Catalytic carbene transfer to olefins is a useful approach to synthesize cyclopropanes in many molecules, particularly biologically and medicinally interesting systems. Recent experimental efforts have made significant progress in achieving excellent reactivity and selectivity results by using artificial heme proteins and biomimetic iron porphyrins. However, mechanisms are largely unknown. Based on quantum chemical calculations that well reproduced many experimental reactivity and selectivity results including experimental kinetic isotope effect, this work for the first time shows that the broadly useful C=C functionalizations by heme carbenes feature Fe<sup>II</sup>-based, non-radical, concerted nonsynchronous mechanism, different from the Fe<sup>IV</sup>-based, radical, stepwise mechanism of native heme enzymes. This mechanism also has early transition state character. A systematic examination of effects of carbene substituent, porphyrin substituent, and protein axial ligand on cyclopropanation barriers was performed to help understand many experimental reactivity results and provide useful structural features to accelerate this kind of reaction. Results especially recommend the exploration of the porphyrin electron-withdrawing substituent in addition to current experimental efforts on artificial heme proteins for non-native chemical synthetic reactions, which has the best barrier reduction effects in both carbene formation and cyclopropanation steps among all studied structural factors here. The first comparison between cyclopropanation and carbene formation barriers was also reported, which clearly indicate the importance of the formation of strong electrophilic heme carbene in catalyst development to reduce the barrier of the overall rate-determining step. These results will help studies of many porphyrin-based carbene transfer reactions and facilitate future sustainable chemical catalysis and biocatalysis.

Cyclopropanations via heme carbenes: Basic mechanism and effects of carbene substituent, porphyrin substituent, and protein axial ligand

255th National Meeting (2018)

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