  and  hydrochloric  acid — 

CgH,N02  +  6H  =  CgH5NH2  +  2H20. 


174  DERIVATIVES   OF  AMMONIA 

Secondary  amines  of  tlie  aromatic  series  may  be  obtained  from 
the  acetyl  derivatives  of  the  primary.  Thus  aniline  heated  with 
acetic  acid  gives  acetanilide, 

CeH^NHlHi  +  CHgCOiOHi  =  Hp  +  CeHgNHfCOCHg), 

and  when  this  substance  is  acted  upon  by  sodium  in  an  indifferent 
solvent,  such  as  toluene,  the  corresponding  sodium  derivative  is 
obtained, 

C6H5NH(GOCH3)  +  Na  =  H  +  CeH5N<(^^(.  jj 

This  readily  reacts  with  an  aliphatic  halogen  derivative  giving 
the  corresponding  alkyl-acetanilide,  which  on  treatment  with  potash 
is  broken  down  into  the  secondary  amine  and  acetic  acid, 

-    C6H.N<ggcH3  +  ^AI  =  NaI  +  C3H,N<gA^^ 

ii.   C6H5N<(^2H^Sjj  +KOH  =  CeHgNHCgHg  +  CHgCOOK 

Ethyl  aniline. 
4.  Acid  amides  of  the  aliphatic  series  on  treatment  with  bromine 
or  potash  give  amines  containing  one  less  carbon  atom.     The  first 
phase  of  the  reaction  consists  in  the  formation  of  bromamides, 

CHaCONHg  +  Br^  +  KOH  =  CHgCONHBr  +  KBr  +  H^O 
These  derivatives  are  then  further  broken  down  into  amines, 

CHgCONHBr  +  SKOH  =  KBr  +  KgCOg  +  CH3NH2 

Methylamine. 

This  method  is  applicable  to  the  amides  of  the  fatty  series  up  to 
those  containing  five  carbon  atoms. 

In  the  aromatic  series  this  reaction  is  used  for  the  commercial 
production  of  anthranilic  acid,  and  has  been  one  of  the  chief  factors 
in  the  success  of  the  indigo  synthesis. 

Mon-amide  of  phthalic  acid. 

iii.  C,H /C0NHBr^3j.0jj 

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  readily  soluble  in  water;  the  higher 
members  are  liquids  also  soluble,  and  it  is  only  in  the  case  of  those 
with  high  molecular  magnitude  that  the  solubility  in  this  liquid 
becomes  slight.  They  are  stronger  bases  than  ammonia,  the  basicity 
increasing  in  proportion  to  the  number  of  alkyl  groups  replacing 
hydrogen  atoms  of  the  original  ammonia. 

On  the  other  hand,  in  the  case  of  aromatic  amines,  this  property 
is  powerfully  depressed,  aniline  is  a  weak  base ;  diphenylamine, 
(CgH5)2NH,  still  weaker;  and  in  triphenylamine,  (CgH5)3N,  this 
characteristic  has  entirely  disappeared.  The  entrance  of  halogen 
atoms  or  nitro  groups  into  the  nucleus  of  aniline  further  depresses 
its  already  slight  basic  properties. 

The  aromatic  amines  are  colourless  liquids  or  solids,  having  a 
peculiar  and  characteristic  smell ;  unlike  the  aliphatic  they  have  no 
alkaline  reaction,  and  are  only  slightly  soluble  in  water. 

The  reactivity  of  primary  and  secondary  amines  of  both  series, 
as  compared  with  the  tertiary,  is  dependent  on  the  ease  with  which 
the  hydrogen  atoms  of  the  original  ammonia  are  replaced.  In  the 
aromatic  series,  unlike  the  aliphatic,  the  hydrogen  atoms  in  the 
primary  and  secondary  amines  may  be  replaced  by  potassium. 

Primary  and  Secondary  Amines  of  both  series  behave  in  a 
characteristic  manner  with  nitrous  acid.  Primary  amines  of  the 
fatty  series  yield  alcohols, 

C2H5NH24-HNO2  =  C^H.OH  +  Hp+Ng. 

In  the  aromatic  series,  the  important  di-azo  reaction  takes  place 

(see  p.  41). 

The  Secondary  Amines  of  both  series  give  nitrosamines, 
i.  (C,H,),NH  +  HNO,  =  H,0  +  (C,H,),NO 

Diethy  1-nitro  samine. 

ii.    C,H,NH.CH3  +  HN02  =  H,0    +    CeH,N<^gg^ 

Nitrosamine  of  methyl  aniline. 
The  nitrosamines  of  the  aromatic  series  undergo  an  interesting 
intramolecular   change,   on  treating  their  alcoholic   solution  with 
hydrochloric  acid,  when^-nitroso  derivatives  are  obtained. 

C6H5N<;^^g     ->    NO.CgH^.NHCHg. 

2)-nitroso-methyl  aniline. 


176  DERIVATIVES   OF  AMMONIA 

The  Tertiary  Amines  of  the  Aliphatic  Series  either  do  not 
react  at  all  with  nitrous  acid_,  or  are  completely  decomposed ;  whereas 
in  the  aromatic  series,  the  hydrogen  atom  in  the  1 : 4  position  in 
the  ring  is  attacked,  with  the  formation  of  jo-nitroso  derivatives. 

(CH3),N.C,H5+HNO,  =  (CH3),N.CeH,.N0  +  H,0. 

^nitroso-dimethyl  aniline. 

The  aliphatic  amines  are  of  little  if  any  physiological  importance, 
and  in  consequence  the  following  statements  and  reactions  will  only 
apply  to  the  amines  of  the  aromatic  series. 

Both  aniline  and  /?-amido  phenol, 

are  very  sensitive  to  oxidizing  agents,  but  their  stability  can  be 
very  largely  increased  by  their  conversion  into  a  group  of  deriva- 
tives called  the  Auilides.  These  may  be  obtained  by  the  action  of 
the  acid,  or  acid  chloride  or  anhydride,  on  the  amine  (see  p.  120). 


CeH^NHiHi  +  CHaCOlOHj  =  CgH^NH.COCHg  +  HgO 

Acetanilide. 
CgH^NHiHi  +  CHgCOiClj  =  CgHsNH.COCHg  +  HCl 

or        CeH^NHJifti  +  CeHgCOICii  =  CgHsNH.COCeHs  +  HCl 

Benzanilide. 

It  is  possible  by  this  means  to  introduce  a  variety  of  different 
radicals  in  place  of  the  hydrogen  of  either  primary  or  secondary 
amines. 

The  acid  anilides  are  very  stable  derivatives,  they  can  often  be 
distilled  without  change,  and  also  directly  nitrated  or  sulphonated. 
They  are  characterized  by  their  great  power  of  crystallization,  and 
consequently  serve  as  a  means  of  detecting  many  of  the  aromatic 
bases. 

The  introduction  of  the  acidic  grouping,  as  might  be  expected,  de- 
presses the  basic  characteristics,  methyl  acetamide,  CH3NH.COCH3, 
is  only  slightly  basic,  the  hydrochloride  of  acetanilide  is  decom- 
posed by  water.  Modified  characteristics  similar  to  this  are  observed 
on  the  entrance  of  acidic  groupings  into  basic  substances.  Thus 
the  powerful  base  methylamine,  CHgNHg,  becomes  glycocol, 
COOH.CHg.NHg,  on  the  replacement  of  hydrogen  by  the  acidic 
COOH  group;  in  this  substance  both  the  basic  properties  of  the 
NHg  group  and  the  characteristics  of  the  COOH  are  very  consider- 


PHYSIOLOGICAL  PROPERTIES  OF  THE  AMINES    177 

ably  modified.  Phenol,  CgHgOH,  has  powerful  acidic  properties, 
and  forms  salts  by  the  replacement  of  the  hydroxyl  hydrogen  atom ; 
»-amido  phenol, 

by  the  entrance  of  the  NHg  group,  has  entirely  lost  this  salt-forming 
power,  the  already  slight  basic  properties  of  aniline  being  still 
further  depressed. 

The  anilides  are  broken  down  into  their  components  on  treatment 
with  alkalis  or  heating  with  mineral  acids,  and  the  physiological 
reaction  of  these  derivatives  is  due  to  this  decomposition  taking 
place  in  the  organism. 

General  Physiological  Properties. 

The  physiological  effect  following  the  entrance  of  the  ammonia 
residue  is  dependent,  firstly  and  chiefly,  on  the  nature  of  the 
nucleus  into  which  it  enters,  and  secondly  on  the  reactivity  of 
the  nitrogen  complex;  thirdly  a  curious  variation  of  physiological 
reactivity  is  noticed  when  trivalent  derivatives  pass  over  into 
those  of  the  ammonium  type. 

Ammonia  itself,  and  its  salts,  are  remarkable  in  differing  from 
the  caustic  alkalis,  which  are  in  combination  depressant,  whereas 
ammonia  is  a  stimulant. 

Intravenously  injected,  ammonia  produces  tetanic  convulsions, 
partly  cerebral  and  partly  spinal  in  origin ;  the  convulsions  are  not  so 
markedly  reflex  in  character  as  those  produced  by  strychnine.  The 
irritability  of  the  spinal  reflexes  is,  however,  increased.  It  also 
quickens  the  heart  and  respiration :  the  latter  action  is  probably  due 
to  stimulation  of  the  centre  in  the  medulla.  The  rise  of  blood 
pressure,  which  almost  immediately  follows  the  preliminary  fall,  is 
not  due  to  central  action,  but  appears  to  be  partly,  at  least,  a  conse- 
quence of  the  increased  cardiac  action.  The  main  difference  between 
the  action  of  ammonia  and  strychnine  is  due  to  the  rapid  paralysis 
of  the  motor  nerve  endings  by  the  former,  which  prevents  the 
supervention  of  tetanus. 

When  the  hydrogen  atoms  are  replaced  by  radicals  of  the  aliphatic 
hydrocarbons  these  characteristics  disappear,  and  the  resulting 
primary,  secondary,  and  tertiary  amines  irritate  the  mucous  mem- 
brane, but  otherwise  have  slight,  if  any,  physiological  reaction. 
Further,  the  replacement  of  two  hydrogen  atoms  by  amido 
groups,  e.  g.  in  tetramethylene  diamine,  NH9.(CH2)4NH2,  or  penta- 

N 


178  DERIVATIVES   OF  AMMONIA 

methylene  diamine,  NHg .  CHg .  (0112)4 .  NHg,  gives  rise  to  similarly 
inactive  substances. 

When  the  amido  group  replaces  hydroxyl  in  the  aliphatic  acids, 
resulting  in  the  formation  of  bodies  of  the  nature  of  acetamide, 
CH3CONH2,  it  is  again  found  that  pharmacologically  inactive  bodies 
result.  If  the  amido  group  replaces  hydrogen  in  the  aliphatic 
nucleus  of  these  acids,  the  result  is  similar.  NHg.  CHg.COOH, 
amido  acetic,  NHg .  CHg .  CHg .  COOH,  j3-amido  propionic  acids, 
&c.,  are  inert,  but  unlike  acetamide  these  are  broken  down  in  the 
organism,  as  previously  described  (p.  74). 

Betaine,  trimethylglycocol,        COO 

(';h,.n(ch3)3, 

is  physiologically  inactive,  and  its  hydrochloride,  under  the  name  of 
Acidol,  has  been  introduced  as  a  solid  substitute  for  hydrochloric 
acid ;  it  is  very  readily  soluble  in  water,  and  contains  23'78  per  cent, 
acid,  which  is  slowly  split  ofE  in  the  stomach. 

When  the  amido  group  replaces  a  hydrogen  atom  in  the  benzene 
nucleus,,  substances  of  the  nature  of  aniline  result,  and  a  com- 
pletely new  and  valuable  set  of  pharmacological  properties  appear ; 
this  observation  has  formed  the  basis  for  the  synthesis  of  a  large 
group  of  so-called  'antipyretics',  which  will  be  described  later. 

The  entrance  of  a  second  amido  group  into  the  aromatic  nucleus 
gives  rise  to  powerfully  toxic  substances  unlike  the  corresponding 
aliphatic  diamines. 

The  passage  of  a  primary  aromatic  amine  to  a  secondary  is 
followed  by  a  corresponding  alteration  in  physiological  properties. 
Methyl,  ethyl,  and  amyl  aniline  are  less  toxic  than  aniline,  and  have 
lost  the  power  which  that  substance  possesses  of  producing  muscular 
spasms,  but,  on  the  other  hand,  they  bring  about  the  paralysis  of 
the  peripheral  endings  of  the  motor  nerves,  in  a  somewhat  similar 
manner  to  the  alkyl  alkaloids,  although  without  the  curare  action 
of  the  quinquevalent  nitrogen  derivatives.  (Compare  action  of 
antifebrin  and  exalgin.) 

The  presence  of  an  imido  group  may  result  in  an  increase  of 
toxicity,  most  probably  due  to  increase  of  reactivity.     Thus,  guanidin 

-NH, 

is  a  powerful  poison.  Xanthine,  with  three  imido  groups,  is,  according 
to  Eilehne,  more  toxic  than  theobromine  with  one,  and  this  more 


NH.C<^] 


PHYSIOLOGICAL  PROPERTIES  OF  THE  AMINES    179 

toxic  than  caffeine,  in  which  all  the  imido  hydrogen  atoms  have  been 
replaced  by  methyl  groups.  Piperidine  is  much  more  toxic  than 
pyridine. 

The  Quaternary  Ammoniuni  Componuds  show  a  most  striking 
difference  from  those  of  the  trivalent  type,  and  to  a  very  large  extent 
their  physiological  reaction  is  independent  of  their  chemical  com- 
position. All  the  following  substances  produce  paralysis  of  the 
peripheral  endings  of  the  motor  nerves  : — ammonium  iodide,  ethyl 
ammonium  chloride,  trimethyl  ammonium  iodide,  tetraethyl 
ammonium  iodide;  aromatic  derivatives,  such  as  phenyl-dimethyl- 
ethyl  ammonium  iodide,  phenyl-triethyl  ammonium  iodide.  Also 
various  alkyl  alkaloids  in  which  nitrogen  is  in  the  quinquevalent 
condition,  such  as  methyl  strychnine,  methyl  quinine,  methyl 
morphine,  ethyl  brucine,  ethyl  nicotine,^  curare.  And  what  is  still 
more  striking,  this  curare-like  action  is  to  be  observed  in  the  corre- 
sponding quinquevalent  arsenic,  antimony,  and  phosphorus  bases, 
substances  which  may  be  regarded  as  ammonium  salts  in  which 
nitrogen  has  been  replaced  by  these  elements  (see  also  p.  53). 

Alteration  in  the  Physiological  Action  of  Bases  by  replace- 
ment of  (A)  Hydrogen  of  Amide  Group  by  Acid  Iladicals. 

The  introduction  of  both  aliphatic  and  aromatic  acid  radicals,  by 
methods  already  mentioned,  is  followed  by  a  drop  in  toxicity, 
depending  entirely  upon  the  greater  stability  of  the  resulting 
compounds,  which  are  but  slowly  decomposed  by  the  organism. 

As  a  rule,  the  replacement  of  both  hydrogen  atoms  of  the  amido 
group  by  such  radicals  of  the  aliphatic  series,  gives  rise  to  substances 
which  are  so  readily  decomposed,  even  by  water,  into  the  mon-acid 
derivatives,  that  these  possess  no  advantages  over  the  former  group. 

The  acetyl  radical  is  that  most  usually  introduced,  and  other 
radicals  of  the  aliphatic  series  do  not  possess  any  great  advantage 
over  this,  with  the  possible  exception  of  the  lactyl,  whose  derivatives 
are  usually  more  soluble  in  water.  The  replacement  of  hydrogen 
by  radicals  of  the  aromatic  acids,  such  as  benzoic  or  salicylic, 
gives  rise  to  substances  which  are  usually  very  insoluble,  and  offer 

^  The  ammonium  compounds  of  the  alkaloids  will  be  further  dealt  with 
when  those  bodies  are  considered  in  detail.  It  must  be  remembered,  how- 
ever, that  for  practical  purposes,  the  result  of  converting  the  nitrogen  from 
a  trivalent  to  a  quinquevalent  condition  may  merely  be  to  diminish  but  not 
otherwise  to  alter  the  physiological  action  of  the  alkaloid  as  far  as  its  purely 
therapeutic  action  is  considered. 

N  2, 


180  DERIVATIVES   OF  AMMONIA 

great  resistance  to  decomposition  in  the  organism,  with  the  result 
that  they  are  usually  completely,  or  almost  completely,  inactive 
physiologically.  But  it  must  be  remembered  that  whereas  the 
aliphatic  radicals,  with  exception  of  perhaps  lactic  and  citric  acids, 
have  no  pharmacological  action,  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  decomposition  products 
of  the  acyl-nitrogen  derivative,  its  action  will  appear  together  with 
that  of  the  basic  residue. 

B.     Hydrogen  of  Hydroxyl  Group  by  Acid  Radicals. 

Whereas  the  replacement  of  hydrogen  of  the  amido  group  by  acid 
radicals  brings  about  a  decrease  in  toxicity,  a  different  action  is 
noticed  when  the  hydrogen  of  an  hydroxyl  group  is  similarly  dis- 
placed. In  this  case  an  increase  in  toxic  properties  is  noticed. 
Ecgonine  methyl  ester,  CjoHjgNOg .  OH,  has  no  local  anaesthetic 
action ;  by  the  replacement  of  the  hydroxyl  hydrogen  by  benzoyl, 
cocaine  results,  CioH^gNOg .  O.COCgHg,  a  powerful  local  anaesthetic. 

Benzoyl  lupinine  is  much  more  toxic  than  lupinine. 

Ci„H,,N.0.C0.C,H5  C,„H,3N.0H 

Benzoyl-lupinine.  Lupinine. 

Mono-acetyl  morphine,  diacetyl  morphine  (Heroine),  benzoyl 
morphine,  and  dibenzoyl  morphine  have  a  similar  physiological 
action  to  codeine  (methyl  morphine),  but  are  far  more  toxic.  The 
depressant  effect  on  the  spinal  cord,  and  especially  on  the  respiratory 
centre,  is  much  greater  than  that  of  morphine.  Compared  with 
codeine,  one-tenth  of  the  dose  will  produce  a  similar  narcotic  effect. 

Veratrine  may  be  split  up  by  the  action  of  an  alkali  into  cevine 
and  tiglinic  acid, 

C3,H«N0,  +  H,0  =  C,H30,  +  C„H^N03 

Veratrine.  Tiglinic  acid.        Cevine. 

Cevine  has  the  same  physiological  action  as  veratrine,  but  its 
toxicity,  owing  to  the  absence  of  the  substituted  acid  group,  is  ten 
times  less. 

The  increase  in  toxicity  produced  by  the  introduction  of  the  acid 
group  does  not  depend  on  the  physiological  action  of  that  group  in 
itself,  but  upon  its  power  of  covering  certain  ^  anchoring '  groups  in 
the  molecule,  so  that  the  latter,  being  more  generally  resistant,  can 
produce  a  specific  action  (i.  e.  on  the  central  or  peripheral  nervous 


DERIVATIVES    OF   AROMATIC   AMINES         181 

system).    The  acid  radical  may  also  form  an  anchoring  group  itself 
for  the  production  of  a  special  physiological  response. 

ANILINE  DERIVATIVES. 

The  discovery  of  Cahn  and  Hepp  that  aniline  (or  acetanilide)  is 
a  powerful  antipyretic^  and  also  possesses  antineuralgic  properties, 
together  with  the  low  price  of  this  substance,  has  led  to  the  pro- 
duction of  a  large  number  of  its  derivatives. 

Aniline  and  its  salts  have  a  powerful  antipyretic  action,  like 
phenol,  and  it  produces  spasmodic  muscular  contractions  of  central 
origin,  as  does  ammonia.  The  main  toxic  symptoms  are  weakness, 
dizziness,  cyanosis,  and  finally  collapse,  with  or  without  vomiting 
due  to  direct  irritation  of  the  gastric  mucosa. 

Aniline  also  breaks  up  the  red  blood  cells,  liberating  the 
haemoglobin. 

Toxic  symptoms  of  a  similar  nature  but  less  pronounced  character 
are  observed  among  workers  in  the  dyeing  industry,  in  which  aniline 
oil  is  used.^  Aniline  was  at  one  time  employed  as  a  remedy  for 
phthisis  and  other  forms  of  tuberculous  disease,  the  vapour  being 
inhaled  in  combination  with  certain  aromatic  antiseptics.  Like 
most  schemes  for  internal  antisepsis,  however,  this  failed  when 
put  to  a  practical  test;  the  tubercle  bacilli  in  the  blood-stream 
remained  unaffected,  whereas  the  patients  exhibited  symptoms  of 
poisoning  due  to  the  presence  of  the  drug. 

It  was  only  to  be  expected  that  when  the  reactive  amido  group  is 
rendered  more  stable  by  replacing  hydrogen  with  the  acetyl  group, 
the  resulting  acetanilide  (antifebrin)  should  be  a  far  less  toxic 
substance. 

Antifebrin,  CgH5NH(COCH3),  shows  the  same  general  reaction 
as  aniline.  It  reduces  fever,  has  similar  antineuralgic  properties, 
and  a  similar  though  less  marked  action  on  the  red  blood  corpuscles ; 
but  the  effect,  dependent  as  it  is  on  the  decomposition  of  the  anilide 
in  the  organism,  is  not  produced  so  rapidly  as  by  the  free  base.  No 
effect  on  nitrogenous  metabolism  occurs  with  therapeutic  doses. 
In  pyrexia  a  slight  diminution  may  occur. 

Acetanilide  is  oxidized  in  the  body  to  jo-aminophenol  and  is 
excreted  in  the  urine  partly  as  oxycarbanile, 

CeH,<g>C.OH, 

*  Dearden,  British  Medical  Association  Meeting,  1902. 


182         DERIVATIVES   OF  AROMATIC  AMINES 

/?-acetyl-aminophenol,  and  jo-aminophenol.  The  latter  is  further 
changed  by  combination  with  sulphuric  and  glycuronic  acids. 
These  changes  in  structure  diminish  the  toxicity  of  aniline  or 
acetanilide,  but  do  not  destroy  entirely  their  antipyretic  action. 

The  most  varied  acid  radicals  have  been  introduced  in  place  of 
the  acetyl  group  in  acetanilide,  but  without  the  production  of  sub- 
stances with  any  novel  physiological  reaction ;  since  this  factor  is 
unquestionably  a  function  of  the  decomposition  of  these  derivatives 
into  aniline,  this  was  hardly  to  be  expected.  It  is  only  when  the 
entering  group  has  physiological  characteristics  of  its  own  that 
these  may  appear  simultaneously  with  those  of  aniline. 

Among  substances  of  this  type  are  the  following  : — 

1.  Formanilide,  CgHgNH(OCH),  formed  by  rapidly  heating 
oxalic  acid  and  aniline,  or  treating  aniline  with  formic  acid.  It 
has  powerful  antipyretic  and  analgesic  properties,  and  acts  as  a 
local  anaesthetic,  but  is  much  more  toxic  than  acetanilide,  this 
being  undoubtedly  due  to  the  fact  that  it  is  much  more  easily 
decomposed  by  dilute  acids. 

2.  Benzanilide,  CQHgNH(C0CgH5),  is  only  broken  down  by  the 
organism  with  difficulty,  and  consequently  larger  doses  are  required 
than  in  the  case  of  acetanilide. 

3.  Salicylanilide,  C6H5NH(COC6H4 .  OH),  and  anisanilide, 
C6H5NH(COCgH^.OCH3),  like  most  derivatives  of  this  type,  are 
only  broken  down  by  the  organism  with  such  difficulty  that  their 
physiological  reaction  is  but  slight. 

Attempts  to  increase  the  solubility  of  acetanilide  by  the  forma- 
tion of  such  substances  as  acetanilidoacetic  acid  and  formanilido- 
acetic  acid,  by  the  action  of  chloracetic  acid  on  acetanilide  or  form- 
auilide, 

CgH^N^^]^  +  CI.CH2 .  COOH  =  HCI  +  CgH4N<(™2  •  COOH, 

when  R  =  (COCH3)'  or  (CHO)',  gave  negative  results,  since  these 
substances,  having  lost  their  basic  characteristics  and  become  acids, 
obey  the  general  rule  that  such  derivatives  thereby  lose  their  physio- 
logical properties.  Formanilidoacetic  acid,  however,  owing  to  its 
instability,  is  about  as  toxic  as  formanilide.  For  similar  reasons, 
Cosparin, 

p    XT    /NHCOCH3 

^6^4\  SO.ONa 
the  j9-sulphonate  of  acetanilide,  obtained  by  the  action  of  acetic  acid 


PHYSIOLOGICAL   PROPERTIES  183 

on  sulphanilic  acid, 

(.jj/SO^OH  ^.^ 

should  have  no  physiological  importance,  since  its  action  can  only 
depend  on  its  decomposition  into  the  inert  sulphanilic  acid. 

In  order  to  increase  the  solubility  of  acetanilide  and  phenacetin, 
derivatives  were  obtained  containing  the  sulphonic  group  in  place  of 
the  hydrogen  of  the  methane  radical ;  these  were  prepared  firstly  by 
dehydrating  the  aniline  salt  of  monochloracetic  acid  by  means  of 
phosphorus  pentoxide, 

CH2Cl.COO(C6H5NH3)>-.H20  =  CH^Cl.CO.NHCgHg, 

and  then  heating  this  latter  substance  in  aqueous  solution  with 
sodium  sulphite — 

C6H5NH.(C0CH2C1)  +  Na^SOg 

=  NaCl  +  C6H5NH.(CO.CH2 .  SOpNa) 

The  resulting  substances  are  much  more  soluble  than  acetanilide  or 
phenacetin,  and,  if  their  action  is  similar,  which  is  stated  to  be  the 
case,  they  must  be  broken  down  in  the  organism,  the  acidic  group- 
ing not  being  sufficiently  stable  for  them  to  obey  the  general  rule. 

Another  method  of  modifying  the  action  of  aniline,  that  is  of 
making  it  more  stable,  consists  in  converting  it  into  a  urethane 
derivative  by  the  action  of  chlorformic  ester — 

CeHgNHjH  +  CiiCOOCaHg  =  HCl  +  CeHsNH.COOCgHg 

Phenyl  urethane. 
The  resulting  substance,  termed  Euphorin,  is  much  less  toxic 
than  aniline.  Physiologically  its  action  resembles  that  of  acet- 
anilide rather  than  that  of  urethane.  It  depresses  the  temperature, 
and  has  considerable  analgesic  properties.  Large  doses  weaken  the 
pulse  and  respiration.  It  has  also  a  bactericidal  action,  and  has 
been  employed  to  check  suppuration.  It  is  not  of  value  as  a 
hypnotic  like  other  urethane  derivatives  (hedonal,  &c.).  It  does 
not  lead  to  the  formation  of  methaemoglobin.  In  large  doses  it  acts 
like  a  urethane  derivative,  paralysing  the  central  nervous  system ; 
the  effect  is  very  similar  to  the  paretic  action  of  alcohol.  In 
moderate  doses  it  is  said  to  decrease  metabolic  processes,  but  its 
antipyretic  action  is  similar  to  that  of  the  other  bodies  of  this  group, 
being  due  to  the  dilatation  of  the  cutaneous  vessels.  It  increases 
the  conjugated  sulphates  in  the  urine,  and  is  partly  excreted  as 
oxyphenyl  urethane,  an  indication  consequently  that  this  derivative 
is  less  toxic  than  euphorin  itself  (see  p.  196). 


184  DERIVATIVES   OF  i?-AMIDO-PHENOL 

Whereas  Exalgin  (methylaeetanilide)  has  powerfully  toxic  pro- 
perties, the  corresponding  Methyleuphorin, 

is  an  almost  indifferent  substance. 

When  aniline  is  converted  into  the  secondary  amine,  methyl- 
aniline,  CgHgNHCHg,  a  substance  is  obtained  which  paralyses  the 
motor  nerve  endings.  Sxalgiu,  which  is  the  acetyl  derivative  of 
this. 


C6H,.N<(; 


CH3 
COCH3, 


has  a  somewhat  similar  action  to  acetanilide,  but  a  powerfully 
toxic  secondary  reaction,  producing  epileptic  convulsions  and  profuse 
salivation.  Death  results  from  respiratory  failure.  The  convulsions 
can  be  stopped  by  the  induction  of  anaesthesia,  and  are  probably 
partly  cerebral  and  partly  spinal.  Smaller  (non-toxic)  doses  pro- 
duce in  mammals  lethargy  and  a  fall  of  arterial  pressure. 

Finally,  the  replacement  of  aniline  by  any  of  the  toluidines  has 
no  advantages,  since  they  act  on  the  red  blood  corpuscles,  forming 
methaemoglobin  in  a  similar  manner  to  aniline  itself. 

On  injection  into  the  jugular  vein  of  a  dog  the  lethal  dose  of 
these  bases  per  kilo,  weight  has  been  found  to  be :  or^^y^o-toluidine 
•208  gm.,  1 :  3-toluidine  -125  gm.,  1 : 4-toluidine  -1  gm. 

But  when  converted  into  their  acetyl  derivatives  a  considerable 
difference  is  noticed ;  both  1 : 3  and  1:4  are  non-toxic,  and  this 
characteristic  is  only  noticed  with  the  1:2  substance.  Then  it  is 
only  the  1 : 3  derivative  that  has  antipyretic  properties,  and  Bar- 
barini  states  that  it  is  less  toxic  and  has  a  stronger  action  than 
antifebrin. 

Aniline  and  ^-toluidine  depress  the  respiratory  capacity  more 
than  either  the  0-  or  ^-derivative ;  further,  the  former  substances 
depress  the  temperature  to  a  greater  extent  than  the  latter. 

DERIVATIVES  OF  i?-AMIDO-PHENOL,  C6H4</^^  l:4.i 

On  their  passage  through  the  organism,  aniline,  acetanilide,  or 
generally  speaking,  any  of  the  physiologically  active  derivatives  of 

^  1 :2-amido  phenol,  unlike  the  1:4  derivative,  is  inactive,  but  when  the 
hydroxyl  hydrogen  atom  is  replaced  by  alkyl  radicals,  bodies  possessing 
narcotic  properties  result ;  the  1 : 2  and  1 : 3  present  no  pharmacological 
advantage,  and  are  both  more  toxic  than  the  para  derivative. 


PHYSIOLOGICAL   PROPERTIES  185 

these  substances,  are  partially  converted  in  /j-amido-plienol,  which 
is  eliminated  as  a  sulphonate  or  as  a  compound  of  glycuronic  acid. 
Since  observations  have  shown  that  such  changes  always  tend  to 
the  production  of  less  toxic  derivatives,  it  was  but  natural  to  in- 
vestigate the  therapeutic  value  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  already  been  described :  the  pharmacological 
properties  are  those  to  be  expected,  viz.  energetic  antipyretic  action, 
but  much  less  toxicity  and  haemolytie  action  than  is  shown  by  aniline. 
The  whole  group  of  physiologically  active  derivatives  of  aniline  or 
j9-amido-phenol  are  broken  down  in  the  organism  with  the  produc- 
tion of  this  latter  substance,  and  the  indophenol  reaction  in  the 
urine  may  be  taken  as  a  test  for  their  reactivity. 

Trenpel  and  Hinsberg  have  stated  that  the  '  antipyretic  action 
of  aniline  and  /^-amido -phenol  derivatives  appears  to  be,  within 
certain  limits,  proportional  or  nearly  proportional  to  the  amount  of 
aniline  or  jo-amido-phenol  or  phenetidin  formed  in  the  organism''. 
On  the  other  hand,  if  these  substances  are  not  formed  (i.  e.  if  no 
indophenol  reaction  with  the  urine  occurs),  then  the  preparation  is 
not  physiologically  active. 

Thus, 

/OPTT  /OP  TT 

Methacetin,  C^H.^j^jj^q^jj^^   Phenacetin,  C,H,<(j^j|^'q(,jj^^ 

and  acetamidophenol-propyl-ether_,  CgH^x^-j^Tj  poPTT 

are  readily  decomposed  in  the  organism,  giving  ;?-amido-phenol,  and 
show  physiological  characteristics  similar  to  those  derivatives  of 
phenacetin, 

/OC2H3 

in  which  R  =  CH3,  CgH^,  C3H7,  or  iw-propyl  groups.  But  ethyl- 
acetamido  phenol, 

.OH 
CJfiH^^'     /C2H5 
^N^COCHg, 

which  is  not  decomposed,  has  no  antipyretic  or  other  action. 

It  will  be  readily  seen  that  the  general  physiological  reaction  of 
the  whole  of  the  //-amido-phenol  derivatives  will  be  that  of  the  free 
base  itself,  or  of  its  ethoxy  or  methoxy  substitution  product,  and  that 


186  DERIVATIVES   OF  i?-AMIDO-PHENOL 

added  to  this  reaction  will  be  that  of  the  radical  attached  to  the 
amido  group ;  in  the  case  of  acid  derivatives  of  the  aliphatic  series, 
for  example,  this  would  be  nil. 

In  the  case  of  /j-amido-phenol,  two  different  classes  of  modific£u 
tions  can  be  carried  out;  either  the  hydrogen  of  the  hydroxyl 
group  can  be  replaced  by  radicals,  or  the  hydrogen  atoms  of  the 
amido  group  can  be  similarly  displaced. 

The  replacement  of  H  in  the  NHg  group  by  acetyl,  giving  acet- 
amido-phenol, 

'OH 
.NHCOCH. 


C^6H4\] 


results  in  the  production  of  a  substance  with  powerful  antipyretic, 
antineuralgic,  and  possibly  slight  narcotic  properties,  but  of  much 
lower  toxicity  than  the  original  substance.  The  further  replace- 
ment of  the  hydrogen  of  the  hydroxyl  group  by  methyl. 


^6^4\NHCOCH, 


(methacetin),  causes  an  increase  in  both  the  former  properties  and 
a  decrease  in  the  action  on  the  blood ;  replaced  by  ethyl, 

C  H  /^^2^5 
^  ^e^^XNHCOCHg 

(phenacetin),  the  narcotic  action  is  increased,  and  a  further  diminu- 
tion in  the  formation  of  methaemoglobin  is  noticed.  The  maximum 
antipyretic  and  antineuralgic  action  is  found  in  the  case  of  methyl, 
but  lesser  toxicity  in  case  of  ethyl.  The  antipyretic  action  di- 
minishes with  the  increasing  molecular  magnitude  of  the  group 
replacing  H  of  the  hydroxyl.  In  one  direction,  then,  the  possible 
variations  as  regards  alkyl  groups  replacing  that  hydrogen  atom  is 
limited  to  either  methyl  or  ethyl. 
In  phenacetin  the  hydrogen  atom  R, 

may  be  replaced  by  acid  groups,  which  will  be  discussed  later,  or  by- 
radicals  of  the  aliphatic  hydrocarbons.  The  entrance  of  methyl 
causes  an  increase  in  the  narcotic  and  also  in  the  antineuralgic 
properties,  but  the  substance  has  only  a  slight  antipyretic  power. 

Replaced   by   ethyl,  a  similar  decrease  in  toxicity,  increase  in 
narcotic,  and  decrease  in  antipyretic  properties  are  noticed. 


PHYSIOLOGICAL   PROPERTIES  187 

As  the  molecular  magnitude  of  the  entering  group  increases,  i.  e.  in 
w-propyl  and  2>o-propyl,  w-butyl  and  n-amylj  the  narcotic  property 
rapidly  diminishes.  In  this  group  the  maximum  narcotic  and  anti- 
neuralgic  action  is  found  when  the  entering  group  is  methyl,  the 
maximum  antipyretic  when  the  groups  are  either  methyl  or  ethyl, 
the  minimum  toxicity  in  the  case  of  ethyl. 

Substances  of  the  above  type  can  be  prepared  by  the  action  of 
alkyl  iodides  on  the  sodium  derivative  of  phenacetin, 

.OC2H5  .OCgHg 

CeH/    /Na         +  IR  =  Nal  +  C,K,<(    yR 

or  by  treating  alkyl  phenetidins  with  acetic  acid, 

<0C2Hg  yOCgHg 

/R  =H,0  +  CeHZ     /E 

KiHi+CHeCOlOHi  \N^COCH„ 

or  by  converting  jo-acetylamido  phenol  into  its  di-sodium  derivative 
and  then  acting  upon  this  with  alkyl  iodides — 

/ONa  /OR 

CgHZ   /Na         +  2RI  =  2NaI  +  C^H Z    /R 

The  best-known  member  of  the  whole  group  is  Phenacetin, 

p  „  /OC2H3 
'-6^4\NHCOCH3 

This   substance  may  be  obtained  from  phenol  by  the  following 
reactions : — 

1.  On  nitration,  phenol  gives  rise  to  a  mixture  of  0-  and  ;}-nitro- 
phenol,  of  which  the  former  may  be  removed  by  distillation  with 
steam. 

2.  ;?-Nitro-phenol  is  converted  into  its  sodium  salt,  and  this  on 
treatment  with  ethyl  iodide  gives  p-nitro-phenetol — 

3.  ;?-Nitro-phenetol  is  reduced  to  the  amido  derivative  by  means 
of  tin  and  hydrochloric  acid, 

p    XT   /NO2  p    TT     /NH2 

The  resulting  ;?-phenetidin  gives  phenacetin  on  treatment  with 
.  glacial  acetic  acid. 


'RCeH^.OH 


188  DERIVATIVES    OF  j!?-AMIDO-PHENOL 

As  the  preparation  of  /(-nitro  phenol  in  a  state  of  purity  is  by  no 
means  easy ;  the  method  of  preparation  is  modified.  ^-Phenetidin 
is  diazotized  and  treated  with  a  phenol  and  sodium  carbonate, 

^^4<\NH2       ^    ^6^4\N  :  N.OH  ^  ^6^4\N 

and  the  resulting  compound  is  readily  converted  into  the  di-ethoxy 
derivative 

^6^4\N:N.CeH,.OCA, 
which,  on  reduction,  gives  two  molecules  of  phenetidin — 

^6^4\NH2 

Half  of  the  yield  is  then  converted  into  phenacetin  by  means  of 
acetic  acid,  and  the  other  half  again  used  for  the  preparation  of 
a  fresh  quantity  of  phenetidin. 

Physiologically  the  toxic  effect  of  this  substance  is  not  great. 
Dujardin  Beaumetz  gave  2-5  grams  to  a  rabbit  weighing  2-26  kilo- 
grams without  any  toxic  effect,  and  2  grams  have  been  given  for 
every  kilogram  body-weight  in  other  animals.  Large  doses  produce 
the  characteristic  aniline  action  on  the  red  corpuscles,  the  blood 
becomes  thick  and  purple,  and  finally  shows  the  spectrum  of  meth- 
haemoglobin.  The  darkening  of  the  urine  also  takes  place,  and 
occasionally  a  reducing  substance  appears.  The  ^  antipyretic  action ' 
is  thus  explained  by  Schmiedeberg.  In  the  first  place,  metabolism 
experiments  have  shown  that  the  nitrogen  excretion  is  increased 
with  small  doses,  and  only  decreased  with  large  ones ;  thus  a  direct 
decrease  in  nitrogenous  metabolism  cannot  be  the  cause  of  the  fall 
in  temperature.  Now,  if  animals  in  which  the  temperature  has  been 
raised  by  puncture  of  the  corpus  striatum  are  given  moderate  doses 
of  phenacetin  or  one  of  its  congeners,  or  even  small  doses  of 
morphine  (-01—02  grams,  |-§  grain),  a  fall  of  temperature  is 
observed  after  one  or  two  hours,  which,  however,  is  only  temporary. 
If  this  experiment,  however,  is  performed,  and  the  animal  placed  in 
an  incubator  at  31-32°  C,  no  fall  of  temperature  takes  place ;  thus, 
the  fall  of  temperature  must  be  induced  by  increased  heat-loss,  and 
not  by  diminished  heat  production.  Large  doses  of  these  drugs, 
however,  paralyse  the  centre  for  heat  production. 

The  heat-loss  is  shown  by  plethysmographic  experiments  to  be 
due  to  dilatation  of  the  cutaneous  vessels,  with  a  corresponding 
contraction  of  the  internal  arterioles. 


PHYSIOLOGICAL  PROPERTIES  189 

The  characteristic  analgesic  action  o£  phenacetin  is  mainly  due 
to  its  effect  on  the  sensory  tracts  in  the  cord. 

Phenacetin  is,  however,  only  slightly  soluble  in  water,  and  con- 
sequently is  only  slowly  absorbed.  Many  attempts  have  been  made 
to  increase  the  solubility  without  so  diminishing  the  stability  of 
the  substance  as  to  cause  its  decomposition  or  rapid  decomposition 
by  a  2  per  cent,  solution  o£  hydrochloric  acid,  whereby  the  toxic 
hydrochloride  o£  phenetidin  would  be  formed  in  the  stomach.  For 
this  purpose  various  acid  radicals  have  been  introduced  into  the 
basic  NHg  group,  and  the  following  examples,  which  are  classified 
according  to  the  type  of  chemical  modification,  show  that  (1)  only  in 
some  cases  has  the  desired  result  followed;  (2)  the  substances  de- 
scribed illustrate  the  modifications  in  the  physiological  reaction  which 
can  be  obtained  by  such  variations  of  the  molecular  structure ;  (3) 
no  substance  has  been  obtained,  by  such  modifications,  with  any 
novel  pharmacoloerical  properties,  nor  of  course  was  this  likely, 
if  the  action  of  these  derivatives  actually  depends,  as  it  most  pro- 
bably does,  on  their  decomposition  into  one  and  the  same  substance, 
jo-amido-phenol  or  its  ethyl  ether. 

Class  I. 

1.  Formyl-phenetidin, 

^6^4\]srH(COH) 

formed  by  acting  with  formic  acid  and  sodium  formate  on  phenetidin, 
has  an  action  entirely  different  from  that  of  the  other  derivatives  of 
this  substance.  The  antipyretic  effect  almost  entirely  disappears, 
and  is  replaced  by  a  powerfully  depressant  action  on  the  cells  of 
the  spinal  cord.  It  is,  in  fact,  a  physiological  antagonist  to  strych- 
nine, but  unfortunately  it  has  no  therapeutic  value  in  checking 
convulsions  caused  by  disease. 

2.  Propyl-phenetidin, 

^6^4\]srH.(COCH2.CH3) 

termed  Triphenin  by  Mering,  has  similar  properties  to  phenacetin, 
but  its  slight  solubility  results  in  slow  absorption,  and  consequent 
mild  physiological  reactivity. 

3.  Lactyl-phenetidin, 


^«^4<(n 


C2H5 


.NH(C0.CH.0H.CH3) 
(Lactophenin),  is  obtained  by  heating  the  lactic  acid  salt  of  the 


190  DERIVATIVES   OF  j^-AMIDO-PHENOL 

base  to  130°-180°,  or  by  heating  lactic  anhydride  or  lactic  ester 
with  the  base  to  this  temperature;  or  it  may  be  obtained  by 
replacing  the  halogen  in  a-brompropionyl-phenetidin  by  OH, 
through  the  agency  of  aqueous  sodium  acetate.  Its  action  appears 
to  be  identical  with  that  o£  phenacetin,  but  it  is  more  soluble ;  the 
narcotic  action  is  well  marked,  though  the  antipyretic  action  is 
slighter.  It  is  mainly  valuable  as  an  antineuralgic.  In  rabbits  its 
effect  closely  resembles  that  produced  by  chloral  hydrate,  the  animal 
remaining  unconscious  and  motionless,  and  irresponsive  to  painful 
reflexes,  though  the  respiration  and  circulation  are  not  affected 
(Schmiedeberg).  It  is  more  liable  than  phenacetin  to  lead  to  the 
formation  of  the  toxic  hydrochloride  of  phenetidin  in  the  stomach. 

4.  j5-Ethoxyphenyl-succinimide  (Fyrantin) 

OC,H, 
CeHZ       XO.CH, 

^CO.CHa 

is  obtained  by  the  action  of  succinic  anhydride  on  the  base. 
The  sodium  salt  is  soluble  in  water.  It  is  an  uncertain  antipyretic 
and  analgesic,  but  is  said  to  have  no  toxic  action  on  haemoglobin. 

5.  Diacet-phenetidin 


coca 

was  thought  likely,  on  theoretical  grounds,  to  prove  a  more  powerful 
antipyretic  than  phenacetin,  but  in  actual  practice  this  was  not 
established.     It  is  very  unstable. 
6.  Salicyl-phenetidin 

n  XT  /OC2H5 
^e^^XNRCO.CeH^.OH 

(Salophen  or  Salipheniu),  like  the  majority  of  such  derivatives,  is 
only  broken  down  in  the  organism  with  difficulty.  It  was  origi- 
nally introduced  to  replace  salol,  in  order  to  avoid  the  formation  of 
phenol  in  the  organism.  It  is  unaffected  by  the  gastric  juice,  but 
decomposed  by  the  pancreatic.  It  is  slightly  antipyretic,  but 
appears  mainly  active  as  to  the  salicyl  portion  of  the  molecule.  It 
is  mostly  excreted  unchanged  in  the  urine.  No  increase  in  the 
conjugated  sulphates  occurs.  Quinic  acid  produces  a  similarly 
inert  compound  with  phenetidin. 


PHYSIOLOGICAL  PROPERTIES  191 

7.  Amygdopheniu, 

^6^4\nHCO.CH(OH).C6H5, 

is  obtained  by  heating  /?ara-pheneticlin  with  mandelic  acid  at 
130°-170°  C.  The  mandelic  acid  diminishes  the  toxicity  and 
the  antipyretic  action  by  diminishing  the  solubility  and  rapidity 
of  absorption. 

Class  II. 

A.  Attempts  to  increase  the  solubility  of  phenacetin  by  the 
ordinary  methods  employed  in  organic  chemistry,  that  is  by  the 
introduction  of  a  (COOH)  or  (SOgOH)  group  into  the  nucleus, 
were  unlikely  to  lead  to  the  desired  result,  since  Nencki  had  shown 
that  such  changes  tend  to  destroy  physiological  activity.  Thus, 
both  the  soluble  phenacetin  sulphonic  acid, 

aHg^NH.COCHg 
\SO2OH 

and  phenacetin  carboxylic  acid, 

/OC2H5 

CgHgf-NH.COCHg 

\COOH 

prepared  in  Schering's  laboratory,  are  but  very  slightly  reactive, 
Fhesin,  the  sodium  salt  of  the  former  acid, 

/OC^H, 
C^Ha^NHCOCHg 
\SOoONa 


is  a  light-brown  powder,  soluble  in  water,  with  a  slightly  astringent 
salt  taste.  It  is  employed  in  doses  of  15-30  grains,  and  apparently 
possesses  analgesic  and  antipyretic  action. 

On  the  other  hand,  the  introduction  of  a  second  amido  group 
into  the  nucleus,  affording  another  possibility  for  the  preparation 
of  soluble  derivatives,  is  not  feasible,  since  it  results  in  a  large 
increase  in  toxicity. 

B.  The  replacement  of  hydrogen  in  the  amido  group  by  acid 
radicals  has  led  to  the  preparation  of  several  substances  of  greater 
solubility  than  phenacetin.  But  it  was  hardly  to  be  expected  that, 
if  the  stability  of  the  body  were  such  as  to  allow  of  its  decompo- 
sition, giving  ;5-amido-phenol  in  the  organism,  there  should  be  any 


192  DERIVATIVES   OF  i?-AMIDO-PHENOL 

considerable  decrease  in  toxicity ;  if^  on  the  other  hand^  the  stability- 
was  great,  then  the  presence  of  acid  groups  might  be  expected  to 
give  rise  to  substances  with  little  if  any  physiological  activity. 

1.  The  citric  acid  derivatives  of  phenetidin  are  : — 

i.    CHoCOOH 

I 
C.OH.COOH  Apolysin, 

I 
CH2 .  CO-NH.CeH^ .  OC2H5 

ii.    CH2.CO.NH.C6H4.OC2H5 
C.OH.COOH 
CH2 .  CO.NH.CeH4 .  OC2H5. 

Apolysin  is  soluble  in  about  80  parts  of  cold  water,  and  freely 
in  hot  water,  alcohol,  and  glycerin.  It  has  been  used  in  migraine, 
but  is  said  by  some  observers  to  have  neither  the  analgesic  nor  the 
antipyretic  properties  of  phenacetin.  It  is,  like  lacfcophenin,  easily 
decomposed  by  the  hydrochloric  acid  in  the  stomach,  giving  rise  to 
the  toxic  phenetidin  salt;  this  produces  both  local  and  general 
symptoms.  If  injected  subcutaneously  no  decomposition  occurs, 
and  the  substance  passes  unchanged  into  the  urine;  its  only 
physiological  action  then  is  due  to  the  acid  radicals. 

CH2 .  CO.NH.C6H4OC2H5 

Citrophen     ioH.CO.NH.CeH.OC^H. 

(Citrophenm),  .  -6425 

CH2 .  CO.NH.CgH^ .  OC2H5 

is  soluble  in  40  parts  of  water,  and  has  a  pleasant  taste.  Its  action 
resembles  that  of  phenacetin.  The  formula  given  above  was  that 
given  by  Roos ;  Hildebrand,  however,  states  that  it  is  merely  the 
citrate  of  phenetidin ;  its  action  physiologically  is  similar  to  that  of 
a  salt  of  phenetidin,  and  not  to  that  of  a  true  substitution  product. 
Chemically  it  gives  a  red  coloration  with  perchloride  of  iron,  which 
apolysin  does  not.  It  is  a  blood  poison  like  the  other  phenetidin 
salts. 

2.  Schmidt  prepared  ethoxy-succinanilic  acid, 

p    TT    //OC2H5 

^6^4\]sg^H.CO.CH2 .  CH2 .  CO.OH, 


PHYSIOLOGICAL  PROPERTIES  193 


and  ethoxytartranilic  acid, 

^6^4\NH.CO.CHOH.CH.OH.COOH, 

but  owing  to  the  introduction  of  the  acid  group,  these  bodies  have 
no  antipyretic  action. 

3.  In  a  similar  manner  ethoxyphenyl-glycin, 


OC,H, 


.NH.CO.CH2 .  COOH, 

has  been  found  to  possess  no  pharmacological  value. 
4.  Fheuosal, 

^6^4\NH.CO.CH2  •  O.CgH^  .  COOH, 

obtained  by  heating  salicylacetic  acid  with  phenetidin  to  120°,  is 
a  white  crystalline  powder,  soluble  with  difficulty  in  water,  alcohol, 
and  ether.  It  has  a  bitter  acrid  taste,  and  has  been  employed  for 
its  antipyretic  and  analgesic  qualities,  which,  however,  are  but 
slight. 

Class  III. 

Schmidt  and  Majert,  in  order  to  increase  the  solubility  of  phe- 
nacetin,preparedamido-phenacetin(glycocoll,-phenetidin,Plienocoll), 

^6^4\NH.CO.CH2NH2 
by  the  action  of  ammonia  on  bromacetyl  phenetidin.  The 
hydrochloride  is  soluble  in  16  parts  of  water,  forming  a  solution 
of  bitter,  saline  taste.  It  has  the  usual  phenacetin-like  action,  and 
a  few  authors  state  that  it  is  an  antiperiodic.  This  is  not,  how- 
ever, generally  accepted.  It  appears  to  have  some  antiseptic  pro- 
perties, as  it  has  been  employed  externally  as  a  substitute  for 
iodoform. 

Phenocoll  hydrochloride,  owing  to  its  solubility,  is  more  rapidly 
absorbed,  and  consequently  acts  more  quickly  than  phenacetin.  It 
is  said  to  be  more  powerfully  analgesic,  and  to  be  an  efficient  substi- 
tute for  salicylates  as  an  antipyretic  in  acute  rheumatism.  It  may 
cause  collapse  and  cyanosis.  Mosse  considers  it  of  value  in  septic 
infections  only.  It  is  rapidly  excreted  by  the  kidneys,  so  that  its 
action  is  but  transitory. 

Salocoll,  its  salicylic  acid  compound,  is  the  only  salt  of  phenocoll 
which  is  insoluble  in  water.  Its  action  resembles  that  of  the  parent 
substances. 

o 


194         DERIVATIVES   OF  i?-AMIDO-PHENOL 

Class  IV. 

Various  condensation  products  of  phenetidin  with  aldehydes  and 
ketones  have  been  prepared  and  investigated. 

1.  Salicyl-phenetidin 

^^^K'N  I'cH.CgH^ .  OH 

(Malakiu),  is  prepared  by  the  action  o£  salicylaldehyde  direct  or  in 
alcoholic  solution  on  phenetidin.  It  is  almost  insoluble  in  water, 
and  only  slightly  soluble  in  alcohol.  As  an  antipyretic,  its  action  is 
said  to  be  slow,  but  it  is  a  useful  analgesic.  The  dose  is  8-25  grains. 
Its  insolubility  interferes  with  its  physiological  action. 

2.  Methyl-benzylidene-phenetidin, 

obtained  by  the  action  of  acetophenone  on  phenetidin.  The  citric 
acid  salt  of  this  derivative  goes  by  the  name  of  Malariu.  The 
original  substance  is  practically  insoluble  in  water,  but  freely  soluble 
in  hot  alcohol.  It  has  a  bitter  taste,  and  is  employed  as  an  anti- 
pyretic and  analgesic  in  doses  of  7  grains  several  times  daily.  It 
has  considerable  action  in  these  directions,  but  is  of  little  value  as  a 
hypnotic  as  it  is  markedly  toxic,  and  its  action  is  too  precipitate. 

3.  Vanillin-phenetidin, 

prepared  by  the  action  of  phenetidin  on  vanillin,  is  antipyretic 
and  antiseptic,  and  also  contracts  the  blood  vessels.  It  is,  however, 
too  expensive  to  be  of  practical  value  as  a  substitute  for  phenacetin. 
Various  jo-amido-phenol  derivatives  of  substituted  vanillins  have 
been  investigated.  Vanillinethyl  carbonate,  prepared  by  the  action 
of  chlorformic  ester  on  an  alcoholic  solution  of  vanillin  in  presence 
of  potassium  hydrate, 

/COH  1 

aHgf-OCHg  3 

\O.COOC2H5  4 
or  phenacetyl- vanillin, 

.COH 

NO.CH^.COOCeHg, 

may  replace  vanillin  in  these  reactions. 


PHYSIOLOGICAL  PROPERTIES  195 

Vanillinethyl-carbonate-/>-plieneti(iin  has  been  prepared  com- 
mercially and  is  termed  EupyHn ;  it  has  but  slight  physiological 
action. 

Vanillin  itself  is  a  convulsive  agent  in  animals,  but  10  to  15  grains 
have  been  given  to  man  without  harmful  results. 

4.  In  a  similar  manner  to  the  above,  protocatechuic  aldehyde, 

yCHO    1  .        C  H  /oCh' 

CgHo^OH      3    and  opianic  acid,        ^    ^Krnnw 
\0H      4  (Ih^^OH 

may  be  condensed  with  phenetidin ;  both  derivatives  have  powerful 
hypnotic  properties. 

Class  V. 

Other  groups,  besides  the  radicals  of  the  aliphatic  hydrocarbons, 
have  been  used  to  replace  the  hydroxyl  hydrogen  atom,  thus 

1.  Lactylamidophenol- ethyl-carbonate, 

^  ^  /O.COOC^H, 
^6^4\NH.CO.CHOH.CH3, 

is  only  slowly  decomposed  in  the  organism ;  it  has  antipyretic  and 
slight  narcotic  properties ;  its  toxic  action  is  similar  to  that  of  phe- 
nacetin  or  methacetin  in  similar  doses. 

2.  Acetamidophenol  benzoate, 

^6^4\NH.C0CH3, 

has  a  weaker  action  than  phenacetin,  since  its  decomposition  in  the 
organism  only  takes  place  slowly. 

3.  Acetethylamidophenol  acetate, 

/O.COCH3 

\N\COCH3, 
produces  intoxication  similar  to  that  produced  by  ethyl  phenacetin ; 
the  stage  of  excitement,  however,  is  more  rapidly  produced  and  the 
narcotic  effect  less  marked.     In  man  it  has  considerable  analgesic 
and  narcotic  power,  but  is  only  a  feeble  antipyretic. 

4.  Oxyphenacetin  salicylate 

p  TT  /O.CH2 .  CHo .  00C.aH4,0H 

is  split  up  in  the  body  into  salicylic  acid  and  probably  oxyphe- 

o  % 


196  DERIVATIVES  OF  j^-AMIDO-PHENOL 

nacetin,  wliich  is  then  converted  into  acetamido  phenol.  It  is  said  to 
be  of  value  in  rheumatism  and  neuralgia,  but  the  antipyretic  and 
narcotic  actions  are  very  slight,  decomposition  within  the  organism 
taking  place  slowly. 

5.  ^-Acetamidophenoxyl  acetamide 

p„//O.CH2.CONH2 
^6^4\;f^H.COCH3 

is  obtained  by  the  action  of  monochlor-acetamide  on  acet-jo-amido 
phenol  in  presence  of  the  calculated  amount  of  alcoholic  potash. 
The  corresponding  lactyl  derivative  is  obtained  in  a  similar  manner 
from  lactyl-/?-amido-phenol.     It  has  marked  antipyretic  action. 


Class  VI. 

On  its  passage  through  the  organism,  phenyl  urethane, 
CgHgNH.COOCgHg  (Enphorin),  is  partially  converted  into  p-oxy~ 
phenyl  urethane,  and,  on  the  same  principles  as  those  previously 
mentioned,  this  substance  and  many  of  its  derivatives  have  been 
introduced  into  pharmacology. 

1.  ;5-oxyphenyl  urethane. 


C, 


„/0H 
6^4\]srH.COOC2H5. 


It  is  practically  non-toxic,  but  may  produce  slight  rigors. 

2.  Acetyl-;?-oxyphenyl  urethane  (Nenrodin), 

/OH 
CgHA     //COCH3 
^NxcoOCgHg. 

The  toxic  effects  are  still  further  reduced  by  the  entrance  of 
the  acetyl  group,  as  are  also  the  antipyretic  and  analgesic  actions. 
It  is  very  insoluble  in  cold  water,  and  its  antipyretic  action,  though 
rapid,  is  somewhat  uncertain. 

3.  /?-ethoxyphenyl  urethane, 

^6^4\NH.COOC2H5, 

although  not  free  from  toxic  effects,  has  a  much  more  certain  action 
in  lowering  the  temperature  than  those  derivatives  previously 
mentioned. 


PHYSIOLOGICAL  PROPERTIES  197 


4.  The  acetyl  derivative  of  this  substance, 

X)C,H, 
CeH.<      /COCH3 

is  named  Thermodin.  Its  antipyretic  effect  is  said  to  be  gradual, 
and  toxic  symptoms  have  not  been  observed.  It  is  very  insoluble  except 
in  acid  media,  and  should  therefore  be  administered  combined  with 
acetic  acid  and  syrup,  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  ;5-phenetidin  in  presence  of  alkali;  the  reaction  which  takes 
place  may  be  represented  by  the  following  equation  : — 

p  TT /OH  nnn^    _  pny^'^6H4  •  NHCOR    ,()^T^^ 

^6^*\NH.COR  +  '"^'"^2  -  ^'^XO.CgH^.  NH.COR  +  '^^^^ 

R  =  OCgHg,  OC3H7;   CH3,  CgH^;   CgHg. 

If  the  reaction  is  carried  out  in  alcoholic  solution  in  presence  of 
sodium  alcoholate,  mixed  carbonates  are  formed.  The  reaction  may 
be  expressed  in  the  following  manner : — 

yOjH 

CfiHZ                 +iCllCO. 
^NH.COR    


Cli  +  iHiOaH. 


^^\OC,H, 

R      =       OCgHg,     OC3H7;        CH3,      CgHg,      CgHg. 


_  2HC1  +  CU  r.r.  TT    ]s[HCOR 


On  varying  the  alcohol,  the  groups  methyl  or  propyl  replace  ethyl 
in  the  above  derivatives. 


CHAPTER   X 

The  Main  group  op  Synthetic  Antipyretics  (continued).— 
Hydrazine  and  its  derivatives. — Physiological  action  of  Phenylhydrazine  and 
its  derivatives.  The  Pyrazolon  group — Antipyrine,  Pyramidon.  General 
Summary  of  Physiological  characteristics  of  the  Ammonia  derivatives. 

11.    DERIVATIVES   OF  PHENYLHYDRAZINE. 

Like  ammonia,  hydrazine,  NHg — NHg,  is  a  strong  base  and  an 
extremely  toxic  substance ;  its  most  important  derivative  is  phenyl- 
hydrazine,  CgHgNH — NHg,  a  body  whicb  is  largely  employed  in 
synthetic  chemistry. 

Preparation  and  Properties. 

Phenyl-hydrazine  may  be  obtained  by  the  reduction  of  the  diazo- 
benzene  salts,  CgHgN  :  N.Cl,  through  the  agency  of  acid  sulphites  of 
the  alkalies  on  the  yellow  potassium  salt  of  diazobenzene  sulphonic 
acid,  whereby  colourless  potassium  benzenehydrazine  sulphonate  is 
formed  directly, 

CeHgN  :  N.SOgOK  +  KHSO3  +  Hp 

=  CgH^NH.NH.SOpK  +  KHSO^. 

When  the  resulting  sulphonate  is  heated  with  hydrochloric  acid, 
phenylhydrazine  hydrochloride  is  formed — 

C6H5NH.NH.SO2OK  +  HCl  +  H2O 

=  CgH^NH.NHa .  HCl  +  KHSO^. 

A  somewhat  simpler  method  for  the  preparation  of  phenyl- 
hydrazine  consists  in  the  reduction  of  diazobenzene  chloride  by 
stannous  chloride, 

CgHgN  :N.Cl  +  2SnCl2  +  4HCl  =  C6H5NH.NH.HCl  +  2SnCl4. 

The  double  salt  of  phenylhydrazine  hydrochloride  and  stannic 
chloride  separates  out,  is  decomposed  by  potash,  and  the  solution 
extracted  with  ether ;  the  free  base  may  then  be  purified  by  distil- 
lation in  vacuo, 

Phenylhydrazine   is   a   strongly   basic   substance,  more   readily 


PHYSIOLOGICAL  PROPERTIES  199 

oxidized  than  aniline  ;  it  reduces  Fehling's  solution,  and  is  a  most 
important  reagent  for  the  identification  of  (i)  aldehydes  and  (ii) 
ketones,  with  which  it  undergoes  the  following  general  reactions  : — 

i.  CHq  CHq 


A 


JHiO  +  H^jN.NHPh  =  H2O  +  CH  :  N.NHPh^ 

Acetaldehyde. 

C6H5CHjO  +  H2iN.NHPh  =  Rfi^C.IlfiB.  :  N.NHPh 

Benzaldehyde. 


ii.  CH3  CHj 


CiO  +  HgiN.NHPh  =  H^  +  C  :  N.NHPh 

I'  I 

CHg  ^Hg 

CHq  CHq 

I.... :.  I 

CiO  +  H„iN.NHPh  =  H„0  +  C  :  N.NHPh 

I  I 

The  development  of  the  chemistry  of  the  carbohydrates  by  Emil 
Fischer  was  largely  based  upon  reactions  similar  to  these,  since  that 
group  is  entirely  composed  of  ketonic  or  aldehydic  alcohols. 

There  are  few  classes  of  organic  substances  which  lend  themselves 
more  readily  to  the  synthesis  of  ring  systems  containing  nitrogen 
than  do  phenylhydrazine  and  its  derivatives.  From  the  phar- 
macological point  of  view,  the  pyrazolon  derivatives,  among  which 
is  antipyrine,  are  by  far  the  most  important,  and  will  be  described 
later. 

Physiological    Properties. 

The  reactivity  of  phenylhydrazine  with  aldehydes  and  ketones, 
together  with  its  powerful  reducing  action,  give  it  very  pronounced 
toxic  properties. 

Like  hydroxylamine,  NHgOH,  hydrazine  itself,  and  to  a  lesser 
extent  aniline,  it  brings  about  destruction  of  the  red  blood  corpuscles 
and  decomposition  of  the  haemoglobin,  besides  being  a  powerful  pro- 
toplasmic poison.  The  brown  pigment  formed  in  the  blood  appears  to 
be  partly  methaemoglobin  and  partly  a  substance  derived  from  phenyl- 
hydrazine  itself  (Hoppe-Seyler).  Death  takes  place  from  general 
paralysis  of  cerebral  origin,  accompanied  by  convulsions.  The  admini- 

1  The  radical  Phenyl,  CgHg,  may  be  written  Ph,  Methyl  Me,  and  Ethyl  Et. 


200         DERIVATIVES  OF  PHENYLHYDRAZINE 

stration  of  phenylhydrazine  is  followed  by  the  appearance  of  allantoin 
in  the  urine.  The  various  attempts  which  have  been  made  to  reduce 
the  toxicity,  or  rather  to  bring  about  a  more  protracted  phenyl- 
hydrazine  reaction  in  the  organism,  follow  very  closely  those 
employed  in  the  case  of  aniline. 

By  a  completely  corresponding  reaction,  the  stability  of  the  base 
can  be  increased  by  the  replacement  of  the  amido  hydrogen  atom  by 
the  acetyl  group,  but  the  resulting  substance,  acetylphenyl-hydra- 
zine,  CgHgNH— NH(C0CH3)  (Hydracetin),  is  still  capable  of 
reducing  Fehling's  solution,  although  to  a  less  extent  than  the 
original  substance.  Intense  depression  and  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 
possible  to  employ  it,  it  would  have  been  much  cheaper  than 
antipyrine. 

The  intense  staining  of  the  tissues  after  death  is  evidence  of  the 
extent  to  which  haemoglobin  is  broken  up  by  this  substance.  It 
has  been  employed,  like  pyrogallic  acid,  in  the  treatment  of 
psoriasis,  but  practically  is  too  toxic  even  for  external  application.^ 

Diacetyl  phenylhydrazine,  CgHgNH— N  (COC  113)2,  ^^  less  toxic, 
but  has  a  cumulative  action  as  a  haemic  poison.  Thus,  though  a 
powerful  antipyretic,  it  is  not  possible  to  employ  it  therapeutically. 

In  this  connexion  it  may  be  mentioned  that  a-/3-diacetyl  phenyl- 
hydrazine, 

/COCH3 
CgHg.N/- NH(C0CH3), 

obtained  by  the  interaction  of  sodium  phenylhydrazine,  ether,  and 
acetyl  chloride,  does  not  appear  to  have  been  tried,  although  from 
the  fact  that  it  is  capable  of  reducing  Fehling's  solution,  its  action 
is  not  likely  to  differ  much  from  that  of  the  above-mentioned  bodies. 

In  a  very  similar  manner  the  amido  hydrogen  atom  has  been 
replaced  by  the  radical  benzoyl,  but  the  resulting  benzoyl  phenyl- 
hydrazine,  CgHgNH— NH(C0CgH5),  acts  on  the  blood  in  doses 
that  have  no  action  on  the  central  nervous  system. 

This  is  also  true  of  ethylene-phenylhydrazine, 

/NH,        /NH, 
C,H,.N^C,H,-N.CeH, 

1  Berl.  KUn.  Woch.,  1899. 


I 


PHYSIOLOGICAL  PROPERTIES  201 

and  its  succinyl  derivative 

/NH(CO.C2H4COOH)    /1<^}1{C0C^11^ .  COOH) 

The  relative  toxicity  o£  phenylhydrazine  is  lowered  by  the  re- 
placement of  hydrogen  by  alkyl  or  acid  groups,  but  the  presence  of 
both,  as  in  the  case  of  acetyl-  methyl-  or  ethyl-phenylhydrazine, 

does  not  decrease  the  general  action  on  the  blood,  although  the  lower- 
ing of  toxicity  is  sufficiently  marked,  and  it  might  be  worth  while 
to  investigate  the  physiological  reactivity  of  dimethylacetyl  phenyl- 
hydrazine, 

which  is  a  more  stable  substance. 

In  the  hope  of  lowering  the  toxicity  attempts  have  been  made  to 
introduce  the  phenylhydrazine  radical  into  substances  containing 
the  acidic  (COOH)  group.     Thus  laevulinic  acid, 

CHg .  CO.CH2 .  CH2 .  COOH, 

reacts  with  the  base,  in  the  form  of  its  acetate  in  aqueous  solution, 
in  the  general  manner  previously  described,  yielding  the  hydrazone 

CH3 .  C.CH2 .  CH2 .  COOH 

II 
N.NH.C^Hg 

This  body  has  been  termed  Antithermin.  Laevulinic  acid  itself 
is  toxic,  and  its  compound,  though  actively  antipyretic,  too  poisonous 
for  general  use ;  it  is  also  liable  to  cause  gastric  irritation. 

Based  on  the  same  idea,  the  substance  Orthiu 


/NH.NH2     1 

PHg^OH  2 

\COOH        5 


has  been  introduced.  The  presence  of  the  acid  grouping  again 
lowers  the  toxicity,  but  the  substance  is  unreliable  as  an  antipyretic 
and  produces  undesirable  by-effects. 

Attempts  to  modify  the  action  of  phenylhydrazine  by  the  intro- 
duction of  the  salicyl  residue  into  a-phenylmethylhydrazine 


CgH^.N^^^^^NHa 


202  PYRAZOLON  DERIVATIVES 

(which  is  somewhat  less  toxic  than  the  unsubstituted  base),  by 
means  o£  salicjl  aldehyde,  result  in  the  formation  of  the  hydrazone 

CgHg .  N-^^^^N  :  CH.CgH^ .  OH 

known  as  Agathiu,  a  tasteless,  odourless  body  insoluble  in  water. 
But  this  substance  shows  its  antineuralgic  action  only  in  doses  of 
4-6  gms.  (3  i-5  i  ss),  a  fact  which  bears  out  the  general  observation 
that  salicyl  derivatives  of  this  type  are  only  decomposed  with  such 
difficulty  by  the  organism  that  they  are  unsuitable  as  antipyretics 
and  antineuralgics.      It  may  produce  violent  headache.^ 

It  will  be  seen  from  the  above  that  it  has  not  been  found  possible 
to  eliminate  the  powerful  action  which  phenylhydrazine  has  on  the 
red  blood  corpuscles,  and  it  does  not  seem  likely  that  any  of  the 
methods  described  can  be  so  modified  as  to  yield  substances  of  the 
slightest  pharmacological  value. 

III.     PYRAZOLON  DERIVATIVES   OF  THE 
TYPE   OF  ANTIPYRINE. 

1.  Phenyl-3-methyl  pyrazolon,  the  first  derivative  of  this  group, 
was  obtained  by  Knorr,  in  1883,  through  the  interaction  of  phenyl- 
hydrazine  and  acetoacetic  ester.  The  formation  of  pyrazolon  is  a 
general  one,  and  other  /3-ketonic  acid  esters  react  in  a  similar  manner. 

As  the  formation  of  antipyrine  will  be  easier  to  follow  if  the 
enolic  formula  ^  for  acetoacetic  ester  is  employed, 

CH3.C(0H)  =  CH.COOC2H,, 
this   explanation   of   the   reaction   will   be   adopted   although   its 
accuracy  is  perhaps  questionable. 

The  first  phase  of  the  reaction  consists  in  the  formation  of  a 
hydrazone — 

i.  CH3  CH, 


C.:OH  +  HiNH— NHaH,       C— 


iOH  +  HiNH— NHCgHs       C— NH— NHCgH 


5 

II  =   II 

CH  CH 

!  I 

COOC2H5  COOC2H5 

^  Pharm.  Journ.,  vol.  xxiii,  p.  86. 

^  Acetoacetic  ester  reacts  under  certain  conditions  as  if  its  constitution 
were  expressed  by  the  formula  CH3 .  CO.CHg .  COOCgHg ;  under  others,  by 
the  formula  CHg .  C(OH) :  CH.COOC2H5.  Such  a  substance  is  termed  '  Tauto- 
meric '  and  the  first  is  called  the  *  Keto '  and  the  second  the  '  Enol '  form. 


SYNTHESIS   OF  ANTIPYRINE 


203 


On  heating,  the  resulting  substance  loses  alcohol- 


11. 


CH. 


CH, 


-NH 


NH 


CH 


OC,H, 


HiN.C.H^ 


CH 

I 
CO-N.aH, 


The  body  which  is  formed,  l-phenyl-3-methyl  pyrazolon,  is  con- 
verted into  antipyrine  by  heating  to  100°-150°C.  under  pressure 
with  methyl  iodide  in  methyl  alcohol  solution — 


111. 


CH, 


CH, 


C NiHi  +  CHgli 

II 
CH 

CO— N.CeHg 


k 


-N.CH, 


CH 

I 
CO— N.CeHg 

Antipyrine  or  1-phenyl- 
2 : 3-dimethyl  pyrazolon. 


This  view  of  its  constitution  is  borne  out  by  its  direct  synthesis 
from  a-/3-phenylmethyl-hydrazine — 


1. 


CH, 

I .: 


CH, 


CHg  CHg 


C.iOH     H:N— NHC.H, 

r 

CH     + 


-N— NHC.H, 


COOC2H5 


CH 


OOC2H5 


2. 


CH, 

I 
C— 


CH 


N.CH, 


CHo 

I 

C N.CH, 

li 
CH 


COiOCoH 


H:N.C«H,       CO— N.C«H. 


2^^5 


The  hydriodic  acid  salt  of  antipyrine,  which  is  obtained  in  the 
first  synthesis,  is  decomposed  by  concentrated  solution  of  potash. 
Antipyrine  dissolved  out  by  chloroform  or  benzene  is  recrystallized 
from  ether. 


204  PHYSIOLOGICAL  PROPERTIES  OF  ANTIPYRINE 

Many  modifications  of  this  synthesis  have  been  made  since  its 
discovery,  and  will  be  found  in  the  larger  textbooks  on  organic 
chemistry. 

Physiological  Properties  of  Antipyrine  and  its  derivatives. 

It  is  interesting  to  note  that  the  characteristic  antipyrine  pro- 
perties are  entirely  absent  in  l-phenyl-3-methyl  pyrazolon, 

CH3 

C NH 

II 
CH 


A 


0-N.CeH„ 

and  it  is  only  when  the  imido  hydrogen  atom  is  replaced  by  methyl, 
that  these  appear  :  - 

CHo 


i 


-N.CH, 

11 
CH 


A 


0-N.C,H,. 

With  Antip3rrine  (Pheuazoue)  the  paralysing  action  on  the  motor 
centres  in  the  mid  brain  is  not  well  marked.  It  is  not  narcotic,  but 
in  large  doses  it  produces  destruction  of  haemoglobin,  collapse,  and 
convulsions.  The  latter  are  well  marked  in  frogs  with  doses  of 
from  50-60  mgm.  It  has  the  great  advantage  of  easy  solubility  in 
water.  Its  antipyretic  action  is  not  due  to  any  influence  on  the 
oxygen  capacity  of  the  blood.  Sweating,  as  accelerating  heat-loss, 
also  has  but  a  small  share,  for  the  fall  of  temperature  produced  by 
antipyrine  occurs  when  sweating  has  been  prevented  by  belladonna. 
It  does  not  act,  however,  when  the  higher  parts  of  the  brain  are  cut 
off  by  section  through  the  cord  or  through  the  crus  cerebri.  In 
fever  experimentally  produced  by  damage  to  the  corpus  striatum 
antipyrine  produces  a  fall  of  temperature. 

Most  probably  this  effect  is  due  to  the  dilatation  of  the  cutaneous 
vessels  and  a  consequent  increase  of  heat-loss. 

In  some  animals  (including  man)  the  thermotaxic  centre  is  so 
stimulated  by  this  process  that  heat  production  is  forthwith  in- 
creased as  a  compensatory  measure.  In  man,  also,  there  is  a  decrease 
in  the  respiratory  activity. 


ANTIPYRINE  DERIVATIVES  205 

Nitrogenous  metabolism,  which  is  practically  uninfluenced  in 
health,  is  decreased  in  pyrexial  conditions  when  this  drug  is  ad- 
ministered. This  is  not  a  direct  action,  but  is  dependent  merely  on 
the  antipyretic  effect  of  the  drug,  which  cannot  influence  the 
increased  nitrogen  waste  due  to  toxic  processes. 

As  an  analgesic,  it  is  largely  used,  and  the  number  of  cases  in 
which  bad  by-effects  have  occurred  does  not  appear  to  be  great. 
When  first  introduced,  S^e  gave  15  grains  every  hour  up  to  50 
or  100  grains,  but  it  is  not  now  given  in  these  large  doses.  In 
cases  in  which  unpleasant  symptoms  (collapse,  oedema,  rashes,  &c.) 
have  appeared,  these  have  not  always  been  the  result  of  large  doses. 
Guttmann  reports  a  case  in  which  a  man  took  15  grains  of  anti- 
pyrine  in  five  days,  which  produced  a  condition  closely  resembling 
cholera,  except  that  diarrhoea  was  not  present,  and  there  was  a 
dusky  rash  on  the  abdomen. 

Antipyrine  is  found  in  the  urine  to  some  extent  unchanged,  but 
chiefly  as  a  glycuronic  acid  derivative;  most  probably  oxidation, 
with  the  formation  of  oxyantipyrine,  precedes  this  synthesis. 

When  j)-to\jl  hydrazine 

n  XT  /^^      3 

^6^4\NH.NHj 

is   employed   in    the   pyrazolon    synthesis,  instead  of  the  phenyl 
derivative,  Tolylpyrine 

CH, 

I 
C N.CH, 


CH 

I 
CO— N.CgH^.CHg 

is  obtained.  It  is  more  irritating  than  antipyrine,  and  affects 
the  circulation  unfavourably,  while  its  analgesic  action  is  not  so 
pronounced. 

The  salicylic  acid  salts  of  both  antipyrine  and  tolylpyrine  have  been 
introduced  under  the  names  of  Salipyrine  and  Tolysal.  These  are 
obtained  by  melting  together  the  constituents  on  the  water  bath ; 
the  resulting  derivatives  contain  a  free  carboxyl  group,  and  from 
them  a  series  of  salts  may  be  obtained.  They  are  readily  decom- 
posed   into    their    constituents    by  hydrochloric   acid,   and   their 

*  Pharm.  Joum,,  vol.  xxiii.  p.  605. 


206 


ANTIPYRINE  DERIVATIVES 


physiological  reaction  corresponds  to  tliat  of  a  mixture  of  anti- 
pyrine  and  salicylic  acid. 

Several  derivatives  of  this  type  have  been  introduced  into 
pharmacology,  for  example  : — 

Tnssol  is  the  mandelic  acid  (CgH5CH.OH.COOH)  salt  of  anti- 
pyrine.  It  has  been  given  as  a  remedy  for  whooping  cough  in 
doses  of  15-30  cgms.  per  diem  for  children  under  one  year,  and  more 
proportionately  to  age  for  older  children.  There  is  no  evidence 
that  it  is  superior  to  antipyrine,  which  is  well  tolerated  by  children. 

Hypual,  or  Hypnol,  is  a  compound  of  chloralhydrate  and  anti- 
pyrine.  It  is  said  to  be  more  soporific  and  to  have  less  action  on 
the  circulation  than  chloral_,  but  its  general  toxicity  is  higher. 
Bichloral-antipyrine  is  still  more  toxic,  and  has  no  advantages 
over  chloral  or  hypnal.^ 

Auilopyrine  (Acetanilide  and  antipyrine)  is  a  soluble  white 
powder,  but  apparently  has  no  particular  advantage  over  a  mixture 
of  the  two  bodies  which  has  long  been  a  favourite  prescription  for 
neuralgia  and  headaches  of  various  sorts. 

Bodies  of  this  type,  owing  to  the  ease  with  which  they  are 
decomposed,  can  only  act  as  mixtures,  and  it  is  consequently  fruit- 
less to  search  for  substances  with  new  physiological  reactions 
amongst  derivatives  of  such  a  nature. 

Fyramidon,  or  4-dimethylamido -antipyrine,  is  the  only  anti- 
pyrine derivative  which  has  proved  of  value.  It  is  obtained  by  the 
following  reactions  : — 

1.  When  nitrous  acid  acts  on  a  solution  of  antipyrine  hydro- 
chloride, nitroso-antipyrine  is  obtained — 


CH, 


CH, 


N.CH, 


N.CH, 


CH 

CO— N.C«H. 


+  HN02=  II 

NO— C 

CO— N. 

2.  This  on  reduction  gives  amido  antipyrine, 

CH3 

I 


^6^5 


-N.CH. 


NH2— C 


CO— N.CgHg 


'  Pharm.  Joum.,  vol.  xxi,  p.  161. 


PHYSIOLOGICAL  PROPERTIES  207 

which  is  isolated  by  means  of  its  benzylidene  derivative,  and  on 
methyiation  gives  Pyramidon — 

CH, 


i 


-N.CH 


^5 


-N.CH3 


NH. .  CO.NH— C 


(CH3),N.C 

io— K.CgH, 

Pyramidon  is  a  solid  which  dissolves  in  water,  giving  an  alkaline 
solution,  and  is  a  more  powerful  base  than  antipyrine.  The  dose  is 
about  one-third  that  usually  given  in  the  case  of  the  latter  drug. 
It  has  no  irritant  effect  on  the  stomach,  and  may  also  be  prescribed 
in  nephritis  and  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  antipyretic  and  an  analgesic,  but  in  this 
country  its  use  is  mainly  as  a  drug  of  the  latter  class.  It  is 
excreted  in  the  urine  partly  unchanged,  partly  as  glycuronic  acid, 
and  partly  as  uramino-antipyrine — 

^Bn  the  urine  which,  on  standing,  becomes  oxidized  and  produces  the 
red  colouring  matter,  rubazonic  acid. 

It  has  been  suggested  that  pyramidon  should  not  be  given  to 
diabetics,  as,  contrary  to  the  general  run  of  antipyrine  derivatives,  it 
increases  nitrogenous  metabolism. 

GENERAL    SUMMARY   OF   THE  PHYSIOLOGICAL 
CHARACTERISTICS  OF  THE  AMMONIA  DERIVATIVES. 

The  three  substances,  antifebrin,  phenacetin,  and  antipyrine 
(phenazone)  may  be  taken  as  representative  of  the  entire  series  of 
synthetic  antipyretics  which  have  just  been  described.  They  are 
not  only  chemically  representative  bodies,  but  therapeutically  they 
are  probably  more  valuable  than  all  the  other  members  of  the 
classes  to  which  they  belong  put  together.  From  the  pharmaco- 
logical point  of  view  they  may  be  considered  as  true  antipyretics; 


CO-N.CeH, 


208  PHYSIOLOGICAL  PROPERTIES 

that  is  to  say,  they  so  influence  the  thermotaxic  centre  that  it 
causes  a  general  cutaneous  vaso-dilatation  to  take  place  during 
pyrexia,  thus  producing  increased  heat-loss  and  a  fall  in  temperature. 
That  they  are  not  mere  general  vaso-dilators  is  shown  by  the  fact 
that  the  deep  vessels  are  not  affected.  This,  a  central  action,  is  very 
different  physiologically  from  the  effect  produced  by  the  external 
application  of  cold,  when  heat-loss  is  increased,  but  the  thermo- 
taxic centre  is  uninfluenced.  In  health,  the  thermotaxic  centre 
maintains  a  certain  fairly  constant  ratio  between  heat-production 
and  heat-loss ;  in  pyrexia  this  ratio  is  altered,  and  increased  heat- 
production  does  not  lead  to  a  sufficient  increase  in  heat-loss;  the 
true  antipyretics  so  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  present  the  tendency  is  to 
consider  it  disadvantageous  to  reduce  the  temperature  in  this  way, 
and  the  antipyretic  drugs  are  mainly  used  for  other  purposes. 

The  antipyretic  action  is  a  function  of  the  benzene  nucleus,  for 
it  is  shared  by  such  varied  derivatives  as  phenol,  pyrocatechin, 
salicyl  acid,  aniline  and  its  derivatives,  phenyl  hydrazine,  and  the 
aromatic  semi-carbazides  R.NH.NH.CO.NHg.     Phenyl-azo-imide, 

CeH,N/|| 

•    .     .        ^.  . 

also  acts  as  an  antipyretic  and  analgesic  in  mammals.  Moreover, 
other  ring  formations,  such  as  pyridine  and  quinoline,  have  the  same 
physiological  action. 

On  the  other  hand,  all  ring  compounds  are  not  active  antipyretics. 
The  ethyl  ester  of  a-naphthylazoacetoacetic  acid, 

a-acetone-naphthalide  and  phenanthren,  are  examples  of  inactive 
substances  with  ring  structures. 

The  side-chains  in  the  above-mentioned  compounds  vary  so  much 
that  it  is  clear  that  no  importance  can  be  attached  to  them  as  anti- 
pyretic agents.  Their  function  is  possibly  to  enable  the  molecule  to 
anchor  itself  to  the  cells  in  the  central  nervous  system,  and  for  this 
purpose  the  basic  chains  are  more  suitable  than  the  acid.  Aniline  is 
a  more  powerful  antipyretic  than  phenol,  but  less  powerful  than 
phenylhydrazine ;  the  latter  owes  its  physiological  activity  partly 
to  its  chemical  instability. 

The  second  therapeutic  action  of  these  bodies,  which,  as  has 


OF  AMMONIA   DERIVATIVES  209 

previously  been  noted  is  at  present  the  most  generally  employed,  is 
the  analgesic  and  slightly  hypnotic  powers  which  they  possess. 
This  is  not  solely  due  to  the  benzene  ring,  but  is  apparently  the 
result  of  two  factors,  either  jointly  or  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  ethoxy  group,  which  apparently  accounts  for  the 
hypnotic  effect  in  some  of  the  jo-amino-phenol  derivatives,  whilst  in 
lactophenin  and  some  other  bodies  both  these  factors  are  united. 

The  two  main  groups  may  now  be  considered  in  detail,  as  they 
present  different  points  of  interest  corresponding  to  their  chemical 
structure. 

The  group  of  which  antipyrine  and  pyramidon  are  types  owes  its 
antipyretic  properties  to  the  ring  formation,  which  contains  a 
nitrogen  element.     The  monomethyl  pyrazolon 


CH, 


i 


NH 


CH 


|t  CO— N 


^6^5 


is  not  antipyretic;  in  antipyrine  itself  the  second  methyl  group 
replacing  the  hydrogen  of  the  imido  radical  apparently  therefore 
acts  as  an  anchoring  group. 

The  phenyl  radical  apparently  intensifies  the  action  ;  some  anti- 
pyretic effect  can  be  obtained  without  it;  in  view,  however,  of  the 
known  antipyretic  effect  of  benzene,  the  pyrazolon  ring  might  be 
regarded  as  intensifying  this  by  the  substitution  of  one  of  the 
hydrogen  atoms.  The  introduction  of  the  basic  group  (in  pyra- 
midon) increases  the  reaction.  wo-Pyrazolon  derivatives  are  toxic, 
but  not  antipyretic. 

The  aniline  and  /?arfl-amino-phenol  derivatives  can  be  considered 
together,  as  the  action  depends  on  the  liberation  of  the  latter  in  the 
organism.     Acetyl-jo-amino-acetophenone, 


COCHg 

HCOCH, 


3f 

1;  has  no  antipyretic  action,  because  the  para  group,  COCH3,  prevents 
I  the  formation  of  CgH^OH.NHg.  These  bodies  may  be  regarded  as 
^     designed  to  produce  a  slow  and  gradual  aniline  or  jo-amino-phenol 


210 


PHYSIOLOGICAL  PROPERTIES 


reaction ;  they  are,  as  it  were,  methods  of  dosage.  This  being  so,  it  is 
obvious  that  those  compounds  from  which  the  parent  substance  is 
slowly  evolved  will  be  little  toxic  and  also  less  efficient  as  anti- 
pyretics, whereas  the  powerful  antipyretics  will  always  be  dangerous 
in  practice. 

The  toxic  properties  of  these  substances  may  be  specified  as 
(1)  a  general  action  on  the  central  nervous  system,  and  (2)  a  special 
action  on  the  blood  (disintegration  of  the  red  cells  and  formation 
of  methaemoglobin).  The  general  toxic  action  is  practically  the 
same  for  aniline  and  phenol,  and  differs  in  degree  only  owing  to  the 
fact  that  primary  amines  are  more  active  physiologically  than 
alcohols.  There  is,  however,  no  general  agreement  in  the  relative 
toxicity  of  the  two  series  of  compounds,  though  as  a  general  rule 
those  which  contain  but  one  side-chain  are  the  most  toxic.  The 
length  of  the  side-chains  also  has  a  certain  influence. 

The  following  table  is  given  by  Frankel : — 


Phenol  series. 

Aniline  series. 

Average 

toxic  dose 

in  gms. 

Physiologi- 
cal action. 

Average 

toxic  dose 

in  gms. 

Physiologi- 
cal action. 

Phenol 
Cresol 

.045—055 
.02—035 

convulsions 
and  rigors, 
convulsions 

Aniline 
Toluidine 

.051—52 
•052—089 

convulsions 
and  rigors, 
convulsions 

Anisol 

p>o>m 
.35—40 

and  rigors, 
slight  con- 
vulsions, no 

Methylaniline 

p>m>o 
•37—40 

and  rigora. 
slight  con- 
vulsions, no 

Benzyl 
alcohol 

.17 

rigors, 
no  convul- 
sions, no 

Benzyl 
amine 

.25 -.5 

ngors.  _ 
characteris- 
tic rigors. 

Oxyphenol 

.2—05 
o>p>m 

convulsions 
and  rigors. 

Phenylene- 
diamine 

.015—05 
o>p>m 

no  convul- 
sions, no 

Oxyhenzoic 
acid 

.09—1 

convulsions. 

Amidohenzoic 
acid 

.2 -.6 
o>m>p 

no  con- 
vulsions. 

The  action  as  blood  poisons  is  dependent  on  the  presence  of  the 
basic  group ;  hence  phenylhydrazine  is  more  active  than  aniline  in 
this  respect;  ammonia  and,  still  more,  hydroxylamine  and  hydra- 
zine produce  the  same  effect.  The  substitution  of  the  two  hydrogen 
atoms  of  the  base  does  not  necessarily  modify  this  action. 

Exalgin, 


OF  AMMONIA  DERIVATIVES  211 

acetyl-methyl-phenylhydrazine, 

and  acetyl-ethyl-phenylhydrazine, 

^6^«^^-^\COCH3, 

are  all  active  blood  poisons. 

Even  if  all  the  free  hydrogen  atoms  are  substituted,  as  in  acetyl- 
phenyl-carbazine, 

NC,H, 

\NCOCH3, 

and  acetyl-phenyl-thioearbazine, 

cs/i 

\NCOCH3, 

the  action  on  the  blood  takes  place,  even  with  doses  too  small  to 
have  any  influence  on  the  central  nervous  system. 

With  regard  to  phenacetin,  the  steps  in  its  construction  are  as 
follows : — ^;o-Amido-phenol  is  less  toxic  than  aniline ;  but  it  is 
unstable  and  still  fairly  toxic.  The  introduction  of  an  acyl  group 
into  the  basic  substituent  does  not  render  the  substance  sufficiently 
stable  to  prevent  a  rapid  formation  of  j?-amido-phenol  in  the  body ; 
but  if  in  addition  the  hydrogen  of  the  hydroxyl  group  is  substituted, 
a  useful  combination  can  be  obtained.  All  the  bodies  so  formed 
depend  for  their  action  on  phenetidin  or  jt?-amido-phenol  formation ; 
and,  if  active,  are  characterized  by  the  production  of  the  indol 
reaction  in  the  urine.  If  this  reaction  fails,  the  drug  must  be 
considered  inert.  Bodies,  on  the  other  hand,  which  are  of  the 
nature  of  salts  of  phenetidin,  or  on  which  the  hydrochloric  acid  in 
the  stomach  can  act  so  as  to  produce  a  salt,  are  too  toxic  and  cannot 
be  safely  employed. 

Of  the  many  acyl  substitution  products  of  phenetidin  which  have 
been  introduced  phenacetin  probably  produces  the  maximum  physio- 
logical effect  with  the  minimum  of  toxicity.  The  only  objection 
to  it  is  its  insolubility;  but  when  this  is  overcome,  as  in  lacto- 
phenin,  the  toxicity  is  at  once  increased  owing  to  the  hydrochloride 
of  phenetidin  being  formed  in  the  stomach. 

The  replacement  of  the  hydrogen  of  the  amido  group  in  phene- 
tidin by  an  aromatic  radical  produces  too  stable  a  compound,  with- 

P  2, 


212  PHYSIOLOGICAL  PROPERTIES 

out  physiological  action;  the  substitution  o£  the  hydrogen  of  the 
hydroxyl  group  by  an  aliphatic  acid  produces  too  unstable  a  com- 
pound, with  toxic  action.  If  the  second  hydrogen  atom  of  the  basic 
residue  in  phenacetin  is  replaced  by  an  alkyl  group  a  narcosis 
similar  to  that  produced  by  alcohol  occurs;  an  acid  group  in 
this  place  is  so  easily  detached  that  it  has  no  physiological 
importance. 

Compounds  derived  from  ortho-  or  ;;2d^fl-phenetidin  are  too  toxic 
for  practical  purposes. 


CHAPTEE   XI 

I.  The  Group  of  Urethanes,  Urea  and  Ureides. — Urethane. 
Hedonal.  Hypnotics  derived  from  Urea.  Thio-urea.  Thiosinamine. 
Veronal  hypnotics. 

II.  The  Purine  Group  and  Pilocarpine;.— Diuretics  and  Cardiac 
tonics.  Modification  of  substances  of  Xanthine  type.  Diaphoretics.  Pilo- 
carpine. 

I.  THE  GKOUP  OF  URETHANES,  UBEA,  AND  THE 

UREIDES. 

Carbonic  acid  forms  amides,  which  are  in  all  respects  analogous 
to  those  of  a  dibasic  acid,  thus — 

CO<OH  CO<gH.  cO<gHj^^  CO<SH^ 

f    Carbonic  acid.      Carbamic  acid.  Urethane.  Urea. 

A.  Carbamic  acid  is  unknown  in  the  free  state,  but  its  ammonium 

salt, 

NH. 


CO<j 


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  consequently  less  toxic ;  they 
possess,  moreover,  hypnotic  properties  depending  upon  the  nature 
of  the  organic  radical  replacing  the  hydroxy  1  hydrogen. 

A.    The  Urethanes. 

The  urethanes  are  obtained  by  the  action  of  ammonia  or  the 
substituted  ammonias,  on  the  esters  of  chlor-carbonic  acid^ : 

CO<Sc,h/2NH3  =  CO<gHjj^  +NH,C1 

-        CO<OCA  +  CANH,=  CO<gHCeH.^HCl 

Phenyl  urethane, 
or  Euphorin. 

'  This  method  of  introducing  the  (COOCaHg)  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 
corresponding  alcohol, 

'  Methyl-propyUarbinol.  Methyl-propyl-carbinol- 

urethane.  Hedonal. 


Physiological  Properties. 

Binet  has  found  that  the  physiological  reactivity  of  these  deriva-; 
tives  increases  according  to  the  magnitude  of  the  alcohol  radical. 
The  introduction  of  the  acetyl  group  lowers  the  toxicity  without 
otherwise  altering  the  physiological  action.  In  the  case  of  warm- 
blooded animals,  the  relative  toxicity  of  these  substances  is  as 
follows : — 

p^/NH.COCHg     when  R  =  CH3     1 

^^\o.R  „    R  =  C2H5  1.5 


NH,  when  X  =  CH,  ...  2 


^^\0.X  „      X  =  C,H,  .  .  4 

Urethane,     CO<g^|j^^ 

in  spite  of  the  presence  of  an  amido  group,  has  no  depressant  effect 
on  the  respiratory  centre ;  on  the  contrary,  it  has  some  stimulant 
action,  but  only  in  doses  which  exceed  those  given  therapeutically. 
It  has  no  action  on  blood  pressure  or  on  the  pulse  rate,  and  is 
markedly  diuretic,  like  all  the  urea  derivatives.  Its  hypnotic 
action  is  rapid,  but  not  sufficiently  powerful  for  use  in  cases  where 
there  is  any  pain  or  distress.  Even  in  large  doses  it  does  not 
appear  in  the  urine,  but  is  apparently  converted  into  urea.  Small 
doses  are  said  to  decrease  nitrogenous  metabolism,  whereas  large 
doses  have  a  contrary  effect. 

Di-urethane,  NH(COOC2H5)2^  is  a  more  powerful  narcotic,  owing 
to  the  presence  of  a  second  alkyl  radical. 

Hedonal,    CO<gH|j /CH, 

acts  similarly  to  urethane,  being  narcotic  and  powerfully  diuretic. 
The  dose  is  double  that  of  chloral.  It  has  been  employed  as 
a  preliminary  to  general  anaesthesia  with  chloroform ;  its  absorp- 
tion is  slow,  and  it  must  be  given  at  least  an  hour  before  the 


■^3 


DERIVATIVES   OF  UREA  215 

anaesthetic.  There  are,  however,  other  more  serious  objections  to 
its  practical  employment  in  this  manner, 

B.   Urea  and  its  Derivatives. 

Urea,     CO<NH. 

was  first  synthesized  by  Wohler  in  1828  from  ammonium  «>o-cyanate, 
which  undergoes  an  intra-molecular  transposition  on  the  evaporation 
of  its  aqueous  solution — 

COiN.NH^    -^    CC)<^Nh' 

It  is  found  in  various  animal  fluids,  chiefly  in  the  urine  of  mammals, 
and  may  be  separated  as  the  somewhat  insoluble  nitrate. 

It  may  also  be  prepared  by  the  following  synthetic  processes : — 

1-  C0<g?;H,+NH3  =  CAOH  +  CO<gH. 

Ure  thane. 


2.  CO<Jg^g5^  +  2NH3  =  2C,H50H  +  CO<^g2 

Diethyl-carbonate. 

3.  CO<^J.  jj  +3NH3  =  C,H,OH+NH,Cl  +  CO/55{J= 


Chlorformic  ester. 
Urea  crystallizes  in  long  needles,  or  rhombic  prisms,  which  have 
a  cooling  taste.     It  is  soluble  in  1  part  cold  water,  5  of  alcohol, 
but  almost  insoluble  in  ether.     It  is  decomposed  by  nitrous  acid,  as 
are  all  substances  containing  the  amido  group. 

CO/555I2  +  2HNO3  =  CO<^°g  +  2N2  +  3H,0. 

2 

The  Alkyl  Ureas  may  be  prepared  by  reactions  similar  to  those 
employed  in  the  case  of  urea  itself. 

1.  Mono-alky  1  ureas. 

CO<S?X  +  CANH,  =  CO<^J^^H^  +  CAOH 

Urethane.        Ethyl-amine.  Ethyl  urea. 

2.  Di-alkyl  ureas. 

A.  Unsymmetrical. 

CO<g?X  +  (CA).NH  =  CO<NH.^jj^^^  +  C,H,OH 

Diethyl-amine.  a-Diethyl  urea. 


216  PHYSIOLOGICAL  PROPERTIES 

B.  Symmetrical. 

S.  Diethyl  urea. 

-    C0<ScA+2CANH,  =  C0<NHCA  +  2CA0H 

Chlorformic  ester. 
3.  Tetra-alkyl  urea. 

CO<8&J:  +  2(C.H,),NH  =  C0<N(C,H,),^3C,H,0H 

Tetra-ethyl  urea. 
The  alkyl  ureas  are  crystalline  substances,  with  the  exception  of 
the  tetra  substitution  derivatives,  and  show  the  same  characteristic 
reactions  and  properties  as  urea  itself,  and,  like  it,  form  salts  with 
one  equivalent  of  acid. 

Physiological  Properties. 

Urea  has  but  slight  toxic  properties  for  animals  or  higher  plants. 
It  has  no  action  at  all  on  the  lower  plants.  Its  chief  effect  in  the 
animal  body  is  to  produce  diuresis,  and  it  also  has  a  very  slight 
narcotic  action.  Toxic  doses  (injections  of  j^q  the  total  body- 
weight  in  rabbits)  produce  spasms  and  opisthotonos.  Ammonia 
is  not  set  free  in  the  blood. 

When  the  hydrogen  of  the  amido  group  is  replaced,  it  is  found 
that  the  simple  alkyl  ureas  have  no  narcotic  action;  with  those 
containing  tertiary  alkyl  groups  the  general  characteristic  is 
observed  (see  p.  92),  viz.  that  a  tertiary  system  containing  methyl 
groups,  such  as 


—c^ch! 


is  less  reactive  than  those  containing  ethyl,  such  as 


— C^CHg    tertiary  butyl  or  tertiary  heptyl,  — Cf-CgH. 


NHaH 


(a)  COZ-jq^jj   2    6  3_4  gms,  without  action. 

3  gms.  produce  drowsiness,  but  no   sleep. 

(b)  C0\2^jjQ  H    Inactive  ethylamine  bases  are  apparently  set 

^    ^  free  in  the  body. 


OF  UREA  DERIVATIVES  217 


.CH 


(c)    COC  \ch:  4  gms.  produce  sleep. 


^NH^ 


,NH— C^CH. 


This  is  more  active  than  amylene  hy- 
,/\^^  drate  as  a  hypnotic ;  but  sleep  occurs 
(fi\    CC\/^^  ^^     ^\p  TT   ^^^®^j  owing  to  the  fact  that  this  deriva- 
'         \nH  ^    ^  ^y^Q,  which  is  not  easily  soluble,  takes 

longer  to  decompose. 

yCH^  This  body  passes  into  the  urine 

^Q /^^""-^X^^^  unchanged.     It  is   very  stable, 

\-xTTT     n/njl  \  ^  n  XT  a-nd  has  no  physiological  action. 


w 


-NTTT r/rjH  "^  ^  C  H  ^^^  ^^^  ^^  physiological  action 

>/^2^5  1    gm.  produces  sleep  after  2  hours, 
/  r\  Po/  \r  w  preceded  by  a  period  of  intoxication. 


Urea  Derivative  containing  Bromine. 

The  a-monobrom-2>o-valeryl  urea  has  been  introduced  by  Saam 
under  the  name  of  Bromural — • 

^^\NH.CO.CHBr.CH,(CH3)2. 

It  is  not  easily  soluble  in  cold,  but  dissolves  readily  in  hot  water, 
ether,  alcohol,  and  weak  alkalies;  Saam  thinks  that  the  narcotic 
action  of  this  drug  depends  upon  three  factors.  The  main  hypnotic 
is  the  m-propyl  radical  in  the  valerianic  acid,  but  its  action  is 
intensified,  firstly  by  the  presence  of  the  urea  grouping,  and 
secondly  by  the  bromine  atom.  The  corresponding  chlorine  com- 
pound is  but  slightly  hypnotic,  the  iodine  compound  is  inactive. 
The  lethal  dose  for  rabbits  begins  at  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  respiratory 
failure,  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, 


CS<( 


NH, 
NH. 


is  obtained  by  heating*  ammonium  thio-cyanate  to  170*-180'*  C. 

csiN.NH^  -^   c;s<^nh' 

Many  of  its  reactions  indicate  a  constitution  expressed  by  the 
formula — 

HN  :  C<NH. 

It  causes  slowing  of  the  pulse  and  respiration,  and  brings  about 
general  paralysis  of  central  origin,  cardiac  failure,  and  death  in 
convulsions. 

AUyl-thio-urea         CS<(gg^(.jj^  ^^ .  ^^^ 

Phenyl-thio-urea     CS/^^2^  ^ 
NH, 


Ethyl-thio-urea       CS/^^a^  ^ 


2^^5 


NH. 


Acetyl-thio-urea      CS(^^^^^^^^^^ 


are  actively  toxic,  as  are  also  compounds  in  which  both  amino 
groups  are  substituted  with  different  radicals,  e.g. 

AUyl- phenyl-thio-urea         ^^\NHC  H  '       ^ 

Methyl-ethyl-thio-urea       CS<^^^^^ 

The  symmetrical  compounds,  however,  like  urea  itself,  and 
dimethyl  or  diphenyl  urea  have  only  very  slight  physiological 
action. 

Of  these  bodies,  allyl-thio-urea,  or  Thiosinamine,  is  the  only 
one  of  pharmacological  importance.  In  toxic  doses  it  produces 
narcosis,  death  occurring  with  oedema  of  the  lungs  and  hydrothorax. 
Very  small  doses  excite  the  central  nervous  system,  larger  doses 
depress  it.  Thiosinamine  appears  to  have  a  characteristic  action 
on  organized  scar  tissue.  When  injected  subcutaneously  it  causes 
absorption  and  softening  of  cicatricial  bands  and  adhesions.  This 
action,  however,  does  not  appear  to  be  constant. 


OPEN  AND   CYCLIC   UREIDES  219 

C.    The  Ureides. 

The  ureides  are  the  urea  derivatives  o£  organic  acids,  and  may 
belong  to  one  of  two  groups. 

A.  Those  containing  open  chains,  such  as  acetyl-urea,  previously 
alluded  to, 

pp,/NH.C0CH3 

^^\NH2 
a  substance  which  is  obtained  by  the  action  of  acid  chlorides,  or 
anhydride,  on  urea,  thus  : — 

.NHjH  +  CliCOCHa  /NTTmrH 

C0<  =HCl  +  C0/^^^^^^3 

or  such  a  substance  as  hydantoic  acid, 

p^ /NH.CH2 .  COOH 
^^\NH2 

the  open-chain  ureide  of  glycollic  acid. 

B.  Those  containing  a  ring-shaped  structure  or  cyclic  ureides, 
such  as  hydantoin, 

.NH—CHa 

co<         I 

^NH— CO 

Emil  Fischer  and  J.  v.  Mering  have  prepared  substances  belong- 
ing to  these  groups,  and  considering  the  fact  that  the  hypnotic  action 
appears  to  be  so  largely  dependent  on  the  presence  of  ethyl  groups, 
they  investigated  the  following  :  diethyl-acetyl-urea, 
Co<NH-COCH<C^H, 

belonging  to  the  first  class ;  and  two  derivatives  of  malonyl-urea, 

NH— CO 

Co/  CHjj 

^NH— CO 

belonging  to  the  second. 

These  two  derivatives  are  diethyl-malonyl-urea 

NH— CO 


\h— CO 


220  UREIDES 

and  the  corresponding  dipropyl-malonyl-urea — 

NH— CO 

NH— CO 

They  state  that  of  the  series  investigated  Hhe  three  mentioned 
stand  out  prominently  in  point  of  hypnotic  action  .  .  .  and 
experiments  have  shown  that  diethyl-acetyl-urea  is  about  equal  in 
hypnotic  power  to  sulphonal,  that  dipropyl-malonyl-urea  is  about 
four  times  as  powerful,  but  not  infrequently  has  a  remarkably  pro- 
longed after-effect.  Diethyl-malonyl-urea  stands  midway  between 
these  two,  and  hence  surpasses  in  intensity  of  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  therapeutic  purposes.^ 

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  ethy.late, 


C,H  .CO;OC,H,    H:NH, 

CaH/      ^COlOC^H^   H;NH 


CO 


=  2C,H,OH+(C,H,),-C<(gO-NH^CO. 


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-intestinal  mucosa.  It  is  said 
to  diminish  nitrogenous  metabolism.  The  toxicity  is  low,  9  gms. 
(135  grains)  having  been  taken  in  a  single  dose  without  serious 
results ;  -7  gm.  per  kilogram  body- weight  can  be  given  to  animals 
before  a  direct  toxic  action  occurs. 


PURINE  AND   ITS   DERIVATIVES  221 

11.    THE   PURINE   GROUP. 

The  compounds  of  this  group  are  all  derived  from  the  substance 

purine — 

N==CH 


<i 


H  C— NHv 

II      II  >H 

N— C ^N^ 

This  complex  is  found  in  a  large  number  of  the  products  of  animal 
and  plant  life,  namely,  uric  acid,  xanthine,  guanine,  theobromine 
(found  in  cocoa  beans),  caffeine,  &c. 

Their  nomenclature  is  based  on  the  scheme 

6 
IN — C 


2C    5C--Nv 

I         I        >C8 
8  N — C— N^ 
4     9 


thus:        NH— CO  CH3.N— CO 


.CH3 


.CH3 


CO      C— NH\  CO  C— N< 

I  II  >C0  I      II        >CH 

NH— 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 

CO     C— N<" 

I         II        >CH 
CH3.N C— N^ 

Theobromine  or 
8 : 7-dimethy  1-2 : 6-diketo-purine. 

The  systematic  investigation  of  this  group  was  carried  out  by 
Emil  Fischer  and  his  students,  and  the  following  synthesis  of  uric 
acid  will  give  some  idea  of  the  general  method  adopted. 

1.  Malonic  acid  condenses  with  urea  in  presence  of  phosphorus 
oxychloride  to  give  malonyl-urea,  or  barbituric  acid, 
NHjH    OHjCO  NH— CO 

CO      +        CH2    =     CO     CH2+2H2O 

NHjH    OHiCO  NH— CO 


222  SYNTHESIS   OF  URIC   ACID 

2.  Malonyl-urea  is  converted  into  an  ^^c)-nitroso  derivative  by- 
means  of  nitrous  acid — 

NH— CO 

CO      C:N.OH 

I  I 

NH— CO 

3.  Reduced  with  hydriodic  acid  this  substance  gives  the  corre- 
sponding amido  derivative 

NH— CO 

CO     CH.NH2 

I  I 

NH— CO 

4.  This  amido-barbituric  acid  gives  pseudo-uric  acid  on  treatment 
with  potassium  cyanate — 

NH— CO  NH— CO 

II  I         i 

CO     CH.NH2  +  C0:NH  =  CO     CH— NHCO— NH^ 

NH— CO  NH— CO 

5.  Pseudo-uric  acid  treated  with  dilute  mineral  acids  loses  water 
and  gives  uric  acid — 

NH— CO  NH— CO 

II  II 

CO     C — NH CO  =  CO     C— NH\ 

I         II     I  I         II  >C0  +  H20 

NH— C— iOH     HINH       NH— C— NIT 

Purine  itself  may  be  isolated  by  the  reduction  of  2  : 6  : 8-trichlor- 
purine,  obtained  by  the  action  of  phosphorus  oxychloride  on 
potassium  urate — 

N=C.OH  N=C.C1 

'  y^  i    1 

OH.C    C— N<  +P0C18  =  CI— C     C— NHv 

II     II        >C.OH  II      II  >C.C1 

N— C— N^  N— C — W 

N=CH 

on  reduction   — >     CH  C — NHv 

11     11  >C.H 

N-C W 


SYNTHESIS   OF  THEOPHYLLINE  223 

Theophylline,  which  Kossel  found  in  tea,  may  be  synthesized 
from  dimethyl-urea  in  a  manner  very  similar  to  the  above: — 

1.  CH,— NiH     OHCO  CH3-N— CO 

I  •■ ■  I  I       I 

CO    +        CH„  =  2H2O+  COCH2 

I I  I       I 

CH3 .  NjH     OHjCO  CHg— N— CO 

2.  CHg— N— CO  CH3.N— CO 


CO  CH2  +  HNO2  =  CO  C :  N.OH  +  Rfi 

CHg.N-^CO  CH3.N— CO 

3.  CHg— N— CO  CHg— N— CO 


C0C:N.0H  +  4H    ->  CO  CHNHj 

CHg .  N— CO  CH3— N— CO 

TMs  derivative      CH3 — N — CO 
acted  upon  with  |        I 

CO:NH      =  CO  CH— NH— CO— NH2 


i-, 


CH3— N— CO 

l:3-dimethyl-p8eudo-uric  acid. 

4.  CH3— N— CO  CHg. N— CO 

CO  C— NH — CO  =  H2O+  CO  C— NHv 

I    II I  I    II        >co 

CH3— N— C.jOH    HjNH  CH3.N— C— NH-^ 

1 : 3-Dimethyl  uric  acid,  or 

1 : 3-Dimethyl-2 : 6 : 9-triketo- 

purine. 

5.  When  this  uric  acid  derivative  is  treated  with  chloride  of  phos- 
phorus, and  the  resulting  substance  reduced,  theophylline  is  formed. 

CH3— N— CO  CH3— N— CO 

CO  C-NH.          ^^'             io  C-NHv 
I      II          >co                     I     II  >CC1 

CH, .  N-C— NH-^  CH,— N-C W 


^z 


CH3— N— CO 


reduced  ^^  ^^ 


NHv 
>CH 


CH3 .  N— C  .  N 

Theophylline,  or 
1 : 3-dimethyl-2 : 6-diketo-purine. 


224 


PILOCARPINE 


Pilocarpine  has  been  introduced  into  this  group,  although  it  does 
not  contain  the  purine  complex.  Like  theobromine,  theophylline, 
and  caffeine,  it  contains  a  glyoxalin  ring.  Jaborandi  leaves  contain 
three  alkaloids,  pilocarpine,  pilocarpidine  and  jaborine,  and  the 
most  recent  researches  point  the  following  constitutional  formula 
for  the  first  substance  : — 


C2H5— CH— CH-CH2 


CR 


•N. 


C       CH2    C- 
\y  II  >CH 

O  CH— N^ 

the  presence  of  the  glyoxalin   ring  being   shown  by  the  many 
relationships  pilocarpine  bears  to  the  methylglyoxalin  derivatives. 

Physiological  Beactions  of  Purine  Derivatives. 

Purine  itself 

N=CH 

HC    C— NHv 

II     II  >CH 


N— C 


-N 


acts  on  the  cerebrum  like  the  ammonium  salts,  and  has  a  tendency 
to  produce  convulsions.  It  also  produces  rigidity  of  the  muscles. 
These  actions  it  transmits  to  its  derivatives,  caffeine  and  theo- 
bromine. 


A.    Ozy-derivatives. 


6-Oxy-purine 


NH— CO 

CH     C— NH\ 

II         II 

N C N 


>CH 


(Esrpozantliine,  Sarcine),  has  a  power  of  producing  tetanic  spasms, 

but  no  rigidity;   in  dogs,  it  is  said  to  be  largely  oxidized  into 

allantoine, 

HN— CH— NH 

I  I 

OC  CO 

I        I 

HN— CO     NH2 


OXY-PURINE   DERIVATIVES  225 

This  substance,  however,  is  stated  by  Baldi  to  increase  the 
excitability  of  the  spinal  cord,  and  to  produce  muscular  rigidity 
in  frogs.  Walker  Hall  injected  rabbits  daily  for  two  months  with 
small  doses,  and  found  degenerative  changes  in  the  liver  cells  and 
alterations  in  the  bone  marrow. 

In  man,  hypoxanthine  is  excreted  mainly  as  uric  acid.  It  is  said 
to  act  in  about  six  hours,  producing  increased  reflex  irritability 
and  spontaneous  spasms,  and  then  general  tonic  contractions. 
50-100  mgms.  constitute  a  fatal  dose  for  dogs. 

8-Oxypurine  produces  no  tetanus,  but  only  muscular  rigidity. 
Its  action  is  but  feeble. 

B.    Alkyl  and  Oxyalkyl  Derivatives. 

To  pass  on  to  the  corresponding  methyl  derivatives,  7-methyl- 
purine  acts  more  powerfully  on  the  muscles  than  purine,  but  is 
nevertheless  a  weak  poison.  1  gram  subcutaneously  has  no  action 
on  dogs. 

1 :  7-Dimethy]-6-oxypurine  is  a  tetanizing  agent,  and  also  pro- 
duces rigidity  in  frogs,  but  acts  less  powerfully  than  caffeine. 

7  : 9-Dimethyl-8-oxypurine  produces  both  muscular  rigidity  and 
tonic  convulsions  similarly  to  the  previous  compound,  and  the 
differences  between  the  two  rnonoxypurines,  from  which  they  are 
derived,  are  probably  due  merely  to  differences  in  rate  of  absorption. 

C.    Dioxy  Derivatives. 

6 : 8-Dioxypurine  is  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 

I       II  >CH 

HN— C W 

has  no  marked  diuretic  action,  but  may  produce  haematuria.     It 
has  the  same  action  on  muscle  and  spinal  cord  as  8-oxypurine. 

D.    Dioxy-alkyl  Derivatives. 

The  two  monomethyl-xanthines  act  similarly  to  caffeine  and 
theobromine,  both  on  the  muscles  and  on  the  nervous  system,  but 
are  more  powerful  tonic  convulsants. 


226 


XANTHINE  DERIVATIVES 


Heteroxanthine  (7-niethyl-xanthme)  has  more  paralysing  action 
on  the  cord  than  3-methyl-xanthine,  and  is  generally  more  powerful, 
though  it  does  not  raise  the  reflex  excitability  so  much.  The 
3-methyl-xanthine  is  a  diuretic  for  dogs. 

Theobromine,  3   7-dimethyl-2 :  6^dioxypurine, 


HN— CO  CH, 


o<! 


C— N 


HgC.N— C— N 


>CH, 


is  a  very  powerful  diuretic.  Its  action  on  the  activity  and 
irritability  of  muscle  resembles  that  of  caffeine,  but  it  has  no  vaso- 
constrictor action.  In  toxic  doses  it  produces  more  rigidity,  but  not 
such  severe  convulsions  as  caffeine.  Like  xanthine,  it  has  a  direct 
coagulating  action  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  Theociue, 


CH3N— CO 


NHv 

_>CH, 


CH3,N— C N 

is  g.  more  powerful  diuretic;  it  has  no  action  on  the  heart  or  central 
nervous  system,  but  acts  more  markedly  on  muscle  than  theobro- 
mine. Its  diuretic  effect  is  said  not  to  last  so  long  as  that  of 
theobromine.  In  two  cases  it  produced  gastric  haemorrhage  and 
death ;  this  was  also  observed  experimentally  in  animals. 
Paraxanthine  (1 : 7-dimethyl-2 : 6-dioxypurine), 


CHg^N— CO 


CH, 


CO  C— N 

I      II 
CH,— N— C— N 


>CH, 


lias  a  yet  more  powerful  diuretic  action,  and  also  produces  more 
muscular  rigidity  and  paralysis  than  either  of  the  other  two 
dimethyldioxypurines. 


CAFFEINE  227 

Desozytlieobromine  (3:7-dimethyl-2-oxy-l  :6-dihydropurme), 
NH— CHg 

CO     C— Nv 
I         II        >CH, 
CH3.N C— N^ 

in  large  doses  diminislies  the  urinary  excretion,  but   is   inactive 
otherwise. 

Caffeine  is  l:3:7-trimethyl-xanthine. 


CH^.N— CO 


CH3 


CO  C~Nv 
I      II        >CH, 
CHg.N— C— N^ 

The  diuretic  action  of  this  body  is  less  marked  than  that  of  theo- 
bromine, but  its  action  on  the  nervous  system  and  heart  is  much 
more  pronounced.  On  the  heart  the  drug  acts  both  locally  and 
centrally.  Probably  the  initial  effect  of  a  moderately  large  dose  is 
to  accelerate  and  weaken  the  beat  (local  action);  later,  the  beat 
is  slowed  and  its  force  increased  (vagus  action).  Constriction, 
followed  by  dilatation,  is  the  action  on  the  blood  vessels,  and  is 
also  partly  central  and  partly  local.  The  vaso  dilatation  ceases 
to  occur  after  a  few  doses.  The  diuresis  is  partly  due  to  the  effect 
of  the  drug  on  the  parenchymatous  renal  cells,  and  is  partly 
vasomotor.  The  action  on  the  central  nervous  system  is  also  partly 
a  direct  stimulation  and  partly  the  result  of  improved  blood  supply. 
Large  doses  raise  the  temperature. 

Desoxycaffeine  (1:3: 7-trimethyl-2-oxy-l :  6-dihydropurine), 


CH3. 


r-cH^ 


CH3 


CO  C—Nv 

>CH, 


CH3.N— C— N 

acts  in  large  doses  like  the  corresponding  theobromine  compound  in 
inhibiting  diuresis,  but  it  is  more  toxic,  producing  death  with 
tetanic  convulsions. 

o  1 


223  XANTHINE   DERIVATIVES 

1 : 3 : 9-Triinethyl-xantliiiie, 

CH3 .  N— CO 


CO  C— N, 


CH3.N— C— N 


>CH, 
CH, 


^3 

is  much  less  active  than  caffeine;  it  produces  the  same  muscular 
rigidity,  but  more  paralysis  and  less  convulsions. 

lr3:7:8-Tetramethyl-xanthine  is  very  similar  in  its  action  to 
caffeine. 

Two  methyl  compounds  of  the  insoluble  6 : 8-dioxypurine  are 
known,  namely  i*(?-caffeine  or  l:7;9-trimethyl-6: 8-dioxypurine, 
which  has  a  much  slighter  action  than  caffeine,  and  7 : 8-dimethyl- 
6:8-dioxypurme,  which  acts  very  slightly  also,  in  a  similar  manner 
to  theophylline. 

£.    Trioxy  Derivatives. 

The  next  oxypurine  is  2 : 6 : 8-trioxypurine,  or  uric  acid,  which  is 
inactive.  But  1 : 3 : 7 : 9-tetra-methyl  uric  acid  is  active,  and  produces 
muscular  rigidity,  paralysis,  and  tetanic  convulsions. 

MODIFICATIONS   OF  SUBSTANCES   OF  XANTHINE 

TYPE. 

Theobromine  is  a  powerful  diuretic,  but  its  practical  value  is 
much  diminished  by  the  fact  that  it  is  only  absorbed  with  difl&culty. 
The  formation  of  double  salts  which  are  easily  soluble  is  achieved 
by  means  of  the  combination  of  this  purine  base  with  an  alkali, 
thus : — 

Dinretin  is  a  compound  of  sodium  theobromine  with  sodium 
salicylate  containing  50  per  cent,  theobromine.  The  salicylate  takes 
no  part  in  the  physiological  effect. 

Uropherin  is  a  similar  compound,  lithium  being  substituted  for 
sodium.  This  may  possibly  make  the  absorption  somewhat  more 
rapid,  but  otherwise  has  no  advantage,  as  lithium  is  not  inert  and 
might  even  produce  undesirable  by-effects. 

Agnrin  is  sodium  theobromine  combined  with  sodium  acetate. 

Theobromine  salicylate  is  an  acid  salt,  and  is  also  soluble 
in  water. 


XANTHINE   DERIVATIVES  229 

Theocine  sodium  acetate  is  said  to  be  somewhat  safer  than 
theocine,  which  has  occasionally  produced  serious  by-effects.  It  is 
a  very  powerful  diuretic. 

The  attempts  to  produce  caffeine  derivatives  of  practical  value 
have  not  been  successful. 

Sympherol  is  a  sulphuric  acid  compound  of  caffeine, 


CHg.N— CO 


CR 


CH3 


CO  C— Nv 

.N— C— N^ 


C.SOoOH. 


Its  salts  are  easily  soluble,  but  with  the  disappearance  of  the  action 
on  the  central  nervous  system  the  diuretic  action  vanishes  also ; 
moreover,  they  have  a  very  bitter  taste  and  are  not  stable. 

Chloral  and  caffeine  have  been  combined  in  the  hope  of  neutra- 
lizing the  stimulating  action  of  the  latter,  but  the  drug  so  produced 
has  no  diuretic  action  and  merely  behaves  like  chloral  hydrate. 

Ethoxycaffeine, 


CH3— N— CO 


CHs 


CH3 


CO  C—Nv 

I II  y 

]^__C— N^ 


aoc.H,, 


is  diuretic,  but  also  narcotic. 

Methoxycaffeine  is  inactive. 

The  acyl-amino-caffeines  are  said  to  be  powerful  diuretics  without 
any  action  on  the  central  nervous  system. 

GENERAL  REVIEW  OF  PURINE   DERIVATIVES. 

The  introduction  of  methyl  groups  increases  both  the  diuretic 
effect  of  the  purines  and  also  their  action  on  voluntary  muscle, 
whereas  it  decreases  the  action  on  the  central  nervous  system  and 
the  general  toxic  effect.  The  introduction  of  oxygen  alters  the 
relative  intensity  of  the  various  actions,  but  in  no  regular  manner. 
The  influence  of  a  CO  group  seems  to  vary  according  as  it  is 
placed  between  NCH3  or  NH  groups.  As  a  general  rule  it  produces 
a  reduction  in  toxicity,  but  on  the  other  hand  guanine  is  less  toxic 
than  xanthine^  though  containing  one  CO  group  less — 


230 


REVIEW   OF   PURINE   DERIVATIVES 


HN— CO 

H2N.C     C— NHv 

II     II  >CH     (Guanine) 

N— C N^ 

The  introduction  of  a  hydroxy!  group  into  the  caffeine  molecule 
reduces  it  to  a  physiologically  inactive  body,  probably  owing  to  the 
fact  that  it  is  thus  converted  into  a  substance  which  is  easily 
decomposed  in  the  organism.  The  formation  of  an  ether  with 
methyl  or  ethyl  produces  a  compound  which  at  first  gives  rise  to  no 
symptoms  except  those  of  a  general  intoxication.  Subsequently, 
however,  a  rigidity  resembling  that  produced  by  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 
distinctly  narcotic,  but  diuresis  only  occufs  with  fatal  doses. 

Caffeine-methyl-hydroxide,  which  is  practically  non-toxic. 


CH, .  N— CO 


CH, 


CH. 


CO  C 
N-^0 


N. 
>CH 
—W 

/\ 
CH,  OH 


has  no  diuretic  action,  nor  has  caffeidine. 


CH3NH— CO 


i 


-N 


yCUs 


CH 


CH3NH— C— N^ 
a  decomposition  product  of  caffeine,  though  this  in  large  doses 
produces  muscular  rigidity  and  paralysis  of  central  origin. 

The  diuretic  action  is,  however,  not  attributable  to  the  larger  but 
to  the  smaller  of  the  two  rings  of  which  the  purine  bodies  are 
formed,  and  the  same  is  true  of  the  action  on  the  muscles  and 
central  nervous  system. 

The  pyrimidine  compounds  are  derived  from  a  nucleus  formulated 
thus : — 

N=CH 


I 


HCH 


N—CH 


PILOCARPINE  231 

1 : 3-dimethyl-4 : 5-diainino-2 : 6-dioxypyrimf(iine^    '^  ^^ *'* ^"^ ^^*^^- 
CH3.N— CO                I        Universi: 
II                                    of 
OC    C-NH,                  Toronto 
CH3 .  N— C— NH2  ^— 

is  inactive  until  the  second  (imidazol)  ring  is  formed  by  linking  the 
two  nitrogen  systems  by  the  (CH)  group,  thus — 

C— NHv 

when  theophylline  results. 

The  introduction  of  chlorine,  like  that  of  hydroxyl,  diminishes  the 
action  of  caffeine,  but  the  cyanogen  group  intensifies  it. 


HLOCARPINE. 

The  imidazol  or  glyoxalin  ring, 

CH— NHv 

II  >CH,- 

CH N^ 

is  common  to  the  purine  bodies  and  to  pilocarpine;  for  which 
reason  the  latter  body  is  described  here. 

This  alkaloid,  Cj^^HigNgOg,  gives  on  oxidation  homopilopic  acid, 
a  substance  represented  in  all  probability  by  the  structural  formula — 

C2H5.  CH— CH.CH2COOH 
CO     CHo 

O 

It  is  thought  to  act  as  a  haptophore  group.  If  the  ketone  structure 
of  this  derivative  is  destroyed  by  means  of  alkalis,  the  resulting 
substance, 

C2H5 .  CH CHo .  CHoCOOH 


h 


OOH   CHgOH 


is  physiologically  inert  (Marshall).     This  seems  generally  true  of 


232  PILOCARPINE 

bodies  with  similar  constitution.     The  alkaloid  in  all  probability 
has  a  constitution  expressed  by  the  formula — 

CH3 

an,— CH— CH— CH„c — n. 

II  II  >CH 

CO    CH,  CH— N"^ 


Y 


The  part  played  by  the  glyoxolin  portion  in  producing  the 
characteristic  effects  of  pilocarpine  has  not  been  determined. 

Pilocarpine  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  lastly  it  acts  on  the  post-ganglionic  nerve  fibres  of  the 
oculomotor  nerve  to  the  iris,  producing  myosis.  It  is  thus  the 
physiological  antagonist  of  atropine. 

It  will  thus  be  seen  that,  physiologically,  pilocarpine  acts  very 
similarly  to  muscarine, 

(CH3)3N<(g52-CH(OH)2, 

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  investigations  have  shown  that 
pilocarpine  does  not  contain  a  pyridine  nucleus. 

Isopilocarpine  is  isomeric  with  pilocarpine  and  acts  in  the  same 
way.  It  is  six  times  weaker  in  efficient  doses  and  at  least  twenty 
times  weaker  in  large  doses  (Marshall). 

FUocarpidiue,  which  differs  from  pilocarpine  in  possessing  one 
CHg  group  less,  is  still  weaker  than  pilocarpine. 

Jaboriue  is  apparently  a  condensation  product  of  two  molecules 
of  pilocarpine.    It  possesses  an  atropine-like  action. 


CHAPTER   XII 

The  Alkaloids.  Chemical  and  physiological  introduction.  Method 
of  classification.  General  principles  of  Alkaloidal  action.  The  Pyridine 
group — Coniine,  Nicotine,  and  allied  substances. 

THE  ALKALOIDS. 

The  vegetable  alkaloids  are  a  group  of  substances,  nearly  all 
tertiary  amines,  which  are  specially  abundant  in  the  dicotyledons. 
It  is  seldom  that  one  alkaloid  only  is  present,  as  a  rule  there  are 
many,  and  they  generally  occur  combined  with  the  so-called  plant 
acids — citric,  malic,  and  tannic,  although  a  considerable  number  are 
found  associated  with  peculiar  acids;  the  quinine  alkaloids,  for 
instance,  with  quinic  acid,  the  opium  group  with  meconic  acid,  and  the 
aconitine  with  aconitic  acid.  The  discovery  of  pyridine  in  1846  by 
Anderson  and  of  quinoline  in  the  previous  year  by  Runge,  together 
with  the  elucidation  of  the  constitution  of  these  substances,  was  the 
first  great  step  in  the  investigation  of  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  pyridine  or  its  homologues.  The 
alkaloids,  then,  appear  to  be  derived  from  pyridine  and  quinoline  in 
the  same  way  that  the  aromatic  substances  are  derived  from  benzene. 
With  the  exception  of  pilocarpine,  caffeine,  and  theobromine,  which 
have  been  described  under  the  purine  derivatives,  this  class  of  organic 
derivatives  may  be  defined  as  products  of  plant  life  derived  from 
those  two  substances  or  from  nuclei  closely  related  to  them. 

Before  discussing  the  physiological  properties  of  the  group,  a 
short  account  of  the  chemistry  of  these  ring  complexes  will  be 
given. 

L    PYRIDINE  AND  PIPERIDINE. 

Pyridine,  C5H5N,  and  many  of  its  homologues  can  be  obtained 
from  bone  oil,  and  are  also  found  in  coal  tar. 

Pyridine  itself  shows  great  stability  towards  oxidizing  agents, 
but  its  homologues  behave  in  a  similar  manner  to  those  of  benzene, 
being  converted  on  oxidation  into  acids  which  still  contain  the 
pyridine  nucleus. 


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  ring  contain- 
ing one  nitrogen  atom — 

CH 

CHj^CH     or,  as  it  will  be  written  in  the  f^ 
following  pages 

N  N 


CH 


The  formation  of  pyridine  from  pentamethylenediamine  by  heat- 
ing the  hydrochloride,  and  the  oxidation  of  the  resulting  piperidine 
is  in  agreement  with  this  conception  : — 

/CH2.CH2.NHiH 

1.  CH2<;  i +HC1 

^CHg.CHgjNHij 

=^H,Cl  +  CH4g^-gH,^NH. 

^'  cK™:Zc2:>^H-f  30  =  3H,0  +  CH<^gZOT> 

One  method  used  in  the  synthetic  formation  of  pyridine  deriva- 
tives is  due  to  Hantzch,  and  consists  in  the  condensation  of 
/3-keto  compounds  (such  as  acetoacetic  ester)  with  aldehydes  and 
ammonia. 

An  example  of  this  condensation  is  seen  in  the  following  forma- 
tion of  dihydro-collidine-dicarboxylic  ester  by  the  interaction  of 
acetaidehyde,  ammonia,  and  acetoacetic  ester^— 

CH3 

I 

CH  /,„ 


/0\_      -^     H,0  i 


C^H.OOC.CiH        HiCCOOC^Hs  /\ 


CgHgOOCCff    >C.COOC,H. 


CH3 .  c -^^-^^c.CH3  CH3 .  C  V^CCH 

i      H  NH 

\      1^      \  ->     2H,0 

NH"' 

On    oxidation,   the   dihydro   derivative   yields  the  corresponding 
pyridine  substitution  product,  which  on  saponification  gives  the 


SYNTHESIS   OF  PYRIDINE 


285 


di-carboxylic  acid.    On  heating  with  lime  the  carboxyl  groups  are 
eliminated  and  aiagy-trimethyl-pyridine  results — 


CH3 

Ah 


CHg 

I 

c 


CoH.OOC.Cil^iC.COOC.H,  CJifiOC.c/^ 


'2"5 


III. 


2"^^5 


CH3.CWC.CH3 

NH 


C.COOCoH 


2"5 


CH3.CvyC.CH3 

N 


CH, 


A 

HOOC.c/Nc.COOH 

CH3.CWC.CH3 

N 


CH, 

I 
C 

ch/^.ch 


CH,.C<  JC.CU 


Y 


The  nomenclature  of  the  pyridine  derivatives  will  be  clear  from 
the  following  diagram.  The  first  system  will  be  adopted  in  this 
work : — 


or 


The  pyridine  bases  are  colourless  liquids  with  a  peculiar  odour ; 
they  are  tertiary  amines  and  form  crystalline  salts  with  one 
equivalent  of  acid. 

Oxidizing  agents  do  not,  as  a  rule,  attack  pyridine  itself,  but  its 
homologues,  even  phenyl  pyridine,  are  converted  into  pyridine- 
carboxylic  acids.     Thus — 


a-Methyl-pyridine 


gives 


V 


CH, 


/\ 


N 


a-pyridine- 
rOOH  carboxylic  aeid. 


236 


SYNTHESIS   OF   CONIINE 


Reducing  agents  convert  pyridine  or  its  derivatives  into  hexa- 
hydro-pyridine  or  piperidine, 

CHo 


CH 


CH. 


/\ 


CH„ 


or 


\/ 
NH 


CH. 


NH 


Piperidine  has  an  odour  of  pepper  and  occurs  as  a  salt  of  piperic 
acid  in  pepper  (piperine). 
Coniine,  a-propyl-piperidine, 

/\ 


CHn .  CHo .  CH 


3J 


NH 


found  in  hemlock  seeds,  was  the  first  alkaloid  to  be  synthesized. 
Starting  from  pyridine,  this  was  carried  out  in  the  following 
manner : — 

1.  Pyridine  acted  upon  by  methyl  iodide  gives  an  iodomethylate. 


<Z>''<™' 


and  when  this  substance  is  heated  to  300°  C.  it  undergoes  an  intra- 
molecular change,  characteristic  of  this  type  of  derivative,  and 
gives  a-methyl-pyridine, 


\/CH3 
N 
2.  a-Methyl-pyridine  condenses  at  high  temperature  with  par- 
aldehyde, forming  a-allyl-pyridine — 


LJCH:H2-hOjCH.CH3  =  HgO-hL^CHrCH.CHg. 

N  N 

3.  a-Allyl-pyridine  on  reduction  gives  a-propyl-piperidine,  but 
the  resulting  substance  is  optically  inactive,  whereas  coniine  is 
dextro-TotBtory.  When  the  synthetic  substance  is  crystallized  with 
dexfro-t2iYta.ric  acid,  ^^^^r(9-coniine-tartrate  separates  out  first;  and 
if  this  is  decomposed  with  potash,  coniine,  identical  with  the 
natural  product,  is  formed. 


PYRROL   AND  ITS   DERIVATIVES 


237 


II.    PYRROL  AND  PYRROLIDINE. 

Pyrrol,  C4H5N,  is  a  feebly  basic  body  found  in  coal  tar  and 
bone  oil,  containing  a  four-membered  carbon  chain  united  by  the 
imide  group ;  its  structure  is  represented  by  the  formula — 

CH— CH 


I 


CH    CH 

\/ 

N 

On  reduction  with  hydriodic  acid  and  phosphorus,  it  gives  tetra- 
hydropyrrol  or  pyrrolidine, 


CHg — CHfl 


CHo    CH 


or 


NH 

This  substance  is  a  much  stronger  base  than  pyrrol,  and  may  be 
obtained  from  penta-methylene-diamine  by  heating  its  hydro- 
chloride (in  a  similar  manner  to  piperidine) — 

CH2— CH 

+  HC1  =  NH4CI  +  CH2    CH2 

NH 

From  ^-methyl-pyrrolidine  a  large  number  of  dijfferent  alkaloids 
of  the  atropine-cocaine  group  are  derived.     They  are  substitution 
products  of  a  combined  piperidine  and  pyrrolidine  nucleus — 
CHo CH CHj 

CH„ 


CH 


CH^CHg.NHiH 
CHa.jNHr 


I 
Pyrrolidine  N.CHg  Piperidine  ^^^^ 

^  I  I 

CHo CH CHo 


Ecgonine,  for  instance,  which  is  formed  by  the  action  of  con- 
centrated mineral  acids  or  baryta  water,  on  cocaine,  has  the  follow- 
ing constitutional  formula : — 

-CH.COOH 


CH2— CH- 


N.CHg  CH.OH 


CH2— CH- 


-CIL 


238 


SYNTHESIS   OF   QUINOLINE 


III.    QUINOLINE. 


The  quinoline  bases  occur  with  pyridine  in  bone  oil,  and  their 
method  of  synthesis  and  decomposition  all  point  to  the  constitu- 
tional formula — 

CH     CH 

or 
CH 


CH 


\/ 


^\/ 


CH    N 

That  is,  a  combination  of  benzene  and  pyridine  nuclei.  This  is 
well  shown,  for  instance,  in  its  synthesis  from  (A)  o-toluidine  and 
glyoxal,  (B)  or  the  production  of  a-methyl-quinoline  from  o-amido- 
benzaldehyde  and  acetone : — 

_   .       .    .    OiCH  CH 


y^/CHjHjj 


\/\NiH: OICH 


B. 


CHO 


H,|CH 


V^NjiIg OiCCH 


CH 
^/VCH 


N 


One  general  method  for  the  formation  of  quinoline  and  its 
derivatives,  substituted  in  the  benzene  nucleus,  is  due  to  Skraup, 
and  consists  in  heating  aniline,  glycerin,  and  sulphuric  acid  with 
some  oxidizing  agent,  such  as  arsenic  acid  or  nitrobenzene.  In  all 
probability  acrolein  is  formed  by  the  dehydration  of  glycerin; 
this  combines  with  aniline,  forming  acrolein-aniline,  which  is 
then  oxidized  to  quinoline : — 

1.  CH,OH  CH2 


i 


HOH     - 


CH2OH 


2H2O      = 


CH 

I 
CHO 


2.  CeHfiNiHg + OiHC.CH  ;  CHg  =  H^O  +  CeH^N :  CH.CH  :  CH^ 


PROPERTIES   OF   QUINOLINE 


239 


N 


CH 


+  0  =  H,0  + 


CH 


CH 


N 

/yvcH 


CH 


The  three  replaceable  hydrogen  atoms  in  the  pyridine  nucleus  of 
quinoline  are  designated  by  a,  Pj  y,  those  of  the  benzene  nucleus 
with  1,  2,  3,  4. 

4       y 


1      N 
Another  method  consists  in  numbering  the  former  Py  1^  2^  3  and 
the  latter  B  1-4. 

4       3 

3/\/N2 


B 


Py 


1     N 


The  quinoline  bases  are  liquids  possessing  a  penetrating  odour, 
and,  like  the  pyridines,  are  tertiary  bases.  They  are  but  slightly 
attacked  by  nitric  or  chromic  acids,  but  are  oxidized  by  potassium 
permanganate  to  a-/3-pyridine-dicarboxylic  acids,  the  benzene 
nucleus  being  destroyed  : — 

/\/^  COOH^^ 


N 


cooH\y 

N 

On  reduction  with  zinc  and  hydrochloric  acid,  the  pyridine  nucleus 
takes  up  four  hydrogen  atoms,  giving  tetra-hydro-quinoline, 
CHo 


cc 


or 


NH  NH 

A  considerable  change  in  chemical  characteristics  follows  this 
reduction,  since  the  resulting  substance  behaves  like  a  secondary 
fatty  amine  attached  to  an  aromatic  nucleus. 


240 


ISO-QUINOLINE 


IV.    ISO-QUINOLINE. 

wo-Quinoline,  CgH^N,  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-dicarboxylic  acid,  and 
for  this  reason  and  others  the  following  formula  has  been  assigned 
to  it: — 

CH  COOH 


Oxidation 


CH 


N 


Y 


On  reduction,  it  gives  a  powerful  base,  tetra-hydro-wo-quinoline. 


IV  (A).    QUINAZOLINE  DERIVATIVES. 

Quinazoline  may  be  regarded  as  quinoline,  in  which  a  (CH)  group 
is  replaced  by  a  second  nitrogen  atom  in  the  1 : 3  position  to  the 
one  already  present. 

N  N 

/V^CH  /V^CH 


\/^V^CH 
CH 


^N 


Quinoline.  Quinazoline. 

The  dihydro  derivative  of  this  substance  is  of  interest,  and,  on 
account  of  its  relationship  to  quinoline,  will  be  alluded  to  in  this 
place,  although,  as  far  as  is  known,  the  quinazoline  nucleus  does 
not  appear  in  any  of  the  alkaloids. 

When  o-nitro-benzylchloride  is  acted  upon  by  aniline  the  follow- 
ing reaction  takes  place : — 

/NO,  /NO, 

CeH/  +  CeH.NH,  =  HCl  +  C,H/ 


^CHoCl 


^CH^-NHC^H^. 


The  resulting  substance  readily  gives  a  formyl  derivative  when 
acted  upon  by  formic  acid. 


/NO 


CoH<SH!.NHaH  +H.COOH  =  H,0  +  CA< 


.NOg   CHO 


CH^.N.CeH, 


QUINAZOLINE   DERIVATIVES  241 

On  reduction  the  formyl  compound  gives  phenyl-dihydro-quina- 
zoline — 

.NOo     CHO  /^L^' 


^CH,— N.C«H, 


This  derivative  of  dihydro-quinazoline  was  expected  to  possess  anti- 
pyretic properties,  but  was  found  to  have  only  slight  toxic  action 
and  to  give  rise  to  a  subjective  feeling  of  hunger.  It  was  intro- 
duced into  pharmacy,  either  as  a  free  base  or  as  the  hydrochloride, 
under  the  name  of  Orexiue,  but  owing  to  the  objectionable  taste  of 
these  substances  they  have  been  replaced  by  the  tannate,  a  chalky, 
white,  odourless  and  tasteless  powder,  readily  soluble  in  dilute  hydro- 
chloric acid  and  hence  also  in  the  gastric  juice,  but,  like  the  base 
itself,  insoluble  in  water. 

It  is  said  to  aid  digestion  and  to  increase  the  secretion  of  hydro- 
chloric acid  in  the  stomach ;  it  has,  however,  in  some  cases  proved 
too  irritating  to  the  gastric  mucosa,  and  unless  well  diluted  may 
produce  vomiting. 

Diphenyl-dihydro-quinazoline 

N 

AAc.aH. 


^^: 


N.C,H5 


■■2 

has  no  action,  whereas  the  methyl  derivative 

N 
/\-Ac.CH3 


N.C^H, 


is  a  very  toxic  substance. 


242    MORPHOLINE  AND  PHENANTHRENE 
V.  MORPHOLINE  AND  PHENANTHRENE. 

A.  Knorr  designated  as  morpholine  the  base  whose  constitutional 
formula  is  represented  as  follows  : — 

O 
CHo/NcH. 


NH 

This  compound  is  extremely  interesting,  owing  to  its  relationship 
to  the  opium  alkaloids.  The  objections  to  the  old  method  of 
preparation  from  diethanol-amine  and  sulphuric  acid  are  the  diffi- 
culties experienced  in  obtaining  the  amine  and  also  its  high  price. 

^^VCH^.CH^.OH    -^     ^a^  +  ^^XCHg.CH^/^' 

In  1901,  however,  Marckwald  and  Chain  found  that  it  could  be 
easily  obtained  by  the  following  reactions  : — 

1.  CeH,<(g ^3^^  +  SBrCH^ .  CH^ .  OC.oH,  +  2K0H 

o-Toluene  sulpha-         Brom-ethyl-i3-naphthyl 
mide.  ether. 

=  ^6H4\s02N(CH2 .  CH2 .  OCioH^)^  +  2KBr  +  2H2O 

2.  This  derivative  is  quantitatively  decomposed  by  mineral  acids 
into  toluene,  sulphuric  acid,  j3-naphthol,  and  morpholine. 

^^^Kso'.  N(CH,.  CH, .  0C,„H,),+3H,0 

=  CeH.CHj  +  H,SO,  +  2Ci„H,0H  +  NH/™^  •  CH,\^ 

2  *  2 

B.  Phenanthrene,  Cj^H^q,  occurs,  together  with  anthracene,  in 
coal-tar,  and  its  constitutional  formula  is  represented  as  follows  : — 


< 


N 


^>-<3 


Owing  to  its  intimate  connexion  with  the  opium  alkaloids,  the 
study  of  its  derivatives  has  received  considerable  attention  during 
the  last  few  years. 

Pschorr  and  his  students  have  devised  new  methods  for  its 
synthesis;  Werner  and  Schmidt  have  investigated  the  sulphonic 
acids  and  their  decomposition  products,  the  nitro  and  amido  com- 
pounds, and  also  the  derivatives  of  phenanthraquinone. 


CHARACTERISTICS   OF  THE   ALKALOIDS       243 

Phenanthraquinone  is  obtained  by  the  oxidation  of  the  hydro- 
carbon in  glacial  acetic  acid  with  chromic  acid,  and  has  the  follow- 
ing constitution :  - 

CO  CO 


The   4:5-dinitro   compound  of  this   quinone  readily  gives  the 
corresponding  diamido  derivative, 

CO  CO 


NH, 
from  which  bodies  closely  related  to  morphine  can  be  obtained. 


GENERAL  PHYSIOLOGICAL   CHARACTERISTICS 
OF  THE   ALKALOIDS. 

Of  the  large  number  of  bodies  of  an  alkaloidal  nature  known, 
a  fair  proportion  are  constantly  administered  as  therapeutic  agents. 
Of  these,  however,  by  far  the  greater  number  are  given  in  a  mixed 
form;  that  is,  in  official  tinctures  and  extracts  which  contain  the 
total  alkaloids  to  be  obtained  from  any  given  plant.  The  practical 
therapist  is  therefore,  as  a  rule,  in  ignorance  as  to  the  physiological 
effect  of  the  majority  of  the  substances  with  which  he  is  dealing, 
a  matter  which  would  perhaps  trouble  him  more  were  it  not  for  the 
fact  that  in  most  cases  these  substances  are  present  in  very  small 
quantities,  and  are  thus  to  all  intents  and  purposes  inactive.  When 
we  exclude  those  ^  less  important  *  alkaloids  the  physiological  bear- 
ing of  which  has  not  been  exhaustively  studied,  the  list  becomes 
notably  diminished  in  length;  perhaps  there  are  some  thirty  or 
forty  bodies  of  such  primary  importance  pharmacologically  that 
a  more  or  less  complete  determination  has  been  made  of  their  action 
on  living  organisms.  But  to  only  a  few  of  these  has  it  hitherto  been 
possible  to  assign  a  definite  chemical  position.  Some  are  of  doubtful 
purity,  many  are  only  known  by  their  empirical  formula,  and  thus 
for  our  present  purposes  there  remains  hardly  a  score  of  substances 
which  can  profitably  be  discussed.     These  are  classified  from  the 


344  CLASSIFICATION   OF  ALKALOIDS 

chemical  standpoint  into  five  or  six  groups^  according  to  the 
character  of  the  nitrogen-bearing  ring  from  which  they  are  derived, 
and  the  various  members  of  the  different  groups  exhibit  a  certain 
rough  resemblance  to  each  other  in  their  physiological  action. 
The  groups,  the  parent  substances  of  which  have  been  previously 
described,  are : — 

I.  The  Pyridine  group,  containing  coniine,  nicotine. 

II.  The  Pyrrolidine  group,  containing  cocaine,  atropine, 
hyoscyamine. 

III.  The  Quinoliue  group,  containing  quinine,  cinchonine, 
strychnine,  brueine. 

IV.  The  iso-Qvdnoline  group,  containing  hydras  tine,  narcotine, 
cotarnine,  berberine. 

V.  The  Morpholine  (?)-Phenanthrene  group,  containing  the 
opium  alkaloids,  morphine,  codeine,  thebaine. 

In  the  first  group  are  contained  substances  which  act  mainly  on 
the  peripheral  nervous  system,  though  central  effects  are  also  to  be 
obtained. 

In  the  second  group  certain  somewhat  specialized  actions  are 
observed,  mainly  on  sensory  nerve  endings,  but  here  also  large 
doses  have  an  effect  on  the  central  nervous  system,  especially  the 
higher  cerebral  centres. 

The  third  group  contains  substances  powerfully  toxic  for  living 
protoplasm;  they  have  a  certain  preferential  action  on  the  nerve 
cells  in  the  spinal  cord,  which  is  more  marked  in  some  members  of 
the  group  than  others;  they  have  very  little,  if  any  peripheral 
action. 

In  the  fourth  group  are  a  number  of  bodies  which  do  not  entirely 
differ  in  their  action  from  those  of  the  third  and  fifth  groups ;  they 
have  a  central  action  mainly  on  the  medulla,  but  to  some  extent 
are  also  muscle  poisons. 

In  the  fifth  group  central  action  again  predominates,  and  in  man 
this  action  is  especially  noticeable,  owing  to  the  high  degree  of 
development  which  the  cerebral  centres  attain.  The  members  of 
this  group  have  also  an  action  on  the  cord  resembling  that  of  some 
members  of  the  fourth  group. 

The  production  of  a  large  number  of  artificial  alkaloids,  differing 
in  various  directions  from  those  natural  alkaloids  the  chemical 
constitution  of  which  is  determined,  has  thrown  considerable  light 
on  various  factors  in  the  physiological  action  of  these  bodies.  Thus 
the  position  of   the   substituting   groups  may  be  altered;  their 


b 


THE  NUCLEUS  AND  THE  SUBSTITUTING  GROUPS   245 

constitution  varied  in  many  ways,  or  they  may  be  removed  altogether. 
As  a  rule,  the  main  physiological  action  of  an  alkaloid  can  only  be 
altered  or  destroyed  by  profound  alterations  in  the  atom-groups 
which  constitute  the  central  ring  or  '  nucleus '  of  the  molecule.  The 
functions  of  the  substituents  appear  to  be  mostly  ^haptophore"'; 
that  is,  they  enable  the  central  groups  to  combine  with  the  proto- 
plasm of  certain  cells  and  thus  to  produce  their  proper  effect.  If  they 
are  removed  or  so  modified  as  to  entirely  destroy  their  haptophoric 
power,  the  pharmacological  action  of  the  drug  will  be  correspond- 
ingly altered.  But  on  replacing  or  restoring  the  haptophoric  group, 
the  original  characteristics  will  return,  as  the  central  nucleus  has 
remained  all  the  while  intact.  Thus  the  phenol-hydroxyl  group  in 
morphine  seems  necessary  for  the  manifestation  of  the  narcotic  action, 
forif  the  hydrogen  is  replaced  by  acid  or  alkyl  radicals  this  effect 
can  no  longer  be  obtained  (p.  293);  on  the  other  hand,  the  well- 
known  physiological  differences  between  morphine  and  apomorphine 
are  due  to  correspondingly  radical  changes  in  the  central  part  of 
the  molecule  (p.  301). 

If  the  side-chain  is  extended  to  a  great  extent,  the  physiological 
action  of  the  ring  may  be  lost,  and  the  effect  of  the  alkyl  portion  of 
the  molecule  become  preponderatingly  obvious.  An  example  of  this 
may  be  found  (p.  251)  in  the  pyridine  compounds. 

An  example,  too,  of  the  effect  of  alkyl  substituents  is  well  seen 
in  the  a-keto-piperidine  series  (or  iso-oximes), 

a-Oxy-a-pipecoline 


CH. 


CH 


CH. 


CHa— CHk^CO 
NH 


is  more  active  than  piperidon- 


CH. 


CH, 


/\ 


CH. 


CH. 


NH 


CO 


/S-methyl-hexanone-^50-oxime   is    five    times    as    active   as  the 
a  compound  (experiments  on  mice). 


246 


EFFECT   OF   SUBSTITUTING   GROUPS 


Trimethyl-heptanone-MO-oxime 
CH 


CH 


CHg — CHg 


CH2— CH- 


CH. 


CHgv 

>C0 
-NH^ 


is  much  more  toxic  than  hexanone-wo-oxime,  and  acts  more  power- 
fully on  the  motor  nerve  endings. 

The  two  isomers  of  methyl-propyl-heptanone-i^o-oxime,  namely. 


CK 


CHo— CH— CH. 


CgH^ 


i 


H2— CH— NH 

I 


> 


CO     and 


CH2— CH- 


CH. 


CH2— CH— NH 

in 


Nco 


C3H7  VVXig 

act  very  similarly  to  one  another,  and  differ  from  the  parent  base 
in  producing  less  convulsive  effect  and  more  narcosis ;  they  are  also 
more  powerful  in  the  paralytic  action  on  the  motor  nerve  endings. 
Trimethyl-z^o-propyl-piperidon 

CHo  C/Hq 


.     CH 


CH,— CH 


CH3— CH 


or 


CH, 


CH— CH, 


is  ten  times  as  poisonous  as  piperidon;  the  alkyl  groups  suppress 
the  convulsive  action  and  accentuate  the  paralyzing  action  on  the 
motor  nerve  endings,  which  is  not  very  marked  even  with  fatal 
doses  of  the  parent  substance. 

Certain  points  as  to  the  structure  of  the  central  ring  are  also  of 
importance.  If  the  ring  itself  is  broken,  the  physiological  action 
is  lost.  Examples  of  this  may  be  seen  in  5-amido-valerianic  acid, 
which  by  the  loss  of  water  gives  piperidon 

CH2  CH2 

CH/^CHg  CHo/NcH. 

=  H2O  + 
COjOH  CH^ 

KHiH  KH 


CH,l^ 


\/ 


CO 


OPEN   AND   CLOSED   RINGS  247 

and  ^-y-Amido-butyric  acid  and  a-pyrrolidon, 


CU^ 1CH2  CH. 

I       =  H,0+        ' 

CR\    'COjOH  CH. 


NHiH 


NH 


CH, 
CO 


The  two  bodies  in  which  the  ring  is  not  closed,  are  without  any- 
marked  action,  whereas  the  closed-ring  derivatives  formed  from 
them  by  loss  of  the  elements  of  water  act  like  strychnine  (or 
perhaps  picrotoxin). 

Similarly,  pentamethylene-diamine 


CH,<; 


CH2.CH2.NH, 

CHo.CHo.NH. 


is  not  toxic,  whereas  the  closed-chain  derivative,  piperidine,  formed 
from  it  by  loss  of  ammonia  (see  p.  234),  has  a  definite  toxic  action. 
Metanicotine,  which  has  only  one-tenth  the  toxic  power  of  nicotine, 
may  also  be  cited  as  an  example  (p.  256). 

The  number  of  groups  in  the  ring  influences  the  activity  of  the 
compound,  but  does  not  produce  any  alteration  in  kind.  Piperidine, 
a  six-membered  ring,  is  more  toxic  than  pyrollidine  with  five.  The 
position  of  the  N  atom  in  the  double  benzene-pyridine  ring  does  not 
appear  to  be  of  importance,  thus  quinoline  and  i«(?-quinoline  are 
physiologically  identical. 

On  the  other  hand,  the  replacement  of  a  CH  group  in  benzene 
by  nitrogen  causes  a  marked  difference  in  the  action  of  the 
resulting  compound  and  its  derivatives.  Thus  bases  derived  from 
the  benzene  ring  alone,  aniline  for  example,  are  characterized  by 
their  power  of  reducing  the  body  temperature  and  breaking  up 
the  red  blood  cells,  whereas  pyridine  has  neither  antiseptic  nor 
antipyretic  power.  The  condensation  of  a  benzene  and  pyridine 
ring  (quinoline)  results  in  powerfully  toxic  and  antiseptic  bodies, 
but  the  double  benzene  nuclei,  diphenyl,  phenanthrene,  and  naph- 
thalene, have  no  antipyretic  derivatives.  The  condensation  of  two 
rings  of  the  pyridine  series  (dipyridine,  parapicoline,  &c.)  gives  rise 
to  bodies  resembling  in  their  action  the  natural  alkaloids,  to  which 
they  are  chemically  related. 

Some  idea  of  the  variations  in  action  which  are  conditioned  by 
changes  in  ring-structure  may  be  gained  from  a  study  of  the 
artificial  ring  compounds — the  cyclic  isoximes,  such  as  piperidon. 


248 


ISO-OXIMES  AND  CYCLIC-KETONES 


ketones,  such  as  cycloliexanone,  and  imines,  piperidine.  The  first 
all  contain  the  group  (CO.NH)  in  the  ring;  they  are  the  least 
toxic  o£  the  three  series,  and  have  least  paralysing  action  on  the 
motor  nerve  endings  and  the  central  nervous  system.  They  are 
characterized  by  producing  picrotoxin-like  convulsions,  i.  e.  convul- 
sions dependent  on  excitation  of  bulbar  and  possibly  cortical 
centres,  unaccompanied  by  increased  reflex  irritability.  The  lower 
members  of  the  series  are  the  least  active,  in  the  higher  members 
the  picrotoxin  effects  are  most  marked. 

CH, 
CH,j/\pjj 


11 

CHo     CHo 

11 
CH,    CO 


The  ketones^ 


NH 

Hexanonisoxime. 


CH„ 


more  toxic,  produce  more  paralysis  of  central  origin,  but  no  con- 
vulsions ;  the  imines  are  the  most  toxic  of  all,  and  have  most  action  on 
the  motor  nerve  endings.  In  all  three  series  the  larger  rings  are 
the  more  active. 

The  variation  in  the  selective  action  of  these  compounds  neces- 
sarily implies  variation  in  the  protoplasm  of  the  different  structures 
in  the  body  on  which  they  act,  a  matter  which  has  already  been 
considered  (p.  19).  From  this  point  of  view  the  alkaloids  may  be 
regarded  as  a  number  of  keys,  each  of  which  will  fit  into  certain 
protoplasmic  locks,  but  it  must  also  be  admitted  that  the  locks  are 
often  very  bad  ones,  as  in  many  instances  differently  shaped  keys 
will  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  examples  will  be  seen  under  such  well-defined  actions  as 
local  anaesthesia  and  mydriasis  (p.  260). 

The  alkaloids  are  classed  by  Loew  as  special  poisons,  that  is,  those 
which  do  not  in  sufficiently  strong  dilution  invariably  destroy  proto- 
plasm. They  act  only  on  certain  kinds  of  protoplasm,  e.  g.  that  of 
the  central  nervous  system,  but  do  not  damage  other  kinds  (see  p.  17). 
The  toxic  action  is  merely  an  exaggeration  of  the  pharmacological 
action  of  the  alkaloids  when  used  as  drugs,  the  dosage  being  so 
regulated  that  stimulation  and  not  destruction  is  produced  in  the 
cell  bodies.  It  may,  of  course,  happen  that  with  smaller  doses  the 
toxic  action  of  the  drug  entirely  disappears,  owing  to  the  dilution 
being  too  great  to  affect  those  structures  on  the  disturbance  of 
which  the  fatal  issue  depends.  For  instance,  quinine,  when  given 
in  large  enough  doses  to  destroy  the  malarial  parasite,  does  not 
necessarily  produce  its  specific  effect  on  the  cerebrum. 

We  shall  now  proceed  to  consider  the  various  alkaloids  of  which 
the  chemical  structure  is  known,  adopting  the  classification  previously 
mentioned.  For  practical  convenience,  the  opium  alkaloids  which 
belong  chemically  to  two  groups  have  been  considered  together. 
Hordenine  is  separately  described  (see  p.  303). 

In  order  not  to  interrupt  unduly  the  arrangement  of  the  alkaloids 
on  a  chemical  basis,  a  chapter  has  been  added  in  which  the  various 
synthetic  substitution  products  recently  introduced  into  practice  are 
described.  These,  though  pharmacologically  similar  to  the  alkaloids 
they  are  intended  to  replace,  are  often  very  different  chemically,  and 
hence  it  was  thought  advisable  to  deal  with  them  separately  in  a 
chapter  supplementary  to  the  systematic  account  of  the  alkaloidal 


I.     THE   PYRIDINE  GROUP. 

The  principal  alkaloids  to  be  considered  in  this  group  are  coniine 
and  its  stereoisomer,  methylconiine,  conhydrine  and  its  isomer 
pseudo-conhydrine  (derived  from  hemlock),  nicotine  and  nicoteine 
(from  tobacco),  and  piperine  (from  black  pepper). 

Physiologically  and  chemically  these  bodies  vary  considerably  in 
complexity,  and  it  will  be  well  to  begin  with  the  simplest,  namely 
that  substance  forming  the  chemical  basis  of  that  group,  pyridine. 


250 


PYRIDINE   GROUP 


This,  containing  as  it  does  one  atom  of  tertiary  nitrogen  in  the  ring, 
is  very  inactive ; 

CH 

ch/\ch 


CHk    JCH 
N 
hydration,  which  results  in  the  formation  of  an  imide  group,  produces 
the  much  more  active  body,  piperidine. 


CH 


/\ 


CH. 


^Hg's^yCH^ 
NH 

Pyridine,  which  is  a  liquid  with  a  powerful  and  distinctive  odour, 
if  inhaled,  stimulates  the  fifth  nerve  and  produces  dyspnoea,  then 
slow,  shallow  breathing,  and  eventually  sleep.  In  very  large  doses 
it  paralyses  the  sensorium,  producing  complete  anaesthesia  and 
abolition  of  reflexes,  smaller  doses  may  inhibit  respiration;  on 
stimulation  of  the  vagus  centre  in  dogs  breathing  stops  in  expira- 
tion. Small  doses  act  on  the  heart,  increasing  the  force  and  slowing 
the  rhythm  of  the  beat ;  large  doses  paralyse  the  muscle,  causing 
a  fall  of  blood  pressure,  and  finally  stop  the  heart  altogether.  Doses 
of  1  gram  (15  minims)  per  diem  produce  no  symptoms. 

Piperidine,  and  also  pyroUidine,  which  is  formulated — 


CHg — CHg 


CHg    CH. 


or 


NH 

and  cyclohexamethylene-imine 

CH, 


NH 


CH„ 


CHo     CHq 
CH„    CHo 

\/ 

NH 


have  much  the   same  action,  producing  in   cold-blooded  animals 


PIPERIDINE   DERIVATIVES  251 

a  rise  o£  blood  pressure  and  general  paralysis  of  central  origin.^ 
Large  doses  inhibit  the  heart. 

The  introduction  of  alkyl  side-chains  into  the  pyridine  ring, 
resulting  in  the  formation  of  such  substances  as  ethyl-pyridine 
(lutidine),  a-propyl-pyridine  (collidine),  has  much  the  same  effect 
as  the  addition  of  hydrogen  atoms,  and  with  the  length  of  the  side- 
chains  the  original  pyridine  action  disappears,,  and  an  intoxicating 
effect  on  the  higher  cerebral  centres  becomes  apparent.  There  is  no 
difference  in  kind  between  compounds  in  which  the  side-chain  is 
attached  to  a  carbon  atom  and  those  in  which  the  alkyl  groups 
replace  the  imido-hydrogen  atom  in  the  reduced  piperidine. 

If  both  these  methods  are  combined,  and  alkyl  side-chains  are 
added  to  a  hydrated  pyridine  ring,  a  series  of  bodies  more 
powerful  than  piperidine,  but  acting  in  a  similar  manner,  is 
produced. 

Pipecoline  is  a-methyl-piperidine 


-CH3 
[H 

and  resembles  curare  in  its  action.     It  does  not  inhibit  the  heart. 
Ethyl-piperidine 


C2H5 


NH 


acts  similarly  in  smaller  doses. 

The  addition  of  higher  alkyls  to  the  piperidine  ring  increases  the 
toxicity  of  the  resulting  compounds;  and  though  the  added  atom 
groups  increase  in  arithmetical  progression,  the  toxicity  increases 
to  a  much  greater  degree,  approximately  in  geometrical  pro- 
gression. 

The  higher  members  of  the  series  approach  in  their  physiological 
action  the  lower  members  of  the  quinoline  series,  but  the  lethal 
doses  of  the  former  are  only  about  half  the  size,  and  there  is  more 
tendency  to  death  from  respiratory  failure. 

^  Some  authorities  state  that  the  action  of  piperidine  is  on  the  motor 
nerve  endings  and  that  it  has  no  central  paralysing  effect. 


252  CONIINE 

Coniiue  is  propyl-piperidine — 


' — CHg  •  CHg .  CHg 
NH 

It  is  more  powerful  stilly  though  similar  in  its  action  to  piperi- 
dine.  It  acts  probably  mainly  on  motor  nerve  endings,  producing 
muscular  paralysis.  It  also  raises  the  blood  pressure,  by  local  action 
on  the  peripheral  vessels,  and  slows  the  pulse  by  action  on  the 
vagus  centre  or  terminations;  there  is  also  slight  quickening  of 
respiration,  followed  by  retardation,  an  effect  probably  partly 
central  and  partly  peripheral.  2>o-Propyl-piperidine  has  a  similar 
action  to  coniine,  but  it  has  only  one- third  of  the  toxicity  of  that 
substance. 

iso-Coniine  apparently  acts  like  coniinSi 

^-Methyl-coniine — 


--CH2.CH2.CH. 


The  imide  hydrogen  of  coniine  in  this  compound  is  now  replaced  by 
a  methyl  group;  no  great  physiological  change,  however,  occurs. 
Dimethyl-coniine  is  much  less  toxic.  The  muscular  spasms  occur- 
ring after  coniine  poisoning  are  said  by  some  authors  to  be  absent 
after  methyl-coniine,  which  also  acts  more  specifically  on  the  spinal 
cord.  Its  fatal  dose  is  one-third  less  than  that  of  coniine. 
Conhydrine 

/\  OH 


-CH2 .  CH  .  CH3 


NH 


and  its  isomer,  pseudo-conhydrine,  act  less  powerfully  than  coniine, 
the  proportional  doses  being  -03,  -2,  and  over  -3  grams  per  kilogram 
body-weight  in  guinea-pigs  (Findlay). 

A  series  of  bodies  known  as  Coniceiues,  having  two  atoms  of 
hydrogen  less  than  coniine,  are  of  interest,  as  they  are  thought  to 
illustrate  the  action  of  the  double  bond  (see  p.  50). 


THE   CONICEINES 


253 


y-Coniceine 


CHo/^CH 


CH. 


NH 


C-~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  8-  and  e-coniceine.  5-Coniceine,  which 
may  be  formulated — 

CH 


CH.CHo .  CHo .  CHc 


is  less  active,  owing  possibly  to  the  presence  of  a  tertiary  nitrogen 
atom. 

jS-Coniceine,  which  has  probably  the  structural  formula — 


CH 


CH 


CH. 


CH2WC.C3H, 
NH 

is  less  toxic  than  a-coniceine.    The  latter  is  more  toxic  than  coniine. 

Pipecoline  and  ethyl-piperidine  have  been  previously  mentioned 
(see  p.  251).  The  piperidine  homologues  of  the  composition  C^H^^N, 
that  is  di-methyl  piperidine  and  ethyl-piperidine,  are  termed 
lupetidines,  whereas  the  methyl-ethyl  derivatives  are  called  copelli- 
dines.  These  substances  are  formed  by  the  reduction  of  the  corre- 
sponding homologous  pyridines  with  sodium  and  alcohol. 

The  toxicity  of  these  compounds  increases  approximately  in 
geometrical  progression,  as  their  molecular  weight  increases  in 
arithmetical  progression.  This  holds  good,  however,  only  up  to 
the  iso-hutyl  and  hexyl  derivatives,  which  both  show  a  marked 
decrease  in  toxicity.     The  proportions  are  1:2:4:8:5:4. 

Lupetidine  (a-a'-dimethyl-piperidine)  acts  like  curare ;  it  has  no 
special  cardiac  action,  but  paralyses  respiration.     It  has  a  toxic 


254 


PIPERIDINE   HOMOLOGUES 


action  on  the  red  blood  cells,  producing  vacuolationj  the  central 
nervous  system  is  slightly  affected,  and  there  is  some  local  anaes- 
thetic action. 

/S-Ethyl-piperidine  (j3-lupetidine)  produces  salivation  and  tetanic 
convulsions.  It  is  not  so  toxic  as  /3-propyl-piperidine,  which  it 
otherwise  resembles ;  the  latter,  again,  is  not  so  toxic  as  coniine. 
Propyl-lupetidine,  the  most  powerful  poison  of  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 
cells  so  much  as  the  other  members  of  the  series. 

wo-Butyl-lupetidine  paralyses  the  heart  and  has  a  true  narcotic 
action;  it  also  paralyses  the  motor  nerve  endings.  In  hexyl- 
lupetidine  this  effect  is  but  slightly  observed. 

Copellidine 


I 


.H5- 


/\ 


\/-CH3 
NH 

is  twice  as  toxic  as  lupetidine,  and  acts  principally  on  the  motor 
nerve  endings. 
Piperylalkin, 


Pipecolylalkin, 


NH 

and  methyl-pipecolylalkin, 

A 


N— CHj.CH2.OH 


CHj.CH^OH 


CH^.CHjOH 


N.CH3 

have  been  physiologically  investigated.     The  first  two  produce 
paralysis  of  central  origin,  the  last  appears  to  be  innocuous. 

From  a  consideration  of  these  compounds  it  will  be  seen  that  not 
only  the  size  but  also  the  position  of  the  side-chain  in  relation  to 


NICOTINE 


265 


the  N  in  the  ring  may  influence  physiological  action  —  asymmetrical 
compounds  do  not  behave  quite  similarly  to  the  symmetrical.  As 
a  rule,  too,  though  not  always,  the  alkaloids  in  which  the  sub- 
stituents  are  attached  to  nitrogen  are  more  active  than  those  in 
which  the  groups  are  linked  to  carbon. 
Stilbazoline 

/\ 


NH 


— CH„ .  CH 


'<Z> 


has  little  power  of  exciting  convulsions,  but  is  powerfully  para- 
lysing. The  fatal  dose  is  about  three  times  as  large  as  that  of 
coniine. 

Fiperine,  which  has  a  structural  formula  represented  by 

CO— CHo 


N— CO.CH  :  CH.CH  :  CH 

acts  similarly  to  piperidine,  but  has  less  action  in  contracting  the 
peripheral  arterioles.  This  appears  to  be  due  to  the  attachment  of 
the  acid  radical  to  the  nitrogen  instead  of  one  of  the  carbon  atoms 
in  the  ring. 

Nicotine  has  a  somewhat  more  complicated  molecular  structure, 
and  in  all  probability  is  a-pyridyl-/3-tetrahydro-;i-methyl-pyrrol; 
it  may  be  represented  by  the  following  formula : — 

CH. 


On  oxidation  it  gives  rise  to  j3-pyridine-carboxylic  acid, 

V-COOH 


256 


NICOTINE   DERIVATIVES 


and  is  consequently  a  /3-derivative  of  pyridine;  starting  from 
/S-amido-pyridine,  Pictet  and  Crepieux  have  synthesized  a  base 
showing  all  the  properties  of  the  natural  alkaloid. 

The  action  of  nicotine  closely  resembles  that  of  coniine,  but  it  is 
more  powerful.  If  given  in  doses  not  large  enough  to  be  immedi- 
ately fatal,  nicotine  causes  clonic  and  tonic  convulsions  of  central 
origin,  stimulation  of  the  respiratory  centre,  a  rise  followed  by  a  fall 
of  arterial  blood  pressure,  and  finally  extreme  depression  of  the  whole 
central  nervous  system,  which  ends  in  death.  Nerve  cells  in  the 
peripheral  ganglia  are  paralysed,  hence  after  preliminary  stimulation 
there  is  diminution  in  the  secretory  activity  of  glands.  Small  doses 
slow  the  heart,  larger  doses  render  its  action  rapid  and  irregular. 
This  is  partly  vagal  and  partly  due  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  period  of  vaso-dilatation. 

Ificoteine 

CHo 


N 
/\     ptt/\ 


— CH 


N 


CH 


CHo 


CH 


has  a  similar  but  more  powerful  action  than  nicotine,  apparently 
traceable  to  the  presence  of  the  double  bond,  whereas  oxynicotine, 
obtained  by  the  action  of  hydrogen  peroxide  on  nicotine,  is 
weaker.  Its  constitution  is  that  of  an  aldehyde,  and  in  its  forma- 
tion the  pyrrohdine  ring  is  probably  broken — 

CH, 


NH 

/V_Ch/      CHO 


N 


CH. 


CH. 


Metauicotine,  which  acts  like  nicotine,  is  much  weaker.  A  dose 
nine  times  as  large  is  required  to  produce  the  toxic  symptoms,  and 
is  only  fatal  in  double  the  time.  The  constitution  of  metanicotine 
is  represented  by  the  formula — 


NICOTINE   DERIVATIVES  257 


NH.CH3 


and  it  is  consequently  methyl-^-pyridyl-5-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  bodies  are  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,  which  are 
hydrated  bodies,  raise  the  arterial  pressure  by  constricting  the 
smaller  arteries.  The  marked  action  which  nicotine  has  in  this 
respect  may  be  due  not  only  to  the  presence  of  the  pyrrolidine 
ring,  but  also  to  some  synergetic  action  from  the  pyridine,  which  is 
latent  in  that  compound  and  requires  the  presence  of  extra  hydrogen 
atoms,  or  of  some  substituent  group  to  give  it  actuality. 


CHAPTER    XIII 

The  Alkaloids  (continued).— Pyrrolidine  group— Cocaine,  Atropine, 
Hyoscyamine.  Quinoline  group— Quinine,  Cinchonine,  and  their  substitutes. 
Strychnine  and  Brucine. 

11.    THE   PYRROLIDINE   GROUP. 

The  constitution  of  Cocaine  is  expressed  by  the  formula — 
CHg— CH CH.COOCH3 

N.CH3  CH.O(C6H5CO) 

I  I 

CHg — CH CHg 

and  is  thus  benzoyl-ecgonine-methyl-ester,  the  two  hydrogen  atoms 
in  the  carboxyl  and  hydroxyl  groups  having  been  replaced  by 
methyl  and  benzoyl  respectively. 

The  chief  physiological  properties  of  cocaine  are : — 

1.  It  stimulates  the  vaso-motor  centre  and  partially  paralyses 
the  vagus.  It  also  acts  slightly  as  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-meduUary  centres  is  at 
first  excitant  and  then  profoundly  depressant.  It  thus  causes  death 
by  convulsions  or  paralysis  of  the  respiratory  centre. 

3.  It  causes  peculiar  '  foam-like '  degeneration  and  vacuolation  of 
the  liver  cells,  which  Ehrlich  says  is  quite  characteristic  in  mice. 

4.  It  raises  the  body  temperature. 

5.  It  dilates  the  pupil. 

6.  It  increases  power  of  muscular  work. 

7.  It  produces  local  anaesthesia. 

Cocaine  thus  differs  remarkably  from  its  immediate  chemical 

predecessor,  ecgonine,  in  its  physiological  action. 

This  substance 

CH2— CH CH.COOH 

I  I 

N.CH3  CH.OH 

I  I 

CHj— CH CH2 


ECGONINE   DEKIVATIVES  259 

is  not  a  very  powerful  poison.  Its  main  action  is  to  cause  degenera- 
tion of  the  liver  cells ;  in  large  doses  it  causes  paralysis  and  death. 
The  former  property  (common  to  all  ecgonine  derivatives)  it  trans- 
mits to  cocaine;  it  appears  to  depend  on  the  presence  of  the 
tertiary  nitrogen  atom,  for  if  methyl  iodide,  CH3I,  is  added  to  the 
(N.CH3)  group,  and  an  ammonium  compound  is  formed,  no  liver 
degeneration  occurs. 

Ecgonine  owes  its  feeble  action  partly  to  the  presence  of  the 
carboxyl  group,  which  affords  no  anchoring  facility  for  the  molecule 
to  the  protoplasmic  substance,  and  is  with  difficulty  broken  up  in 
the  organism.  Ecgonine  itself  is  derived  from  two  single  rings, 
w-methyl-pyrrolidine  and  ;2-methyl-piperidine, 

CHo — CHg  CHo CHo 

I  I        I 

N.CH,     and      N.CH,    CH, 

I                            11 
CHg — CHg  CHg CH2 

substances   having  similar  physiological  actions.     They  raise  the 

blood  pressure,  depress  the  peripheral  cardiac  inhibitory  mechanism, 

and  cause  general  paralysis  of  central  origin.     These  actions,  lost 

in  ecgonine,  reappear  in  cocaine,  owing  to  the  substitution  of  the 

alkyl  radical  for  the  hydrogen  in  the  carboxyl  group. 

Benzoyl-ecgonine 

CH2— CH CH.COOH 

I  I 

N.CH3  CH.O(C6H5CO) 

CHg — CH CHg 

is  twenty  times  less  powerful  a  poison  than  cocaine,  owing  to  the 
presence  of  the  COOH  group;  its  action,  moreover,  differs  from 
that  of  cocaine,  and  resembles  that  of  curare.  Whatever  action 
it  has  seems  due  to  the  presence  of  the  benzoyl  group ;  where  this 
is  absent,  as  in  ecgonine-methyl-ester, 

CH2— CH CH.COOCH3 

I  I 

N.CH3   CH.OH 

CH2— CH CH2 

a  similar  diminution  of  toxicity  occurs.  Thus  there  are  two  groups 
of  physiological  effects,  firstly,  the  one  which  may  be  called  the 
generally  toxic  action,  and  secondly,  the  action  on  the  liver  cells, 

s  % 


260  PHYSIOLOGICAL   ACTION 

both  of  which  are    correlated  to  the   chemical  structure   of  the 
molecule.     The  remaining  groups  will  now  be  considered. 

4.  Elevation  of  Temperature.  This  is  quite  a  marked  property, 
and  the  only  substance  which  exhibits  it  in  a  more  powerful  manner 
is  /S-tetrahydro-naphthylamine — 

CHg 

CH.NR 


It  appears  that  its  physiological  effect  is  not  only  similar  but  due 
to  the  same  process  in  the  body,  namely,  increased  heat  production 
by  central  stimulation.  It  does  not  occur  in  animals  under  the 
influence  of  chloral. 

5.  Mydriatic  Action.  This  action  is  due  to  a  stimulating  effect 
on  the  motor  nerves  to  the  dilator  fibres  of  the  iris,  and  thus  cannot 
be  abolished  by  muscarine.  Its  exact  relation  to  the  chemical  struc- 
ture of  the  molecule  of  cocaine  is  not  known,  but  it  appears  to 
be  derived  from  the  ecgonine  ring,  which,  though  not  generally 
mydriatic,  causes  some  dilatation  of  the  pupil  in  cats.  The  benzoyl 
group  is  essential  for  the  appearance  of  this  action.  It  is  probably 
dependent  on  the  structural  arrangement,  which  is  associated  with  the 
rise  of  temperature,  as  )3-tetrahydro-naphthylamine  is  also  mydriatic. 

6.  The  effect  on  muscular  action  which  has  been  attributed, 
apparently  with  accuracy,  to  cocaine,  has  not  been  shown  to  depend 
on  any  special  chemical  groups  contained  in  the  molecule.  It  may, 
perhaps,  be  attributed  partly  to  the  true  stimulant  action  of  cocaine 
on  the  central  nervous  system,  which  is  accompanied  by  a  decrease 
in  nitrogenous  elimination.  A  diminution  in  the  oxidizing  processes 
in  the  body  is  said  to  follow  on  the  administration  of  the  drug. 

7.  By  far  the  most  important  physiological  attribute  of  cocaine 
from  a  practical  point  of  view  is  its  power  of  producing  local 
analgesia  and  anaesthesia.  Not  only  pain  but  all  sensations  are 
affected ;  for  instance,  taste  is  abolished  when  cocaine  is  applied  to 
the  mucous  membrane  of  the  mouth,  and  heat  and  cold  cannot  be  felt. 

The  local  anaesthetic  action  of  cocaine  depends  partly  on  the 
structure  of  the  ecgonine  nucleus,  and  partly  on  the  presence  and 
relative  positions  of  the  two  substituting  groups. 

The  ecgonine  nucleus  is  possibly  the  least  important  factor  in  the 
production  of  anaesthesia,  as  it  has  been  found  that  many  other 


OF   COCAINE  261 

substances,  provided  they  possess  similar  substituents,  can  produce 
this  effect.  Various  theories  have  been  put  forward  to  explain  the 
part  played  by  the  ecgonine  ring,  several  of  which  have  subse- 
quently been  disproved.  The  most  striking  feature  of  ecgonine  is 
its  arrangement  in  a  double  ring,  and  this  suggested  itself  as 
a  causal  factor  in  the  physiological  action  of  cocaine.  However, 
a  substance,  w-methyl-benzoyl-oxy-tetramethyl-piperidin-carboxyl- 
methyl-ester,  is  a  local  anaesthetic,  though  containing  but  a  single 
ring— 


CH2     CH         CH.COOCH3 

CH3— C(CH3)— CH2 

N.CH3   CH.O(C6H5CO) 

|™.    c<g»a 

CH2— CH CHg 

CH3— C(CH3)— CH2 

Cocaine. 

f2-Methyl-benzoyl,  &c. 

In  fact,  it  has  been  found  that  a  large  number  of  substances, 

such  as  phenol,  para-chlorphenolj  picric  acid,  salicyl-methyl-ester, 

phenacetin,    &c.,   have   anaesthetic   or   analgesic   properties.     The 

simplest  body  producing  these    effects    is   the  methyl   ester   of 

benzoic  acid,  C5H4COOCH3.    The  (N.CHg)  group  may  be  replaced 

by  (NH),  the  resulting  product  being  nor-^-ecgonine — 

CH2— CH— CH.COOH 

I    I 
NH  CH.OH 

I     T 

CHg — CH — CHg 

This,  when  benzoyl  and  methyl  groups  are  introduced,  as  in 
ordinary  cocaine,  produces  nor-cocaine,  a  powerful  anaesthetic,  but 
too  toxic  for  practical  purposes — the  toxicity  probably  being  due  to 
the  presence  of  the  imide  group  (NH)'^ 

That  the  ecgonine  ring  has  its  influence  on  the  anaesthetic 
properties  of  cocaine  seems  to  be  shown  by  the  fact  that  certain 
alterations,  not  affecting  the  substituting  groups,  may  be  accompanied 
by  alterations  in  the  anaesthetic  potency  of  cocaine.  Thus  its  con- 
version into  a  quaternary  base  by  the  addition  of  methyl-iodide 
destroys  the  distinctive  cocaine  action,  and  substitutes  a  curare-like 
one  in  its  place. 

cf^^o-Chlor-cocaine  and  meta-mtro-cocsime  have  only  slight 
anaesthetic  properties ;  meta-oxj-cocame  has  no  anaesthetic  action, 
but  is  slightly  toxic,  and  in  large  doses  produces  degeneration  of 
the  liver  cells.     The  meta-ajnido  compound  produces  neither  anaes- 


262  COCAINE  DERIVATIVES 

thesia  nor  destruction  of  liver  cells.  The  latter  property  can, 
however,  be  restored  by  introducing  benzoyl  or  acetyl  into  the 
amido  group,  and  a  powerfully  anaesthetic  body  is  produced  by  this 
means.  By  the  action  of  chlorformic  ester  on  the  amido  derivative, 
cocaine-urethane  is  produced,  a  strong  anaesthetic,  acting  on  the 
liver  characteristically,  and  giving  rise  to  toxic  symptoms — 

CHg— CH CH.COOCH3 

N.CH3   CH.0(C„H5C0) 

I  I 

(COOC2H5)NH— CH — CH CHg 

Cocaine  urethane. 

The  (CH3.COO)  group  is  essential  to  the  action  of  cocaine,  as  acti- 
vating the  inhibitory  carboxyl  group.  It  may  be  replaced  by  other 
acyls. 

Thus  coca-ethyline,  containing  the  (CgHgCOO)  group,  coca- 
propyline  (CgH^COO),  coca-2>o-butyrine,  &c.,  have  been  prepared, 
but  have  no  advantages  over  cocaine  in  practice. 

Benzoyl-ecgonine,  benzoyl-nor-ecgonine,  and  ecgonine  itself, 
have  no  anaesthetic  action. 

By  the  abstraction  of  water  an  anhydride  of  ecgonine  can  be 

formed, 

CH2— CH CH.COOH 

I  I 

N.CH3   CH 

I  II 

CH2— CH CH 

which,  like  ecgonine,  has  no  anaesthetic  action.  Its  ester  is  also 
inactive — 

CH.— CH CH.COOCH3 

II 
N.CH3   CH 

I  II 

CHg— CH CH 

In  the  first  case  the  inactivity  may  be  explained  by  the  presence 
of  the  carboxyl  group.  In  the  second  case  this  explanation  cannot 
hold  good,  and  recourse  must  be  had  to  the  essential  change  in  the 
ecgonine  ring,  and  possibly  to  the  presence  of  the  double  bond. 

The  (CH3.COO)  group  has  also  been  thought  to  exercise  a  specific 
strengthening  effect  on  the  physiological  action.     This  view  may 


TROPINONE   DERIVATIVE 


263 


be  supported  by  the  fact  that  laevo-rot&tory  benzoyl-ecgonine-nitrile, 
though  anaesthetic,  is  comparatively  weak  in  its  action — 

-CH.CN 


CHg— CH- 


N.CH3  CH.0(CeH5C0) 


CHo— CH- 


CH, 


As  against  this  are  the  facts  that  the  benzoyl  ester  of  pseudo- 
tropine, 

CHo — CH CHo 


N.CH, 


CH 


.— CH 


OH.CH 


CK 


which  contains  no  (CH3COO)  group,  is  a  powerful  anaesthetic  (though 
tropine-benzoyl-ester  is  a  weak  one),  while  the  methylated  benzoyl 
ester  of  a-cocaine  (an  isomeric  body  obtained  from  tropinone)  has 
no  anaesthetic  action. 

OH 
.CN 


CH,— CH CO 


CH.— CH- 


CH2 

I 
N.CH, 


CH„— CH- 


HCN 


CR 


CH. 


N.CH, 


\( 


CH. 


Tropinone. 


CH2— CH- 

Tropinone-cyanhydrine. 


CH2— CH- 


CH. 


I 
N.CH, 


CH„— CH- 


(^OH 
^COOH 


CH, 


CH2— CH- 
CH, 


C<^2 


N.CH, 


CH,— CH- 


.COCeH, 
\COOCH, 


-CHo 


a-Ecgonine.  a-Cocaine. 

It  would  be  safer,  therefore,  to  attribute  the  weakening  of  the 
physiological  action  of  the  nitrile  of  laevo-Totaiorj  benzoyl-ecgonine 
to  some  actual  antagonistic  effect  of  the  (CN)'  group,  similar  to 
that  of  the  original  carboxyl. 

The  importance  of  the  benzoyl  group  is  shown  by  the  fact  that 
in  its  absence  no  anaesthetic  effect  occurs,  and  moreover  many 
substances  containing  it,  such  as  benzoyl-tropine,  the  benzoyl 
derivatives  of  morphine,  hydro-cotarnine,  quinine,  and  cinchonine 


264  ANAESTHIOPHORE   GROUP 

are  local  anaesthetics.  In  the  ecgonine  derivatives  it  cannot  act 
without  simultaneous  replacement  of  the  carboxyl  by  a  COOR 
group,  and  the  presence  of  these  two  groups  alone  in  such  a  simple 
substance  as  benzoic  methyl-ester,  CgH^COOCHg,  is  sufficient  to 
produce  local  anaesthesia. 

In  accordance  with  the  nomenclature  of  the  theory  of  dye-stuffs, 
it  is  called  by  Erhlich  the  '  anaesthiophore  ^  group,  while  the 
(N.CHg)  group  he  calls  '  auxotox '  (see  p.  22).  The  former  cannot  be 
replaced  by  any  acid  of  the  aliphatic  series;  and  if  replaced  by 
another  aromatic  acid,  the  anaesthetic  effects  are  either  abolished 
or  much  diminished. 

Phenylacetyl  (CgHgCHgCO)  ecgonine  has  a  slight  anaesthetic 
action. 

Again,  atropine  has  slight  anaesthetic  properties.  This  is  a 
compound  of  tropeine  with  tropic  acid — 

Homatropine,  in  which  tropic  acid  is  replaced  by  mandelic  acid, 

has  more  anaesthetic  action. 

Benzoyl  tropine,  where  benzoic  acid,  CgHgCOOH,  replaces  the 
tropic  acid,  is  a  powerful  local  anaesthetic. 

Cocaine  exists  naturally  as  a  Iaevo-Yot2iiorj  body.  A  dextro-Toi2A<)Yy 
cocaine  can  be  prepared  which  only  differs  from  the  ordinary 
cocaine  in  producing  a  more  rapid  and  intense  anaesthesia,  and  one 
which  passes  off  in  a  shorter  time. 

The  general  conclusions  to  be  drawn  from  the  observations  on 
the  relation  between  the  chemical  constitution  and  physiological 
action  of  cocaine  are : — 

(1)  The  action  on  the  central  nervous  system  (including  the  vaso- 
motor effect)  are  due  to  the  pyrrolidine  ring,  from  which  cocaine  is 
originally  derived. 

(2)  The  peculiar  action  on  the  liver  is  a  special  attribute  of 
ecgonine,  and  is  partly  dependent  on  the  presence  of  tertiary 
nitrogen. 

(3)  The  elevation  of  temperature  and  the  peculiar  effect  on 
muscular  energy  cannot  be  traced  to  any  special  chemical  factors. 

(4)  The  mydriatic  effect  also  is  not  yet  accounted  for  in  the 
chemical  structure. 


ATROPINE  265 

(5)  The  anaesthetic  efPect  is  largely  dependent  on  the  presence 
of  the  alkyl  and  benzoyl  radicals,  but  is  also  due  to  the  ecgonine 
ring_,  as  this  cannot  be  materially  altered  without  destroying  or 
diminishing  this  action.  Of  all  these  factors  the  presence  of  the 
benzoyl  group  appears  to  be  the  most  important,  as  numerous  other 
compounds  containing  this  radical  exhibit  a  similar  pharmacological 
effect. 

ATROPINE. 

The  chemical  similarity  between  atropine  and  cocaine  is  accom- 
panied by  a  physiological  similarity  which  is  no  less  remarkable. 
Both  are  esters  combined  witb  bases  which  differ  from  one  another 
merely  in  respect  of  one  carboxyl  group — 

CH2— CH CH2  CH2— CH CH.COOH 


N.CH3    CH.OH 


N.CHg   CH.OH 


CH2— CH CH2  CHg— CH CH2 

Tropine.  Ecgonine. 

Atropine  is  the  ester  of  tropine  and  tropic  acid,  the  latter  body 
containing  a  benzyl  nucleus  and  an  asymmetric  carbon  atom — 

pxr       ^xr/CH^OH 

^A-^^\co6h 

Tropic  acid. 
Thus  atropine  is — 

CHg — CH CHg 


N.CH3    CH.O(CO.CH<;^^^^^j 


'CHpH^ 

CHg — CH CHg 

The  physiological  action  of  atropine  is  complicated;  its  effects 
on  the  organism  depend  largely  on  dosage,  and  divergent  views 
are  still  held  on  the  details  of  its  mode  of  action.  Atropine  acts 
firstly  on  the  central  nervous  system,  producing  (in  large  toxic 
doses)  delirium,  followed  by  profound  depression.  In  small  medi- 
cinal doses  its  action  on  the  cerebrum  is  generally  not  noticeable. 
Toxic  doses  also  raise  the  temperature,  sometimes  to  a  very  con- 
siderable extent.  Its  peripheral  action  paralyses  the  terminations 
of  the  nerves  to  secretory  glands  and  unstriped  muscle  (including 
the  sphincter  iridis  in  mammals) ;  it  has  some  action  on  sensory 
nerve  endings,  but  on  the  nerves  supplying  striped  muscle  it  has 
practically  no  action.     It  also  paralyses  the  vagus  terminations  to 


266 


ATROPINE  AND   COCAINE 


the  heart.     The   comparison   between  atropine  and  cocaine  may 
thus  be  set  forth  in  tabular  form  : — 


Atropine. 

Cerebral  and  f  (large  doses)      deliriant 
medullary     <  (smaller  doses)  no  sedative  effect 
centres  (  (final  action)  profound  depression 

Cardiac  1 

vagus  > 

terminations  1 

Temperature 

Bloodvessels 


Eye 

Sensory  nerves 

Nerves  to  un- 
striped  muscle 

Nerves  to 
striped  muscle 

Muscle  < 


Nerves  to 
secreting 
glands 

Liver 


raised 

contracted  (central) 
(rise  of  blood  pressure) 

powerful  mydriatic 

slight  local  anaes- 
thetic 

paralysed 

no  action,  except  in  very  large 
doses,  when  they  are  paralysed 

by  large  doses, 

unstriped  muscle  paralysed 
by  small,      „  ,,      stimulated 

striped    muscle,    unaffected 


paralysed 

no  special  action 


Cocaine. 

deliriant 
sedative 
profound  depression 

depressant 

raised 

contracted  (central) 
(rise  of  blood  pressure) 
less  powerful  mydriatic 
powerful  local  anaes- 
thetic 
no  action 

no  action,  except  when 
locally  applied 

possibly      increases 
power  of  action  in 
striped  muscle 

no  action, 'unless  ap- 
plied locally  to 
glands,  when  secre- 
tion is  paralysed 

specific  degeneration 
(mice) 


When  these  actions  are  analysed^  the  first  fact  which  is  brought 
out  is  that  the  general  toxic  action  of  atropine  and  cocaine  is  some- 
what similar.  The  excitation^  followed  by  depression  of  the  cerebral 
and  medullary  centres,  the  rise  of  blood  pressure  and  temperature, 
and  the  inhibitory  action  on  the  vagus  terminations  seem  common 
characteristics  of  the  two  drugs.  The  mydriatic  and  local  anaes- 
thetic actions  difEer  mainly  in  degree. 

The  action  of  atropine  on  unstriped  muscle  is  to  a  certain  extent 
analogous  to  the  action  of  cocaine  on  striped  muscle.  Very  small 
doses  of  atropine  stimulate  involuntary  muscle  fibres  and  increase 
their  conducting  power:  cocaine  taken  internally  has  probably  a 
stimulating  effect  on  voluntary  muscle,  and  here  the  dose  which 
actually  reaches  the  muscle  must  be  very  small. 

The  main  differences  are,  then,  the  characteristic  action  of  atropine 
on  the  nerves  to  unstriped  muscle  and  secreting  glands  (though 
cocaine  is  said  to  act  on  these  glands  when  locally  applied),  and  the 


PHYSIOLOGICAL  ACTION 


267 


no  less  characteristic  action  of  the  ecgonine  derivative  on  the  liver 
cells. 

We  can  now  proceed  to  consider  the  physiological  action  o£  atro- 
pine in  detail. 

(1)  Central  actions.     Generally  the  action  of  atropine  on  the 

higher  cerebral  centres  and  also  on  those  in  the  medulla  is  primarily 

one  of  stimulation,  followed  eventually  by  depression.     This  action 

may  be  attributed  in  part  to  the  tropine  nucleus,  as,  though  but 

slightly  toxic,  such  action  as  it  has  is  entirely  central.     Tropine 

combined  with  aliphatic  acids  gives  rise  to  a  series  of  tropeines  with 

central  stimulating  action ;  one  of  them,  lactyl-tropeine, 

CHo — CH CHo 

I  I 

N.CHg   CH.0(C0.CH0H.CH3) 

CHg— CH CH 

has  been  used  as  a  cardiac  stimulant. 

Cinnamic  acid  produces  a  powerfully  toxic  body, 
CHo — CH CHn 


N.CHg   CH.O(CO.CH:CH.C6H5) 


CH,— CH 


CH 


which  also  only  possesses  a  central  action. 

This  primary  stimulating  action  may  therefore  be  considered  as 
derived  partly  from  the  tropine  ring,  but  it  is  much  intensified  by 
the  addition  of  certain  side-chains.  The  rise  of  blood  pressure  is 
possibly  a  pyrrolidine  effect,  as  in  cocaine,  while  the  rise  of  tem- 
perature, observed  in  both  atropine  and  cocaine,  is  as  yet  incapable 
of  any  satisfactory  correlation  with  their  chemical  structures.  It  is 
remarkable,  however,  that  it  is  frequently  associated  with  a  my- 
driatic effect  of  peripheral  origin. 

(2)  It  is  to  the  peripheral  action  of  atropine  that  the  greatest 
attention  has  been  paid  by  investigators,  owing  to  its  therapeutic 
importance.  Generally,  it  may  be  described  as  involving  depression 
of  the  nerve  endings  to  involuntary  muscle,  secreting  glands,  and 
the  sensorium. 

(i)  Paralysis  of  nerve  endings  to  involuntary  muscle.  It  is 
to  this  power  that  the  important  practical  effect  of  atropine  is  due 
— the  power  of  dilating  the  pupils  and  paralysing  accommodation. 
The  tropine  nucleus  must  be  considered  as  playing  some  small  part 


268  LADENBURG^S    GENERALIZATION 

in  this,  as  in  toxic  doses  it  causes  mydriasis  in  cats.  But  it  is  only 
when  tropine  is  combined  with  certain  aromatic  acids  that  the  full 
effect  is  obtained.  These  aromatic  acids  all  resemble  one  another 
in   containing   alcoholic  hydroxyl.     Thus   the   combinations  with 

tropic  acid  (forming  atropine),      CgHgCH^PQ^xj 
mandelic  acid  (forming  homatropiue),      CgHgCH<^QQTT 

and  atrolactinic  acid  CgHgC^CHg 

\COOH 

are  all  mydriatic,  whilst  those  containing  either  (1)  no  aromatic  acid, 
like  lactyl-,  acetyl-,  or  succinyl-tropeine,  or  (2)  an  aromatic  acid  with- 
out hydroxyl,  like  cinnamic  acid,  CgHgCH :  CH.COOH,  or  (3)  an  aro- 
matic acid  with  hydroxyl  of  the  phenol  type,  like  salicyl-tropeine, 
CHo — CM CHo 

I       I 

N.CH3   CH.O(CO.CeH^.OH) 

CHg — CH CHg 

are  without  mydriatic  action. 

The  influence  of  an  aromatic  acid  containing  alcoholic  hydroxyl 
in  calling  forth  mydriatic  properties  in  the  base  is  not  confined  to 
the  derivatives  of  tropine,  but  also  occurs  in  such  allied  substances 
as  »-methyl-triacetone-alkamine  ^  and  ;i-methyl-vinyl-diacetone- 
alkamine,  of  which  the  mandelic  acid  esters  are  mydriatic,  but  only 
in  one  stereo-isomeric  form. 

The  principle  thus  illustrated,  which  is  known  as  '  Ladenburg's 
generalization^,  may  thus  be  expressed  : — 'Those  tropeines  only  are 
possessed  of  mydriatic  action  which  are  combined  with  an  acid  side- 
chain  possessing  a  benzene  ring  and  an  aliphatic  hydroxyl/ 

Marshall,  Jowett  and  Hann,  and  Jowett  and  Pyman^  have 
shown  that  this  generalization  is  not  absolute.  Thus  terebyl 
tropeine  (in  following  formulae  R  =  tropine  radical), 

(CH3)2:C— CH.CO.R 

I       I 
C     CHo 


X 


*  The  hydrochloride  has  been  introduced  into  medicine  as  euphthalmine 
(see  pp.  306,  316).  *  Trans.  Chem.  Soc,  1900,  1906  and  1907. 


MYDRIATIC  ACTION 


269 


which  contains  neither  a  benzene  ring  nor  aliphatic  hydroxy!,  is 
distinctly  mydriatic,  though  its  action  is  much  weaker  than  that  of 
atropine. 

Phthalide-carboxyl-tropeine, 


which  is  similar  to  homatropine. 


/\ 


\/ 


CH 


<: 


OH 
CO.R 


has  also  marked  mydriatic  action.     On  the  other  hand,  the  lactone 
of  o-carboxyphenyl-glyceryl-tropeine, 


-CH 


CH.CO.R 


)— COO 

which  contains  a  benzene  group  and  alcoholic  hydroxyl,  is  only 
feebly  mydriatic ;  intravenous  injections  are  moderately  active,  but 
not  direct  instillations  into  the  conjunctiva. 

The  relative  position  of  the  benzoyl  and  nitrogen  groups  appears 
to  be  of  importance.  Tropine,  like  ecgonine,  is  a  combination  or 
condensation  of  two  rings,  a  pyrrolidine  and  piperidine.  It  is  to 
the  latter  that  the  side-chains  are  attached  : — 


CH. 


-CH^ 
N.CH, 


CH« 


CHo CHr 


N.CH, 


CH. 


-CH, 

I 
CHs 

I 
-CH. 


CH,— CH- 


CH. 


N.CHg   CH.OR 


2  ^"2 

w-Methyl  piperidine. 


CHg— CH 


-CH, 


n-Methyl  pyrollidine. 

The  radical  E  is  in  the  para  or  y  position  relatively  to  the  nitrogen, 
and  this  is  also  the  case  with  the  alkamines  having  mydriatic  action, 
thus : — 

(CH3),:C CH, 

N.CH,    CH.OR 


(CH3),:C- 


CR 


The  mydriatic  effect  which  is  thus  brought  into  action  by  the 
presence  of  certain  side-chains  is  a  property  inherent  in  the  parent 


270  MYDRIATIC  ACTION 

substance.  Stereo-isomers  are  found  to  behave  difPerently  in 
this  respect.  Tropine  exists,  as  has  already  been  noted,  in  two 
such  forms.  The  second,  pseudo-tropine,  forms  with  mandelic 
acid  an  isomer  of  homatropine  which  has  no  mydriatic  action. 
Moreover,  the  addition  of  methyl  bromide  to  the  nitrogen  group 
enfeebles  the  physiological  action  ^ : — 

CHo CH CHg 

CH3-j<?^^     iH.0(C0.CH<g50H^ 

CHg CH CHg 

It  must  be  remarked  that,  physiologically,  the  effect  of  atropine 
on  the  eye  differs  somewhat  from  that  of  cocaine.  The  effect 
of  cocaine  is  to  stimulate  the  dilator  fibres  supplied  by  the  sym- 
pathetic, and  only  partially  to  paralyse  the  sphincter  fibres  from 
the  oculo-motor  nerve.  There  is  no  action  on  the  ciliary  muscle 
or  on  the  light  reflex.  Atropine,  on  the  other  hand,  certainly 
paralyses  the  sphincter  nerve  fibres  and  the  circular  muscle  fibres  of 
the  iris  themselves ;  it  also  abolishes  the  reaction  for  accommodation 
and  light  by  paralysis  of  the  nerve  terminations  in  the  ciliary 
muscle.  Whether  it  also  stimulates  the  sympathetic  nerve  fibres  is 
a  disputed  point,  and  the  experimental  evidence  has  been  variously 
interpreted.  It  seems  more  in  consonance  with  the  general  physio- 
logical action  of  atropine  to  suppose  that  it  has  no  exciting  influence 
on  the  terminations  of  the  dilator  nerve. 

The  mydriatic  action  of  atropine  is  clearly  only  part  of  its  general 
action  on  the  nerves  to  unstriped  muscle,  and  on  the  unstriped  muscle 
fibres  themselves;  and  though  direct  evidence  as  to  the  chemical 
factors  producing  the  well-known  action  of  atropine  on  the  intes- 
tine, bladder,  &c.,  is  not  forthcoming,  there  is  no  reason  to  suppose 
that  these  factors  are  other  than  those  which  produce  its  effects  on 
the  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  peripheral  effects  of  atropine,  the  secreto-inhibitory  action 
is  antagonized  by  pilocarpine,  it  may  perhaps  be  assumed  to  rest  on 
a  similar  constitutional  basis. 

Atropine  is  optically  inactive ;  hyoscyamine,  its  isomer,  exists  in 
two  forms,  dextro-  and  /aez;o-rotatory.  It  is  possible  that  the  tropine 
nucleus  in  the  isomers  hyoscyamine  and  atropine  is  optically  inactive, 

*  This  substance,  like  homatropine,  acts  more  rapidly  and  for  a  shorter 
time.    This  is  due  to  more  rapid  absorption  and  excretion. 


THE   QUINOLINE  GROUP  271 

and  that  the  isomerism  of  these  substances  depends  only  on  the 
activity  or  inactivity  of  the  tropic  acid  radical  present ;  it  has  been 
suggested  that  in  the  living  plant  only  dextro^  and  /aet?o-hyoscyamine 
occur,  but  that  on  drying  these  combine  to  give  the  inactive  atropine. 
Considerable  difPerences  are  observed  in  the  physiological  action  of 
these  optical  isomers.  In  respect  of  the  excitant  action  on  the 
spinal  cord : — 

^-Hyoscyamine  is  strongest ;  then  atropine  ;  then  /-hyoscyamine. 

On  the  other  hand,  in  respect  of  the  action  on  the  iris,  secreting 
glands,  and  the  vagus,  the  order  is : — 

(1)  /-Hyoscyamine  ;  (2)  atropine  ;  (3)  d^-hyoscyamine. 
The  conclusion  is  that  the  action  of  atropine  depends  on  its  con- 
taining the  two,  /-  and  fi?-hyoscyamine,  each  of  which  exerts  its 
specific  physiological  action. 

(ii)  Paralysis  of  sensory  nerve  endings.  This  is  not  so  marked 
a  property  of  atropine  as  of  cocaine.  Benzoyl  tropine,  which  only 
differs  from  cocaine  in  the  absence  of  the  COOCH3  group,  is  a  local 
anaesthetic,  though  not  so  powerful  as  cocaine.  Its  isomer,  benzoyl 
pseudo-tropine  (tropo-cocaine),  is  a  more  powerful  local  anaesthetic 
than  cocaine.  Aliphatic  esters  of  tropine  have  no  anaesthetic 
properties.  Thus  in  atropine,  as  in  the  substances  which  have  been 
enumerated  when  dealing  with  cocaine,  the  benzoyl  group  seems  to 
be  of  great  importance  in  calling  out  the  anaesthetic  power  of  the 
base. 

III.    THE   QUINOLINE   GROUP. 

The  alkaloids  belonging  to  this  group  form  the  chief  active 
principles  of  cinchona  and  nux  vomica.  The  parent  substance, 
quinoline 


has  an  action  which  somewhat  resembles  that  of  quinine,  as  it  is 
an  antiseptic  and  antipyretic.  It  cannot,  however,  be  used  thera- 
peutically, as  it  provokes  vomiting,  and  even  in  small  doses  is  liable 
to  produce  collapse,  respiratory  disturbances,  and  oedema  of  the 
lungs. 

Qninoline  has  a  marked  antiseptic  action;  it  also  affects  the 


272  QUINOLINE  DERIVATIVES 

metabolic  cell  processes  so  that  the  intake  of  oxygen  is  decreased,  and 
the  amount  o£  energy  produced  is  diminished;  thus  the  heat 
production  is  lowered. 

Compared  with  quinine,  however,  it  is  a  feeble  antipyretic,  with 
little  action  on  the  malarial  parasite ;  in  pneumonia  it  completely 
failed  to  reduce  the  temperature  (Brieger). 

•6-1-0  gram  produces  paralysis  of  voluntary  muscles  and  loss  of 
reflexes  in  rabbits,  and  is  eventually  fatal.  Quinoline  is  not  ex- 
creted as  such,  but  appears  in  the  urine  in  the  form  of  a  body 
precipitable  by  bromine,  stated  by  Donart  to  be  carboxypyridine. 

The  action  of  hydrogen  when  added  to  the  quinoline  molecule  is 
the  same  as  was  noted  with  pyridine. 

Tetrahydro-jo-oxy-quinoline  kills  rabbits  in  two  hours  in  doses  of 
•6  gram ;  a  similar  dose  of  jo-oxy-quinoline  has  hardly  any  effect. 

u<?-Quinoline,  quinoline,  and  pyridine  present  some  remarkable 
analogies.  The  first  two  are  not  only  similar  in  physiological 
action,  but  identically  acting  compounds  may  be  derived  from 
either,  an  important  practical  point  owing  to  the  expensiveness  of 
the  first-named  body.  Hydration  has  a  similar  intensifying  effect 
on  all  three. 

Decahydro-quinoline,  ^^x         r^TT 


CH„  CH       C 


Hg  CH       CHo 
CH2      NH 

is  a  powerful  blood  poison,  even  in  small  doses.  Generally,  quino- 
line and  pyridine  act  more  powerfully  on  the  central  nervous 
system,  and  on  the  heart,  whereas  decahydro-quinoline  and  piperi- 
dine  have  a  more  rapidly  destructive  effect  on  the  red  blood  cells. 
Hexahydro-quinoline,  an  intermediately  placed  body,  more  closely 
resembles  the  non-hydrated  base.  It  has  marked  action  on  the 
heart  and  nervous  system,  and  less  on  the  blood. 

As  a  rule,  the  quinquevalent  nitrogen  derivatives  of  quinoline  and 
«5<?-quinoline  do  not  show  a  curare-like  action,  thus  contrasting  with 
the  corresponding  aniline  derivatives,  and  the  bodies  obtained  from 
the  natural  alkaloids.  The  methyl  iodides  of  both  quinoline  and 
w*o-quinoline,  oxyethyl-quinoline-ammonium  chloride  and  diquino- 
line-dimethyl-sulphate, 


QUINOLINE    DERIVATIVES 


273 


Quinotoxine 


CHg    SO4H  CHg      SO4H 

(a  body  containing  two  quinquevalent  nitrogen  atoms)  are  exceptions, 
and  all  act  like  curare. 


Quinaldine  (a-methyl-quinoline), 


I 


lepidine  (y-methyl-quinoline), 


CHg 

/\y\ 


N 


a-y-dimethyl-quinoline. 


1-tolu-quinoline, 


CH. 


CH3N 


and  3-tolu-quinoline 


CH3/\/\ 


^Y 


have  been  investigated  by  Stockman,  wbo  finds  that  the  physio- 
logical activity  as  regards  the  nervous  system  varies  inversely  with 
the  number  of  substituted  methyl  groups,  but  that  the  relative 
positions  of  the  methyl  and  nitrogen  are  not  of  any  importance. 

T 


274 


KAIEOLINE 


The  introduction  o£  methoxyl  in  the  para  position  in  the  benzene 
nucleus  weakens  the  antipyretic  action  of  quinoline. 
jD-Methoxy-quinoiinCj  or  jo-quinanisol. 


CH3O 


/\/\ 


N 


on  reduction  becomes  Thalline, 


/\/\. 


CII3O 


NH 

which  has  no  specific  action  in  malaria,  is  a  powerful  anti- 
pyretic and  is  also  very  actively  destructive  to  the  red  blood  cells. 
It  produces,  moreover,  necrosis  of  the  renal  papillae,  as  do  tetra- 
hydro-quinoline,  (?r^/^o-thalline,  awa-thalline,  acetyl-thalKne,  and  its 
urea  and  thio-urea  compounds. 

The  introduction  of  an  acid  or  alkyl  radical  into  the  NH  group  of 
tetrahydro-quinoline  does  not  affect  the  physiological  action. 

The  presence  of  OH  groups  in  the  benzene  nucleus  of  the  reduced 
quinoline  compounds  has  the  general  effect  of  accelerating  the  anti- 
pyretic action  and  also  of  rendering  it  more  transitory,  possibly 
owing  to  more  rapid  absorption  and  elimination.  Two  substances 
illustrate  these  points  : — 


I 


Sairolin  A,  or  ;t-ethyl-tetrahydro-quinoline, 


and  Eairolin  B,  or  ;i-methyl-tetrahydro-quinoline 


KAIRINE  275 

(in  the  form  of  sulphates)  are  not  so  rapid  in  action  as  Eairine,  or 
w-ethyl-l-hydroxy-tetrahydro-quinoline — 


These  substances  are  practically  useless,  owing*  to  their  destructive 
action  on  red  blood  cells ;  they  do  not,  however,  act  on  the  kidneys. 
The  introduction  of  a  carboxyl  group  produces  a  powerfully  anti- 
septic substance,  the  sodium  salt  of  which  has  an  action  on  the 
heart  and  arterioles,  raising  the  blood  pressure  and  slowing  the 
pulse — 

?i-methyl-hydroxy-2-earboxy-tetrah3''dro- 

quinoline  (COOR)\y^ 

OHN 

I 
CH3 

It  is  excreted  as  the  corresponding  di-oxy  derivative — 


COOH 


OH  N 


CH3 

Of  all  the  alkaloids  derived  from  bark,  quinine  and  cinchonine 
are  the  only  two  of  which  a  detailed  account  need  be  given. 
Physiologically,  quinine  is  characterized  by  its  action  as  a  proto- 
plasmic poison  j  possibly  it  checks  oxidation  processes  in  the  cell 
(Binz),  and  to  this  may  be  due  its  value  in  protozoic  diseases.  It  also 
poisons  the  leucocytes,  and  in  large  doses  acts  as  a  gastro-intestinal 
irritant.  It  has  a  direct  action  on  the  walls  of  the  blood-vessels  and 
heart ;  in  small  doses  it  quickens  the  pulse  and  slightly  raises  the 
blood  pressure,  but  in  large  doses  it  produces  a  gradual  fall  and 
finally  cardiac  failure.  Some  vaso  dilatation  probably  occurs 
towards  the  end.  The  effect  of  quinine  on  the  uterus  is  analogous 
to  its  action  on  other  muscular  structures ;  that  is,  it  has  a  direct 
action,  but  here  individual  variations  in  reactivity  are  great.    It 


276    CONSTITUTION  OF  QUININE  AND  CINCHONINE 


poisons  the  cells  of  the  nervous  system,  and  the  effects  of  quinine 
on  the  special  senses  must  probably  be  attributed  to  a  direct 
action  on  the  sensory  epithelium.  General  metabolism  is  certainly 
depressed,  as  might  be  expected  from  a  protoplasmic  poison. 
There  is  also  diminished  heat  production  and  probably  increased 
heat  loss. 

Quinine,  C20H24N2O2,  and  Cinchonine,  CigHggNgO,  differ  chemi- 
cally in  that  a  hydrogen  atom  in  cinchonine  is  replaced  in  quinine 
by  oxymethyl;  physiologically,  quinine  is  much  the  more  active. 
Both  consist  of  two  parts,  a  quinoline  ring,  the  existence  of  which 
has  long  been  established,  and  a  residual  part,  the  constitution  of 
which  is  still  a  matter  of  discussion. 

Skraup  gives  the  following  formulae  : — 

CH  CH 


CHg/TXcH.CH :  CHs 

\jtin 


HO.C 


CHo/l\cH.CH:CH. 


CH, 

\|/ 

N 


CH, 


HO.C 


CH,-^"^N 


CH, 


'  Loipon-anteir,  or 
residual  portion 


N 


CH2-/        \ 


N 


Cinchonine. 


OCH, 


> 


Quinine. 

Cinchonine  is  more  toxic  than  cinchonidine,  its  laevo-rotsdjory 
isomer,  and  than  the  two  oxycinchonines  of  Hesse  and  Langlois. 
The  methyl  group,  however,  which  constitutes  the  chemical  differ- 
ence, does  not  in  itself  seem  to  produce  the  typical  quinine  effect ; 
it  may  be  replaced  by  ethyl,  propyl,  or  amyl,  with  an  intensification 
rather  than  a  diminution  of  physiological  action. 

Cupreine,  an  alkaloid  found  in  an  allied  species  of  plant,  the 
remijia,  has  considerable  resemblance  to  quinine  and  cinchonine, 

Cupreine,  C^gHgoNg .  (0H)2 , 
Cinchonine,  C19H21N2 .  OH, 
Quinine,  Ci9H2oN2 .  OH.OCH3, 

quinine  being  methyl-cupreine.^      Cupreine  is  less  active  physio- 
logically   even    than    cinchonine,    and    only    half    as    toxic    as 

^  Schmiedeberg. 


CINCHOTOXINE 


277 


quinine^  but  its  alkyl  substitution  products  are  active,  as  are  the 
homologous  quinine  bodies.  It  thus  appears  that  the  alkyl  groups 
merely  act  as  a  protective  to  the  hydroxyl,  and  the  fact  that  the 
higher  alkyls  are  more  active  than  methyl  may  be  explained  by  the 
relative  difficulty  with  which  the  latter  is  oxidized. 

It  is  thought  that  in  the  organism  part  of  the  cinchonine  is 
oxidized  to  cupreine,  the  introduction  of  OH  in  the  para  position 
being  a  usual  form  of  oxidation  in  the  body,  and  that  thus  the  typical 
quinine  action  is  produced.  The  largeness  of  the  dose  of  cinchonine 
necessary  to  produce  a  marked  effect  is  thought  to  be  due  to  the 
small  amount  of  cupreine  formed.  The  artificial  removal  of  CHg 
from  quinine  does  not  result  in  cupreine,  but  in  an  isomeric  body, 
apoquinine,  though  conversely  it  is  possible  to  produce  quinine 
from  cupreine.  The  small  amount  in  which  the  latter  substance 
occurs  in  nature  prevents  this  being  a  practically  valuable  procedure. 

It  is  not,  however,  now  thought  that  the  specific  quinine  action 
is  due  to  the  quinoline  portion,  but  to  the  residual  portion  of  the 
molecule,  the  so-called  ^  Loipon-Anteil ' ;  and  in  this  portion  certain 
groups  are  considered  to  be  the  principal  factors.  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  rupture  of  the 
ring  complex.  The  product  is  known  as  cinchotoxine,  and  is 
entirely  without  the  physiological  action  of  quinine  j  it  is  very  much 
more  toxic,  and  somewhat  resembles  digitoxin — 


CH 
H,C/1\CH.CH:CH, 

CHo 


HOC 


CHo 


I 

CHa 


-CH,.C,H,N 

Cinchonine. 


CH 
H,C/ \CH.CH :  CH^ 


0:C 


CH. 


CH2 

1/ 
NH 


-CH,.C,HeN 

Cinchotoxine. 


But  it  cannot  be  decided  whether  the  characteristic  effects  of 
quinine  are  lost  owing  to  the  breaking  of  the  ring  or  the  appearance 
of  the  ketone  group  in  place  of  the  alcoholic  hydroxyl. 

The  vinyl  group  is  not  apparently  of  importance  in  determining 
the  general  toxicity,  but  it  is  remarkable  that  quinine  is  the  only 
antipyretic    drug   containing   a  side-chain   with  a  double  bond. 


278  ANTIPYRETIC  ACTION  OF   QUININE 

S.  Frankel  has  synthesized  a  body  (acetylamino-safrol)  resembling 
phenacetin,  but  containing  an  allyl  group,  but  though  it  appeared 
to  reduce  the  temperature  in  experimental  animals,  it  had  no  action 
resembling  that  of  quinine  in  malaria. 

It  must  be  remembered  that  the  so-called  antipyretic  action  of 
quinine  is  to  a  large  extent  due  to  its  toxic  action  on  lower  organ- 
isms, such  as  the  plasmodium  malariae.  It  is  this  action  really 
which  places  it  at  the  head  of  the  list  of  antipyretics.  It  has, 
however,  been  shown  experimentally  to  possess  a  slight  power  of 
reducing  temperature,  apart  from  any  paraciticidal  action.  This  is 
most  probably  a  result  of  diminishing  heat  production  due  to  a  general 
inhibition  of  protein  metabolism  j  in  other  words,  by  a  toxic  action 
on  living  protoplasm. 

It  is,  however,  probable  that  the  double  bond  is  associated  here 
as  elsewhere  with  considerable  physiological  activity.  The  body 
known  as  quitenine,  in  which  vinyl  is  replaced  by  carboxyl, 

CisHgiNaOg— CH  :  CH2      Oxidation      Ci8H2,N202-COOH 

Quinine.  Quitenine. 

has  very  little  action  as  a  protoplasmic  poison,  but  whether  this 
is  due  to  the  presence  of  carboxyl,  the  absence  of  vinyl,  or  both, 
cannot  be  decided.^ 

It  is  clear,  however,  that  the  residual  portion  of  the  quinine  mole- 
cule is  the  one  on  which  its  physiological  action  depends,  and  that 
the  quinoline  portion  merely  acts  as  a  link  which  enables  it  to 
exert  its  specific  action;  in  the  quinoline  portion  the  presence  of 
oxymethyl  in  the  para  position  is  also  essential. 

Quinidine  is  a  ^/(?a;^r(?-rotatory  quinine,  with  a  similar  action  physio- 
logically. It  is  also,  however,  narcotic.  The  numerous  isomers  of 
cinchonine  produce  convulsions. 

Hydroquinine,  in  which  hydrogen  is  introduced  into  the  quinoline 
ring,  is  a  very  poisonous  body,  producing  paralysis  and  inhibiting 
respiration  in  quite  small  doses.  Half  a  gram  subcutaneously  has 
been  fatal  to  an  animal. 

Desoxy-quinine,  a  substance  which  differs  from  quinine  in  con- 
taining no  hydroxyl  in  the  residual  portion,  gives  all  the  reactions 

■•  Hunt,  however,  has  shown  that  quinine  derivatives  in  which  the  vinyl 
group  has  been  altered  to  .CHj.CHg,  .CHOH.CH3,  .CHCI.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  corresponding  substance  can  be  formed  from  cin- 
chonine. 

These  bodies  are  ten  times  more  toxic  than  their  precursors. 
CH  CH 


CH 


/\ 


CH 


CH, 
I 
CHj 

\l/ 

N 


CH.CH  :  CH, 


CHo/1\cH.CH :  CH„ 

0X12 


CH. 


CH 


CH2.C9H5N.OCH3 

Desoxy-quinine. 


CH2 

N 


CH„ 


CH^.C^H^.N 

Desoxy-cinchonine. 


SUBSTITUTES    INTENDED   TO   REPLACE    QUININE. 

Apart  from  the  occurrence  of  the  toxic  symptoms  known  as 
'  cinchonism  \  which  the  administration  of  quinine  may  produce,  this 
drug  has  two  special  drawbacks  in  practice^  its  intensely  bitter  taste 
and  its  relatively  insoluble  character.  Hence  a  number  of  salts  of 
quinine  and  other  compounds  have  been  introduced,  on  the  one  hand 
with  a  view  of  abolishing  the  taste,  and  on  the  other  of  increasing 
the  solubility  of  the  drug.  As  a  matter  of  fact  these  two  aims  are 
not  compatible  with  one  another.  The  only  quinine  compounds 
which  are  tasteless  are  the  insoluble  ones.  In  the  soluble  salts  of 
these  compounds  the  characteristic  bitter  taste  is  restored.  For 
convenience^,  therefore,  quinine  substitutes  will  be  divided  into  two 
classes,  the  insoluble  ones  intended  for  oral  administration,  and  the 
soluble  ones  suitable  for  hypodermic  or  intravenous  injection. 

I.    1x1801111)16  in  Water. 

Among  the  ordinary  salts,  the  tannate,  an  amorphous  powder 
obtained  by  acting  on  the  sulphate  with  a  tannic  acid  solution,  is 
practically  tasteless.  It  is,  however,  uncertain  in  its  action,  and 
is  first  broken  down  in  the  small  intestine.  Esters  formed  from  the 
hydroxy  1  group  in  the  residual  portion  have  also  been  produced. 
Euquinine  is  the  propionic  acid  ester  of  quinine,  is  practically 
tasteless,  and  is  said  not  to  irritate  the  stomach.  A  carbonic  acid 
ester  of  diquinine  is  known  as  Aristoquin.  This  body  is  soluble  in 
dilute  acids,  so  that  it  dissolves  in  the  stomach;  it  is  not  reprecipitated 
in  the  intestine. 

C,H,C00.0C,.H^N20 

Euquinine. 


Aristoquin. 


^6^^\( 


280  QUININE   SUBSTITUTES 

Aristoquin  is   not  so  rapidly  excreted  as  the  hydrocliloride  of 
quinine,  and  its  toxicity  for  man  is  stated  to  be  lower. 
Saloquiniue  is  the  salicylic  acid  ester — 

'OH 
.COOC^oH^sN.O 

It  is  said  to  be  less  active  therapeutically,  and  to  show  un- 
pleasant by-effects  more  frequently.  The  dosage  must,  of  course,  be 
double  that  of  ordinary  quinine.  A  salicylate  of  saloquinine  has 
also  been  produced,  which  is  insoluble,  and  is  intended  to  combine 
the  advantages  of  salicylates  and  quinine  without  their  bitter  taste. 
These  two  compounds  are  soluble  in  dilute  acids,  and  are  conse- 
quently decomposed  in  the  stomach. 

An  t5o-valeryl  ester  of  quinine  has  also  been  synthesized,  but  is 
not  on  the  market.     It  is  similar  to  the  salicyl  compound. 

Quinaphthol  is  )S-naphthol-a-monosulphate  of  quinine — • 

(Ci„H,.0H.S03H).C,„H,,NA 
and  is  a  yellow  powder,  containing  about  42  per  cent,  quinine,  very 
slightly  soluble  in  hot  water  and  alcohol.     It  is  decomposed  in  the 
intestine,  and  is  primarily  intended  as  an  intestinal  antiseptic. 
Qninaphenin  is  quinine-phenetidin-carboxylic  acid — 


C0<; 


NHC,H,.OC,H, 
OC^^H^aN^O 


It  is  a  white,  very  insoluble  powder.  Therapeutically  it  has  no 
advantage,  beyond  that  of  tastelessness,  over  a  mixture  of  the  two 
bodies. 


ZI.    Soluble  in  Water. 

Besides  the  ordinary  salts  of  quinine,  some  of  which  are  suffi- 
ciently soluble  for  hypodermic  injection,  two  bodies  have  been 
introduced  for  this  purpose,  namely,  Quinopyrine  and  Quinine 
Hydrochloro-Carbamide.  The  first  of  these  is  a  compound  of 
quinine  hydrochloride,  and  antipyrine,  and  is  a  white  powder  easily 
soluble  in  water.  It  is  unsuitable  for  internal  administration,  owing 
to  its  toxicity.  The  second  is  a  compound  of  urea  with  quinine 
and  hydrochloric  acid,  soluble  in  one  part  of  water.  Its  disadvantage 
is  that  it  contains  very  little  quinine. 


STRYCHNINE  281 


STRYCHNINE  AND   BRUCINE. 

Our  knowledge  o£  the  chemical  structure  of  these  two  bodies  is 
very  imperfect.  But  little  is  known  as  to  the  nature  of  the  carbon 
rings  of  which  they  are  constructed^  or  as  to  the  parts  played  by  the 
oxygen  and  nitrogen.  It  appears  probable  that  one  nitrogen  is 
situated  in  a  reduced  quinoline  or  indol  ring,  and  that  its  basic 
character  is  modified  by  the  presence  of  a  carboxyl  group.  The 
formula  for  strychnine  will  be  represented  thus : — 

(C,,H,,0)^CO 

^N 

The  physiological  action  of  strycliuine  is  mainly  on  the  cells  of 
the  spinal  cord,  whereby  the  resistance  to  the  translation  of  slight 
sensory  stimuli  into  reflected  muscular  action  is  removed.  The 
evidence  points  to  some  structure  between  the  anterior  motor  cells 
and  the  terminations  of  the  sensory  nerve  fibres  in  the  cord. 
S chafer  has  described  intermediate  cells  in  the  posterior  horns 
which  link  the  pyramidal  tract  with  the  lower  motor  neurons,  and 
which  are  intimately  connected  with  the  sensory  nerve  endings  in 
the  posterior  horns.  Its  action  on  the  medulla  may  be  said  roughly 
to  correspond  to  that  on  the  cord,  while,  with  regard  to  the 
cerebrum,  the  special  senses  appear  to  be  rendered  more  acute, 
though  there  is  no  evidence  to  show  how  this  takes  place.  Light  and 
tactile  impressions,  the  most  easily  tested,  have  been  shown  to  be 
improved  by  small  doses.  The  remaining  actions  of  strychnine, 
though  important  therapeutically,  are  not  of  much  theoretical 
interest,  as  they  depend  either  upon  the  central  action  (e.  g.  vagus 
and  vaso-constrictor  effects),  or  on  the  convulsions  (increased  forma- 
tion of  carbon  dioxide,  and  increased  heat  production).  Of  more 
interest,  from  the  present  point  of  view,  is  the  action  of  strychnine  on 
lower  forms  of  life.  The  higher  animals,  owing  to  the  preponderating 
effect  of  strychnine  on  the  nervous  system,  show  none  of  its  action 
as  a  protoplasmic  poison.  But  on  protozoa  its  action  is  very  similar 
to  that  of  quinine,  to  which  it  is  chemically  related,  and  it  is 
possible  that  its  effects  on  higher  invertebrates  (e.g.  Ascaris)  are 
mainly  due  to  its  toxic  action  on  protoplasm.^ 

^  Shrieder  explains  the  resistance  of  some  ascarides  to  strychnine  as  due 
to  their  closing  their  mouths  when  placed  in  a  solution  of  the  drug,  which 
can  thuB  act  only  through  the  skin. 


282  STRYCHNINE  DERIVATIVES 

Piperidon,  X\ 

IJco 

NH 

which  is  a-keto-piperidine,  is  stated  by  some  authorities  to  have  the 
same  action  on  the  spinal  cord  as  strychnine.  Its  activity  depends, 
as  previously  stated  (see  p.  246),  on  the  closure  of  the  ring ;  at  any 
rate,  5-amino-valerianic  acid,  in  which  carhoxyl  is  of  course  present, 
has  no  action. 

The  question  whether  the  action  of  strychnine  on  the  spinal  cord 
depends  upon  the  presence  of  the  piperidon  group 

60 

NH 

is  complicated  by  the  presence  of  the  second  oxygen  atom  in  the 
strychnine  molecule.  Briefly,  it  may  be  said  that  the  characteristic 
action  depends  on  the  presence  of  bofk  oxygen  atoms ;  removal  of 
either  lessens  the  activity,  removal  of  both  destroys  it. 

Thus  Desoxystrychnino  -^ 

(C,oH,e)^CO 

^N 
is  more  bitter  than  strychnine  but  less  toxic. 
Dihydrostryclinoline  -^ 

(C2oH,e)^CH, 

^N 
has  no  action  on  the  cord. 

Strychnidine  ^N 

(C,,H,,0)^CH, 

^N 
is  bitter,  and  physiologically  stands  between  strychnine  and  desoxy- 
strychnine. 

Strychnoline  ^N 


^N 


is  inactive. 


Electrolytic  reduction  of  strychnine   gives   rise  to  two  bodies 
(Tafel), 


BRUCINB  283 

Tetraliydrostrychnine  ^N 

(C,„H2,0)^CH,0H 

and  strychnidine,  of  which  the  first  is  more  powerful ;  both  produce 
strychnine-like  effect. 

Methyl  strychnine,  a  secondary  base. 


(C.„H,,0)fCO 


and  iso-stTjchma  acid 

(C,oH,,0)^COOH 

act  in  exactly  the  same  way  as  strychnine.  The  latter  is  fatal  to 
frogs  in  doses  of  -0005  gram :  the  former  has  no  bitter  taste ;  some 
authorities  state  that  its  action  is  similar  to  curare. 

The  alkaloid  Bruciue,  which  is  dimethoxy-strychnine, 

has  a  similar  action  to  that  of  strychnine.  It  is,  however,  less 
powerful  and  its  taste  is  less  bitter. 


CHAPTER   XIV 

The  Alkaloids  (coNXii^UED).  tso-quinoline  group  —  Hydrastine, 
Cotarnine,  Berberine.  Morplioline  (?)-Phenanthrene  group  —  Morphine, 
Codeine,  and  Opium  Alkaloids.     Hordenine. 

IV.     i5o-QUINOLINE   GROUP. 

In  this  group  are  contained  a  number  of  alkaloids,  the  therapeutic 
effects  of  which  differ  considerably,  in  degree  if  not  in  kind.  Some 
of  them  are  derived  from  Opium, 

viz.  Papaverine, 
Narcotine, 
Narceine ; 
others  from  Hydrastis  Cannadensis, 
viz.  Hydrastine, 
Berberine. 

The  latter  plant  has  been  extensively  used  in  order  to  arrest 
haemorrhage,  owing  to  its  action  as  a  vaso-constrictor,  and  it  has 
also  been  employed  in  place  of  ergot  to  stimulate  uterine  contrac- 
tions. It  has  thus  very  little  in  common  with  opium  from  the 
therapeutic  point  of  view,  and  it  is  a  curious  fact  that  its  alkaloidal 
principles  should  be  so  closely  related  chemically  to  some  of  those 
found  in  the  last-named  plant. 

Hydrastine j  CgjHgiNOg,  has  the  formula — 

OCHo 


and  differs  from  narcotine  in  possessing  one  methoxyl  group  less. 
Its  physiological  action  is  still  a  matter  of  some  doubt,  especially  as 
regards  its  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  it  is  also  a  direct  muscle  poison  and  a  gastro- 
intestinal irritant.  In  moderate  doses,  it  stimulates  and  then 
paralyses  the  centres  in  the  medulla  and  cord,  and,  after  possibly 
a  short  stage  of  excitation,  depresses  both  voluntary  and  involuntary 
muscle.  Many  authors  assert  that  it  has  a  direct  ecbolic  action. 
In  medicine  its  main  value  lies  in  its  action  on  the  medullary 
centres,  whereby  the  vagus,  vaso-constrictor,  and  respiratory  centres 
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-like  action  is  interesting,  the  latter 
alkaloid  belonging  to  a  group  which  is  chemically  so  closely  related 
(quinoline). 

When  hydrastine  is  decomposed,  water  is  taken  up,  and  two 
bodies,  hydrastinine  and  opianic  acid,  are  produced. 

C,,H,,NOe  +  H,0  =  Ci„H,A  +  C„Hi3NO, 

Hydrastine.  Opianic  acid.    Hydrastinine. 

Opianic  acid  has  the  constitutional  formula 

CHO 


COOH 
OCH3 


Similarly,  narcotine  yields  opianic  acid  and  cotarnine. 

C,3H„N0,  +  H,0  =  C,„H,„0.  +  Ci,H,,NO, 

Narcotine.  Cotarnine. 

Hydrastinine  and  cotarnine  have  very  similar  constitutions — 


CH2  CH3O- 


NH.CH3         o- 


NH.CH, 


!H0  CH^-O^    bHO 

Hydrastinine.  Cotarnine. 


The  position  of  dioxymethylene-  and  methoxy-groups  are  not 
known  with  certainty. 

The  aldehyde  group  CHO,  in  the  formula  for  hydrastinine,  best 
explains  its  physiological  characters,  most  alkaloidal  vaso-con- 
strictors  having  this  group  (cf.  yohimbine,  which,  however,  has  but 
a  slight  effect  on  the  arterioles). 


286  HYDEASTININE 

The  action  of  hydrastinine  differs  markedly  from  that  of  its 
parent  substance.  It  has  no  convulsant  action^  and  it  does  not 
weaken  the  heart ;  on  the  other  hand,  it  is  a  depressant  of  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  raising  the  blood  pressure  is  more 
sustained  owing  to  cardiac  stimulation.  It  is  also  a  mydriatic. 
Death  occurs  owing  to  respiratory  failure.  The  action  of  hydrastine 
on  the  blood  pressure  may  be  regarded  as  part  of  its  strychnine-like 
properties.  Hydrastinine,  on  the  other  hand,  has  a  more  specialized 
power,  and  heightens  the  contractility  of  the  cardiac  muscle.  The 
same  effect,  namely,  a  rise  in  blood  pressure,  is  thus  produced  by 
a  somewhat  different  means  in  the  two  bodies,  and  is  moreover 
much  more  marked  in  hydrastinine.  According  to  the  aldehyde 
formula,  it  contains  the  group  —  NH.CHg.  It  is  thus  a  secondary 
amine,  and  contains  a  hydrogen  atom  replaceable  by  methyl. 
A  pentavalent  body  of  this  kind,  trimethyl-hydrastyl  ammonium 
chloride,  has  been  prepared.  It  has  but  little  vaso-constrictor 
action;  it  produces  a  general  paralysis,  with  an  initial  rise  of  blood 
pressure  followed  by  a  fall.  Death  occurs,  as  with  curare,  from 
paralysis  of  the  respiratory  muscles  (peripheral). 

An  oxidation  product,  hydrastininic  acid. 


CH, 


0CO.NH.CHg 
CO.COOH 


is  physiologically  inactive. 

Opiauic  acid  CHO 

-^COOH 


oc 


oca 

CHo 


has  slight  narcotic  properties.  It  is  almost  inactive  in  the  case  of 
warm-blooded  animals,  but  in  the  case  of  cold-blooded  animals  it 
produces  narcosis,  paralysis  of  central  origin,  and  very  slight  muscular 
contractions.  Its  combination  with  the  hydrastinine  molecule  seems 
to  produce  a  diminution  of  physiological  activity,  as  well  as  certain 
marked  alterations  in  the  latter  which  have  already  been  noted. 

Narcotine,   Cotarnine,    and    Hydrocotarnine    resemble    other 
alkaloids  of  the  morphine  group ;    they  may  be  considered  here  in 


COTARNINE  287 

their  relation  to  hydrastinine.  Two  o£  the  salts  o£  cotarnine  have 
recently  been  introduced  into  medicine,  the  hydrochloride,  known  as 
'Stypticin',  and  the  phthalate,  'Styptol'.  These  trade  names 
indicate  the  use  for  which  they  are  intended,  but  it  is  probable  that 
that  result  is  produced  by  these  drugs  in  a  somewhat  different 
manner.  Cotarnine  hydrochloride,  which  retains  slightly  the  nar- 
cotic properties  of  narcotine,  has  no  vaso-constrictor  action,  nor 
does  it  increase  the  coagulability  of  the  blood.  Its  effect  as  a 
styptic  is  thought  to  be  due  to  its  slowing  the  respiratory  move- 
ments, whereby  the  blood  stream  is  somewhat  retarded  and  the 
formation  of  a  clot  favoured.  The  phthalic  acid  compound  has 
also  a  distinct  sedative  effect,  followed,  if  large  doses  are  given,  by 
convulsions,  paralysis,  and  death.  It  has  no  action  on  the  heart, 
but  death  occurs  from  respiratory  failure.  It  is  said  to  induce 
uterine  contractions.  It  appears  to  have  some  direct  action  in 
checking  capillary  bleeding,  for  it  is  not  a  vaso-constrictor.  This 
action  is,  at  any  rate,  in  part  due  to  the  phthalic  acid, 

p„/COOH  ,    o 
^6^4\cOOH  ^"^ 

as  neutral  phthalate  of  ammonium  acts  similarly  but  not  so 
powerfully. 

Narcotine  and  hydrastine,  with  their  various  derivatives  and 
compounds,  act  on  the  whole  in  very  similar  manner,  and  the 
secondary  products  correspond  fairly  closely  with  one  another.  The 
main  points  of  difference  are  that  all  narcotine  derivatives  tend  to 
reproduce  the  narcotine  action  of  the  original  substance,  while  the 
products  formed  from  hydrastine  act  most  markedly  on  the 
arterioles  and  the  blood  pressure. 

Methyl-narcotimide  is  a  marked  local  anaesthetic ;  the  amide  is 
uncertain  in  its  action  on  man,  sometimes  resembling  morphine  and 
sometimes  codeine. 

Methyl-hydrastamide  is  a  vaso-dilator,  and  has  been  unsuccess- 
fully tried  as  an  emmenagogue. 

Berberiue,  CgoHj^NO^,  the  remaining  alkaloid  of  hydrastis,  has 
very  little  action  in  the  amount  in  which  it  is  present  in  the  drug. 
20  grams  (300  grains)  have  failed  to  produce  any  symptoms  in 
man.  It  is  said  to  be  completely  decomposed  in  the  body,  thus 
differing  from  hydrastine,  which  is  excreted  unchanged  in  the 
urine.  Its  constitution  is  expressed,  in  all  probability,  by  the 
formula — 


288     MORPHOLINE  (?)-PHENANTHIlENE   GROUP 

.Or 


CH 


< 


0' 


Large  doses  lower  the  blood  pressure,  raise  the  body  temperature, 
increase  peristalsis,  and  finally  produce  general  paralysis  of  central 
origin.  As  a  constituent  of  hydrastis  canadensis,  it  probably  acts 
only  as  a  '  bitter  \ 

Hydro-berberine,  which  contains  four  atoms  more  of  hydrogen, 
is  a  vaso-constrictor,  raising  the  blood  pressure  by  its  action  on  the 
centre  in  the  medulla.  It  also  produces  convulsions  of  spinal 
origin  before  the  final  paralysis.  The  general  change  in  physio- 
logical action  produced  by  the  addition  of  hydrogen  is  thus  well 
illustrated.     Berberilic  acid, 


CH3.O 
CH, 


;  g)>CeH2 .  CO.NH.CH2 .  CH^ .  CeH2<g)>CH, 


COOH 


COOH 


like  the  corresponding  oxidation  product  of  hydrastine,  is  physio- 
logically inactive. 


V.    MORPHOLINE(?)-PHENANTHRENE   GROUP. 
Alkaloids  of  Opium, 

Opium  is  said  to  contain  no  less  than  twenty-one  alkaloids,  besides 
five  non-basic  substances,  some  of  which  are  physiologically  active. 
Besides  these  there  are  numerous  alkaloidal  bodies  which  have  been 
artificially  produced  from  the  opium  bases,  and  of  these  a  few  are  of 
pharmacological  importance. 

Chemically,  the  opium  alkaloids  fall  into  two  main  groups,  the 
w6'-quinoline  group  and  the  phenanthrene  group.  Physiologically 
also,  two  main  groups  may  be  described,  namely,  those  with  the 
physiological  attributes  of  morphine  and  those  resembling  thebaine. 
Unfortunately  these  two  groups  do  not  correspond  in  the  very 


OPIUM    ALKALOIDS  289 

least ;  both  morphine  and  thebaine,  for  instance,  belong  chemically 
to  the  phenanthrene  group. 

Before  considering  the  composition  and  properties  of  these  bodies 
in  detail,  a  few  general  observations  may  be  made.  Chemically,  the 
question  of  the  structure  of  morphine  cannot  be  regarded  as  settled, 
as  neither  of  the  suggested  formulae  is  in  consonance  with  all  the 
facts.  Physiologically,  much  attention  must  be  given  to  the  details 
of  any  experiments  on  the  action  of  these  bases  in  the  organism. 
The  discordant  results  which  have  occasionally  been  obtained  make 
it  clear  that  much  depends  both  on  the  size  of  the  dose  of  any  given 
alkaloid,  and  the  species  of  animal  employed  in  the  experiment.  For 
instance,  originally  C.  Bernard  described  morphine  as  soporific  and 
thebaine  as  tetanizing,  and  the  other  alkaloids  have  been  classed  as 
belonging  to  one  or  other  of  these  groups.  As  a  matter  of  fact, 
however,  careful  experiment  with  graduated  doses  has  shown  that 
all  the  opium  alkaloids  possess  hoth  actions,  but  that  they  are 
developed  in  very  different  proportions.  Thus  though  Bernard's 
classification  is  very  convenient  and  marks  the  main  action  of  these 
bodies,  it  must  be  remembered  that  intermediary  substances  occur, 
and  that  in  no  substance  is  either  the  soporific  or  the  tetanizing 
action  entirely  absent. 

With  regard  to  the  various  artificial  products  which  have  been 
constructed  from  morphine,  it  will  be  found  that  in  general  they 
only  differ  from  that  substance  physiologically  in  a  qualitative 
manner,  so  long  as  only  the  circumferential  portions  of  the  molecule 
are  altered.  If,  however,  the  intimate  structure  is  broken  down, 
products  will  result  differing  entirely  in  their  pharmacological 
properties  (cf.  apomorphine). 

The  principal  alkaloids  belonging  to  the  phenanthrene  group 
are : — 

Morphine, 

Codeine, 

Thebaine. 
Those  of  the  e«o-quinoline  group  are  : — 

Papaverine, 

Narcotine, 

Narceine, 

Laudanosine, 

Laudanine, 

Cotarnine, 

Hydro-cot  amine. 


290  MORPHINE 

Of  these^  narcotine,  cotarnine  and  hydro-cotarnine  have  already 
been  partially  considered  in  connexion  with  the  /50-quinoline  group. 
They  will,  however,  be  briefly  dealt  with  in  this  section  in  so  far 
as  their  pharmacology  connects  them  with  the  opium  alkaloids. 


Morphine,    C17H19NO3. 

Knorr^s  formula  for  morphine  is  based  on  its  apparent  origin 
from  two  bodies,  phenanthrene  and  morpholine,  just  as  cocaine  and 
atropine  originate  in  a  double-ring  tropine. 

Phenanthrene  is  represented  by  the  formula 

6 5  4 3 


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  glycuronic  acid.  This  reaction,  however,  appears 
not  to  be  universal,  as  in  some  animals  it  has  a  narcotic  effect.  If, 
however,  one  or  more  hydroxy]  groups  are  introduced,  e.g.  2,  3, 
and  9-phenanthrol,  substances  are  obtained  producing  severe  tetanic 
convulsions  in  warm-blooded  animals.  Phenanthrene- 9-carboxy lie 
acid,  4-methoxy-phenanthrene-9-carboxylic  acid,  and  phenanthrene- 
3-sulphonic  acid  have  a  similar  action.  The  introduction  of  more 
oxymethyl  or  acetyl  groups,  however,  has  the  effect  of  lessening 
both  the  toxicity  and  the  tetanizing  action.  It  does  not  appear 
that  any  phenanthrene  derivatives  as  yet  known  have  any  narcotic 
effect,  though  one  compound  of  phenanthrene-quinone, 

CO  CO 


namely   2-brom-phenanthrene-l-sulphonic  acid,  is  said  to  have  a 
morphine-like  action  on  the  respiratory  centre. 

Morphine  is  supposed  to  be  a  derivative  of  tetrahydro-dioxy- 
phenanthrene,  to  which  the  morphohne  complex  is  united.  Knorr 
assigned  to  the  alkaloid  the  structural  formula — 


CONSTITUTION  OP  MOEPHINE  291 


OHx„        / 

iJ-J-in 


OH 


>«] 


but  more  recent  investigators  have  amplified  their  view  of  dts  con- 
stitution, and  the  following  formula  expresses  in  more  detail  the 
facts  at  present  known  (see  also  p.  302). 


CH^ 


The  three  oxygen  atoms  have  thus  three  different  significations. 
That  attached  to  the  first  benzene  ring  is  in  the  form  of  phenolic 
hydroxyl;  that  connecting  the  phenanthrene  with  the  morpholine 
ring  is  indifferent,  corresponding  to  that  in  the  ethers,  and  both  of 
these  may  be  traced  in  two  decomposition  products,  the  constitution 
of  which  is  known. 


The  first  is  morphol, 


OH  OH 


0^53 


and  the  second  morphenol- 


O 


OH 


< 


The  oxygen  connected  with  the  third  ring  is  united  with  H  as 
simple  alcoholic  hydroxyl. 

Naphthalan-morpholine,  a  substance  isolated  by  Knorr,  or  one  of 
its  active  alkyl  substitution  products,  comes  nearer  to  morphine 

u  2, 


292 


NAPHTHALAN-MORPHOLINE 


and  codeine  in  its  chemical  relationships  than  any  o£  the  synthetic 
morpholine  bases.    It  is  a  combination  of  tetrahydro-naphthalene, 


CH. 


/\/\ 


H 


CH„ 


CH, 


and  morpholine. 


and  has  the  formula — 


S.  Frankel  throws  doubts  on  the  resemblance  between  the  physio- 
logical action  of  this  substance  and  that  of  morphine  on  man_,  but 
Leubuscher  ^  states  that  it  is  very  close. 

Vahlen,  on  the  assumption  that  the  phenanthrene  nucleus  was 
the  more  important  portion  of  the  morphine  molecule,  synthesized 
an  amido-oxy-phenanthrene,  to  the  hydrochloride  of  which  he  gave 
the  name  Morphigenin — 


HCI 


Many  derivatives  of  this  body  were  obtained  which  acted  like 
morphine  physiologically,  but  chemically  they  were  not  pure.  One, 
however,  called 


1  Annalen,  307,  172,  1899. 


THE    PHENOLIC    HYDROXYL  293 


EpiosixL  /         \ /         \ 

\ /    \ / 


< 


N     N.CH, 
\/ 

was  said  to  have  analgesic  and  slight  narcotic  action,  and  to 
produce  convulsions,  thus  resembling  codeine.  It  did  not,  however, 
slow  the  pulse,  whereas  it  did  raise  the  blood  pressure,  thus  differ- 
ing from  morphine.  There  were  also  great  quantitative  differences, 
•12  gm.  corresponding  to  about  -S  gm.  dionine.  Pschorr,  however, 
holds  that  all  this  work  is  at  fault,  and  states  that  the  original 
substance  was  not  morphigenin  but  a  nitrogen-free  phenanthrene 
derivative. 

It  is  to  the  presence  of  the  phenolic  hydroxyl  group  that  mor- 
phine owes  its  acid  properties.  The  hydrogen  may  be  replaced 
by  an  alkyl  group,  or  an  acid  radical.  If  this  is  done,  a  remark- 
able change  in  the  physiological  action  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 development  of  the  highest  nervous  centres,  and  its  toxic 
effect  is  also,  for  similar  reasons,  far  greater.  The  diminution  of 
this  action,  and  the  increase  in  tetanizing  power  which  accompanies 
any  substitution  of  the  hydrogen  of  the  phenolic  hydroxyl  by 
another  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  product 
shows  the  same  physiological  effect,  those  compounded  with  in- 
organic acids  are,  however,  rather  more  easily  dissociated  in  the 
organism ;  (2)  a  dimorphine,  in  which  two  morphine  molecules  are 
united  by  an  ethylene  residue,  e.  g. 

Ethylene-dimorphine, 


C.,H,,NO. 
C„H,3N0, 


is  without  narcotic  effect. 

Of  the  numerous  substances,  both  natural  and  artificial,  more  or 
less  resembling  morphine  in  action,  it  will  only  be  necessary  to 
mention  a  few  which  either  illustrate  a  pharmaco-dynamic  principle, 
or  have  been  actually  used  in  medicine. 


294  CODEINE  AND   DIONINE 

Codeine,   Ci^HigNOg.  OCH3. 

This  is  the  methyl  ether  of  morphine  in  which  the  hydrogen  of 
the  phenol-hydroxyl  group  has  been  replaced  by  methyl,  and  the 
constitutional  formula  for  this  alkaloid  is  consequently  dependent 
on  that  of  morphine.  It  was  obtained  in  1881  by  Grimaux  by  the 
action  of  methyl-iodide  and  an  alkali  on  morphine, 

>CuHxo<        I 
OW  ^N— CH2 

Alcohol  hydroxyl. 

CH3 

Owing  to  its  small  toxicity  in  man  and  its  sedative  action  on  the 
respiratory  mucosa,  it  is  largely  employed  in  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  constipation  is  not  so  marked. 

Codeine  is  incapable  of  forming  an  ether  corresponding  to  the 
morphinether  of  morphine,  in  which  linkage  takes  place  through 
phenolic  hydroxyl,  as  the  distinctive  methyl  group  would  in  that 
case  be  lost. 

Acetyl  codeine 

CH3.OV  /O— CH2 

(CH3C0)0^  ^N— CH2 


CH3 


has  been  prepared,  but  is  practically  useless,  as  it  does  not  affect 
respiration  and  causes  extreme  reflex  irritability  (Dreser). 


Dionine  C^Hg .  Ov  O— CHg 


!>"«^»<!' 


R<y  ^N— CH2 


CH3 


is  the  hydrochloride  of  ethyl  morphine,  and  differs  somewhat 
markedly  from  the  numerous  morphine  substitution  products  which 
have  been  constructed  and  tested  physiologically.  In  the  first  place 
it  is  very  easily  soluble  in  water,  and  is  therefore  suitable  for 
hypodermic  injection,  and  in  the  second  place  it  is  rather  more 
powerful  in  its  action  than  the  corresponding  methyl  derivative 
(codeine).     In  this  it  illustrates  a  general  practical  rule,  ethylic 


HEROINE  295 

compounds  being  usually  more  efrective  physiologically  than  those 
of  methyl.  Higher  homologues  and  substitutions  with  aromatic 
radicals  act  less  powerfully  than  codeine  and  dionine. 

Dionine  has  also  analgesic  properties,  and  has  been  employed  in 
ophthalmic  practice.  It  is  not  a  local  anaesthetic,  and  occasionally 
sets  up  some  irritation  of  the  conjunctiva  with  considerable  chemosis 
(Hinshelwood). 

Heroine. 

This  is  a  diacetyl  compound,  both  the  alcoholic  and  phenolic 
hydroxyl  groups  being  substituted.  It  is  thus  a  diacetic  ester  of 
morphine — 

CHgCO.Ox  yO— CHg 

CHgCO.O^  ^N— CH2 

CH3 

Its  action  on  the  respiration  is  in  some  way  selective,  and  is  said 
to  be  more  sedative  than  that  of  morphine.  It  is,  at  any  rate, 
more  powerful  than  codeine.  The  frequency  of  the  respiration  is 
diminished,  and  cough  is  checked.  It  has  no  marked  anaesthetic 
action,  but  is  generally  soporific.  Harnack,  who  objected  to  its  use 
therapeutically,  owing  to  its  toxic  properties,  remarked  that  acetyl 
substitution  products  of  hetero-cyclic  compounds  usually  manifested 
high  toxicity.  This,  however,  is  not  exactly  true,  and  the  fact 
seems  to  be  that  the  acetyl  group  renders  a  substance  more  toxic 
when  it  replaces  hydroxyl  hydrogen,  and  less  toxic  when  it  replaces 
amide  hydrogen  (S.  Frankel).  Examples  may  be  found  in  atropine, 
scopolamine,  and  homatropine,  which  are  more  toxic  than  tropine, 
and  cocaine,  which  again  is  more  toxic  than  ecgonine.  The  best 
example,  however,  may  be  found  in  aconitine,  where  the  substitu- 
tion of  acetyl  for  the  hydroxyl  group  converts  an  almost  inert  body 
into  a  powerful  poison,  while  the  introduction  of  two  more  acetyl 
groups  has  no  effect  except  to  slightly  decrease  the  toxicity  (Cash 
and  Dunstan).  Heroine  is  largely  used  owing  to  its  specific  action 
on  the  respiratory  centre.  The  minimal  fatal  dose  for  rabbits  is 
said  to  be  a  little  larger  than  that  of  codeine  (-1  gram  per  kilo, 
body- weight),  but  the  minimal  effective  dose  in  practice  is  only 
one-tenth  that  of  codeine.  The  hydrochloride  is  usually  prescribed 
owing  to  its  solubility.  The  mono-acetyl  compound  is  not  employed, 
it  is  more  like  morphine  in  its  action,  having  less  tendency  to  pro- 


296     MOEPHINE   AND   CODEINE   DERIVATIVES 

duce  tetanic  convulsions^  greater  hypnotic  power,  and  less  toxicity 
than  heroine.  It  has,  however,  no  special  action  on  the  respiratory 
organs. 

Benzoyl  morphine — 

CgHsCO.Ov  /O— CH2 

HO^  ^N— CH2 

I 
CH3 

The  action  of  this  compound  is  very  similar  to  that  of  codeine, 
and  thus  illustrates  the  rule  that  the  substitution  products  of  mor- 
phine owe  their  physiological  action  to  the  fact  that  the  anchoring 
group  for  the  narcotic  effect  is  partly  covered,  and  that  the  group 
introduced  for  this  purpose  is  of  comparatively  small  importance. 
Practically,  however,  benzoyl  morphine,  which  has  been  introduced 
into  pharmacy  under  the  name  of  Feronine,  has  the  disadvantage 
of  being  less  soluble  than  either  heroine  or  dionine,  and  also  of 
possessing  a  burning  taste. 

Less  Important  Artificial  Derivatives. 
Morpho-chinoline  ether 

OCaH«Nv  /0~CHo 


OR^  ^N— CH. 

I 
CH3 

is  interesting,  though  of  no  practical  value.  It  has  the  main 
characteristics  of  codeine,  causing  spasm,  especially  of  the  respira- 
tory muscles,  and  a  rise  of  blood  pressure.  It  acts  through  the 
centres  in  the  medulla. 

Chlorine  and  bromine  have  been  substituted  for  various  hydroxyl 
and  hydrogen  atoms,  with  the  general  result  of  destroying  the 
narcotic  effect. 

The  chloride  of  codeine 

CHgOv  /O— CH, 

>C. 


CV  ^N— CH2 


CH3 

is  a  powerful  muscle  poison,  in  addition  to  possessing  a  general 
codeine-like  action.     This  is  supposed  to  be  due  to  the  halogen. 


METHO-CODEINE    AND   e*o-MORPHINE  297 

which  is  known  as  a  muscle  poison  (as  for  example  in  CHCI3),  but 
it  is  curious  that  morphine  trichloride, 

CL  /O— CHCl  (?) 

I 
CH3 

which  contains  three  chlorine  atoms  is  only  a  slight  muscle  poison. 
Metho-codeine — 

/O CH2 

HO^  N CH2 

CH3 

The  ring- structure  in  this  compound  is  broken_,  with  a  consequent 
change  in  the  physiological  action.  There  are  no  narcotic  and 
tetanizing  actions,  but  only  muscle  poisoning  and  slight  depression 
of  the  cord.  There  is  some  blood  change  also,  so  that  the  urine 
becomes  deep  green.  It  thus  clearly  resembles  apomorphine,  except 
that  it  produces  no  vomiting;  it  was  formerly  considered  to  be 
identical  in  composition  with  that  body. 

It  has  no  action  on  the  pupils,  but  depresses  the  respiratory 
centres  like  morphine;  unlike  that  drug  it  increases  the  blood 
pressure,  and  frequency  of  the  heart.  Its  stereo-isomer  has  a  similar 
action. 

iso-'SILovphiiie  is  a  substance  obtained,  together  with  small 
quantities  of  an  isomeric  derivative  /S-z^o-morphine,  by  the  action 
of  water  on  brom-morphine.  The  following  formula  has  been 
suggested : — 

0-CH,-CH, 
H,    H,     "\|     OH 
, /       \ 

\ /    \ z 


OH        NCHa 


The  corresponding  2>o-codeine  has  also  been  prepared,  but  neither 
of  these  derivatives  has  any  narcotic  action,  even  when  given  in 
gram  doses.  If  the  constitutional  formula  given  above  is  correct, 
the  failure  in  physiological  action  may  be  attributed  to  the  change 
in  position  of  the  morpholine  ring,  which  is  there  represented  as 
attached  to  one  benzene  nucleus  only. 

Compounds  of  morphine  and  codeine,  in  which  the  nitrogen  is 


298 


THEBAINE 


quinquevalent,  have  been   investigated, 
brommethylates  and  have  the  formulae- 


They  are   the   so-called 


HOs 


HO' 


.0 


^^14^10 


/cH3 


CHgBr 


CH. 


■CH. 


CH, .  O 


\ 
/ 


C14H10; 


.0- 
CH. 


CH. 


ca 


CHgBr 

Physiologically,  they  are  characterized  by  a  great  diminution  of 
toxicity,  due  to  their  rapid  and  complete  elimination  in  the  urine. 
In  cats  the  tetanizing  action  is  especially  diminished. 

Thebaine,     C19H21NO3. 

This  substance,  a  possible  structural  formula  for  which  is  written 
below,  is  not  only  physiologically  different  from  morphine,  as  it 
produces  practically  no  narcosis  and  is  an  active  tetanizing  agent, 
but  differs  also  chemically  in  being  derived  from  a  dihydrophenan- 
threne,  instead  of  a  tetrahydrophenanthrene,  and  in  having  both  its 
hydroxyl  hydrogens  replaced  by  methyl  groups. 


CHo-CH.— N.CH, 


O.CH,    O 


<=> 


* 
CH' 


O.CH3 
■^>CH 


tih;^ 


The  fact  that  it  does  not  produce  a  morphine  effect  is  probably 
owing  to  the  absence  of  an  'anchoring'  OH  group,  as  well  as  to 
differences  in  the  number  of  hydrogen  atoms  combined  with  the 
phenanthrene  ring. 

By  the  action  of  dilute  HCl,  a  substance  known  as  thebenine  can 
be  produced,  which  has  a  general  paralysing  action.  Its  structure 
may  possibly  be  represented  as  follows  : — 


CH 


•CH 


OCR 


2  ^"2 

NH.CH 


/ 


3)0 

CH/ 

>CH 

"CH 


The  position  of  these  hydrogen  atoms  is  not  certain. 


PAPAVERINE   AND   LAUDANOSINE 


299 


Concentrated  hydrocliloric  or  hydrobromic  acids  convert  thebaine 
into  an  absolutely  inert  body^  morphothebaine,  CigHjgNOg,  probably 
constituted — 


OH.CH2— CH2 


O.CH, 


< 


N.CH 

/oh 


The  composition  of  these  two  bodies  is,  however,  not  definitely 
settled.  It  has  been  argued  that  morphothebaine,  with  its  two  free 
hydroxyls,  should  act  like  morphine,  and  hence  another  structure 
has  been  suggested,  involving  more  profound  changes  in  the  nitro- 
gen-bearing ring,  and  the  presence  of  only  one  methoxyl  group. 


Opium  Alkaloids  containing   an  iso-QxLinoliiie  Ring. 

Papaverine,  in  its  physiological  action,  comes  midway  between 
morphine  and  codeine,  and  is  said  to  have  a  slightly  sedative  effect 
on  the  intestinal  movements.  Its  constitutional  formula  was  deter- 
mined by  G.  Goldschmiedt — 

O.CH, 


CH3.O 


/V^ 


CH,0 


/No 


3^\/\Z 


N 


-CH. 


.CH, 


and  it  is  thus  tetramethoxy-benzyl-z^o-quinoline. 

The  conversion  of  this  into  its  ?2-methyl-tetrahydro-compound 
gives  rise  to  a  racemic  body,  the  ^-variety  of  which  is  identical  with 
landanosine,  ^-«-methyl-tetrahydro-papaverine  (one  of  the  alkaloids 
occurring  in  minute  quantities  in  opium) — 

CH,  O.CH, 


CH,.0 


/"V^ 


CH3.O 


CH. 


N.CH3 
CH CH. 


O.CH. 


\/ 

— I 


The  action  of  the  methyl  group,  attached  to  the  nitrogen  togerther 
with  the  hydrogen  atoms,  is  to  convert  the  mild  papaverine  into 
a  powerful  convulsive  poison  ranking  next  to  thebaine  itself.     It 


300 


NARCOTINE  AND   COTARNINE 


has  practically  no  narcotic  action,  as  the  OH  group  is  absent,  which 
serves  as  an  anchoring*  group  to  the  cells  of  the  cerebrum.  The 
anchoring  group  for  the  spinal  cord  (tetanizing)  has  not  been 
identified. 

Landanine,  CgoHggNO^,  which  also  occurs  in  two  stereo-isomers, 
has  a  constitution  similar  to  that  of  laudanosine,  but  contains  only 
three  methoxy  groups,  and  one  hydroxy  1,  in  place  of  the  four  methoxy 
groups  contained  in  that  alkaloid.  The  racemic  form  can  be 
converted  into  racemic  laudanosine.  It  should  be  less  powerful 
a  poison  than  laudanosine,  owing  to  the  fact  that  it  has  one  less 
methoxy  group. 

ITarcotiue,  CggHggNO^,  closely  resembles  hydrastine  (p.  284) 
in  its  chemical  structure,  it  is  methoxy-hydrastine — 


O.CR 


CH 


O.CH3  CH 

Its  action  resembles  that  of  morphine,  but  is  much  feebler ;  it 
produces  a  short  period  of  slight  exaltation  of  sensibility,  and  a 
little  shivering,  and  then  loss  of  sensation,  intoxication,  and  paralysis. 
Some  loss  of  sensibility  in  the  eyes  and  of  the  nerves  to  electrical 
stimulation  occurs.  The  soporific  action  predominates.  It  is  said 
that  in  cats  tetanic  convulsions  precede  the  stage  of  narcosis  (Mohr), 
while  in  man  therapeutic  doses  are  only  used  as  an  antipyretic.  It 
is  also  stated  to  be  aphrodisiac. 

Cotarnine  is  a  decomposition  product  of  narcotine,  and  its  con- 
stitution is  most  probably  represented  by  the  formula — 

CHs 


NH.CH, 


O.CH, 


The  other  product  is  the  non-nitrogenous  opianic  acid,  CjoHioOg 
(p.  286).  It  has  a  slight  paralysing  action  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 


similarly  to  codeine,  but  is  less  toxic.     It  is,  however,  more  toxic 
than  morphine. 

ITarceine,  the  constitution  of  which  is  very  probably  represented 
by  the  formula  written  below,  since  it  may  be  obtained  by  the 
action  of  potash  on  the  iodomethylate  of  narcotine,  is  said  to  be 
inactive  in  doses  of  1  gram  or  more  (Mohr).  It  is  a  tertiary  base, 
and  a  substituted  phenyl-benzyl  ketone. 


O.CH, 


A  sodium  compound  of  narceine  combined  with  sodium  salicylate 
has  been  introduced  into  pharmacy  under  the  name  of  Antispasmin. 
Its  action  resembles  that  of  morphine,  but  is  forty  to  fifty  times 
weaker. 

Narceine-phenyl-hydrazone  is  said  to  produce  convulsions  and 
respiratory  paralysis  in  doses  of  •!  gram  per  kilo,  body-weight. 

Narceine-ethyl-hydrochloride  has  recently  been  introduced,  under 
the  name  of  Narcyl,  as  a  remedy  for  irritable  cough.  The  medi- 
cinal dose  is  -06  gram. 


Apomorphine  and  Apocodeine. 

Dehydrating  agents  act  on  morphine  in  two  ways,  either  by 
producing  condensation  products — trimorphine  and  tetramorphine, 
&c.,  or  by  simply  abstracting  one  molecule  of  water,  giving  rise  to 
apomorphine,  Ci^Hi^NOg  —  HgO  =  Cj^Hj^NOg.  This  substance  can 
be  shown  to  contain  (1)  two  free  hydroxyl  groups,  and  (2)  tertiary 
nitrogen  in  ring  formation ;  according  to  Pschorr,  it  is  a  derivative 
of  phenanthrene-quinoline — 

CHo  N.CHo 


HO 


jCH, 


302  APOMORPHINE  AND  APOCODEINE 

The  position  of  the  hydroxyl  in  the  ring  is,  however,  conjectural. 
Physiologically,  apomorphine  is  marked  by  slight  narcotic  action, 
but  by  a  considerable  degree  of  excitory  power,  followed  by  paralysis 
of  the  spinal  cord  and  medulla.  The  emetic  action  of  morphine  is 
immensely  increased.  It  will  be  noted  that  the  constitution  given 
above  for  apomorphine  does  not  resemble  that  of  morphine  at  all 
closely.  The  phenanthrene  ring  is  indeed  represented,  but  not  the 
morpholine.  Hence  Pschorr  has  suggested  an  alternative  structure 
for  morphine,  the  so-called  '  pyridine  ■*  formula — 

CH3 

I 

CHjN 


/^\/X^|CH, 


HO 


H 


I        CI 


CH 
CH 

oLJCH 

CHOH 


This  arrangement,  however,  does  not  explain  certain  chemical 
reactions,  e.  g.  the  splitting  off  of  morphol  and  morphenol  from 
morphine. 

It  will  be  seen  that,  whatever  the  real  structure  of  morphine  may 
be,  apomorphine  is  not  derived  from  it  solely  by  the  abstraction  of 
water,  but  that  its  production  also  involves  profound  alterations  in 
the  ring  systems  to  which  the  physiological  differences  must  be 
attributed. 

The  methylbromide  of  apomorphine  (Euporphin)  is  a  less  power- 
ful emetic,  and  has  less  action  on  the  heart.  The  removal  of  the 
elements  of  water  from  codeine  gives  rise  to  a  substance  (apocodeine) 
having  similar  physiological  reactions,  though  not  so  powerful. 
Its  constitution  is  not  definitely  known,  as  it  has  been  found 
impossible  to  prove  the  presence  of  one  free  OH  group,  which  by 
analogy  it  should  contain. 

Apocodeine  has  been  shown  by  Dixon  to  exert  a  nicotine-like 
action  on  nerve  cells,  and  this  fact  suggests  that  the  purgative 
action  of  opium  alkaloids  varies  directly  with  their  paralysing  action 
on  the  sympathetic  ganglia.  Larger  doses  paralyse  motor  nerve 
endings — first  those  of  skeletal  muscles  and  then  those  of  the  arterial 
walls;  later  those  of  intestine  and  bladder,  and  the  accelerator  fibres  to 


HORDENINE  303 

the  heart   are   affected.      Owing  to  its  action  on  the  ganglionic 
nerve  cells^  he  has  suggested  its  use  as  a  hypodermic  purgative. 

Addendum  to  Alkaloids. 

Sordeniue,^  CjoHjgON,  is  an  alkaloidal  body  obtained  by  E.  Leger 
from  malt.  It  is  a  colourless  crystalline  substance,  dissolving  readily 
in  alcohol,  chloroform,  or  ether ;  Leger  ^  has  suggested  for  it  the 
following  formula : — 

1 : 4  C.U/^^jj^^  (. jj^  N<!cH3 

It  forms  a  number  of  salts  which  are  readily  soluble  in  water,  and 
whose  pharmacological  action  has  been  investigated  by  Camus. ^ 

The  sulphate  is  not  very  toxic,  the  minimum  lethal  dose  for 
a  dog  being  -3  gm.  per  kilo  intravenously.  After  small  doses  the 
vagus  is  stimulated,  and  the  heart  beats  more  slowly  and  vigorously ; 
larger  doses  paralyse  the  vagus  centre.  A  rise  of  blood  pressure 
and  acceleration  of  the  pulse  rate  follows  on  the  administration  of 
1  gram  per  kilo,  to  a  dog  or  rabbit  j)er  os.  When  a  fatal  dose  is 
given  death  occurs  from  respiratory  failure.  The  action  of  this 
body  therefore  closely  resembles  that  of  phenol  itself. 

^  Comp.  Bend.,  1906, 142,  108.  >  ib.,  1906, 143,  234. 

'  ih.,  1906, 142,  110. 


CHAPTER  XV 

Synthetic  Products  with  Physiological  action  similar  to 
Cocaine,  Atropine,  Hydrastis.— Derivatives  of  Piperidine,  Pyrrolidine, 
Amide-  and  Oxy-amido-benzoic  acid,  ^am-Amido-pli end,  Guanidine,  Tertiary 
Amyl-alcoliol.  Halogen  and  other  derivatives.  Substitutes  for  Atropine, 
Hydrastis. 

A  lauge  number  o£  synthetic  products  have  recently  been  intro- 
duced,, the  physiological  action  o£  v^rhich  resembles  that  of  various 
natural  alkaloids.  Structurally  they  often  closely  resemble  the 
bodies  they  are  intended  to  replace,  and  in  some  cases  they  have 
certain  pharmacological  advantages  as  regards  toxicity,  rapidity  of 
action,  &c.  For  convenience  they  will  here  be  grouped  according 
to  the  alkaloid  they  are  intended  to  replace,  i.  e.  according  to  their 
physiological  properties.  The  various  salts  of  quinine  and  other 
bodies  introduced  as  improvements  on  quinine  have  already  been 
described,  as  these  are  not  true  substitutes  but  merely  modifications 
of  the  original  alkaloid. 

I.     SUBSTITUTES   FOR   COCAINE. 
A.     Derivatives  of  Piperidine  and  Pyrrolidine. 

A  group  of  bodies  has  been  introduced  as  cocaine  substitutes,  the 
study  of  which  admirably  illustrates  the  relationship  between  physio- 
logical action  and  chemical  structure,  namely,  those  derived  from 
diacetone-amine,  triacetone-amine,  and  their  corresponding  alcohols. 
The  first  two  of  these  are  formed  by  the  action  of  ammonia  on 
acetone : — 

(a)  CH3  CH3 

2CO  +  NH3  =  C<^§,CO.CH+H^^ 


'3 


CHg  CH3 


diacetone-amine. 


SYNTHESIS   OF  TRIACETONE-AMINE 


305 


(^) 


CH, 


3  CO  +  2NH,    = 


CO 
CHo.-'^CH, 


CH, 


C(CH3), 


+  2H,0 


(CH3),, 

NH 
triacetone-amine. 
Diacetone-amine,  on  heating  with  acetone,  gives  triacetone-amine — 
CO  CO 


CH 


(CH 


3/2 


CH3 

+  C0(CH3) 


CH. 


3/2- 


CH. 


NH. 


(CH3),C\  /C(CH3), 
NH 


+  H,0 


Aldehyde  reacts  in  a  similar  manner,  and  by  this  means  a  series  of 
bases  similar  to  triacetone-amine  may  be  synthesized.    Thus  acet- 
aldehyde  gives  the  so-called  vinyl-diacetone-amine — 
CO  CO 


CH 


/\, 


CR 


CH. 


ca 


+  C0H.CH3  = 
{Cn,).^  (CH3),C 

NH, 


+  H,0 


NH 


CH(CH3) 


By  the  action  of  methylamine  and  ethylamine  on  acetone,  alkyl 
derivatives  of  diacetone-amine  are  formed. 
Triacetone-amine 

CH, 


CH3— C 


CH. 

I  I 

NH    CO 

I  I 

CH,— c — ca 


CH, 


has  a  powerful  curare-like  action ;  its  reduced  derivative  alkamine 

CH, 


CH3- 

-c 

1 

-CH2 

1 

NH 

1 

CH.OH 

1 

CH3- 

1 
-C 

CH3 

1 
-CH2 

306  COMPARISON  OF  ECGONINE  &TRIACETONE-AMINE 

and  the  compounds  derived  therefrom  manifest  a  similar  action; 
the  introduction  of  a  carboxyl  group 

CH3 

I 

CHg — C      — CHg 


i/OH 


^^    V\COOH 
CHg — C CHg 

I 
CH3 

abolishes  this  action  altogether  but  produces  a  substance  which  is 
more  powerfully  toxic. 

A  comparison  of  the  structure  of  the  methyl  derivative  of  tri- 
acetone-alkamine  with  that  of  tropine  and  ecgonine  reveals  a  re- 
markable similarity,  so  that  it  was  possible  for  Merling  to  predict 
the  physiological  action  of  the  derivatives  of  methyl-triacetone- 
alkamine  by  a  knowledge  of  those  of  the  corresponding  ecgonine 
compounds. 

CH3 

C  H3 — C  — — — C  H  J 

I  I 

N.CH,     CH.OH 


CH. 


CH3— C- 


CH3 

Triacetone-methyl-alkamine. 


CHj— CH CH.COOH  CH^— CH CH^ 


I 
N.CHo    CH.OH 


■^3 


N.CH3    CH.OH 


CH2— CH CHj  CH2— CH CHa 

Ecgonine.  Tropine. 

If  a  carboxyl  group  is  introduced  into  the  first  of  these  derivatives, 
a  body  is  produced  resembling  ecgonine  still  more  closely,  the  main 
differences  being  that  the  carboxyl  stands  in  a  different  relation  to 
the  nitrogen,  and  the  second  ring  is  not  closed : — 


THE   EUCAINES  307 

CH3  I 

CH3 — C— — — — CHg 

N.CH3  y<((.QQjj 

CHg — C— — — — CHg 

I 
CH3 

This  body  is  inactive  physiologically,  like  ecgonine.  If  the 
hydrogen  of  the  carboxyl  group  is  replaced  by  methyl  and  the 
hydroxyl  hydrogen  by  benzoyl,  as  is  done  in  the  case  of  cocaine,  the 
following  body,  known  as  Eucaine  A  (or  a-eucaine),  is  produced  : — 

CH3 

I 

CH3— C CH2 

NCH      i/0-COC,H, 

JN.Uilg  KCOOCH3 

CH3 — C CHg 

I 
CH3 

This  substance  is  cheaper  than  cocaine,  and  resembles  tropacocaine 
in  its  action.  It  does  not  act  on  the  pupil  or  contract  the  arterioles ; 
it  is  less  toxic,  and  its  solution,  unlike  that  of  cocaine,  may  be 
sterilized  by  boiling :  on  the  other  hand  it  has  an  irritant  action  on 
the  mucous  membrane  and  is  not  haemostatic. 

Benzoyl-vinyl-diacetone-alkamine  has  lost  some  of  these  dis- 
advantages, and  is  less  toxic  than  eucaine  A,  in  the  proportion  of 
one  to  four.  It  is,  however,  somewhat  painful  to  inject,  and  it 
dilates  the  blood  vessels  and  so  promotes  bleeding. 

The  hydrochloride  of  this  substance  is  known  as  /S-Encaine  or 
Eucaine  B, 

CH3 — CH CHg 

I         I 

NH.HCl    CH.0(C0CeH5) 
CH3 — C CHo 


i 


H, 


These  disadvantages  may  be  overcome  by  (1)  injecting  /3-eucaine 

X  2 


308        DERIVATIVES   OF   TRI ACETONE-AM INE 

in  normal  saline  at  body  temperature,  (2)  mixing  some  adrenalin 
solution  with  the  local  anaesthetic. 

The  benzoyl  group  in  eucaine  cannot  be  replaced  by  acetyl  with- 
out loss  of  anaesthetic  action  (as  is  the  case  with  cocaine),  but  other 
aromatic  radicals  may  replace  the  benzoyl  and  leave  the  local  anaes- 
thetic action  intact.  The  amygdalic  acid  derivative,  however,  is  an 
exception. 

The  derivatives  o£  triacetone-alkamine  behave  similarly  to  those 
of  the  carboxyl  derivative,  though  neither  of  the  parent  substances 
has  any  local  anaesthetic  power.  The  alkyl  group  in  eucaine 
which  replaces  the  carboxylic  hydrogen  is  not  of  physiological 
importance,  thus  forming  a  contrast  to  cocaine. 

Benzoyl-triacetone-alkamine-carboxyl  is  a  local  anaesthetic — 

CH, 


I 
CH,— C CH 


™  kSSi-"- 


CHo — C CHq 

I 

CH, 

Triacetone-amine,  and  triacetone-alkamine 

CHq  CHq 

I  I 

CH,— C CHj  CH,— C CH» 

II  II 

NH    CO  NH    CH.OH 


i 


CHq — C CHn  CHq — C CHq 

CH3  CH3 

produce  only  slight  local  irritation,  whereas  triacetone-alkamine- 
carboxyl 

CHo 


CH3- 

r 

-CH2 

in 

1 

I//OH 
|\COOH 

CH3- 

-C — 

CH3 

-CHg 

PYRROLIDINE   DERIVATIVES  309 

is  a  powerful  local  irritant.  The  carboxyl  group  seems  therefore  to 
be  responsible  for  this  effect,  which  may  be  much  modified  by 
esterification.  These  esters  are,  however,  two  or  three  times  more 
toxic  than  the  bodies  from  which  they  are  derived;  thus  the 
derivative  produced  by  the  substitution  of  cinnamyl  for  benzoyl 
in  a-eucaine — the  methyl-ester  of  cinnamyl-w-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  least  toxic  bodies  of  the 
series ;  the  phenyl  and  amygdyl  derivatives  are  the  most  toxic.  The 
alkyl  derivatives  (ethyl  and  methyl),  though  much  more  toxic  than 
the  mother  substances,  are  less  so  than  the  aromatic  substitution 
products. 

A  lower  homologue  of  benzoyl-triacetone-alkamine,  benzoyl- 
/3-hydroxy-tetramethyl-pyrrolidine  has  a  powerful  local  anaesthetic 
action,  and  is  less  toxic  than  )3-eucaine — 

CH3 

I 
CHg — C        CHg 

NH 

CHg— C CH.0.C0CeH5 

CH3 

The  mandelic  acid  ester 

CH, 

I 
CH3 — C        CH<> 

NH 

CH3— C CH.0.C0.(CH0H)C6Hg 

CH3 

has  a  slighter  action  on  the  pupil  than  euphthalmine,  which  it 
closely  resembles.  In  fact,  a  complete  series  of  derivatives  can  be 
obtained  from  the  pyrrolidine  base  corresponding  physiologically 
to  those  from  pyridine,  thus  illustrating  the  close  relationship 
between  these  two  bodies. 

The  general  action  of  the  bodies  of  the  eucaine  group,  when  given 


310  OXY-AMIDO-BENZOIC   ACIDS 

in  larger  doses  than  those  necessary  to  produce  the  therapeutic 
effect,  is  paralysis  of  the  central  nervous  system  after  a  more  or 
less  marked  period  of  excitation.  Those  which  contain  carboxyl 
(either  with  or  without  the  ester  group)  produce  increase  in  reflexes, 
excitement,  general  tonic  and  clonic  convulsions,  and  finally  para- 
lysis.    The  peripheral  nervous  system  is  unaffected. 

In  the  bodies  without  a  carboxyl  group  the  excitement  is  of 
shorter  duration,  the  general  paralysis  appears  earlier,  and  is  more 
complete.  The  motor  nerve  endings  are  acted  on  as  in  the  case  of 
curare,  and  larger  doses  paralyse  the  vagus.  Generally  speaking, 
the  two  classes  are  typified  by  the  toxic  symptoms  of  a-eucaine  and 
/3-eucaine  respectively. 

B.     Derivatives  of  Amido  and  Oxyamido  Benzoic  Acid. 

Another  series  of  local  anaesthetics  has  been  introduced,  of  which 
orthoform  is  typical.  Einhorn  and  Heintz  found  that  the  benzoyl 
esters  of  oxy-amido-benzoic  acid  possessed  anaesthetic  properties, 
and  on  the  analogy  of  cocaine  thought  that,  if  the  benzoyl  group 
were  removed,  the  anaesthetic  action  would  disappear.  This,  how- 
ever, was  found  not  to  be  the  case,  and  by  replacing  the  benzoyl 
group  more  intensely  powerful  substances  were  in  some  instances 
produced. 

Many  of  these  compounds,  however,  are  irritating  or  painful  on 
injection,  and  some  have  but  a  slight  anaesthetic  effect. 

The  methyl  ester  of  o-amino-^-oxybenzoic  acid 

COOCH3 

produces  an  anaesthesia  which  is  hardly  perceptible,  but  the  methyl 
ester  of  j!?-amido-»2-oxybenzoic  acid 


H^N^  >C00CH3 


rET 

is  well  known  as  the  local  anaesthetic  Orthoform.  This  body 
being  very  slightly  soluble  is  also  but  feebly  toxic.  It  is, 
however,  only  active  when  directly  applied  to  the  nerve  endings, 
and  is  useless  when  applied  to  the  unbroken  skin  or  mucous  mem- 
brane. Its  soluble  hydrochloride  is  not  available  in  practice,  owing 
to  the  pain  produced  by  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 
(rather  more  so  than  morphine  hydrochloride). 

Orthoform-nen    (the    new    orthoform),    the    methyl    ester    of 
7?-hydroxy-»z-amido-benzoic  acid. 


H0<'         j>C00CH3 

is  much  cheaper,  and  equally  active  physiologically,  but  except 
for  this  it  appears  to  have  the  same  disadvantages  as  orthoform. 
Its  hydrochloride  is  soluble,  but  irritant.  It  may  be  obtained  from 
jo-oxy-benzoic  acid,  a  substance  which  results  from  the  action  of 
carbon-dioxide  on  potassium  phenate  at  a  temperature  of  200-220  °C. 
When  this  acid  is  acted  upon  by  dilute  nitric  acid,  ;;2-nitro-oxy- 
benzoic  acid  results,  which  is  then  converted  into  its  methyl  ester 
and  reduced : — 

COOH      COOH       COOCH.     COOCH3 


/\  /\  /\ 


•NO. 


NO. 


NH„ 


OH  OH  OH 


A  very  large  number  of  bodies  have  been  prepared  which  re- 
semble orthoform,  but  only  a  few  are  of  any  practical  use.  It  has  been 
found  generally  that  those  containing  a  hydroxyl  group  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 
glycocoll  derivatives  of  the  amido  and  carboxy-amido  acids  of  this 
series.  These  compounds  proved  to  have  anaesthetic  properties,  but 
differed  from  the  mother-substance  in  being  strongly  basic  and 
easily  soluble  in  water.  Their  anaesthetic  powers  do  not  in  any 
way  correspond  quantitatively  to  the  substances  from  which  they  are 
derived. 

Nirvanine  is  the  methyl  ester  of  diethyl-glycocoll-/»-amido-o-oxy- 
benzoic  acid — 

OH 


C3 


COOCH 


NH.COCH2N(C2H5)2 


812  ANAESTHESIN  AND  NOVOCAIN 

It  is  less  toxic  than  orthoform,  and  has  also  an  antiseptic  action. 
It  is  very  soluble  in  water.  It  has  no  action  on  the  unbroken  skin ; 
injections  produce  pain  and  local  oedema,  and  it  is  far  too  irritating 
for  ophthalmic  work. 

The  ethyl  ester  of  7?-amino-benzoic  acid  is  a  local  anaesthetic, 
and  is  known  as  Anaesthesin, 


■<z> 


NH./  >COOCoH 


2^^6 


It  is  obtained  by  the  series  of  reactions  formulated  as  follows  : — 

Toluene.  ^NO^  ^NO^ 

^-nitrotoluene.  _p-nitro-benzoic  acid. 

.COOC2H5  ,„^   ,  /COOC2H5 

^NO^  ^NHj 

ethyl  ester  of 
p-nitro-benzoic  acid. 

Its  action  is  similar  to  that  of  orthoform. 

ITovocain  is  the  hydrochloride  of  the  diethyl-amino-ethynol  ester 
of  jt?-amido-benzoic  acid — 

^n/      ^COO.C2H^N(C2H5)2.  HCl 

It  is  said  to  be  non-irritant  even  in  strong  solutions.  It  is  soluble 
in  one  part  of  water,  and  the  solution  may  be  boiled  without 
decomposition.     Its  toxicity  is  slight. 

The  substances  above  enumerated,  with  the  possible  exception  of 
novocain,  are  obviously  unsuitable  for  producing  surgical  anaes- 
thesia. They  have,  however,  been  employed  with  varying  success 
to  allay  gastric  pain,  due  either  to  an  organic  lesion  or  to  functional 
derangement. 

Anaesthesin  has  also  been  employed  to  allay  vomiting,  when  due 
to  causes  within  the  stomach,  but  seeing  that  in  most  of  these  cases 
the  vomiting  serves  to  remove  an  irritant  and  nocuous  substance, 
the  field  of  utility  for  the  drug  in  this  direction  appears  to  be  some- 
what limited.  As  illustrating  the  purely  local  action  of  anaes- 
thesin on  the  gastric  mucosa,  it  is  found  that  it  will  counteract  the 
effects  of  tartar  emetic,  but  not  those  of  apomorphine  (Reiss). 


HOLOCAINE  313 

C.     Derivatives  of  jt^-Amido  Phenol. 

The  aniline  derivatives,  though  mainly  used  as  general  analgesics, 
have  a  slight  local  anaesthetic  action,  and  in  some  this  property  is 
sufficiently  marked  to  give  them  a  practical  value. 

Phenetidin, 

OC^H, 


when  combined  with  a  second  ring,  gives  rise  to  the  compound 
known  as  Holocaine. 

Holocaine,  the  condensation  product  of  /?-phenetidine  and  phen- 
acetin, 


OC^HX^        7-NjH 


+  CHj.  CiOiNH.CeH^ .  OCjH, 


=  OCaH,<(^        ^N ;  C.NH.C,H,OC,H, 

CH3 

as  employed  in  practice,  is  the  hydrochloride  of  j»-diethoxy-ethenyl- 
diphenylamine — 


CH3C< 


K 


OC,H, 


■NH<^OC,H, 


It  is  more  toxic  than  cocaine,  but  it  produces  a  rapid  anaesthesia. 
It  keeps  well,  but  has  the  disadvantage  of  being  only  slightly 
soluble.  In  toxic  doses  it  produces  general  convulsions.  Its  prac- 
tical application  has  been  limited  to  ophthalmic  operations ;  two  or 
three  drops  of  a  1  per  cent,  solution  produce  anaesthesia  within 
one  minute,  and  two  or  three  instillations  at  intervals  of  five 
minutes  will  render  the  eye  anaesthetic  for  about  forty  minutes. 

Numerous  similar  compounds  have  been  tried  experimentally, 
but  are  found  to  have  no  advantage  over  holocaine.  They  are,  all 
of  them,  also  antiseptics.  It  appears  that  in  this  series  the  oMo 
and  para  compounds  have  equal  physiological  properties. 


314  STOVAINE  AND  ALYPIN 

D.     Guauidine  Derivatives. 

The  guanidine  compounds,  of  which  a  large  number  have  been 
tested,  are  less  toxic  than  cocaine ;  they  act  more  promptly  and  for 
a  longer  time,  and  their  solutions  are  stable.  They  are,  however, 
irritating;  and  the  solution  of  the  most  powerful  of  the  series  is 
decomposed  by  light.  This  body,  known  as  Acoiue,  is  the  hydro- 
chloride of  di-jo-anisyl-monophenetyl-guanidine. 


\       > 

nh/ 

"^OCHa.HCl 
^0CH3 

E.    Derivatives  of  Tertiary  Amyl  Alcohol. 

A  group  represented  by  stovaine  and  alypin  may  be  regarded 
as  derivatives  of  dimethyl-ethyl-carbinol — 

CH3 

I 
n  H.— C— OH 

I 
CH3 

Stovaine : —  Alypin : — 

CH3  CH2.N(CH3), 

C,H,-C-0.C0C,H5  C,H,_C-0.C0C,H5 

CH2.N(CH3)2.HC1  CH2.N(CH3)2.HC1 

or,  dimethyl-amino-benzoyl-  or,  tetra-methyl-diamino-benzoyl- 

dimethyl-ethyl-carbinol.  ethyl-dimethyl-carbinol. 

Stovaine  differs  from  cocaine  in  many  important  points ;  whilst  it 
is  about  as  powerful  in  anaesthetic  action  it  is  only  half  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  decomposed 
in  the  presence  of  alkalis.  It  appears  to  be  unsuitable  for  instilla- 
tion into  the  conjunctiva,  but  may  be  usefully  employed  for  infil- 
tration anaesthesia.     As  much  as  20  grains  have  frequently  been 


CHLORETONE  315 

given  hypodermically  without  ill-effect,  and,  in  fact,  no  cases  of 
poisoning  are  recorded.  Its  main  use  hitherto  has  been  in  the  pro- 
duction of  spinal  anaesthesia,  as  little  as  -3  cc.  of  a  10  per  cent, 
solution  being  sufficient  to  produce  anaesthesia  in  the  legs  below 
the  knees.  For  more  extensive  anaesthesia  as  much  as  10  cc.  may 
be  injected  in  divided  doses. 

Alypin,  on  the  other  hand,  has  been  mainly  employed  in  ophthal- 
mic work.  It  possesses  for  this  purpose  certain  advantages  over 
stovaine.  It  is  not  acid,  and  consequently  is  compatible  with  alka- 
line solutions ;  it  is  slightly  more  active  as  an  anaesthetic,  and  has 
no  mydriatic  action,  whereas  stovaine  in  2  per  cent,  solution  is  said 
to  dilate  the  pupil,  though  only  slightly.  Alypin  appears,  however, 
to  have  given  rise  to  local  irritation  in  some  cases.  It  has  also  been 
employed  to  produce  lumbar  anaesthesia.  It  may  be  efficiently 
sterilized  by  ten  minutes^  boiling.    It  has  a  slight  vaso-dilator  action. 


F      Halogen  and  other  Derivatives. 

Two  further  groups,  namely  those  containing  chlorine,  and  those 
of  the  phenol  class,  may  be  mentioned.  The  first  is  represented  in 
practice  by  the  substance  known  as  Cliloretone  (Chloroform  Ace- 
tone, Aneson).     Chemically  it  is  tertiary  trichlorbutyl-alcohol — 

OH 

I 

CHq C CHq 

i 

It  is  used  as  a  sedative  and  also  as  an  antiseptic ;  a  practical  objec- 
tion to  its  employment  is  that  the  toxic  and  therapeutic  doses  are 
too  nearly  alike,  but  it  may  be  employed  in  small  doses  to  produce 
local  anaesthesia,  for  dressing  wounds,  gynaecological  applications, 
&c.  Phenol  itself,  creosote,  and  guaiacol,  are  popularly  used  to 
inhibit  the  aching  of  a  tooth,  and  indeed  it  appears  that  all  phenols 
containing  at  least  one  free  hydroxyl  are  anaesthetic,  though 
their  use  is  very  limited,  owing  to  their  caustic  action.  Their 
derivatives,  such  as  eugenol  acetamide  and  eugenic  acid,  do  not 
appear  to  be  powerful  anaesthetics,  though  they  are  strong  anti- 
septics, and  the  last-named  is  said  to  be  non-caustic.  Eugenol  is 
1 :3 :4-allyl-dioxybenzene,  CgHg .  03115(011)2.  It  occurs  in  clove-oil 
andallspice.  Vanillin, CgHs.  (CH0).(0CH3) (OH).  1:3:4 j  Piperonal 


316  EUPHTHALMINE 

(Heliotropin),  CgHg.  (CHOXOCHjO).  1:3:4,  are  less  pronounced 
local  anaesthetics. 


IL    SUBSTITUTES   FOR  ATROPINE. 

Not  only  can  bodies  having  a  physiological  resemblance  to  cocaine 
be  derived  from  triacetone  alkamine  (see  p.  306),  but  by  altering  the 
side-chain  a  mydriatic  substance  similar  in  constitution  and  action 
to  atropine  may  be  obtained.  Atropine,  it  will  be  remembered,  is 
the  ester  of  tropic  acid  and  tropine;  homatropine  the  ester  with 
mandelic  acid.  The  mandelic  acid  ester  of  methyl-triacetone 
alkamine  is  mydriatic — 

CH3 


CH3— C CH3 

|.CH3   (t<g 

CH3— C 
CH, 


I  W.CO.CHOH.C6H5 
CH. 


■^3 

It  will  be  noted  that  the  hydroxyl  is  in  the  para  position  as  regards 
the  nitrogen,  as  in  tropine. 
Vinyl-diacetone-alkamine, 

CH3— CH CH2 

N.CH3       CH.OH 

I  I 

CHo — C CH2 

H3 

may  be  treated  in  a  similar  manner  with  like  results.  Two  stereo- 
isomeric  w-methyl-vinyl-diacetone-alkamines  exist,  owing  to  the 
presence  of  an  asymmetric  carbon  atom  in  the  ring,  marked  with 
an  asterisk  on  the  above  formula. 

The  a-mandelic  acid  derivative  is  not  mydriatic;  just  as  the 
mandelic  acid  ester  of  '\//"-tropine,  isomeric  with  homatropine,  is 
inactive ;  the  hydrochloride  of  the  /3-ester  is  known  as  Eaphthal- 
mine.  It  is  easily  soluble  in  water,  and  has  no  anaesthetic 
properties. 


h. 


ADRENALIN  817 

Euphthalmine  resembles  atropine  in  checking  the  secretion  of 
the  gastric  mucosa,  and  in  counteracting  the  effects  of  pilocarpine 
and  eserine.  In  toxic  doses  it  causes  in  frogs  paresis,  convulsions, 
dyspnoea,  and  death  from  cardiac  failure.  It  differs  from  atropine 
in  its  retarding  action  on  the  pulse  rate,  due  to  its  action  on  the 
vagus  centre  and  the  cardiac  muscle. 

Enmydrine  is  atropine  methyl-nitrate,  and  is  similar  in  its  action 
to  the  methyl  bromide ;  it  produces  a  mydriasis  of  a  somewhat  en- 
during nature,  and  is  thus  not  a  suitable  substitute  for  homatropine. 
Mydriasine  is  the  trade  name  for  a  preparation  of  the  methyl  bro- 
mide; the  properties  of  this  body  have  already  been  described  (p.  270). 

The  corresponding  mandelic  acid  ester  of  pyrrolidine  merely 
destroys  the  reactivity  of  the  sphincter  iridis  to  light;  that  of 
jS-hydroxy-tetramethyl-pyrrolidine 

CH3 

I 
CHg — C CHo, 

NH 

CH.— C CHOH 

I 
CH, 

is  similar  to  euphthalmine  physiologically,  but  is  weaker  in  mydri- 
atic and  toxic  action. 

III.    SUBSTITUTES   FOR  HYDRASTIS. 

The  most  important  body  recently  introduced  into  medicine  is 
the  extract  prepared  from  the  supra-renal  glands,  and  known  as  Adre- 
nalin, supra-renalin,  epinephrin,  hemisine,  &c.  The  chemical  consti- 
tution of  this  body  is  not  absolutely  decided,  but  the  balance  of 
evidence  is  in  favour  of  the  formula 

CH.OH.CH2  •  NHCH3 


Its  action  physiologically  is  chiefly  on  unstriped  muscle,  which  it 
causes  to  contract  by  direct  stimulation.  Thus  Elliott  has  shown 
that  after  the  dilator  pupillae  muscle  has  been  entirely  separated 


318  ADRENALIN  DERIVATIVES 

from  its  nervous  connexions  for  some  months  it  will  contract  on 
the  application  of  adrenalin  more  rapidly  and  completely  than  an 
iris  whose  nervous  supply  is  intact.  It  does  not  act,  however,  on 
plain  muscle  which  is  not  normally  innervated  by  the  sympathetic, 
and  thus  is  without  action  on  the  muscles  of  the  bronchioles,  and 
the  pulmonary  and  cerebral  blood-vessels.  A  dose  of  ^^  mgm.  intra^ 
venously  injected  in  rabbits  doubles  the  general  arterial  blood 
pressure,  and  less  than  one-millionth  of  a  gram  gives  a  distinct 
action.  In  addition  to  its  specific  action  on  unstriped  muscle  sup- 
plied by  the  sympathetic,  adrenalin  has  certain  toxic  actions.  The 
NH.CHg  grouping  is  resistant  in  the  body,  and  suggests  a  proto- 
plasmic poison.  As  a  matter  of  fact,  it  produces  glycosuria  and 
inflammatory  changes  in  the  liver  and  kidneys.  It  appears  also  to 
have  a  specially  toxic  action  on  the  cardiac  muscle  of  dogs  (Elliott). 
Death  may  occur  from  large  doses,  with  symptoms  of  collapse, 
coma,  and  paralysis  of  the  central  nervous  system  without  any 
increase  in  blood  pressure. 

Catechol,  r<  tr  /OH  ,  .  „ 

^6^4\0H  ^  •  "^ 
the  parent-substance  from  which  adrenalin  is  chemically  derived,  in 
doses  of  about  2  mgms.  per  kilogram  body-weight  produces  an 
appreciable  rise  of  arterial  pressure,  and  this  is  also  the  case  with 
many  of  its  simpler  chemical  derivatives;  for  instance,  pyrocate- 
chuic  aldehyde,  chloracetyl-pyrocatechin,  &c.  Replacement  of  the 
phenolic  hydroxyl-hydrogen  renders  these  bodies  inactive. 

Adrenalone  is  a  ketone  obtained  by  the  oxidation  of  the  optically 
active  tribenzene-sulphone  derivative  of  adrenalin.  An  optically 
inactive  product,  which  otherwise  is  apparently  identical  with  the 
corresponding  derivative  of  the  ketone,  has  been  synthesized  by  the 
action  of  methylamine,  CHgNHg,  on 

.OH 1 

CgHg^OH 2 

\CO.CH2Cl  .   4 
(a  derivative  which  has  much  the  same  physiological  activity  as 
catechol). 

CO.CHgCl  CO.CH2 .  NHCH3 


+  CH3NH2  = 
OH 


OH  OH 


&« 


ADRENALONE  319 


The  synthetic  ketone  on  reduction  gives  the  corresponding  alcohol, 

.CHOH.CH2NHCH3 
CgHa^OH 
'    '\0H 

which  produces  as  great  a  physiological  reaction  as  adrenalin,  although 
it  is  not  identical  with  the  natural  product,  differing  chiefly  in  its 
optical  inactivity.  The  ketone  itself  has  a  vaso-constrictor  action, 
but  is  hardly  more  powerful  than  some  of  the  simpler  pyrocatechin 
derivatives  mentioned  above. 

From  synthetic  adrenalone  a  large  number  of  bodies  have  been 
prepared  which  may  be  grouped  into  the  following  clashes  ^ : — 
I.  C6H3(OH)2.CO.CH2NH2. 
II.  Derivatives  of  the  type  C6H3(OH)2.  CO.CHgNHR. 

(a)  Where  R  is  in  an  aliphatic  group,  e.  g.  methyl,  ethyl, 

amyl,  and  heptyl. 

(b)  Where  R  is  a  mixed  group,  e.  g.  benzyl. 

(c)  Where  R  is  purely  aromatic,  e.  g.  phenyl,  tolyl,  naphthyl. 

III.  Derivatives    of    the    type    C6H3(OH)2.  CO.CHg.NRa,   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  kilogram  body- 
weight,  their  reduction  bases  acting  similarly  to  adrenalin.  Sub- 
stances in  Class  II  (b)  act  similarly  but  less  powerfully,  and  approxi- 
mate to  those  in  Class  II  (c)  which  cause  a  fall  of  pressure  followed 
by  a  slight  rise.  Their  reduction  products  in  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  products  are  very  powerful.  Class  IV 
is  apparently  less  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  place  among  the  alkaloids,  and 
therefore  need  not  be  further  noticed  here;  they  cannot,  more- 
over, from  a  practical  standpoint,  be  considered  as  substitutes  for 
hydrastis. 

*  H.  D.  Dalkin,  Joum.  Physiol.^  xxxii,  May,  1905. 


\  CHAPTER    XVI 

The  GlucosidSs.— Sinigrin,  Sinalbin,  Jalapin,  Amygdalin,  Coniferin, 
Phlorizin,  Strophanthin,  Saponarin,  &c.  Purgatives  derived  from  Anthra- 
quinone. 

^HE  GLUCOSIDES. 

The  Glucosides  are  a  class  of  vegetable  substances  whicli  on 
hydrolysis  give  rise  to  various  aromatic  derivatives  and  sugars — 
chiefly  glucose,  but  often  rhamnose  or  pentose,  and  occasionally 
to  a  mixture  of  several  sugars. 

The  name  indicates  botanical  rather  than  pharmacological  or 
chemical  relationships.  The  common  chemical  characteristic,  the 
carbohydrate  nucleus,  is  probably  of  great  importance  in  plant 
physiology,  being  the  nutritive  portion  of  the  molecule ;  the  residual 
portion  is  also  of  importance,  and  is  probably  not  a  mere  excretion, 
as  was  at  one  time  thought.  From  the  pharmacological  point  of 
view,  the  carbohydrate  nucleus  appears  to  increase  but  not  to  deter- 
mine the  activity  of  these  bodies.  The  one  exception  to  the  rule 
that  the  glucoside  is  more  active  than  its  non-carbohydrate  moiety 
is,  according  to  Frankel,  consolidine,  a  glucoside  obtained  from 
burrage.  This  body  produces  paralysis  of  central  origin,  and  its 
decomposition  product,  consolein,  is  three  times  more  toxic.  A  num- 
ber of  glucosides  can  be  prepared  artificially,  though  few  of  these  are 
of  pharmacological  importance.  Van  Rijn  ^  classifies  the  naturally 
occurring  glucosides  according  to  the  plants  from  which  they  are 
derived.  He  remarks  that,  in  the  present  state  of  our  knowledge 
of  the  structure  of  these  bodies,  a  complete  chemical  classification 
is  not  possible;  but  even  were  the  structure  of  all  glucosides 
accurately  known,  a  botanical  classification  would  still  stand,  as,  in 
general,  plants  of  allied  species  contain  similar  chemical  components. 

For  the  present  purpose,  however,  a  chemical  classification  will 
be  found  more  convenient.  As  with  the  alkaloids,  so  with  the 
glucosides,  only  a  few  out  of  a  large  number  of  natural  products 
are  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,  according*  to  the  chemical  character  of  the  non-glucose 
portion  o£  the  molecule.  He  divided  them  into  four  groups,  as 
ethylene,  benzene,  styrolene,  and  anthracene  derivatives,  and,  as  far 
as  possible,  this  classification  will  be  followed.  Some  glucosides, 
not  in  Umney^s  original  list,  have  been  added  to  his  groups,  of 
which  the  last  is  the  most  interesting  from  a  pharmacological  point 
of  view. 

It  will  be  seen  that  very  little,  if  anything,  is  known  in  this 
group  of  the  interdependence  of  constitution  and  physiological 
action. 

Class  I. 

The  ethylene  derivatives  include  a  number  of  bodies  derived  from 
mustard  and  tropaeolum  seeds,  characterized  by  their  sharp  burning 
taste,  and  all  allied  to,  or  derived  from,  mustard  oil. 

Sinigrin,  CjoHjgNSgKOg  4-  HgO,  is  the  glucoside  of  black  pepper, 

and  is  also  found  in  horse-radish  root.    It  is  the  potassium  salt 

of  myronic   acid,  and  probably  has  the  following  constitutional 

formula — 

O.SO.OK 

I 
C~S.CeH,A 

II 
N.C3H3 

On  decomposition  it  gives  rise  to  allyl-mustard  oil,  C3H5N ;  C  :  S, 
glucose,  and  potassium  bisulphate. 

Sinalbin,  CgoH^gNgSgOjs,  the  corresponding  glucoside  derived 
from  white  pepper  is 

0-SO,OC,eH,A 

6-S.CeH,A 

N.CHg.CgH^.OH 

When  decomposed,  it  gives  sinalbin-mustard  oil,  C7H70.N:C:S, 
glucose,  and  the  sulphuric  acid  ester  of  sinapin. 

Sinapin  is  a  compound  of  choline  and  sinapinic  acid — 
OH 

CHjO/^OCHg 

0H\ 
V  (CH3)3^N 

CH ;  CH— CO.CgH.O/ 


322  SALICIN  AND   HELICIN 

Glycotropaeolin,  which  has  not  yet  been  isolated,  is  the  origin  of 
benzoyl-mustard  oil  and  benzoyl-cyanide,  in  the  seeds  of  Tropaeolum 
majus.  Experiments  on  its  aqueous  solution,  and  the  investigation 
of  its  derivatives,  suggest  the  constitutional  formula — 

O— SO.OK 

I 
C.S.CeHiiOgH-ajAq 

N.CH^CeH^ 

Jalapin (Scammonin),  Cg^HggOjg,  the  active  principle  of  Scammony 
{Convolvulus  scammonia)y  is  a  glucoside,  splitting  up  when  heated 
with  dilute  acids  into  glucose  and  jalapinolic  acid,  to  which  Kramer 
assigns  the  constitution — 

(?]^3\cHCH.OH.(CioHJCOOH 

This  acid  has  the  same  composition  as  the  substance  obtained 
from  ipomoein  (the  glucoside  from  Ipomoea  panduratus)  by  heating 
it  with  dilute  acids,  when  decomposition  into  sugar,  )8-methyl- 
crotonic  acid  (?),  and  ipomeolic  acid,  CjgHggOg,  takes  place. 


Class  II. 

The  benzene  group  contains  bodies  allied  to  Salicin,  Q-^^^fi^^ 
a  glucoside  which  is  decomposed  by  dilute  acids  into  glucose  and 
saligenin — 

kJoH 

Ganltherin,  Cj^HigOg,  the  glucoside  from  Gaultheria  procumbens^ 
gives  salicylic  acid  methyl  ester  and  glucose,  when  decomposed  by 
dilute  acids. 

Helicin,  CigHjgO^,  is  the  corresponding  aldehyde  to  salicin — 


a 


iCHO 
CeHyO. 


It  exists  also  in  an  amorphous  form  (wo-helicin),  which  gives  no 
aldehyde  reactions. 

Michael  obtained  this  glucoside  synthetically  by  the  action  of  an 


POPULIN  AND  ARBUTIN  323 

alcoholic  solution  of  aceto-chlorhydrose  upon  the  sodium  derivative 
of  salicyl-aldehyde — 

CeH,C10,(C3H30),  +  CeH,<g^Q  +  4C,H,0H 

Fopuliu,  CgoHggOg,  which  splits  up  into  glucose,  benzoic  acid, 
and  saligenin,  is  remarkable  in  possessing  a  sweet  taste,  whereas 
salicin  is  bitter,  and  helicin  tasteless. 

The  conversion  of  populin  into  salicin  and  benzoic  acid,  and  its 
synthesis  from  salicin  and  benzoic  anhydride,  leads  to  the  following 
constitutional  formula — 

^x.CH,0.(COC,H,) 


\/\C.CeHjA 
The  aldehyde,  helicin,  is  a  more  powerful  poison  than  the  corre- 
sponding alcohol,  saligenin;  both  are  oxidized  to  salicylic  acid  in 
the  small  intestine ;  neither  liver  nor  kidney  extracts  can  decompose 
them  (Grisson). 

Arbutin,  the  glucoside  found  in  bearberry  and  allied  plants,  has 
the  formula — 

OH 
/\ 


Yc 


It  is  decomposed  by  emulsin  into  glucose  and  hydroquinone 
l:4C,H,<OH 

(methyl-hydroquinone  is  also  found,  apparently  owing  to  the  fact 
that,  besides  arbutin,  a  methyl  compound  is  always  present).  It  is 
non-poisonous,  and  is  used  as  a  urinary  antiseptic  and  diuretic. 
In  the  body  the  greater  part  is  unchanged,  but  some  hydroquinone 
is  formed,  causing  the  usual  greenish  tint  to  appear  in  the  urine. 
The  living  cells  in  muscle  and  blood  appear  to  have  the  power  of 
splitting  up  arbutin,  but  apparently,  as  with  other  glucosides  of  this 
group,  the  main  decomposing  agency  is  the  putrefactive  process  of 
the  small  intestine.  Benzoyl-arbutin  (Cellotropin)  has  been  tried  as 
a  remedy  for  tuberculosis ;  it  is  said  to  have  an  injurious  action  on 

Y  2, 


324  AESCULIN 

the  B.  Tuberculosis,  mainly  as  a  stimulant  to  the  activity  of  the 
cells  of  the  host. 

Amygdalin,  contained  in  almonds  and  many  other  plants  (prunus, 
j)^rusj  mespilusj  &c.),  is  a  derivative  of  the  nitrile  of  mandelic  acid, 

CgHg.CH/QQ      TT      Q 

and  the  sugar  is  probably  maltose,  or  a  similar  di-glucose,  which 
does  not  contain  a  free  aldehyde  group,  since  amygdalin  has  no 
action  of  Fehling's  solution. 

Its  physiological  action  depends  on  its  decomposition  in  the  small 
intestine,  with  liberation  of  HCN. 

C2oH2,NOi,  +  2H20  =  2C,I{,fi,  +  CgHgCHO  +  HCN 

Benzaldehyde.      Pruasic  acid. 

Class  III. 

With  few  exceptions  this  group  does  not  contain  bodies  of  any 
great  physiological  interest. 

Styrolene  is  phenyl-ethylene,  CgHgCHtCHg. 

Aescnlin,  CjgHjgOg,  a  glucoside  obtained  from  the  horse-chestnut 
and  other  plants,  gives,  when  treated  with  dilute  acids,  glucose,  and 
aesculetin,  a  body  which  is  isomeric  with  daphnetin  (from  Daphne 
Mezereum)',  the  constitution  of  these  substances  is  probably  ex- 
pressed by  the  formulae — 

OH 
Oh/\o CO  Ho/No CO 


OHk^— CH:CH 


— CH:CH 


Aesculetin.  Daphnetin. 

Both  are  dioxy-coumarin.  A  tincture  of  the  horse-chestnut  has 
been  prescribed  as  an  emmenagogue.  The  dried  bark  of  Daphne 
Mezereum  is  a  gastric  stimulant,  and  externally  a  rubefacient,  but 
this  action  is  probably  due  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  hypodermic 
injection.  It  has  been  used  in  lupus  as  an  auxiliary  to  the  Finsen 
light  treatment,  apparently  its  value  is  due  to  the  fluorescence. 

Coniferin,  CigHggOg,  has  the  structural  formula — 

.CH  :  CH.CH2OH  1 

CgH3fO.CgH,,0,  3 

\OCH,  4 


PHLORIZIN  325 


Derivatives  of  it  are  (i)  gluco-vanillin, 

/CHO  1 

aHsf  O.CeHnO,  3 

\OCH,  4 


'6■^■^3^ 


obtained  by  the  careful  oxidation  of  coniferin,  and  (ii)  glucovanillic 
acid, 

/COOH        1 

CeH3^0.C,H,,0,  3 

\OCH3  4 

obtained  b}^  oxidation  of  coniferin  by  means  of  potassium  perman- 
ganate. The  former  is  a  convulsant  poison  for  some  animals,  but 
10-15  grams  have  no  action  on  man. 

Hesperidiu  occurs  in  resinous  varieties  of  citrus,  on  heating  with 
dilute  sulphuric  acid  gives  rhamnose,  glucose,  and  hesperetin  : — 
^60^60^^27  +  SHgO  =  CgHj^Og  +  2  CgHjgOg  +  2  CigH^^Og 
Rhamnose.         Glucose.  Hesperetin. 

Hesperetin  has  probably  the  following  constitution  : — 
XH :  CH.COO.CgH3(OH)2 

CgHg^OH 

'    '\0CH3 

In  the  alkaloid  the  hydrogen  atoms  of  the  hydroxyl  groups  are 
joined  to  rhamnose  and  glucose. 

Phlorizin  is  the  only  glucoside  of  this  group  which  is  interesting 
from  a  physiological  standpoint.  Its  action  is  well  known,  and  is 
shared  in  a  less  degree  by  phloretin,  the  body  formed  when  glucose 
has  been  split  off. 

Phloretin  has  a  constitution  expressed  by  the  formula — 
OH 

-CO— CH- 

OH        CH3  ^^—OH 

This  is  based  on  its  decomposition  by  potash  into  phloroglucin  and 
phloretinic  acid — 

1  •  ^  ^6^4<^CH(CH3).COOH 

In  its  chemical  reactions  phloretin  is  similar  to  Cotoin,  a  glucoside 
obtained  from  coto  bark  (species  undetermined),  which  has  a  special 
action  on  the  intestinal  vessels.  These  are  dilated,  and  thus  absorp- 
tion is  favoured.     It  has  no  astringent  or  antiseptic  action,  but  is 


326  STROPHANTHIN 

largely  used  in  anti-diarrhoeic  mixtures  in  the  form  of  a  tincture. 
The  sugar-free  nucleus  is  stated  to  have  the  constitution  (Schmiede- 
berg) — 

/(OH), 
CeH^^CO.CeH, 
\OCH3 

Fortoin  is  methylene  dicotoin,  CliJ^CiJi^fi^)^ ;  it  has  not  the 
bitter  taste  of  cotoin,  is  more  powerful  in  action,  and  is  also 
bactericidal  {Pkarm.  J.,  i.  1900,  p.  531). 

Several  substances  have  been  described  under  the  name  of 
Strophauthiu ;  two  of  these  are  crystalline  glucosides  obtained 
from  Stro^Mntkus  Komhcj  and  the  other  an  amorphous  preparation 
from  Stroj)hanthus  hispidus.  Arnaud,  and  later  Kohn  and  Kulisch, 
isolated  a  substance  of  the  composition,  Cg^H^gOjg,  from  S.  Kombe. 
This  glucoside  has  a  bitter  taste,  and  its  aqueous  solution  is  optically 
inactive.  On  hydrolysis  it  yields  strophanthidin,  and  a  sugar  or 
mixture  of  sugars  whose  composition  has  not  been  determined. 
Strophanthidin,  CjgHggO^,  or  CggH^oOg,  although  a  very  hygroscopic 
substance  is  not  soluble  in  water. 

Merck's  preparation,  which  is  termed  ^-strophanthin,  was  isolated 
from  Strophanthis  gratus  by  Thoms.  The  formula  CgoH^gO^g .  9  HgO 
has  been  assigned  to  it ;  Schedel  showed  its  value  in  conditions  of 
cardiac  weakness.  The  amorphous  strophanthin  obtained  from  the 
seeds  of  Strophanthus  hispidus,  is  given  in  much  smaller  doses  than 
the  previous  derivative,  but  whether  it  is  more  powerful  in  its  action, 
or  has  more  toxic  properties,  has  not  yet  been  decided. 

In  these  groups  must  also  be  included  Iridin,  C24H25O13,  a  gluco- 
side with  a  complex  structure,  obtained  from  the  Iris  florentina  and 
Iris  versicolor. 

It  breaks  down  primarily  on  saponification  into  glucose  and 
irigenine,  CjaHigOg.  This  latter  body  yields  iretol  (oxymethyl- 
phloroglucin), 

OH 

CH30<^~~~\0H 
OH 
formic  acid,  and  iridinic  acid, 

OH 


CH30<(^        ^CH2.C00H 

on  heating  with  concentrated  solution  of  potash. 


SAPONARIN 


327 


Iridin  is  a  cholagogue  purgative. 

Saponarin,  a  glucoside  found  in  Saponaria  officinalis ,  and  other 
plants  may  probably  be  classed  here.  With  iodine  this  derivative 
gives  rise  to  the  blue  colour  characteristic  of  starch,  and  hence  was 
formerly  regarded  as  an  amorphous  variety  of  that  substance. 

Barger,  who  has  recently  investigated  this  substance,  found  on 
hydrolysis  that  it  yielded  glucose,  a  body  named  saponaretin,  and 
another  identical  with  vitexin,  a  colouring  matter  obtained  by 
Perkin  from  the  decomposition  of  the  glucoside  of  Fiteas  littoraliSj 
and  supposed  to  have  a  constitution  represented  by  the  formula — 


HO 
HO 


O 


OHCO 


CH— CgH^.OH  1:4 
CH.OH 


Saponaretin  may  be  identical  with  homovitexin  (Perkin). 

Scoparin  may  be  methoxy-vitexin. 

Bhaxnuetin,  the  decomposition  product  of  the  glucosides  of 
various  species  of  Ekamnus,  including  R.  PursMana,  is  stated  to 
have  the  following  constitution  : — 


CH30. 


It  also  is  a  colouring  matter,  like  Quercitrin  CgiHggOjg,  which,  on 
hydrolysis,  gives  rise  to  quercetin  and  the  carbohydrate  rhamnose. 
Quercetin 

O  OH 


IJJ^'C.OH 
OHCO 


is  found  combined  and  free  in  many  varieties  of  plants,  such  as  the 
leaves  and  flowers  of  the  horse-chestnut,  and  the  berries  of  Hippo- 
phoea  rhamnoides.  Perkin  and  Hummel  found  an  identical  pigment 
in  onion  rinds.  E-hamnetin  is  mono-diethyl-quercetin,  Fisetin 
(from  Rhus  Cotinus)  is  mono-oxy-quercetin,  and  a  pigment  in  the 


328 


ANTHRAQUINONE 


leaves  and  steins  of  some  species  of  tamaris  is  a  methyl  ether  of 
quercetin — 

Chrysin,  O 

HCy'VNc-CeH, 
CH 

which  has  three  atoms  of  oxygen  less,  can  be  decomposed  into 
phloroglucin,  benzoic  acid,  and  acetic  acid,  just  as  quercetin  yields 
phloroglucin,  protocatechuic  acid,  and  glycolic  acid. 

Class  IV. 

This  group  contains  a  number  of  purgative  bodies  derived  from 

anthraquinone — 

CO 


Chrysophanic  acid,  dioxy-methyl-anthraquinone, 

CH3X  /COv 

>C,h/      >CeH30H 


OH^ 


C(X 


is  a  purgative  principle  present  in  rhubarb.  As  a  glucoside,  it 
occurs  as  chrysophan,  which  has  not  yet  been  isolated  in  the  same 
plant.  Increase  in  the  hydroxyl  groups  produces  increased  purga- 
tive action,  as  in  Emodin,  trioxy-methyl-anthraquinone — 


CH. 
OH 


\        /^^\ 


.OH 
^\0H 


(The  orientation  of  these  derivatives  is  not  certain.) 

An  identical  emodin  occurs  in  rhubarb,  and  combined  with  rham- 
nose  as  a  glucoside  in  frangula  bark  (Buckthorn) ;  the  form  obtained 
from  aloes  differs  slightly.^  The  oxidation  product  of  emodin, 
aloechrysin,  is  intermediate  physiologically  between  emodin  and 
chrysophanic  acid. 


There  are  fifteen  theoretically  possible  isomers. 


DERIVATIVES  329 

Whereas  the  oxygen  appears  to  increase  the  intensity  of  the 
action,  and  its  position  is  also  of  importance,  the  methyl  group 
appears  to  be  of  little  importance.  Vieth,  from  the  synthetic  side, 
arranged  the  following  table. 

The  numbers  in  the  formula  show  the  position  of  the  substituting 
groups : — 

8      CO    1 


Most  active,  Anthrapurpurin,  l:2:7-trioxy-anthraquinone. 

^  as  strong,  Flavopurpurin,      1:2:6      „  ,,. 

1^  as  strong,  Anthragallol,         1:2:3      „  „ 

J  as  strong,  Purpur-oxy-anthin,  l:3-dioxy-anthraquinone. 

y\^  as  strong.  Alizarin  (Bordeaux),  1 :2 :3 :4-tetraoxy-anthraquinone. 

■^^  as  strong,  Purpurin,  l:2:4-trioxy-anthraquinone. 

A  number  of  products  such  as  rufigallic  acid  (hexa-oxy-anthra- 
quinone),  acetyl-rufigallic-tetramethyl  ether,  ordinary  alizarin,  nitro- 
purpurin,  and  cyanin  are  inactive.  Some  of  the  active  bodies  contain 
a  methyl  group  and  some  do  not. 

The  purgative  properties  have  been  variously  attributed  to  the 
anthracene  group,  to  the  ketonic  groups  in  anthraquinone,  and  to 
the  latter  in  the  presence  of  hydroxyl  and  aliphatic  side-chains. 
The  greater  activity  of  the  natural  glucosides  as  purgatives,  when 
compared  with  their  hydrolytic  decomposition  products,  is  due  to  the 
fact  that  the  latter  are  too  rapidly  absorbed  from  the  intestine,  and 
thus  lose  their  laxative  effect. 

A  number  of  synthetic  bodies  have  been  prepared  from  anthracene 
— starting  from  aloin,  which  has  the  formula  Cj^H^fi^  +  l^Hfi, 
and  contains  several  hydroxyl  groups;  these  have  been  variously 
combined  in  order  to  produce  bodies  which,  while  possessing  the 
purgative  action,  have  not  the  bitter  taste  of  the  parent  substance. 
The  compounds  should  also  be  more  stable  and  thus  more  active 
for  reasons  already  noted. 

The  methylene  radical  may  replace  two  hydrogen  atoms  of 
hydroxyl  groups,  and  tribromaloin,  Ci^Hi^BrgO^,  and  triacetyl- 
aloin,  Ci^}i^^(C2B.fi)fi^,  have  been  prepared  and  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). 

Exodiue  is  apparently  diacetyl-rufigallic-tetramethyl-ether  (rufi- 
gallic  acid  is  1:2:3:5: 6 :7-hexaoxy-anthraquinone);  its  action  is 
mild.  The  hexamethyl  ether  of  rufigallic  acid  has  purgative  pro- 
perties, but  these  are  not  possessed  by  acetyl-rufigallic  acid,  the  penta- 
methyl  ether,  or  the  diacetyl-tetramethyl  ether  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  glucosidic  bodies,  of  which  the  empirical  formulae  alone 
are  known,  are  of  great  importance  from  the  pharmacological  point 
of  view,  as  among  them  are  many  drugs  frequently  used  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 

Various  groups  have  been  constructed,  according  to  the  number 
of  carbon  atoms,  but  a  definite  correspondence  between  these  groups 
and  special  pharmacological  properties  has  not  been  made  out.  The 
bodies  produced  by  hydrolysis  (sapogenins)  are  usually  inert. 

Some  confusion  exists  as  to  the  terms  employed.  Schmiedeberg 
calls  the  entire  class  Sapotoxins,  and  the  hydrolytic  decomposition 
products  Saponins.  Van  Rijn  calls  the  entire  class  Saponins,  apply- 
ing the  term  Sapotoxin  to  some  individual  members  of  Robertas 
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,  quillaiac  acid, 
polygallic  acid,  sarsa-saponin,  and  smilax-saponin  are  among  the 
more  important  members  of  the  group. 


CHAPTEE   XVII 

Dependence  of  Taste  and  Odour  on  Chemical  Constitution, — 
The  Organic  Dyes.  I.  Sternberg's  views.  Saccliarin  and  its  derivatives. 
Dulcin.  II.  Odour:  Physical  and  Chemical  factors  in  its  production. 
III.  Organic  dyes.— Ehrlich's  criticisms  of  Loew's  theory  of  poisons. 
Picric  acid,  Aurantia,  Chrysoidin,  Bismarck  brown,  Methyl  violet,  Me- 
thylene blue,  Phosphorine. 

I.    TASTE. 

Investigations  as  to  the  relationships  subsisting  between  the 
chemical  constitution  of  substances  and  their  effects  on  the  special 
senses  are  peculiarly  interesting,  in  that  here  the  application  is 
direct,  and  such  factors  as  digestion,  absorption,  elimination,  &c., 
which  obscure  many  points  in  the  physiological  action  of  drugs  as 
a  whole,  can  hardly  be  considered  of  preponderating  importance. 
The  two  special  senses  of  taste  and  smell  may  be  regarded,  so  far 
as  our  present  purpose  is  concerned,  as  differing  from  that  of  vision 
in  one  important  particular,  namely  that  the  peripheral  end  organs  of 
taste  and  smell  in  the  epithelium  of  the  mouth  and  nose  are  stimulated 
directly  by  certain  substances,  whereas  the  rods  and  cones  in  the 
retina  are  stimulated  by  etherial  vibrations  of  a  certain  character 
and  frequency  which  travel  from  a  distance. 

Taking  the  sensorium  generally,  a  series  may  be  noted,  in  which 
the  chemical,  as  opposed  to  the  physical,  element  in  the  stimulant 
becomes  more  and  more  pronounced.  End  organs  responding  to 
stimuli  of  touch,  heat  and  cold,  muscular  or  pressure  sense,  &c., 
which  are  widely  distributed  over  the  surface  of  the  body,  are 
absolutely  outside  the  domain  of  chemical  influences.  The  slow 
vibrations  which  are  transmuted  into  nerve  impulses  by  the  organs 
of  Corti  are  also  conditioned  by  physical  processes.  The  distinction 
between  regular  and  irregular  vibrations,  however,  is  well  marked. 

Passing  to  the  rapid  vibrations  which  are  known  as  light, 
chemical  and  physical  factors  modify  the  vibrating  particles,  and 
hence  also  the  waves  set  up  in  the  ether,  of  which  only  a  limited  num- 
ber are  perceptible  to  the  eye.    But  in  the  case  of  taste  sensations. 


332   DEPENDENCE   OF   TASTE   ON   CONSTITUTION 

owing  to  the  fact  that  the  body  in  solution  is  applied  directly  to 
the  nerve  terminations,  chemical  structure  becomes  of  great  import- 
ance; and  this  is  also  true  in  the  case  of  smell,  where  the  end 
organs  are  directly  stimulated  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  nearly  analogous  to  the  process  by  which  a 
thread  (or  an  animal  cell)  takes  up  a  dye-stuff  than  that  by  which 
the  retina  records  the  impressions  of  various  kinds  of  light. 

Our  present  knowledge  of  the  subject  of  intra-molecular  vibra- 
tions is  so  slight  that  nothing  more  than  the  mere  suggestion  can 
be  thrown  out  that  the  stimulus  in  the  case  of  taste  and  smell  is 
likewise  due  to  some  type  of  vibratory  movement,  transmitted 
directly,  not  indirectly,  to  the  sensitive  end  organs  by  the  sapid  or 
odorous  substance.  Several  facts  in  the  general  relationships 
which  have  been  shown  to  exist  between  chemical  structure  and 
taste  are  at  any  rate  consonant  with  such  a  view. 

In  Mendeleeff^s  periodic  classification  of  the  elements  it  will  be 
noticed  that  those  possessing  a  sweet  taste  are  mostly  found  in  the 
third  (boron,  aluminium,  scandium,  yttrium,  lanthanum)  and 
fourth  (lead,  cerium)  groups.  It  is  interesting  to  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  mainly  in 
the  second  group  (magnesium,  zinc,  cadmium,  mercury);  while 
sulphur  in  the  sixth  group  often  gives  rise  to  bitter  compounds, 
and  chlorine  in  the  seventh  group  to  sweet  ones. 

The  characteristic  taste  of  acids  and  bases  depends  upon  their 
dissociation,  the  hydrogen  ion  giving  rise  to  the  acid  and  the 
hydroxyl  to  the  alkaline  taste ;  consequently  the  stronger  the  acid 
(that  is,  the  greater  the  degree  of  dissociation)  the  more  pronounced 
is  the  acidic  taste.  A  similar  relationship  holds  good  with  the 
alkalis.  Organic  acids  consequently  lose  their  taste  on  conversion 
into  esters. 

The  remaining  facts  concerning  the  relationships  between  taste 
and  smell  and  chemical  constitution  are  too  disjointed  for  anything 
like  systematic  arrangement.  They  will  therefore  be  grouped  under 
a  few  main  headings,  which,  while  not  showing  any  mutual  inter- 
dependence, will  enable  the  experimental  evidence  to  be  presented 
in  a  more  orderly  manner. 


HYDROXYL  DERIVATIVES  333 

Among  organic  compounds,  substances  with  very  low  or  with 
very  high  molecular  weight  are  usually  tasteless. 

1.  Sternberg^  has  pointed  out  that  among  organic  substances 
a  certain  '  harmony '  or  equilibrium  is  necessary  in  order  to  produce 
a  sweet  taste ;  if  this  is  much  disturbed,  the  sweet  taste  is  lost. 

The  alkyl  and  hydroxyl  groups  must  be  equal  in  number,  or  the 
former  only  exceed  the  latter  by  one.    Thus 

OH 

CHgOH  y^ 

I  OH.CHr  Vh.oh 

glycerin,  CHOH  inosite, 

I  OH.C 

CHgOH 


?<g 


OCH 


Ah-- 

methyl  glucoside,   |  and  rhamnose,  (CHOH)^ 

;ho 


(CH0H)3  I 


CH2OH 

are  all  sweet ;  so  are  the  di-saccharides,  but  the  tri-  and  poly- 
saccharides are  tasteless. 
But  methyl  rhamnoside 

CH, 


(CH0H)3 
CH. 

I   )o 

^^\0CH3 

is  bitter,  and  the  ethyl  derivative  still  more  so — 

CH3 

(CH0H)3 

CR 

*  Geschmack  und  Geruch^  Dr.  Wilhelm  Sternberg,  and  many  papers. 


334      INFLUENCE   OF   THE  PHENYL   RADICAL 


2.  In  the  aliphatic  series  the  polyhydric  alcohols,  oxy-aldehydes, 
and  oxy-ketones  are  characterized  by  their  sweet  taste.  In  the 
series  from  ethyl  alcohol  to  mannite,  CgHg(OH)g ,  the  taste  increases 
in  proportion  to  the  number  of  hydroxy  1  groups.  Grape  sugar, 
CH20H(CHOH)4.  CHO,  containing  an  aldehyde  group,  is  sweeter 
than  mannite.  Slight  alterations  in  the  composition  of  the  sugars 
completely  alter  their  taste,  and  the  condensation  products  of  the 
sugars  with  ketones  are  all  bitter.  The  replacement  of  hydroxyl 
hydrogen  by  acid  radicals  converts  the  sugars  into  bitter  substances, 
and  further  replacement  produces  tasteless  derivatives.  Although 
grape  sugar  is  sweet,  glycuronic  acid,  COOH .  (CHOH)^ .  CHO, 
has  the  characteristic  acid  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-phenol  are  sweet.  Trinitro-phenol  (picric  acid) 
and  dinitro-monochlor-phenol  are  bitter.  Nitro-dichlor-phenol  is 
tasteless. 

4.  Another  fact,  connected  most  probably  with  molecular  equili- 
brium, is  the  passage  of  a  sweet  substance  into  a  bitter  by  the 
replacement  of  positive  alkyl  groups  by  negative  phenyl  radicals, 
thus : — 


Sweet. 

Bitter. 

(1)          CH3.CHOH.CH2OH 
1 : 2-Dioxy-propane. 

CeHs.CHOH.CHaOH 
Phenyl-glycol. 

(2)  CH3.CHOH.CHOH.CH2OH 
1:2:  3-Trioxy-butane. 

CeHg.CHOH.CHOH.CHaOH 
a-phenyl-glycerol. 

(3)  CH20H.(CHOH)3.CH.CH.OCH3 
0 

CH20H.(CHOH)3 .  CH.CH.O.CH^CeHg 
0 

Methyl-glucoside. 

Benzyl-glucoside. 

Possibly   it   is  the  presence  of  aromatic  radicals  in  the  natural 
glucosides  which  accounts  in  a  similar  way  for  their  bitter  taste. 

The  introduction  of  -CHgOH  or  chlorine  or  bromine  into  the 
aromatic  nucleus  of  phenyl -glucoside  does  not  diminish  the  bitter 
taste,  thus : — 


phenyl-glucoside, 
salicin, 

mono-chlor  salicin, 


CeHaO. 


C,HiA 


O.CsH^.CH^OHlia, 
r>  p  Ti  /CHjOH 


INFLUENCE   OF  AMIDO   GROUPS  835 

are  bitter,  but  benzoyl-salicin  (populin), 

CeH,  A  •  O .  CeH, .  CH,0(COC,H,), 
is  sweet,  and  the  introduction  of  a  second  benzoyl  group  gives  rise 
to  a  tasteless  body. 

Tetra-acetyl-chlor-salicin 

CeH,(C0CH3)  A  •  O.CeH3<gi^2^H 

is  also  tasteless,  and  so  is  helicin,  the  aldehyde  of  salicin, 
CeHjA-O.C,H,.CHO. 

5.  Hydrocarbons,  either  of  aliphatic  or  aromatic  series,  are  usually 
tasteless.  The  introduction  of  oxygen  or  nitrogen,  however,  or  of 
both,  under  definite  conditions  may  cause  the  appearance  of  a 
substance  possessing  this  quality.  Sternberg  hence  calls  them 
'  Sapiphore  ^  groups. 

Positive  and  negative  radicals  must  be  combined  in  order  to  pro- 
duce the  effect,  negative  hydroxyls  with  positive  alkyls,  and  positive 
amido  groups  with  negative  carboxyls.  Thus  when  NHg  and 
COOH  groups  occur  in  close  proximity  in  a  molecule  (i.  e.  the 
a  position)  the  effect  is  more  pronounced  than  when  they  are 
separated  by  carbon  atoms  (/3  and  y  positions) ;  a-amido-carboxylic 
acids  of  the  aliphatic  series,  for  instance,  are  sweet,  but  /S-amido- 
valerianic  acid  is  only  slightly  so,  and  has  a  bitter  after-taste, 
whereas  y-amido-butyric  acid  has  lost  the  sweet  taste.  a-Amido- 
/3-oxy-propionic  acid, 

CH3.CH.OH.CH<NH3jj_ 

and  a-amido-^-oxy-valerianic  acid, 

CH3 .  CH^ .  CHOH.CH<(^J^ jj^ 

are  quite  sweet,  whereas  a-oxy-)S-amido-propionic, 

CHg.  CHNHg.  ^H<^^QQjj 

is  not.    In  this  connexion  it  is  interesting  to  note  that  a-pyrroli- 
dine  carboxyhc  acid 

CH. 


has  also  a  sweet  taste. 


CH.COOH 
NH 


336  INFLUENCE   OF  AMIDO   GROUPS 

In  the  aromatic  series  this  does  not  always  hold  good,  the 
negative  phenyl  nucleus  playing  an  important  part,  as  mentioned 
previously  in  the  case  of  phenyl- glycerin.  Thus  phenyl-amido- 
acetic  acid, 

is  tasteless,  but  a-amido-/3-phenyl-propionic  acid  is  sweet — 

CgHg .  CH2 .  cjh<^co6h 

When  the  substituents  (NHg  and  COOH)  are  in  the  ring,  Stern- 
berg compares  the  ortko  derivatives  to  the  a-aliphatic  substances. 
Thus 

^6^4\co6h^-^ 

is  sweet,  whereas 

^6^4<co6h^'^ 

is  tasteless.     Further,  l:2-amido  salicylic  acid  is  slightly  sweet, 
whereas  the  1 : 3  and  1 : 4  amido  acids  are  tasteless. 
The  ort/io  sulphonated  derivative  of  benzoic  acid, 
^jj/SO^OH 

has  the  characteristic  acid  taste ;  the  sulphamide, 
•  (.jj/SO^NH 

is  tasteless,  but  the  corresponding  inner  anhydride,  o-anhydrosulph- 
amine-benzoic  acid, 

has  an  intensely  sweet  taste,  and  has  been  introduced  under  the 
name  of  Saccharin.  It  is  obtained  from  toluene  by  firstly  sulpho- 
nating  at  100°  C,  which  gives  the  best  yield  of  l:2-toluene- 
sulphonic  acid, 

then  converting  the  resulting  substance  into  the  sulphochloride  by 
means  of  phosphorus  pentachloride,  and  this  into  the  amide, 

(.jj/SO,NH, 

through  the  agency  of  ammonia.  o-Tolyl-sulphamide  is  then 
oxidized  by  potassium  permanganate,  and  if  the  solution  is  kept 
alkaline  the  potassium  salt  of  o-sulphamine-benzoic  acid. 


SACCHARIN  337 

'SO2NH2 
.COOK, 


^6^4\CO 


is  formed,  but  when  the  free  acid  is  liberated  by  means  of  a  mineral 
acid,  dehydration  occurs  and  saccharin  results — 

.SO^NHiH  /SO2. 

CeH/      \     =Hp  +  CeH/       >NH 

\COiOH  ^CO-^ 

Up  to  1891  the  commercial  saccharin  usually  contained  40  per  cent, 
of  the  tasteless  1 :4  derivative.  One  method  of  separation  is  based 
on  the  differing  solubility  of  these  substances  in  xylene,  saccharin 
being"  soluble,  but  the  other  insoluble. 

Saccharin  passes  unchanged  through  the  organism ;  the  sodium 
salt  goes  by  the  name  of  Crystallose,  the  ammonium'  is  termed 
Sucr  amine. 

Saccharin  still  retains  its  sweet  taste  when  a  hydrogen'  atom  of 
nucleus  is  replaced  by  NHg- — 

/\— SO^v 


NH^ 


yNH 

— CO^ 


but  a  corresponding  replacement  by  a  nitre  group  gives  rise  to 
a  substance  with  bitter  taste. 

The  replacement  of  the  imide  hydrogen  by  the  ethyl  group 

results  in  a  tasteless  substance. 

6.  Salicylic  acid  is  sweet,  and  its  amide, 

1  : 2-CeH,<^^Q^jj^^ 

is  tasteless;    but  although  7;z-oxybenzoic  acid   is   also   sweet,   its 
amide, 

1 : 3-C6H4<;^(.Q^jj^^ 
is  bitter ;  its  dehydration  product,  however,  the  nitrile 

is   sweet.     Among  the  nitro  derivatives    of  ^-oxybenzoic  only 
one,  viz. 

/OH  1 

C«H,^NO, 


'6-^-^3 


\co6h  3 


338  DIBASIC  ACIDS 

is  sweet,  the  others  are  tasteless ;  all  the  (iinitro-»2-oxybenzoic  acids 
are  also  tasteless,  but  the  trinitro  acid  is  bitter. 

The  dioxybenzoic  acids  are  tasteless. 

7.  The  presence  of  two  carboxyl  groups  in  the  molecule  and  the 
effect  of  NHg  groups  on  taste  is  illustrated  by  the  following  facts  : — 

Malonic  acid,  CH2(COOH)2,  and  succinic  acid 
CH2 .  COOH 

I 
CH2.COOH 

have  the  ordinary  acid  taste ;  methyl-amido-malonic  acid 

COOH 


CH3.C(NH2)<^^^g 
is  sour,  and  so  is  aspartic  acid — 


CHNH2.COOH 


i 


Diamido-succinic  acid. 


H2.COOH 
CH.NH2.COOH 


CH.NH2.COOH 


a  substance  which  is  only  very  slightly  soluble  in  water,  is  tasteless. 
Dextro-glutaminic  acid 

PXT/CH2.COOH 

^^2\cH.NH2.COOH 

is  sweet,  and  so  is  the  amide  of  aspartic  acid,  i.  e.  dextro-asparagin, 

CH.NH2.COOH 

I 
CH2.CONH2 

Imido-SQccinic-ethyl  ester 

CH.COOH 

>NH 


I  > 

CH.C 


COOC2H5 
is  bitter^  whereas  its  amide 

CH.CONH2 
I     >H 
CH.COOC2H5 
is  sweet. 

8.  The  effects  of  stereochemical  influences  upon  the  sense  of 
taste  have  been  previously  mentioned  (see  p.  53).  This  influence 
is  but  slight,  or  at  all  events  has  so  far  only  been  noticed  in  a  few 


INFLUENCE  OF  SYMMETRY   OF  MOLECULE   339 

cases.  Dextro-3LSi^a,ragm  is  sweet,  the  laevo  modification  is  not; 
both  d-  and  /-aspartic  acids  have  the  same  taste.  Bextro- 
glutaminic  has  a  sweet  taste,  the  laevo  form  is  tasteless. 

9.  The  symmetry  of  aromatic  hydroxyl  derivatives  appears  to  be 
of  importance  in  determining-  the  sweet  taste,  thus  : 


OH 


CH 


OH 


CH 


/\, 


OH.CH 


CH, 


CH.OH 


Trioxy-methylene, 
phloroglucite, 


Resorcin, 


\y 


OH 


CH, 


OH 


OH 


Hydroquinone, 


Yk 


HO 


OH 


/\ 


Phloroglucin, 


OH 


\/ 


OH 


Y^ 


Orcinol, 


are  all  more  or  less  sweet,  whereas 


OH 


OH 


OH 

/\0H 


Pyrocatechin,  and 


are  bitter,  and 


v- 


OH 


Pyrogallol 


CH, 


/3-orcin 


HO 


CH, 


OH 


is  tasteless,  and  the  previously-mentioned  orcinol  is  the  only  sweet 
dioxy-toluene. 

10.  The  effect  of  the  symmetry  of  the  molecule  is  also  seen  in 
the  substituted  ureas;  many  of  the  unsymmetrical  have  a  sweet 
taste,  whereas  the  symmetrical  are  tasteless,  thus  : 


a-a-dimethyl  urea. 
Sweet. 


^^/NHCH, 
^^XNHCHj 

a-/3-dimethyl  urea. 
Tasteless. 


z  % 


840  CYCLIC   CONSTITUTION  AND  TASTE 

,0<™.O.H..OC.„..:*  C0<™g.H..0C.H. 

1 : 4-phenetol  carbamide  (Duloin).  Di-p-phenetol  carbamide. 

Sweet.  Tasteless. 

Dulcin,  or  Sucrol,  breaks  down  in  the  organism,  giving  rise  to 
the  toxic  substance  phenetidin, 

consequently  its  physiological  action  is  similar  to  that  of  the  phena- 
cetin  derivatives. 

11.  The  conversion  of  chain  into  cyclic  derivatives  also  affects 
taste.     Thus : 
y-amido-butyric  acid,  NH2 .  CHg .  CHg .  CH2 .  COOH,  is  tasteless, 

CH2 .  CHg .  CHg 

pyrrolidon  |  |        is  bitter, 

NH CO 

CH2 .  CH2 .  CH2 .  CH2 .  COOH 

^-amido-valerianic  acid   |  is  tasteless, 

NH, 

CH2.CrI2CH2.CH2 

oxy-piperidon   |  |        is  bitter. 

NH CO 

CH2.N<(g^3 
Sarcosin  |  is  slightly  sweety 

COOH 

whereas  its  anhydride 

CH3 

I 
CH„— N— CO 


is  bitter.. 
CH, 

CH. 


CO — N— CH2 


N(CH3)3.CH(C,H,).COOH 

Trimethyl-amido-butyric  acid    |  is  sweet, 

OH 

the  anhydride  bitter. 

Sternberg  ascribes  the  bitter  taste  of  the  alkaloids  to  their  cyclic 
constitution. 


ODOUR  AND   CHEMICAL    CONSTITUTION      841 

II.    ODOUR. 

Our  knowledge  of  the  correlation  of  odour  and  structure  has 
been  mainly  acquired  for  the  purpose  of  producing  synthetic  per- 
fumes, an  industry  largely  carried  on  in  Germany  and  France.  In 
the  short  sketch  which  follows  the  authors  are  mainly  indebted  to 
the  works  of  Georg  Cohn  ^  and  Zwaardemaker  2,  the  former  from 
the  chemical,  and  the  latter  from  the  physiological  side. 

The  most  necessary  condition  for  the  production  of  an  odorous 
substance  is  volatility,  since  it  is  found  that  bodies  of  low  volatility 
— generally  associated  with  high  molecular  weight — have  no  effect 
on  the  olfactory  organs.  But  the  molecular  magnitude  must  fall 
within  certain  limits ;  frequently  those  with  low  molecular  weight 
— such  as  the  volatile  aldehydes  of  the  aliphatic  series — have 
unpleasant  odours,  whereas  the  higher  members  have  none  at  all; 
between  these  limits  lie  citral  and  citronellal  (p.  344),  which  are 
typical  scents,  and  the  aromatic  aldehydes,  of  higher  molecular 
weight,  which  also  have  pleasant  odours. 

Some  importance  must  also  be  ascribed  to  the  concentration  of 
the  odorous  substance  and  most  probably  to  the  nature  of  the 
solvent.  Such  substances  as  vanillin,  piperonal,  cumarin,  and  ionone, 
have  a  very  different  odour  when  in  strong  solution  to  that  which 
they  possess  when  much  diluted.  The  natural  essential  oils  used 
in  perfumery  owe  their  pleasant  odour  to  several  constituents,  and 
small  variation  in  the  concentration  of  one  may  bring  about  great 
alterations  in  the  odour  of  the  oil  itself.  It  is  generally  stated  that 
artificial  benzaldehyde  cannot  be  used  for  the  more  expensive  varieties 
of  scent,  owing  to  the  impossibility  of  freeing  it  from  minute  traces 
of  impurities.  Phenylacetic  acid  and  /3-naphthylamine  have  no  odour 
in  the  crystalline  condition,  but  smell  disagreeably  when  in  solution. 

This  property  has  been  compared  to  the  variation  in  colour 
sometimes  observed  when  a  solid  dye-stuff  is  dissolved  in  water,  and 
a  further  similarity  has  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  clearly  of  primary 
importance  in  determining  its  odour,  but  at  present  little  is  known 
of  the  general  correlation  between  these  two.  Following  the  analogy 
with  the  dyes,  certain  '  Osmophore '  groups  have  been  described,  such 

*  Die  Biechstqfe,  1904.  *  Physiologie  des  Geruchs,  1895. 


342  OSMOPHORE   GROUPS 

as  hydroxyl  (OH),  aldehyde  (CHO),  ketone  (.CO.),  ether  (.0.), 
nitrile  (CN),  nitro  (NOg),  azoimide  (N3),  which  may  condition 
odour  in  various  bodies  previously  odourless,  and  such  groups  may 
obviously  give  rise  to  substances  of  pleasant  or  unpleasant  odour. 
But  a  classification  on  the  basis  of  the  osmophores  is  impossible  in  the 
present  state  of  our  knowledge.  Equally  impossible  is  a  classification 
based  on  the  character  of  the  odour,  as  there  are  no  words  in  any 
language  by  which  odours  may  be  described,  the  only  terms  in  use 
being  those  which  point  a  similarity  to  some  other  odour,  such  as 
'  camphoraceous ',  '  vinous ',  &c. 

2.  Two  or  more  osmophore  groups  may  be  present  in  the  same 
body,  or  one  may  often  replace  another  without  materially  altering 
the  odour;  thus  benzaldehyde,  nitrobenzene,  benzonitrile,  phenyl- 
azoimide,  have  all  a  very  similar  smell.  The  introduction  of  several 
substituent  groups,  however,  leading  to  an  increase  in  the  molecular 
weight,  may  account  for  the  observed  diminution  in  the  intensity  of 
the  odour  of  the  resulting  derivative. 

3.  Homologous  derivatives  usually  have  a  similar  smell ;  this  is 
noticed  in  the  case  of  the  methyl  and  ethyl  esters  of  salicylic  acid, 
or  the  methyl  and  ethyl  ethers  of  /3-naphthol,  or  the  corresponding 
di-derivatives  of  hydroquinone. 

But  the  ethyl  group  in  the  esters  and  ethers  may  lead  to  a 
striking  diminution  in  the  odour,  whereas  the  methyl  derivatives 
are  scented  (compare  p.  49).    Thus  the  ethyl  ester  of  anthranilic  acid. 


1  . 9  P  XT  y^  Hg 
^"^^c^^xcOOCaH., 


has  only  a  slight  smell;  the  iso-hutjl  ester  has  none,  but  the 
methyl  ester  has  the  odour  of  orange  blossoms. 

In  the  aromatic  series  the  entrance  of  a  methyl  group  into  the 
ring  does  not  cause  much  alteration  in  the  odour ;  thus  nitro-benzene 
and  nitro-toluene  are  very  similar,  and  methyl- vanillin,  methyl- 
cumarin,  smell  very  like  the  substances  from  which  they  are  derived. 
Radicals  rich  in  carbon  have  a  considerable  influence  on  odour,  as 
illustrated  in  the  table  on  the  next  page. 

The  amyl  radical  appears  to  have  a  special  function,  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  halogens  only  influence  odour  when  introduced  into  the 
side-chains,  and  not  when  substituted  in  the  nucleus  of  aromatic 
derivatives;  thus  brom-/?-naphthol -methyl-ether  and  the  chlori- 
nated benzaldehydes  have  a  similar  smell  to  the  parent  substances. 


INFLUENCE  OF  NITROGEN  RADICALS        343 

5.  Phenols  and  phenol  ethers  have  characteristic  odours,  and 
those  with  olefine  substituents,  especially  the  allyl  or  propenyl 
groups,  are  found  in  several  volatile  oils.  The  carboxyl  group 
destroys  the  odour  of  alcoholic  and  phenolic  substances. 

6.  Nitrogen-containing  radicals  play  an  important  part  in  deter- 
mining odour,  and  for  this  purpose  the  nitro  group  is  of  more 
importance  than  the  nitrile. 


MO-propyl-phthalide, 

CH.CH(CH3)2 

CeH,<     >0 

CO 

Phthalide  has  no  smell. 

e>o-propylidene-phthalide, 

CH^ 

C:C(0H3), 

CeH,<      >0 
CO 

O.H.<^ 

CH.C^Hg 

butyl-phthalide,  C^H/^      ^0 
no 

all  smell  of  celery* 

1 : 4-tolyl-acetylene, CHg .  CgH^ .  C  j  CH, 

1 : 4-ethyl-phenyl-acetylene, 

C2H,.CeH,.C:CH, 

Phenyl-acetylene  has 

both  smell  of  anise. 

an  unpleasant  smell. 

1 1 4-2>o-propyl-phenyl-acetylene, 

CeHg.CjCH 

(CH3)2CH.C6H4.C:CH, 

*-trimethyl-phenyl-acetylene, 

(CH3)3CA.C:CH, 

have  a  pleasant  etherial  smell. 

wo-Nitriles  generally  have  extremely  disagreeable  odours.  The 
higher  homologues  of  trinitro-benzene  smell  of  musk.  Methyl- 
benzoate  has  the  characteristic  slight  smell  of  so  many  of  the 
aromatic  esters,  whereas  the  l:4-amido  derivative  smells  of  orange 
blossom.  In  the  series  of  nitro  derivatives  smelling  of  musk  a 
nitro  group  may  be  replaced  by  the  azoimide  without  altering  the 
odour  of  the  original  substance. 


344 


PERFUMES 


7.  It  is  among  tlie  higher  alcohols  and  ketones,  and  especially  the 
aldehydes^  that  the  majority  of  substances  used  in  perfumery  is  to 
be  found.  The  following  list  contains  a  few  typical  examples  of 
each  class.  The  isolation  and  identification  of  such  substances 
from  the  essential  oils  and  their  artificial  production^  or  the 
synthesis  of  closely  allied  derivatives,  has  been  developed  with 
great  success  during  the  last  twenty-five  years,  and  has  resulted 
in  an  industry  of  considerable  importance : — 

Alcohols : 
1.  Linalool  ....      odour  resembles  that  of  may  flower 

/OH 
(CH3)2 .  C :  CH.CH2 .  CH2 .  C^CH  :  CHg 


2.  Citronellol 


(CH3)2.C:CH.CH, 


CH2 .  CH{CH3).  CH2 .  CHgOH 


roses 


roses 


3.  Geraniol  . 

(CH3)2 .  C  :  CH.CH2 .  CH2 .  C(CH3) :  CH.CHgOH 

4.  Among  ring  structures  are  found  borneol,  menthol,  terpineol 

(lilac  odour). 
These  alcohols — and  so  far  only  those  with  more  than  eight  carbon 
atoms  have  been  found  in  volatile  oils — may  be  converted  into 
esters  (see  p.  122)  and  variations  in  odour  obtained.  Thus  the 
linalool  and  geraniol  esters  of  acetic  acid  have  an  odour  of  oil 
of  bergamot.  The  esters  of  borneol  all  possess  an  odour  similar  to 
the  acetate,  the  intensity  of  which  diminishes  with  an  increase  in 
the  molecular  weight  of  the  acid.  The  acetate  of  /-borneol  is  present 
in  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 . 

3.  Vanillin 

4.  Piperonal 


CeHgCH  :  CH.CHO 


.CHO     1 
C„Ho^OCH,    3 

4 


'    '\0H  ' 


cmnamon 


vanilla 


„   heliotrope 


/CHO        1 


PERFUMES  345 

Ketones : 

1.  Methyl-ethyl-acetone     .         .  odour  resembles  that  of  peppermint 

CH3.CO.CH<CH3^ 

2.  Various  derivatives  of  cyclo-hexanone,  e.g.  pulegone  „ 

3.  Camphor,  fenchone,  carvone  (odour  of  caraway) 

4.  lonone  .         .         .  odour  resembles  that  of  fresh  violets 

5.  Various  substitution  products  of  acetophenone,  CgH5.CO.CH3. 

Phenols  and  Phenol-ethers : 

1.  Carvacrol        ....      odour  resembles  that  of  thyme 

.OH     1 

^6^3^-0  Hg         3 

XCgH,  6 

2.  Thymol „  „         thyme 

.OH     1 

3.  jS-naphthol-methyl  ether         .         .         „  oilofneroli 

^^0^7  •  O.CH3 

4.  Safrol ,  oil  of 


^^0^7  •  O.CH3 

CgHg^O/^^^  2 

\CH2.CH:CH2    4 

5.  Eugenol „  oil  of  cloves 

.OH        1 

C,H3^0CH3    2 

\C3H5      4 

8.  Isomeric  relationships  naturally  play  an  important  part  in 
conditioning  odour^  as  they  do  with  regard  to  other  physical  charac- 
teristics of  organic  compounds.  Thus  ?^o-vanillin  is  scentless,  and 
in  the  artificial  musks — e.  g.  in  trinitro-'\|/'-butyl-ethyl-benzol, 

CH,~CH<^H3 


NO 


—NO 


C2H5 


NO2 


and  in  many  similar  derivatives  having  the  same  odour,  the  three 


346  INFLUENCE   OF   ISOMERIC  RELATIONSHIPS 

nitro  groups  must  be  symmetrically  placed,  otherwise  this  charac- 
teristic is  lost. 

The  1:2  and  1:4  (but  seldom  the  1:3)  positions  in  the  benzene 
nucleus  are  substituted  in  many  of  the  artificial  scents.  Thus 
1 :4-methoxy-acetophenone,  CHg  .  CO.CgH^ .  OCH3,  has  a  pleasant 
smell;  the  1:3  isomer  is  without  scent.     l:2-amido-acetophenone, 

ri  XT  /COCH3 

1: 2-amido-benzaldehyde, 

p  XX  /CHO 

^6^4\nH3 

and  1 :2-nitro-phenol  have  strong  odours,  whereas  the  corresponding 
1:3  and  1:4  derivatives  have  none.  In  this  connexion  it  may  be 
mentioned  that  although  salicyl  {prtho  derivative)  and  anis-alde- 
hydes  i^ard)  both  occur  in  nature,  neither  the  corresponding 
?;2-oxy-benzaldehyde  nor  its  derivatives  are  found. 

9.  Reduction  may  alter  a  scent,  but  does  not  render  it  disagree- 
able, as  seen  in  the  following  cases.     Cinnamic  aldehyde, 

C6H5CH:CH.CHO, 

smells  of  cinnamon.  The  reduced  derivative,  CgHg .  CHg .  CHg .  CHO, 
has  a  most  characteristic  odour  of  lilac  and  jasmine.     Coumarin 

/O CO 

\CH=CH 

has  the  odour  of  woodruff,  also  noticeable  in  melilotin — 

/O CO 

c,h/         I 

^CHg— CHg 

10.  Unsaturated  sub^ances  generally  have  powerful  odours. 
Triply-linked  carbon  systems  are  frequently  associated  with  un- 
pleasant odours,  thus  phenyl-propiol-aldehyde,  CgH^C  \  C.CHO,  and 
1 : 2-nitro-phenyl-acetylene,  NOg .  CgH^ .  C  j  CH,  are  most  disagree- 
able. This  may  be  contrasted  with  the  effect  of  the  double  bond, 
which  usually  gives  rise  to  bodies  with  pleasant  smells ;  compare 
styrene,  CgH5CH:CHg,  which  is  found  in  storax  oil,  and  various 
other  instances  which  have  been  previously  given. 


THE   ORGANIC  DYES  347 

III.     THE   ORGANIC   DYES. 

Spectroscopic  investigations  have  shown  that  no  open-chain  hydro- 
carbon causes  selective  absorption,  but  that  benzene  and  allied 
hydrocarbons  are  characterized  by  selective  absorption  of  the  most 
refrangible  rays,  and  are  thereby  differentiated  from  all  other 
classes. 

Consequently,  it  may  be  stated  that  benzene  has  'invisible^ 
colour  (Hartley)  which  will  become  visible  when  the  rate  of  vibra- 
tion of  the  molecule  is  so  slackened,  that  it  will  be  possible  for  the 
molecule  to  absorb  rays  having  an  oscillation  frequency  occurring 
within  the  limits  of  visibility.  Phenol,  CgHgOH,  is  *  invisibly' 
coloured;  it  shows  selective  absorption  in  the  ultra  violet  region, 
but  the  replacement  of  these  hydrogen  atoms  by  three  nitro  groups 
gives  the  yellow  picric  acid.  The  mere  fact,  then,  that  an  aromatic 
substance  is  coloured  or  has  dyeing  properties  does  not  necessarily 
mean  that  it  will  in  consequence  show  any  novel  pharmacological 
action. 

The  reduction   of  a  dye-stuff  results  in  the  formation  of  the 
so-called  '  leuco '  compound.     For  instance,  pararosaniline 
NH2.CeH,-C-C,H,.NH2 


Y 

NH2CI 

becomes  the  colourless  leuco*pararosaniline — 

NH2 .  CgH^— CH— CgH^ .  NH2 

CeH^.NH^ 
This  derivative,  on  oxidation,  gives  the  corresponding  colourless 
carbinol,  the  base  of  the  dye, 

NH2 .  CgH^— C(OH)— C6H4NH2 

I 
CeH^.NH^ 

which  on  treatment  with  hydrochloric  acid  gives  the  dye  itself. 

In  general,  the  accumulation  of  carbon  atoms  deepens  the  tint, 
as  also  does  the  introduction  of  substituting  groups.  Thus  rosaniline 
is  red,  and  as  th«  hydrogen  atoms  of  the  NHg  groups  are  replaced 


348  CRITICISM   OF  LOEW^S   THEORY 

by  methyl  radicals,  the  colour  passes  from  red  to  violet-red,  and  in 
hexa-methyl  rosaniline  becomes  violet-blue.  The  replacement 
of  hydrogen  atoms  by  ethyl  or  phenyl  groups  intensifies  this  effect. 
Hexa- ethyl  rosaniline  is  violet  with  a  blue  nuance,  and  the  tri- 
phenyl  substitution  product  is  blue. 

Allusion  has  already  been  made  (p.  22)  to  the  auxochrome  groups 
described  by  Witt.  These  are  of  two  kinds,  basic  and  acid,  so  that 
from  each  chromogen  two  series  of  analogous  dyes  may  often  be 
obtained,  thus  : — 


Acid  Dyes. 

Auxochrome  (OH). 

Oxy-azo-benzene. 

Dioxy-azo-benzene. 

Rosolic  acid. 

Thionol. 
Aposafranone. 


Basic  Dyes. 

Auxochrome  (NHj). 

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  deepen  the  intensity  of  the 
colour. 

Largely  on  the  grounds  of  his  observations  on  the  action  of  dye- 
stuffs  Ehrlich  has  criticized  the  '  substitution '  theory  of  Loew,  to 
which  allusion  has  been  made  in  an  earlier  chapter  (p.  17).  The 
evidence  he  has  collected  on  this  point  may  be  summarized  as 
follows  ^ : — In  some  basic  dyes  the  amido  group,  or  groups,  undergo 
interaction  with  substances  containing  aldehyde  radicals,  and  a 
change  of  colour  is  produced.  Thus  red  fuchsin  becomes  violet  when 
treated  with  an  aldehyde.  Now,  in  the  case  of  the  substituting 
poisons,  Loew  supposed  that  an  interaction  took  place  between 
these  and  amido  or  aldehyde  groups  present  in  the  living  proto- 
plasm. But  Ehrlich  has  never  been  able  to  observe  that  colour 
changes  of  the  type  mentioned  occur  in  the  body,  either  with  this 
basic  dye  which  reacts  with  aldehyde  groups,  or  with  certain  other 
dyes  (e.g.  Kehrmann's  azoniumbase  obtained  from  safranine)  which 
interact  with  substances  containing  amido  groups,  causing  char- 
acteristic changes  of  colour. 

Other  bodies,  such  as  anilin  and  benzaldehyde,  which  very  readily 
condense  to  benzylidene-anilin,  have  also  been  employed,  but  no 
derivative  of  either  anilin  and  an  aldehyde-containing  substance,  or 

*  Studies  in  Immunity ^  1906,  chap,  xxxiv. 


EHRLICH'S   HYPOTHESES  849 

of  benzaldehyde   and  an   amido  group,  has   ever  been  extracted 
from  the  tissues. 

Ehrlich  has  also  employed  the  aromatic  dyes  to  elucidate  the 
distribution  of  poisons  and  drugs  in  the  animal  body,  or,  in  other 
words,  to  throw  light  on  the  selective  action  of  cells.  Thus  he 
shows  that  the  brown  staining  with  /jara-phenylene-diamine,  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  copious 
blood  supply  of  these  muscles,  that  is,  to  the  presence  of  an  abun- 
dance of  oxygen.  Similarly,  in  these  situations  the  motor  nerve 
endings  were  more  intensely  stained  with  methylene  blue. 

From  observations  of  this  character  Ehrlich  deduces  the  hypothesis 
that  the  various  cells  of  the  body  take  up  different  chemical  sub- 
stances in  a  greater  or  less  degree  according  to  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  dye  alizarin,  but  when  the  surrounding  reac- 
tion is  alkaline  it  is  stained  by  quite  a  different  substance,  namely, 
methylene  blue. 

It  is  possible  to  modify  the  distribution  of  a  dye-stuff  by  the 
addition  of  other  substances ;  thus  the  staining  of  the  nerve  endings 
by  means  of  methylene  blue,  which  occurs  intra  vitanij  may  be 
prevented  by  the  addition  of  the  soluble  acid  dye  called  orange 
green.  The  latter,  that  is,  has  a  stronger  affinity  for  the  methylene 
blue  than  the  nerve  endings  possess.  On  this  principle  is  com- 
pounded the  well-known  '  Triacid '  stain. 

The  introduction  of  a  second  body  may  also  render  a  dye  active 
in  the  tissues ;  thus  Bismarck  brown  does  not  stain  peripheral  nerve 
endings  (e.  g.  taste  buds)  in  the  frog,  but  the  addition  of  methylene 
blue  causes  the  nerve  endings  to  take  a  double  colour.  In  perma- 
nent preparations  the  blue  quickly  fades,  and  the  brown  stain  only 
remains.  Ehrlich  believes  that  this  principle  underlies  many  of  the 
'abnormal  actions  of  drugs,  especially  in  inherited  or  acquired 
hyper-sensitiveness  ^ 

Besides  these  somewhat  theoretical  results,  observations  on  the 
physiological  action  of  the  organic  dye-stuffs  have  also,  of  recent 
years,  begun  to  lead  to  results  of  practical  value;  and  it  is  quite 
possible  that  important  developments  in  therapeutics  may  result 
from  a  further  study  of  these  derivatives.  Many  possess  a  remark- 
able bactericidal  action,  but  it  has  not  as  yet  proved  possible  to 
employ  them  against  ordinary  bacterial  infections.     The  parasitic 


350  PICRIC  ACID 

trypanosomes  have,  however,  been  shown  to  be  markedly  influenced 
both  in  experimental  animals  and  in  man  by  treatment  with  certain 
dye-stuffs,  such  as  malachite  green  G  (see  p.  354),  and  trypan  red 
(see  p.  352).  These  bodies  are  thought  to  act  by  favouring  the 
development  of  immunizing  substances  within  the  organism. 

Malachite  green  has  also  been  employed  by  F.  Loeffler  for 
separating  colonies  of  B.  coli  and  B.  typhi  abdominalis ;  the  growth 
of  the  former  organism  was  prevented  by  an  admixture  of  this  dye 
with  the  culture  medium,  the  colonies  of  the  latter  remaining 
unaffected. 


Class  I. 

NiTRO  Derivatives  of  the  Phenols. 

Picric  Acid,  CgH2(N02)30H,  and  Diuitro-cresol — 

CH3 


OH 

The  introduction  of  the  nitro  group  into  phenolic  substances  in- 
creases the  antiseptic  and  toxic  action.  Both  are  powerful  blood 
poisons,  renal  irritants,  and  respiratory  depressants,  especially  the 
latter,  possibly  owing  to  its  greater  solubility.  The  group  of 
naphthol  nitro-derivatives  includes  Martins  yellow, 

OH 
/V^NO, 

NO2 

which  is  similar  in  its  action  to  dinitro-cresol.  The  introduction 
of  a  sulphonic  grouping,  resulting  in  the  formation  of  dinitro- 
l-naphthol-7-sulphonic  acid, 

OH 

so.oh/V^'^no. 


N02 

naphthol  yellow  S,  has  the  usual  effect  of  destroying  the  toxicity. 


AZO-DYES  351 

Anrantia  or  Kaiser  Yellow  is  the  ammonium  or  sodium  salt  of 
hexa-nitro-diplieiiylamine, 

j^jj/C,H,(N03)3 
^"\CeH,(N03)3 

and  is  stated  to  have  toxic  properties. 

Class  II. 
Azo  -  Dyes. 

The  azo-dyes  are  a  class  of  substances  which  contain  as  chromo- 
phore  the  group  .N:N.  As  previously  mentioned,  azo-benzene 
itself,  CgHg.NiN.CgHg,  although  possessing  a  red  colour,  is  not 
a  dye-stuff ;  by  the  entrance  of  auxochrome  groups,  such  as  hydroxy! 
and  amido,  the  colouring  power  appears,  and  the  shade  is  modified. 
The  simplest  azo-dyes,  like  most  simple  dyes,  are  yellow,  and  their 
tint  is  dependent  firstly  on  the  nature  of  the  auxochrome  group,  and 
secondly  on  that  of  the  carbon  complex.  They  may  be  made  to  pass 
through  red  to  violet,  and  in  some  cases  to  brown.  Blue  azo-dyes 
have  so  far  only  been  obtained  from  those  substances  containing 
several  azo- groups  in  the  molecule.  Those  containing  the  benzene 
nucleus  are  yellow,  orange  or  brown ;  those  containing  the  naph- 
thalene, red ;  by  the  entrance  of  several  of  the  latter  nuclei,  violet- 
blue  or  black  dyes  are  produced. 

As  a  general  rule  their  technical  preparation  is  extremely  easy. 

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-benzene  or  Tropaeolin  .Y.  is  formed — 

1.  CeHgNHa    ->     CeHgNrNCl. 

2.  CeHgN :  N.Cl  +  CeHgONa  =  NaCl  +  CeH^N :  N.CeH^OH. 

In  this  reaction  phenol  may  be  replaced  by  resorcin,  a-  or  /3-naph- 
thol,  their  various  sulphonates,  or  salicylic  acid.  Sulphanilic  acid 
and  benzidine 

CeH.NH^ 
may  be  used  in  place  of  aniline,  and  consequently  a  large  number 
of  dye-stuffs  can  be  obtained. 

The  combination  of  diazo  bodies  with  amines,  as  a  rule,  is  not 
so  easy.     Some,  such  as  1 : 3-phenylene-diamine, 


CeH,<] 


2 


352  AZO-DYES 

combine  directly  in  neutral  aqueous  solution ;  thus  chrysoidin  is 
obtained  by  mixing  equivalent  solutions  of  diazo-benzene  chloride 
and  l:3-phenylene-di amine, 

C,H5 .  N  :  N.Cl  +  CeH,<(^g2^  =  CeH.N :  N.C3H,/5}22  +  HCI. 

But  in  other  cases,  as  with  diphenylamine,  solution  in  methylated 
spirits  and  treatment  with  a  strong  solution  of  the  diazo  derivative 
is  requisite. 

The  azo-dyes,  containing  a  sulphonic  acid  group,  are,  as  might 
be  expected,  but  slightly  toxic  substances,^  and  are  used  for 
colouring  wines  (Rouge  soluble,  Bordeaux  B,  Ponceau  R,  Orange  1, 
Jaune  solide).  Those  without  such  groups  have  also,  as  a  rule,  but 
slight  poisonous  properties. 


Chrysoidin         C,U, .  N  :  N.C6H3<^^][][2 .  hCI 


produces  slight  albuminuria  and  a  marked  reduction  of  body-weight. 
In  very  dilute  solution  it  agglutinates  cholera  and  other  vibrios. 
It  has  antiseptic  properties,  but  no  specific  action. 

Bismarck  brown       C,H /gf|j  p.H^^JJJ, 

has  toxic  properties. 

OH 
Sudan  1  CgH^ .  N :  N— < 


produces  slight  albuminuria,  but  the  »2-nitro  compound  is  non-toxic. 

OH 


NO2 


/        \— N  :  N- 


V 


Trypan  Red  is  a  benzidine  dye  obtained  from  benzidine-mono- 
sulphonic  acid  by  diazotization  and  combination  with  the  sodium 
salt  of  the  disulphonic  acid  of  jS-naphthylamine.  It  has  the  follow- 
ing constitutional  formula : — 


^  For  toxicity  of  dye-stuffs,  see  G.  M.  Meyer,  American  Chem.  Soc,  vol.  29, 
p.  892,  1907. 


AZO-DYES  353 

SOoONa     NH2  SOpNa  NH,     SO.ONa 


A_N  :N— CgHa— CfiH^— N  :  N— < 

> 


SOgONa  S020Na 

Ehrlich  and  Shiga  experimented  with  this  substance  on  mice 
infected  with  trypanosomiasis.  1  per  cent,  solutions  were  injected 
subcutaneously  in  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  special  effect  on  the  body  of  the  host, 
leading  to  the  production  of  parasiticidal  substances.  Animals 
after  cure  were  protected  to  a  great  extent  against  a  second  infection. 

Trypan  Blue  (prepared  by  Nicolle  and  Mesnil),  though  differing 
in  chemical  constitution,  has  an  action  similar  to  that  of  trypan  red 
on  the  trypanosomes ;  Ehrlich  states  that  strains  rendered  resistant  to 
the  one  are  also  immune  to  the  other,  though  they  may  be  destroyed 
by  fuchsin  or  by  the  use  of  atoxyl  (the  sodium  salt  of  para 
amido-phenyl-arsenic  acid).  Thus  in  Ehrlich's  words  ^  this  specific 
resistance  constitutes  a  cribrum  therapeuticum  or  therapeutic  sieve,  by 
which  any  new  remedy  of  this  type  may  be  classified.  He  possesses 
a  strain  of  trypanosomes  which  are  resistant  to  all  these  pharmaco- 
dynamic agents ;  and  thus,  if  a  mouse  infected  with  this  strain  is 
cured  by  any  new  drug,  the  latter  cannot  belong  to  one  of  these 

OH 

is  non-toxic. 


Ponceau 4 G.B.   C6H5.N:N< 


Di-phenylamine  orange 


SOgONa 


.SOgONa 


CgHX      1:4 


.h/    1 

^NrN.CeH^.NH.CeHs 
produces  albuminuria,  but  otherwise  has  only  slight  toxic  action ; 
on  the  other  hand  its  isomer  Metanil  yellow 

/SO.ONa 
CeH/  1:3 

^N:N.C6H4.NH.C6H5 

is  toxic  for  dogs  in  doses  of  20  gms.  after  4  days.    This  is  probably 
due  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  Tri-phenyl-methane  Dyes. 

Among*  the  diphenyl-methane  dyes  is  Fyoktanin,  in  its  pure 
state  termed  Anramin  O  (mixed  with  dextrin  it  goes  by  the  name 
of  Auramin  I,  II,  III).  It  is  the  hydrochloride  of  imido-tetramethyl- 
diamido-diphenyl  methane — 

(CH3),N.CeH4 .  C.CeH,N(CH3)2HCl 

NH 

Brilliant  Green,  also  known  as  malachite  green  G,  and  diamond 
green  G,  or  ethyl  green,  is  the  sulphate  of  tetraethyl-di-jt?flfa-amido- 
triphenyl-carbidride, 

^6^5 .  ^\CeH, :  N(C,H,)2 .  H^SO,. 

It  has  already  been  mentioned,  owing  to  the  fact  that  it  has  been 
employed  by  Wendelstadt  to  destroy  the  trypanosomes  of  tse-tse 
fly  disease. 

Methyl  Violet  is  a  mixture  of  the  hydrochlorides  of  the  hexa- 
methyl-pararosaniline, 

[(CH3),N.C,H  J, :  C=<Z>=N<(CH3),, 

and  penta-methyl-benzyl-pararosaniline ;  it  is  a  stronger  antiseptic 
than  the  yellow  pyoktanin  and  relatively  less  toxic.  It  has  been 
used  locally  for  inoperable  cancer. 

A  large  number  of  similar  derivatives  have  been  studied  and 
found  to  have  antiseptic  properties,  which  differ  but  slightly  from 
those  of  the  parent  dyes. 

Brosaniline  or  Fuchsin  has  a  constitution  expressed  by  the 
following  formula — 

NHg .  C2H4.  /=\ 

;?-Fuchsin  or  jo^m-Magenta  (pararosaniline)  does  not  contain  a 
methyl  group. 

The  antiseptic  powers  of  these  bodies  have  never  been  shown  to 
be  in  direct  relation  with  their  staining  properties,  but  appear  to 
depend  entirely  on  the  presence  of  the  aromatic  nuclei. 

Eosin,  the  alkali  salt  of  tetrabromfluorescein,  has  been  shown  by 
Noguchi  to  have  the  power  of  neutralizing  certain  toxins  occurring 


THIAZINE   DYES  355 

in  cobra  and  other  snake  venoms.  Although  possessing  no  power 
of  neutralizing  the  neurotoxins,  it  has  marked  action  on  the 
haemorrhagin  and  thrombokinase,  which  are  important  consti- 
tuents of  the  venoms  of  the  crotalus  (rattlesnake)  and  daboia. 

Class  IV. 
Thiazine  Dyes. 

Methylene  bine  (tetramethyl-diamido-phenazthionium  chloride), 

CI 

I 
(CH3)2Nv  /v     /S^  yv    /N(CH3)2 


has  been  tried  in  malaria,  but  does  not  compare  with  quinine ;  its 
power  of  staining  motor  nerve  endings  suggested  its  use  in 
neuralgia  and  rheumatic  affections,  but  its  action  is  uncertain.  It 
has  slight  antipyretic  and  diuretic  properties.  In  large  doses  it  is  a 
powerful  irritant.  Gautrelet  and  Bernard  showed  that  in  rabbits 
it  caused  a  fall  in  urea  excretion  and  some  decrease  in  the  secretory- 
activity  of  the  kidneys.  Other  aniline  dyes  acted  similarly,  namely, 
neutral  red,  fuchsin,  methyl  violet,  gentian  violet,  and  eosin.  On 
the  other  hand,  nigrosin  (an  indulin  dye),  and  blue  marine  (water 
blue,  china  blue),  a  sulphonated  triphenyl-rosaniline,  did  not  pro- 
duce this  effect. 

Class  V. 
AcRiDiNE  Dyes. 
Fhosphine   (Philadelphia  yellow)  is  a  mixture  of  the  hydro- 
chlorides    of    asymmetrical    diamido-triphenyl-acridine    with    its 
homologue  diamido-?»-tolyl-acridine — 


NH,.C„H,_/ \n 


< 


NH, 


Phosphine  is  a  powerful  protoplasmic  poison,  especially  for  protozoa. 
It  is  a  local  irritant  and  moderately  toxic.  It  has  been  tried  as 
a  substitute  for  quinine  in  malaria,  but  does  not  seem  to  have  been 
successful.     It  is  absorbed  with  difiiculty  from  the  stomach. 

A  a  :} 


APPENDIX 

Page  20.  The  following  table,  showing  the  curare-like  action  of 
various  ammonium  bases,  has  been  modified  from  one  given  by 
H.  Hildebrandt  and  Loos.  In  place  of  the  minimum  dose  of  each 
substance  capable  of  producing  complete  paralysis  per  kilo,  body- 
weight,  curarine  has  been  taken  as  unity  and  proportional  values 
assigned  to  the  others. 

The  minimum  dose  of  curarine  is  '008  m.  gm. 

Curarine 1 

1.  Methyl-strychnine  sulphate 100 

Methyl  ester  of  Btrychnine-iodoacetic  acid        .        .  187 

Ethyl-strychnine  sulphate 312 

2.  Benzyl-atropine  bromide 75 

3.  Benzyl-brucine  bromide 187 

Methyl-brucine  iodide 312 

4.  Methyl-cinchonine  sulphate 312 

Methyl  ester  of  cinch onine-iodoacetic  acid         .        .  375 

Amyl-cinchonine  iodide 625 

5.  Tetra-methyl-ammonium  iodide          ....  625 

6.  Benzyl-nicotine  iodide 3750 

Methyl-nicotine  sulphate 12500 

Ethyl-nicotine  iodide 18750 

7.  Benzyl-tropine  iodide 7500 

Methyl  ester  of  tropine-iodoacetic  acid     .        .        ,  12500 

Page  54.  There  are  a  certain  number  of  ammonium  bases  which 
do  not  produce  a  curare-like  effect.  Thus  Eraser  and  Crum  Brown 
showed  that  when  the  methyl  and  halogen  groups  were  attached  to 
the  nitrogen  in  the  pyrrolidine  ring  of  nicotine  there  was  no  curare 
action ;  this  appeared,  however,  when  the  nitrogen  in  the  pyridine 
ring  was  made  quinquevalent.  Loos  showed  many  years  ago  that 
the  intensity  of  the  curare-like  action  depended  largely  on  the  nature 
of  the  added  alkyl  groups.  Thus  ethyl  strychnine  sulphate,  ethyl 
nicotine  sulphate,  and  amyl  cinchonine  sulphate  are  respectively  less 
active  than  the  corresponding  methyl-sulphates.  The  chlormethylate 
of  papaverine  (Pohl)  and  the  corresponding  derivatives  of  cotarnine  and 
hydrastinine  (Fuhner)  have  no  action  whatever.  The  variety  of 
halogen  makes  no  difference  to  the  production  of  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 
(salicylic  acid)  leaves  the  body  conjugated  with  glycine,  the  para 


APPENDIX 


357 


compound  is  eliminated  as  a  glycuronic  acid  derivative  (Zeitschr. 
physiol.  chem.  1904,  Bd.  xliii). 

Page  207.  Kobert  has  investigated    various  substances  of  the 
antipyrine  type  with  the  following  results : —  J^-m^i. 

3-Antipyrine  according  to  Michaelis  is  constituted  as  follows — 

CO— N.CHg 

I 
CH 

II 
CH3.C N.CeHs 

It  is  a  more  active  poison  than  the  ordinary  5-antipyrine ;  this  is 
apparently  directly  traceable  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 


CeHg .  C- 


-N.CH, 


i 


OH 
!0— N.CH3 


is  less  toxic  than  3 -antipyrine,  but  more  so  than  ordinary  antipyrine  ; 
whereas  pyramidon  has  a  more  powerful  action  than  antipyrine, 
3-pyramidon 

CO-N.CH3 


(CH3)2N.C 
OH, .  0 


■N.CeH^ 


has  a  slighter  action,  and,  further,  is  much  less  toxic  than  the  parent 
substance,  3-antipyrine  ;  that  is  to  say,  the  entrance  of  the  N  (0113)2 
group  into  ordinary  antipyrine  increases  the  action,  whereas  a  decrease 
follows  its  introduction  into  3-antipyrine  or  into  iso-antipyrine. 

Page  272.  Fuhner  has  recently  shown  that  quinoline  is  oxidized 
in  the  body  to  ^am-oxy-quinoline,  thus  exactly  resembling  aniline. 


Page  288.  Hydroberberine  is  the  stereo-isomer  of  canadine,  an 
alkaloid  occurring  in  very  small  quantities  in  Hydrastis  canadensis  ; 
corydaline,  from  Corydalis  cava,  is  structurally  very  similar  to  the 
methyl  substitution  product  of  hydroberberine  (F.  Meyer),  and  is 
physiologically  inactive.  The  corresponding  ethyl  derivative  slows 
the  respiration  and  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 
differences  on  taste  are:  (1)  leucin,  the  ?aevo-rotatory  variety  of  which 
is  bitter,  whilst  the  dextro-rot&toTy  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  of  an  aromatic  ring  does 
not  necessarily  produce  any  alteration  in  the  odour  of  a  substance. 
He  instances  the  aliphatic  terpineol — 

fOxX C'H9\  y/CHg 


HgC^  >CH-C^CH3 

H3C-CH/  \0H 

and  the  corresponding  cyclic  body 

<CH — CHgN.  yCHj 

>CH.cf-CH3 
CH2-CH/  \0H 

Page  352.  Ehrlich  ^  has  investigated  various  substituted  rosanilines 
with  regard  to  their  action  on  trypanosomes. 

There  is  a  decreased  activity  in  the  di-  and  tri-oxy  derivatives  of 
malachite  green  and  in  orf/?o-oxy-hexamethyl-rosaniline  ;  on  the  other 
hand,  trimethoxy-pararosaniline  is  a  more  powerful  trypanocide  than 
the  oxy  derivatives  of  malachite  green  or  methyl  violet. 

The  introduction  of  carboxyl  radicals  has  a  much  more  marked 
effect  in  diminishing  the  action ;  thus  chrome- violet,  chrome-blue  and 
azo-green  are  almost  inactive. 

*  Berl.  Klin.  Wochenschr.  Nos.  9-12,  1907. 


INDEX 


Abrastol,  189. 

Acetal,  physiological  action  of,  104. 

Acetaldehyde,  preparation  of,  36. 

Acetamide,  124. 

Acetamide  and  oxamide,  partial  oxi- 
dation in  body  of,  74. 

Acetami do-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- 
logical action  of,  45  ;  preparation  of, 
33,  34. 

—  di-iodo-,  50. 
Acetyl-pyrogallol,  147. 

—  radical,  120 ;  introduction  of,  dur- 
ing passage  of  substances  through 
body,  65. 

Acetyl -salicyclic  acid,  158. 

Acid-amides,  physiological  properties 
of,  124,  178 ;  preparation  and  pro- 
perties, 123. 

Acid  radicals,  introduction  of,  into 
basic  substances,  120. 

Acid,  salicylic,  dissociation  of,  16. 

Acldol,  178. 

Acids,  amido-,  taste  of,  335. 

—  aromatic,  physiological  action,  119, 
120 ;  syntheses  with  glycine  in  body, 
63. 

—  halogen  substitution  products  of 
aliphatic,  121,  122. 

—  hydroxy  aromatic,  149. 

—  physiological  effect  following  re- 
placement of  H  in  COOH  group, 
48. 

—  physiological  properties  of  the,  118; 
preparation  and  properties  of,  117, 
118. 

Acoine,  314. 
Aconitic  acid,  51. 
Aconitine,  121. 


Acrolein,  50. 
Adrenalin,  317. 
Adrenaloue,  318. 

—  derivatives,  319. 
Aescnlin,  324. 
Agathin,  202. 
Agrurin,  228. 
Aitken,  on  smell,  332. 
Alcaptonuria,  75. 

Alcohols,  aliphatic,  classification,  87. 

Alcohols  and  derivatives,  81 ;  taste  of, 
334. 

Alcohols,  chemical  characteristics,  90  ; 
comparison  of  physiological  action 
of  primary,  92  ;  comparison  of 
primary  and  secondary,  52 ;  compari- 
son of  physiological  action  of  primary, 
secondary,  and  tertiary,  92;  effect 
on  physiological  action  of  replace- 
ment of  hydrogen  of  OH  group,  47  ; 
general  methods  of  preparation,  88  ; 
general  physiological  properties,  91 ; 
general  properties,  89;  polyhydric, 
90  ;  secondary  and  tertiary  prepar- 
ation of,  89 ;  used  in  perfumery, 
344. 

Aldehydes,  action  of  sodium  bi-sul- 
phite  on,   106. 

—  aromatic,  physiological  action,  107  ; 
halogen  substitution  products  of  ali- 
phatic, 108  ;  physiological  action  of, 
107 ;  polymerization  of,  107 ;  pre- 
paration of,  106  ;  properties  of,  104, 
105  ;  used  in  perfumery,  344. 

Aliphatic  alcohols,  classification,  87. 

Aliphatic  and  aromatic  derivatives, 
subdivisions,  13. 

Aliphatic  and  aromatic  series,  relative 
pharmacological  action,  20. 

Aliphatic  derivatives,  general  methods 
of  synthesis,  35 ;  synthesis  from 
acetic  acid,  36 ;  synthesis  from  alco- 
hols, 36 ;  synthesis  from  halogen 
derivatives,  37. 

Aliphatic  dibasic  acids,  taste  of,  838. 

Aliphatic  hydrocarbons,  24  ;  physio- 
logical characteristics,  45. 

Alkali -iodides,  organic  substitutes, 
167. 

Alkaloids,  233  ;  action  of  substituting 
groups,  245 ;  alkyl  substituents, 
action  of,  245 ;  bitter  taste  of,  340 ; 


360 


INDEX 


classification  of,  244 ;  curare  action  of 
quinquevalent  nitrogen  derivatives, 
54  ;  general  physiological  character- 
istics, 243 ;  Loevv's  special  poisons, 
249  ;  opium,  288 ;  opium,  containing 
tso-quinoline  ring,  299 ;  pyridine 
group  of,  249. 
Alkyl  and  oxy-alkyl  derivatives  of  uric 
acid,  225. 

—  ureas,  preparation  of,  215, 
Ally] -alcohol,  50. 

—  sulphide,  127. 

—  thiourea,  218. 

—  trimethyl  ammonium  hydrate,  51. 
Allylamine,  50. 

Aloin,  329. 
Alypin,  314. 
Amido-acetamide,  124. 
Amido-acetic      acid,     derivatives    of, 
formed  in  body,  63. 

—  (glycine),  formation  of  derivatives 
in  body  with  : —  benzoic  acid,  63 ; 
p-brom -benzene,  63  ;  chlorbenzoic 
acid,  63  ;  cuminic  acids,  63 ;  mesity- 
lenic  acid,  63  ;  naphthoic  acids,  63  ; 
nitrobenzoic  acid,  63 ;  jp-nitro-tolu- 
ene,  63  ;  phenyl-  acetic  acid,  64 ; 
salicylic  acid,  63 ;  xylene,  63. 

•^  syntheses  with,  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. 
y-Amido-phenol,  derivatives  of,   184 ; 

types  of  derivatives,  186. 
Amido-salicylic  acid,  formation  of  urea 

derivative  in  body,  64. 
Amido-valerianic  acid,  taste  of,  335. 
Amines,    action    of   nitrous  acid  on, 

89. 

—  aliphatic,  physiological  action  of, 
47. 

—  aromatic,  preparation  of,  173,  174. 

—  classification,  171  ;  effect  produced 
by  entrance  of  acidic  groups,  176, 
177  ;  general  methods  of  preparation, 
172 ;  physiological  properties  of,  177 ; 
preparation  of,  37  38 ;  primary, 
171 ;  primary,  secondary,  and  tertiary 
reactions  of,  175  ;  properties  of,  175 ; 
tertiary,  171. 

Aminoform,  108. 

Ammonia,  derivatives  of,  171 ;  sum- 
mary of  physiological  action  of, 
207. 

—  physiological  properties  of,  177. 
Ammonium  bases,  curareform  action, 

14,  20. 


Ammonium  compounds,   quaternary, 

physiological  action  of,  179. 
Amysfdalin,  324. 
Amygrdopheuin,  191. 
Amyl-acetate,  122. 

—  alcohol,  derivatives  with  local 
anaesthetic  action,  314. 

—  nitrite,  100. 

—  radical,  influence  on  odour,  842. 
Amylene  hydrate,  93. 
Anaesthesiu,  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. 

Anilides,  physiological  action  of,  179 ; 
preparation  of,  176 ;  stability  of, 
176. 

Aniline  and  phenol  derivatives,  com- 
parison of  physiological  action  of, 
210. 

—  and  thiophene,  increased  toxicity  on 
introduction  of  alkyls,  46. 

—  methyl  and  ethyl,  physiological 
properties  of,  178. 

Aniline,  derivatives,  181. 

physiological  action  of,  181. 

primary  and  secondary  deriva- 
tives, 47. 

AnUopyrine,  206. 

Anisanilide,  182. 

Anisol,  129. 

Aunidalin,  163. 

Anthracene,  30. 

Anthraquinone  derivatives,  829 ;  pur- 
gatives, 328. 

Antifebrin,  181. 

Antiosin,  167. 

Antipyretics,  main  group  of  synthetic, 
171. 

Autipyxine,  48,  204. 

—  chloral,  111. 

—  physiological  action  of,  204,  205, 
209. 

—  preparation  of,  202. 

—  salicylic  acid  salts  of,  205. 
Antiseptics,  aromatic,  128. 

—  containing  iodine,  161 ;  comparison 
of,  167. 

Antispasmin,  301. 
Antithermin,  201. 
Anytin,  169. 
Anytols,  169. 
Apocodeine,  301,  302. 
Apolysin,  192. 
Apoiuorpliine,  301. 
Arabino-chloralose,  111. 


INDEX 


861 


Arbutin,  323. 
Aristol,  163. 
Arlstoqtiin,  279,  280. 
Aromatic  acids,  physiological  action  of, 
119,  120. 

—  antiseptics,  128. 

—  derivatives,  action  of  nitric  and  sul- 
phuric acid  on,  40 ;  outline  of  syn- 
thetic methods  for  preparation  of, 
40 ;  oxidation  of  in  organism,  75. 

—  esters  of  halogen  acids,  99. 

—  halogen  derivatives,  preparation 
from  diazo-compounds,  40  ;  stability 
of,  99. 

—  hydrocarbons,  preparation  from 
diazo-derivatives,  40. 

—  hydroxy  acids,  149. 

—  hydroxyl  derivatives,  128. 

—  ketones,  preparation  of,  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-propionic  acid, 
77 ;  propyl-benzene,  76 ;  toluene, 
76. 

—  substances,  physiological  action  fol- 
lowing introduction  of  COOH  group, 
119. 

Arsonium  bases,  physiological  action, 
54. 

Asaprol,  139. 

Asparagine,  dextro,  and  laevOy  difFerence 
in  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 ;  mydriatic 
action,  270  ;  paralysis  of  nerve  end- 
ings to  involuntary  muscle,  267  ; 
paralysis  of  sensory  nerve  endings 
caused  by,  271 ;  physiological  action 
dependent  on  two  optical  isomers, 
271 ;  physiological  action  of,  265  ; 
substitutes,  316. 

Auramin  0,  354. 

Aurantia,  351. 

Auxochrome  groups  of  Witt,  348. 

Avogadro's  hypothesis,  1. 

Azo-dyes,  351. 

—  physiological  action  of,  352. 

Bactericidal  action  of  dyes,  349. 
Baglioni,  theory  of  narcosis,  86. 
Bauman  and  Kast  on  sulphonals,  114, 

115. 
Bechhold  and  Ehrlich,  antiseptic  value 

of  phenols,  134. 


Benzaldehyde,  preparation  of,  105. 

Benzamide,  124. 

Benzanilide,  182. 

Benzene,  determination  of  constitu- 
tional formula,  11,  12. 

Benzene-derivatives,  comparison  of 
toxicity  of  isomers,  62;  different 
types  of,  43. 

Benzene  homologues,  oxidation  of,  30  ; 
reduction  of,  31 ;  physiological  ac- 
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,  physiological  action  of,  45; 
sources  of,  30 ;  stability  of  ring 
complex,  30. 

Benzene  sulphonic  acids,  preparation 
of,  41. 

Benzenes,  di-oxy,  taste  of,  339. 

Benzidine,  not  oxidized  in  body,  78 ; 
value  in  dye  industry,  351. 

Benzoic  acid,  149 ;  derivatives,  with 
local  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. 

Berberine,  287. 

Betaine,  178. 

Betel,  139. 

Bile,  action  of,  55. 

Bismark  brown,  352. 

Bisulphide  of  carbon,  127. 

Bokorny,  comparison  of  toxicity  of 
benzene  isomei's,  52. 

Borneol,  glycuronic  acid  derivatives 
of,  62. 

Bredig  on  colloidal  solutions,  86. 

Brilliant  green,  354. 

Brom-acetic  ; 

Bromal,  109. 

Bromalin,  98. 

Brom-benzene,  99. 

Bromine,  derivatives  of  urea,  217. 

Bromine,  organic  preparations  of,  for 
epilepsy,  98. 

Bromipin,  98. 

Bromoform,  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. 
iso-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,  synthesis  with  glycuronic 

acid,  61. 
Carvacrol,  130. 
Cash  and  Dunstan,  on  nitrous  esters, 

100. 
Catalytic  poisons,  17. 
Catechol,  causing  rise  of  arterial  pres- 
sure, 318. 
Cellotropin,  323. 
Cells,  selective  action  of,  19  ;  staining 

reactions,  19. 
Cevine,     decomposition     product     of 

veratrine,  180. 
Chain  into  cyclic  derivatives,  effect  on 

taste,  340. 
'  Chemical     Environment,'    Ehrlich's 

views,  349. 
Chloracetic  acids,   physiological    pro- 
perties of,  121. 
CMoral,  108,  109. 
Chloral -acetophenone,  110. 
Chloral-alcoholate,  110. 
CMoral-amide,  110. 
Chloral-ammonia,  111. 
Chloral-antipyrine,  111. 
Cliloral-forinaniide,  110. 
Chloral,  formation  of  urochloralic  acid 

in  body,  60;  reduction  of,  in  body,  79. 
Chloral-hydrate,  106. 

—  production  of  surgical  anaesthesia, 
81. 

Chloral-urethane,  110. 

Chloralose,  111. 

Chlorbenzene,  99. 

Chlor-caffeine,  physiological  action  of, 

95. 
CMoretone,  96,  315. 
Chlorides     of     carbon,    physiological 


Chlorinated  phenols,  antiseptic  action 
of,  134. 

Chlorine,  physiological  characteristics 
following  entrance  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,  preparation  of 
aromatic  aldehyde,  105. 

Chrysin,  328. 

Chrysoidin,  352. 

Chrysophanic  acid,  328. 

Cinchona  alkaloids,  271. 

Cinchonine,  oxidation  of  in  organism, 
277. 

Cinchonine  and  cLuinine,  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. 

a-Cocaine,  263. 

Cocaine,  action  of  (CH3COO)  group, 
262;  action  of  (CeHjCOO)  group, 
263  :  '  anaesthiophore  '  group,  264  ; 
classification  of  physiological  action, 
258 ;  comparison  with  atropine,  266 ; 
derivatives,  261  ;  dextro,  laevo,  differ- 
ence in  action  of,  53 ;  elevation  of 
temperature  effect,  260  ;  mydriatic 
action  of,  260  ;  production  of  local 
anaesthesia,  260  ;  relations  between 
physiological  action  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. 

iso-Coniine,  252. 

Coniine  derivatives,  252. 

Coniine,  synthesis  of,  236. 

Constitutional  formulae,  factors  re- 
quired, 9 ;  acetic  acid,  10 ;  benzene, 
11. 

Copellidine,  254. 


INDEX 


363 


Cosparln,  182. 
Cotaruine,  285,  286,  300. 
Cotoiu,  325. 
Coumarin,  346. 
CreoUn,  133. 
Creosotal,  142. 
Creosote,  141. 

—  derivatives,  general  remarks  on, 
146. 

—  esters  of,  141. 
Cresol,  tri-iodo,  166. 
Cresols,  130,  132. 

—  action  on  nitrogenous  equilibrium, 
133,  134. 

Cresotinic  acids,  151. 

Crum  Brown  and  Fraser,  ammonium 

compounds,  20. 
Crystallose,  337. 
Cupreine,  276. 
Curare-like  action  of  ammonium  bases, 

20,  179;    of  arsenic,  antimony,  and 

phosphorus  bases,  179 ;   of  quinoline 

derivatives,  272. 
Cushny,  benzene  derivatives  with  high 

distribution  coefficient,  85, 
Cushny,  hyoscyamine,  271. 
Cyanogen,  126. 
Cyclic  ketones,  246,  248. 
Cyclic  ureides,  219. 
Cyclo-paraflfins,  preparation  of,  33. 
CylUn,  133. 

Cymene,  oxidation  of  in  body,  76. 
Cystaiuine,  108. 
Cystin    derivatives,  formation    of   in 

body,  66. 
Cystogen,  108. 

Decahydro-quinoline,  272. 

Desichtliyol,  169. 

Desoxy-caflfeine,  227. 

Desoxy-quinine,  278. 

Desoxy-strychnine,  282. 

Desoxy-theobromine,  227. 

Diabetes,  formation  of  acids  in,  77. 

Di-acetone-amine,  304. 

Di-azo  derivatives,  preparation  and 
reactions,  40,  41. 

Dichlorethane,  97. 

Diethylamine,  preparation  of,  173. 

Diethyl-ketone,  113. 

Diethyl-malonyl-urea,  219. 

Diffusion  velocity  in  relation  to  physio- 
logical reactivity,  16. 

Digitonin,  380. 

Dihydrostrychnoline,  282. 

p-Dihydroxy-diphenyl,  135. 

Dimethyl-benzamide,  124. 

Dimethyi-ethyl-acetic  acid,  119. 

Dimethyl-sulphide,  physiological  ac- 
tion on  passage  to  tetravalent  deri- 
vatives, 54. 

Dinitro-cresol,  350. 


Dionlae,  294. 

Dioxybenzenes,    physiological    action 

of,  132,  140. 
Diphenyl-dihydro-quinazoline,  241. 
Diphenyl  derivatives,  antiseptic  value 

of,  135. 
Diphenyl-methane  dyes,  354. 
Diphenyl,    oxidation    in     body,    78 ; 

physiological  action  of,  45. 
Dipropyl -ketone,  113. 
Dissociation  and  physiological  action, 

15,  16. 
Distribution,  coefficient,  83,  84. 

—  coeflScient    and     liminal    values, 
comparison  of,  84. 

—  coefficient  of  sulphonals,  84. 

—  of    dye-stuffs,   influence    of    other 
substances  on,  349. 

—  of  poisons  and  drugs  in  body,  349. 
Di-thymol-di-iodide,  163. 
Diuretin,  228. 

Doriniol,  110. 

Dosage,  effect  of,  16. 

Drug,  *  anchoring '  group,  21. 

— ,  its  main  action  and  bye-effects,  16. 

Drugs,  selective  action  of,  18j  23. 

Dujardin-Beaumetz,  influence  of  sub- 

stituents  in  aromatic  series,  21. 
Dulcin,  340. 
Dunstan  and  Cash  on  nitrous  esters, 

100. 
Ductal,  142. 
Dyes,  347. 

—  azo  series  of,  351. 

—  bactericidal  action  of,  349. 

—  di-  and   tri-phenyl  methane  series 
of,  354. 

—  nitro  derivatives  of  paraffins,  350. 

—  theory  of,  22,  348. 

—  thiazine  group  of,  355. 


Ecgonine,  259. 

—  anhydride  of,  262. 

—  benzoyl  derivative,  259. 

—  complex,  theory  of  physiological 
action  of,  260. 

—  methyl  ester,  180,  259. 

—  phenyl-acetyl  ester  of,  264. 
Ehrlich,   criticism   of  Loew's  theory, 

348 ;  observations  on  dyeing  pro- 
perties of  substances  containing 
C2H5  groups,  49;  physiological  action 
compared  with  theory  of  dyes,  21; 
side-chain  theory,  19. 

Ehrlich  and  Bechholdt,  antiseptic 
value  of  phenols,  134. 

Einhom  and  Heintz,  on  esters  of  oxy- 
amido-benzoic  acids,  310. 

Emodine,  328. 

Empirical  formulae,  9,  10. 

Enzymes,  53. 


364 


INDEX 


Eosin,  354 

EoBote,  144. 

Epicarin,  140. 

Epiosin,  293. 

Erythrol  tetranitrate,  101. 

Esters,  general  methods  of  prepara- 
tion, 90,  94, 122 ;  general  properties, 
94 ;  physiological  properties,  122, 
123. 

—  of  halogen  acids,  93. 

—  of  hydriodic  acid,  99. 

—  of  hydrobromic  acid,  98. 

—  of  hydrochloric  acid,  96. 

—  of  inorganic  acids,  93-103. 

—  of  nitrous  and  nitric  acids,  100. 

—  of  salicylic  acid,  odour  of,  342. 

—  of  sulphurous  and  sulphuric  acids, 
102. 

—  used  in  perfumery,  344. 

Ethers,  formation  from  alcohols  re- 
sulting in  lessened  toxicity,  47 ; 
physiological  action  of,  103  ;  prepara- 
tion and  properties  of,  103,  104. 

Ethoxy-caffeine,  229. 

p-Ethoxy-phenyl-succinimide,  190. 

Ethyl  acetate,  122,  123. 

Ethyl  alcohol,  preparation  of,  88. 

Ethylamine,  decomposition  by  nitrous 
acid,  89. 

Ethyl-benzamide,  124. 

Ethyl  bromide,  98. 

Ethyl  chloride,  96. 

Ethyl  ester  of  tyrosin,  123, 

Ethyl-formate,  122. 

Ethyl-guaiacol  carbonate,  142. 

Ethyl  iodide,  99. 

Ethyl  mercaptan,  114. 

Ethyl  and  methyl  groups,  physiological 
differences,  49. 

Ethyl -salicylate,  153. 

Ethylene,  physiological  action  of,  45. 

Ethylene  dibromide,  98. 

Ethylene-diethyl-sulphone,  115. 

Ethylene-dimorphine,  293. 

Ethylene  hydrocarbons,  preparation 
of,  33,  34. 

Ethylidene-dimethyl-sulphone,  115. 

Bucaine,  A  and  B  (a  and  jS),  307. 

Eudoxin,  167. 

Eugallol,  147. 

Eugenol,  131. 

—  use  in  perfumery,  345. 

Btunydrine,  317. 

Euplioriu,  183,  196,  213. 

Buphthalmine,  316. 

Euporphin,  302. 

Eupyrin,  195. 

BtLquinine,  279. 

Euresol,  141. 
Buroplieu,  163. 

Bxalgin,  184,  210. 
Exodiue,  330. 


Ferrlchthyol,  169. 

Fischer  and  Filehne  on  Kairine,  49. 

Pisetin,  327. 

Formaldehyde,  71. 

—  compoimds  of,  107,  108. 
Formalin,  71. 
Formamide,  124. 
Formamint,  107. 
Formanilide,  182. 

Formic  acid,  antiseptic  properties,  118. 

Formin,  108. 

Formyl-phenetidin,  189. 

Formyl-urea,  108. 

Fortoin,  326. 

Eraser  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,  physiological  action  of,  45. 

Furfurol,  synthesis  with  acetic  acid  in 
body,  66. 

Gallacetophenone,  58,  148. 
Gallic  acid,  132,  159. 
Ganltherin,  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,  preparation  of,  88. 

Olycosal,  154. 

Glycuronic  acid  derivatives,  59. 

Glycuronic  acid,  derivatives  of,  formed 
in  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 ;  syntheses 
with,  in  body,  56. 

Oriseriu,  165. 

Onaiacetin,  146. 

Gnaiacol,  142. 

—  attempts  to  increase  solubility  of, 


INDEX 


865 


145;  carbamic  esters  of,  143;  inor- 
ganic esters  of,  142, 143  ;  oleate,  143  ; 
organic  esters  of,  143 ;  sulphonates 
of,  145. 

Onaiacolsalol,  144. 

Gtiaiacoplxosphal,  148. 

Onalamar,  146. 

Oualasanol,  145. 

Guanidine,  178. 

Halogen  acids,  aromatic  esters  of,  99. 
Halogen  derivatives  of  aromatic  series, 

stability  of,  173. 
Halogens,  influence  on  odour,  342. 
Hedonal,  82,  214. 
HeUcin,  322. 
Heptane,  25. 
Heroine,  180,  295. 
Hesperidln,  325. 
Heteroxanthine,  226. 
Eetocresol,  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. 

Hontliin,  160. 

Eordeniue,  303. 

Hydracetin,  200. 

Eydrastine,  284. 

Hydrastinine,  285,  286. 

Hydrastininic  acid,  286. 

Hydriodic  acid,  esters  of,  99. 

Hydrobromic  acid,  esters  of,  98. 

Hydrocarbons,  alipbatic,  24. 

Hydrocarbons,  aliphatic  aromatic  taste 
of,  335  ;  aliphatic  not  oxidized  in 
the  body,  71 ;  benzene,  28 ;  benzene, 
sources  of,  30 ;  methods  of  prepara- 
tion, 32 ;  paraffins,  24 ;  paraffins,  pre- 
paration of,  32  ;  physiological  clmrac- 
teri sties,  45. 

Hydrochloric  acid,  esters  of,  98. 

Hydrocotamine,  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.  '     ' 

Hyoscyamine,  270. 


Hypnal,  111,  206. 

Eypnone,  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.  o      *-      » 


XcMhalbln,  169. 
Ichtlxargran,  169. 
Zclitlioforxa,  169. 
Ichtliyol,  169. 

—  efficacy  dependent  on  several  fac- 
tors, 170. 

Imido  acids,  taste  of,  338. 

Imi  do -derivatives,  eflFect  of  replacing 
H  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. 

lodalbin,  167. 

lodeljfon,  162. 

Iodide  of  tso-butyl-o-cresol,  163. 

Iodides,  organic  substitutes,  167. 

Iodine  antiseptics,  comparison  of,  167. 

Iodine,  containing  antiseptics,  161  ; 
entrance  into  aliphatic  and  aromatic 
substances,  163. 

lodipin,  167. 

lodo-anisol,  166. 

lodo-compounds,  aromatic,  99. 

Iodoform,  99,  161,  162. 

Iodoform,  classes  of  substitutes,  161, 
162. 

Zodoformal,  162. 

lodoforxuin,  162. 

lodoformogreu,  162. 

lodol,  164. 

Zodolene,  162. 

lodylofonn,  162. 

lonone,  345. 

lothion,  168. 

Iridin,  326. 

Irigenin,  326. 

Isomeric  relationships,  influence  on 
sense  of  smell,  345. 

Isomerism,  4,  5. 

—  interdependence  of  physiological 
action,  51. 

Iso-oximes,  cyclic  ketones,  246,  248. 

Iso-pilocarpine,  232. 

Isopral,  95. 

tso-quinoline,  constitution  of,  240. 

Jaborine,  232. 
Jalapin,  322. 


866 


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,  36,  37  ; 
properties  of,  112;  reaction  with 
phenyl-hydrazine,  &c.,  112 ;  used  in 
perfumery,  345. 

Ketonic  acids,  stability  of,  113. 

Kobert's  paradox,  19. 

Lactamide,  124. 

Lactic  acid,  appearance  in  urine,  78. 

Zaactoplienin,  189. 

Lactylamido-phenol-ethyl-carbonate, 
195. 

Lactyl-phenetidin,  189. 

Lactyl  radical,  120. 

Lactyl-tropeine,  267. 

Ladenburg's  generalization  on  mydri- 
atic action,  268. 

Laudanine,  300. 

Iiaudanosine,  299. 

lenigallol,  147. 

Lepidine,  273. 

*  Leuco '  compounds,  347. 

Levulinic  acid,  113. 

Liminal  values,  83,  84. 

Linalool,  344. 

Lipoid  substances,  solubility  of  nar- 
cotics in,  83. 

Loew's '  substitution '  theory,  criticism 
by  Ehrlich,  348  ;  theory  of  poisons, 
17. 

loretin,  164. 

Ziosophane,  166. 

Lupetidines,  253,  254. 

Lupinene,  180. 

Lysol,  133. 

Lysol,  sulphur  preparation,  169. 


Magnesium,  organic  derivatives,  38 ; 
synthesis  with,  38. 

Malachite  green,  354  ;  action  on  bacte- 
ria, 350. 

Malakin,  194. 

Malarin,  194. 

Maleic  acid,  119. 

Malonic  acid,  119. 

Mannitol  hexanitrate,  101. 

Marsh  gas,  physiological  action  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, 


Merling,  physiological  action  of  ace- 
tone-amine  derivatives,  306. 

Mesotan,  154. 

Metabolic  changes  of  sulphonals,  116. 

Metabolic  processes,  55. 

Metakalln,  133. 

Metanicotine,  256. 

Metanil  yellow,  353. 

Methacetin,  185. 

Methane,  preparation  of,  32. 

Metho-codeine,  297. 

Methylacetate,  123. 

Methyl  alcohol,  preparation  of,  88. 

Methyl  and  ethyl  groups,  physiological 
differences,  49. 

Methyl -benzamide,  124. 

Methylbromide,  98. 

Methyl- chloroform,  97. 

Methyl-coniine,  252. 

Methylecgonine,  120. 

Methyl-ethyl-ether,  probable  value  of, 
104. 

Methyleuphorin,  184. 

Methyl  group,  introduction  of,  during 
passage  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  Koaf,  hypothesis  on  action 
of  anaesthetic  substances,  85 ;  on 
chloroform,  85. 

Morphenol,  291. 

MorpU^enin,  292. 

MorpMue,  290. 

—  benzoyl  derivative,  296  ;  constitu- 
tion of,  291 ;  derivatives  of,  293 ; 
di-acetyl  derivative,  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- 


INDEX 


367 


Naphthalan-morpholine,  291. 
Naphtlialene,  30. 

—  oxidation  of,  in  body,  76  ;  physio- 
logical action  of,  45. 

Naphthol,  o-  and  j8-,  glycuronic  acid 

derivatives  of,  62. 
Naphthol -sulphonic  acid,  139. 
Naphthols,  139. 

Naphthylamine-sulphonic  acid,  140. 
ITarceine,  301. 
Narcotic  action,  enhanced  by  entrance 

of  chlorine  into  molecule,  82. 

—  of  alcohols,  aldehydes,  ketones, 
82. 

Narcotic  effects,  depressed  by  carboxyl 

group,  82. 
Narcotic  properties  of  sulphones,  115, 

116. 
Narcotics,    aliphatic,    groups    of,    82; 

physiological  action  of,  81. 
Warcotine,  286,  300. 
Narcyl,  301. 
Nencki,  salol  principle,  55,  129 ;  sul- 

phocyanic  acid  in  stomach,  65. 
Neurine,  51. 
Neurodin,  196. 
XTicoteiue,  256. 
Nicotine,  255. 
Nicotine,  difference  between  dexiro  and 

laevo,  53. 
Virvanine,  311. 
Nitriles,  aromatic,  126. 

—  aromatic,  preparation  of,  41,  42. 

—  formation  of  sulphocyanides  in 
body,  65. 

—  of  fatty  series,  toxicity  of,  126. 

—  odour  of,  343  ;  physiological  pro- 
perties, 125,  126  ;  preparation  of, 
37,  125;  reactions  of,  37,  125. 

tso-Nitriles,  odour  of,  343. 

Nitrites,    chemical    action    on    tissue 

cells,  101. 
Nitrobenzaldehyde,  oxidation  in  body, 

63. 
»w-Nitrobenzaldehyde,  changes   of,    in 

body,  65. 
Nitrobenzene,  reduction  of,  in  body,  79. 
Nitro-corapounds,  aromatic,  reduction 

of,  173. 
Nitro-derivatives,      aromatic      series, 

physiological  action,  101,  102. 

—  odour  of,  342. 
Nitro-glycerine,  101,  102. 
Nitro-group,  influence  on  taste,  334. 
Nitro-naphthol,   physiological    action 

of,  102. 

Nitro-paraffins,  101. 

Nitro-phenol,  129. 

Nitro-phenols,  reduction  of,  by  organ- 
ism, 80. 

Nitro-phenyl-propiolic  acid,  reduction 
of,  by  organism,  80. 


Nitro-thiophene,   physiological  action 

of,  102. 
Nitro-toluene,  oxidation  in  body,  77. 
Nitrogen,  influence  on  odour,  343. 
Nitrous  and  nitric  acid,  esters  of,  100  ; 

physiological  action  of,  100. 
N5lting,    on    oxidation    processes    in 

body,  78. 
ZTosopliexi,  166. 
ITovoeaixi,  312. 
Nux  vomica,  271. 

Octane,  25. 

—  physiological  action  of,  45. 
Odour,  341. 

—  dependence  on  physical  factors, 
341. 

Oil  of  Wintergrreen,  153. 

Olefines,  chemical  properties  of,  26. 

Opianic  acid,  physiological  properties 
of,  286. 

Opium  alkaloids,  288 ;  classification, 
289;  containing  iso-quinoline  ring, 
299. 

Optical  isomers,  5. 

Optically  active  tartaric  acids,  6. 

Orcin,  131. 

Orcinol,  taste  of,  389. 

Orezlne,  241. 

Organic  dyes,  347. 

Orthin,  201. 

Orthoform,  310. 

Orthoforxu-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 ; 
toxicity  of,  118. 

Oxalic  and  succinic  acids,  synthesis 
from  ethylene,  39. 

Oxidation,  differences  between  methyl 
and  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's 
rule,  78. 

—  of  stereochemical  isomerides,  69. 

—  processes  in  the  body  taking  place 
with  : — Alanin,  74  ;  alcohols,  71 ; 
aliphatic  acids,  73;  aliphatic  sub- 
stances, 71  ;  amido-acids,  74  ;  dex- 
trose, 69  ;  esters,  71 ;  formaldehyde, 
71;  formate  of  soda,  69;  glutaric  acid, 
74 ;  glycerol,  72  ;  glycolic  acid,  73 ; 
hydrocarbons,  71 ;  malic  acid,  74 ; 
malonic  acid,  73 ;  mannite,  69,  72 ; 
methyl  alcohol,  71  ;  methylamine, 
71  ;  nitriles,  71 ;  oxalic  acid,  73 ; 
oxy -acids,  73 ;  oxy-butyric  acid,  73  ; 


368 


INDEX 


phenylalanine,  69;  secondary  alco- 
hols, 71 ;  succinic  acid,  73 ;  sugars, 
69,  72  ;  tartaric  acid,  69,  70,  73 ;  tar- 
tronic  acid,  78;  tertiary  alcohols, 
71. 

Oxidation,  selective,  69,  70. 

Oxidizing  poisons,  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. 

Parafiin  hydrocarbons,  24 ;  preparation 
of,  32. 

Paraffins,  chemical  properties,  26; 
isomerism  in  the,  25 ;  nitro-com- 
pounds  of,  101  ;  occurrence  in 
nature,  25;  physical  properties  of, 
24. 

Paraldehyde,  108. 

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,  glucosides  of,  321. 

Peptoiodeig-on,  162. 

Peroniue,  296. 

Petroleum  emulsion,  45. 

Petrostaphol,  169. 

Pharmacology,  relation  to  therapeutics, 
14. 

Phenacetin,  186,  187,  188. 

Phenacetin>  attempts  to  increase  solu- 
bility of,  191 ;  theory  of  physio- 
logical action,  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  aliphatic  ethers, 
104 ;  formation  of  chinaethonic 
acid  from,  in  body,  62. 

PhenocoU,  193. 

Phenol  and  aniline  derivatives,  com- 
parison of  physiological  action  of, 
210. 

Phenol  and  phenol-ethers  used  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,  antiseptic  values,  and  general 
conclusions,  139 ;  elimination  of 
acidic  nature  of,  129,  130;  homo- 
logous, 130  ;  introduction  of  COOH 
group  into,  150;  local  anaesthetic 
action  of,  315;  physiological  action 
of,  131,  132;  polyhydric,  130;  pre- 
paration of,  128 ;  preparation  from 
diazo-compounds,  41;  properties  of, 
129. 

Phenol-sulphonic  acid,  57. 

Fheuosal,  193. 

Phenylacetamide,  124. 

Phenyl  acetate,  129. 

Phenyl-acetic  acid,  antiseptic  pro- 
perties of,  118. 

—  synthesis  with  glycine  in  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),  preparation  of,  34. 
Phenylhydrazine,  action  on  aldehydes, 

106  ;  action  on  ketones,  113  ;  deriva- 
tives of,  200,  201,  202  ;  physiological 
action  of,   199  ;   preparation  of,  41, 
198;   reactions  of,  199. 
Phenyl-methane,  183. 

—  derivatives,  196. 
Phenyl-propionic  acid,  oxidation  of,  in 

body,  64. 
Phenyl  radical,  effect  on  taste,  334. 
Phesiu,  191. 

Philadelphia  yellow,  355. 
PMoretin,  325. 
PMorizin,  325. 
Phloroglucin,  physiological  action  of, 

132  ;  taste  of,  339. 
Phosphate  and  phosphite  of  guaiacol, 

143. 
Fhosphatol,  143. 
PhospMue,  355. 
Phosphonium      bases,      physiological 

action,  54. 
Phosphotal,  143. 
Phthalic  acid,  oxidation  of,  in  body, 

76  ;  preparation  of,  117. 
Phthalide   and  its   derivatives,  odour 

of,  343. 
Phthalimide,  in  preparation  of    am- 


INDEX 


369 


ines,  1 72 ;   oxidation   in  the  body, 

76. 
Picric  acid,  129,  350. 
Picryl  chloride,  173. 
Pilocarpidine,  232. 
Pilocarpine,  231,  232. 

—  constitution  of,  224. 
Pinacol,  131. 

Pinacones,  physiological  action  of,  93. 

Pipecolylalkin,  254. 

Piperidine,  physiological  action  of,  46, 

250. 
Piperidon,  245. 

—  derivatives,  246. 
Piper ine,  255. 

Piperonal,  use  in  perfumery,  344. 

Piperylalkin,  254. 

Poisons,  'catalytic,'  17 ;  Loew's  theory, 

17,    348;    'oxidizing,'    17;    special, 

18  ;  '  substituting/  17,  348. 
Polygallic  acid,  330. 
Polyhydric  phenols,  130. 
Polymerization  of  aldehydes,  107. 
Ponceau,  4  G.  B.,  353. 
Populln,  323. 
Populin,  taste  of,  335. 
Primary  amines,  171. 
Propion,  113. 
Propionamide,  124. 
Propionitrile,  126. 
Propyl-phenetidin,  189. 
Propyl,  n-  and  iso-,  physiological  action 

of,  92. 
Protein,    occurrence   of    tyrosin    and 

phenylalanin  in,  75. 
Proteins,  difficulty  in   determination 

of  composition,   7. 
Protocatechuic  acid,  58. 
Protoplasm,  Loew's  theory,  17. 
Prussic  acid,  125. 
Pseudo-tropine,  270. 

—  benzoyl  ester,  263. 
Psoriasis,  148. 
Purgatin,  329. 
Purgatol,  329. 
Purgren,  330. 

Purification  of  organic  compounds,  8  ; 

methods  used,  8. 
Purine  derivatives,  general  review  of, 

229. 

—  group,  221. 

—  nomenclature,  221. 

Purine,  physiological  action  of,  224  ; 
synthesis  of,  222. 

Pyoktanin,  354. 

Pyramidon,  206. 

Pyrantin,  190. 

Pyrazolon  derivatives,  202. 

Pyridine,  action  of  oxidizing  agents 
on,  235;  action  of  reducing  agents  on, 
286  ;  and  piperidine,  233  ;  changes 
of,  during  passage  through  body,  66  ; 


comparison  with  quinoline,  &c., 
272  ;  derivatives,  differences  in 
physiological  action,  257  ;  group  of 
alkaloids,  249  ;  homologues,  physio- 
logical action,  46,  251,  253 ;  physio- 
logical action  of,  45,  250 ;  synthesis 
of,  234. 

Pyrocatechol,  130,  140. 

Pyrogallic  acid,  131,  140,  147  ;  taste 
of,  339. 

Pyrrol  and  pyrrolidine,  constitution  of, 
237. 

—  physiological  action  of,  45. 

—  tetra-iodo-,  164. 
Pyrrolidine  alkaloids,  258. 
Pyrrolidon,  248. 

Quaternary  ammonium  compounds, 
physiological  action  of,  179. 

Quercetiu,  327. 

Quillaia,  330. 

Quillaiac  acid,  330. 

Quinaldine,  273. 

p-Quinanisol,  274. 

Quiuaphenin,  280. 

Quinaphthol,  280. 

Quinazoline  derivatives,  240. 

Quinidine,  278. 

Quinine,  action  of  vinyl  radical,  277, 278. 

Quinine  and  clnclionine,  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  agents 
on,  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- 
sul phonic  acid,  164  ;  physiological 
action,  272 ;  reduced  derivatives, 
272  ;  synthesis  of,  238  ;  tetrahydro- 
>? -ethyl-,  274  ;  tetrahydro-w-methyl, 
274. 

iso-Quinoline-alkaloids,  284;  classifica- 
tion, 289;  nucleus,  opium  alkaloids, 
299. 
Qninopyrine,  280. 
Quitenine,  278. 

Racemic  acid,  6;  Pasteur's  investiga- 
tions on,  6. 

Reduction,  influence  on  sense  of  smell, 
346  ;  processes  taking  place  in  body, 
79. 

Resacetophenone,  58. 

Resorcinol,  131,  140. 

Resorcin,  thio-,  168. 


Bb 


370 


INDEX 


Hhamnetin,  327. 

Rhamnose,  methyl^,  taste  of,  333. 

Bhodin,  methyl-,  158. 

Roaf  and  Moore,  anaesthetic  substances, 

85. 
Rosaniline,  354. 

—  its  derivatives,  347* 

Saccliaxln,  336. 

—  derivatives,  336,  337. 
Safrol,  345. 

—  toxic  properties  of,  50  ;  iso-,  50. 
Salacetol,  154. 

Salen,  155. 

SaUcin,  322. 

Salicyl  -  acetyl  -p  -  amidophenol  ether, 
157. 

Salicylanilide,  182. 

Salicyl-phenetidin,  190,  194. 

Salicyl  radical,  120. 

Salicylic  acid,  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. 

Saliphenlu,  190. 

EaUpyrine,  205. 

SalocoU,  193. 

Salol,  155. 

Salol  group,  156,  157. 

—  principle,  55,  152 ;  derivatives 
synthesized  on,  156. 

—  substances  of  type  of,  156. 
Salopheii,  157,  190. 
Saloqtiiiiine,  280. 

'  Sapiphore '  groups  of  Sternberg,  335. 

Saponaretin,  327. 

Saponarin,  327. 

Saponification,  55. 

Saponins,  330. 

Sapotoxines,  330. 

Sarsa-saponin,  330. 

Saturated  and  unsaturated  derivatives, 
26. 

Scaxnmonin,  322. 

Schmiedeberg,  classification  of  nar- 
cotics, &c.,  20 ;  relation  of  therapeu- 
tics to  pharmacology,  14. 

Scoparin,  327. 

Secondary  amines,  171. 

Senegin,  330. 

Senses  of  taste  and  smell,  331. 

Sesame  oil,  iodine  preparation  of,  167. 

Sinalbln,  321. 

Sinapin,  321. 

Siniffrin,  321. 


SiroUu,  146. 

Smilax-saponin,  330. 

Snake  venoms,   action  of  eosin    on, 

355. 
Solubility  and  volatility  in  relation  to 

physiological  action,  14,  15,  46. 
Somnal,  110. 
Somnoform,  96. 

Sozoiodol,  preparations,  164,  165. 
Sozoiodolic  acid,  165. 
Stereochemical  influences  on  sense  of 

taste,  338. 
—  relationships  and  physiological  ac- 
tion, 53. 
Stereo-isomerism,  5. 
Sternberg  on  taste,  333. 
Stilbazoline,  255. 
Stibonium  bases,  physiological  action, 

54. 
Stockman,     physiological     action     of 

quinoline  derivatives,  273. 
Stomach,  action  of  hydrochloric  acid 

in,  55;  presence  of  sulphocyanic  acid 

in,  65. 
Stovaine,  314. 
Stropliantliin,  326. 
Structural  formulae,  3  ;  determination 

of,  3. 
Strychnidine,  282. 
Strychnine,  281,  283. 
Stypticin,  287. 
Styptol,  287. 
Styracol,  150. 
Styrolene,  324. 

Substituted  ureas,  preparation  of,  215. 
Substituting  poisons,  17. 
Succinic  acid,  119. 
Succinic  and  oxalic  acids,  synthesis 

from  ethylene,  39. 
Sncramiue,  337. 
Sucrol,  340. 
Sudan  1,  352. 
Sulphaminol,  168. 
Sulphocyanides,  formation  of  in  body, 

65. 
Sulphonal,  115,  116. 
Sulphonals,  preparation  of,  114. 
Sulphones  and  sulphonals,  distribution 

co-efBcient  of,  84. 
Sulphonic    acid    group,   influence    on 

physiological  action,  103  ;  protection 

against  oxidation  in  organism,  72. 
Sulphonic    esters,   formation    in    the 

body  with  : — Gallacetophenone,  58  ; 

gentisinic  acid,  57  ;  homogentisinic 

acid,  57 ;  hydroquinone,  57  ;  paeonol, 

58  ;   phenol,  57  ;   vanillic  acid,  58 ; 

tso-vanillic  acid,  58 ;  veratric  acid,  59, 
Snlphosote,  146. 
Sulphur,  antiseptics  containing,  186 ; 

derivatives,  126  j  derivatives  of  urea, 

218. 


INDEX 


371 


Sulphuric  acid,  synthesis  in  body,  56. 
Sulphuric  and  sulphurous  acids,  estors 

of,  102. 
Sulphuric  ester  of  morphia,  103. 
Symmetry,  influence  on  taste,  339. 
Sympherol,  229. 
Synthetic  antipyretics,  171. 
Synthetic  processes  in  body,  56. 

Tannal,  160. 

Tannalbin,  160. 

Tannate  of  aluminium,  160. 

Tannic  acid,  159;  acetyl  derivatives, 
159. 

Tannigen,  159. 

Tannocase,  160. 

Tannocol,  160. 

Tannoform,  160. 

Tannon,  160. 

Taunopin,  160. 

Tar,  coal-,  substances  present  in,  30. 

Tartaric  acids,  oxidation  of  isomers  in 
organism,  53  ;  toxicity  of,  118. 

Taste  and  smell,  stimulation  of  senses 
of,  332. 

Taste  and  periodic  classification  of 
elements,  332 ;  dependence  on  che- 
mical constitution,  331 ;  influence 
of  ring-formation  on,  340. 

—  of  acids  and  bases,  332  :  of  alcohols, 
332. 

—  di-  and  poly-saccharides,  333. 

—  glucosides,  333. 

Taurine,  formation  of  urea  derivative 

in  body,  64. 
Tellurium,  formation  of  tellurium  di- 

methide  in  body,  66. 
Tertiary  amines,  171. 
Tetrabrom  -  hydroq uinone  -  phthalein, 

137.  ' 

Tetra-iodo-pyrrol,  164. 
Tetronal,  116. 
Thalline,  274.^ 
Thebaine,  298. 
Theobromine,  226. 

—  efifects  of  NH  groups,  178. 
Theobromine-salicylate,  228. 
Theocine,  226. 
Theophylline,  226. 

—  synthesis  of,  223. 

Theory  of  narcosis,  Baglioni,  86. 

—  of  Overton  and  Meyer  on  hypnosis, 
83,  84. 

Therapeutics,  rational  and  empiric, 
13;  rational,  14;  obstacles  to,  14; 
relation  to  pharmacology,  14. 

Thermodine,  197. 

Thiazine  dyes,  355. 

Thlocol,  145. 

Thiol,  169. 

Thiophene  and  aniline,  increased  toxi- 
city on  introduction  of  alkyls,  46. 


Thiophene,  physiological  action  of,  45. 

relation  to  ichthyol  derivatives,  170. 
Thio-resorcin,  168. 
Thiosinamine,  218. 
Thujon,   conversion   into  hydrate   in 

body,  62. 
Thymol,  130,  133. 

—  synthesis  with  glycuronic  acid,  61 ; 
use  in  perfumery,  345. 

Tiodine,  169. 

Tolan,  preparation  of,  34. 

Toluidines,  comparison  of  toxicity,  52  ; 
toxicity  of,  184. 

Tolyl-hydrazine,  205. 

Tolyl-nitrile,  126. 

Tolylpyrine,  205. 

Tolysal,  205. 

Traube,  views  on  hypnosis,  85. 

Trenpel  and  Hinsberg  on  aniline  deri- 
vatives, 185. 

Triacetone-amine,  305. 

—  derivatives,  306,  307,  308. 
Tri-acetyl-pyrogallol,  147. 
Tribromhydrin,  98. 

Tri-chlor  butyrate  of  sodium,  122. 

Tri-ethyl  carbinol,  physiological  action 
of,  92. 

Trigremin,  109. 

Tri-methyl-carbinol,  physiological  ac- 
tion of,  92. 

Trional,  116. 

Tri-oxy -benzenes,  147,  148. 

Triphenin,  189. 

Tri-phenyl-methane  dyes,  354. 

Trithio  aldehyde,  127. 

Tropaeolin  .Y.,  351. 

Tropine,  cinnamic  acid  derivative, 
267 ;  derivatives,  mydriatic  action 
of,  268;  lactyl-,  267;  physiological 
nature  of  ring,  267. 

Tropines,  with  central  stimulating 
action,  267. 

Tropinone,  263. 

—  conversion  into  a-cocaine,  263. 
Trypan  blue,  353. 

Trypan  dyes,   Ehrlich's    observations 

on,  353, 
Trypan  red,  352. 
Tumenol,  169. 
Tussol,  206. 
Tyrosin,  123. 

—  ethyl  ester  of,  123 ;  oxidation  of, 
in  body,  75. 


Unsaturated    condition    of  molecule, 

influence  on  smell,  346. 
Unsaturated  substances,  physiological 

properties,  50. 
Ural,  110. 
Uralium,  110. 
Urea,  125. 


372 


INDEX 


Urea,  derivatives  containing  bromine, 
217  ;  derivatives,  taste  of,  339. 

—  formation  of  derivatives  in  body 
with: — Taurine,  64;  amido-benzoic 
acid,  64  ;  amido-salicylic  acid,  64 ; 
ethylamine-carbonate,  64. 

—  preparation  of,  215 ;  quinine  de- 
rivatives of,  280. 

—  ureides,  and  urethanes,  213, 
Ureas  substituted,  physiological  action 

of,  216;    sulphur  derivatives,  218; 

synthesis  of,  1. 
Ureides,  classification  of,  219. 
Urethane,  214. 
Urethane,  phenyl,  183  ;  d&rivatives  of, 

196. 
Urethanes,  preparation  of,  213. 

—  urea,  and  ureides,  213. 
Uretone,  108. 

Uric  acid,  alkyl  and  oxy-alkyl  deriva- 
tives, 225  ;  dioxy  derivatives,  225 ; 
synthesis,  221,  222. 

Urine  indican,  79. 

Urisol,  108. 

Uropherin,  228. 

TTrotropixi,  108. 

Valency,  theory  of,  1,  2 ;  variation 
of,  2. 

Valeronitrile,  126. 

Vanillic  acid,  58. 

iso- Vanillic  acid,  59. 

Vanillin,  piperonal,  &c.,  odour  of,  de- 
pending on  concentration,  341. 


Vanillin,  phenetidin,  194. 

—  use  in  perfumery,  344. 

Vaselines,  26. 

Velocity  of  reactions,  8. 

Veratric  acid,  59. 

Veratrine,  decomposition  products  of, 

180. 
Veratrol,  146. 
Veronal,  220. 
Vesaloine,  108. 

Vinylamine,  toxic  properties  of,  50. 
Vinyl-diacetone-amine,  305. 
Vioform,  165.      * 
Volatility  and  solubility  in  relation  to 

physiological  action,  14,  15,  46. 


Wintergreen  oil,  153. 

Witt,  theory  of  dyes,  22. 

Wurtz,  synthesis  of  hydrocarbons,  32. 


Xanthates,  127. 
Xanthine,  225. 
Xanthine  derivatives,  225,  226. 

—  effect  of  NH  groups,  178. 

—  mono-,  di-,  and  tri-methyl  deriva- 
tives, physiological  action  of,  48. 

—  tri-  and  tetra- methyl  derivatives, 
228. 

Xanthines,     methylated,     action     of 


organism  on,  66. 


Yohimbine,  285. 


OXFOBD  :    HORACE   HABT 
PBIHTER  TO   THE   UNIVEESITT 


« 

Un?? ersity  of  Toronto 

217154 
:dale,John 

1 

i 

• 

2.  ( library 

o 

•H 

M 

DO  NOT        /^ 

13 

iH 

O 

o 

REMOVE     / 

O 

THE            // 

1 

o 

CARD 

cd 

s 

11 

(0 
•H 
CQ 

FROM         'i 
THIS            \ 
POCKET       ^ 

^ 

i 

o 

<D  . 
«-»  . 

NN 

U 

Acme  Library  Card  Pocket 

x:       oj      1 

Under  Pat  "Ref .  Index  FUe" 

Aut 
Titl 

Made  by  LIBRARY  BUREAU