Hydrolysis of the Model Carcinogen N-(Pivaloyloxy)-4-methoxyacetanilide: Involvement of N-Acetyl-p-benzoquinone Imine

Article abstract of DOI:10.1021/ja00261a019

Results of kinetic, ¹H NMR, and HPLC studies show that N-(pivaloyloxy)-4-methoxyacetanilide (1a), a model for suspected carcinogenic metabolites of phenacetin (10), decomposes predominately into N-acetyl-p-benzoquinone imine (3) in aqueous solution.The only other product isolated from the decomposition of 1a is 4-methoxyacetanilide (7), which is produced in moderate yield at pH > 6.0.The available evidence indicates that both of these materials are produced by a nitrenium ion mechanism.In aqueous solutions containing KCl at pH < 6.0, 3 decomposes in a first-order manner by an acid-catalyzed process into p-benzoquinone (6) and 3-chloro-4-hydroxyacetanilide (5).An intermediate in the reaction, which decomposes into 6, has been detected. ¹H NMR results indicate that the intermediate is a carbinolamine (8).At pH > 6.0, the decomposition of 3 becomes very complicated.At high concentrations, 3 decomposes by a non-first order path into a material which appears to be oligomeric.At sufficiently low concentrations (ca. 2.5 x 10^-6 M), the decomposition of 3 returns to a first-order process.Under these conditions, the major products of the reaction are 6 and acetaminophen (4).The measured standard reduction potential for 3 of 0.978 +/- 0.001 V indicates that it is a much stronger oxidizing agent than either p-benzoquinone or p-benzoquinone monoimine.However, at this time it is not possible to determine the identity of the species responsible for the reduction of 3 into 4 in aqueous solution.