Radical Sorting Catalysis via Bimolecular Homolytic Substitution (S_H2): Opportunities for C(sp³)-C(sp³) Cross-Coupling Reactions

The development of efficient C(sp³)-C(sp³) cross-coupling methods that expand access to a pharmaceutically relevant three-dimensional chemical space represents a key frontier in organic synthesis. Traditional cross-coupling strategies readily achieve C(sp²)-C(sp²) and C(sp²)-C(sp³) bond formation but face significant challenges in C(sp³)-C(sp³) coupling due to issues of sluggish inner sphere reductive elimination, β-hydride elimination, and limited cross-selectivity. Recent advances in C(sp³)-C(sp³) cross-coupling have highlighted the potential of an alternative bond-forming mechanism, bimolecular homolytic substitution (S_H2), as an outer sphere pathway to overcome these limitations. This strategy leverages a “radical sorting effect”, in which sterically distinct alkyl radicals are partitioned based on their substitution patterns. This perspective provides a comprehensive analysis of S_H2-mediated C(sp³)-C(sp³) cross-coupling reactions from 2021 to 2024, focusing on iron, nickel, and cobalt catalysis and their powerful applications in quaternary carbon center (QCC) formation. We also highlight emerging opportunities in single functional group cross-coupling and alkene functionalization, demonstrating the versatility of S_H2 in accessing complex molecular architectures from abundant feedstock chemicals. By addressing key challenges in C(sp³)-C(sp³) cross-coupling, S_H2 radical sorting catalysis holds significant promise for expanding the C(sp³)-rich chemical space and enabling transformative advances in organic synthesis.