Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions

The present study describes the kinetic analysis of the 3-chloropiperidine alkylation mechanism. These nitrogen mustard-based compounds are expected to react via a highly electrophilic bicyclic aziridinium ion, which is readily attacked by nucleophiles. Halide abstraction using silver salts with weakly coordinating anions lead to the isolation of these proposed intermediates, whereas their structure was confirmed by single crystal XRD. Kinetic studies of the aziridinium ions also revealed notable reactivity differences of the C5 gem-methylated compounds and their unmethylated counterparts. The observed reactivity trends were also reflected by NMR studies in aqueous solution and DNA alkylation experiments of the related 3-chloropiperidines. Therefore, the underlying Thorpe-Ingold effect might be considered as another option to adjust the alkylation activity of these compounds.