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

Abstract

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 °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.

Dynamic combinatorial chemistry at the phospholipid bilayer interface

“…A comparison of the data shows that rates of thioester exchange are comparable for DCLs containing 1a (Figure 2a and 2c) or 1b (Figure 2b and 2d) when subjected to the same conditions, whereas hydrolysis of 1b proceeds significantly faster than that of benzoic acidderived thioester 1a. This observation is consistent with reports that aliphatic thioesters are prone to hydrolysis, particularly at higher pH [51,59,60]. These plots also demonstrate that thioester exchange proceeds considerably faster with increased pH.…”

Native Chemical Ligation and Extended Methods: Mechanisms, Catalysis, Scope, and Limitations

“…A remaining yet very important question to address is how heteroatoms or functional groups close to the thioester group can promote its reactivity (group 3, Figure /Table ). For example, the abnormally high reactivity of alkyl thioesters featuring basic or acidic groups in their thiol limb has been noticed. , Recent work has also shed light on the abnormally high reactivity of some strained thiolactone intermediates (group 3.1, Table ). , Understanding which internal factors can promote the reactivity of thioesters and how they act should facilitate future progress in this area.…”

Kinetics and Mechanisms of Reactions of Thiol, Thiono, and Dithio Analogues of Carboxylic Esters with Nucleophiles

“…The hydrolysis of 4-nitrothiolbenzoate esters of ethyl 2-mercaptoacetate, thioglycolic acid, 2-(dimethylamino)ethanethiol, and 2-( N , N , N -trimethylammono)ethanethiol ( 4 − 7 ) at different pH values has been investigated kinetically . Plots of log k obs vs pH are linear for 4 and 7 , which indicates exclusive OH - nucleophilic attack.…”