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Mesoporous halloysite nanotubes modified by CuFe2O4 spinel ferrite nanoparticles and study of its application as a novel and efficient heterogeneous catalyst in the synthesis of pyrazolopyridine derivatives

In this study, mesoporous halloysite nanotubes (HNTs) were modified by CuFe2O4 nanoparticles for the first time. The morphology, porosity and chemistry of the CuFe2O4@HNTs nanocomposite were fully characterized by Fourier transform infrared (FT-IR) spectroscopy, field-emission scanning electron microscopy (FE-SEM) image, transmission electron microscope (TEM) images, energy-dispersive X-ray (EDX), X-ray diffraction (XRD) pattern, Brunauer-Emmett-Teller (BET) adsorption-desorption isotherm, thermogravimetric (TG) and vibrating sample magnetometer (VSM) curve analyses. The results confirmed that CuFe2O4 with tetragonal structure, uniform distribution, and less agglomeration was located at HNTs. CuFe2O4@HNTs nanocomposite special features were high thermal stability, crystalline structure, and respectable magnetic property. SEM and TEM results showed the nanotube structure and confirmed the stability of basic tube in the synthetic process. Also, inner diameters of tubes were increased in calcination temperature at 500 °C. A good magnetic property of CuFe2O4@HNTs led to use it as a heterogeneous catalyst in the synthesis of pyrazolopyridine derivatives. High efficiency, green media, mild reaction conditions and easily recovery of the nanocatalyst are some advantages of this protocol.

macroporosity of HNTs have been applied in several areas such as environmental uses 14 , tissue engineering 15 , cosmetic 16 , medicine 17 and catalysis 18 . HNTs with two kinds of hydroxyl groups in the inside and outside walls can be modified by different functional groups. Recently, several studies have been carried out for deposition of MNPs onto the HNTs and the developed nanocomposites with enhanced abilities could be used in various applications 19,20 .
Multicomponent reactions (MCRs) with features like atom economy, experimental simplicity, synthetic efficiency and formation of several bonds in one unit operation have been proposed in the synthesis of biologically-active organic compounds particularly in the case of heterocycles such as pyrazolopyridines 21 . Pyrazole derivatives are one of the most important nitrogen-containing heterocyclic compounds with antileishmanial 22 , antimicrobial 23 and antiviral 24 properties. Due to these biological and pharmacological properties, synthesis of pyrazoles has received considerable attention in chemistry. Several methods have been reported for the synthesis of pyrazolopyridines in the presence of diverse catalysts such as L-proline in [bmim]BF 4 25 , acetic acid 26 , CuCr 2 O 4 NPs 27 and cellulose-based magnetic nanocomposite 28 . Most reports have some disadvantages like using non-reusable and toxic catalysts, harsh reaction conditions, low yields of products and long reaction times. As a result, for the synthesis of heterocyclic compounds with more efficient procedures, improvement of existing methods by using the natural-based nanocatalyst has been emphasized.
From the above-mentioned viewpoints and according to previous scientific reports 29,30 , in this research, CuFe 2 O 4 @HNTs as a novel, eco-friendly and mesoporous magnetic nanocatalyst was designed, synthesized, characterized and applied in a one-pot multicomponent reaction as a heterogeneous catalyst. Synthesis of pyrazolopyridine derivatives (5a-k) starting from hydrazine hydrate, ethyl acetoacetate, aromatic aldehydes and ammonium acetate were achieved in high-to-excellent yields at ambient conditions (Fig. 1).

Results and Discussion
In this research, CuFe 2 O 4 @HNTs as a mesoporous nanocomposite was synthesized by a simple method using eco-friendly materials. The properties of this novel and retrievable magnetic nanocomposite such as nanotube morphology, thermal stability, porosity, magnetic properties were examined by different analyses like FT-IR, FE-SEM, TEM, BET, EDX, XRD, TGA and VSM. The catalytic performance of CuFe 2 O 4 @HNTs was checked in the synthesis of pyrazolopyridines. The sustainable nanocatalyst can be easily reused after 8 runs.
Characterization of the prepared CuFe 2 o 4 @HNTs nanocatalyst. FT-IR spectroscopy as a primary method was performed to indicate the formation of CuFe 2 O 4 @HNTs nanocomposite (Fig. 2). As can be seen, the absorption bands at 543 and 470 cm −1 were assigned to the bending vibration of Al-O-Si and Si-O-Si, respectively. The absorption band at 910 cm −1 is related to deformation of inner hydroxyl groups of Al-O-H, also, the absorption band at 1114 cm −1 is ascribed to the Al-OH bending vibration. Si-O stretching band was appeared at  The thermal stability of the synthesised nanocomposite was studied by TGA analysis in the air atmosphere and heating rates at 10 °C/min, over the temperature range of 50-800 °C (Fig. 2b). As can be seen in HNTs TGA curve, the losing weight of HNTs was about 20% between 50 to 800 °C and is related to molecules which are physically absorbed on to the surface of HNTs and loss of hydroxyl groups. The thermal stability of HNTs was improved in the presence of CuFe 2 O 4 NPs. CuFe 2 O 4 @HNTs nanocomposite doesn't decompose easily and at high temperatures showed a little weight loss.
EDX was applied to identify the elements of CuFe 2 O 4 @HNTs nanocomposite. The nanocatalyst included different elements such as iron, copper, oxygen, aluminum and silicon. The result of the EDX analysis shown in Fig. 3a, confirms the presence of all elements at different percentages.
The magnetic recovery of a nanocomposite is one of its most important properties. In the previously reported study, the magnetization of neat CuFe 2 O 4 NPs was around 45 electromagnetic units per gram (emu g −1 ) 33 . As displayed by VSM analysis (Fig. 3b), the saturation magnetization values of CuFe 2 O 4 @HNTs nanocomposite was around 30 emu g −1 . The loading of CuFe 2 O 4 NPs on HNTs causes the saturation magnetization level to decrease and confirms the synthesis of the nanocomposite. However, this magnetic property is acceptable and nanocomposite can be easily separated from the reaction mixture.
The size distribution and the morphology of the nanocomposite were examined by FE-SEM image analysis. As can be seen in Fig. 4a, the structure of the basic tubes of HNTs were stable but the inner diameters of tubes were increased during the synthesis of the nanocomposite at 500 °C and have the capacity for greater loading of CuFe 2 O 4 NPs on the outer and inner surface of HNTs. Roughness and particles with regular shapes on the surface of nanotubes confirmed the synthesis of CuFe 2 O 4 NPs. These MNPs were distributed with uniform size of 35.88 nm.
Also, TEM image analysis was used to reveal the MNPs location (Fig. 4b,c). The TEM images of the nanocomposite clearly showed the cylinder-shaped of the HNTs and loading of CuFe 2 O 4 NPs in inside and outside of nanotubes in gray color.
The surface area, pore volume and pore size properties of CuFe 2 O 4 @HNTs nanocomposite were determined by nitrogen adsorption and desorption analyses. Adsorption isotherm is shown in Fig. 5a. As can be seen, this  www.nature.com/scientificreports www.nature.com/scientificreports/ isotherm could be categorized to the class of type IV as a mesoporous material l according to IUPAC classification 34 . As stated in reported articles, BET surface area of HNTs is around 47.8 m 2 g −1 , while, CuFe 2 O 4 @HNTs nanocomposite show a slight increase to 51.13 m 2 g −1 . This result confirmed the loading of CuFe 2 O 4 on HNTs . Also, due to the placement of CuFe 2 O 4 inside the HNTs, the pore volume of CuFe 2 O 4 @HNTs decreased to 0.126, by comparison with the reported pore volume 35 . In addition, owing to the calcination process, the pore size of CuFe 2 O 4 @HNTs increased to 9.87 (Fig. 5b).
In order to investigate the morphology and crystallinity of CuFe 2 O 4 @HNTs, XRD pattern was studied. As shown in Fig. 6b, CuFe 2 O 4 NPs with tetragonal structure was loaded in inner and outer of HNTs. The diffraction angles (2θ) 18.59, 30.14, 36.12, 38.99, 44.00, 54.18 and 62.37 are fully complied with the characteristic data of (JCPDS card no. 00-034-0425). The typical diffraction peaks of HNTs appeared at 12.62° and 20.26° (Fig. 6a), but during the synthesis of nanocomposite and calcination in the temperature of 500 °C, crystalline structure of HNTs changed to amorphous structure and gentle peak in 25.61 appeared 35 . Catalytic application of CuFe 2 o 4 @HNts nanocatalyst in the synthesis of pyrazolopyridine derivatives. The catalytic application of the nanocomposite has been investigated in the synthesis of pyrazolopyridine derivatives. In order to optimize the reaction condition, the four-component reaction of hydrazine hydrate 1 (2 mmol), ethyl acetoacetate 2 (2 mmol), benzaldehyde 3 (1 mmol), and ammonium acetate 4 (3 mmol) was chosen as the model reaction. Different catalysts, solvent and their ratios were studied. It was found that CuFe 2 O 4 @HNTs nanocomposite shows an excellent catalyst activity as compared with the single component of CuFe 2 O 4 or HNTs. Apparently, the HNTs structure caused loading the MNPs inside and outside of the tubes and  www.nature.com/scientificreports www.nature.com/scientificreports/ increasing the efficiency of the catalyst. Also, composite CuFe 2 O 4 and HNT S prevent the agglomeration of MNPs and improved the efficiency of the catalyst. A considerable yield was obtained in the presence of 50 mg of the catalyst. In addition, this procedure showed significant improvements in the time and yield. The results summarized in Table S1 in Supplementary Information File.
The efficiency of this protocol was examined by using a series of different aldehydes. All of the aromatic aldehydes having either electron-withdrawing or electrondonating substituents produced pyrazolopyridine derivatives (5a-k) in high-to-excellent yields. The results are summarized in Table 1.
A Hantzsch-type mechanism for the formation of pyrazolopyridine derivatives was proposed in Fig. 7. As can be seen, CuFe 2 O 4 @HNTs nanocomposite as a Lewis acid plays an important role in all parts of the reaction and accelerated the multicomponent process.
According to the reported article 36 Table 1. Synthesis of pyrazolopyridine derivatives 5a-k in optimal conditions a . www.nature.com/scientificreports www.nature.com/scientificreports/ III in the presence of CuFe 2 O 4 @HNTs gave compound IV. Finally, intramolecular cyclization, dehydration and, tautomerization of compound IV provided 5a-k.

Reusability study of CuFe 2 o 4 @HNTs nanocomposite.
Catalyst's reusability is among the most significant factors in view of industrial and commercial aspects. For that reason, recoverability and reusability of CuFe 2 O 4 @HNTs nanocatalyst was explored. After the first test, the catalyst was recovered by the use of an external magnet from the model reaction. The recovered catalyst was washed several times with ethanol to remove any organic products and dried. Then, it was used again in the next runs under the same reaction conditions. Recyclability of the catalyst was evaluated for eight runs without significant decrease in activity (Fig. S5). Also, in order to investigate the stability of the recycled catalyst, it was identified by FT-IR and EDX analyses (see Figs S6 and S7 in Supporting Information File). experimental General. Chemicals were purchased from Sigma-Aldrich and Merck companies and applied without any further purifications. Fourier transforms infrared (FT-IR) spectra were recorded on a Shimadzu IR-470 spectrometer by the method of KBr pellet. Melting points were measured on an Electrothermal 9100 apparatus. Fieldemission scanning electron microscopy (FE-SEM) was performed by a MIRA 3 TESCAN microscope with an attached camera. Transmission electron microscopy (TEM) images were obtained by a Philips CM120 instrument. Brunauer-Emmett-Teller (BET) analysis was achieved by micromeritics ASAP 2020. Thermogravimetric analysis (TGA) was taken by Bahr-STA 504 instrument. X-ray diffraction (XRD) measurements were reported on a JEOL JDX-8030 (30 kV, 20 mA). Elemental analysis of the nanocatalyst was carried out by energy-dispersive X-ray (EDX) analysis recorded Numerix DXP-X10P. Lakeshore 7407 (Meghnatis Kavir Kashan Co., Iran) vibrating sample magnetometers (VSMs) was used for examining the magnetic measurement of the solid sample. 1 H and 13 C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker DRX-300 Avance spectrometer at 300 and 75 MHz, respectively.
Preparation of CuFe 2 o 4 @HNTs. 0.477 g (1.17 mmol) of Fe(NO 3 ) 3 .9H 2 O and 0.14 g (0.58 mmol) of Cu(NO 3 ) 2 .3H 2 O dissolved in 20 mL distilled water. Then, 0.50 g of HNTs was added to metal ions solution and the mixture was stirred for 1 h at room temperature. To provide nanocomposite, 5 mL solution of NaOH (0.50 g, 12 mmol) was added dropwise during 10 min to the initial mixture at room temperature. The final mixture was warmed at 90 °C and stirred for 2 h. The black precipitate of CuFe 2 O 4 @HNTs was separated by an external magnet and washed 4 times with distilled water. The synthesized nanocomposite was dried in air oven at 80 °C for 4 h and kept in a furnace at 500 °C for 5 h.
General procedure for the synthesis of pyrazolopyridine derivatives 5a-k. A mixture of hydrazine hydrate 1 (2 mmol), ethyl acetoacetate 2 (2 mmol), aromatic aldehydes 3 (1 mmol), and ammonium acetate 4 (3 mmol), in the presence of CuFe 2 O 4 @HNTs nanocatalyst (5 mg) was reacted in ethanol at room temperature. After 20 min, completion of the reaction was screened by thin layer chromatography (TLC). Then, the catalyst was separated simply by an external magnet. By addition of water to the reaction mixture, pure precipitated products were obtained, filtered and washed with further water. In most cases, no further purification was necessary. All the product were known compounds which were identified by comparison of their melting points with those authentic literature samples (Table 1).
Spectral data of the selected products. 3

Conclusions
In summary, a novel, environmentally-friendly, low-cost and reusable magnetic mesoporous HNTs were achieved via an efficient synthetic process at 500 °C. The structure, morphology, magnetic properties and thermal stability of the nanocomposite were assessed by using different analytical techniques. SEM and TEM images confirmed the stability and integrity of basic tube structure of HNTs and also, good dispersion of CuFe 2 O 4 NPs. The porosity of CuFe 2 O 4 @HNTs nanocomposite was calculated by BET analysis and the loading of CuFe 2 O 4 into and onto the HNTs were confirmed by pore volume and pore size information. XRD analysis approved the loading of CuFe 2 O 4 NPs by the tetragonal structure. In addition, other unique features of the nanocomposite such as thermal stability and magnetic property were examined by TG and VSM analyses. To prove the catalytic ability of the present nanocomposite, it was used as an efficient and recyclable heterogeneous nanocatalyst in the synthesis of pyrazolopyridine derivatives via a four-component reaction. The products were obtained in high-to-excellent yields at room temperature under mild reaction conditions. The catalyst can be easily recovered and reused several times without significant activation loss by simple washing and drying. Furthermore, this is the first report on design, preparation, functionalization and characterization of the present nanocomposite and its performance as a heterogeneous catalyst in an important organic reaction.