Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acyloxymethylbenzamides

Abstract

Acyloxymethyl derivatives of secondary and tertiary amides undergo hydrolysis via. acid-catalysed, base-catalysed and pH-independent processes. The pH-independent pathway involves rate-limiting iminium ion formation and is characterised by the following: a Hammett ρ 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; ΔS^‡ 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 substrate followed by iminium ion formation, and is characterised by the following: a Hammett ρ 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]; ΔS^‡ values > 0 J K^–1 mol^–1; higher reactivity of the tertiary substrates over their secondary counterparts; and a value of 0.85 for the Brønsted coefficient, β_Ig 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 ρ value of +0.38, a solvent deuterium isotope effect, k^OH–/k^OD–, of 0.85, and a ΔS^‡ 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 acyloxymethylamides are some 7 × 10⁴ times more reactive than their tertiary counterparts in the base-catalysed region. Hammett ρ 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 Brønsted β coefficient identifies the amide proton as approximately 50% transferred to the buffer species in the transition state.

Heats of formation, ΔH_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.