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

Abstract

The present study describes the kinetic analysis of the 3chloropiperidine 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.

Separation of the Thorpe−Ingold and Reactive Rotamer Effect by Using the Formation of Bicyclic Aziridinium Ions

“…A similar effect resulting from gem-dimethylation can be assumed for the N-benzyl and N-butyl substituted derivatives, considering that the reaction of 1 a and 1 b as well as 6 a and 6 b with 2'-desoxyguanosine in aqueous solution provided similar relative rate constants in our previous work (k rel (1 b/1 a) = 4.67; k rel (6 b/6 a) = 4.08). [32] In addition, we obtained a relative rate constant of k rel = 1.66 in a separate kinetic study of 6 a and 6 b in methanol-d 4 at 50 °C (see Figure S6), which is comparable to the values of the respective N-butyl compounds reported in Table S1 and Table 1. Furthermore, we investigated the structure of the examined 3chloropiperidine derivatives computationally using the orca program package (version 5.0.3.)…”

“…Since a crystal structure of the dimethylated compound 1 b could not be obtained, the angles of the crystal structures of compounds 6 a and 6 b (see Tables S8–S20), which represent the N ‐benzyl substituted derivatives of 1 a and 1 b , were added. A similar effect resulting from gem ‐dimethylation can be assumed for the N ‐benzyl and N ‐butyl substituted derivatives, considering that the reaction of 1 a and 1 b as well as 6 a and 6 b with 2'‐desoxyguanosine in aqueous solution provided similar relative rate constants in our previous work ( k rel ( 1 b / 1 a )=4.67; k rel ( 6 b / 6 a )=4.08) [32] . In addition, we obtained a relative rate constant of k rel =1.66 in a separate kinetic study of 6 a and 6 b in methanol‐d 4 at 50 °C (see Figure S6), which is comparable to the values of the respective N ‐butyl compounds reported in Table S1 and Table 1.…”

“…In recent kinetic studies with substituted 3‐chloropiperidines we noticed an enhanced reaction rate for the 5,5‐dimethyl derivative 1 b compared to the corresponding unsubstituted compound 1 a [32] . The reaction of these compounds with nucleophiles proceeds via the highly electrophilic bicyclic aziridinium intermediate 2 , which is rapidly consumed by nucleophilic attack (Scheme 1).…”

“…In recent kinetic studies with substituted 3-chloropiperidines we noticed an enhanced reaction rate for the 5,5-dimethyl derivative 1 b compared to the corresponding unsubstituted compound 1 a. [32] The reaction of these compounds with nucleophiles proceeds via the highly electrophilic bicyclic aziridinium intermediate 2, which is rapidly consumed by nucleophilic attack (Scheme 1). The observed increase in reaction rate is assumed to be the result of a gem-dialkyl effect, since a bicyclic system is obtained in the rate-determining formation of the aziridinium intermediate (k 1 ), for which the steady state approximation (k 2 @ k -1 ) can be applied.…”

Secondary 3‐Chloropiperidines: Powerful Alkylating Agents

“…[10,11] Our most recent advancements included the isolation of the bicyclic aziridinium ion as the key intermediate to gain further inside in the mechanism of action by NMR kinetics. [12] Figure 1. Natural compounds with known alkylating properties as lead structures.…”