Dendritic structured palladium complexes: magnetically retrievable, highly efficient heterogeneous nanocatalyst for Suzuki and Heck cross-coupling reactions

The recyclable nanomagnetic Pd-complex PAMAM G0-Pd@γ-Fe2O3 is reported for catalytic C–C cross-coupling reactions of challenging substrates. Mainly, a great variety of aryl chlorides can be used as substrates for Suzuki–Miyaura and Mizoroki–Heck reactions under mild reaction conditions (60–90 °C) and low catalyst loading (<1 mol% Pd) in aqueous media. The presence of numerous polar groups in the polymer matrix increases the solubility of the catalyst in water, thus facilitating its operation in aqueous environments. The immobilization of the catalyst on the surface of a magnetic platform allows its effective recovery and reuse without significant loss of catalytic activity for at least six cycles with total leaching of <1% palladium metal, meeting the requirements for acceptable metal residues in the pharmaceutical industry.


Introduction
The development of new protocols and methods according to green chemistry standards to meet the growing demands of human society for energy, health, and agricultural purposes remains a pressing challenge for chemistry and the related sciences. 1,2 Arguably, catalysis stands at the forefront of such efforts, providing innovation by the development of new chemical transformations. Nevertheless, making catalysis feasible for large-scale applications by improving catalytic activity and selectivity, and especially in the case of transition metal catalysis, obviating metal leaching is equally essential even for well-established transformations. 3 In this context, palladium-catalyzed cross-couplings have been manifold proven to be of particular signicance for synthesizing medicinally relevant compounds even though palladium is one of the scarcest metals in the world. [4][5][6] Efficient recycling of such species is economically desirable; moreover, the considerable toxicity of palladium mandates its removal below 10 ppm in pharmaceuticals. 7 Separating homogeneous palladium catalysts from products is challenging; consequently, heterogenization of palladium catalysts is a viable approach to overcome these difficulties. However, typical heterogeneous palladium catalysts such as Pd/C, being most successful for hydrogenations, 8 are less efficient in cross-coupling reactions, especially with industrially relevant aryl chlorides. 9 Such substrates remain challenging with any catalyst despite some impressive advances in designing molecular palladium complexes with specialized ligands. [10][11][12][13][14][15][16][17] Considering large-scale and recycling, many efforts have been made to develop heterogeneous Pd-catalysts, 10-14 including molecular palladium-ligand complexes deposited onto various solid supports. [15][16][17][18][19] Among them, iron oxide nanoparticles have emerged as an attractive platform for metal catalysts 20 and especially for palladium complexes to arrive at eco-friendly and robust heterogeneous catalysts for Suzuki-Miyaura and Heck-Mizoroki C-C cross-coupling reactions. [21][22][23][24] Such catalysts can be easily manipulated and retrieved by external magnets avoiding cumbersome centrifugation or ltration processes. [25][26][27] Moreover, iron oxide nanoparticles have a high surface-tovolume ratio, which allows generating a large number of active sites that are available to promote catalytic reactions. 28,29 Polyamidoamine (PAMAM) dendrimers have a particularly well-dened structure favorable for the encapsulation of metal nanoparticles. 30 The nanoparticle size and the metal loading can be controlled by the dendrimer generation, whereas the solubility in common solvents can be adjusted by the nature of the dendritic end group. 31 Despite these attractive properties, dendrimers are oen difficult to recycle and to reuse; thus, attaching them to magnetic supports holds the promise to combine tunability of the dendritic core to generate a suitable environment of catalytically active moieties with magnetic properties benecial for recovery and reuse. 32 Previously, various homogeneous and heterogeneous systems of palladium nanoparticles encapsulated in modied PAMAM dendrimers of generation G 2 -G 6 have been reported for Suzuki-Miyaura and Mizoroki-Heck cross-coupling reaction. [33][34][35][36] For example, PAMAM-G 3 graed on functionalized multiwall carbon nanotubes (MWCNTs-NH 2 ) showed good activity for aryl chlorides in Heck reactions employing N-methyl-2-pyrrolidone (NMP) as a solvent, 33 and the Fe 3 O 4 -G 4 -PAMAM-Pd(0) could convert aryl chlorides in DMF as a solvent in Suzuki-Miyaura couplings. 34 Moving towards environmentally more benign solvent systems, the G 6 -OH(Pd 74 Cu 73 ) PAMAM 34 dendrimer or Fe 3 O 4 @SiO 2 -PAMAM-Pd 36 were competent catalysts for aryl chlorides in Suzuki-Miyaura reactions in a mixture of EtOH/H 2 O. Similar to the PAMAM structure, polypropylene polybenzyl isocyanate (PPI) dendrimers modied by diphosphines as coordination site for Pd(II) complex have been employed successfully in Suzuki-Miyaura reactions with aryl chlorides in a THF/H 2 O solvent mixture. 37 More Pd-PAMAMbased systems were reported, but these only catalyze the coupling of aryl iodides and bromides effectively and show little activity at best for aryl chlorides. [38][39][40][41][42] We report here the synthesis of a hybrid material, consisting of a superparamagnetic g-Fe 2 O 3 core decorated with zerogeneration PAMAM dendrimer G 0 in which palladium nanoparticles were encapsulated (Fig. 1). This catalytic system shows unusual high activity for Suzuki-Miyaura and Heck coupling reactions, most notably with a wide variety of aryl chlorides as substrates.

General procedure for the Suzuki-Miyaura crosscoupling reaction (9a-r)
PAMAM G 0 -Pd@g-Fe 2 O 3 (0.47 mol%, 0.007 g) was added to a mixture of K 2 CO 3 (2 mmol), phenylboronic acid (1.2 mmol), and aryl halide (1.0 mmol) in water (2 mL), under stirring and heated at 60 C (90 C when we used aryl chlorides). The progress of reaction was monitored by TLC until completion (15 min), then the nanocatalyst was separated by an external magnet. The reaction mixture was extracted with ethyl acetate (3 Â 5 mL), and the combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. The residue was puried on silica to give rise to the pure products 9a-r.
2.2 General procedure for the Mizoroki-Heck cross-coupling reaction (12a-r) PAMAM G 0 -Pd@g-Fe 2 O 3 (0.61 mol%, 0.009 g) was added to a mixture of K 2 CO 3 (2 mmol), alkene (1.5 mmol), and aryl halide (1.0 mmol) in water (2 mL), under stirring and heated at 80 C (90 C when we used aryl chlorides). The reaction progress was screened by TLC at different time intervals. Aer the completion of the reaction, the nanocatalyst was separated by an external magnet. The reaction mixture was extracted with ethyl acetate (3 Â 5 mL), and the combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. The residue was puried on silica to give rise to the pure products 12a-r.  (JCPDS card no. . 43,44 The unit cell is assigned as the space group P4 1 32 with the crystallographic parameters a ¼  . 65-2867, Fig. 2). 45,46 The decrease of the XRD peak intensity of PAMAM G 0 -Pd@g-Fe 2 O 3 can be attributed to the formation of palladium complexes on the surface of g-Fe 2 O 3 MNPs being stabilized by various functional groups present in the PAMAM dendrimer acting as ligands.

Results and discussion
The FE-SEM images of g-Fe 2 O 3 NPs, g-Fe 2 O 3 -CPTES and supported catalyst were shown in Fig. S10. † According to the FE-SEM images, the g-Fe 2 O 3 and g-Fe 2 O 3 -CPTES NPs have a uniform spherical morphology (Fig. S10A †). Also, the particles of the supported catalyst on the surface of g-Fe 2 O 3 NPs have a homogeneous spherical morphology and uniform size distribution. This clearly shows the synergistic effect of organic and inorganic diverse ingredients in a homogeneous network of PAMAM G 0 -Pd@g-Fe 2 O 3 (6) (Fig. S10B †).
The TEM image of PAMAM G 0 -Pd@g-Fe 2 O 3 is in line with the proposed core-shell structure placing palladium nanoparticles at the surface of magnetic Fe 2 O 3 nanoparticles (Fig. 3). Energydispersive X-ray (EDX) choosing a point at random on the surface of PAMAM G 0 -Pd@g-Fe 2 O 3 NPs (Fig. 4)  Elemental mapping analysis by energy dispersive spectroscopy (EDS) of PAMAM G 0 -Pd@g-Fe 2 O 3 (Fig. 5) indicates that Pd NPs are distributed almost uniformly and without aggregation        (Fig. 6a). In the XPS elemental survey of PAMAM G 0 -Pd@g-Fe 2 O 3 , the peaks corresponding to carbon, oxygen, nitrogen, chlorine, silicon, palladium and iron are clearly observed (Fig. 6a). Also, Pd(0)/(II) existence in the catalyst structure were conrmed through XPS analysis through studying binding energy range of 335.15 to 340.97 eV (Fig. 6b). As shown in Fig. 6b, the peaks located at 335.15 (3d5/2) and 340.35 eV (3d3/2) correspond to Pd(II) species, and also the peaks appeared at 336.11 (3d5/2) and 340.97 eV (3d3/2) are attributed Pd(II) (Fig. 6b). According to XPS results, the ratio of Pd(0)/Pd(II) is equal to 0.40 (in atomic number).

Evaluation of the catalytic activity of PAMAM G 0 -Pd@g-Fe 2 O 3 MNPs in cross-coupling reactions
Taking the Suzuki-Miyaura C-C coupling reaction between iodobenzene and phenylboronic acid as the model reaction, PAMAM G 0 -Pd@g-Fe 2 O 3 was evaluated varying solvent, temperature, base, and catalyst loading (see ESI for details, Fig. S17 †), suggesting that the best results were achieved with polar solvents. Being green and safe, we were pleased to see that the reaction proceeded exceptionally well in water, giving rise to 95% yield with a catalyst loading of 0.47 mol% within 15 minutes of reaction time at 60 C.
With the optimized reaction conditions in hand, we evaluated the substrate scope of PAMAM G 0 -Pd@g-Fe 2 O 3 for Suzuki-Miyaura coupling reactions (Table 1). A wide variety of electron-decient or electron-rich aryl halides or phenylboronic acids were amenable, and functional groups that could be potentially sensitive under the basic, aqueous reaction conditions employed (CHO, CN, NH 2 ) were tolerated well. As expected, the reactivity decreased from aryl iodides via aryl bromides to aryl chlorides, but even for the latter high yields could be obtained by raising the reaction temperature to 90 C and prolonging the reaction time 100-220 min.
Analogously, the catalytic activity of PAMAM G 0 -Pd@g-Fe 2 O 3 was evaluated for Mizoroki-Heck C-C coupling reactions. Screening of conditions for the reaction of iodobenzene with styrene (see ESI for details, Fig. S18 †) also revealed for this transformation water to be a suitable choice in combination with K 2 CO 3 at a reaction temperature of 80 C, giving rise to 1,2diphenylethylene in 95% yield within 60 minutes at a catalyst loading of 0.61 mol%.
Evaluating the substrate scope under the optimized reaction conditions demonstrated that a great variety of electronically and sterically differentiated aryl halides reacted smoothly in the coupling with styrene or n-butyl acrylate (Table 2). Noteworthy, electron-rich and electron-poor aryl chlorides could be converted, requiring only slightly longer reaction times and higher temperatures (90 C).
Control experiments conrmed for both, the Suzuki-Miyaura as well as the Mizoroki-Heck reactions that no coupling is observed with the parent materials PAMAM G 0 @g-Fe 2 O 3 and PAMAMG 0 , but also that PdCl 2 as a stand-alone catalyst does not promote the transformations. The high activity and efficiency of the PAMAM G 0 -Pd@g-Fe 2 O 3 catalyst compares well to other catalysts examined for comparison (see Fig. S19 †).

Recyclability study
The recyclability, activity, and stability of PAMAM G 0 -Pd@g-Fe 2 O 3 catalyst were examined using the hot-ltration method taking the Mizoroki-Heck reaction between iodobenzene and styrene (Table 2, entry 5) as a representative example.
Aer the catalyst was magnetically removed from the reaction medium (28 min, 50% yield of 1,1-diphenylethylene monitored by GC), the reaction, by and large, did not proceed further (53% yield aer 90 min, Fig. S20 †), indicating that little to no catalytically active species were present outside the support.
ICP analysis of the Mizoroki-Heck model reaction solution was performed to determine the amount of palladium leaching for six consecutive catalytic runs (Fig. S21 †).
Base on the results, Pd catalyst, showed high stability, with little leaching of Pd (total less than 1%), while consistent yields (95-93%) of 1,1-diphenylethylene were obtained for each cycle (see ESI for details, Table S1 †).
Likewise, recyclability of the PAMAM G 0 -Pd@g-Fe 2 O 3 complex was evaluated for the Suzuki-Miyaura reaction between iodobenzene and phenylboronic acid for 6 sequential runs (see ESI for details, Table S1 †), giving rise to 93-95% yield in each run. The comparison of TEM and SEM images of fresh and the used catalyst aer 6 runs in the Mizoroki-Heck reaction did not show signicant changes in size and morphology ( Fig. 7a and b). In addition, VSM measurements (Fig. 7c) and FT-IR spectra (Fig. 7e) further conrmed that the catalyst did not change in its structure and magnetic properties. Also, evaluation and comparison leaching, some of hydrophilic/ amphiphilic catalysts effective in c-c cross coupling reactions with PAMAM G 0 -Pd@g-Fe 2 O 3 catalyst were performed to better understand the activity of the PAMAM G 0 -Pd@g-Fe 2 O 3 (see Table 3. ESI † for found more details).

Summary and conclusions
In conclusion, we developed a recyclable magnetic nano Pdcomplex, formulated as PAMAM G 0 -Pd@g-Fe 2 O 3 MNPs, which proved to be an efficient catalyst for the Suzuki-Miyaura and Mizoroki-Heck coupling. Notable features are its high activity in water, which allows the employment of aryl chloride at moderately forcing conditions (90 C), facile recyclability and reuse, as well as little palladium leaching (<1% in a total of 6 runs).

Conflicts of interest
All the authors, declare that they haven't any of conicts of interest.