Ind. Eng. Chem. Res. 2009, 48, 6287–6290
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Synthesis of Dimethyl Pimelate from Cyclohexanone and Dimethyl Carbonate over Solid Base Catalysts Dudu Wu* and Zhi Chen School of Pharmacy, Guangdong Medical College, Dongguan 523808, China
The synthesis of dimethyl pimelate (DMP) was carried out from cyclohexanone and dimethyl carbonate in the presence of solid base catalysts. The results showed that the intermediate carbomethoxycyclohexanone (CMCH) was produced from cyclohexanone with DMC in the first step, and then CMCH further converted to DMP by reacting with methoxide group. The function of basic catalysts was mainly attributed to the activation of cyclohexanone via the abstraction of proton in the R position by base sites, and solid base with moderate strength, such as MgO, facilitated the formation of DMP. 1. Introduction Dimethyl pimelate (DMP) is valued as an important intermediate in pharmaceuticals, perfumes, lubricants, and other organic compounds.1 It was usually obtained by esterification from pimelic acid with alcohols. However, the process of pimelic acid production often entailed concerns relative to high toxicity, corrosion, and separation problems. And the esterification, with alcohols also involved in two or more stages, led to highly complex products.1,2 In particular, a stoichiometric amount of water was produced in this process, which required tedious procedures for disposal.1,2 Dimethyl carbonate (DMC), as an effective additive to gasoline, has been attracting much attention in recent years because of its high oxygen content and high octane value in the energy field.3 It could also be an environmentally benign building block in fine chemistry due to its versatile chemical property and low toxicity.4 DMC is a safe substitute for methyl halides or dimethyl sulfate as methylating and carboxylating agents.5,6 In the presence of a base, it can also react with a number of nucleophilic anions generated from different substrates such as ketones, amines, oximes, indoles, and phenols to give the methoxycarbonylation products.7-12 The synthetic route for DMP from cyclohexanone with DMC was an ecofriendly alternative due to the gentle reaction condition and environmentally benign reactant sources. In the 1970s, Ruset first reported such a route for the synthesis of carbomethoxycyclohexanone (CMCH), which might be the intermediate to DMP, from the reaction of cyclohexanone with organic carbonates over NaH.13 Later, others reported that DMC reacted with cyclohexanone to produce DMP in the presence of homogeneous catalysts such as Cs2CO3-crown ether, CH3ONa, and organic amine.14-17 However, homogeneous reactions gave rise to the problems of products separation and the catalyst reuse. Recently, due to its economic and ecological significance, the study of solid base catalysts has become an important research topic. The replacement of homogeneous bases by solid base catalysts would have the advantages of decreasing corrosion and environmental problems, while allowing easier separation and recovery of the catalysts.18,19 Thus, solid bases were used as catalysts for the production of DMP from DMC with * To whom correspondence should be addressed. Tel.: +86 769 22896376. Fax: +86 769 22896560. E-mail:
[email protected].
cyclohexanone, and the function of the solid base catalysts has been discussed in the present work. 2. Experimental Section 2.1. Preparation of Catalysts. CaO, MgO, and ZrO2 were prepared by thermal decomposition of calcium carbonate (CaCO3, Tianjin Kermel Chemical Reagent Co. Ltd., A.R. grade) at 800 °C for 2 h, magnesium hydroxide (Mg(OH)2, Tianjin Kermel Chemical Reagent Co. Ltd., A.R. grade) at 500 °C for 5 h, and zirconium hydroxide (Zr(OH)4, Tianjin Kermel, A.R. grade) at 500 °C for 5 h under nitrogen atmosphere, respectively. Lanthana (La2O3, Tianjin Kermel, A.R. grade) and alumina (Al2O3, Tianjin Kermel, A.R. grade) were purchased and then calcined at 700 and 500 °C, respectively, for 5 h in N2 before use. A series of Al/MgO catalysts with molar ratios of 0.01-0.3 were also prepared using the impregnation method. The desired amount of aluminum isopropoxide was dissolved in benzene solution before being added into Mg(OH)2 to form the impregnated samples. The samples were dried at 100 °C overnight and then thermally decomposed to Al/MgO catalysts at 500 °C for 5 h. BET surface areas of the samples were determined with the BET method using a Micromeritics ASAP-2000 apparatus. Basic properties of the catalysts were measured by temperature programmed desorption of CO2 (CO2-TPD). The measurement was performed with 0.10 g of sample at a rate of 10 °C/min under N2 flow (50 mL/min), and the CO2 desorbed was detected by a Balzers Omnistar mass spectrometer after the catalysts were pretreated under the preparation conditions. 2.2. Experimental Setup and Procedure. The catalytic performance was carried out in a 150 mL batch reactor with assigned mole ratios of DMC and cyclohexanone, catalysts amounts, reaction temperature, and reaction time. After the reaction, the reactor was cooled to room temperature, and the products were analyzed by a gas chromatograph with a flame ionization detector and a HP-5 column after filtration from the catalyst. The main reaction products were DMP and CMCH. The methlylated product (2-methylcyclohexanone and 2-methyl dimethyl pimelate) and the self-condensation products of cyclohexanone such as 2-(1-cyclohexenyl)cyclohexanone were also detected. The selectivity was defined as mA/∑mA × 100%, where mA was the weight of product A, and ∑mA was the total weight of the products.
10.1021/ie801852e CCC: $40.75 2009 American Chemical Society Published on Web 05/22/2009
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Figure 1. CO2-TPD profiles of solid bases (where, for example, 4.00E-013 represents 4.00 × 10-13).
Figure 2. CO2-TPD profiles of MgO with different Al contents (where, for example, 4.00E-013 represents 2.50 × 10-13).
Table 1. CO2 Uptake of Solid Bases
Table 2. Synthesis of DMP from DMC and Cyclohexanone over Solid Bases
CO2 uptake catalyst ZrO2 La2O3 CaO MgO Al/MgO(0.01) Al/MgO(0.05) Al/MgO(0.1) Al/MgO(0.2) Al/MgO(0.3)
BET surface area (m2/g) 152 7.4 12.3 122.5 100.1 75.3 75.8 69.6 58.7
selectivity (%)
mmol/m2
mmol/g -3
3.22 × 10 1.69 × 10-3 6.37 × 10-2 1.78 × 10-2 6.49 × 10-3 3.61 × 10-3 3.56 × 10-3 1.57 × 10-3 8.78 × 10-4
-5
2.12 × 10 2.28 × 10-4 5.18 × 10-3 1.45 × 10-4 6.48 × 10-5 4.79 × 10-5 4.70 × 10-5 2.26 × 10-5 1.50 × 10-5
3. Results and Discussion 3.1. Catalyst Characterization. Figure 1 depicts the CO2 desorption profiles on ZrO2, MgO, La2O3, and CaO. CaO exhibited the strong basic sites with a sharp desorption peak at 550 °C. La2O3 showed relatively strong basic strength with CO2 desorption peak at 450 °C. As for MgO, there were three desorption peaks at 150, 210, and 310 °C, respectively, suggesting that MgO had weak and moderate strength basic sites, but, for ZrO2, only weak basic sites with CO2 desorption peak at 170 °C were observed. Their basic strength followed the order CaO > La2O3 > MgO > ZrO2, but the basic numbers of catalysts ranked in this order: CaO > MgO > La2O3 > ZrO2 (see Table 1). The addition of alumina did not change the basic character of MgO (see Figure 2), but the basicity decreased with the increase of the Al contents (see Table 1). 3.2. Catalytic Performance. Table 2 gives the catalytic performance of solid catalysts in synthesis DMP from cyclohexanone with DMC. In the absence of catalyst, no products were detected. Over solid acids such as Al2O3, only the aldol condensation products of cyclohexanone and a trace amount of DMP and CMCH were detected (entry 4). This suggested that solid acids were inactive toward the methoxycarbonylation reactions. With solid bases as the catalysts, the methoxycarbonylation products were obtained, which were consistent with the literature,13-17 and the catalytic performance was strongly dependent on both total basicity and basic strength (entries 5-9). Selva had reported this route by using K2CO3 as the catalysts, and the yield of DMP reached 11%;14 likewise, a similar result was observed when we repeated this experiment (entry 2). While MgO, which possessed the moderate basic strength, was employed as the catalyst, the major methoxycarbonylation product was CMCH at lower temperature (entry 6). However, with the rise of reaction temperature, higher DMP yield was
cyclohexanone other entry catalyst temp (°C) conversion (%) DMP CMCH productsc 1a 2b 3a 4a 5a 6b 7a 8a 9a
K2CO3 K2CO3 Al2O3 ZrO2 MgO MgO La2O3 CaO
260 200 260 260 260 200 260 260 260
31.6 66.5 57.0 41.2 11.0 83.6 19.2 65.0
40.2 24.2 traces 12.0 5.61 51.8 38.2 51.5
8.91 0.93 traces 7.80 34.6 6.33 15.8 2.24
50.9 74.9d 100 80.2 59.8 41.9 46.0 46.3
a Reaction conditions: cyclohexanone:DMC ) 1:4; time ) 5 h: catalyst wt % ) 1.5%. b Reaction conditions: cyclohexanone:DMC: catalyst (molar ratio) ) 1:20:2; time ) 11.4 h. c Other products ) 2-methylcyclohexanone + 2-methyl dimethyl pimelate + 2-(1-cyclohexenyl)cyclohexanone. d Selectivity of 2-methyl dimethyl pimelate was 40.8%.
obtained over MgO (entry 7), which was even higher than that of K2CO3 (the major product was 2-methyl dimethyl pimelate at 260 °C; entries 3 and 7). This suggested that solid bases with moderate strength (MgO) could show excellent catalytic performances, better than the best known basic systems such as K2CO3. As for other solid base, ZrO2 and La2O3 showed lower DMP yields, which might be due to the relatively lower basic numbers than those of MgO. As far as CaO was concerned, it also showed lower cyclohxanone conversion and DMP selectivity despite its high basic numbers. This could be attributed to the acid strength of Ca cation being too weak to stabilize the carbanion species.20 As a result, both basic numbers and basic strength played an important role in the reaction, and the basic sites with moderate strength were effective for the synthesis of DMP from cyclohexanone with DMC. To further understand the effect of moderate basic strength on catalytic performance, a series of MgO with different Al contents were prepared to supply the different amount of moderate basic sites (see Figure 2). It was found that the DMP yield could be linearly correlated with the amount of moderate basic sites (see Figure 3). Thus, this confirmed again the synthesis of DMP should be closely related to the moderate basic sites. The recycling of MgO in the reaction of DMC with cyclohexanone is given in Table 3. It was found that cyclohexanone conversion decreased by 24.9% and DMP selectivity
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Figure 4. Effect of reaction time on the conversion of cyclohexanone and selectivity of products over MgO. Figure 3. Relationship between DMP yield and moderate basicity. Table 3. Recycling of MgO in the Reaction of DMC and Cyclohexanone selectivity (%)
a
catalyst MgO MgO MgO MgO MgO MgO MgO MgO MgO
(r1)b (r2)b (r3)b (r5)b (r1)*c (r2)*c (r3)*c (r5)*c
cyclohexanone conversion (%)
DMP
83.6 71.3 68.7 62.9 58.7 82.1 83.8 83.5 81.4
51.8 41.7 40.8 32.6 30.3 50.9 52.3 50.4 51.5
CMCH
2-methyl dimethyl pimelate
other productsd
6.33 3.38 3.05 2.87 1.57 7.38 5.87 7.77 5.24
8.09 20.2 25.3 33.4 39.5 8.83 8.15 8.46 9.05
33.8 34.7 30.8 31.1 28.6 32.9 33.7 33.4 34.2
a Reaction conditions: cyclohexanone:DMC ) 1:4; T ) 260 °C; time ) 5 h; catalyst wt % ) 1.5%. b The used catalysts obtained from the filtration of the reaction mixture. c The used catalysts obtained by calcination at 500 °C for 5 h under nitrogen atmosphere after filtration from the reaction mixture. d Other products ) 2-methylcyclohexanone + 2-(1-cyclohexenyl)cyclohexanone.
decreased by 21.5% after the catalysts were used five times. Meanwhile, the selectivity of 2-methyl dimethyl pimelate reached 39.5%, which was comparable with that of K2CO3 (see Table 2). These may illustrate that Mg salts of carbonates were generated, which was due to the formation of carbon dioxide in the methylation reaction. Fortunately, the activity of used catalysts could be recovered through calcination; under the preparation conditions even the catalysts were used several times (see Table 3). 3.3. Plausible Reaction Mechanism. Figure 4 shows the effect of reaction time on the reaction of DMC with cyclohexanone over MgO. The conversion of cyclohexanone gradually increased and then became stable after 5 h. The selectivity of CMCH decreased, while the selectivity of DMP increased, and the selectivity of other products almost remained unchanged. A similar tendency was also observed for the influence of the reaction temperature (see Figure 5). These suggested that the reaction proceeded via CMCH as the intermediate. On the basis of the above facts, the plausible reaction mechanism for the synthesis of DMP was proposed as follows (see Scheme 1a): initially, a carbanion of cyclohexanone (1-) was generated due to the abstracting of the proton in R position (HR) by the solid base, and 1- and proton were absorbed on acidic sites (Mn+) and basic sites (O2-) of the solid base surface, respectively. Then, 1- attacked the carbonyl group of DMC molecule, which
Figure 5. Effect of reaction temperature on the conversion of cyclohexanone and selectivity of products over MgO.
Scheme 1. Plausible Mechanism of the Reaction of DMC with Cyclohexanone
led to CMCH as the primary product. Afterward, the resulting intermediate reacted with methoxide anion to yield the corresponding carbanion (2-), which was subjected to opening the ring to give DMP as the final product.
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Similarly, the aldol condensation products (2-(1-cyclohexenyl)cyclohexanone) and the methylation products (2-methylcyclohexanone, 2-methyl dimethyl pimelate) were also produced as the byproduct. As shown in Scheme 1b, 1- could attack a second cyclohexanone molecule to produce 2-(1-cyclohexenyl)cyclohexanone and water. Likewise, 1- reacted with the methyl group of DMC to produce the methylation products of 2-methylcyclohexanone, which was accompanied by the formation of methanol and carbon dioxide (see Scheme 1c). Then, 2-methylcyclohexanone could react with DMC to give 2-methyl dimethyl pimelate as a further product (see Scheme 1c). 4. Conclusions The synthesis of DMP from cyclohexanone with DMC was investigated over solid base catalysts. The results revealed that MgO showed the best performance among the solid base investigated. The reaction was found to be closely related to the moderate basic sites, and the function of basic catalysts was mainly to activate the ketone via abstraction of proton in R position by base sites. The possible reaction pathway, which included CMCH as intermediate, was thus proposed. Acknowledgment We acknowledge the financial support from State Key Program for Development and Research of Guangdong province. (Grant No. 2006B14701008). Literature Cited (1) Koehler, G. Process for the preparation of pimelic esters. U.S. Patent No. 5,436,365, 1995. (2) Werber, F. X.; Jansen, J. E.; Gresham, T. L. The synthesis of pimelic acid from cyclohexene-4-carboxylic acid and its derivatives. J. Am. Chem. Soc. 1952, 74, 532. (3) Pacheco, M. A.; Marshall, C. L. Review of dimethyl carbonate (DMC) manufacture and its characteristics as a fuel additive. Energy Fuels 1997, 11, 2. (4) Shaikh, A. G.; Sivaram, S. Organic carbonates. Chem. ReV. 1996, 96, 951.
(5) Jyothi, T. M.; Raja, T.; Talawar, M. B.; Rao, B. S. Selective O-methylation of catechol using dimethyl carbonate over calcined Mg-Al hydrotalcites. Appl. Catal., A 2001, 211, 41. (6) Shivarkar, A. B.; Gupte, S. P.; Chaudhari, R. V. J. Mol. Catal. A 2005, 226, 49. (7) Tundo, P.; Selva, M. The chemistry of dimethyl carbonate. Acc. Chem. Res. 2002, 35, 706. (8) Tundo, P.; Moraglio, G.; Trotta, F. Gas-liquid phase-transfer catalysis: A new continuous-flow method in organic synthesis. Ind. Eng. Chem. Res. 1989, 28, 881. (9) Tundo, P.; Trotta, F.; Moraglio, G.; Ligorati, F. Continuous-flow processes under gas-liquid phase-transfer catalysis (GL-PTC) conditions: The reaction of dialkyl carbonates with phenols, alcohols, and mercaptans. Ind. Eng. Chem. Res. 1988, 27, 1565. (10) Marques, C. A.; Selva, M.; Tundo, P.; Montanari, F. Reaction of oximes with dimethyl carbonate: A new entry to 3-methyl-4,5-disubstituted4-oxazolin-2-ones. J. Org. Chem. 1993, 58, 5765. (11) Shieh, W. C.; Dell, S.; Bach, A.; Blacklock, T. J. Dual nucleophilic catalysis with DABCO for the N-methylation of indoles. J. Org. Chem. 2003, 68, 1954. (12) Mei, F.; Pei, Z.; Li, G. The transesterification of dimethyl carbonate with phenol over Mg-Al hydrotalcite catalyst. Org. Process Res. DeV. 2004, 8, 372. (13) Ruest, L.; Blouin, G.; Dislongchamps, P. A. Convenient synthesis of 2-caromethoxycyclohexanone. Synth. Commun. 1976, 6, 169. (14) Selva, M.; Marques, C. A.; Tundo, P. The addition reaction of dialkyl carbonates to ketones. Gazz. Chim. It. 1993, 123, 515. (15) Tundo, P.; Memoli, S.; Selva, M. Synthesis of R,ω-diesters. WO Patent No. 0,214,257, 2002. (16) Fisher, R. Preparation of R,ω-dicarboxylic acid diesters. U.S. Patent No. 5,453,535, 1995. (17) Koehler, G.; Metz, J. Process for preparing diesters of higher R,ωdicarboxylic acids. U.S. Patent No. 5,786,502, 1998. (18) Ono, Y. Solid base catalysts for the synthesis of fine chemicals. J. Catal. 2003, 216, 406. (19) Hattori, H. Heterogeneous basic catalysis. Chem. ReV. 1995, 95, 527. (20) Zhang, W.; Wang, H.; Wei, W.; Sun, Y. Solid base and their performance in synthesis of propylene glycol methyl ether. J. Mol. Catal. 2005, 231, 83.
ReceiVed for reView December 3, 2008 ReVised manuscript receiVed February 19, 2009 Accepted May 2, 2009 IE801852E
