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Abstract This work demonstrates the dominance of a Ni(0/II/III) cycle for Ni‐photoredox amide arylation, which contrasts with other Ni‐photoredox C‐heteroatom couplings that operate via Ni(I/III) self‐sustained cycles. The kinetic data gathered when using different Ni precatalysts supports an initial Ni(0)‐mediated oxidative addition into the aryl bromide. Using NiCl2as the precatalyst resulted in an observable induction period, which was found to arise from a photochemical activation event to generate Ni(0) and to be prolonged by unproductive comproportionation between the Ni(II) precatalyst and the in situ generated Ni(0) active species. Ligand exchange after oxidative addition yields a Ni(II) aryl amido complex, which was identified as the catalyst resting state for the reaction. Stoichiometric experiments showed that oxidation of this Ni(II) aryl amido intermediate was required to yield functionalized amide products. The kinetic data presented supports a rate‐limiting photochemically‐mediated Ni(II/III) oxidation to enable C−N reductive elimination. An alternative Ni(I/III) self‐sustained manifold was discarded based on EPR and kinetic measurements. The mechanistic insights uncovered herein will inform the community on how subtle changes in Ni‐photoredox reaction conditions may impact the reaction pathway, and have enabled us to include aryl chlorides as coupling partners and to reduce the Ni loading by 20‐fold without any reactivity loss.
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This content will become publicly available on June 10, 2026
Unraveling a Complex Mechanistic Picture of Photochemical Nickel-Catalyzed THF Arylation through Product Enantioselectivity Analysis
This study provides a comprehensive mechanistic understanding of asymmetric THF α-O-arylation via Ni photochemical catalysis, leveraging enantioinduction data to refine the reaction pathway. Originally reported in a racemic fashion by Molander and Doyle, this transformation was re-examined using chiral bis(oxazoline) ligands, revealing distinct enantioselectivity trends depending on the halogen present in the aryl halide and Ni pre-catalyst. Stoichiometric experiments demonstrated that the Ni(II) oxidative addition complex is primarily responsible for trapping the THF radical, while multivariate linear regression modeling confirmed that the halide remains coordinated during the enantiodetermining step. Time-course experiments uncovered an alternative initial pathway when Ni(0) was used as the pre-catalyst, which ultimately converged to the main Ni(II) pathway. EPR analysis further revealed rapid comproportionation between Ni(0) and Ni(II), forming Ni(I) species that engage in radical trapping at early stages, accounting for the observed reactivity differences. By integrating enantioselectivity data with experimental techniques such as EPR spectroscopy, this study establishes enantioinduction analysis as a powerful tool for mechanistic investigations in Ni photochemical catalysis. The insights gained not only refine our understanding of this transformation, but also provide a framework for probing similar Ni/Ir dual photocatalytic systems.
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- Award ID(s):
- 2235778
- PAR ID:
- 10659042
- Publisher / Repository:
- Thieme
- Date Published:
- Journal Name:
- Synlett
- Volume:
- 36
- Issue:
- 11
- ISSN:
- 0936-5214
- Page Range / eLocation ID:
- 1469 to 1475
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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