THEORETICAL INVESTIGATION INTO THE POTENTIAL OF HALOGENATED METHANES TO UNDERGO REDUCTIVE METABOLISM

The density-functional theory (DFT)-based computational chemistry soft ware package DMol was used to provide insight into the reductive poten tials of a series of halomethanes. It is known that certain members of this series are readily reduced in vivo via catalysis by cytochrome P 450. DMol was used to calculate the electron affinities of these molec ules to be used as measures of their reduction potentials. Our results are consistent with experimental electrochemical reduction potentials and indicate that electron affinity is dependent upon the number and type of halogens present in the molecule. Calculated bond lengths and angles also compared favorably with experimental results and estimates derived from other ab initio methods of calculation. Concurrent with this study was the observation of a linear empirical relationship betw een electron affinity and the lowest unoccupied molecular orbital ener gy. It is possible that these values could be used as indicators of re ductive potentials and ultimately of metabolic rates for use in PB-PK models designed to predict the dose associated with the toxicity of mo lecules of this and other classes. (C) 1993 by John Wiley & Sons, Inc.