Catalysis of amide hydrolysis and formation under neutral conditions by a zwitterionic imidazolium thiolate

Article abstract of DOI:10.1021/ja00090a015

As a simple model for the hydrolysis of peptides mediated by the cysteine proteases, 2-(mercaptomethyl)-1-methylimidazole (1) was used to catalyze the hydrolysis of four nonactivated amides, namely, formamide, dimethylformamide, N-formylmorpholine, and formanilide (3a-d), at 98 °C, pD 7.6-8.0, μ = 1.0 (KC1). Progress of the hydrolysis reactions was followed by ¹H NMR, and the kinetics as a function of added [1] were used to determine the second-order catalytic rate constants (k_cat). A putative intermediate 5-formyl thiolester of 1 (4) was not observed to build up during the course of the hydrolysis: the partitioning of authentic 4 between H₂O and morpholine and between H₂O and aniline was determined (98 °C, pD 8.0). The hydrolysis of N-formylmorpholine was observed to be catalyzed by added phosphate buffer under the same conditions. When the hydrolysis of a 200 mM D₂O solution of N-formylmorpholine was allowed to proceed to completion, an equilibrium position of 33 mM amide, 167 mM HCO₂H, and 167 mM morpholine was attained: that same equilibrium position was obtained starting with a solution 200 mM in each of HCO₂H and morpholine. The conditional equilibrium constant, K′_eq = [NFM]/([HCO₂H]_tot-[morpholine]_tot), was found to be 1.2 M^-1.