(229f) COSMO-RS for the Estimation of Pka in Non-Aqueous Solvents

Experimental measurement of non-aqueous phase pKa values is still a demanding task. The rapid development of efficient quantum chemical (QC) methods in the last years has opened new perspectives for the rigorous prediction of liquid phase pKa. The Conductor-like Screening Model for Real Solvents (COSMO-RS) [1,2], is a combination of QC with a statistical thermodynamics method for local surface interactions, which takes into account local deviations from dielectric behaviour as well as hydrogen bonding. In this approach all information about solutes and solvents is extracted from initial continuum solvation QC calculations. COSMO-RS is widely validated in the chemical engineering thermodynamics for the prediction of activity coefficients, solubility and vapour pressures of demanding compounds in pure and mixed solvents. This presentation reports some novel extensions and applications of the COSMO-RS methodology towards the prediction of acidity and basicity pKa of solutes in non-aqueous solvents such as acetonitrile, dimethylsulfoxide (DMSO), 1,2-dimethoxyethane (DME) and heptane. Correlating the quantum chemical dissociation free energy ΔGdiss of a molecule solvated in a solvent, with its experimental pKa via a linear free energy relationship (LFER) a theoretical a priori prediction method for pKa in non-aqueous solvents has been achieved, which has the regression constant and the slope as only adjusted parameters. The method is not restricted to certain compound classes. For all solvents considered in the study a standard deviation below 1.5 pKa units was found in the correlations and independent test sets. In concordance with findings for aqueous pKa predictions [3] for all non-aqueous solvents the slope of experimental pKa vs. ΔGdiss was found to be smaller than the value of 1/RTln(10) that is expected from electrostatic theory.

[1] F. Eckert, A. Klamt, AlChE Journal, 2002, 48, 369.

[2] A. Klamt, F. Eckert, Fluid Phase Equilibria, 2000, 172, 43.

[3] A. Klamt, F. Eckert, M. Diedenhofen, M. E. Beck, J. Chem. Phys. A., 2003, 107, 9380.