Tetrazoles as Carboxylic Acid Analogs 153 



Acylation of the amino group causes some striking changes in the 

 acidity of 5-aminotetrazole. Acetylation brings about a 25-fold in- 

 crease in acid strength; 10 the resulting compound is almost twice as 

 strong an acid as the unsubstituted tetrazole. Nitration, which in a 

 sense may also be considered as acylation, causes at least a 10,000-fold 

 increase in the acidity of 5-aminotetrazole. 11 5-Acetylaminotetrazole 

 still behaves as a monobasic acid in aqueous media, but 5-nitramino- 

 tetrazole is a dibasic acid. The presence of the moderately electro- 

 negative acetyl group might be expected to favor tautomerism of the 

 lactam-lactim type or resonance forms involving the amino nitrogen 

 and the carbonyl group (scheme XIV). Resonance of the aniline 

 type involving the tetrazole ring and the amino group is likely to be 

 repressed. Of the several resonance and tautomeric forms shown in 

 scheme XIV those on the left would presumably make the smallest 

 contribution to the hybrid. The forms on the right would cause the 

 amino nitrogen to exert a strong inductive effect in such a direction 

 as to increase the electronegativity and decrease the proton affinity 

 of the ring; a stronger acid should result. 



OH 



I 



HN C=N— COCH., HN C— NHCOCH 3 HN C— N=C— CH 3 



II ^ I II - I || 



N NH N N N N 



\ / \ / % / 



N N N 



/ \ 



/ \ (XIV) 



H H _ 



I I I 



HN C=N— COCH3 HN==C-N=C-CH 3 



I I + <— ■» I II + 



N N_ N N 



\ / \ / 



N N 



A large variety of tetrazole derivatives have been prepared for 

 investigation of their pharmacological properties. Most of these com- 

 pounds have carried a nitrogen substituent in addition to the carbon 

 substituent. The group is of interest because pharmacological activity 

 has been associated with the large majority of compounds studied. 

 They have almost uniformly exhibited effects upon the central nervous 

 system that varied from purely depressive to highly stimulatory types. 

 In some instances certain centers of the central nervous system have 

 been rather selectively affected. In addition new types of structures 

 having highly bactericidal and fungicidal action have been encountered. 



The close analogy in acidic properties between the 5-tetrazolyl group 

 and the carboxyl group suggests that analogies might be found in the 

 physiological actions of compounds in which the carboxyl group is 



