144 Essays in Biochemistry 



o—i 



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(V) 



From schemes IV and V it might be anticipated that resonance sta- 

 bilization would be greater in the tetrazolyl anion than in the car- 

 boxylate ion owing to the greater number of forms contributing to the 

 resonance hybrid in the former instance. Although such a situation 

 might suggest that tetrazole and the 5-substituted tetrazoles should 

 be stronger acids than formic acid and the correspondingly substituted 

 carboxylic acids, experimental observations do not support this sup- 

 position. It is more likely that other factors, particularly the greater 

 electronegativity of oxygen as compared with nitrogen, are the decisive 

 factors in determining the relative strength of the tetrazoles as com- 

 pared with the carboxylic acids of the aliphatic series. 



In general, factors influencing the electronegativity of the tetrazole 

 system or the carboxyl group should have similar effects upon acid 

 strengths in both series. Thus replacement of the hydrogen attached 

 to the carboxyl carbon of formic acid by an alkyl group is assumed 

 to cause a decrease in the electronegativity (increase in proton affinity) 

 of the carboxyl group through the operation of an inductive effect with 

 a resultant decrease in the apparent acidic dissociation of the carboxyl 

 group. A similar effect is noted in the 5-alkyltetrazoles where replace- 

 ment of the hydrogen in the 5-position on the tetrazole ring by an alkyl 

 group causes a decrease in apparent acidic dissociation roughly com- 

 parable to that noted in the carboxylic acid series. 



When aromatic groups are introduced as substituents in the 5- 

 position of the tetrazole ring a different situation develops. Although 

 the apparent dissociation constant of tetrazole is only about one-tenth 

 as large as that of formic acid, the apparent dissociation constant of 

 5-phenyltetrazole is more than three times as large as that of benzoic 

 acid. A similar relationship exists between a group of substituted 

 5-phenyltetrazoles and the correspondingly substituted benzoic acids 

 (Table 2). 



Since the intrinsic inductive effect of the aryl group upon the 

 5-tetrazolyl and the carboxyl groups may be assumed to be of about 

 the same order of magnitude, some other factor must be operating to 

 cause the tetrazolyl group to exhibit a greater electronegativity than 

 the carboxyl group in these instances. It will be noted that the phenyl 

 group may participate in the resonance of 5-phenyltetrazole thus in- 



