PROTONATION OF PHOSPHORAMIDE MUSTARD AND OTHER PHOSPHORAMIDES

The chemistry of the bifunctional alkylating agent phosphoramide musta rd and model phosphoramides was probed by multinuclear NMR spectroscop y as a function of pH. Between pH 1 and 11, both the P-31 and N-15 res onances for phosphoramide mustard displayed a single monobasic titrati on curve with a pK(a) of 4.9. The protonation below pH 4.9 correlates with the loss in reactivity of the mustard. The O-17 NMR spectrum of O -17-enriched phosphoramide mustard shows little change with pH. The da ta on the mustard was compared to N-15 and P-31 NMR data on N-15-enric hed phosphoramidic acid, phosphorodiamidic acid, and phosphoric triami de. Contrary to the conclusions of previous studies, our combined P-31 , N-15, and O-17 NMR results are more consistent with N-protonation of phosphoramide mustard rather than an O-protonation. Theoretical calcu lations on the phosphoramidic acid, phosphorodiamidic acid, and phosph oric triamide show O-protonation to be more stable in the gas phase. F or the latter two compounds, the calculations suggest that N-protonati on may be the most stable protonated form in the aqueous phase. These findings influence our understanding of the structure-activity relatio nships of phosphoramide mustards.