|
 |
| REVIEW ARTICLE |
|
| Year : 2021 | Volume
: 12
| Issue : 4 | Page : 321-326 |
|
|
Comparison of various synthesis methods and synthesis parameters of pyrazoline derivates
Meilinda Setya Praceka1, Sandra Megantara1, Rani Maharani2, Muchtaridi Muchtaridi1
1 Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, 45363, Jatinangor, West Java, Indonesia
2 Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Padjadjaran, Sumedang, West Java, Indonesia
| Date of Submission | 23-Mar-2021 |
| Date of Decision | 22-Apr-2021 |
| Date of Acceptance | 06-Jul-2021 |
| Date of Web Publication | 20-Oct-2021 |
Correspondence Address:
Prof. Muchtaridi Muchtaridi
Ph.D,Jl. Bandung, Sumedang Km. 21, Jatinangor, 45363
Indonesia
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/japtr.JAPTR_252_21
Pyrazoline plays an important role in the development of heterocyclic chemistry theory and is widely used as a synthesis useful in organic synthesis. The structure of the pyrazoline derivative compound contains a 5-membered heterocyclic framework with two nitrogen atoms and one endocyclic double bond. The function of pyrazoline as a fragment was stable enough in the bioactive group to synthesize new compounds with various biological activities. Various methods that could be used for the synthesis of pyrazole derivatives were ultrasonic irradiation, microwave assistance, ionic liquids, grinding techniques, and conventional methods. However, the synthesis of pyrazoline derivatives using conventional methods had many problems, one of which is the product yield, which was <70%. Therefore, this article will discuss the importance of optimizing the synthesis reaction conditions by taking into account several synthesis parameters to get the best organic product results based on conventional methods. A literature search was conducted by employing PubChem, Chemspider Google Scholar, Research Gate, Science Direct, and Elsevier by selecting pyrazoline synthesis based on physicochemical profile, reaction mechanism, and synthesis method.
Keywords: Parameter synthesis, pyrazoline derivates, synthesis methods
How to cite this article:
Praceka MS, Megantara S, Maharani R, Muchtaridi M. Comparison of various synthesis methods and synthesis parameters of pyrazoline derivates. J Adv Pharm Technol Res 2021;12:321-6 |
How to cite this URL:
Praceka MS, Megantara S, Maharani R, Muchtaridi M. Comparison of various synthesis methods and synthesis parameters of pyrazoline derivates. J Adv Pharm Technol Res [serial online] 2021 [cited 2023 Mar 30];12:321-6. Available from: https://www.japtr.org/text.asp?2021/12/4/321/328631 |
| Introduction | |  |
Pyrazoline derivate synthesis is carried out in two stages. In Stage 1, Claisen-Schmidt condensation[1] was conducted between acetophenone and aromatic aldehyde analogs called the aldol condensation reaction[2] to get the desired enone. In Step 2, enones are reacted to give the desired pyrazoline by a regioselective synthesis of 1, 3, 5-triarylpyrazolines. Aryl hydrazine is used as a hydrochloride salt to reduce the reaction side of the product and improve the results of the cyclization reaction.[3] The reaction of aromatic ketones and aldehydes involving base catalysts will produce unsaturated ketones and αβ-unsaturated (chalcones) was reacted with hydrazine, which is a very popular reaction method for 2-pyrazoline synthesis[4] in reflux under certain reaction conditions.[5],[6]
Pyrazoline is known as nitrogen in a five-membered ring of heterocyclic compounds.[7] Pyrazoline contains an acarbonyl aldehyde group that interacts with a series of substitution acetophenone to give an α-β unsaturated carbonyl compound called chalcones.[8] The existence of this structure is very important in pharmacological chemical drugs because the pyrazole ring structure has an active part that can provide many different biological activities. Pyrazoline derivatives have broad biological activity properties that are used effectively[9] as anti-inflammatory,[10] antimalarial,[1],[11] antidepressant,[12] antimicrobial,[11],[13] antileukemic,[14] antioxidant,[15] analgesic,[16] anticancer,[2],[17],[18] immunosuppressant,[19] antidiabetic,[20] cytotoxic,[21],[22] antihepatotoxic,[23] and antitumor agents.[19]
The process of standardization and optimization of reaction conditions is done by comparing the literature used for the synthesis of pyrazoline derivatives related to catalysts, solvents, reaction times, temperatures, etc.[24] Based on organic reactions, a compound must be synthesized easily and quickly, and the product must be easily separated and pure.[25] However, there are some disadvantages to this conventional method, for example, higher temperatures, longer reaction times, general inspection procedures, the formation of by-products, and environmental influences.[6] The development strategy for synthesis methods is carried out by selecting various synthesis methods and taking into account various synthesis parameters that can affect the results of the synthesis product [Table 1].
| Synthesis Methods of Pyrazoline Derivate | | |
Various methods that could be used for the synthesis of pyrazole derivatives are.[26]
Ultrasonic irradiation
Green chemistry from ultrasonic irradiation had been applied to the fields of green chemistry and pharmacy. Sonication provided an advantage in the synthesis of pyrazoline derivate because of the cavitation effect created under local conditions in the media as shown in [Figure 1]. Therefore, the reaction could be resolved in a short time and the number of products that could be obtained was very high. This method could promote the synthesis of pyrazoline derivate with a short reaction time and good results.[27],[28],[29] | Figure 1: Synthesis of pyrazoline derivatives using ultrasonic irradiation[27]
Click here to view |
Microwave irradiation
Green chemistry used benign synthetic procedures that were very efficient and environment friendly to synthesize a variety of bioactive heterocyclic frameworks that were useful for the synthesis of drugs, plastics, petrochemicals, agricultural chemicals, cosmetics, and many more. Hence, green chemistry was a daily necessity. In this methodology, pyrazolines were synthesized under microwave irradiation as shown in [Figure 2].[30] The structure of this compound was established by elemental analysis and spectral data. This method had several advantages compared to conventional synthesis including clean reaction procedures, easy inspection, and short reaction times, giving excellent results for the product.[31] The development of a sensitive and fast method was carried out for these samples. Thus, a pyrazoline derivative was obtained as the one giving better results than conventional methods. The current use of microwave energy was very broad because it was more environment friendly, was safer, had a better selectivity and no need for catalysts, and was faster, cleaner, and able to provide more products than conventional methods.[15],[31] It was often used as an alternative in more efficient synthesis due to the ease of operation and mild reaction conditions when mixed with free solvents. Previous studies had shown that microwave irradiation was a reaction condition in dry media that was energetically beneficial and saved more reaction time.[11],[30] | Figure 2: Synthesis of pyrazoline derivatives using microwave irradiation[30]
Click here to view |
Ionic liquid
Ionic liquid is salt in 100°C liquid state. Liquid salt is certainly different from liquid because it requires a higher temperature to melt salt. In 1948, the first ionic liquid and chloroaluminate were discovered, and since then many studies had found various ionic liquids that could be implemented in the synthesis. 1-n-butyl-3-methylimidazolium and 1-ethyl3-methylimidazolium (EMIM) had developed green route to compounds 1, 3, 5-pyrazoline derivatives substituted in liquid media EMIM hydrogen ionic sulfate liquid, which was useful as a catalyst in reflux conditions as shown in [Figure 3].[24] In addition, 1, 3, 5-tri-substitute-2-pyrazoline compounds used one-pot cyclocondensation between arylhydrazines and chalcones to obtain better results. The catalyst was recycled without losing much of its catalytic activity.[32] The used catalyst could be used without losing its catalytic activity.[24]
Grinding technique
Milling was an effective instrument for mixing substrates very efficiently under solvent-free reaction conditions. The method applied to the simple apparatus was suitable for use in mechanochemical reactions with pestles and mortars, through mixing and triturating mills as shown in [Figure 4].[33],[34] The grinding technique was developed as a new method in the synthesis of organic heterocycles using mechanical techniques from ball milling. Mechanical engineering was needed to grind the powder into finer particles. The reactants were broken down with solvent molecules in the classical method. In addition, the reactants were broken down by mechanical forces in ball milling which led to an amorphous mixture approach of all reagents and the reaction took place on a larger surface. The implementation of solvent-free ball milling was very rare in organic synthesis. However, this technique was attracting attention because of its low cost, simplicity, and good results in pure form without the need for further purification. This technique was also environment friendly. Therefore, this ball grinding technique was superior to conventional methods.[33],[35] | Figure 4: Synthesis of pyrazoline derivatives using grinding technique under solvent-free conditions[33]
Click here to view |
This procedure had many advantages including high selectivity, efficiency, purification, easy separation, and mild reaction conditions. Apart from being safe for the surrounding environment, economically, toxic waste could be eliminated or minimized so that the waste treatment costs were not too large.[34]
Conventional methods
One of the simplest methods was the conventional method which was carried out with conventional equipment such as reflux with the reaction shown in [Figure 5].[36] The heating reaction was slow but also caused hot surfaces at certain reaction sites, which led to the decomposition of the substrate, reagents, and products over time of synthesis.[11] In contrast to this, green chemistry techniques assisted by microwave energy allowed the heating of vessels over a long distance to be more uniform, resulting in relatively smaller decomposition products. The heating reaction with conventional equipment was not only slow but also created a hot surface at the reaction site which led to the breakdown of products, substrates, and reagents over time.[37] | Figure 5: Synthesis of pyrazoline derivatives using conventional methods[36]
Click here to view |
Conventional heating used an oil well that is heated first, then the solvent. The decomposed product results in an uneven distribution due to temperature differences in the solvent and bath wall.[38],[39]
| Pyrazoline Derivate Synthesis Parameters | | |
In the synthesis of pyrazoline derivate, various factors affected the parameters that needed to be considered when synthesis took place to get better product results, one of which was: [40]
Based on the above parameters, a comparison can be made between the green synthesis method and the conventional method.
The temperature used in conventional methods with reflux was the highest temperature achieved with restrictions on boiling certain points of the mixture. The temperature in conventional methods was higher than in other methods. The decrease in reaction rate was caused by an increase in the number of perfect collisions with higher kinetic energy.[6] Temperatures that were too high could lead to product decomposition and poor results on the synthesis of pyrazoline derivate.[11]
The constant in the reaction rate used an exponential function as the temperature increases. The high reduction in total at the time of synthesis was due to the benefits of exposure to microwave-assisted heat in chemical pyrazole synthesis. The decrease in the rate of reaction at the time of synthesis was due to the increase in the perfect collision of the number of collisions, which resulted in higher kinetic energy.[6]
Reaction time in conventional methods was longer than in other methods.[15],[25],[30] A decrease in reaction time was carried out in line with the increase in the resulting product.[41] The reaction time required for the microwave and ultrasonic methods tended to decrease from a few hours to a few minutes.[25] A decrease in reaction time was carried out in line with the increase in the resulting product.[41]
The energy source needed for microwave irradiation-assisted synthesis by applying green synthesis was very beneficial in terms of energy saving and to make it easier to control than conventional methods.[15]
The results of products in conventional methods tended to be less good compared to other methods due to high heating, a longer time, and more solvent consumption.[25] Therefore, it is recommended that the synthesis of pyrazoline derivate in conventional methods uses green chemistry.[42]
| Conclusion | | |
In the synthesis of pyrazoline derivatives, various synthesis methods could be used. One of the simplest synthetic methods was the conventional method. However, the conventional method was not as superior as the green synthesis method because it produced a product yield of <70%. This became a challenge in the world of synthetic chemistry to optimize reaction conditions by considering various parameters to obtain good-resulting products. Parameters that needed to be considered were temperature, reaction time, energy source, and product yield. One of the efforts to optimize the reaction conditions was to modify the variation in the concentration of solvent, temperature, and catalyst used during the reaction.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Suwito H, Jumina, Mustofa, Pudjiastuti P, Fanani MZ, Kimata-Ariga Y, et al. Design and synthesis of chalcone derivatives as inhibitors of the ferredoxin - Ferredoxin-NADP+ reductase interaction of Plasmodium falciparum: Pursuing new antimalarial agents. Molecules. 2014;19:21473–88.  |
| 2. | Jadhav SA, Kulkarni KM, Patil PB, Dhole VR, Patil SS. Design, synthesis, and biological evaluation of some novel pyrazoline derivatives. Der Pharma Chem 2016;8:38-45. |
| 3. | Abdel-Halim M, Diesel B, Kiemer AK, Abadi AH, Hartmann RW, Engel M. Discovery and optimization of 1,3,5-trisubstituted pyrazolines as potent and highly selective allosteric inhibitors of protein kinase C-χ. J Med Chem 2014;57:6513-30. |
| 4. | Indorkar D, Chourasia OP, Limaye SN. Synthesis and characterization of some new synthesis of 1-acetyl-3-(4-nitrophenyl)-5-(substituted phenyl) pyrazoline derivative and antimicrobial activity. Int J Curr Microbiol Appl Sci 2015;4:670-8. |
| 5. | Fazaeli R, Aliyan H, Mallakpour S, Rafiee Z, Bordbar M. Tungstophosphoric acid supported on highly organosoluble polyamide (PW12/PA): Highly efficient catalysts for the synthesis of novel 1, 3, 5-triaryl-2-pyrazoline derivatives. Cuihua Xuebao/Chinese J Catal 2011;32:582-8. |
| 6. | Kitawat BS, Singh M. Synthesis, characterization, antibacterial, antioxidant, DNA binding and SAR study of a novel pyrazine moiety bearing 2-pyrazoline derivatives. New J Chem 2014;38:4290-9. |
| 7. | Ardiansah B, Mardiana L, Bakri R, Aziza NP, Baramanda TA. Design, synthesis and radical scavenging performance of 2,2'-(4,5-dihydro-1 H -pyrazol-3,5-dyl) diphenol. AIP Conf Proc. 2018;2023:020086–1–020086–6. |
| 8. | Alkazmi AA, Hawais FE, Alasadi YK. Synthesis and Characterization of Some Pyrazoline Derivatives from Chalcones Containing azo and Ether Groups Synthesis and Characterization of some Pyrazoline Derivatives from Chalcones Containing Azo and Ether Groups; 2017. |
| 9. | Wadhal Sa, Khan I. Microwave Assisted Improved Method for the Synthesis, Characterization of 1-(2-Hydroxy Phenyl)-Methanone-3,5-Disubstituted Pyrazolines. Rasayan J Chem. 2017;10:630-33. |
| 10. | Holota S, Derkach H, Demchuk IL, Vynnytska RB, Antoniv OI, Furdychko LO, et al. Synthesis and In vivo evaluation of pyrazoline-thiazolidin-4-one hybrid Les-5581 as a potential non-steroidal anti-inflammatory agent. Biopolym Cell. 2019;35:437-47. |
| 11. | Akhtar W, Khan MF, Verma G, Akhter M. Coumarin-Pyrazoline Derivatives : Their One-Pot Microwave Assisted Synthesis and Antimalarial Activity Coumarin-Pyrazoline Derivatives : Their One-Pot Microwave Assisted Synthesis and Antimalarial Activity. J Pharm Med Chem. 2017;3 Number 1:5-9. |
| 12. | Badavath VN, Kumar A, Jadav SS, Pattnaik AK, Jayaprakash V, Sinha BN. Synthesis and Antidepressant activity of pyrazoline-based MAO-inhibitors. J Pharm Chem 2016;3:1. |
| 13. | Tupare SD, Dake SA, Nalage SV, Bhosale SV, Ingle RD, Pawar RP. Synthesis and biological evaluation of novel 6- (3- (4, Pyridazin-3 (2H) -one derivatives. Int J Org Chem 2012;2:371-6. |
| 14. | Shaabanzadeh M, Torbati MB. Synthesis and cytotoxic evaluation of 2-pyrazoline derivative on leukemia cancer cell line K562. J Chem Heal Risks 2018;8:323-8. |
| 15. | Jasril, Yuda HT, Aisyah, Nurlaili, Hendra R. Microwave Assisted Synthesis and Evaluation of Toxicity and Antioxidant Activity of Pyrazoline Derivatives. Indones J Chem. 2019;19:583-91. |
| 16. | Tanwer N, Kaur R, Rana D, Singh R, Singh K. Synthesis and characterization of pyrazoline derivatives. J Integr Sci Technol 2015;3:39-41. |
| 17. | Karabacak M, Altintop MD, Çiftçi HI, Koga R, Otsuka M, Fujita M, et al. Synthesis and evaluation of new pyrazoline derivatives as potential anticancer agents. Molecules 2015;20:19066-84. |
| 18. | George RF. Facile synthesis of simple 2-oxindole-based compounds with promising antiproliferative activity. Future Med Chem 2018;10:269-82. |
| 19. | Zhang L, Peterson TE, Lu VM, Parney IF, Daniels DJ. Antitumor activity of novel pyrazole-based small molecular inhibitors of the STAT3 pathway in patient derived high grade glioma cells. PLoS One 2019;14:e0220569. |
| 20. | Datar PA, Jadhav SR. Design and synthesis of pyrazole-3-one derivatives as hypoglycaemic agents. Int J Med Chem 2015;2015:670181. |
| 21. | Fan NJ, Feng LY, Liang S, Tang JJ. Synthesis and cytotoxic activity of novel steroidal derivatives containing a [1,2,4] triazolo [1,5-a] pyrimidine ring. J Chem Res 2017;41:413-5. |
| 22. | Wahyuningsih TD, Suma AA, Astuti E. Synthesis, anticancer activity, and docking study of N-acetyl pyrazolines from veratraldehyde. J Appl Pharm Sci 2019;9:14-20. |
| 23. | Khalilullah H, Khan S, Ahsan MJ, Ahmed B. Synthesis and antihepatotoxic activity of 5-(2,3-dihydro-1,4-benzodioxane-6-yl)-3-substituted-phenyl-4,5-dihydro-1H-pyrazole derivatives. Bioorg Med Chem Lett 2011;21:7251-4. |
| 24. | Kagne DR, Kalalawe VG, Niwadange SJ. A novel assent for synthesis of pyrazoline derivatives by adopting graphene oxide nanosheets as carbocatalyst at reflux condition. Int J Green Herb Chem 2018;7:469-76. |
| 25. | Mermer A. Microwave- and ultrasound-promoted greener synthesis of thiazolyl- pyrazoline derivatives and investigation of their biological activities. JOTCSA. 2020;7:25-36. |
| 26. | Kharatmol MG, Jagdale D. Eco-friendly synthesis of pyrazoline derivatives. Int J Pharm Clin Res 2017;9:302-8. |
| 27. | Emayavaramban M, Santhi N, Gopi C, Manivannan C, Raguraman A. Synthesis, characterization and anti-diabetic activity of 1,3,5-triaryl-2-pyrazolines in acetic acid solution under ultrasound irradiation. Int Lett Chem Phys Astron 2013;14:172-85. |
| 28. | de Albuquerque DY, Damim AC, Faoro E, Casagrande GA, Back DF, Moura S, et al. Ultrasound-Promoted Synthesis, Structural Characterization and. 2019;00:1-10. |
| 29. | Ashok SP, Sunil DJ, Arvind SB, Santosh S, Ramesh BG. Ultrasound Assisted Synthesis of 1,5-Diaryl and 1,3,5-Triaryl-2-pyrazolines by Using KOH/EtOH System with Cu(I) Catalyst. Asian J Chem. 2018;32:894-96. |
| 30. | Sharma BK, Ameta SC, Dwivedi VK. Ecofriendly Synthesis Of Chalcones And Their 2-Pyrazoline And Isoxazolines Derivatives As Potential Microbial Agents. Int J Chem Sci. 2014;12:1121-34. |
| 31. | Prajapati J, Dulawat M, Prajapat P, Rathore R, Dulawat SS. Microwave Induced Synthesis of Pyrazoline Compounds Containing Substituted Benzyloxy Phenyl Ring System. IRA-International J Appl Sci. 2016;04:145-51. |
| 32. | Peter W, Wilhelm K. Ionic Liquids New Solutions for Transition Metal Catalysis. Angew Chem Int. 2000;39:3772-89. |
| 33. | Zangade SB, Mokle SS, Shinde AT, Vibhute YB. An atom efficient, green synthesis of 2-pyrazoline derivatives under solvent-free conditions using a grinding technique. Green Chem Lett Rev 2013;6:123-7. |
| 34. | Safaei-Ghomi J, Masoomi R. Grinding-induced synthesis of heterocyclic fullerene derivatives under solvent-free conditions. Chem Heterocycl Compd 2015;51:39-43. |
| 35. | M'Hamed MO. Ball milling for heterocyclic compounds synthesis in green chemistry: A review. Synth Commun 2015;45:2511-28. |
| 36. | Trilleras J, González-López E, León-Jaramillo J, Pérez-Gamboa A, Puello-Polo E, Romo P, et al. Syntheses, experimental and theoretical studies on absorption/emission properties of pyrazoline-containing aryl/methoxynaphthyl substituents. J Braz Chem Soc. 2018;29:1210-17. |
| 37. | Patil PO, Belsare DP, Kosalge SB, Fursule RA. Microwave-assisted Synthesis and antidepressant activity of some. Int J Chem Sci 2008;6:717-25. |
| 38. | Nayak J, Devi C, Vidyapeeth L. Microwave-assisted synthesis : A green chemistry approach. Int Res J Pharm Appl Sci 2016;3:278-85. |
| 39. | Nain S, Singh R, Ravichandran S. Importance of microwave heating in organic synthesis. Adv J Chem A 2019;2:94-104. |
| 40. | Desai NC, Bhatt MJ. Optimized synthesis of novel pyrazole based thiazole derivatives and their antimicrobial evaluation. Int Lett Chem Phys Astron 2016;66:109-18. |
| 41. | Patel VM, Desai KR. Eco-friendly synthesis of fluorine-containing pyrazoline derivatives over potassium carbonate. Arkivoc 2004;2004:123-9. |
| 42. | Bhat P, Shridhar G, Ladage S, Ravishankar L. Eco-friendly synthesis of 2-pyrazoline derivatives catalyzed by CeCl 3 7H 2 O. J Chem Sci 2017;129:1441-8. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1]
| This article has been cited by | | 1 |
Thiazole-Pyrazoline Hybrids as Potential Antimicrobial Agent: Synthesis, Biological Evaluation, Molecular Docking, DFT Studies and POM analysis |
|
| Rezan Huseen Hama Salih, Aso Hameed Hasan, Narmin Hamaamin Hussen, Farouq Emam Hawaiz, Taibi Ben Hadda, Joazaizulfazli Jamalis, Faisal A. Almalki, Adedapo S. Adeyinka, Louis-Charl C. Coetzee, Abel Kolawole Oyebamiji | | Journal of Molecular Structure. 2023; : 135191 | | [Pubmed] | [DOI] | | | 2 |
Recientes investigaciones en la síntesis sustentable de pirazolinas |
|
| Jorge Trilleras, José-José De-La-Ossa-Alían, Alfredo Pérez-Gamboa | | Revista Científica. 2022; 45(3): 315 | | [Pubmed] | [DOI] | |
|
 |
|
|
|
Search Pubmed for