Quantifying Breslow Intermediate Reactivity in Intermolecular Stetter Reactions

• Published in: Chemical science (Cambridge)
• Main Authors: Duan, Zhuan, Zhu, Jiayun, Majhi, Pankaj K., Goodfellow, Alister S., O'Donoghue, AnnMarie Christine, Young, Claire M., Smith, Andrew D.
• Format: Journal Article
• Language: English
• Published: 2025
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/D5SC05021A

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 nitrolefin 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.