Highly regioselective oxidation of C–H bonds in water using hydrogen peroxide by a cytochrome P450 mimicking iron complex

Abstract

Cytochrome P450, one of nature's oxidative workhorses, catalyzes the oxidation of C–H bonds in complex biological settings. Extensive research has been conducted over the past five decades to develop a fully functional mimic that activates O₂ or H₂O₂ in water to oxidize strong C–H bonds. We report the first example of a synthetic iron complex that functionally mimics cytochrome P450 in 100% water using H₂O₂ as the oxidant. This iron complex, in which one methyl group is replaced with a phenyl group in either wing of the macrocycle, oxidized unactivated C–H bonds in small organic molecules with very high selectivity in water (pH 8.5). Several substrates (34 examples) that contained arenes, heteroaromatics, and polar functional groups were oxidized with predictable selectivity and stereoretention with moderate to high yields (50–90%), low catalyst loadings (1–4 mol%) and a small excess of H₂O₂ (2–3 equiv.) in water. Mechanistic studies indicated the oxoiron(V) to be the active intermediate in water and displayed unprecedented selectivity towards 3° C–H bonds. Under single-turnover conditions, the reactivity of this oxoiron(V) intermediate in water was found to be around 300 fold higher than that in CH₃CN, thus implying the role water plays in enzymatic systems.