Preparation and catalytic application of two different nanocatalysts based on hexagonal mesoporous silica (HMS) in synthesis of tetrahydrobenzo[b]pyran and 1,4-dihydropyrano[2,3-c]pyrazole derivatives

The present study describes the synthesis, characterization, and investigation of catalytic activity of xanthine-Ni complex (Xa-Ni) and 4-phenylthiosemicarbazide-Cu complex (PTSC-Cu) incorporated into functionalized hexagonal mesoporous silica (HMS/Pr-Xa-Ni and HMS/Pr-PTSC-Cu). These useful mesoporous catalysts had been synthesized and identified using various techniques such as FT-IR, XRD, adsorption–desorption of nitrogen, SEM, TEM, EDX-Map, TGA, AAS and ICP. These spectral techniques successfully confirmed the synthesis of the mesoporous catalysts. The catalytic activity of HMS/Pr-a-Ni (Catalyst A) and HMS/Pr-PTSC-Cu (Catalyst B) were evaluated for synthesis of tetrahydrobenzo[b]pyran and 1,4-dihydropyrano[2,3-c]pyrazole derivatives. HMS/Pr-PTSC-Cu exhibited higher efficiency in green media under milder reaction condition at room temperature. Furthermore, the synthesized nanocatalysts, exhibited appropriate recoverability that can be able to reuse for several times without significant loss of catalytic activity.

www.nature.com/scientificreports/ attributed to Si-O-Si symmetric and asymmetric stretching vibration respectively 6 . The C-H stretching vibrations, in spectrum of HMS/Pr (b), are appearing in the range of 2854-2959 cm −1 . As shown in spectrum of HMS/ Pr-Xa (c), the peak at 3436 cm −1 could be ascribed to the N-H stretching vibration also carbonyl of amid group contributed to xanthine, located at 1654 cm −1 . In the spectrum of HMS/Pr-Xa-Ni (d) this peak shifts to 1635 cm −1 due to the coordination with the metal of Ni.
Low angle X-ray diffraction (XRD) patterns of HMS and HMS/Pr-Xa-Ni are indicated in Fig. 4. In these patterns, there was distinct peak at 2θ angles about of 2.6 4 . After functionalization, the hexagonal structure of  www.nature.com/scientificreports/ HMS was preserved also the location of peak was consistent with the standard diffraction pattern of HMS. As shown in Fig. 4, the decrease in intensity of the characteristic diffraction peak belongs to catalyst, rather than HMS, was confirmed that organic moieties on the pore wall of HMS was successfully immobilized. The reason can also be known as the decrease in the mesoscopic order of the materials. The thermo-gravimetric analysis (TGA) was applied for investigation of the thermal stability of HMS/Pr-Xa-Ni and determination of the amount of organic groups incorporated into HMS. As shown in Fig. 5, the weight loss below 150 °C contributed to the removal of physically adsorbed water and organic solvent. Immobilization of Pr-Xa-Ni in the surface of pores was revealed with their decomposition, that weight loss about 12% was indicated at temperatures 150-600 °C. Also, Ni content loaded in modified HMS in the HMS/Pr-Xa-Ni was 0.09 mmol g −1 that defined by ICP-AES analysis.
The morphology and particle size of the synthesized catalyst was defined by a scanning electron microscopy (SEM) (Fig. 6) and TEM analysis (Fig. 7). Figure 6 illustrates the SEM images of HMS/Pr-Xa-Ni. This analysis has shown that the prepared catalyst has regular and ordered structure. Also, the SEM images illustrated that synthesized nanocatalyst has nanometer-sized particles with an average diameter less than 27 nm. The nanocatalyst A sample is further studied by transmission electron microscopy (TEM) to obtain insight into its structural and morphological features. The nanocatalyst A TEM images display the distribution of catalyst nanoparticles of size below 50 nm.
The particle size distribution histogram of HMS/Pr-Xa-Ni was indicated in Fig. 7c. The average size of the particle is 10.00 nm with 1.93 nm standard deviation.
EDX spectrum of synthesized catalyst characterized elemental composition in the catalyst. As shown in Fig. 8, the presence of elements of Si, O, N, C and Ni were confirmed in the EDX analysis of HMS/Pr-Xa-Ni. Also the map image revealed dispersion of all elements (Si, O, N, C and Ni) of the catalyst and confirmed the good dispersion of Ni on the surface of the HMS/Pr-Xa-Ni (Fig. 9). Figure 10 shown the nitrogen adsorption-desorption isotherms of HMS and HMS/Pr-Xa-Ni. According to the IUPAC classification, N 2 adsorption/desorption isotherms of HMS and HMS/Pr-Xa-Ni showed typically   11 . By N 2 isotherms, physicochemical and structural parameters of the samples were obtained containing BET surface area (S BET ), total pore volumes (V total ) and pore diameters (D BJH ) ( Table 1). More importantly, the decrease in S BET , D BJH and V total of HMS/Pr-Xa-Ni rather than HMS, are due to successfully immobilization of Pr-Xa-Ni in pore of the HMS. For confirmation of functional groups, in catalyst B, in HMS (a), HMS/Pr (b), HMS/Pr-PTSC (c) and HMS/ Pr-PTSC-Cu (d) the FT-IR spectroscopy was investigated that indicated in Fig. 11.
In the FT-IR spectra of HMS (a), the peak appeared at 3433 cm −1 contributed to silanol group. Also, the peaks at 804 cm −1 and 1074 cm −1 demonstrated that ascribed to Si-O-Si symmetric and asymmetric stretching vibration respectively 4 . The FT-IR spectrum of HMS/Pr which is illustrated in Fig. 11b shows peaks at 784 cm −1 and 1048 cm −1 relating to the Si-O-Si symmetric and asymmetric stretching vibration respectively. Another peak at 2864 cm −1 is contributed to the C-H stretching vibrations. In the spectrum of HMS/Pr-PTSC (C) C-H stretching of the alkyl group are detected by the peaks at 2913-2945 cm −1 . As shown in spectrum of HMS/Pr-PTSC (C) and HMS/Pr-PTSC-Cu (d), symmetric and asymmetric stretching vibration of Si-O-Si are appearing in 806 cm −1 and 1090 cm −1 . Also, the peaks of 1400 cm −1 and 1631 cm −1 are contributed to (C=C) aromatic ring. In the spectrum of catalyst the existence of NH is confirmed by peak that appears in 3436 cm −1 .
Thermogravimetric curves of HMS and HMS/Pr-PTSC-Cu at the temperature range of 25 °C to 800 °C shown in Fig. 12. The thermal behaviour of catalyst shows three weight losses. The first weight loss (mass change: 5.7%) below 220 °C contributed to volatilization of the physically adsorbed water and organic solvent. The second step contains 17% weight loss between 220-600 °C and for the third step 5.6% weight loss between 590-800 °C observed. These results indicated that HMS/Pr-PTSC-Cu is stable to 220 °C (only 5.7% weight loss in this temperature range). In addition, about 17% weight loss observed between 220-600 °C attributed to decomposition of groups that attached in the surface of pores of support that confirmed successful synthesis of the catalyst. www.nature.com/scientificreports/ In order to define the exact amount of Cu loaded on functionalized HMS in synthesized catalyst, atomic adsorption spectroscopy (AAS) was performed whereupon, the exact loading of Cu in the HMS/Pr-PTSC-Cu was obtained 0.63 mmol/g.
The crystallinity of HMS and synthesized mesoporous catalyst (HMS/Pr-PTSC-Cu) was observed by low angle XRD pattern (Fig. 13). Patterns display one sharp reflection. This comparison explains and confirms this fact that, there is no changes in the phase of HMS during functionalization process 4 . Figure 14 presents the SEM images of HMS/Pr-PTSC-Cu. SEM analysis was applied to determine its morphology and size distribution. It can be seen from SEM images that HMS/Pr-PTSC-Cu possessed regular and ordered structure with particle sizes of less than 23 nm. TEM images of HMS/Pr-PTSC-Cu (a, b) and particle      www.nature.com/scientificreports/ Also, for specification of dispersion of all elements of the synthesised catalyst, the map analysis was applied that as illustrated in Fig. 17, the elemental map images confirmed the good dispersion of C, N, O, Si, S and Cu in HMS/Pr-PTSC-Cu.
A textural property of HMS/Pr-PTSC-Cu was obtained by nitrogen adsorption/desorption analysis and indicated in Table 2. Based on this analysis, BET surface area (S BET ), total pore volumes (V total ) and pore diameters (D BJH ) of prepared catalyst were determined. Also, N 2 adsorption-desorption isotherm showed in Fig. 18.
In order to optimize the reaction conditions, many reactions were undertaken wherein the amount of catalyst, various solvents and different temperature were checked (Table 3). In this light the reaction of 4-chlorobenzaldehyde (1 mmol), malononitrile (1 mmol), dimedone (1 mmol) and HMS/Pr-Xa-Ni as catalyst was selected as model reaction. After evaluation of effect of mentioned factors on the model reaction, the results were revealed that 0.04 g of HMS/Pr-Xa-Ni in H 2 O: EtOH (3:1 mL) at 80 °C was found to be ideal reaction condition for the synthesis of tetrahydrobenzo[b]pyran. For investigation of necessity of presence of nickel in promote of the reaction, the reaction was under taken in presence of HMS/Pr-Xa. The yield of this reaction was 30% (Table 3, entry 12).
In order to explore the scope and the limitations of this novel and heterogenous catalytic system, for the synthesis of tetrahydrobenzo[b]pyran (1a-k), we evaluated the reaction using wide range of electron-withdrawing and electron-donating substituted aldehyde (Fig. 19). The results are summarized in Table 4.
The suggested mechanism for the synthesis of tetrahydrobenzo  pyran produces with rearrangement 11 . In the second part for determination of the optimal reaction conditions, for synthesis of 1,4-dihydropyrano[2,3c]pyrazole, the reaction of 4-chlorobenzaldehyde (1 mmol), malononitrile (1 mmol), ethyl acetoacetate (1 mmol) and hydrazine hydrate (1 mmol) in the presence of HMS/Pr-Xa-Ni as catalyst was undertaken. For this purpose, various effective factors on the model reaction such as: amount of catalyst (catalyst free, 0.008, 0.01 and 0.02 g), solvents (H 2 O, EtOH, PEG, H 2 O: EtOH and solvent free) and also the effect of temperature (35, 80 and 100 °C) were checked. As screened in Table 5, the obtained results were demonstrated that 0.01 g of catalyst, mixture of H 2 O: EtOH at 35 °C were the most effective condition. For indicating necessity of presence of nickel in catalytic activity, the model reaction investigated in presence of HMS/Pr-Xa. That result indicated that yield of this reaction was obtained 28% (Table 5, entry 12).
A possible mechanism for the synthesis of 1,4-dihydropyrano[2,3-c]pyrazole using HMS/Pr-Xa-Ni as catalyst is demonstrated in Fig. 22. The Knoevenagel condensation of malononitrile and aldehyde (activated by Ni of the catalyst), leads to obtain the intermediate of arylidenemalononitrile (intermediate I). Also, pyrazolone (intermediate II) is produced by the condensation of hydrazine and ethyl acetoacetate (activated by Ni of the catalyst). In To define the optimal condition of reaction, various amount of catalyst (0.02 g, 0.015 g, 0.01 g, 0.008 g, 0.006 g, 0.004 g, 0.002 g and catalyst free condition), different solvent (EtOH, H 2 O, PEG, H 2 O:EtOH and solvent free condition) and temperatures of 45 °C, 60 °C and room temperature were examined. Comparison of obtained results revealed that the best efficiencies were obtained in the presence of 0.004 g of catalyst in ethanol at room temperature (Table 7, entry 7).
To investigate the effectiveness of the presented catalytic system, the model reaction was carried out in the absence of catalyst (Table 7, entry 1) and in the presence of HMS/Pr-PTSC (lack of Cu) ( Table 7, entry 15). The yields for these reactions were obtained 41% and 38% respectively.
To specify the extent of the reaction we reacted various of substituted of aldehydes under optimized conditions to produce tetrahydrobenzo[b] pyran derivatives (3a-k) (Fig. 23, Table 8).
According to the results it was found that electron-withdrawing groups (such as nitro and halides) rather than electron-donating groups (such as methoxy, methyl and hydroxy) on aldehyde provide better results from the viewpoint of time and yield. For optimization of the conditions, catalyst dosing (0.02 g, 0.015 g, 0.01 g, 0.008 g, 0.006 g, 0.004 g and catalyst free condition), type of solvent (H 2 O:EtOH, H 2 O, PEG, EtOH and solvent free condition) and temperature (room temperature, 45 °C and 60 °C) were studied. With evaluation of these parameters, we found that in the presence of 0.006 g of HMS/Pr-PTSC-Cu as catalyst in H 2 O:EtOH at room temperature the best conversion is achieved (Table 9, entry 6).   www.nature.com/scientificreports/ In another study, the reaction was performed in the presence of HMS/Pr-PTSC to investigate the effect of copper in the catalyse of reaction (Table 9, entry 15). The obtained yield (40%) showed that the presence of Cu was necessaries for progress of reaction.
After optimization of the reaction conditions, benzaldehyde, electron-donating containing aldehydes as well as electron-withdrawing bearing aldehydes were applied as substrate and 1,4-dihydropyrano[2,3-c]pyrazole derivatives (4a-l) were obtained in high to excellent yield as summarized in Table 10 (Fig. 24). Assessment of results indicated that electron-withdrawing bearing aldehydes have higher yield and shorter reaction time.
Comparison of efficiency of catalysts. In this work, two heterogeneous HMS supported metal catalysts were screened in the synthesis of tetrahydrobenzo[b]pyran and 1,4-dihydropyrano[2,3-c]pyrazole derivatives. Turnover frequency (TOF) value is an important parameter to evaluate the efficiency of the catalyst, which quantifies how many catalytic reaction cycles proceed per site and per unit of time 4 . TOF was measured for all products and is given in the Tables 4,6,8 and 10. Based on the results achieved from ICP and AAS, Ni and Cu histograms at TEM and turnover frequency (TOF) obtained from yield, time and amount of catalyst (mol% of Cu and Ni), the investigated metals can be ranked as copper metal has performed better. Judging by the contrast of TEM images, the size distribution of copper particles is better visible.
Recyclability of the catalysts. Reusability and recycling of the HMS/Pr-Xa-Ni. Reusability of the catalysts is one of the most crucial aspects of organic synthesis. In this respect, reusability of HMS/Pr-Xa-Ni was investigated for synthesis of 2-amino-4-(4-chlorophenyl)-3-cyano-7,7-dimethyl-5-oxo-4H-5,6,7,8-tetrahydro benzo[b]pyran. After completion of the reaction, hot EtOH was added to the crude mixture and centrifuged several times. The separated catalyst was washed, dried for overnight and applied for the next run. The HMS/ Pr-Xa-Ni was found to be reusable for five successive runs with a negligible decrease in its activity (Fig. 25).  www.nature.com/scientificreports/ Reusability and recycling of the HMS/Pr-PTSC-Cu. Since the recycling of catalyst is of great importance in the industry, the recyclability of HMS/Pr-PTSC-Cu in the synthesis of 2-amino-3-cyano-7,7-dimethyl-4-(4chlorophenyl)-5-oxo-4H-5,6,7,8-tetrahydro benzopyran and 6-amino-4-(4-chlorophenyl)-3-methyl-1,4dihydropyrano[2,3-c]pyrazole-5-carbonitrile was studied. After completion of the reaction, the catalyst was separated by centrifuge instrument and dried. Then, dried separated catalyst was reused in the same reaction for six successive runs with minimal decrease in the yield of product (Fig. 26).   It can be seen that the structure of catalyst was preserved after recovery. Also AAS analysis contributed to recovered HMS/Pr-PTSC-Cu was done that base on this analysis copper concentration in recovered catalyst was obtained 0.50 mmol.g −1 . This analysis confirmed that copper leaching was low.
The hot filtration experiment was investigated to determine leaching of copper in the reaction mixture and to show that HMS/Pr-PTSC-Cu is a heterogeneous catalyst. For this regard the reaction between 4-chlorobenzaldehyde, malononitrile, ethyl acetoacetate, hydrazine hydrate, HMS/Pr-PTSC-Cu in H 2 O: EtOH (2:1 mL) at room temperature was choose. In this experiment the product was obtained in the half time of the reaction (10 min) in 66% yield. Then, the same reaction was repeated but in this reaction in the half time of the reaction (after 10 min), the catalyst was filtered from the reaction mixture and the reaction mixture was allowed to react for another 10 min. The yield of product in this experiment was 69%. The results from hot filtration test confirmed that leaching of copper during the reaction hasn't been significant.

Experimental
Materials and physical measurements. All reagents and solvents were provided from Aldrich and Merck chemical companies. 1 H-NMR and 13 C-NMR spectra of the DMSO-d 6 solutions were determined at 300 MHz. The FT-IR spectra were recorded as KBr pellets by FT-IR, VERTEX 70, Bruker, Germany spectroscopy. The analysis of X-ray diffraction was conducted using a XRD, X'Pert PRO MPD, PANalytical, Netherland. Thermogravimetric analysis (TGA) was performed from room temperature to 800 °C by TGA, PerkinElmer Pyris Diamond, U.K. Scanning electron microscopy (SEM) images were carried out on a FE-SEM, TESCAN MIRA III, Czech. Transmission electron microscopy (TEM) were carried out on TEM Philips EM 208S. Elemental analysis was recorded with instruments EDX-MAP, FE-SEM, TESCAN MIRA, SAMX, Czech. The content of Ni was investigated using inductively coupled plasma optical emission spectrometry (ICP-OES, Arcos EOP, company of Spectro, Germany). The content of Cu was measured by atomic adsorption spectroscopy (AAS, Analytikjena-Nov AA 400/ Germany). The instruments of adsorption-desorption of nitrogen that was applied have this character: BET, Micromeritics, Asap2020, USA.

Synthesis of catalysts (HMS/Pr-Xa-Ni and HMS/Pr-PTSC-Cu). Synthesis of HMS. HMS was syn-
thesized similar to a previously reported research. In this light, 5 gr of dodecylamine was dissolved in 70% w/w ethanol aqueous solution. Then 20.8 gof tetraethyl orthosilicate (TEOS) was added dropwise, stirred for 5 h at room temperature under vigorous stirring and aged for 18 h at room temperature. The resultant precipitate was filtered and dried at room temperature. Finally, the dried powder was soxhelt extraction at 80 °Cfor 24 h. For the removing the template, synthesized support was calcined at 500 °C in air for 5 h 4 .

Reaction of 3-chloropropyltrimethoxysilane with 4-phenylthiosemicarbazide.
In order to prove the reaction between linkage and ligand, a mixture of 4-phenylthiosemicarbazide (1 mmol), 3-chloropropyltrimethoxysilane (1 mmol) and K 2 CO 3 (2 mmol) in EtOH were stirred with a magnetic stirrer at reflux condition for 24 h. Then the obtained precipitation separated by filtration and washed with EtOH. Purification of product was done through recrystallization in EtOH. According to the results obtained from FT-IR, 1 H and 13 C NMR, the structure of product determined and spectra have entered in supporting information.  www.nature.com/scientificreports/ in order to examine the stability of HMS/Pr-PTSC-Cu after recovering, IR and hot filtration test revealed that the structure of catalyst was preserved after recovery. Generally, the advantages of these process including mild reaction conditions, good to high yields, short reaction times, eco-friendly solvent, simple workup, lack of byproducts, simple purification of products, economic availability of the materials, environmentally friendly nature and compliance with the green chemistry protocols, simple separation of catalyst, no extraction or separation by column chromatography. Also, easily recoverable of synthesized catalysts and medicinal applications of product are among the other advantages of this method.