Vincent Blanchard

Zakariae Asbai

Kevin Cottet

Guillaume Boissonnat

Marc Port

Zacharias Amara
email: zacharias.amara@lecnam.net

Continuous Flow Photo-oxidations Using Supported Photocatalysts on Silica

Keywords: Visible-light photochemistry, Photo-oxidation, Singlet oxygen, Heterogenized catalysts, Flow chemistry, Juglone

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Visible-light photocatalysis has recently witnessed a huge development in organic synthesis as it enables powerful transformations and efficiently complements ultraviolet-light (UV) photochemistry. [START_REF] Stephenson | Visible Light Photocatalysis in Organic Chemistry[END_REF] This technology is attractive from a sustainability standpoint because photocatalysis can induce very selective reactions and visible-light is less energy demanding than UV light. [START_REF] Yoon | Visible Light Photocatalysis as a Greener Approach to Photochemical Synthesis[END_REF] However, visible-light photocatalysis requires the addition of catalytic amounts of soluble dyes (photocatalysts (PC) or photosensitizers) which are difficult to recover after the reaction. [START_REF]For sake of clarity, we use in this paper the term "photocatalyst" instead of "photosensitizer", although the reaction studied relies on energy transfer which is[END_REF] This can generate important sustainability and costs issues, especially in the case of organometallic PCs which are made of expensive rare-earth transition metals. [START_REF] Teegardin | Advances in Photocatalysis: A Microreview of Visible Light Mediated Ruthenium and Iridium Catalyzed Organic Transformations[END_REF] Therefore, ingenious recycling strategies have been recently developed, such as supporting these chemicals on solid materials to allow simple reuse and limit time consuming and/or costly purifications. [START_REF] Wilson | Photoredox Catalysis of Intramolecular Cyclizations with a Reusable Silica-Bound Ruthenium Complex[END_REF] Some of these recycling options have also been successfully demonstrated in flow reactors, where continuous catalyst separation can be carried out either downstream or in a single operation using fixed-bed reactors. 5d, 6d,e The latter is very attractive because it allows to generate a localized excess of catalyst by circulating the substrate over a packed catalytic bed, thereby promoting faster conversions, but it is also challenging in the case of photochemistry, because light has to efficiently penetrate in the reactor. [START_REF] Maggini | Fullerene-Promoted Singlet-Oxygen Photochemical Oxygenations in Glass-Polymer Microstructured Reactors[END_REF] This approach has been successfully exploited in the field of continuous hydrogenation reactions, however, it has so far found little application in photochemical manufacturing with visible-light. [START_REF] Maggini | Fullerene-Promoted Singlet-Oxygen Photochemical Oxygenations in Glass-Polymer Microstructured Reactors[END_REF][START_REF] Amara | large scale application of an asymmetric hydrogenation using an immobilized homogeneous chiral catalyst in a packed bed continuous flow reactor[END_REF] An early example was reported by Carofiglio and Maggini who used a covalently linked fullerene photosensitizer on silica or polystyrene beads hosted in microstructured photoreactors. 7a More recently, Poliakoff and George used a porphyrin immobilized by acid base interaction on a sulfonated resin in scCO2 to produce the antimalarial drug artemisinin. 6e Belecki and Gupton reported on the production of the same target using rose bengal covalently linked to a Merrifield resin in a packed bed photoreactor. 7b The same PC was used in a more recent work by Monbaliu and Heinrichs but as covalently linked to mesoporous silica nanoparticles. The system was efficiently exploited as a colloidal suspension in a flow reactor. 7c Although the conversions of the heterogeneous system were slightly lower than the homogeneous version, the catalyst had a higher stability. Similarly, Seeberger and Gilmore elegantly expanded on Blechert's work, who initially explored the reactivity of the visible-light semiconductors (C3N4) in a fixed bed photochemical flow reactor, by exploiting this same PC as a moving colloidal catalytic bed in a photochemical flow system. 7d,e Recently, our group has exploited the non-covalent immobilization of the cationic PC, bipyridine ruthenium(II) [Ru(bpy)3Cl2], on negatively charged silica (SiO2) particles in order to develop a simple and cost competitive recycling strategy. 6a This approach was successfully applied to the intensification of the photochemical oxidation of terpenes with singlet oxygen ( 1 O2) as it enabled an up to ten-fold increase in reaction rate as well as a four-fold improvement in catalyst stability. Given the success of this approach, we were interested in investigating its performance in a continuous flow process where the catalyst is contained in a fixed bed reactor.

In order to evaluate how this strategy compares with the batch process, we investigated the photo-oxidation of 1,5-dihydroxynaphtalene (1,5-DHN) to produce juglone, which represents a key building block in the synthesis of commercially important anthraquinones. [START_REF] Suchard | Photooxygenations of 1-naphthols: an Environmentally Friendly Access to 1,4-Naphthoquinones[END_REF] This reaction is highly selective under neutral pH conditions since juglone is obtained as the sole product.

Despite the high selectivity of this reaction, juglone remains relatively expensive and difficult to source on large scale. The photo-oxidation of naphtols with photochemically generated 1 O2 has been well reported, including using heterogeneous photocatalysis 9d-fe and once in a continuous flow falling film system. 9g However, the combination of both has not been reported.

RESULTS AND DISCUSSION:

Poly-cationic dyes can efficiently interact with negatively charged SiO2 and this interaction is sufficiently stable to drive adsorption in aqueous mixtures without leaching even after multiple washings. 6a With this observation in mind, we prepared two classes of PC@SiO2 by mixing either [Ru(bpy)3Cl2] or the sulfonate salt of tetramethylpyridinium porphyrin (TMPyP) in water with commercial SiO2 (Figure 1). [START_REF]Standard commercial amorphous micrometric silica for column chromatography was used as solid support in all our experiments 0,04-0,063 mm for column chromatography) was purchased from[END_REF] The corresponding adsorbate/adsorbent mixtures were recovered by filtration and the colored powders were used after drying in the photocatalytic reaction without further treatment. We first performed preliminary studies in batch in order to compare the activity of the PCs when used either in solution or supported on SiO2. Our investigations were carried out using CH3CN as a solvent as it was found to combine high 1,5-DHN and oxygen solubility as well as a long 1 O2 lifetime (81 µs). [START_REF] Bregnhøj | Solvent-Dependent Singlet Oxygen Lifetimes: Temperature Effects Implicate Tunneling and Charge-Transfer Interactions[END_REF] These series of experiments clearly showed an improved efficiency of the porphyrin dye compared to the organometallic one (Figure 2). These results can be explained by the difference in 1 O 2 quantum yields between the two sensitizers. [START_REF] Frederiksen | The reported 1 O2 quantum yields (ΦΔ) for TMPyP and Ru(bpy)3 in water are 0.77 and 0.41 respectively[END_REF] Juglone also absorbs visible light (λ ab max = 420 nm) and could therefore compete with the sensitizers absorptions. As porphyrins can be excited at lower energy wavelengths (Q-bands), which are not absorbed by juglone, we speculate that this can also contribute to the higher conversions provided by TMPyP compared to Ru(bpy)3. In the case of TMPyP we were able to measure a maximum Space Time Yield (STY) of 0.22 g.L -1 .h -1 (conversion of 76% at 0.01 M, 20 °C, 6 h, using TMPyP@SiO2 4.5 mg/g, 0.16 mol%). Notably, we found that for both PCs, the soluble systems displayed better performances compared to the heterogeneous ones. This difference could be attributed to the fact that the reaction is carried out in a polar solvent which could disfavor the previously reported surface effects. 6a Indeed, when we performed the same transformation in a mixture of CH3CN/CH2Cl2 (1/1 ratio), the heterogeneous system gave faster conversion to juglone compared to the homogeneous ones, although with lower productivity compared to CH3CN (see ESI, part 9a). Remarkably, in the two heterogeneous systems, no leaching of PC was observed (see ESI, part 9b).

Conversion (%) Time (h)

TMPyP@SiO2 TMPyP [1,5-DHN] = 0.01 M was used for all trials. [Ru(bpy)3]@SiO2 2.5 mg/g (0.16 mol%) and of

[TMPyP]@SiO2 4.5 mg/g (0.16 mol%) were used. [START_REF]A range of catalytic systems with different PS density from 0.5 to 9 mg/g on the silica particles were prepared but we did not find any significant difference[END_REF] Given the known advantages of flow over batch chemistry, such as mixing, heat and mass transfers, and control of residence time, the synthesis of juglone was investigated using a homemade flow photo-reactor (Figure 3). [START_REF] Cambié | Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment[END_REF] Briefly, the reactor consists of a transparent tube containing the PC@SiO2 catalyst (1.3 g per cartridge, 1/4'' PTFE tubing, vol = 1.5 mL) stoppered with cotton wool. [START_REF]Continuous flow experiments were duplicated with PFA tubes[END_REF] Continuous irradiation was carried out with white LED strips surrounding the tube. The substrate was delivered by means of an HPLC pump and oxygen or air was dosed via a high pressure switching valve (Rheodyne) The reactants were mixed via a T-piece prior to entering the reactor. As explained above, the advantage of this design is that the fixed catalytic bed will generate a localized increase in PC concentration. The concentrations of PC are therefore supposed to be significantly higher than in the corresponding batch process. The heat generated by the LEDs was expelled by a fan localized under the reactor. This allowed to maintain an average temperature of 24°C throughout the entire operation. Our first experiment started with [Ru(bpy)3]@SiO2 2.5 mg/g, by using a substrate concentration of 0.006 M, air as an oxygen source and a residence time of 15 min (Table 1, entry 1). This gave a stable and clean conversion of 81 % in juglone with no apparent loss of activity during the time of the experiment. By keeping all parameters the same but replacing air with pure oxygen, the conversion increased to 96 % without formation of any side product or degradation (entry 2). Increasing the organic flowrate to 1.0 mLꞏmin -1 and the oxygen flowrate to 1.0 mLꞏmin -1 resulted in a decrease in conversion to 40 % (entry 3). Increasing the concentration to 0.01 M had similar effects, leading to a conversion of 45 % (entry 4). By modifying the catalyst to TMPyP@SiO 2 4.5 mg/g but maintaning all other parameters the same, a promising yield of 77 % was obtained (entry 7). This result is equivalent to a STY of 5.35 g.L -1 .h -1 . By adding a second cartridge, which is equivalent to a 2-fold increase in residence time (30 min), the conversion reached 78 % and 100 % for Ru(bpy)3 and TMPyP respectively (entries 6 and 8). While increasing the concentration provided lower yields, in all these experiments a steady conversion was maintained for 6 to 8 hours of run showing no catalyst deactivation throughout the entire operation.

CONCLUSIONS

In conclusion, a simple catalyst immobilization strategy was developed allowing to easily interchange a commercially available photocatalyst or photosensitizer on inexpensive and readily available SiO2 to generate 1 O2 and produce the commercially important synthetic intermediate juglone. This proved to be a highly efficient approach for the synthesis of juglone in batch and in flow with STYs of 0.22 g.L -1 .h -1 and 5.35 g.L -1 .h -1 respectively when using TMPyP as a sensitizer. In all our experiments, no leaching was observed and the production remained stable throughout the entire time of our experiments (typically 6 to 8 h). In addition, this low pressure flow process can incorporate multiple cartridges in series without increasing its footprint. Its potential to be easily and safely reproduced in other laboratories should also be underlined as this low pressure reactor does not require specialized engineering and expensive high pressure equipment. This photochemical production approach should therefore find more widespread applications in organic synthesis.

EXPERIMENTAL SECTION

General procedure for batch reactions

Homogeneous conditions

A 100 mL solution of 1,5-DHN (concentration depending of the experiment) was prepared in a given solvent and sonicated for 3 min. Then, 1 mL from a 10 mL solution of photocatalyst (0.16 mol% in relation to 1,5-DHN) in the same solvent was added to the solution of 1,5-DHN. The solution was then transferred in the thermo-regulated batch reactor. An oxygen balloon with a needle bubbling in the liquid was used to continuously oxygenate the solution throughout the entire experiment with slow magnetic stirring. The reactor was irradiated by LEDs and the temperature was maintained at 20 °C.

Heterogeneous conditions

A 100 mL solution of 1,5-DHN (concentration depending of the experiment) in a given solvent was prepared to which supported photosensitizer (quantum satis 0.16 mol% equivalent of TMPyP) on silica was added. The slurry was then transferred in the thermo-regulated batch

reactor. An oxygen balloon with a needle bubbling in the liquid was used to continuously oxygenate the solution throughout the entire experiment with slow magnetic stirring. The reactor was irradiated by LEDs and the temperature was maintained at 20 °C.

General procedure for continuous flow reactions

A solution of 1,5-DHN (concentration depending of the experiment) was prepared in 100 mL of acetonitrile, sonicated for 3 min and protected from light with an aluminum foil. After this the cartridge was filled with 1.3 g of supported PS and placed at the center of a tube where LED strips are attached. The 1,5-DHN solution was pumped in the system at a constant flow rate throughout the entire experiment.

ASSOCIATED CONTENT

Supporting information

Scheme 1 .

 1 Scheme 1. Scope of the study: (a) immobilization of off-the-bench PCs on commercial silica; (b) application to the batch or continuous flow production of juglone.

Figure 1 .

 1 Figure 1. Structures of the two PCs (also named "dyes" or "photosensitizers") 3 used in this study.

Figure 2 .

 2 Figure 2. Batch conversions of 1,5-DHN to juglone measured by GC-MS vs time. The reactions were carried out at 20°C in thermo-regulated double jacketed photo-reactors irradiated with white LEDs and continuously oxygenated with air balloons. Experiments were carried out using 100 mL of acetonitrile,

Figure 3 .

 3 Figure 3. Representation of the home-made flow photo-reactor (1/4'' PTFE tube, vol = 1.5 mL), fitted with 1/16'' pipes connected to the different components using Swagelok fittings. A fan is added at the bottom to remove the heat generated by LEDs.

Table of Contents graphic:

 of

Table 1 :

 1 optimization of the photo-oxidation of 1,5-DHN in a continuous flow fixed bed photoreactor

	Entry	PS	[1,5-DHN] mol/L	Flow rate (mLꞏmin)	Number of cartridge	O2 source (mLꞏmin)	Yield (% GC-MS)
	1	Ru(bpy)3Cl2	0.006	0.1	1	Air (0.2)	81
	2	Ru(bpy)3Cl2	0.006	0.1	1	O2 (0.2)	96
	3	Ru(bpy)3Cl2	0.006	1.0	1	O2 (1.0)	40
	4	Ru(bpy)3Cl2	0.01	0.1	1	O2 (0.2)	45
	5	Ru(bpy)3Cl2	0.01	0.1	2	O2 (0.2)	78
	6	TMPyP	0.006	0.1	1	O 2 (0.2)	100
	7	TMPyP	0.01	0.1	1	O2 (0.2)	77
	8	TMPyP	0.01	0.1	2	O2 (0.2)	100
	9	TMPyP	0.05	0.1	2	O2 (0.2)	40
	10	TMPyP	0.1	0.1	2	O2 (0/2)	15

The supporting information is available free of charge on the ACS Publications website at DOI: General procedures, reaction analysis and spectroscopic characterizations of photocatalysts and product.

ACKNOWLEDGMENTS

The authors are grateful to the National Conservatory of Arts and Crafts for the funding of flow chemistry equipment and to Damien Cabrera from the Molecular Chemistry team (GBCM laboratory) for useful technical assistance.

AUTHOR INFORMATION

Corresponding Author *E-mail: zacharias.amara@lecnam.net (Z.A.).

ORCID

Zacharias Amara: 0000-0001-6824-1116

Notes

The authors declare no competing financial interest.


domain: chim phys

text:
Mario Andrés Gomez Fernandez

Marllon Nascimento De Oliveira

Andrea Zanetti

Geoffrey Schwertz

Janine Cossy

Zacharias Amara

Photochemical Hydrothiolation of Amorphadiene and Formal Synthesis of Artemisinin via a Pummerer Rearrangement

A new access to artemisinin is reported based on a selective photochemical hydrothiolation of amorphadiene, a waste product of the industrial semi-synthetic route. This study highlights the discovery of two distinctive activation pathways, under solvent-free conditions or using a photocatalyst promoting H-abstraction. Subsequently, a chemoselective oxidation of the resulting photochemically generated thio-ether, followed by a Pummerer rearrangement afford dihydroartemisinic aldehyde, a key intermediate in the synthesis of artemisinin.

The development of new cost-competitive manufacturing routes to the antimalarial drug artemisinin represents a major strategy to fight malaria. [START_REF] Peplow | Synthetic malaria drug meets market resistance[END_REF] Plant extraction has long been the only commercial source, but the increase in global demand has raised the need for alternative production methods. 2 This challenge has fueled impressive developments in synthetic biology and organic chemistry which have led to a new large-scale semi-synthesis where the key metabolic intermediate, artemisinic acid, is obtained by fermentation using bioengineered yeasts (Saccharomyces cerevisiae), and is then transformed into artemisinin by means of synthetic chemistry (Scheme 1a). [2][START_REF] Paddon | High-level semi-synthetic production of the potent antimalarial artemisinin[END_REF] Artemisinic acid (AA) is obtained at around 25 g/L and is then converted into dihydroartemisinic acid (DHAA) by a quantitative and diastereoselective hydrogenation utilizing a transition metal chiral catalyst. 2a DHAA is then transformed into artemisinin in a complex reaction cascade initiated by a photooxidation process involving singlet oxygen. 2a,4 These developments have successfully complemented plant extraction, but have failed to provide a cheaper access to artemisinin (Scheme 1a). In this context, a critical look at the cost determining issues of the current semi-synthesis of artemisinin is key to understand which variables need to be addressed to provide a genuinely low-cost access to this antimalarial drug. This goal could be achieved by performing chemical transformations on a considerably cheaper and less advanced fermentation intermediate than AA. Part of this solution relies on the valorization of amorphadiene (AD), a high yielding fermentation intermediate treated as a waste in the current semisynthetic production and likely to be available at very high titers (up to 120 g/L) and on industrial scale. 5 To date, the conversion of AD to DHAA has been reported either using hydroboration, 5b,6a hydrosilylation, 6b epoxidation 5a or allylic chlorination. 6c However, these procedures feature important drawbacks such as the use of costly catalysts or reagents, or involve protection/deprotection steps of the internal double bond.

Scheme 1: Current semi-synthesis of artemisinin and proposed semi-synthetic route to dihydroartemisinic aldehyde (DHAAl) from amorphadiene (AD).

Herein, we report our preliminary developments of a metal-free and protecting group-free approach which relies on the use of very low cost reagents. This approach implies a three-step sequence involving a key regioselective photochemical hydrothiolation which should, in principle, be compatible with the currently operated large scale photooxidation process to access artemisinin (Scheme 1b). 2a The photo-hydrothiolation of AD would produce a thioether 1 which would then be oxidized to the corresponding sulfoxide 2. The last step of the sequence would rely on a Pummerer reaction which, when applied to sulfoxide 2, would give rise to the key artemisinin intermediate DHAAl. This intermediate was previously transformed into diasteromerically pure DHAA in good yields. 6,[START_REF] Zanetti | Crystallization-induced diastereoisomer transformation of dihydroartemisinic aldehyde with the Betti base[END_REF] The anti-Markovnikov hydrothiolation of alkenes (also called thiol-ene reaction) has been extensively studied and is known to proceed through addition of a thiyl radical which is either generated by hydrogen abstraction from a thiol (Hydrogen Atom Transfer process, HAT) or by the homolytic cleavage of a disulfide. [START_REF] Hoyle | For selection of reviews on hydrothiolation "thiol-ene" chemistry[END_REF] As a consequence, hydrothiolations are typically initiated by thermal decomposition of radical precursors, such as tert-butyl peroxide or azo-bis-isobutyronitrile (AIBN), [START_REF] Hoyle | For selection of reviews on hydrothiolation "thiol-ene" chemistry[END_REF] or by photochemical activation either by UV irradiation, [START_REF] Hoyle | For selection of reviews on hydrothiolation "thiol-ene" chemistry[END_REF][START_REF] Brummelhuis | H. Thiol-ene modifi-cation of 1,2-polybutadiene using UV light or sunlight[END_REF] or visible-light photocatalysis. [START_REF] Abu Bakar | Visible light promoted thiol-ene reactions using titanium dioxide[END_REF] Photochemistry is in principle appealing since the current industrial synthesis of artemisinin already operates with large scale semi-batch photochemical reactors irradiated with medium pressure mercury lamps emitting in the near-UV to visible-light regions of the electromagnetic spectrum. 2a In addition, while radical initiators are often used in excess and, at elevated temperatures, photochemical activation is very attractive since photons are traceless initiators "operating" at close to room temperature. 11 We started our investigations in the development of a photochemical hydrothiolation addition of AD by screening literature conditions using UV or visible-light irradiation. Reactions were performed in a commercially available photochemical screening device (PhotoRedOx Box ® ; see ESI, part 2) 11 with alkyl-and arylthiols in either polar or non-polar solvents, as well as under air or under degassed conditions. However, these preliminary efforts were vain as no traces of the desired thio-ethers were detected in these experiments. Instead, under UV and blue light irradiation, variable amounts of AD isomers were formed together with the corresponding disulfide as a result of the dimerization of the thiols (5 equiv of thiol were used in each case). 13 Interestingly, no isomerization occurred in the absence of thiol using the same photochemical conditions. These results seem to indicate that the generation of a thiyl radical might actually occur under such conditions but the thiol is promoting isomerization of AD instead of undergoing hydrothiolation. We therefore speculated that increasing the concentration of AD could favor the addition of the thiol onto the double bond. [START_REF] Firdaus | Terpene-based renewable monomers and polymers via thiol-ene additions[END_REF] Indeed, this hypothesis was confirmed by running the experiment with thiophenol (5 equiv) and AD, under solvent-free conditions and irradiation at 365 nm. To our delight, we observed the formation of the desired adduct 1a with 18% selectivity at 36% AD conversion together with several unidentified side products and diphenylsulfide (detected by GC/MS). However, despite our efforts, product 1a could not be isolated, and its presence was only detected by GC/MS and 1 H NMR analysis. [START_REF]The reaction profile was also very similar by carrying out the reaction under continuous flow conditions, although with higher conversion of AD ([END_REF] By monitoring the reaction with an excess of PhSH (5 equiv) under UV irradiation (365 nm), we obtained a selectivity of 53% in favor of 1a after 4 h irradiation, with 71% AD conversion (Table 1, entry 1). However, pure 1a could not be isolated, as the isomerization of the double bond followed by hydrothiolation occurred systematically and the resulting isomers could not be separated. Longer reaction times led to a decrease in selectivity as the hydrothiolation took place on the two double bonds (detected by GC/MS). Lowering the reaction temperature from 25 °C to 0 °C did not improve the selectivity toward the desired thio-ether (25% conversion of AD and 16% selectivity after 1 h). We also attempted to improve the selectivity of the process by using either electron-rich or electron-poor thiophenol derivatives but this also turned out to be unsuccessful.

We therefore investigated the addition of alkyl thiols under similar conditions [5 equiv of RSH under UV irradiation LED (365 nm) at 25 °C and under solvent-free conditions]. To our delight, the use of alkyl thiols gave, in all cases, very clean conversion of AD to 1b-e compared to thiophenol (Table 1), thus enabling the selective functionalization of the exocyclic double bond. The use of ethylthiol (EtSH) resulted in an excellent conversion of AD after 18 h, and the corresponding adduct 1b was isolated in 73% yield (Table 1, entry 2). Mercaptoethanol and 3-thiopropan-1-ol exhibited higher reactivity compared to EtSH, as high AD conversions were observed after only 1 h and 3 h, providing the corresponding products with 81% and 77% isolated yields, respectively (Table 1, entries 3 and4). The secondary thiol, 2-propanethiol, furnished 78% conversion of AD, and 1e was isolated in 75% yield although, a longer reaction time, 44 h, was required to obtain a high conversion (Table 1, entry 5). On the other hand, very poor conversion of AD was observed with t-butylthiol (t-BuSH) or with 3-mercapto-3-methylbutan-1-ol, even after a prolonged reaction time (Table 1, entries 6 and 7), clearly indicating that increasing the bulkiness of the thiol disfavors this addition process. In all cases, the diastereoselectivity was modest (dr ~ 60:40) which would ultimately lead to a low yield in (11R)-DHAAl. However, this low dr is not a limiting factor since we recently disclosed an efficient epimerization procedure using the Betti base as a mediator for a Crystallization Induced Diastereoselective Transformation process (CIDT), enabling the conversion of the undesired isomer [(11S)-DHAAl] into the desired one [(11R)-DHAAl]. [START_REF] Zanetti | Crystallization-induced diastereoisomer transformation of dihydroartemisinic aldehyde with the Betti base[END_REF] Table 1. Screening of thiols in the hydrothiolation of AD under solvent-free conditions.

entry RSH time (h)

AD conversion [a] 1 yield [b] 1 C6H5SH 4 71% 1a 53% [c] 2 Reactions were performed on a 0.59 mmol scale of AD using 5 equiv of thiol. [a] Determined by GC/MS analysis. [b] Isolated yields after purification on silica gel chromatography. [c] Isolated with unidentified by-products with the same mo-lecular weight according to GC/MS analysis, presumably isomers originating from an isomerization/hydrothiolation process.

According to literature precedents, H-abstraction (or HAT) could occur in the absence of a photocatalyst or a photoinitiator thanks to the formation of a weak Electron-Donor-Acceptor complex (EDA) between the thiol and AD. 16 This type of pre-complexation would preferentially occur under neat conditions facilitating the addition step. However, in our case, we were not able to ascertain this hypothesis using absorption spectroscopy. 16b, c To enable the addition of sterically hindered thiols, we extended our screening to photocatalytic conditions using radical photoiniators. Gratifyingly, we identified that in the presence of 5 mol % of 2,2-dimethoxy-2-phenylacetophenone (DPAP), the addition of secondary and tertiary thiols was significantly accelerated (Table 2). 17 Under UV-light, DPAP undergoes a Norrish type I fragmentation to give a benzoyl radical which can initiate a radical chain process by H-abstraction. 8e, 17 As a result, the coupling between AD and iPrSH delivered the corresponding thio-ether 1e in 77% yield in a significantly shorter reaction time compared to the initiator-free method (3 h versus 44 h) (Table 2, entry versus Table 1, entry 2). Interestingly, under these photoinitiated conditions, the hydrothiolation also worked well under diluted conditions (0.5 M), with good selectivity, albeit with slower conversion rates (Table 2, entries 3-5). DPAP also enabled the more challenging hydrothiolation of AD by t-BuSH, yielding the desired product in 45% isolated yield after 24 h and 68% yield after 72 h (Table 2, entries 6 and 7). All reactions were run on a 0.59 mmol scale and were monitored by GC/MS analysis before purification. The reaction was then carried out on gram scale (1 g, 4.90 mmol) using 20 mol % of DPAP and required longer reaction time to reach high conversion (Table 2,entry 7). Similar results were obtained with 3-mercapto-3-methylbutan-1-ol (Table 2, entry 8). It is important to note that the addition of thiophenol remained problematic under these catalytic conditions, which might be due to a competition between the addition of aryl thiyl radicals and the isomerization of AD.

Table 2. Screening of thiols in the hydrothiolation of AD in the presence of DPAP as a photoinitiator. [a] entry RSH solvent time (h) AD conversion [a] 1, yield [b] 1 Reactions were performed on a 0.59 mmol scale of AD using 5 equiv of thiol. [a] Determined by GC/MS analysis. [b] Isolated yields after purification by silica gel flash chromatography, the diastereoselectivity (60:40) was estimated by 1 H NMR analysis. [c] The reaction was carried out on gram scale using 20 mol % of DPAP.

According to these results, it is likely that two distinctive photochemical activation pathways occur during the AD hydrothiolation. One pathway would rely on the direct absorption of light at 365 nm by either an EDA complex or a solvated charge transfer (CT) complex, 16b or even induced by small amounts of impurities 16c which could initiate the radical process. In this scenario, no reaction occurs with bulky thiols for which UV irradiation in the presence of DPAP is crucial. Therefore, the efficiency of the reaction seems to be dictated by the concentration of the thiyl radical and, for less reactive thiols, such as t-BuSH, DPAP enables to restart the radical chain propagation which is otherwise disfavored. Interestingly, the reaction proceeds with shorter reaction time in the presence of DPAP than without which could also be due to lower inner filtering effects related to the difference in light absorption.

Having successfully prepared a range of thio-ethers with moderate to high yields, we next evaluated the transformation of 1 to the desired aldehyde, DHAAl. Our first attempts to develop a single step transformation of 1 to DHAAl using chlorinating reagents failed, either using sulfuryl chloride or N-chlorosuccinimide. 18 We therefore decided to develop a two-step process involving a chemoselective sulfoxidation followed by a Pummerer rearrangement. 19,[START_REF] Padwa | Application of the Pummerer reaction toward the synthesis of complex carbocycles and heterocycles[END_REF] In a preliminary study, we synthesized diastereomerically enriched thio-ethers prepared from pure iododihydroartemisinin (11R)-A (see ESI, Section 2.4). [START_REF] Schwertz | Synthesis of amorpha-4,11-diene from dihydroartemisinic acid[END_REF] The thioethers (S)-1a, (S)-1e and (S)-1f were oxidized to the corresponding sulfoxides 2a, 2e, 2f, after treatment with m-CPBA (1.1 equiv) in CH2Cl2 at -10 °C for 1 h, and these latter were isolated in up to 87% yield as a mixture of two diastereomers in a ratio 1 to 1 (Table 3). With the sulfoxides in hand, the investigation of the Pummerer rearrangement started using literature conditions. 19,[START_REF] Padwa | Application of the Pummerer reaction toward the synthesis of complex carbocycles and heterocycles[END_REF] With acetic anhydride or benzoic anhydride, no reaction was observed. On the other hand, the reaction proceeded very selectively when performed with trifluoroacetic anhydride (TFAA) in the presence of trimethylamine (Et3N) (Table 4). In this case, full conversion of the sulfoxide 2a into a diastereomeric mixture of α-substituted sulfide intermediates I was observed by 1 H NMR at room temperature (see ESI, Section 3.2). After workup with a saturated aqueous solution of NaHCO3, DHAAl was isolated in 57% yield from 2a. This result was significantly improved to 71% yield, without epimerization of the (11R)-stereocenter, by realizing the workup with a NaOH aqueous solution (0.1 M) (Table 4, entry 1). However, when subjecting 2e or 2f under the same room temperature Pummerer conditions, only traces of DHAAl were detected. A temperature screening revealed that DHAAl can be obtained from alkyl sulfoxides by conducting the experiment at lower temperature. Indeed, DHAAl was isolated in 18% yield from 2e at -10 ºC and in 59% from 2f when the reaction was performed at -20 ºC (Table 4, entries 3 and 4). Lowering the temperature to -40 ºC did not help to improve the yield. The major side product, isolated from the Pummerer rearrangement of 2f, was the thioenol compound 3 (see ESI, part 3.4). Noteworthy, in the case of alkyl sulfoxides possessing α-CH next to the sulfur atom (2e, R = iPr)), the selectivity was lower than in the case of 2a (2a, R = Ph) or 2f (2f, R = t-Bu).

Once the feasibility of each step was demonstrated, the entire sequence to access DHAAl from AD was performed as a proof of concept using t-BuSH on gram scale (see ESI, Section 3.4). have demonstrated experimentally that this step can proceed with high selectivity when performed at ambient temperature and under solvent-free conditions with non-sterically hindered alkyl thiols. We also provided evidence that this step does not require additives to be initiated, probably due to the formation of a EDA/CT complex or to weakly absorbing species. In addition, we have been able to extend this study to the addition of bulkier thiols by adding DPAP as a radical photoinitiator. We demonstrated, as a proof of concept, that the thio-ether intermediate 1 can be converted to DHAAl by a chemoselective sulfoxidation using m-CPBA, followed by a Pummerer rearrangement using TFAA. This study provides encouraging results towards the development of a potentially cost-competitive process for the synthesis of artemisinin from AD. We are currently investigating potential strategies to increase the overall yield in DHAAl, through the development of a continuous flow process.

Table 3 : Synthesis of sulfoxides 2a, 2e and 2f.

 3

	entry	1 (R group)	2, yield
	1	1a (Ph)	2a, 87%
	2	1e (iPr)	2e, 70%
	3	1f (t-Bu)	2f, 87%

Table 4 : Pummerer rearrangement of sulfoxides 2.

 4 In conclusion, we have investigated the development of an original route towards artemisinin from AD, relying on a chemoselective photochemical hydrothiolation step. We

	entry	2 (R)	T °C	time	DHAAl, yield
	1	2a (Ph)	rt	2.5 h	71%
	2	2e (iPr)	rt	1.0 h	traces
	3	2e (iPr)	-10°C	1.0 h	18%
	4	2f (t-Bu)	-20°C	0.5 h	59%
	All reactions gave full conversion of 2

ACKNOWLEDGMENT

This work was supported by the Bill & Melinda Gates Foundation [OPP1190174]. We would like to thank Dr Kai Rossen (Sanofi) for his input and for very fruitful advices throughout the development of this project, and Dr Trevor Laird (Scientific Updates). We would also like to thank Dr Fabienne Dioury ((GBCM), EA 7528, Conservatoire national des arts et métiers) for providing help in the preparation of amorphadiene and other intermediates.

ASSOCIATED CONTENT Supporting Information

The Supporting Information is available free of charge on the ACS Publications website. Detailed experimental procedures, characterization data, and spectra copies of 1 H and 13 C NMR (PDF)

AUTHOR INFORMATION

Corresponding Author zacharias.amara@lecnam.net. Phone: +33 1 40 27 26 14; ORCID 0000-0001-6824-1116 janine.cossy@espci.fr. Phone: +33 1 40 79 44 29. Fax: +33 1 40 79 44 54; ORCID 0000-0001-8746-9239.

Author Contributions

The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript. / ‡These authors contributed equally.

Notes

The authors declare no competing financial interest.


text:
Bruno Fabre

Franck Camerel

Soraya Ababou-Girard

Photoactive Silicon Surfaces Functionalized with High-Quality and Redox-Active Platinum Diimine Complexes Monolayers

New platinum diimine dichloro (PtCl2) and dithiolene (Ptdithiolene) complexes have been synthesized and covalently bound to hydrogen-terminated, oxide-free silicon (111) surfaces using a two-step procedure. This immobilization route resulted in the formation of ca. 2.0-2.5 nm-thick densely packed and perfectly clean Pt complex monolayers with the expected structure of the grafted molecular chains. The surface coverages of attached PtCl2 and Ptdithiolene were electrochemically estimated at 8.9 x 10 -11 and 7.5 x 10 -11 mol.cm -2 , respectively, corresponding to 0.07 PtCl2 and 0.06 Ptdithiolene per surface silicon atom. The Pt complex-functionalized photoactive silicon surfaces showed under simulated sunlight a redox activity similar to that observed for the complexes in solution at a non-photoactive electrode. The two one-electron reduction processes centered on the bipyridine ligand were however observed at much less negative potentials, owing to the photovoltage generated at the silicon/monolayer interface. These modified photocathodes showed great promises for solar photoelectrocatalysis, as exemplified with the photoassisted electrocatalytic reduction of CO2. Based on the measured cathodic photocurrent densities, the Ptdithiolene-modified surface showed superior catalytic performance.

Introduction

Well-defined platinum (Pt) complexes with polypyridine, vinylsiloxane, N-heterocyclic carbene or phosphine ligands have been widely used in very efficient and selective homogenous catalytic reactions. 1 A few attempts have been performed to immobilize these molecular systems on solid supports such as silica but it has not been established in all cases whether the catalytically active site is an isolated surface complex or a metal(0) aggregate. 2 Nevertheless, the immobilization of such complexes on photoactive semiconducting surfaces, such as silicon, appears us to be a promising strategy to elaborate lightactivated functional devices. Surprisingly, only one example of a Pt molecular complex covalently grafted onto silicon has been reported so far and belongs to the family of heteroleptic Pt complexes, namely diimine-dithiolene complexes. This intriguing class of complexes has been widely studied for their photophysical and redox properties. They have mainly been studied for their luminescence properties arising for the deactivation of a charge-transfer band between the diimine and the dithiolate fragments coordinated to the Pt center. 3 The proper choice of the diimine ligand and the dithiolate ligand allows the fine tuning of their photophysical and redox properties. Pt diimine-dithiolene complexes have been proposed as light harvester in the visible region for light-driven water reduction to hydrogen 4 but also in solar cells. 5 Crown ethers have been introduced on the dithiolate ligand in the [Pt(NN)(SS)] system for developing optical and electrochemical sensors for alkali metal cations. 6 It has also been demonstrated that the proper functionalization of the diimine or the dithiolate fragment with several long carbon chains or biphenyl fragments allows the complexes to self-organize into thermotropic liquid crystalline materials. 7 Recently, our group has indeed demonstrated that such metal complexes could be covalently attached on hydrogen-terminated silicon(100) surfaces through a hydrosilylation reaction with a dithiolate fragment ωsubstituted with alkyne chains. 8 The so produced Si-C linked organometallic monolayers retained the redox activity of the Pt complexes exhibited in solution. Nevertheless, an oxidative decomposition of the grafted dithiolate ligand upon light exposure was observed impeding the photoelectrochemical investigation of the functional semiconducting surfaces. Herein, the precursor structure has been judiciously revisited to avoid such light-induced degradation phenomenon. In particular, the unstable imino function present in the previously investigated Pt complexes has been eliminated in the present work because of its propensity to be hydrolyzed. Moreover, Si(111) surface was selected as the immobilization substrate preferentially to Si(100) which is extensively used in semiconductor technology. Indeed, it has been demonstrated that the organic functionalization of hydrogen-terminated Please do not adjust margins Please do not adjust margins Si(111) yielded usually both more densely packed and ordered monolayers, with a higher surface coverage. 9,10,11 Two approaches have been tested to elaborate well-defined redox-active organometallic monolayers from the covalent derivatization of Si-H surfaces with Pt diimine-dithiolene complex. The first is based on the direct grafting of an alkeneterminated Pt diimine-dithiolene complex (denoted Ptdithiolene hereafter) onto Si-H through a hydrosilylation route (route a, Scheme 1). The second is a two-step method and consists first of a hydrosilylation reaction of di(dec-9-en-1-yl) [2,2'-bipyridine]-4,4'-dicarboxylate dichloro platinum complex (PtCl 2) with Si-H, followed by the conversion of the PtCl2 moiety to the Pt diimine-dithiolene using a tin salt (route b, Scheme 1). In order to control both the quality, the composition and the compactness of the covalently bound organometallic monolayers, various experimental techniques have been used including cyclic voltammetry, X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). Moreover, the promising catalytic effects exhibited by such complexes in solution for the electrochemical reduction of CO 2 prompted us to examine if such an activity was retained once immobilized on a photoactive surface.

Results and Discussion.

Synthesis of Pt complexes.

An original bipyridine ligand carrying two long olefinic terminal chains has been developed for further grafting onto oxide-free Si(111) surfaces through a hydrosilylation reaction (see Scheme 1). The functional ligand was synthesized by reacting [2,2'bipyridine]-4,4'-dicarboxylic acid chloride with 2.5 equivalents of 9-decen-1-ol in the presence of triethylamine. The synthesis of all the molecules and their principal physicochemical characterizations are fully described in the Supporting Information (Figures S1 to S5). The ligand was then reacted with 1 eq. of PtCl 2(DMSO)2 to afford the corresponding dichloroplatinum diimine complexes PtCl2 in 80 % yield (Figures S6 to S11). Finally, the 5,6-dihydro-1,4-dithiin-2,3-dithiolato (dddt) ligand was introduced by a ligand metathesis by reacting the dichloroplatinum diimine complexes with one equivalent of 2,2-dibutyl-5,6-dihydro-1,3,2-dithiastannolo[4,5-b][1,4]dithiin in acetone to afford the corresponding diimine-dithiolene complexes Ptdithiolene as dark-green powders in 70 % yield (Figures S12 to S16). The purity and the molecular structure of all the compounds were confirmed by elemental analyses, 1 H NMR, 13 C NMR, mass spectrometry, IR spectroscopy and UV-vis analyses. The UV-vis-NIR absorption spectra for all the compounds have been measured in CH 2Cl2 solutions (Supporting Information). The absorption spectrum of the starting ligand showed two absorption bands with a maximum at 242 and 300 nm (Figure S3). These large absorption bands are assigned to π-π* and nπ* transitions localized on the bipyridine core. 12 After coordination by the PtCl 2 fragment, an additional absorption band with a weaker extinction coefficient appeared at 422 nm on the UV-vis spectrum of PtCl2 complex (Figure S8). This absorption band arises from a charge transfer transition from a filled Pt (d) orbital to an unoccupied π* diimine orbital (MLCT). 13 Substitution of the chloride atoms by the dddt 2-fragment in Ptdithiolene was characterized by the appearance of an intense absorption band at 774 nm (15700 M -1 cm -1 ), associated to mixed metal ligand-to-ligand charge transfer transition (MMLL'CT) corresponding to excitation from the electron donor dithiolate ligand having orbital contributions from the metal ion to the electron acceptor bipyridine ligand (Figure S14). 7b, 14 The thermal properties and stability of the ligand and associated metal complexes were also investigated upon repeated heating and cooling cycles by differential scanning calorimetry (DSC) and polarized optical microscopy (POM). The starting ligand melted around 63 °C and recrystallized with a strong supercooling around 20 °C (Figures S4 andS5). Upon cooling from the isotropic state, PtCl2 entered into a liquid crystalline state below 170 °C and characteristic textures of a columnar mesophase of hexagonal symmetry were observed by POM (Figures S9 andS10). The crystallization of this compound started below 70 °C. Ptdithiolene was in a liquid crystalline state from room temperature up to the degradation temperature at 140 °C (Figures S15 andS16) but no typical texture could have been developed. All the compounds were found to be stable up to 140 °C.

Electrochemical Properties of the Pt complexes and Electrocatalytic Activity for the CO2 Reduction.

The electrochemical characteristics of the Pt complexes have been examined by cyclic voltammetry (CV) in CH 2Cl2 medium, prior to their covalent immobilization on photoactive p-type Si(111) surfaces. In reduction and under argon, the CVs of PtCl2 and Ptdithiolene were characterized by two reversible waves at E°' Red1 = -0.75 V and E°'Red2 = -1.38 V vs Saturated Calomel Electrode (SCE) for PtCl2 and at E°'Red1 = -0.88 V and E°'Red2 = -1.48 V for Ptdithiolene (average of anodic and cathodic peak potentials). The reversible and monoelectronic character of both systems is supported by a peak-to-peak separation close to 60 mV (after Ohmic drop correction) and a ratio between the Please do not adjust margins Please do not adjust margins anodic and cathodic peak current intensities close to 1 within the investigated potential scan range (i.e., 0.1-0.6 V s -1 ). They correspond to the reduction of the neutral bipyridine ligand into its monoanionic and dianionic species, respectively. 8,15 Compared with PtCl2, the reduction potentials of Ptdithiolene were slightly negatively shifted by 100-130 mV. Such a trend can be reasonably explained by the occurrence of a charge transfer between the dithiolate and the bipyridine ligands, as revealed by UV-visible measurements (vide supra), which renders the bipyridine fragment more electron rich and thus more difficult to reduce. An additional monoelectronic and reversible system was observed in oxidation at E°' Ox = +0.46 V only for Ptdithiolene and was attributed to the oxidation of the Pt dithiolate moiety to its radical cation form. 16 In a CO2-saturated electrolyte solution, the CVs of PtCl2 and Ptdithiolene showed an increase in the cathodic current related to the second wave of the Pt complex whereas no significant current enhancement was observed in the absence of the Pt complex down to -1.8 V vs SCE (Figure 2). Such observations provide experimental evidence for the electrocatalytic activity of both Pt complexes towards the CO 2 reduction in homogeneous phase. Based on measured catalytic current densities, it cannot be however concluded that Ptdithiolene exhibits a higher activity than that of PtCl2.

Figure 2. Comparative cyclic voltammograms at 0.2 V s -1 under argon (dotted lines) or CO2 (solid lines) atmosphere of PtCl2 (red) and Ptdithiolene (blue) at 2 mM in CH2Cl2 + 0.2 M Bu4NPF6 on glassy carbon (GC) electrode. The black lines correspond to the electrochemical response of GC in the Pt complex-free electrolytic solution.

Covalent Grafting of Pt Complexes onto

Photoactive Si(111) Surfaces.

The covalent derivatization of oxide-free, hydrogen-terminated Si(111) surfaces with Pt complexes was carried out following two grafting routes (Scheme 1). The first one based on the UVor thermally-activated direct grafting of Ptdithiolene onto Si-H failed to produce high-quality and densely packed monolayers (see the Supporting Information for details and Table S1). Instead, an organometallic polymer film or a monolayer with low surface coverage (i.e. 3 x 10 13 atoms cm -2 , i.e. 0.04 Pt complex per surface silicon atom) was deposited. In contrast, clean, high-quality and more densely packed Pt complex monolayers were produced from the two-step grafting consisting first of a hydrosilylation reaction at 300 nm of PtCl2 with Si-H, followed by the chemical conversion of the PtCl 2 moiety into a platinum-dithiolene moiety (route b, Scheme 1). The composition of the optimized modified surfaces was determined by XPS. The survey spectra revealed characteristic peaks of the Si substrate itself (Si 2s and Si 2p), as well as characteristic signals of C 1s, Cl 2s, N 1s, S 2p, and Pt 4f, confirming the successful grafting of PtCl2 and Ptdithiolene (Figure S17). More specifically, for the PtCl 2-modified surface (denoted Si-PtCl2 hereafter), the high-resolution C 1s spectrum could be reasonably fitted using three components at 285.0, 286.7 and 289.4 eV, corresponding to different carbon atoms, namely [C-C + C=C], [CO + CN] and (C=O)O, respectively (Figure 3). The experimental ratios between the areas under the [C-C + C=C] and [CO + CN] peaks, and under the [CO + CN] and (C=O)O peaks, were estimated at 2.9 and 2.8, respectively, in relatively close agreement with the theoretical ratios of 4 (24:6) and 3 (6:2), respectively. The presence of Cl was supported by the presence of one peak at 269.4 eV on the Cl 2s signal and the area under the [C-C + C=C] and Cl peaks was also perfectly consistent with the expected ratio, 11.8 against 12 (24:2). Additionally, the N 1s signal showed a single component at 401.3 eV corresponding to nitrogen atoms of the bipyridine ligand, and the experimental atomic ratio between the total C and N was ca. 19.6 which is close to the expected ratio of 16 (32:2). The Pt 4f spectrum showed two components, the first one located at 72.7 eV (Pt 4f 7/2) and 76.0 eV (Pt 4f5/2), and the second at 71.2 eV (Pt 4f 7/2) and 74.9 eV (Pt 4f5/2). These are believed to correspond to two different geometrically Pt complex forms bound to the surface. From the approximate ratio, the contribution of the second minor component could be estimated at about 15% of total Pt. After conversion of the PtCl2 to Ptdithiolene, no additional component was visible on the high-resolution C 1s spectrum of the Ptdithiolene-modified surface (Si-Ptdithiolene). We notice however that the second component attributed to heteroelement-bound carbon atoms (CO, CN and CS) was 0.3 eV-shifted towards lower binding energies. As expected, the replacement of the Cl atoms by the dithiolene unit was supported by the disappearance of the Cl 1s signal (indicating that the conversion was quantitative) and the emergence of a shoulder at approximately 162.6 eV on the plasmon loss peak of Si 2s corresponding to unresolved contributions of S 2p 3/2 and 2p 1/2 levels. The position of the N 1s peak was unchanged while the two components observed on the Pt 4f spectrum with their respective doublets were 0.4 eV-shifted to lower binding Please do not adjust margins Please do not adjust margins energies compared with Si-PtCl2. Such a shift would be rather consistent with a differently coordinated Pt complex, as previously reported for other organometallic monolayers bound to Si(111) surfaces. 17,18 The experimental ratio between the areas under the S 2p and N 1s peaks was estimated at 1.5, which is very close to 4S/2N expected for the terminal Pt complex. Finally, the chemical conversion of PtCl2 to Ptdithiolene was thought to indroduce some oxidation of the underlying silicon surface, as evidenced by the presence of a small peak at a binding energy of 103-104 eV attributable to silicon oxides. S19).

The cleanliness of the optimized modified Si(111) surfaces was monitored by AFM. Both Si-PtCl2 and Si-Ptdithiolene showed a structure identical to that of Si( 111)-H and other high-quality ωfunctionalized organic monolayers, 19,20,21,22 with atomically flat, defect-free terraces separated by about 3 Å-high steps (Figure 4). Some oxidation pits were visible in the AFM image of Si-Ptdithiolene which were absent in that of Si-PtCl2. The measured root-mean-square (rms) roughness was about 2 Å for both surfaces. Moreover, any contrast in friction images was not observed and any adventitious material was not removed upon a prolonged AFM tip scanning on the same place, thus providing experimental evidence that the surfaces were perfectly clean. 2.4 Photoelectrochemical Properties of the Pt complex-Functionalized Silicon Photocathodes and Photoelectrocatalytic Activity for the CO2 Reduction.

The electrochemical activity of the two Pt complexfunctionalized silicon photocathodes has been examined in CH 3CN medium preferentially to CH2Cl2 used in homogeneous conditions owing to its higher electrical conductivity, its propensity to provide better resolved voltammetric peaks for redox monolayer-modified silicon surfaces 23 and the higher solubility of CO 2 in this solvent. 24 We have checked beforehand that the electrochemical behavior and the redox potentials of PtCl2 were quite similar in both solvents (Figure S21), Ptdithiolene having not been tested because of its poor solubility in CH 3CN. As shown in Figure 5, negligible current densities were measured in the dark for both Si-PtCl2 and Si- Ptdithiolene surfaces. This situation is common for charge depleted semiconducting electrodes. Under these conditions, the concentration of majority charge carriers (i.e. holes) at the p-type silicon surface is not sufficient to promote the reduction processes assigned to the bipyridine ligand. [START_REF] Zhang | Electrochemistry of silicon and its oxide[END_REF] By contrast, much higher current densities were observed at illuminated modified silicon surfaces because the high concentration of photogenerated minority charge carriers (i.e. electrons) will promote efficiently the reduction processes. Importantly, due to the photogenerated electron-induced activation of the redox processes, the two reversible cathodic waves were observed at much less negative potentials than those determined at a nonphotoactive electrode for the complexes in solution, namely E°' Red1 = -0.65 V and E°'Red2 = -1.03 V for Si-PtCl2 (Fig. 5a) and E°' Red1 = -0.67 V and E°'Red2 = -0.97 V for Si-Ptdithiolene (Fig. 5b). Such a potential shift called photovoltage is common for illuminated semiconducting photoelectrodes and is a desired characteristic for photoelectrocatalytic purposes. [START_REF] Gimenez | Photoelectrochemical Solar Fuel Production: From Basic Principles to Advanced Devices[END_REF] It is worth however noting that the difference in formal potentials between the two redox processes (E°' Red1 -E°'Red2) was much smaller for the immobilized systems than for the systems in solution. Such a trend could be ascribed to ion pairing effects with the electrolyte cation that may exist in solution but are most likely exacerbated for surface-attached electroactive molecules. [START_REF] Evans | [END_REF] Another plausible explanation could be the presence of a strong carrier inversion layer in the semiconductor at the most negative potentials which would yield a higher photovoltage for the second redox process. 28 Moreover, the total amount of Pt complexes attached to the surface was determined from the variation of cyclic voltammograms with the potential scan rate v. The cathodic peak photocurrent densities j pc corresponding to the first redox process were found to be proportional to v within the range 0.0 -1.0 V s -1 (Figure S22), as expected for surface-confined redox species. [START_REF] Bard | Electrochemical Methods. Fundamentals and Applications[END_REF] The slopes of the linear jpcv plots yielded surface coverages of attached PtCl2 and Ptdithiolene of 8.9 x 10 -11 and 7.5 x 10 -11 mol cm -2 , respectively (see SI for details) which correspond to surface coverages of 0.07 PtCl2 and 0.06 Ptdithiolene per surface silicon atom, considering that the atomic density of Si(111) is 7.8 x 10 14 atoms cm -2 . [START_REF] Allongue | [END_REF] Such values give specific areas of about 185 Å 2 per grafted PtCl2 and 220 Å 2 per grafted Ptdithiolene, which compare well with the theoretical specific areas determined from DFT calculations assuming that the two spacer arms of the grafted molecule are strongly spread on the surface, namely 184 Å 2 and 291 Å 2 , respectively (Figure S18). At the opposite, these experimental values are somewhat greater than 118 Å 2 per grafted PtCl2 and 106 Å 2 per grafted Ptdithiolene by considering the two spacer arms of the molecule are closed together on the surface (Figure S19). Because the monolayer structure is probably between these two extreme cases, this indicates a reasonably dense packing of the Pt complex-terminated chains for both Si-PtCl2 and Si-Ptdithiolene. DFT calculations performed on monoanionic and dianionic species confirmed that the charge of the complex weakly affects the orientation and the conformation of the pendant aliphatic chains (Figure S20). Now, the photoelectrocatalytic response of these functional surfaces was examined for the electrochemical reduction of CO 2. A clear enhancement in the cathodic photocurrent density was observed below -1.3 V vs SCE upon addition of CO 2 (Figure 6), in agreement with a catalytic activity of the modified photoelectrodes. The ratios between the cathodic photocurrent densities measured at -1.5 V in the presence (j cat) and in the absence of CO 2 (j°) were estimated to be 3.1 and 6.6 for Si-PtCl2 and Si-Ptdithiolene, respectively, demonstrating the superior catalytic performance of Ptdithiolene in heterogeneous conditions. These preliminary results are promising and demonstrate that Pt diimine-dithiolene complexes show great potential for electrocatalytic applications.

Conclusions

In this work, we have demonstrated that platinum diimine complex monolayers could be covalently grafted onto oxidefree silicon(111) surfaces through a hydrosilylation reaction. Toward this goal, an original bipyridine ligand carrying two long carbon chains with a terminal alkene has been synthesized and the corresponding platinum complexes bearing chloride atoms and dithiolate fragment have been isolated. Both complexes displayed two reversible one-electron reduction processes centered on the bipyridine fragment. Cyclic voltammetry experiments performed in a CO 2-saturated electrolytic solution demonstrated that they exhibited an electrocatalytic activity towards the CO 2 reduction in homogeneous phase. Their covalent immobilization on oxide-free photoactive silicon surfaces was sequentially carried out by starting first by the grafting of the dichloro Pt complex followed by its chemical conversion to the diimine-dithiolene derivative. Such a strategy resulted in the formation of densely packed, clean and highquality Pt complex monolayers, as supported by Please do not adjust margins Please do not adjust margins electrochemistry, XPS, AFM and DFT geometry optimization calculations. The redox activity of both complexes was retained once immobilized but the two reversible cathodic waves were favorably shifted to less negative potentials thanks to the photogenerated electrons-induced activation of the redox processes. Both illuminated Pt complex-functionalized silicon photocathodes showed a photoelectrocatalytic activity towards the cathodic reduction of CO 2 but superior performance was observed for the Ptdithiolene-functionalized photocathode. Work is currently in progress in order to determine the performance metrics of these novel modified photoelectrodes and the selectivity of this catalytic reaction. The photothermal effect observed with the platinum diimine dithiolene complexes in solution could also be of great interest to boost the catalytic processes under laser irradiation in the NIR region. 31 Preliminary measurements have shown that the charge transfer Ptdithiolene complex, displaying a strong absorption band in the NIR region, could efficiently convert light under 808 nm laser irradiation with a photothermal efficiency around 29 % (Figure S23). 32

Scheme 1 .

 1 Scheme 1. Chemical Pathways for the Preparation of Pt Complex Monolayers Covalently Bound to Hydrogen-Terminated Si(111) Surfaces.

Figure 1 .

 1 Figure 1. Cyclic voltammograms under argon of PtCl2 (a) and Ptdithiolene (b) at 2 mM in CH2Cl2 + 0.2 M Bu4NPF6 on glassy carbon (GC) electrode.

b

  This journal is © The Royal Society of Chemistry 20xx

Figure 3 .

 3 Figure 3. High-resolution XP spectra of Si 2p, C 1s and Cl 2s, Pt 4f, N 1s and S 2pfor Si-PtCl2 (left column) and Si-Ptdithiolene (right column). The peak observed at about 276-277 eV on the C 1s spectra is attributed to satellite peaks of the used XPS source. Experimental data and fitting envelopes are represented by black and red lines, respectively. The colored lines are fitted curves using Gaussian-Lorentzian mixed peaks corresponding to different components.

Figure 4 .

 4 Figure 4. Tapping-mode AFM images (top) and corresponding cross-section profiles taken in the middle of the images (bottom) of PtCl 2 -(left) and Ptdithiolene-(right) modified Si(111) surfaces.

Figure 5 .

 5 Figure 5. Ohmic drop-corrected CVs under illumination (AM 1.5G, 100 mW cm -2 ) of Si-PtCl2 (a) and Si-Ptdithiolene (b) in CH3CN + 0.1 M Bu4NClO4. The black traces correspond to the CVs in the dark at 0.2 V s -1 . Details on the Ohmic drop correction method are provided in SI.

Figure 6 .

 6 Figure 6. Ohmic drop-corrected CVs at 0.2 V s -1 in the dark (dotted lines) and under illumination (solid lines) of Si-PtCl2 (a) and Si-Ptdithiolene (b) under argon-(black) or CO2-(red) saturated CH3CN + 0.1 M Bu4NClO4 solution. Details on the Ohmic drop correction method are provided in SI.

b

  This journal is © The Royal Society of Chemistry 20xx

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 5

Acknowledgements

This work was granted access to the HPC resources of CINES under the allocation 2021-A0100805032 awarded by GENCI. Frédéric Barrière is gratefully acknowledged for his helpful discussion on DFT calculations. The authors thank Jean-François Bergamini for AFM experiments.

Author Contributions

Conflicts of interest

The authors declare no conflict of interest.