Modelling pKa of Carboxylic Acids and Chlorinated Phenols

Estimation of aqueous pKa through quantum chemical gas‐phase and solution‐phase calculations is investigated for 16 carboxylic acids and 15 phenols with experimental data taken from literature. Parameters based on the AM1 hamiltonian include enthalpy and free energy differences between the ground state of the ionizable compounds and their anion counterparts as well as respective transition states and intermediates along the reaction path of the aqueous proton transfer. With carboxylic acids, additional ab initio calculations are performed to evaluate the semiempirical level of theory. Aqueous solvation is modelled in three different ways: Application of continuum‐solvation methods AM1‐COSMO and AM1‐SM2, microsolvation of the solutes through formation of clusters with three water molecules, and combination of both approaches to include both bulk water polarization and solute‐solvent coupling effects. Regression equations with r values up to 0.93 for carboxylic acids and 0.96 for phenols suggest, that continuum‐solvation models can be recommended to estimate aqueous pKa through electronic structure calculations.