Mechanism of Hydrolysis of Benzamidomethyl Derivatives of Phenols and Its Implications for Prodrug Design

Article abstract of DOI:10.1021/jo00032a020

A series of O-benzamidomethyl derivatives of phenols was synthesized, and their rates of hydrolysis were investigated.The hydrolyses of the compounds follow pseudo-first-order kinetics resulting in quantitative and rapid regeneration of the phenol.The rates of hydrolysis were shown to be dependent on phenol nucleofugicity as well as the pK_a of the amide.The mechanism of hydrolysis apparently involves as elimination of the phenol anion from the conjugate base of the amide (E1cB-like).