Controllable Enhanced Reactivity of Radical Intermediates in Olefin Cyclopropanation via Electron‐Withdrawing Substituents in Biomimetic Catalysts

Comprehensive Summary Cyclopropane serves as a pivotal structural motif in numerous pharmaceuticals, fuels, and natural products. Iron‐containing heme enzymes have recently been extensively explored as biocatalysts for olefin cyclopropanation via electrophilic carbene transfer. However, mechanistic and structural constraints pose significant challenges for transforming electron‐deficient olefins and modulating reactivity using these systems. Herein, we report the design of biocompatible biomimetic catalysts inspired by free radical reactivity, integrating heme‐active iron porphyrin and axial ligands to study cyclopropanation of challenging electron‐deficient olefins and transient radical regulation mechanisms. Owing to their electronic tunability, substituent‐induced electronic effects were identified for the first time as dominating the catalytic activity of radical intermediates in cyclopropanation. The electron‐withdrawing Fe III (Cl)‐CF 3 catalyst exhibited enhanced activity with a reaction rate of 4.86 x 10 –5 M·s –1 , reaching max 27.2 x 10 –5 M·s –1 after system optimization. DFT calculations revealed that electron‐withdrawing substituents stabilize transition states by generating strong Fe–C bonds through high positive charge localization on the central metal, thereby reducing energy barriers in rate‐limiting steps. Additionally, the highly reactive α ‐C alkyl radicals generated post‐reaction contribute substantially to the catalytic efficacy. As anticipated, [Fe III (Cl)‐TFMPP] demonstrated efficient cyclopropanation across diverse olefins (up to 99% yield and 99 : 1 dr).