Mechanism of the Alkyl Chloroformate Mediated Esterification of Carboxylic Acids in Aqueous Media was elucidated
We studied the reaction mechanism of the carboxylic acids esterification in aqueous media mediated by alkyl chloroformates on macroscale and microscale by 1H NMR, LC-MS, GC-MS, stable isotope labeling and computational quantum chemistry.
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Protection of the carboxyl group by esterification has been the most common method in chemistry. Esterification is usually conducted under anhydrous conditions; however, in biological chemistry and related fields, the reaction is of major concern in aqueous environment. The instant esterification of carboxyl in aqueous alcoholic media driven by an alkyl chloroformate and pyridine has been such a method which has found widespread use in many research and industrial laboratories. Nevertheless, the reaction mechanism has not been studied and is not well understood. In this article, we describe the reaction intermediates and demonstrate that the reaction proceeds via a continual formation of the N-acylpyridinium intermediate decomposed by several reaction channels to the final ester. We finally tried to evaluate the scope and limitations of the reaction by producing ethyl esters of more than 200 metabolites with carboxyl functional group. Understanding the mechanism could promote new laboratory applications of this important esterification method.
Opekar S., Kvíčala J., Moos M., Pejchal V., Šimek P. (2021) Mechanism of the Alkyl Chloroformate Mediated Esterification of Carboxylic Acids in Aqueous Media, J. Org. Chem. 86. DOI: 10.1021/acs.joc.1c01546