Triazene drug metabolites. Part 16.1 Kinetics and mechanism of the hydrolysis of aminoacyltriazenes

Abstract

Kinetic studies of the hydrolysis of 3-aminoacyl-1-aryl-3-methyltriazenes to the corresponding 1-aryl-3-methyltriazenes were carried out in pH 3–12 aqueous buffers at 25 °C. Pseudo-first-order rate constants were found to depend both on pH and buffer concentration. pH–Rate profiles for the compounds derived from α-amino acids, 3a–e, exhibit sigmoidal curves consistent with an HO^–-catalysed reaction proceeding via both protonated and unprotonated forms of the structure. For the β-amino acid derivative, 3f, the difference in reactivity between these two substrate forms is much less pronounced. For the N-acetylated derivative, 3g, only the unprotonated form is kinetically significant. Solvent deuterium isotope effects for the reaction of HO^– with the protonated substrate are ca. 0.8 and for the unprotonated substrate ca. 1.0, suggesting nucleophilic catalysis by HO^– for both forms. Both protonated and unprotonated forms of the substrate are subject to buffer catalysis. The Brönsted β value of 0.65 is consistent with general-base catalysis, as are the solvent deuterium isotope effect of ca. 1.3 for the imidazole-catalysed hydrolysis of the protonated substrate and the ratio of 1.1 for the piperidine- and 2,2,4,4-tetramethylpiperidine-catalysed hydrolyses of the unprotonated form.