Intramolecular Catalysis of Thiol Ester Hydrolysis by a Tertiary Amine and a Carboxylate

The syntheses of 4-nitro thiol benzoate esters of ethyl 2-mercaptoacetate, thioglycolic acid, 2-(dimethylamino)ethanethiol, and 2(N,N,N,-trimethylammono)ethanethiol iodide (10-13) have been carried out and their rates of hydrolysis at 50 degrees C studied as a function of pH. Thiol esters 10 and 13 have linear pH-log k(obs) profiles indicative of an exclusive specific base attack of OH-. Thiol esters 11 and 12 exhibit a plateau in their pH/log k(obs) profiles due to the participation of pendant carboxylate and dimethylamino groups, respectively, most probably as intramolecular general bases. At higher pH, specific base catalysis becomes predominant for both 11 and 12. In the plateau region, the hydrolysis of 12 is subject to a solvent deuterium kinetic isotope effect of 2.2, consistent with the operation of a general base role for the pendant dimethylamino group. The hydrolysis of 12 in the presence of Ellman's reagent produces the Ellman's anion at a rate that is identical to that for disappearance of the thioester, consistent with a general base process where the thiolate anion product of hydrolysis is produced in the rate-limiting step.