A bifunctional cerium phosphate catalyst for chemoselective acetalization

A CePO4 catalyst exhibits high catalytic performance for the chemoselective acetalization of 5-hydroxymethylfurfural with alcohols, in sharp contrast to other homogeneous and heterogeneous acid and/or base catalysts.


Introduction
Synergistic and cooperative activation by two or more catalytically active sites with acidic, basic or redox properties can allow high catalytic activity and specic selectivity. 1 In particular, acid-base bifunctionality has received much attention because such concepts are widely applied to catalyses related to hydrocarbon conversion, atom-efficient functional group transformation, tandem reactions, and asymmetric syntheses. 2 In the elds of heterogeneous catalysis, the acid-base properties of metal oxide-based materials have been extensively studied, and various effective simple and mixed oxide catalysts have been reported. 3 However, difficulty in the construction of uniform electrically and structurally controlled acid-base sites oen leads to a problem where the ne-tuning of the catalyst structure and the reactivity are restrained. While the modication of oxide surfaces with organic acids and/or bases is a powerful method, 4 the susceptibility of the organic parts to oxidative/thermal degradation has limited the usefulness of such catalysts. Therefore, the design and development of new high-performance all-inorganic heterogeneous acid-base catalysts remains a strongly desired and challenging subject of research.
We have recently reported unique base catalysis using oxoanions including [WO 4 ] 2À and [PO 4 ] 3À . 5 Despite their basicities being weaker than those of inorganic and organic strong bases, their specic activation of nucleophiles such as alcohols and amines results in atom-efficient reactions such as the chemical xation of CO 2 , regioselective N-alkylation of indoles, and chemoselective acylation of alcohols. On the other hand, rare earth (RE) metal species act as Lewis acid catalysts for various carbon-carbon bond forming reactions through the activation of carbonyl compounds. 6 Against this background, we anticipated that RE orthophosphates, REPO 4 , would be good candidates as bifunctional acid-base catalysts that can work in concert to promote electrophilicity and nucleophilicity in reactive partners. In this communication, we report the highly chemoselective acetalization of 5-hydroxymethylfurfural (1a), which has alcohol and aldehyde functionalities, 7 with alcohols using a monoclinic CePO 4 catalyst synthesized by a hydrothermal method ( Fig. 1(a)). Compound 1a is a versatile carbonyl compound with sensitive functional groups. For reactions of 1a with alcohols in the presence of acid catalysts, 8,9 ethers or a complex mixture of products are typically obtained due to the presence of the Brønsted acid-sensitive hydroxyl groups in 1a. 8 The present system has the following signicant advantages: (i) high yields and chemoselectivity toward acetals, even for substrates with hydroxyl groups, (ii) applicability to various combinations of substrates and larger-scale syntheses, and (iii) reusability as a heterogeneous catalyst system. While metal phosphates and related materials have been extensively investigated for the conversion of carbohydrates into 1a, 10 acid-base catalysis over CePO 4 has not been reported to date 11 and the present bifunctionality can lead to the chemoselective acetalization of carbonyl compounds containing sensitive functional groups, such as 1a.

Synthesis and characterization of CePO 4
Monoclinic CePO 4 was synthesized through the hydrothermal reaction of Ce(NO 3 ) 3 and (NH 4 ) 2 HPO 4 at 180 C, followed by calcination at 900 C (see details in the ESI †). Fig. 1 (b) shows the powder X-ray diffraction (XRD) pattern measured for CePO 4 , which is in good agreement with that reported for the monoclinic CePO 4 structure, in which a Ce 3+ ion connects to seven tetrahedral PO 4 3À groups [space group P2 1 /n]. 12 The impurity phases of other cerium and phosphorus oxides were not observed. The infrared (IR) spectrum of CePO 4 is shown in Fig. S1. † Asymmetric stretching vibrations of the PO 4 3À groups were split into bands at 1091, 1062, 1028, 994, and 956 cm À1 due to a decrease in the symmetry of PO 4 3À from T d to C 1 . 13 The bands in the range of 500-700 cm À1 are assigned to the bending of the P-O links in the distorted PO 4 3À tetrahedra, and these band positions are similar to those previously reported for monoclinic CePO 4 . 13 The elemental analysis of bulk CePO 4 using energy dispersive X-ray spectroscopy (EDX) revealed that the molar ratio of Ce : P is 1 : 1. The valence state of the surface Ce was investigated using X-ray photoelectron spectroscopy (XPS) (Fig. 1(c)). The Ce 3d 3/2,5/2 spectra are composed of two multiplets (v and u), which correspond to the spin-orbit split 3d 5/2 and 3d 3/2 core holes. 14 The Ce 3d spectrum of CePO 4 exhibits four peaks with binding energies of 904.9, 901.0, 806.5, and 883.0 eV, which correspond to the u 0 , u 0 , v 0 , and v 0 peaks, respectively, and are in good agreement with the reported Ce 3d spectra for Ce(III) oxides. 15 The specic surface area of CePO 4 calculated from a Brunauer-Emmett-Teller (BET) plot of the N 2 adsorption isotherm (77 K) was up to 37 m 2 g À1 . Fig. 1(d) shows a scanning electron microscopy (SEM) image of CePO 4 with rodlike shaped particles 100-500 nm long and 20-50 nm wide.
The acidic properties of CePO 4 were evaluated using IR spectroscopy for a sample with adsorbed pyridine as a probe base (see details in the ESI †). 3,10,16 Differential IR spectra of CePO 4 with adsorbed pyridine are shown in Fig. 2(a) and S2. † The band at 1445 cm À1 is assigned to the pyridine species coordinated to the Lewis acid sites, while no band due to pyridinium ions bonded to the Brønsted acid sites was observed at ca. 1540 cm À1 . The amount of Lewis acid sites on CePO 4 was estimated from the intensity of the band at 1445 cm À1 to be 0.096 mmol g À1 . The difference IR spectrum for CePO 4 with adsorbed CHCl 3 is shown in Fig. 2 (b). The red-shi of the original C-H stretching mode of the CHCl 3 molecule (from 3034 cm À1 to 3008 cm À1 ) indicates the presence of basic sites on the surface. 16 In addition, a new broad shoulder band appeared at 1250 cm À1 , which was assigned as d(ClC-H) for the CHCl 3 molecules due to the interaction of the acidic hydrogen and chlorine atoms with the basic oxygen and Lewis acid sites, respectively. 16 Thus, the base sites on CePO 4 could be located in close proximity to the Lewis acid sites, in agreement with the structure of CePO 4 .

Catalytic acetalization of 1a with methanol
The reaction of 1a with methanol was examined rst in the presence of various catalysts that have been reported to be effective for acetalization, 17 and the results are summarized in Table 1. The three products 5-(dimethoxymethyl)-2-furanmethanol (2a), 5-methoxymethylfurfural (3a), and 2-(dimethoxymethyl)-5-(methoxymethyl)furan (4a) were mainly formed. The reaction did not proceed in the absence of a catalyst (entry 27). Among the catalysts tested, CePO 4 exhibited the highest activity for the acetalization of 1a to give 2a in 78% yield (entry 1). In this case, the selectivity toward 2a reached 96% without the formation of 3a or 4a. In the presence of homogeneous Brønsted acid catalysts (H 2 SO 4 , p-toluenesulfonic acid (TsOH), and H 3 PW 12 O 40 ) and Lewis acid catalysts (scandium tri-uoromethanesulfonate (Sc(OTf) 3 ) and Ce(OTf) 3 ), only 3a and/or 4a were obtained in low to moderate yields (entries 2-6). The reaction of 1a with methanol in the presence of these homogeneous acid catalysts was carried out by reducing the amounts of the catalysts to match the surface Ce content (i.e. 9.6 mmol) with the Lewis acid sites measured using pyridine-IR (Table S1 †). While the conversions using these homogeneous acid catalysts were higher than that using CePO 4 , 2a was not formed under the reaction conditions. In addition, no product was obtained using the homogeneous base catalysts of K 3 PO 4 , K 2 HPO 4 , and KH 2 PO 4 (entries 7-9). Thus, homogeneous acid or base catalysts themselves are not deemed as effective for the chemoselective acetalization of 1a. Acetalization over Nb 2 O 5 was less effective than over CePO 4 , and other metal oxide catalysts including SiO 2 , ZrO 2 , CeO 2 , Al 2 O 3 , MgO, TiO 2 , and SnO 2 were almost inactive (entries 13-20). Typical solid acid catalysts such as sulfated zirconia, sulfonated carbon, Naon, mordenite, and montmorillonite gave complex mixtures of 2a, 3a, and 4a (entries [21][22][23][24][25][26]. The catalyst precursors of Ce(NO 3 ) 3 , (NH 4 ) 2 HPO 4 , and a mixture of Ce(NO 3 ) 3 and (NH 4 ) 2 HPO 4 were not effective for acetalization (entries 10-12), which indicates that CePO 4 plays an important role in the acetalization reaction. 18 To verify whether the observed catalysis is derived from solid CePO 4 or from leached cerium or phosphorus species, the reaction of 1a with methanol was conducted under the conditions described in entry 1 of Table 1, and CePO 4 was removed from the reaction mixture by hot ltration at ca. 30% conversion of 1a (at t ¼ 15 min). The ltrate was then heated again under the same reaction conditions. In this case, no further production of 2a was observed, as shown in Fig. 3. No leaching of cerium or phosphorus species into the ltrate was observed using inductively coupled plasma atomic emission spectroscopy (ICP-AES, with detection limits for Ce and P atoms of ca. 1 and 3 ppb, respectively). Therefore, there was no contribution to the observed catalysis from cerium or phosphorus species leached into the reaction solution, and the nature of the observed catalysis is conrmed as truly heterogeneous. 19 The used CePO 4 catalyst could be readily recovered from the reaction mixture by simple ltration (96% recovery). The recovered CePO 4 catalyst could then be reused without a signicant decrease in the yield of 2a or the selectivity: 78% yield of 2a at 81% conversion (fresh) and 78% yield of 2a at 80% conversion (reused). There was no signicant difference in the XRD patterns of the fresh and reused CePO 4 catalysts, which indicates the high durability of CePO 4 (Fig. S3 †).

Reaction mechanism for the CePO 4 -catalyzed acetalization
While it has been reported that other metal oxides (e.g. CeO 2 ) can function as effective acid-base catalysts, 3,17d only CePO 4 exhibited high catalytic activity and chemoselectivity for acetalization. Thus, the activation mode of substrates with CePO 4 and CeO 2 was conrmed using IR measurements of samples with adsorbed acetone and methanol. As shown in Fig. 2(c), one strong C]O stretching band of acetone adsorbed on CePO 4 was observed at a lower wavenumber (1699 cm À1 ) than that of acetone in the gas phase (1731 cm À1 ). 20 In addition, the IR spectrum of acetone adsorbed on CeO 2 exhibited a shoulder at 1700 cm À1 and a strong band at 1673 cm À1 due to acetone molecules coordinated to different types of Lewis acid sites, and absorptions at 1627 cm À1 and 1570-1550 cm À1 are assignable to condensed species (Fig. S4 †). 20 These results indicate the interaction between the carbonyl oxygen of the ketone and the uniform Lewis acid sites on CePO 4 without the promotion of aldol condensation. 21,22 Fig. 2(d) shows the IR spectrum of methanol adsorbed on CePO 4 . In the n(O-H) region, negative OH bands were observed with the appearance of broad bands between 3000 and 3500 cm À1 . In addition, the IR spectrum shows bands at 2952 and 2849 cm À1 that were assigned to asymmetric and symmetric CH 3 stretching modes, respectively. The appearance of such broad bands and the band positions of n(CH 3 ) indicate that methanol is adsorbed molecularly on CePO 4 via hydrogen bonds, which is consistent with previous reports for the non-dissociative adsorption of methanol on metal oxides. 23 On the other hand, the IR spectrum for methanol adsorbed on CeO 2 has bands at 2911 and 2805 cm À1 that were assigned to the n as (CH 3 ) and n s (CH 3 ) modes of methoxide species, respectively (Fig. S4 †). Therefore, CePO 4 most likely acts as a bifunctional catalyst through interaction of the uniform Lewis acid sites and weak base sites with 1a and alcohol molecules, respectively, which results in highly efficient and chemoselective acetalization. 24 The present acetalization of 1a with methanol possibly proceeds as follows (Fig. 4). First, the activation of both 1a and methanol by CePO 4 facilitates nucleophilic attack of the OH group in methanol on the carbon atom of the carbonyl group in 1a to give the corresponding hemiacetal derivative. Further reaction of the hemiacetal with methanol then occurs, most likely with the assistance of the CePO 4 catalyst, to give the corresponding acetal derivative.

Substrate scope for the CePO 4 -catalyzed acetalization
To investigate the effectiveness of the bifunctional properties of CePO 4 , CePO 4 -catalyzed acetalization was explored with various substrates. In the presence of CePO 4 , various combinations of carbonyl compounds and alcohols were efficiently converted into the corresponding acetal derivatives in good to excellent yields ( Table 2). The acetalization of 1a with methanol and with diols such as ethylene glycol and 1,3-propanediol proceeded selectively (entries 1-3). CePO 4 effectively catalyzed the acetalization of other aldehydes containing heteroatoms, such as furfural (1b) and 2-thiophenecarboxaldehyde (1c), into the corresponding dimethyl acetals, while the acetalization of a Reaction conditions: catalyst (0.1 g), 1a (1.0 mmol), methanol (5 mL), and reux for 1 h. Conversion and yield were determined by GC analysis. Conversion (%) ¼ converted 1a (mol)/initial 1a (mol) Â 100. Yield (%) ¼ product (mol)/initial 1a (mol) Â 100. b Catalyst (0.43 mmol; i.e. equivalent to the Ce content in CePO 4 (0.1 g)).   2-pyridinecarboxaldehyde (1d) did not proceed (entries 4-6). The catalytic reactivity of CePO 4 in the presence of pyridine was investigated. It was conrmed that the presence of pyridine strongly inhibited the reaction of 1a with methanol (Fig. 5). The yield of 2a decreased with an increase in the small amount of pyridine added (3-12 mmol; ca. 0.3-1.3 equivalents with respect to the Lewis acid sites on CePO 4 ). The nitrogen atom of pyridine would strongly coordinate to the cerium metal center, which would inhibit the reaction. The reactions of benzaldehydes with electron-donating and electron-withdrawing para-substituents (1e-1g) proceeded to afford the corresponding dimethyl acetals in high yields (entries 7-9). Even the bulkier aldehyde 1-naphthaldehyde (1h) could be efficiently acetalized when the reaction time was prolonged to 20 h (entry 10). The acetalization of cinnamaldehyde (1i) with methanol proceeded smoothly without inuence on the C]C double bond (entry 11). Not only were aromatic and a,b-unsaturated aldehydes converted but also 3-phenylpropionaldehyde (1j) and cyclohexanecarboxaldehyde (1k) were efficiently converted into the corresponding acetals in high yields (entries 12 and 13). Furthermore, the present system could effectively catalyze aliphatic and aromatic ketones with ethylene glycol. Cyclohexanone (1l) was quantitatively converted into 2,2-pentamethylene-1,3-dioxolane (2l), and acetophenone (1m) gave its corresponding ketal (2m) in moderate yield (entries 14 and 15). Even in the presence of hydroxyl groups in the substrate (5-hydroxy-2-adamantanone (1n)), the corresponding ketal (2n) was obtained in good yield (entry 16). The present catalytic system was applicable to a gram-scale reaction of 1a (10.5 mmol scale) with methanol and 1.46 g of analytically pure 2a could be isolated (eqn (1)). In this case, the turnover number (TON) based on surface Lewis acid sites reached 177 and the corresponding turnover frequency (TOF) was 44 h À1 . In addition, CePO 4 efficiently catalyzed the gramscale regioselective acetalization of acetone (1o) with glycerol into the industrially important chemical 2,2-dimethyl-1,3-dioxolan-5-ol (solketal (2o)). 25,26 Solketal has been used as a highly soluble additive to increase the octane number of fuel, and as such many catalyst systems to aid its synthesis have been reported. 25,26 CePO 4 exhibited high regioselectivity (2o/2o 0 ¼ 98/2) and 1.29 g of analytically pure 2o was successfully isolated (eqn (2)), while the condensation of glycerol with 1o under acidic conditions sometimes affords a mixture of veand sixmembered acetals (2o and 2o 0 , respectively). 25 (1) (2)

Conclusions
In conclusion, CePO 4 efficiently catalyzes the acetalization of various aryl and aliphatic carbonyl compounds containing hydroxyl groups, C]C bonds, and heteroatoms with alcohols. This study suggests that the development of bifunctional solid catalysts with uniform active sites is of particular importance. This approach is a promising strategy for the development of highly efficient heterogeneously-catalyzed reactions through the non-dissociative activation of both electrophiles and nucleophiles under very mild conditions.