Origins, and formulation implications, of the pKa difference between boronic acids and their esters: A density functional theory study

Abstract

The purpose of this study is to try to identify the etiology and formulation implications of the significant pKa drop in aqueous solution that occurs when boronic acids are reversibly esterified by reaction with alcohols, especially 1,2-diols. Experimental studies have shown that conversion of a boronic acid to a boronic acid ester, both Lewis acids, is accompanied by an increase in the acidity, that is, a lowering of the pKa value in aqueous solution. The drop in pKa value has significant implications for the formulation of boronic acid-based drugs. Specifically, in the presence of 1,2-diols, a ΔpKa, a drop, of about 3 pKa units has been observed for several boronic acids, including boron-based drugs that have demonstrated value as active pharmaceutical ingredients. Boric acid itself shows an even larger drop of about 4 units. Here, electronic structure calculations are used to investigate the origins of this pKa change. Specifically, density functional theory (DFT) is used to predict the ΔpKa for a model boronic acid, methylboronic acid, to two of its esters, the dimethyl ester and the cyclic ester with ethylene glycol. The approach is validated by accurately predicting the experimentally observed increased acidity of the cyclic boronic acid ester relative to the corresponding boronic acid. The origins of the acidity difference are examined in detail. Analysis shows that the primary origin is an electronic effect with a smaller contribution due to the reduced structural flexibility of the boronic ester.