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# Formate Dehydrogenases Mimics as Catalysts for Carbon Dioxide Reduction

Thibault Fogeron, Yun Li, Marc Fontecave

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## To cite this version:

Thibault Fogeron, Yun Li, Marc Fontecave. Formate Dehydrogenases Mimics as Catalysts for Carbon Dioxide Reduction. Molecules, 2022, 27, pp.5989. 10.3390/molecules27185989. [hal-03934635](https://hal.sorbonne-universite.fr/hal-03934635)

HAL Id: hal-03934635

https://hal.sorbonne-universite.fr/hal-03934635

Submitted on 11 Jan 2023

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# Formate Dehydrogenases Mimics as Catalysts for Carbon Dioxide Reduction

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Thibault Fogeron,ᵃᵇ Yun Li,ª and Marc Fontecave*ª

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ªLaboratoire de Chimie des Processus Biologiques, UMR 8229 CNRS, Collège de France, Paris Sorbonne University, 11 Place Marcelin Berthelot, 75231 Paris Cedex 05, France.

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ᵇCurrent address : Laboratoire de Chimie, Ecole Normale Supérieure de Lyon, Université de Lyon, CNRS UMR 5182, 46 allée d'Italie, 69364 Lyon, France

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* Corresponding author. Marc fontecave@college-de-france.fr

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## Abstract

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Formate dehydrogenases (FDH) catalyze reversibly the interconversion of CO₂ to formate. They belong to the family of molybdenum and tungsten-dependent oxidoreductase. For several decades, scientists have been synthesizing structural and functional model complexes inspired by these enzymes. These studies not only allow for finding certain efficient catalysts, but also in some cases to better understand the functioning of the enzymes. However, FDH models for catalytic CO₂ reduction are less studied compared to the oxygen atom transfer (OAT) reaction. Herein, we present recent results of structural and functional models of FDH.

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## Keywords

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formate dehydrogenases, structural models, functional models, dithiolene complexes, carbon dioxide Reduction

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## I. Introduction

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Storage of diluted and intermittent sources of energy such as solar and wind energy is a great challenge of the 21st century. It can be accomplished by the conversion of solar or wind electricity into chemical energy, via formation of chemical bonds that can durably store the energy. For this reason, the reduction of CO₂ is particularly appealing since, through its transformation into a variety of energy-dense carbon compounds, it not only allows energy storage but also gives access to fuels, allowing the use of renewable energy as a source of energy without important shift of technology. The reduction of CO₂ can also be used as a
carbon feedstock to form precursors for organic synthesis, leading to valuable organic compounds useful for the chemical industry [1, 2].

CO₂ is a thermodynamically stable molecule. Furthermore, its reduction implies multi-electron and multi-proton transfers which results in very low kinetics. As a consequence, catalysts are absolutely needed. If heterogeneous materials are generally considered as more stable and more efficient catalysts for CO₂ reduction, molecular metal complexes can offer more tunability and selectivity [3]. For these reasons, the molecular approach has been extensively developed over the last decades. Among the most remarkable and studied complexes reported in the literature, one can mention Re- and Mn-bipyridine complexes (1 and 2), metal complexes using N-based macrocycles, such as porphyrins 3, phtalocyanins and quaterpyridines, and Ni-cyclam complexe 4 (Figure 1) [4]. Nevertheless, the library of complexes able to catalyse the reduction of CO₂ efficiently and selectively remains narrow, especially if we compare it with molecular complexes for hydrogen production.

<figure><img src="image_4.png" /><figcaption>**Figure 1.** Some of the most known molecular catalysts for CO₂ reduction.</figcaption></figure>

In order to expand this library and develop catalysts with non-noble metals the bioinspired approach, yet at its infancy, is likely to be useful. In fact, while a number of enzymes have shown the ability to catalyse the conversion of CO₂ into CO or formic acid, using unique metal active sites, very little has been done to synthesize bioinspired complexes mimicking these active sites and to evaluate their catalytic activity. In this review, we focus on the models based on molybdenum- and tungsten-dependent formate dehydrogenases [5]. We show that this bioinspired approach can lead to new classes of interesting molecular catalysts for CO₂ photo- and electro-reduction.
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## II. Formate Dehydrogenases (FDHs)

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FDHs catalyze the reversible transformation of CO₂ to HCOOH according to a two-electron redox process (eq. 1). There are two classes of FDHs: NAD-dependent ones that do not contain any metal ion and metal-dependent ones that possess a mononuclear molybdenum (or tungsten) center. Several excellent reviews described the different aspects of this enzyme in detail [5-8]. We will herein focus on the metal-dependent FDH and settle for a short summary.

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$$ \mathrm{HCOO}^{-} \rightleftharpoons \mathrm{CO}_{2}+2 \mathrm{e}^{-}+\mathrm{H}^{+} \quad \mathrm{E}^{0}=-420 \mathrm{~mV} \quad(\mathrm{eq} \ 1) $$

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The structures of several FDHs from different organisms have been elucidated by X-ray diffraction [9-12]. The Mo (or W) atom is coordinated by two guanidine phosphate esterified pyranopterin cofactors called PGT (Figure 2, top). The [Mo(PGT)₂] (or [W(PGT)₂]) structure is well conserved in FDHs from different organisms and during the catalytic cycle. The cofactor without the guanosine moiety is called molybdopterin (MPT, Figure 2, top). MPT is a highly unstable organic molecule and has never been isolated without the protein backbone. It is composed of a pterin with a fused pyran ring carrying a dithiolene chelate (Figure 2, top). The redox state of the Mo (or W) atom varies from +VI to +IV during the catalytic cycle. Additional apical ligands are present; however, their exact coordination configuration remains controversial. It is generally admitted that, in the oxidized form, the Mo VI /W VI atom is coordinated by a selenocysteine (in a few cases a cysteine) residue and a terminal sulfido ligand (Mo/W=S) that is essential for catalytic activity. But at first and for a long time, this ligand was thought to be a terminal oxo ligand. It was only recently (2006) that this result was reinterpreted by Romão *et al.*, who determined it to be a sulfido ligand [12]. The reduced form of the enzyme is still a subject of controversy: the Mo IV /W IV center is presumably coordinated with a terminal hydrosulfido ligand (Mo/W-SH), along with the selenocysteine (or cysteine) residue (Figure 2, bottom). However, some publications suggest that the selenocysteine (or cysteine) residue is no longer present and the metal center is pentacoordinated with a SH ligand [12].
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<figure><img src="image_11.png" /><figcaption>**Figure 2.** Structures of **PGD** and **MPT** (top) and active site of FDHs: M = Mo/W (bottom). The presence of the selenocysteine ligand in the reduced form is debated.</figcaption></figure>

<figure><img src="image_12.png" /><figcaption>**Scheme 1.** One of the possible proposed mechanisms of FDHs (M = Mo/W).</figcaption></figure>

Recent studies show that there is no clear-cut experimental evidence that formate/carbon dioxide coordinates to the metal center during the catalytic oxidation/reduction process. Furthermore, the formation of a M(IV)-H hydride species could not be detected during the reduction of carbon dioxide process. Due to the fact that there are some ambiguities over the reduced form, the mechanism of this enzyme is not unanimously established. We herein show one mechanism among other proposals with M(IV)-SH for hydride transfer during the carbon dioxide reduction step (Scheme 1) [13]. More experimental studies are needed for unambiguously determine the mechanism.
## III. Structural models of FDH

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As mentioned earlier, the exact nature of the axial ligand and its role in the mechanism has been only recently emphasized [7]. It was thought that FDHs catalyze oxygen transfer reactions, as most molybdenum and tungsten enzymes do, which was compatible with the first crystallographic structure of an enzyme of this family having $M^{VI}=O/M^{IV}-OH$ as the axial ligands. This is probably why, so far, most models were synthesized with a terminal oxo ligand.

As a result, very few $M^{VI}=S/M^{IV}-SH$ complexes have been developed (M = Mo/W). The main challenges for the development of synthetic models of the active site of FDHs resided in the stabilization of bis-dithiolene Mo/W-complexes. The first models of **MPT** containing enzymes were synthesized as models of oxotransferases such as DMSO reductase (DMSOR). Most of this work was done by the group of Richard Holm in the 90's [14], who developed various synthetic routes to obtain bis-dithiolene Mo(W)-oxo complexes. Quite simple dithiolene ligands were used. Other groups also contributed to this effort with simple dithiolene ligands [15-18].

Two other challenges to be addressed for close mimics of FDHs regarded the nature of the axial ligands and the structure of the dithiolene ligands.

### III.1. Variation of the axial ligands

With simple dithiolene ligands (R = Me, Ph), Holm and al. developed a method allowing the introduction of different axial ligand thanks to substitution of carbon monoxide ligands on molybdenum or tungsten carbonyl complexes [19-23]. The precursors $Mo/W(dithiolene)_{2}(CO)_{2}$ were prepared by a trans-metalation reaction from a Ni(IV)-bisdithiolene complex. Unfortunately, the overall yields for the preparation of such complexes are quite low, which is a strong limitation if one wants to use more elaborate ligands. It seems that this methodology can only be applied to simple dithiolene ligands with Me and Ph groups. More recently, Elvers et al. synthesized similar complexes thanks to the photochemical deprotection of 1,3-Dithiol-2-ones and *in situ* complexation [24]. In this case, the yields remained modest (max 20 %) and aliphatic dihiolenes ligands could also be used.
<figure><img src="image_13.png" /><figcaption>**Scheme 2.** Synthetic route of bis-dithiolene Mo(W) complexes with different axial ligands developed by Holm and co-workers.</figcaption></figure>

### III.2. Pyrazine containing ligands

However, the active site of FDH cannot be modeled only by its first coordination sphere, as the pterin part of the ligands plays an important role as a proton relay and also as a mediator of the red-ox properties of the active site. Schulzke and co-workers performed DFT calculations with model complexes Mo/W(O)(dithiolene)₂ and showed that in order to reproduce accurately the molecular/electronic properties of **MPT**, a simple dithiolene ligand was not appropriate even within a pyran ring and that the minimal ligand should be a fused pyran-tetrahydropyrazine-functionalized dithiolene, denoted **prz**. The third pyrimidine cycle seems not to be mandatory (Figure 3) [25].

Hence, in the following paragraph we will describe only ligands bearing such a structure, with different oxidation states for the pyrazine cycle. The formation of a pyran cycle fused with a pyrazine unit represents the most challenging synthetic step.
<figure><img src="image_14.png" /><figcaption>**Figure 3.** Prz as minimum required ligand according to the DFT calculations.</figcaption></figure>

One of the earliest and most elaborate syntheses of MPT-like ligands was developed by the groups of Joule and Garner at the end of the 90's [26-30]. It was specified that without the protection of the secondary amine N10, **5** was not stable and the pyran ring could open up in a proton assisted reaction (Scheme 3) [27]. In contrast, MPT is stable in the tricyclic form within FDHs, possibly because the active site does not contain a proton exchange site that favors pyran ring opening. One should note that, under very specific conditions, during protein crystallization for example, open forms of MPT have been obtained, reflecting the sensitivity of such pterin-pyran-dithiolene molecules [10, 31, 32]. However, the physiological relevance of these open forms is not established [33].

<figure><img src="image_15.png" /><figcaption>**Scheme 3.** Pyran ring scission according to Joule and co-workers.</figcaption></figure>

In all the syntheses, the formation of the pyran ring was achieved by using a chloroformiate reagent to activate the nitrogen on the pyrazine cycle, after the protection of the dithiolene moiety. This activation also allowed the protection of the amine N10 and thus avoided an opening of the pyran cycle. The second imine of the cycle was then reduced and the resulting amine could be protected to prevent the reoxidation. In these remarkable syntheses, even the stereochemistry of the asymmetric carbons was matching with the natural ligand. **6a, 6b and 6c** were obtained (Scheme 4). Unfortunately, no molybdenum or tungsten complexes were described with these ligands. Nevertheless, $CoCp(dithiolene)$ ($Cp=$
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cyclopentadienyle) complexes were obtained proving the possibility for the molecules to
coordinate a metal center once deprotected (Scheme 4).

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<caption>**Scheme 4.** MPT-like Ligands synthesized by Joule and co-workers.</caption>

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Later, Basu's group obtained a family of dithiolene ligand containing the **prz** moiety
**7a – 7g** (Scheme 5). Here again, after the protection of the dithiolene function in **8**, a
chloroformate activation through an intramolecular reaction between an amide and an alcohol
in **9** allowed the formation of the pyran cycle **7**. However, in these cases, the carbamate
derivatives were not obtained, and a fully oxidized pyrazine cycle was instead formed
(Scheme 5). The main drawback of this strategy was the relatively low global yield, especially
when the di-amine used in the Gabriel-Isay condensation was asymmetric due to the poor
regioselectivity of this step. Again, no tungsten or molybdenum complexes using these
ligands were reported [34, 35].
<figure><img src="image_17.png" /><figcaption>7a</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>7b</figcaption></figure>

<figure><img src="image_19.png" /><figcaption>7c</figcaption></figure>

<figure><img src="image_20.png" /><figcaption>7d</figcaption></figure>

<figure><img src="image_21.png" /><figcaption>7e</figcaption></figure>

<figure><img src="image_22.png" /><figcaption>7f</figcaption></figure>

<figure><img src="image_23.png" /><figcaption>7g</figcaption></figure>

<figure><img src="image_24.png" /><figcaption>8</figcaption></figure>

<figure><img src="image_25.png" /><figcaption>9</figcaption></figure>

<figure><img src="image_26.png" /><figcaption>7a</figcaption></figure>

**Scheme 5.** MPT-like Ligands synthesized by Basu and co-workers.

Burgmayer *et al.* used a rather original approach to prepare a closed pyran cycle. They observed a tautomerism between a closed and an open pyran cycle **10a** and **10b** directly on a molybdenum complex with a dithiolene ligand and a tris(3,5-dimethylpyrazolyl)hydroborate (Tp*) chelate (Scheme 6) [36, 37]. The spontaneous cyclisation depends upon the polarity of the solvent in which the complex was studied. This reaction was also studied with a simpler ligand **11** (Scheme 6) [38]. In this case, the cyclisation was not spontaneous but was promoted by the addition of trifluoroacetic acid (TFA). Unfortunately, the closed form was not stable, and dehydration of the ligand was observed yielding to a pyrrolo-quinoxaline ligand.

This study brings interesting insights for the catalytic site of FDH. However, the nature of the Tp* ligand is quite different from the natural ligand. Moreover, due to the equilibrium phenomenon, a mixture of two forms could be obtained, so it is hard to envisage organic reactions on the ligand to stabilize the pyran form once it is formed. Thus, these systems are not appropriate for catalytic studies.
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<figure><img src="image_28.png" /></figure>

<figure><img src="image_29.png" /><figcaption>**Scheme 6.** Solvent-dependent equilibrium between the open chain forms and the cyclized pyran forms.</figcaption></figure>

In a quest for the bioinspired catalyst for CO₂ reduction, we developed a **prz** containing ligand with an oxidized pyrazine cycle similar to the one obtained by Basu *et al* (Scheme 5). However, we adopted a new synthetic strategy, wherein we chose to first prepare the tricyclic skeleton and then to introduce a protected dithiolene moiety [39, 40]. Starting from 2,3-dichloroquioxaline **12**, the tricyclic molecule **13** was prepared in two steps according to a reported method [41]. The enol ether was hydrolyzed to the corresponding enol **14**, which was functionalized by bromination to **15** and activated by triflation to give **16**. Finally, a double cross-coupling reaction catalyzed by palladium allowed to introduce the protected dithiolene moiety. The protected ligand **17** was prepared in a straightforward and easily scalable way (Scheme ).
<figure><img src="image_30.png" /><figcaption>**Scheme 7.** Synthesis of the protected ligand **17** and structure of ligand **qpdt**.</figcaption></figure>

After deprotection of **17**, the quinoxaline-pyran-fused dithiolene ligand **qpdt** (Scheme 7) could be obtained and directly used for complexation. The biomimetic complex $(Bu_4N)_2[Mo^{IV}O(qpdt)_2]$ (**18**) (Figure 5) was thus synthesized and fully characterized including via X-ray crystallography, showing that it is sharing a number of structural properties with the active site of FDHs. It proved to be a quite good catalyst for both electro- and photoreduction of protons into hydrogen [39]. However, further analysis showed that **18** was not the active catalyst, but a pre-catalyst. Indeed, under acidic and reductive conditions the ligand could undergo a ring opening of the pyran cycle [42]. This was unambiguously observed in the case of the $[Co^{III}Cp(qpdt)]$ complex **19**, for which the product of electro-reduction **20** could be isolated and characterized. A possible mechanism is illustrated in Scheme 8. This reaction was promoted by the protonation of the quinoxaline cycle. A similar reaction was also observed when the protected ligand **17** was treated with sodium dithionite as a source of electrons.
<figure><img src="image_31.png" /><figcaption>19: [Co<sup>III</sup>Cp(qpdt)]</figcaption></figure>

<figure><img src="image_32.png" /><figcaption>20</figcaption></figure>

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<figure><img src="image_36.png" /><figcaption>**Scheme 8.** Electro-reduction of [Co<sup>III</sup>Cp(qpdt)] resulting in an unusual ring scission.</figcaption></figure>

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These observations emphasized the necessity to better mimic MPT by reducing the pyrazine cycles. In order to obtain such molecules, we decided to work with the tricyclic skeleton previously described (Scheme 9). Indeed, we showed that obtaining such a motif was the key step of the synthesis. Moreover, these molecules could be easily obtained on a 10 g scale and as such constituted a good basis to develop new synthesis. Starting with molecule **16**, the reduction of the first imine on the pyrazine cycle was possible tby the activation of N10 with a methylation reaction [43]. The iminium obtained **21** could be easily reduced by NaBH(OAc)₃. Then, following the same methodology as for **qpdt**, the protected dithiolene moiety was introduced, leading to molecule **23**, with a partially reduced pyrazine cycle. The reduction was completed by treatment with NaBH₃CN to give the secondary amine **24**, followed by acylation, in order to avoid reoxidation of the obtained amine, leading to **25**. Interestingly, the two protons of the junction of the pyrazine and pyran cycles in **25** adopt a *cis* configuration (racemic mixture), as it is the case, with R, R absolute configuration, in MPT.
<figure><img src="image_37.png" /></figure>

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[Co**III**Cp(2H-qpdt)] : 27

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[Co**III**Cp(H-qpdt)] : 26

* relative stereochemistry is indicated

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**Scheme 9.** Synthesis of dithiolene ligands **23**, **25** and complexes [Co**III**Cp(H-qpdt)] (26) and [Co**III**Cp(2H-qpdt)] (27). Conditions: i) (Me₃O)(BF₄); ii) Me₄NBH(OAc)₃; iii) Pd(dba)₂ (10 %), Xantphos (10 %), HSCH₂CH₂CO₂Et, iPr₂NEt; iv) Pd₂(dba)₃ (15 %), Xantphos (30 %), HSCH₂CH₂CO₂Et, iPr₂NEt; v) NaBH₃(CN), AcOH; vi) AcCl, iPr₂NEt; vii) CoCpI₂(CO).

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Since the two red-ox states of the pyrazine cycles of **23** and **25** could be found in nature, they were used for further complexation. Following Joule and Garner's methodology [26], [Co**III**Cp(dithiolene)] complexes were first prepared in order to structurally characterize the ligands. Structures of the different complexes obtained are shown in Figure 4. As expected, the ligand went from a fully planar structure in **qpdt** to a bent structure with an significant angle between the pyrazine and the pyran cycle in **2H-qpdt**. As a comparison, a 3D representation of ligand MPT in FDHs is shown in Figure 4d and underline the structural similarity between 2H-qpdt and MPT. Electronic properties were assessed thanks to NMR, UV-Visible spectroscopy and electrochemistry, which showed that with reduction of the pyrazine cycle the ligand has a more electron-donating effect onto the metal. In particular, 2H-qpdt was much more donating than H-qpdt which in good agreement with the hypothesis
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that the co-existence of both reduced states in natural active sites helps the modulation of their
red-ox activities.

<figure><img src="image_47.png" /><figcaption>b</figcaption></figure>

<figure><img src="image_48.png" /><figcaption>c</figcaption></figure>

<figure><img src="image_49.png" /><figcaption>d</figcaption></figure>

<figure><img src="image_50.png" /></figure>

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**Figure 4.** Structure representations of (a) [Co<sup>III</sup>Cp(qpdt)] **19**, (b) [Co<sup>III</sup>Cp(H-qpdt)] **26**, (c) [Co<sup>III</sup>Cp(2H-qpdt)] **27** and (d) Mo<sup>IV</sup>(MPT)<sub>2</sub> 3D simplified representation of a MPT ligand in FDHs.

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More interestingly, both K₂[MoIVO(H-qpdt)₂] (28) and (Bu₄N)₂[MoVO(2H-qpdt)₂] (29) (Figure 5) could be prepared, constituting the closest mimics of the FDH active site obtained so far. K₂[MoIVO(H-qpdt)₂] (28) could be structurally characterized, confirming the structure of the ligand found in the structure of [CoIII Cp(H-qpdt)] 26 (Figure 4b). Two different structures were obtained, one with the dithiolene chelate in a *trans* orientation with respect to MoS₄ core and one with a *cis* orientation. Unfortunately, no crystal structure of (Bu₄N)₂[MoVO(2H-qpdt)₂] (29) could be obtained, probably due to the existence of many stereoisomers. Indeed, since 2H-qpdt exists in the form of a mixture of two enantiomers and the two ligands could be *cis*- or *trans*-oriented with respect to the MoS₄ core, a mixture of seven stereoisomers was expected. Nevertheless, indirect evidence led us to propose that the structure of 2H-qpdt around the metal is similar to the one found in [CoIII Cp(2H-qpdt)] 27 (Figure 4c). Additionally, (Bu₄N)₂[MoVO(2H-qpdt)₂] (29) was well-characterized by other technics and we could confirm its red-ox state (MoV) thanks to UV-Visible and EPR spectroscopy as well as cyclovoltammetry.
<figure><img src="image_51.png" /><figcaption>**Figure 5.** Structures of complexes **18**, **28** and **29**.</figcaption></figure>

## IV. Functional models

Until now most of dithiolene complexes studied for their catalytic activity have been tested for the reduction of protons into $H_2$ [40, 44-51]. In a first part, we will focus on the few examples of tungsten or molybdenum-bis(dithiolene) complexes that were shown to react with carbon dioxide. In a second part, we will discuss metal dithiolene complexes, with other metal ions than molybdenum or tungsten, which catalyze the reduction of $CO_2$. Finally, we will also present those active complexes containing tungsten or molybdenum, but without sulfur-based ligands.

### IV.1. Mo/W-(dithiolene)₂ complexes

#### IV.1.a. Equimolar reaction with $CO_2$

The first reaction between a tungsten bis-dithiolene complex and $CO_2$ was described by Sarkar and Das [52]. They reported that $[W^{IV}O(mnt)_2]^{2-}$ (30) could slowly react with bicarbonate to give formate and $[W^{VI}O_2(mnt)_2]^{2-}$ (31). The yield in formate was 55% based on 30 (Scheme 10).
<figure><img src="image_52.png" /></figure>

<figure><img src="image_53.png" /><figcaption>**Scheme 10.** Non-catalytic reduction of CO₂ by tungsten bis-dithiolene complexes.</figcaption></figure>

Kim and co-workers also described an equimolar reaction between the tungsten complex $[W^{IV}O(Me_2C_2S_2)_2]^{2-}$ (32) and CO₂ which led to formate [53]. This reaction was accompanied by the formation of a triply bridged dinuclear W(V) complex (33) (Scheme 10).

### IV.1.b. Catalytic reduction of CO₂

The three complexes $[Mo^{IV}O(qpdt)_2]^{2-}$ (18), $[Mo^{IV}O(H-qpdt)_2]^{2-}$ (28) and $[Mo^{V}O(2H-qpdt)_2]^{2-}$ (29) (Figure 5) were tested for the photocatalytic reduction of CO₂ [43]. Catalytic CO₂ reduction activity was assessed under photochemical conditions, using $[Ru(bpy)_3]_2^+$ as a photosensitizer (PS), BIH (1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzoimidazole) as the sacrificial electron donor and CH₃CN/TEOA (triethanolamine) in a 5:1 ratio as the solvent, saturated with CO₂. Complex 18 was highly selective for proton reduction into H₂, while complexes 28 and 29 showed ability to catalyze CO₂ reduction into a mixture of formic acid and carbon monoxide. The most selective complex was complex 29, with a much larger proportion of CO₂-derived products accounting for almost 60% (39% formate and 19% CO) and a total TON of 210 after 15 hours. Complex 28 was less active (TON= 95) and less selective (53% H₂). Thus, the redox state of the central pyrazine ring seems to be determinant to selectively catalyze the reduction of CO₂ into formate. While FDHs are highly selective for CO₂ reduction and do not produce any H₂ during catalysis, the FDHs mimics discussed here are also good catalysts for proton reduction. DFT calculations suggested that the axial oxo ligand played a key role for driving this reaction (Scheme 11). Indeed, protonation of the reduced complex Mo(O) generates a doubly protonated intermediate Mo(OH)(H) 34, in which one proton bound to the O ligand is very well positioned to react with the Mo-H hydride species, thus generating H₂, in competition with this hydride reacting with CO₂ to form formic
acid [40]. It is interesting to note that, in contrast, the enzyme has different mainly S-based axial ligands (Figure 2). We made the tentative proposition that this axial coordination is critical for controlling the selectivity. However this requires the functional characterization of appropriate mimics (as shown in Scheme 2) be functionally characterized.

<figure><img src="image_54.png" /></figure>

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<caption>**Scheme 11.** Proposed catalytic cycle for proton reduction by complex **18**.</caption>

To date, these complexes which are the closest mimics of the active site of FDHs are the only Mo/W-dithiolene complexes able to catalyze the reduction of CO₂. It is quite interesting to note that not only formate could be obtained, but also that the most selective and active catalyst toward the formation of formate is the one bearing the closest mimic of the natural MPT-ligand.

Recently, Kumar *et al.* suggested, thanks to DFT calculations, that adding an imidazole moiety close to the axial position of the metal center could ease the reduction of CO₂ into formate (Figure 6) [54]. This could be an interesting modification, however in this purely theoretical work one of the ligand is not a dithiolene but only a disulfide chelate.

<figure><img src="image_55.png" /></figure>

Mol I = R₁, R₂, R₃ and R₄ are changed

Mol II = L₁ is changed

Mol III = R₅ is changed
**Figure 6.** Some Mo-dithiolene complexes potentially interesting for CO₂ reduction according to the DFT calculations.

## IV.2. Mo/W-Cu complexes, models of CO-dehydrogenases

Here, we describe bimetallic complexes containing a Mo/W-dithiolene subunit coupled to a monuclear copper subunit. While the first component mimics FDH active site, the combination of both metal centers is reminiscent of the active site of CO-dehydrogenase (CODHs). CODH is another metalloenzyme able to reversibly reduce CO₂ into CO. There are two major families of CODHs: [Mo-Cu] [55] and [Ni-Fe] [56] CODHs. The former contains a heterobimetallic Mo-Cu active site in which the two metal ions are bridged by a sulfide ion, the Mo ion also being coordinated by the MPT ligand and an oxo/hydroxo moiety, and Cu(I) completing its coordination with a cysteinate from the polypeptide chain (Figure 7a); the latter contains a NiFe₄ cluster (Figure 7b), in which the Ni atom is used as the redox center and the pending Fe atom of the cluster is used exclusively as a Lewis acid to activate CO₂ and facilitate the cleavage of one of the C-O bonds.

<figure><img src="image_56.png" /></figure>

<figure><img src="image_57.png" /></figure>

**Figure 7.** Active sites of (a) [MoCu]CODHs with M = Mo and (b) [NiFe]CODHs.

<figure><img src="image_58.png" /></figure>

35: [(bdt)Mo⁶⁺(O)S₂Cu¹CN]²⁻

<figure><img src="image_59.png" /></figure>

38: [(bdt)(O)W⁶⁺(µ₂-O)(µ₂-S)Cu¹(NHC)]⁻

**Figure 8.** Two model complexes of [MoCu]CODHs.

Few synthetic dithiolene Mo/W dinuclear complexes have been explored as catalysts for catalytic CO₂ reduction. The complex [(bdt)Mo⁶⁺(O)S₂Cu¹CN]²⁻ (**35**, Figure 8, left) has been studied by our group as a catalyst for CO₂ electroreduction. As a result, complex **35** proved stable during CO₂ electroreduction in acetonitrile in the presence of a source of protons and formic acid was obtained as the major product (Faradic Efficiency: 70 – 75 %),
365

together with H₂ (20 %) and very small amounts of CO. Spectroscopic studies and DFT calculations (Scheme 12) proved that the complex was in fact just a pre-catalyst. Indeed, the first reaction was the loss of the oxo-ligand by a 2-electron reduction, via an efficient oxo-transfer to CO₂ leading to carbonate which eventually dissociates to give **36**, as shown by *in-situ* infra-red spectroelectrochemistry. The release of this coordination site allowed, after another reduction, the formation of a metal-hydride complex **37** which promoted the reduction of CO₂ into formate [57] (Scheme 12).

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<figure><img src="image_60.png" /></figure>

35

<figure><img src="image_61.png" /></figure>

<figure><img src="image_62.png" /></figure>

36

<figure><img src="image_63.png" /></figure>

<figure><img src="image_64.png" /></figure>

37

<figure><img src="image_65.png" /></figure>

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**Scheme 12.** Proposed mechanism of CO₂ electroreduction catalyzed by [Mo VI (O)S₂(bdt) Cu I CN]²⁻ **35**, based on spectroscopic studies and DFT calculations. TFEH=Trifluoroethanol.

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This complex is so far the only mimic of [Mo-Cu]CODH to have the ability to catalyze the reduction of carbon dioxide. However, the difference of selectivity between this synthetic model (generating formate) and the enzyme (generating CO) still remains to be explained.

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In that perspective, it is interesting to mention the work of Mankad's group [58]. They synthesized the [(bdt)(O)W(μ<sub>2</sub>-S)(μ<sub>2</sub>-O)Cu(NHC)]<sup>-</sup> complex (38, Figure 8) as a synthetic model (NHC = N-heterocyclic carbene) (Figure 8, right). With this complex they failed to detect any oxidation of carbon monoxide. Supported by DFT calculations they explained that this absence of reactivity was due to the two μ<sub>2</sub>-O and μ<sub>2</sub>-S bonds between W and Cu. Indeed, in the natural active sites, the backbone of the enzyme forces the two metals to be far apart from each other, allowing only one μ<sub>2</sub>-S bridge between the two atoms thus creating a frustrated Mo<sup>VI</sup>O/Cu<sup>I</sup> Lewis pair. These features seemed to be mandatory to obtain CO oxidation.

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### IV.3. Other Mo/W complexes

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Several Mo/W complexes that do not contain any dithiolene ligand have been described as catalysts for the reduction of CO<sub>2</sub>. Even if these complexes are structurally quite different from the active site of FDH, they can bring interesting insights on the role of these metal centers for the reduction of CO<sub>2</sub>.

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Based on the previous work on manganese complexes, Kubiak's group studied the bipyridine-Mo/W(CO)<sub>4</sub> complex 39 (Figure 9) [59]. After the loss of one carbon monoxide ligand, the active catalyst was formed and could directly reduce CO<sub>2</sub> into CO. These complexes were very selective toward the formation of CO with faradaic yield close to 100%. However, their activity was low with an important overpotential. These results were confirmed by cyclovoltammetry and spectroscopic studies by Tory *et al.* [60]. Other diamine complexes such as 40[61] and 41[62] (Figure 9) have been tested but were too unstable to efficiently catalyze the reduction of CO<sub>2</sub>. Finally, Grice and Saucedo showed that the presence of a non-innocent ligand was not mandatory to promote the reduction of CO<sub>2</sub>, using hexacarbonyl Mo and W complexes [63]. These complexes were functioning at a similar overpotential to produce CO but were less selective with the formation of formate in the presence of water.
<figure><img src="image_66.png" /></figure>

39

<figure><img src="image_67.png" /></figure>

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<figure><img src="image_68.png" /></figure>

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<caption>**Figure 9.** Some Mo/W based complexes active for CO₂ reduction.</caption>

### IV.4. Ni(dithiolene)₂ complexes

As mentioned earlier, the Ni center of [Ni-Fe]-CODH, in a tetra-sulfur environment, is the only redox active metal in the cluster (Figure 7). For this reason, we considered [Ni(dithiolene)₂] complexes as a reasonable bioinspired complex for mimicking this active site. The availability of the **qpdt** ligand afforded the possibility to prepare the complex (Bu₄N)[Ni³⁺(qpdt)₂] (42) in which the Ni ion is tetracoordinated in a S₄ environment with a square planar geometry (Figure 10) [64]. We showed by electrolysis that in the presence of trifluoroethanol as a proton source, this complex was able to promote the reduction of CO₂ into formate as the major product (60%), together with small amounts of CO and H₂. However, these results could only be obtained on a mercury electrode. This observation was reminiscent of the case of [Ni(cyclam)]²⁺, and this might originate from favourable transient interactions between the complex and the Hg surface. However, it is very likely that this complex was only a pre-catalyst and that ligand pyran ring opening occurred during electro-reduction. For this reason we also assessed Ni-bisdithiolene complexes with dithiolene versions having a fully reduced pyrazine ring (Figure 10) [65]. (Bu₄N)[Ni³⁺(H-qpdt)₂] (43) was first prepared. **44a** and **44b** were obtained *via* chemical and electrochemical reduction of **42** respectively. (Bu₄N)[Ni³⁺(2H-qpdt)₂] (45) was also obtained using the ligand 2H-qpdt. All these complexes catalyzed the reduction of CO₂ to formate as the major product. **44b** proved to be the most active (larger TONs) and the most selective (FY for formate 70%) among all Ni(bis-dithiolene) complexes studied. This was quite surprising, especially knowing that the only difference between **44a** and **44b** resided in the configuration of the ring junction, *cis* vs. *trans*. It is very likely that this is also the consequence of using a Hg electrode. Thus, we postulate that noncovalent interactions between the complexes and the Hg surface are strong enough to affect the activity of stereoisomers differently.
<figure><img src="image_69.png" /></figure>

42

<figure><img src="image_70.png" /></figure>

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<figure><img src="image_71.png" /></figure>

44a

* relative configuration

<figure><img src="image_72.png" /></figure>

44b

<figure><img src="image_73.png" /></figure>

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<caption>**Figure 10.** Structures of complexes [Ni<sup>III</sup>(qpdt)<sub>2</sub>]<sup>-</sup> (42), [Ni<sup>III</sup>(H-qpdt)<sub>2</sub>]<sup>-</sup> (43) and [Ni<sup>III</sup>(2H-qpdt)<sub>2</sub>]<sup>-</sup> (45); chemical reduction of **43** gave **44a** and electroreduction of **43** gave **44b**.</caption>

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The mechanism of CO<sub>2</sub> reduction by complex **42** was studied by the DFT calculations. **42** was the pre-catalyst and under electrolysis, the ring-opening reaction first took place to furnish **46**, which gave after protonation the key intermediate Ni<sup>III</sup>-H **47**. After the departure of formate, **47** was regenerated by a 2-electron reduction process (Scheme 13).
<figure><img src="image_74.png" /></figure>

42

<figure><img src="image_75.png" /></figure>

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<figure><img src="image_76.png" /></figure>

<figure><img src="image_77.png" /></figure>

<figure><img src="image_78.png" /></figure>

<figure><img src="image_79.png" /></figure>

<figure><img src="image_80.png" /></figure>

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<caption>**Scheme 13.** Proposed reaction mechanisms of CO₂ reduction by complex 42 to formate.</caption>

V. Conclusion

CO₂ reduction remains a challenging reaction, and a variety of strategies has been followed in order to optimize both solid and molecular catalysts. However, there is still progress to be made, in terms of selectivity, efficiency and stability. The bio-inspired approach, consisting in the design of metal complexes mimicking enzyme active sites, is an original approach that has been exploited only very recently and is still at its infancy. FDHs and CODHs are a family of enzymes that represent remarkable targets for understanding CO₂ binding, activation and transformation into formate and CO respectively. Unfortunately, these enzymes are difficult to study structurally and mechanistically, in particular because of their extreme sensitivity towards O₂. Bioinspired complexes might thus be ideal to understand CO₂ reduction mechanisms by natural active sites as well as to discover novel catalysts. The very first studies described here nicely demonstrate that FDHs and CODHs mimics can display interesting catalytic activities. However, more work is needed to better incorporate key components of the active sites, such as S-based axial ligands in FDH mimics, single S bridges in Mo-Cu complexes as well as Ni-(S)n sites in NiFe clusters. This research might result in fascinating synthetic challenges as well as in novel efficient catalysts.

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