Acyloxymethyl derivatives of secondary and tertiary amides undergo hydrolysis via acid-catalysed, based-catalysed and pH-independent processes. The pH-independent pathway involves rate-limiting iminium ion formation and is charaterised by the following: a Hammett rho value for the substituent in the benzamide moiety of ca. -1.2 for both types of substrate; the absence of general-base or nucleophilic catalysis; a common benzoate ion effect; a solvent deuterium isotope effect, K(Obs)H2O/K(obs)D2O, of ca. 1.6; DELTA-S-double-ended-dagger values of -4 and -12 J K-1 mol-1 for secondary and tertiary substrates respectively; and higher reactivity of the tertiary amides over their secondary counterparts. The acid-catalysed process involves protonation of the substrates followed by iminium ion formation, and is characterised by the following: a Hammett rho value of ca. -1.5 for the substituent effect of the benzamide moiety; a solvent deuterium isotope effect of ca. 0.4; a monotonic rise in the pseudo-first-order rate constant K(obs) with increasing [H2SO4]; DELTA-S-double-ended-dagger values > O J K-1 mol-1; higher reactivity of the tertiary substrates over their secondary counterparts; and value of 0.85 for the Bronsted coefficient, beta-lg, for the carboxylate nucleofuge. The base-catalysed hydrolysis of tertiary substrates involves normal ester hydrolysis via acyl-oxygen bond cleavage, and is characterised by a Hammett rho value of + 0.38, a solvent deuterium isotope effect, k(OH-)/k(OD-), of 0.85, and a DELTA-S-double-ended-dagger value of -96 J K-1 mol-1. The corresponding base-catalysed process for the secondary substrates involves imine formation via an E2 elimination reaction. The secondary acyoxymethylamides are some 7 x 10(4) times more reactive than their tertiary counterparts in the base-catalysed region. Hammett rho values of + 1.1 and + 0.6 are obtained for the substituents in the ester and amide moieties, respectively. Buffer catalysis is observed, and the value of ca. 0.5 for the Bronsted beta coefficient identifies the amide proton as approximately 50% transferred to the buffer species in the transition state. Heats of formation, DELTA-H(f), calculated using the AM1 SCF MO package reveal that iminium ion formation is thermodynamically equi-energetic for cyclic and acyclic systems. Iminium ion formation from tertiary substrates is favoured by ca. 25 kJ mol-1 over the corresponding secondary analogues.
