Hydrolysis mechanisms for A-series (Novichok) nerve agents at different pH V and computational simulant screening

A-series nerve agents (Novichok agents) are ultratoxic organophosphorus agents that were listed in Schedule 1 of the Chemical Weapons Convention in 2019. Their extreme acute toxicity precludes direct experimental manipulation, and theoretical investigations into their aqueous degradation mechanisms and safe simulant development are scarce. This study investigated the dominant hydrolysis pathways of three A-series nerve agents (A230, A232, and A234) under various pH conditions, along with their corresponding hydrolysis half-lives, using computational methods. The hydrolysis rates of the nerve agents exhibited a strong pH dependence, with acid- and base-catalyzed hydrolysis resulting in a characteristic bell-shaped curve of half life <i>versus</i> pH. Computational screening identified <i>N</i>'-diphenoxyphosphorylethanimidamide (ADPP) and 4-nitrophenyl (<i>E</i>)-<i>N</i>-(1-(diethylamino)ethylidene)-P-methylphosphonamidate as optimal hydrolysis simulants. The experimental hydrolysis results for ADPP strongly agreed with the theoretical predictions, confirming the reliability of the methodology. Overall, this study established a predictive framework to determine the dominant hydrolysis pathways and half-lives of amidinofluorophosphonates, enabling the estimation of hydrolysis properties for potential A-series agents based solely on their molecular formulas.