142 BACTERIOLOGICAL CHEMISTRY 



atoms and the pull is transmitted to the electrons on 

 the amide nitrogen atom, which, consequently, exerts 

 less attraction for the hydrogen atom which, accordingly, 

 becomes capable of ionisation. It behaves as a very weak 

 acid with a dissociation constant of Ka = 3-7 X IQ-^^ in 

 the case of sulphanilamide (B in Fig. 5). In the ionised 

 state the electron pair which formed the covalent bond 

 with the hydrogen atom is available to increase the 

 electronegative character of the — SO2 group, although 

 the effect is not very great because the degree of ionisation 

 is low. The combined effect is approximately equivalent 

 to the ionised — CO.O" of the carboxyl group. Substitu- 

 tion of a group R on the amide group has two opposing 

 effects : (1) a competition with the — SOg group for the 

 electron pair, which decreases the resemblance to the 

 charge distribution on the carboxyl ion and so reduces 

 the activity of the drug ; this effect is considerable when 

 both hydrogen atoms in the amide group are substituted 

 so that ionisation is impossible ; the second effect (2) is 

 observed when the hydrogen atom is present, since then 

 ionisation is increased because the extra competition for 

 the ions by the substituent group reduces still more the 

 attraction of the nitrogen atom for the hydrogen atom. 

 As a result the more electronegative the substituent 

 group, the greater is the acid strength of the derivative, 

 with corresponding increase in activity. There is, 

 however, an optimum degree of electronegativity since 

 increase beyond a certain value involves too great com- 

 petition for electrons, to the extent that they are with- 

 drawn from the — SO2 group to the R group with loss of 

 similarity to the carboxyl ion ; that is, the activity of 

 the drug is lowered. It is possible, therefore, to predict 

 the activity of a new derivative from a knowledge of 

 the electronegative character of the substituent group R. 

 These effects are illustrated by Table 13 and Fig. 6 

 which are taken from Bell and Roblin's paper (J.A.C.S. 

 64, (1942) 2905). 





