A nickel nanoparticle engineered CoFe2O4@GO–Kryptofix 22 composite: a green and retrievable catalytic system for the synthesis of 1,4-benzodiazepines in water

A composite of Ni nanoparticles incorporated in Kryptofix 22 conjugated magnetic nano-graphene oxide, CoFe2O4@GO–K 22·Ni, was synthesized via the grafting of Kryptofix 22 moieties on the magnetic nano-graphene oxide surface, followed by reaction of the nanocomposite with nickel nitrate. The Kryptofix 22 host material unit cavities can stabilize the Ni nanoparticles effectively and prevent their aggregation and separation from the surface. Characterization of the catalysts by FT-IR, FE-SEM, TGA, ICP, EDX, XRD, VSM and BET aided understanding the catalyst structure and morphology. This catalyst was efficiently applied for the synthesis of 1,4-benzodiazepine derivatives. The main advantages of the method are mild reaction conditions, inexpensive catalyst, it is environmentally benign, has high to excellent yields and shorter reaction times. This organometallic catalyst can be easily separated from a reaction mixture and was successfully examined for six runs with a slight loss of catalytic activity.


Introduction
Green chemistry is the study of the design and application of chemical products and processes to reduce or to eliminate negative impacts to human health and the environment, and where possible to utilize renewable raw materials. The development of green methods with high catalytic activity systems has received a great deal of research attention in organic synthesis for environmental and economic reasons. [1][2][3][4][5] The aim of the eld of catalysis in terms of green chemistry is to develop environmentally benign, practical, clean, economical and efficient processes for catalyst separation and recycling. To achieve these goals, graphene oxide (GO) has been widely explored to replace conventional catalysts or use as supporting material for improving the performance of catalysts due to its large specic surface area, unique layered structure, high thermal stability, intrinsic mechanical, electrical properties, and excellent exibility. [6][7][8][9] However, the expensive and tedious separation and recovery of powdered GO is a barrier for its widespread industryscale applications. To control these problems, magnetic separation techniques is a fast, simple, economical, and green approach, which makes removing and reusing of the catalyst is possible without the need to lengthy, cumbersome and expensive centrifuge. [10][11][12][13] Therefore, the magnetic GO nanocatalysts are regarded as ideal supports for the heterogenize the homogeneous catalysts support due to their unique properties such as simple procurement, good dispersion properties, excellent catalytic activity, outstanding stability, selectivity and well separation of the catalyst via an external magnet. 14,15 Among metal ferrite nanoparticles, cobalt ferrite (CoFe 2 O 4 ) have gained a great deal of attention due to their moderate saturation magnetization, high chemical stability and mechanical hardness. CoFe 2 O 4 nanoparticles decorated on graphene oxide to obtain CoFe 2 O 4 @GO composite, will achieve further stabilization of these nanoparticles, and also prevents formation of aggregates in solution. [16][17][18][19] On the other hand, Kryptox 22 (K 22) as a specic class of aza-crown ether have been known for their high affinity and selectivity to bind transition metals (Fig. 1). The unique structure and properties of K 22 have made them a popular choice for a wide range of applications over the past few decades. They have been widely utilized in many disciplines such as supramolecular chemistry, biochemistry, materials science, catalysis, separation and biomedicine. They are exceptionally versatile in selectively binding a range of metal ions, providing development of the area of host-guest chemistry. [20][21][22][23][24][25] The incorporation of metal onto support material has received signicant attention due to the sustainable green chemistry uses it presents. Nevertheless, we anchored nickel nanoparticles incorporated Kryptox 22 onto the surface of magnetic nano-graphene oxide as efficient and recyclable nanocatalyst for the synthesis of 1,4-benzodiazepine.
Benzodiazepine derivatives represent one of the most active classes of heterocyclic possessing a wide spectrum of physiological and pharmacological properties. [26][27][28] Recently, many methods have been reported for the preparation of benzodiazepines through two-component or three-  32 Despite the merits of these procedures, each of them suffers at least from one of the following limitations: low yields, unavailability of the reagents, long reaction times, high toxicity, operational costs, use of strong acids, harsh reaction conditions, and tedious workup procedures. The drawbacks mentioned above can be solved via the development of a more versatile and also environmentally friendly method. The present study was conducted to develop new, synthetic, and useful methodologies using organometallic based catalyst for the preparation of various biologically active heterocyclic compounds.
The aim of this presented work is to highlight the synergistic effects of the combined properties of highly mesoporous surface of magnetic nano-graphene oxide, and Kryptox 22 cavity, in the trapping and stabilizing of the Ni nanoparticles and explored its application in the synthesis of 1,4-disubstituted benzodiazepines as a procient, harmless to the environment, recyclable and magnetic powerful solid catalyst with good stability.

Materials and physical measurements
All the chemicals and solvents used in this work were purchased from Merck and Sigma-Aldrich and were used without further purication. The morphology of nanocomposites was revealed by a scanning electron microscope (FESEM-TESCAN MIRA3). FT-IR spectra were taken on a PerkinElmer Spectrum Version10.4.4 spectrophotometer in KBr pellets and reported in cm À1 . 1 H NMR spectra were measured on a Bruker 400 MHz spectrometer in DMSO with chemical shi (d) given in ppm. The TGA curve of the catalyst was recorded on a BAHR, SPA 503 at heating rates of 10 C min À1 . The X-ray powder diffraction (XRD) data were collected with Co Ka radiation (l ¼ n1.78897 A) operating at n40 keV. VSM measurement was recorded by a Vibrating Sample Magnetometer (VSM) MDKFD. The size of the as-synthesized nanoparticle was determined by transmission electron microscopy (TEM) techniques using Zeiss-EM10C transmission electron. Energy-dispersive X-ray spectroscopy (EDX) analysis was obtained by MIRA3TESCANXMU instrument. Nitrogen adsorption measurements were conducted at 77.4 K on a Belsorp18. The specic surface area and the  pore size distribution were calculated by Brunauer-Emmett-Teller method (BET) and Barrett-Joyner-Halenda (BJH) model, respectively. ICP analyzer (PerkinElmer, Optima 8300) was used for measuring the Ni loading of the catalyst.

Synthesis of graphene oxide (GO)
The graphene oxide was got ready according to the previously reported methods. 33,34 The graphite powder (2.0 g) was treated with NaNO 3 (1.0 g) in the cooled concentrated sulfuric acid (50 mL) under stirring in ice bath. Then, KMnO 4 (7 g) was added slowly into the dispersion, and the mixture was stirred at lower than 15 C. Aer 10 min, the ice bath was removed and the mixture was stirred at 40 C for 6 h. In continue, deionized water (100 mL) was added under vigorous stirring and the diluted suspension was stirred at 90 C for 30 min. Next step, hydrogen peroxide (30%, 7 mL) was added dropwise along with stirring to the mixture until the color of the reaction media was changed from black to the yellow. The solution was ltered and washed by HCl (5%) and deionized water several times to remove the excess of manganese and residual acid. The resulting GO solid was dried in air, at room temperature.    Table 1). Progress of the reaction was monitored by TLC (n-hexane/ EtOAc, 10 : 3). Aer completion of the reaction, diethyl ether (10 mL) was added and the catalyst was removed by using an external magnet and washed with ethanol, vacuum dried, then subjected to the next run directly. The remaining solid product was recrystallized from aqueous ethanol to provide pure benzodiazepines. The nal products data were specied by 1 H and 13 C NMR spectroscopy (see ESI †).

Results and discussions
The synthetic route for the preparation of the Ni nanoparticles incorporated Kryptox     The method for the green and efficient synthesis of Ni nanoparticles stabilized by Kryptox 22 conjugated magnetic nano-graphene oxide and investigatione of their catalytic activity for the synthesis 1,4-benzodiazepine derivatives in water are shown in (Scheme 2). This new nanocatalyst operates efficiently and safely in water and can be easily separated using an external magnet.
To characterize the nanocatalyst, and to conrm the immobilization of the active components on the pore surface of magnetic graphene oxide was characterized by various techniques such as FESEM, XRD, TGA, ICP-OES, EDX, BET, FT-IR and VSM.    (Fig. 2C), that show K 22 was covalently graed onto the surface of CoFe 2 O 4 @GO, also, the shi on spectrum to lower wave numbers belong to symmetrical and asymmetrical modes of the Kryptox 22 bonds and metal is happened, that is due to a robust interaction between the O, N group of the nickel complex on the magnetic graphene oxide (Fig. 2D). The TGA curves of the GO, CoFe 2 O 4 @GO-K 22$Ni indicates the weight loss of the organic material as they decompose upon heating (Fig. 3). Fig. 3 presents three weight loss steps in the TGA curve of the CoFe 2 O 4 @GO-K 22$Ni catalysts. The rst weight loss (11.85%) between 20-220 C due to the removal of adsorbed water moisture at the hybrid material surface of the mentioned catalyst is occurred. The next two weight losses (35.5%) from 210 to 660 C are due to the decomposition and burning of GO and Kryptox 22. On the basis of the results of the TGA curve the well graing of GO and K 22 onto CoFe 2 O 4 is veried.

Catalyst characterization
EDX elemental analysis of the CoFe 2 O 4 @GO-K 22$Ni shows the existence of cobalt, iron, nitrogen, carbon, oxygen and nickel in the catalyst and the spectrum is depicted in Fig. 4. Also, the elemental mapping images indicate the uniform dispersion of Ni in the nanocomposite. This has been further conrmed from the EDX spectrum of the nanocatalyst.
Inductively ICP-OES analysis determined the exact amount of nickel loaded on graphene oxide-magnetite nanocomposite was found to be 0.41 mmol g À1 .
As seen in Fig. 6, the characterization of the magnetic feature of CoFe 2 O 4 (A), CoFe 2 O 4 @GO (B) and CoFe 2 O 4 @GO-K 22$Ni (C) were carried out using vibrating sample magnetometry (VSM) with a peak eld of 15 kOe. It is clear from the hysteresis loops that the saturation magnetization (M s ) of CoFe 2 O 4 , CoFe 2 O 4 @-GO and CoFe 2 O 4 @GO-K 22$Ni are 79.05, 55.22, and 32.60 emu g À1 , respectively. The decrease in mass saturation magnetization in the last two composites can be attributed to the decoration of COFe 2 O 4 magnetic nanoparticles on GO and the graing of K 22, Ni, respectively, over CoFe 2 O 4 . Although, a signicant reduction was observed in the M s values of the nanocatalyst, it is enough for any magnetic separation. Fig. 7 the nitrogen adsorption-desorption isotherms and pore size distributions of CoFe 2 O 4 @GO-K 22$Ni is illustrated. The materials had type IV isotherms, indicating that the mesostructure remained. According to Brunauer-Emmett-Teller (BET) analysis, the surface area, the pore volume, and the pore size of the catalyst is 109 m 2 g À1 , 0.143 cm 3 g À1 , 8.91 nm, respectively. Results indicate that immobilizing of K 22$Ni   complex into the magnetic graphene oxide may be the reason of reduction the pore volume, pore size, and surface area of the catalysts. The SEM is a useful method which is used to determine the morphology and size distribution of prepared nanoparticles. SEM images of the CoFe 2 O 4 , GO and CoFe 2 O 4 @GO-K 22$Ni catalyst are displayed in Fig. 8. As it is clearly seen, the CoFe 2 O 4 spherical core-shell is structured with nano dimension ranging under 10 nm (Fig. 8a). Furthermore, as shown in the image CoFe 2 O 4 @GO-K 22$Ni comparing to the SEM image of GO, it was conrmed that some particles were anchored onto the surface of GO and the surface of GO became less transparent due to the presence of the CoFe 2 O 4 nanoparticles and K22.Ni complex (Fig. 8d). Transmission electron microscopy (TEM) studies of the CoFe 2 O 4 @GO-K 22$Ni nanocomposite conrm that the nickel nanoparticles were incorporated in the CoFe 2 -O 4 @GO-K 22 successfully (Fig. 8e).
We investigated catalytic activity of CoFe 2 O 4 @GO-K 22$Ni as a heterogeneous nanocatalyst in the synthesis of benzodiazepine in water as an easily available and green solvent as shown in Scheme 2.
To optimize the reaction conditions, we surveyed the synthesize of benzodiazepine on the basis of the reaction between dimedone, o-phenylenediamine and benzaldehyde as beginning materials under different reaction conditions. The results of these tests are summarized in Table 1.
Initially, the reaction was performed without any catalyst, but it did not proceed aer a long time ( Table 1, entry 8). The reaction proceeded with high speed and the corresponding products were isolated in excellent yields with 0.03 g of the catalyst (Table 1, entry 5). To investigate the best reaction temperature, this procedure was studied at various temperatures and the best one was 60 C ( Table 1, entry 5). The reaction was repeated in different solvents such as water, ethanol, CH 2 Cl 2 , and EtOAc and it was found that water is more suitable for this reaction. Furthermore, the reaction was performed in the presence CoFe 2 O 4 @GO as catalyst, but it did not proceed aer a long time. The obtained result conrmed that nickel nanoparticles play the main role of catalytic activity of the prepared CoFe 2 O 4 @GO-K 22$Ni for the synthesis of product.
To study the efficiency of this catalyst, benzaldehyde derivatives with electron releasing, and electron withdrawing groups were checked for the synthesis of 1,4-benzodiazepine derivatives. The results showed that both groups have high yields in short reaction time ( Table 2).
Aer successful synthesis of benzodiazepine derivatives, a plausible reaction pathway has been suggested in Scheme 3.
Initially, the oxygen atoms of dimedone interact via lone pairs of electrons with nickel nanoparticles of the catalyst surfaces, and the NH 2 groups of o-phenylenediamine attack the carbonyl group of dimedone with elimination of water molecule leading to imine intermediate 1. The amine group of intermediate 1 would then react with the activated carbonyl group of aldehyde to form the corresponding imine 2, which would undergo tautomerism, intramolecular cyclization, and proton transfer reactions to give product 3.
A comparison of this work with other reported methods is collected in Table 3. The results shows that this procedure is  better to some previously reported methods in terms of easy of catalyst separation, yield, the amount of used catalyst and the reaction time.

Recycling of CoFe 2 O 4 @GO-K 22$Ni
For studying the recyclability of CoFe 2 O 4 @GO-K 22$Ni, the catalyst was isolated by an external magnet aer the completion of each reaction run and washed several times with Et 2 O. The recovered catalyst was then reused in 6 cycles with minimal loss of activity (Fig. 9).
To characterize the changes in the chemical structure of the catalysts following the sixth cycle, TGA, XRD, FT-IR and SEM analyses were carried out and the results are displayed below (Fig. 10). These analyses showed that CoFe 2 O 4 @GO-K 22$Ni nanocomposite maintained its chemical structure aer the longevity tests.
The efficiency and activity of prepared catalyst was investigated by hot ltration test. The heterogeneity of the CoFe 2 O 4 @GO-K 22$Ni was examined by carrying out a hot ltration test using dimedone, o-phenylenediamine and benzaldehyde as model substrates. No nickel could be detected in the liquid phase using AAS and, more signicantly, aer hot ltration, the reaction of the residual mixture was completely stopped.

Conclusions
In this study we successfully reported an effective practice for the synthesis of efficient recoverable heterogeneous catalytic system, CoFe 2 O 4 @GO-K 22$Ni, achieved by anchoring Ni on the Kryptox 22-modied magnetic nano-graphene oxide. The catalytic behavior of the catalyst was investigated as a recyclable system for the synthesis of 1,4-benzodiazepine. The introduced catalyst can promote the yields and reaction times over 6 repeated runs with very low leaching amounts of supported catalyst into the reaction mixture. The reaction conditions (H 2 O as solvent and without exclusion of air) coupled with the sustainability of the catalyst make the described heterogeneous catalyst highly desirable from the point of view of green chemistry. We expect that this new and practical protocol will be useful in pharmaceutical development and in academic research.

Conflicts of interest
There are no conicts to declare.