Hydrolysis of an ester group has been among the most important reactions in organic synthesis. However, hydrolyzing only one of the two identical ester groups in a symmetric diester has been a challenging task. To this end, we previously reported highly efficient selective monohydrolysis reactions of symmetric diesters in a practical manner. The products of this reaction, called half-esters, have been very versatile building blocks for a variety of significant compounds. The procedures are quite simple. The starting diester is dissolved in the aqueous media that may contain a small amount of a polar aprotic co-solvent and diluted aqueous base is added at around 0 oC. Under these simple conditions, a series of half-esters have been obtained in high to near-quantitative manner. However, the mechanism behind such high selectivity remains unknown. Here we performed theoretical studies in order to explain the high selectivity by examining the energy barriers for the first hydrolysis and the second hydrolysis for dimethyl maleate, which exhibited among the highest selectivity. The theoretical studies were performed for the selective monohydrolysis of a symmetric diester, dimethyl maleate. The GAUSSIAN 09 program was employed for all calculations. The geometry optimization and the transition state search were performed at the B3LYP/6-31+G(d,p) and single point energy calculations at the MP2/6-31+G(d,p)//B3LYP/6-31+G(d,p) level were conducted. Frequency analyses were also performed for confirmation of the optimized geometry and transition structures. Intrinsic reaction coordinate (IRC) calculations were also performed for verification of the transition structures on the potential energy surface. Although several mechanisms have been proposed for ester hydrolysis, we focused only on the bimolecular base-catalyzed acyl-oxygen cleavage (BAC2) pathway, which is the most generally accepted pathway under basic conditions. As a result, it was found that the activation energy for the hydrolysis of the second ester group is far higher than that of the first ester group, leading to the high selectivity for production of the half-ester, monomethyl maleate. The structure of the intermediate for the hydrolysis of the second ester group was also found unstable, potentially leading to the valley-ridge inflection.

Theoretical studies on the mechanisms of the highly efficient selective monohydrolysis reactions of symmetric diesters

ACS Fall 2021

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