Comparison of (5 + 2) Cycloadditions Involving Oxidopyrylium and Oxidopyridinium Ions: Relative Reactivities

Lu, Yining; Tantillo, Dean J.

doi:10.1021/acs.joc.1c00396

Cited by 6 publications

(1 citation statement)

References 54 publications

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“…Figure B shows this model schematically. Recent studies by Houk and Tantillo groups further evaluated distortion factors versus interaction effects governing cycloadditions. − The interaction energy from the D/I-AS model has further been divided into multiple components with various energy decomposition schemes. The Bickelhaupt and Hamlin groups have been especially active in applying energy decomposition to the analysis of cycloadditions.…”

Section: Introductionmentioning

confidence: 99%

Cycloaddition Reactivities Analyzed by Energy Decomposition Analyses and the Frontier Molecular Orbital Model

Sengupta

Svatunek

et al. 2022

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations * sı Supporting Information CONSPECTUS: This Account describes our quest to understand and predict organic reactivity, a principal goal of physical and theoretical organic chemistry.The focus is on the development and testing of models for the prediction of cycloaddition reactivities and selectivities. We describe the involvement of the Houk group, and other groups, in the evolution of theoretical models that can achieve ever greater accuracy as well as provide practical heuristic models for understanding and prediction. Is the venerable frontier molecular orbital (FMO) model, the basis of Kenichi Fukui's 1981 Nobel Prize, still useful, or must it be replaced with more advanced models? In particular, models such as Conceptual Density Functional, the Pauli Exclusion Model, and the recent popularity of Electrostatic Potential Plots and Dispersion Energies have not only added to our understanding, but they have also created uncertainty about whether the simple FMO heuristic model has a place in 21st century discussions. This Account addresses this issue and asserts the value of the FMO model. Beginning with brief descriptions of selected models for cycloaddition reactivity starting with early donor−acceptor (nucleophile− electrophile) charge-transfer concepts, this Account reviews Fukui's frontier molecular orbital model, Salem and Klopman's orbital, electrostatic and Pauli repulsion model, the conceptual DFT model by Parr and later by Domingo and others, the recent Houk and Bickelhaupt Distortion/Interaction Activation Strain model, and the Bickelhaupt-Hamlin's Pauli-repulsion lowering model. Computations and analyses of four well-studied Diels−Alder cycloadditions, both normal and inverse electron-demand types, are presented. Most were studied earlier in our published work but are presented here with new insights from calculations with modern methods.Depending on the types of substrates (cycloaddends), the dominant factors controlling reactivity can be orbital interactions, electrostatics and polarization, or Pauli repulsion and dispersion effects, or a combination of all of these. By comparing orbital interactions, especially the frontier molecular orbital interactions, with the other factors that influence reactivity, we show why the FMO model is such a powerful�and theoretically meaningful�heuristic for understanding and predicting reactivity. We also present a method to understand Pauli repulsion effects on activation barriers, ρ(1.1). The use of a new reaction coordinate, the extent of Pauli repulsion along the reaction path, is advocated to emphasize the role of repulsive occupied orbital interactions on reactivity. Fukui's frontier molecular orbital model is effective because FMO interactions parallel all the quantities that influence reactivity. The FMO model continues to provide a practical model to understand and guide experiments.

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Section: Introductionmentioning

confidence: 99%

Cycloaddition Reactivities Analyzed by Energy Decomposition Analyses and the Frontier Molecular Orbital Model

Sengupta

Svatunek

et al. 2022

Acc. Chem. Res.

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Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3‐Dipolar Cycloaddition of 3‐Oxidopyridinium Betaines and Dienamines

Lamhauge,

McLeod,

Barløse

et al. 2023

Chemistry A European J

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Tropane alkaloids constitute a compound‐class which is structurally defined by a central 8‐azabicyclo[3.2.1]octane core. A diverse bioactivity profile combined with an unusual aza‐bridged bicyclic framework has made tropanes molecules‐of‐interest within organic chemistry. Enantioselective examples of (5+2) cycloadditions between 3‐oxidopyridinium betaines and olefins remain unexplored, despite 3‐oxidopyridinium betaines being useful reagents in organic synthesis. The first asymmetric (5+2) cycloaddition of 3‐oxidopyridinium betaines is reported, affording tropane derivatives in up to quantitative yield and with excellent control of peri‐, regio‐, diastereo‐, and enantioselectivity. The reactivity is enabled by dienamine‐activation of α,β‐unsaturated aldehydes combined with in situ formation of the pyridinium reaction‐partner. A simple N‐deprotection protocol allows for liberation of the tropane alkaloid motif, and synthetic elaborations of the cycloadducts demonstrate their synthetic utility to achieve highly diastereoselective modification around the bicyclic framework. DFT computations suggest a stepwise mechanism where regio‐ and stereoselectivity are defined during the first bond‐forming step in which the pyridinium dipole exerts critical conformational control over its dienamine partner. In the second bond‐forming step, a kinetic preference toward an initial (5+4) cycloadduct was identified; however, a lack of catalyst turn‐over, reversibility, and thermodynamic bias favoring a (5+2) cycloadduct rendered the reaction fully periselective.

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The case for an oxidopyrylium intermediate in the mechanism of quercetin dioxygenases

Rymbai,

Klausmeyer,

Farmer

2023

Journal of Inorganic Biochemistry

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Comparison of (5 + 2) Cycloadditions Involving Oxidopyrylium and Oxidopyridinium Ions: Relative Reactivities

Cited by 6 publications

References 54 publications

Cycloaddition Reactivities Analyzed by Energy Decomposition Analyses and the Frontier Molecular Orbital Model

Cycloaddition Reactivities Analyzed by Energy Decomposition Analyses and the Frontier Molecular Orbital Model

Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3‐Dipolar Cycloaddition of 3‐Oxidopyridinium Betaines and Dienamines

The case for an oxidopyrylium intermediate in the mechanism of quercetin dioxygenases

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