Use of electron densities in comparative molecular field analysis (CoMFA): O?H bond dissociation energies in phenols

Abstract

The ability to successfully predict the bond dissociation energies of the phenol OH bond is important in medicinal chemistry for a variety of therapeutic applications. Previous reports utilized rigorous approaches with semi-empirical, ab initio and density functional theory, as well as more empirically based quantitative structure activity relationship (QSAR) approaches. Here we report the use of a three-dimensional quantitative structure activity relationship method incorporating electron densities computed using the Austin Method 1 (AM1) method followed by correlation of the electron density with the relative bond dissociation energies. The QSAR is determined for both the ground-state phenol as well as the singlet phenoxy radical with a set of compounds for which the bond dissociation energies have been measured. The model developed using the ground-state phenol model is more predictive. The coefficients of the QSAR have also been interpreted. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 75: 187–195, 1999