The Partitioning of Phosphoramide Mustard and Its Aziridinium Ions among Alkylation and P−N Bond Hydrolysis Reactions

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Abstract
NMR (1H and 31P) and HPLC techniques were used to study the partitioning of phosphoramide mustard (PM) and its aziridinium ions among alkylation and P−N bond hydrolysis reactions as a function of the concentration and strength of added nucleophiles at 37 °C and pH 7.4. With water as the nucleophile, bisalkylation accounted for only 10−13% of the product distribution given by PM. The remainder of the products resulted from P−N bond hydrolysis reactions. With 50 mM thiosulfate or 55−110 mM glutathione (GSH), bisalkylation by a strong nucleophile increased to 55−76%. The rest of the PM was lost to either HOH alkylation or P−N bond hydrolysis reactions. Strong experimental and theoretical evidence was obtained to support the hypothesis that the P−N bond scission observed at neutral pH does not occur in the parent PM to produce nornitrogen mustard; rather it is an aziridinium ion derived from PM which undergoes P−N bond hydrolysis to give chloroethylaziridine. In every buffer studied (bis-Tris, lutidine, triethanolamine, and Tris), the decomposition of PM (with and without GSH) gave rise to 31P NMR signals which could not be attributed to products of HOH or GSH alkylation or P−N bond hydrolysis. The intensities of these unidentified signals were dependent on the concentration of buffer.