Synthesis, Structure and Reactivity of a Mononuclear N,N,O-Bound Fe(II) α-Keto-Acid Complex

A bulky, tridentate phenolate ligand (ImPh2NNOtBu) was used to synthesise the first example of a mononuclear, facial, N,N,O-bound iron(II) benzoylformate complex, [Fe(ImPh2NNOtBu)(BF)] (2). The X-ray crystal structure of 2 reveals that the iron centre is pentacoordinate (τ=0.5), with a vacant site located cis to the bidentate BF ligand. The Mössbauer parameters of 2 are consistent with high-spin iron(II), and are very close to those reported for α-ketoglutarate-bound non-heme iron enzyme active sites. According to NMR and UV-vis spectroscopies, the structural integrity of 2 is retained in both coordinating and non-coordinating solvents. Cyclic voltammetry studies show that the iron centre has a very low oxidation potential and is more prone to electrochemical oxidation than the redox-active phenolate ligand. Complex 2 reacts with NO to form a S=3/2 {FeNO}7 adduct in which NO binds directly to the iron centre, according to EPR, UV-vis, IR spectroscopies and DFT analysis. Upon O2 exposure, 2 undergoes oxidative decarboxylation to form a diiron(III) benzoate complex, [Fe2(ImPh2NNOtBu)2(μ2-OBz)(μ2-OH)2]+ (3). A small amount of hydroxylated ligand was also observed by ESI-MS, hinting at the formation of a high-valent iron(IV)-oxo intermediate. Initial reactivity studies show that 2 is capable of oxygen atom transfer reactivity with O2, converting methyl(p-tolyl)sulfide to sulfoxide

Mechanistic Investigations into the Selective Reduction of Oxygen by a Multicopper Oxidase T3 Site-Inspired Dicopper Complex

Understanding how multicopper oxidases (MCOs) reduce oxygen in the trinuclear copper cluster (TNC) is of great importance for development of catalysts for the oxygen reduction reaction (ORR). Herein, we report a mechanistic investigation into the ORR activity of the dinuclear copper complex [Cu2L(μ-OH)]3+ (L = 2,7-bis[bis(2-pyridylmethyl)aminomethyl]-1,8-naphthyridine). This complex is inspired by the dinuclear T3 site found in the MCO active site and confines the Cu centers in a rigid scaffold. We show that the electrochemical reduction of [Cu2L(μ-OH)]3+ follows a proton-coupled electron transfer pathway and requires a larger overpotential due to the presence of the Cu-OH-Cu motif. In addition, we provide evidence that metal-metal cooperativity takes place during catalysis that is facilitated by the constraints of the rigid ligand framework, by identification of key intermediates along the catalytic cycle of [Cu2L(μ-OH)]3+. Electrochemical studies show that the mechanisms of the ORR and hydrogen peroxide reduction reaction found for [Cu2L(μ-OH)]3+ differ from the ones found for analogous mononuclear copper catalysts. In addition, the metal-metal cooperativity results in an improved selectivity for the four-electron ORR of more than 70% because reaction intermediates can be stabilized better between both copper centers. Overall, the mechanism of the [Cu2L(μ-OH)]3+-catalyzed ORR in this work contributes to the understanding of how the cooperative function of multiple metals in close proximity can affect ORR activity and selectivity

Bioinspired Model Complexes of Non-Heme Iron Enzymes: Modelling the 2-His-1-Carboxylate Facial Triad with a Family of N,N,O Phenolate Ligands

Metal sites in biology catalyse some of the most challenging and consequential reactions on Earth, ranging from oxygen transport in animals to photosynthesis in plants and nitrogen-fixation in bacteria. This astounding breadth of reactivity includes attractive features such as small molecule activation and late-stage functionalisation, all of which are achieved under physiological conditions and with exquisite stereo- and regioselectivity. For bioinorganic chemists, the direct deployment, engineering or mimicry of metalloenzymes and metal-containing biomolecules in research and commercial applications holds great potential for improving the green credentials of today’s chemical industry. The present thesis describes the synthesis, structure and reactivity of bioinspired iron complexes that model O2-activating non-heme iron enzymes such as isopenicillin N synthase (IPNS), which contains the 2-His-1-Carboxylate facial triad (2H1C) at its active site. A family of bioinspired N,N,O phenolate ligands was developed to structurally model the 2H1C and their coordination chemistry to iron and zinc was explored. These efforts resulted in the creation of an interesting series of N,N,O-bound iron and zinc thiolate complexes that model important structural aspects of the substrate-bound active site of IPNS. This research also showed that mononuclear N,N,O-bound iron(II) alpha-ketoacid complexes could be synthesised, opening up a new field of exploration related to alpha-ketoglutarate-dependent enzymes, the largest sub-family of 2H1C-containing non-heme iron enzymes

Bioinspired Model Complexes of Non-Heme Iron Enzymes: Modelling the 2-His-1-Carboxylate Facial Triad with a Family of N,N,O Phenolate Ligands

Metal sites in biology catalyse some of the most challenging and consequential reactions on Earth, ranging from oxygen transport in animals to photosynthesis in plants and nitrogen-fixation in bacteria. This astounding breadth of reactivity includes attractive features such as small molecule activation and late-stage functionalisation, all of which are achieved under physiological conditions and with exquisite stereo- and regioselectivity. For bioinorganic chemists, the direct deployment, engineering or mimicry of metalloenzymes and metal-containing biomolecules in research and commercial applications holds great potential for improving the green credentials of today’s chemical industry. The present thesis describes the synthesis, structure and reactivity of bioinspired iron complexes that model O2-activating non-heme iron enzymes such as isopenicillin N synthase (IPNS), which contains the 2-His-1-Carboxylate facial triad (2H1C) at its active site. A family of bioinspired N,N,O phenolate ligands was developed to structurally model the 2H1C and their coordination chemistry to iron and zinc was explored. These efforts resulted in the creation of an interesting series of N,N,O-bound iron and zinc thiolate complexes that model important structural aspects of the substrate-bound active site of IPNS. This research also showed that mononuclear N,N,O-bound iron(II) alpha-ketoacid complexes could be synthesised, opening up a new field of exploration related to alpha-ketoglutarate-dependent enzymes, the largest sub-family of 2H1C-containing non-heme iron enzymes

Bioinspired Non-Heme Iron Complexes: The Evolution of Facial N, N, O Ligand Design

Iron-containing metalloenzymes that contain the 2-His-1-Carboxylate facial triad at their active site are well known for their ability to activate molecular oxygen and catalyse a broad range of oxidative transformations. Many of these reactions are synthetically challenging, and developing small molecular iron-based catalysts that can achieve similar reactivity and selectivity remains a long-standing goal in homogeneous catalysis. This review focuses on the development of bioinspired facial N,N,O ligands that model the 2-His-1-Carboxylate facial triad to a greater degree of structural accuracy than many of the polydentate N-donor ligands commonly used in this field. By developing robust, well-defined N,N,O facial ligands, an increased understanding could be gained of the factors governing enzymatic reactivity and selectivity

Crystal structure of tetra­kis­(tetra­hydro­furan-κO)bis­(tri­fluoro­methane­sulfonato-κO)iron(II)

The title compound, [Fe(CF3SO3)2(C4H8O)4], is octa­hedral with two tri­fluoro­methane­sulfonate ligands in trans positions and four tetra­hydro­furane mol­ecules in the equatorial plane. By the conformation of the ligands the complex is chiral in the crystal packing. The compound crystallizes in the Sohncke space group P212121 and is enanti­omerically pure. The packing of the mol­ecules is determined by weak C—H...O hydrogen bonds. The crystal studied was refined as a two-component inversion twin

Mechanistic Investigations into the Selective Reduction of Oxygen by a MCO T3 site-inspired Copper Complex

Understanding how multicopper oxidases (MCOs) efficiently and selectively reduce oxygen in the trinuclear copper cluster (TNC) is of great importance. Previously it was reported that when the T2-site is removed from the TNC, all O2 binding activity at the dinuclear T3-site is lost. Computational studies attribute this loss of activity to the flexibility of the protein active site, where the T3-copper centers move apart to minimize electrostatic repulsions. To address the question if and how a more constrained T3-site will catalyze the reduction of oxygen, we herein report a mechanistic investigation into the oxygen reduction reaction (ORR) activity of the dinuclear copper complex [Cu2L(μ-OH)]3+ (L=2,7-bis[bis(2-pyridylmethyl)aminomethyl]-1,8-naphthyridine). This T3-inspired complex confines the Cu centers in a rigid scaffold in close proximity instead of the flexible scaffold found in the protein active site and we demonstrate that under these constraints the dinuclear copper site displays ORR activity. Compared to the ORR mechanism of MCOs, we show that electrochemical reduction of [Cu2L(μ-OH)]3+ follows a similar pathway as the reduction of the resting enzyme due to the presence of the Cu-OH-Cu motif. By identification of key intermediates along the catalytic cycle of [Cu2L(μ-OH)]3+ we provide for the first time evidence that metal-metal cooperativity takes place during electrocatalysis of the ORR by a copper-based catalyst, which is achieved by the ability of the rigid ligand framework to bind two copper atoms in close proximity. Electrochemical studies show that the mechanisms of the ORR and hydrogen peroxide reduction reaction (HPRR) found for [Cu2L(μ-OH)]3+ are different from the ones found for analogous mononuclear copper catalysts. In addition, the metal-metal cooperativity results in an improved selectivity for the four-electron ORR of more than 70%. This selectivity is achieved by better stabilization of reaction intermediates between both copper centers, which is also essential for the ORR mechanism observed in MCOs. Overall, the mechanism of the [Cu2L(μ-OH)]3+-catalyzed ORR in this work gives insight into the ORR activity of a T3-site and contributes to understanding of how the ORR activity and selectivity are established in MCOs

Bioinspired Non-Heme Iron Complexes: the Evolution of Facial N, N, O Ligand Design

Iron-containing metalloenzymes that contain the 2-His-1-Carboxylate facial triad at their active site are well known for their ability to activate molecular oxygen and catalyse a broad range of oxidative transformations. Many of these reactions are synthetically challenging, and developing small molecular iron-based catalysts that can achieve similar reactivity and selectivity remains a long-standing goal in homogeneous catalysis. This review focuses on the development of bioinspired facial N,N,O ligands that model the 2-His-1-Carboxylate facial triad to a greater degree of structural accuracy than many of the polydentate N-donor ligands commonly used in this field. By developing robust, well-defined N,N,O facial ligands, an increased understanding could be gained of the factors governing enzymatic reactivity and selectivity

Structurally Modelling the 2‐His‐1‐Carboxylate Facial Triad with a Bulky N,N,O Phenolate Ligand

We present the synthesis and coordination chemistry of a bulky, tripodal N,N,O ligand, ImPh2NNOtBu (L), designed to model the 2-His-1-carboxylate facial triad (2H1C) by means of two imidazole groups and an anionic 2,4-di-tert-butyl-subtituted phenolate. Reacting K-L with MCl2 (M = Fe, Zn) affords the isostructural, tetrahedral non-heme complexes [Fe(L)(Cl)] (1) and [Zn(L)(Cl)] (2) in high yield. The tridentate N,N,O ligand coordination observed in their X-ray crystal structures remains intact and well-defined in MeCN and CH2Cl2 solution. Reacting 2 with NaSPh affords a tetrahedral zinc thiolate complex, [Zn(L)(SPh)] (4), that is relevant to isopenicillin N synthase (IPNS) biomimicry. Cyclic voltammetry studies demonstrate the ligand's redox non-innocence, where phenolate oxidation is the first electrochemical response observed in K-L, 2 and 4. However, the first electrochemical oxidation in 1 is iron-centred, the assignment of which is supported by DFT calculations. Overall, ImPh2NNOtBu provides access to well-defined mononuclear, monoligated, N,N,O-bound metal complexes, enabling more accurate structural modelling of the 2H1C to be achieved

2H1C Mimicry: Bioinspired Iron and Zinc Complexes Supported by N,N,O Phenolate Ligands

In pursuit of mimicking the ubiquitous 2H1C motif in mononuclear non-heme iron enzymes, two new bioinspired N,N,O phenolate ligands, BenzImNNO and ImPh2NNO, are synthesised and their coordination chemistry with zinc(II) and iron(II) is explored. BenzImNNO coordinates by means of an anionic κ3-N,N,O donor set and readily forms homoleptic bisligated complexes, also in the presence of equimolar amounts of metal salt. In contrast, the increased steric bulk of ImPh2NNO promotes the formation of dinuclear complexes, [M2(ImPh2NNO)2(OTf)2] (M=Fe, Zn), with facially opposing metal sites, as a result of its unique bridging μ2:κ2-N,N:κ1-O coordination mode. We investigate the robustness of the ligand's dinucleating coordination mode during oxidative transformations and demonstrate that its coordination mode is retained upon triflate substitution for a biorelevant thiophenolate co-ligand