Molecular Pharmacology, Vol 9, 152-162, Copyright © 1973 by the American Society for Pharmacology and Experimental Therapeutics

Quantum Chemical Studies of the Metabolism of a Series of Chlorinated Ethane Anesthetics

¹ Departments of Genetics, Anesthesia, and Chemistry, Stanford University School of Medicine, Stanford University Medical Center, Stanford, California 94305

Using a working molecular orbital program based on an iterative extended Hückel method, we have calculated the conformational and electronic properties of a series of nine chloroethane anesthetics. The object of this study was to determine the molecular factors which correlated with the observed specificity of the extent of dechlorination in vitro of these compounds, all believed to be substrates of the same liver microsomal enzyme system. The results of our energy conformation studies reveal that all these compounds have a common minimum energy conformer, characterized by adjacent chlorine atoms as far apart as possible. Chemically, our calculations point to a unique and striking correlation between the extent of dechlorination and the extent of electron deficiency in the most electron-deficient carbon valence atomic orbital in each compound. No such correlation was found with other calculated molecular properties such as C-Cl or C-H bond strengths, or the net charge on the carbon, hydrogen, or chlorine atoms in this series of compounds. Our calculation also show that the electron-deficient carbon atom orbital is used in bonding to a chlorine atom in each compound. Our results are most consistent with a mechanism of dechlorination in which the rate-determining step involves an anionic attack on the electron-deficient carbon atomic orbital. Other calculated molecular characteristics reinforce this conclusion, and allow the further inference that such an anionic attack is accompanied by a chlorine displacement, perhaps aided by a proton on a nearby acidic residue in the metabolizing enzyme.

Note:
ACKNOWLEDGMENT We wish to acknowledge helpful discussions with Professor E. N. Cohen.