tHe
relationship between toxicity and
c^Emical
reactivity
in
certain
benzene
DERIVATIVES.
Lecturer
on
Oliver C. M. Davis, D.Sc., Materia Medica in the University of
Bristol.
^
determining the pharmacological value of best be obtained Olllpound, information
^Periments estigation
on
living animals, regarded as
must be
^
and of
all
organic
an
can
other
by
direct
means
of
secondary importance.
many cases it appears that this may be largely due to ^ ^act that the nature of the decomposition which a compound
R.NH2
of the free base
are
+ AcOH.
gradually intr?
thus
duced into the system, and a medicinal effect produced w1 by side with a very greatly diminished toxicity compared that of the parent amine. One of the first members of derl series to be used for medicinal purposes was the acetyl vative of aniline or acetanilide, commonly known as antifet>rl11' under this name, and als? which has been a
largely employed proprietary headache powders. alimentary system this compound
constituent of Within the
with liberation of free aniline and acetic acid
Experiments have of
numerous
drawn (l)
or
is
hydr?lyse
their salts-
anilides, and the
*
compounds gradually dimm1 as the length of the carbon chain in the acyl group thus formanilide, unlike its immediate homologue acetani That the
toxicity
^
by physiologists on the toxi following conclusions have
been made
:?
of these
"
"
^
hes*
increaS^
is far too toxic for internal administration, and in the arorfla ac series benzanilide is practically without physiological Some few years ago the rates of
decomposition
j
of
a
consider
^
^
TOXICITY AND CHEMICAL REACTIVITY.
239.
dumber of anilides were investigated, hydrolysis being brought about by boiling with standard sodium hydroxide, according
*? the
equation (J)
:?
R.NHAc. + NaOH
following
^noting
results
the average
b-v
RNHa
velocity
of
K
"
being decomposition :?
Time for 50
Compound.
"
obtained,
were
+ AcONa. a
constant
K.
% decomp
Formanilide Acetanilide
0.14 hrs.
87.1
3-79
,,
3.20
Propionanilide
6.30
,,
i-93
N. Butyranilide N. Valeranilide
13.0
,,
0-934
18.5
,,
0.656
Benzanilide
Not affected
n
assumption
.
that the
physiological
action of this series-
due to the liberation of the free amine, it is quite lQus from these results that formanilide would prove far
ob^rirnarily
toxic than acetanilide, j1101"6 rrHer
since the constant indicates that the
compound is decomposed approximately twenty-seven es as quickly as the latter ; the results also lead us to uPpose that toxicity would diminish with increasing molecular *%ht of the acid from which the compounds are formed,
^
during the last twenty years a considerable amount of Search has been carried out on the rates of formation and of
organic compounds ob^?mposition amed of great interest, incomplete but
^
re
aU
c^rrn^ne
^
?
themselves. involved, which
are
in
probability two distinct factors are the reactivity of organic compounds, namely their erniCal affinity or power to react, and also the frictional ance which they offer to any given reaction. It is obvious that rates of reaction may be influenced by
^ln ?
the results
;
numerous
are
"
"
"
?^re^0reboth ?r
veloCif y
of these
constants
^forces 1Ve
does not
only affinity. There
^cheraicalthis
and thus
factors,
property,
one
are
give
us
two
being
a
a
determination of
direct measurement
recognised
methods for
to determine the electro
of the substances under
investigation,
and the
DR.
.240 other to find the and calculate the
the
are
OLIVER C. M.
DAVIS
position of equilibrium in affinity from recognised
equilibrium constant is introduced. Although from a theoretical standpoint cases
balanced action,
formulae in
all chemical
which
reaction5
chosen, yet the number where distinct equilibria can be attained and
reversible if suitable conditions
?of definite
a
are
accurately measured is not great. A series of such reactions has recently been investigated,3 the interaction of fornHc acid with aniline bases in pyridine-water solution having been traced from both sides of the equation :? R.NH2
+ HCOOH
R.NH.HCO +
HaO.
large number of bases were experimented with, and equilibrium constants calculated from the formula? A
Ca Kw?
,
C2
x
where
C3
Kw = equilibrium constant, and C1( C2 and C3 the ?concentrations of anilide, amine and acid at the position
respect^
equilibrium. Unfortunately, at the present time only a few of the bases investigated have had their relative toxicities determme j Diagram I was obtained by plotting both the reciprocals Kw and the toxic doses per kilogramme body-weight of toluidines4 on equidistant ordinates to empirically represe the ortho, meta, and para-orientations. It is well shown ^ toxicity is approximately directly proportional to affinity, since this property varies with the equilibrium consta and toxicity is inversely proportional to toxic dose. ^
^
c^ernlC^
this
connection
thoroughly practice.
worked out,
In
two
well-marked
showing
the
cases
application
have
of theory wn
^
by Breinl and Nierenstein that is ^ p. amino-phenyl-arsenic acid, the sodium salt of which ^ as atoxyl, acts promptly on trypanosomes, the meta-comp at ^ has a less effect, and the ortho-compound no effect ^ in A similar regularity was noticed by the same observers -case of the corresponding antimony compounds. It has been found
5
8
24I
TOXICITY AND CHEMICAL REACTIVITY.
AIztcu.
Uvuz-
DIAGRAM I.
Th 6
represents the toxic doses of the isomeric toluidines, the '?Wer VVer curve denotes the the reciprocals of the equilibrium constants of the -t0l Uldines reacting with formic acid (N/i solutions in pyridine and water). upper UPPer
curve
toie
The
relationship
l?wing
formulae
between the
compounds
is shown
by
the
:?
Arsenic Arsenic Combounds. Compounds.
^OH
^OH
^OH
AsO
AsO
AsO
Ar
A"0H
A"0H
V
V"1 V
(k
v
Vxxx.
,
effect. No. 117.
Meta?Slight effect. 17
V NH*
Para?Effective.
DR.
242
OLIVER C. M.
DAVIS
Antimony Compounds. .OH SbO
^OH SbO
A"0H
A?!" V
V
Ortho?No effect. These
SbO
A
nh2
.
V m* Para?Effective-
Meta?Slight effect.
investigators
are
of the
opinion
.
that these
difference*
due to the different reactivities of the amino groups toward e the proteins, as they were able to show that the action of have comon the takes after are
parasites only place they protein.7 Some further interesting work on the importance of have also amino group (? NH2) as an anchoring group and been carried out with atoxyl by Nierenstein, Breinl others, who showed that by replacing ?NH2 by ?n N (CH3)2 and H, the compound loses its action drugs
bined with
"
"
"
"
?
?
trypanosomes best
by
8
both in vitro
the aid of
^-OH AsO
A
OH
graphic
^OH
^-OH AsO \OH
A
v
OH
NH2
This is
AsO A ^OH
V
V
and in vivo.
expresse(^
formulas.
AsO
^
v
N(CH3)2
Effective.
Not effective.
b Ehrlich's co-worker, Bertheim, haS v ^ becomes ineffective that the well-known drug 606
Ouite
recently
"
?
NH2 is replaced by ?N(CH3)2.
"
9
J
TOXICITY AND CHEMICAL REACTIVITY.
?-As=As?
?As =As?
A
A
NH
A A 3* W. Ostwald, loc. cit., p. 247.
Hildebrandt,
Ztschr.
Physiol. Chem.,
1904, Bd. 43.