§ 26 .] TOXIC ACTION AND CHEMICAL COMPOSITION. 37 
If the theory is true, then substances with “ labile ” amido groups, 
on the one hand, must increase in toxic activity if a second amido group 
is introduced ; and, on the other, their toxic qualities must be diminished 
if the amido group is changed into an imido group by the substitution 
of an atom of hydrogen .for an alkyl. 
Observation has shown that both of these requirements are satisfied ; 
phenylenediamine is more poisonous than aniline ; toluylenediamine 
more poisonous than toluidine. Again, if an atom of hydrogen in the 
amido (NH 2 ) group in aniline be replaced by an alkyl, e.g. methyl or 
ethyl, the resulting substance does not produce muscular spasm ; but if 
the same alkyl is substituted for an atom of hydrogen in the benzene 
nucleus, the convulsive action remains unaffected. 
If an acidyl, as for example the radicle of acetic acid, enter into the 
amido group, then the toxic action is notably weakened ; thus, acetani¬ 
lide is weaker than aniline, and acetylphenylhydrazine is weaker than 
phenylhydrazine. If the hydrogen of the imido group be replaced by 
an alkyl or an acid radicle, and therefore tertiary bound nitrogen 
restored, the poisonous action is also weakened. 
In xanthine there are three imido groups ; the hydrogen of two of 
these groups is replaced by methyl in theobromine ; and in caffeine the 
three hydrogens of the three imido groups are replaced by three methyls, 
thus :— 
NH—CH 
i II 
CO C—NH 
CO 
NH—C=N 
Xanthine. 
N . CH 3 —CH 
I II 
CO C—N . CH, 
NH- 
CO 
N. CH 3 —CH 
I II 
CO C—N . CH 3 
\co 
-C=N 
Theobromine. 
N . CH 3 —C=N 
Caffeine. 
—and experiment has shown that theobromine is weaker than xanthine, 
and caffeine still weaker than theobromine. 1 
Loew 2 makes the following generalisations :— 
I. Entrance of the carboxyl or sulpho groups weakens toxic 
action. 
1 V. Lusini ( UOrsosi , 1898, xxi. 257) gives the following lethal doses for frogs per 
100 grms. body weight:— 
Monomethylxanthine . ...... 0-03 
Theobromine . . . . . . . . 0-02 
Caffeine ......... 0-012 
—successive introduction of methyl groups being accompanied by an increased toxic 
action. 
J. T. Cash and W. R. Dunstan ( Proc . Roy. Soc., xviii. 384, 1901) have shown that 
withdrawal of the acetyl group both in pyraconitine and in benzaconine almost destroys 
their toxicity ; by substituting methyl for acetyl in aconitine there is also a reduction 
of toxicity. 
2 Ein naturliches System der Gift-wirkungen, Munchen, 1893. 
