# Quantifying Breslow intermediate reactivity in intermolecular Stetter reactions

## TL;DR

A new method is developed to measure the reactivity of a Breslow intermediate in Stetter reactions, avoiding interference from competing reactions.

## Contribution

A novel kinetic approach was developed to quantify Breslow intermediate reactivity without interference from the benzoin reaction.

## Key findings

- Pseudo first-order rate constants for over 40 Michael acceptors were measured using the new method.
- Electron-withdrawing substituents in chalcones significantly enhance reactivity, supported by Hammett and Swain–Lupton analysis.
- An unexpected additive substituent effect in 4,4′-disubstituted chalcones was observed and analyzed using DFT.

## Abstract

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.

A kinetic method that allows quantification of Michael acceptor reactivity with a Breslow intermediate (BI) derived from pyridine-2-carboxaldehyde and an NHC is described.