Designing biomimetic catalytic systems for CO₂ reduction to formate using NAD(P)H

Abstract

Artificial photosynthesis refers to a synthetic method of transforming solar radiation into storable fuels that are suitable for transport and practical applications, mimicking the natural photosynthesis found in plants and algae. Successfully replicating this natural energy conversion system could represent a major breakthrough in renewable energy technology, simultaneously providing clean fuel and reducing atmospheric carbon dioxide levels. Growing concerns over excessive CO₂ emissions have led to considerable interest in developing technologies that convert CO₂ into value-added fuels and raw materials by artificial photosynthesis. Essential processes such as photon absorption, charge transfer, water splitting, NAD(P)⁺ reduction, and carbon dioxide fixation have attracted significant research interest. Nevertheless, these individual processes have predominantly been studied independently. For the combination of NAD(P)H oxidation and CO₂ reduction reactions, formate dehydrogenase (FDH) is a key enzyme in natural CO₂ recycling systems, catalysing both the oxidation of formate to CO₂ and the reduction of CO₂ to formate via electron transfer involving NAD(P)H/NAD(P)⁺. Mimicking the metal active sites of such enzymes is crucial for designing efficient catalysts for CO₂ conversion. However, no biomimetic in vivo catalysts have been reported for formate production from CO₂ using NAD(P)H. This review focuses on catalytic studies involving the conversion of CO₂ into formic acid using NAD(P)H with FDH as well as FDH-mimetic metal complexes. It covers enzymatic, photochemical, and electrochemical methods for CO₂ reduction, highlighting the structure and mechanism of FDH and recent advances in the design of FDH mimetics. Additionally, this review explores strategies for enhancing the stability of the catalyst and catalytic performance through molecular tuning, offering insights into future research directions for developing efficient and sustainable CO₂ reduction systems.

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1. Introduction

The rapid increase in greenhouse gas emissions driven by human civilization poses a significant threat to the safety of the Earth, ecosystems, and humanity.^1–3 Among these greenhouse gases, carbon dioxide (CO₂) is the most critical contributor to the greenhouse effect, primarily generated through the combustion of fossil fuels.^4–6 The escalating CO₂ emissions resulting from the use of excessive fossil fuels have spurred considerable interest in the development of technologies to convert CO₂ into value-added raw materials and fuels.^7–10 One of the promising approaches is the catalytic reduction of CO₂ to produce C1 compounds, such as carbon monoxide (CO), formic acid, and methanol.^11–20 Catalytic conversion of CO₂ into liquid fuels offers advantages over gaseous products, including improved storage and transportation, enabling efficient CO₂ recycling and positively impacting the global carbon balance.

The development of efficient catalysts requires mimicking the metal active sites found in natural enzymes. Formate dehydrogenase (FDH) serves as a representative enzyme in CO₂ recycling systems, catalysing the oxidation of formate to CO₂ while transferring electrons to NAD(P)⁺ (nicotinamide adenine dinucleotide phosphate, Fig. 1) to produce NAD(P)H (Fig. 1) in the case of NADP-dependent FDH. Conversely, FDH can catalyse the reduction of CO₂ to formate, transferring electrons from NAD(P)H to regenerate NAD(P)⁺ in the reverse reaction (see eqn (1)).^21–25 Consequently, the most essential approach for biocatalytic conversion of CO₂ is using in vivo biocatalysts and mimics of these catalysts. Despite the potential of these systems, there are no reported research studies on the development of mimetic in vivo biocatalysts capable of producing formate from CO₂ using NAD(P)H.

Fig. 1 Chemical structures of NAD(P)⁺ and NAD(P)H.

This review focuses on catalytic studies related to the conversion of CO₂ into formic acid, as a value-added chemical, by NAD(P)H with the use of FDH and FDH mimetic metal complexes. Specifically, it describes studies on the production of formic acid in the reduction reaction of CO₂ by NAD(P)H through photochemical, electrochemical, or enzymatic methods using enzymes or molecular catalysts. First, it highlights a representative biocatalyst, FDH, which enzymatically reduces CO₂ to formic acid using NAD(P)H. The characteristics and structures of the active site of FDH, as well as the CO₂ reduction reaction mechanism by NAD(P)H using FDH, are detailed. In addition, this review discusses the synthesis of FDH mimetics and the analysis of CO₂ reduction reaction mechanisms and NAD(P)H oxidation/reduction reaction mechanisms via photochemical and electrochemical methods. Therefore, it not only provides an overview of FDH and FDH mimetics and recent progress in this field but also proposes research directions and prospects for developing catalysts. It also discusses the utilization of novel FDH mimetics through the tuning of molecular catalysts, to enhance the stability of molecular catalysts and their catalytic performance.

2. Enzymatic CO₂ reduction to formate

2.1. Mechanism of formate dehydrogenase (FDH) catalysis

Enzyme-based catalysis is advantageous due to its high efficiency (high total turnover numbers) and 100% selectivity, as well as the mild reaction conditions it requires.²⁶ Formate dehydrogenases (FDHs) can be classified into metal-based and non-metal-based enzymes. Metal-dependent FDHs possess a highly conserved catalytic centre typically composed of either molybdenum (Mo) or tungsten (W), which is coordinated by two molybdopterin guanine dinucleotide cofactors, a sulfide ligand, a selenocysteine residue, and additional histidine and arginine residues within the secondary coordination environment.^27–32 The structural details of the catalytic sites in metal-containing FDHs are presented in Fig. 2a and b, illustrating the proposed active-site configurations for Mo- and W-dependent enzymes, respectively. The active-site structures of metal-based FDHs differ according to their roles in formic acid oxidation or CO₂ reduction. During formic acid oxidation, the central metal atom (Mo or W) adopts a hexavalent state, forming a double bond with sulfur, M=S (M = Mo or W) (Fig. 2a). Conversely, in the CO₂ reduction pathway, the metal centre is tetravalent and bonded to sulfur in a thiol configuration, represented as M–SH (Fig. 2b). These FDHs function as enzymatic catalysts facilitating both the oxidation of formate to CO₂ and the reverse conversion of CO₂ into formate, depending upon available redox couples.^31–35 The proposed catalytic mechanism for formic acid oxidation mediated by metal-containing FDHs is shown in Fig. 2c.^31,32 Initially, formate ions are electrostatically stabilized by positively charged arginine residues at the active site of the enzyme. Subsequently, a hydride from the formate attacks the sulfur atom coordinated to the metal, leading to the reduction of the metal from a hexavalent to a tetravalent oxidation state.^31,32 The reaction is completed as the metal returns to its original hexavalent state through oxidation, releasing CO₂ and a proton. Conversely, the hypothesized mechanism for CO₂ reduction by metal-dependent FDHs is presented in Fig. 2d.^31,32 Initially, CO₂ is similarly stabilized electrostatically by positively charged arginine residues. A proton from the metal-bound thiol then nucleophilically attacks the arginine-trapped CO₂, prompting oxidation of the metal centre from tetravalent to hexavalent.^31,32 Finally, the metal reverts to its tetravalent state via reduction, accompanied by proton and electron uptake, resulting in formic acid formation and active-site regeneration.^31,32

Fig. 2 Metal-containing FDHs (formate dehydrogenases). The proposed structural configurations of metal active centres in their (a) oxidized and (b) reduced states. Additionally, the suggested catalytic mechanisms are presented for (c) the oxidation reaction converting formate into CO₂, and (d) the reverse reaction, in which CO₂ is reduced to formate by metal-dependent FDHs. Reprinted with permission from ref. 31 and 32. Copyright 2024, 2016, Multidisciplinary Digital Publishing Institute and American Chemical Society.

The active site of the second type of FDH, which lacks a metal centre, is composed exclusively of amino acid components. A plausible configuration of the catalytic site for these non-metal FDHs is presented in Fig. 3.^36,37 Typically, the active site comprises eight amino acids, such as Ile, Asn, Thr, Arg, Asp, Gln, His, and Ser.^36,37 These residues collectively form binding sites for substrates such as NAD(P)⁺, formic acid, or CO₂. Nearly all metal-independent FDHs identified in microbial systems utilize NAD(P)H as a necessary cofactor, enabling close docking with the active site of the enzyme and promoting the enzymatic reduction of CO₂ to formate. In particular, NAD(P)H in the active site of CbFDH (Candida boidinii FDH) is stabilized by interactions with specific residues, predominantly Thr282, Asp308, Ser334, His332, and Gln313, positioning NAD(P)H proximal to CO₂, thereby facilitating efficient hydride transfer for carbon reduction.³⁶ Upon addition of CO₂, NAD(P)H undergoes conformational adjustments, stabilizing the CO₂ molecule through interactions with residues such as Asn146, Ile122, and Arg284. Subsequently, the hydride from the C4 position of the NAD(P)H nicotinamide ring transfers electrons directly to CO₂, forming formate.³⁸ The central catalytic step involves hydride transfer from the carbon atom of formate to the C4 atom on the pyridine ring of NAD(P)⁺, and this hydride transfer is the rate-determining step.³⁸ Structural analyses demonstrate that the enzyme generates an optimal microenvironment that promotes hydride transfer and stabilizes interactions through targeted hydrogen bonding with the FDH peptide backbone.^38,39 After hydride ion transfer, the resulting formate ions dissociate from the NAD(P)⁺-associated active centre of the FDH enzyme.³⁸

Fig. 3 Proposed structural configuration of the catalytic centre in metal-independent FDH. Reprinted with permission from ref. 36 and 37. Copyright 2008, 2015, American Chemical Society and the Royal Society of Chemistry.

In the catalytic process of CO₂ reduction, metal-free FDHs directly associate with NAD(P)H at their active sites, whereas metal-based FDHs indirectly utilize NAD(P)H via an electron-conducting subunit rather than through direct binding to the metal catalytic centre. The electrons originating from NAD(P)H traverse sequentially arranged [4Fe–4S] clusters before ultimately arriving at the metal-containing active site. Nevertheless, the detailed catalytic mechanism involving NAD(P)H in metal-dependent FDHs remains intricate and warrants further investigation.

2.2. Engineering of formate dehydrogenases for enhancement of catalytic efficiency in CO₂ reduction

Formate dehydrogenases (FDHs) have attracted significant attention as biocatalysts for CO₂-to-formate conversion. To further enhance their catalytic efficiency toward CO₂ reduction, various genetic engineering approaches have been explored.^19,40–56 Despite their promising catalytic potential, native FDHs often suffer from limited operational stability and high enzyme production costs, restricting their broader application in practical CO₂ reduction systems. Consequently, extensive research has been conducted on genetically modifying bacterial and yeast-derived FDHs to enhance thermal and chemical stability, elevate catalytic activity, alter coenzyme specificity toward NAD(P)⁺, and optimize enzyme expression in host systems such as Escherichia coli.^40–44 Although native FDHs predominantly catalyse the oxidation of formate to CO₂ using NAD(P)⁺, their efficient use in CO₂ reduction demands specific improvements in catalytic activity toward this reverse reaction. Accordingly, genetic modifications aimed at significantly enhancing FDH activity for CO₂-to-formate reduction have been widely studied.^42–53 In addition, recent studies have focused on designing Mo- and W-containing FDHs to develop novel catalysts specifically tailored for efficient CO₂ reduction reactions.^31,54,55

2.3. Integration of photochemical NAD(P)⁺ reduction with enzymatic CO₂ conversion to formate

Solar and electric energy are more cost-effective and sustainable for driving NAD(P)H regeneration, offering new research directions for enzymatic CO₂-to-formate conversion. By employing advanced photocatalysts or electrocatalysts, NAD(P)H regeneration can overcome efficiency challenges. Recent studies on enzymatic CO₂-to-formate conversion have demonstrated that certain metalloenzymes can bypass NAD(P)H by utilizing stable electron mediators. By mimicking natural photosystems, artificial photosystems utilize photocatalysts to excite electrons, employ electron mediators to transfer these electrons, and ultimately drive enzymatic CO₂-to-formate conversion. The optimal selection of photocatalysts and mediators is crucial for determining the rate of photochemical formate biosynthesis.

Upon illumination, photosensitizers undergo excitation, resulting in the formation of electron–hole pairs, where the generated electrons subsequently transfer to NAD(P)⁺ through an electron mediator. Simultaneously, an electron-donating compound acting as a sacrificial reagent provides electrons to neutralize the holes generated in the photosensitizer (Fig. 4).^57–61 To achieve compatibility with biological systems, molecular photosensitizers have been explored extensively as alternative semiconductor materials in photochemical NAD(P)H regeneration processes. Molecular photocatalysts frequently employed in enzymatic photocatalysis include xanthene-derived dyes such as fluorescein, eosin Y, and their modified analogues, along with porphyrin-based compounds, including porphyrin itself and its metal-containing derivatives.

Fig. 4 Photocatalytic CO₂ reduction to formate using NADH catalysed by a metal catalyst and FDH in the presence of a photosensitizer.

The artificial photosynthetic production of 1-benzyl-1,4-dihydro nicotine amide (BNAH) or nicotinamide adenine dinucleotide (NADH) has been demonstrated under green- or red-light irradiation and an argon atmosphere, utilizing a photocatalytic system that integrates a tin(IV)-meso-tetrakis(N-methylpyridinium)-chlorin complex (SnC) (Scheme 1).⁶² This system enables efficient NADH analogue formation while recycling the selective hydride transfer mediator [Cp*Rh(bpy)H]⁺ in a neutral aqueous solution. The use of SnC as a multielectron transfer sensitizer selectively excited by red light allows for the formation of NADH analogues, thus enabling the photocatalytic reduction of NAD⁺ analogues. To facilitate the redox-mediated photocatalytic process, the rhodium complex [Cp*Rh(bpy)Cl]⁺ was introduced as a redox mediator.⁶² The process involves the formation of a rhodium-hydride intermediate [Cp*Rh(bpy)H]⁺, which generates the enzymatically active 1,4-NADH form of the reduced cofactor. This highlights the integration of transition metal catalysts with light-driven redox processes to efficiently and selectively generate 1,4-NADH. The photocatalytic process mimics the natural photosystem I (PSI), integrating a primary electron donor, SnC, and an additional redox mediator for NADH analogue formation.

Scheme 1 Red-light-driven photocatalytic mechanism for BNA⁺ or NAD⁺ reduction using Sn(IV)-meso-tetrakis(N-methylpyridinium)-chlorin (SnC) as a multielectron transfer sensitizer, enabling selective hydride mediator [Cp*Rh(bpy)H]⁺ recycling in neutral aqueous solution. Reprinted with permission from ref. 62. Copyright 2008, 2015, American Chemical Society and the Royal Society of Chemistry.

NADH is an essential cofactor involved in numerous biologically significant redox transformations. Consequently, the photochemical regeneration of its oxidized counterpart (NAD⁺) under biologically compatible conditions has become increasingly important in both photocatalytic and biocatalytic applications. Water-soluble, tri-anionic iridium complexes have shown remarkable efficiency as photocatalysts for reducing NAD⁺ analogues.⁶³ The improved catalytic activity results from the robust electron-donating characteristics of the excited states of the tri-anionic Ir^III complexes, their enhanced chemical stability, and beneficial electrostatic interactions with the positively charged rhodium co-catalyst (Scheme 2).⁶³ The photocatalytic process utilizes triethanolamine (TEOA) as a sacrificial electron donor, ensuring continuous electron transfer. The rhodium co-catalyst, initially present as [CpRh(bpy)(H₂O)]²⁺, undergoes a two-electron reduction coupled with protonation, forming the catalytically active Rh^III hydride complex [CpRh(bpy)H]⁺. This complex is responsible for the selective reduction of the NAD⁺ mimic (BNA⁺) to its 1,4-reduced form (1,4-BNAH), which is enzymatically active. The Ir^III photosensitizers showed significantly improved catalytic performance, with turnover frequencies (TOFs) ranging from 88 to 146 h⁻¹, surpassing [Ru^II(bpy)₃]²⁺ (TOF = 16 h⁻¹). This enhancement directly relates to the substantially stronger electron-donating capacity of the excited-state Ir^III species compared to [Ru^II(bpy)₃]²⁺. Additionally, among the tested Ir^III photosensitizers, a clear correlation emerged between the observed TOF and the facility of ground-state reduction from Ir^IV back to Ir^III, indicating that efficient regeneration of the photosensitizer by TEOA could become a limiting factor. These outcomes underscore the necessity of optimizing both the excited-state electron-donating and ground-state electron-accepting properties of photosensitizers for effective catalytic activity.

Scheme 2 Photochemical mechanism for 1,4-BNAH generation using TEOA as an electron and proton donor, a water-soluble iridium photosensitizer, and a rhodium co-catalyst for regioselective 1,4-reduction of BNA⁺. Reprinted with permission from ref. 63. Copyright 2023, American Chemical Society.

The bimetallic Ru–Rh system enhances catalytic efficiency by enabling fast electron transfer, optimizing light absorption and catalysis separately, and ensuring compatibility with biological systems.⁶⁴ In this system, a heterodinuclear Ru–Rh complex [(bpy)₂Ru(tpphz)Rh(Cp)Cl]Cl₃ is employed as a photocatalyst to drive the simultaneous production of NADH upon irradiation with visible light (Scheme 3).⁶⁴ The Ru–Rh dyad functions through a photoinduced electron transfer mechanism, where the Ru-based chromophore absorbs light and transfers an electron through the bridging tetrapyridophenazine (tpphz) ligand to the Rh catalytic centre. This ultrafast intramolecular charge transfer facilitates the formation of the catalytically active [Cp*Rh(bpy)H]⁺ species, which selectively reduces NAD⁺ to 1,4-NADH.

Scheme 3 Schematic depiction of the photo-biocatalytic system integrating photocatalytic NADH production from [(bpy)₂Ru(tpphz)Rh(Cp)Cl]Cl₃ with enzymatic reactions. Reprinted with permission from ref. 64. Copyright 2022, John Wiley & Sons.

Efficient electron mediators can potentially replace NADH to improve the efficiency of formate production. Employing the electron mediator cobaloxime in combination with eosin Y as a photosensitizer successfully facilitated the conversion of NAD⁺ to NADH with a yield of approximately 36%, ultimately achieving a high conversion rate of 95% for CO₂-to-formate synthesis (Scheme 4).⁶⁵ Specifically, cobaloxime derivatives, including [Co(dmgH)₂pyCl], [Co(dmgH)₂(py-NMe₂)Cl], and [Co(dmgH)₂(py-COOMe)Cl] (where py = pyridine, py-NMe₂ = 4-(dimethylamino)pyridine, and py-COOMe = methyl isonicotinate), acted as catalysts within a visible-light-driven photocatalytic system. This system utilized eosin Y as the photosensitizing agent and triethanolamine as the sacrificial electron donor to produce NADH from aqueous protons. The mechanistic pathway proposed involves sequential electron transfers from photoexcited eosin Y, reducing Co^III species first to Co^I, followed by protonation to yield a Co^III-hydride intermediate. It is this hydride intermediate that is suggested to directly transfer a hydride to NAD⁺, thereby generating NADH.

Scheme 4 Proposed catalytic cycles for the photo-driven generation of NADH using the cobalt catalyst/Eosin Y/TEOA system and subsequent enzymatic conversion of CO₂ to formate using FDH. Reprinted with permission from ref. 65. Copyright 2012, American Chemical Society.

Modified cobalt diamino-dioxime complexes, including [Co(DO)(DOH)pnX₂] (where X = Cl and Br) and the BF₂-bridged analog [Co((DO)₂BF₂)pnBr₂], demonstrated notable photocatalytic efficiency in regenerating NADH (Scheme 5).⁶⁶ These catalytic systems integrate diverse photosensitizers (PSs), such as [Ru^II(bpy)₃]²⁺ (RuPS²⁺) and 4,8,12-tri-n-butyl-4,8,12-triazatriangulenium hexafluorophosphate (TATA⁺), and xanthene derivatives, including Rose Bengal (RB²⁻) and Eosin Y (EY²⁻), along with triethanolamine (TEOA) as an electron donor. Under visible-light exposure (λ = 420 nm), photoinduced electron transfer from the excited-state photosensitizer to the cobalt catalyst initiates a catalytic sequence, ultimately facilitating the selective reduction of BNA⁺ to its corresponding 1,4-dihydro derivative (1,4-BNAH).

Scheme 5 Molecular structures of cobalt diimine–dioxime catalysts and photosensitizers. Reprinted with permission from ref. 66. Copyright 2020, the Royal Society of Chemistry.

Recent studies have successfully reproduced the stoichiometric reaction of natural photosynthesis through photocatalytic systems that convert NAD(P)⁺ to NAD(P)H using water as the electron source, simultaneously producing oxygen (O₂) (Scheme 6).^67–72 Upon photoexcitation, Acr⁺-Mes forms a stable, long-lived charge-separated state (Acr˙-Mes˙⁺).⁶⁷ Electron transfer from X-QH₂, such as QH₂ and Me₄QH₂, to the Mes˙⁺ moiety of Acr˙-Mes˙⁺, resulting in the formation of X-QH₂˙⁺ and Acr˙-Mes, is energetically favorable, as indicated by the oxidation potentials of X-QH₂ (E_pa vs. SCE = 0.85–1.05 V) and the corresponding reduction potential of Mes˙⁺ within Acr˙-Mes˙⁺.⁶⁷ Under these conditions, particularly at physiological pH, electron transfer from the Cl₄QH⁻ species to the Mes˙⁺ moiety of Acr˙-Mes˙⁺ generates Cl₄QH˙ and neutral Acr˙-Mes, subsequently followed by electron transfer from Acr˙-Mes to Co^III(dmgH)₂pyCl, forming [Co^II(dmgH)₂pyCl]⁻ and regenerating Acr⁺-Mes.⁶⁷ On the other hand, the generated X-QH₂˙⁺ is rapidly deprotonated to produce X-QH˙. Then hydrogen atom transfer or proton coupled electron transfer from X-QH˙ to [Co^II(dmgH)₂pyCl]⁻ produce [Co^III(H)(dmgH)₂pyCl]⁻ and X-Q. This [Co^III(H)(dmgH)₂pyCl]⁻ reacts with NAD⁺ to generate Co-NAD⁺ adduct to produce NADH.⁶⁷

Scheme 6 Illustrated mechanism for NAD⁺ photocatalytic reduction to NADH using X-QH₂, with Acr⁺-Mes acting as a photoredox catalyst and Co^III(dmgH)₂pyCl as an NAD⁺ reduction catalyst. Reprinted with permission from ref. 67. Copyright 2024, American Chemical Society.

Although the overall photocatalytic mechanism closely resembles typical water-splitting reactions,⁶⁶ achieving NAD(P)H synthesis directly from water marks a major advance. This is particularly significant since the resulting NAD(P)H can subsequently serve as a reducing agent for CO₂ conversion into formate using formate dehydrogenase (FDH) (Scheme 7).⁷³

Scheme 7 Molecular photocatalytic cycle involving the photosensitized generation of NAD(P)H from water, in combination with enzymatic CO₂ hydrogenation to formate.

To enhance electron transfer efficiency from the excited-state photosensitizer to NAD⁺, the development and exploration of novel electron mediators remain essential. Effective photocatalytic systems and optimal electron mediators can then be applied to assess the enzymatic reduction of CO₂ to formate.⁷⁴ As previously described, molecular photocatalysts regenerate NAD(P)⁺ to NAD(P)H, which, in combination with FDH, facilitates the enzymatic reduction of CO₂ to formate, regenerating NAD(P)⁺ in the process.^75,76

2.4. Integration of electrochemical NAD(P)⁺ reduction with enzymatic CO₂ conversion to formate

Bioelectrochemical systems (BESs), composed of an anode, cathode, electrodes, and a proton-exchange membrane, have frequently been employed to facilitate electrocatalytic regeneration of NAD(P)H, along with simultaneous conversion of CO₂ to formate at the cathode.⁷⁷ Compared to single-chamber photocatalytic setups, BESs provide distinct advantages, notably the capability to maintain anaerobic conditions for the CO₂ reduction process by physically separating the reaction compartments.⁷⁸

Electrochemical CO₂ reduction into formate can be carried out using two distinct strategies, which are the direct immobilization of the catalyst onto the electrode surface or indirect attachment via mediators. Formate dehydrogenase (FDH) serves as a representative example of direct immobilization, efficiently catalyzing the electrochemical reduction of CO₂ to formate under mild conditions when immobilized on an electrode surface (Fig. 5).⁷⁹ FDH-driven electrocatalysis is characterised by thermodynamic reversibility and minimal overpotential, with the equilibrium reduction potential determined by the zero net catalytic current point. Notably, formate is selectively generated as the exclusive product under mild reaction conditions. FDH thus demonstrates feasibility for reversible electrochemical interconversion between CO₂ and formate and serves as a valuable model for the design and optimization of stable synthetic catalysts for real-world CO₂ reduction technologies.⁷⁹

Fig. 5 Cartoon showing molybdenum/tungsten-containing FDH directly adsorbed onto an electrode surface catalysing the electrochemical reduction of CO₂ to formate. Reprinted with permission from ref. 79. Copyright 2008, Proceedings of the National Academy of Sciences of the United States of America.

The reduction of NAD⁺ was confirmed by attaching not only enzymes but also molecular metal catalysts to the electrode.^80–82 In particular, electrode modifications employing noble metal-based catalysts are frequently studied to enhance NAD⁺ reduction efficiency. In such systems, mediators rapidly receive two electrons directly from the electrode surface along with a proton from the solution, generating hydride species capable of transferring electrons to NAD⁺ to yield NADH.⁸³

Biomimetic metal complexes as additional mediator candidates have also been investigated for NAD⁺ regeneration in enzymatic CO₂-to-formate conversion in an indirect way (Fig. 6).^84–90 Indirect electrochemical methods utilizing electron-transfer mediators represent an effective strategy for cofactor regeneration.⁹¹ In such methods, electron mediators facilitate homogeneous reduction of the substrate, such as NAD⁺, and are subsequently regenerated at the electrode surface. This indirect pathway circumvents several limitations typically encountered in direct electrochemical approaches, including high overpotentials and the formation of inactive NAD dimers. Nonetheless, mediator selection is crucial for performance. Cp*Rh^III(bpy)-based complexes are commonly employed. These mediators undergo a two-electron reduction at the cathode from Rh^III to Rh^I, followed by protonation to yield a rhodium-hydride intermediate. The hydride intermediate subsequently transfers two electrons and a hydride to NAD(P)⁺, regenerating the initial Rh^III catalyst (Scheme 8).⁹⁰ Despite extensive investigation, direct electrochemical NAD⁺ reduction to enzymatically active NADH with complete yield, without electrode surface modification, has rarely been achieved. Following these foundational studies, subsequent research efforts have explored various electron mediators, evaluating their effectiveness in regenerating reduced nicotinamide cofactors and minimizing undesirable NAD dimerization.^92–97 Furthermore, a rhodium-based complex incorporating bis(hydroxymethyl)-pentamethyl bipyridyl ligands exhibited a notably lower reduction peak at 0.549 V versus SHE, approximately 0.17 V more anodic than the NAD dimerization potential.⁹⁷ Although NAD⁺ reduction by this mediator occurred at 0.592 V vs. SHE, the specific yield of the biologically active 1,4-NADH was not detailed. Generally, by applying a constant potential across the electrodes, electrons are transferred, allowing NAD⁺ conversion into NADH through direct, mediator-driven, or enzyme-coupled electrochemical processes.

Fig. 6 Reactor configuration of electrochemical formate generation.

Scheme 8 Proposed catalytic mechanism for electrochemical NADH generation mediated by the rhodium-based complex [Cp*Rh(bpy)Cl]⁺. Reprinted with permission from ref. 90. Copyright 2011, Elsevier.

2.5. Integration of chemical NAD(P)⁺ reduction with enzymatic CO₂ conversion to formate

Beyond photo- and electrocatalytic methods, chemical catalytic systems coupled with enzymatic approaches have also been explored for the reduction of NAD⁺ to NAD(P)H.⁹⁸ Particularly in the early 1980s, rhodium-containing organometallic complexes garnered substantial research interest because of their exceptional performance as electron-transfer mediators in proton reduction reactions.⁹⁹ Leveraging these favorable redox characteristics, a pentamethyl bipyridyl Rh^III complex was subsequently investigated for the direct chemical conversion of NAD⁺ into NADH, utilizing formate as the hydride donor.¹⁰⁰

To gain deeper mechanistic insights into the hydride-transfer process, an intermediate rhodium complex bearing a pentamethylcyclopentadiene ligand was successfully isolated from a short-lived rhodium hydride intermediate.¹⁰¹ Subsequently, the hydride-donating capability of this intermediate complex was evaluated, including its efficiency in reducing NAD⁺ to NADH. Remarkably, the direct involvement of the pentamethylcyclopentadienyl ligand in hydride transfer represented a previously unrecognized mechanistic feature of these rhodium-catalysed NAD⁺ reductions. The mechanism proposed was also supported by density functional theory (DFT) computational studies conducted on related rhodium and iridium organometallic complexes (Scheme 9).¹⁰¹

Scheme 9 Proposed catalytic mechanism for NAD⁺ reduction involving a [(Cp*H)Rh(bpy)]⁺ intermediate species. Reprinted with permission from ref. 101. Copyright 2016, the Royal Society of Chemistry.

Analogous to enzymatic methods employing formate as a hydride donor, ruthenium¹⁰² complexes of the general type [(η⁶-arene)Ru(en)Cl]PF₆ (arene = hexamethylbenzene, p-cymene, or indan; en = ethylenediamine) have also been investigated for catalysing the reduction of NAD⁺ to 1,4-NADH using formate as the hydride source.¹⁰³ The catalytic efficiency of these [(η⁶-arene)Ru(en)Cl]⁺ complexes is influenced by two critical factors.¹⁰³ First, the identity of the coordinated arene significantly affects the turnover frequency (TOF), with performance declining in the order: hexamethylbenzene > indan > p-cymene.¹⁰³ This trend highlights the importance of the arene ligand in facilitating hydride transfer from formate to the ruthenium centre, a process likely serving as the rate-limiting step. Second, substituting the chelating ligand also strongly impacts catalyst performance. Specifically, the replacement of the neutral N,N-chelating ligand ethylenediamine with the negatively charged O,O-chelating ligand acetylacetonate (acac) in p-cymene complexes resulted in a threefold reduction in catalytic efficiency under the same experimental conditions.¹⁰³ This decreased activity was initially explained by stronger binding interactions between the adenine portion of NAD⁺ and the ruthenium catalyst, potentially obstructing access for formate. While the [(η⁶-arene)Ru(en)Cl]⁺ complexes exhibit relatively weak adenine affinity, derivatives such as [(η⁶-p-cymene)Ru(acac)Cl] display notably enhanced binding to adenine.

3. Biomimetic CO₂ reduction to formate

In natural biological environments, hydrogenation reactions are commonly catalysed by enzyme systems that rely on cofactors such as NAD(P)H or flavin mono- and dinucleotides. Transition metal complexes designed as hydrogenation catalysts, functioning analogously to these enzyme-cofactor systems, are emerging as promising biomimetic catalysts. Furthermore, these metal-based complexes are also increasingly explored for biorthogonal catalytic applications within living cellular environments, thereby presenting exciting opportunities for innovative catalytic and medical applications. Recent research indicates that organometallic catalysts can function effectively under physiological conditions, including inside living cells.^104–107 In addition to conventional transfer hydrogenation and electron transfer reactions, the utilization of transition-metal complexes in biological settings has rapidly broadened, paving the way for new catalytic strategies and therapeutic methodologies.

In particular, in studies mimicking photosynthesis, two catalytic pools namely the oxygen-evolving complex (OEC)^108,109 and ferredoxin/ferredoxin-NADP⁺ reductase^110–114 play key roles by providing viable kinetic pathways for both water oxidation and NADP⁺ reduction.¹¹⁵ The reaction of water with NADP⁺, which represents the net electron transfer reaction in the Z-scheme of oxygenic photosynthetic organisms, results in the formation of NADPH, which is subsequently used to reduce CO₂ in light-independent reactions, along with the production of O₂ (Fig. 7).¹¹⁶ Many organometallic complexes have been successfully utilized to independently catalyse water oxidation,^108–120 the hydrogenation of NAD⁺,^{100,121–124} and the dehydrogenation of NADH.^125–128

Fig. 7 Cartoon showing biomimetic transition metal catalysis by mimicking the Z-scheme in nature.

In the final stage of photosynthesis, the Calvin cycle, CO₂ reduction takes place.¹²⁹ Developing a catalytic system that integrates the aforementioned ferredoxin/ferredoxin-NADP⁺ reductase with CO₂ reduction would represent a significant advancement toward artificial photosynthesis. No biomimetic metal catalysts combining NAD(P)H oxidation and CO₂ reduction reactions have been reported, highlighting the need for research in this area. Establishing such a system requires the utilization of previously reported CO₂ reduction catalysts, which are FDH mimetic metal complexes.^130–148 The development of an artificial photosynthesis system could enable practical fuel production by employing an efficient and eco-friendly catalytic system, contributing to both the understanding of biological reaction processes and industrial applications. In this context, we discuss biomimetic metal complexes that catalyse the oxidation of NAD(P)H to NAD(P)⁺ and those that catalyse the reduction of CO₂ to formate, and we propose the potential for developing a catalyst capable of facilitating both reactions simultaneously.

3.1. Biomimetic metal complexes for catalytic NAD(P)H oxidation to NAD(P)⁺

Few studies have been published on homogeneous catalysts in catalytic NAD(P)H oxidation to NAD(P)⁺.^149–153 In the oxidative conversion of 1,4-NADH to NAD⁺ mediated by Ru^II arene bipyrimidine complexes, a plausible mechanism has been proposed (Fig. 8).¹⁴⁹ In this mechanism, hydride transfer from 1,4-NADH to the Ru^II centre occurs via a kinetically favored six-membered ring transition state, which is enabled by the generation of an available coordination site through a ring-slippage process (Fig. 8a). A comparable mechanism is suggested for Ir^III complexes, where a cyclopentadienyl ligand undergoes slippage from η⁵⁻ to η³⁻ coordination (Fig. 8b). Subsequent protonation of the metal-bound hydride leads to H₂ evolution, and coordination of water completes the catalytic cycle.

Fig. 8 Suggested mechanism for hydride transfer from 1,4-NADH to (a) Ru^II complexes and (b) Ir^III complex. Reprinted with permission from ref. 149. Copyright 2003, John Wiley & Sons.

Ir^III cyclopentadienyl complexes can mediate the oxidation of NADH to NAD⁺ via a hydride transfer mechanism (Fig. 9a).¹⁵⁰ In experiments with the chloro complex, [(η⁵-Cp^xbiph)Ir(phpy)(Cl)], the complex was found to accept a hydride from NADH, thereby converting it into its oxidized form, NAD⁺.¹⁵⁰ Similar investigations with the pyridine-bound complex, [(η⁵-Cp^xbiph)Ir(phpy)(py)]⁺ (Fig. 9b and 9c), demonstrate that the nature of the ancillary ligand significantly influences redox behavior and may also lead to the generation of reactive oxygen species. These findings underscore the importance of hydride transfer in the redox cycling of NADH/NAD⁺ and offer insights into the oxidant mode-of-action (MoA) of these Ir^III complexes.

Fig. 9 (a) Cartoon showing the potent oxidant and anticancer activity of organoiridium catalysts. (b) Synthetic pathway of 1-py·PF₆. (c) X-ray crystal structure of [(η⁵-Cp^xbiph)Ir(phpy)(py)]PF₆·(CH₃OH)_0.5. Reprinted with permission from ref. 150. Copyright 2014, John Wiley & Sons.

As shown in Fig. 10a, under mildly acidic conditions, the complex [Cp*Ir(pica)Cl] (1; with pica representing the picolinamidate, or κ²-pyridine-2-carboxamide ion) catalyses the dehydrogenation of β-NADH.¹⁵¹ In this process, β-NADH is oxidized to NAD⁺, which occurs via the removal of a hydride ion along with two electrons. This redox transformation, central to cellular metabolism, underscores the ability of complex 1 to modulate the NADH/NAD⁺ cycle effectively (Fig. 10b). Based on the mechanism, previously reported kinetic experiments and the supporting literature, a catalytic cycle has been proposed for the reduction of NAD⁺ via transfer hydrogenation using potassium formate (HCOO-K⁺) (Fig. 10c). Initially, substitution of the chloride ligand by water forms an aquo complex (A). This species can then either react with formate to yield an intermediate (B) or reversibly bind NAD⁺ to form an off-cycle adduct (E). The formation of adduct E appears to slow the reaction when NAD⁺ concentrations are high, suggesting that NAD⁺ can approach the catalyst in two distinct orientations. Additionally, the generation of intermediate B is likely favored by a hydrogen bond between the carboxylate oxygen and a coordinated –NH group. Subsequent β-elimination from B, accompanied by the release of CO₂, produces a hydridic species (C) that rapidly transfers a hydride to NAD⁺, thereby forming NADH and regenerating the aquo complex A.

Fig. 10 (a) Suggested mechanism for water oxidation to molecular oxygen and NAD⁺/NADH transformations using complex 3. (b) Structure of Ir complexes 1–3. (c) Illustrated mechanism for NAD⁺ hydrogenation using HCOOK as a hydrogen source, catalysed by an iridium complex. Reprinted with permission from ref. 151. Copyright 2017, American Chemical Society.

A series of Ru^II monocarbonyl complexes were reported, all incorporating the bidentate phosphine 1,4-bis(diphenylphosphino)butane (dppb) ligand alongside various bidentate nitrogen ligands (Fig. 11).¹⁵² The general formula of these complexes is [Ru(OAc)CO(dppb)(N^N)]ⁿ (with n = + 1 or 0, and OAc representing acetate). Three complexes were synthesised in which the dppb framework was maintained, while the N^N ligands were varied among 2,2′-bipyridine (bipy), 1,10-phenanthroline (phen), and pyrazino[2,3-f][1,10]phenanthroline (pzphen). Mechanistically, the catalytic cycle for these Ru^II complexes is initiated either directly from the parent complex or from an aquo-species formed upon ligand substitution.¹⁵² This aquo-species reacts with formate to yield a hydride intermediate via β-hydride elimination with concurrent CO₂ release. The resulting hydride complex is then capable of transferring hydrogen to NAD⁺, generating 1,4-NADH and regenerating the aquo-species. In a complementary set of experiments, the catalytic oxidation of NADH was also examined. Under appropriate conditions, such as in a buffered aqueous medium at pH 7.4, formation of the Ru^II hydride species facilitates the oxidation of NADH back to NAD⁺.

Fig. 11 Proposed mechanism for NADH oxidation catalysed by ruthenium complexes and bidentate N^N donor ligands. Reprinted with permission from ref. 152. Copyright 2023, American Chemical Society.

Recent investigations have demonstrated that [Cp*Ir(pyza)Cl] complexes (with pyza denoting pyrazine amidate) function as efficient reversible electrocatalysts for NAD⁺/NADH interconversion (Fig. 12).¹⁵³ Designed to lower the overpotential required for NAD⁺ reduction relative to the earlier [Cp*Ir(pica)Cl] (pica = picolinamidate) system, the unique electronic properties of pyza, which is a weaker σ-donor yet a stronger π-acceptor compared to pica, enable an electronic reduction process at a notably lower potential (approximately −0.29 V) that is very close to the equilibrium potential of the NAD⁺/NADH redox couple (−0.32 V vs. NHE, 298 K, pH 7).¹⁵³ Moreover, the catalyst is capable of driving both NAD⁺ reduction and NADH oxidation with a bias towards reduction, as evidenced by a catalytic current ratio (|ip_red/ip_ox|) of 6.2 at 333 K. The reversible nature of this redox process is underscored by the rapid attainment of equilibrium between the hydride species and NAD⁺ with an equilibrium constant of about 3 and a ΔG_rxn of −0.6 kcal mol⁻¹ at 298 K, along with similar hydridicity values for NADH (28.9 kcal mol⁻¹) and the corresponding iridium hydride (28.3 kcal mol⁻¹).

Fig. 12 Proposed thermochemical mechanism for calculating (kcal mol⁻¹). Reprinted with permission from ref. 153. Copyright 2024, American Chemical Society.

3.2. Biomimetic metal complexes for catalytic CO₂ reduction to formate

Due to the unsustainability of fossil fuels, the development of renewable energy alternatives is necessary. In one strategy, naturally abundant small molecules, such as H₂O and CO₂, are electrochemically converted into value-added products.^154,155 One possible route is the reduction of CO₂ to formate, due to its ability of energy storage and conversion.^156,157 Formic acid can be directly used in fuel cells and can be effectively used as a non-toxic liquid H₂ carrier.^158,159 Among homogeneous electrocatalysts in the CO₂ reduction reaction, production of formate is rare, with a high turnover number due to the competitive hydrogen evolution reaction. This section focuses on homogeneous catalysts with high selectivity for formate.

Ru(II) trimethylphosphine complexes have been identified with the general formula RuX(Y)(PMe₃)₄ (where X, Y = H, Cl, or O₂CMe) as exceptionally active catalyst precursors for this reaction (Fig. 13a).¹³⁰ In particular, the complex RuCl(O₂CMe)(PMe₃)₄ has been recognized for its robust stability and high catalytic efficiency. Moreover, employing the RuCl(OAc)(PMe₃)₄ precursor in conjunction with the salt formed from DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and methylcarbonic acid has yielded remarkable improvements in reaction rates.¹³⁰ This system outperforms other bases by delivering an 8-fold enhancement over tetramethylethylenediamine (TMEDA) and a 10-fold increase compared to triethylamine (Et₃N), which was used in earlier studies. Under these optimized conditions, turnover frequencies have reached up to 95 000 h⁻¹, and there is potential for even greater activity through further optimization of cocatalyst and amine combinations.¹⁴¹

Fig. 13 Structure and TOF of (a) RuCl(OAc)(PMe₃)₄, (b) [Cp*Ir(H₂L₁)Cl]⁺ and (c) PNP-Ir^III trihydride complex.

Deprotonation of the phenolic hydroxyl group occurs in the 4,4′-dihydroxy-2,2′-bipyridine iridium complex [Cp*Ir(H₂L₁)Cl]Cl, resulting in a stabilized catalyst with a characteristic pK_a value of −2.30 (Fig. 13b).¹³¹ These iridium-based catalysts have demonstrated turnover frequencies (TOF) reaching 42 000 h⁻¹, highlighting their impressive catalytic efficiency in hydrogenation processes.¹⁴² Investigations have revealed that a PNP-Ir^III trihydride complex bearing isopropyl groups on its phosphorus atoms exhibits superior catalytic performance, with turnover numbers (TONs) and turnover frequencies (TOFs) exceeding those of any other catalysts reported to date (Fig. 13c).¹³² Deprotonation of the PNP ligand is proposed to play an essential role in the catalytic cycle. Under conditions of 200 °C, this complex achieves a TON of 150 000 h⁻¹.¹³²

Scheme 10 illustrates the proposed catalytic cycle for the reduction of carbon dioxide by an iron catalyst.¹³³ In this cycle, the active iron hydride species is generated initially from the precatalyst.¹³³ This iron hydride then engages in the insertion of CO₂ to form a metal-bound formate intermediate. Depending on the reaction conditions and the presence of appropriate substrates, such as alcohols or amines, the formate intermediate can be transformed further. Protonation releases free formate, and reaction with alcohols leads to the formation of alkyl formats. The cycle is closed by regeneration of the active iron hydride.¹⁴⁴

Scheme 10 Proposed mechanism for CO₂ hydrogenation catalysed using Fe(BF₄)₂·6 H₂O/PP₃. Reprinted with permission from ref. 133. Copyright 2010, John Wiley & Sons.

The Fe^II pincer complex trans-[(^tBu-PNP)Fe(H)₂(CO)] has been identified as a highly active catalyst for the hydrogenation of both carbon dioxide and sodium bicarbonate to formate salts (Scheme 11).¹³⁴ Under aqueous conditions at 80 °C and at low hydrogen pressures (6–10 bar), complex 4 achieves a turnover number of up to 788 and a turnover frequency as high as 156 h⁻¹.¹³⁴ Initial investigations with complex 4 for the hydrogenation of sodium bicarbonate revealed that significant activity is observed only when water is used as the solvent with small amounts of THF as a co-solvent. Experiments conducted at an H₂ pressure of 8.3 bar indicated that the highest activity is achieved at 60 °C with TON = 200.¹³⁴ A proposed mechanism for the hydrogenation of carbon dioxide (Scheme 11) begins with the direct attack of CO₂ on the hydride ligand of complex 4 to form an oxygen-bound formate intermediate (complex 5).¹³⁴ The formate ligand is then readily displaced by a water molecule to yield a cationic species (complex 6). Formation of a dihydrogen-coordinated intermediate (A) is envisaged, which subsequently regenerates the active catalyst. This regeneration may proceed via heterolytic cleavage of coordinated H₂ by hydroxide (pathway B) or through a mechanism involving dearomatization followed by proton migration (pathway C), thereby completing the catalytic cycle.¹³⁴

Scheme 11 Proposed reaction mechanism for CO₂ reduction to produce formate using an Fe pincer complex. Reprinted with permission from ref. 134. Copyright 2011, John Wiley & Sons.

Using well-established thermodynamic parameters for hydricity (ΔG_H⁻) and acidity (pK_a), researchers have designed a cobalt-based catalyst system for converting CO₂ and H₂ into formate (Scheme 12).¹³⁵ In this system, the complex Co(dmpe)₂H [with dmpe = 1,2-bis(dimethylphosphino)ethane] serves as the active catalyst for CO₂ hydrogenation. The proposed catalytic cycle involves three key reactions: hydride transfer from the metal hydride to CO₂, forming a metal-bound formate intermediate, subsequent addition of H₂ to the resulting metal complex and regeneration of the metal hydride via deprotonation.

Scheme 12 Proposed mechanism for CO₂ hydrogenation using Co(dmpe)₂H. Reprinted with permission from ref. 135. Copyright 2013, American Chemical Society.

The reaction mechanisms for the hydrogenation of carbon dioxide catalysed by PNP-ligated metal pincer complexes such as (PNP)IrH₃ (PNP = 2,6-bis(di-iso-propylphosphinomethyl)pyridine) are shown in Scheme 13.¹³⁶ As shown in Scheme 13, two reaction pathways were considered for formic acid formation: one involving direct H₂ cleavage by hydroxide (OH⁻) without any participation from the PNP ligand, and the other involving H₂ cleavage through a mechanism that involves the aromatization and dearomatization of the pyridine ring in the PNP ligand. This finding underscores the vital role played by OH⁻ as a base in the catalytic CO₂ reduction cycle.¹⁴⁷ The computed overall enthalpy barriers for the formation of formic acid from H₂ and CO₂ catalysed by (PNP)IrH₃ were calculated to be 18.6 kcal mol⁻¹.¹⁴⁷

Scheme 13 Proposed mechanism for CO₂ hydrogenation using Co(dmpe)₂H. Reprinted with permission from ref. 136. Copyright 2011, American Chemical Society.

The Fe^II formate carbonyl hydride complexes, (RPNP)Fe(H)CO(HCO₂) (RPNP = HN{CH₂CH₂(PR₂)}₂; R = iPr), bearing a bifunctional amine ligand, have been shown to achieve up to 10⁶ turnovers for formate production with a turnover frequency near 200 000 h⁻¹ (Scheme 14).¹³⁷ A plausible catalytic pathway for CO₂ hydrogenation starting from these complexes involves an initial 1,2-addition of H₂ across the Fe–N bond, followed by the insertion of CO₂ into an Fe–H bond, and finally N–H deprotonation accompanied by formate extrusion to regenerate the active species.¹⁴⁸

Scheme 14 Proposed mechanism for (RPNP)Fe(H)CO/Li⁺ catalysed CO₂ hydrogenation. Reprinted with permission from ref. 137. Copyright 2015, the Royal Society of Chemistry.

In a comprehensive study on the catalytic reduction of CO₂ to formate, it was observed that the Ir^III trihydride complex with a bifunctional PNP ligand shows exceptional selectivity for formate formation, even in the presence of water as a solvent (Fig. 14).^138–140 The reduction proceeds with a faradaic yield of 93%, with formate being the only reduced carbon product, and no formation of carbon monoxide (CO) (Fig. 14a).¹³⁸ In a related investigation, an In^III trihydride complex ((PN^HP)IrH₃) supported by a bifunctional PNP ligand was reported as an exceptionally mild electrocatalyst for this transformation, delivering near-quantitative faradaic efficiencies (up to 99%) for CO₂ reduction to formate (Fig. 14a and 14c).¹³⁹ The catalytic cycle for the reduction of CO₂ to formate involves the extrusion of the formate product and subsequent proton–electron transfer steps to regenerate the tri-hydride iridium complex and complete the cycle. These findings are consistent with a similar reaction mechanism proposed for a (POCOP)IrH₂ catalyst (Fig. 14a and 14b), where a cationic acetonitrile adduct of iridium is implicated as the initial formate-lost product in the cycle.¹⁴¹ Mechanistic insights indicate that, following CO₂ insertion into an Ir–H bond, the extrusion of the formate product and subsequent proton–electron transfer to the iridium centre regenerate the active Ir(III) trihydride species. A similar sequence has been proposed for (POCOP)IrH₂, where a cationic acetonitrile adduct is suggested to form initially upon formate loss; however, hydrogen bonding between the bound formate and an ancillary N–H moiety can impede product release.¹³⁹ The product release from this iridium complex is believed to be influenced by hydrogen bonding between the bound formate and the N–H group in the ancillary ligand, which could potentially hinder the release process. A parallel electrocatalytic mechanism has been seen in the (POCOP)IrH₂(MeCN) complex (Fig. 14a), which exhibits an impressive 85% faradaic efficiency. The proposed mechanism involves the formation of an acetonitrile adduct of the dihydride species, which exists in rapid equilibrium with the cationic species. Upon electron reduction, cationic species undergoes a sequential two-electron, one-proton reduction to generate the dihydride species again, resulting in the formation of bicarbonate (HCO³⁻) as CO₂ reacts with hydroxide.¹⁴⁰ Both the dihydride species and its cationic form in the form of BArF⁴⁻ salts have been independently synthesised and characterised, further validating this catalytic cycle. Overall, these studies not only unravel the operational mechanisms of highly efficient iridium catalysts for CO₂ reduction but also provide critical insights into the roles of auxiliary ligands, proton sources, and the equilibrium dynamics that govern their catalytic activity. Additionally, another study on an Ir^III trihydride complex with a bifunctional PNP ligand confirmed its remarkable selectivity for formate production, achieving a faradaic efficiency as high as 99%.¹³⁹

Fig. 14 (a) Molecular structures of four Ir complexes. (b) Proposed mechanism for electrocatalytic CO₂ reduction catalysed by (b) the (POCOP)IrH₂(MeCN) complex or (c) the (PN^HP)IrH₃ complex. Reprinted with permission from ref. 137. Copyright 2020, American Chemical Society. Reprinted with permission from ref. 138–140. Copyright 2013, 2015 and 2012, the Royal Society of Chemistry and American Chemical Society.

cis-H,T-Rh₂(L)₂(phen)₂ (phen = 1,10-phenanthroline) complexes with L being trifluoroacetamidate (complex 1), N-tolylacetamidate (complex 2), or N,N′-bis(tolyl)ethanimidamidate (complex 3) were prepared as shown in Fig. 15.¹⁴¹ The Rh₂(II,I)-hydride acts as a key intermediate. Electrochemical data indicate that, at around 1.6 V, complex 2 undergoes a three-electron reduction followed by protonation in the presence of water to form an axial Rh₂(II,I)-hydride.¹⁴¹ This intermediate is proposed to transfer a hydride to CO₂, thereby releasing formic acid upon subsequent protonation. In contrast, complex 1 is inactivated via oligomer formation during reduction, and complex 3 exhibits the lowest reactivity and selectivity toward CO₂ reduction.¹⁴¹ The reduced performance of complex 3 is attributed to the steric hindrance imposed by two tolyl groups at the axial sites, which likely interferes with the approach of CO₂ to the active centre.¹⁴¹

Fig. 15 (a) Schematic representation of the molecular structures of 1–3. (b) The proposed electrocatalytic cycle for CO₂-to-HCOOH conversion using complexes 1 and 2. Reprinted with permission from ref. 141. Copyright 2021, the Royal Society of Chemistry.

A series of manganese carbonyl complexes bearing elaborated bipyridine or phenanthroline ligands have been developed that selectively reduce CO₂ to either formic acid or CO, depending on the ligand design (Figs. 16a and 16b).¹⁴² When the ligand framework incorporates strategically positioned tertiary amines, the complexes preferentially produce formic acid. Conversely, if the amine groups are absent or located far from the metal centre, CO is the predominant reduction product.¹⁴² Notably, the amine-modified complexes rank among the most active catalysts for CO₂ reduction to formic acid, achieving turnover frequencies as high as 5500 s⁻¹ at an overpotential of 630 mV.¹⁴² Furthermore, it was observed that decorating the bipyridine ligand with benzylic diethylamine groups at the ortho positions shifts the product selectivity from CO to formic acid. Mechanistic investigations indicate that these amine groups play a critical role by delivering a proton to the manganese centre to generate a Mn-hydride intermediate. This intermediate then undergoes CO₂ insertion and, following an additional protonation step, yields formic acid. As shown in Fig. 16c, two pathways were proposed for forming [Mn(OCOH)]⁻ from CO₂ reduction. In one route (referred to as the LO pathway), a Mn-H intermediate undergoes CO₂ insertion and then is reduced, thereby yielding [Mn(OCOH)]⁻ species. Alternatively, in the HO pathway the same intermediate is first reduced and then undergoes CO₂ insertion, with protonation to produce formic acid. Another suggested role for the amine group is that it could capture CO₂, forming a carbamate intermediate. However, carbamates were not detected in the other amine-containing complexes exposed to CO₂, which suggests that this pathway is unlikely to occur. A more plausible role of the amine groups is to function as Brønsted bases that sequester protons and deliver them to the metal centre, thereby generating a manganese-hydride intermediate. This proton relay mechanism has been invoked to explain the formation of a minor amount of formic acid under electrocatalytic conditions and has been observed in photochemical CO₂ reduction studies. Importantly, the acidity of the reaction medium is critical; for instance, using a strong acid such as HCl may favor H₂ evolution via Mn-hydride intermediates over the desired CO₂ reduction.

Fig. 16 (a) Proposed mechanism illustrating ligand-dependent product selectivity in Mn-bipyridine-catalysed electrochemical CO₂ reduction. (b) Chemical structures of modified bipyridine–Mn complexes. (c) Proposed catalytic cycle for CO₂ reduction to HCOOH. Reprinted with permission from ref. 142. Copyright 2020, American Chemical Society.

The iron carbonyl cluster, [Fe₄N(CO)₁₂]⁻, has been identified as an effective electrocatalyst for the selective reduction of CO₂ to formate across a wide pH range (5–13) (Scheme 15).¹⁴³ Under conditions with low applied overpotentials (230–440 mV), formate is produced with a high current density of 4 mA cm⁻² and boasts a faradaic efficiency of 96%. These remarkable catalytic performances are further complemented by the long-term stability of the catalyst, with a lifetime exceeding 24 hours. As shown in Scheme 15, the CO₂ reduction mechanism involves the reduction of the electrocatalyst from 1⁻ to an oxidation state, followed by protonation to form the hydride species (H-1)⁻. Analysis of the solution and gas phase reveals that (H-1)⁻ selectively interacts with CO₂, facilitating the formation of a C–H bond and subsequently producing formate as the final product. Operating at low overpotentials (230–440 mV), this catalyst produces formate with impressive metrics, achieving a current density of 4 mA cm⁻² and a faradaic efficiency of 96%, while maintaining a long operational lifetime (>24 h).

Scheme 15 Mechanistic proposal for CO₂ reduction to formate by 1⁻ in a proton-rich environment. Reprinted with permission from ref. 154. Copyright 2015, American Chemical Society.

Moreover, the proposed mechanism for the electrocatalytic reduction of CO₂ is shown in Scheme 16,¹⁴⁴ integrating both experimental electrochemical findings and DFT computational insights. In this mechanism, the catalytically active species is a Co^II-hydride intermediate that plays a central role in both H₂ evolution and CO₂ reduction. The cycle is initiated by a Co^III precursor that undergoes two successive electron transfers to generate a Co^I species.¹⁴⁴ This low-valent species is then protonated and further reduced, leading to the formation of a Co^II–hydride intermediate. DFT calculations, performed on models of the acetonitrile derivative of the catalyst, support a concerted proton-coupled electron transfer (PCET) process in this conversion.¹⁴⁴ In particular, computed redox potentials that account for the involvement of a pendant amine group align closely with the experimentally observed potential, reinforcing the role of PCET in a purely sequential electron–proton transfer. Once formed, the Co^II-hydride intermediate reacts with CO₂ to produce a CO₂ adduct. This intermediate subsequently undergoes an internal hydride transfer, yielding a formate-bound species. The final step involves the extrusion of formic acid, which regenerates the active cobalt species and completes the catalytic cycle.

Scheme 16 DFT-optimized mechanism for CO₂ reduction using the CpCo(PCy₂NBn₂)I₂MeCN-real model. Reprinted with permission from ref. 144. Copyright 2017, American Chemical Society.

One of the CO₂ reduction catalysts to produce formate, an iron complex, [Fe(PP₃)(MeCN)₂](BF₄)₂, was reported.¹⁵⁶ The proposed mechanism for electrocatalytic CO₂ reduction is shown in Scheme 17 via the formate pathway.¹⁴⁵ In this pathway, free CO₂ is directly reduced to formate. Under reductive conditions, [Fe(PP₃)(MeCN)₂](BF₄)₂ is reduced by 2e⁻ and Fe(PP₃)⁺ to generate Fe(PP₃)⁺.¹⁴⁵ The resulting Fe(PP₃)⁺ then reacts with CO₂ to form the formate adduct [(PP₃)Fe(HCO₂)]⁺. Finally, the formate is dissociated, regenerating [Fe(PP₃)(MeCN)₂](BF₄)₂ and thereby completing the formate pathway.

Scheme 17 Proposed mechanism for CO₂ reduction to formate catalysed by [Fe(PP₃)(MeCN)₂](BF₄)₂. Reprinted with permission from ref. 145. Copyright 2019, the Royal Society of Chemistry.

A series of cobalt(III) pyridine–thiolate complexes have been investigated as electrocatalysts for CO₂ reduction to produce formate.¹⁴⁶ The detection of CO as a minor product suggests that an alternative pathway may be operative, in which CO₂ initially binds to a reduced Co^I centre and subsequently undergoes proton-mediated C=O bond cleavage (Scheme 18).¹⁴⁶ These experimental observations, together with the DFT calculations performed, led to the proposal of an overall reaction mechanism for the reduction of CO₂ to formic acid (HCOOH), H₂, and CO, as illustrated.

Scheme 18 Proposed reaction mechanism for the generation of HCOOH and H₂, with relative Gibbs free energies (ΔG, kcal mol⁻¹) and transition state barriers (ΔG^‡, kcal mol⁻¹) referenced to the preceding intermediate. Reprinted with permission from ref. 146. Copyright 2020, John Wiley & Sons.

The proposed reaction mechanisms for CO₂ reduction to formate and hydrogen by complex 3 derived from the pre-catalyst [(bdt)Mo^VI(O)S₂CuICN]₂ offer an exciting advancement in the field of electrocatalysis using Earth-abundant metals (Scheme 19).¹⁴⁷ In this system, the active catalyst species is generated in situ by the loss of an oxo group, which, in other contexts, would be involved in carbonate formation.¹⁴⁷ This unprecedented strategy creates a vacant coordination site that facilitates the formation of a highly reactive metal hydride intermediate. Notably, the Cu^I centre is critical for the activity of the catalyst, although further studies are needed to fully understand the interplay between the molybdenum and copper sites. This work not only enriches the family of electrocatalysts that catalyze the conversion of CO₂ to formate but also paves the way for designing new systems based on sustainable metal resources.

Scheme 19 Proposed reaction mechanisms for CO₂ reduction to formate and hydrogen catalysed by complex 3, derived from pre-catalyst 1. Relative Gibbs free energies (ΔG, kcal mol⁻¹) and transition state barriers (ΔG^‡, kcal mol⁻¹) are referenced to the preceding intermediate, with standard one-electron reduction potential (E°, V) given vs. Fc/Fc⁺. The added electron in complex 3_red is localized on the S_3p orbitals of the ligands. Reprinted with permission from ref. 147. Copyright 2020, the Royal Society of Chemistry.

Stable Ni-dithiolene complexes, structurally similar to molybdopterin, were prepared and characterised for the electroreduction of CO₂ (Fig. 17a).^148,160 These complexes efficiently catalyse CO₂ reduction, with formic acid as the major product. Among them, [Ni^III(qpdt)₂]⁻ achieves 13 turnovers in 4 hours, with a faradaic yield of formic acid of 60%.¹⁴⁸ Notably, [Ni^III(2H-qpdt)₂]⁻ exhibited the highest selectivity for CO₂ reduction to produce formic acid, with a faradaic yield of 70%, significantly outperforming hydrogen reduction, which showed a faradaic yield of only 4%. In parallel, the corresponding Mo(O)(dithiolene)₂ complexes have also been synthesised.¹⁶⁰ These represent the first functional and stable catalysts inspired by the Mo centre of formate dehydrogenases. Under photoreduction conditions, the Mo-based catalysts predominantly generate formic acid, with carbon monoxide as a minor product, achieving more than 100 turnover numbers in approximately 8 hours (Fig. 17b).

Fig. 17 (a) Structures of [Ni^III(qpdt)₂]⁻ and [Ni^III(2H-qpdt)₂]⁻. (b) Scheme for electrocatalytic CO₂ reduction to formate using Mo complexes. Reprinted with permission from refs. 148 and 160. Copyright 2019 and 2018, American Chemical Society and John Wiley & Sons.

A mechanistic pathway for the electrochemical reduction of CO₂ to formate using the [Co(triphos)(bdt)]⁺ complex has been established through a combination of experimental electrochemical data and DFT calculations.¹⁶¹ Cyclic voltammetry (CV) measurements show an anodic shift at the [Co(triphos)(bdt)]⁰/⁻ couple under a CO₂ atmosphere and in the presence of a proton source, indicating favorable interactions between the catalyst and reaction substrates. DFT calculations suggest that the catalytic cycle proceeds via an ECEC mechanism, wherein an initial one-electron reduction of [Co(triphos)(bdt)]⁰ (II) generates [Co(triphos)(bdt)]⁻ (III), a necessary precursor for catalytic activity (Fig. 18). A subsequent protonation step leads to the formation of the cobalt-hydride intermediate [Co(triphos)(bdt)(H)]⁰ (IV-H), with a computed hydricity (ΔG_H⁻) of 58.7 kcal mol⁻¹. However, this hydricity value is insufficient to drive direct CO₂ reduction thermodynamically. Instead, an additional electron transfer is required, reducing IV-H to [Co(triphos)(bdt)(H)]⁻ (V), which exhibits a significantly lower hydricity of 37.8 kcal mol⁻¹, making it competent for CO₂ reduction. The reduction potential of the IV-H/V couple was calculated to be −1.61 V vs. Fc⁰/⁺, well within the electrochemical window where catalytic turnover occurs. This suggests that electron transfer to the metal hydride species is an essential step in the catalytic cycle, facilitating the hydride transfer to CO₂. The formation of the formato complex [Co(triphos)(bdt)(HCOO)] (VI) is favored, followed by dissociation of formate and regeneration of the active catalyst.

Fig. 18 Proposed mechanism for electrocatalytic CO₂ reduction to formate using [Co(triphos)(bdt)]⁺. Reprinted with permission from ref. 161. Copyright 2024, the Royal Society of Chemistry.

To the best of our knowledge, there has been no report on the use of molecular biomimetic compounds as catalysts in catalytic CO₂ reduction to formate using NAD(P)H. In order to develop a catalyst and clarify the mechanism by capturing the intermediates formed in CO₂ reduction to formate using NAD(P)H, experiments should be conducted using the biomimetic metal complexes mentioned above.^162–164 This will be a process of developing the most effective catalyst using all chemical, photochemical, and electrochemical catalytic reactions. In particular, the optimal ligand system and experimental reaction conditions related to the stability of the molecular catalyst will be a big key to the success of the catalytic reaction. By anchoring effective homogeneous catalysts on heterogeneous supports, highly efficient hybrid catalytic systems can be developed that combine the advantages of both the tunability of homogeneous catalysts and the practicality of heterogeneous supports (Fig. 19). Such systems are expected to evolve significantly in the future, as exemplified by recent studies reporting the highest selectivity for CO₂-to-formate conversion using hybrid catalysts.¹⁶⁵ Therefore, this strategy could serve as a foundational platform for the next generation of catalyst design and development.

Fig. 19 Cartoon showing hybrid catalytic systems by anchoring effective homogeneous catalysts on heterogeneous catalysts.

4. Conclusion

Cascade biocatalysis involving enzymatic conversion of CO₂ into formate represents an attractive sustainable strategy for CO₂ utilization, potentially contributing significantly to mitigating climate change and global warming. To further optimize catalytic efficiency, extensive research has focused on enhancing enzyme stability, decreasing catalyst costs, and improving overall system robustness. To realize the full potential of enzymatic CO₂ reduction technologies, ongoing efforts continue to explore methods to enhance catalytic stability, reaction efficiency, and economic feasibility. Catalytic reduction of CO₂ to formate using NAD(P)H represents a promising strategy for mitigating carbon emissions and producing value-added chemicals. Formate dehydrogenase (FDH) serves as a natural biocatalyst for this conversion, and its structural and mechanistic insights have inspired the development of FDH mimetic metal complexes. Despite significant progress in enzymatic and biomimetic systems for CO₂ reduction, no molecular biomimetic catalysts have yet been reported that effectively couple NAD(P)H oxidation with CO₂ reduction to formate.

Future research should focus on designing and optimizing biomimetic metal complexes with an emphasis on stabilizing molecular catalysts through optimal ligand design and reaction conditions. Furthermore, enzymatic catalysis integrated with photochemical or electrochemical technologies is anticipated to serve as a leading approach for efficient, selective, and economically viable conversion of CO₂ to formate. Such systems leverage renewable energy sources, enabling sustainable and affordable CO₂ transformation. Specifically, formate generation catalysed by engineered enzymes combined with renewable photo/electrochemical systems could facilitate the subsequent synthesis of valuable industrial platform chemicals. Consequently, substantial efforts are being dedicated to developing catalytic systems characterised by affordability, selectivity, durability, and sustainability, thereby advancing practical whole-cell CO₂ fixation strategies. This review may hopefully provide more productive insights into the successful development of such catalysts and could pave the way for efficient artificial photosynthesis systems and sustainable fuel production, contributing significantly to global carbon management and industrial applications.

Author contributions

Young Hyun Hong: supervision, conceptualization, and writing – original draft & review. Chanwoo Park: investigation and writing – editing & review. Chaeyeon Kwon: formal analysis and visualization – editing & review.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors gratefully acknowledge the contributions of their collaborators and coworkers cited in the listed references, and the work at Sogang was supported by the National Research Foundation (NRF) through the G-LAMP program funded by the Korean government (MOE, RS-2024-00441954).

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