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Photocatalytic Cross-Coupling of Phenols and Heteroaryl Halides With Machine Learning-Guided Reaction Prediction
Matthew C Carson1, Alice Wu1, Kalyana B Duggal1
1Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Angewandte Chemie (International Ed. in English)
|March 6, 2026
Summary
This study introduces a new photochemical method for sustainable C-C bond formation using phenols and N-heteroarenes (azines). The approach avoids transition metals and prefunctionalized substrates, achieving efficient cross-coupling via complementary radicals.
Area of Science:
- Organic Chemistry
- Photochemistry
- Sustainable Synthesis
Background:
- Developing sustainable C(sp2)-C(sp2) bond formation methods is crucial in synthetic chemistry.
- Phenols and N-heteroarenes (azines) are abundant but challenging to cross-couple due to redox and selectivity issues.
Purpose of the Study:
- To develop a transition-metal-free photochemical strategy for cross-coupling phenols and heteroaryl halides.
- To achieve efficient C-C bond formation under redox-neutral conditions.
Main Methods:
- Photochemical cross-coupling using an organic dye photocatalyst and base.
- Concurrent oxidation of phenols and reduction of azines to generate radicals.
- Mechanistic studies including DFT, substrate clustering, HTE, and ML.
Main Results:
- Efficient cross-coupling of phenols with heteroaryl halides yielding up to 91% product.
- High functional group tolerance demonstrated.
- ML models successfully predicted reactivity (C-C vs. SNAr).
Conclusions:
- The developed photochemical strategy offers a sustainable route for C-C bond formation.
- Radical intermediates and reaction pathways were elucidated.
- Predictive models enhance the scope and application of the method.
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