Estimation of pKa using semiempirical molecular orbital methods. Part 1: application to phenols and carboxylic acids

The electronic properties of small molecules can be calculated quickly and with a reasonable degree of accuracy using semiempirical QM methods. In this study a set of QM properties derived from frontier electron theory have been used to produce a predictive model of the dissociation constants of phenols, benzoic acids and aliphatic carboxylic acids. The pKa values and structures of nearly 500 compounds were extracted from the Physprop database for this purpose. Multiple linear regression was used to search for relationships between pKa and the calculated QM properties. In most cases only a single independent variable, electrophilic superdelocalisability, was needed to produce a good model of pKa. The advantages of our approach are in the speed of calculation and the simplicity of the resultant models. The merits of using semiempirical methods to predict pKa are discussed in relation to previous studies