Phosphine-Built-In Porous Organic Cage Supported Ultrafine Pd Nanoclusters Enable Highly Efficient and Regioselective Hydrogenation of Epoxides

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLES20 Feb 2024Phosphine-Built-In Porous Organic Cage Supported Ultrafine Pd Nanoclusters Enable Highly Efficient and Regioselective Hydrogenation of Epoxides Xin Zhou, Zhaozhan Wang, Zhe-Ning Chen and Yong Yang Xin Zhou CAS Key Laboratory of Bio-Based Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao 266101 Shandong Energy Institute, Qingdao 266101 , Zhaozhan Wang CAS Key Laboratory of Bio-Based Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao 266101 Shandong Energy Institute, Qingdao 266101 College of Environment and Safety Engineering, Qingdao University of Science and Technology, Qingdao 266101 , Zhe-Ning Chen *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002 University of Chinese Academy of Sciences, Beijing 100049 Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen University, Xiamen 361005 and Yong Yang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] CAS Key Laboratory of Bio-Based Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao 266101 Shandong Energy Institute, Qingdao 266101 University of Chinese Academy of Sciences, Beijing 100049 https://doi.org/10.31635/ccschem.024.202303468 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Selective hydrogenation of epoxides has been regarded as an atom-economical and straightforward method for the synthesis of alcohols. However, it remains a big challenge in the precise control of regioselectivity. To date, the reaction enabled by a reusable and high-performance heterogeneous catalyst with excellent regioselectivity is very scarce. Herein, we develop highly loaded and ultrafine Pd nanoclusters (NCs) encapsulated on a phosphine-built-in porous organic cage (FPPOC) for the catalytic hydrogenation of epoxides by molecular hydrogen. Benefiting from the unique characters of uniform dispersion and strong interaction between Pd NCs and FPPOC, the resultant Pd NCs exhibited superior catalytic activity and excellent regioselectivity for the hydrogenation of epoxides under milder conditions. A diverse set of terminal and internal epoxides was efficiently reduced to the corresponding linear or branched alcohols in an extremely regioselective manner, well tolerating diverse functional groups. Remarkably, the catalyst demonstrates high stability and could be reused up to 10 times with marginal decay in activity and regioselectivity. Furthermore, the catalyst is applicable for scale-up synthesis with a record turnover number as high as 16,111, to the best of our knowledge, outperforming those previous state-of-the-art catalysts. Control experiments and characterizations in combination with density functional theory calculations provide insight into the superior activity and excellent regioselectivity. Download figure Download PowerPoint Introduction Alcohols have a broad range of application in bulk and fine chemicals, pharmaceuticals, agrochemicals, fragrance, and flavoring chemistry.1 As a result, the development of efficient methodologies for their synthesis has been attracting considerable attention in both academia and industry, and several synthetic methods have been developed over the past decades. Among them, the selective hydrogenation of epoxides in the presence of molecular hydrogen represents one of most straightforward and atom-economic strategy for synthesizing alcohols but remains challenging.2–4 Remarkably, epoxides are readily available from alkenes by a one-step oxidation process using peroxyacids or hydrogen peroxide, or from other methods.5,6 A key challenge for the catalytic hydrogenation of epoxides lies in the control of regioselectivity due to the high ring strain and strong polarization of the C–O bond with two competitive epoxide ring opening possibilities, affording primary and/or secondary (i.e., Anti-Markovnikov and/or Markovnikov) alcohols.4,7–10 To this end, several transition metal-catalyzed hydrogenations using homogeneous catalysts have been developed, including Ru,11–13 Ir,14 Ti,15,16 Co,17,18 Fe,19,20 Ni,21,22 and Zr,23 which successfully achieved tuning the regioselectivity to alcohols (Scheme 1a). However, they generally suffer from several issues of difficulty in separation and recycle of the metal catalysts, high catalyst loading, auxiliary of expensive and sophisticated ligands, limited substrate scope, and forcing reaction conditions, which severely hinder their practical potential. Therefore, it is highly desirable to develop efficient heterogeneous catalysts for catalytic hydrogenation of epoxides with excellent regioselectivity. Scheme 1 | General overview and present work for epoxide hydrogenation. Download figure Download PowerPoint As a matter of fact, heterogeneous catalysts have previously been applied for hydrogenation of epoxides, while only a handful cases are available thus far. Pd nanoparticles (NPs) supported on various supports or stabilized by varying capping agents were developed due to their very high affinity toward H2 molecules (Scheme 1b).24–30 As demonstrated in previous studies, heterogeneous Pd NPs could effectively address the issues of the difficulty in separation and reuses of catalyst, while the challenges of relatively lower activity, limited substrate scope, and difficulty in controlling regioselectivity are not well resolved. In recent years, well-defined and discrete three-dimensional (3D) porous organic cages (POCs) with guest accessible cavities have been employed as ideal carriers for the size-controlled synthesis of ultrafine metal NPs or nanoclusters (NCs) (∼1–3 nm in core size) for diverse organic transformations.31–36 Different from frequently used supports, POCs have several unique features, including (1) easy functionalization of the skeleton to tune the local environment, (2) readily tunable size of the cavity, (3) excellent solubility with a well-kept prefabricated skeleton in common organic solvents, (4) inherently built-in heteroatoms (N, S, and P) in the cage. As the hosts, a number of ultrafine metal NPs/NCs, such as Pd,37–42 Au,43–45 Rh,46 Pt,47,48 Ir,49 Ag,50 and Co,51 have been encapsulated into POCs with well-controlled size and narrow distribution mainly due to the inherent heteroatoms as binding and nucleation sites and nanometer-sized porous cavity. More importantly, the excellent solubility of POCs in certain organic solvents could enable the heterogeneous NPs/NCs to be well-dispersed in solution to form a single phase as homogeneous catalysis, thereby substantially boosting the catalytic activity and selectivity, which could hardly be realized for those insoluble porous hosts.33–41,46,47,52,53 Very recently, we reported a bench-stable triphenyl phosphine-built-in porous organic cage (PPOC) for the controlled growth of well-dispersed ultrafine Pd NCs (Pd@PPOC) via a strong coordination approach based on the hard-soft acid-base principle. The presence of multiple phosphine units in the PPOC not only favors the coordination with Pd centers to form ultrafine Pd NCs with strong stability but also effectively modulates the surface electron density of the Pd NPs via the positive electronic interaction. Benefiting from the advantages of ultrafine NCs, strong interaction, and excellent solubility in solution, the Pd@PPOC catalyst demonstrated superior catalytic activity and selectivity (including regioselectivity) for the cross-coupling reactions of aryl halides as well as hydroaminocarbonylation of alkenes and alkynes.54,55 In this work, a new trifuranyl phosphine-built-in POC (named as FPPOC) was prepared and employed as the host to encapsulate Pd NCs. Ultrafine Pd NCs with narrow size distribution and high loading of 19.3 wt % were uniformly dispersed on FPPOC. The as-synthesized Pd@FPPOC showed superior catalytic activity and extremely high regioselectivity for hydrogenation of epoxides under milder reaction conditions (Scheme 1c). A broad substrate scope of aromatic and aliphatic epoxides was efficiently hydrogenated toward the corresponding alcohols with good tolerance of diverse functional groups. Remarkably, the Pd@FPPOC catalyst demonstrates a record turnover number (TON) as high as 16,111, which is applicable for scale-up synthesis, and could be readily separated and reused up to 10 times without negligible loss in both activity and regioselectivity. Control experiments and characterizations in combination with density functional theory (DFT) calculations reveal the reason behind the superior activity and regioselectivity. Experimental Methods General procedure for Pd@FPPOC catalyzed hydrogenation of epoxides A 25 mL glass vessel containing a stirring bar was sequentially charged with Pd@FPPOC (2 mg, 0.9 mol %), epoxide (0.4 mmol), and EtOH (2.0 mL). The flask was evacuated and backfilled with H2 three times with a H2 balloon. The reaction mixture was stirred at 30 °C for 12 h for aromatic epoxides (or 60 °C for 16 h for aliphatic epoxides). The reaction mixture was filtered and analyzed by gas chromatography in ethyl acetate. Finally, the filtrate was concentrated and purified by silica gel column chromatography to afford the desired alcohols as isolated yields. Results and Discussion Material synthesis and characterization According to our previous report,54,55 the FPPOC was synthesized through dynamic imine chemistry of tri(furan-2-yl) phosphine-based trialdehyde and [(S,S)-1,2-cyclohexanediamine]. Briefly, a 2:3 stoichiometric ratio of trialdehyde and diamine was stirred at 40 °C in dichloromethane (DCM)/MeOH (1:1, v/v) for 5 days to afford a pale-yellow solid after recrystallization in methanol (Figure 1a and Supporting Information Scheme S1). The formation of the [2 + 3] assembled molecular cage was unambiguously confirmed by 1H/13C/31P NMR, electrospray ionization mass spectroscopy analysis, and Fourier transform infrared spectroscopy ( Supporting Information Figures S2–S9). The solid FPPOC is bench-stable and insoluble in strong polar solvents (e.g., alcohol, H2O), but is soluble in DCM or DCM-MeOH mixture while maintaining the prefabricated skeleton structure. Thermogravimetric analysis demonstrates that FPPOC has a good thermal stability ( Supporting Information Figure S10). Pd NCs supported on FPPOC (named as Pd@FPPOC) was prepared via a typical impregnation-reduction process using Pd(OAc)2 as Pd source and sodium borohydride (NaBH4) as the reductant.54 Figure 1 | (a) Illustration of synthesis of phosphine-built-in POC (FPPOC) and Pd@FPPOC. (b, c) HR-TEM images and particle size distribution (inset) of Pd@FPPOC. (d) HAADF-STEM image and corresponding C, N, O, P, and Pd elemental distribution mappings of Pd@FPPOC. Download figure Download PowerPoint To clearly characterize the structure of the obtained material, comprehensive characterizations were performed. The transmission electron microscopy (TEM) image (Figure 1b) shows that ultrafine Pd NCs (∼2.4 nm) with a narrow size distribution were uniformly dispersed on the surface of FPPOC. Given that the cavity size of FPPOC54 is significantly smaller than that of Pd NCs, Pd NCs are mainly on the outside of the cage cavity. The high-resolution TEM (HR-TEM) image (Figure 1c) resolves a characteristic lattice fringe with d spacing of 0.222 nm, which corresponds to the (111) plane of a typical metallic Pd face-centered cubic (fcc) structure, a high-angle annular dark-field scanning TEM (HAADF-STEM) image, and the corresponding energy-dispersive X-ray mapping images (Figure 1d) verify that C, N, P, O, and Pd elements were homogeneously distributed without any sign of agglomeration, which is supportive of the excellent dispersity of ultrafine Pd NCs in the FPPOC again. X-ray diffraction (XRD) patterns (Figure 2a) show a broad diffraction peak centered at 20° for the as-synthesized FPPOC, while a less intensive peak at 40.1° was detected in Pd@FPPOC, which is indexed to the (111) lattice plane of metallic Pd (JCPDS# 46-1043) with a fcc structure, and is consistent with TEM observation. This observation indicates that Pd NCs are successfully loaded. The Pd loading amount of Pd@FPPOC was determined to be 19.3 wt % by inductively coupled plasma optical emission spectrometry (ICP-OES). Hence, a molecular cage with high Pd loading content of ultrafine NCs and uniform distribution was successfully prepared. Surprisingly, no aggregation of ultrafine Pd NCs was observed in Pd@FPPOC with such a high Pd loading, which can be attributable to the strong coordination effect of phosphorus within the molecular cage40 as well as the favorable geometric structure of the POC.56 Figure 2 | (a) XRD pattern, (b) P 2p, and (c) Pd 3d (XPS) spectra for FPPOC and Pd@FPPOC. (d) Pd K-edge XANES and (e) FT k3-weighted Pd K-edge EXAFS spectra of Pd@FPPOC with Pd foil and PdO as references. Download figure Download PowerPoint X-ray photoelectron spectroscopy (XPS) measurements were conducted to further investigate the chemical state and surface composition of the as-prepared Pd@FPPOC (Figure 2b,c and Supporting Information Figure S12). As shown in Figure 2b,c, two intense peaks centered at 340.5 and 335.2 eV were observed in the Pd 3d XPS spectrum, which can be assigned to two distinct spin-orbitals 3d3/2 and 3d5/2 states of Pd, respectively, confirming the formation of metallic Pd once again.57,58 Besides, another two small peaks at higher binding energies of 343.0 and 337.8 eV were also detected, which can be ascribed to the Pd atoms chemically interacting with the trifuranyl phosphine ligand rather than the formation of PdO.59,60 This was further confirmed by comparison with Pd 3d XPS spectrum of PdO as a reference ( Supporting Information Figure S11). Moreover, the P 2p XPS spectrum of Pd@FPPOC shows one single peak at 132.8 eV, attributable to the P–C bond, which has a positive shift in binding energy compared to that of FPPOC (131.6 eV).61 This indicates a strong interaction between Pd NCs and FPPOC. Furthermore, to further analyze the electronic structures, X-ray absorption fine structure (XAFS) measurements were performed (Figure 2d). As shown in the Pd K-edge position of Pd@FPPOC, it is very close to Pd foil but differs greatly from PdO, strongly indicating the formation of positively charged metallic Pd NCs, which is in accordance with the XRD, TEM, and XPS results. Simultaneously, the Fourier transform k3-weighted Pd K-edge extended XAFS (EXAFS) spectrum in R space shows a main peak at 2.46 Å accompanied with a less intense peak at 1.82 Å, which can be assigned to the Pd–Pd and Pd–P bonds, respectively (Figure 2e).54,62,63 Of note, the formation of Pd–P bonding clearly verifies the interaction between the surface Pd atoms and trifuranyl phosphine sites in coordination mode. In addition, there is no Pd–O bond formation in Pd@FPPOC. Taken all characterization results together, it can be concluded that ultrafine Pd NCs were supported on FPPOC with chemical interaction between phosphine sites and Pd NCs. More importantly, such an interaction not only effectively stabilizes Pd NCs and prevents from oxidation and aggregation but also greatly enhances the surface electronic density of Pd NCs, thereby strengthening the stability and improving the catalytic performance of Pd@FPPOC. Catalytic performance for hydrogenation of epoxides With the catalyst Pd@FPPOC in hand, we began to investigate its catalytic activity and selectivity in the hydrogenation of epoxides. The catalytic hydrogenation of styrene oxide ( 1a) was initially selected as a model to optimize the reaction conditions. After intensive investigation ( Supporting Information Table S1), it was found that the reaction in the presence of Pd@FPPOC (0.9 mol %) under atmosphere pressure of H2 in EtOH as an environmentally friendly medium at 30 °C gave the best result, where the linear alcohol 2-phenyl ethanol ( 2a) was quantitively produced in 99% isolated yield with exclusive regioselectivity after 12 h (Figure 3 and Supporting Information Table S1). To demonstrate the unique advantage of the phosphine-containing POC, we employed two soluble vicinal diamine-containing POCs (CC2 and CC3) as the support to encapsulated Pd NCs. For details, see our previous work.54,55 The resultant catalysts, Pd@CC2 and Pd@CC3, with nearly identical Pd NCs size showed relatively lower activity compared with Pd@FPPOC under otherwise identical conditions, and a mixture of linear and branched alcohol ( 2a and 3a) was simultaneously produced albeit with high l/b ratio. In parallel, the commercially available heterogeneous Pd/C and the conventional surfactant polyvinylpyrrolidone (PVP) protected Pd NPs (Pd@PVP) display even worse activity and regioselectivity related to Pd@FPPOC, Pd@CC2, and Pd@CC3. These results clearly indicate that phosphine as coordination sites in the supports indeed execute an essential role for improving the catalytic activity and regioselectivity. Furthermore, the precise structure of built-in phosphine unit in the POC also impacts the catalytic performance, in which trifuranyl phosphine-based POC (Pd@FPPOC) exhibited better activity and regioselectivity than that of triphenyl phosphine-based one (Pd@PPOC) due to its stronger electron donation capability to Pd NCs. Figure 3 | Comparative results of styrene oxide hydrogenation over different Pd catalysts. Download figure Download PowerPoint Substrate scope studies Having identified the optimized reaction conditions, the generality of this Pd-catalyzed hydrogenation of aromatic epoxides was further explored for the synthesis of diverse alcohols (Table 1). Starting from monosubstituted terminal epoxides ( 1a– 1q), a set of aromatic epoxides with various substituents in the phenyl ring at the ortho, meta, or para position could be efficiently and exclusively hydrogenated to the linear alcohols in good to excellent yields with tolerance of methyl, methoxy, halides, amide, trifluoromethyl, and ester substituents. Electron-withdrawing substituents and ortho-position substituents have a negative effect on the reaction efficiency and gave relatively lower activities compared with those bearing electron-donating ones or at meta, para-positions, implying both electronic and steric effect. Second, disubstituted terminal aromatic epoxides ( 1r– 1ab) are compatible with the reaction conditions, high to excellent yields to the respective anti-Markovnikov-type alcohols were achieved. Again, the electron-deficient nature of the aromatic moiety and steric-hindrance substituents negatively influenced the reaction, delivering the desired alcohols in comparatively lower yields. Third, 1,2-di- and 1,2,2-trisubstituted internal aromatic epoxides ( 1ac– 1ah) were also subjected to the optimized reaction conditions, and we were delighted to find that this protocol was also suitable for these internal epoxides, affording their respective secondary or tertiary alcohols in excellent yields and regioselectivities. Encouraged by these results, we decided to extend this protocol for the reductive ring-opening of pharmaceutically related epoxides, such as the entities of Ibuprofen ( 1ai), Fenoprofen ( 1aj), and Flurbiprofen ( 1ak), which are widely used for relieving various mild and moderate pain (e.g., headache, toothache, muscle pain, neuralgia, and arthritis).64 Delightfully, high yields to the desired linear alcohols with excellent regioselectivities were accomplished under milder conditions, offering an alternative method for the synthesis of these existing drugs. Table 1 | Substrate Scope for Hydrogenation of Aromatic Epoxidesa aReaction conditions: epoxide (0.4 mmol), Pd@FPPOC (0.9 mol % Pd), EtOH (2 mL), 30 °C, 12 h. b18 h. Isolated yield. Given the generality of the substrate scope and superior catalytic performance in the catalytic hydrogenation of aromatic epoxides, we then applied this Pd-catalyzed protocol to the more challenging alkyl epoxides (Table 2). We conducted the hydrogenation reactions using the optimized conditions for aromatic epoxides with slightly elevated temperature. As demonstrated in Table 2, a range of aliphatic epoxides with varying carbon-chain lengths ( 4a– 4g) could be effectively hydrogenated to their corresponding alcohols in good to excellent yields. Disubstituted internal epoxides ( were also applicable for the reaction, delivering their respective alcohols in yields. epoxide could also be hydrogenated but showed a lower yield related to or indicating a steric effect. Of note, in these or branched alcohols were exclusively which is to the aromatic epoxides, a strong substrate on the regioselectivity. We were delighted to find that several monosubstituted terminal epoxides ( from were suitable for this protocol with high Among them, alcohols ( and could be further to alcohols after the while and are two pharmaceutically related from and As a result, this protocol a solution for functionalization of the In addition, the ( and are also for the hydrogenation to the as functional molecules in and of the results the of this protocol for the synthesis of alcohols and functionalization as Table 2 | Substrate Scope for Hydrogenation of Epoxidesa aReaction conditions: epoxide (0.4 mmol), Pd@FPPOC (0.9 mol % Pd), EtOH (2 mL), 60 °C, 16 h. Isolated yield. To demonstrate the practical of this a scale-up reaction for the synthesis of linear alcohol was As shown in Figure and Supporting Information Scheme 2a could be prepared on a in yield with a catalyst loading of mol % of Pd under milder reaction conditions. Surprisingly, a was achieved as high as 16,111, which is the all previous state-of-the-art metal catalysts to the best of our ( Supporting Information Table the of the catalyst Pd@FPPOC for the stability and of the catalyst Pd@FPPOC were further using two model aromatic and aliphatic epoxides, respectively, under the optimized reaction conditions and 60 After of the catalyst was readily separated and from the reaction solution by with and at °C for 2 and then used for the To our the catalyst could be and up to 10 times with a negligible loss in both activity and as shown in Figure and Supporting Information Figure The loading of Pd for the used catalyst was determined to be and wt % after 10 by which is very close to the the stability of the of HR-TEM and XPS for the used catalyst ( Supporting Information Figures and show that there is marginal in the particle and chemical state of Pd NCs compared with that of the further the high stability of the catalyst the Figure | (a) (b) for the catalyst Pd@FPPOC. Download figure Download PowerPoint studies To better the superior activity and unique regioselectivity of the catalyst Pd@FPPOC in the catalytic hydrogenation of aromatic and aliphatic epoxides, a set of control experiments were performed. experiments using the model substrate styrene epoxide ( 1a) were used to the nature of catalyst (Scheme The of an of into the reaction under the conditions not any on the catalytic activity, while the reaction was of This indicates the homogeneous nature of the heterogeneous Pd NCs in the hydrogenation of epoxides ( Supporting Information Figure which is for the superior Second, control experiments were to the reaction a process as previously The reaction aromatic or aliphatic epoxide ( 1a or as the substrate under an atmosphere without the presence of hydrogen and not any or (Scheme the of the Furthermore, a control ( of styrene epoxide ( 1a) under the reaction conditions gave only amount to the corresponding alcohol 2a (Scheme indicating that the desired alcohol not from hydrogenation of the or which further the of Third, studies using styrene oxide ( 1a) or ( as the substrate showed no formation of any the reaction A linear was in which the a linear as a of reaction accompanied by a of epoxide ( 1a or ( Supporting Information Figures and To control experiments strongly that the hydrogenation of epoxides catalyzed by Pd@FPPOC in a rather than via Scheme 2 | Control Download figure Download PowerPoint To better insight into the reaction a that applied of H2 (Scheme was conducted under otherwise identical reaction conditions. A effect was observed for the hydrogenation of styrene oxide ( that the of H2 molecules to form Pd is a into the desired linear alcohol 2-phenyl ethanol at the position was confirming that H2 molecules are the hydrogen for this (Scheme 2d). This was further by as the substrate under an atmosphere of affording in yield with at the the in the 2a and molecules was most due to the easy More was used for the reaction under a mixture of and was in a ratio of The formation of to the between and ethanol at a higher 60 To support was employed as the for the In this with was exclusively produced in yield. all results strongly indicate that the reaction catalyzed by Pd@FPPOC through a process via the formation of to the linear and branched alcohols. To the in the regioselectivity toward linear or branched alcohol in the hydrogenation of aromatic and aliphatic epoxides, calculations were conducted by the model

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