Intramolecular Single-Electron Transfer Mechanism for Nitrogen-Centered Radical Generation in Copper-Catalyzed Aminofluorinations

Single-electron transfer (SET) processes are central to radical generation in transition-metal catalysis, yet their precise mechanistic origins in complex catalytic systems remain elusive. Herein, density functional theory (DFT) combined with multireference second-order N-electron valence perturbation theory (NEVPT2) reveals a previously unrecognized pathway for nitrogen-centered radical (NCR) formation in copper-catalyzed three-component aminofluorination reactions. Four possible mechanisms were examined, including direct N−O bond homolysis, outer-sphere SET (oSET), inner-sphere SET (iSET), and our proposed intramolecular SET (intraSET) pathway. Among these, the intraSET pathway is energetically preferred, proceeding with a low free-energy barrier of 14.0 kcal/mol to generate copper-coordinated metal-combined nitrogen-centered radicals (MCNCRs). These intermediates are thermodynamically stabilized (Δ G = −6.7 kcal/mol) relative to species formed through the other conventional pathways. Multireference NEVPT2 analysis further reveals that the MCNCRs possess weak Cu−N bonding interactions (bond order = 0.40−0.43) and pronounced diradical character. This electronic structure provides a balance between radical stability and reactivity, facilitating efficient NCR generation under mild conditions. Guided by these mechanistic insights, the concept was extended to alkene cyclopropanation, highlighting the broader synthetic potential of the intraSET strategy. These findings uncover a different mechanistic paradigm for radical generation in copper catalysis and provide conceptual guidance for the design of nitrogen-centered radical transformations in organic synthesis.