The Prominent Motif of the Leaving Group in Chemical and Biological Processes of Phosphonoesters: Understanding the Behavior of V‐type Nerve Agents

The solvolysis of the extremely toxic nerve agent VX and its derivatives ((OEt)MeP(O)LG, LG is leaving group), promoted by nucleophiles such as fluoride, hydroxide/water or methoxide/methanol, revealed major differences in both reaction rates and products distribution. To rationalize these differences, which are of high relevance for different issues such as toxicity, persistence and decontamination of V-type nerve agents, we conducted a combined experimental and computational (DFT) study on a series of derivatives in which only the LG was varied (O/S, N/C and more replacements). Experimentally, a high dependence of these solvolysis reactions on the LG's nature, mainly its pKa value and the presence of beta-amine moiety was observed. The DFT calculations showed that the transition states energies for P-LG bond cleavage, by fluoride or hydroxide are roughly similar for P-S scission while for P-O cleavage sharp difference was observed in favor of hydroxide. This LG ' s effect was also found to be an important determinant in biochemical processes as shown by the relative phosphonylation rates and toxicity of the described V-type nerve agents and analogues.