4339371

Computational investigation of the reactivity of alkyl radical intermediates generated from pyridinium salts

Date
August 18, 2025

Pyridinium salts are valuable synthetic building blocks present in many natural products and biologically active molecules and have applications in drug delivery, DNA binding, and as acetylcholinesterase inhibitors. Prepared from ubiquitous primary amines and pyrylium salts, they provide a way to incorporate amines as coupling partners in reactions aimed at forming C−C bonds, such as cross-electrophile couplings and Michael additions. While the cross-electrophile coupling of secondary alkyl pyridinium salts and alkyl zinc halides proceeds without obstacles, the analogous coupling of tertiary alkyl pyridinium salts has proven challenging, despite density functional theory (DFT) calculations suggesting the formation of the tertiary alkyl radical intermediate is facile. To understand this transformation which has an experimental outcome that cannot be explained by energy calculations, we have turned to quasi-classical molecular dynamics (MD) simulations. In this work, a combined DFT and MD approach is used to study the formation of tertiary alkyl radicals from pyridinium salts, with an emphasis on understanding the role of steric and electronic factors of the pyridinium salt on the formation of the alkyl radical. The mechanistic insight gained from this study is used to inform our experimental design utilizing these tertiary alkyl pyridinium salts as coupling partners with Michael acceptors.

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