Quantifying Breslow intermediate reactivity in intermolecular Stetter reactions

Quantification of the reactivity of the archetypal Breslow intermediate in NHC-mediated transformations has not been achievable to date and is regarded as a significant challenge due to multiple competitive pathways and their deconvolution. This manuscript describes the development of a kinetic approach to this challenge that avoids the influence of the competitive benzoin reaction and allows quantification of the reactivity of a Breslow intermediate derived from 2-pyridine carboxaldehyde and an in situ generated N-pentafluorophenyl substituted triazolinylidene NHC with a diverse range of Michael acceptors in the intermolecular Stetter reaction. Using this approach the pseudo first-order rate constants of >40 Michael acceptors, primarily derived from (E)-chalcones but also including a nitroolefin and malonic esters, were measured. Notably, incorporating electron-withdrawing substituents within the C(1)-aryl group of (E)-chalcones leads to a substantial enhancement in reactivity, with Hammett and Swain-Lupton analysis used to understand these observations. In addition, an unexpected additive substituent effect associated with the 4,4'-disubstitution of chalcones was observed, with DFT analysis offering insights into this intriguing phenomenon.