Accurate prediction of basicity in aqueous solution with COSMO-RS

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Abstract

The COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for realistic solvation simulations, has been used for the prediction of base pK_a constants. For a variety of 43 organic bases the directly calculated values of the free energies of dissociation in water showed a very good correlation with experimental base pK_a values (r2 = 0.98), corresponding to a standard deviation of 0.56 pK_a units. Thus, we have an a priori prediction method for base pK_a with the regression constant and the slope as only adjusted parameters. In accord with recent findings for pK_a acidity predictions, the slope of pK_a vs. ΔG_diss was significantly smaller than the theoretically expected value of 1/RTln(10). The predictivity of the presented method is general and not restricted to certain compound classes, but systematic corrections of 1 and 2 pKa units for secondary and tertiary aliphatic amines are required, respectively. The pK_a prediction method was validated on a set of 58 complex multifunctional drug-like compounds, yielding an RMS accuracy of 0.66 pK_a units. © 2005 Wiley Periodicals, Inc. J Comput Chem 27: 11–19, 2006