Microwave-assisted preparation of polysubstituted imidazoles using Zingiber extract synthesized green Cr₂O₃ nanoparticles

Abstract

Cr₂O₃ nanoparticles were prepared using Zingiber officinal extract which were used as an efficient and reusable catalyst in the practical synthesis of polysubstituted imidazoles by means of a convenient reaction of aromatic aldehydes with ammonium acetate and benzil under microwave irradiation and H₂O as solvent. The structure of the compounds was studied by IR and ¹H-NMR spectrum. The most important benefits of this process are operational simplicity, reasonable reaction times, and excellent yield of products. The results show that the optimal conditions for the formation of imidazole derivatives are as follow: power of 400 W, reaction time of 4–9 min, H₂O as a solvent, and 15 mmol of catalyst amount.

Introduction

In recent years, metal and metal oxide nanomaterials have attracted significant attention in various synthesis processes¹. Functional nanomaterials have stupendous applications in different areas such as biomedical, environment, food preservation, and health care, cosmetics, water purification, fuel cells, drug delivery and gene delivery, defense, chemical industries, space industries, ceramics, energy, sensors, single-electron transistors, textiles, agriculture, solar cells, catalysis, light emitters, fuel, and antimicrobial². Among the metal oxides, Cr₂O₃ is more considerable due to their specific thermodynamic stability, antiferromagnetic, chemical resistance, hardness, and good catalytic reusability attributes³.

Chromium oxide has various crystal states such as CrO₂ (rutile), CrO₃, CrO₄, Cr₂O₃ (corundum), Cr₂O₅, and Cr₅O₁₂. In this respect, Cr₂O₃ is known to be the most stable magnetic-dielectric oxide⁴. Cr₂O₃ depicts p-type and n-type semiconductor behavior⁵ that all these characteristics make Cr₂O₃ a suitable material for a variety of industrial applications.

Based on previous reports, numerous studies have been accomplished about applications of Cr₂O₃ nanoparticles (NPs) involving sensors⁶, catalysis⁷, protective coating and green pigment⁸, fuel cell⁹, solar cell¹⁰, piezoelectric devices¹¹, photocatalysis¹². Moreover, Cr₂O₃ NPs are known to be one of the significant compounds in the field of medicine and pharmacy, having anticancer, antibacterial, antileishmanial, and antioxidant specifications⁵.

Various techniques are used to synthesize Cr₂O₃ nanoparticles such as hydrothermal¹³, solid thermal decomposition¹⁴, combustion¹⁵, sol-gel¹⁶, precipitation-gelation¹⁷, oxidation of chromium in oxygen¹⁸, sonochemical¹⁹ mechanochemical reaction and subsequent heat treatment²⁰, laser induced deposition²¹, and biological methods²². Besides, there are several reports introducing the synthesis of nanoparticles by green method using extracts, including CuO²³, Cu²⁴, AgCl²⁵, Ag²⁶, etc.

In contrast to chemical and physical methods, biological approaches are critical because of their rapid, ease in use, economic production and less generation of waste products. Different and nearly all parts of a plant such as flowers, fruit, and leaves are consisted of bio-based components like flavonoids, alkaloids, etc. The mentioned components prove the rich ingredients of the plants and exhibit their great potential to be used as a base for medical and pharmaceutical applications²⁷.

A research has been accomplished on the extract of Callistemon Viminalis and examining its possible usage as a capping reagent for Cr₂O₃ NPs synthesis²². The fabrication of Cr₂O₃ NPs was investigated in another research through Callostemon viminalis extraction that were used for biological purposes⁵. In another study by Sharma and their group²⁸, the extract obtained from the Cannabis Sativa leaves was used for Cr₂O₃ NPs preparation. Sphere-shaped Cr₂O₃ NPs were fabricated with Hyphaene thebaica extraction in other research²⁹. The investigations in this field are vast, and in this respect, the extractions of Artemisia herba-alba leaves³⁰, Melia Azedarach fruits³⁰, and Nephelium Lappaceum³¹ were used for Cr₂O₃ synthesizing. It has been reported that the leaves of Opuntia Ficus can be a potential reducing, and capping agent for Cr₂O₃ preparation³². Rhamnus Virgata³³, Ipomoea batatas³⁴ and Tridax Procumbens³⁵ are among the other reported plants that their extraction has been used for Cr₂O₃ NPs production.

Effect of pH, temperature, concentration of extract and reaction time on the green synthesis of nanoparticles have been investigated. For instant, changing the pH value of the reaction mixture solution changes the grain size of the synthesized sample. Synthesis of nanoparticles in the green rout requires less than 100 °C. The temperature range governs the formed nanoparticles nature³⁶. Plant extract is a complex concoction of several phytochemicals, for example, phenolics, sugars, flavonoids, xanthones, and several others. In general, it is said that hydroxyl-rich phenolics act as reducing agents for metal ions, but little is discussed about the stabilizing ligands of metal nanoparticles (NPs). Thus, despite the popularity of plant extract-mediated synthesis of NPs, the phytochemical basis of the process and the exact mechanism are still unclear³⁷.

Zingiber, known as Ginger as well is one of the mainly used herbals containing bioactive compounds such as phenols, paradols, curcumin, etc. Ginger is associated with the Zingiberaceae family involving about 800 species.

The ginger is used for therapeutic purposes in as much as its phytochemical’s components. This characteristic of ginger is very effective on bacterial pathogens in a wide range³⁸. Zingiber extract can perform both as a reducing and stabilizing agent (Fig. 1).

Figure 1.

Schematic representation of the biosynthetic pathway of Cr₂O₃ nanoparticles using Zingiber officinale extract.

The N-heterocyclic compounds are considered as a group of precious compounds existing in many structures exhibiting potential features in medical materials^39,40. In the group of numerous heterocyclic structured materials, imidazoles are very substantial within biological compounds⁴¹. The imidazole structural scaffolds and analogs are used as antibacterial, herbicides, fungicides, anti-inflammatory, antitumor, therapeutic, and plant growth regulators agents⁴². Moreover, this class of compound act as an inhibitor of B-Raf, p38 MAP kinase, and glucagon receptors⁴³ (Fig. 2).

Figure 2.

Some biological heterocyclic compounds containing imidazole moieties.

Such compounds are used as the base of some other structures. In this respect, imidazole synthesis obtains a high effect in the preparation of medically essential compounds. Several improved methods and procedures for the preparation of polysubstituted imidazoles have been reported, that best-reported route is a three-component, cyclo-condensation reaction between aldehyde, benzil, and NH₄OAc in the presence of a different catalyst such as zeolite HY/silica gel⁴⁴, ionic liquid^45,46, iodine⁴⁷, sodium bisulfite⁴⁸, ZrCl₄⁴⁹, Yb(OTf)₃⁵⁰. Alternative methods with the application of microwave source energy and appropriate catalyst through using 1,2-diketone and aldehyde for imidazole synthesis have been proposed such as MW/Silica-gel⁵¹, glyoxylic acid⁵², InCl₃.3H₂O⁵³.

Using the microwave energy source within the synthesis of different compounds is an environmental friendly technique. The energy of microwaves is high; therefore, short times are needed for the accomplishment of the reactions, hence, having great superiority from the time point of view. In this respect, microwave technology has an ascending usage in synthesizing various compounds⁵⁴.

In continuation of our investigation towards designing novel catalysts in the synthesis of heterocyclic compounds^55–60, we synthesized Cr₂O₃ nanoparticles using Zingiber officinal extract, and used it as a Lewis acid catalyst for the preparation of polysubstituted imidazoles (Fig. 3). To the best of the authors’ knowledge, this study is the first investigation in this manner. Besides, the significance of the present study is the green and facile synthesis of the Cr₂O₃ nanomaterial, and application of the synthesized compound as efficient catalyst for the preparation of imidazole derivatives 4a–j.

Figure 3.

Synthesis of imidazole derivatives 4a–j with Cr₂O₃ as catalyst under microwave irradiation.

Experimental

Materials and instruments

The chemicals were obtained from Merck company, and no excess purification was carried out. Zingiber was purchased from local market, Urmia, West Azerbaijan, Iran and the collection of plants materials used in current study complied with institutional, national or international guidelines. X-ray Powder Diffraction (XRPD) pattern was recorded by the X-ray diffractometer (D5000 Siemens AG, Germany) using CuKα radiation to make phase identification. The FESEM image was taken on a Hitachi model S-4160 for morphology study. FT-IR spectra were obtained with FT-IR spectrometer (Bruker, Germany). Thin-layer chromatography using petroleum ether/ethyl acetate (9:1) mixture was used to evaluate the purity of the products. ¹H-NMR spectra of compounds were run on a Bruker Avance DRX-400 spectrometer using tetramethylsilane as an internal standard and dimethyl sulfoxide-d₆ as solvent. Microwave-assisted procedures were performed in the Milestone Microwave Oven.

Preparation of plant extract

The purchased dried root of Zingiber was ground and a fine powder was obtained. Then, 300 mg of the prepared powder was poured into 30 mL of distilled water. The mixture was stirred at 70 °C for 20 min. Finally, the extraction was cooled to room temperature and filtered out. The product was kept at decreased temperature (4 °C) for subsequent use (Fig. 4).

Figure 4.

The synthesis scheme of extraction of ginger.

Green synthesis of Cr₂O₃ nanoparticles

Ginger aqueous extract (3 mL) was added to Cr(NO₃)₃·9H₂O (0.1 M) under continuous stirring. Sodium hydroxide 2 M solution was used to adjust the pH on 12 at 80 °C. The formed precipitate was centrifuged for 15 min, then rinsed with distilled water, and dried at 90 °C for 12 h in an oven (Fig. 5).

Figure 5.

The stepwise synthesis pathway of Cr₂O₃ nanoparticles.

General procedure for the synthesis of imidazole derivatives 4a–j

A mixture of aromatic aldehydes (1a–j, 1 mmol), ammonium acetate (2, 3 mmol), and benzil (3, 1 mmol) in water (2 mL), and Cr₂O₃ nanoparticles (15 mmol) were prepared. The obtained mixture was kept under agitation and microwave (400 W) was used to treat the mixture with irradiation for an appropriate time (Table 5, reaction time in the range of 4–9 min). TLC was used to investigate the reaction progress (ethyl acetate/petroleum ether; 1:9 as eluent). Next, the obtained mixture temperature was decreased to room temperature by adding it to an ice containing beaker. Afterward, the achieved product was filtered out under reduced pressure, following by rinsing with water for several times and drying. Finally, recrystallization was done using ethanol in order to obtain a highly pure products 4a–j (89–98% yield).

Table 5.

Cr₂O₃ catalyzed the synthesis of imidazole derivatives 4a–j.

Entry	Aromatic aldehyde	Product	Time (min)	Yielda (%)	M.p.b (°C)
					Found	Refs.
1			6	97	269–271	270–27263
2			5	94	249–251	250–25264
3			6	92	197–199	198–20065
4			5	93	260–263	260–26563
5			6	94	238–240	239–24166
6			4	97	234–236	235–23763
7			4	96	230–233	232–23464
8			5	96	207–209	208–21065
9			4	98	219–221	220–22367
10			9	89	300–303	302–30465

^aIsolated yields.

^bThe measured melting points comparison with those in literature confirmed the products.

Results and discussions

Powder X-ray diffractometry analysis

XRD pattern of the prepared catalyst is shown in Fig. 6, and nine different Bragg’s diffraction peaks can be observed associated with crystal planes of (012), (104), (110), (113), (024), (116), (214), (220), and (306) at 2θ = 24.3°, 33.7°, 36.3°, 41.4°, 50.1°, 54.8°, 63.5°, 76.7°, and 79.0° respectively. The obtained pattern for Cr₂O₃ nanoparticles is in agreement with Joint Committee on Powder Diffraction Standards (JCPDS) 38–1479⁶¹. No peak related to any impurity was seen that confirm the high purity of the particles.

Figure 6.

XRD analysis of green synthesized Cr₂O₃ nanoparticles.

In addition, the mean crystallite size of the Cr₂O₃ sample was evaluated using the Scherrer formula as follows:

$$\text{D}=\text{K}\lambda /\left(\beta \text{cos}\theta \right)$$

where K (0.9), λ (1.54056 Å), β, and θ are Scherer constant, X-ray radiation wavelength, full peak width at half maximum, and Bragg diffraction angle, respectively. In this respect, Cr₂O₃ crystallite size, in average was calculated at about 14 nm.

FT-IR analysis

The FT-IR spectrum of Cr₂O₃ nanoparticles is illustrated in Fig. 7. The peaks below 1000 cm⁻¹ may be due to the inter-atomic vibrations and in this study, may be associated with the Cr–O bands. This phenomenon can be seen in the spectrum of the metal oxide frequently. The high intensity of the peaks of Cr₂O₃ bands indicates the good crystalline nature of the material. Two sharp peaks at 651 cm⁻¹ and 560 cm⁻¹ could be related to Cr–O stretching modes are clear evidence of the attendance of the crystalline Cr₂O₃⁶². The broadband around 3400 cm⁻¹ can be due to the hydroxyl groups of water.

Figure 7.

FT-IR spectrum of the green synthesized Cr₂O₃.

Morphology analysis

Figure 8, shows the FESEM image of the as-synthesized nanomaterial. It can be seen that the main morphology of the material is a mixture of rod and particle. TEM image exhibits that the diameter size of the as-prepared sample is 30–40 nm.

Figure 8.

FESEM (a) and TEM (b) image of synthesized Cr₂O₃.

Magnetic property

Figure 9, shows the hysteresis loop for a sample at room temperature. Accordingly, the synthesized particle possesses a soft magnetic nature. The value of magnetization saturation (M_s) is about 42 emu/g. Remnant magnetization M_r is the magnetization strength of the materials remaining after removing the external magnetic field or descending to a zero level. M_rs as the square of magnitudes is achieved using (M_rs = M_r/M_s) formula. Magnetic parameters are summarized in Table 1. The particle with homogenous distribution and magnetization with no inter-grain interactions will give a M_rs below 0.5. This value can be interpreted through multiple domains of the structure formed due to the exchange coupling among adjoining grains. In this study, the M_rs is 0.19 affirming that the sample has no preferred direction in magnetization. Moreover, a normal (S-shaped) narrow hysteresis loop was observed as well. The narrow loop is an indication of a low coercivity. Therefore, the prepared sample can be easily demagnetized.

Figure 9.

VSM curves of the as-synthesized nanomaterial.

Table 1.

Magnetic parameters of the sample.

Sample	Mr (emu/g)	Ms (emu/g)	Mrs = Mr/Ms	Hc (Oe)
Cr2O3	4.9	42.3	0.115	50.7

Evaluation of the catalytic activity of the as-prepared Cr₂O₃ nanoparticles for the synthesis of imidazoles 4a–j

The synthesized catalyst was evaluated, and their efficiency in the imidazoles preparation was studied. The one-pot, three-component reaction of benzaldehyde (1a), ammonia source (2, AcONH₄), and benzil (3), was chosen as a trial reaction. Some prerequisite conditions were assessed by initial experiments regarding the optimum conditions.

Different aryl aldehydes 1a–j were used to evaluate the reaction process. Manifestly, in the reactions with no nanocatalyst usage, no considerable progress was observed. Hence, in order to investigate the as-prepared nanocatalyst effect in the present procedure, different amounts of catalyst ranging from 5 to 25 mmol was applied (Table 2). Interestingly, excellent yield was observed using 15 mmol of nanocatalyst (Table 2, entry 4) in water as a green solvent.

Table 2.

Effect of Cr₂O₃ nanoparticles as nanocatalyst on the synthesis yields of compound 4a.

Entry	Catalyst (mmol)	Time (min)	Yield (%)
1	–	6	–
2	5	6	35
3	10	6	51
4	15	6	97
5	20	6	97
6	25	6	97

Reaction conditions: Benzaldehyde (1a, 1 mmol), AcONH₄ (2, 3 mmol), benzil (3, 1 mmol), and catalyst in H₂O (2 mL) under microwave irradiation (400 W).

Significant values are in bold.

Moreover, increase in the amount of catalyst had no significant effect on the outcome (Table 2, entries 5 and 6). Also, the lower quantities of the nanocatalyst afford moderate yield of the product at a longer reaction time (Table 2, entries 2 and 3).

Microwave effect with power in the range of 200–500 W was exanimated (Table 3). According to the results, 400 W was chosen as the optimized power for synthesizing substituted imidazole derivatives.

Table 3.

Effect of microwave power on the synthesis of trial reaction.

Entry	Catalyst (mmol)	Microwave power (W)	Time (min)	Yielda (%)
1	15	200	6	65
2	15	300	6	80
3	15	400	6	97
4	15	500	6	97

Reaction conditions: 1a (1 mmol), 2 (3 mmol), 3 (1 mmol), and catalyst (15 mmol) in water (2 mL).

Significant values are in bold.

^aIsolated yield.

In addition, the solvent effect was assessed, and the results are shown in Table 4. No progress in the reaction was observed without a solvent, even after a considerable time. This finding affirms the requirement for an appropriate solvent.

Table 4.

Optimization of reaction conditions for the synthesis of compound 4a.

Entry	Solvent	Yield (%)
1	–	–
2	Et2O	–
3	CHCl3	–
4	DMSO	14
5	THF	17
6	DMF	33
7	CH3CN	28
8	H2O	97
9	EtOH	89
10	H2O/EtOH (1:1)	90
11	H2O/EtOH (2:1)	91

The reaction of 1a (1 mmol), 2 (3 mmol), 3 (1 mmol), catalyst (15 mmol) and solvent (2 mL) under microwave irradiation was carried out.

Significant values are in bold.

According to the results, no considerable reaction progress was observed while using nonpolar solvents such as Et₂O. However, by using polar aprotic solvents such as DMF, low yields were achieved. Nonetheless, polar protic solvents like water, and ethanol had a better effect and the yields of 97% and 89% were obtained for H₂O and EtOH respectively.

Encouraged by this success, using the obtained optimum reaction parameters, the scope and efficiency of this approach were demonstrated for the synthesis of polysubstituted imidazoles 4a–j and the results are outlined in Table 5. As can be seen, the extension of substrate scope, the different aryl aldehyde containing the various functional groups on the benzene ring such as halogens, hydroxyl, methyl, methoxy, and nitro was examined with ammonium acetate and benzil under the optimized conditions for imidazoles synthesis. However, aryl aldehyde with electron-withdrawing groups, like nitro, require more reaction time to form the product 4j (89%).

Recycling of Cr₂O₃ nanoparticles as a catalyst under microwave irradiation

The catalytic performance of Cr₂O₃ after multiple cycles of usage was investigated. It has been proved that the prepared nanocatalyst can be used even after 6 runs with no considerable decrease in its efficiency (Fig. 10).

Figure 10.

Reusability of Cr₂O₃ in the synthesis of compound 4a.

To show the advantages of the current work, we compared the results with literature. As shown in Table 6, Cr₂O₃ is the most efficient catalyst and gives excellent product yields in reduced reaction times. In addition, the merit of Cr₂O₃ is its recyclability and easy work-up.

Table 6.

Comparison of various heterogeneous catalysts in the formation of compound 4a.

Entry	Catalyst	Time (min)	Yield (%)
1	Schiff base nickel complex (Ni–C)	20	9068
2	ZrO2–Al2O3	20	9969
3	Rochelle salt	10	9370
4	Fe3O4	20	8571
5	TiCl4–SiO2	10	9372
6	CuCl2·2H2O	13	8754
7	Triflate	30	9673
8	BTPPC	10	9274
9	MgAl2O4	14	9375
10	Cr2O3	6	97 (this work)

Figure 11, presents a suggested synthesis mechanism for the imidazoles. In the first step, the catalyst increased the electrophilicity of the aromatic aldehydes carbonyl groups 1a–j. Then, the ammonia's nitrogen (2, obtained from ammonium acetate) intermolecular nucleophilic attack to the activated center of the carbonyl group generated diamine intermediate I. Next, intermediate II is produced by nucleophilic attack of the intermediate I nitrogen to the carbonyl groups of benzil (3). Afterwards, the typical intramolecular condensation of the intermediate II followed by a heterocyclization, afforded the intermediate III, while the removal of two water molecules occurs and the conjugate intermediate IV is obtained. Finally, the aromatization of intermediate IV takes place leads to the corresponding five membered heterocyclic compounds as the desired imidazoles 4a–j under 1,5-proton exchange.

Figure 11.

Plausible reaction mechanism for the synthesis of imidazole derivatives.

Conclusion

In summary, an easy, cost-effective, and eco-friendly biological successful technique was used for synthesizing of Cr₂O₃ nanostructures using Cr(NO₃)₃.9H₂O as a precursor, and Zingiber officinal extract as a stabilizing and reducing agent. The green synthesized Cr₂O₃ nanoparticles was characterized using SEM, XRD, TEM, FT-IR, and VSM analyses. The mean crystallite size was 14 nm, as confirmed by the analysis of XRD pattern using the Scherrer equation. Then, the synthesized Cr₂O₃ was used as a heterogeneous Lewis acid catalyst for efficient synthesis of imidazole derivatives by condensation of aromatic aldehydes took place with ammonium acetate and benzil in the attendance of a catalytic amount of Cr₂O₃, and H₂O as solvent under microwave illumination. High reaction yield (97%) was obtained when benzaldehyde was used as aldehyde derivative. The prepared nanocatalyst was recovered and its high efficiency even after six runs was proved. Reasonable reaction times, excellent yields, easy work-up, and the absence of any hazardous and volatile organic solvents were the main merits of this benign protocol.

Author contributions

L.K.-A.: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, visualization, writing-original draft, and writing-review and editing. S.K.: conceptualization, data curation, formal analysis, investigation, methodology, supervision, and writing-review and editing. A.P.M.: conceptualization, data curation, formal analysis, investigation, methodology, supervision, validation, visualization, and writing-review and editing. E.N.: Investigation, writing–review and editing.

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Competing interests

The authors declare no competing interests.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-022-24364-6.