Accurate prediction of basicity in aqueous solution with COSMO-RS.

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. DeltaG(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.