A multistep mechanism of nucleophilic substitution of vitamin B 1 in methanol

Abstract

Thiamin (1) and an analog (2) having a pyridine ring in place of the thiazole portion react with amine nucleophiles in methanol at 71.5°C to give substitution products 3. The nucleophiles replace the thiazole and pyridine rings. The course of the substitution reactions which were followed by PMR are first order in substrate and zero order in amine. Proposed is a multistep mechanism analogous to that observed for second-order reactions between sulfite ion, for example, and thiamin, its derivatives, and analogs. The conjugate acid of the substrate forms a sigma adduct with methoxide ion. Following fragmentation to a resonance-stabilized cation the amine nucleophile becomes incorporated into this charged intermediate. Loss of methoxide ion generates the aromatic substitution product. Substrate protonation and methoxide ion addition are kinetically equivalent to the addition of solvent, a process that cannot be detected kinetically. Addition of the amine occurs in a fast step. Overall then, the scheme is only first order in substrate as required by the experimental observations.