Sulfite-Catalyzed Nucleophilic Substitution Reactions with Thiamin and Analogous Pyrimidine Donors Proceed via an SNAE Mechanism
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Authors
Howe, Graeme
Grenade, Neil
Date
2022-09-23
Type
journal article
Language
en
Keyword
Adducts , Chemical calculations , Crystal cleavage , Free energy , Substitution reactions , Organic Chemistry , Theoretical Chemistry , Computational Chemistry , Reaction mechanisms
Alternative Title
Abstract
When treated with SO32–, thiamin undergoes a substitution reaction to release a thiazole leaving group and the corresponding sulfonate. Although this reaction could proceed via a simple SN2-like mechanism, a multistep addition–elimination (SNAE) mechanism involving the addition of SO32– 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 SO32–-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 SNAE mechanism over an SN2-like process and illustrate that the unique ability of SO32– to activate thiamin toward nucleophilic displacement is due to the combined nucleophilicity and relatively poor leaving group ability of SO32–. 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 SNAE pathway is significantly lower in energy than the direct substitution, illustrating that this SO32–-catalyzed multistep process is likely to be broadly applicable both in solution and in catalysis by thiaminases.
Description
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Organic Chemistry, copyright © 2022, American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see the Publisher's website at https://doi.org/10.1021/acs.joc.2c01685.
Citation
Graeme W. Howe and Neil L. Grenade, Sulfite-Catalyzed Nucleophilic Substitution Reactions with Thiamin and Analogous Pyrimidine Donors Proceed via an SNAE Mechanism. The Journal of Organic Chemistry (2022). DOI: 10.1021/acs.joc.2c01685
Publisher
American Chemical Society