Indian Journal of Chemistry Vol. 49B, July 2010, pp. 944-947
Note An efficient synthesis of bio-active fluorescent benzylidine tetralones R Kamakshi, S Swarna Latha & B S R Reddy* Industrial Chemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, India E-mail:
[email protected] Received 1 December 2007; accepted (revised) 10 June 2009 Benzylidine tetralones have been synthesized in excellent yields in PEG 600 at room temperature and short time periods. The synthesized compounds are found to have antibacterial activity towards both gram-positive and gram-negative bacteria. The N,N-dialkyl substituted benzylidine tetralones are found to possess fluorescent properties. Keywords: Benzylidine tetralones chalcones, PEG, fluorescence, antibacterial activity
Chalcones are unsaturated compounds that are major intermediates in the synthesis of natural products1. They are known to possess antimicrobial2, fungicidal3, antiinflammatory4 and antibacterial5 properties. Recently, chalcones are also being considered as antitumor6 and antiviral7 agents. The presence of the enone function imparts antibiotic activity and some compounds of this genre are claimed to be toxic to animals and insects. Chalcones find applications as stabilizers, scintillators, fluorescent whitening agents, brightening additives and dyes. Fluoresence properties in chalcones arise from the extended conjugation prevalent in them. Substituted chalcones may have both the donor and acceptor moieties that cause internal charge transfer (ICT) during excitation. Fluorescent properties in bioactive materials are highly useful for monitoring the penetration in cellular membranes. The emission state from ICT state has attracted great interest both in photochemistry and in biochemistry because of its large susceptibility to microenvironment8. This class of compounds has been extensively used for various optical applications including photoalignment layer of liquid crystal display, photorefractive polymers and fluorescent probes for the sensing of DNA or metal ions9. Chalcones are important precursors in the synthesis of flavones, flavanols, chromans, pyranones, substituted pyridines, quinolines, pyrimidinones and
quinazolines10-15. Synthesis of chalcones has generally been done by the Claisen Schmidt reaction that is time-consuming and requires reflux for many substituted chalcones. Herein, we report a modified and efficient procedure for the synthesis of chalcones in polyethylene glycol. (Scheme I). We have synthesized tetralone-based chalcones and report their bioactive and fluorescent properties. Results and Discussion The chalcones were synthesized in polyethylene glycol (PEG 600) within a span of 5 min to half an hour (Table I). It was noted that a minimum amount of water was required for the reaction to proceed smoothly. The reaction was found to give excellent yields compared to the conventional reaction in ethanol. Also, the initial cooling period was not required because the amount of sodium hydroxide was very less. During conventional reaction methods some chalcones require reflux to give good yields. However this is avoided while conducting the reaction in PEG 600. It is noted that the time required for the reaction to complete in PEG 600 was reduced considerably (Table I). It was found that the less soluble m-nitrobenzaldehyde dissolved completely in PEG 600 giving a higher yield. The product isolation is also simple. The reaction-mixture was cooled in the refrigerator and washed with filtered using ice-cold ethanol. The isolated product is sufficiently pure and may be further purified using recrystallisation from ethanol. Polyethylene glycol is being sought after as a solvent for many synthetic transformations. This is due to the fact that the solvent has both hydrophobic and hydrophilic properties that make it a good choice for compounds with diverse properties. Also, the solvent aids the reaction through hydrogen bonding effects16. Absorption and emission characteristics The absorption and emission characteristics of the synthesized benzylidine tetralones were monitored. The studies were performed with 10 micromolar concentrations. The maximum absorption of the compounds (1h-6h) are given in Table II.
NOTES
O
O H
O
PEG, NaOH
+
Ar
945
H3 C
R
5-25 min
R
Ar
O
O
O
O
HO b
a CHO
CHO
d
c CHO
Cl
2
1
4
3
Et2N
Me2N
MeO
NO2
CHO
CHO
CHO
6
5
O O
O Ar
+
Ar
H d
Scheme I Table I ― Synthesis of chalcones in PEG O
+
H
Ar
a a a a a a b b b b b b c c c c c c d d d d d d
1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6
Ar
30 min
Entry Ketone Aldehyde Product 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
O
PEG 600, NaOH
O
1e 2e 3e 4e 5e 6e 1f 2f 3f 4f 5f 6f 1g 2g 3g 4g 5g 6g 1h 2h 3h 4h 5h 6h
Table II ― Absorption maxima of the substituted benzylidine tertalones
Time (hr) Yield (%) EtOH PEG EtOH PEG 4 4 4 4 4 4 6 6 6 6 6 6 6 6 6 6 6 6 8 8 8 8 8 8
0.2 0.2 0.2 0.2 0.2 0.2 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
75 69 70 63 58 68 71 57 70 64 63 61 54 57 60 58 63 65 52 45 65 59 62 61
87 82 90 85 82 86 90 81 95 75 82 86 76 79 82 80 82 83 75 65 90 80 85 82
Compd
Absorption maxima (λmax)
1h 2h 3h 4h 5h 6h
301, 322 297, 325 277, 283 246, 338 269, 406 244, 341
The absorption maxima show an increase with the presence of electron donating groups present in the chalcone. The fluorescence emission was recorded at the absorption maxima. It was noted that the unsubstituted 1h and chloro 2h, nitro 3h substituted chalcones did not give a fluorescence emission. The emission of methoxy substituted benzylidine tetralone 4h was weak with a low intensity signal. The emission spectra of 5h and 6h, on the other hand, showed strong emission that are characteristic of charge transfer compounds. The N,N, dialkyl group is an electron donor while the carbonyl is an electron acceptor and thus the compounds form a donor-acceptor complex upon excitation. The diethyl substituted compound 6h showed higher intensity signals because the donating
INDIAN J. CHEM., SEC B, JULY 2010
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Table III ― Anti bacterial activity of the synthesized benzylidine tetralones Compd Bacillus subtillus 1h 2h 3h 4h 5h 6h
Staphylococcus aureus
Shigella flexineri
Klebsiella pneumonia
+ ++ +++ + + +
+ +++ ++ + + +
+ +++ +++ + + -
+ ++ ++ + + +
capacity of the ethyl group is greater than that of the methyl group. Biological studies The antibacterial properties of the synthesized benzylidine tetralones were studied for both gram positive (Bacillus subtillus and Staphylococcus aureus) and gram negative bacteria (Klebsiella pneumonia and Shigella flexineri). The results are tabulated in Table III. Bacterium were grown in nutrient agar medium at 37ºC for a growth time of 24 hr. 50 μL of the solution (1mg/1mL DMSO) was used for studying the antimicrobial activity. It was found that the compounds showed activity in low concentrations and the maximum inhibition of bacterial growth was seen with the nitro-substituted compound followed by the chloro-substituted compound. Experimental Section All aldehydes, ketones and polyethylene glycol (PEG 600) were purchased from SD-fine Chem., India. Analytical thin layer chromatography was performed on pre-coated plastic silica gel plates of 0.25 mm thickness containing PF 254 indicator (Merck, Darmstadt). Melting points were noted on a Concord melting point apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer RX I FT-IR spectrometer. 1H and 13C NMR spectra were recorded in CDCl3 on a 500 MHz Jeol spectrometer (chemical shifts in δ, ppm) using TMS as an internal standard. Cary-Varian UV-Vis absorption and emission spectrometer was used to perform absorbance and fluorescence measurements. The slit bandwidth while recording fluorescence was kept at 5 nm for excitation and emission at a scan speed of 800 nm per min.
Typical Procedure To a mixture of freshly distilled acetophenone (4.3 mmoles) and pure benzaldehyde (4.3 mmoles) in 5 mL of polyethylene glycol were added KOH (25 mg, 0.455 mmole) and few drops of water. The reaction-mixture was stirred for 25 min at room temperature. After stirring the reaction-mixture was cooled in refrigerator overnight and filtered using ice-cold ethanol and dried in air. Pure chalcone was obtained through recrystallization from ethanol warmed to 50°C. Conclusions Chalcones have been synthesized in PEG-600 in good yields at very short time periods. New substituted benzylidine tetralones have been synthesized that are found to possess fluorescent and these compounds may be used as fluoroprobes. All the benzylidine tetralones are found to have antibacterial properties which make them attractive synthons for further transformations. Spectral data 2-Benzylidene-3,4-dihydronaphthalen-1(2H)-one, 1h: m.p: 96ºC, pale yellow crystals, IR (KBr): 1656.2, 1596.1 cm-1; 1H NMR (500 MHz, CDCl3): δ 3.13 (2H, t), 2.99(2H, t), 6.7(1H, s), 7.6-7.2 (Ar-H, 9H); 13 C NMR (125 MHz): δ 27.2, 28.9, 68.24, 127.1, 128.3, 128.5, 128.6, 129, 132.5, 136, 136.7, 144, 188. MS: 234 2-(3-Chlorobenzylidene)-3,4-dihydronaphthalen1(2H)-one, 2h: m.p. 72°C, brown solid, IR (KBr): 1667, 1593 cm-1; 1H NMR (500 MHz, CDCl3): δ 2.952.93(2H, t), 3.14-3.08(2H, t), 5.6(1H, s), 8.1 -7.2 (Ar-H, 8H); 13C NMR (125 MHz): δ 27.2, 28.8, 127.2, 124.2, 127.4, 128.5, 129.8, 131.2, 144.5 187.8. 2-(3-Nitrobenzylidene)-3,4-dihydronaphthalen1(2H)-one, 3h: m.p.118°C, white crystals, IR (KBr): 1661.3, 1596.3, 1528.8, 1343.4, 738.9 cm-1; 1H NMR (500 MHz, CDCl3): δ 2.99-2.97 (2H, t), 3.13-3.10 (2H, t), 6.8 (1H, s), 8.3- 7.2 (Ar-H, 8H); 13C NMR (125 MHz): δ 27.2, 28.7, 123.1, 124.2, 127.3, 128.4, 129.6, 133.1, 133.6, 133.8, 135.8, 137.5, 137.8, 143.2, 148.3, 187.3. 2-(4-Methoxybenzylidene)-3,4-dihydronaphthalen1(2H)-one, 4h: m.p. 92ºC, pale yellow crystals, IR (KBr): 1664, 1592 cm-1; 1H NMR (500 MHz, CDCl3):
NOTES
δ 2.95-2.92(2H, t), 3.1(3H, s), 3.19(2H, t), 6.7 (1H, d, J = 8.1Hz), 8.1- 7.2 (Ar-H, 8H); 13C NMR (125 MHz): δ 27.8, 28.7, 60.1, 111.6, 124.1, 126.8, 127.3, 128, 131, 132.1, 132.7, 142.9, 150.6, 187.8. 2-{4-(Dimethylamino)benzylidene}-3,4-dihydronaphthalen-1(2H)-one, 5h: m.p. 35°C, yellow solid, IR (KBr): 1664, 1592 cm-1; 1H NMR (500 MHz, CDCl3): δ 2.95-2.92(2H, t), 3.0(6H, s), 3.19(2H, t), 6.7 (1H, d, J = 8.3Hz), 8.1- 7.2 (Ar-H, 8H); 13C NMR (125 MHz): δ 27.8, 28.7, 40.1, 111.6, 123.6, 126.8, 127.3, 128, 131, 132.1, 132.7, 142.9, 150.6, 187.8. 2-{4-(Diethylamino)benzylidene}-3,4-dihydronaphthalen-1(2H)-one, 6h: m.p. low melting brown solid, IR (KBr): 1677, 1597 cm-1; 1H NMR (500 MHz, CDCl3): δ 1.4 (6H, m), 2.8 (4H,m) 2.95-2.92(2H, t), 3.19(2H, t), 6.7 (1H, d, J = 8.2Hz), 8.1- 7.2 (Ar-H, 8H); 13C NMR (125 MHz): δ 20.5, 27.8, 28.7, 40.1, 111.6, 123.6, 126.8, 127.3, 128, 131, 132.1, 132.7, 142.9, 150.6, 187.8. Acknowledgement Authors thank Mr. E Madhavan and D A Gnanamani for their help in antibacterial studies. Help from Dr. Somanathan, Polymer Lab, CLRI in obtaining fluorescence measurements is greatly acknowledged. One of the authors thank CSIR-New Delhi for fellowships. References 1 Dhar D N, The Chemistry of Chalcones and related compounds, (John Wiley, USA) 1981. 2 Boeck P, Falcão C A B, Leal P C, Yunes R A, Filho V C, Torres-Santos E C & Bergmann B R, Bioorg Med Chem, 14, 2006, 1538.
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