A versatile and environmentally friendly method for α,α’-bis(substituted ben-zylidene) cycloalkanones has been developed using a heterogeneous catalysis technology. We have synthesized a series of the α,α’-bis(substituted benzylidene) cycloalkanones, a biologically important class of compounds, via the cross aldol condensation between arylaldehydes and cycloketones using sodium-modified fluorapatite (Na/FAP) as a highly efficient solid catalyst under conventional heating in aqueous media and solventless conditions under microwave. Catalyst reuse, ease of separation of the pure product, and high yields are some of the unique features of this process. Shorter reaction times (4 - 7 min) and higher yields (80% - 94%) were achieved under microwave irradiation conditions.
The concept of “green chemistry” has been widely adopted to meet the fundamental scientific challenges of protecting human health and the environment while simultaneously achieving commercial viability [
Organic reactions in aqueous media have become one of the most challenging areas in organic synthesis due to the environmental benefits and favorable effects of water on chemical transformations [
A general method for the formation of a carbon-carbon bond in many classes of carbonyl compounds is aldol condensation [
The last few years have witnessed considerable resurgence of interest in the activity of fluorapatite activated by sodium nitrate (Na/FAP), induced organic transformations. In a series of publications from our group, we have exploited the catalytic potential of Na/FAP for various organic transformations, e.g. knoevenagel condensation [
Crossed aldol was first carried out in water using FAP as a catalyst under conventional heating. In general, the yields obtained are poor. Thus, in 48 h reaction, the obtained recoveries in 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m and 3n were 10%, 08%, 13%, 11%, 07%, 10%, 20%, 20%, 16%, 13%, 12%, 10%, 11% and 25% respectively. To increase its catalytic activity, FAP was impregnated by sodium nitrate to yield a more efficient catalyst (Na/FAP), as described previously [
The study of the influence of the volume of the solvent showed that 5 mL of water resulted in optimal yield (
Based on the results obtained above, other substrates have also been studied for the preparation of α,α’-bis(substituted benzylidene) cycloalkanone derivatives (Scheme 1). The results are summarized in the
The development of a more sustainable and benign strategy that minimizes energy consumption and time for reaction completion maximizing the conversions and/or yields has been reported through the use of microwaves [
Entry | Ketone | Aldehyde | Productd | Isolated yielda (%) | |
---|---|---|---|---|---|
Method Ab | Method Bc | ||||
3a | 91 (150) | 90 (6) | |||
3b | 98 (180) | 80 (6) | |||
3c | 88 (150) | 94 (7) | |||
3d | 80 (180) | 88 (7) | |||
3e | 86 (255) | 87 (7) | |||
3f | 90 (180) | 86 (6) | |||
3g | 98 (90) | 80 (5) | |||
3h | 95 (120) | 92 (5) | |||
3i | 96 (150) | 82 (5) | |||
3j | 98 (150) | 89 (6) | |||
3k | 91 (120) | 83 (6) | |||
3l | 87 (240) | 85 (7) | |||
3m | 97 (150) | 80 (6) |
3n | 90 (60) | 83 (4) |
---|
aValues given in parentheses denote the time in minutes. bReaction carried out in water under conventional heating. cSolvent-free synthesis under microwave irradiation. dAll products are reported in the literature.
Scheme 1. Cross-aldol condensation over sodium-modified fluorapatite.
catalyst (Na/FAP). The results are summarized in
The results of the reactions at microwave irradiation conditions are compared with the reflux conditions and short reaction times were observed, which is more economic in terms of time. It was noticed that there was no reaction under microwave without catalyst, and to what was observed in traditional heating without solvent. This shows a certain synergy between catalyst and the microwave. It is thus completely reasonable to think that the effect of the temperature is a determining factor to promote this condensation. Unfortunately, domestic microwave was used and therefore it was impossible to measure the exact temperature during the reaction. The structures of α,α’(EE)-bis-(benzylidene)- cycloalkanones (3a - 3n) were characterized by comparison of their spectroscopic data (1H NMR and IR) and melting points with those reported in the literature.
One of the most important features of a heterogeneous catalyst is the ease of the recovery and reuse. Na/FAP was recovered and dried at 150˚C before being tested for the synthesis of 3a. After a 4 cycle run, a progressive decrease in yield was observed as shown in
The synthesis of fluorapatite [Ca10(PO4)6F2] is carried out by a co-precipitation method. An amount of 250 mL of an aqueous solution containing 7.92 g of diammonium phosphate and 1.00 g of NH4F, maintained at a pH greater than 12 by addition of ammonium hydroxide (15 mL), was dropped under constant stirring into 150 mL of an aqueous solution containing 23.6 g of calcium nitrate [Ca(NO3)2, H2O]. The suspension was then refluxed for 4 h. The obtained FAP was filtered, washed with doubly distilled water, dried overnight at 80˚C, and calcined at 700˚C. The final product is identified by X-ray diffraction (space group hexagonal system; a = 9364 Ǻ and c = 6893 Ǻ), infrared spectra IR and chemical analysis (Ca = 38.29%, P = 17.78% and Ca/P = 1.66). The BET specific surface area was found to be S = 15.4 m2/g. The total pore volume was calculated by the BJH method at P/P0 = 0.98 (Vt = 0.0576 cm3/g) [
The modified FAP (Na/FAP = 1/2 w/w) was prepared by addition of FAP (10 g) to an aqueous sodium nitrate solution (50 mL, 1.17 M). The mixture was stirred at room temperature for 15 min and then the water evaporated under vacuum. The resulting solid was calcined under air for 1 h at 650˚C. The XRD patterns of calcined Na/FAP showed the apparition of new phases, so the CaO phase (2θ = 32.2, 37.5 and 54.0) is clearly identified [
The typical reaction procedure for the cross-aldol condensation of aldehydes with cycloalkanones catalyzed by fluorapatite alone or modified was as follows.
Method A: to a 5 mL of distilled water in a round bottom flask, was added arylaldehydes 1 (2 mmol), cycloalkones 2 (1 mmol) and 1g of the catalyst, and the mixture was refluxed in water.
Method B: to a solution of aldehydes 1 (2 mmol) and cycloalkanes 2 (1 mmol), 1 g of the Na/FAP was added and the mixture was stirred with a spatula at room temperature and was irradiated by domestic microwave for the appropriate time at (450 W). Hot water (2 × 20 mL) was added, followed by simple filtration. For both methods, after filtration and extraction with hot water, the solutions were concentrated and purified by silica gel chromatography (n hexane/ethyl acetate: 7 mL/3mL). The products were identified by melting points, 1HNMR, and IR spectroscopies. Na/FAP was reactivated by drying at 150˚C or, alternatively washed with acetone and calcined at 500˚C for 1 h.
Effect of solvent for the synthesis of the α,α’-(EE)-bis(benzylidene)- cyclohexanone
To a 5 mL of solvent (methanol, ethanol, n-butanol and water) of different solvents such as methanol, ethanol, n-butanol and water in a round bottom flask, was added benzaldehyde 1 (2 mmol), cyclohexanone 2 (1 mmol) and 1 g of the catalyst, and the mixture was refluxed for 2.5 h.
Spectral data of the products
Melting points were measured on Electro thermal 9100 apparatus. Fourier transform infrared (FT-IR) spectra of samples in KBr pellets were measured on a Bruker Vector 22 spectrometer. 1H NMR spectra were determined on a Bruker ARX 300 spectrometer as CDCl3 solutions. Chemical shifts (d) were expressed in ppm downfield from the internal standard tetramethylsilane and coupling constants J were given in Hz.
3a: mp 116˚C - 118˚C ; IR (KBr, ν cm−1): 773; 1144; 1268; 1440; 1570; 1609; 1675; 2926; 3024.
1H NMR (CDCl3, 300 MHz) δ: 1.76 - 1.83 (2H, CH2-CH2-CH2-, m); 2.95 (4H, CH2-CH2-CH2-, t, J = 5.6 HZ); 7.30 - 7.48 (10H, arom, m); 7.80 (2H, = CH, s).
3b: mp: 148˚C - 149˚C, IR (KBr, ν cm−1): 828; 1262; 1576; 1440; 1606; 1665; 2930.
1H NMR (CDCl3, 300 MHz) δ: 1.78 - 1.84 (2H, CH2-CH2-CH2-, m); 2.89 (4H, CH2-CH2-CH2-, t, J = 6 HZ); 7.36 - 7.41 (8H, arom, m); 7.73 (2H, =CH, s).
3c: mp: 167˚C - 169˚C, IR (KBr, ν cm−1): 1600; 1660; 2918; 2942.
1H NMR (CDCl3, 300 MHz) δ: 1.75 - 1.79 (2H, CH2-CH2-CH2-, m); 2.39 (3H, -CH3, s); 2.92 (4H, CH2-CH2-CH2-, t, J = 5.6 HZ); 7.18 - 7.39 (8H, arom, m); 7.78 (2H, =CH, s).
3d: mp: 203˚C - 204˚C, IR (KBr, ν cm−1): 833; 1021; 1248; 1505; 1552; 1595; 1661; 2937.
1H NMR (CDCl3, 300 MHz) δ: 1.80 - 1.83 (2H, CH2-CH2-CH2-, m); 2.94 (3H, -CH3, s); 2.92 (4H, CH2-CH2-CH2-, t, J = 6 HZ); 3.86 (s, 6H, OCH3); 6.94 (4H, arom, d, J = 8.6 Hz); 7.47 (4H, arom, d, J = 8,6 Hz); 7,77 (2H, = CH, s).
3e: mp: 189˚C - 190˚C, IR (KBr, ν cm−1): 807; 1346; 1525; 1576; 1606; 1633; 2925.
1H NMR (CDCl3, 300 MHz) δ: 1.84 - 1.90 (2H, CH2-CH2-CH2-, m); 2.97 (4H, CH2-CH2-CH2-, t, J = 6 HZ); 7.58 - 7.81 (6H, arom, m); 8.22 (2H, arom, d, J = 8 Hz); 8.33 (s, 2H, = CH).
3f: mp: 177 - 178˚; IR (KBr, ν cm−1): 1600, 1690, 2900, 3050.
1H NMR (CDCl3, 300 MHz) δ: 1.75 (m, 2H), 2.91 - 2.74 (t, 4H, J = 5.6 Hz), 7.35 - 7.02 (s, 2H), 7.65 (m, 10H).
3g: mp: 140˚C - 142˚C, IR (KBr, ν cm−1) : 752; 1594; 1643; 2903; 3183.
1H NMR (CDCl3, 300 MHz) δ: 1.95 - 2.05 (2H, CH2-CH2-CH2-, m); 2.95 - 2.72 (4H, CH2-CH2-CH2-, m); 6.95 - 7.63 (8H, furyl et = CH, m).
3h: mp: 188˚C - 189˚C, IR (KBr, ν cm−1): 1600; 1625; 1688; 2910; 3017; 3052.
1H NMR (CDCl3, 300 MHz) δ: 3.13 (4H, -CH2-CH2-, s); 7.36 - 7.45 (6H, arom, m); 7.58 - 7.60 (6H, arom et = CH, m).
3i: mp: 228˚C - 229˚C, IR (KBr, ν cm−1): 1587; 1604; 1620; 1693; 2912.
1H NMR (CDCl3, 300 MHz) δ: 3.03 (4H, -CH2-CH2-, s); 7.33 - 7.36 (4H, arom, m); 7.45 - 7.47 (6H, arom et = CH, m).
3j: mp: 243˚C - 244˚C, IR (KBr, ν cm−1): 1589; 1602; 1622; 1686; 2912;.
1H NMR (CDCl3, 300 MHz) δ: 2.32 (6H, -CH3, s); 3.03 (4H, -CH2-CH2-, s); 7.17 - 7.18 (4H, arom, m); 7.43 - 7.55 (4H, arom, m); 7.58 (2H, = CH, s).
3k: mp: 211˚C - 212˚C, IR (KBr, ν cm−1): 1590; 1684; 2851; 3080.
1H NMR (CDCl3, 300 MHz) δ: 3.07 (4H, -CH2-CH2-, s); 3.88 ( 6H, -OCH3, s); 6.89 (4H, arom, d, J = 8 Hz); 7.58 (2H, = CH, s); 7.59 (4H, arom, d, J = 8 Hz).
3l: mp: 224˚C - 226˚C, IR (KBr, ν cm−1): 1528; 1613; 1691; 2922.
1H NMR (CDCl3, 300 MHz) δ: 3.26 (4H, -CH2-CH2-, s); 7.67 (4H, arom, m); 7.91 (2H, arom, d, J = 7.5 Hz); 8.28 (2H, arom, d, J = 6.3 Hz); 8.49 (2H, = CH, s).
3m: mp: 213˚C - 214˚C; IR (KBr, ν cm−1): 1585, 1616, 1671, 3027.
1H NMR (CDCl3, 300 MHz) δ: 2.95 (s, 4H); 6.98 - 7.02 (m, 4H), 7.25 - 7.42 (m, 8H), 7.53 (d, 4H, J = 7.2 Hz).
3n: mp: 162˚C - 163˚C, IR (KBr, ν cm−1): 1600; 1620; 1681; 2917; 3115.
1H NMR (CDCl3, 300 MHz) δ: 3.09 (s, 4H, -CH2-CH2-); 6.54 (2H, furyl, s); 6.71 (2H, furyl, d, J = 3.2 Hz); 7.36 (2H, furyl, s); 7.60 (.s, 2H, = CH).
In conclusion, we have developed a clean and easy method for the synthesis of α,α’-bis(substituted benzylidene, furfurylidene and cinnamylidene) cyclopentanone and cyclohexanone using an inexpensive, reusable, easy to handle, noncorrosive, and environmentally benign catalyst (sodium-modified fluorapatite). The reaction can be carried out in water under classical heating. The microwave-assisted procedure in solvent-free system has provided a soft and cleaner approach for the cross-aldol condensation. The use of Na/FAP offers diverse advantages including simplicity of operation due to the heterogeneous nature of reaction, easy workup, high yields, and catalyst reusability.
Mounir, B., Bazi, F., Mounir, A., Toufik, H. and Zahouily, M. (2018) Sodium-Modified Fluorapatite: A Mild and Efficient Reusable Catalyst for the Synthesis of α,α’-Bis(Substituted Benzylidene) Cycloalkanones under Conventional Heating and Microwave Irradiation. Green and Sustainable Chemistry, 8, 156-166. https://doi.org/10.4236/gsc.2018.82011