Novel Ionic Liquid-Functionalized Chitosan [DSIM][AlCl3] x -@CS: Synthesis, Characterization, and Catalytic Application for Preparation of Substituted Pyrazine Derivatives.

Pyrazines are renowned heterocyclic compounds that have played an important role in drug design and are part of many polycyclic compounds of biological and industrial significance. In this article, a novel chitosan-immobilized ionic liquid, [DSIM][AlCl3] x -@CS, has been synthesized easily at ambient temperature and used for catalyzing the synthesis of a series of biologically relevant pyrazine derivatives. The catalyst is well characterized by various techniques such as Fourier transform infrared spectroscopy, Raman spectroscopy, solid-state 13C MAS nuclear magnetic resonance, scanning electron microscopy/energy-dispersive X-ray, elemental mapping, transmission electron microscopy, powder X-ray diffraction, and thermal gravimetric analyses. The advantageous features of the present energy-sustainable methodology include high yield of product (>99%), shorter reaction time periods, and recyclability of the catalyst.

Introduction

Over the last few decades, the popularity of ionic liquids (ILs) has significantly increased because of their unique properties such as non-inflammability, non-volatility, low vapor pressure, high chemical and thermal stability, environmental compatibility, high selectivity, potential recoverability, greater selectivity, and so forth.[1] Because of these properties, ILs have been extensively employed in organic synthesis as green solvents and reagents,[2] catalysis,[3] electrochemistry,[4] and liquid–liquid extraction.[5] Many ILs, having a Brønsted acidic character, show useful characteristics of solid acids and mineral liquid acids. Because of these properties, these ILs have been designed to replace conventional mineral liquid acids, such as sulfuric acid and hydrochloric acid, in a variety of organic transformations.[6] Solvent-free synthesis using ILs has attracted considerable attention from a green chemistry view point.[7] Among the ILs, sulfonic acid-functionalized imidazolium salts have been used as homogeneous catalysts in various organic transformations such as protection of hydroxyl groups,[8] nitration of phenols,[9] synthesis of N-sulfonyl imines,[10] bis(indolyl)methanes,[11] benzimidazoles,[12] and so forth.

One of the major drawbacks of homogeneous catalysis using ILs is the use of excess of ILs as a solvent or a catalyst producing a large amount of waste materials. Moreover, disposal of these waste materials is extremely difficult which makes the overall process unacceptable from an environmental view point. To avoid the limitations of homogeneous catalysis involving ILs, various ILs have been immobilized on solid supports to combine the advantages of ILs and heterogeneous support materials.[13] For this, different support materials such as chitosan,[14] silica,[15] graphene oxide,[16] zeolite,[17] and so forth have been used so far to synthesize supported ILs as heterogeneous catalysts. Among the solid support materials, chitosan, a natural biopolymer, is an excellent support material because of its exclusive properties such as unique three-dimensional structure, biodegradable nature, chemical reactivity due to the presence of hydroxyl and amino groups, excellent chelating and mechanical properties, and so forth.[18] Particularly, IL-based catalysts have been widely used in various organic reactions such as Baeyer–Villiger reactions,[19] hydroformylation,[20] hydrogenation,[21] alkylations,[22] nitration,[20a] and acetal formation.[23] Moreover, IL-based materials have also found application in electrochemical detection of atrazine in wastewater,[24a] determination of rutin,[24b] determination of ceftizoxime,[24c] electrochemical sensing of ractopamine,[24d] sensing of raloxifene,[24e] and electrocatalytic oxidation of methanol.[24f]

Pyrazine constitutes an important class of nitrogen containing heterocyclic compounds that have been very much exploited for their interesting pharmaceutical and biological activities such as anti-thrombotic,[25] COX-2 inhibiting, and analgesic effects;[26] relaxing cardiovascular and uterine smooth muscles;[27] antifungal,[28a] antibacterial,[28a] antitubercular,[28a] anticancer,[28b] antimalarial,[29] and antimicrobial[30] properties, and so forth.

In view of our ongoing research on supported heterogeneous catalysts,[31] combining the advantages of IL and solid support materials, we, herein, report an efficient method for the synthesis of a chitosan-supported IL, [DSIM][AlCl3]–@CS, at ambient temperature. The supported IL has been studied for its catalytic activity by synthesizing a library of biologically important pyrazines.

Results and Discussion

Synthesis and Characterization of the Catalyst

The catalyst, [DSIM][AlCl3]–@CS, was synthesized as outlined in Scheme and well-characterized by various techniques such as Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, solid-state 13C MAS NMR, scanning electron microscopy/energy-dispersive X-ray (SEM/EDX), elemental mapping, transmission electron microscopy (TEM), powder X-ray diffraction (XRD), and thermal gravimetric analysis (TGA).

Scheme 1

Synthesis of the Catalyst [DSIM][AlCl3]–@CS

FTIR spectra of pure chitosan, disulfonyl imidazolium chloride ([DSIM]Cl–), [DSIM]AlCl4–, [DSIM][AlCl3]–@CS, and recycled catalyst are shown in Figure . The spectrum of chitosan (Figure a) showed a characteristic broad peak at 3421 cm–1 which corresponded to −OH and −NH stretching vibrations of the chitosan framework, whereas the −CH stretching mode of methylene groups of chitosan appeared at 2923 cm–1. The other bands centered at 1589, 1381, and 1078 cm–1 corresponded to N–H bending, C–N stretching, and C–OH stretching vibrations, respectively.[31c] In Figure b, a broad band at 3392 cm–1 indicated the presence of two OH groups of a SO3H moiety in the IL system.[32] The bands at 1626 and 1588 cm–1 were assigned to C=C and C=N stretching vibrations,[32] respectively, whereas the stretching band of the SO3H group appeared at 1192 cm–1.[33] The other peaks at 1179, 1050, and 885 were assigned to S–O symmetric stretching, S–O antisymmetric stretching, and N–S stretching vibrations, respectively,[32] whereas the band centered at 576 cm–1 attributed to the bending vibration of the SO3H group. When [DSIM]Cl– was treated with AlCl3, no significant change in the FTIR spectrum of [DSIM]AlCl4– was observed in the range of 400–4000 cm–1 (Figure c). However, the presence of [(AlCl3)–] was confirmed by the Raman spectrum of the catalyst (Figure b). In the spectrum of [DSIM][AlCl3]–@CS (Figure d), the characteristic peaks for chitosan appeared at their appropriate values with some additional bands at 1626, 1194, 1054, and 579 cm–1 which were due to presence of IL {[DSIM]AlCl4–}. The N–H bending mode of chitosan merged with C=N stretching vibration of the IL and appeared at 1583 cm–1. The band centered at 534 cm–1 was due to the Al–N and Al–O bond (Figure d).[34]

Figure 1

FTIR spectra of (a) chitosan, (b) [DSIM]Cl–, (c) [DSIM]AlCl4–, (d) [DSIM][AlCl3]–@CS, and (e) recycled catalyst after the sixth run.

Figure 2

Raman analysis of the (a) chitosan and (b) catalyst [DSIM][AlCl3]–@CS.

Raman spectra of pure chitosan and catalyst [DSIM][AlCl3]–@CS were obtained in the range of 150–1650 cm–1 and are shown in Figure . The presence of bands at 942.04, 1101.47, and 1142.29 cm–1 was attributed to the out-of-plane vibration of the amine group,[35] C–O–C stretching vibration,[19] and C–N stretching vibrations[36] of chitosan, respectively (Figure a). The strong band at 349.72 cm–1 was assigned to the (AlCl3)– ion present in the catalyst[37] (Figure b).

In the solid-state 13C MAS NMR spectrum of the catalyst, two signals at 56.45 and 61.07 ppm were assigned to C2 and C6 carbons of chitosan, whereas other signals present at 74.98, 83.72, and 101.68 ppm were attributed to C3, C4, and C1 carbons, respectively (Figure ). The two signals at 23.60 ppm and 175.14 were assigned to the N-glucosamine unit of chitosan.[38] The carbon atoms of the imidazolium cation (Ca and Cb) appeared at 120.79 and 135.64 ppm, respectively.[39]

Figure 3

13C MAS NMR spectra of the catalyst [DSIM][AlCl3]–@CS.

The surface morphology of chitosan showed clean surfaces (Figure a,b), but a morphological change was obtained when IL ([DSIM][AlCl4–) was supported on chitosan (Figure c,d). EDX analysis (Figure ) confirmed the presence of C, N, S, O, Cl, and Al elements, whereas elemental mapping of the catalyst indicated the uniform distribution of these elements (Figure a–f) which confirmed the formation of a desired catalytic system, that is, [DSIM][AlCl3]–@CS.

Figure 4

SEM images of (a) chitosan at 1 mm, (b) chitosan at 200 μm, (c) catalyst [DSIM][AlCl3]–@CS at 500 μm, (d) catalyst [DSIM][AlCl3]–@CS at 50 μm, (e) recycled catalyst at 500 μm, and (f) recycled catalyst at 50 μm.

Figure 5

EDX analysis of the catalyst [DSIM][AlCl3]–@CS.

Figure 6

Elemental mapping of the elements (a) carbon, (b) oxygen, (c) nitrogen, (d) sulfur, (e) chlorine, and (f) aluminum.

TEM images of chitosan and the catalyst [DSIM][AlCl3]–@CS are shown in Figure . The presence of IL [DSIM]AlCl4– on the surface of chitosan, clearly shown in Figure b, further ascertains the proper immobilization of the IL on chitosan to form [DSIM][AlCl3]–@CS.

Figure 7

TEM images of (a) chitosan and (b) catalyst [DSIM][AlCl3]–@CS.

TGA of the catalyst showed two-stage decomposition. First thermal decomposition at 244.94 °C (weight loss = 41.023%) was due to depolymerization and decomposition of the glucosamine unit of chitosan and absorbed moisture which was trapped during synthesis of the catalyst.[40] Second thermal decomposition at 457.44 °C (weight loss = 55.642%) was attributed to some other changes in the catalytic system such as oxidative decomposition of the chitosan moiety[41] and removal of the organic functional group such as the sulfonyl group (SO3H) of IL incorporated in the material framework (Figure ).[42]

Figure 8

TGA of the catalyst [DSIM][AlCl3]–@CS.

In the XRD spectrum of the catalyst, the appearance of characteristic broad peaks at 2θ = 10° and 20° was attributed to the chitosan moiety (Figure a).[43] The IL supported chitosan showed a similar XRD pattern to that of chitosan which was due to the low amount and uniform distribution of IL on the surface of the chitosan.

Figure 9

XRD pattern of (a) chitosan, (b) [DSIM][AlCl3]–@CS, and (c) recycled catalyst.

Catalytic Activity

In order to select the most suitable reaction conditions, a reaction involving 1,2 diketone 1a (2 mmol) and diamine 2b (2 mmol) to give pyrazine 3a at room temperature was chosen as the model reaction (Scheme ) for optimizing different reaction parameters such as different catalysts, solvents, catalyst loadings, and catalyst amounts. First, we investigated the effect of different catalysts on the model reaction. It was observed that chitosan alone could not catalyze the reaction effectively and afforded low yield of the product in a longer reaction time (Table , entry 1). The reaction was then tested with sulfonyl imidazolium ILs with different anions such as [DSIM]Cl–, [DSIM]HSO4–, and [DSIM]CH3COO– (Table , entries 2–4). Among these ILs, [DSIM]Cl– catalyzed the reaction more effectively than others (Table , entry 2). To improve the yield and reduce the reaction time period, [DSIM]Cl– was further treated with different metal salts to form new IL systems such as {[DSIM]AlCl4–}, {[DSIM]FeCl4–}, {[DSIM]NiCl4–}, and {[DSIM]ZnCl4–} (Table , entries 5–8). It was observed that among the ILs containing metal halide anions, best results were obtained with {[DSIM]AlCl4–} in terms of product yield and reaction time (Table , entry 5).

Scheme 2

Model Reaction for Optimization of Different Parameters

Table 1

Effect of Different Catalysts on the Model Reactiona

entry	catalyst	timeb	yieldc (%)
1	chitosan	6 h	43
2	[DSIM]Cl–	1.5 h	66
3	[DSIM]HSO4–	2 h	60
4	[DSIM]CH3COO–	2.5 h	54
5	[DSIM]AlCl4–	42 min	75
6	[DSIM]FeCl4–	52 min	64
7	[DSIM]NiCl4–	56 min	62
8	[DSIM]ZnCl4–	1.2 h	68
9	[DSIM][AlCl3]x–@SiO2	33 min	88
10	[DSIM][AlCl3]x–@ZrO2	37 min	83
11	[DSIM][AlCl3]x–@CS	<1 min	99

Reaction conditions: benzil 1a (2 mmol), o-phenylenediamine 2b (2 mmol), catalyst (100 mg), T = 25 °C, and stirring.

Reaction progress monitored by TLC.

Isolated yield.

The above results showed that the rate of reaction was affected by changing the anions of ILs and hence confirmed that the model reaction was catalyzed by the synergic effect of both cations and anions present in the catalysts (Table , entries 2–8). Furthermore, in order to choose an appropriate support material, the model reaction was carried out with the IL supported on SiO2, ZrO2, and chitosan (Table , entries 9–11). Among these materials, chitosan was found as the best material for the said reaction.

A pH test was performed for [DSIM]Cl–, [DSIM]AlCl4–, and [DSIM][AlCl3]–@CS and pH values were found to be 1.2, 1.8, and 3.4, respectively. This confirmed that the final catalyst was acidic in nature because of the presence of sulfonic acid groups in the catalytic system. The exact role of the catalyst composition can be to provide the synergic effects of cationic and anionic parts leading to increased activity. Individually, the role of the imidazolium cation was to provide enough acidity to the catalyst (pH = 1.2) due to the presence of sulfonic acid groups which activated the carbonyl carbons of diketones to facilitate the reaction,[32] the presence of AlCl4– provided the lewis acidic sites to bind with hydroxyl and amine groups of chitosan,[20a] and the role of chitosan was to introduce heterogeneity into the catalyst.

We then examined the model reaction with various green solvents such as isopropanol, water, dimethyl sulfoxide, polyethylene glycols (PEGs) (200 400 600), methanol, and ethanol (Figure ) and also under solvent-free conditions. It was found that moderate to good yields of the product were obtained when the reaction was carried out with green solvents (Figure , entries 1–7). On the other hand, solvent-free reaction conditions afforded excellent yield in a minimum reaction time (Figure , entry 8).

Figure 10

Effect of solvent on the model reaction (reaction conditions: benzil 1a (2 mmol), o-phenylenediamine 2b (2 mmol), [DSIM][AlCl3]–@CS (100 mg), T = 25 °C, and stirring).

In order to find out the optimum loading amount of {[DSIM]AlCl4–} on chitosan, the model reaction was carried out with different loading amounts varying from 5 to 25% w/w (Figure ). It was observed that the maximum product yield was obtained with 25% w/w loading (Figure , entry 4).

Figure 11

Effect of [DSIM]AlCl4– loading on the support for the model reaction (reaction conditions: benzil 1a (2 mmol), o-phenylenediamine 2b (2 mmol), [DSIM][AlCl3]–@CS (100 mg), T = 25 °C, and stirring).

The amount of the catalyst suitable to catalyze the reaction was checked by varying the amount of catalyst (30, 50, 60, 80, and 100 mg) in the model reaction. It was found that the yield of the product increased on increasing the amount of the catalyst from 30 to 100 mg (Figure ). Thus, the optimum amount of catalyst required for the maximum conversion of the reactant to product was found to be 100 mg (Figure , entry 5).

Figure 12

Effect of the amount of catalyst on the model reaction (reaction conditions: benzil 1a (2 mmol), o-phenylenediamine 2b (2 mmol), [DSIM][AlCl3]–@CS (30–100 mg), T = 25 °C, and stirring).

After ascertaining optimized reaction conditions, a series of pyrazine derivatives were synthesized using an equimolar ratio of diamines and diketones in the presence of the catalyst [DSIM][AlCl3]–@CS under solvent-free conditions at room temperature (Scheme ).

Scheme 3

Synthesis of Substituted Pyrazines[444546]

Reaction conditions: 1a–e (2 mmol), 2a–c (2 mmol), [DSIM][AlCl3]–@CS (100 mg), T = 25 °C, and stirring. bReaction progress monitored by TLC. cIsolated yield.

Many efficient heterogeneous catalysts have been reported for the synthesis of pyrazine derivatives. A comparison with these catalytic systems reveals that the present catalyst was more efficient in terms of time period and reaction temperature (Table ).

Table 2

Comparison of Catalytic Performance of [DSIM](AlCl3)–@CS with Previously Reported Procedures

entry	catalyst	solvent	temperature	time	% yield	refs
1	HClO4·SiO2	CH3CN	r.t.	15 min	92	(47a)
2	silica-bonded S-sulfonic acid	EtOH/H2O	r.t.	5 min	96	(47b)
3	polyvinylpolypyrrolidone supported triflic acid	H2O	r.t.	1 h	95	(47c)
4	montmorillonite K-10	H2O	r.t.	2.5–6 h	100	(47d)
5	sulfated polyborate	Solvent free	100 °C	5 min	99	(47e)
6	Zr(IV) Schiff-base/SBA-15	H2O	reflux	6 min	99	(47f)
7	silica sulfuric acid/PEG	PEG-400	120 °C	2 h	90	(47g)
8	[DSIM](AlCl3)x–@CS	no solvent	r.t.	<1 min	99	this work

Stability and Recycling Study of the Catalyst

Furthermore, recycling capability of the catalyst was tested by choosing the model reaction of benzil 1a and o-phenylene diamine 2b in the presence of 100 mg of the catalyst [DSIM][AlCl3]–@CS under solvent-free conditions at room temperature. After completion of the reaction, the catalyst was separated from the reaction mixture by extraction with ethyl acetate. The catalyst was found to be active up to six runs with insignificant changes (Figure ). The FTIR spectrum of the recycled catalyst after the sixth run showed a similar pattern of peaks to that of the fresh catalyst showing characteristic bands of chitosan and IL system at 3419, 1628, 1588, 1193, 1076, and 534 cm–1 (Figure e). The morphology of the recycled catalyst was almost similar to that of the fresh catalyst (Figure e,f). An XRD pattern of the recycled catalyst was also found to be similar to that of the fresh catalyst (Figure c).

Figure 13

Recycling data of the catalyst [DSIM][AlCl3]–@CS.

Conclusions

In summary, we have synthesized an efficient chitosan-based IL easily at ambient temperature. The catalyst shows good stability and is found to be a suitable catalyst for the synthesis of six-membered nitrogen heterocycles such as pyrazines. Simple operational procedure, cost-effectiveness, high yield, and short reaction time period are added features of the present energy sustainable protocol.

Experimental Section

Preparation of [DSIM][AlCl3]–@CS

The IL, [DSIM]Cl–, was prepared by the reported procedure.[48] Imidazole (0.340 g, 5 mmol) was taken in a round-bottom (100 mL) flask containing 50 mL dry CH2Cl2, and chlorosulfonic acid (1.1885 g, 10.2 mmol) was added drop-wise over a period of 20 min at room temperature. After the complete addition, the reaction mixture was stirred for 12 h under inert atmosphere and stood for 5 min. A viscous pale yellow oil, settled down at the bottom, was separated using a separating funnel, washed with dry CH2Cl2 (3 × 50 mL), and dried under vacuum to get [DSIM]Cl– as a viscous pale yellow oil. In the second step, AlCl3 was added to the prepared [DSIM]Cl– and the mixture was heated at 50 °C for 30 min to get [DSIM]AlCl4–. The final catalyst [DSIM][AlCl3]–@CS was obtained by employing an impregnation method. Chitosan powder was suspended in the mixture containing IL [DSIM]AlCl4– in CH2Cl2 for 4 h. Excess solvent was evaporated to dryness to give the catalyst [DSIM][AlCl3]–@CS as yellowish brown powder.

General Procedure for Synthesis of Pyrazine Derivatives 3a–n

A mixture of diketones 1a–e (2 mmol), diamines 2a–c (2 mmol), and [DSIM][AlCl3]–@CS (100 mg) was stirred at room temperature for 1–2 min. The reaction progress was monitored by thin-layer chromatography (TLC). After completion of the reaction, ethyl acetate was added to the reaction mixture. The catalyst was filtered, washed with ethanol thrice, and dried in an oven for reuse. The ethyl acetate solution was concentrated and kept at room temperature to afford the products (3a–n). Recrystallization of products was carried out with ethanol.