Alkane Oxidation: Methane Monooxygenases, Related Enzymes, and

Review pubs.acs.org/CR

Alkane Oxidation: Methane Monooxygenases, Related Enzymes, and Their Biomimetics Vincent C.-C. Wang,†,‡ Suman Maji,‡,§ Peter P.-Y. Chen,∥ Hung Kay Lee,⊥ Steve S.-F. Yu,† and Sunney I. Chan*,†,#,○ †

Institute of Chemistry, Academia Sinica, 128, Section 2, Academia Road, Nankang, Taipei 11529, Taiwan School of Chemical Engineering and Physical Sciences, Lovely Professional University, Jalandhar-Delhi G. T. Road (NH-1), Phagwara, Punjab India 144411 ∥ Department of Chemistry, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 402, Taiwan ⊥ Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong # Department of Chemistry, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan ○ Noyes Laboratory, 127-72, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, United States §

ABSTRACT: Methane monooxygenases (MMOs) mediate the facile conversion of methane into methanol in methanotrophic bacteria with high efficiency under ambient conditions. Because the selective oxidation of methane is extremely challenging, there is considerable interest in understanding how these enzymes carry out this difficult chemistry. The impetus of these efforts is to learn from the microbes to develop a biomimetic catalyst to accomplish the same chemical transformation. Here, we review the progress made over the past two to three decades toward delineating the structures and functions of the catalytic sites in two MMOs: soluble methane monooxygenase (sMMO) and particulate methane monooxygenase (pMMO). sMMO is a water-soluble three-component protein complex consisting of a hydroxylase with a nonheme diiron catalytic site; pMMO is a membrane-bound metalloenzyme with a unique tricopper cluster as the site of hydroxylation. The metal cluster in each of these MMOs harnesses O2 to functionalize the CH bond using different chemistry. We highlight some of the common basic principles that they share. Finally, the development of functional models of the catalytic sites of MMOs is described. These efforts have culminated in the first successful biomimetic catalyst capable of efficient methane oxidation without overoxidation at room temperature.

CONTENTS 1. Introduction 2. Recent Reviews on Methane Oxidation and Focus of This Review 3. Methanotrophs and Methane Monooxygenases 4. Soluble Methane Monooxygenase: Protein Structure, Active Site, and Catalytic Mechanism 4.1. Priming of the Active Site of sMMO for O2 Binding 4.2. Activation of the Catalytic Site by O2 4.3. Intermediate Q 4.4. Alkane Hydroxylation versus Alkene Epoxidization 4.5. Overall Catalytic Cycle 5. Particulate Methane Monooxygenase: Protein Structure, Active Site, and Catalytic Mechanism 5.1. Purification of the Membrane Protein: Challenges and Pitfalls 5.2. Metal Cofactors: Cu/Fe/Zn 5.3. X-ray Structures 5.4. Metal Ions of pMMO 5.4.1. A Site or Mononuclear Copper Site © 2017 American Chemical Society

5.4.2. B Site or Dicopper Site 5.4.3. C Site or “Zinc” Center 5.4.4. D Site or Tricopper Cluster Site 5.4.5. Other Copper Ions 5.5. Substrate Specificity, Regiospecificity, and Stereoselectivity 5.6. Hydrocarbon Binding Site and the Aromatic Box 5.7. Supplying Reducing Equivalents to the ECluster Domain in the PmoB Subunit 5.8. Catalytic Mechanisms for CH Activation and Functionalization 5.9. Catalytic Cycle in pMMO 6. Other Enzymes from Alkane-Oxidizing Bacteria 7. Engineering Cytochrome P450 BM3 for the Oxidation of Small Alkanes

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Chemical Reviews 8. Free Energy Landscape of Methane Oxidation: Insights Derived from Studies on Various Methane-Oxidizing Systems 8.1. Two-Step Radical Mechanism 8.1.1. Metal Oxides 8.1.2. Cu Exchange Zeolites 8.1.3. Copper Mordenites 8.1.4. Intermediate Q in sMMO 8.2. Singlet-Oxene Transfer or Biradical Mechanism 8.3. Density Functional Theory (DFT) Calculations on MMOs 8.3.1. Theoretical Models for Methane Hydroxylation Mediated by sMMO 8.3.2. Theoretical Models for Methane Hydroxylation Mediated by pMMO 9. Toward the Development of a Biomimetic Catalyst 9.1. Strategic Considerations 9.2. Tricopper Models 9.2.1. Complexes Constructed with Multidentate Ligands 9.2.2. Complexes Assembled by Macrocyclic Ligands 9.2.3. Other Tricopper Systems 9.3. Dicopper Models 9.3.1. Complexes Constructed with Multidentate Ligands 9.3.2. Complexes Containing a [Cu2O2]2+ Core Assembled by Reactions of Cu(I) Compounds with O2 9.3.3. Complexes Containing a [Cu2O]2+ Core Assembled by Reactions of Cu(I) Compounds with O2 9.3.4. System Capable of Catalytic Turnovers 9.4. Nonheme Diiron Models 10. An Efficient Catalyst for Room-Temperature Methane Oxidation: A Bioinspired Tricopper Cluster Complex 11. Summary and Outlook: Prospects for a Methanol Economy Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments Abbreviations References

Review

sources become mature and deployed.3 In particular, recent exploitation of shale gas has boosted the available supplies of natural gas.3,4 However, CH4 is also a greenhouse gas that is 33 times more potent than CO2.5 Human activities account for approximately two-thirds of the total CH4 emissions, including seepage from the exploitation of coal, oil, and natural gas.6 Presently, because of the physical properties of CH4, its direct liquefaction and storage is too costly. The conversion of CH4 into liquid methanol (CH3OH) is much more economical and energy-efficient. In addition, CH3OH is a major carbon chemical feedstock. A methanol economy is generally regarded as one of the most promising alternative energy platforms that can be employed to replace fossil fuels in the near future.7,8 Currently, the conventional syngas reaction depicted in reaction 1 is the main route to the production of CH3OH in industry.9 The syngas comes from the steam reforming of CH4 (reaction 2). At this juncture, no method has been discovered to convert CH4 into CH3OH directly with dioxygen (O2) on an industrial scale (reaction 3). The direct oxidation of CH4 to CH3OH without overoxidation is extremely difficult. The obstacles are both kinetic and thermodynamic. First, the CH bonds of CH4 are extremely inert because of their high bond dissociation energies (104 kcal mol−1). Moreover, the ground state of O2 is a triplet 3Σ state, and the direct reaction of triplet O2 with singlet CH4 to form singlet CH3OH is a spin-forbidden process. From a thermodynamic perspective, whereas reaction 3 proceeds with spontaneity and with a substantial release of heat, the further oxidations of CH3OH to formaldehyde (H2CO), formic acid (HCOOH), and CO2 are more exergonic and more exothermic (Figure 1). Thus, the product CH3OH is

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Figure 1. Values of the free energy (ΔG) and the enthalpy (ΔH) for each step of the oxidation reactions of CH4 to CO2 by O2. The values are given at a temperature of 298 K.

prone to further oxidation to H2CO and HCOOH. On the basis of these considerations, it follows that substantial energy input, for example, high temperatures, is required to activate the reaction and the selective oxidation of CH4 to CH3OH is difficult to control. Also, the pKa value of CH4 is very high, precluding direct activation of the CH bond by ionization through conventional acid−base chemistry under ambient conditions. With a negligible electron affinity and four strong CH bonds, redox and radical reactions are also very difficult. Therefore, the oxygenation of CH4 under ambient conditions has long been considered one of the holy grails of organic chemistry.10

1. INTRODUCTION Methane (CH4), the primary component in natural gas, is one of the major energy sources on Earth. It is estimated that natural gas contributes 21.4% of the total primary energy sources (TPES) in the world.1 Compared to oil and coal (31.3% and 28.9% of TPES, respectively), the combustion of natural gas for energy generates approximately one-third and one-half, respectively, of the amounts of CO2 emissions, because of the low C/H ratio of CH4.2 It has been suggested that natural gas can be a potential transitional energy source to replace the more polluting coal and oil until carbon-free energy 8575

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CH4 + [Pt(IV)Cl 6]2 − + H 2O

CO(g) + 2H 2(g) ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ CH3OH(g) ΔH298 = −21.7 kcal mol−1

→ CH3OH + [Pt(II)Cl4]2 − + 2H+ + 2Cl−

(1)

In the field of heterogeneous catalysis, early studies conducted by Lunsford and co-workers showed that the methoxide ion can be formed from CH4 on the surface of MoO3/SiO2 catalysts using N2O as an oxidant.21 The addition of water to the system generates CH3OH, but the conversion yields and selectivity are poor. Other important examples include the transition-metal-containing zeolites Cu-ZSM-5 studied by Schoonheydt and co-workers22,23 and Fe-ZSM-5 reported by Panov and co-workers,24,25 which can be activated by N2O for the selective conversion of methane into methanol at room temperature. The key reactive intermediate species in these two systems were recently identified as a bent [Cu2O]2+ core26,27 and a mononuclear high-spin Fe(IV)O species with a constrained coordination environment imposed by the zeolite structure,28 respectively. It is noteworthy that, recently, the Ni-containing enzyme methyl-coenzyme M reductase was found to catalyze the anaerobic oxidation of CH4 and generate the formation of a CS bond.29,30

Ni

CH4(g) + H 2O(g) → CO(g) + 3H 2(g) ΔH298 = 49.3 kcal mol−1

(2)

CH4(g) + 1/2O2 (g) → CH3OH(l) ΔH298 = −39.2 kcal mol−1

(4)

(3)

For the direct oxidation of CH4, it is necessary to first harness the oxidizing power of O2. The nature of the reactive oxygen species is expected to play a vital role in the details of the oxygenation reaction. For example, the reactivity of the O atom (1D) with CH4 has been studied in molecular beam experiments. In such experiments, one observes the formation of a transition-state species [CH3OH]* with a long lifetime upon the insertion of the singlet “oxene” into CH4. Subsequent multiple reactive channeling of this species leads to different products, including •CH3 and •OH radicals (77%), H2COH/ H3CO + H (18%), and H2CO/HCOH and H2 (5%).11,12 Metal atoms and ions have also been used to activate O2. The formation of CH3OH in reactions of CH4 with metal-oxide cations (MO+, M = metal) in the gas phase under ambient conditions has been widely investigated in experiments and in theoretical calculations.13−15 From these studies, it was found that the formation of H3CM+OH followed by recombination of the •CH3 and •OH fragments is a key step toward obtaining CH3OH as the product, but the reactivity involves two transition states with spin crossover occurring in most cases. In nature, the members of a class of bacteria known as methanotrophs employ enzymes, called methane monooxygenases (MMOs), to convert CH4 into CH3OH under ambient environments using O2.16 There are two forms of MMO. One is water-soluble and is an iron-containing soluble methane monooxygenase (sMMO); the other is membrane-bound and is a copper-containing particulate methane monooxygenase (pMMO). Both enzymes reveal remarkable abilities to harness O2 for the oxidation of CH4 to produce CH3OH. They mediate the selective oxidation of CH4 to CH3OH efficiently and, amazingly, at ambient temperatures and pressures. pMMO is the most efficient CH4 oxidizer discovered to date, and it is capable of catalyzing the oxidation at a rate approaching one CH4 molecule per second per enzyme.17 Clearly, understanding the mechanisms of the chemistry behind these enzymes can shed light on how to design efficient and robust catalysts that might eventually be adapted for CH3OH production from natural gas on an industrial scale. In organometallic chemistry, the seminal works conducted by Shilov and others demonstrated that the selective conversion of CH4 into CH3OH can be accomplished using PtCl2 as a catalyst in aqueous HCl at 100 °C, with [PtCl6]2− itself acting as the oxidizing agent.18,19 The net reaction is described by reaction 4. Subsequently, Periana et al. developed a bipyrimidylsubstituted Pt complex that has higher efficiency and stability but that requires concentrated H2SO4 to achieve the needed strong oxidizing conditions.20 However, the selectivities, yields, and operating environments of the noble-metal-based molecular catalysts are far from those of the MMOs.

2. RECENT REVIEWS ON METHANE OXIDATION AND FOCUS OF THIS REVIEW In this review, we begin by providing a general explanation of the structures and mechanisms of the active sites in both sMMO and pMMO, including a comparison of their similarities and differences. Several excellent reviews on different aspects of MMOs have been written over the years.31−33 Here, we focus on the latest progress on the active sites and catalytic chemistry of both sMMO and pMMO, as well as other alkane oxidation enzymes, because this information has the greatest bearing on the development of potential molecular catalysts to accomplish this difficult chemistry in the laboratory. Based on knowledge of the active sites of the two MMOs, attempts have been made by numerous laboratories to develop biomimetic catalysts for hydrocarbon oxidation. Progress in these developments is reviewed, including successes and failures. Second, the free energy landscape of CH4 oxidation is enormously complex. Theory has played a pivotal role in relating chemical structures to catalytic function in bioinorganic model complexes and systems. These studies have also been invaluable in the interpretation of the outcome of biochemical and biophysical studies on the active sites of these enzymes as well as guiding the design of model bioinorganic complexes toward the development of functional catalysts. The operations of an MMO are enormously complex. Each enzyme works on four substrates, namely, O2, electrons, protons, and CH4, and the protein scaffold and protein dynamics are essential in orchestrating the delivery of substrates and cosubstrates to the active site along specific pathways, in an orderly fashion, controlling each and every step of the catalytic cycle. As a biological machine, the operations of the enzyme are kinetically controlled to optimize the performance of the machine and control molecular slips or futile catalytic cycles. Moreover, theory can provide insights into the operations of active sites within enzymes that are difficult to derive from experiments on model catalysts. Finally, we end with prospects for the methanol economy7,8 based on the progress in this field during the past decade. 8576

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Readers who are interested in the exploitation of microbiology for CH4 oxidation and biotechnology applications are advised to read the excellent review article written by Strong et al.34 For CH bond activation of hydrocarbons, several excellent articles have been published in this journal.35

3. METHANOTROPHS AND METHANE MONOOXYGENASES Methanotrophic bacteria comprise a unique family of aerobic Gram-negative microorganisms that occupy a unique niche in lakes, oceans, and wet soil at the interface of the aerobic and anaerobic environments. There, they oxidize CH4 generated from anaerobic methanogenic metabolism to CO2 as their sole source of carbon and energy, as illustrated in Figure 2.36 Molecular oxygen is the oxidant for this process. Figure 3. Electron microscopy section of the membrane system of Methylococcus capsulatus (Bath) grown at high copper/biomass ratio. Reproduced with permission from ref 44. Copyright 1982 Academic Press, Inc. (London).

pMMO versus sMMO but also provide the main metal cofactors of the pMMO17,40,41 The sMMO is an iron enzyme, whereas the pMMO is a copper protein. The Km values of sMMO toward O2 and CH4 are approximately 3 and 16.8 μM, respectively.36 In comparison, the corresponding Km values of pMMO are approximately 1−2 and 0.1 μM, respectively. Thus, pMMO is a more active enzyme. Indeed, the activity of pMMO-expressing cells has been shown to be higher than that of sMMO-expressing ones,17,42 although the turnover frequency (TOF) for propylene oxidation catalyzed by purified sMMO (0.7−4.4 s−1) is higher than that by purified pMMO (0.003−0.27 s−1).31 The low activity of the purified pMMO has been explained by the instability of the enzyme during purification. Although pMMO is the predominant CH4 oxidation catalyst in nature, it has proven difficult to isolate and purify for biochemical and biophysical characterization because of its instability in detergents used to solubilize the enzyme.31,43 As a membrane protein, it is also difficult to clone and overexpress for biochemical and biophysical studies. By contrast, purified sMMO is much more stable and has been studied in depth.33 Here, we summarize the current understanding of the structure and function of both sMMO and pMMO and the progress that has been made toward understanding how these MMOs mediate the selective oxidation of CH4.

Figure 2. General scheme of metabolism for methanotrophs. The enzymes involved are sMMO, soluble methane monooxygenase; pMMO, particulate methane monooxygenase; MDH, methanol dehydrogenase; FADH, formaldehyde dehydrogenase; and FDH, formate dehydrogenase.

The first known methanotrophic bacterium was called Bacillus methanicus, first isolated in 1906,37 reisolated in 1956 as Pseudomonas methanica,38 now renamed Methylomonas methanica. Approximately 130 strains of methanotrophs are now known.17,36 Based on primary features, such as cell morphology, fine structure, metabolic pathways, and type of resting stages, methanotrophs are divided into two types.17,36,39 Type I methanotrophs (such as Methylococcus, Methylomonas, and Methylobacter) contain vesicular disk-shaped bundles of intracytoplasmic membranes (ICMs) and assimilate carbon by the ribulose monophosphate pathway. This type of methanotroph lacks a complete tricarboxylic acid cycle. Type II methanotrophs (such as Methylosinus and Methylocystis) contain paired peripheral layers of ICMs, utilize the serine pathway for carbon assimilation, and exhibit a complete tricarboxylic acid cycle. Type X methanotrophs [such as Methylococcus capsulatus (Bath) (Mc)] belong to a subset of type I methanotrophs that have been shown to be capable of N2 fixation and to contain ribulose bisphosphate carboxylase.36,39 The oxidation of CH4 by aerobic methanotrophs is mediated by the MMOs. Two different MMOs have been identified in methanotrophs as described earlier. Most methanotrophs are capable of expressing the pMMO.17,36 Only a few strains produce both sMMO and pMMO,17,36 and even for these methanotrophs, the sMMO is expressed only under conditions of low copper availability (2.6 Å). Extended X-ray absorption fine structure (EXAFS) spectroscopy is an auxiliary tool for probing the ligand structure of the dicopper site. EXAFS experiments revealed that the distances between CuO/N ligand are ca. 1.97 Å and that the Cu···Cu distance is ca. 2.5 Å in all four strains of as-isolated pMMO.97−99,110 Similar Cu···Cu distances were also found in pMMO_BMc and its variants.93 This Cu···Cu distance is much shorter than those in other known dicopper8584

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ions upon replacing Tyr374 with phenylalanine or serine, indicating the importance of this tyrosine in stabilizing the coordination environment of the copper ions occupying the A and B sites. EXAFS measurements indicated that a pair of Cu(I) ions are in sufficiently close proximity for Cu···Cu backscattering in the Cu EXAFS spectrum, with a Cu···Cu distance of ∼2.7 Å. Interestingly, the contribution of the Cu··· Cu scattering to the EXAFS spectrum, and also the Cu···Cu distance, varies from system to system. The Cu···Cu scattering contribution to the EXAFS spectrum decreases from ∼100% occupancy of the dicopper site in the membranes of the fulllength MBP-PmoB1−414 protein to ca. 68% in the case of the MBP-PmoB55−414 protein. Finally, all of the MBP-PmoB proteins reveal backscattering from approximately one sulfur atom per copper ion with a Cu−S distance of 2.30−2.36 Å, implying the involvement of methionine coordination with many of the Cu(I) ions, which would explain the high redox potentials of these copper ions. No activity has been observed for either CH4 or propylene oxidation mediated by the E. coli membranes with either the expressed MBP-PmoB33−414 or MBP-PmoB55−414 proteins, regardless of whether duroquinol or NADH was used as the reductant to drive the catalytic turnover. Both the MBPPmoB33−414 and MBP-PmoB55−414 proteins react with O2 (but not the full-length MBP-PmoB protein), and in the case of the MBP-PmoB 55−414 protein, a well-defined μ-(η 2 :η 2 )peroxodicopper(II,II) or bis(μ-oxo)dicopper(III,III) structure, with a Cu···Cu distance of ∼3.6 Å, is formed based on EXAFS measurements. Also, slow production of H2O2 is observed, until all of the reducing equivalents are drained away from the six or seven Cu(I) ions in the C-terminal domain with concomitant change in the coordination environment of these copper ions. 5.4.3. C Site or “Zinc” Center. As described earlier, zinccontaining buffer is required for the crystallization of pMMOMc and pMMOMM. The amino acids coordinating the Zn atom in pMMOMc are Asp156, His160, and His173 from PmoC and Glu195 from PmoA, which are highly conserved (Figure 9). In the X-ray crystal structure of pMMOMR, a single copper atom is seen at the C site, but this copper ion could be replaced by a zinc ion after the crystals had been soaked in a ZnSO4 buffer without displacing the copper at the B site.97 Evidently, the C site is a copper-binding site in pMMOMc and pMMOMM as well, and the zinc ion observed in the X-ray crystals is merely an artifact of growing the crystals from concentrated ZnSO4 solution. Mössbauer spectroscopy conducted by Münck and coworkers revealed a quadrupole doublet with ΔEQ = 1.05 mm/s and an isomer shift of δ = 0.5 mm/s from purified pMMOMc, which is similar to the spectra observed for the diiron(III) centers in sMMOMc and sMMOMt.96 Further investigation of whole cells of Methylococcus capsulatus (Bath) cultured at high copper (80 μM) and iron (40 μM) concentrations also showed this characteristic Mössbauer signal; however, this signal was not observed for cells cultured at low copper concentrations. They proposed that a diiron(III) center occupies the C site based on potential amino acids from the crystal structure, such as two nearby carboxylate amino acids, Asp168 and Glu176, which can provide a similar coordination environment for such a diiron center. However, no iron atoms were observed in the pMMO crystal structures of crystals that had been presoaked with iron ions.97 Moreover, reconstruction of membrane-bound apo-pMMO Mc and pMMO_BMc with iron ions failed to restore activity.93

center proteins, such as tyrosinase (∼3.5 Å), hemocyanin (∼4 Å), and known type III dicopper enzymes (∼6 Å).115 It has been proposed that the dicopper center is the site of CH4 hydroxylation or propylene epoxidation in pMMO.31,93 The most compelling evidence for this is that the specific activity of the pMMO_BMc variant with H137A and H139A is entirely abolished compared to that os the H48N variant of pMMO_BMc, which is lacking the mononuclear copper ion at the A site. A lack of activity was also observed for the H48N, H137A, and H139A variants, where both the A and B sites are mutated. Furthermore, when membrane-bound apo-pMMOMc is obtained by adding cyanide to remove all of the copper atoms, the addition of 2−3 equiv of copper ions to membranebound apo-pMMOMc can provide the best recovery of activity. Approximately 90% of the CH4 oxidation reactivity and 70% of the propylene epoxidation reactivity were restored.93 However, these activities were already low in the as-isolated membranes. An absorption feature at 345 nm was generated after the reduced form of pMMO_BMc was incubated with O2 or H2O2.117 This absorption is ascribed to the μ-(η2:η2-peroxo)Cu(II)Cu(II) species that has been found in model compounds and dicopper-center enzymes.117 Interestingly, the intensity of this absorption decreases after the addition of CH4 to the samples. With purified pMMOMc, this absorbance feature can be generated only with H2O2, not with O2.117 However, the key mixing experiment for the reaction of CH4 with H2O2-treated pMMOMc has not been reported. The different behaviors in the activation of the dicopper center between the pMMOMc enzyme and its pMMO_BMc variants might originate from the different redox states of the copper ions occupying the B site. Further comparison of EPR signals between pMMO_BMc and variants of pMMO_BMc generated by site-directed mutagenesis as described before indicates that the copper ion is Cu(I) at the A site but a mixture of valence-trapped Cu(I)/ Cu(II) species at the B site.113 More recently, Chang et al.118 cloned and overexpressed the full-length PmoB subunit of pMMOMc, as well as its N-terminal truncated PmoB33−414 and PmoB55−414, mutants, each fused to the maltose-binding protein (MBP), in E. coli K12 TB1 cells. These PmoBs are expressed as Cu(I) proteins in the E. coli membranes, which is different from the water-soluble pMMO_BMc studied by the Northwestern group.93 In the latter, the PmoB N-terminal soluble fragment (residues 33− 172) containing both the A and B sites is tethered to the Cterminal soluble fragment (residues 265−414) by a Gly-LysGly-Gly-Gly (GKGGG) linker rather than the two membranespanning helices in the full-length PmoB. In addition, pMMO_BMc differs from the full-length PmoB protein in that the N-terminal leader sequence is not part of the water-soluble construct. This part of the PmoB sequence does not seem to appear in the X-ray structures of the pMMO proteins reported to date.82,98,99 The full-length MBP-PmoB protein contains as many as 10−11 reduced copper ions, as previously reported for the PmoB subunit in the holo pMMO.90,92,101,111 In addition to the three total copper ions occupying the A and B sites in the N-terminal domain, there are ca. seven Cu(I) ions associated with the remaining part of the PmoB subunit. The latter copper ions exhibit high redox potentials, and the Cu(I) ions cannot be directly oxidized by O2, as previously noted for the watersoluble C-terminal fragment cloned and expressed in E. coli.119 Comparison of the copper contents of the MBP-PmoB55−414 Y374F and MBP-PmoB55−414 Y374S mutants with that of the N-truncated MBP-PmoB55−414 indicates a loss of three copper 8585

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the absence of CH4 .43,121 When the pMMO-enriched membranes are at a more negative cell potential, such as at −121 mV, only the trinuclear Cu(II)Cu(II)Cu(II) signal is observed. It should be noted that the samples investigated by these spectroscopic tools were mostly membrane-enriched pMMOMc samples, but similar results have also been obtained for purified pMMOMc.92 Except for these Cu(II) ions, the remaining copper ions in the protein remain as Cu(I) under these conditions. A peptide (HIHAMLTMGDWD) based on the sequence of this putative D site from the PmoA subunit has been shown to accommodate three copper ions in acetate and chloride solutions.120 Both Cu(I)Cu(I)Cu(I) and Cu(II)Cu(II)Cu(II) complexes are formed, and they have been characterized by fast atom bombardment mass spectrometry (FAB-MS) and X-ray absorption spectroscopy, including EXAFS spectroscopy, to support the putative Cu(II)Cu(II)Cu(II) tricopper cluster modeled in Figure 10. Also, the key ligands that are involved in the formation of the tricopper complexes have been identified by amino acid substitutions. Further characterization of the Cu(II)Cu(II)Cu(II) tricopper−peptide complex by EPR and SQUID measurements confirmed a trinuclear copper cluster.120 These data strongly suggest that a tricopper cluster center resides at the D site in the structure of pMMOMc. The functional form of the D site would be the Cu(I)Cu(I)Cu(I) cluster. The Cu(I)Cu(I)Cu(I) tricopper−peptide complex was found to mediate facile hydroxylation of CH4 to CH3OH and the epoxidation of propylene to propylene oxide upon activation by O2. It is on the basis of these studies that Chan et al.120 concluded that the tricopper cluster at the D site is the catalytic site or the site of alkane hydroxylation in the enzyme. 5.4.5. Other Copper Ions. As noted earlier, aside from the copper ions occupying the A−D sites, there exist six or seven additional reduced copper ions associated with C-terminal domain of the PmoB subunit in pMMOMc. These copper ions exhibit very high redox potentials and are inert toward direct oxidation by O2. However, these reducing equivalents can be drained away upon reaction of the dicopper center at the B site by O2 to form H2O2. These results support the results of earlier studies on a water-soluble recombinant C-terminal subdomain of PmoBMc constructed from residue 257 to 394, cloned and overexpressed in E. coli, which show that this domain of the PmoB subunit is a “copper sponge” capable of sequestering ca. 10 Cu(I) atoms.119 The binding of the Cu(I) ions was found to be cooperative. Interestingly, Cu(II) ions exhibit very low affinity for this domain, suggesting that it is necessary to involve copper chaperone(s) to incorporate these copper ions into this region of the PmoB subunit for proper assembly of the native protein fold. It has been proposed that these Cu(I) ions provide a reservoir of reducing equivalents to support the catalytic turnover of pMMO in Methyloccocus capsulatus (Bath), and this grouping of copper ions was dubbed E-clusters (E = electron transfer) by the Chan laboratory.92,108,111,119

5.4.4. D Site or Tricopper Cluster Site. The D site is an “empty” hydrophilic cavity in the X-ray crystal structure of pMMOMc consisting of the amino acids His38, Met42, Asp47, Asp49, and Glu100 from the PmoA subunit and Glu154 from PmoC. These amino acids are highly conserved100,120 (Figure 9). A putative Cu(II)Cu(II)Cu(II) tricopper cluster has been modeled into this site43,92 (Figure 10). Although no metal ions

Figure 10. Model of a tricopper cluster at the D site based on the crystal structure of pMMOMc. Reproduced with permission from ref 92. Copyright 2007 John Wiley & Sons.

have been observed at this site in crystal structures, spectroscopic evidence for such a tricopper cluster has been obtained based on biophysical studies of the functional pMMOMc, which contains the full complement of ∼15 copper ions, as noted earlier.90,91,101 When pMMO-enriched membranes are isolated from cells with the pMMO overexpressed in Methylococcus capsulatus (Bath) in air with no substrate, one typically obtains a composite EPR spectrum containing a type II Cu(II) EPR signal superimposed with an isotropic EPR signal near g ≈ 2.1, and superconducting quantum interference device (SQUID) measurements suggest an average total spin of 1.4.40,108 Chan et al. assigned the isotropic EPR signal near g ≈ 2.1 to an oxidized (μ3-oxo)-Cu(II)Cu(II)Cu(II) tricopper cluster (vide infra).92 The type II Cu(II) signal is sensitive to power saturation in EPR experiments. When sufficiently high microwave power is employed, only the isotropic EPR signal remains, consistent with its assignment to a transition from the ground-state quartet manifold of a weakly ferromagnetic coupled tricopper Cu(II)Cu(II)Cu(II) cluster with low-lying doublet states (refs 40, 43, 108, 109, 111, and 121). Further EPR-redox titration experiments were subsequently used to isolate this isotropic EPR signal from the type II Cu signal based on their different redox potentials.92 First, an EPR signal consisting of a mononuclear type II copper center and trinuclear Cu(II)Cu(II)Cu(II) was observed with a redox potential of ca. − 50 mV relative to the standard hydrogen electrode (SHE).92 This reduction potential is significantly lower for this type II copper center compared to those of the ∼10−11 copper ions in the PmoB subunit, including the mononuclear copper ion occupying the A site, which show reduction potentials significantly higher than +200 mV.119 This finding is consistent with the role suggested for this copper center, which is to abort the hot Cu(II)Cu(II)(μ-O)2Cu(III) species formed at the catalytic site (D site) by transfer of one reducing equivalent from the Cu(I) ion at the C site when the Cu(I)Cu(I)Cu(I) tricopper cluster is activated by O2 or air in

5.5. Substrate Specificity, Regiospecificity, and Stereoselectivity

pMMO exhibits greater chemical selectivity, regioselectivity, and stereoselectivity than sMMO.122,123 pMMO can only hydroxylate straight-chain alkanes containing five or fewer carbons and epoxidize corresponding alkenes. Hydroxylation primarily occurs at the C2 position. The R-alcohol products are dominant for the hydroxylation of n-butane and n-pentane at the secondary carbon, whereas low stereoselectivity to give the 8586

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Figure 11. Proposed substrate pocket site near the tricopper cluster (D site) in pMMOMc. Adapted with permission from ref 100. Copyright 2014 John Wiley & Sons.

S-epoxide products is observed in the epoxidation of propylene and 1-butene. The enantiomeric excess observed for each substrate reflects its orientional preference in the substrate binding pocket with respect to the activated tricopper cluster in the active site (Figure 11). Based on these findings, cryptically chiral ethanes124 and chiral deuterated butanes125 were synthesized to further probe the nature of the stereoselectivity and the substrate binding cavity in pMMOMc.125 Total retention of configuration was observed for the hydroxylation products of the cryptically chiral ethanes with a kinetic isotope effect (KIE) of kH/kD ≈ 5.2− 5.5.124 Total retention of configuration and similar KIEs were also observed for the chiral butanes.125 Moreover, no significant carbon KIE (k12C/k13C) from the hydroxylation of propane was observed.126 These results suggest that hydroxylation mediated by pMMO proceeds through the concerted singlet-oxene insertion mechanism rather than a two-step process consisting of hydrogen-atom abstraction followed by radical rebound. In the concerted mechanism, there is limited stretching of the C H bond in the transition state, whereas in the hydrogenabstraction/radical-rebound mechanism, there is complete cleavage of the CH bond.43 Further epoxidation experiments on the alkenes trans-2-butene and cis-2-butene revealed only 10% ee for (2S,3S)-2,3-dimethyloxirane and the meso product, respectively, suggesting that epoxidation also proceeds through concerted electrophilic syn addition with low stereochemical differentiation between the re and si faces.127

ketene, which can migrate and attack nucleophilic amino acids to form a chemical adduct inside enzymes.128 Therefore, acetylene is a good probe for investigating the nature of the hydrocarbon binding site(s) and the active site. The ketene adduct from the reaction of acetylene with pMMO was recently reinvestigated by high-resolution mass spectroscopy.89 These experiments revealed that chemical modification occurs at Lys 196 from PmoC.89 This site is distant from the proposed active sites mentioned earlier: ca. 40 Å from the A or D site and ca. 60 Å from the B site. With the bulkier propyne as the suicide substrate, methyl ketene is produced, and chemically modified adducts are found at Lys48/49, S228, and Lys196 in PmoC. These results indicate that the catalytic site resides within the membrane and that the ketene derivatives are formed by Oatom transfer from the catalytic site to acetylene/propyne, which then diffuse along substrate/product channels to chemically modify potential nucleophilic amino acid side chains. Upon adduct formation, the product/substrate channel(s) are then blocked, inhibiting or deactivating the enzyme. Similar formation of ketene is inferred from reactions of acetylene with a model tricopper complex shown to mediate alkane hydroxylation.89 In contrast, similar oxidation of acetylene is not observed with a model dicopper complex. pMMO is unique in its limited hydrocarbon substrate range (only C1C5 straight-chain alkanes and alkenes). Also, branched hydrocarbons are not substrates. These observations indicate that the cross section and length of the substratebinding site in pMMO is capable of accommodating only a straight-chain hydrocarbon with up to five carbon atoms. Based on this supposition, molecular docking experiments have been conducted to search for potential substrate-binding loci within the three-dimensional protein fold provided by the crystal structure of pMMOMc.89,127 A hydrophobic pocket was found to accommodate all known substrates adjacent to the D site (Figure 11). This substrate-binding pocket is formed by the aromatic amino acids Trp48, Phe50, Trp51, and Trp54 from PmoA, all residing along the same stretch of the α-helix that contains the bulk of the amino acids that sequester the putative

5.6. Hydrocarbon Binding Site and the Aromatic Box

Several substrate-binding sites have been proposed on the basis of pMMO crystal structures. A hydrophobic cavity composed of Pro94 from PmoB and Leu78, Ile163, and Val164 from PmoC was found to be suitable to accommodate CH4 and is adjacent to the B site.82,89 A plausible channel for substrate entry and delivery to the active site was suggested by cryo-electron microscopy (cryo-EM).83 Acetylene is known to act as a suicide substrate of pMMOMc because acetylene is oxidized by pMMO to the highly reactive 8587

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Figure 12. Conserved region at the N-terminus of the PmoB subunit in pMMO.

Figure 13. Conserved region at the C-terminus of the PmoB subunit in pMMO.

profiling study of M. capsulatus (Bath).132 It is possible that the levels of NADH in the cytosol alone can maintain the reduced cellular environment to sustain the redox levels of the E-clusterdomain copper ions in an overall Cu(I) state. The redox potentials of these E-cluster copper ions are certainly high enough. However, there are also quinone species, such as plastoquinone, existing in the intracytoplasmic membranes of methanotrophic bacteria that can presumably act as electron donors as well. In addition, many c-type cytochromes have been observed and expressed in the aforementioned microarray study of M. capsulatus (Bath),132 and this pool of cytochrome c can serve as an electron supply. As mentioned earlier, pMMO is a Cu(I) protein. In fact, pMMO-enriched membranes can be isolated and prepared anaerobically in the presence of 0.5 mM NADH (E°′ = −0.320 V vs SHE). The X-ray absorption near-edge structure (XANES) spectra recorded for these membranes are almost identical to those of as-isolated pMMO treated with excess chemical reductants, including 25 mM dithionite (E°′ = −0.527 V vs SHE) and the noncoordinating reductant thionein (E°′ = 0.064 V vs SHE).133 For the Cu EXAFS spectra, the best fits are obtained with the following nearest-neighbor ligand structure for the fully reduced samples: 0.5 O/N at 1.90 Å, 2.0 O/N at 2.11 Å, and 1.0 S/Cl at 2.32 Å. A second-shell or outer-shell scattering with short metal−backscatterer distances of 2.84 and 2.70 Å for 1 S and 0.5 Cu, respectively, is obtained.133 Multiple Cu···C scattering components refined to the distances of ∼3.1− 3.2 and 3.3−3.4 Å are taken into consideration for improvement of the fitting in the outer-shell scattering data.

tricopper cluster mentioned earlier. These amino acids are also highly conserved (Figure 9), just like the ones that have been used to model and construct the tricopper cluster site at the D site. To emphasize that CH/π interactions with the aromatic side chains might make a significant contribution to stabilizing the binding of the hydrocarbon in addition to hydrophobic forces, this binding site has been referred to as the “aromatic box”.43,127,129 In addition to the substrate binding pockets highlighted above, other hydrocarbon binding sites for different substrates have been suggested.89,123 5.7. Supplying Reducing Equivalents to the E-Cluster Domain in the PmoB Subunit

Aside from having an active site to mediate hydroxylation of CH4, pMMO is expected to contain additional cofactors for the input and storage of electrons, as well as to gate or control the flow of reducing equivalents to the catalytic site to mitigate futile cycles. These functions are performed by the various copper centers in the enzyme. In addition, there must be provisions to transfer reducing equivalents from electron donors outside in the cellular milieu. So far, the only known reductants for pMMO are NADH and duroquinol. However, duroquinol is not a native reductant. No reductase associated with pMMO has been discovered or identified to date. It has been suggested that the membrane-associated quinoprotein formaldehyde dehydrogenase and the type II NADH dehydrogenase are possible initial electron donors to pMMO.130,131 However, no copper-dependent expression of these potential reductases was found in a recent transcriptome 8588

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Figure 14. Proposed catalytic cycle in pMMOMe with an O2/H2O2 redox loop linking the tricopper catalytic site at the D site and the dicopper center at the B site.

addition, quantum mechanics/molecular mechanics (QM/ MM) calculations conducted by Yoshizawa and co-workers suggested that (μ-oxo)(μ-hydroxo)-Cu(II)Cu(III), a doublet species, is the key intermediate species that mediates the hydroxylation of CH4. Here, it is proposed that the tyrosine residue Tyr374 in the PmoB subunit of pMMOMc can participate in the second coordination sphere of the dicopper center at the B site and donate a reducing equivalent to facilitate the cleavage of the OO bond in the μ-(η2:η2)peroxo-Cu(II)Cu(II) to generate the (μ-oxo)(μ-hydroxo)Cu(II)Cu(III) intermediate for facile hydrogen-atom transfer or proton-coupled electron transfer in the hydrogen-abstraction/radical-rebound chemistry.139−141 Similarly, the bis(μ3oxo)-trinuclear copper Cu(II)Cu(II)(μ-O)2Cu(III) intermediate, a singlet species, has been proposed as the intermediate for mediating facile concerted oxo transfer to the CH bond of CH4. As discussed later in this review, this activation and functionalization of the CH is significantly more facile compared to the corresponding processes mediated by the bis(μ-oxo)-Cu(III)Cu(III) and bis(μ-oxo)-Cu(II)Cu(III) intermediates.137 More detailed discussions of these theoretical perspectives on the hydroxylation of the CH bond in CH4 can be found later in this review. Model compounds mimicking the active sites of enzymes offer another approach to exploring catalytic mechanisms. The biomimetic model compounds for the proposed active sites of pMMO, including the dicopper site (B site) and tricopper site (D site), are discussed later in this review.

Sequence alignments of the PmoB subunit among a variety of methanotropic bacteria indicate that three methionines (residues 44, 141, and 163) at the N-terminus (33−172) are highly conserved (Figures 12 and 13), but these methionines do not appear to be associated with copper ions. In the Cterminal domain (265−414), there are multiple aspartate or glutamate motifs that presumably comprise the ligands for the E-cluster copper centers. These copper ions are considered as an electron reservoir for the reducing equivalents required for the turnover of the enzyme. The presence of multiple negatively charged residues, including both Asp and Glu, at the C-terminus of the PmoB subunit was also seen in CusA, the copper-sensing protein in E. coli, the function of which is to accommodate groups of reduced copper ions.134 It is possible that this domain of PmoB participates in copper transport or trafficking in the assembly of the three-dimensional structure during the biosynthesis of pMMO. However, these Cu(I) ions are also coordinated to the methionines for some sort of a redox switch in response to the O2 chemistry at the dicopper B site (vide infra). 5.8. Catalytic Mechanisms for CH Activation and Functionalization

Two prominent chemical mechanisms are widely invoked in the discussion of CH activation and functionalization by O2 mediated by a metal center or metal cluster. The most popular is the hydrogen-atom-abstraction/geminal-radical-recombination mechanism, and the other is concerted oxene transfer. These same mechanisms have been used to describe the oxidation of hydrocarbons by the celebrated cytochrome P450 enzymes.135,136 However, unlike the electronic structure of Compound I in cytochrome P450 or that of the intermediate Q in sMMO, both of which can exist in multiple electronic states, all of the metal sites that could be activated by O2 in pMMO exist in the singlet state or possibly in a doublet state if the metal site requires the introduction of an additional reducing equivalent to activate it for CH functionalization.100,137 This greatly simplifies the free energy landscape for CH4 oxidation. Theoretical calculations provide an alternative methodology for investigating catalytic mechanisms. For example, The electronic structure of μ-(η2:η2)-peroxo-Cu(II)Cu(II), a singlet species, was suggested by theoretical calculations.138 In

5.9. Catalytic Cycle in pMMO

Experimental studies on the detailed catalytic mechanisms and the turnover cycle of pMMO have been hampered by the slow progress in elucidating the structure of the metal cofactors and the instability of the enzyme. At this juncture, there are still no time-resolved studies on the catalytic cycle as have appeared for the sMMO enzyme. However, based on the current understanding of the metal cofactors and studies on the biomimetics of the putative tricopper cluster at the D site, the following catalytic cycle for the enzyme was recently proposed as a working hypothesis. We begin with functional pMMO with seven reduced copper ions occupying the A−D sites and seven additional Cu(I) ions in the C-terminal domain of the PmoB 8589

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with flavin and Fe−S cofactors, and a small regulatory component protein. Like sMMO, sBMO exhibits similar substrate ranges, including gaseous and liquid alkanes, alkenes, and halogenated xenobiotics. BMOH can also accomplish ethene oxidation mediated by the peroxide shunt.143 Reconstitution of the purified enzyme complex yields a preparation that can oxidize C3−C6 linear and branched aliphatic alkanes.143 Regiospecificity of sBMO is strongly biased toward primary hydroxylation, with greater than 80% of the oxidation occurring at the terminal carbon atom. Although sBMO itself can oxidize CH4 to CH3OH with a high turnover rate, the Km value for CH4 is substantially higher relative to those for C2−C5 alkanes.144 Accordingly, during bacterial growth on linear alkanes, sBMO oxidizes alkanes C2 and higher in preference to CH4. Moreover, T. butanivorans cannot assimilate the C1 compound into biomass. Alkane monooxygenase is an integral membrane-bound diiron ω-hydroxylase that can introduce O2 regioselectively into the unactivated terminal methyl group of C5−C12 linear normal alkanes to yield 1-alcohols. With AlkB, the Gramnegative bacterium Pseudomonas putida Gpo1 (formerly known as Pseudomonas oleovorans) utilizes linear medium-chain-length alkanes (C 5 −C 12 ) as the sole source of carbon and energy.145−148 The purified AlkBGT complex, which accomplishes the ω-hydroxylation of n-octane, comprises three components: (i) a soluble rubredoxin-2, (ii) a soluble NADH-dependent rubredoxin reductase, and (iii) an integral membrane nonheme diiron alkane hydroxylase.145−151 These proteins are encoded by two distinct operons located on the large OCT plasmid.152 One of the operons, corresponding to the AlkBFGHJKL gene cluster, encodes alkane hydroxylase (AlkB)153 and rubredoxin-2 (AlkG). The other operon, AlkST, encodes the third component of the AlkBGT complex, the flavoprotein (AlkT).154 AlkT mediates the transfer of reducing equivalents from NADH to rubredoxin-2. Sequence alignment data in comparison with the fatty acid desaturase superfamily showed the highly conserved His-box (8-histidine motif) that is essential for the coordination of the diiron core of AlkB depicted in the recent crystal structure of a mammalian stearoyl-CoA desaturase.155 Although Pseudomonas putida GPo1 can metabolize n-propane and n-butane, there is no direct molecular evidence yet to show the production of 1propanol and 1-butanol.156 However, several mutations implemented in the recombinant AlkB in vivo have demonstrated the production of 1-butanol.149

subunit. We believe that the latter cluster of reduced copper ions provides a reservoir of reducing equivalents to facilitate catalytic turnover.121 With the C-terminal domain of the PmoB subunit resting on top of the cytoplasmic membrane interface in close contact with the cytosol, the high redox potentials of the E-cluster copper ions ensure that the redox levels of these coppers will be well buffered by the strong reducing power of the cell.119 Given what is now known about the properties of the putative tricopper cluster at the D site and the facile chemistry of the class of biomimetic tricopper complexes that were recently demonstrated to exhibit efficient hydrocarbon oxidation, we assert that the catalytic site of the enzyme resides here. Upon activation of the Cu(I)Cu(I)Cu(I) tricopper cluster by O2 and O-atom transfer to CH4, the “spent” catalyst is regenerated by a molecule of H2O2 produced by reaction of the reduced dicopper center with O2 at the B site with the assistance of two protons from a group of Asp and Glu residues lining the interface between the PmoA and PmoC subunits in this region of the transmembrane helix bundle. Because this reaction generates a molecule of O2 and H2O, there is no net consumption of O2 by the activation of the dicopper center and the transfer of the H2O2 to the tricopper cluster at the D site in this O2/H2O2 loop. This catalytic cycle is summarized in Figure 14. As with the chemistry mediated by sMMO, the overall reaction is RH + O2 + 2H+ + 2e− → ROH + H 2O

(6)

In this manner, pMMO mediates alkane hydroxylation as a methane monooxygenase. However, if CH4 or an alternative substrate is not available for O-atom transfer to the hydrocarbon substrate, the hot activated Cu(II)Cu(II)(μ-O)2Cu(III) species at the D site will be aborted by the transfer of a reducing equivalent from the reduced copper ion occupying the C site to produce the fully oxidized Cu(II)Cu(II)Cu(II) tricopper cluster with a “capping” oxo or the (μ3-oxo)Cu(II)Cu(II)Cu(II) species, as described earlier, leaving the enzyme in a nonfunctioning or “dead-end” state. Regeneration of the functional tricopper catalyst will require the infusion of reducing equivalents into the transmembrane domain of the enzyme, so these abortive processes are wasteful of O2 and reducing equivalents.

6. OTHER ENZYMES FROM ALKANE-OXIDIZING BACTERIA A number of bacteria have been isolated for their ability to utilize gaseous or liquid alkanes as growth substrates. These alkane-oxidizing bacteria have been conveniently categorized into three groups based on the alkane lengths of the growth substrates.142 Methane-oxidizing bacteria such as methanotrophic bacteria belong to the first group. Other gaseous alkanes (C2−C4) support the growth of the second group of alkaneoxidizing bacteria, whereas those bacteria that grow on the liquid alkanes (C5−C12) constitute the third group. We mention in passing two other alkane-oxidizing enzymes, one each from the second and third categories above, as part of this review: soluble butane monooxygenase (sBMO) and alkane monooxygenase (AlkB). Soluble butane monooxygenase is a three-component diiron monooxygenase complex expressed by the C2−C9 alkaneutilizing bacterium Pseudomonas butanovora or Thanuera butanovorans.143,144 The sBMO complex consists of an ironcontaining hydroxylase (BMOH), an NADH-oxidoreductase

7. ENGINEERING CYTOCHROME P450 BM3 FOR THE OXIDATION OF SMALL ALKANES Cytochrome P450s are ubiquitous heme monooxygenases found in eukaryotes and prokaryotes. Nearly all P450s are membrane proteins, with two notable exceptions: cytochrome P450 Cam from the bacterium Pseudomonas putida and cytochrome P450 BM3 from the bacterium Bacillus megaterium. Both water-soluble P450Cam and P450 BM3 exhibit high substrate promiscuity and have been engineered to catalyze regio- and stereoselective reactions of a variety of substrates with high efficiencies, including steroids, terpenes, natural products, pharmaceutical analogues, and alkanes, as well as fatty acids.157−164 To oxidize gaseous small alkanes, Wong and coworkers159,165 and Arnold and co-workers166 used rational protein engineering to obtain both single and multiple mutations of the amino acid residues around the active site in P450Cam and directed evolution of P450 BM3 in the laboratory, 8590

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Figure 15. Active site of cytochrome P450 BM3. Reproduced with permission from ref 129. Copyright 2014 Elsevier B.V.

hydroxylation of n-butane and n-propane and allow these gaseous alkanes to be converted into secondary alcohols with reasonable turnover numbers.172 More excitingly, under high pressures, this enzyme is capable of performing primary-carbon oxidation of ethane and n-propane, and even CH4 oxidation.157,164,173 The mechanism of substrate hydroxylation mediated by the cytochrome P450 enzyme has been well studied over the years, and it is now well established that the hydroxylating species is the oxyferryl porphyrin cation radical, Compound I.174,175 This active intermediate exists in two electronic states, namely, the low-spin (LS) doublet state and the high-spin (HS) quartet state, corresponding to antiparallel and parallel orientations, respectively, of the spin of the unpaired electron occupying the half-filled lowest unoccupied molecular orbital (LUMO) of the porphyrin cation π system relative to the S = 1 spin of the Fe(IV)O heme-iron center. According to the theoretical calculations of Shaik et al.136 and Li and Shaik,176 these two electronic states are essentially degenerate and, hence, thermally accessible under ambient conditions. However, they exhibit different reactivities in the hydroxylation reaction. Even though oxidation is initiated by PCET for both states, that is, transfer of an electron from the CH of the substrate to be oxidized to the half-filled LUMO of the porphyrin cation radical and proton transfer to the Fe(IV)O iron center, respectively, the subsequent reaction between the alkyl radical R• and Fe(III)OH depends on the spin of the unpaired electron of R•, and the calculations predicted a substantially higher kinetic barrier for the HS state compared to the LS state. The predicted outcome was that subsequent rearrangement of the Fe(III)OH···R• is facile or that O-atom transfer was essentially concerted for the LS state. On the other hand, for the HS state, the rearrangement to give the product is significantly slower, or the alcohol is formed by radical rebound.

respectively. They could achieve very reasonable activity toward n-propane and n-butane to form the corresponding secondary alcohols. The tendency for the oxidation of propane and butane to occur exclusively at the secondary carbon reflects the contribution of the active-site volume, binding orientation, and mobility to the CH bond oxidation process in these engineered alkane monooxygenases. These results provided an impetus to engineer cytochrome P450 into a methane monooxygenase, but with only limited success. The obstacle seems to be related to the difficulty of engineering or creating a small but well-defined cavity to restrict the small and symmetric CH4 molecule near the hydroxylating heme center above the flat porphyrin ring in the hydrophobic pocket of the enzyme. The native substrates of cytochrome P450 BM3 are C12−C16 fatty acids. It has been suggested from crystallographic studies that the stereochemical controls are exerted on the substrate at a site within the heme pocket some 6−8 Å above (distal) the iron porphyrin.167−169 According to crystal structures (PDB IDs 1JPZ167 and 1FAG168), this asymmetric pocket can be divided into three subpockets designated as L (large), M (medium), and S (small) zones (Figure 15). For the native substrates of cytochrome P450 BM3, C12−C16 fatty acids, the outer polar residues including Arg 47, Tyr 51 and Ser 72, together with a water network, serve as hydrogen-bonding acceptors or donors to anchor the carboxylate end of the fatty acid, and in this manner, they exert distal controls for the oxidations of C12−C16 fatty acids at the ω-x positions (x = 1− 3).158,159,164,170 However, in addition to the hydrogen bonding of the carboxylate end of the fatty acid with the distal water networks, there exist van der Waals interactions between the acyl chain and the wall of the hydrophobic pocket in the M zone. Chiang et al.171 showed that these van der Waals interactions could be substantially enhanced by the introduction of fluorinated substituents into the acyl chain in the vicinity of the M zone of the hydrophobic pocket (Figure 15). For example, by substituting the terminal methyl group of the lauric acid by one, two, and three fluorine atoms, they found that the regioselectivity was significantly improved, especially for the trifluorinated lauric acid, which exhibits a single product with the hydroxylation occurring at the position of ω-3. Similarly, long-chain perfluorocarboxylic acids have been exploited as rigid chemical space fillers or “dummy atoms” to compress the size of the substrate binding pocket of cytochrome P450 BM3 for the hydroxylation of small gaseous alkanes. With this strategy, the wild-type cytochrome P450 BM3 can mediate the

8. FREE ENERGY LANDSCAPE OF METHANE OXIDATION: INSIGHTS DERIVED FROM STUDIES ON VARIOUS METHANE-OXIDIZING SYSTEMS In principle, there can be many ways to oxidize CH4 to CH3OH. As mentioned earlier, the pathway of CH4 oxidation depends on the nature of the oxidant. The strongest oxidant is, of course, the oxygen atom in its different electronic states. Even so, the details of the oxidation depend on the electronic structure of the oxygen atom, whether it is in its ground 3P state, the excited 1D state, or even the excited 1S state. As an 8591

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example, the reaction of CH4 with thermal O(3P) has been extensively studied in the gas phase.177−181 The reaction proceeds by direct hydrogen-atom abstraction to form preferentially a collinear OHCH3 transient species, which then dissociates into •CH3 and •OH radicals. The energy barrier for this reaction estimated from crossed-beam experiments and by theoretical calculations is ca. 14−15 kcal mol−1.180,181 Interestingly, the recombination of •CH3 and •OH to form CH3OH, through either the singlet-state or triplet-state energy surface, was not detected in the molecular beam experiments. In contrast, the formation of CH3OH was observed when the reaction between CH4 and O(1D) was studied in crossed-beam experiments,182 suggesting the formation of an associated complex followed by structural rearrangement, as well as other products. The oxidizing power of the O atom can also be harnessed by a metal center for direct oxidation of CH4 to CH3OH. Examples of these transitionmetal catalysts include the first-row or late transition-metal oxides,14,15,183−191 polyoxometalates (POMs),192,193 the copper centers in Cu-exchanged zeolites (Cu-ZSM-5),26,194−196 FeZSM-5 zeolite,197 Cu−Fe-ZSM-5,198,199 and copper mordenites,22,23,200−202 the nonheme diiron center in sMMO,203 and the tricopper cluster in pMMO.100 With these metal catalysts, the CH4 hydroxylations proceed through either a two-step radical mechanism or a single-step concerted O-atom insertion. We now illustrate these mechanisms in turn with a few specific examples, including CH4 hydroxylation in both sMMO and pMMO and discuss the insights that theory has brought to the current understanding of these mechanisms in the two MMOs.

efficiency with CuO+ was found to be better, 51%, with 20% converted into CH3OH. These results suggest multiple reactive channeling upon formation of the associated complex, with the product branching ratio to yield the neutral CH3OH determined by two steps: (i) hydrogen-atom abstraction and (ii) the rebound recombination of the •CH3 and •OH radical fragments. The reactivity for the hydrogen-atom abstraction of MO+ is singularly correlated with the spin density residing at the O atom. According to molecular orbital analysis (Figure 17), the

Figure 17. Molecular orbitals and electronic configurations of the firstrow transition-metal oxides. Reproduced with permision from ref 15. Copyright 2000 American Chemical Society.

greater the spin density localized on the O atom as O(3P), the higher the reaction efficiency. For the oxides of the late transition metals, such as MnO+, FeO+, and CuO+, the 2π and 3σ orbitals are singly occupied. In the case of the oxides of the early transition metals, such as ScO+, TiO+, and VO+, the 2π and 3σ orbitals are empty, and these metal oxides do not exhibit hydrogen-atom abstraction. Very recently, results from ion cyclotron resonance mass spectroscopy, in conjunction with QM calculations, suggested that the activation of methane by the homo- and heteronuclear oxide clusters [XYO2]+ (X, Y = Al, Si, Mg) exhibits competition between PCET and hydrogenatom-abstraction mechanisms depending on electronic structure.204 On the other hand, the efficiency of the rebound recombination is influenced by many more factors, including the strength of the MO bond, the possible spin states, the feasibility of spin crossing among different potential energy surfaces, and the structure of the second transition state, which, in sum, determine the size of the second energy barrier. If this barrier is much larger than that associated with the hydrogenatom-abstraction step, the formation of the CH3OH product does not easily take place, stopping at the hydroxo intermediate, unless spin inversion occurs to convert the electronic structure to other channels with lower potential energy surfaces that culminate in the formation of CH3OH. According to Yoshizawa and co-workers’ density functional theory (DFT) study of the conversion of CH4 into CH3OH by these active transition-metal oxides, these reactions belong to the nonradical type, and the spin states of the ground state, the first transition state (TS1), and the second transition state (TS2) might not always stay the same in the catalytic pathway under adiabatic conditions.15,188−190 For example, the sextet is lower than the quartet for FeO+ in the ground state, but the spin inverts to the quartet at the TS1 and again to the sextet at TS2. Similar results have been seen for many late transitionmetal oxides.

8.1. Two-Step Radical Mechanism

The conversion of CH4 into CH3OH by the two-step hydrogen-atom abstraction followed by geminal-radical recombination has been demonstrated in a diverse range of oxygenactivated transition-metal catalysts. These transition-metal catalysts have been found among the first-row or late transition-metal oxides,14,15,183−191 POMs,192,193 Cu-ZSM5,26,194−196 Fe-ZSM-5 zeolite,197 Cu−Fe-ZSM-5,198,199 copper mordenites,22,23,200−202 and the active diiron intermediate Q of sMMO.203 8.1.1. Metal Oxides. Schroder and Schwarz discovered that monoxide cations of the late transition metals MO+ (M = Mn, Fe, Co, Ni, Cu, Pt), all two-atom species, can react with CH4 by hydrogen-atom abstraction to give three branching products in the gas phase, as shown in Figure 16.185 The reaction efficiency

Figure 16. Possible activations of CH4 by reactions with transitionmetal-oxide cations.13

varies with the metal. For example, MnO+ shows a reaction efficiency (kR/kADO) of 40% toward CH4, mainly yielding MnOH+ and the •CH3 radical; the CH3OH product is less than 1%. In kR/kADO, kR refers to the rate constant, and kADO denotes the collision rate constant for average dipole orientation. A lower reaction efficiency of 20% was observed for FeO+, but more CH3OH product was formed. The reaction 8592

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Figure 18. DFT-calculated structure and location of the [Cu3(μ-O)3]2+ cluster in copper mordenite. Adapted with permission from ref 202. Copyright 2015 Nature Publishing Group.

8.1.2. Cu Exchange Zeolites. Zeolites are silicate microprorous materials, in which the tetrahedral [SiO4]4− is the structural unit to extend a variety of three-dimensional latticeworks. With slight fractional substitutions of Al3+ for Si4+, the negatively charged zeolite framework forms readily with adsorption of different transition-metal ions. Zeolites loaded with copper and iron ions, including Cu-based zeolites,26,194−196 Fe-ZSM-5,197 and Cu−Fe-ZSM-5,198,199 and copper mordenites,22,23,200−202 have recently been shown to be potential heterogeneous materials for selective oxidation of CH4 to CH3OH. Cu-ZSM-5, activated either by N2O at 100 °C or by O2 at 175 °C, was the first reported Cu-based zeolite with the capability to convert CH4 into CH3OH in the temperature range of 373−473 K.196 Based on spectroscopic evidence, the catalytic species was identified as the mono-(μ-oxo)-bridged dicopper core, namely, [Cu2O]2+. On the basis of DFT calculations, the CH4 hydroxylation is proposed to be initiated by the formation of a [CuOHCu]2+ intermediate through hydrogen-atom abstraction of CH4 and the CH3OH formed by radical rebound.26 8.1.3. Copper Mordenites. Results similar to those for the Cu-based zeolites have been reported for the copper mordenites (Cu-MOR).22,23,200−202 However, Grundner et al.202 recently developed a copper-based mordenite with uniform reactive sites that showed high reactivity toward the selective oxidation of CH4. This Cu-MOR consists of tricopper copper−oxo clusters, [Cu3(μ-O)3]2+, anchored to two framework Al atoms located at the pore mouth of the eightmembered-ring (8-MR) pockets in the mordenite structure (Figure 18). As with the Cu-based zeolites, the system can only convert CH4 into CH3OH stoichiometrically and produce CH3OH in yields that are dependent on the levels of the tricopper copper−oxo cluster in the Cu-MOR. The structure of the tricopper cluster was deduced from Cu K-edge X-ray absorption spectroscopy by comparisons of the XANES and EXAFS data with similar data on the dimeric [Cu(μ-O)Cu]2+ active center of Cu-ZSM-5. On the basis of UV−visible experiments on the activated Cu-MOR in situ with CH4 at 200 °C, the [Cu3(μ-O)3]2+ tricopper cluster is very stable, consistent with the slow rate of the CH4 oxidation reaction. DFT calculations suggested that the CH4 oxidation is initiated by homolytic CH bond breaking, followed by radical rebound, and the role of the extra copper in the tricopper

system is to reduce the CH bond activation barrier by 4 kJ mol−1 (or ca. 1 kcal mol−1) compared to that of the binuclear [Cu(μ-O)Cu]2+ center in Cu-ZSM-5, enhancing the reaction efficiency accordingly. 8.1.4. Intermediate Q in sMMO. As described earlier, the catalytic center for converting CH4 into CH3OH in sMMO is the active Q intermediate species in MMOH, a weakly coupled Fe(IV)Fe(IV) dinuclear species with two bridging μ-oxos, often referred to as the diamond core. (Figure 6). The electronic structure of Q can be very complicated, because each iron center can be either intermediate-spin (S = 1) or high-spin (S = 2), and exchange coupling between the two Fe(IV) centers gives rise to an ensemble of accessible electronic states for the diiron species at room temperature. Aside from the spin state, the charge [Fe(III) or Fe(IV)] and the coordination number (four-, five-, and six-coordinate) of each iron center are still being debated. In the postulated radical mechanism, CH4 hydroxylation is mediated by the bis(μ-oxo)-Fe(IV)Fe(IV) species in a highspin state (S = 4 or S = 5). The CH bond is first homolytically cleaved by one of the bridging μ-oxos in the diiron center to form a “free” or loosely bound •CH3 radical and a μ-bridging •OH radical, and subsequent rebound recombination of these radicals yield the CH3OH product. In support of the radical mechanism, the results of chiral ethane experiments gave 69−84% retention of the stereochemical configuration of the chiral carbon center in the hydroxylation of cryptically chiral ethanes by sMMO. However, experiments with radical-clock substrates suggested that the putative radical intermediate exists only for ∼150 fs, which is too short to support the formation of a well-defined radical chemical species. To account for these observations, many models with distinct assumptions have been constructed, and related DFT calculations have been used to distinguish among these corresponding reaction mechanisms in terms of energetics, transition state, and intermediates. These studies have focused on the nonradical, radical, and “nonsynchronous concerted” mechanisms (vide infra).48,205−207 8.2. Singlet-Oxene Transfer or Biradical Mechanism

The electronic configurations of the partially 2p orbitals of atomic oxygen are 3P, 1D, and 1S. These states of the isolated O atom or the oxene differ in the arrangement of the four 2p electrons in the 2px, 2py, and 2pz orbitals. Both the ground state 8593

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(3P) and the second excited state (1S) have two unpaired electrons occupying separate 2p orbitals, but with their spins in the same and opposite directions, respectively. Both are biradicals, but with dire consequences in their reactivity toward the CH bonds in a hydrocarbon. The two-step radical mechanism is expected for transfer of O(3P), but the concerted insertion mechanism is expected for O(1S). These dramatically different reactivities would also be manifested when the oxene is harnessed by a transition metal. Thus, the 3P character or the spin density residing at the O atom of the oxygen-activated reactive metal species influences its reactivity toward hydrogenatom abstraction, as we described above for the metal oxides (MO+). Presumably, this criterion would apply in the case of Cu-ZSM, Cu-based zeolites, copper mordenites, and the intermediate Q in sMMO, as well, as the reactive metal-oxo species are paramagnetic in these systems. In contrast, when the reactive metal-oxo species is diamagnetic (a singlet), then the single-step concerted insertion mechanism is more likely. Note that, in such a singlet reactive metal-oxo species, the 1S and 1D states of the oxene are now electronically mixed in the harnessed O atom. In the case of pMMOMc, as discussed in an earlier section (section 5.5), the experimental results are highly suggestive of a concerted oxene insertion pathway for the mechanism of O-atom transfer mediated by this MMO, and the observations are consistent with the prevailing evidence that the activated metal-oxo species mediating the chemistry is a Cu(II)Cu(II)(μ-O)2Cu(III) singlet species. When the Cu(I)Cu(I)Cu(I) cluster at the D site is activated by O2, it formally gives the Cu(II)Cu(II)(μ-O)2Cu(III) species. In the activated tricopper cluster, the ligands of Cu1 are PmoA His38 and PmoC Glu154; Cu2, PmoA Asp47 and Met42; and Cu3, PmoA Asp49 and Glu100,92,120 in addition to the two bridging μ-oxos. Cu3 has two of the hardest ligands and, hence, is more likely to be formally Cu(III). However, the electrophilic Cu(III) ion might have an electronegativity similar to that of the bridging μ-oxo, so that the oxo is likely to share one of its lone pairs with the Cu(III) to form a covalent Cu(II)O bond. At the same time, Cu2, with Met42 and Asp47, is an excellent leaving group when it is reduced, so this Cu(II) might prefer to form a covalent bond with the other lone pair of the bridging μ-oxo as well. Given this arrangement of ligands for Cu2 and Cu3, the electronic structure of the Cu(II)O Cu(III) linkage in the copper triad is poised for homolytic cleaving of the two CuO bonds to give a singlet biradical when the O atom approaches the CH bond of CH4 to form the transition state during the substrate oxidation.100 Upon O2 activation of the Cu(I)Cu(I)Cu(I) tricopper cluster, the resultant Cu(1)IICu(2)II(μ-O)2Cu(3)III species is an electronic singlet because of the strong antiferromagnetic coupling between the two unpaired spins on Cu2 and Cu1. Similar antiferromagnetic coupling obtains between the two unpaired spins on Cu3 and Cu1 after transfer of the O atom to the substrate, so that the Cu(2)IICu(1)II(μ-O)Cu(3)II species is also a singlet. Thus, the chemistry must proceed along a singlet reaction potential surface, and the O atom is transferred to the substrate as a singlet “biradical” or the “singlet oxene” in the transition state. Details of this reaction mechanism are highlighted for the direct insertion of a singlet oxene across one of the CH bonds in CH4 (Figure 19).121

Figure 19. Details of the adiabatic singlet-oxene transfer from an O2activated trinuclear copper cluster to CH4 to form the transition state. ↑ and ↓ denote up and down spins, respectively, of the unpaired electrons. Adapted with permission from ref 121. Copyright 2004 American Chemical Society.

8.3. Density Functional Theory (DFT) Calculations on MMOs

8.3.1. Theoretical Models for Methane Hydroxylation Mediated by sMMO. Friesner and Lippard and co-workers reported a hydroxylation mechanism, shown in Figure 20, based on the Fe(IV)(μ-O)2Fe(IV) model inferred from the crystal structure of MMOHred.48 As CH4 approaches the diiron core, a hydrogen-atom abstraction or PCET initially occurs from one of the CH bonds of CH4 to one of μ-oxos of the diFe(IV) centers with activation energy of 17.9 kcal mol−1. After the crossing of the first transition state, the DFT calculations reveal two reaction channels: the rebound pathway and the nonsynchronous concerted pathway. In the rebound mechanism, upon completion of the first PCET, •CH3 recoils to the bridging hydroxyl group in the intermediate with an O H···C distance of 1.97 Å, which is unfavorable for free tumbling of the •CH3 radical to accomplish CO bond closure to give the final CH3OH product. However, the formation of the C O bond can occur with a second electron transfer through the second transition state with a barrier height of 3.9 kcal mol−1. The second channel is similar to the “rebound” reaction channel in the aforementioned two-electron-transfer pathway. In this mechanism, the methyl group is tightly connected to the bridging hydroxyl group at all times so that a well-defined •CH3 radical is not strictly formed. Nevertheless, the production of CH3OH proceeds with a much smaller kinetic barrier of 1.3 kcal mol−1. Accordingly, this mechanism approaches being a “concerted” one, and the pathway has been referred to as the nonsynchronous concerted mechanism. Yoshizawa and co-workers proposed a nonradical mechanism in which the Fe(IV)(μ-O)2Fe(IV) intermediate is directed at the CH4 molecule in the antiferromagnetically coupled state (S = 0) in the DFT calculations206 (Figure 21). The outcome is that one of the hydrogen atoms of CH4 is first abstracted with an activation energy of 30.4 kcal mol−1 through a four-centered transition state with an imaginary vibration mode at 1822 cm−1, indicating cleavage of the CH bond. Unlike direct hydrogen abstraction in a transition state that contains a linearly aligned H3CH···O fragment, the methyl group shifts toward the unsaturated Fe center. Upon crossing over the first transition state, the hydroxyl intermediate forms an FeCH3 bond without the production of a radical species. In the following step, the methyl group moves toward the OH group through a three-centered structure, with an activation energy of 15.7 kcal mol−1 in the transition state, and the recombination leads to the formation of the CH3OH product. Because of the much higher kinetic barrier, abstraction of the hydrogen atom is the ratelimiting step for the overall process. Although the calculated 1 H/ 2 H KIE value associated with the hydrogen-atom 8594

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Figure 20. Friesner−Lippard-proposed nonsynchronous mechanism of CH4 oxidation mediated by the Fe(IV)(μ-O)2Fe(IV) diamond core of the intermediate Q in MMOH of sMMO. Adapted with permission from ref 48. Copyright 2003 American Chemical Society.

Figure 21. Nonradical mechanism proposed by Yoshizawa and co-workers.206

abstraction208,209 is much smaller than the experimental values of 23−28,69 42,210 50−10075 reported by different laboratories, the theoretical KIE value is consistent with the analysis of CH4/ CD2H2 experiments mediated by sMMO at 277 K205 when corrections are made for the effects of hydrogen tunneling on the rate constants. 8.3.2. Theoretical Models for Methane Hydroxylation Mediated by pMMO. Because of the paucity of structural data, the pMMO system has been theoretically explored to only a limited extent. However, given the discrepancy in the mechanism of alkane hydroxylation implied by the spectroscopic experiments on the active preparation versus that suggested by the X-ray crystal structures, quantum chemical calculations have provided useful and important insights into the plausibility of various mechanistic scenarios for CH4 hydroxylation by pMMO. DFT calculations of three possible models of the pMMO active site were performed by Chen and Chan to gain insight into the CH4 hydroxylation chemistry.137 As depicted in Figure 22, these models included (i) the trinuclear copper cluster, bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) tricopper cluster 1, originally proposed by the Chan laboratory; (ii) the more popular bis(μoxo)-Cu(III)Cu(III) dicopper cluster 2; and (iii) the mixedvalence bis(μ-oxo)-Cu(II)Cu(III) dicopper cluster 3. Supporting ligands around the copper ions are each set by two neutral ammonia ligands. Based on the spectroscopic data, both the

Figure 22. Three familiar pMMO active-site models: (1) the bis(μ3oxo)-Cu(II)Cu(II)Cu(III) trinuclear cluster; (2) the bis(μ-oxo)Cu(III)Cu(III) dinuclear cluster; and (3) the mixed-valence bis(μoxo)-Cu(II)Cu(III) dicopper cluster. Adapted with permission from ref 137. Copyright 2006 Elsevier B.V.

bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) trinuclear cluster and the bis(μ-oxo)-Cu(III)Cu(III) dinuclear cluster were taken to be in their singlet ground states (ST = 0), and an electronic doublet (ST = 1/2) was used to treat the mixed-valence bis(μoxo)-Cu(II)Cu(III) dicopper cluster. The conversion of CH4 into CH3OH mediated by the trinuclear copper cluster (1) was found to proceed by a concerted side-on O-atom-insertion step hindered by a kinetic barrier of 15 kcal mol−1 (Figure 23, left). In contrast to the direct hydrogen-atom-abstraction iron-containing or coppercontaining model complexes, the optimized transition-state (TSCu(II,II,III)) structure was found to have an imaginary mode at 593i cm−1, which implies that CO and OH bond formation, as well as CH bond dissociation, are closely correlated (or strongly coupled) in the transition state. 8595

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Figure 23. Energetics and computed structures for the conversion of CH4 into CH3OH mediated by (left) the singlet bis(μ3-oxo)Cu(II)Cu(II)Cu(III) tricopper cluster (1) and (right) the singlet bis(μ-oxo)-Cu(III)Cu(III) dicopper cluster (2). Adapted with permission from ref 137. Copyright 2006 Elsevier B.V.

Subsequent dissociation of the •OH radical and geminal radical recombination gave the diamagnetic CH3OH (Figure 24). The

The Mulliken charges on the bridging O1 and O2 atoms in the ground state of the bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) tricopper cluster were calculated to be −0.526 and −0.628, respectively, with corresponding charges in the transition state of −0.403 and −0.656. Meanwhile, the charges on the three copper ions of the bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) copper cluster were calculated to be +0.754, +0.754, and +0.607 in the ground state and +0.726, +0.740, and +0.592, respectively, in the transition state. The reduction in the charges on the copper ions and the changes in the charges on the bridging oxygen atoms indicate that the O1 oxygen in the bis(μ3-oxo)Cu(II)Cu(II)Cu(III) cluster becomes more like a singlet oxene as the system traverses the ground state to the transition state but the O2 oxygen transforms into more of an “oxo” instead. This is exactly the result expected for direct insertion of a singlet oxene across the CH bond as the reaction coordinate approaches the transition state. The hydroxylation of CH4 mediated by bis(μ-oxo)-Cu(III)Cu(III) dicopper cluster 2 (Figure 23, right) was found to proceed along almost the same course as that of bis(μ3-oxo)Cu(II)Cu(II)Cu(III) tricopper cluster 1. As in the case of 1, the charge reduction on the copper ions is consistent with a trajectory leading to the formation of an outgoing “singlet” oxygen atom. The imaginary mode of the optimized TSCu(III,III) structure during the O-atom transfer was calculated to be 799i cm−1, and the kinetic higher barrier was calculated to be 20.1 kcal mol−1. Thus, transition state TSCu(III,III) was found to appear at a much higher energy than TSCu(II,II,III) in the case of tricopper cluster 1. Regardless, hydroxylation was found to occur by concerted side-on oxene insertion within the singlet manifold. In contrast, the hydroxylation of CH4 mediated by mixedvalence bis(μ-oxo)-Cu(II)Cu(III) dicopper cluster 3 was found to proceed by the two-step radical mechanism. Based on the conservation of spin multiplicity, the system was treated as a doublet state. Hydrogen-atom abstraction was found to yield the •CH3 radical, a doublet-state product, together with a singlet dicopper-containing product [CuII(μ-O)(μ-OH)CuII].

Figure 24. Reaction energy profile for the conversion of CH4 into CH3OH mediated by the mixed-valence bis(μ-oxo)-Cu(II)Cu(III) dicopper cluster (3). Adapted with permission from ref 137. Copyright 2006 Elsevier B.V.

activation barrier associated with the hydrogen abstraction was calculated to be higher than that in the one-step oxo transfer mediated by tricopper cluster 1, with a value of 19.1 kcal mol−1. The corresponding imaginary mode of the optimized transition-state TSCu(II,III) structure was predicted to be 1289i cm−1, suggesting hydrogen-atom abstraction. The higher frequency is distinct from those of the TSCu(II,II,III) and 8596

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conditions. Diiron models have been developed to mimic the active site of sMMO, dicopper complexes have been developed to model the dicopper site seen in the X-ray crystal structures on pMMO, and tricopper complexes based on the tricopper cluster have been inspired by the biochemical/biophysical studies of pMMO performed by the Chan laboratory.

TSCu(III,III) in Figure 23 and implies that the primary motion occurring in the transition state involves CH bond breaking. A comparison of the first-order rate constants and the 1H/2H KIEs for the “oxo-transfer” reactions at a temperature of 300 K, predicted by models 1 and 2, and for the hydrogen-abstraction step in the case of model 3, is provided in Table 2. From these

9.1. Strategic Considerations

Table 2. DFT-Predicted First-Order Rate Constants (k) and KIE Values for the Hydroxylation of CH4 by the Bis(μ3-oxo)Cu(II)Cu(II)Cu(III) Tricopper Cluster, the Bis(μ-oxo)Cu(III)Cu(III) Dicopper Cluster, and the Bis(μ-oxo)Cu(II)Cu(III) Dicopper Cluster at 300 Ka reactivity

kHb (s−1)

kDc (s−1)

Because the catalytic sites in MMOs are metal clusters that are activated by O2 during catalysis, the obvious biomimetic models are Fe(II)Fe(II), Cu(I)Cu(I), and Cu(I)Cu(I)Cu(I) clusters that can react directly with O2 in a facile manner. To accomplish such a facile reaction, at least two of the metal ions would need to be in close juxtaposition to form the appropriate metal-oxo cluster, for example, the Fe(IV)(μ-O)2Fe(IV) core in the case of a diiron model, the Cu(III)(μ-O)2Cu(III) core for a dicopper model, and the bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) core from a Cu(I)Cu(I)Cu(I) tricopper cluster. Clearly, the Fe(IV)(μ-O)2Fe(IV), Cu(III)(μ-O)2Cu(III), and bis(μ3-oxo)Cu(II)Cu(II)Cu(III) complexes could also be prepared from the corresponding Fe(III)Fe(III), Cu(II)Cu(II), and Cu(I)Cu(I)Cu(I) complexes, respectively, upon reaction with H2O2. If the mixed-valence bis(μ-oxo)-Cu(II)Cu(III) dicopper complex is desired, it could be obtained by a simple one-electron reduction of the bis(μ-oxo)-Cu(III)Cu(III) dicopper complex. Similarly, the Cu(II)(μ-O)Cu(II) core could be formed by reducing a Cu(III)(μ-O)2Cu(III) complex by two reducing equivalents in the presence of two protons, should the target catalyst be the [Cu2O]2+ core. In the ligand design, a multidentate ligand provides one simple means of bringing the desired number of metal ions together for activation by O2 or H2O2. Multinucleating ligands are generally flexible and do not necessarily facilitate the positioning of two or three copper ions in place to facilitate the formation of the desired dioxo binuclear or trinuclear species by reaction with O2, unless cooperativity effects are somehow built into the ligand design. The desired complexes could also be assembled with macrocyclic ligands. However, such complexes usually lack the essential feature of reactivity with O2 to activate them for alkane hydroxylation chemistry. Another popular strategy is to form the desired catalyst by using O2 or H2O2 to self-assemble mononuclear complexes or, in the case of a trinuclear catalyst, to self-assemble binuclear and mononuclear complexes, often with the assistance of an external bridging ligand, such as an imidazole or alkoxide. The problem with this second kind of complex is that the nuclearity is difficult to control and often binuclear complexes are the final products. The self-assembled complexes also suffer from the drawback that the complexes lose their multicenter character and break up into complexes of lower nuclearity after the catalytic chemistry is completed or upon reduction. In principle, these shortcomings could be overcome by immobilizing the model complexes in the confined space of a mesoporous nanoparticle, as demonstrated recently with a tripodal tridentate copper complex designed to mimic the active site of a copper enzyme for hydrocarbon oxidation.211 In this case, the mononuclear Cu(II) complex was immobilized within the nanochannels of functionalized mesoporous silica nanoparticles, and a stable bis(μ-oxo)-Cu(III)Cu(III) species was formed in situ upon one-electron reduction of the mononuclear Cu(II) complexes, followed by reaction with O2. This system was found to be capable of sustaining the aliphatic oxidation of toluene to yield benzyl alcohol and benzaldehyde in the presence of O2 with

kH/kD

Bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) Tricopper Cluster facile 2.91 × 104 6.829 × 103 4.3 (5.2d) Bis(μ-oxo)-Cu(III)Cu(III) Dicopper Cluster inert 5.67 × 10−1 1.491 × 10−1 3.8 (4.9d) Mixed-Valence Bis(μ-oxo)-Cu(II)Cu(III) Dicopper Cluster slow 1.19 × 102 7.653 15.5 (49.1d) a

Adapted with permission from ref 137. Copyright 2006 Elsevier B.V. Rate constant for CH4 as the substrate. cRate constant for CD4 as the substrate. dTunneling corrections included.

b

calculations, it is clear that CH4 hydroxylation is most facile when mediated by bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) tricopper cluster 1. The hydroxylation mediated by bis(μ-oxo)-Cu(III)Cu(III) dicopper cluster 2 or mixed-valence bis(μ-oxo)Cu(II)Cu(III) dicopper cluster 3 is slower by several orders of magnitude. Furthermore, small classical KIEs of 4.3 and 3.8 were obtained for the oxo-transfer chemistry mediated by bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) tricopper cluster 1 and bis(μoxo)-Cu(III)Cu(III) dicopper complex 2, respectively, at room temperature. Even when nuclear tunneling effects were included, the KIEs increased to only 5.2 and 5.4, respectively. These KIE values are in essential agreement with experiments on pMMO. The Chan laboratory has measured KIEs for the hydroxylation of cryptically chiral ethanes, propanes, and butanes in the range of 5.2−5.7.124,125 Although the oxo transfers mediated by bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) tricopper cluster 1 and bis(μ-oxo)-Cu(III)Cu(III) dicopper cluster 2 exhibit similar 1H/2H KIEs, the process mediated by the trinuclear copper cluster is significantly more facile. In contrast, the radical mechanism exhibited by mixed-valence bis(μ-oxo)Cu(II)Cu(III) dicopper cluster 3 predicts a significantly larger KIE of 16 for the hydrogen-abstraction step, and the KIE increases to 49 when tunneling effects are included in the calculations. Several different mixed-valence dicopper model clusters with different supporting ligands using the same transition-state structure have been reported to have similar KIEs or even higher values (as described in section 5.8) .139−141 In summary, the above DFT analysis of the catalytic pathways for CH4 hydroxylation mediated by the three different copper models indicates that bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) trinuclear cluster offers the most facile pathway and yields rate constants (kcat) and KIEs that are consistent with experiments.

9. TOWARD THE DEVELOPMENT OF A BIOMIMETIC CATALYST Building on progress toward understanding the catalytic sites in sMMO and pMMO, numerous attempts have been made over the past two decades to develop biomimetic catalysts capable of the selective oxidation of CH4 to CH3OH under ambient 8597

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Figure 25. Compilation of the multidentate ligands that have been used to construct tricopper complexes (see refs 213−215, 217−221, 231, 235, and 243−246). 8598

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Figure 26. Some of the tricopper complexes reported in the literature as prepared by various approaches described in the text (see refs 214, 220, 223, 235, 239, 240, 255, and 257).

Cu(II) center along with an isolated Cu(II) in these complexes.223 Although these tricopper complexes do not typically support hydrocarbon oxidation, they represent a popular approach to the problem, and ligand-assisted formation of trinuclear complexes has been reported for other metal ions such as manganese, iron, cobalt, and zinc, as well.224−230 Recently, the Chan laboratory prepared a number of oxidation catalysts based on the ligand 3,3′-(1,4-diazepane1,4-diyl)bis[1-(4-ethylpiperazine-1-yl)propan-2-ol] (7-NEtppz) and related variants (see Figure 25).120,231−234 These ligands can assemble both Cu(I)Cu(I)Cu(I) and Cu(II)Cu(II)Cu(II) tricopper complexes. The fully reduced tricopper complex can be activated by O2 (as well as H2O2) to form the bis(μ3-oxo)-Cu(II)Cu(II)Cu(III) complex. The latter intermediate was found to mediate facile oxidation of a range of hydrocarbons, including cyclohexane; benzene; hexane; pentane; and the gaseous alkanes CH4, ethane, propane, and butane at room temperature, but with the catalytic efficiency varying with the ligand and the substrate. Significantly, the tricopper complex with the 7-N-Etppz ligand can mediate efficient conversion of CH4 into CH3OH under ambient

multiple turnovers at ambient temperature, albeit very slowly, as expected. 9.2. Tricopper Models

9.2.1. Complexes Constructed with Multidentate Ligands. We present a compilation of the multidentate ligands that have been used for the construction of tricopper complexes, adapted from Maiti et al.,212 in Figure 25. Using these ligands, many tricopper complexes have been assembled, but in most cases, the three coppers are not strongly linked or coupled to one another. The structures of some of these tricopper complexes are illustrated in Figure 26. For example, trinucleating ligands having dipicolylamine or similar groups arranged symmetrically around a central triethyl amine, phenyl, mesityl, or triethylbenzene have been reported.213−219 These tricopper(I) complexes, upon oxidation, produce azide- or hydroxo-bridged dicopper species with the third copper dangling at a distance of about 7.5 Å.214 This conclusion was supported by EPR analysis of the oxygenated complexes, which showed the signal for a mononuclear Cu(II) center and the remaining two Cu(II) centers linked by hydroxo groups.220−222 Magnetic studies revealed a ferromagnetically coupled Cu(II)8599

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selective catalysts or catalyst precursors for the liquid biphasic (MeCN/H2O) peroxidative oxidation of cyclohexane and cyclopentane to the corresponding alcohols and ketones.256 The [Cu3(μ3-O)2] moiety, however, is a weak oxidant and does not perform CH oxygenations.

conditions, just like the pMMO enzyme. Given the significance of this development, we discuss the performance of this catalyst in depth later in this review. 9.2.2. Complexes Assembled by Macrocyclic Ligands. Macrocyclic ligands have also been employed for assembling tricopper complexes. In one of the complexes reported, [Cu3L4(OH)][ClO4]3·2H2O, a single Cu(II) atom is 4.9 and 5.9 Å from a pair of Cu(II) atoms that are hydroxy-bridged and 3.6 Å from each other.235 Interestingly, when a symmetrical macrocycle based on cyclohexyldiamine residues linked through 2,6-dimethylpyridine spacers was used, the resultant tricopper(II) species contained three almost equivalent Cu(II) centers that were strongly ferromagnetically coupled to one another through a double hydroxy bridge (μ3-OH). The trigonal bipyramidal core was made up of the three coppers at the base and the two μ3-hydroxo groups at the apex positions.236 9.2.3. Other Tricopper Systems. Tricopper complexes have also been synthesized by combining a dicopper complex and a monocopper complex of a Schiff base ligand along with an external imidazole237,238 (see Figure 26). Triazacyclononane- (TACN-) based complexes with external ligands such as an imidazole group bridging two copper centers and a phosphate or arsenate ion bridging three copper centers have also been reported. EPR and magnetic susceptibility measurements established the latter tricopper complexes as antiferromagnetically coupled spin-frustrated systems.239,240 Finally, calix[3]dipyrrins have been used to preorganize the coordination positions of three copper ions that are bridged through μ-alkoxo oxygen atoms to form a Cu3O3 hexagonal core.241 Tricopper complexes have also been assembled with the [O3N4]−trisphenoxide−trisimine−amine framework that binds a yttrium ion at the base to bring the three dipicolylamine substitutents, each containing one Cu(I), close to one another. Low-temperature oxygenation of this complex was found to produce a (μ3-O) complex.242 For other reported trinuclear copper complexes, oxygenation first generates a μ-peroxodicopper complex, and upon binding with the third Cu(I) ion, the dicopper complex is converted into the corresponding bis(μ3-O) complex.247−250 Similar hydroxyl-bridged complexes have been reported with different ligands. The structure of one of the compounds was reported to consist of three Cu(II) atoms, each having distorted squarepyramidal geometry, linked by oxo bridges to form an equilateral triangular array.251 The magnetic behavior of this compound corresponds to that of an antiferromagnetically coupled triangular system with J = −114.2 cm−1. Under aerobic conditions, copper-mediated CH oxidation has been reported on trispyridylmethane ligands that can assemble three Cu(II) ions with alkoxide oxygen bridging the copper centers. There is weak antiferromagnetic coupling between the Cu(II) centers due to weak interaction of the dz2 orbitals containing the unpaired electrons.252 Karlin and coworkers have prepared a tricopper(I) complex and its carbonyl and phosphine analogues. Oxygenation at low temperature stabilized a mononuclear Cu(II)-superoxo species and a binuclear peroxo species simultaneously within one complex.212 Monocopper(I) complexes with sterically demanding secondary diamine ligands have also been reported to react with O2 at low temperature to produce tris(μ-hydroxy)-tricopper(II) complexes.253−255 Pombeiro and co-workers reported symmetric self-assembled metal−organic frameworks (MOFs) having μ3-hydroxy-bridged tricopper centers that were found to be remarkably active and

9.3. Dicopper Models

In pMMO, the binuclear site is fully reduced in its resting state, as demonstrated by X-ray absorption and EPR measurements.108 With the appropriate geometry, especially, the Cu··· Cu distance, such binuclear Cu(I) species should react readily with O2, resulting in partial or complete cleavage of the OO bond with concomitant structural changes at the site. However, the Cu···Cu distance is unusually short (ca. 2.6 Å) in pMMO. Also, one of the Cu ions is coordinated by the histidine brace, which is different from the traditional N2N2 ligand structure found in other proteins with binuclear copper active sites. Thus, it is not clear that synthetic models developed for the active sites of hemocyanin, tyrosinase, and laccase are relevant to the dicopper site seen in the X-ray structures of pMMO. In any case, the same strategy as described earlier for the development of tricopper models has also been used to develop dicopper models to mimic the active sites of these enzymes. 9.3.1. Complexes Constructed with Multidentate Ligands. Early studies on the use of binucleating N-donor ligand systems focused on developing binuclear Cu(I) complexes to mimic the reactivity of hemocyanin and monooxygenases. For example, Karlin et al. examined the oxygenation reactivity of a dicopper(I) system supported by the dinucleating m-XYLpy2 ligand (Figure 27). Treatment of this

Figure 27. Oxygenation of a dicopper(I) complex supported by the mXYLpy2 ligand, leading to hydroxylation of the xylyl ligand framework. Adapted with permission from ref 258. Copyright 1984 American Chemical Society.

Cu(I) system with O2 was found to lead to the hydroxylation of a CH bond of the xylyl ligand framework and formation of hydroxy- and phenolate-bridged dicopper(II) compounds.258 Conceivably, this oxygenation reaction might involve a peroxodicopper(II) intermediate species. However, structural details of these intermediate species remained elusive at that time. 9.3.2. Complexes Containing a [Cu 2O 2] 2+ Core Assembled by Reactions of Cu(I) Compounds with O2. A variety of synthetic ligands have been reported to assemble the Cu(II)(μ-(η2:η2)-peroxo)Cu(II) and Cu(III)(μ-O)2Cu(III) cores by reactions of Cu(I) complexes containing the corresponding ligands with O2.249,259−263 Reactions of 2:1 mixtures of these Cu(I) complexes with O2 generally lead to the formation of the corresponding dicopper peroxo, bis(μoxo), or oxo complexes, as depicted in Figure 28. Among these complexes, the ones containing Cu(II)(μ-(η2:η2)-peroxo)Cu(II) and Cu(III)(μ-O)2Cu(III) cores are the best studied biomimetic models. Studies of these biomimetic complexes 8600

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Figure 28. Activation of dioxygen by two Cu(I) centers.

containing the [Cu2O2]2+ cores have provided significant insights to the understanding of copper−dioxygen interactions in various dicopper proteins. For example, a binuclear Cu(II)(μ-(η2:η2)-peroxo)Cu(II) moiety was correctly predicted for O2 binding at the dicopper(I) active site of hemocyanin.264 In 1988, Karlin and co-workers reported the first X-ray structure of a binuclear Cu2O2 complex.265 Oxygenation of Cu(I) complexes of the form [(TPA)Cu(RCN)]+ [TPA = tris(2-pyridylmethyl)amine; RCN = MeCN, EtCN, PrCN] at low temperatures resulted in the isolation of the binuclear [{(TPA)Cu}2(O2)]2+ complex. X-ray crystallography revealed that the [{(TPA)Cu}2(O2)]2+ complex contained a trans-(μ(1,2)-peroxo) ligand bridging two Cu(II) ions with a Cu···Cu distance of 4.36 Å (Figure 29). Although the spectroscopic

Figure 30. Side-on μ-(η2:η2)-peroxodicopper(II) complex supported by tridentate TpziPr ligands. Adapted with permission from ref 267. Copyright 1992 American Chemical Society.

mixture of binuclear complexes containing [Cu(II)2(μ-(η2:η2)peroxo)]2+ and [Cu(III)2(μ-O)2]2+ cores (Figure 31). The relative ratio of the two binuclear complexes was controlled by the steric bulkiness of the supporting ligands as well as reaction conditions. The bis(μ-oxo)dicopper(III) complexes were found to be highly unstable and to decompose rapidly upon warming at temperatures greater than −40 °C, leading to oxidation of the ligand framework and N-dealkylation. The most important feature of this work was the occurrence of core isomerization, which involved a facile interconversion of the two isoelectronic [Cu(II)2(μ-(η2:η2)-peroxo)]2+ and [Cu(III)2(μ-O)2]2+ cores. These findings led to a proposed mechanism for OO bond cleavage and subsequent substrate hydroxylation in copper monooxygenases.271 The bulky, facially capped tridentate tris(pyrazolyl)borate and triazacyclononane ligands have proven to be successful in stabilizing (peroxo)dicopper(II) and bis(μ-oxo)dicopper(III) complexes at low temperatures.267,269,270 However, the latter complexes have limited reactivity toward intramolecular ligand oxidation and intermolecular substrate oxidation. The reactivity of copper−dioxygen species can be tuned through modification of the tridentate TpzR ligand system. Recently, Herres-Pawlis and co-workers demonstrated that μ-(η2:η2)-peroxodicopper(II) species, generated by the oxygenation of the copper(I) complexes of a bis(pyrazolyl)imidazolylmethane ligand system at low temperatures, displayed enhanced reactivity toward the hydroxylation of phenols.272 Other examples of ligand modification include the use of unsymmetrical dinucleating systems that contain two different binding pockets for copper(I) ions. Limberg and co-workers reported on the use of hybrid dinucleating systems for the generation of dicopper(I) complexes in which the two copper centers exhibit different coordination numbers and geometries. However, these hybrid dicopper(I) complexes show different reactivities toward O2.273 To develop copper−dioxygen complexes as synthetically useful oxidants, a suitable ligand design that can generate stable yet reactive metal complexes is essential. Toward this end, the coordination chemistry of bidentate N-donor ligands has attracted increasing attention. For example, Stack and coworkers studied the oxygenation chemistry of Cu(I) complexes supported by a series of diamine ligands.274−278 They suggested that these bidentate diamine ligands can provide a less encapsulated environment that can facilitate substrate access to the Cu2O2 core of the corresponding copper−dioxygen intermediate species. An initial study by the Stack group using N,N,N′,N′-tetramethyl-(1R,2R)-cyclohexanediamine (LTMCHD) led to the isolation of a bis(μ-oxo)dicopper(III) complex [(LTMCHD)2Cu(III)2(O)2]2+.274 However, this bis(μ-oxo)dicopper(III) complex was found to be thermally very robust with limited reactivity toward exogenous substrates. The use of the related peralkylated cyclohexanediamine ligands led to the corresponding bis(μ-oxo)dicopper(III) complexes with only

Figure 29. End-on trans-(μ-(1,2)-peroxo)dicopper(II) complex supported by tripodal tetradentate TPA ligands. Adapted with permission from ref 265. Copyright 1988 American Chemical Society.

properties of the [{(TPA)Cu}2(O2)]2+ complex were found to be different from those reported for oxyhemocyanin,266 a noteworthy feature of the former complex is its ability to undergo reversible O2 binding without the presence of a binucleating supporting ligand. Soon after the report of the crystal structure of [{(TPA)Cu}2(O2)]2+, additional progress in the field was achieved by the successful synthesis and structural characterization of several side-on μ-(η2:η2)-peroxodicopper(II) complexes by research groups led by Kitajima, Moro-oka, Kitagawa, and Tatsumi.267 Oxygenation of the Cu(I) complex [Cu(TpziPr)]2, where TpziPr is the tridentate [HB(3,5-iPr2C3HN2)3]− ligand, was found to lead to the binuclear [{(TpziPr)Cu}2(O2)] complex. (The binuclear [{(TpzR)Cu}2(O2)] (R = Me, iPr) complexes could also be prepared by treatment of the di-μhydroxodicopper(II) complexes {(TpzR)Cu}2(OH)2 (R = Me, iPr) with H2O2 at low temperatures.) The molecular structure of this binuclear complex was determined by X-ray crystallography, which showed the coordination of a side-on μ-(η2:η2)peroxide ion to two Cu(II) centers with a Cu···Cu distance of 3.560(3) Å (Figure 30). The spectroscopic data of this side-on peroxo complex showed a striking similarity to those of the active site of oxyhemocyanin. Moreover, a μ-(η 2 :η 2 )peroxodicopper(II) species is generally accepted to be the active oxidant in binuclear copper enzymes such as tyrosinase and catechol oxidase.266,268 Tolman and co-workers have investigated the reactions of Cu(I) complexes of macrocyclic ligands with O2.269−271 Oxygenation of the Cu(I) complexes [(iPr3-TACN)Cu(CH3CN)](X) (iPr3-TACN = 1,4,7-triisopropyl-1,4,7-triazacyclononane; X = PF6−, SbF6−) at low temperatures yielded a 8601

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Figure 31. Interconversion between [Cu(II)2(μ-(η2:η2)-peroxo)]2+ and [Cu(III)2(μ-O)2]2+ cores. Adapted with permission from ref 270. Copyright 1999 American Chemical Society.

modest oxidation reactivity. Subsequent modifications of the supporting ligands through the incorporation of more flexible 1,2-ethanediamine and 1,3-propanediamine backbones275−279 or the introduction of histamine280,281 and imidazole282 ligation led to a successful modulation of the reactivity of the Cu2O2 core. A [Cu(III)2(μ-O)2]2+−[Cu(II)2(μ-(η2:η2)-peroxo)]2+ equilibrium was observed with the peralkylated diamine complexes.275−278 The oxo-transfer reactivities and hydrogenatom-abstraction reactivities of these Cu2O2 cores toward exogenous substrates such as PPh3, phenols, 1,4-cyclohexadiene, and acridine were also examined. Under aerobic conditions, the μ-(η2:η2)-peroxodicopper(II) species supported by the peralkylated diamine system was shown to exhibit a better oxo-transfer reactivity than its bis(μ-oxo)dicopper(III) counterpart.275−278 In light of these results, Stack et al. proposed a plausible mechanism for the oxidation reactions: initial substrate coordination to one of the Cu(II) ions of the μ(η2:η2)-peroxodicopper(II) core, followed by OO cleavage to give a bis(μ-oxo)dicopper(III) species. The latter species was believed to be an “active oxidant” for the oxidation reactions. However, the role of the bis(μ-oxo) species in this oxidation mechanism was subsequently reinvestigated, as it is not consistent with the results of DFT calculations283 or model studies reported by other research groups.284,285 New insights into the mechanism of oxo transfer from the bis(μ-oxo)dicopper(III) core to exogenous substrates were provided by Chan and co-workers.285 The oxo-transfer reactivity of the known [(LTEED)2Cu(III)2(μ-O)2]2+ (LTEED = N,N,N′,N′-tetraethylethylenediamine) complex276 to PPh3 was re-examined under three different conditions, namely (i) aerobic, (ii) anaerobic, and (iii) limiting O2 conditions. Although the [(LTEED)2Cu(III)2(μ-O)2]2+ complex was found to react readily with PPh3 to generate OPPh3 under an excess-O2 atmosphere (i.e., aerobic conditions), it was surprisingly found to be inert toward oxo transfer under anaerobic conditions in argon. According to kinetics data, the oxo-transfer reaction was found to be first-order in O2. To understand the mechanistic details and to clarify the role of O2 in the oxo-transfer reaction, a detailed investigation of the chemistry of the bis(μ-oxo)dicopper(III) complex was carried out using various spectroscopic methods, as well as kinetic and isotopic-labeling studies. Based on the results of these studies, Chan and co-workers proposed a mechanism for the oxotransfer reaction from the [Cu(III)2(μ-O)2] complex to PPh3 (Figure 32). The initial step (reaction 7 in Figure 32) of the oxo-transfer reaction involves the formation of an O2 adduct (A) of the bis(μ-oxo)dicopper(III) complex. This dioxygen adduct A is believed to be an “active species” that mediates the transfer of one of the bridging oxo atoms in the [Cu(III)2(μ-O)2] moiety to PPh3 (reaction 8 in Figure 32). In other words, the oxygenatom transfer is catalyzed by exogenous O2, and the bis(μ-

Figure 32. Proposed mechanism for oxo transfer from the [(LTEED)2Cu(III)2(μ-O)2] complex to PPh3 through intermediate species A. Adapted with permission from ref 285. Copyright 2004 The Royal Society of Chemistry.

oxo)dicopper(III) complex is reduced to a dicopper(II) mono(μ-oxo) species in the reaction. Three possible structures for the O2 adduct A have been proposed (Figure 33). The oxo-transfer reaction was further examined under limiting O2 conditions [i.e., under conditions of insufficient O2 in the reaction mixtures for the oxidation of all Cu(I) precursors to the bis(μ-oxo) complex]. Under these conditions, a new mixed-valence [Cu(II)Cu(III)(μ-O)2]+ species was observed, together with a facile oxo transfer to PPh3 even under an argon atmosphere. The formation of the mixedvalence species was ascribed to the presence of excess Cu(I) precursor complex in the reaction mixture, which could provide a source of reducing equivalents to partially reduce some of the bis(μ-oxo)dicopper(III) complex already formed in the solution. A possible mechanism for the oxo-transfer reaction under limiting O2 conditions is summarized in Figure 34. Although the stability of the μ-oxo groups renders the [Cu(III)2(μ-O)2]2+ complex inert toward PPh3 under anaerobic conditions, oxo transfer from the corresponding mixed-valence species (B) to PPh3 was found to be facile and thermodynamically more favorable. In fact, these findings are consistent with a mechanism proposed earlier by Chan and co-workers for alkane hydroxylation chemistry mediated by particulate methane monooxygenase (pMMO), in which a mixed-valence bis(μoxo)dicopper(II,III) species is an active intermediate in the enzymatic hydroxylation reaction.121 9.3.3. Complexes Containing a [Cu2O]2+ Core Assembled by Reactions of Cu(I) Compounds with O2. The chemistry of the more reactive mono-(μ-oxo)dicopper(II) complexes bearing the [Cu2O]2+ core has also attracted considerable attention over the past decade.263 Mono-(μoxo)dicopper(II) complexes can be generated by the oxygenation of appropriate Cu(I) compounds containing two Cu(I) centers at low temperatures.286−303 It has been proposed that the oxygenation reaction involves the initial formation of a peroxodicopper(II) species, which undergoes OO bond cleavage and disproportionation to give the corresponding Cu(II)OCu(II) species. In addition to O2, iodosobenzene (PhIO) and NO were also found to be useful oxidizers.296−298 Molecular Cu(II)(μ-O)Cu(II) species are generally temperature-labile, and thus, their identification is based mainly on spectroscopic analysis. Most Cu(II)(μ-O)Cu(II) species have 8602

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Figure 33. Possible structures for O2 adduct A. Adapted with permission from ref 285. Copyright 2004 The Royal Society of Chemistry.

Figure 34. Possible mechanism for oxo transfer from a [Cu(III)2(μ-O)2]2+ species to PPh3 under O2-limited conditions through mixed-valence intermediate species B. Adapted with permission from ref 285. Copyright 2004 The Royal Society of Chemistry.

OH bond (90 kcal mol−1) in the Cu(I)···HOCu(II) intermediate. 9.3.4. System Capable of Catalytic Turnovers. The oxidation of the CH bonds of hydrocarbons by smallmolecule copper complexes with multiple turnovers under ambient conditions is rare. One major obstacle to this endeavor is the stabilization of the copper−dioxygen intermediates under ambient conditions. In general, the Cu(III)(μ-O)2Cu(III) intermediate species are unstable. They undergo dissociation at various stages of catalytic turnovers. As a consequence, most biomimetic systems yield only a single turnover of exogenous substrate oxidation. In native enzymes, the copper−dioxygen intermediates are protected within the hydrophobic cavities of the protein core. Recently, Guilard and co-workers reported that it is possible to stabilize a copper−dioxygen intermediate species in a porous silica framework, without oxidation of the supporting ligand or exogenous substrates.308 Following this strategy, Liu et al. immobilized the bis(μ-oxo) species [{Cu(III)Imph}2(μ-O)2]2+ on mesoporous silica nanoparticles (MSNs) and used this system to study the catalytic conversion of toluene to benzyl alcohol and to benzaldehyde.211 The catalytic system consisted of Cu(II)Imph, a Cu(II) complex of the tripodal tridentate histidine-like ligand bis(4-imidazolyl methyl)benzylamine (Imph), immobilized in the nanochannels of the MSN. The immobilized Cu(II)Imph complex in MSN was first activated by reduction with ascorbate to yield the corresponding Cu(I) species. Subsequent oxygenation led to the immobilized bis(μ-oxo)dicopper(III) species [{Cu(III)Imph}2(μ-O)2]2+. The bis(μ-oxo) species in this system was found to be reactive and capable of catalyzing the aerobic oxidation of the aliphatic CH bond of toluene to yield benzyl alcohol and subsequently benzaldehyde. No overoxidation to benzoic acid was observed. It is believed that the nanochannels of MSN provide proper anchorage sites for oxygenation of two monovalent Cu(I)Imph complexes to form the [{Cu(III)Imph}2(μ-O)2]2+ intermediate species. The confined space and geometry constraints within the nanochannels protect the binuclear copper catalyst from dissociation

been reported to be relatively reactive, probably because of an electron-rich oxo atom.263 They are reactive toward CO2 and H2O, yielding the corresponding dicopper(II) μ-carbonato and bis(μ-hydroxo) species, respectively.286−289,296−299 It has also been reported that an intermediate Cu(II)(μ-O)Cu(II) species could undergo nucleophilic attack on the keto group of a binucleating ligand system to yield a gem-diolate product.304,305 In addition, Cu(II)(μ-O)Cu(II) complexes can mediate direct oxo transfer to PPh3, as well as oxidative coupling of phenols (refs 293, 296−298, 300, and 304−306). Even though the reactivities of Cu(II)(μ-O)Cu(II) complexes have been reported for almost four decades,290 investigations of their reactivities toward the oxidation of CH bonds are rare. A mono-(μ-oxo)dicopper(II) species has been reported to be a reactive intermediate responsible for the oxidation of CH4 to CH3OH on the surface of a Cu-exchanged zeolite (Cu-ZSM-5) at temperatures of 100−200 °C.26,195,307 However, it was found that only a small fraction of the total copper sites in the Cu-ZSM-5 zeolite were involved in the oxidation.23 Results of spectroscopic analysis and computational studies have suggested that the oxygenation of Cu-ZSM5 leads to the initial formation of a μ-(η2:η2-peroxo)diopper(II) species, followed by reduction of the peroxo O O bond by spectator Cu(I) sites to generate a CuII(μ-O)CuII intermediate species. Apparently, the first of the two O atoms is reduced to form water, and the Cu(II)(μ-O)Cu(II) species thus formed is responsible for the oxidation chemistry. Although the Cu(II)(μ-O)Cu(II) species appears to be inert (at least at room temperature), results of additional computational analysis have suggested that this mono-(μ-oxo) species can undergo rearrangement to give the more reactive Cu(II) oxyl (CuI···•OCuII) or Cu(III) oxene (CuI OCuIII) species.26 The latter species can abstract a hydrogen atom from a CH bond of an organic substrate and then undergo rebound of the •OH species with the corresponding alkyl radical to form an alcohol product. Apparently, the hydrogenatom-abstraction process is driven by the formation of a stable 8603

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range of hydrocarbon substrates with tBuOOH or H2O2 in the presence of O2, yielding a mixture of the respective alcohols and ketones (or aldehydes).315−317 Interestingly, in the case of the [(tmima)2Fe2(μ-O)(μ-OAc)](ClO4)3 complex, the CH oxidation reactivity could be enhanced by replacing the μ-OAc ligand with terminal H2O ligands.318 Similar carboxylatebridged MnOMn complexes have also been found to be catalysts for CH oxidation.319,320 Based on the results of mechanistic studies of the oxidation of cyclohexane by H2O2/O2, a free-radical mechanism involving an alkyl hydroperoxide intermediate was proposed by the Fish group for the FeOFe model systems. It is believed that a highvalent iron−oxo species, formed upon addition of the oxidant to the respective FeOFe complex, can abstract a hydrogen atom from a hydrocarbon substrate to generate a carbon radical. This carbon radical is subsequently trapped by O2 to form an alkyl hydroperoxide intermediate, which is eventually converted to the corresponding alcohol and ketone (or aldehyde) by the FeOFe complex/oxidant in the reaction mixture. A similar mechanism has also been proposed for the model systems with tBuOOH and O2 as oxidants. It is believed that the oxidation reactions in the latter systems might proceed through a tBuOO• radical that initiates subsequent formation of carbon radicals. Utilizing the biomimetic complexes [Fe2O(η1-H2O)(η1OAc)L2]3+ {L = tris[(2-pyridyl)methyl]amine (TPA) or bis[(2-pyridyl)methyl][2-(1-methylimidazolyl) methyl]amine (BPIA)} and an appropriate surfactant, Fish and co-workers have also reported the first example of hydrocarbon oxidation by tBuOOH/O2 in water.321−323 In addition to using a suitable surfactant, one can also carry out the biomimetic hydrocarbon oxidation reactions in an aqueous medium by embedding the catalysts in surface-derivatized silica.323 Other examples of the iron-mediated oxidation of alkanes or arenes by O2, alkylhydroperoxides, or H2O2, in the presence of an appropriate reductant, have also been reported in the literature.324−329 However, the involvement of high-valent diiron−oxo species has not been observed in these oxidation reactions. Indeed, their reactivity resembles that of Gif systems.330 Apparently, these iron-based oxidation systems react by a radical mechanism or through a mononuclear, highvalent iron intermediate species. Treatment of the carboxylate-bridged (μ-oxo)diiron(III) complex [{(MBEN)Fe}2(μ-O)(μ-OAc)]− with H2O2 or O2 in the presence of excess ascorbate as a reductant, leads to hydroxylation of an aryl CH bond of the MBEN ligand (Figure 35).331 It is noteworthy that hydroxylation of a CH bond on the supporting ligands has also been observed in a number of biomimetic copper models.332,333 A few synthetic analogues for the high-valent Fe(μ-O)2Fe diamond core have been developed to understand the details of the O2 activation and CH hydroxylation process in the MMOH unit of sMMO. A general method for the preparation of high-valent bis(μ-oxo)diiron complexes involves the addition of H2O2 to appropriate diiron(II) or diiron(III) precursor compounds. Que and co-workers reported the isolation of the first high-valent nonheme iron−oxo complexes [Fe2(μO)2L2]3+ [L = tris(2-pyridylmethyl)amine or its methylated derivatives] by oxidation of the corresponding mono-(μoxo)diiron(III) precursor complexes with H2O2 at low temperatures.334,335 The [Fe2(μ-O)2L2]3+ complexes were shown to be potent one-electron oxidants: They readily oxidized 2,4-di-tert-butylphenol to the corresponding phenoxyl

after the oxo-transfer reaction. Moreover, a new bis(μ-oxo) species can be regenerated upon reaction with the next O2 molecule. This work also led to further understanding of CH bond oxidation by biomimetic copper complexes.211 The most notable feature of this catalytic system is its capability to perform an exogenous substrate oxidation with multiple turnovers under ambient conditions. Moreover, this heterogeneous copper system can catalyze controlled oxidation of toluene by O2 to benzyl alcohol and benzaldehyde with multiple turnovers at room temperature without the addition of reducing equivalents other than the small amounts required to initiate the process [reduction of Cu(II) to Cu(I) in the beginning of the reaction]. The specified system is a catalytic system with self-sustaining reactivity that does not require sacrificial reductants to drive the catalytic turnover. 9.4. Nonheme Diiron Models

The development of efficient functional models for sMMO has been a challenging task for bioinorganic chemists. One challenge is the generation of a high-valent bis(μ-oxo)diiron(IV) intermediate that can mediate the controlled hydroxylation of exogenous substrates instead of the ligand framework. Another challenge is the regeneration of the diiron(II) precursor complex after oxo transfer. Typically, a diiron(III) species is generated after oxo transfer from the high-valent bis(μ-oxo)diiron(IV) species to a substrate molecule. To sustain the catalytic cycle, addition of an appropriate reducing agent is necessary to regenerate the diiron(II) precursor compound, but this will also reduce the diiron(IV) active species. To date, only a few molecular systems that resemble the hydroxylation reactivity of the nonheme diiron enzyme have been reported in the literature. In this section, we summarize the progress achieved in the past three decades on the development of nonheme diiron models that can mediate the oxidation of organic substrates using O2 or oxygen-atomdonor compounds. A large number of binuclear iron complexes have been reported as synthetic analogues for the active site of the hydroxylase subunit of sMMO.309−313 Various types of supporting ligands with appropriate steric bulkiness and flexibility have been employed to provide suitable binucleating platforms for the binding of two iron centers without the formation of undesirable polynuclear species. Most of these binuclear iron complexes serve as structural models that resemble the structures and spectroscopic properties of the diiron intermediate species proposed at different stages of the catalytic cycle at the hydroxylase (MMOH) active site. Attempts to develop functional models of the nonheme diiron site of the sMMO hydroxylase were reported by several laboratories even before the X-ray structure of the enzyme appeared in 1993.47 Kitajima et al. demonstrated that a carboxylate-bridged diiron(III) complex, [(Tpz)2Fe2(μ-O)(μOAc)2] [Tpz = tris(pyrazolyl)borate], could mediate the oxidation of exogenous hydrocarbon substrates by O2 in the presence of acetic acid and zinc powder,314 although its oxidation reactivity was low [turnover number (TON) ≈ 2/30 h for cyclohexane and TON ≈ 4/30 h for adamantane). Fish and co-workers have also shown that the carboxylated-bridged FeOFe complexes [(bipy)2Fe2(μ-O)(μ-OAc)2Cl2] (bipy = 2,2′bipyridine), [(bipy)2Fe4(μ-O)2(μOAc)7](ClO4), and [(tmima)2Fe2(μ-O)(μ-OAc)](ClO4)3 {tmima = tris[(1-methylimidazol-2-yl)methyl]amine} could mediate the oxidation of a 8604

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Lee and Lippard synthesized the carboxylate-bridged diiron(II) complex [Fe2(μ-O2CArTol)2(O2CArTol)2(N,N-Bn2en)2] [ArTol = 2,6-di(p-tolyl)phenyl, N,N-Bn2en = N,N-dibenzylethylenediamine], which resembles the structure of the diiron(II) center of the MMOHred species.337,338 Exposure of this diiron(II) complex to O2 under ambient conditions leads to isolation of a bis(μ-hydroxo)diiron(III) complex, [Fe2(μOH)2(μ-O2CArTol)(O2CArTol)3(N,N-Bn2en)(N-Bnen)] (NBnen = N-benzylethylenediamine), and benzaldehyde (Figure 37). The latter diiron(III) complex can be considered as a

Figure 35. Treatment of diiron(III) complex [{(MBEN)Fe}2(μ-O)(μOAc)]− with H2O2 or O2 in the presence of excess ascorbate, leading to hydroxylation of the supporting ligand. Adapted with permission from ref 331. Copyright 1996 VCH Verlagsgesellschaft GmbH.

radical, as the Fe2(μ-O)2 complexes were reduced to the corresponding mono-(μ-oxo)diiron(III) precursor compounds (Figure 36). In addition, they could also oxidize cumene to

Figure 37. Oxygenation of diiron(II) complex [Fe2(μ-OH)2(μO2CArTol)(O2CArTol)3(N,N-Bn2en)(N-Bnen)], leading to the isolation of a bis(μ-hydroxo)diiron(III) complex and benzaldehyde. Adapted with permission from ref 337. Copyright 2001 American Chemical Society.

synthetic analogue of the MMOHox species. One notable feature of this oxygenation reaction is the formation of benzaldehyde (in ∼60% yield), arising from oxidative Ndealkylation of a metal-bound N,N-Bn2en diamine ligand. These workers proposed that a high-valent bis(μ-oxo)diiron(IV) species might be involved in this transformation. It is interesting to note that the oxidative N-dealkylation of metalbound ligands has also been observed in di(μ-oxo)dicopper(III) systems.332,333 A diiron(II) complex supported by a ligand with two parallel malonate binding sites was prepared by Limberg and coworkers339 (Figure 38). This diiron(II) complex could activate O2 through the cooperative action of both iron centers to yield a high-valent intermediate species bearing (oxido)iron(IV) units. It is proposed that the latter intermediate is an active species leading to subsequent hydroxylation of the ligand. Although high-valent iron−oxo complexes have been suggested to be the active species responsible for hydroxylation of CH bonds, the structural basis of their reactivity could be subtle. In 2007, the group of Suzuki reported on the oxygenation reactivities of the two carboxylate-bridged diiron(II) complexes [Fe2(LPh4)(μ-O2CR)]2+ (R = Ph3C and Ph), where LPh4 is a binucleating histidine-like ligand.340 These two iron complexes exhibit different reactivities toward O2, depending on the substituent of the bridging carboxylate ligand: Oxygenation of [Fe2(LPh4)(μ-O2CCPh3)]2+ leads to the formation of a (peroxo)diiron(III) intermediate, which mediates regioselective hydroxylation of a phenyl substituent on the LPh4 ligand, whereas [Fe2(LPh4)(μ-O2CPh)]2+ exhibits

Figure 36. Synthetic models with a bis(μ-oxo)diiron(III,IV) diamond core that can mediate the oxidation of 2,4-di-tert-butylphenol and cumene. Adapted with permission from ref 336. Copyright 1997 American Chemical Society.

yield cumyl alcohol and α-methylstyrene. Que et al. proposed a mechanism for the latter hydroxylation and desaturation reactions. Presumably, the highly reactive [Fe2(μ-O)2L2]3+ complex abstracts a hydrogen atom from an α-CH bond of cumene, leading to the formation of a cumyl radical. Subsequent reaction of the cumyl radical with the [Fe2(μO)2L2]3+ complex affords cumyl alcohol and α-methylstyrene.336 8605

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In addition to O2, the use of oxygen-atom-donor compounds such as iodosyl arenes, alkyl hydroperoxides, and mchloroperbenzoic acid (m-CPBA) for the oxidation of organic substrates has also been examined.348−353 Using a N2O2-type binucleating ligand, Caradonna and co-workers synthesized a series of binuclear iron complexes separately containing Fe(II)Fe(II), Fe(II)Fe(III), and Fe(III)Fe(III) cores. Both the diferrous Fe(II)Fe(II) and mixed-valence Fe(II)Fe(III) complexes were found to be active catalysts toward the oxidation of hydrocarbon and sulfide substrates by PhIO.348 Further studies using the diferrous Fe(II)Fe(II) complex as a catalyst and 2-methyl-1-phenylprop-2-yl hydroperoxide (MPPH) as an oxygen-atom donor suggested that oxygenatom transfer to substrates involves the heterolytic cleavage of the peroxide OO bond, evidence that excludes the involvement of hydroxyl radicals in the oxo-transfer reactions.349−351 Latour and co-workers reported that treatment of a mixed-valence diiron(II,III) system with oxygen-atom-donor compounds such as iodosyl arene, H2O2, and m-CPBA leads to intramolecular hydroxylation of the ligand framework.352,353 It is noted that the hydroxylation reactions occurred through different reaction mechanisms depending on the oxygen-atom donors used. Using a pyridine-based binucleating system, the group of Kodera synthesized a mono-(μ-oxo)diiron(III) complex, [Fe2(6-HPA)(μ-O)(H2O)2]4+ (6-HPA = 1,2-bis[2{bis(2-pyridylmethyl)amino-methyl}-6-pyridyl]ethane), which could mediate the epoxidation of alkenes with H2O2 as an oxidant.354 The results of mass spectrometric analysis suggested that the epoxidation reactions occur through a dioxo-(μoxo)diiron(IV) intermediate. The latter is proposed to be an active species responsible for epoxidation of alkenes.

Figure 38. Diiron(II) complex that can activate O2 through the cooperative action both iron centers to form high-valent (oxido)iron(IV) species. Adapted with permission from ref 339. Copyright 2008 John Wiley & Sons.

reversible O2 binding with no observed hydroxylation reactivity (Figure 39). Dendrimers are highly branched molecules that have been used in some biomimetic studies for mimicking the hydrophobic sheaths surrounding the metal active sites of some metalloproteins.341−346 The use of a dendrimer-appended terphenyl carboxylate system led to the successful synthesis of diiron(II) complexes with the general formula [Fe2([G-3]CO2)4(4-RPy)2], where [G-3]CO2− is a third-generation dendrimer-appended terphenyl carboxylate ligand and 4-RPy is a pyridine derivative (Figure 40).347 It is anticipated that dendritic encapsulation can enhance the stability of those transient oxygenation intermediates and, hence, facilitate the studies of their structures and reactivity. Exposure of the [Fe2([G-3]-CO2)4(4-RPy)2] complexes to O2 at low temperatures led to the identification of mixed-valence diiron(II,III) intermediates that underwent subsequent oxidation of exogenous organic substrates. Results of spectroscopic analysis and theoretical prediction led Lippard and co-workers to propose a unique FeII(μ-(η2:η1)-superoxo)FeIII core structure for these intermediates.

10. AN EFFICIENT CATALYST FOR ROOM-TEMPERATURE METHANE OXIDATION: A BIOINSPIRED TRICOPPER CLUSTER COMPLEX In 2013, Chan et al. reported that the Cu(I)Cu(I)Cu(I)(7-NEtppz) tricopper complex described earlier could be activated by O2 to mediate the facile oxidation of CH4 to CH3OH at room temperature.120 Thus, the Cu(I)Cu(I)Cu(I)(7-N-Etppz) tricopper complex represents the first biomimetic model of the putative tricopper cluster site in pMMO. As expected, without a

Figure 39. Formation of (μ-peroxo)diiron(III) species that can undergo subsequent ligand hydroxylation or reversible O2 binding. Adapted with permission from ref 340. Copyright 2007 American Chemical Society. 8606

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Figure 40. Oxygenation of a diiron(II) complex encapsulated by a dendritic ligand environment, leading to formation of a unique FeII(μ-(η2:η1)superoxo)FeIII species. Adapted with permission from ref 347. Copyright 2008 American Chemical Society.

“sacrificial” reductant, the chemistry is only stoichiometric; that is, only one CH3OH is produced per tricopper complex. However, upon addition of a small amount of H2O2 to the system, it is possible to eliminate the remaining oxidizing equivalents in the tricopper cluster after O-atom transfer to the CH4 using two reducing equivalents from a molecule of H2O2. In this manner, the Cu(I)Cu(I)Cu(I)(7-N-Etppz) complex is regenerated, meaning that an oxidation catalyst with the capability for multiple turnovers is now in hand. To elaborate, in the presence of sufficient concentrations of both O2 and H2O2, the Cu(I)Cu(I)Cu(I)(7-N-Etppz) complex is activated by O2 to produce the bis(μ3-oxo)- Cu(II)Cu(II)Cu(III) intermediate containing the hot [Cu3O2]3+ core. Following singlet-oxene transfer to CH4 to produce CH3OH, the catalyst loses two oxidizing equivalents to give the Cu(I)Cu(II)(μ-oxo)Cu(II) species. Interestingly, the [Cu3O]3+ core in the spent catalyst has sufficient residual oxidizing power to accept two reducing equivalents from a H2O2 molecule in the solution. This chemistry appears to be inner-sphere, with the H2O2 forming a hydrogen bond with the bridging μ-oxo in the spent catalyst. Following transfer of two electrons to the [Cu3O]3+ core, with the assistance of the two protons from H2O2, O2 is produced, and a H2O molecule is released from the tricopper cluster to regenerate the Cu(I)Cu(I)Cu(I) catalyst. This catalytic cycle of the tricopper cluster complex is illustrated at the top of Figure 41. Because there is no net consumption O2 in the turnover cycle (the molecule of O2 consumed in activation of the tricopper catalysis is replenished during the regeneration of the catalyst), the net overall reaction is CH4 + H2O2 → CH3OH + H2O, namely, the oxidation of CH4 by H2O2, albeit indirectly. To accomplish this chemistry, the catalyst harnesses the oxidizing power of a molecule of O2 to transfer one of the O atoms to the CH4 and

uses H2O2 to regenerate the O2 and the tricopper cluster for another round of catalysis. The chemistry sounds convoluted, but it works, beautifully illustrating the intricacies of how a catalyst can overcome the kinetically challenging step. It is significant that the CH4 oxidation mediated by the tricopper catalyst that we just described, which operates in the presence of O2 and relatively low levels of H2O2 (0.1 M or lower), is fundamentally different from the mechanism of CH4 oxidation reported by Hutchings et al.198 over the Fe-ZSM-5 catalyst in aqueous H2O2 solution (0.5 M), where the initial product was found to be methyl hydroperoxide (CH3OOH) formed at the [Fe2O2]2+ sites in the framework, and subsequently, an iron-bound methoxy species is thought to be formed at the iron site upon the loss of an •OH radical from the CH3OOH. With this system, H2O2 is the oxidant, whereas with the tricopper catalyst, O2 is the oxidant, and H2O2 is merely used as a reductant to regenerate the catalyst. As expected, aside from CH3OH, other CH4 oxygenates (HCHO and HCOOH) are produced at high levels with the Fe-ZSM-5 catalyst, although the introduction of Cu into the Fe-ZSM-5 seems to significantly improve the CH3OH selectivity. In contrast, no CH4 overoxidation is observed with the tricopper catalyst. As discussed earlier, the formation of an alkyl hydroperoxide intermediate was also invoked by Fish et al.316 in their mechanistic studies of alkane functionalization by FeOFe models in the presence of high concentrations of H2O2. The above chemistry was discovered when various tricopper cluster complexes were being developed as oxidation catalysts for the controlled oxidation under ambient conditions of various hydrocarbons, including the conversion of cyclohexane to cyclohexanol and cyclohexanone, benzene to phenol and benzophenone, and small alkanes to their corresponding alcohols and ketones.100,231,232,355 In these studies, H2O2, 8607

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product turnover numbers can be obtained when the turnover is undertaken in the presence of both O2 and H2O2, with one molecule of O2 being consumed for activation of the tricopper cluster catalyst and one molecule of H2O2 being expended to drive the catalytic turnover of the catalyst. Multiple turnovers, indeed, were observed with the CuICuICuI(7-N-Etppz) catalyst when the CH4 oxidation was carried out in the presence of O2 and H2O2.120 However, only a small turnover number (TON) was obtained, even though the rate of CH3OH formation was similar to the rates of oxidation of other substrates, including both liquid and gaseous hydrocarbons. For example, a maximum TON of only ∼6 was obtained when 20 equiv of H2O2 was used to initiate the turnover. At higher concentrations of H2O2, the TON decreased precipitously.233 This observation suggested that, with increasing H2O2, a H2O2-dependent process occurs that competes with the productive CH4 hydroxylation. To confirm this reaction, the CH4 oxidation was repeated in aliquots of 20 equiv of H2O2, with each increment added after the previous aliquot had been consumed. Indeed, the TON increased progressively and proportionally with each successive 20-equiv aliquot of H2O2. On the basis of these observations, it was concluded that, because of the limited solubility or low concentration of CH4 in the solution, the activated tricopper cluster could be aborted by reduction with H2O2 if the latter concentration exceeded a certain threshold. This scenario holds when kabortive[H2O2] ≫ kOT[CH4], where kOT denotes the second-order rate constant for O-atom transfer to the CH4 substrate and kabortive is the corresponding rate constant for reduction of the hot activated tricopper cluster by H2O2 to abort the cycle. The abortive cycling of the tricopper catalyst is compared with the productive cycling in Figure 41. To overcome the limited solubility of CH4 in the solvent system used for the catalysis, the Cu(I)Cu(I)Cu(I)(7-NEtppz) complex was recently immobilized in MSN to reformulate the tricopper complex as a quasi-heterogeneous catalyst.356 Selective conversion of CH4 into CH3OH was achieved, and the conversion proceeded at room temperature with high catalytic efficiencies, high TONs, and excellent product yields. With the best-performing formulation, CuEtp@ AlMSN30-ex (see Figure 42c), namely, the Cu(I)Cu(I)Cu(I)(7-N-Etppz) complex immobilized in Al-MSN30-ex, we obtained a limiting TON of 171.2 and a conversion yield of 17.4%, when the catalytic turnover was initiated with 200 equiv of H2O2, for an overall catalytic efficiency of 86%. This performance is quite remarkable. This strategy takes advantage of the oversolubility of CH4 and O2 in nanoconfined spaces.357 It has now been established that the solubilities of nonpolar gases such as N2, O2, CH4, and CO2 are much higher in solvents confined in the mesopores/nanopores of nanoparticles. The interactions of these gas molecules with the nanoporous solid or with the solvent are significantly weaker than the interactions of the solvent molecules with the walls of the confining host framework. The stronger solvent−solid interactions create regions of low solvent density in the confined solvent. The solubility can be as high as several hundred times higher than that expected from the bulk solubility, enhancing gas intakes. In addition to the significantly enhanced local concentration of nonpolar gases, the distribution of substrates and cosubstrates between the solvent and the nanomaterial also leads to high turnovers in the pore-confined catalytic system.

Figure 41. (Top) Productive cycling and (bottom) abortive cycling in the oxidation of CH4 by O2 mediated by the [Cu(I)Cu(I)Cu(I)(7-NEtppz)]+ complex in the presence of H2O2. L denotes the organic ligand 7-N-Etppz used to construct the tricopper cluster complex. Adapted with permission from ref 356. Copyright 2016 The Royal Society of Chemistry (London).

rather than O2, was used to activate the Cu(I)Cu(I)Cu(I)(L) tricopper catalysts, where L represents various supporting ligands used to assemble the tricopper complexes. In every case, the rate-determining step in the catalytic cycle is the reduction of the spent catalyst to regenerate the Cu(I)Cu(I)Cu(I) catalyst; the transfer of the oxene from the activated tricopper cluster to the substrate is always extremely facile under typical substrate concentrations. Accordingly, the TOF of the catalyst is proportional to the concentration of H2O2 in the solution and essentially independent of the substrate. The TOFs typically ranged from 5 × 10−2 to 10−1 s−1 when 200 equiv of H2O2 was used to drive the catalytic turnover. These are reasonable TOFs for the selective oxidation of aliphatic hydrocarbons (sp3 carbons) at room temperature. With the exception of CH4, the catalytic efficiencies were also found to be very high, approaching 100%; that is, one substrate molecule is oxidized for every three molecules H2O2 consumed. This approach is, of course, wasteful of H2O2. Three times higher 8608

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Figure 42. Time course of the TONs for the CH4 oxidation reaction catalyzed by each of the two tricopper complexes immobilized on two types of MSNs at room temperature. The catalytic turnover was initiated with 200 equiv of H2O2: (a) CuEtp@MSN-TP, (b) CuEthp@MSN-TP, (c) CuEtp@AlMSN30-ex, and (d) CuEthp@AlMSN30-ex. In each case, the MSN sample was well-dispersed in O2-free acetonitrile before 100 mL of CH4 and 10 mL of O2, each at a pressure of 2.44 atm, were injected into the sample. After the mixture had been stirred for 10 min, an aliquot of 200 equiv of H2O2 solution (35%) was finally added. The TONs of CH3OH are expressed in terms of the number of moles of CH3OH formed per mole of tricopper complex mediating the catalytic conversion of CH4 into CH3OH. Reproduced with permission from ref 356. Copyright 2016 The Royal Society of Chemistry (London).

Figure 42 summarizes the TONs for CH4 oxidation mediated by the Cu(I)Cu(I)Cu(I)(7-N-Etppz) complex, as well as by [Cu(I)Cu(I)Cu(I)(7-N-Ethppz)]+ immobilized in two different types of MSNs.356 The ligand 7-N-Ethppz represents the multidentate trinucleating ligand 3,3′-(1,4-diazepane-1,4-diyl)bis[1-(4-ethylhomo-piperazin-1-yl)propan-2-ol], which differs from 7-N-Etppz in the replacement of the six-membered piperazine ring in the latter by the seven-membered homopiperazine ring. These heterogeneous formulations of the tricopper complexes can be seen to be highly active toward CH4 oxidation. Dramatically higher TONs were obtained when the Cu(I)Cu(I)Cu(I)(7-N-Etppz) complex was reformulated as a heterogeneous catalyst compared to when it was used as a homogeneous catalyst for CH4 oxidation in an organic solvent. As a homogeneous catalyst, a maximum TON of only 6.5 was observed when the catalytic turnover was initiated by 20 equiv of H2O2 in acetonitrile and essentially no CH3OH was detected with 200 equiv of H2O2. In the case of the [Cu(I)Cu(I)Cu(I)(7-N-Ethppz)]+ complex, no CH4 oxidation was observed when this complex was used as a homogeneous catalyst. However, CH4 oxidation was observed for the heterogeneous formulation, even though the TONs were dramatically lower than for the Cu(I)Cu(I)Cu(I)(7-N-Etppz) catalyst. Thus, the Cu(I)Cu(I)Cu(I)(7-N-Etppz) complex is a much better catalyst than the Cu(I)Cu(I)Cu(I)(7-N-Ethppz) complex. This dramatic difference between the two tricopper catalysts reflects the smaller hydrophobic pocket at the base of the copper triad in the case of the Cu(I)Cu(I)Cu(I)(7-N-Etppz) complex (Figure 43). This smaller hydrophobic cleft is more conducive to effective binding of the small and symmetric CH4 for conversion into methanol. This result underscores the importance of substrate recognition and binding in the catalyst design to optimize the performance of the catalyst for the hydrocarbon oxidation. By design, the substrate-binding site is

Figure 43. (Left) CPK and (right) ball-and-stick models of the bis(μ3oxo)-Cu(II)Cu(II)Cu(III)(7-N-Etppz) trinuclear cluster complex formed by activation of the Cu(I)Cu(I)Cu(I)(7-N-Etppz) complex by O2. Also shown is the small hydrophobic cleft, where CH4 binds at the base of the copper triad. Adapted with permission from ref 120. Copyright 2013 John Wiley & Sons.

built into the tricopper complex. This feature of the biomimetic catalyst is distinct from the design in the enzyme, where the site at which the tricopper cluster is activated and the site at which the substrate binds (the aromatic box in pMMO) are quite distinct. For oxene transfer to take place in the enzyme, the substrate must be brought closer to the activated tricopper cluster by allosteric protein interactions or by conformational switching. Interestingly, the Cu(I)Cu(I)Cu(I)(7-N-Etppz) complex catalyzes the oxidation of CH4 to CH3OH without overoxidation. It also mediates the conversion of ethane into ethanol, as well as the conversion of propane to 2-propanol, without overoxidation. n-Butane, n-pentane, and n-hexane are converted into their secondary alcohols and the corresponding 8609

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technologies and employment for young scientists in many fields, especially in chemistry, chemical engineering, and biotechnology. We end this review on this optimistic note.

ketone, and cyclohexane is oxidized to cyclohexanol and cyclohexanone. Earlier, we described Cu-ZSM-5 and Cu-MOR materials that show good results toward CH4 oxidation to CH3OH at temperatures near 200 °C, where the active species have been shown to be [Cu2O]2+ and [Cu3(μ-O)3]2+ clusters, respectively. Both of these are copper−oxo clusters that exhibit the apparent capability to abstract a hydrogen-atom from CH4 under these conditions. These species are distinct from the Cu(II)Cu(II)(μO)2Cu(III) and [Cu3(μ-O)2]3+ intermediates obtained by O2 activation of a Cu(I)Cu(I)Cu(I) tricopper cluster described above. Compared with the [Cu2O]2+ and [Cu3(μ-O)3]2+ clusters, the [Cu3(μ-O)2]3+ species contains an extra oxidizing equivalent and can be expected to be more reactive toward CH4 oxidation. In fact, the activated tricopper cluster mediates efficient CH4 hydroxylation even at room temperature.

AUTHOR INFORMATION Corresponding Author

*Tel. : +886-2-2789-8654. Fax: +886-2-2783-1237. E-mail: [email protected]. ORCID

Sunney I. Chan: 0000-0002-5348-2723 Author Contributions ‡

V.C.-C. W. and S.M. contributed equally to the writing of this review. Notes

The authors declare no competing financial interest.

11. SUMMARY AND OUTLOOK: PROSPECTS FOR A METHANOL ECONOMY Substantial progress has been made in recent years toward understanding biological CH4 oxidation. Aside from delineating the active sites and their mechanisms of action in both sMMO and pMMO, attempts have also been made to develop biomimetic catalysts to accomplish this chemistry in the laboratory. These efforts have culminated in the successful development of the first biomimetic catalyst capable of mediating CH4 oxidation efficiently under ambient conditions. With the tricopper cluster catalyst, the CH4 oxidation is selective; that is, there is no overoxidation of the hydrocarbon. Interestingly, this exercise has led to the discovery of novel chemistry as well. To optimize the performance of the biomimetic oxidation catalyst, the tricopper complex was reformulated as a heterogeneous catalyst by immobilizing the tricopper complex in MSN. This formulation of the catalyst functions essentially like an enzyme, with high turnover numbers and with excellent catalytic efficiencies and product yields. In addition, the formulation is robust, and the catalyst is reusable. With the physiochemical principles for designing an efficient room-temperature catalyst now in place, it is perhaps now possible to begin to consider developing a catalytic system capable of CH4 oxidation on an industrial scale based on these concepts. The successful development of a robust heterogeneous catalyst capable of mediating efficient CH4 oxidation to CH3OH and other components of natural gas to their corresponding alcohols will pave the way toward the eventual replacement of petroleum as the source of chemical feedstocks in the chemical industry. The developed process will be much more cost-effective and environmentally friendly because of the abundant presence of CH4, which is also a potential greenhouse gas. Many technical obstacles remain, of course. However, this is an important step toward realizing the methanol economy proposed by Nobel laureate George Olah.7 The methanol economy is a suggested future economy in which methanol replaces petroleum as a means of energy storage, ground transportation fuel, and raw materials for synthetic hydrocarbons and other chemical feedstocks and products. From CH3OH, new methods can be developed for the manufacturing of fuels, fine chemicals, fibers, plastics, advanced materials, pharmaceuticals, and foodstuff that will be cheaper, greener, and more energy-efficient with lower carbon footprints on the environment. This will revitalize the chemical industry globally, creating intellectual opportunities for new science and

Biographies Vincent Wang obtained his B.S. and M.S degrees from National Taiwan University. After working with Professor Sunney Chan for several years studying the chemistry of CH4 oxidation, he joined the Fraser Armstrong group at the University of Oxford as a D.Phil. student to study the chemistry of CO2 reduction. Upon completion of his D.Phil. studies, Vincent moved to the University of British Columbia and worked with Professor Curtis Berlinguette developing novel materials for CO2 reduction. Also, he spent several months with Dr. Tiow-Gan Ong at Academia Sinica, Taiwan, investigating the mechanisms of photoredox catalysis reactions. Most recently, he joined the Leif Hammarström group at Uppsala University. Suman Maji grew up in India and completed his Ph.D. degree in 2008 in the field of bioinorganic chemistry from Indian Institute of Technology Kanpur. He then joined the Institute of Chemistry at Academia Sinica, Taiwan, for postdoctoral research with Professor Sunney Chan. He is currently working as an Assistant Professor at Lovely Professional University, Punjab, India. His research interests are focused on the biomimetic modeling of metalloproteins. Peter Chen obtained his Ph.D. degree in 2001 under Professor Ru-Jen Cheng at National Chung Hsing University, Taiwan, and studied as a postdoctoral scholar with Professor Sunney I. Chan from 2001 to 2007 at the Institute of Chemistry at Academia Sinica, Taiwan. He then spent two years as a postdoctoral fellow, working with Professor Gary W. Brudvig at Yale University. In 2009, he became Assistant Professor of Chemistry at Taiwan Normal University, Taiwan. He is currently an Associate Professor of Chemistry at National Chung Hsing University. Peter’s research interests are in the areas of bioinspired catalysts for the oxygenation of the CH bonds of alkanes. Hung Kay Lee was born in Hong Kong. He obtained his B.Sc. and Ph.D. degrees from The Chinese University of Hong Kong in 1990 and 1995, respectively. After working as a postdoctoral researcher with Professor Sunney Chan at the California Institute of Technology, he joined the Department of Chemistry at The Chinese University of Hong Kong as an Assistant Professor in 1997, and he is now an Associate Professor. His research interests include (i) the chemistry of low-coordinate transition-metal and lanthanide complexes supported by sterically bulky ligand systems and (ii) synthetic and structural studies of metal complexes of biological relevance. Steve Yu grew up in Taiwan. He graduated from National Tsing Hua University, Taiwan, with a B.S. degree in chemistry in 1991 and a Ph.D. in 1998. Following postdoctoral study with Professor Sunney Chan, he joined Academia Sinica as an Assistant Research Fellow at the Institute of Chemistry. He is currently an Associate Research 8610

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Fellow. His research program focuses on biocatalysis mediated by metalloenzymes in microbial cells and membranes, as well as the nanocatalysis of their biomimetics. Sunney Chan was born in San Francisco, CA. He attended the University os California at Berkeley, graduating with a B.S. degree in chemical engineering in 1957 and a Ph.D. degree in physical chemistry in 1960. After postdoctoral study as an NSF Fellow in physics at Harvard, he joined the chemistry faculty at Caltech in 1963. In 1997, Sunney took early retirement from Caltech and moved to Academia Sinica, Taiwan, as a Distinguished Research Fellow (1997−2006), Director of the Institute of Chemistry (1997−1999), and Vice President of Research at Academia Sinica (1999−2003). He is currently George Grant Hoag Professor of Biophysical Chemistry, Emeritus, at Caltech; a Distinguished Visiting Scientist at Academia Sinica; and Research Chair Professor of Chemistry at National Taiwan University in Taipei. He also holds honorary appointments at the National Taiwan University of Science & Technology (in chemical engineering) and the National Chung Hsing University (in bioinorganic chemistry). His research interests include membrane metalloenzymes, biocatalysis, and the development of biomimetic catalysts for the selective oxidation of alkanes.

ACKNOWLEDGMENTS This work was supported by the National Taiwan University and Academia Sinica Innovative Joint Program (NTU-SINICA104R104502 and NTU-SINICA-105R104502) and the Academia Sinica Research Program on Nanoscience and Nanotechnology (2393-105-0200). V.C.-C. W. thanks Dr. Tiow-Gan Ong for financial support from Academia Sinica Career Development Award (104-CDA-M08). ABBREVIATIONS AlkB alkane monooxygenase AMO ammonia monooxygenase BMM bacterial multicomponent monooxygenase EPR electron paramagnetic resonance EXAFS extend X-ray absorption fine structure HS high spin ICM intracytoplasmic membranes KIE kinetic isotope effect LS low spin Mc Methylococcus capsulatus (bath) MM Methylocystis species strain M MMOB methane monooxygenase regulatory protein MMOH methane monooxygenase hydroxylase MMOR methane reductase MR Methylocystis sp. str. Rockwell Mt Methylosinus trichosporium OB3b MSN mesoporous silica nanoparticle PCET proton-coupled electron transfer pMMO particulate methane monooxygenase pMMOMc_B soluble recombinant subunit B of pMMOMc RR resonance Raman sBMO soluble butane monooxygenae sMMO soluble methane monooxygenase TOF turnover frequency TON turnover number TPES total primary energy source REFERENCES (1) Key World Energy Statistics 2015; International Energy Agency: Paris, 2015. 8611

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