Accurate prediction of basicity in aqueous solution with COSMO‐RS

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 (r 2 = 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. Δ Gdiss was significantly smaller than the theoretically expected value of 1/RT ln(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