Fabrication of copper(II)-coated magnetic core-shell nanoparticles Fe3O4@SiO2-2-aminobenzohydrazide and investigation of its catalytic application in the synthesis of 1,2,3-triazole compounds

In the present work, an attempt has been made to synthesize the 1,2,3-triazole derivatives resulting from the click reaction, in a mild and green environment using the new copper(II)-coated magnetic core–shell nanoparticles Fe3O4@SiO2 modified by isatoic anhydride. The structure of the catalyst has been determined by XRD, FE-SEM, TGA, VSM, EDS, and FT-IR analyzes. The high efficiency and the ability to be recovered and reused for at least up to 6 consecutive runs are some superior properties of the catalyst.

www.nature.com/scientificreports/ In this work, we report on a new silica-supported magnetic copper catalyst used in 1,2,3-triazole synthesis. How to prepare, the identification and characterization and the application in AAC reaction are described below.

Results and discussions
Fe 3 O 4 nanoparticles were synthesized using the co-precipitation method reported in the literature 25,26 . In the next step, to prepare the core-shell nanoparticles, silica coating was done under the Stober process. Then, the core-shell nanoparticles have been modified by isatoic anhydride (Scheme 1).
The FT-IR spectra corresponding to each stage of catalyst preparation are shown in Fig. 3. In the spectrum of sample A 1 , the two bands exhibited at 561, and 630 cm −1 are attributed to the Fe-O stretching vibration. Furthermore, the band located at 1627 cm −1 is assigned to O-H vibrations absorbed on the surface of Fe nanostructures. In sample A 2, four new bands at 1085 and 950, 802, and 466 cm −1 have been appeared, which correspond to the asymmetric stretching vibration of Si-O-Si, stretching vibration of the silica shell Si-OH, symmetric stretching vibrations of Si-O-Si, and the Fe-O-Si stretching vibration, respectively. In sample A 3 , the C-Cl bond absorption is expected to be about 800 cm −1 which is covered by Si-O-Si symmetric stretching vibration band. The new bands appearing in the 2981 cm −1 , which is partially covered by the wide range of the O-H band, and the band at 1400 cm −1 are attributed to the C(sp 3 )-H stretching, and bending vibrations. In sample A 4 , bands related to the stretching vibrations of the first and second types of amines appear at 3379 and 3440 cm −1 . This area is also entirely covered with wide O-H band. In sample A 5 , the new band that appeared in 1652 cm −1 is related to the absorption of C = O of the amide group.
Energy-dispersive X-ray spectroscopy (EDS) analysis shows copper ions in the structure of the catalyst, along with C, N, O Si, and Fe atoms (Fig. 4). The quantitative results from EDS analysis of Cu(II)MNPs are given in Table 1.
The    On the other hand, due to the scattering and small amount of copper ions in the catalyst structure, no new peak is observed in the spectrum of the final sample. The peak list of the samples A 1 , A 2 and A 5 has been given in Table 2. This is a fact that magnetite (Fe 3 O 4 ), and maghemite (γFe 2 O 3 ) present a cubic structure and lattice parameters very close together; for this reason, it is difficult to differentiate these structures even if both phases exhibit high crystallinity. However, some authors report that in the XRD pattern associated with the maghemite phase, there exist two additional peaks located at 23.77° (210) and 26.10° (211). These intensities can be used to differentiate the magnetite phase 25 . We did not observe these two peaks in the XRD obtained (Fig. 5). To prevent the formation of other phases of iron oxide (e.g., γ-Fe 2 O 3 and FeO) in the co-precipitation method, we removed the oxygen from the reaction environment during the formation of the magnetic nanoparticle by applying a nitrogen atmosphere as suggested in literature 26 .
Field emission scanning electron microscopy (FE-SEM) images in Fig. 6 show the nanoparticles morphology. According to these images, the diameter of Fe 3 O 4 particles is approximately 26 ± 8 nm. The diameter is 42 ± 10 nm for Cu(II)MNPs particles. This increase in size is mainly due to the multi-layered coating of silica and functionalization by organic matter around the core.
Vibrating-sample magnetometry (VSM) has been performed to investigate the magnetic properties of Fe 3 O 4 NPs (A 1 ), Fe 3 O 4 @SiO 2 -(CH 2 ) 3 Cl (A 3 ), and Cu(II)MNPs with thick silica shell at room temperature. In Fig. 7, the hysteresis loops characteristic of superparamagnetic behavior can be observed for all samples. Super-paramagnetism implies re-dispersion of the magnetic nanoparticles in solution without the occurrence of severe aggregation that ferromagnetic nanoparticles usually suffer from.
The thermogravimetric analysis (TGA) curves in Fig. 8 provide information on the thermal stability and material weight loss by temperature. In sample Cu(II)MNPs, in the temperature range of 35-170° C, 1% of the mass is reduced due to the loss of tiny amounts of water and solvent molecules that were adsorbed. The second stage begins gradually with the burning of the organic part of the catalyst at 170 °C and ends at 540 °C. A 12% reduction in mass has been observed, which is related to the organic materials stabilized on the catalyst.
We investigated the performance of the catalyst by applying it to the click reaction and forming 5-membered heterocycles, and performed the reaction between an alkyne and an azide in aqueous and organic environments.
Some azides are first made separately, and then added to the reaction mixture. If organic halides are used instead of prefabricated azides, the reaction is performed by adding sodium azide under one-pot conditions. Also, the addition of sodium ascorbate is necessary to convert copper(II) to copper(I) (Scheme 2). www.nature.com/scientificreports/   www.nature.com/scientificreports/   www.nature.com/scientificreports/ In Scheme 3, the amount of catalyst and the effect of temperature on the reaction between phenyl acetylene and benzyl bromide as a model reaction is optimized. The highest yield is obtained in 3 h at 50 °C, by using 0.05 g catalyst or more for one mmole of reactants. We considered this value as the optimal value. Also, in the absence of the catalyst (even by applying a temperature of 50 °C), the reaction did not take place after 18 h. On the other hand, in 3 h and with the optimal amount of the catalyst, lowering the temperature causes the reaction yield to decrease.
The scope of the method has been investigated by using different starting materials (Tables 3, 4). According to the results of Table 3, it is observed that better leaving of bromide group than chloride in organic halides, facilitates the reaction conditions and the products are formed under milder conditions. Also, if an acetylene with less space congestion was used, the reaction proceeded smoothly. The best result in the shortest time was related to the use of benzyl bromide and propargyl alcohol. The results from using pre-formed organic azides has been listed in Table 4. Table 5 shows the comparison between the catalytic activity of Cu(II)MNPs and some other heterogeneous and homogeneous catalytic systems reported before in the reaction of benzyl bromide, NaN 3 , and phenylacetylene. According to Table 5, in addition to improving the efficiency and reaction time in this work, the reaction environment is more green.  www.nature.com/scientificreports/ Figure 9 investigates the catalyst reusability in the reaction between phenylacetylene, benzyl bromide, and sodium azide. The reaction time for each step was 3 h. The results showed no significant reduction in efficiency up to at least six stages of recovery and reuse of the catalyst. After each run, the catalyst was separated with an external magnet and washed once or twice with ethyl acetate, ethanol, and distilled water. Then, to dry and reuse, it was placed in an oven at 80 °C for 12 h. At each step, the reaction efficiency was calculated separately, and no significant reduction in reaction efficiency was observed after repeated cycles.
A plausible mechanism for the reaction is given in Scheme 4. It is postulated that the copper-catalyzed azidealkyne cycloaddition (CuAAC) is carried out by the 1,3-dipolar cycloaddition reaction, between alkyl azide and acetylenic compound. The suggested mechanism has been studied and approved elsewhere [27][28][29] .
The present catalyst is supposed to supply Cu(I) ions in situ from the reaction of Cu(II)MNPs with ascorbic acid. Propyltrimethoxysilane moiety in the catalyst structure was intended to be the boundary between the chelating group and the inorganic substrate. The purpose of this work was preparing a tridentate ligand linked to a heterogenous magnetic substrate (capable of being separated from the reaction mixture easily), binding cupper ions effectively, to avoid a leaching in the solvent.

Experimental
General. All materials used were commercially available and purchased from Merck and used without any additional purification. 1 H NMR spectra were recorded on a Varian-INOVA 500 MHz spectrometer using DMSO as solvent at room temperature. Chemical shifts δ were reported in ppm relative to tetramethylsilane as an internal standard. FTIR spectra of samples were taken by KBr pellets using a Shimadzu FTIR-8400S spectrophotometer. Surface morphology was observed using a Tescan MIRA3 Field Emission Scanning Electron Microscopy (FE-SEM). Thermogravimetric analyses were performed under an air atmosphere in a TGA Q50 with a rate of ca. 20 °C per minute. Magnetization measurements were carried out on a BHV-55 vibration sample magnetometer (VSM). Elemental analysis was performed using EDS analysis, which was recorded by Tescan VEGA/XMU. X-ray diffraction (XRD) powder patterns were obtained using a Bruker D8 ADVANCE, with Cu www.nature.com/scientificreports/ Kα radiation. The melting points of the prepared derivatives were measured by an Electrothermal 9100 apparatus reported without any correction. Coating with silica shell by Stober method. One g of Fe 3 O 4 , 20 mL of distilled water, and 60 mL of ethanol were added to the reaction container. Then, the reaction mixture was placed in an ultrasonic bath for half an hour. After that, 3 mL of 25% ammonia solution was added to the reaction container and stirred by a mechanical stirrer at room temperature. Simultaneously, 5 mL of tetraethyl orthosilicate was added dropwise to the reaction container. After 12 h, the product was collected by an external magnet and washed several times with distilled water and ethanol, and then dried in an oven at 60°C 32,33 .

Synthesis of Fe 3 O 4 by co-precipitation method.
Functionalization of the surface of the silica shell with 3-chloropropyltrimethoxysilane. One g of Fe 3 O 4 @SiO 2 and 40 mL of ethanol were added to the reaction container and placed in an ultrasonic bath for 10 min. The temperature was adjusted to 70 °C, and 1.75 mL of CPTMS was added dropwise to the reaction mixture. After 24 h, the reaction product was collected by an external magnet and washed several times with ethanol, and then dried in an oven at 60 °C.
Substitution of hydrazine hydrate with chlorine positions on the nanomagnetic substrate. The product obtained from the previous step was added to 30 mL of ethanol. 0.2 mL of hydrazine hydrate was added dropwise to the reaction mixture at 70 °C and vigorous stirring. After overnight, the product was collected by an external magnet and washed several times with water and alcohol, and then dried in an oven at 60 °C.
Increase of isatoic anhydride to hydrazine positions. 30 mL of ethanol was added to the product obtained from the previous step, and the reaction mixture was stirred continuously with a mechanical stirrer. Then, isatoic anhydride (2.4 mmol, 0.4 g) was added to the reaction container at 70 °C. After one day, the product was separated by an external magnet and washed several times with acetone, and dried in an oven at 60 °C.
Loading of copper (II) metal cation. The product obtained from the previous step was added to 25 mL of ethanol, and the reaction temperature was set at 70 °C. Then, 0.24 g of copper (II) acetate was added to the reac- www.nature.com/scientificreports/ tion container, and the reaction mixture was stirred vigorously. After 24 h, the reaction product was separated by an external magnet and washed several times with water and ethanol. Finally, Cu(II)MNPs were dried at 60 °C. Copper-catalyzed 1,3-dipolar cycloaddition of azides to alkynes. First, NaN 3 (1.1 mmol, 72 mg) was added to 1 mmol of organic halides to prepare the organic azides, then 1 mmol of alkyne was added to the  Table 4. Synthesis of 1,2,3-triazole derivatives from organic azides. www.nature.com/scientificreports/ corresponding mixture. In the next step, the reaction mixture was added to the pre-prepared suspension of 3 mL of distilled water or DMF, catalyst (0.5 g), and sodium ascorbate (the size of a Scoopula tip). The reaction temperature was adjusted according to the solvent type, and the reaction was followed by TLC. At the end of the reaction, 30 mL of distilled water was added and extracted with ethyl acetate (3 × 10 mL), dried with MgSO 4 , and filtered. Finally, the solvent was evaporated by rotary. If organic azides are used in the reaction instead of organic halides, NaN 3 is not added to the reaction mixture.

Conclusion
Synthesis of 1,2,3-triazole derivatives was performed using a copper(II)-coated magnetic core-shell nanoparticles Fe 3 O 4 @SiO 2 modified by isatoic anhydride, as a new high-performance catalytic system. Due to its magnetic properties, it is effortless to separate this catalyst by applying an external magnetic field. On the other hand, due to the complete removal of the catalyst from the reaction environment, it is possible to use this catalyst in drug synthesis applications. High thermal stability makes it possible to use this catalyst in organic reactions under high temperatures. Dispersability in organic and aqueous solvents provides conditions for use in both environments. The simple and easy manufacturing method of this catalyst, along with the ability to recover and reuse, makes it economical. The high efficiency of the click reaction in polar solvents and the high boiling point of the solvent to facilitate the reaction led to the selection of DMF as an alternative solvent for those reactions that do not occur in an aqueous environment. Also, the dispersion of catalyst particles in DMF is higher than in water.