From Mechanisms to Materials: Oximate Reactivity and Emerging Strategies for Organophosphate Detoxification

The development of effective strategies for the detoxification of organophosphorus (OP) nerve agents has evolved from the early mechanistic studies of François Terrier and collaborators, who first elucidated the exceptional nucleophilicity of α-effect species such as oximes and hydroxamates, to the modern design of supramolecular and material-based systems. Terrier's pioneering kinetic investigations and the conceptual framework established by Clifford A. Bunton and Erwin Buncel on micellar catalysis provided a foundation for understanding how medium effects and local organization modulate α-nucleophile reactivity. Building on these insights, contemporary research has expanded the chemical landscape of oxime-based reactivators through synthetic modification, computational modeling, and the development of functional scaffolds capable of efficient acetylcholinesterase (AChE) reactivation and direct OP hydrolysis. This review examines the evolution of oxime-based detoxification, with emphasis on structure-reactivity relationships, mechanistic insights, and advances in reaction media. Micellar systems were the first colloidal environments explored, while supramolecular assemblies such as lipids and cyclodextrins combine molecular recognition with catalytic function. Recent developments include inorganic and nanostructured catalysts that enable organophosphate degradation under mild conditions. The transition from α-nucleophile chemistry to multifunctional materials reflects not only the progress of physical organic chemistry in detoxification but also its convergence with supramolecular and materials science.