Rapid, modular secondary sphere assembly for enhanced Fe-catalyzed C(sp3)–H oxidation

Abstract

The inert nature of C(sp 3 )-H bonds makes their oxidative cleavage a difficult task. While metalloenzymes employ an array of non-covalent interactions to facilitate C(sp 3 )-H oxidation, this strategy is underexplored in abiotic catalysts due to time-consuming and lowyielding ligand syntheses, which impedes iterative design. To surmount these obstacles, we, herein, have developed a highly modular and rapid synthetic strategy that capitalizes on the efficiency of solid-phase peptide synthesis, which enables the generation of a ligand platform displaying at least four unique residues of varying electronics and sterics in the secondary coordination sphere of a C-H oxidizing Fe catalyst. Modulating the non-covalent interactions in seven variants significantly influences cyclohexane oxidation catalysis, with one variant that boosts the catalytic activity by more than two-fold. To better understand the catalytic trends, we have determined the catalysts' solution-state structures by 2D NMR spectroscopy, which suggests that peptide conformation can control substrate access and binding. This work demonstrates that (1) tunable, diverse, and complex active sites can be made readily, and (2) these active sites can be optimized to significantly increase catalytic activity.