Accurate prediction of basicity in aqueous solution with COSMO-RS

✍ Scribed by Frank Eckert; Andreas Klamt

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 178 KB
• Volume: 27
• Category: Article
• ISSN: 0192-8651
• DOI: 10.1002/jcc.20309

✦ Synopsis

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__G~diss~ 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