Triazene drug metabolites. Part 4. Kinetics and mechanism of the decomposition of 1-aryl-3-benzoyloxymethyl-3-methyltriazenes in mixed aqueous–organic solvents

Abstract

Kinetic studies for the hydrolysis of 1-aryl-3-benzoyloxymethyl-3-methyltriazenes to 1-aryl-3-hydroxymethyl-3-methyltriazenes in mixed aqueous–organic media are reported. Reactions are first-order in the benzoyloxymethyltriazene, and are independent of pH above pH 8. Below pH8, specific acid catalysis is observed. No nucleophilic catalysis is detected at any pH. The observed first-order rate constant, k_obs, vary with the substituent in both the 1-aryl and benzoyl rings. Hammett σ values of 1.28 and 1.41 are obtained for substituents in the benzoyl group in 50% MeCN–H₂O and 60% dioxane–H₂O respectively. A Hammett ρ value of –1.84 is obtained in 50% MeCN–H₂O for substituents in the 1-aryl ring. Observed first-order rate constants also vary with the composition of aqueous dioxane mixtures and a linear correlation between logk_obs and the Grunwald–Winstein Y parameter is found to give a slope of 0.99. The solvent deuterium isotope effect, k_H2O/k_D2O, is 1.26 for the 4-methoxybenzoyl derivative. Values of the activation parameters are ΔH^‡ca. 80 kJ mol^–1 and ΔS^‡ca.–5 J K^–1 mol^–1. The data are best interpreted in terms of a unimolecular ionisation of the benzoyloxymethyltriazene to form a iminium cation and a benzoate anion. Hydroxymethyltriazene formation results from the capture of the intermediate iminium ion by water. Consistent with this mechanism, a common ion effect of the benzoate anion is observed, and the benzoate ion is ca. 75 times more effective than water at trapping the iminium ion.