Sulfite-Catalyzed Nucleophilic Substitution Reactions with Thiamin and Analogous Pyrimidine Donors Proceed via an S N AE Mechanism.

When treated with SO 3 2- , thiamin undergoes a substitution reaction to release a thiazole leaving group and the corresponding sulfonate. Although this reaction could proceed via a simple S N 2-like mechanism, a multistep addition-elimination (S N AE) mechanism involving the addition of SO 3 2- to C6' of the 4-aminopyrimidine of thiamin has also been proposed. Although this reaction has potential utility in the synthesis of substituted pyrimidines and provides a direct analogue to reactions catalyzed by thiaminases, a detailed mechanistic picture of the SO 3 2- -catalyzed cleavage of thiamin has remained elusive. Here, DFT calculations have been used to probe the relative energetics and the factors that shape the potential energy surfaces that define the possible mechanisms of substitution. These calculations provide clear support for the S N AE mechanism over an S N 2-like process and illustrate that the unique ability of SO 3 2- to activate thiamin toward nucleophilic displacement is due to the combined nucleophilicity and relatively poor leaving group ability of SO 3 2- . Both of these factors favor the forward partitioning of the sulfite adduct toward the cleavage products whereas adducts formed with other nucleophiles overwhelmingly revert to reactants. Calculations performed with a range of substrates with various electrophilicities and nucleofugalities consistently suggest that the S N AE pathway is significantly lower in energy than the direct substitution, illustrating that this SO 3 2- -catalyzed multistep process is likely to be broadly applicable both in solution and in catalysis by thiaminases.