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Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones
Published on: February 7, 2019
A quantitative approach to nucleophilic organocatalysis
Herbert Mayr1, Sami Lakhdar, Biplab Maji
1Department Chemie, Ludwig-Maximilians-Universität München, Butenandstr. 5-13 (Haus F), 81377 München, Germany.
Beilstein Journal of Organic Chemistry
|September 29, 2012
Summary
This study quantifies organocatalyst reactivity using electrophilicity (E) and nucleophilicity (N) parameters. It clarifies mechanistic details for iminium and enamine catalysis, aiding in the rational design of new organocatalytic reactions.
Area of Science:
- Organic Chemistry
- Catalysis
- Reaction Kinetics
Background:
- Organocatalytic cyclizations involve electrophile-nucleophile reactions.
- Reaction rates are governed by the linear free-energy relationship log k(20 °C) = s(N)(E + N).
- Electrophilicity (E) and nucleophilicity (N) parameters characterize reactants.
Purpose of the Study:
- To determine electrophilicity parameters for iminium ions derived from cinnamaldehyde and common organocatalysts.
- To rationalize the reactivity of enamine-activated reactions with specific electrophiles.
- To investigate the nucleophilicity and Lewis basicity of N-heterocyclic carbenes (NHCs) and Breslow intermediates.
Main Methods:
- Determining electrophilicity parameters (E) for iminium ions via reaction rate studies with reference nucleophiles.
- Analyzing nucleophilicity parameters (N) for enamines derived from phenylacetaldehyde and MacMillan's imidazolidinones.
- Conducting kinetic investigations on the reactions of N-heterocyclic carbenes (NHCs) with benzhydrylium ions.
Main Results:
- Electrophilicity parameters (E) for iminium ions were found to be in the range -10 < E < -5.
- Suitable nucleophiles for iminium-activated reactions have N parameters between 2 and 14.
- NHCs exhibit similar nucleophilicities to common organocatalysts but are stronger Lewis bases.
- Aromaticity gain explains the higher nucleophilicity of 2-benzylidene-imidazoline compared to 2-benzylidene-imidazolidine.
Conclusions:
- The established E and N parameters allow for prediction and understanding of organocatalytic reaction outcomes.
- Mechanistic ambiguities in iminium and enamine catalysis can be resolved through reactivity studies of intermediates.
- Differences in reactivity among Breslow intermediates are linked to structural and electronic factors, such as aromaticity.
Keywords:
NHC activationenamine activationiminium activationkineticsorganocatalysisstructure reactivity relationshipsMore Related Videos
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