Prediction of acidity in acetonitrile 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 pK_a values in acetonitrile. For a variety of 93 organic acids, the directly calculated values of the free energies of dissociation in acetonitrile showed a very good correlation with the pK_a values (r² = 0.97) in acetonitrile, corresponding to a standard deviation of 1.38 pK_a units. Thus, we have a prediction method for acetonitrile pK_a with the intercept and the slope as the only adjusted parameters. Furthermore, the pK_a values of CH acids yielding large anions with delocalized charge can be predicted with a rmse of 1.12 pK_a units using the theoretical values of slope and intercept resulting in truly ab initio pK_a prediction. In contrast to our previous findings on aqueous acidity predictions the slope of the experimental pK_a versus theoretical ΔG_diss was found to match the theoretical value 1/RT ln (10) very well. The predictivity of the presented method is general and is not restricted to certain compound classes. However, a systematic correction of −7.5 kcal mol⁻¹ is required for compounds that do not allow electron-delocalization in the dissociated anion. The prediction model was tested on a diverse test set of 129 complex multifunctional compounds from various sources, reaching a root mean square deviation of 2.10 pK_a units. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009