Accurate pKa Determination for a Heterogeneous Group of Organic Molecules

Abstract Single‐molecule studies that allow to compute pK a values, proton affinities (gas‐phase acidity/basicity) and the electrostatic energy of solvation have been performed for a heterogeneous set of 26 organic compounds. Quantum mechanical density functional theory (DFT) using the Becke‐half&half and B3 LYP functionals on optimized molecular geometries have been carried out to investigate the energetics of gas‐phase protonation. The electrostatic contribution to the solvation energies of protonated and deprotonated compounds were calculated by solving the Poisson equation using atomic charges generated by fitting the electrostatic potential derived from the molecular wave functions in vacuum. The combination of gas‐phase and electrostatic solvation energies by means of the thermodynamic cycle enabled us to compute pK a values for the 26 compounds, which cover six distinct chemical groups (carboxylic acids, benzoic acids, phenols, imides, pyridines and imidazoles). The computational procedure for determining pK a values is accurate and transferable with a root‐mean‐square deviation of 0.53 and 0.57 pK a units and a maximum error of 1.0 pK a and 1.3 pK a units for Becke‐half&half and B3 LYP DFT functionals, respectively.