The palladium (Pd)-catalysed Suzuki-Miyaura reaction is one of the most powerful protocols used in the synthesis of agrochemicals, pharmaceuticals, natural products and other materials, and has been studied extensively in the past few decades [1-10]. Recently, numerous homogeneous catalysts have been developed, and lots of efficient ligands for the Suzuki-Miyaura reaction have been designed. However, ligands for Pd homogeneous catalysts are usually expensive and complicated to synthesise [11-15]. The recovery of active Pd/ligand catalyst systems is valuable not only for economic reasons but also to avoid product contamination. Thus, much effort has been devoted to designing heterogeneous Pd catalysts, such as Pd supported on metal-organic frameworks, carbon, mesoporous zeolites, metal oxides and polymers, for use in Suzuki-Miyaura coupling reactions [16-24]. However, heterogeneous Pd catalysts are usually not as active as homogeneous Pd/ligand systems. Although some remarkably active heterogeneous Pd catalysts for the Suzuki-Miyaura cross coupling of aryl bromides with arylboronic acids have been reported, it is still desirable to develop highly active heterogeneous Pd catalysts for the Suzuki-Miyaura reaction of aryl chlorides[25-28]. Because the C-Cl bond is stronger than the C-Br bond, aryl chlorides are difficult to activate. Despite this, aryl chlorides are attractive substrates in Suzuki-Miyaura reactions because they are inexpensive and widely commercially available, so more active Pd catalysts are required. Few heterogeneous Pd catalysts able to activate aryl chlorides for Suzuki-Miyaura reaction have been reported (for example, turnover number (TON) > 1000 with chloroanisole) [29-34].

Recently, we have developed the C-O and C-CN coupling reactions of aryl chlorides and bromides with phenols and K₄Fe (CN)₆ using heterogeneous and homogeneous catalyst systems [35-37]. Moreover, Pd nanoparticles formed in situ in ionic solid polymers have been reported as highly active heterogeneous catalysts for the Suzuki-Miyaura reaction; only 10^-7 Pd catalysts were required for the Suzuki-Miyaura reaction of aryl bromides [38]. In addition, heterogeneous catalysts with highly active Pd nanoparticles immobilised in situ have been designed and used in Suzuki-Miyaura reactions; these catalysts can be reused several times without evident deactivation [39]. It was found that electron-rich and bulky phosphorus (P) ligands enhanced the activity of these Pd catalysts. Besides, Pd nanoparticles immobilised in N-containing polymers by Pd-catalysed C-N coupling of tris (4-bromophenyl) amine with piperazine have been applied as catalysts, achieving a TON and turnover frequency (TOF) as high as 250000 and 41666 h^-1, respectively, in Suzuki-Miyaura reactions [40]. We are still interested in the development of highly active Pd catalysts for Pd-catalysed cross-coupling reactions.

In homogeneous Pd catalyst systems, good ligands for cross-coupling reactions combine both favourable electronic and steric properties. On the one hand, electron-rich ligands can aid oxidative addition to the Pd center to activate aryl halides. On the other hand, bulky ligands can improve the reductive elimination from the Pd center to form products. Moreover, Pd nanoparticles supported on polyaniline (PAN) have been reported as highly active and reusable catalysts for Suzuki-Miyaura reactions, but the recycling process was not easy [41-44]. Inspired by these advances, have we attempted to combine a PAN support and bulky ligands with Pd nanoparticles to form highly active, reusable Pd catalysts. Pd nanoparticles are encapsulated in situ in cross-linked PAN by Pd-catalysed C-N coupling of tris (4-iodophenyl) amine with p-phenylenediamine as highly active catalysts for Suzuki-Miyaura reactions (see Scheme 1). The resulting Pd catalysts exhibit high efficiency for the Suzuki-Miyaura coupling of aryl bromides and chlorides with aryl boronic acids. No Pd leaching is detected in the reaction solution after filtration of the Pd catalysts, revealing that we attained active, clean Pd catalysts for Suzuki-Miyaura reactions.

All chemicals used in this work were purchased from Alfa Aesar, Aladdin Reagent Company and Sigma-Aldrich and used without further purification. ¹H NMR spectra were measured with a Bruker AVANCE 400D spectrometer in CDCl₃ using tetramethylsilane as an internal reference. Thermogravimetric analysis (TGA) was performed with a STA409 instrument under dry nitrogen at a heating rate of 20 ℃/min. Gas sorption/desorption analysis was performed on a Micromeritics ASAP2010 analyser at-196 ℃ with liquid nitrogen. Samples were pretreated at 140 ℃ under vacuum before analysis. The amount of Pd was measured with a Jarrell-Ash 1100 inductively coupled plasma-atomic emission spectrometer (ICP-AES). Transmission electron microscope (TEM) images were captured using a JEOL JEM-2010 (200 kV) TEM and scanning electron microscope (SEM) images were obtained using a Hitachi S-4800 field-emission SEM. Fourier transform infrared (FT-IR) spectra were recorded in the 500-4000 cm^-1 region using a Nicolet 360 FT-IR spectrometer with a scan rate of 0.4747 cm/s. X-ray photoelectron spectroscopy (XPS) was conducted with an ESCALab 220i-XL electron spectrometer from VG Scientific using 300-W Al K_α radiation. Binding energies were calibrated using the C1s peak at 284.6 eV. X-ray diffraction (XRD) patterns were collected on a Bruker D8 Advance powder diffractometer using a Ni-filtered Cu K_α radiation source at 40 kV and 20 mA from 5° to 80° with a scan rate of 0.5°/min.

Synthesis of Pd@PAN-Ad-0.5 catalyst: The C-P coupling reaction was conducted according to a reported method with modification [45]. Di-1-adamantylphosphine (HPad₂, 77.2 mg, 0.25 mmol), tris (4-iodophenyl) amine (1.25 mmol, 778.8 mg), Pd (OAc)₂ (32.7 mg, 0.145 mmol), 1, 1'-bis (diisopropylphosphino) ferrocene (dippf, 6.4 mg, 0.015 mmol) and NaOtBu (36 mg, 0.37 mmol) were added into a 100-mL Schlenk tube containing toluene (15 mL) under argon. After the Schlenk tube was heated at 100 ℃ with stirring for 22 h, the reaction mixture was cooled to room temperature. Then, p-phenylenediamine (189.3 mg, 1.75 mmol), NaOtBu (673.0 mg, 7 mmol) and toluene (20 mL) were added to the tube under argon. After heating at 100 ℃ with stirring for another 24 h under argon, the reaction mixture was again cooled to room temperature. The dark blue solid catalyst was obtained via centrifugation, and then washed with water and ethanol three times. The Pd@PAN-Ad-0.5 catalyst was obtained after drying under vacuum for 24 h at room temperature. The Pd content of the Pd@PAN-Ad-0.5 catalyst measured by ICP-AES was 0.58 wt%. A Pd@PAN-Cy-0.5 catalyst was prepared similarly using dicyclohexylphosphine instead of di-1-adamantylphosphine. The amount of Pd in the Pd@PAN-Cy-0.5 catalyst was 0.53 wt%.

The catalyst Pd@PAN-Ad-0.2 was prepared similarly to the Pd@PAN-Ad-0.5 catalyst, but 16.3 mg of Pd (OAc)₂ was added instead of 32.7 mg. The Pd content in the Pd@PAN-Ad-0.2 catalyst measured by ICP-AES was 0.25 wt%.

Aryl chloride (1.0 mmol), phenylboronic acid (1.5 mmol), Pd@PAN-Ad-0.5 catalyst (13.7 mg, 0.075 mol% Pd), K₂CO₃ (280.5 mg, 2.0 mmol) and i-PrOH/water (2.0 mL, 1:1 volume ratio) were added to a 20-mL pressure tube under argon. After the tube was heated at 100 ℃ for 18 h with stirring in an oil bath, the reaction mixture was cooled to room temperature. The crude product was purified by column chromatography on silica gel and analysed by ¹H NMR spectroscopy to confirm the product.

Aryl bromide (1.0 mmol), phenylboronic acid (1.5 mmol), Pd@PAN-Ad-0.5 catalyst (13.7 mg, 0.075 mol% Pd), K₂CO₃ (280.5 mg, 2.0 mmol) and i-PrOH/water (2.0 mL, 1:1 volume ratio) were added to a 20-mL pressure tube under argon. The tube was put into an oil bath at 100 ℃ and stirred for 6 h. After the reaction mixture was cooled to room temperature, the organic layer was extracted with ethyl acetate. The crude product was purified by column chromatography on silica gel.

In this coupling reaction, 2-nitrochlorobenzene (157.5 mg, 1.0 mmol), 4-chlorophenylboronic acid (188.5 mg, 1.2 mmol), Pd@PAN-Ad-0.5 (13.7 mg, 0.075 mol% Pd), K₂CO₃ (280.5 mg, 2.0 mmol) and i-PrOH/water (2.0 mL, 1:1 volume ratio) were added to a 20-mL pressure tube under argon. The tube was put into an oil bath at 100 ℃ and stirred for 12 h. After the reaction mixture had cooled to room temperature, the organic layer was extracted with ethyl acetate. The crude product was purified by column chromatography on silica gel.

First, 2-chlorobenzonitrile (4.0 mmol, 630.2 mg), 4-methylphenylboronic acid (6.0 mmol, 811.2 mg), Pd@PAN-Ad-0.5 (55.0 mg, 0.075 mol% Pd), K₂CO₃ (1.12 g, 8.0 mmol) and i-PrOH/water (8.0 mL, 1:1 volume ratio) were added to a Schlenk tube containing a stir bar. The mixture was stirred in a preheated oil bath at 100 ℃ for 8 h. The reaction mixture was cooled to room temperature and then hexadecane (100 μL) was added as an internal standard. The organic layer was analysed by gas chromatography (GC) to determine the yield. The solid catalyst Pd@PAN-Ad-0.5 was collected by centrifugation and washed with ethyl acetate, water and i-PrOH. The recycled Pd@PAN-Ad-0.5 was used again in the same procedure.

Initially, the Pd catalysts were tested in the Suzuki-Miyaura coupling reaction of 4-chloroanisole with phenylboronic acid to optimise conditions. As shown in Table 1, i-PrOH/H₂O (1:1 volume ratio) was found to be the best solvent, providing 4-methoxybiphenyl in 42% yield (Table 1, entry 1). Other solvents gave lower yields than i-PrOH/H₂O (Table 1, entries 2-11). Base optimisation was also performed; K₂CO₃ was a suitable base, although K₃PO₄ was similarly efficient for the Pd-catalysed Suzuki-Miyaura coupling reactions (Table 1, entries 12-16). When the loading of the Pd catalyst (Pd@PAN-Ad-0.5) was decreased to 0.075 mol% and 0.05 mol%, 4-methoxybiphenyl was obtained in 99% and 85% yield, respectively, with TOF values of 73.3 and 94.4 h^-1, respectively (Table 1, entries 17 and18). For comparison, Pd/C, Pd@PAN-Ad-0.2 and Pd@PAN-Cy-0.5 catalysts were also used for the Suzuki-Miyaura coupling reaction of 4-chloroanisole with phenylboronic acid. These catalysts provided 4-methoxybiphenyl with lower yield than that obtained using the Pd@PAN-Ad-0.5 catalyst (Table 1, entries 19-21).

Using the optimised reaction conditions, the application scope of the Pd@PAN-Ad-0.5-catalysed Suzuki-Miyaura reactions of aryl chlorides was studied with phenylboronic acids; the results are listed in Table 2. The Pd@PAN-Ad-0.5 catalyst showed high efficiency for the Suzuki-Miyaura reaction of aryl chlorides with phenylboronic acids, providing the corresponding products in good to excellent yields with quite low Pd catalyst loading (Table 2, entries 1-12). A range of functional groups were well tolerated under the reaction conditions. Aryl chlorides containing MeCO, CN, Me, MeO and HCO groups were converted to the corresponding biphenyl products in high yields (Table 2, entries 1-9). Moreover, the Suzuki-Miyaura coupling reactions of chlorobenzene with functional phenylboronic acids also gave the corresponding biphenyl products in high yields (Table 2, entries 10 and 11). Sartanbiphenyl is an important pharmaceutical intermediate for the synthesis of sartan antihypertensive drugs, so the Suzuki-Miyaura coupling reaction of 2-chlorobenzonitrile with 4-methylphenylboronic acid was studied; sartanbiphenyl was obtained quantitatively

Because aryl bromides are widely available, we also studied the Suzuki-Miyaura reactions of aryl bromides with phenylboronic acids; the results are presented in Table 3. The Suzuki-Miyaura reaction of aryl bromides containing functional groups, such as 4-MeO, 4-HCO, 4-MeCO, 4-NO₂, 4-Me, 4-CN, 2-CN, 2-NO₂, 2-Me, 2-MeO and 4-tert-Bu, gave the corresponding biphenyls in high yields with low Pd loading (Table 3, entries 1-11). Thus, the application scope of the developed catalyst systems is wide.

To investigate the relationship between catalyst performance and structure, the catalysts were characterised. First, TEM was used to observe the Pd particles in the support. The TEM image in Fig. 1(a) reveals that the Pd nanoparticles were distributed well in the support and has an average diameter 2-3 nm. The recycled Pd@PAN-Ad-0.5 catalyst after five runs was also characterised by TEM (Fig. 1(b)). The average diameter of these Pd nanoparticles was 4-5 nm. Although Pd@PAN-Ad-0.5 was only slightly deactivated after five reaction cycles, the Pd nanoparticles aggregated to form particles that were about 5 nm in diameter. Moreover, nitrogen sorption-desorption analysis was performed for the Pd@PAN-Ad-0.5 catalyst. Its Brunauer-Emmett-Teller specific surface area was about 155.76 m²/g with an average pore diameter of 5.5 nm (Fig. 2).

SEM images at 1.0 μm and 2.0 μm (Fig. 3) showed that the Pd@PAN-Ad-0.5 catalyst was irregular with particles intertwined with each other. The energy-dispersive X-ray (EDX) elemental spectra of the Pd@PAN-Ad-0.5 catalyst (Fig. 4) indicated that it contained C, N, P, Pd and I. Additionally, the FT-IR spectrum in Fig. 5 contained bands from 1500 to 500 cm^-1 originating from phenyl rings, and between 3000 and 2750 cm^-1 and at about 1500 cm^-1 from adamantyl groups, which implies the diadamantylphosphine was anchored into the cross-linked PAN. The bands from 1500 to 1250 cm^-1 are ascribed to C≡N bonds. Moreover, TGA (Fig. 6) showed that the Pd@PAN-Ad-0.5 catalyst lost only a small amount of mass between room temperature and 450 ℃, which should be related to the loss of water and solvent. The obvious mass loss from 450 to 760 ℃ was attributed to the decomposition of the catalyst. Therefore, the catalyst was stable up to 450 ℃ without evident mass loss. No characteristic diffraction peak of Pd was observed in the XRD pattern of the Pd@PAN-Ad-0.5 catalyst (Fig. 7). This is because the Pd nanoparticles were small and the Pd content of the catalyst was low. XPS analysis of the Pd@PAN-Ad-0.5 catalyst revealed it contained two types of palladium species (Pd²⁺ and Pd⁰) (Fig. 8(a)). The peaks at binding energies of 340.2 eV (Pd 3d_3/2) and 335.5 eV (Pd 3d_5/2) were assigned to Pd⁰ species, and those at 341.8 (Pd 3d_3/2) and 337.1 eV (Pd 3d_5/2) corresponded to Pd²⁺ species (calibrated by C 1s at 284.6 eV). Therefore, both Pd²⁺ and Pd⁰ are present in the Pd@PAN-Ad-0.5 catalyst.

The Pd@PAN-Ad-0.5 catalyst was prepared firstly by Pd-catalysed C-P coupling to form the P ligand with aryl iodide. Then, the Pd-catalysed C-N coupling reaction of aryl iodides with p-phenylenediamine was conducted with the Pd nanoparticles along with the P ligand. At the same time, Pd nanoparticles with the P ligand were immobilised in the cross-linked PAN to give the heterogeneous Pd@PAN-Ad-0.5 catalyst. Because PAN is a good support for Pd nanoparticles in Suzuki-Miyaura reactions, cross-linked PAN with a P ligand was designed and used in the developed Pd nanoparticle catalysts. The formation of cross-linked PAN with a P ligand not only improved the electron properties of the bulky ligand diadamantylphosphine, but also immobilised the active Pd nanoparticles. Thus, the Pd@PAN-Ad-0.5 catalyst is highly active and reusable in cross-coupling reactions.

To explore the industrial application of the Pd@PAN-Ad-0.5 catalyst, we investigated the Suzuki-Miyaura coupling reaction of 2-nitrochlorobenzene with 4-chloro-phenylboronic acid, because the corresponding product 4'-chloro-2-nitro-1, 1'-biphenyl is an important pharmaceutical intermediate for the synthesis of boscalid (see Scheme 2). The intermediate was obtained in 96% yield. Moreover, the reusability of the Pd@PAN-Ad-0.5 catalyst in the Suzuki-Miyaura coupling reaction of 2-chlorobenzonitrile with 4-methylphenylboronic acid was investigated, as illustrated in Fig. 9. The Pd@PAN-Ad-0.5 catalyst could be reused at least five times without marked deactivation. The yield of target product was 86% after the fourth cycle. During the recycling process, the Pd content in the reaction solution was measured by ICP-AES. No Pd was detected in the solution (that is, Pd content was below the detection limit of 7 ppb), so the Pd@PAN-Ad-0.5 catalyst is clean.

We fabricated supported Pd catalysts on cross-linked PAN with a P ligand. The Pd catalysts showed high efficiency in the Suzuki-Miyaura reaction of aryl chlorides and bromides with phenylboronic acids. Moreover, functional groups, such as CN, MeO, CHO, MeCO and NO₂, were tolerated well, and the corresponding biphenyls were obtained in high yields. The Pd catalysts could be reused at least five times without evident deactivation. We believe that this kind of catalyst shows potential for the synthesis of biphenyl chemicals in the laboratory and industry.