Elucidating Fluorine Steering Effects in Diels-Alder Reactions Interfaced with Charge-Enhanced Reactivity
Sabrina Hoford1, Julius Jan2, Jeffrey N Johnston2
1Department of Chemistry, Brock University, 1812 Sir Isaac Brock way, St. Catharines, Ontario L2S 3A1 (Canada).
European Journal of Organic Chemistry
|August 25, 2025
Summary
Fluorinated dienophiles slow Diels-Alder reactions, but computational and experimental studies reveal factors controlling selectivity. This research enhances understanding of fluorinated molecule reactivity for drug discovery.
Area of Science:
- Organic Chemistry
- Computational Chemistry
- Medicinal Chemistry
Background:
- Fluorinated molecules are essential in drug discovery and various scientific fields.
- Diels-Alder cycloaddition products featuring fluorine atoms offer significant utility.
- Understanding fluorine's impact on reactivity is crucial for developing new synthetic methods.
Purpose of the Study:
- To investigate the effects of fluorine substitution on dienophile reactivity in Diels-Alder reactions.
- To elucidate the reasons behind reaction rate deceleration with fluorinated dienophiles.
- To determine the factors governing endo- vs. exo-selectivity in these reactions.
Main Methods:
- Density Functional Theory (DFT) calculations.
- Distortion/Interaction-Activation Strain (DIAS) models.
- Energy Decomposition Analysis (EDA) and Natural Bond Orbital (NBO) analysis.
- Exploration of oriented external electric field effects (OEEFs) and local electric fields.
- Experimental studies on charge-enhanced Diels-Alder reactions.
Main Results:
- Fluorine substitution in dienophiles leads to reaction rate deceleration.
- Specific computational models identified key factors influencing selectivity.
- External and local electric fields were explored for their impact on reactivity.
- Experimental validation confirmed computational predictions.
Conclusions:
- Novel mechanistic insights into Diels-Alder reactions involving fluorinated dienophiles were achieved.
- This study provides a deeper understanding of fluorine's electronic effects on cycloaddition reactions.
- The findings offer valuable knowledge for synthesizing fluorinated scaffolds in drug discovery.
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