Magnetic nano-Fe₃O₄@TiO₂/Cu₂O core–shell composite: an efficient novel catalyst for the regioselective synthesis of 1,2,3-triazoles using a click reaction

Abstract

A magnetic nano-Fe₃O₄@TiO₂/Cu₂O core–shell composite, optimized for the loading amount of Cu₂O, was successfully prepared and fully characterized by analyzing FT-IR, XRD, XPS, FEG-SEM, EDS, and VSM data. The catalytic activity of the nano-Fe₃O₄@TiO₂/Cu₂O core–shell composite was examined in a classical one-pot and three-component reaction of terminal alkynes, benzyl halides, and sodium azide in water that was observed to proceed smoothly and completed in good yields with high regioselectivity. The catalyst was conventionally recovered using an external magnet and was reused in at least five successive runs without an appreciable loss of activity.

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Introduction

One of the most important developments in catalyzed organic reactions is the synthesis of novel catalysts or reagents that are readily available, inexpensive, selective, recyclable, and environmentally benign.¹ In this context, nanoparticles find vast applications due to their high surface-to-volume ratio and their unique electronic properties, resulting in high catalytic activity and tenability.² Nanocatalysts can often be isolated and recovered through filtration or centrifugation methods. Despite several advantages and merits accompanying the utilization of nanocatalysts, the inconvenience and tedious separation due to the nanosize particles impose few limitations to the sustainability of the nano catalytic strategy in organic synthesis.³

To circumvent the problem of tedious separation, we contemplated using a heterogeneous nanocatalyst that can be operationally separated with a method other than filtration. Magnetite nanoparticles (Fe₃O₄) have increasingly attracted interest over the past few years due to their unique features, including low preparation cost, high thermal and mechanical stability, and adaptability for large-scale production. Furthermore, their paramagnetic nature allows their simple and efficient separation from the reaction mixture without using standard filtration, which is required for the separation of heterogeneous catalysts. Magnetite nanoparticles (Fe₃O₄) can be easily separated from a reaction mixture by simply using an external magnet.^4–7 However, using naked magnetic nanoparticles (MNPs) is suboptimal because the particles are inherently subjected to aggregation in the reaction mixture, mainly due to their small interparticle distance, high surface energy, and the existence of van der Waals forces.⁸ This aggregation affects their unique properties that are associated with catalytic reactions. To solve this problem, MNPs are frequently modified using suitable stabilizing coating materials in order to prevent irreversible aggregation, retain their nanoscale properties, and preserve their finely dispersed active sites. Many materials have been explored for use as an outer shell of iron oxides, such as polymers,⁹ silica,¹⁰ titanium dioxide,¹¹ zeolites,¹² and carbon.¹³ Recently, titanium dioxide has attracted great attention as a support due to its unique surface properties, high chemical and thermal stability, non-toxicity, and high catalytic activity, as well as its great accessibility and moderate cost. The appropriate electronic band structure and excellent surface activity endowed TiO₂ with very promising potentials in hydrogen production, photovoltaics, photocatalysts, lithium-ion batteries, fuel cells, gas sensors, detoxification, and supercapacitors.¹⁴ Thus, further study on the performance of TiO₂-based nanostructures is still in much demand. Furthermore, the inclusion of a Fe₃O₄ core in TiO₂ nanospheres makes them easily recoverable with a magnetic field for further possible effective use. In recent years, multi-component reactions (MCRs) have gained eminence as an efficient method to assemble complex molecules with attractive biological features using simple and readily available starting materials in a one-pot operation.¹⁵

Among them, Huisgen 1,3-dipolar cycloaddition, which is the reaction of a terminal alkyne and alkyl halide and sodium azide, providing 1,2,3-triazoles, has attracted much attention from biological and chemical points of view. The 1,2,3-triazole moieties are widespread in pharmaceuticals, agrochemicals, dyes, corrosion inhibitors, photostabilizers, and photographic materials.¹⁶ Since its discovery, the regioselectivity of the catalyzed Huisgen reaction has been continuously under substantial and wide investigation and has attracted enormous attention of organic chemists, worldwide.¹⁷

There has been ongoing interest to develop homogeneous and heterogeneous metal catalysts such as CuO–CeO₂,¹⁸ nano-Cu,¹⁹ Cu/C,²⁰ copper nanoparticles supported on agarose,²¹ Cu-MOF,²² copper immobilized onto triazole-functionalized magnetic nanoparticles,²³ Cu/SiO₂,²⁴ ruthenium complex,²⁵ supported CuBr on graphene oxide/Fe₃O₄ ²⁶ and mesoporous graphitic carbon nitride²⁷ for a regioselective, three-component reaction of alkyl halides, sodium azide, and terminal alkynes. However, most of the above methods suffer from drawbacks such as the use of organic solvents and tedious experimental procedures to separate the catalyst as well as the requirement for reducing agents and stabilizing ligands. Therefore, there is still much demand to develop an efficient and well-defined heterogeneous catalyst for a one-pot, three-component reaction of terminal alkynes, alkyl halides, and sodium azide.

Recently, we used nano-Fe₃O₄ as an efficient and easily separable catalyst in different organic reactions.²⁸ As part of our continued interest in multi-component reactions²⁹ and our efforts to develop the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles via click reaction,³⁰ herein, we wish to report the preparation of a novel and recyclable catalyst system composed of a magnetic Fe₃O₄ core and TiO₂ shell with microcrystals of Cu₂O. The Fe₃O₄@TiO₂/Cu₂O composite was conveniently prepared, and its structure was fully characterized by XRD, FTIR, XPS, SEM, TEM, EDX, and VSM analysis. The catalytic activity of this system was examined via the model reaction of phenyl acetylene, benzyl bromide, and sodium azide in water, which proceeded smoothly to regioselectively afford the corresponding 1,4-substituted 1,2,3-triazole as the sole product.

Experimental

Materials and instruments

Chemical reagents in high purity were purchased from Merck and Aldrich and were used without further purification. Melting points were determined in open capillaries using an Electrothermal 9100 melting point apparatus without further corrections. ¹H NMR and ¹³C NMR spectra were recorded using a Bruker DRX-400 spectrometer at 400 and 100 MHz, respectively. FT-IR spectra were obtained with potassium bromide pellets in the range of 400–4000 cm⁻¹ using a Shimadzu 8400 s spectrometer. The purity of the synthesized compounds was monitored by TLC on commercial aluminum-backed plates of silica gel 60 F254 and visualized using ultraviolet light. X-ray diffraction (XRD) was detected by Philips using Cu-Kα radiation of wavelength 1.54 Å. Field emission scanning electron microscopy and energy dispersive X-ray (FE-SEM-EDX) analysis was performed using a Tescanvega II XMU digital scanning microscope. Samples were coated with gold at 10 mA for 2 min prior to analysis. The magnetic properties were characterized using a vibrating sample magnetometer (VSM, Lakeshore7407) at room temperature. XPS spectra of the sample were obtained using a Gammadata-scienta ESCA 200 hemispherical analyzer equipped with an Al Kα (1486.6 eV) X-ray source.

Preparation of composite

Preparation of Fe₃O₄. The nano-Fe₃O₄ particles were prepared in accordance with a protocol that was described in our earlier report.²⁸

Preparation of nano-Fe₃O₄@TiO₂. Nano-Fe₃O₄@TiO₂ was synthesized according to a previously reported method,³¹ subjected to modification. The prepared nanomagnetic Fe₃O₄ particles were dispersed in a mixture of 250 mL of absolute ethanol/90 mL of acetonitrile. This mixture was sonicated for 15 min, and then 1.5 mL of NH₃·H₂O solution (25 wt%) was added. After continuous mechanical stirring for 30 min, 3 mL of tetrabutyl titanate (TBOT) dissolved in 20 mL of absolute ethanol was added dropwise to the above suspension under continuous mechanical stirring at 30 °C. The reaction mixture was further mechanically stirred for 1.5 h to obtain Fe₃O₄@TiO₂ core–shell nanoparticles. The obtained product was collected by magnetic separation and washed three times with absolute ethanol.

Preparation of nano-Fe₃O₄@TiO₂/Cu₂O core–shell magnetic composite. Four types of composites with different molar ratios of Fe₃O₄@TiO₂ : Cu₂O were synthesized. Nano-Fe₃O₄@TiO₂ (0.036–0.324 g) was dispersed in 80 mL of deionized water. 5 mL of (0.1 mol L⁻¹) CuCl₂ solution was added to the aqueous Fe₃O₄@TiO₂, and then the solution was sonicated for 15 min. Next, 1.8 mL of (1.0 mol L⁻¹) NaOH solution was added dropwise under ultrasonic radiation. The resulting solution instantly turned light blue, indicating the formation of Cu(OH)₂. Then, 12 mL of (0.1 mol L⁻¹) NH₂OH·HCl was immediately injected over 5 s into the solution. The solution was kept in a water bath for 1 h and centrifuged for 3 min, and then the solution was decanted as much as possible. The remaining precipitate was washed three times with 6 mL of a 1 : 1 volume ratio of water and ethanol. The nano-Fe₃O₄@TiO₂/Cu₂O was collected as a brown solid that can be stored in a tightly sealed vessel for several months without any changes in color or activity.

General procedure for synthesis of 1,2,3-triazoles

In a round-bottomed flask, an appropriate alpha-haloketone (1 mmol) or alkyl halide (1 mmol), terminal alkyne (1 mmol), and sodium azide (1.1 mmol) were placed in water (10 mL). To this mixture, a nano-Fe₃O₄@TiO₂/Cu₂O magnetic composite (0.01 g) was added. The suspension was magnetically stirred under reflux for the indicated time (Table 3). The progress of the reaction was monitored by TLC (n-hexane : ethyl acetate; 7 : 3). After the completion of the reaction, the solution was decanted as much as possible. The leftover residue was diluted with hot ethanol, and then the catalyst was separated from this mixture by an external magnet and washed with acetone (2 × 10 mL), dried in an oven, and stored for use in subsequent runs under the same conditions. After separation of the catalyst, the solution was evaporated to dryness, and a crude product was obtained. The crude products in some cases were washed with 10 mL of ether and were re-crystallized from EtOH : H₂O (3 : 1 v/v) to afford pure crystalline products. Some products had to be purified by chromatography on silica gel using a short column (Table 3).

Results and discussion

Synthesis of composite

Scheme 1 shows an illustration for the synthesis of the Fe₃O₄@TiO₂/Cu₂O core–shell magnetic composite. The Fe₃O₄@TiO₂ based on Cu₂O composite was prepared from inexpensive commercially available materials. In the first step, the magnetic Fe₃O₄ nanoparticles were prepared by the co-precipitation of Fe(II) and Fe(III) ions in alkali medium. The TiO₂ shell was prepared by the hydrolysis of tetrabutyl titanate (TBOT) in an absolute ethanol–acetonitrile mixture in the presence of well-dispersed Fe₃O₄ nanocrystals by a sol–gel process. The as-prepared Fe₃O₄@TiO₂ nanoparticles were removed by magnetic separation. The Fe₃O₄@TiO₂/Cu₂O composite was obtained by reducing Cu(II) hydroxide using hydroxylamine hydrochloride in the presence of Fe₃O₄@TiO₂.

Scheme 1 Preparation of nano-Fe₃O₄@TiO₂/Cu₂O core–shell composite.

The structure of Fe₃O₄@TiO₂/Cu₂O composite was fully characterized using the corresponding data provided by FT-IR, SEM, TEM, XRD, XPS, and VSM techniques.

Structural characterization of the composite

FT-IR spectra

Fig. 1 gives the FT-IR spectral pattern of Fe₃O₄, Fe₃O₄@TiO₂, and Fe₃O₄@TiO₂/Cu₂O in the range of 4000–500 cm⁻¹. The FT-IR spectra show a broad peak at 700–500 cm⁻¹, which is attributed to the vibration of the Metal-O functional group. The peak appearing at approximately 545 cm⁻¹ can be assigned to the vibration of the Fe–O functional group.³² Ti–O and Cu–O absorption peaks appeared at approximately 500 and 625 cm⁻¹, respectively. Notably, in the Fe₃O₄@TiO₂ and Fe₃O₄@TiO₂/Cu₂O samples, the observed peak is relatively broader. This may be attributed to the overlapping of Fe–O, Ti–O, and Cu–O peaks. The peaks appearing at 1118 and 1465 cm⁻¹ for the Fe₃O₄@TiO₂ and Fe₃O₄@TiO₂/Cu₂O samples could be associated with the presence of stretching vibrations of Ti–O and Fe–O–Ti bonds.³³ The bands at 1628 cm⁻¹ belong to the H–O–H bending vibration, indicating that several OH groups are present in the sample as a result of TiO₂ coating.

Fig. 1 The FT-IR spectra of Fe₃O₄, Fe₃O₄@TiO₂, and Fe₃O₄@TiO₂/Cu₂O.

X-ray diffraction spectra

Fig. 2 shows the X-ray diffraction patterns of Fe₃O₄@TiO₂ and as-made samples with different Cu₂O molar ratios (from 9 : 1 to 6 : 4 molar ratio of Fe₃O₄@TiO₂ to Cu₂O). The typical diffraction peaks located approximately at 30.1, 35.5, 43.2, 53.4, 57.1, and 62.7 can be well assigned to the diffraction of Fe₃O₄ nanoparticles with cubic phase from the (220), (311), (400), (422), (511), and (440) planes, respectively. In addition, a broad diffraction peak appearing at 2θ = 20–30 nm can be indexed to amorphous TiO₂.³⁴ The main peaks for Fe₃O₄@TiO₂ are similar to the standard Fe₃O₄ particles (JCPDS card no. 19-629), which reveal that the crystal structure of Fe₃O₄@TiO₂ is well coated. No obvious diffraction peak for TiO₂ is observed, suggesting that an amorphous TiO₂ coating is formed by the hydrolysis of tetrabutyl titanate (TBOT) in the presence of the well-dispersed Fe₃O₄ nanocrystals by a sol–gel process. Compared to Fe₃O₄@TiO₂, new diffraction peaks located at 29.5 (110), 36.7 (111), 42.5 (200), 52.7 (211), 61.6 (220), and 73.7 (311) can be indexed to the diffraction of Cu₂O rhombic dodecahedral crystals in the cubic phase (JCPDS card no. 05-0667), which suggests the presence of Cu₂O in the desired prepared composites. No additional diffraction peaks were observed, indicating the complete reduction of Cu(II) to Cu(I). It was also observed that by increasing the Cu₂O content in the samples, the intensity of the XRD patterns gradually becomes stronger due to the increase in the Cu₂O/Fe₃O₄@TiO₂ weight ratio.

Fig. 2 XRD patterns of Fe₃O₄@TiO₂ and Fe₃O₄@TiO₂/Cu₂O with different weight ratios.

FE-SEM-EDS and TEM analysis

The morphology and chemical purity of Fe₃O₄, Fe₃O₄@TiO₂, and Fe₃O₄@TiO₂/Cu₂O core–shell composites (optimized amounts) were visualized by SEM and EDX analysis (Fig. 3). The appearance of elemental Au in the EDX analysis as well as the SEM characterization proves that the material was coated by a layer of Au. The SEM image of Fe₃O₄ shows that nearly spherical nanoparticles were obtained with an average diameter of 15–20 nm. Moreover, the energy-dispersive X-ray (EDAX) spectrum depicted in Fig. 4b indicated that the product is mainly composed of nano-Fe₃O₄. It can be observed from Fig. 3c that the as-synthesized Fe₃O₄@TiO₂ core–shell is still maintaining the morphological properties of Fe₃O₄ except for a slightly larger particle size and stifled surface, where TiO₂ is uniformly coated on the Fe₃O₄ particles. The EDAX spectrum shows that the Fe₃O₄@TiO₂ (Fig. 3d) core–shell nanoparticles are elementally composed of Fe, Ti, and O.

Fig. 3 The FEG-SEM-EDS analysis of (a and b) Fe₃O₄, (c and d) Fe₃O₄@TiO₂, and (e and f) Fe₃O₄@TiO₂/Cu₂O (8 : 2) composite.

Fig. 4 TEM image of the Fe₃O₄@TiO₂/Cu₂O (8 : 2) composite.

Fig. 3e shows the SEM image of the Fe₃O₄@TiO₂/Cu₂O composite with the optimized amount of Cu₂O required for catalytic activity in the synthesis of 1,4-disubstituted 1,2,3-triazoles. The Cu₂O shows a rhombic dodecahedral structure and can be easily distinguished from the hybrid material by its different shape, as marked in Fig. 3e. The EDX analysis of the obtained Fe₃O₄@TiO₂/Cu₂O composite reveals the existence of elemental Fe, Ti, Cu, and O, re-confirming the formation of Cu₂O species on the Fe₃O₄@TiO₂ nanospheres.

The TEM image in Fig. 4 vividly shows a uniform coating of thin-layer TiO₂ (approximately 4 nm) around the entire surface of the Fe₃O₄ (approximately 20 nm). The Cu₂O is a bigger and dark particle that can be seen and distinguished in the TEM image.

Magnetization study

The magnetic properties of synthesized Fe₃O₄, Fe₃O₄@TiO₂, and Fe₃O₄@TiO₂/Cu₂O core–shell composite were assessed by a vibrating sample magnetometer at ambient temperature. As illustrated in Fig. 5, the saturation magnetization of the Fe₃O₄ MNPs is 61.6 emu g⁻¹, and those for Fe₃O₄@TiO₂ and the Fe₃O₄@TiO₂/Cu₂O core–shell composite are 29.9 and 24.11 emu g⁻¹, respectively. The decrease in the saturation magnetization of Fe₃O₄ MNPs after surface coating with TiO₂ and Cu₂O can be ascribed to the contribution of the non-magnetic materials. Nonetheless, there was adequate magnetism so that the Fe₃O₄@TiO₂/Cu₂O core–shell composite could be completely, efficiently, and rapidly separated from the reaction mixture.

Fig. 5 The magnetization curves of Fe₃O₄, Fe₃O₄@TiO₂, and Fe₃O₄@TiO₂/Cu₂O.

XPS analysis

The XPS elemental survey scans of the surface of the Fe₃O₄@TiO₂/Cu₂O composite are shown in Fig. 6. The peaks, corresponding to oxygen, titanium, and copper, are clearly observed.

Fig. 6 XPS pattern of the as-synthesized Fe₃O₄@TiO₂/Cu₂O composite.

The corresponding high resolution XPS spectra of the Ti2p, O1s, and Cu2p regions are shown in Fig. 7. The Ti2p XPS spectra showed two major peaks with binding energies of approximately 466.5 and 472.1, corresponding to Ti2p3/2 and Ti2p1/2, respectively, and characteristic of the presence of the TiO₂ phase (Fig. 7a).³⁵ Fe signals were not observed, indicating that the Fe₃O₄ core was well coated by the TiO₂ shell. The observed carbon peak belongs to the carbon tape that is used for XPS analysis. The peak at 931.8 eV is assigned to Cu2p3/2, and the other peak at 952.54 eV is assigned to Cu2p1/2. The additional peaks assigned to Cu2p3/2 and Cu2p1/2 are the two shake-up satellite peaks, appearing at binding energies of 942.3 and 962.5 eV. These are expected for an open 3d⁶ shell and correspond to the Cu¹⁺ state; they are assigned to Cu₂O in accordance with the data given in literature.³⁶ The O1s peak at 538.3 eV found over the catalyst surface can be assigned to OH species in the composite.

Fig. 7 High resolution XPS spectra of the Fe₃O₄@TiO₂/Cu₂O composite showing (a) Ti2p, (b) Cu2p, and (c) O1s.

Catalytic application of the Fe₃O₄@TiO₂/Cu₂O core–shell magnetic composite

After the successful preparation and full characterization of the Fe₃O₄@TiO₂/Cu₂O core–shell magnetic composite, its catalytic activity in different weight ratios of Cu₂O were examined by a model reaction of benzyl bromide, phenyl acetylene, and sodium azide (Huisgen cycloaddition reaction), to obtain 1-benzyl-4-phenyl-1H-1,2,3-triazole 4a (Scheme 2) as the sole product using a 0.01 g magnetic composite under reflux in water. The products were obtained in high yield and with excellent regioselectivity. The result showed that this click reaction proceeded regioselectively, among the other merits concluded from the use of this novel catalyst system for the aforementioned model reaction. In order to establish the strategy, various terminal alkynes, different substituted benzyl bromides, and sodium azide were reacted in the presence of catalytic amounts of Fe₃O₄@TiO₂/Cu₂O core–shell to afford the corresponding 1,4-disubstituted-1,2,3-triazoles, regioselectively and in good yields (Table 3).

Scheme 2 Click reaction catalysed by the nano-Fe₃O₄@TiO₂/Cu₂O core–shell composite.

As shown in Table 1, the catalytic performance of the Fe₃O₄@TiO₂/Cu₂O magnetic composite with a weight ratio of 8 : 2 gave the best result. It was found that no change in yield was obtained with an increase of Cu₂O loading in the magnetic composite. Therefore, the weight ratio of 8 : 2 for Fe₃O₄@TiO₂ : Cu₂O was selected as one of the optimal reaction conditions. The reaction of benzyl bromide (1 mmol), phenylacetylene (1 mmol), and sodium azide (1.3 mmol) was also conducted in various solvents, at different temperatures, and with various loading amounts of the magnetic composite.

Table 1 Optimization of Cu₂O for the magnetic composite in the model reaction^a

Entry	Fe3O4@TiO2 (%)	Cu2O (%)	Yield^b (%)
a Reaction conditions: benzyl bromide (1 mmol), sodium azide (1.3 mmol), phenylacetylene (1 mmol), and catalyst (0.010 g) in water under reflux.b Isolated yield.
1	60	40	93
2	70	30	93
3	80	20	93
4	90	10	82

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The results for the optimization of the reaction conditions are summarized in Table 2. The reaction performed in refluxing water gave the highest product yield, indicating that an inert atmosphere is not required (Table 2, entry 7). We carried out the model reaction in the presence of Fe₃O₄@TiO₂ as a catalyst under reflux in water, and even after 2 h, the product yield was poor (Table 2, entry 8). As expected, the reaction did not proceed in the absence of the catalyst, even after a prolonged reaction time (Table 2, entry 9). This indicates that the magnetic composite as catalyst plays a crucial role in the regioselective synthesis of 1-benzyl-4-phenyl-1H-1,2,3-triazole 4a. A higher reaction temperature or catalyst amount did not make an obvious difference in the product yield (Table 2, entries 6 and 10). However, a lower amount of catalyst decreased the yield of the reaction.

Table 2 Optimization of the three-component click synthesis of 4-phenyl-1H-1,2,3-triazole 4a, using a Fe₃O₄@TiO₂/Cu₂O magnetic composite^a

Entry	Catalyst (g)	Condition	Time (h:min)	Yield^b (%)
a Reaction condition: benzyl bromide (1 mmol), sodium azide (1.3 mmol), and phenylacetylene (1 mmol).b Isolated yield.
1	Fe3O4@TiO2/Cu2O (0.020)	H2O/r.t	2	Trace
2	Fe3O4@TiO2/Cu2O (0.020)	H2O/60 °C	0:15	43
3	Fe3O4@TiO2/Cu2O (0.020)	H2O/80 °C	0:15	79
4	Fe3O4@TiO2/Cu2O (0.020)	H2O/110 °C	0:15	91
5	Fe3O4@TiO2/Cu2O (0.010)	H2O/reflux	0:15	69
6	Fe3O4@TiO2/Cu2O (0.015)	H2O/reflux	0:15	82
7	Fe3O4@TiO2/Cu2O (0.020)	H2O/reflux	0:15	93
8	Fe3O4@TiO2 (0.020)	H2O/reflux	2	Trace
9	—	H2O/reflux	24	—
10	Fe3O4@TiO2/Cu2O (0.025)	H2O/reflux	0:15	93
11	Fe3O4@TiO2/Cu2O (0.020)	H2O/DMSO (2 : 1)/reflux	1:40	58
12	Fe3O4@TiO2/Cu2O (0.020)	CH3CN/reflux	1	75
13	Fe3O4@TiO2/Cu2O (0.020)	EtOH/reflux	0:45	86
14	Fe3O4@TiO2/Cu2O (0.020)	DMF/100 °C	1:45	46
15	Fe3O4@TiO2/Cu2O (0.020)	DMSO/100 °C	1:45	50
16	Fe3O4@TiO2/Cu2O (0.020)	Solvent free/100 °C	2	65

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Thus, with the optimized reaction conditions in hand, the substrate scope of reaction was extended to various structurally diverse terminal alkynes and benzyl halides (Table 3). In an attempt to broaden the generality of the Fe₃O₄@TiO₂/Cu₂O magnetic composite, we further investigated the possibility of reaction of phenacyl bromide with various terminal alkynes and sodium azide in the presence of our novel catalyst and found it promising and fruitful (Scheme 3). The results are listed in Table 4. Under optimal conditions for this one-pot, multi-component reaction, phenacyl bromide 1 mmol, phenylacetylene 1 mmol, and sodium azide 1.3 mmol were reacted in the presence of 0.01 g magnetic composite under reflux in water.

Table 3 Three-component click reaction of benzyl halides, terminal alkynes, and sodium azide using a Fe₃O₄@TiO₂/Cu₂O magnetic composite^a

Entry	Halide precursor	Alkyne	Product	Time (min)	Yield^b (%)	Mp. °C ^Lit
a Reaction condition: alkyl halide (1 mmol), NaN3 (1.3 mmol), acetylene (1 mmol), Fe3O4@TiO2/Cu2O (0.020 g), H2O (2 mL), reflux.b Isolated yield.
1				15	93	127–128 (126–127)^30d
2				20	89	104–106 (105–106)^39
3				30	84	153–156 (156–157)^39
4				20	87	147–149 (150)^40
5				20	91	77–79 (78–78.5)^39
6				20	85	76–77 (77)^39
7				20	89	127–128 (126–127)^30d
8				25	83	104–106 (105–106)^38
9				25	84	143–146 (142–145)^41
10				25	84	147–149 (150)^40
11				20	89	77–79 (78–78.5)^39
12				25	86	76–77 (77)^39

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Scheme 3 Click reaction of phenacyl bromide, phenylacetylene, and sodium azide.

Table 4 Three-component click reaction of phenacyl halides, terminal alkynes, and sodium azide using a Fe₃O₄@TiO₂/Cu₂O magnetic composite^a

Entry	Phenacyl halide	Alkyne	Product	Time (min)	Yield^b (%)	Mp. °C ^Lit
a Reaction condition: α-haloketones (1 mmol), NaN3 (1.3 mmol), acetylene (1 mmol), Fe3O4@TiO2/Cu2O (0.020 g), H2O (2 mL), reflux.b Isolated yield.
1				20	89	169–171 (171–172)^30d
2				25	83	115–118 (116–119)^30d
3				25	86	102–104 (100–103)^30d
4				30	87	157–159 (156–158)^30d
5				50	76	111–113 (110–113)^30d
6				60	75	180–183 (180–183)^30d
7				50	82	156–158 (157–160)^30a
8				75	80	153–155 (151–154)^30a
9				70	78	154–155 (154–155)^30d
10				80	76	168–171 (167–170)^30d

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In general, different substituted phenylacetylenes and benzyl halides bearing electron-donating substituents as well as electron-withdrawing groups smoothly and cleanly provided an array of 1,4-disubstituted 1,2,3-triazoles, in good to excellent yields (75–93%) within relatively short reaction times of 15–80 min. As shown in Tables 3 and 4, the aliphatic terminal alkynes bearing hydroxyl as a functional group gave the desired triazoles in higher yields.

Recycling and leaching of the catalyst

One of the main advantages of heterogeneous catalysis is the ease of separation and possible reusability in further runs.³⁷ Thus, the recyclability of the Fe₃O₄@TiO₂/Cu₂O magnetic composite was examined in a one-pot synthesis of 1-benzyl-4-phenyl-1H-1,2,3-triazole 4a under optimized conditions. No significant loss in catalytic activity was observed after five runs, suggesting that Cu₂O leaching is not meaningful for the Fe₃O₄@TiO₂/Cu₂O magnetic composite (Fig. 8). Another test was performed to determine if the dissolved Cu^I species in the solution was solely responsible for the catalytic activity of the Fe₃O₄@TiO₂/Cu₂O composite. An unfinished experiment was performed whereby we took starting materials and catalyst, the Fe₃O₄@TiO₂/Cu₂O composite, in 3 mL water and refluxed the mixture for 5 min to simulate the actual conditions. At this point, the catalyst was removed by an external magnet while we allowed the reaction to normally proceed. Then we permitted the mixture to reflux in the absence of the magnetically removed catalyst. No appreciable progress was observed even after 2 h (monitored by TLC). Thus, it can be concluded that the dissolved Cu^I species is not actually involved in catalysis, at least solely by itself.

Fig. 8 The recycling results of the Fe₃O₄@TiO₂/Cu₂O composite.

Conclusion

In summary, we have developed an efficient method for the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles through a one-pot multi-component reaction of alkyl halides or phenacyl bromide, terminal alkynes, and sodium azide, catalyzed by a novel and well-characterized nano-Fe₃O₄@TiO₂/Cu₂O core–shell magnetic composite under reflux in water. The merits of this method are that commercially and readily available starting materials are used, and water is used as the solvent, which is green and abundant. Conducting the reaction under conventional conditions with a convenient workup procedure, easy recovery, and efficient reusability of catalyst are conspicuous features of this methodology. Further studies on the scope and application of nano-Fe₃O₄@TiO₂/Cu₂O magnetic composite are underway in our laboratory.

Acknowledgements

The authors gratefully acknowledge Semnan University Research Council for financial support of this work.

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