Unexpected Z/E isomerism of N -methyl- O -phosphothioyl benzohydroxamic acids, their oxyphilic reactivity and inertness to amines

Thiophosphinoylation of N -methyl p-substituted benzohydroxamic acids using disulfanes (method A) or diphenylphosphinothioyl chloride (method B) provides only one conformer of the respective O -phosphothioyl derivative (X-ray and NMR analysis). Undergoing the P -transamidoxylation reaction is an evidence of the reversibility of thiophosphinoylation. Only those products containing strong EWG substituents in the aroyl residue or bulky substituents at the phosphorus atom possess E conformation. DFT calculations confirmed the energetic domination of each isomer. The Z -isomers are distorted amides having both high degree of nitrogen pyramidalization (38–55°) and amide twist (12–30°). In solution they exist in a defined conformation that is evidenced by the presence of a sharp signal of N -methyl protons at low temperature. They do not isomerize in solutions. Some of them slowly undergo the N-O bond scission above 100 °C. Both isomers are not as sensitive to neutral hydrolysis as twisted amides can be and are inert toward amines. The rate of alkaline hydrolysis can be correlated with pKa of hydroxamic acid. Because of their outstanding oxyphilicity, these compounds can be defined as nerve agent surrogates and safer alternatives of phosphorus fluorides for serine-active enzyme inhibition studies.