Kebbell, Michael James (1984) A study of the chemistry of nitrogen mustard by N.M.R. spectroscopy. PhD thesis, University of Warwick.

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Abstract

This thesis describes the use of high-field n.m.r. spectroscopy, in part combined with stable isotope labelling, to study the solution chemistry of nitrogen mustard (2-chloro-(N-2-chloroethyl)-N-methylethanamine). Reactions with a range of nucleophiles were monitored by ¹H n.m.r. spectroscopy which demonstrated the generation of N-2-chloroethyl-N-methylaziridinium chloride from nitrogen mustard and step-wise substitution of nitrogen mustard except where polymerisation or hydrolysis occurred. The ¹H n.m.r. spectrum of the N-2-chloroethyl-N-methyl- aziridinium ion was resolved and fully assigned. The intermediacy of this species in reactions of nitrogen mustard is implied by experiments in which identical products are derived from a given nucleophile when added to either the aziridinium ion or the parent nitrogen mustard. Intermediacy of two successive aziridinium ions in alkylation of nucleophiles by nitrogen mustard was confirmed by examination of the 13c label distribution in products arising from alkylation of [2,2'-13c]-2-chloro-(N-2-chloro- ethyl)-N-methylethanamine. Applying a consideration of the stereochemistry of ring closure to N-methylpiperazine arising from alkylation of ammonia demonstrated that the observed 13c label distribution could only arise if aziridinium ion formation was irreversible. The isotope effect on ring opening of the aziridinium ion was measured under a range of reaction conditions for several different nucleophiles.
Observation of the reaction between nitrogen mustard and methionine was simplified by the use of (S)-[13cH3]-methionine to demonstrate rapid formation of sulphonium salts and a slow breakdown to homocysteine and 2-methylthio-N-[2-(methylthio)ethyl]-N-methylethanamine.
The synthesis of [2,2'-¹3C]-2-chloro-(N-2-chloro- ethyl)-N-methylanamine is described and a general synthesis of isotopically enriched nitrogen mustards is suggested based on this route. Efficient syntheses of (S)-[¹3CH₃]- methionine, (S)-[C²H₃]- methionine, (S) -ɑ - ²H-alanine and (S0 – (1-¹3C] - leucine are also described.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Nitrogen mustards, Chemistry, Organic, Mustard gas -- Research, Nitrogen mustards -- Research, Nuclear magnetic resonance spectroscopy
Official Date:	September 1984
Dates:	Date Event September 1984 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Golding, Bernard T.
Sponsors:	Science and Engineering Research Council (Great Britain)
Extent:	[13], 185 leaves : illustrations.
Language:	eng

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