QSAR Treatment of Electronic Substituent Effects Using Frontier Orbital Theory and Topological Parameters

Abstract

A methodology for the estimation of Hammett substituent constants from computational-based descriptors utilizing quantitative structure activity/property relationships (QSAR/QSPR) formalism is presented. Electronic descriptors derived from quantum chemical calculations and molecular topology were used to generate computational-based analogues of empirical Hammett substituent constants from statistical analysis. Global quantum chemical reaction indices were drawn from frontier orbital theory and density functional theory and formulated from AM1-based calculations. A localized index based on the electrotopological state index was used to encode information on individual group properties. From a training set consisting of 150 meta and para-substituted benzoic acids, statistical analysis of computational-based descriptors as a function of empirical substituent constants yielded a five-parameter QSAR/QSPR model which generates computational-based constants exhibiting a strong correlation with empirical values (r2 = 0.958). Both internal (PRESS) and external (independent testing set of benzoic acids) validation procedures suggest that the electronic effects QSAR/QSPR model derived in this work from computational-based parameters is a statistically viable paradigm. Both predicted and empirical constants were used in Hammett-type validation analyses as functions of chemical, biological, and spectroscopic data for thirty structurally diverse meta and parasubstituted aromatic testing sets. Statistical measures of ensuing correlations were examined and compared, and the empirical and predicted results were of similar quality. Validation results reveal that a large number of computational-based substituent constants can be accurately estimated from semiempirical AM1 frontier orbital energies and electronic structure information obtained directly from substituted benzoic acids without the aid of empirical parametrization.

Predicting the photoinduced electron transfer thermodynamics in polyfluorinated 1,3,5-triarylpyrazolines based on multiple linear free energy relationships

“…This approach has the advantage that the overall electronic contribution of the substituent ensemble is captured in an unbiased manner, and that potential steric effects specific to the pyrazoline fluorophore architecture can be later evaluated on the basis of the LFER. A number of studies showed that several quantum chemical parameters linearly correlate with experimentally derived Hammett constants 18,24–29. Recently, Galabov et al demonstrated that the theoretical electrostatic potentials at the nuclei (EPN) of carbon atoms in substituted benzenes represent an excellent reactivity descriptor 30.…”

A Survey of Quantitative Descriptions of Molecular Structure

“…For example, partial charges, Highest Occupied Molecular Orbital (HOMO) and Lowest Occupied MOlecular Orbital (LUMO) energies are commonly evaluated using semiempirical methods, while Eroglu and Turkmen [29] described density functional theory (DFT) derived descriptors such as electronegativity, hardness and ionization potential (though Puzyn et al question the need for such a high level of theory [30]). Sullivan et al [31] employed frontier orbital theory and DFT to generate quantum mechanical analogs of Hammett substituent constants [32] and showed that they agreed well with empirically derived constants.…”

A Survey of Quantitative Descriptions of Molecular Structure

“…For example, partial charges, Highest Occupied Molecular Orbital (HOMO) and Lowest Occupied MOlecular Orbital (LUMO) energies are commonly evaluated using semi-empirical methods, while Eroglu and Turkmen [29] described density functional theory (DFT) derived descriptors such as electronegativity, hardness and ionization potential (though Puzyn et al question the need for such a high level of theory [30]). Sullivan et al [31] employed frontier orbital theory and DFT to generate quantum mechanical analogs of Hammett substituent constants [32] and showed that they agreed well with empirically derived constants.…”