Copper(II)-β-cyclodextrin immobilized on graphitic carbon nitride nanosheets as a highly effective catalyst for tandem oxidative amidation of benzylic alcohols

In this study, an efficient catalyst based on graphitic carbon nitride nanosheets (CN) and copper(II) supported β-cyclodextrin (β-CD/Cu(II)) was synthesized and used for tandem oxidative amidation of benzylic alcohols. In this regard, CN was functionalized by β-CD/Cu(II) via 1,3-dibromopropane linker (CN-Pr-β-CD/Cu(II)). The prepared catalyst was characterized using FT-IR, XRD, FE-SEM, EDS, TGA, ICP-OES, BET, and TEM analyses. CN-Pr-β-CD/Cu(II) was subsequently applied in a direct oxidative amidation reaction and it was observed that different benzyl alcohols were converted to desire amides with good to excellent efficiency. This reaction was performed in the presence of amine hydrochloride salts, tert-butyl hydroperoxide (TBHP), and Ca2CO3 in acetonitrile (CH3CN) under nitrogen atmosphere. CN-Pr-β-CD/Cu(II) can be recycled and reused five times without significant reduction in reaction efficiency.


Preparation of CN.
The procedure utilized to prepare the nanosheet form of the g-C 3 N 4 was introduced by Li and et al. 46 . First, 1 g of the synthesized g-C 3 N 4 was dispersed in a mixture containing 20 ml of nitric acid (65 wt%) and 20 ml of sulfuric acid (98 wt%) for 2 h at ambient temperature. Then, 1 L of deionized water was added to dilute the mixture. The precipitate was collected and washed several times with deionized H 2 O, and finally dried in an oven at 60 °C. In the next step, 1 mg of g-C 3 N 4 was dispersed in 100 ml of H 2 O/isopropanol (1:1) for 6 h by an ultrasonic bath. Eventually, a centrifuge with speed of 5000 RPM was used to separate the synthesized CN.
Preparation of CN-Pr-Br. 1 g of the synthesized CN was added to 25 ml of dry toluene and the mixture was sonicated for 1 h. Then, 1 mmol of sodium iodide and 2.02 ml of 1,3-dibromopropane were added to the dispersed mixture and the reaction suspension was refluxed under nitrogen atmosphere for 2 days. The functionalized CN was separated by centrifugation and dried at ambient temperature.
Preparation of β-CD/Cu(II). The copper and β-CD complex was constructed using a method reported by Kaboudin and et al. 47 . Initially, 1 mmol of β-CD was added to 250 ml beaker including 50 ml of 1 M sodium hydroxide solution, and the mixture was stirred until a clear solution was formed. Afterward, 75 ml solution contain 0.04 M of CuSO 4 (H 2 O) 5 salt was added to the clear solution prepared in the previous step. The dark blue solution obtained at this stage was stirred at 25 °C for 6 h. After this time, the mixture was passed through filter paper to separate the excess copper as copper (II) hydroxide. Finally, 400 ml of ethanol was added to the remaining solution to form a pale blue suspension. The precipitate was separated by the Buchner funnel and after washing with ethanol, dried at 60 °C.
Preparation of CN-Pr-β-CD/Cu(II). 0.1 g of the functionalized CN and 20 ml of dry toluene were added to a 50 ml flask and sonicated for 30 min. Then, 0.1 g of β-CD/Cu(II) complex, 0.1 mmol of sodium iodide and 0.1 mmol of potassium carbonate were added to the reaction vessel and refluxed under N 2 for 2 days. Eventually, the precipitate was collected by centrifugation, washed several times with water and ethanol, and dried in a 60 °C oven.
General Procedure for the Tandem oxidative amidation of benzylic alcohols catalyzed by CN-Pr-β-CD/Cu(II). To a 10 ml round bottom flask, 1.5 mmol of benzyl alcohol, 1 mmol of hydrochloride salt of amine, 1/1 equivalents of calcium carbonate, 3 equivalents of TBHP, 15 mg of CN-Pr-β-CD/Cu(II), and 3 ml of CH 3 CN were added. The mentioned materials were then refluxed under N 2 for 3 h at 80 °C. After the completion of the reaction was confirmed using TLC, the catalyst was separated by filter paper and washed

Results and discussion
Catalyst characterization. In this study, CN-Pr-β-CD/Cu(II) was prepared by a facile procedure. Initially, CN with two-dimensional morphology were prepared via exfoliation in liquid phase and then the layers were separated by ultrasonic treatment. XRD, FT-IR and EDS analysis were used to confirm the correct formation of CN and they were demonstrated in Fig. 1. According to information obtained from XRD analysis, bulk g-C 3 N 4 has been converted to nanosheets form of the g-C 3 N 4 . The XRD spectrum of bulk g-C 3 N 4 has two main peaks in 2θ = 27.4° and 13.1° which is related to the interaction between conjugated aromatic part of the system and tri-s-triazine units of the structure (Fig. 1a). After exfoliation, the peak intensity of the (002) decreases and its 2θ position shifts from 27.4° to 27.8°, which may be related to the distance between the g-C 3 N 4 layers. Also during this process, another g-C 3 N 4 peak in 2θ = 13.1° was removed 26 . In addition, the value of d-spacings for the peaks observed in 27.4° and 13.1° for bulk g-C 3 N 4 is 0.325 nm and 0.675 nm, respectively 48 . After the exfoliation process and CN synthesis, the value of d-spacings for the peak in 2θ = 27.8° is equal to 0.321 nm. The slight decrease observed in d-spacings during peak displacement from 27.4° to 27.8° is due to the flattening of the undulated layers in g-C 3 N 4 . In other words, the heat and oxidation applied to convert bulk g-C 3 N 4 to nanosheets, compress the CN monolayers together and shorten the interplane distance of the CN sample 49 . The FT-IR spectra of bulk g-C 3 N 4 and CN are similar to each other. According to Fig. 1b, the peak observed in the range of 3000−3500 cm -1 was related to N-H present on the g-C 3 N 4 . Also, the observed peaks in the range of 1614 cm −1 and 1550 cm −1 corresponded to the stretching vibration of C=N. C-N stretching peaks were located in 1406 cm −1 , 1319 cm −1 , and 1234 cm −1 . Also sharp peak at 808 cm −1 was related to the breathing vibration of the tri-s-triazine components. EDS confirmed the presence of carbon and nitrogen in the g-C 3 N 4 structure (Fig. 1c). Subsequently, 1,3-dibromopropane was used to modify the CN and the linker binding process was examined by FT-IR and EDS analyzes. As can be seen in Fig. 2a, the FT-IR spectrums of CN-Pr-Br and linker-free CN were identical. On the other hand and based on Fig. 2b, EDS analysis confirmed the presence of the Br atoms. Finally, to increase the stability of β-CD/Cu(II) and also to promote the catalytic properties and dispersion of CN in water, CN-Pr-β-CD/Cu(II) were synthesised. As presented in Fig. 3a, the main peaks for the β-CD structure, including the sharp peak at 2920 cm −1 and the wide peak at 3369 cm −1 , can be related to the stretching vibrations of the C-H and OH bonds, respectively. In addition, glucose peaks, including C-C, C-O, and C-O-C, are found in the areas of 1027 cm −1 , 1155 cm −1 , 1340 cm −1 , 1417 cm −1 , 1647 cm −1 . FT-IR spectrum of copper (II) supported β-CD, confirm complex formation of the β-CD with copper (II). According to this spectrum, the In the next step, the elements in the structure of the β-CD/Cu(II) and CN-Pr-β-CD/Cu(II) were examined by EDS analysis. As can be seen in Fig. 3b,c, β-CD/Cu(II) contains carbon, oxygen, copper and on the other hand, CN-Pr-β-CD/Cu(II) includes carbon, nitrogen, bromine, oxygen and copper. ICP-OES was also utilized to determine the amount of copper in the structure of the CN-Pr-β-CD/Cu(II) and the presence of 12.7% copper in the catalyst structure was confirmed. FE-SEM and TEM imaging were performed to evaluate the structure and morphology of the catalyst. The FE-SEM images of CN and CN-Pr-β-CD/Cu(II) are shown in Fig. 4a and Fig. 4b,c respectively. Accordingly, CN plates and the functionalization process were well observed. On the other hand, as seen in the TEM image of CN-Pr-β-CD/Cu(II) in Fig. 4d,e, acceptable dispersion for metal particles were observed in the catalyst structure.
The XRD patterns of CN, β-CD, and CN-Pr-β-CD/Cu(II) were indicated in Fig. 5a. As shown in spectrum of the CN-Pr-β-CD/Cu(II), diffractions peaks related to the structure of β-CD were observed in the XRD diagram of the catalyst which confirm the functionalization of the CN. Furthermore, the diffractions peak at 2θ about 60.0° is related to the copper in the structure of the CN-Pr-β-CD/Cu(II) catalyst. TGA used to investigate the thermal stability of the synthesized samples. The TGA diagram for CN and the final catalyst was shown in Fig. 5b,c respectively. According to the Fig. 5b, the main mass loss of the CN begin at 600 °C. Figure 5c shows the CN-Pr-β-CD/Cu(II) TGA curve. In this diagram, three main mass reduction steps were observed, 3% mass reduction observed in the range of 201-106 °C, which can be related to the evaporation of water and the exit of solvents trapped in the structure. The 16% mass drop in the range of 401-203 °C was related to the breakdown of the linker and part of the β-CD. Finally, the mass drop at temperatures above 400 °C was due to the complete loss of β-CD and CN. Finally, it can be concluded that the functionalization process occurred well and during this process, the thermal stability of β-CD/Cu(II) increased. BET analysis was also performed to evaluate the surface area of the synthesized catalyst via nitrogen adsorption-desorption equilibrium (Fig. 5d). According to the obtained results, the BET surface area of the synthesized catalyst was 90.2127 m 2 /g. The catalytic capacitance of CN-Pr-β-CD/Cu(II) was reconnoitered for the preparation of amide derivatives via oxidation of benzylic alcohols with the amine hydrochloride salts. An overview of this process can be found in Fig. 6. To perform the reaction, the effective parameters in the reaction were first optimized to achieve the highest efficiency. As shown in Table 1, the effect of different factors on the reaction including catalyst, oxidizing agent, base, temperature and solvent was investigated.
The model reaction performed by 20 mg CN-Pr-β-CD/Cu(II) catalyst and 3 equivalents of TBHP in the presence of calcium carbonate. Based on the observed results, the presence of both base and oxidizing agents www.nature.com/scientificreports/ is necessary for the reaction to take place (Rows 1-3, Table 1). This reaction was accomplished at 80 °C in CH 3 CN solvent under N 2 atmosphere (Row 4, Table 1). Under these conditions, N-benzylbenzamide was obtained with 80% efficiency. Then, the effect of various factors including the amount of oxidizing agent, the type of oxidizing agent, the quantity of catalyst, the reaction temperature, the type of base, and the reaction solvent were investigated. Reducing the amount of TBHP to 3 equivalents, increases the production efficiency of the target product (90%) (Row 6, Table 1). In the next step, the amount of catalyst used in the reaction was  Table 1, 15 mg of CN-Pr-β-CD/Cu(II) catalyst had the best effect at reaction efficiency (95%). Hydrogen peroxide (H 2 O 2 ) and oxygen (O 2 ) were used as green oxidizing agents in this reaction (rows 10-11, Table 1). The best yield of the desired amide product was obtained by TBHP under nitrogen atmosphere. In the next step, different temperatures in the range of 60 to 100 were examined (rows 8, 12 and 13, Table 1) and it was observed that increasing the reaction temperature to 100° C reduces the reaction efficiency to 86% (Row 12, Table 1). Decreased in the reaction efficiencies may be related to the oxidation of benzyl alcohol to the related benzoic acid as a by-product that occurred at higher temperatures (benzoic acid by-product formation was confirmed by TLC). Further studies in this area have shown that the best temperature for the reaction was 80 °C. Various bases including Na 2 CO 3 , K 2 CO 3 and CaCO 3 were used to optimize the reaction conditions (rows 8, 14 and 15, Table 1). Among them, calcium carbonate minimized the adverse oxidation reaction of amine via slow deprotonation of the amine hydrochloride salt. As a result, the yield of the target product was increased. Eventually, the model reaction was done in CH 3 CN, toluene, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) solvents (rows 8, 16, 17 and 18, Table 1) and the best yield for N-benzylbenzamide was obtained in CH 3 CN solvent.
To demonstrate the potential and importance of using the CN-Pr-β-CD/Cu(II) catalyst in the tandem oxidative amidation of benzylic alcohols, the model reaction was performed under optimal condition with the presence of other catalysts such as copper sulfate salt, CN, β-CD, CN/Cu(II) and copper (II) supported β-CD (Table 2). Based on the obtained results in the mentioned table, the CN-Pr-β-CD/Cu(II) catalyst had the highest efficiency in the amide synthesis reaction. The presence of copper is an essential factor in promoting this reaction.  Table 3. Based on the information shown in Table 3, the oxidative amidation of benzylic alcohols with different aliphatic and aromatic amine hydrochloride salts (types 1, 2, and 3) and different type of benzylic alcohols including electron donor and withdrawing groups has been studied. In all cases the desired amide was obtained with the appropriate yield.  www.nature.com/scientificreports/ The outline of the possible mechanism for tandem oxidative amidation of benzylic alcohols was indicated in Fig. 7. TBHP is an excellent source of oxygen and can be used for oxidation reactions after activation by a suitable transition metal complex 66 . In this regard, benzyl alcohol in the presence of CN-Pr-β-CD/Cu(II) and TBHP was oxidized to aldehyde through a radical mechanism and tert-butanol was released. In addition, tertbutylperoxyl and tert-butoxyl radicals were also produced through Eqs. (1) and (2), respectively 20,67 . In the next step, calcium carbonate as the base separates the proton from the amine hydrochloride salt, and the resulting free amine reacts with the aldehyde and eventually producing the hemiaminal intermediate (III) 20,68 . Reduction of copper (II) ions in the CN-Pr-β-CD/Cu(II) catalyst leads to the production of tert-butyl peroxy radical. Subsequently, the hemiaminal was converted to intermediate (IV) in the presence of the activated tert-butyl peroxy radical. Finally, intermediate (IV) by the CN-Pr-β-CD/Cu(II)-TBHP catalytic system produces the desired amide through a radical mechanism by removing the tert-butanol. Then, to ensure the radical process of the reaction mechanism, 2,6-Di-tert-butyl-4-methylphenol (BHT) was used as a radical scavenger in the model reaction and no product was observed during the reaction. From this, it can be concluded that the oxidation reaction of benzyl alcohols has proceeded in a radical way.
The ability to recycle and reuse the catalyst is one of the most important aspects of catalyst design. In this regard, the CN-Pr-β-CD/Cu(II) catalyst was separated from the other components of the reaction by filter paper     Fig. 8, the prepared catalyst can be reused up to 5 times in the model reaction. Catalyst leaching was also evaluated and according to the obtained results from ICP-OES, Cu% decreased from 12.7% to 12.65% after five cycles. Following the study of catalytic properties, a comparison between the synthesized catalyst and previous articles was made. Based on information summarized in the Table 4, the CN-Pr-β-CD/Cu(II) catalyst is competitive with other reports in product efficiency, reaction time and conditions, as well as the ability to recyclability the catalyst.

Conclusions
In this study, CN-Pr-β-CD/Cu(II) was synthesized and evaluated as an effective catalyst for the tandem oxidative amidation of benzylic alcohols. Catalyst synthetic processes were performed via modification of CN by 1,3-dibromopropane and β-CD/Cu (II) respectively. CN-Pr-β-CD/Cu(II) was evaluated and identified by using analysis such as FT-IR, XRD, FE-SEM, EDS, TGA, ICP-OES, BET, and TEM. The mentioned catalytic reaction was performed in the presence of amine hydrochloride salts, TBHP, and Ca 2 CO 3 in CH 3 CN solvent. The transition metal by activating the TBHP plays a key role in the progress of the reaction. According to the obtained results, the tandem oxidative amidation of benzyl alcohols with various aromatic and aliphatic amine hydrochloride salts (types I, II and III) as well as various benzyl alcohols including electron withdrawing and donor groups have been investigated. In all cases the desired amides were obtained with the appropriate yields.