Metabolite Predictions for Para-Substituted Anisoles Based on ab Initio Complete Active Space Self-Consistent Field Calculations

Abstract
The cytochrome P450 mediated oxidative metabolism of a series of para-substituted anisoles has been examined using ab initio CASSCF (complete active space self-consistent field) calculations. On the basis of these calculations, oxidative metabolites were rationalized using the concept of hydrogen atom abstraction, spin delocalization, and hydroxyl radical recombination, which is believed to govern part of the oxidation and oxygenation reactions catalyzed by cytochrome P450. Spin distributions and energy differences between substrates, metabolic intermediates, and products were calculated. A comparison of the predictions with recent experimental findings from other laboratories supports the applicability of the currently used computational model for predicting qualitatively the oxidative metabolism by cytochrome P450.

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