Morpholine-Based Novel Ionic Liquid for Synthesis and Characterization of Triazolidinethiones and Their Biological Properties
Department of Chemistry, Tuljaram Chaturchand College, Baramati, Maharashtra, 413102, India
Department of Chemistry, Vidya Pratishthan’s Arts, Science & Commerce College, Baramati, Maharashtra, 413133, India
Academic Editor: Narendra Kumar
Received: December 03, 2022 | Accepted: February 26, 2023 | Published: March 12, 2023
Catalysis Research 2023, Volume 3, Issue 1, doi:10.21926/cr.2301011
Recommended citation: Dige NC, Randive CS, Tamhane OS, Ghorpde RS, Kale SR, Mahajan PG. Morpholine-Based Novel Ionic Liquid for Synthesis and Characterization of Triazolidinethiones and Their Biological Properties. Catalysis Research 2023; 3(1): 011; doi:10.21926/cr.2301011.
© 2023 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
In modern synthetic chemistry, developing heterocyclic compounds from simple precursors is a challenging and emerging area for the scientific community [1,2,3,4,5,6]. The five membered heterocycles with 3 nitrogen and 2 carbon atoms in the skeleton are known as Triazole, one of the prime class of heterocycles [7,8]. The positions of nitrogen atoms divide triazoles into two categories viz. 1,2,3- and 1,2,4-triazoles. The variety of triazole compounds especially 1,2,4-triazoles are widely studied and owe a significant impact because of their curious pharmacological properties. The literature survey reveals that diversity of biological aspects of 1,2,4-Triazoles have been discovered through the analysis of antifungal, cytotoxic, antibacterial, anti-inflammatory, antidepressant, anti-tubercular, analgesic, and anticancer properties [9,10,11,12,13,14,15,16,17]. Additionally, plant growth regulating activity of triazole increases agriculture demand through research and development. Such biodiversity and applications imply the voyage for new synthetic methodologies in developing 1,2,4-triazole-based thiones derivatives amongst the researchers.
It is well known that organic chemistry is always on the edge of the pharmaceuticals, petrochemicals and biotechnology area. Organic synthesis can be simplified by using ionic liquids (ILs), well-known as eco-friendly catalysts, versatile reaction mediums, and safe solvents. ILs attributed to low vapor pressure, high chemical, thermal and electrochemical stability, significant viscosity and low flammability make them more suitable and important materials in synthetic methodologies. Organic synthesis, catalysis, extraction and CO2/SO2 capture are a few areas where ILs are widely applied . The non-corrosive and non-volatile nature of ILs resists air oxidation. The recycling ability received notable research of interest in bromide-functionalized ILs and their application in synthesizing heterocycles [19,20].
1,2,4-triazolidinethiones or their interrelated derivatives showed interesting biological properties, including acetylcholinesterase inhibition, anti-cancer, anti-HIV, antimycobacterial, anti-viral, antiepileptic, anti-allergic, antidepressant, carbonic anhydrase, and analgesic activities [20,21,22,23,24,25,26,27]. Nowadays, the design and synthesis of 1,2,4-triazolidine-3-thiones and evaluating their biological aspects are in challenging, demanding and advantageous research interest mode. The reported methods fail to follow the green synthetic approach or have no remarkable biological activities. Now it’s time to replace hazardous methods with a greener and more sustainable process. Green chemistry is an emerging tool for maximizing the efficiency of eco-friendly processes and products and minimizing the generation of hazardous substances. The environmentally friendly solvents are known as Green solvents [28,29,30,31]. Many green solvents include ionic liquids, supercritical fluids, water, and supercritical water. These green solvents are much more eco-friendly, less toxic, and less hazardous than traditional volatile organic solvents (VOCs). Green chemistry helps to conserve natural resources and reduces pollution by eliminating waste and hazardous materials. Therefore, we design to adopt a green chemistry approach such as using green solvents and some catalyst with the solvent-free condition. Therefore, the main motivation to perform the present research work was the synthesis of 1,2,4-triazolidine-3-thiones by using novel ionic liquid for their bio-evaluation against antibacterial activity. We have disclosed an efficient, one-pot multi-component approach for 5-aryl–[1,2,4]triazolidine-3-thione from various aldehydes as precursors in the presence of the catalytic amount of synthesized IL. Ethanol is classified as an environmentally preferable green solvent because it is available by fermenting renewable sources, including sugars, starches, and lignocelluloses. Hence, we have used ethanol as a green solvent for this transformation. The main merits of the present research work are the high practical yield, ease in the workup procedure, and novelty in multi-component strategy.
2. Experimental Section
The various substituted aldehydes (Alfa Aesar), thiosemicarbazide (spectrochem), morpholine (spectrochem), and N- butyl bromide (spectrochem) were used as received without further purification. The open capillary method was followed to determine the melting points of synthesized derivatives. IR spectra were recorded on a Shimadzu IR Affinity 1- S Diamond ATR spectrophotometer. NMR spectra were recorded on a Bruker AVANCE NEO 500 MHz FT-NMR spectrometer in DMSO- d6 using tetramethylsilane as an internal standard.
2.2 General Procedure for Synthesis of Ionic Liquid (NBMMorph]+Br-
1 mmol of N-butyl bromide and 1 mmol of N-methyl morpholine were taken in 50 mL round bottom flask. This reaction mixture was heated in the sand bath for 5 hours. The progress of the reaction was monitored by using TLC. The corresponding semi-solid product was obtained in appreciable yield which was further allowed to filter. The obtained product was kept in a sealed amberlite bottle. The structure of the product was confirmed by UV, IR, 1H and 13C NMR.
2.3 General Procedure for Synthesis of -5-Aryl-[1,2,4]Triazolidine-3Thiones Derivatives from Various Aldehyde
1 mmol of corresponding aldehyde and 1 mmol of thiosemicarbazide in ethanol were mixed in 25 mL round bottom flask. To the same mixture 10 mol% of synthesized acidic ionic liquid was added. The reaction mixture was allowed to stir for a specific time as mentioned in Table 1. To examine the movement of the reaction, the TLC method was used. After getting the confirmation from TLC about the completion of the reaction, the reaction mixture was added to ice-cold water, followed by rapid stirring. Then the product was separated by a simple filtration technique. After filtration the product was recrystallized with ethanol. The corresponding products were received in appreciable yield. The formation of expected product was confirmed by using IR and Melting point.
2.4 Antimicrobial Activity
All the synthesized compounds in the present work were examined for their biological activity such as antibacterial aspects of designed 5-aryl-[1,2,4]triazolidine-3-thiones derivatives from aldehyde on pseudomonas aeruginosa. The disc diffusion assay (Quantity per disc-10) method was used to determine the antibacterial properties & minimum inhibitory concentration (MIC) of different derivatives against gram-negative bacteria pseudomonas aeruginosa. The growth media was maintained at pH 6.7. All the derivatives show good results and exhibit antibacterial activities against tested microorganisms. The following conditions for the analysis include The Disc Diffusion Assay (Quantity per dise-10 μl) with inoculums used: 1 × 10 CFU/ml at incubation temperature: 37°C or the incubation Time of 24 hr in growth media of sterile nutrient agar at pH 6.7 against the bacterial culture of Pseudomonas aeruginosa [32,33,34].
3. Result and Discussion
3.1 Synthesis of Catalyst-Ionic Liquid – [NBMMorph]+Br-
Firstly we focused on the synthesis of catalyst by considering the advantages of morpholine, we decided to synthesize morpholine-based IL. First, we performed the reaction between Morpholine and N-butyl bromide at equimolar conditions. Scheme 1 shows a representation of the reaction between morpholine and N-butyl bromide. The reaction was carried out in a sand bath for 5 hours. The formation of desired IL was confirmed using spectral techniques, i.e., IR, 1H NMR (Figure 1) and 13C NMR (Figure 2). All the spectral data is in accordance with the structure.
Scheme 1 Synthesis of ionic liquid [NBMMorph]+Br–.
Figure 1 1H NMR of ionic liquid.
Figure 2 13C NMR of ionic liquid.
3.2 Synthesis of Target 1,2,4-Triazolidine-3-Thiones
After the successful synthesis of IL we used the reaction between various substituted aldehydes and thiosemicarbazide to deliver the expected target products of 1,2,4-triazolidine-3-thiones in ethanol using synthesized acidic IL as catalyst (Scheme 2) at room temperature.
Scheme 2 Synthesis of 1,2,4-triazolidine-3-thione derivatives at room temperature.
The detailed mechanism of formation of target thiones is discussed in brief herein and shown in Scheme 3. When catalytic amount of IL was added to the starting aldehyde it forms complexation because the hydrogen in –CH2 of morpholine near oxygen is more reactive. It forms a weak bond with the oxygen of carbonyl functionality in aldehyde. The highly soluble complexation indicates an increase in the charge on the oxygen of carbonyl moiety. Subsequently instability increase and the reactivity of the carbonyl group at the carbon center increases. Adding an equimolar quantity of thiosemicarbazide shows an attack of –NH2 (hydrazine side of thiosemicarbazide) on carbon of carbonyl functionality. In order to achieve stability, the cyclization plays a pivotal role in forming a five-membered ring structure by the attack of –NH2 (amine side of thiosemicarbazide) on carbon by leaving the homogeneous (hydrophilic) IL in the last step of reaction work-up. The proposed mechanism for the transformation is given in Scheme 3.
Scheme 3 Proposed mechanism for the synthesis of 1,2,4-triazolidine-3-thione.
Initially, optimizing the reaction conditions for the synthesis of target compounds was crucial. In order to achieve the optimization of reaction conditions, we studied the reaction of anisaldehyde (1 mmol) and thiosemicarbazide (1 mmol) as the model reaction. The catalyst screening was done using various acidic catalysts such as sulphuric acid, p-TSA, CAN and synthesized ionic liquid [NBMMorph]+Br- at room temperature (Table 2, entries 1-6). When H2SO4, p-TSA and CAN (Table 2, entries 1-3) were used as catalysts (20 mol%), we found that the time required to complete the reaction was significant and the yield of the product was low compared to the same loading of synthesized IL. However, loading the same 20 mol% of synthesized IL for the same reaction approach delivers superior results for the reaction time of 30 minutes along with about 78% product yield. Hence, we conclude that satisfyingly superior catalytic activity was found in the case of synthesized ionic liquid with excellent product yield in a short period of reaction time as compared with the other catalytic conditions.
Further, optimizing IL loading by varying its amount (Table 2, entries 4-6) suggests that lesser reaction time and excellent product yield could be obtained under only 10 mol% loading of synthesized IL to drive the reaction forward (Table 2, entry 5). However, an increase in the amount of catalyst to 20 mol% indicates a slight decline in the product yield but the time to complete the transformation remains comparably the same (Table 2, Entries 4). Hence, it was concluded that to perform the present organic transformation, only 10 mol% of synthesized IL is enough as a catalyst.
The generality of the protocol was then investigated using a variety of aldehydes (Table 1, Entries 1-10). It was noted that whatever the nature of the substituent on the aldehyde, it furnished the expected substituted -5-aryl- [1,2,4]triazolidine-3thiones in good yields within a short reaction time. The reaction was also carried out using heterocyclic aldehyde, i.e., furfuraldehyde (Table 1, Entry 8). This reaction proceeded well with an excellent yield of the desired product. The structure of all the synthesized products has been confirmed by IR and by comparing the melting points with available literature.
As 1,2,4 triazole derivatives are biologically important, we were interested in studying the biological importance of synthesized compounds. Hence we have screened all the synthesized compounds for their antimicrobial activity.
3.3 Antimicrobial Activity
Antibacterial activity is the most important characteristic of medical materials, to provide adequate protection against microorganisms, biological fluids, and aerosols, as well as disease transmission [10,11,12,13,14,15,16,17,18]. We have tested all synthesized derivatives of -5-aryl-[1,2,4]triazolidine-3thiones for the antimicrobial activity using disc diffusion assay as protocol (Figures 3A and 3B) and the results obtained are interpreted in Table 3. The antimicrobial activity is proven by observing the zone of inhibition. All the samples exhibited exceptional antimicrobial activity. Out of these R6D indicated fewer inhibitions zone. The compound R6D has phenolic -OH and methoxy group –OCH3. The bacteria pseudomonas aeruginosa resists this derivative.
Figure 3 Test of antibacterial activity using disc diffusion assay (quantity per disc -10 µ) A) for R8D, B) for all synthesized 5-aryl-[1,2,4]triazolidine-3-thiones.
R8D shows significant results. It shows more inhibitions zone (Figure 3). R8D is a compound having a furan ring in its structure. In this report, wet disc assay and agar well diffusion assay results were compared testing the susceptibility of Pseudomonas aeruginosa. Based on the results it can be concluded that all the samples showed admirable antibacterial activity.
Herein we have synthesized an efficient and versatile IL ([NBMMorph]+Br-) based catalyst for the preparation of 5-aryl-[1,2,4]triazolidine-3-thiones. The formation of synthesized IL was confirmed by well know own spectroscopic techniques such as IR, NMR and Mass analysis. Compared to the hazardous catalyst, synthesized IL shows a superior response in terms of reaction time and yield of products. The derivatives of triazolidinediones were successfully derived by using IL as a catalyst in the present proposed protocol which signifies ease in workup procedures, lesser reaction time and a high yield of products. The derived all thiones derivatives were examined for their antibacterial properties using the disc diffusion method. Surprisingly, it was found that all the derived derivatives of thiones show excellent antibacterial properties against Pseudomonas aeruginosa with minimum inhibition concentration. To conclude, the merits of the present research work are the modified approach of synthetic protocol, synthesized bromide functionalized IL, and antibacterial properties of derived thiones. The biological properties of synthesized compounds could open a new window for the further application of these derivatives in pharmaceuticals, paint industries, agrochemicals, etc.
Randive CS, Tamhane OS and Ghorpade RS performed experimental part. Dr. S. R, Kale, Dr. N. C. Dige and Dr. P. G. Mahajan discussed analysis of results. Dr. P. G. Mahajan and Dr. N. C. Dige designed proposed work, analysis of results and writing.
The authors have declared that no competing interests exist.
The following additional materials are uploaded at the page of this paper.
- Dige NC, Mahajan PG, Pore DM. Serendipitous formation of novel class of dichromeno pyrano pyrimidinone derivatives possessing anti-tubercular activity against M.tuberculosis H37Rv. Med Chem Res. 2018; 27: 224-233. [CrossRef]
- Dige NC, Korade SN, Pore DM. Design of task-specific ionic liquid, 1-(ethylaceto acetate)-1-(2-hydroxyethyl) piperidinium tetrachloroaluminate for multicomponent synthesis of 3,3′-disubstituted oxindoles. Res Chem Intermed. 2017; 43: 7029-7040. [CrossRef]
- Dige NC, Pore DM. Green aspect for multicomponent synthesis of spiro[4Hindeno[1,2-b]pyridine-4,3′-[3H]indoles]. Synth Commun. 2015; 45: 2498-2510. [CrossRef]
- Mahajan PG, Dige NC, Vanjare BD, Raza H, Hassan M, Seo SY, et al. Synthesis and studies of fluorescein based derivatives for their optical properties, urease inhibition and molecular docking. J Fluoresc. 2018; 28: 1305-1315. [CrossRef]
- Mahajan PG, Dige NC, Suryawanshi SB, Dalavi DK, Kamble AA, Bhopate DP, et al. FRET between riboflavin and 9-anthraldehyde based fluorescent organic nanoparticles possessing antibacterial activity. J Fluoresc. 2018; 28: 207-215. [CrossRef]
- Mahajan PG, Dige NC, Vanjare BD, Phull AR, Kim SJ, Hong SK, et al. Synthesis, photophysical properties and application of new porphyrin derivatives for use in photodynamic therapy and cell imaging. J Fluoresc. 2018; 28: 871-882. [CrossRef]
- Maddila S, Pagadala R, Jonnalagadda SB. 1,2,4-Triazoles: A review of synthetic approaches and the biological activity. Lett Org Chem. 2013; 10: 693-714. [CrossRef]
- Maddila SN, Maddila S, Gangu KK, Zyl WE, Jonnalagadda SB. Sm2O3/Fluoroapatite as a reusable catalyst for the facile, green, one-pot synthesis of triazolidine-3-thione derivatives under aqueous conditions. J Fluor Chem. 2017; 195: 79-84. [CrossRef]
- Palaska E, Şahin G, Kelicen P, Durlu NT, Altinok G. Synthesis and anti-infammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones. Il Farmaco. 2002; 57: 101-107. [CrossRef]
- Varvaresou A, Siatra-Papastaikoudi T, Tsotinis A, Tsantili-Kakoulidou A. Synthesis, lipophilicity and biological evaluation of indole-containing derivatives of 1,3,4-thiadiazole and 1,2,4-triazole. Il Farmaco. 1998; 53: 320-326. [CrossRef]
- Jin JY, Zhang LX, Zhang AJ, Lei XX, Zhu JH. Synthesis and biological activity of some novel derivatives of 4-amino-3-(D-galactopentitol-1-yl)-5-mercapto-1,2,4-triazole. Molecules. 2007; 12: 1596-1605. [CrossRef]
- Dogan HN, Duran A, Rollas S. Synthesis and preliminary anticancer activity of new 1H-4,5-dihydro-3-(3-hydroxy-2-naphthyl)-4-substituted-1,2,4-triazoline-5-thiones. Part II. Indian J Chem Sect B. 2005; 44: 2301-2307. [CrossRef]
- Kumar GVS, Prasad YR, Mallikarjuna BP, Chandrashekar SM. Synthesis and pharmacological evaluation of clubbed isopropylthiazole derived triazolothiadiazoles, triazolothiadiazines and mannich bases as potential antimicrobial and antitubercular agents. Eur J Med Chem. 2010; 45: 5120-5129. [CrossRef]
- Li Z, Gu Z, Yin K, Zhang R, Deng Q, Xiang J. Synthesis of substituted-phenyl-1,2,4-triazol-3-thione analogues with modified d-glucopyranosyl residues and their antiproliferative activities. Eur J Med Chem. 2009; 44: 4716-4720. [CrossRef]
- Colanceska-Ragenovic K, Dimova V, Kakurinov V, Molnar DG, Buzarovska A. Synthesis, antibacterial and antifungal activity of 4-substituted-5-aryl-1,2,4- triazoles. Molecules. 2001; 6: 815-824. [CrossRef]
- Salgın-Gökşen U, Gökhan-Kelekçi N, Göktaş Ö, Köysal Y, Kılıç E, Işık Ş, et al. 1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones, 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones: Synthesis, analgesic-anti-infammatory and antimicrobial activities. Bioorg Med Chem. 2007; 15: 5738-5751. [CrossRef]
- Demirbas N, Karaoglu SA, Demirbas A, Sancak K. Synthesis and antimicrobial activities of some new 1-(5-phenylamino-[1,3,4]thiadiazol-2-yl) methyl-5-oxo-[1, 2,4]triazole and 1-(4-phenyl-5-thioxo-[1,2,4]triazol-3-yl) methyl-5-oxo-[1,2,4] triazole derivatives. Eur J Med Chem. 2004; 39: 793-804. [CrossRef]
- Modak A, Barui AK, Patra CR, Bhaumik A. A luminescent nanoporous hybrid material based drug delivery system showing excellent theranostics potential for cancer. Chem Commun. 2013; 49: 7644-7646. [CrossRef]
- Al-Soud YA, Al-Dweri MN, Al-Masoudi NA. Synthesis, antitumor and antiviral properties of some 1,2,4-triazole derivatives. Il Farmaco. 2004; 59: 775-783. [CrossRef]
- Modak A, Ghosh A, Mankar AR, Pandey A, Selvaraj M, Pant KK, et al. Cross-linked porous polymers as heterogeneous organocatalysts for task-specific applications in biomass transformations, CO2 fixation and asymmetric reactions. ACS Sustain Chem Eng. 2021; 9: 12431-12460. [CrossRef]
- Modak A, Jana S. Advancement in porous adsorbents for post-combustion CO2 capture. Microporous Mesoporous Mater. 2019; 276: 107-132. [CrossRef]
- Bohre A, Modak A, Chourasia V, Jadhao PR, Sharma K, Pant KK. Recent advances in supported ionic liquid catalysts for sustainable biomass valorization to high-value chemicals and fuels. Chem Eng J. 2022; 450: 138032. [CrossRef]
- Cioc RC, Ruijter E, Orru RV. Multicomponent reactions: Advanced tools for sustainable organic synthesis. Green Chem. 2014; 16: 2958-2975. [CrossRef]
- Capello C, Fischer U, Hungerbühler K. What is a green solvent? A comprehensive framework for the environmental assessment of solvents. Green Chem. 2007; 9: 927-934. [CrossRef]
- Mahajan PG, Dige NC, Vanjare BD, Raza H, Hassan M, Seo SY, et al. Synthesis and biological evaluation of 1,2,4-triazolidine-3-thiones as potent acetylcholinesterase inhibitors: In vitro and in silico analysis through kinetics, chemoinformatics and computational approaches. Mol Divers. 2020; 24: 1185-1203. [CrossRef]
- Taslimi P, Osmanova S, Gulçin I, Sardarova S, Farzaliyev V, Sujayev A, et al. Discovery of potent carbonic anhydrase, acetylcholinesterase, and butyrylcholinesterase enzymes inhibitors: The new amides and thiazolidine-4-ones synthesized on an acetophenone base. J Biochem Mol Toxicol. 2017; 31: e21931. [CrossRef]
- Pagliai F, Pirali T, Del Grosso E, Di Brisco R, Tron GC, Sorba G, et al. Rapid synthesis of triazole-modified resveratrol analogues via click chemistry. J Med Chem. 2006; 49: 467-470. [CrossRef]
- Witkowski JT, Robins RK, Khare GP, Sidwell RW. Synthesis and antiviral activity of 1,2,4-triazole-3-thiocarboxamide and 1,2,4-triazole-3-carboxamidine ribonucleosides. J Med Chem. 1973; 16: 935-937. [CrossRef]
- Thakur M, Pandey S, Mewada A, Patil V, Khade M, Goshi E, et al. Antibiotic conjugated fluorescent carbon dots as a theranostic agent for controlled drug release, bioimaging, and enhanced antimicrobial activity. J Drug Deliv. 2014; 2014: 282193. [CrossRef]
- Kumar VB, Natan M, Jacobi G, Porat ZE, Banin E, Gedanken A. Ga@C-dots as an antibacterial agent for the eradication of pseudomonas aeruginosa. Int J Nanomed. 2017; 12: 725-730. [CrossRef]
- Selvaraju N, Ganesh PS, Palrasu V, Venugopal G, Mariappan V. Evaluation of antimicrobial and antibiofilm activity of Citrus medica fruit juice based carbon dots against Pseudomonas aeruginosa. ACS Omega. 2022; 7: 36227-36234. [CrossRef]
- Bakunov SA, Bakunova SM, Wenzler T, Ghebru M, Werbovetz KA, Brun R, et al. Synthesis and antiprotozoal activity of cationic 1,4-diphenyl-1H-1,2,3-triazoles. J Med Chem. 2010; 53: 254-272. [CrossRef]
- Alvarez R, Velazquez S, Felix AS, Aquaro S, Clercq DE, Perno FC, et al. 1,2,3-Triazole-[2,5-Bis-O-(tert-butyldimethylsilyl)-.beta.-D-ribofuranosyl]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole 2″,-2″-dioxide) (TSAO) analogs: Synthesis and Anti-HIV-1 activity. J Med Chem. 1994; 37: 4185-4194. [CrossRef]
- Sonawane AD, Rode ND, Nawale L, Joshi RR, Joshi RA, Likhite AP, et al. Synthesis and biological evaluation of 1,2,4-triazole-3-thione and 1,3,4-oxadiazole-2-thione as antimycobacterial agents. Chem Biol Drug Des. 2017; 90: 200-209. [CrossRef]