Copper adorned magnetic nanoparticles as a heterogeneous catalyst for Sonogashira coupling reaction in aqueous media

A nanomagnetic hydrophilic heterogeneous copper catalyst, termed γ-Fe2O3@PEG@PAMAM G0-Cu, has been successfully prepared and characterized using FT–IR, XRD, FE-SEM, TEM, EDX, mapping, TGA/DTG, VSM and ICP analyses. The catalyst displayed excellent activity for the palladium-free Sonogashira cross coupling reaction of various aryl iodides and bromides with phenylacetylene derivatives in pure water. The presence of polyethylene glycol coupled with hydrophilic character of the Cu-catalyst adorned on γ-Fe2O3 MNPs provides the ready dispersion of the catalyst particles in water, leading to higher catalytic performance as well as facile catalyst recovery via simple magnetic decantation. The recovered catalyst was reused for at least six successive runs with little reduction in its catalytic activity and any noticeable changes in its structure. The use of water as a green solvent, without requiring any additive or organic solvent, as well as the exploitation of abundant and low-cost copper catalyst instead of expensive Pd catalyst along with the catalyst recovery and scalability, make this method favorable from environmental and economic points of view for the Sonogashira coupling reaction.


Experimental section
Preparation of γ-Fe 2 O 3 @PEG@PAMAM-Cu MNPs. The various steps of catalyst preparation are depicted in Fig. 3. Initially, γ-Fe 2 O 3 MNPs were synthesized via co-precipitation method as reported in the literature 33 . Subsequently, γ-Fe 2 O 3 @PEG MNPs were prepared using the previous described method 34 .
To obtain γ-Fe 2 O 3 @PEG@APTES, γ-Fe 2 O 3 @PEG MNPs (1.0 g) was dispersed by sonication in dry toluene (30 mL) for 30 min. Then, (3-aminopropyl)triethoxysilane (APTES, 0.885 g, 0.83 mL, 4.0 mmol) was added dropwise to resulting dispersed solution of γ-Fe 2 O 3 @PEG MNPs, while the reaction was stirred under N 2 , at 25 °C. Then, the temprature was raised to reflux conditions and heating continued for 24 h. After completion of the reaction, the solid product was separated from the solvent using an external magnet and washed twice with anhydrous toluene and diethyl ether and then dried under vacuum 50 °C overnight, to obtain γ-Fe 2 O 3 @ PEG@APTES (1.12 g).
Subsequently, methyl acrylate (MAc, 7 mL, 6.6 g) was added dropwise to mixture of γ-Fe 2 O 3 @PEG@APTES (1.0 g) dispersed in ethanol (30 mL), while the reaction was stirred under N 2 atmosphere, at 25 °C. In the next step, the mixture was stirred and heated at 40 °C and the reaction continued for 24 h under N 2 . After completion of the reaction, solid product was separated by an external magnet and washed with ethanol three times and followed by vacuum drying at 50 °C overnight, to acquire γ-Fe 2 O 3 @PEG@MAc (1.21 g).
Subsequently, the γ-Fe 2 O 3 @PEG@PAMAM G 0 , was prepared by dispersion of 1 g of γ-Fe 2 O 3 @PEG@MAc in ethanol (40 mL) via sonication for 30 min, followed by addition of ethylenediamine (EDA, 0.1 mmol, 6.3 g) dissolved in ethanol (30 mL), while the reaction was being stirred under N 2 , at 25 °C. Then, the temprature was   www.nature.com/scientificreports/ raised to 50 °C and continued the reaction for 48 h. The ensued solid product was separated by an external magnet, washed with ethanol three times, and finally dried at 50 °C overnight to obtain γ-Fe 2 O 3 @PEG@PAMAM (1.09 gr). Finally, the earlier prepared γ-Fe 2 O 3 @PEG@PAMAM MNPs (1 g) was dispersed in ethanol (30 mL) for 30 min, and then, Cu(OAc) 2 ·H 2 O (0.199 g, 1 mmol) dissolved in ethanol (20 mL) was added to ethanolic dispersed mixture, while the reaction was stirred at 50 °C. Then, the reaction was allowed to proceed for 24 h. Finally, γ-Fe 2 O 3 @PEG@PAMAM-Cu (1.08 g) was obtained following the sequence of separation by an external magnet, washing with ethanol and after drying the particles in vacuum at 50 °C overnight (Fig. 3). ICP-OES analysis showed presence 0.96 mmol of Cu on 1 gr of γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu (0.96 mmol, 0.06 gr, 0.25 wt%)).
General Procedure for the Sonogashira cross coupling reaction (1a-p). γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu (0.8 mol%, 0.006 g) was added to a mixture of NaOH (2.0 mmol), phenylacetylene (1.5 mmol), and aryl halide (1.0 mmol) in water (5 mL), under stirring in air and heated at 80 °C. The progress of reaction was monitored by TLC until completion. After the completion of the reaction, the nanocatalyst was separated by an external magnet and washed with ethyl acetate (3 × 3 mL). The desired product (liquid phase) was extracted with ethyl acetate (3 × 6 mL), and the organic layers were dried over anhydrous Na 2 SO 4 . After evaporation of the solvent, crude product was purified by column or flash chromatography to afford the pure products 1a-p.
The loading of the Cu amount on catalyst was determined by ICP-OES analysis which according to the results amount of copper incorporated on 1.0 g of γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu complex was determined to be 0.96 mmol.
The TGA curve of γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu showed weight loss at five stages, totaling 18.57% that demonstrate the good thermal stability of γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu, at a heating rate of 10 °C min -1 in the temperature range of 25-800 °C under nitrogen atmosphere (Fig. 10).
The first weight loss is attributed to the removal of trapped water content in the crystalline structure of the Cu complex (− 1.60 W%, ~ 150 °C) (Fig. 10). The second to fifth weight loss of γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu were observed in the regions 243-600 °C (− 1.60, − 5.60, − 1.21, and − 1.64 W%) which are attributed to decomposition of the organic compounds grafted on the surface of γ-Fe 2 O 3 , including, PEG, amino-siloxy linker, and PAMAM dendrimer (Fig. 10). The weight loss, in the temperature range of 800 °C (− 7.10 W%) probably are related to the removal of PEG and N 2 , CO 2 gases, and as well as mineral impurities in the γ-Fe 2 O 3 (Fig. 10).
Evaluation of the catalytic activity of γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu MNPs. Subsequent to the characterization and structural confirmation of the γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu, the Sonogashira C-C cross coupling reaction was explored for assessing its performance and reactivity in aqueous medium as a green solvent, the main objective of our strategy being to provide an active catalyst in water as an ideal alternative to conventional organic solvents for performing such coupling reactions. Figure 13 clearly show the hydrophilic properties of γ-Fe 2 O 3 @PEG@ PAMAM G 0 -Cu catalyst.
Optimization study for the Sonogashira cross-coupling reaction. In this section, the optimal reaction conditions were explored for the Sonogashira cross-coupling reaction, using γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu as a hydrophilic catalyst. To this end, phenylacetylene and aryl iodide were selected as model substrates to identify appropriate parameters on the progress of the target reaction. Thus, the effect of temperature changes,   entry 10). Decreasing the amount of base used (NaOH, 1 mol) also did not have a favorable effect, which afforded moderate conversion of 1a (70%, entry 8). Also, increase the amount of base used (NaOH, 3 mol) also was not effective in progressing the model reaction (Table 1, 94%, entry 9). In general, the best results were found using 0.8 mol% loading of the γ-Fe 2 O 3 @ PEG@PAMAM G 0 -Cu catalyst (0.006 g), NaOH as a base (2 mmol), in H 2 O (5 mL) at 80 °C for 180 min giving compound 1a in 94% isolated yield (see Table 1 for more details).

Substrate scope.
To the overall performance appraisement and to ascertain the limitation of Sonogashira reaction using γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu catalyst, a series of assorted aryl iodides and aryl bromides were examined in reaction with phenylacetylene under the optimal reaction conditions (0.8 mol% of Cu catalyst with NaOH, in pure water, at 80 °C, see Table 2). As depicted in the Table 2, a broad range of 1,2-diphenylacetylene products were synthesized, emanating from both, the aryl bromide and aryl iodide substituted with electrondonating (-NH 2 , -OMe, -Me) and electron-withdrawing functional groups (Cl, -CO 2 Me, -COMe, -CN, -NO 2 ) and affording good to excellent yields (45-90%). However, the results related to aryl iodides (55-94%) were better than aryl bromide (45-80%), I > Br. In general, the results of using γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu for Sonogashira cross coupling reactions to the corresponding 1,2-diphenylacetylene products, were encouraging which led to the production a range of 1,2-diphenylacetylene products (see Table 2 entries 1a-p for additional details).

Experimental controls.
To demonstrate the catalytic role and uniqueness of the nano γ-Fe 2 O 3 @PEG@ PAMAM G 0 -Cu complex, some control experiments were conducted for the model reaction of Sonogashira (Fig. 14). For this goal, the model reaction was performed and compared using the parent materials. The results clearly indicated the high activity and efficiency of the γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu catalyst, compared to the other examined catalysts (Fig. 14).
Recyclability study. Recyclability aspects of the γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu catalyst complex were evaluated for model reaction to achieve of 1a, under the optimized reaction conditions for 6 serial runs (see Table 3). According to the obtained results, the highly activated catalyst represented just 0-1% loss of efficiency after the 6 successive runs for preparation of 1a (Table 3). In addition, FT-IR analysis was performed for the γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu catalyst used after the 6th runs in the model reaction (see Fig. 15a,b). Study of the FT-IR spectra related to 6th runs of catalyst, demonstrate the stability structure of the catalyst that have been retained after 6th recovery in the model reaction (see Fig. 15).
The comparison of TEM and SEM images of fresh copper catalyst and the used catalyst after 6th run in the model reaction, did not reveal any detectable and noticeable change in size and morphology (Fig. 16A, B). Moreover, a good dispersion and small NPs of Cu-complex even after six recovering times, is related to the stability of  www.nature.com/scientificreports/  www.nature.com/scientificreports/ the γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu catalyst. However, minimal agglomeration can be seen in the TEM image that is associated with the dipole-dipole interactions of magnetic nano particles (Fig. 16A, B). ICP analysis was performed for measurement of the copper leaching for the six catalytic run steps of model reaction (Fig. 17). ICP analysis results of Cu complex after the 6th run demonstrated a stable catalytic structure with a small amounts of Cu leaching (average up to 2.4%) (Fig. 17).
Moreover, a rigorous investigation was conducted to elucidate the stability and heterogeneous nature of the catalyst using the hot-filtration method on the model reaction (ESI, Fig. S3). After the catalyst was magnetically  www.nature.com/scientificreports/ removed from the reaction medium (t = 70 min, 46% yield of 1,2-diphenylacetylene monitored by GC), and the reactants were allowed to undergo further reaction, when the reaction did not progress (49% yield after 180 min, Fig. S3). This confirmed that the catalyst functioned heterogeneously in the reaction and consequently only slight leaching occurred during the reaction.
Catalytic performance. Catalytic efficiency of the γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu complex in terms of the reaction time, and yield was compared with the other reported catalysts for the Sonogashira reaction (see Table 4). The high activity of the catalyst in water media, as an abundant, and available solvent is notable. Additional benefits of this catalytic methodology in comparison with the others catalytic protocols are presented in Table 4 are the simplicity of catalyst separation, higher yield of the corresponding products during the shorter reaction times, eco-friendly and economic aspects, as well as the use of available and inexpensive copper metal complex (see Table 4. For more details).

Summary and conclusions
In brief, we have developed an environmentally friendly and economical methodology using a water-dispersible, recyclable copper catalyst (γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu) based on the γ-Fe 2 O 3 nanoparticles coated with polyethylene glycol to promote the Sonogashira coupling reaction in water as a solvent. The physicochemical properties of γ-Fe 2 O 3 @PEG@PAMAM G 0 -Cu catalyst were characterized using various techniques such as, FT-IR, FE-SEM, XRD, VSM, EDS, TGA and TEM analysis. Polyethylene glycol on the surface of iron oxide nanoparticles instigated the good dispersion of the catalyst in the aqueous media and thus increased the interaction between the precursor materials and the catalyst like homogeneous systems. A wide range of aryl halides (aryl iodide and aryl bromide) reacted with phenylacetylene using copper catalyst in the water and led to attainment of the desired products with good to excellent efficiencies. The easy recyclability of the catalyst using an external  www.nature.com/scientificreports/ magnet and its reusability, as well as the good performance of the catalyst in water solvent without the use of additives such as alcohol or added surfactant are other salient advantages of this developed catalyst.

Data availability
All data generated or analyzed during this study are included in this published article [and its supplementary information files].