Prediction of the Dissociation Constant pKa of Organic Acids from Local Molecular Parameters of Their Electronic Ground State

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• 作者：Haiying Yu ; Ralph Ku虉hne ; Ralf-Uwe Ebert ; Gerrit Schu虉ü ; rmann
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2011
• 出版时间：September 26, 2011
• 年：2011
• 卷：51
• 期：9
• 页码：2336-2344
• 全文大小：854K
• 年卷期：v.51,no.9(September 26, 2011)
• ISSN：1549-960X

文摘

A quantum chemical method has been developed to estimate the dissociation constant pK_a of organic acids from their neutral molecular structures by employing electronic structure properties. The data set covers 219 phenols (including 29 phenols with intramolecular H-bonding), 150 aromatic carboxylic acids, 190 aliphatic carboxylic acids, and 138 alcohols, with pK_a varying by 16 units (0.38鈥?6.80). Optimized ground-state geometries employing the semiempirical AM1 Hamiltonian have been used to quantify the site-specific molecular readiness to donate or accept electron charge in terms of both charge-associated energies and energy-associated charges, augmented by an ortho substitution indicator for aromatic compounds. The resultant regression models yield squared correlation coefficients (r²) from 0.82 to 0.90 and root-mean-square errors (rms) from 0.39 to 0.70 pK_a units, corresponding to an overall (subset-weighted) r² of 0.86. Simulated external validation, leave-10%-out cross-validation and target value scrambling demonstrate the statistical robustness and prediction power of the derived model suite. The low intercorrelation with prediction errors from the commercial ACD package provides opportunity for a consensus model approach, offering a pragmatic way for further increasing the confidence in prediction significantly. Interestingly, inclusion of calculated free energies of aqueous solvation does not improve the prediction performance, probably because of the limited precision provided by available continuum-solvation models.