Chemistry of nitrogen mustard [2-chloro-N-(2-chloroethyl)-N-methylethanamine] studied by nuclear magnetic resonance spectroscopy

Abstract

Reactions of the nitrogen mustard drug 2-chloro-N-(2-chloroethyl)-N-methylethanamine with nucleophiles in aqueous solution have been studied by ¹H and ¹³C n.m.r. spectroscopy. Conditions have been devised for converting the mustard into the N-2-chloroethyl-N-methylaziridinium ion which has been characterised by ¹H n.m.r. spectroscopy. To assist the studies of reactions of the mustard by ¹³C n.m.r. spectroscopy, it has been prepared labelled at both C-2 atoms by ¹³C. It is shown that reactions of the mustard with strong nucleophiles (e.g. thiosulphate) proceed to a product of disubstitution, without the aziridinium ion being detected spectroscopically, although its intermediacy is inferred by examining the distribution of ¹³C in product from ¹³C-labelled mustard. Less reactive nucleophiles (e.g. thiourea) yield a product of disubstitution via spectroscopically detected intermediates (aziridinium ion and monosubstituted intermediate). Relatively weak nucleophiles (e.g. guanosine) did not give detectable products of substitution; cis- and trans-NN′-2-chloroethyl-NN′-methylpiperazinium dichloride were formed via the aziridinium ion. The reaction of the mustard with excess of ammonia gives a 3:2 ratio of 2-amino-N-(2-aminoethyl)-N-methylethanamine and N-methylpiperazine. The distribution of ¹³C label in these products derived from ¹³C-labelled drug shows that the triamine is formed via aziridinium intermediates, whilst the piperazine arises via intramolecular cyclisation of the intermediate 2-amino-N-(2-chloroethyl)-N-methylethanamine.