Nano-NiFe₂O₄ as a versatile and recyclable catalyst: an efficient protocol for the synthesis of aryl-1,2,4-triazolidine-3-thiones under ball milling conditions

Abstract

In this research, the catalytic efficiency of nano-NiFe₂O₄ is examined in the production of aryl-1,2,4-triazolidine-3-thiones under ball-milling conditions. The reactions of thiosemicarbazides with a range of substrates, such as aryl and heteroaryl aldehydes, have been effectively shown to give the corresponding aryl-1,2,4-triazolidine-3-thiones under solvent-free conditions in a ball-milling method. This process is characterised by high EcoScale values and a relatively low E-factor. The methodology outlined in the present study follows the concepts of green chemistry, which include optimized ball milling conditions, shortened reaction times, increased product yields, recyclability of the catalyst, and high atom economy.

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1 Introduction

Heterocyclic compounds are some of the most intriguing and important classes of organic molecules because of their abundance in a large range of natural products, pharmaceuticals, agrochemicals and functional materials.^1–3 Heterocycles containing nitrogen and sulphur have attracted a lot of attention due to their extensive range of biological functions and chemical reactivity.^4,5 Triazole and triazolidine analogues play a major role in medicinal chemistry because their structural alterations can have a considerable impact on their biological response.^6a–d–8 Green, safe and friendly synthetic procedures have been developed to suit the ever-growing requirement of structurally varied, physiologically active heterocyclic compounds.^9,10

The aryl-1,2,4-triazolidine-3-thione nucleus, a reduced form of 1,2,4-triazole containing a thiocarbonyl (C=S) group, is very important in hydrogen bonding and biological interactions and the coordination of metals.^11a,b,12 Pharmacological activities of compounds with this moiety are excellent, and they consist of antifungal, antiviral, anticancer, antituberculous, and antimicrobial activities.^13–17 Sulphur and nitrogen make them more lipophilic, thereby enhancing their biological target binding capacity (Fig. 1). They are thus good alternatives when designing new drugs.^18a,b

Fig. 1 A few compounds with 1,2,4-triazole groups that have pharmacological activity.

Biological activity is enhanced by the change in electronic and steric properties of the triazolidine ring at the position of the 5-aryl group.¹⁹ Electron-contributing or withdrawing substituents of the aryl ring influence membrane permeability, receptor affinity and stability of metabolites.^20,21 Consequently, substituted-5-aryl-1, 2,4-triazolidine-3-thiones have emerged as interesting models in the development of new medicines.²² Many investigations have demonstrated the high antimicrobial and antifungal effects of substituted triazolidine-3-thione analogs.^23,24 Some of the derivatives have a profound inhibitory effect on the growth of many species of Aspergillus, Candida albicans, Staphylococcus aureus and Escherichia coli.²⁵ The thiocarbonyl group is believed to interfere with the enzyme systems of the microbes through chelation or covalent interaction.²⁶

These compounds have also been found to exhibit potent anticancer effects on a broad range of human cancer cell lines, including liver, colon, breast and lung cancer cell lines.²⁷ Their action mechanism is frequently to induce cell death, arrest the cell cycle and inhibit enzymes that promote tumour growth.²⁸ The heterocyclic structure acts as an antioxidant to remove free radicals and alleviate oxidative stress, which are two conditions associated with chronic diseases such as cancer and neurological disorders.²⁹

Moreover, 1,2,4-triazolidine-3-thione analogs are used as anti-inflammatory and analgesic agents in blocking the COX (cyclooxygenase) and lipoxygenase (LOX) pathways.³⁰ Some derivatives have been proven to be effective against TB and viruses, which points to the importance of this scaffold in medicine.^31–33 The variety of exemplified biological activities highlights the necessity to develop effective synthetic approaches for the production of a broad selection of substituted derivatives.

The significance of the synthesis of substituted triazolidine-3-thiones has been associated with the challenges of long reaction time, harsh conditions, excessive use of solvents, low yield, and the inability to reuse catalysts, which are associated with conventional methods used in the synthesis of substituted triazolidine-3-thiones.³⁴ Conventional heating systems demand high temperatures and long reflux periods, which consume more energy and thus lead to adverse environmental effects.³⁵

The identified limitations are contrasted with the concepts of green chemistry, which strongly focus on utilizing non-toxic reagents, increased energy efficiency, minimized waste, and recyclable catalysts, which is apparent in the area of sustainable chemistry.^36,37 As a result, new synthetic approaches, which will be both environmentally friendly and economically viable, must be developed without affecting the efficiency of operations or the range of product diversification.

Mechanochemistry, of which the key modality is that of ball milling, has become a powerful and sustainable approach to the synthesis of organic compounds.^38,39 In ball milling, chemical transformations occur through the mechanical energy generated as the collisions between the milling media and the reactants take place.⁴⁰ This leads to solvents being either obviated or restricted to small amounts. Such a solvent-reducing strategy is in line with the values of green chemistry and has received significant academic interest in the past few years.^41,42

The benefits of ball milling compared to traditional solution-phase synthesis are an increase in the reaction rate, improved yields, increased selectivity, and ease of operation. Besides, mechanochemical reactions often occur at room temperature, reducing energy use, thus avoiding the need for harmful solvents.⁴³ The mentioned features make ball milling an attractive method in the production of biologically relevant heterocyclic substances.⁴⁴

The combination of nanocatalysis and mechanochemistry makes organic changes more sustainable and efficient to a significant extent.⁴⁵ Nanocatalysts have more active sites, a greater surface-to-volume ratio and more catalytic activity than their bulk counterparts.⁴⁶ Magnetic ferrite nanoparticles, including NiFe₂O₄, are especially an appealing type of nanomaterial; recently, they have been receiving extensive attention because of their high thermal stability, easy magnetic separation, and productive catalytic capabilities.^47,48

Spinel ferrite nanostructured NiFe₂O₄ has better magnetic properties, chemical inertness and reusability.⁴⁹ As a result, filtration or centrifugation processes are not required, since the material can be easily removed from the reaction mixtures using an external magnetic field. In addition, NiFe₂O₄ can also be used as an environmentally friendly catalyst, and the magnetic recoverability of the NiFe₂O₄ catalyst significantly reduces the loss of catalyst and makes it easy to recycle it.⁵⁰

Additionally, the solvent-less ball milling process yields remarkably pure goods with no environmental impact.⁵¹ The fact that the catalyst may be magnetically retrieved and reused without any activity loss demonstrates its economic and environmental benefits.⁵²

In addition, the solvent-free ball-milling process produces extremely pure products that do not have any effect on the environment.⁵¹ The economic and environmental benefits of the catalyst can be seen in the fact that the catalyst can be easily reused and recovered through a magnetic process without any significant activity loss.⁵² Scheme 1 shows the previously reported synthesis of substituted aryl-1,2,4-triazolidine-3-thione scaffolds.^53–60

Scheme 1 Some previously reported substituted aryl-1,2,4-triazolidine-3-thiones.

This study aims to come up with a solvent-free mechanochemical reaction that makes use of nickel ferrite (NiFe₂O₄) nanoparticles as a recycling catalyst under ball-milling conditions for the formation of substituted-5-aryl-1,2,4-triazolidine-3-thiones, essential biological scaffolds that are progressively being synthesized using green chemistry (Scheme 2). This strategy would have offered a more efficient, green and fast alternative path to synthesis instead of dealing with the constraints of the traditional processes.

Scheme 2 Synthesis of 5-aryl-1,2,4-triazolidine-3-thiones.

Synthetic compounds have considerable potential in pharmacological studies to be conducted in the future due to the anticipated high level of biological activity. This innovation opens up the frontiers of medicinal chemistry by merging mechanochemistry and magnetic nanocatalysts, making it possible to conduct sustainable heterocyclic synthesis.

The use of nanoscale NiFe₂O₄ as a heterogeneous catalyst using ball-milling conditions has been proven to be an innovative, environmentally benign methodology of synthesizing substituted-5-aryl-1,2,4-triazolidine-3-thione scaffolds. Typically, the activation of the functional groups found in the reactants and the facilitation of the intermolecular interactions are two synergistic processes that lead to bond formation through the collaboration of mechanical energy and nanocatalysis. These increases in yield and decrease in reaction time can be ascribed to the fact that the NiFe₂O₄ nanoparticles have surface Lewis acid sites that aid in both the process of condensation and cyclization.

2 Experimental section

2.1 Materials and methods

Chemicals needed were purchased from SRL, TCI, and ANCOTT and used without further purification. A Retsch agate grinding jar (250 mL) and planetary ball mill 100 (01.462.0220) have been used. Physical and chemical characterisation of all the identified products showed properties that were practically identical to those of the actual materials as demonstrated by ¹HNMR, ¹³CNMR, FT-IR, and mass spectral characterisation. The melting points were determined with the help of a B-540. The data were collected using Bruker Avance Neo spectrometers at 500 MHz (SAIF, Chandigarh, India), and high-resolution mass spectrometry (HRMS) was also done. The FT-IR spectra were recorded using a SHIMADZU at R. T. M. Nagpur University, Nagpur.

2.2 Method for the preparation of NiFe₂O₄

The NiFe₂O₄ nanoparticles were synthesised via a straightforward sol–gel method⁶¹ using readily available precursors: ferric chloride (FeCl₃·6H₂O), nickel chloride (NiCl₂·6H₂O), distilled water, and sodium hydroxide. In the typical procedure, a 0.2 M ferric chloride solution (20 mL) and a 0.1 M nickel chloride solution (20 mL) were prepared and mixed under vigorous stirring for 2 hours at 80 °C. Subsequently, 0.3 M NaOH was incrementally added until the pH reached 12, resulting in the formation of brown precipitates. The precipitates were then isolated through centrifugation and dried in a hot air oven for 4 hours at 100 °C, followed by calcination at 550 °C for 6 hours.

2.3 General procedure for synthesis of 5-aryl-1,2,4-triazolidine-3-thione scaffolds

2.3.1 Representative procedure for 5-phenyl-1,2,4-triazolidine-3-thione (3a, Table 5). Ball-milling was carried out using a 25 mL stainless steel beaker at a rotation rate of 600 rpm and took place for 30 minutes using six milling balls with a nominal diameter of 1/4 10 mm. In this process, nano-NiFe₂O₄ (10 mol%, 23.44 mg) as a catalyst was added to benzaldehyde 1a (1.0 mmol, 106.12 mg) and thiosemicarbazide (1 mmol, 91.14 mg)/4-methylthiosemicarbazide (1 mmol, 105.17 mg). The operation of ball-milling was carried out by reversing directions of rotation, with a 30-second pause between consecutive sessions of milling. After the reaction was complete, an external magnet was used to collect the NiFe₂O₄ nanoparticles out of the reaction medium. The crude product (3a) was then recrystallized using ethanol. The recovered nano-NiFe₂O₄ was washed with a solution of ethanol and water, 1 : 1, after which it was dried in a hot-air oven at 60 °C for 1 hour. The catalyst was dried and reused in subsequent cycles of reaction.

3 Results and discussion

The powder XRD pattern (Fig. 2) indicates that the Bragg reflection peaks correspond to the face-centered cubic structure of NiFe₂O₄, classified under the Fd3m space group (JCPDS file No. 10-0325). The diffraction peaks at 30.35°, 35.76°, 37.38°, 43.44°, 53.93°, 57.44°, and 63.11° are associated with the {220}, {311}, {222}, {400}, {422}, {511}, and {440} planes of NiFe₂O₄, respectively. The average particle size, estimated using the Scherrer formula with XRD plane 311, is determined to be 21.98 nm. The high-resolution transmission electron microscopy (HRTEM) picture in Fig. 3(a) demonstrates the creation of spherical nano-NiFe₂O₄ with an average particle size of 27.21 nm, as shown in the histogram in Fig. 3(b). The selected area electron diffraction (SAED) pattern in Fig. 3(c) demonstrates the development of face-centered cubic spinel nano-NiFe₂O₄, with the corresponding planes {440}, {422}, {400}, {220}, and {311} accurately indexed, corroborating the findings from X-ray diffraction (XRD).

Fig. 2 The powder XRD pattern of nano-NiFe₂O₄.

Fig. 3 HRTEM (a), histogram (b) and SAED pattern (c) of nano-NiFe₂O₄.

The magnified HRTEM picture (Fig. 4) of NiFe₂O₄ nanoparticles reveals lattice fringes with a spacing of 0.255 nm, corresponding to the (311) plane of NiFe₂O₄. The EDAX analysis (Fig. 5) reveals that the substance contains Fe, Ni, and O, with no other elements detected. The SEM picture of NiFe₂O₄ corroborated the presence of spherical particles (Fig. 6).

Fig. 4 Image of nano-NiFe₂O₄ displaying lattice fringes, magnified by HRTEM.

Fig. 5 EDS image of nano-NiFe₂O₄.

Fig. 6 SEM image of nano-NiFe₂O₄.

An inherent stretching vibration at 630 and 532 cm⁻¹ was attributed to the tetrahedral site of ferrite (Fe–O), whereas 873 cm⁻¹ was allocated to the Fe–OH group, as found in the FT-IR spectrum of nano-NiFe₂O₄ (Fig. 7).

Fig. 7 FTIR spectrum of nano-NiFe₂O₄.

The subsequent investigation focused on optimizing the reaction conditions for the synthesis of 5-phenyl-1,2,4-triazolidine-3-thiones under ball milling conditions, as detailed in Table 1.

Table 1 Optimisation of reaction conditions^a

a Reaction conditions: benzaldehyde (1 mmol), thiosemicarbazide (1 mmol), solvent free, room temperature under ball-milling conditions (600 rpm), NR: not recovered.b Isolated yield.
Entry	Products (3a)	Catalyst/additives	Time (min)	Catalyst (mol%)	Yield (%)^b
1	Assembly (I)	NiFe2O4 NPs	15 min	5	35
2		NiFe2O4 NPs	20 min	5	41
3		NiFe2O4 NPs	25 min	5	44
4		NiFe2O4 NPs	30 min	5	57
5		NiFe2O4 NPs	35 min	5	59
6		NiFe2O4 NPs	40 min	5	63
7		NiFe2O4 NPs	45 min	5	66
8	Assembly (II)	NiFe2O4 NPs	15 min	10	78
9		NiFe2O4 NPs	20 min	10	81
10		NiFe2O4 NPs	25 min	10	88
11		NiFe2O4NPs	30 min	10	97
12		NiFe2O4 NPs	35 min	10	94
13		NiFe2O4 NPs	40 min	10	91
14		NiFe2O4 NPs	45 min	10	90
15	Assembly (III)	NiFe2O4 NPs	15 min	15	74
16		NiFe2O4 NPs	20 min	15	80
17		NiFe2O4 NPs	25 min	15	82
18		NiFe2O4 NPs	30 min	15	86
19		NiFe2O4 NPs	35 min	15	85
20		NiFe2O4 NPs	40 min	15	83
21		NiFe2O4 NPs	45 min	15	81
22	Assembly (IV)	NiFe2O4 NPs	50 min	10	88
23		NiFe2O4 NPs	55 min	10	85
24		NiFe2O4 NPs	60 min	10	83
25		NiFe2O4 NPs	60 min	15	87
26	Assembly (V)	CoFe2O4 NPs	30 min	10	22
27		CuFe2O4 NPs	30 min	10	25
28		Fe3O4 NPs	30 min	10	10
29		ZnFe2O4 NPs	30 min	10	22
30		No catalyst	30 min	—	NR

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The product yield (3a) in assembly (I) was noted to be only 35% when the reaction between benzaldehyde and thiosemicarbazide was conducted using 5 mol% of NiFe₂O₄ NPs for a duration of 15 minutes under ball milling conditions at 600 rpm (entry 1, Table 1). As the reaction time is extended up to the range of 20 minutes to 45 minutes, the yield of product (3a) exhibits a gradual increase, from 41% to 66% (entry 2 to entry 7, Table 1), respectively.

It was found that the product yield (3a) in assembly (II) was only 78% when the reaction between benzaldehyde and thiosemicarbazide was conducted in the presence of 10 mol% of NiFe₂O₄ NPs in 15 minutes under ball milling conditions at 600 rpm (entry 8, Table 1). The longer the period of the reaction (20 minutes to 45 minutes), the higher the proportion of product (3a) in the reaction (entry 9 to entry 14, Table 1).

When 15 mol% of NiFe₂O₄ NPs was used to carry out the reaction between the benzaldehyde and thiosemicarbazide under 15 minutes of ball milling at 600 rpm (entry 15, Table 1), the product yield (3a) in assembly (III) was found to be only 74%. With an extended reaction period of a range of 20–45 minutes, there is a gradual increase in the yield of product 3a to 80 and 81 percent (entry 2 to entry 7, Table 1).

Upon extending the reaction time to 30 minutes and employing 10 mol% of NiFe₂O₄ nanoparticles as a catalyst, a maximum yield of 97% for product (3a) is achieved, as indicated in (entry 11, Table 1). Upon extending the reaction time to 50 min, 55 min, and 60 min in assembly (IV), a corresponding decrease in product yield was observed, with yields of 88%, 85%, and 83% respectively (entries 22, 23, and 24, Table 1).

The investigation of the same reaction utilizing various catalysts, specifically 10 mol% of CoFe₂O₄ NPs, CuFe₂O₄ NPs, Fe₃O₄ NPs, and ZnFe₂O₄ NPs, conducted for a duration of 30 minutes under ball milling conditions at 600 rpm i.e. optimised reaction conditions, reveals that no significant enhancement in the yield of product (3a) is noted (entry 26 to entry 29, Table 1). The reaction was not observed in the absence of a catalyst (entry 30, Table 1).

Analysis of the results presented in Table 1 indicates that NiFe₂O₄ nanoparticles exhibit superior catalytic activity for the formation of product (3a) when compared to CoFe₂O₄ nanoparticles, CuFe₂O₄ nanoparticles, Fe₃O₄ nanoparticles, and ZnFe₂O₄ nanoparticles. In this study, NiFe₂O₄ nanoparticles were chosen as a catalyst for the synthesis of 5-aryl-1,2,4-triazolidine-3-thiones under ball milling conditions.

Following the optimization of catalytic loading, the yield of the product (3a) was assessed at varying catalytic mol% and rpm under ball milling conditions (Table 2). The results indicate that the maximum yield of the product (3a) was achieved with 10 mole% of nano-NiFe₂O₄ at a rotational speed of 600 rpm (entry 6, Table 2).

Table 2 Effect of reaction conditions on the yield of 3a

Entry	Catalyst	Catalyst (mole%)	Time (min)	Rotation (rpm)	Yield (%) ^a
a Isolated yield, model reaction (3a): benzaldehyde (1.0 mmol), thiosemicarbazide (1.0 mmol) under ball milling conditions.
1	NiFe2O4 NPs	5	30	400	51
2	NiFe2O4 NPs	5	30	500	54
3	NiFe2O4 NPs	5	30	600	57
4	NiFe2O4 NPs	10	30	400	95
5	NiFe2O4 NPs	10	30	500	96
6	NiFe2O4NPs	10	30	600	97
7	NiFe2O4 NPs	15	30	400	83
8	NiFe2O4 NPs	15	30	500	84
9	NiFe2O4 NPs	15	30	600	86
10	NiFe2O4 NPs	20	30	400	88
11	NiFe2O4 NPs	20	30	500	91
12	NiFe2O4 NPs	20	30	600	93

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In order to assess the effects of ball milling, a conventional reaction was performed. In a 25 mL round bottom flask, 1 mmol of benzaldehyde and 1 mmol of thiosemicarbazide were subjected to reflux in a solvent mixture of ethanol and water (1 : 1), utilizing 5–20 mole% of various NiFe₂O₄ nanoparticles as a catalyst (Table 3). Product (3a) was yielded by the reaction, but the yield was less than that of the ball milling conditions (see entry 11, Table 1). The reaction was not observed in the absence of a catalyst, and therefore, the product was not obtained in this control experiment (entry 30, Table 1).

Table 3 Comparison of nano-NiFe₂O₄-catalyzed conventional methodologies for the synthesis of 3a

Entry	Catalyst	Catalyst (mol%)	Reaction conditions	Time (min)	Yield (%) ^a
a Isolated yield, model reaction (3a): benzaldehyde (1.0 mmol), thiosemicarbazide (1.0 mmol) under conventional conditions, NR: not recovered.
1	NiFe2O4 NPs	5	Reflux/EtOH : H2O (1 : 1)	30	22
2	NiFe2O4 NPs	5	Reflux/EtOH : H2O (1 : 1)	60	30
3	NiFe2O4 NPs	5	Reflux/EtOH : H2O (1 : 1)	90	38
4	NiFe2O4 NPs	5	Reflux/EtOH : H2O (1 : 1)	120	43
5	NiFe2O4 NPs	10	Reflux/EtOH : H2O (1 : 1)	30	50
6	NiFe2O4 NPs	10	Reflux/EtOH : H2O (1 : 1)	60	55
7	NiFe2O4 NPs	10	Reflux/EtOH : H2O (1 : 1)	90	57
8	NiFe2O4 NPs	10	Reflux/EtOH : H2O (1 : 1)	120	56
9	NiFe2O4 NPs	15	Reflux/EtOH : H2O (1 : 1)	30	52
10	NiFe2O4 NPs	15	Reflux/EtOH : H2O (1 : 1)	60	54
11	NiFe2O4 NPs	15	Reflux/EtOH : H2O (1 : 1)	90	56
12	NiFe2O4 NPs	15	Reflux/EtOH : H2O (1 : 1)	120	55
13	NiFe2O4 NPs	20	Reflux/EtOH : H2O (1 : 1)	30	50
14	NiFe2O4 NPs	20	Reflux/EtOH : H2O (1 : 1)	60	51
15	NiFe2O4 NPs	20	Reflux/EtOH : H2O (1 : 1)	90	49
16	NiFe2O4 NPs	20	Reflux/EtOH : H2O (1 : 1)	120	52
17	No catalyst	—	Reflux/EtOH : H2O (1 : 1)	90	NR

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We have investigated the methods for the synthesis of a library of 5-aryl-1,2,4-triazolidine-3-thiones (3a–3n) utilizing optimum reaction conditions and a combination of thiosemicarbazide/4-methylthiosemicarbazide and different substituted aromatic aldehydes under ball milling conditions (Scheme 3). The reactions exhibited high levels of cleanliness, with yield percentages ranging from 86% to 98%. Upon completion of the reaction, the catalyst, in the form of nanoparticles (NPs), was isolated utilizing an external magnetic field. Subsequently, the NPs were subjected to washing with a mixture of ethanol and water in a 1 : 1 ratio, followed by drying in a hot-air oven at 60 °C for a duration of 1 hour. The catalyst was then prepared for reuse in subsequent reactions. The synthesized products were further purified through washing with ethanol, resulting in analytically pure products. The synthesized products are subsequently validated through spectroscopic techniques, including FTIR, ¹H NMR, ¹³C NMR, and HRMS (refer to the SI file).

Scheme 3 Synthesis of substituted 5-aryl-1,2,4-triazolidine-3-thiones (3a–3n). Reaction conditions: a mixture of 1a (1 mmol), 2 (1 mmol), and nano-NiFe₂O₄ (10 mol%). Yields refer to those of isolated products, EcoScale indices and atom economy respectively.

Subsequently, an investigation was conducted to examine the reusability and stability of the NiFe₂O₄ nanoparticles in the synthesis of product (3a). Upon completion of the reaction, the catalyst was separated using a strong external magnet, followed by washing with a 1 : 1 mixture of ethanol and water. Subsequently, the catalyst was dried in a hot air oven at 60 °C for 1 hour. The catalyst that was recovered was subsequently employed in the model reaction, resulting in the production of (3a) with a yield of 97%. The catalyst was successfully recovered and subjected to recycling on three additional occasions, demonstrating a modest variation in product yield under the optimized reaction conditions, as illustrated in Fig. 8. An illustration of the HRTEM and histogram of the recycled catalyst can be found in Fig. 9. The average size of the particles has been established as 28.10 nm, which suggests that the structural stability is high up to the fourth cycle.

Fig. 8 Reusability study of the NiFe₂O₄ NP catalyst in the synthesis of 3a.

Fig. 9 HRTEM (a) and the histogram (b) of reused nano-NiFe₂O₄.

Motivated by these findings, we directed our efforts towards expanding the applicability of the protocol to include cyclic ketones and aryl ketones for the synthesis of the corresponding 1,2,4-triazolidine-3-thiones under the optimized reaction conditions. Regrettably, the acquisition of the product is not feasible at this time. This observation may be attributed to the reduced electrophilic character of the carbonyl carbon in ketones.

The catalytic transformation of benzaldehyde (1a) and thiosemicarbazide (2) into 5-phenyl-1,2,4-triazolidine-3-thione (3a) with the help of nano-NiFe₂O₄ is shown in Scheme 4. The benzaldehyde carbonyl moiety is activated at the onset by interaction with the Lewis-acidic sites (Ni²⁺/Fe³⁺) available at the surface of the nanocatalyst. This coordination enhances the electrophilicity of the carbonyl carbon, thus making it more susceptible to nucleophilic attack by the terminal –NH₂ group of the thiosemicarbazide. The resultant dehydration gives an imine intermediate. The milling process promotes the separation of the liberated water with the mechanical forces acting on it and shifts the equilibrium of the condensation process to product synthesis without the need to apply external heat or organic solvents. These are then followed by intramolecular nucleophilic attack of the thiosemicarbazide nitrogen on the imine carbon, leading to ring closure. The resultant system is further subjected to tautomerization and rearrangement eventually affording the substituted-5-aryl-1, 2,4-triazolidine-3-thione.

Scheme 4 Plausible mechanistic pathway for synthesis of 5-phenyl-1,2,4-triazolidine3-thione.

In adherence to the principles of green chemistry, we assess various green parameters, including the EcoScale, E-factor, and atom economy, which serve to evaluate the greenness, efficiency, and sustainability of the reaction (refer to the SI file).

Green measuring tools like Eco-Scale and E-factor show that the mechanochemical protocol complies with the principles of green chemistry. The Eco-Scale, which is commonly used to determine the generality and operational simplicity of an approach, provides quantitative scores that describe the overall effectiveness of the process. The E-factor is a dimensionless measure that combines waste production with ancillary factors such as cost, safety, technological infrastructure, energy use and purification needs to give a holistic picture of the environmental impact. Table 4 shows the calculated values of the Eco-Scale of the synthesis of compounds (3a–3n). All the entries exceed a mark of 80, which supports a high sustainability rating of the procedure (see the SI; Table 4). These green metrics are calculated in detail in the SI; the E-factor of synthesizing compound (3a) is 0.13. Compared with a traditional thermal approach, the mechanochemical approach produced a better Eco-Scale value and a lower E-factor.

4 Conclusion

Finally, the direct and cost-effective preparation of 5-aryl-1,2,4-triazolidine-3-thione was made possible by the use of nano-NiFe₂O₄ in ball-milling reactions as a recyclable catalyst. The activation of the carbonyl functionality of the acidic Lewis site of nano-NiFe₂O₄ initiated a sequence of reactions, which was followed by condensation and then by the nucleophilic attack to accomplish ring closure. The current methodology enables high rates of transformations (30 min), high isolated yields (86–98%) and catalyst reusability; ball-milling allows high yielding protocols to be performed expeditiously.

Conflicts of interest

There are no conflicts to declare.

Data availability

All data that support the findings of this study are included in the article.

Supplementary information (SI) is available. See DOI: https://doi.org/10.1039/d6na00160b.

Acknowledgements

The author, P. V. Ledade, gratefully appreciates the Principal, SSES Amravati's Science College, Congress Nagar, Nagpur, for providing excellent research facilities and SAIF Chandigarh for NMR and HRMS analysis.

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