The 2-His-1-carboxylate facial triad is a widely used scaffold to bind the iron center in mononuclear nonheme iron enzymes for activating dioxygen in a variety of oxidative transformations of metabolic significance. Since the 1990s, over a hundred different iron enzymes have been identified to use this platform. This structural motif consists of two histidines and the side chain carboxylate of an aspartate or a glutamate arranged in a facial array that binds iron(II) at the active site. This triad occupies one face of an iron-centered octahedron and makes the opposite face available for the coordination of O and, in many cases, substrate, allowing the tailoring of the iron-dioxygen chemistry to carry out a plethora of diverse reactions. Activated dioxygen-derived species involved in the enzyme mechanisms include iron(III)-superoxo, iron(III)-peroxo, and high-valent iron(IV)-oxo intermediates. In this article, we highlight the major crystallographic, spectroscopic, and mechanistic advances of the past 20 years that have significantly enhanced our understanding of the mechanisms of O activation and the key roles played by iron-based oxidants.

[Fe(β-BPMCN)(CHCN)] (1, BPMCN = N,N' -bis(pyridyl-2-methyl)- N,N' -dimethyl- trans-1,2-diaminocyclo-hexane) is a relatively poor catalyst for cyclohexane oxidation by HO and cannot perform benzene hydroxylation. However, addition of Sc activates the 1/HO reaction mixture to be able to hydroxylate cyclohexane and benzene within seconds at -40 °C. A metastable S = 1/2 Fe-(η-OOH) intermediate 2 is trapped at -40 °C, which undergoes rapid decay upon addition of Sc at rates independent of [substrate] but linearly dependent on [Sc]. HClO elicits comparable reactivity as Sc at the same concentration. We thus postulate that these additives both facilitate O-O bond heterolysis of 2 to form a common highly electrophilic Fe═O oxidant that is comparably reactive to the fastest nonheme high-valent iron-oxo oxidants found to date.

Nonheme iron enzymes generate powerful and versatile oxidants that perform a wide range of oxidation reactions, including the functionalization of inert C−H bonds, which is a major challenge for chemists. The oxidative abilities of these enzymes have inspired bioinorganic chemists to design synthetic models to mimic their ability to perform some of the most difficult oxidation reactions and study the mechanisms of such transformations. Iron‐oxygen intermediates like iron(III)‐hydroperoxo and high‐valent iron‐oxo species have been trapped and identified in investigations of these bio‐inspired catalytic systems, with the latter proposed to be the active oxidant for most of these systems. In this Review, we highlight the recent spectroscopic and mechanistic advances that have shed light on the various pathways that can be accessed by bio‐inspired nonheme iron systems to form the high‐valent iron‐oxo intermediates.

Ribonucleotide reductases (RNRs) are essential enzymes required for DNA synthesis. In class Ib Mn2 RNRs superoxide (O2.−) was postulated to react with the MnII2 core to yield a MnIIMnIII‐peroxide moiety. The reactivity of complex 1 ([MnII2(O2CCH3)2(BPMP)](ClO4), where HBPMP=2,6‐bis{[(bis(2‐pyridylmethyl)amino]methyl}‐4‐methylphenol) towards O2.− was investigated at −90 °C, generating a metastable species, 2. The electronic absorption spectrum of 2 displayed features (λmax=440, 590 nm) characteristic of a MnIIMnIII‐peroxide species, representing just the second example of such. Electron paramagnetic resonance and X‐ray absorption spectroscopies, and mass spectrometry supported the formulation of 2 as a MnIIMnIII‐peroxide complex. Unlike all other previously reported Mn2‐peroxides, which were unreactive, 2 proved to be a capable oxidant in aldehyde deformylation. Our studies provide insight into the mechanism of O2‐activation in Class Ib Mn2 RNRs, and the highly reactive intermediates in their catalytic cycle.

Ribonucleotide reductases (RNRs) are essential enzymes required for DNA synthesis. In class Ib Mn2 RNRs superoxide (O2.−) was postulated to react with the MnII2 core to yield a MnIIMnIII‐peroxide moiety. The reactivity of complex 1 ([MnII2(O2CCH3)2(BPMP)](ClO4), where HBPMP=2,6‐bis{[(bis(2‐pyridylmethyl)amino]methyl}‐4‐methylphenol) towards O2.− was investigated at −90 °C, generating a metastable species, 2. The electronic absorption spectrum of 2 displayed features (λmax=440, 590 nm) characteristic of a MnIIMnIII‐peroxide species, representing just the second example of such. Electron paramagnetic resonance and X‐ray absorption spectroscopies, and mass spectrometry supported the formulation of 2 as a MnIIMnIII‐peroxide complex. Unlike all other previously reported Mn2‐peroxides, which were unreactive, 2 proved to be a capable oxidant in aldehyde deformylation. Our studies provide insight into the mechanism of O2‐activation in Class Ib Mn2 RNRs, and the highly reactive intermediates in their catalytic cycle.