IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725.
International Journal of Green and
An International Peer Review E-3 Journal of Sciences
Available online at www.ijghc.com
Section A: Green Chemistry
Research Article CODEN (USA): IJGHAY
17 IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725.
Microwave Assisted Synthesis of Potent Antifungal
Bis-Heterocyclic Chalcone from N-Phenyl Substituted
Department of chemistry S.S.V.P.S College Shindkheda, Dist-Dhule (Maharashtra) Department of chemistry S.V.S’S DadasahebRawal College Dondaicha. (Maharashtra)
Received: 22November 2017; Revised: 12December 2017; Accepted: 20 December 2017
In this work we developed new method of synthesis for reported
synthesis bis-heterocyclic chalcone by conventional method. In this new method N-phenyl substituted succinamide5 allowed to react with substituted benazaldehydes 6a-e in presence of neutral alumina in microwave oven as solid phase solvent free condition afforded bis-heterocyclic chalcone7a-e. The structures of all synthesized compounds were confirmed by FT IR, 1HNMR Spectral analysis. The bis-heterocyclic chalcones were screened for microbial evaluation in vitro by disc diffusion method.The anti-microbial activity have tested against pathogenic bacteria E.Coli and fungi C.albicans at minimum inhibitory concentration 100 µgm/ml among all chalcone derivatives the compound 7a exhibited promising antibacterial activity and potent antifungal activity
18 IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725.
The Cyclic imides are well known class of heterocyclic compounds as they are part of many naturally occurring heterocycles and have diverse application in the field of synthetic chemistry. Cyclic imdie have found to posses Analgesic activity1,Anti-tumeractivity2, some derivatives of succinamides play an important role in management of Alzheimer disease3, they have Anti-convulsant activity4, Antiinflamatory5, DNA binding and apoptotic inducing Activity6, Antifungal and antibacterial activities7 Including such diverse application of succinamide8-9 in field of medical and pharmaceutical science. It is also powerful synthon for synthesis of various heterocyclic compounds10 in modern synthetic chemistry. By considering all these fact here we synthesized succinamide and bis-heterocyclic chalcone from succinamide. The succinamide have two active methylene groups are capable of reacting with two aldehyde molecule by using Claisen-Aldol condensation reaction and we reported synthesis (3Z,4Z)-3,4-bis(substituted)-1-p-tolylpyrrolidine-2,5-dione derivatives11from N-Phenyl substituted succinamide by conventional method. In this study we developed new solvent free solid phase environmental benign method for synthesis of bis-hetrocyclic chalcone that eliminates hazardous solvents and reduce waste high yield of products obtained in short period of time.
All chemicals used in the present work are of synthetic grade. The melting points were taken in to open capillaries and are uncorrected. The I.R spectra were recorded on FTIR shimazdu spectrophotometer using KBr disc method. The 1H NMR spectra were recorded on Bruker mx-500 MHz in DMSO d6 . The chemical shift was recorded in δ unit relative to TMS as internal standard. All the compounds synthesized by using domestic microwave oven in hours. All reactions were executed in solid phase solvent free synthesis. The reaction was monitored by thin layer chromatography by using pre-coated silica gel aluminum plates and mixture of n-hexane: ethyl acetate 7:3 proportion was used as mobile phase. The identification of spots was done by visualizing plate in U.V chamber
Generalprocedure for Synthesis of cyclic imide:A mixture of succinic acid 0.1 M (11.8 gm) and thionyl chloride 2.2 M (15ml) was refluxed for 30 min. The P-Toludiene 0.1 M (10.70 gm) was dissolved in suitable amount of benzene. Then solution of P- Toludiene added drop wise in to reaction mixture. The reaction mixture was then refluxed till complete evolution HCl gas. Thus crude product was obtained and recrystallised it from ethanol.
1-p-tolylpyrrolidine-2, 5-dione (5): Yellow solid; Yield: 61.95 %, MF: C11H11NO2; M.W.: 189.21; M.P:230 °C, FTIR (KBr, cm-11700.31 Cm-1(C=O), 2932.78(C-H of OCH3).
General procedure for preparation of bis-heterocyclic chalcone
A) Synthesis of Chalcone by using conventional method: Substituted phenyl pyrolidine-2, 5 dione (0.01M) and (0.02 M) of substituted benzaldehyde in 15 ml acetic acid taken in a conical flask. The reaction mixture was heated on sand bath for 15-20 minutes and kept it for overnight at room temperature the solid obtained was filtered and recrystallised from ethanol.
B) MW assisted solvent free synthesis of chalcone a green method: The bis-hetrocyclic chalcone (7a-e) was synthesized by reaction of (0.01M) 1-p-tollylpyrolodine-2, 5-dionewith (0.02 M) of substituted benzaldehyde in presence 1.5 to 2 gm neutral Al2O3 under microwave assisted solvent-
19 IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725.
free condition at 450 w power for 3 to 4 min. thus colored compound was obtained and recrystalised from ethyl alcohol.
(3Z,4Z)-3,4-bis(2-hydroxybenzylidene)-1-p-tolylpyrrolidine-2,5-dione (1a) :M F: C25H19NO4; M W: 397.42; Anal Cal.: C, 75.55; H, 4.82; N, 3.52; O, 16.10; Found: C, 75.15; H, 4.22; N, 3.72; O, 16.30; FTIR (KBr, cm-1):1705 (C=O), 3368 (-OH), 2937(-CH3), 1611(C=C); 1H NMR (500 MHz, DMSO d6, δ ppm): 2.40 (s, 1H, CH3), 5.1(s, 1H, -OH), 7.31-7.17(m, 6H, Ar-H and =CH).
(3Z,4Z)-3,4-bis(3-nitro benzylidene)-1-p-tolylpyrrolidine-2,5-dione (1b):M F; C25H17N3O6; M W: 455.42; Anal Cal.: C, 65.93; H, 3.76; N, 9.23; O, 21.08; Found: C, 65.33; H, 3.21; N, 9.53; O, 21.28;FTIR (KBr, cm-1):2937(-CH3), 1705 (C=O), 1611(C=C) 1345 (Ar-NO2);1H NMR (500 MHz, DMSO d6, δ ppm): 2.40 (s, 1H, CH3), 8.47-6.67(m, 6H,Ar-H and =CH )
(3Z,4Z)-3,4-bis(2-chloro benzylidene)-1-p-tolylpyrrolidine-2,5-dione (1c):M F C25H17Cl2NO2; M W: 434.31; Anal Cal.: C, 69.14; H, 3.95; Cl, 16.33; N, 3.23; O, 7.37; Found: C, 69.34; H, 3.86; Cl, 16.43; N, 3.63; O, 7.57;FTIR(KBr, cm-1):1705 (C=O), 2937(-CH3), 713 (C-Cl), 1611(C=C);1H NMR (500 MHz, DMSO d6, δ ppm): 2.40 (s, 1H, CH3), 7.40-7.12(m, 6H,Ar-H and =CH ).
(3Z,4Z)-3,4-bis(4-methoxy benzylidene)-1-p-tolylpyrrolidine-2,5-dione (1d):M F: C27H23NO4 M W: 425.48;Anal Cal.: C, 76.22; H, 5.45; N, 3.29; O, 15.04;Found: C, 76.42; H, 5.75; N, 3.59; O, 15.24; FTIR (KBr, cm-1):1705 (C=O)-, 2937(-CH3), 1178 (C-O ether) 1611(C=C);1H NMR (500 MHz, DMSO d6, δ ppm): 2.40 (s, 1H, CH3), 3.7(s, 3H, -OCH3), 8.22-6.43(m, 6H,Ar-H and =CH ).
(3Z,4Z)-3,4-bis(4-methylbenzylidene)-1-p-tolylpyrrolidine-2,5-dione (1e):M. F: C27H23NO2 M W: 393.48; Anal Cal.: C, 82.42; H, 5.89; N, 3.56; O, 8.13; Found: C, 82.62; H, 5.69; N, 3.76; O, 8.43;FTIR (KBr, cm-1):1705 (C=O), 2937(-CH3), 1611(C=C);1H NMR (500 MHz, DMSO d6, δ ppm): 2.40 (s, 1H, CH3), 8.22-6.43(m, 6H, Ar-H and =CH). O O OH OH SOCl2 H2N CH3 O O Cl Cl 30 min Benzene N O O CH3 1 2 3 4 5 Scheme 1
20 IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725. O O OH OH
SOCl2 O O Cl Cl H2N CH3 N O O CH3
21 IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725. N O O CH3 CHO CHO R R N O O CH3 Al2O3 MW 450 time 3- 4 min CH3COOH, 20-30 min keep over night
at room temp R: a= 1-OH, b= 3-NO2, c= 2-Cl, d= 4 -OCH3, e= 4-CH3 R R 5 6a-e 6a-e 7a-e Scheme 2 RESULT AND DISCUSSION
The cyclic imides 5 required for synthesis of bis-heterocyclic chalcone was prepared by reactions of succinic acid with thionyl choride which provide succinylchloride in situ which was condensed with p-toludine in presence of benzene the ring clouser reaction was took place with loss of HCl gas (Schem-1)
22 IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725.
membered imide group CO-N-CO and 2931.90 Cm-1 is corresponds to C-H stretching frequency of –CH3 group. The 1H NMR Spectrum in CDCl3 shows characteristic peak of four succinamide protons shows peak around 2.8 δ and methyl proton at aromatic ring shows singlet at 2.33 δ. The IR Spectra of Compound shows frequency at 1700.31 Cm-1 is due to presence of cyclic five membered imide and carbonyl group The Bis-heterocyclic compound 7a-e were synthesized by reaction of compound 5with Ortho-hydroxybenzaldehyde, Meta-nitrobenzaldehyde Ortho-chlorobenzaldehyde Para-methoxy benzaldehyde, Para-methylbenzaldehyde in presence of acetic acid the Claisen-Aldol condensation reaction was took place. The two active methylene groups of cyclic imide forms bond with two molecules of aldehydic carbonyl carbon atom and subsequent loss of water molecule during the course of reaction leads to formation of bis-chalcone (Scheme-2).
Similarly same reaction executed but different method have used in spite of conventional method. In new method chalcone have been synthesized from succinamide in solvent free solid phase conditionin presence of neutral alumina. The imide irradiated with substituted benzaldehydes in presence of 2 gm of neutral alumina in microwave oven at 450 watt power for 3-4 min high yieldof chalcones were obtained with achieving high purity and spectral analysis revels successful synthesis of target molecule.For both method the peak around 2.8 δ and methyl proton of imide is disappeared and the peak appeared at around 6.4-8.3 δ indicates the formation of bond between imide and aldehyde. The green method is advantageous than conventional method the comparative data is given in (Table-1)
Table 1: It shows percent yield and time required for reactions carried out by conventional method and green method
Physical Properties ConventionalMethod Green Method
Nature M.P ( 0C) Reactiontime (hrs/min)
Yield (%) Reaction time (hrs/min)
7a Yellow solid 166-168 14 hrs 72 3-4 min 95
7b Yellow solid 198-200 14 hrs 70 3-4 min 96
7c Yellow solid 173-175 14 hrs 69 3-4 min 94
7d Yellow solid 162-164 14 hrs 74 3-4 min 96
7e Yellow solid 144-146 14 hrs 67 3-4 min 94
The all synthesized bis-heterocyclic chalcones were evaluated for microbial study for that purpose these were tested against selective strain of pathogenic micro-organisms. For anti bacterial activity E.coli bacteria and for antifungal activity against Fungi (Yeast) Candida albicans were used. The DMSO was used to prepare aliquots 7a-e compounds and the final concentration 100µg per disc was adjusted. The
23 IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725.
disc diffusion method was used to evaluate antimicrobial activity. For this, nutrient agar was employed as culture media. The results were obtained in the form of zone of inhibition and were noted after the period of incubation (at 370c for 24-28 hrs). The zone of inhibitions was measured in mm and the data is presented in (Table-2).
Table 2: It shows anti-microbial activity in the form of zone of inhibition in mm.
MIC 100 µgm/ml for Fungal and bacterial strains
E.coli C.albicans 7a 15.16 12.66 7b - - 7c - - 7d - - 7e - - Ciprofloxacin 19.70 NA Amphotericine-B NA 11.12
Note: ‘NA’ means Not Applicable, ‘-’ means no zone of inhibition.
Grhap1: Shows antifungal activities of synthesized compounds against fungi C.albicans compared with Standard Antibiotic drug Amphotericin-B
11.12 12.66 0 0 0 0 0 2 4 6 8 10 12 14
24 IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725.
Fig. 1: Agar plate display zone of inhibition by chalcone (3Z, 4Z)-3, 4-bis (2-hydroxybenzylidene)-1-p-tolylpyrrolidine-2, 5-dione (7a) against fungi C.albicans at 100 µgm/ml conc.
The study concluded that projected new green method of synthesis of bis-hetrocyclic chalcone is very fruitful and safer than conventional method.The product obtained by this method in greater yield and higher purity. Microbial evaluation shows that the (3Z, 4Z)-3, 4-bis (2-hydroxybenzylidene)-1-p-tolylpyrrolidine-2,5-dione (7a) shown good antibacterial activity and potent anti-fungal activity against pathogenic fungi C.albicans at the Concentration of100 µgm/ml.This method has future scope in field of chemistry and pharmacy.
Authors are thankful to Department of chemistry of Savitribai fhule University pune for providing spectral analysis facilities and Department Microbiology of R.C.Patel College Shirpur for providing Antimicrobial evaluation facilities.
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25 IJGHC, December 2017 – February 2018; Sec. A; Vol.7, No.1, 017-025. DOI: 10.24214/IJGHC/GC/7/1/01725.
Department of chemistry S.S.V.P.S College Shindkheda, Dist-Dhule (Maharashtra
Online publication date: 20.12.2017
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