An optimized method for synthesis of 2’hydroxy chalcone
Nikunj Patadiya1*, Vipul Vaghela2
1Research Scholar, Department of Pharmaceutical Chemistry,
A.R College of Pharmacy and G.H Patel Institute of Pharmacy, Vallabh Vidhyanagar, Anand, Gujarat, India.
2Professor, Department of Pharmaceutical Chemistry,
A.R College of Pharmacy and G.H Patel Institute of Pharmacy, Vallabh Vidhyanagar, Anand, Gujarat, India.
*Corresponding Author E-mail: nikunj20899@gmail.com
ABSTRACT:
Chemistry:
In present work, synthesis of 2’hydroxy chalcone was carried out by Claisen–Schmidt condensation using different solvent and variety of strong bases.
In this study, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide screened as base catalyst for synthesis. Methanol, ethanol, isopropyl alcohol (IPA), tetrahydrofuran (THF), dichloromethane (DCM) and acetonitrile (ACN) was screened as solvent. Highest yield condition was selected for the optimization. In optimization step effect of solvent and base quantity, stirring time and temperature were screened.
RESULTS AND DISCUSSION:
Table 1. Effect of base catalyst and solvent on product (2’hydroxy chalcone) yield.
|
Sr. No. |
Base |
Solvent |
%yield |
|
1 |
LiOH |
Methanol |
1.24% |
|
2 |
NaOH |
Methanol |
70.56% |
|
3 |
KOH |
Methanol |
68.25% |
|
4 |
Ba(OH)2 |
Methanol |
5.25% |
|
5 |
Ca(OH)2 |
Methanol |
No Reaction |
|
6 |
Mg(OH)2 |
Methanol |
No Reaction |
|
7 |
LiOH |
Ethanol |
2.28% |
|
8 |
NaOH |
Ethanol |
75.74% |
|
9 |
KOH |
Ethanol |
72.95% |
|
10 |
Ba(OH)2 |
Ethanol |
4.35% |
|
Sr no. |
Base |
Solvent |
%yield |
|
11 |
Ca(OH)2 |
Ethanol |
No Reaction |
|
12 |
Mg(OH)2 |
Ethanol |
No Reaction |
|
13 |
LiOH |
IPA |
No Reaction |
|
14 |
NaOH |
IPA |
80.56% |
|
15 |
KOH |
IPA |
76.34% |
|
16 |
Ba(OH)2 |
IPA |
6.23% |
|
17 |
Ca(OH)2 |
IPA |
No Reaction |
|
18 |
Mg(OH)2 |
IPA |
No Reaction |
|
19 |
LiOH |
THF |
No Reaction |
|
20 |
NaOH |
THF |
1.56% |
|
21 |
KOH |
THF |
1.42% |
|
22 |
Ba(OH)2 |
THF |
No Reaction |
|
23 |
Ca(OH)2 |
THF |
No Reaction |
|
24 |
Mg(OH)2 |
THF |
No Reaction |
|
25 |
LiOH |
DCM |
No Reaction |
|
26 |
NaOH |
DCM |
1.36% |
|
27 |
KOH |
DCM |
2.04% |
|
28 |
Ba(OH)2 |
DCM |
No Reaction |
|
29 |
Ca(OH)2 |
DCM |
No Reaction |
|
30 |
Mg(OH)2 |
DCM |
No Reaction |
|
31 |
LiOH |
ACN |
No Reaction |
|
32 |
NaOH |
ACN |
No Reaction |
|
33 |
KOH |
ACN |
No Reaction |
|
34 |
Ba(OH)2 |
ACN |
No Reaction |
|
35 |
Ca(OH)2 |
ACN |
No Reaction |
|
36 |
Mg(OH)2 |
ACN |
No Reaction |
Reaction Condition: Temperature 28˚C; Stirring Time: 24hr; Amt. of Solvent: 50ml; Amt. of reactants:0.05mol; Amt. of base: 40% W/V 30ml
Table 2. Effect of base and solvent quantity, temperature and stirring time on product (2’hydroxy chalcone) yield.
|
Sr No. |
Amount of 40% NaOH (ml) |
Amount of IPA (ml) |
Temp. (˚C) |
Stirring time (hr) |
% yield |
|
1 |
15 |
50 |
28 |
24 |
50.75% |
|
2 |
20 |
50 |
28 |
24 |
81.54% |
|
3 |
25 |
50 |
28 |
24 |
81.35% |
|
4 |
30 |
50 |
28 |
24 |
80.56% |
|
5 |
35 |
50 |
28 |
24 |
* |
|
6 |
40 |
50 |
28 |
24 |
* |
|
7 |
20 |
10 |
28 |
24 |
10.56% |
|
8 |
20 |
20 |
28 |
24 |
15.75% |
|
9 |
20 |
30 |
28 |
24 |
34.12% |
|
10 |
20 |
40 |
28 |
24 |
60.78% |
|
11 |
20 |
60 |
28 |
24 |
81.24% |
|
12 |
20 |
50 |
0 |
24 |
92.04% |
|
13 |
20 |
50 |
10 |
24 |
84.21% |
|
14 |
20 |
50 |
15 |
24 |
83.41% |
|
15 |
20 |
50 |
20 |
24 |
81.12% |
|
16 |
20 |
50 |
25 |
24 |
81.01% |
|
17 |
20 |
50 |
0 |
1 |
15.25% |
|
18 |
20 |
50 |
0 |
2 |
40% |
|
19 |
20 |
50 |
0 |
4 |
92% |
|
20 |
20 |
50 |
0 |
8 |
92% |
|
21 |
20 |
50 |
0 |
10 |
92% |
|
22 |
20 |
50 |
0 |
12 |
92% |
|
23 |
20 |
50 |
0 |
15 |
92% |
|
24 |
20 |
50 |
0 |
18 |
92% |
|
25 |
20 |
50 |
0 |
20 |
92.% |
|
26 |
20 |
50 |
0 |
22 |
92.04% |
*By product formation. After stirring the mixture, refrigerated it for 2h; Amt. of reactants: 0.05mol
Variety of bases and solvents was screened for synthesis of 2’hydroxy chalcone. NaOH gives highest yield and purity compare to other bases. IPA was proved beneficial solvent compare to methanol, ethanol, DCM, ACN and THF. Excess amount of base shows byproduct formation. 20ml of 40% W/V NaOH amount show good result compare to other concentration. Sufficient amount of IPA was necessary for synthesis of 2’hydroxy chalcone, 50ml IPA show best result compare to lower concentration and no major change screened after increasing amount of IPA. Temperature change gives significant effect on %yield. At 0˚C highest yield obtained without formation of any by product. %yield drastically decreased upon temperature increases, also byproduct formation occurred. For the completion of reaction minimum 4h was required, after stirring not more effective.
Scheme 1. Synthesis of 2’hydroxy chalcone
CONCLUSION:
2’hydroxy chalcone were successfully synthesized by Claisen–Schmidt condensation between benzaldehyde and 2’hydroxy chalcone. Variety of bases and solvent were tried for synthesis of 2’hydroxy chalcone. Lithium hydroxide shows slight catalytic activity in methanol and ethanol, in other solvent catalytic activity lost. Barium hydroxide also show slight catalytic in methanol, ethanol and IPA, in other solvent no product was formed. Calcium and magnesium hydroxide shows no catalytic activity in any solvent. Sodium hydroxide shows better activity than potassium hydroxide in all solvents. IPA proved better solvent than other solvents. In optimization process effect of solvent and base quantity, stirring time and temperature were screened. Product yield increases with amount of base level, but higher amount of base leads to byproduct formation. Amount of solvent also shows significant effect on product yield. Temperature shows significant effect on product yield. At 0˚C, best results obtained. In 4h, reaction mostly completed, further stirring was not effective. So the main aim of study, to develop optimized method for synthesis of 2’hydroxy chalcone was successfully completed.
EXPERIMENTAL:
Chemistry:
General:
All purchased chemicals were of analytical grade and used without further purification. The synthesis of 2’ Hydroxy chalcone were carried out as per the procedure detailed in Scheme 1. The progress of the reactions was monitored by thin‐layer chromatography analysis (Silica gel G60 F254; Merck). Melting points of the synthesized compounds were determined in open capillary tubes using Veego Melting Point Apparatus model VMP-D. Infrared spectra were recorded on Perkin Elmer spectrum GX FTIR spectrophotometer using KBr discs. 1H-NMR was recorded on Bruker Advance–II NMR-400MHz instrument using DMSO as a solvent and tetra methyl silane (TMS) as internal standard. Mass spectra were recorded on LCQ Fleet and TSQ quantum surveyor plus HPLC system spectrophotometer.
General procedure for the synthesis of 2’ Hydroxy Chalcone:
Mixed benzaldehyde (0.05mol, 5.3gm) and o-hydroxy acetophenone (0.05mol, 6.8gm) in 50ml of isopropyl alcohol and stirred for 15min at 0˚C. Add 40% NaOH 20ml dropwise (1ml/min) with stirring. After 6h stirring at 0˚C solution kept refrigerate for 2h. Add 100ml water in reaction mixture so pale-yellow precipitate observed. Filter the precipitate and recrystallized using methanol. Pale yellow needles shape; %yield 92% (9.56gm); mp 88-90˚C; IR (KBr, cm-1) vmax: 3432 (-OH),3026 (C-H Aromatic), 2926 (C-H Aliphatic), 1639 (C=O), 1485 (C=C Aromatic); 1H NMR (400 MHz, DMSOd6) δ ppm: 13.05 (s, 1H, OH), 7.94 (d, 1H alkene), 7.86 (d, 1H alkene), 6.90-8.31 (m, 9H Aromatic CH). MS (ESI+): m/z 224[M+], 225[M+1].
REFERENCES:
1. Shima H. M. E. Ketabforoosh et al. Synthesis and Anti-Cancer Activity Evaluation of New Dimethoxylated Chalcone and Flavanone Analogs. Arch. Pharm. Chem. Life Sci. 2014; 347: 1–8.
2. Bhagyesh Baviskar, Sureshbhi Patel, Bhushan Baviskar, SS Khadabadi, Mahendra Shiradkar. Design and Synthesis of Some Novel Chalcones as Potent Antimicrobial Agent. Asian J. Research Chem. 2008; 1(2): 67-69.
3. Bhaskar S. Dawane, Baseer M Shaikh, Namdev T. Khandare, Gajanan G. Mandawad, Santosh S. Chobe, Shankaraiah G. Konda. Synthesis of Some Novel Substituted Pyrazole Based Chalcones and Their In-Vitro Antimicrobial Activity. Asian J. Research Chem. 2010; 3(1): 90-93.
4. H.V. Shahare, G.R. Pawar, S.S. Patil, P.D. Patil. Synthesis and Biological Evaluation of New Chalcone Analogs. Asian J. Research Chem. 2011; 4(2): 237-240.
5. Gopi C., Dhanaraju M. D. Synthesis, Characterization and Anti-Microbial Evaluation of Derivative of Chalcone. Asian J. Research Chem. 2011; 4(2): 181-182.
6. Gondu Eswara Rao, S.A. Rahaman, A. Prameela Rani, Ch. M.M. Prasada Rao. Synthesis, Characterization and Antimicrobial Activity of Novel Chalcones from 1-[4-(1H-imidazol-1-yl) Phenyl] Ethanone. Asian J. Research Chem. 2013; 6(7): 687-689.
7. Pushkar Pratap Singh, B. Jayalakshmi, N. Senthil Kumar. Synthesis, Characterization and Antimicrobial Evaluation of Some New Chalcones. Asian J. Research Chem. 2013; 6(12): 1133-1136.
8. Suha K. Al-Mosawi, Hanan A. Al-Hazam, Abbas F. Abbas. Synthesis, Characterization and Biological Study of Some Chalcones derived from Terphthaldehyde. Asian J. of Research Chem. 2019; 12(3): 153-156. DOI: 10.5958/0974-4150.2019.00031.2
9. M. Safavi et al. Halogenated flavanones as potential apoptosis-inducing agents: Synthesis and biological activity evaluation. European Journal of Medicinal Chemistry. 2012; 58: 573-580.
10. Y. Murti and P. Mishra. Synthesis and Evaluation of Flavanones as Anticancer Agents. Indian Journal of Pharmaceutical Sciences. 2014; 76(2): 163-166.
11. Yeonjoong Y, Hwang SA and Yoon H. 1H and 13C NMR spectral assignments of 2-hydroxychalcones. Magn. Reson. Chem. 2013; 51: 364–370.
12. Cabrera M., Simoens M., Falchi G. and Lavaggi M.L. Synthetic chalcones, flavanones, and flavones as antitumoral agents: Biological evaluation and structure activity relationships. Bioorganic and Medicinal Chemistry. 2007; 15: 3356–3367.
13. Laxmi Lal Dangi, Mangal S. Dulawat, Parul Tiwari, Shiv Singh Dulawat. New substituted m-Phenoxy chalcones; their synthesis by microwave irradiation and antifungal activity. Asian J. Research Chem. 2013; 6(5): 461-463.
14. Albogami A.S., Karama U., Amousa A.A, Khan M., Al-mazroa S.A and Alkhathlan A.Z. Simple and Efficient One Step Synthesis of Functionalized Flavanones and Chalcones. Orient. J. Chem. 2012; 28(2): 619-626.
15. Sharma N and Joshi YC. Synthesis of substituted chalcones under solvent–free microwave irradiation conditions and their antimicrobial evaluation. International Journal of Pharmacy and Pharmaceutical Sciences. 2012; 4(4): 436-439.
16. Borse SL. PhD. Thesis. Microwave Assisted Synthesis of Substituted Flavonoids and Pharmacological Evaluation.” Shri Jagdish Prasad Jhabarmal Tibrewala University, 2010.
17. Thornton M.T. PhD. Thesis. Synthesis of flavonoids and flavonoid-based designed multiple ligands for hypertension. Deakin University January, 2013, 32-33.
18. K. Ishwar Bhat, Ranee Kumari, Abhishek Kumar, Pankaj Kumar. Synthesis of Some Novel Flavanones and Evaluation of Antioxidant Activities. Research J. Pharm. and Tech. 2019; 12(5): 2141-2144 DOI: 10.5958/0974-360X.2019.00355.X
19. Pramod Kulkarni, Pradip Wagh and Pudukulathan Zubaidha. An Improved and Eco-Friendly Method for the Synthesis of Flavanone by the Cyclization of 2’-Hydroxy Chalcone using Methane Sulphonic Acid as Catalyst. Chemistry Journal. 2012; 2(3): 106-110.
20. Preet Anand and Baldev Singh. Synthesis and evaluation of novel carbamate-substituted flavanone derivatives as potent acetylcholinesterase inhibitors and anti-amnestic agents. Med Chem Res. 2013; 22: 1648–1659. doi 10.1007/s00044-012-0162-3.
21. Yuh-Meei Lin, Yasheen Zhou, Michael T. Flavin, Li-Ming Zhou, Weiguo Niea and Ching Chen. Chalcones and Flavonoids as Anti-Tuberculosis Agents”, Bioorganic & Medicinal Chemistry. 2002; 10: 2795–2802.
22. Yogesh Murti and Pradeep Mishra. Flavanone: A Versatile Heterocyclic Nucleus. International Journal of ChemTech Research. 2014; 6(5): 3160-3178.
23. Srinivasu V. N. Vuppalapati, Likai Xia, Naushad Edayadulla, Yong Rok Lee. Mild and Efficient One-Pot Synthesis of Diverse Flavanone Derivatives via an Organocatalyzed Mannich-Type Reaction. Synthesis. 2014; 46: 465–474.
24. Moorthy N.S.H.N, Singh R.J, Singh H.P, and Gupta S.D. Synthesis, Biological Evaluation and In Silico Metabolic and Toxicity Prediction of Some Flavanone Derivatives. Chem. Pharm. Bull. 2006; 54(10): 1384-1390.
25. S. Saravanamurugan, M. Palanichamy, Banumathi Arabindoo, V. Murugesan. Solvent free synthesis of chalcone and flavanone over zinc oxide supported metal oxide catalysts. Catalysis Communications. 2005; 6: 399-403.
26. Elzbieta Budzisz et al. Biological Evaluation of 3-Benzylidenechromanones and Their Spiropyrazolines-Based Analogues. Molecules. 2020; 25: 1613.
27. Lincy Joseph, Mathew George. Analgesic and Anti-Oxidant Activities of Certain (E)-3 Arylidene Flavanones Synthesized by One Pot Method. Asian Journal of Research in Chemistry. 2009; 2(3): 318-321.
Received on 29.01.2022 Modified on 26.03.2022
Accepted on 23.05.2022 ©AJRC All right reserved
Asian J. Research Chem. 2022; 15(3):210-212.
DOI: 10.52711/0974-4150.2022.00036