CHAPTER 1: Dioxygen Binding and Activation Mediated by Transition Metal Porphyrinoid Complexes

The dioxygen molecule, O₂, is a primary component of the atmosphere and is essential for sustaining aerobic life. This diatomic molecule reacts with a number of heme proteins that are involved in the physiological transport of dioxygen, and in the oxidative metabolism and hydroxylation of a wide range of metabolites. The latter processes typically involve a series of highly reactive heme–oxygen intermediates. The preparation of synthetic analogues of these heme sites and metal/oxygen intermediates not only provides spectroscopic benchmarks for comparison with enzymatic data, but also affords structurally well-characterized species through which detailed structure–function relationships can be investigated. While metallo-enzymes can perform a range of substrate hydroxylations with relative ease, the development of a synthetic catalyst that can utilize O₂ as the sole oxidant in the oxidation of commodity or specialty chemicals has remained the ultimate challenge for the inorganic chemist. Synthetic metalloporphyrinoid compounds have been prepared as model systems for addressing fundamental questions regarding the structural and electronic requirements for binding and activating O₂, as well as for catalyzing the oxidation of organic substrates with O₂ as the oxidant and/or oxygen source.

The aim of this chapter is to outline the basic chemical principles of O₂ binding and activation by heme proteins, and their synthetic analogues constructed from porphyrin-related, or porphyrinoid, systems. Examples of O₂-binding proteins and O₂-activating heme enzymes, particularly mono- and dioxygenases, will be described to gain insight into the biological requirements for O₂ reactivity. Recent examples of Fe and Mn porphyrinoid models for O₂ binding and activation, together with organic catalytic applications will be discussed.

Due to the low solubility of molecular O₂ in blood plasma, O₂-binders are required for proper transport, storage, and subsequent incorporation of oxygen into substrates. The binding of dioxygen is typically facilitated by first-row transition metals, in part because of their fast substitution kinetics.¹  A vacant site on the metal center is a requirement, as well as access to multiple metal oxidation states. The stoichiometry of O₂ binding can differ depending on the steric requirements of the coordination environment. Transition metals allow binding of dioxygen in different redox states (Figure 1.1), which can be distinguished experimentally using various spectroscopic techniques, including those that measure O–O bond distances, vibrational stretching frequencies, oxidation states, and spin states.² 

Dioxygen has a triplet ground state, ³Σ_g⁻, with a molecular configuration of (1sσ_g)² (1sσ_u*)² (2sσ_g)² (2sσ_u*)² (2p_zσ_g)² (2p_xπ_u)² (2p_yπ_u)² (2p_xπ_g*)¹ (2p_yπ_g*)¹ (2p_zσ_u*)⁰. Oxidation reactions mediated by O₂ are unusual processes; even though oxidation by O₂ is thermodynamically favorable in many cases, dioxygen is relatively kinetically unreactive. The low kinetic reactivity and triplet ground state of O₂ seems counterintuitive, given the inherent reactivity of diradicals in other molecules.³  This lack of kinetic reactivity can be traced to the very large resonance stabilization energy of O₂ (ca. −100 kcal mol⁻¹), arising from the four O₂ resonance structures that arise from assigning six electrons, four α-spin and two β-spin, to the four 2p_x and 2p_y π atomic orbitals in the triplet ground state of the O₂ molecule.⁴  The triplet ground state of O₂ also makes its reaction with most biological molecules, which have singlet ground states, a spin-forbidden process, adding to the kinetic barrier. On the other hand, the weak O–O σ bond makes reactions with O₂ very favorable thermodynamically. Nature overcomes the large kinetic barrier inherent to reactions of triplet O₂ by utilizing transition metals that also exist in open-shell spin ground states. The function of metal ions here is two-fold: they serve as O₂ binding sites for transport, and as reaction centers, where they can perform multi-electron redox chemistry that ultimately leads to the incorporation of oxygen atoms in organic substrates.

There are three general classes of metalloproteins that have evolved to bind and transport dioxygen in multicellular organisms: hemoglobins, hemerythrins, and hemocyanins (Figure 1.2). Hemoglobins (Hb), including myoglobins (Mb), are generally found in vertebrates and in all mammals. Their active site consists of an Feⁱⁱ center chelated by a protoporphyrin IX ligand and an axial imidazole ligand from a histidine residue, all enclosed in a hydrophobic protein pocket. Dioxygen binding to the Feⁱⁱ center occurs in an η¹ fashion, and typically involves one electron transfer from Feⁱⁱ to O₂ to form an Feⁱⁱⁱ–superoxo complex. In most cases, hydrogen-bonding interactions between the O₂ molecule and the amino acid residues in the distal side can be observed by X-ray crystallography and resonance Raman spectroscopy, and are a key structural element for O₂ binding. Mimicking the structural properties of hemoglobins in a synthetic system has been the subject of several studies, and significant efforts have focused on incorporating the necessary secondary coordination sphere elements that promote binding of O₂ and discourage side reactions that inhibit reversible oxygen binding.^5–8  However, the secondary coordination sphere can also be exploited to tune the properties of the complex away from reversible O₂ binding, and toward O₂ activation and cleavage of the O–O bond. This subtle interplay between O₂ binding and activation will be discussed further in detail in Section 1.4.

The other two metalloproteins, hemerythrin and hemocyanin, have dinuclear metal centers directly ligated to protein side chains, obviating the need for the production of a complex protein cofactor such as protoporphyrin IX. Hemerythrin (Hr), found in several marine invertebrates, possesses an unsymmetrical (5-coordinate/6-coordinate) diiron active site linked by carboxylate groups and a µ-hydroxo bridge, and ligated to the protein backbone through the imidazole groups of His side-chains.⁹  Dioxygen binds to the reduced Feⁱⁱ center with a vacant site as an η¹-hydroperoxide ligand. Two electrons are transferred from the diiron (Feⁱⁱ)₂ core to O₂, yielding an oxidized diferric (Feⁱⁱⁱ)₂ core and a peroxo (O₂²⁻) species, which is protonated by transfer of H⁺ from the µ-hydroxide ligand proximal to the coordinated oxygen. Hemocyanins (Hc), found in arthropods and molluscs, have several features in common with Hr. They bind dioxygen at a reduced dinuclear Cuⁱ active site coordinated to the protein scaffold through His groups. Reaction with O₂ leads to an oxidized dicopper(ii) center and the transfer of two electrons to O₂ to give a µ-η² : η² peroxo ligand that bridges the oxidized cupric ions.¹⁰  Several reviews have outlined examples of synthetic models of hemocyanin and hemerythrin,^11–13  and these will not be discussed here.

The binding of dioxygen to Feⁱⁱ porphyrins comprises the first step in the biological function of many heme proteins. Processes that involve cleavage of the oxygen–oxygen bond require proteins that typically have several specific structural and chemical features designed to promote O₂ activation. These proteins can then incorporate one or both of the oxygen atoms from dioxygen into organic substrates. A wide range of metabolic transformations rely on these latter proteins.^14–17  Heme enzymes that perform substrate oxygenation using O₂ as the O-atom source are called heme-dependent oxygenases. They can be classified into either monooxygenases or dioxygenases, depending on whether one or both oxygen atoms from O₂ are transferred to the substrate (Figure 1.3). For monooxygenases, the oxygen atom that is not incorporated into the substrate is eliminated as water.

Examples of monooxygenation reactions catalyzed by cytochrome P450 (CYP) include alkane and aromatic hydroxylations, olefin epoxidations, as well as N-, S- or O-dealkylations. While CYP can perform oxygenation reactions with a variety of organic substrates through diverse mechanisms, these reactions share common mechanistic intermediates. A consensus mechanism for the catalytic hydroxylation of C–H bonds by CYP is shown in Figure 1.4.¹⁵  Electronic tuning, substrate orientation, and control over electron and proton transfer all combine to form an efficient and well-choreographed sequence that delivers a reaction utilizing molecular oxygen. The resting ferric heme state is a 6-coordinate, low-spin species, and substrate binding to the active site pocket displaces the aqua ligand and turns the heme into a high-spin 5-coordinate iron complex with an increased redox potential. Reduction of the high-spin ferric heme, usually by nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) reducing equivalents, generates a high-spin Feⁱⁱ heme, which is activated for O₂ binding. Addition of O₂ gives a ferric superoxo complex. A second reduction event occurs to give a ferric peroxo complex, which is then protonated to form a ferric hydroperoxo intermediate labeled “Compound 0” (Cpd 0). Heterolytic cleavage of the O–O bond of Cpd 0 generates a high-valent iron–oxo porphyrin species, Fe^iv(O)(porphyrin˙⁺)(Cys), labeled Compound I (Cpd I). The generally accepted mechanism for substrate hydroxylation is the radical rebound mechanism,¹⁸  where Cpd I abstracts an H-atom from the C–H substrate to form Fe^iv(OH)(porphyrin)(Cys) or protonated Compound II (Cpd II). The newly generated carbon-centered radical then rapidly recombines with protonated Cpd II to give an alcohol product and the ferric heme resting state.

The intramolecular H-bonding network within the active site of CYP plays a key role in O₂ activation, i.e. O–O bond cleavage. Upon binding of O₂, a catalytic water molecule moves into the active site, establishing an H-bonding network with the local amino acid residues. A proposed proton relay mechanism in CYP101 involving the highly conserved residues Asp251 and Thr252 promotes the protonation of the distal oxygen atom from the water molecule in the active site (pull effect). The role of the Asp251 is linked to the conformational change required to position Thr252 for oxygen activation, while the Thr252 O atom serves as a H-bond acceptor to stabilize the hydroperoxy intermediate formed, thereby promoting dioxygen protonation.^19,20  The strong electron-donating character of the axial cysteinate ligand (push effect) then helps to stabilize the high-valent iron–oxo species formed as a result of the heterolytic cleavage of the O–O bond (Figure 1.5).^21,22  It is both the highly directed proton relay network and the electron-rich axial cysteinate ligand that helps to separate CYP from Hb/Mb and favor O₂ activation and O–O bond cleavage versus reversible O₂ binding.

Nitric oxide (NO) synthase is a heme monooxygenase that catalyzes the oxidation of l-arginine to l-citrulline and nitric oxide. Similar to CYP, NO synthase heme is axially ligated by a cys thiolate donor. The enzyme architecture, however, is very different from that of CYP, and a tetrahydrobiopterin (BH4) cofactor is also found in the active site pocket.^23,24  The first step of the reaction, the hydroxylation of l-arginine to N-hydroxy-l-arginine, is generally described to proceed via a classic CYP hydroxylation mechanism with the BH4 serving as an electron source. The second step of the reaction, the conversion of N-hydroxy-l-arginine to l-citrulline and NO, has been more challenging to assess, and a proposed mechanism is shown in Figure 1.6. The requirement of only one exogenous electron for this reaction has ruled out the involvement of Cpd I (which typically requires two exogenous electrons to assist with O–O bond cleavage on the way to Cpd I). Current proposals have focused instead on a superoxo/peroxo–iron intermediate as the key species needed to initiate attack of the substrate. The substrate may or may not serve as a direct electron donor to the Fe/O₂ intermediate, depending on whether the BH4 cofactor is oxidized,^25,26  as shown in Figure 1.6. Following NO˙ production, the ferric heme can then be reduced by NADPH to regenerate the ferrous form for another round of O₂ activation and N-hydroxylation. It is interesting to note that NO synthase demonstrates the versatility of the heme–thiolate center in activating O₂ for different purposes within the overall transformation of l-arginine to NO.

Heme oxygenase catalyzes the first key step in heme catabolism, the conversion of heme to biliverdin and carbon monoxide. While most reactions with heme monooxygenases involve the incorporation of an oxygen atom into an exogenous substrate, this process involves the intramolecular oxygenation of the porphyrin ring by a heme–oxygen species.²⁷  For the purposes of this chapter, we will focus on the initial hydroxylation reaction that converts heme to α-meso-hydroxyheme via O₂ and an Feⁱⁱ porphyrin (Figure 1.7).

Early work on this enzyme focused on determining the possible intermediate Fe^iv(O) species as the key oxidizing species. The His axial ligand in heme oxygenase makes the possibility of generating a ferryl species less likely due to the lack of the electron-donating Cys donor found in monooxygenases such as CYP, which helps to stabilize the high-valent iron. In addition, evidence has shown that a compound I species in heme oxygenase would be incapable of directly hydroxylating the heme.²⁸  A mechanism for heme hydroxylation is shown in Figure 1.7, where an Feⁱⁱⁱ-hydroperoxo species (compound 0) is the active oxidant and makes a direct attack on the target meso-carbon atom. The proton delivery to the hydroperoxo intermediate occurs in concert with heterolytic O–O cleavage and C–O bond formation at the meso-carbon atom. This mechanism is supported by results from electron paramagnetic resonance/electron nuclear double resonance (EPR/ENDOR) studies.^29,30  Computational studies, however, have suggested that a stepwise mechanism involving homolytic cleavage of the O–O bond, followed by OH˙ attack on the meso-carbon atom, would be more energetically favorable.³¹  As with CYP, an intricate network of H-bonded water is found in the secondary coordination sphere, which facilitates the proper delivery of protons to dioxygen to promote O–O bond cleavage.³² 

The oxidation of l-tryptophan to N-formylkynurenine (NFK), the first and rate-limiting step in the kynurenine pathway, is catalyzed by the O₂-dependent heme enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). These enzymes play a large role in tryptophan catabolism, and the metabolites formed have been implicated in a wide range of diseases, including cancer.³³  While TDO is a homotetramer³⁴  and IDO is a monomer,³⁵  a comparison of the active site structures of TDO and IDO reveals some structural similarities (Figure 1.8). A conserved arginine residue is found in the distal position, which holds in place the substrate carboxylate groups. A nearby histidine is also found in the active site of TDO, while in IDO it is replaced by serine. The original proposed mechanism for the dioxygenation begins with a base-catalyzed abstraction of the indole proton, and this proposal was based on the activity observed only with substrates that contain a proton on the indole nitrogen.³⁶  A number of experiments have since shown that this mechanism is not feasible.³⁷  IDO was found to form a stable compound II ferryl intermediate, as well as an epoxide intermediate with a single O atom from O₂.^38,39  These observations gave rise to the proposed mechanisms shown in Figure 1.9. It has been widely assumed that TDO and IDO react via the same intermediates, however, recent analysis has shown that a compound II species is unlikely to form in TDO, although a ternary [Feⁱⁱ–O₂–L–Trp] complex was detected under steady state conditions.⁴⁰  Whether the initial reaction of the substrate with the Fe–O₂ species proceeds through an electrophilic or a radical addition mechanism remains to be determined, however, quantum mechanics/molecular mechanics (QM/MM) simulations favor the latter.⁴¹  Recent reports of the structures of the hTDO–O₂–Trp (hTDO = human TDO)⁴²  and the related hIDO–CN–Trp (hIDO = human IDO)⁴³  ternary complexes also show that the protonation of the epoxide by the NH₃⁺ group of tryptophan is key in triggering the O-atom transfer of the ferryl (cpd II) species to the C₂ position, ultimately leading to the breakage of the C₂–C₃ bond (shown as a blue line in Figure 1.9).

It should be pointed out that the second reaction performed by NO synthase (see Section 1.4.1.2) involving the oxygenation of N-hydroxy-l-arginine to l-citrulline, H₂O and NO, and the dioxygenation of indole by TDO/IDO, as shown in Figure 1.9, both suggest that the first Fe–O₂ intermediate is a critical actor in initiating the attack on the substrate. The proposed Fe–O₂ species in TDO/IDO incorporates both oxygen atoms into the tryptophan substrate, while the same species in NO synthase functions exclusively as a monooxygenase to give citrulline and NO˙. These observations highlight the facility of the heme Fe–O₂ species to effect the oxygenation of diverse substrates, even when generated with very different axial ligands (N-his versus S-cys).

The study of dioxygen reactivity in a synthetic metalloporphyrin framework has helped provide a fundamental understanding of the O₂ binding and activation process at heme centers. This approach also provides a means for determining how to control these processes in a systematic manner. Porphyrinoids are a general class of compounds that have been utilized as synthetic models for O₂ binding and activation by heme enzymes. They are macrocyclic compounds consisting of four pyrrole rings linked by methine or azamethine bridges, and exhibit aromaticity based on the 18 π electrons in the conjugated, tetrapyrrolic ring. The modification of organic functionalities in porphyrins has resulted in systematic variations of the first and second coordination sphere near the central metal ion, providing a means to approximate the structural elements found in heme protein active sites. While iron porphyrin complexes have been the most widely-used system for synthetic models, substitution of the central metal with surrogates such as Mn or Co, and modification of the porphyrin core structures has produced a variety of chemical properties that were not accessible from iron porphyrin complexes alone. In this chapter, we discuss some examples of synthetic iron porphyrin complexes, as well as other metal complexes with various porphyrinoid core structures (Figure 1.10). Ring contraction of the porphyrin, wherein one of the meso-carbon atoms is removed, results in a direct pyrrole–pyrrole linkage to give a corrole. Due to this contraction, the cavity size is smaller, and the macrocycle becomes trianionic when deprotonated. The combination of these effects endows the corrole with the ability to stabilize high-valent oxidation states at the central metal ion. Replacement of the meso-carbon atoms of porphyrins with nitrogen atoms results in the formation of a porphyrazine, or tetraazaporphyrin derivative. These compounds are similar to phthalocyanines, which have a porphyrazine core, but contain benzene rings fused at the β-pyrrole positions. Unlike their porphyrin counterparts, there have been limited studies on metalloporphyrazine reactivity, in part due to their poor solubility in water and organic solvents. Modification of the peripheral substituents, typically by halogenation or addition of polar groups, improves their solubilities in organic solvents.^44–46  The meso-N-substituted corroles, also called corrolazines, provide a stabilizing effect to high-valent metals similar to that of corroles, but with the additional influence of the electron-withdrawing properties of the N-meso atoms. This section is divided into two main parts: iron and manganese complexes, and is further divided by ligand type. We have previously outlined the biomimetic reactivity of oxygen-derived iron and manganese porphyrinoid complexes in some reviews,^47,48  and here we focus on the intermediates formed exclusively with dioxygen. Catalytic applications using O₂ as an oxidant are also discussed. Electrocatalytic reduction of oxygen with metalloporphyrins and metalloporphyrinoid complexes is discussed in detail elsewhere^49–55  and will not be covered in this chapter.

Iron porphyrin complexes, which have the same core structure as the heme cofactor, are perhaps the most widely used compounds in O₂ binding and activation studies. Early efforts were made in stabilizing an Fe–O₂ moiety as a functional mimic of O₂-bound hemoglobin and myoglobin, to gain structural and electronic insights into the nature of the Fe–O₂ bonding in these heme proteins. As early as 1936, Pauling and Coryell determined that the Fe–O₂ group in oxyhemoglobin was diamagnetic.⁵⁶  This led to the proposal of several models to describe the nature of Fe–O₂ bonding (Figure 1.11), which are detailed in several reviews.^57,58  Three limiting electronic descriptions have been considered: low-spin Feⁱⁱ with a singlet O₂ (the Pauling model), low spin Feⁱⁱⁱ antiferromagnetically coupled to an S = 1/2 superoxide (the Weiss model) and an intermediate-spin Feⁱⁱ coupled to a triplet O₂ (the McClure–Goddard model). Various spectroscopic techniques, such as Mössbauer,⁵⁹  resonance Raman,⁶⁰  and X-ray absorption spectroscopies,⁶¹  have now lent credence to the Weiss description for oxyhemoglobin (i.e. that it is a ferric superoxo species).

A major hurdle in stabilizing the Fe–O₂ moiety for reversible oxygen binding in simple iron(ii) porphyrins is the unwanted auto-oxidation reactions that lead to the formation of iron(iii) porphyrin µ-oxo/peroxo dimers.^63,64  Several studies have led to a description of the synthetic requirements needed to stabilize an Fe–O₂ adduct. In synthetic model complexes, reversible O₂ binding often requires an axial ligand, usually an aromatic nitrogen base (e.g. pyridine, N-methylimidazole), to stabilize the Fe–O₂ adduct against further oxidation and dimerization reactions. The structure of the porphyrin has also been found to directly affect the stability of the O₂ adduct. The axial ligand could be covalently attached to the porphyrin to direct O₂ binding. On the other hand, incorporation of H-bonding groups (such as pivalamide) into the secondary coordination sphere stabilizes the Feⁱⁱⁱ-superoxo species without the need for an axial ligand. Steric hindrance about the porphyrin ligand also prevents unwanted dimer formation. Perhaps the earliest and most well-known example of the application of these synthetic strategies is the “picket-fence” porphyrin discovered by Collman and co-workers (Figure 1.12).^65,66  The diamagnetic Fe–O₂ adduct of this complex was isolated and characterized using X-ray crystallography, to show the bent, end-on binding of dioxygen to the iron porphyrin. Forty years after the picket-fence, the structural characterization of a five-coordinate Fe–O₂ adduct was achieved with a sterically bare porphyrin site-isolated inside a metal–organic framework.⁶⁷  A number of examples since the picket-fence have shown that similar synthetic strategies can be successful for the stabilization of a ferric superoxo complex in a porphyrin scaffold, and these have been summarized in several reviews.^5–8,13,68 

While the inherent reactivity of Feⁱⁱ(porphyrin) with O₂ is circumvented by synthetic design to mimic O₂ binding, such reactivity can be exploited for oxygenation reactions. One of the early products observed in the reaction between an Feⁱⁱ porphyrin and O₂ was a ferryl complex, Fe^iv(O) porphyrin, which could transfer its O-atom to triphenylphosphine (PPh₃) quantitatively to form triphenylphosphine oxide (PPh₃O) in toluene at −80 °C.⁷²  This observed substrate reactivity at low temperature opened up the possibility for catalytic turnover at ambient temperatures. Exposure of a solution of Feⁱⁱ(TPP) (TPP = tetraphenylporphyrin) and excess PPh₃ to a stream of O₂ in toluene at 25 °C resulted in the catalytic formation of PPh₃O (with a turnover number of approximately 27). The catalyst is inactivated by the formation of a µ-oxo dimer, which is unreactive to triphenylphosphine (Figure 1.13).

The related ferric peroxo porphyrins, the one-electron reduced analogs of ferric superoxo porphyrins, were synthesized following the addition of 2 equivalents of KO₂ (solubilized in crown ether) to an Feⁱⁱⁱ(Cl)(TPP) complex via the reduced Feⁱⁱ porphyrin.^73–76  Alternatively, the ferric peroxo porphyrin can be generated by electrochemical reduction of the ferric superoxo complex.⁷⁷  Reactivity studies performed on these complexes showed that they are not electrophilic and are instead nucleophilic (i.e. they are capable of oxidizing electron-poor alkenes).^78,79  Naruta and co-workers demonstrated that a ferric hydroperoxo species can be selectively prepared by different synthetic routes. The ferric peroxo complex Feⁱⁱⁱ(O₂)(TMPIm) (TMPIm = imidazole-tethered trimesitylporphyrin) was prepared by either addition of O₂ and 1 equiv of cobaltocene (CoCp₂) in methanol, or addition of KO₂ to a solution of Feⁱⁱ(TMPIm). EPR and resonance Raman spectroscopies show results consistent with a side-on bound, η²-peroxo ferric species. Protonation of this complex results in a spin-state change from high-spin to low-spin Feⁱⁱⁱ, with a concomitant change from an η² to an η¹ O₂ binding mode for the ferric hydroperoxo complex, Feⁱⁱⁱ(OOH)(TMPIm).⁸⁰  Interestingly, porphyrin modification using a bulky xanthene group to provide steric hindrance results in the transient formation of an η¹, end-on bound ferric peroxo porphyrin complex (Figure 1.14).⁸¹ 

The ability to mimic efficient catalytic alkane oxygenations performed by heme monooxygenases using simple metalloporphyrins and O₂ has been an active field of research, due to its enormous industrial potential. A primary requirement for these catalysts is the formation of a metal–oxo species, which is the key oxidizing species in the heme enzymes. While catalytic C–H bond oxidation has been demonstrated with iron porphyrins and O₂ congeners such as PhIO, mCPBA and H₂O₂,^17,47,48,82  oxidation with O₂ remains a significant challenge, in part due to the need for protons and exogenous reductants to cleave the O–O bond. Ellis and Lyons have reported the catalytic oxidation of light alkanes, propane and isobutene, with β-halogenated (Br, Cl) Feⁱⁱⁱ porphyrins and O₂.⁸³  An increase in the oxidation activity was observed with an increase in the number of halogens in the porphyrin ring. In particular, the perhalogenated complex, Feⁱⁱⁱ(Cl)(TPPF₂₀β-Br₈), showed the highest activity with a TON (turnover number) of >13 000 in in the hydroxylation of isobutane to t-butanol at room temperature (25 °C). A mechanism was proposed (Figure 1.15a), similar to the catalytic oxygenation of triphenylphosphine, where the active oxidant is a ferryl species activated by the electron-withdrawing halogen substituents. Subsequent studies by Labinger and Gray have shown that this mechanism is not viable, due to the stability of the Feⁱⁱ species of the perhalogenated porphyrins (Fe^iii/ii = 0.31 V vs. AgCl/Ag) toward O₂.⁸⁴  Instead, a radical-chain autoxidation mechanism was proposed (Figure 1.15b), wherein the Feⁱⁱⁱ porphyrin complex catalyzes the decomposition of the alkyl hydroperoxide that was formed over the course of the radical chain reaction with O₂. Moreover, the oxidative activity of this catalyst was inhibited upon addition of a radical trap. This mechanism is different in that it does not undergo a pathway analogous to those found in heme enzymes, but instead relies on the redox power and durability of the catalyst in reacting with alkyl hydroperoxides that are formed in the process.

Iron(iii) porphyrin, by itself, does not react with O₂. Catalytic turnover with O₂ is typically achieved by the addition of external co-reductants to generate Feⁱⁱ(porphyrin) and initiate the reaction, as shown in Figure 1.15a. Catalytic substrate oxidation has been previously demonstrated with Feⁱⁱⁱ(porphyrins) and reductants, such as H₂ in colloidal Pt.^85,86  Another possible point of entry into a catalytic oxygenation cycle is via the photolytic cleavage of a bis-iron(iii)-µ-oxo porphyrin. Nocera and coworkers have shown that the use of Pacman porphyrin systems enables facile turnover due to greater substrate access to the photogenerated Fe^iv(O) species.⁸⁷  Irradiation of a solution of a bis-iron(iii)-µ-oxo pacman porphyrin (DPDF)Fe₂O (DPDF = fluorinated Pacman porphyrin with a dibenzofuran spacer) in the presence of 1 atm of O₂ and hydrocarbons, such as toluene, cumene, diphenylmethane, and fluorene, results in the catalytic oxidation of these substrates with modest turnover numbers of up to 287. The key oxidizing species upon photolysis is proposed to be an Fe^iv(O) species, and the Feⁱⁱ porphyrin product after substrate oxidation reverts back to the bis-iron(iii)-µ-oxo porphyrin upon exposure to O₂. This photocatalytic oxidation cycle using Pacman systems has also been used to oxidize O-atom acceptors such as phosphines, sulfides, and olefins.^88–90 

Iron phthalocyanines, and the related iron porphyrazines, can also perform the same bioinspired catalytic oxidation reactions with O₂ typically associated with porphyrin complexes. For example, the catalytic oxygenation of PPh₃ has been observed with iron phthalocyanine catalysts and O₂.⁹¹  The catalytic substrate oxidation properties of iron phthalocyanines and other related complexes have been discussed in detail in several reviews.^46,92–95  Interestingly, there have been no examples of structurally characterized O₂ adducts of iron phthalocyanines or iron porphyrazines. Fitzgerald and coworkers showed that iron(ii) tetraanthracenotetraazaporphyrin (Feⁱⁱ(TATAP)), shows no affinity for O₂, and this was explained in terms of an unusually positive Fe^iii/ii redox potential.⁹⁶  For comparison, the highly electron-withdrawing species Feⁱⁱ(TPFPBr₈) (TPFPBr₈ = octabromotetrakis(pentafluorophenyl)porphyrin), which undergoes O₂-mediated alkane oxidation via a radical chain autoxidation mechanism, was also shown to be inert towards O₂.⁸⁴ 

In contrast to iron(ii) porphyrins, which readily react with dioxygen, O₂ reactivity with iron corroles and corrolazines remains relatively unexplored. Examples of characterized Fe–O₂ adducts in corroles are non-existent in the literature, perhaps arising from the stabilization of the high-valent redox states in corroles, which is the opposite of what is required for O₂ reactivity (i.e. an electron rich metal center). Reduction to the anionic Fe(ii) corrole may be performed electrochemically to access the iron(ii) state for O₂ binding. Kadish and coworkers have shown that reduction of Feⁱⁱⁱ(oec) (oec = octaethylcorrole) to Feⁱⁱ(oec)⁻ occurs in a reversible manner at −0.68 V vs. SCE (saturated calomel electrode) in benzonitrile,⁹⁷  however the reactivity of this species with O₂ was not studied. Murakami has shown that Feⁱⁱⁱ corroles can be reduced to the Feⁱⁱ state by the addition of hydroxide ion (OH⁻) in the presence of olefins,⁹⁸  but in the presence of O₂ at 25 °C, the Feⁱⁱ species undergoes outer-sphere electron transfer with O₂ to revert back to the Feⁱⁱⁱ corrole complex.

Iron(iii) corroles, in concentrated solutions, react with O₂ to form bis-corrole-diiron(iv)-µ-oxo dimer complexes.^99,100  The mechanism by which the µ-oxo dimer forms has not been investigated, but is presumed to proceed through a mechanism similar to that of the formation of the µ-oxo dimer of the iron porphyrins, wherein an iron–superoxo species is transiently formed. Catalytic oxygenation of olefins and hydrocarbons has been reported by Newcomb using the formally tetravalent bis-corrole–diiron µ-oxo dimer complex (TPFC)Fe₂O (TPFC = tris(pentafluoro)corrole).¹⁰¹  Photolysis of this complex by irradiation with a 355 nm laser pulse results in the formation of a putative Fe^v(O) corrole complex that oxidizes cyclooctene to cyclooctene oxide with ca. 200 turnovers in the presence of excess O₂ (Figure 1.16). The iron(iv) complex Fe^iv(Cl)(TPFC) is also capable of oxidizing the C–H bonds of hydrocarbons such as cyclohexane and adamantane in the presence of tert-butyl hydroperoxide (t-BuOOH). Based on mechanistic studies, a radical-chain autoxidation mechanism was proposed, similar to that of the analogous Feⁱⁱⁱ(Cl) porphyrins.¹⁰²  Although corroles are known to stabilize formally high-valent oxidation states, the possibility of ligand non-innocence in these systems complicates electronic structure assignments.¹⁰³  For example, recent X-ray absorption spectroscopy studies on Fe(X)(tpc) (X = Ph, Cl, NO; tpc = triphenylcorrole) suggest that their iron centers can be described as Feⁱⁱⁱ-like for X = Cl, NO, consistent with an Feⁱⁱⁱ(X)(tpc˙⁺) configuration, or Fe^iv-like for X = Ph, which is closer to an Fe^iv(X)(tpc) description.¹⁰⁴ 

While iron(iii) corroles form µ-oxo dimers in the presence of O₂, iron(iii) corrolazine Feⁱⁱⁱ(TBP₈Cz) (TBP₈Cz = octakis(tert-butylphenyl)corrolazine) is remarkably unreactive towards dioxygen. However, in the presence of the oxidant H₂O₂, catalytic oxygenation of sulfides has been observed.¹⁰⁵  Performing the oxygenation reaction of thioanisole with Feⁱⁱⁱ(TBP₈Cz)/H₂O₂ in the presence of a large excess of H₂¹⁸O resulted in no incorporation of ¹⁸O into the methylphenyl sulfoxide product, indicating that a high-valent iron–oxo species was not formed in the catalytic process. A competing pathway was indicated, where disproportionation of H₂O₂ to O₂ was observed. A mechanism was proposed (Figure 1.17) that accounts for all of the observations, which suggests the formation of an iron(iii)–hydroperoxide Feⁱⁱⁱ–OOH adduct as the key oxidizing species in the sulfoxidation reaction.

As early as 1959, Mnⁱⁱ phthalocyanine in pyridine was reported to bind O₂ at 20 °C to form an exceptionally stable Mn–O₂ adduct.^106–109  The data from infrared (IR) and EPR spectroscopies led to the conclusion that the Mn–O₂ adduct can be best described as an end-on bound Mnⁱⁱⁱ–superoxo species (Figure 1.18). Studies on the O₂ binding of manganese porphyrins began with the early work in the 1970s by Hoffman and co-workers on Mn-substituted myoglobin and hemoglobin,¹¹⁰  which were found to bind dioxygen irreversibly. Subsequent work by Hoffman and Basolo on O₂ binding by synthetic Mn porphyrins led to the description of an Mn(iv)–peroxo adduct with a side-on bound dioxygen ligand, as opposed to the anticipated Mn(iii)–superoxo configuration (Figure 1.18).^111–114  The Mn^iv(O₂)(porphyrin) complex exhibits a high spin (S = 3/2) EPR spectrum, and IR stretching frequencies of 900–990 cm⁻¹, lower than those found for end-on bound metal superoxo complexes (1100–1200 cm⁻¹).

The related O₂-bound Mn porphyrin, Mnⁱⁱⁱ(O₂)(TPP)⁻ (TPP = tetraphenylporphyrin) has been crystallographically characterized.¹¹⁵  This complex, formed by the addition of KO₂ to Mnⁱⁱ(TPP), shows a Mnⁱⁱⁱ ion coordinated to a peroxo ligand in an η² side-on fashion. This Mnⁱⁱⁱ–peroxo species was shown to be reactive with the strongly electron poor olefin tetracyanoethylene to give cyclic peroxy adducts,¹¹⁶  which have been characterized using IR and nuclear magnetic resonance (NMR) spectroscopies. Comparison with the Feⁱⁱⁱ–peroxo porphyrin analog showed that the Mnⁱⁱⁱ–peroxo species was less nucleophilic.¹¹⁷  This Mnⁱⁱⁱ–peroxo complex has provided an important structural precedent for the side-on O₂ binding mode in Mn porphyrins, however, structural characterization of an Mn^iv(O₂) species has remained elusive for many years. More recently, a peroxomanganese(iv) porphyrin complex has been structurally characterized for the first time in a metal–organic framework.¹¹⁸  A side-on, η² binding mode is observed for this complex, which confirms the previous spectroscopic characterization. More importantly, this complex exhibits reversible O₂-binding at room temperature, reverting back to the Mnⁱⁱ complex.

The use of Mn porphyrins in the catalytic oxidation of substrates with O₂ has been examined by a number of research groups. As with the Fe porphyrin analogs, an external reductant is a key requirement to prime the Mnⁱⁱⁱ porphyrin (e.g. Mnⁱⁱⁱ(TPP)) for O₂ binding and activation. Examples of reducing agents include NaBH₄,^119,120  Bu₄NBH₄,¹²¹  sodium ascorbate,¹²²  H₂ in the presence of Pt,⁸⁷  dihydropyridine,¹²³  electrons (in the form of electrochemical reduction),¹²⁴  or Zn powder.¹²⁵  The catalytic oxygenation of alkene and alkane substrates was achieved with these systems, but generally resulted in modest yields. The catalytic epoxidation cycle can be formulated as shown in Figure 1.19, which contains the essential elements of the cytochrome P450 catalytic cycle.¹²⁴  Reduction of the Mnⁱⁱⁱ porphyrin promotes O₂ binding with concurrent reduction to form an unusual Mnⁱⁱ–superoxide complex,¹²⁶  which reacts with the anhydride additive to form a Mn–acylperoxy adduct. The O–O bond heterolysis of this species results in a Mn^v(O) species, capable of transferring an O-atom to an alkene substrate. Similar epoxidation yields can be obtained using O-atom donors such as m-CPBA, cumyl hydroperoxide or H₂O₂, which suggests the presence of a common Mn^v(O) intermediate in these reactions.^127–129 

Photo-induced excitation of metalloporphyrin complexes presents an alternative option to enhance the electron–donor ability of these complexes to O₂ without the need for a co-reductant. Goldberg and Fukuzumi reported the photocatalytic oxidation of acridine (AcrH₂) to acridone (Acr = O) using Mnⁱⁱⁱ(TMP) (TMP = tetramesitylporphyrin) and Mnⁱⁱⁱ(TPFPP) (TPFPP = tetrakis(pentafluorophenyl)porphyrin), O₂, and visible light (hν > 480 nm) in benzonitrile. A modest product turnover was observed, and a proposed catalytic cycle (Figure 1.20) was formulated based on kinetic isotope effects and the electron transfer reactivity of the photoexcited Mn porphyrin complexes.^131,132 

Mnⁱⁱⁱ corrolazines are typically stable under aerobic conditions, and by themselves do not react with dioxygen. However, conversion of Mnⁱⁱⁱ(TBP₈Cz) to high-valent Mn^v(O)(TBP₈Cz) was observed in the presence of air or pure O₂ and visible light (hν > 400 nm) in toluene or cyclohexane.¹³³  While no O₂-bound Mn-corrolazine complex has been spectroscopically characterized to date, the former photogeneration of Mn^v(O)(TBP₈Cz) is proposed to go through an Mn^iv(OOH) intermediate, with the solvent acting as a proton/electron source to assist with O–O cleavage. Further systematic analysis of this reaction with benzylic C–H substrates (C₆H_m(CH₃)_n (m = 5–0, n = 1–6)), replacing the solvent as the proton/electron source, led to the controlled production of Mn^v(O)(TBP₈Cz) in benzonitrile under ambient conditions.¹³⁴  The stoichiometric formation of a benzyl alcohol product was also observed. Analysis of this reaction by femtosecond laser flash photolysis revealed two short-lived excited states, and together with kinetic isotope effect measurements for C–H versus C–D substrates, a mechanism was proposed for the benzylic C–H oxidation (Figure 1.21). The stability of the Mn^v(O) product limited this reaction to a stoichiometric process. Catalytic turnover was only observed with weak C–H bond substrates such as acridine,¹³¹  or O-atom acceptors such as PPh₃, leading to the rapid reaction of the Mn^v(O) product with the substrate to regenerate the Mnⁱⁱⁱ corrolazine catalyst.¹³³  However, the addition of two equivalents of a strong H⁺ donor such as H⁺[B(C₆F₅)₄] to Mnⁱⁱⁱ(TBP₈Cz) led to catalytic turnover with the benzylic C–H substrates, producing both benzyl alcohol and benzaldehyde. This interesting change in reactivity was ascribed to the proton-induced activation of a transient high-valent Mn^v(O) corrolazine. A comparison of the mechanisms for stoichiometric and catalytic substrate oxidation is shown in Figure 1.21.^135,136  It was also found that the conjugate base of the acid used for catalysis had an effect on the catalytic activity. The use of a triflate counterion (OTf⁻) results in a dramatic increase in the catalytic turnover, and it was postulated that the ability of triflate to serve as an axial ligand to the Mn center was responsible for this effect. The turnover number for the alcohol product increased from 18 for H⁺[B(C₆F₅)₄], to 563 for HOTf. Excellent turnover numbers (TON = 903) were also observed for the catalytic oxidation of thioanisole.¹³⁷  Thus, it was demonstrated that the catalytic activity of Mn corrolazines can be modulated by the addition of strong proton donors, which can bind to the meso-N position of the corrolazine ligand, or by axial ligands, which bind to the Mn center. This work also suggests that photoirradiation of other Mnⁱⁱⁱ porphyrinoid complexes could be a potentially new avenue into Mn-mediated dioxygen activation chemistry.

The reverse of O₂ activation in O₂-dependent heme monooxygenases is metal-mediated O–O bond formation. This process is critical to the water oxidation reaction of the oxygen evolving complex (OEC) in Photosystem II. The relative stability of Mn^v(O) corroles and corrolazines enables researchers to test proposed ideas regarding the O–O bond formation step relevant to the OEC. One proposed mechanism for O–O bond formation is the nucleophilic attack of a hydroxide ion on an Mn^v(O) species. Sun and Åkermark showed that rapid oxygen evolution could be seen from the addition of NBu₄OH to a solution of a Mn^v(O) corrole.¹³⁸  The nucleophilic attack of OH⁻ on the Mn^v(O) species presumably results in the formation of a Mnⁱⁱⁱ–hydroperoxo species, which is oxidized to a Mn^iv–hydroperoxy complex. The Mn^iv–peroxo species is then formed after deprotonation of the Mn^iv–hydroperoxy complex. The Mn^iv–peroxo complex disproportionates with the loss of O₂ and reverts back to the Mnⁱⁱⁱ species. An alternative pathway to the formation of this Mn^iv–peroxo corrole is via the addition of 1 equiv of H₂O₂ in the presence of excess base, as confirmed from mass spectrometry and EPR spectroscopic measurements.¹³⁹  Interestingly, this species can be interconverted to the Mn^v(O) corrole (either via homolytic or heterolytic pathways) by addition of acids. A criticism of the proposed cycle for these conversions is the unexplained missing electron in the oxidation of the Mnⁱⁱⁱ(OOH) species to the Mn^iv(OOH) species. More recently, Fukuzumi, Nam, and coworkers extended these observations by demonstrating that Mn^iv–peroxo and Mn^v–oxo corroles can be generated with O₂ in the presence of weak C–H substrates (tetrahydrofuran (THF) and cyclic olefins) as proton/electron sources.¹⁴⁰  The Mn^iv–peroxo corrole was structurally characterized using X-ray absorption spectroscopy, and was found to have 2 Mn–O bonds measuring 1.83 Å, and 4 Mn–N bonds measuring 1.96 Å, consistent with a side-on bound peroxide to the Mn^iv center. In the same report, mechanistic studies showed new O₂ activation pathways distinct from those in previous O–O bond formation studies. The proposed mechanisms are shown in Figure 1.22. Binding of OH⁻ to Mnⁱⁱⁱ lowers the redox potential for the facile binding of dioxygen. The solvent THF or cyclic olefins can then act as a H˙ source to form the Mn^iv–hydroperoxo complex, which, in the presence of excess base deprotonates to the Mn^iv–peroxo complex. In the presence of smaller amounts of base, the O–O bond in the Mn^iv–hydroperoxo complex cleaves homolytically to the Mn^v(O) species.

This chapter provides both a historical perspective and a summary on recent progress in the development of synthetic metalloporphyrinoid models of O₂-dependent heme enzymes. Some of the key chemical principles that govern the binding and activation of dioxygen can be gleaned from the examples presented here. A brief overview of the function and mechanism of heme mono- and dioxygenases is provided, and emphasis is given on the structural factors that stabilize, or activate, heme-oxygen intermediates. The structure and function of the heme mono- and dioxygenases described here should provide inspiration for the synthetic bioinorganic chemist striving to develop metalloporphyrinoid complexes for O₂ activation and challenging substrate oxygenation reactions. Focus was given to iron and manganese complexes, which represent some of the most O₂-reactive systems in porphyrinoid chemistry. It is clear that high-valent iron–oxo or manganese–oxo species formed upon O–O cleavage play a dominant role in catalytic activity, but they are not the only metal/oxygen species that can interact with the substrate. A common theme in these reactions is the need to prime the starting metalloporphyrinoid complex such that it can bind and activate dioxygen (with the exception of radical chain autoxidation pathways). This priming was achieved by either addition of a co-reductant or photo-excitation of the metal complex.

The field of synthetic bioinorganic chemistry has enjoyed immense growth over the past few decades, and a large driver for this growth has been the symbiotic relationship between the fields of biochemistry and synthetic inorganic chemistry. The development of well-defined, observable synthetic models of reactive metal–oxygen intermediates has helped to define or clarify the enzyme mechanism. At the same time, progress in the clarification of the mechanisms for the biological systems has provided chemists with a blueprint for designing potent and selective catalysts. New, and sometimes unexpected reactive intermediates emerge from the further development of spectroscopic techniques employed to study both the enzymes and synthetic models. While some modest successes have been reported over the years in carrying out catalytic oxygenations with synthetic models, several problems remain to be solved. Utilizing only O₂ together with a synthetic catalyst to oxygenate substrates via selective metal–oxo chemistry, and not radical chain autoxidation, remains an elusive goal. While addition of external co-reductants has resulted in catalytic turnover, the oxidation yields remain poor, and the hydroxylation of unactivated C–H substrates, such as those in alkanes, remains relatively rare. Solving these problems would have a large impact on many applications, including the commercial oxidation of organic compounds, as well as employing transition metal complexes for carrying out energy-related transformations. It is clear that developing biomimetic transition metal complexes for O₂-dependent, selective oxygenations and oxidations, remains a rich and complex problem; but, with the exciting progress being made in this area over the past several years, the future holds significant promise.

The authors are grateful to NIH (GM101153) for financial support.