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.

Establishing redox and thermodynamic relationships between metal-ion-bound O 2 and its reduced (and protonated) derivatives is critically important for a full understanding of (bio)chemical processes involving dioxygen processing. Here, a ferric heme peroxide complex, [(F 8 )Fe III -(O 2 2− )] − (P) (F 8 = tetrakis(2,6-difluorophenyl)porphyrinate), and a superoxide complex, [(F 8 )Fe III -(O 2•− )] (S), are shown to be redox interconvertible. Using Cr(η-C 6 H 6 ) 2 , an equilibrium state where S and P are present is established in tetrahydrofuran (THF) at −80 °C, allowing determination of the reduction potential of S as −1.17 V vs Fc +/0 . P could be protonated with 2,6-lutidinium triflate, yielding the lowspin ferric hydroperoxide species, [(F 8 )Fe III -(OOH)] (HP). Partial conversion of HP back to P using a derivatized phosphazene base gave a P/HP equilibrium mixture, leading to the determination of pK a = 28.8 for HP (THF, −80 °C). With the measured reduction potential and pK a , the O−H bond dissociation free energy (BDFE) of hydroperoxide species HP was calculated to be 73.5 kcal/mol, employing the thermodynamic square scheme and Bordwell relationship. This calculated O−H BDFE of HP, in fact, lines up with an experimental demonstration of the oxidizing ability of S via hydrogen atom transfer (HAT) from TEMPO-H (2,2,6,6tetramethylpiperdine-N-hydroxide, BDFE = 66.5 kcal/mol in THF), forming the hydroperoxide species HP and TEMPO radical. Kinetic studies carried out with TEMPO-H(D) reveal second-order behavior, k H = 0.5, k D = 0.08 M −1 s −1 (THF, −80 °C); thus, the hydrogen/deuterium kinetic isotope effect (KIE) = 6, consistent with H-atom abstraction by S being the rate-determining step. This appears to be the first case where experimentally derived thermodynamics lead to a ferric heme hydroperoxide OO−H BDFE determination, that Fe III -OOH species being formed via HAT reactivity of the partner ferric heme superoxide complex.

Reductive cleavage of C6F5SeSeC6F5 with elemental M (M = Cu, In, Sn, Pb) in pyridine results in the formation of (py)4Cu2(SeC6F5)2, (py)2In(SeC6F5)3, (py)2Sn(SeC6F5)2, and (py)2Pb(SeC6F5)2. Each group adopts a unique structure: the Cu(I) compound crystallizes as a dimer with a pair of bridging selenolates, two pyridine ligands coordinating to each Cu(I) ion, and a short Cu(I)-Cu(I) distance (2.595 Å). The indium compound crystallizes as monometallic five-coordinate (py)2In(SeC6F5)3 in a geometry that approximates a trigonal bipyramidal structure with two axial pyridine ligands and three selenolates. The tin and lead derivatives (py)2M(SeC6F5)2 are also monomeric, but they adopt nearly octahedral geometries with trans pyridine ligands, a pair of cis-selenolates, and two "empty" cis-positions on the octahedron that are oriented toward extremely remote selenolates (M-Se = 3.79 Å (Sn), 3.70 Å (Pb)) from adjacent molecules. Two of the four compounds (Cu, In) exhibit intermolecular π-π stacking arrangements in the solid state, whereas the stacking of molecules for the other two compounds (Sn, Pb) appears to be based upon molecular shape and crystal packing forces. All compounds are volatile and decompose at elevated temperatures to give MSex and Se(C6F5)2.The electronic structures of the dimeric Cu compound and monomeric (py)2M(SeC6F5)2 (M = Sn, Pb) were examined with density functional theory calculations.

Following up on the characterization of a new (heme)FeIII-superoxide species formed from the cryogenic oxygenation of a ferrous-heme (PPy)FeII (1) (PPy = a tetraarylporphyrinate with a covalently tethered pyridine group as a potential axial base), giving (PPy)FeIII-O2•- (2) (Li Y et al., Polyhedron 2013; 58: 60–64), we report here on (i) its use in forming a cytochrome c oxidase (CcO) model compound, or (ii) in a reaction with nitrogen monoxide (•NO; nitric oxide) to mimic nitric oxide dioxygenase (NOD) chemistry. Reaction of (2) with the cuprous chelate [CuI(AN)][B(C6F5)4] (AN = bis[3-(dimethylamino) propyl]amine) gives a meta-stable product [(PPy)FeIII-(normalO22−)-CuII(AN)][B(C6F5)4] (3a), possessing a high-spin iron(III) and Cu(II) side-on bridged peroxo moiety with a μ-η2:η2-binding motif. This complex thermally decays to a corresponding μ-oxo complex [(PPy)FeIII-(O2-)-CuII(AN)][B(C6F5)4] (3). Both (3) and (3a) have been characterized by UV-vis, 2H NMR and EPR spectroscopies. When (2) is exposed to •NO(g), a ferric heme nitrato compound forms; if 2,4-di-tert-butylphenol is added prior to •NO(g) exposure, phenol ortho-nitration occurs with the iron product being the ferric hydroxide complex (PPy) FeIII(OH) (5). The latter reactions mimic the action of NOD’s.

A series of ferrous-heme 2,6-dimethylphenyl isocyanide (DIMPI) and ferrous-heme mononitrosyl complexes have been synthesized and characterized. The heme portion of the complexes studied is varied with respect to the nature of the axial ligand, including complexes, where it is covalently tethered to the porphyrinate periphery. Reduced heme complexes, [(F8)FeII], [(PPy) FeII], [(PIm)FeII], and [(PImH)FeII], where F8 = tetrakis(2,6-difluorophenyl)-porphyrinate and PPy, PIm, and PImH are partially fluorinated tetraaryl porphyrinates with covalently appended axial base pyridyl/imidazolyl or histamine moieties, were employed; PImH is a new construct. Room temperature addition of DIMPI to these iron(II) complexes affords the bis-isocyanide species [(F8)FeII-(DIMPI)2] in the case of [(F8)FeII], while for the other hemes, mono-DIMPI compounds are obtained, [(PPy)FeII-(DIMPI)] [(2)-DIMPI], [(PIm)FeII-(DIMPI)] [(3)-DIMPI], and [(PImH) FeII-(DIMPI)] [(4)-DIMPI]. The structures of complexes (3)-DIMPI and (4)-DIMPI have been determined by single crystal X-ray crystallography, where interesting H…F(porphryinate aryl group) interactions are observed. 19F-NMR spectra determined for these complexes suggest that H…F(porphyrinate aryl groups) attractions also occur in solution, the H atom coming either from the DIMPI methyl groups or from a porphyinate axial base imidazole or porphyrinate pyrrole. Similarly, we have used nitrogen monoxide to generate ferrous-nitrosyl complexes, a five-coordinate species for F8, [(F8)FeII-(NO)], or low-spin six-coordinate compounds [(PPy)FeII-(NO)], [(PIm)FeII-(NO)], and [(PImH)FeII-(NO)]. The DIMPI and mononitrosyl complexes have also been characterized using UV–Vis, IR, 1H-NMR, and EPR spectroscopies.