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.

Non‐heme iron oxygenases contain either monoiron or diiron active sites, and the role of the second iron in the latter enzymes is a topic of particular interest, especially for soluble methane monooxygenase (sMMO). Herein we report the activation of a non‐heme FeIII‐OOH intermediate in a synthetic monoiron system using FeIII(OTf)3 to form a high‐valent oxidant capable of effecting cyclohexane and benzene hydroxylation within seconds at −40 °C. Our results show that the second iron acts as a Lewis acid to activate the iron–hydroperoxo intermediate, leading to the formation of a powerful FeV=O oxidant—a possible role for the second iron in sMMO.

Non-heme iron oxygenases contain either monoiron or diiron active sites,and the role of the second iron in the latter enzymes is atopic of particular interest, especially for soluble methane monooxygenase (sMMO). Herein we report the activation of anon-heme Fe III -OOH intermediate in asynthetic monoiron system using Fe III (OTf) 3 to form ah igh-valent oxidant capable of effecting cyclohexane and benzene hydroxylation within seconds at À40 8 8C. Our results showt hat the second iron acts as aL ewis acid to activate the iron-hydroperoxo intermediate,l eading to the formation of ap owerful Fe V =Ooxidant-a possible role for the second iron in sMMO.

Nicht‐Häm‐Eisenenzyme generieren leistungsstarke und vielfältige Oxidantien, die eine Vielzahl an Oxidationsreaktionen vermitteln, einschließlich der Funktionalisierung von inerten C‐H‐Bindungen, die eine anspruchsvolle Aufgabe für Chemiker darstellt. Die oxidativen Fähigkeiten dieser Enzyme inspirieren Bioorganiker zur Entwicklung synthetischer Modelle, um die Fähigkeit solcher Enzyme zur Vermittlung schwierigster Oxidationsreaktionen nachzuahmen und die Mechanismen derartiger Transformationen zu erforschen. Eisen‐Sauerstoff‐Intermediate wie Eisen(III)‐Hydroperoxo‐Spezies und hochvalente Eisen‐Sauerstoff‐Spezies wurden bei Untersuchungen dieser bioinspirierten katalytischen Systemen abgefangen und identifiziert, wobei Letztgenannte als aktives Oxidationsmittel für die meisten dieser Systeme vorgeschlagen wurden. In diesem Aufsatz heben wir die jüngsten spektroskopischen und mechanistischen Fortschritte hervor, die Licht auf die verschiedenen Wege geworfen haben, die von bioinspirierten Nicht‐Häm‐Eisensystemen zur Bildung der hochvalenten Eisen‐Sauerstoff‐Zwischenprodukte genutzt werden können.