Photocatalytic Dehalogenative Deuteration of Halides over a Robust Metal–Organic Framework

Abstract Deuterium labelling of organic compounds is an important process in chemistry. We report the first example of photocatalytic dehalogenative deuteration of both arylhalides and alkylhalides (40 substrates) over a metal–organic framework, MFM‐300(Cr), using CD3CN as the deuterium source at room temperature. MFM‐300(Cr) catalyses high deuterium incorporation and shows excellent tolerance to various functional groups. Synchrotron X‐ray powder diffraction reveals the activation of halogenated substrates via confined binding within MFM‐300(Cr). In situ electron paramagnetic resonance spectroscopy confirms the formation of carbon‐based radicals as intermediates and reveals the reaction pathway. This protocol removes the use of precious‐metal catalysts from state‐of‐the‐art processes based upon direct hydrogen isotope exchange and shows high photocatalytic stability, thus enabling multiple catalytic cycles.

Possessing high porosity, structural diversity and semiconductor-like behaviour, metal-organic framework (MOF) materials have been reported as photocatalysts for CO 2 reduction, [21] water splitting, [22] and organic redox reactions. [23]MOF-based photocatalysts operate via a threestep process [24] involving light absorption and photo-induced charge-hole separation; migration of photogenerated electrons and holes to reactive sites through ligand-to-metal charge-transfer (LMCT) or metal-to-ligand charge-transfer (MLCT); half-reaction of oxidation or reduction with redox equivalents.Thus, the precise mechanism of electron transfer often plays an important role in determining the overall catalytic performance.Furthermore, as reported for supramolecular cages [25][26][27] and zeolites, [28,29] host-guest interactions between the porous scaffolds and adsorbed substrates have significant impact on the activation of substrates and thus the catalytic activity.We have recently found that the formation of hydrogen bonds between the metalhydroxyl groups immobilised in a MOF catalyst and adsorbed ketone/aldehyde compounds can effectively promote the photo-reduction of carbonyl groups. [30]Moreover, the host-guest interaction can also facilitate the transfer of photo-induced electrons, thus mitigating electron-hole recombination and promoting the catalytic efficiency. [31]However, deuterium labelling of organic compounds over MOFbased photocatalysts has not been reported to date.
Here, we report the efficient photocatalytic dehalogenative deuteration of a broad range of aryl-and alkyl-halides over the robust material MFM-300(Cr) under visible light (350-780 nm) irradiation, with CD 3 CN and Na 2 SO 3 acting as deuterium source and sacrificial agent, respectively.High deuterium incorporation and excellent regioselectivity have been achieved at room temperature for 40 substrates, including 25 iodides and 15 bromides.The confined binding of halogenated substrates via formation of host-guest π•••π interactions and hydrogen bonding within the MOF pores has been confirmed by synchrotron X-ray powder diffraction (SXPD) of substrate-loaded MFM-300(Cr).In situ electron paramagnetic resonance (EPR) spectroscopy reveals the generation of de-halogenated carbon radicals as the reaction intermediate to drive the photocatalytic process, and a reaction pathway proposed.

Research Articles
68 %, exceeding that of TEOA and TEA (55 % and 29 %, respectively).A biphasic system comprising of H 2 O and CH 3 CN was employed to dissolve Na 2 SO 3 and the organic substrate, respectively, and, powder X-ray diffraction (PXRD) analysis confirmed that Na 2 SO 3 was partially oxidised to Na 2 SO 4 (Figure S6).To gain further insight into this reaction, a set of control experiments were conducted (Table S1).In the absence of MFM-300(Cr), only a low yield of 34 % for anisole was observed.Replacing MFM-300(Cr) with an equivalent amount powdered mixture of CrCl 3 • H 2 O and H 4 L also resulted in a low yield of 34 %.These results identified the role of MFM-300(Cr) as the photocatalyst and the importance of its framework structure.In the absence of Na 2 SO 3 , with or without MFM-300(Cr), less than 7 % yield of anisole was observed.Under dark conditions, no product was formed confirming the photocatalytic nature of this reaction.Moreover, in the absence of H 2 O or reducing the concentration of Na 2 SO 3 results in reduced yields of 12 % and 48 %, respectively.Thus, the reaction conditions were optimised for 0.5 mmol of substrate at a catalyst loading of 10-20 mol%, 0.5 M of Na 2 SO 3 in CH 3 CN/H 2 O for 24 h.Importantly, MFM-300(Cr) could be recycled readily and retained its catalytic activity for at least five cycles with only minor change in the structure (Figure 2d and Figure S2a).
To investigate the source of deuterium, a set of control experiments were conducted in different solvents using 4iodoanisole and 4'-bromoacetophenone as the iodo and bromo substrates, respectively (Table 1).The reaction of 4iodoanisole gives a CÀ I/CÀ H exchange yield of 68 % in solvents rather than water serve as the deuterium source in this protocol, which is distinct to the examples reported in the literature, [19,38] reflecting the strong adsorption of organic solvents by the MOF.For example, when porous inorganic CdSe nanosheets were employed as photocatalyst for deuterodehalogenation of aryl halides in CH 3 CN/D 2 O, D 2 O Reaction conditions: Substrate (0.50 mmol), MFM-300(Cr) (10 mol%, 0.05 mmol), organic solvent/H 2 O (15 mL/15 mL), Na 2 SO 3 (0.5 M), 25 °C, 350-780 nm, 24 h.splitting occurs to supply deuterium free radicals to drive the reaction. [19]he reactivity of a wide range of halogenated substrates was monitored under the above optimised conditions (Figure 3).Aryl, heteroaryl and alkyl halides show excellent yields of hydrodehalogenated (using CH 3 CN) and deuterodehalogenated (using CD 3 CN) products, with excellent functional group tolerance due to the mild reaction conditions applied.Importantly, 16 substrates show yields of > 90 %.The substituents of iodobenzene (À COOH, 2 g-2 i) and bromobenzene (À CHO andÀ COCH 3 , 4 a-4 f) at para-, meta-, and ortho-positions give yields of 77-99 %, and these variations are ascribed to the effects of steric hindrance.The deuteration of halides containing carbonyl groups was more successful in CD 2 Cl 2 /H 2 O, which can suppress the sidereaction of reductive coupling to form 1,2-diols. [33] Interestingly, substrates with different halogen substituents (F, Cl, Br) on the aryl rings show excellent chemoselectivity (iodides: 2 o, 2 s, 2 t, 2 u; bromides: 4 i, 4 j, 4 k, 4 l, 4 m and 4 n), attributed to the different bond dissociation energies and reduction potentials. [39,40]Heteroaryl and alkyl halides have also been exploited (2 v, 2 w, 2 x, 2 y and 4 o), and broadens further the scope of this approach.Importantly, the photocatalytic efficiency is retained even with a 10 fold loading of the substrate (Figure S7), demonstrating the scalability of this method.
To investigate the location of adsorbed substrates within the pores of MFM-300(Cr), SXPD data were collected for MFM-300(Cr) loaded with 4-iodoanisole (IÀ PhOCH 3 ), 1iodonaphthalene (IÀ Nap), 4'-bromoacetophenone (BrÀ PhCOCH 3 ) and bromopentafluorobenzene (BrÀ PhF 5 ).Full structural analyses of the SXPD data have yielded highly satisfactory Rietveld refinements (Figures S8-S11, Tables S2-S6).As illustrated in Figure 4, the guest-loaded MFM-300(Cr) show full retention of the framework structure, and the substrate molecules are mainly stabilised by π•••π interactions between the benzene rings of guest molecules and ligands of MFM-300(Cr) with an inter-planar distance of 3.04(3), 3.77(2), 3.41(2) and 3.88(1) Å for adsorbed IÀ PhOCH 3 , IÀ Nap, BrÀ PhCOCH 3 and BrÀ PhF 5 , respectively.Additional hydrogen bonding between O or halogen atoms of guest molecules and the bridging À OH groups of MFM-300(Cr) further stabilise the substrates within MFM-300(Cr).Also, trace amounts of free water molecules were found in the structures, interacting with adsorbed guest substrates via additional hydrogen bonding.Thus, the SXPD studies reveal the confined binding of substrate molecules within the cavity of MFM-300(Cr), and this has been confirmed by FTIR spectroscopic analyses (Figure S12 and SI).Host-guest interactions can effectively promote the transfer of the photo-induced electrons and activate the substrate for redox reactions, thus boosting the photocatalytic efficiency.
To investigate the reaction mechanism, in situ EPR spectroscopy was used to investigate any free radicals generated under photocatalytic conditions. [41]α-Phenyl Ntertiary-butyl nitrone (PBN), a nitrone spin-trap known for trapping short lived radicals to generate a more stable free radical, was used as the spin trap to reactions with the four model substrates, IÀ PhOCH 3 , IÀ Nap, BrÀ PhCOCH 3 and BrÀ PhF 5 , under optimised photocatalytic conditions.An intense six-line signal characteristic of PBN-radical adducts was found for each substrate, with subtly different hyperfine splitting parameters to the 14 N and β-1 H of the nitroxide adduct formed (a H and a N ; Figure 5, Table S7).These parameters are consistent with C-centred radicals, similar to ). [44] All models were obtained from Rietveld refinements of SXPD data.The substrate molecules are disordered over two equally distributed sites in the pore and only one site is shown for clarity.

Research Articles
those observed for PBN-trapped Ph radicals, [42,43] and assigned to the aryl-based radicals PBN-* PhOCH 3 , PBN-* Nap, PBN-* PhCOCH 3 and PBN-* PhF 5 , respectively.No radical was trapped or observed for reactions conducted without substrate (Figure S13) or under dark conditions (Figure 5).Thus, an aryl-based radical has been identified as the reaction intermediate to the formation of dehalogenation products.
The following reaction mechanism is thus proposed (Figure 5d).Upon light irradiation, MFM-300(Cr) is activated and photo-induced electrons generated.These are transferred though single electron transfer (SET) to the adsorbed substrates via host-guest π•••π interactions and hydrogen bonding, and the CÀ X bond of the substrate is cleaved to yield free aryl-based radicals as confirmed by the EPR trapping experiments.The aryl-based radicals can abstract a hydrogen or deuterium radical from the organic solvent molecules to afford the product.No * CH 2 CN or * CD 2 CN radicals were detected suggesting that the free radicals are rapidly scavenged.The hole left in MFM-300(Cr) is reduced by Na 2 SO 3 , which is oxidised to Na 2 SO 4 , thus driving the electron-hole separation and cycles of successive charge transfer reactions.

Conclusion
MFM-300(Cr) shows an excellent catalytic activity to promote the dehalogenative deuteration of a range of halides under mild conditions, representing the first example of MOF-based photocatalyst for deuterium labelling of organic compounds.The photoinduced electrons have a high reduction potential (up to À 2.55 V) that can reduce a wide range of substrates to their corresponding free radicals under mild conditions.The photocatalytic efficiency and selectively of MOFs can be tailored by the inherent flexibility in the design of MOFs, most notably for the control and refinement of host-guest interactions.Thus, using MOFs as photocatalysts for challenging organic reactions has significant prospects in medicinal and pharmaceutical chemistry.
CH 3 CN/H 2 O and a CÀ I/CÀ D exchange yield of 66 % with a yield for deuterium exchange of 95 % in CD 3 CN/D 2 O. Interestingly, CÀ I/CÀ H exchange was observed in CH 3 CN/ D 2 O with no detectable amount of deuterium incorporated, and CÀ I/CÀ D exchange in CD 3 CN/H 2 O shows a yield for deuterium exchange of 92 %, indicating that the deuterium source for this reaction is CD 3 CN rather than D 2 O.The same result was observed for 4-bromoacetophenone, for which CÀ Br/CÀ H exchange was observed in CH 2 Cl 2 /H 2 O and in CH 2 Cl 2 /D 2 O, and CÀ Br/CÀ D exchange in CD 2 Cl 2 / H 2 O and in CD 2 Cl 2 /D 2 O, confirming CD 2 Cl 2 as the deuterium source.These control experiments confirm that organic

Figure 3 .
Figure 3. Photocatalytic dehalogenation of iodides and bromides over MFM-300(Cr).Yields are given under the structure of each product and are determined by 1 H NMR spectroscopy using nitromethane or cyclohexane as an internal standard.Several isolated yields (2 n', 2 q, 2 r', 4 d, 4 f', 4 n') were also obtained.Full details are described in the Supporting Information.Typical reaction conditions: substrate (0.50 mmol), MFM-300(Cr) (10 %, 0.05 mmol), CH 3 CN/H 2 O (15 mL/ 15 mL), Na 2 SO 3 (0.5 M), 25 °C, 350-780 nm, 24 h. a 20 mol% of catalyst loading, b 48 h of reaction time, c in CH 2 Cl 2 /H 2 O or CD 2 Cl 2 /D 2 O solvent system, d isolated yield.The 1 H and 13 C NMR spectra of reaction mixtures of 2 a, 2 a', 4 d and 4 d' are given in the Supporting Information.

Table 1 :
Control experiments for mechanistic studies on the deuterium source.