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Quantifying Breslow intermediate reactivity in intermolecular Stetter reactions.
Zhuan Duan1, Jiayun Zhu2, Pankaj K Majhi1
1EaStCHEM, School of Chemistry, University of St Andrews Fife KY16 9ST UK alister.s.goodfellow@gmail.com claireyoungchemistry@gmail.com ads10@st-andrews.ac.uk.
Chemical Science
|October 20, 2025
Summary
Researchers developed a kinetic method to quantify the reactivity of Breslow intermediates in N-heterocyclic carbene (NHC)-catalyzed reactions. This approach successfully measured the rates of over 40 Michael acceptors in the Stetter reaction.
Area of Science:
- Organic Chemistry
- Catalysis
- Reaction Kinetics
Background:
- Quantifying Breslow intermediate reactivity in N-heterocyclic carbene (NHC)-mediated reactions is challenging due to competing pathways.
- A robust kinetic method is needed to accurately assess Breslow intermediate behavior.
Purpose of the Study:
- To develop and apply a kinetic approach for quantifying the reactivity of a specific Breslow intermediate.
- To investigate the influence of substrate structure on reactivity in the intermolecular Stetter reaction.
Main Methods:
- A novel kinetic method was developed to isolate and measure the rate of Breslow intermediate reactions, avoiding interference from the benzoin reaction.
- The reactivity of a Breslow intermediate derived from 2-pyridine carboxaldehyde and an N-pentafluorophenyl substituted triazolinylidene NHC was quantified.
- Over 40 Michael acceptors, including chalcones, nitroolefins, and malonic esters, were studied in the intermolecular Stetter reaction.
Main Results:
- Pseudo first-order rate constants were measured for >40 Michael acceptors.
- Electron-withdrawing substituents on the C(1)-aryl group of chalcones significantly enhanced reactivity.
- An unexpected additive substituent effect was observed for 4,4'-disubstituted chalcones, with DFT analysis providing mechanistic insights.
Conclusions:
- The developed kinetic approach successfully quantifies Breslow intermediate reactivity in the intermolecular Stetter reaction.
- Substituent effects on chalcones play a crucial role in modulating reactivity, offering valuable insights for catalyst and substrate design.
- DFT analysis provides a deeper understanding of the observed substituent effects, aiding in reaction mechanism elucidation.
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