A theoretical examination of substituent effects on the detoxification reaction between glutathione and halogenated methanes

Abstract

An important metabolic pathway for halogenated methanes is the detoxification reaction with glutathione in the cell cytosol fraction. Experimental studies have shown that the rate of this SN2 displacement reaction is directly related to the leaving group ability of the dissociating halide; the rate increases in order of the ions F−, Cl−, Br−, and I− leaving. In this study, we examine the role of the other halomethane substituents on the rate of this reaction for compounds with a common leaving anion. To this end, reaction Cl− + CY3Cl → ClCY3 + Cl− (Y = H,F,Cl) is examined using ab initio methods. The barrier for this exchange process may arise from requiring an inversion of the CY3 group in the transition structure, the energy required to homolytically cleave the CCl bond, or from unfavorable steric and electronic interactions in the five‐coordinated transition structure. Of these three factors, only the third explains the calculated ordering of barrier heights. This suggests that successive halogenation of methane not only increases its activity as a substrate for anaerobic reduction, as was shown earlier, but also decreases its ability to take part in the detoxification reaction with glutathione. Copyright © 1986 John Wiley & Sons, Inc.