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Accurate prediction of basicity in aqueous solution with COSMO‐RS
Author(s) -
Eckert Frank,
Klamt Andreas
Publication year - 2005
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.20309
Subject(s) - solvation , cosmo rs , chemistry , thermodynamics , quantum chemical , dielectric , aqueous solution , dissociation constant , computational chemistry , a value , quantitative structure–activity relationship , base (topology) , standard deviation , dissociation (chemistry) , molecule , mathematics , organic chemistry , statistics , physics , stereochemistry , quantum mechanics , mathematical analysis , ionic liquid , biochemistry , receptor , catalysis
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