American Journal of Organic Chemistry

p-ISSN: 2163-1271    e-ISSN: 2163-1301

2018;  8(1): 8-12

doi:10.5923/j.ajoc.20180801.02

 

Monomodal vs Multimodal Microwave Irradiation Applied in the Synthesis of Fluorochalcones

José Eladio Antonio-Arias1, Verónica del C. Díaz-Oliva1, Nancy Romero-Ceronio1, Abraham Gómez-Rivera1, Hidemi Aguilar-Mariscal2, Luis F. Roa de la Fuente1, Carlos E. Lobato-García1

1División Académica de Ciencias Básicas. Universidad Juárez Autónoma de Tabasco, Tabasco, México

2Laboratorio de Farmacología, Unidad de Protección, Cuidado y Experimentación de Animales, Universidad Juárez Autónoma de Tabasco, Tabasco, México

Correspondence to: Nancy Romero-Ceronio, División Académica de Ciencias Básicas. Universidad Juárez Autónoma de Tabasco, Tabasco, México.

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Abstract

The synthesis of o-, m- and p-fluorine-substituted chalcones at the ring “B” was accomplished by a Claisen-Schmidt condensation between the benzaldehyde and acetophenone. The reaction was performed in solvent-free conditions with microwave activation and good yields (> 75%) were obtained. It is noteworthy that the application of conventional reaction conditions produced very low yields and in some cases, the reaction did not proceed at all. The methodology implemented considerably reduces reaction times.

Keywords: Fluorine-substituted Chalcones, Claisen-Schmidt Condensation, Solvent-free reaction

Cite this paper: José Eladio Antonio-Arias, Verónica del C. Díaz-Oliva, Nancy Romero-Ceronio, Abraham Gómez-Rivera, Hidemi Aguilar-Mariscal, Luis F. Roa de la Fuente, Carlos E. Lobato-García, Monomodal vs Multimodal Microwave Irradiation Applied in the Synthesis of Fluorochalcones, American Journal of Organic Chemistry, Vol. 8 No. 1, 2018, pp. 8-12. doi: 10.5923/j.ajoc.20180801.02.

Article Outline

1. Introduction
2. Experimental
    2.1. General Procedure for Conventional Synthesis of Chalcones 2a-c
    2.2. General Procedure for the Solvent-Free Synthesis of Chalcones 2a-c
    2.3. (E)-3-(2-Fluorophenyl)-1-Phenylprop-2-en-1-one, 2a
    2.4. (E)-3-(3-Fluorophenyl)-1-Phenylprop-2-en-1-one, 2b
    2.5. (E)-3-(4-Fluorophenyl)-1-Phenylprop-2-en-1-one, 2c
3. Results and Discussion
4. Conclusions
ACKNOWLEDGEMENTS

1. Introduction

Chalcones constitute an important group of biomolecules, some of which exhibit a wide range of biological activities [1] for example: antifungal [2], antibacterial [3], anti-inflammatory [4, 5], antitumor [6], and antioxidant properties [7].
Structurally, the chalcone moiety is formed by two aromatic rings bonded by a three carbon skeleton which is present as a carbonyl α, β-insaturated system (Figure 1) [8].
Figure 1. General structure of the chalcone moiety
The condensation between acetophenone derivatives and aromatic aldehydes is the general procedure to obtain chalcones. The Claisen-Schmidt condensation, either catalyzed by strong bases or Lewis acids, has been proved as one of the most efficient procedure for the synthesis of this kind of products [9]. There are several reports which present variations, such as: reflux conditions with organic solvents [10], free-solvent reactions [11], use of ultrasound as source of energy [12] and microwave activation [13]. Among the catalysts employed to perform this condensation are reports with bases such as NaOH [14], KOH/MeOH [15], LiOH.H2O [16], and NaOH-K2CO3 [17]; Lewis acids have also been reported for this reaction, for example: SOCl2 [18]. There are also reports of the application of special reagents likewise: SiO2-H2SO4 [19], PdCl2 [20], TiO2-P25-SO4-2 [21], or I2-Al2O3 [22]. Several procedures described in the literature present methodological disadvantages such as prolonged reaction times, special infrastructural requirements or the preparation of specific reagents. These inconveniences have driven the search of eco-friendly synthetic procedures, according with the twelve principles of green chemistry [23, 24].
This paper reports the preparation of three fluoro-substituted chalcones at the ring B (compounds 2a, 2b and 2c), through the Claisen-Schmidt condensation between acetophenone and (o, m, p)-fluorobenzaldehyde; both conventional and green chemistry procedures were applied.

2. Experimental

The synthesis of the three fluorochalcones (2a, 2b and 2c) was conducted by the Claisen-Schmidt condensation of o-fluorobenxaldehyde (1a), m-fluorobenzaldehyde (1b) and p-fluorobenzaldehyde (1c) with acetophenone. All the substances were analytical-grade reagents and were employed without further purification. The reactions were performed through conventional (use of solvents, stirring and/or reflux conditions) and green chemistry (free-solvent conditions, microwave irradiation) procedures (Figure 2).
Figure 2. Reaction scheme for the synthesis of compounds 2a-2c. Reaction conditions: a) NaOH/CH3CH2OH, continuous stirring and/or reflux; b) p-TsOH, free solvent, microwave activation
Melting points were determined with a melting point apparatus (Scorpion Scientific A50360) and they are not corrected. The IR spectra were recorded on KBr pellets using a Perkin-Elmer Precisely Spectrometer. The NMR spectra were recorded on a Varian VX-400, using CDCl3 as solvent and TMS as an internal standard.

2.1. General Procedure for Conventional Synthesis of Chalcones 2a-c

The conventional procedure was performed by dissolving sodium hydroxide (0.6 eq. aq. 0.1 mMol) in ethanol (1mL), this mixture was put into an ice-bath at 0°C; once this temperature was reached, acetophenone (1 equivalent) and the corresponding fluorobenzaldehyde (1 equivalent) were slowly added. The reaction mixture was removed from the ice-bath and maintained with magnetic stirring until no further changes were observed. The reaction was monitored by TLC (silica gel 60 F254, hexane/ethyl acetate 95:5). Where no substantial changes were observed, the reaction mixture was heated under reflux conditions. The reaction crude was cooled at 0°C during 24 h; and the solid products were filtered and washed with cold ethanol. The crystallization was made from an ethanol/dichloromethane mixture. The recrystallized products were dried, weighed and characterized.

2.2. General Procedure for the Solvent-Free Synthesis of Chalcones 2a-c

The eco-friendly synthetic procedures were performed in solvent-free conditions and acid catalysis. A mixture of p-toluensulfonic acid (PTSA) (0.5 eq), acetophenone (1 eq) and the corresponding fluorobenzaldehyde (1 eq) were placed in a proper reactor. The system was microwaved irradiated employing a monomodal microwave system (MW) (VICHI, model: MW-600 MIC-1). For comparative purposes, a domestic microwave oven (MO) was also employed (MABE, model: HMM74MB). The reaction was monitored by TLC (silica gel 60 F254, hexane/ethyl acetate 95:5). The reaction crude was purified by CC (silica 60 mesh, hexane/ethyl acetate 98:2). The eluents were removed by vacuum distillation. The solid products were recrystallized from a mixture of hexane/ethyl acetate. The purified products were dried, weighed and characterized.

2.3. (E)-3-(2-Fluorophenyl)-1-Phenylprop-2-en-1-one, 2a

Pure product 2a was obtained as a yellow solid (highest yield = 70%); m.p. 44°C (reported: 38° to 40°C, [25]). Spectroscopic analysis:  (neat KBr) = 1700 (s), 1600 (s), 1250-1300 (s). 1H NMR (400 MHz, CDCl3): δ7.09-7.19 (m, 2H), 7.33-7.39(m, 1H), 7.47-7.51 (m, 2H), 7.56-7.65 (m, 3H), 7.62-7.66(d, 1H, J=15.92 Hz, Hα), 7.88-7.92 (d, 1H, J=15.92 Hz), 8.00-8.8.03 (d, 2H); 13C NMR (100 MHz, CDCl3): 116.18, 116.66, 124.74, 124.77, 124.80, 128.51, 128.99, 129.96, 132.06, 132.12, 133.08, 137.52, 138.19, 163.22, 190.60.

2.4. (E)-3-(3-Fluorophenyl)-1-Phenylprop-2-en-1-one, 2b

Pure product 2b was obtained as a yellow solid (highest yield = 75%); m.p. 48°C (reported: 48°C, [26]). Spectroscopic analysis: (neat KBr) = 1660 (s), 1590-1600 (s), 1200 (s). 1H NMR (400 MHz, CDCl3): 7.11-7.06 (m, 1H), 7.31-7.38 (m, 3H), 7.51-7.59 (m, 3H), 7.53-7.49 (d, 1H, J=15 Hz, Hα), 7.72-7.72 (d, 1H, J=15 Hz, Hβ), 8.02-8.00 (d, 2H, 15 Hz). 13C NMR (100 MHz, CDCl3): 114.18, 117.27, 122.92, 124.39, 128.41, 128.58, 130.37, 132.79, 137.03, 137.76, 143.13, 164.11, 189.96.

2.5. (E)-3-(4-Fluorophenyl)-1-Phenylprop-2-en-1-one, 2c

Pure product 2c was obtained as a yellow solid (highest yield= 95.5%); m.p. 79°C (reported: 78.85°C, [27] and 83 to 84°C, [28]). Spectroscopic analysis: (neat KBr)= 1662 (s), 1605 (s), 1510 (s); 1217 (s). 1H NMR (400 MHz, CDCl3):8.01(2H, dd,1.2, J=8.4 Hz), 7.76 (1H,d, J=16Hz), 7.61(2H, ddt, J=2.0,5.2,8.4 Hz), 7.56 (1H, dt, J=1.2,6.4 Hz), 7.48 (2H, dd, J=6.4, 8.4 Hz), 7.45 (1H, d, J=16 Hz), 7.08 (2H, tt, J=2.0,8.4 Hz). 13C NMR (100 MHz, CDCl3): 190.15, 165.19, 162.69, 143.38, 137.98, 132.77, 130.31, 130.22, 128.38, 121.58, 116.13, 115.91.

3. Results and Discussion

Chalcones 2a-2c were prepared by a conventional procedure with basic catalysis in ethanol with mechanical stirring at room temperature and/or reflux conditions. A solvent-free procedure was also employed for the preparation of these compounds with acid catalysis using PTSA and MW or MO as energy source. Table 1, presents a resume of: reaction conditions, reaction yields, and physical appearance of products 2a-2c. All of them were obtained as yellow solids, and their melting point varies from 44 to 79°C. The solvent-free synthesis mediated either by monomodal (MW) or domestic (MO) microwave irradiation presented higher yields (>65%) when compared with both the mechanical agitation and the reflux methods. It is noteworthy that for compound 2a neither the conventional nor the domestic microwave irradiation procedures were suitable for its synthesis, which was only successful by monomodal microwave irradiation.
Table 1. Experimental conditions, reaction yields and melting points of compounds 2a-2c
     
The spectroscopical data for compounds 2a-2c are summarized in table 2. For the infrared spectra the identification of characteristic signals confirmed the presence of the functional groups expected. The carbonyl absorption band was recognized in the range of 1650-1700 cm-1, and the carbon-carbon double bond vibration band was located around 1600 cm-1. The bands corresponding to the aromatic rings, were observed around 1450-1500 cm-1 and the carbon-fluorine bond vibrations were observed in the region of 1230-1300 cm-1.
Table 2. IR absorption bands (KBr pellets), 1H NMR (400 MHz, CDCl3) and 13C NMR (100MHz, CDCl3) chemical shifts, for compounds 2a-2c
     
The analysis of the 1H NMR spectra of the three compounds showed that the hydrogen atoms of the α,β-insaturated system were observed as doublets with coupling constants larger than 15 Hz, which is consistent with a trans orientation of both hydrogen atoms around the double bond. The signals observed in the 13C NMR spectra are consistent with the expected structures and with the data reported previously in the literature [6, 21].
Previously, we reported the crystal structure of 2c as a second monoclinic polymorph (Figure 3) [27], The elucidation was performed at 293 K. The new polymorph crystallizes in space group P21/c, which is different from the first monoclinic polymorph, [29]. The cell parameters of the current monoclinic polymorph vary significantly from the earlier form [a = 24.926 (9), b = 5.6940 (19), c = 7.749 (3) A and β = 94.747 (5)°]. Compound 2c shows an (E) configuration on the C═C bond with p-fluorophenyl group opposite to the 1-phenylketone. Torsion angle of p-fluorophenyl to 1-phenylketone group is 10.53 (6)°.
Figure 3. Molecular structure of 2c, with 30% probability displacement ellipsoids for non-H atoms

4. Conclusions

The solvent-free/microwave activation strategy proved to be a satisfactory procedure for the synthesis of fluoro-substituted chalcones; rather than the conventional methods which presented longer reactions times and poorer yields. The spectroscopic data are in accordance with the expected structures and previous reports in the literature.

ACKNOWLEDGEMENTS

The authors wish to thank UJAT for the financial support via the project PFICA UJAT-2013-IB-13 and the Centro de Química of the BUAP for the support in obtaining the NMR spectra.

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