Practical calculation of molecular acidity with the aid of a reference molecule

A set of linear free energy models are presented for determining the pK(a) values of amines, alcohols, and carboxylic acids. Models are determined from a series of pK(a) predictors, taken both from traditional natural atomic orbital analysis (NAO) and from a novel approach introduced here of using a reference molecule: an ammonium ion for amines and a hydrogen sulfide molecule for alcohols and carboxylic acids. Using these reference molecules, we calculate the barrier to proton transfer and show that a number of properties associated with the transition state are correlated with the pK(a). By considering 38 predictors, we obtain a four-variable model for amines and a three-variable model for oxygen-containing compounds. The model for amines is based on 145 compounds and has a root mean squared error (RMSE) of 0.45 and R(2) = 0.98. The oxygen set has 48 molecules: RMSE = 0.26, and R(2) = 0.993. Similar, linear, and multilinear models are constructed after separating the sets into chemically similar categories: alcohols, carboxylic acids, and primary, secondary, tertiary, and aromatic amines. This separation gives simpler models with relatively low RMSE values, where the most important predictor of the pK(a) is the difference in energy between transferring the proton from the reference molecular base to the conjugate acid from the data set.