Acyloxymethyl as a drug protecting group. Part 5. Kinetics and mechanism of the hydrolysis of tertiary N-acyloxymethylsulfonamides

Tertiary acyloxymethylsulfonamides undergo hydrolysis via pH-independent an d acid- and base-catalysed processes. Reactions are also buffer catalysed f or buffer species with pK(a) values > ca. 10.5. For the pH-independent path way, hydrolysis takes place via formation of an N-sulfonyl iminium ion. The re is no general-base or nucleophilic catalysis in this region. The mechani sm of the acid-catalysed process involves pre-equilibrium protonation of th e substrate followed by iminium ion formation. General-acid catalysis is no t observed. The base-catalysed pathway involves the normal B-Ac2 mechanism of ester hydrolysis. The buffer-catalysed reaction gives rise to a curved B ronsted plot, with beta values of 1.6 and 0.25 for nucleophiles with pK(a) values <12.5 and >13, respectively. This is indicative of nucleophilic cata lysis associated with a change in rate-limiting step from formation of the tetrahedral intermediate for buffer species with pK(a) > 13 to decompositio n of the tetrahedral intermediate for buffer species with pK(a) < 12.5. Acyloxymethylsulfonamides have similar reactivity to, and follow similar re action mechanisms as, the corresponding carboxamide derivatives. Semi-empir ical PM3 SCF-MO calculations of the heats of formation, Delta H-f, and atom ic charges, q, for acyloxymethyl- and chloromethyl-sulfonamides and amides and their derived iminium ions were performed. These reveal that (1) iminiu m formation from the sulfonamide series is thermodynamically slightly favou red, and (2) the charge difference at the nitrogen atom, Delta q(N), betwee n the neutral molecule and the iminium ion is similar for both sulfonamides and amides.