KIT-5 Supported Copper (II) Oxide Mesoporous Materials: An Efficient Catalyst for Regioselective Synthesis of 1,4- Disubstituted-1H-1,2,3-Triazoles in Water

Abstract We have synthesized copper-incorporated KIT-5 mesoporous materials which were characterized thoroughly by powder XRD, N2-sorption, UV-Vis, HR-SEM & EDS and HR-TEM techniques. The low angle PXRD with theta values of 0.609, 0.660, 0.704 and 0.746 confirmed the mesoporosity of the synthesized materials. In addition, the materials showed type-IV isotherms which are spherical in morphology and fringes with pores of materials supporting the formation of mesoporous materials. The catalytic activity of synthesized materials was also investigated. We have used our materials as catalyst for the synthesis of 1,2,3-triazole derivatives via three component reaction of alkyl/aryl halide, terminal alkynes and sodium azide in water as a solvent. The desired triazole products were obtained in very good yields. This study indicates the importance of Cu element, solid support with uniformity of metal nanoparticles over the materials. The recyclability study with PXRD data of the catalyst confirmed the existence of the mesoporosity of the catalyst after the reaction and the yield decreased marginally from 98 to 91% over three cycles. This reaction has broad substrate scope and is compatible for aliphatic, aromatic, allyl substrates giving high yield of triazole products. Graphical Abstract


Introduction
Heterocyclic compounds containing nitrogen atom/s have wide range of application in industry such as photo-stabilizers, lubricants and dyes as well as in pharmaceutical industry. Among these, synthesis of 1,2,3-triazoles have attracted many researchers due to its wide applications. In 2002, Sharpless and Meldal independently introduced a regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles via copper-catalyzed azide-alkyne cycloaddition (CuAAC) which is also commonly known as click reaction. 1 Huisgen first reported the thermal synthesis of 1,2,3-triazoles. However, this method has the drawback of the formation of both 1,4-and 1, 5-regioisomers. 2 Click reaction is one of the most important reactions in the area of synthetic organic chemistry and has broad range of applications. 2-6 Moreover, 1,2,3-triazole compounds are known to possess biological activity. 7 Although, homogeneous CuAAC reactions have shown promising results for the synthesis of triazoles and their derivatives but it has limited interest in industry. Most of the chemical industries prefer nano-porous heterogeneous catalysts than the homogeneous catalysts. Environmentally benign processes and easy separation of products from the reaction mixture are the advantages of reactions involving heterogeneous catalysts. Metallic copper (Cu 0 ) as catalyst is also used to carry out the CuACC reaction but has drawbacks like high loading of catalyst and longer reaction time. 8 Use of heterogeneous copper catalyst supported over different solid materials such as activated carbon, zeolites, montmorillonite, NHC-modified silica, polystyrene, chitosan, or microporous metal organic frameworks (MOFs) is becoming increasingly popular to carry out the click reaction. 9 Schwab et al. reported magnetically recoverable copper(I)-exchanged b-zeolite materials which showed efficient catalytic activity for the synthesis of 1,2,3-triazoles via the one-pot three-component reaction of organic halides, terminal acetylenes, and sodium azide in water. 10 Because of the magnetic properties of the materials, the catalyst could be easily separated from the reaction mixtures. The catalyst could be reused for several consecutive reactions. The Cu has been incorporated into different eco-friendly supports such as rhizobial cyclic b-1,2 glucan, WEB (water extract of banana), biosourced cyclosophoraose (CyS), egg shell powder (ESP), cyclodextrin (b-CD), fish bone powder and have been reported as heterogeneous catalysts for the synthesis of 1,2,3-triazoles, where the catalysts could be easily recovered. 11 The incorporation of Cu into mesoporous silica nanoparticles was found to be of rod-shaped morphology that showed promising catalytic activity for one-pot synthesis of 1,4-dibustituted-1,2,3-triazole derivatives under microwave-assisted reaction condition in aqueous medium. The high yield of the desired product was explained on the basis of high dispersion of copper over the surface of the materials which generate the more active sites. 12 The functionalization of b-cyclodextrin into hybrid materials of PEGylated mesoporous silica and graphene oxide and further immobilization of copper led to the heterogeneous catalyst which was used for the synthesis of 2-arylbenzimidazoles and 1,2,3-triazoles using water as a green solvent. 13 Ordered mesoporous materials have attracted much attention among the researchers due to various advantages such as crystallinity, high surface areas, tunable compositions and pore diameter of nanoscale dimensions, chemical and thermal stability, can accommodate various functional groups and metals onto the surface, etc. Thus these materials have become one of the most widely investigated classes of materials, and find applications in many areas, in particular catalysis. 14 Use of heterogeneous catalysts for any reaction is cost effective, recyclable and would not produce toxic material as side products. Copper catalysts are also used for making C-C and C-N bond formation reaction using multi-component reactions (MCRs). MCRs are used to develop methodologies for the synthesis of complex molecules starting from simple and easily available substrates and thus becoming one of the important tools for the pharmaceutical companies. 15 This type of reaction is carried out in one-pot without isolation and purification intermediate product thus reducing the number of steps involved and overcoming purification steps. It thus favors the chemical industry sectors due to low costs, time saving, waste product minimization, energy saving and atom economy. 16 MCRs have several advantages over conventional multi-step synthesis and are in demand for synthesis of libraries of complex structures in drug discovery and developments. Our group is actively perusing in developing different methodologies using MCR approach. 17 In this paper, we have developed Cu-incorporated KIT-5 three-dimensional cage-like mesoporous materials which shows good catalytic activity in the synthesis of 1,2,3-triazole giving high yields of products.

Materials and reagents
The triblock copolymer [Pluronic F127 (EO 106 PO 70 EO 106 ), molecular weight ¼ 12,500] was obtained from Sigma-Aldrich Co. and used as the structure-directing agent. Tetraethylorthosilicate (TEOS) was purchased from Aldrich and used as a source for silicon. Cusalts and all other chemicals were purchased from Aldrich and Merck chemicals and used without further purification.

Synthesis of mesoporous silica KIT-5 material
Mesoporous silica KIT-5 material was synthesized using Pluronic F127 as the template in an acidic medium. In a typical synthesis, 120 gm of distilled water and 10.5 gm of concentrated hydrochloric acid (35 wt% HCl) were added to the 5.0 gm of Pluronic F127. To obtain a homogeneous solution by hydrolysis process, the reaction mixture was vigorously stirred for few hours. Then, 24.0 gm of TEOS was added at once to the reaction mixture at 45 C. The mixture was stirred at 45 C for 24 h for the formation of the mesostructured product. Subsequently, the reaction mixture was heated for 24 h at 100 C under static conditions for hydrothermal treatment, filtered, and then dried at 100 C without washing. The samples were calcined in air at 550 C for 8 h.

Synthesis of in-situ Cu-incorporated mesoporous KIT-5 material
We have attempted the incorporation of Cu into the KIT-5 mesoporous structure through in situ addition of copper salt during the synthesis (direct method). In a typical synthesis, 5.0 gm of F127 is dissolved in the required amount of HCl (35 wt%) and 240 gm of distilled water. To this mixture, 24.0 gm of TEOS and X (5,10,12) weight % of copper salt were added, and the resulting mixture was stirred for 24 h at 50 C. Subsequently, the reaction mixture was heated for 24 h at 100 C under static conditions for hydrothermal treatment. The solid product was filtered off and then dried at 100 C without washing. The product was calcined at 540 C for 10 h. The final material is designated by 'D.'

Synthesis of Cu-incorporated mesoporous KIT-5 material via impregnation
In another method, Cu-incorporated mesoporous KIT-5 materials were prepared by the impregnation method. The catalyst was prepared in a two-necked round bottom flask under the N 2 atmosphere, where X represents the different percentages of preformed CuO nanoparticle (CuONP) content in the catalyst. In a typical procedure, 1 gm of mesoporous KIT-5 material was mixed with 10 mL of ethanol and then added X (5,10,12) percentage of CuONP. After refluxing for 6 h, the reaction mixture was cooled and then filtered off and washed with 1:1 mixture of acetone and ethanol and dried for 10 h at 100 C. The same procedure was followed to make different amount of CuONP (5 to 12 wt%) loaded KIT-5 catalyst. The prepared Cu-incorporated KIT-5 samples were calcined at 500 C for 10 h to explore the catalytic activity. The final material is designated by 'I.' 2.5. General procedure for synthesis of 1,2,3-triazole The catalytic activity of the synthesized Cu-incorporated KIT-5 mesoporous materials was investigated for the synthesis of 1,2,3-triazole via one-pot three component reaction of benzyl chloride, sodium azide and phenyl acetylene using catalysts under liquid-phase aqueous conditions (Scheme 1). In a typical reaction, the catalyst (15 mg) was added to the mixture of benzyl chloride (1 mmol), sodium azide (1.1 mmol) and phenyl acetylene (1 mmol) and 3 mL of water. The reaction was stirred for 6 h in the temperature range of 30-70 C. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the catalyst was removed by centrifugation process. The filtrate was extracted with organic solvent (diethyl ether). Solvent was removed by rotary evaporator and the product was purified through column chromatography using silica gel (100-200 mesh) as a stationary phase and petroleum ether þ ethyl acetate (3:1) as eluent. The final products were identified with the help of 1 H NMR, 13 C NMR and compared with literature reports.

Characterization of the catalysts
The powder X-ray diffraction (PXRD) patterns of the synthesized samples were collected on a Rigaku diffractometer using CuKa (k ¼ 0.154 nm) radiation. The diffractograms were recorded in the 2h range of 0.1-6 with a 2h step size of 0.01 degree and a step time of 6 s. BET surface area with N 2 -sorption isotherms were recorded at À196 C using Autosorb analyzer. Before analysis, samples were degassed at 250 C for 3 h. For TEM analysis the samples were dispersed with pure ethanol (99.9%) and sonicated for 15 min. Then, the mixture was dropped successively onto a copper microgrid and images were recorded at 160 kV using JEOL instrument, model JEM-2100.

Powder X-ray diffraction
The powder X-ray diffraction (PXRD) pattern for all Cu-incorporated KIT-5 calcined samples synthesized through the impregnation method is shown in Figure 1. It is observed that all Cuimpregnated KIT-5 sample show the phases of (111), (200), and (220) and consist of face-centered-cubic Fm3m symmetry which reflect the properties of mesoporous materials even at high loading of copper precursor (Figure 1). The similar patterns of PXRD of Al-KIT5 were reported by Vinu et al. 14 g and our group. 19 a From XRD pattern, it is seen that the peaks are slightly shifted toward the higher 2h values with increasing the loading of metal into the surface of KIT-5 mesoporous materials. This result shows that more number of defect sites and definite bond strain in the Cu-impregnated KIT-5 samples. Moreover, a decrease in the peak intensities of Cu-KIT-5 samples indicates the marginal loss of crystalline character of mesoporous materials. Scheme 1. Synthesis of 1,2,3-triazole using Cu-incorporated KIT-5 catalysts.

Sorption study
Nitrogen adsorption-desorption isotherm of calcined copper impregnated KIT-5 samples are shown in Figure 2. The physicochemical properties are summarized in Table 1. It is seen that all samples showed type IV adsorption with a H2 hysteresis isotherm with a cage-type pore structure. From Table 1, it is observed that surface areas decreases from 720 to 510 m 2 g À1 with the increase in the loading of metal through impregnation method. This result indicates the   incorporation of metal into silica network and similar result was observed in our previous publication. 18 It is observed that the capillary condensation was almost same for all Cu-impregnated calcined samples shown as a function of relative pressure P/Po (Figure 2). This result indicates the pore diameter of the mesoporous materials. In our present study, pore diameter was found to be almost same ( Figure 3, samples b, c and d) for all Cu-impregnated calcined samples (5.8, 5.7 and 5.8 nm). Moreover, pore volume of the samples did not change with increasing the loading of copper into the KIT-5 silica network. The decrease of surface area, unit cell parameter indicates the high condensation of silica group with metal precursor that leads to the high penetration of copper into the silica matrix.

UV-Visible spectroscopy
The UV-Vis absorption spectra of different calcined samples showed absorption peak in the range of 200-300 nm (Figure 4). Among the samples, the clear absorption band is observed at approximately 235 nm for the sample of Cu-KIT-5-12 (I). Where, peaks are shifted to the lower wavelength for other two samples like Cu-KIT-5-10 (I) and Cu-KIT-5-12 (D). These results clearly indicate that attribution of copper into the silica matrix is in þ2 states. For comparison purpose, the result of the sample of Cu-KIT-5-12 (D) is also recorded and plotted. It is seen that the less intense with broad peak is observed here. In this case, we obtained very poor catalytic activity which may be due to less copper bounded with KIT-5 material.

Scanning electron microscopy
Incorporation of Cu into the three dimensional KIT-5 mesoporous material was analyzed by HRSEM-EDS (high resolution scanning electron microscopy-energy dispersive spectroscopy of X-rays) technique. The peaks for Si, O and Cu are clearly seen in Figure 5. Moreover, peak intensities increased as increasing loading of Cu from 5 to 12 wt% ( Figure 5A-C). Besides, the same morphology is retained at different loading of copper into KIT-5 mesoporous materials ( Figure 5).

Transmission electron microscopy
The topology of the Cu-incorporated into three-dimensional cubic cage like mesoporous materials were studied with the help of HRTEM (high resolution transmission electron microscope) technique ( Figure 6). All the catalysts exhibited typical property of the highly ordered mesoporous KIT-5 materials with an array of fringes and distinct pores. Moreover, TEM images indicate the uniform distribution of copper over silica matrices. As expected, more amount of copper was observed in the case Cu-KIT-5-12wt% (I) (Figure 6c). In this case high crystallinity of the material is retained although higher amount of copper is loaded into KIT-5 solid mesoporous materials ( Figure 6d). Again, Cu-incorporated KIT-5 mesoporous material was also prepared by co-condensation method (direct method) and TEM image is presented in inset Figure 6c. It is noticed that clear fringes of arrays was observed. This result indicates that copper could not be incorporated by co-condensation method and there is no copper in the KIT-5 mesoporous materials.

Screening of the catalysts
The one-pot three component reaction of benzyl chloride, sodium azide and phenyl acetylene for synthesis of 1,2,3-triazoles was carried out using Cu-incorporated KIT-5 mesoporous materials as catalysts and the results are shown in Table 2. Characterization of Cu-KIT-5-12 (I) catalyst by XRD and UV-Vis techniques confirm that oxidation state of Cu is in þ2 states. The progress of the reaction was observed by thin layer chromatography (TLC). The reaction was stirred for 5 h at 60 C in aqueous medium. The yields of the 1,2,3-triazole products were found to be 73, 84 and 98% for Cu-KIT-5-5 (I), Cu-KIT-5-10 (I) and Cu-KIT-5-12 (I) catalysts, respectively (Table  2, entries 5-7). The increase in the yield of the product could be explained on the basis of enhanced metal dispersion over the mesoporous materials. It is observed that with increasing Si/Cu ratio from 5 to 12, the TONs also increased and this is may be due to the uniform dispersion of copper into the silica matrices. As a result, it increases the catalyst active sites in the solid KIT-5 mesoporous materials and this is supported by HRTEM study (Figure 6c,d). The similar explanation for increase in yield is given by Mnasri et al. 12 We have also performed the reaction using Cu-KIT-5-12 (D) catalyst giving 15% yield. After calcination of the sample, the color of the sample prepared by direct method is off white whereas Cu-impregnated samples were black. The result indicated that very less amount of copper was dispersed over the sample prepared by direct method. Moreover, it has been observed that several other research groups have emphasized using zeolites and mesoporous materials for catalytic activities. In order to find out the best catalysts, we have also conducted Al-incorporated cage like three dimensional pure KIT-5 mesoporous materials and no reaction was observed (Table 2, entry 17). Besides, we have also used different zeolites like ZSM-5 and mordenite for preparation of 1,2,3-triazoles (Table 2, entries 18  and 19). Interestingly, we have not observed any chemical reaction. Among the investigated catalysts, the higher catalytic activity was found for copper incorporated cage like three dimensional mesoporous materials.
We have screened different solvents for the reaction in order to get optimum yield of the 1,2,3-triazole products. It was observed that Cu-KIT-5-12 (I) has superior catalytic activity using water as a solvent than any other solvents like methanol, ethanol, acetonitrile, chloroform, dichloromethane, and toluene, etc. Polarity of the solvents plays a major role in the yield of the   products obtained. We observed that the yield of the product decreases as the polarity of the solvents decreases using our catalyst.

Amount of catalyst and role of temperature
To optimize the amount of catalyst required for the synthesis of 1,2,3-triazoles we have carried out the reaction using different amount of Cu-KIT-5-12 (I) material under the identical reaction condition. As expected, yields of the desired product increased from 68% to 98% with increasing the amount of catalysts from 3 mg to 15 mg. The reaction data are plotted in Figure 7. It is reasonable to explain that with increasing the amount of catalyst, the rate of the reaction increases since the reaction medium has higher number of active catalytic sites. However, no further improvement in the yield was observed when increasing the amount of to 20 mg. Hence, 15 mg of catalyst was used for further reactions.
For any reaction, the temperature has a critical role to produce the desired product. We have performed the reaction under different temperatures maintaining the other reaction conditions similar using Cu-KIT-5-12 (I) catalyst. Individual experiments were carried out at each temperature. The progress of the reaction was monitored by thin layer chromatography (TLC) and isolated yield was calculated after purification of products by column chromatography. Initially, the reaction was carried out at 30 C and the yield of the product obtained is 17%. With further increase of temperature to 40 C, 50 C and 60 C the yield increases to 40%, 74% and 98% respectively. This result indicates that the catalyst become more activated at particular temperature that leads to a higher yield of the product. No further increase in yield was observed when the reaction temperature is increased to 70 C or increase of reaction time (up to 6 h). These results clearly show that Cu-KIT-5-12 (I) catalyst could be used for preparation of 1,2,3-triazole under mild reaction temperature (Figure 8).

Recycle studies and scale up reaction
To find out the reusability and stability of the catalyst, the recycling experiments for the synthesis of 1,2,3-triazole by reaction with benzyl chloride, sodium azide and phenyl acetylene were studied for three consecutive cycles under the identical reaction conditions. The catalyst could be easily separated by centrifuging after the reaction and washing with dichloromethane. The catalyst was dried in oven and reused for the next reaction. The reactants were taken with respect to the amount of the catalyst recovered after each reaction cycle. The corresponding yields over the three cycles were 98, 96, 93 and 91% for fresh catalyst, first, second and third cycle, respectively. The decrease in yield of product could be due to the leaching of metal, blockage of pore in the matrices of silica. We have also recorded XRD pattern for Cu-KIT-5-12 (I) catalyst obtained from after three consecutive reactions and plotted with fresh XRD pattern of Cu-KIT-5-12 (I) catalyst for comparison, shown in Figure 9. It is clearly seen that mesoporosity of used Cu-KIT-5-12 (I) catalyst remained the same even after several recycles of the catalyst but intensity of the peak (100) is found to be decreased. The catalytic activity of used catalyst such as Al-KIT-5 and triflic acid loaded KIT-5 matched with our present study. 19 Moreover, we have also performed the reaction using our optimized conditions in 5 gm scale and obtained the desired product in 96% yield using the Cu-KIT-5-12 (I) catalyst. This result shows the efficiency of the catalyst in scale up reaction.

Reaction with different substrates
To extend the substrate scope of our method for the synthesis of 1,2,3-triazoles, we have used different types of substrates using the optimized conditions (Scheme 2). Apart from benzyl chloride, we have taken other alkyl halides such as hexyl bromide, a-bromo acetophenone, allyl bromide and a-bromo ester as organic halide which reacted with phenylacetylene/1-hexyne and sodium azide under the standard reaction conditions to afford the corresponding 1,4-disubstituted 1,2,3triazoles in good to excellent yields (Scheme 2). The desired 1,4-disubstituted 1,2,3-triazoles could also be prepared using aromatic azides and alkyl or aryl acetylene substrates. Substrates with both electron withdrawing or donating groups  on the aromatic azides gave very good yield of the products (Scheme 2). The results showed that the catalyst could be used for broad range of substrates. A plausible mechanism is proposed based on the literature reports (Scheme 3). The formation of the triazole is believed to proceed through the following mechanism involving copper catalyst. The terminal alkyne reacts with the mesoporous copper catalyst forming the copper acetylide. This then undergoes cycloaddition reaction with the in organic azide counterpart which is formed in situ from the reaction of the corresponding organic halide and sodium azide to furnish the 1,2,3-triazole products.
We have also compared the efficiency of our catalyst with some previously reported Cu-incorporated other heterogeneous catalyst systems for the synthesis of 1,2,3-triazole (Table 3). 19 Although few methods gave good yields of product using Cu-incorporated catalyst, the drawback of the protocol are either microwave reaction condition, prolong reaction time or catalyst preparation need several steps with precaution ( Table 3, entries 1-3). Moreover, a very low yield was observed using Cu-incorporated spion and graphene catalyst ( Table 3, entries 4 and 5). Therefore, our reported three-dimensional cage-like Cu-KIT5 mesoporous material showed excellent catalytic activity for the preparation of triazole under mild reaction conditions followed by easy and simple catalyst preparation method than that of the mentioned catalysts (Table 3).

Conclusion
We have developed a copper-impregnated cage-like three dimensional KIT-5 mesoporous heterogeneous catalyst for the regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles through a multicomponent alkyne-azide 1,3-dipolar cycloaddition reaction in water. Characterization of catalysts by several tools like PXRD, BET, HRSEM-EDAX, and TEM confirms the ordered mesoporosity of the materials, type IV isotherms, spherical and fringes in morphology and topology, respectively. Moreover, UV-Vis spectroscopy suggested that Cu is in þ2 states in the silica KIT-5 network. The catalyst is easy to synthesize and have broad substrate scope giving very good yield of the product. The catalyst is stable and could be used for several cycles without significant loss in catalytic activity. The gram scale reaction showed the utility of the catalyst in scale up reaction. This method is simple, convenient and easy to handle.

Disclosure statement
No potential conflict of interest was reported by the author(s).