Empirical Conversion of pKa Values between Different Solvents and Interpretation of the Parameters: Application to Water, Acetonitrile, Dimethyl Sulfoxide, and Methanol

An empirical conversion method (ECM) that transforms p K a values of arbitrary organic compounds from one solvent to the other is introduced. We demonstrate the method's usefulness and performance on p K a conversions involving water and organic solvents acetonitrile (MeCN), dimethyl sulfoxide (Me 2 SO), and methanol (MeOH). We focus on the p K a conversion from the known reference value in water to the other three organic solvents, although such a conversion can also be performed between any pair of the considered solvents. The ECM works with an additive parameter that is specific to a solvent and a molecular family (essentially characterized by a functional group that is titrated). We formally show that the method can be formulated with a single additive parameter, and that the extra multiplicative parameter used in other works is not required. The values of the additive parameter are determined from known p K a data, and their interpretation is provided on the basis of physicochemical concepts. The data set of known p K a values is augmented with p K a values computed with the recently introduced electrostatic transform method, whose validity is demonstrated. For a validation of our method, we consider p K a conversions for two data sets of titratable compounds. The first data set involves 81 relatively small molecules belonging to 19 different molecular families, with the p K a data available in all four considered solvents. The second data set involves 76 titratable molecules from 5 additional molecular families. These molecules are typically larger, and their experimental p K a values are available only in Me 2 SO and water. The validation tests show that the agreement between the experimental p K a data and the ECM predictions is generally good, with absolute errors often on the order of 0.5 pH units. The presence of a few outliers is rationalized, and observed trends with respect to molecular families are discussed.