Acyloxymethyl as a drug protecting group. Part 5.1 Kinetics and mechanism of the hydrolysis of tertiary N-acyloxymethylsulfonamides

Abstract

Tertiary acyloxymethylsulfonamides undergo hydrolysis via pH-independent and acid- and base-catalysed processes. Reactions are also buffer catalysed for buffer species with pK_a values > ca. 10.5. For the pH-independent pathway, hydrolysis takes place via formation of an N-sulfonyl iminium ion. There is no general-base or nucleophilic catalysis in this region. The mechanism of the acid-catalysed process involves pre-equilibrium protonation of the substrate followed by iminium ion formation. General-acid catalysis is not observed. The base-catalysed pathway involves the normal B_Ac2 mechanism of ester hydrolysis. The buffer-catalysed reaction gives rise to a curved Brønsted plot, with β values of 1.6 and 0.25 for nucleophiles with pK_a values <12.5 and >13, respectively. This is indicative of nucleophilic catalysis associated with a change in rate-limiting step from formation of the tetrahedral intermediate for buffer species with pK_a > 13 to decomposition of the tetrahedral intermediate for buffer species with pK_a < 12.5.

Acyloxymethylsulfonamides have similar reactivity to, and follow similar reaction mechanisms as, the corresponding carboxamide derivatives. Semi-empirical PM3 SCF-MO calculations of the heats of formation, ΔH_f, and atomic charges, q, for acyloxymethyl- and chloromethyl-sulfonamides and amides and their derived iminium ions were performed. These reveal that (1) iminium formation from the sulfonamide series is thermodynamically slightly favoured, and (2) the charge difference at the nitrogen atom, Δq^N, between the neutral molecule and the iminium ion is similar for both sulfonamides and amides.