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.

The Relationship between Toxicity and Chemical Reactivity in Certain Benzene Derivatives.

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