A theoretical model for the evaluation and prediction of electronic substituent effects from frontier orbital energies and molecular topology

The notion that the molecular and electronic structure of a molecule contains the features responsible for its physical, chemical, and biological properties is pre-eminent in organic chemistry. The Hammett equation is one of the first and most successful paradigms utilized for the systematic identification and quantification of such features. Yet despite its numerous successful applications in organic and applied organic chemistry, the empirical nature of the Hammett equation has restricted its interpretive capabilities and conclusions drawn from its use must rely entirely on inference and chemical intuition and experience. To help amend this situation, an increasing number of studies are being performed in which the theoretical treatment of substituent effects is explored.; In this dissertation, a new methodology for the calculation of Hammett substituent constants from theoretical 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 theory-based analogs of empirical Hammett substituent constants from statistical analysis. Global quantum chemical reaction indices were drawn from density functional theory and formulated from AM1-based frontier orbital energies. A localized index based on the electrotopological state was used to encode information on individual group properties. From a training set consisting of 225 meta and para-substituted benzoic acids, statistical analysis of theoretical descriptors as a function of empirical substituent constants yielded a five-parameter QSAR/QSPR model which exhibits a strong correlation with empirical values (r2 = 0.947). Both internal (PRESS) and external (independent testing set) validation procedures indicate that the QSAR/QSPR-based electronic effects model derived in this work from theoretical parameters is a statistically viable paradigm. Predicted and empirical constants were also employed in extended correlation analyses as functions of experimentally determined rates of hydrolysis of a congeneric series of O,O-diethylphenylphosphorothionate pesticides and as functions of reaction data for thirty-four independent datasets of meta and para-substituted aromatics taken from the literature. The statistical parameters of ensuing correlations were examined and compared and the empirical and predicted results were found to be of equitable quality.