An Unusual Double Beckmann Fragmentation Reaction Under Physiological Conditions

Pyridinium aldoximes, which are best-known as therapeutic antidotes for organophosphorus chemical warfare nerve-agents and pesticides, have been found to markedly detoxify polyhalogenated quinones which are a class of carcinogenic intermediates and recently identified disinfection byproducts in drinking water. However, the exact chemical mechanism underlying this detoxication remains unclear. Here we demonstrate that pralidoxime can remarkably facilitate the dechlorination/hydroxylation of the highly toxic tetrachloro-1, 4-benzoquinone in two-consecutive steps to generate the much less toxic 2, 5-dichloro-3, 6-dihydroxy-1, 4-benzoquonine, with rate enhancements of up to 180,000-times. On the contrary, no accelerating effect was noticed with O-methylated pralidoxime. The major reaction product from pralidoxime was identified as its corresponding nitrile (2-cyano-1-methylpyridinium chloride). Along with oxygen-18 isotope-labeling studies, a reaction mechanism was proposed that nucleophilic substitution coup...