Mechanism of nucleophilic substitution of thiamine and its analogs: Methanol and water solvents

Abstract

4-Amino-1,2-dimethyl-5-(substituted methyl)pyrimidinium ions undergo lyate ion-catalyzed nucleophilic substitution in methanol and in water. The substituents at position 5 of these thiamine analogs include phenols and pyridinium ions. The observation of separate rate- and product-determining steps indicates a multistep mechanism of substitution. Linear free energy relationships suggest that addition of lyate ion to the pyrimidinium ring is rate-limiting when phenoxide ions act as leaving groups and that a change occurs when pyridines depart. Elimination of the pyridine becomes the rate-limiting step following rapid addition of the lyate ion. Reactivities of phenol substrates in methanol and in water are similar but, when pyridine departs, changing from water to methanol gives rise to a large rate acceleration. An increase in ground state electrostatic destabilization of the dicationic substrate in the less polar alcohol provides the rate enhancement.