Synthesis and characterization of highly efficient and recoverable Cu@MCM-41-(2-hydroxy-3-propoxypropyl) metformin mesoporous catalyst and its uses in Ullmann type reactions

The functionalized MCM-41-(2-hydroxy-3-propoxypropyl) metformin was prepared and anchored by copper ions to employ as a catalyst for the Ullmann C-X coupling reaction. The catalyst was characterized by Fourier-transform infrared spectroscopy, thermogravimetric analysis, X-ray diffraction, transmission electron microscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy measurements and, N2 adsorption–desorption isotherms. The benefits of this catalyst are the use of inexpensive and non-toxic metformin ligand, easy catalyst/product separation, and catalyst recycling. The catalyst can be reused at least for five repeated cycles without a significant loss of its catalytic activity or metal leaching.

. Also, cellulose-supported poly(hydroxamic acid) − Cu(II) complex was successfully applied to the Ullmann etherification 24 . Various functionalized 2-aminobenzo[b]thiophenes have been synthesized at room temperature by the Ullmann coupling reaction in the presence of different Cu salts and 1 10 phenanthroline as ligand 25 . Ge research group prepared three different types of functionalized chitosan and anchored with copper salts for use as the catalyst for the Ullmann C-X coupling reaction 26 . Following the interest in Ullmann-type reactions and mesoporous materials, in this work, we report a new recoverable catalyst based on modified MCM-41 anchored with copper ions, which is an efficient catalyst for the Ullmann type reactions.

Experimental
Materials. All commercially available chemicals, solvents, reagents and were purchased from Sigma-Aldrich and Merck company, briefly cetyltrimethylammonium bromide (CTAB) (Sigma-Aldrich, ≥ 99%), ammonium hydroxide solution (Sigma-Aldrich, ≥ 99.99%), tetraethyl orthosilicate (TEOS) (ACROS, 98%), EtOH (Sigma-Aldrich, ≥ 99.8%), anhydrous N, N-dimethylformamide (Sigma-Aldrich ≥ 99.8%), metformin hydrochloride (Merck, ≥ 99.9%). The melting points of the prepared derivatives were measured by an Electrothermal 9100 apparatus, which was reported without any correction. The FT-IR spectra were recorded in the range of 400-4000 cm −1 using a Shimadzu IR-470 spectrometer by using KBr pellets. 1 H-NMR spectra were recorded using the Bruker DRX-500 and 300 AVANCE spectrometer. Elemental analysis was provided by EDX analysis, which was recorded by TES-CAN4992. The morphology of the synthesized catalyst was studied by SEM using VEGA2 TESCAN instrument. TGA of the prepared catalyst was obtained by an STA504. The XRD measurement of the catalyst was recorded with the X′ Pert Pro diffractometer operating with (40 mA, 40 kV). N 2 adsorption-desorption isotherms of Cu@ MCM-41-HPr-Met nanocomposite were measured at the temperature of liquid nitrogen with a Micromeritics system. The surface area of the nanoparticles was calculated using the Brunauer-Emmett-Teller (BET) method. All products we compared based on their spectra and physical data recorded in the references.
Catalyst preparation. The catalyst has been prepared according to Scheme 1, as follows. The given protocol has been used for the preparation of the catalyst on a 5 g scale.
Preparation of MCM-41. The MCM-41 synthesis is performed according to the reported procedure by Zanjanchi 27 . In brief, 2.7 g ethylamine was added to 42 ml of deionized water and the mixture was stirred at room temperature for 10 min. The amount of 1.47 g of the surfactant cetyltrimethylammonium bromide (CTAB) was gradually added to the above solution under stirring for 30 min. After further stirring for 30 min, a clear solution was obtained. Then, 2.1 g of TEOS solution was added dropwise to the solution. The pH of the reaction mixture was adjusted to 8.5 by the slow addition of the hydrochloric acid solution (1 M) to the mixture. After precipitate formation, slow stirring for 2 h is necessary, and then the precipitate was separated by centrifuge and washed 3 times. The product was dried at 45 °C for 12 h and calcined at 550 °C for 5 h to decompose the surfactant to obtain the white powder. This powder was used as the parent material to prepare the main catalyst.
Preparation of MCM-41-EPTMS. In a typical procedure, a round-bottom flask charged with 0.5 g MCM-41 and 10 mL of n-hexane was added, then 0.5 g (2.11 mmol) [3-(2,3-epoxypropoxy)-propyl]-trimethoxysilane added into the reaction mixture. Reaction after stirring for 24 h under inert N 2 atmosphere and reflux condition in oil bath, was cooled to room temperature. The solid product MCM-41-EPTMS filtered off and was washed twice with n-hexane, dried in an oven at 70 °C for 24 h. General procedure for diaryl sulfide derivatives catalyzed by Cu@MCM-41-HPr-Met. A mixture of aryl halide (1 mmol), thiophenol (1.2 mmol), K 2 CO 3 (2 mmol), and 30 mg Cu@MCM-41-HPr-Met as a catalyst in 3 ml DMSO/EtOH (2:1) was stirred for 6 h at 90 °C. The test tube was filled with inert N 2 gas and sealed. The progress was monitored by TLC, after the reaction was complete, the test tube was cooled to room temperature. First, the EtOAc solvent was added to the reaction mixture to separate catalyst by filtration, the mixture of reaction was poured in distilled water and extracted with EtOAc (3 × 15 ml). The organic phase was separated with a separatory funnel and the solvent was evaporated with rotary. The final net product was obtained by column chromatography (EtOAc: n-hexane).

General procedure for diaryl ether derivatives catalyzed by Cu@MCM-41-HPr-Met. A mixture
of aryl halide (1 mmol), phenol (1.5 mmol), K 2 CO 3 (2 mmol), and 50 mg Cu@MCM-41-HPr-Met as a catalyst in 3 ml DMF/EtOH (2:1) was stirred for 6 h at 90 °C under inert N 2 gas in a sealed tube. The progress was monitored by TLC, after the reaction was complete, the test tube was cooled to room temperature. To separate catalyst by filtration the EtOAc solvent was added to the reaction mixture, after catalyst filtration, the mixture was poured in distilled water and extracted with EtOAc (3 × 15 ml). The organic phase was separated with a separatory funnel and the solvent was evaporated with rotary. The final net product was obtained by column chromatography (EtOAc: n-hexane).

Result and discussion
In this research, the preparation of Cu@MCM-41-HPr-Met was done as outlined in Scheme 1.   Scanning electron microscopies (SEM). SEM images of the Cu@MCM-41-HPr-Met catalyst are presented in three scales: 5, 10, and 20 µm are shown in Fig. 3. This analysis shows the morphology and size of the synthesized particles. These images show that the particles have spherical morphology as well as a layered structure. As we can see in Fig. 3, we can estimate the particle size between 0.37-0.64 µm.
Transmission electron microscopies (TEM). TEM analysis was performed to more accurately study the morphology and particle size of the mesostructured catalyst (Fig. 4A, B). The TEM micrograph in Fig. 4B indicates the ordered mesoporous channels of silica after modification.  BET analysis. The N 2 adsorption-desorption isotherm and BJH pore size distribution of the Cu@MCM-41-HPr-Met are shown in Fig. 7A,B. The isotherm is classified as type IV, characteristic of mesoporous materials, with a sharp capillary condensation of nitrogen into the mesoporous channels at high relative pressure and H1 hysteresis loop, which reveals the presence of large channel-like pore structures. Also, based on the shape of its hysteresis, Cu@MCM-41-HPr-Met catalyst has cylindrical pores and the initial structure is retained after functionalization. The structural data of the Cu@MCM-41-HPr-Met catalyst nanoparticles are summarized in Table 1.

Application of catalyst in Ullmann type reaction.
We applied MCM-41-HPr-Met to Ullmann-type reactions to show the catalytic utility of the newly constructed structure. We assume that, as shown in Scheme 2, the copper first enters the C-X bond of the aryl halide and produces the intermediate A.

S-Arylation of thiols.
To begin with, the reaction between 4-nitro-1-bromobenzene and thiophenol was selected as the model reaction. Then, by optimizing the amount of catalyst and selecting the appropriate solvent and base, accurate time, and temperature measurement, the further reaction progression and product yield increased. As seen in Table 2, by repeating the experiment under different conditions, K 2 CO 3 was selected as the appropriate base and DMSO/EtOH as a solvent for the reaction. After testing different Cu@MCM-41-HPr-Met catalyst amounts, 30 mg was selected as the optimum amount (Table 3). After determining the optimal conditions for the reaction of the model, to prove the repeatability of this method and the efficiency of the catalyst, the reaction of derivatives of aryl halides and thiophenols was performed under optimal conditions and diaryl sulfide products were obtained with a high yield. As shown in Table 4, the reactivity with the derivatives of iodobenzene and bromobenzene is higher than that of chlorobenzene. However, studies have shown that doing a reaction with chlorobenzene derivatives with good yield shows Cu@MCM-41-HPr-Met catalyst's high efficacy. In general, the placement of electron-donating groups on aryl halide derivatives increases reactivity, and placing electron-withdrawing groups decreases it.
O-Arylation of phenols. In this type of reaction, as before, the model reaction was investigated in the presence of DMF/EtOH as the solvent, and K 2 CO 3 as the base, and reaction time, temperature, and Cu@MCM-41-HPr-Met catalyst amount was optimized ( Table 5).
The reactivity of aryl halides with electron-withdrawing groups in the para position is better than aryl halides with the electron-withdrawing group in the ortho position. Also, the order of reactivity of aryl halides is that aryl bromides are more reactive than aryl chlorides (Table 6).
To show the capability and efficiency of this method and the Cu@MCM-41-HPr-Met as a catalyst, a comparison has been summarized in Table 7 with the previous methods of synthesis diaryl sulfides and diaryl ethers reported in some literature.
Reusability of the catalyst. One of the most important issues with heterogeneous catalysts is their effective lifespan and their ability to be recycled and reused. Therefore, this was also examined in the present catalytic system. For this purpose, after the reaction was complete, the Cu@MCM-41-HPr-Met catalyst was separated www.nature.com/scientificreports/ using a strainer and washed several times using ethyl acetate. The Cu@MCM-41-HPr-Met catalyst was then placed in an oven to dry. We used the catalyst again in the (thio)phenol's reaction with 1-bromo-4-nitrobenzene as a model reaction. This operation was repeated 5 times and they give the results for both types of reactions in Fig. 8. As you can see, there were no significant changes in the efficiency or activity of the catalyst after repeated use.

Conclusion
In this paper, we were able to synthesize a new functionalized catalyst based on mesoporous silicates and investigate its reactivity in C-S and C-O bond formation. Considering the advantages of heterogeneous catalysts, Cu@ MCM-41-HPr-Met catalyst has such as ease of use, easy separation of products, adaptability to the environment, mild reaction conditions, and most importantly, recyclability of the catalyst.      Table 7. Comparison of the results obtained in the synthesis of diaryl sulfides (1-5) and diaryl ethers (6)(7)(8)(9)(10) in the presence of Cu@MCM-41-HPr-Met and other catalysts.