Heme-copper oxidases (HCOs) are terminal enzymes on the mitochondrial or bacterial respiratory electron transport chain, which utilize a unique heterobinuclear active site to catalyze the 4H+/4e− reduction of dioxygen to water. This process involves a proton-coupled electron transfer (PCET) from a tyrosine (phenolic) residue and additional redox events coupled to transmembrane proton pumping and ATP synthesis. Given that HCOs are large, complex, membrane-bound enzymes, bioinspired synthetic model chemistry is a promising approach to better understand heme-Cu-mediated dioxygen reduction, including the details of proton and electron movements. This review encompasses important aspects of heme-O2 and copper–O2 (bio)chemistries as they relate to the design and interpretation of small molecule model systems and provides perspectives from fundamental coordination chemistry, which can be applied to the understanding of HCO activity. We focus on recent advancements from studies of heme–Cu models, evaluating experimental and computational results, which highlight important fundamental structure–function relationships. Finally, we provide an outlook for future potential contributions from synthetic inorganic chemistry and discuss their implications with relevance to biological O2-reduction.

The mononuclear hydroxomanganese(III) complex, [Mn(III)(OH)(dpaq)](+), which is supported by the amide-containing N5 ligand dpaq (dpaq = 2-[bis(pyridin-2-ylmethyl)]amino-N-quinolin-8-yl-acetamidate) was generated by treatment of the manganese(II) species, [Mn(II)(dpaq)](OTf), with dioxygen in acetonitrile solution at 25 °C. This oxygenation reaction proceeds with essentially quantitative yield (greater than 98% isolated yield) and represents a rare example of an O2-mediated oxidation of a manganese(II) complex to generate a single product. The X-ray diffraction structure of [Mn(III)(OH)(dpaq)](+) reveals a short Mn-OH distance of 1.806(13) Å, with the hydroxo moiety trans to the amide function of the dpaq ligand. No shielding of the hydroxo group is observed in the solid-state structure. Nonetheless, [Mn(III)(OH)(dpaq)](+) is remarkably stable, decreasing in concentration by only 10% when stored in MeCN at 25 °C for 1 week. The [Mn(III)(OH)(dpaq)](+) complex participates in proton-coupled electron transfer reactions with substrates with relatively weak O-H and C-H bonds. For example, [Mn(III)(OH)(dpaq)](+) oxidizes TEMPOH (TEMPOH = 2,2'-6,6'-tetramethylpiperidine-1-ol), which has a bond dissociation free energy (BDFE) of 66.5 kcal/mol, in MeCN at 25 °C. The hydrogen/deuterium kinetic isotope effect of 1.8 observed for this reaction implies a concerted proton-electron transfer pathway. The [Mn(III)(OH)(dpaq)](+) complex also oxidizes xanthene (C-H BDFE of 73.3 kcal/mol in dimethylsulfoxide) and phenols, such as 2,4,6-tri-t-butylphenol, with BDFEs of less than 79 kcal/mol. Saturation kinetics were observed for phenol oxidation, implying an initial equilibrium prior to the rate-determining step. On the basis of a collective body of evidence, the equilibrium step is attributed to the formation of a hydrogen-bonding complex between [Mn(III)(OH)(dpaq)](+) and the phenol substrates.

A copper complex, [CuI(tmpa)(MeCN)]+, effectively reductively couples NO(g) at RT in methanol (MeOH), giving a structurally characterized hyponitrito-dicopper( II) adduct. Hydrogen-bonding from MeOH is critical for the hyponitrite complex formation and stabilization. This complex exhibits the reverse redox process in aprotic solvents, giving CuI + NO(g), leading to CuI-mediated NO(g)-disproportionation. The relationship of this chemistry to biological iron and/or copper mediated NO(g) reductive coupling to give N2O(g) is discussed.

A mononuclear hydroxomanganese(III) complex was synthesized utilizing the N5 amide-containing ligand 2-[bis(pyridin-2-ylmethyl)]amino-N-2-methyl-quinolin-8-yl-acetamidate (dpaq(2Me) ). This complex is similar to previously reported [Mn(III)(OH)(dpaq(H))](+) [Inorg. Chem. 2014, 53, 7622-7634] but contains a methyl group adjacent to the hydroxo moiety. This α-methylquinoline group in [Mn(III)(OH)(dpaq(2Me))](+) gives rise to a 0.1 Å elongation in the Mn-N(quinoline) distance relative to [Mn(III)(OH)(dpaq(H))](+). Similar bond elongation is observed in the corresponding Mn(II) complex. In MeCN, [Mn(III)(OH)(dpaq(2Me))](+) reacts rapidly with 2,2',6,6'-tetramethylpiperidine-1-ol (TEMPOH) at -35 °C by a concerted proton-electron transfer (CPET) mechanism (second-order rate constant k2 of 3.9(3) M(-1) s(-1)). Using enthalpies and entropies of activation from variable-temperature studies of TEMPOH oxidation by [Mn(III)(OH)(dpaq(2Me))](+) (ΔH(‡) = 5.7(3) kcal(-1) M(-1); ΔS(‡) = -41(1) cal M(-1) K(-1)), it was determined that [Mn(III)(OH)(dpaq(2Me))](+) oxidizes TEMPOH ∼240 times faster than [Mn(III)(OH)(dpaq(H))](+). The [Mn(III)(OH)(dpaq(2Me))](+) complex is also capable of oxidizing the stronger O-H and C-H bonds of 2,4,6-tri-tert-butylphenol and xanthene, respectively. However, for these reactions [Mn(III)(OH)(dpaq(2Me))](+) displays, at best, modest rate enhancement relative to [Mn(III)(OH)(dpaq(H))](+). A combination of density function theory (DFT) and cyclic voltammetry studies establish an increase in the Mn(III)/Mn(II) reduction potential of [Mn(III)(OH)(dpaq(2Me))](+) relative to [Mn(III)(OH)(dpaq(H))](+), which gives rise to a larger driving force for CPET for the former complex. Thus, more favorable thermodynamics for [Mn(III)(OH)(dpaq(2Me))](+) can account for the dramatic increase in rate with TEMPOH. For the more sterically encumbered substrates, DFT computations suggest that this effect is mitigated by unfavorable steric interactions between the substrate and the α-methylquinoline group of the dpaq(2Me) ligand. The DFT calculations, which reproduce the experimental activation free energies quite well, provide the first examination of the transition-state structure of mononuclear Mn(III)(OH) species during a CPET reaction.

A facile and high-yielding protocol to the known Ti(II) complex trans-[(py)4TiCl2] (py = pyridine) has been developed. Its electronic structure has been probed experimentally using magnetic susceptibility, magnetic circular dichroism, and high-frequency and high-field electron paramagnetic resonance spectroscopies in conjunction with ligand-field theory and computational methods (density functional theory and ab initio methods). These studies demonstrated that trans-[(py)4TiCl2] has a (3)Eg ground state (dxy(1)dxz,yz(1) orbital occupancy), which, as a result of spin–orbit coupling, yields a ground-state spinor doublet that is EPR active, a first excited-state doublet at ∼60 cm(–1), and two next excited states at ∼120 cm(–1). Reactivity studies with various unsaturated substrates are also presented in this study, which show that the Ti(II) center allows oxidative addition likely via formation of [Ti(η(2)-R2E2)Cl2(py)n] E = C, N intermediates. A new Ti(IV) compound, mer-[(py)3(η(2)-Ph2C2)TiCl2], was prepared by reaction with Ph2C2, along with the previously reported complex trans-(py)3Ti═NPh(Cl)2, from reaction with Ph2N2. Reaction with Ph2CN2 also yielded a new dinuclear Ti(IV) complex, [(py)2(Cl)2Ti(μ2:η(2)-N2CPh2)2Ti(Cl)2], in which the two Ti(IV) ions are inequivalently coordinated. Reaction with cyclooctatetraene (COT) yielded a new Ti(III) complex, [(py)2Ti(η(8)-COT)Cl], which is a rare example of a mononuclear “piano-stool” titanium complex. The complex trans-[(py)4TiCl2] has thus been shown to be synthetically accessible, have an interesting electronic structure, and be reactive toward oxidation chemistry.