Hydrolysis of N-(Pivaloyloxy)-p-acetotoluidide: N-O Bond Cleavage Reactions of a Model Proximate Carcinogen

Article abstract of DOI:10.1021/jo00224a047

The hydrolysis reactions of N-(pivaloyloxy)-p-acetotoluidide (1a), a model for the carcinogenic metabolites of polycyclic aromatic amides, were investigated by a combination of UV spectroscopy, product analyses, and HPLC methods at 70 deg C over the pH range 2.0-8.0.Under these conditions 1a undergoes exclusive N-O bond cleavage to yield products characteristic of processes involving nitrenium ion pairs.In many ways the reactions of 1a in aqueous solution parallel those of the analogous sulfuric acid ester, 1b.However, two unique products, 3-(pivaloyloxy)-4-methylacetanilide (2b) and 4-acetotoluidide (9), which have no analogues in the reactions of 1b under these conditions, were isolated.The first-order rate constant for the decomposition of 1a, which is independent of pH and buffer composition, is (380 +/- 60)-fold less than the corresponding rate constant for 1b under the same conditions.The characteristics of the hydrolysis reaction of 1a are considerably different from those of the N-acetoxy-N-arylacetamides which undergo a considerable amount of acyl transfer under similar conditions.These results indicate that pivalic acid esters may be more appropriate models for the proximate carcinogens derived from N-hydroxy-N-arylacetamides than are the acetic acid estrs if, indeed, nitrenium ions are the ultimate carcinogens.