Polyvinylpyridine-Supported Palladium Nanoparticles: An E ﬃ cient Catalyst for Suzuki–Miyaura Coupling Reactions

: Palladium nanoparticles (Pd NPs) synthesized by the metal vapor synthesis technique were supported on poly(4-vinylpyridine) 2% cross-linked with divinylbenzene (Pd / PVPy). Transmission electron microscopy revealed the presence of small metal nanoparticles (d m = 2.9 nm) highly dispersed on the PVPy. The Pd / PVPy system showed high catalytic e ﬃ ciency in Suzuki-Miyaura carbon–carbon coupling reactions of both non-activated and deactivated aromatic iodides and bromides with aryl boronic acids, carried out under an air atmosphere. The high turnover of the catalyst and the ability of the PVPy resin to retain active Pd species are highlighted. By comparing the catalytic performances of Pd / PVPy with those observed by using commercially available Pd-based supported catalysts, the reported system showed higher selectivity and lower Pd leaching.


Introduction
The palladium-catalyzed coupling of organoboron reagents with aryl halides, known as the Suzuki-Miyaura reaction [1-3] is one of the most convenient and powerful synthetic methods for the preparation of biaryl and alkene derivatives that are essential components of natural products, pharmaceuticals, agrochemicals, and polymers [4][5][6]. The reaction is mainly unaffected by water, tolerating a huge range of functionality and leading to non-toxic by-products [7]. Traditional reaction conditions for Suzuki-Miyaura couplings involve the use of homogeneous palladium catalysts containing phosphine ligands [1, [8][9][10][11] or N-heterocyclic carbene ligands [12][13][14].
This reaction is the most intensively investigated among C−C couplings in the last decade [15][16][17]. Buchwald and coworkers [18,19] and Fu and coworkers [20] reported the possibility of exploiting this reaction with different compounds such as less-active aryl chlorides, hindered substrates, hetero-aromatic compounds, and alkenyl derivatives as well as at room temperature and in the presence of low-catalyst-loading. However, the main disadvantages are the availability, stability, and cost of the palladium organometallic complexes as well as of the ligands. Furthermore, homogeneous palladium catalysts are typically not reusable and the products are often contaminated by residual palladium and/or ligands, which in turn are difficult to separate from the products [3,21]. These limitations of Figure 1. Representative transmission electron microscopy micrograph and histogram of particle size distribution of the polyvinylpyridine-supported palladium catalyst (Pd/PVPy).

Catalytic Activity in Suzuki-Miyaura Reaction
The reaction between 4-bromotoluene (1a) and phenylboronic acid (2a) was chosen as a model reaction to evaluate the catalytic behavior of the Pd/PVPy system. In order to optimize the experimental conditions, the factors affecting the conversion and the selectivity of the reaction (i.e., solvent and base) were initially evaluated in the presence of 0.50 mol % of Pd/PVPy, under an argon atmosphere (Table S1). The best results were obtained using DMA/H2O (4:1) as the solvent and K3PO4 as the base (3 equivalent) at 120 °C. In these conditions after 7 h of reaction, the conversion into the 4-methylbiphenyl (3a) cross-coupling product with a yield of 64% occurred along with a complete selectivity. Surprisingly, inorganic bases commonly used for Suzuki-Miyaura reaction (i.e., Na2CO3, NaHCO3, and NaOH) led to poor results. On the other hand, using strong bases such as KF promoted an extensive dehalogenation of the aryl halide as well as the formation of homo-coupling side product. Regarding the solvent employed in the reaction, the mixture DMA/H2O (4:1) led to the best results without the presence of side reaction products. As a matter of fact, the use of water alone or in combination with alcohols such as i-PrOH/H2O (1:1) and EtOH/H2O (1:1), and aprotic polar/aqueous solvents (i.e., NMP/H2O (4:1) and 1,2-dioxane/H2O (4:1)) resulted in lower yields of the cross-coupling product. Further investigations revealed that the amount of Pd/PVPy can be effectively decreased from 0.5 to 0.15 Pd mol % without significant loss of yield of the 3a product (Table 1, entries 1-3). Nevertheless, a further decrease of the catalyst amount to 0.10 Pd mol % led to a drop in the yield of 3a (entry 4). Finally, the possibility of carrying out the Suzuki-Miyaura coupling under aerobic conditions was investigated. Under these latter conditions, the activity of the Pd/PVPy catalyst was remarkably enhanced, while the selectivity appeared comparable with that obtained under an inert atmosphere (entry 5). As expected, the reaction needed less mild conditions (e.g., higher temperature and longer reaction time) than those reported with Pd organometallic complexes for reactions carried out in the homogeneous phase (see e.g., [13]). However, as discussed above, the use of supported catalysts is a valid alternative in order to (i) facilitate the reaction workup, (ii) limit the Pd contamination of the reaction product, and (iii) favor the reusability of the catalyst.

Catalytic Activity in Suzuki-Miyaura Reaction
The reaction between 4-bromotoluene (1a) and phenylboronic acid (2a) was chosen as a model reaction to evaluate the catalytic behavior of the Pd/PVPy system. In order to optimize the experimental conditions, the factors affecting the conversion and the selectivity of the reaction (i.e., solvent and base) were initially evaluated in the presence of 0.50 mol % of Pd/PVPy, under an argon atmosphere (Table S1). The best results were obtained using DMA/H 2 O (4:1) as the solvent and K 3 PO 4 as the base (3 equivalent) at 120 • C. In these conditions after 7 h of reaction, the conversion into the 4-methylbiphenyl (3a) cross-coupling product with a yield of 64% occurred along with a complete selectivity. Surprisingly, inorganic bases commonly used for Suzuki-Miyaura reaction (i.e., Na 2 CO 3 , NaHCO 3 , and NaOH) led to poor results. On the other hand, using strong bases such as KF promoted an extensive dehalogenation of the aryl halide as well as the formation of homo-coupling side product. Regarding the solvent employed in the reaction, the mixture DMA/H 2 O (4:1) led to the best results without the presence of side reaction products. As a matter of fact, the use of water alone or in combination with alcohols such as i-PrOH/H 2 O (1:1) and EtOH/H 2 O (1:1), and aprotic polar/aqueous solvents (i.e., NMP/H 2 O (4:1) and 1,2-dioxane/H 2 O (4:1)) resulted in lower yields of the cross-coupling product. Further investigations revealed that the amount of Pd/PVPy can be effectively decreased from 0.5 to 0.15 Pd mol % without significant loss of yield of the 3a product (Table 1, entries 1-3). Nevertheless, a further decrease of the catalyst amount to 0.10 Pd mol % led to a drop in the yield of 3a (entry 4). Finally, the possibility of carrying out the Suzuki-Miyaura coupling under aerobic conditions was investigated. Under these latter conditions, the activity of the Pd/PVPy catalyst was remarkably enhanced, while the selectivity appeared comparable with that obtained under an inert atmosphere (entry 5). As expected, the reaction needed less mild conditions (e.g., higher temperature and longer reaction time) than those reported with Pd organometallic complexes for reactions carried out in the homogeneous phase (see e.g., [13]). However, as discussed above, the use of supported catalysts is a valid alternative in order to (i) facilitate the reaction workup, (ii) limit the Pd contamination of the reaction product, and (iii) favor the reusability of the catalyst.
These results agree with evidence previously reported by other authors on the beneficial effect of the oxygen [43,[49][50][51][52]. The observed increase in catalytic activity has been ascribed to the formation of oxidized Pd species onto the surface of Pd NPs. As a consequence, the oxidized Pd atoms can be easily released into the solution, leading to "peroxo-palladium complexes" that are stable against aggregation. Moreover, they can directly undergo transmetalation with the arylboronic due to the enhancement of the electron density of palladium.  These results agree with evidence previously reported by other authors on the beneficial effect of the oxygen [43,[49][50][51][52]. The observed increase in catalytic activity has been ascribed to the formation of oxidized Pd species onto the surface of Pd NPs. As a consequence, the oxidized Pd atoms can be easily released into the solution, leading to "peroxo-palladium complexes" that are stable against aggregation. Moreover, they can directly undergo transmetalation with the arylboronic due to the enhancement of the electron density of palladium.
Additionally, we investigated the Pd leached into the reaction mixture by inductively coupled plasma-optical emission spectroscopy analysis in order to evaluate the amount of Pd released in solution from the Pd/PVPy catalysts under the above mentioned reaction conditions. Furthermore, with the same analysis, we can also obtain information on the capability of the polymeric support to quench the Pd species in solution. For this purpose, after 7 h, the reaction mixture was filtered through a polytetrafluoroethylene syringe filter (0.22 µ m diameter) and a portion of the filtrate was dissolved by nitric acid after solvent evaporation. The levels of Pd contamination detected on reactions carried out both in argon and in air atmosphere were exceptionally very low. The obtained values of 0.44 ppm and 0.48 ppm for reaction in argon and air, respectively, corresponded to a Pd leached of 1.2 and 1.3 wt. % of the initial available Pd amount in the catalyst. Moreover, the filtrate solution was newly heated at 125 °C and the reaction conversion was monitored to check that the catalytic species was still present in the mixture ( Figure 2). The results show that the reaction without the solid catalyst afforded only 1% of conversion after 17 h, indicating that the catalytically active Pd species were effectively removed.
It is worth noting that the leaching test and filtration test alone cannot univocally establish the real nature of the active catalyst (i.e., heterogeneous or homogeneous), as the support can catch the leached Pd so fast that it may not be revealed by the leaching or hot filtration test [43,53]. However, the ability of the PVPy resin to coordinate palladium active species formed in carbon-carbon coupling reactions was previously described [54,55]. Additionally, we investigated the Pd leached into the reaction mixture by inductively coupled plasma-optical emission spectroscopy analysis in order to evaluate the amount of Pd released in solution from the Pd/PVPy catalysts under the above mentioned reaction conditions. Furthermore, with the same analysis, we can also obtain information on the capability of the polymeric support to quench the Pd species in solution. For this purpose, after 7 h, the reaction mixture was filtered through a polytetrafluoroethylene syringe filter (0.22 µm diameter) and a portion of the filtrate was dissolved by nitric acid after solvent evaporation. The levels of Pd contamination detected on reactions carried out both in argon and in air atmosphere were exceptionally very low. The obtained values of 0.44 ppm and 0.48 ppm for reaction in argon and air, respectively, corresponded to a Pd leached of 1.2 and 1.3 wt % of the initial available Pd amount in the catalyst. Moreover, the filtrate solution was newly heated at 125 • C and the reaction conversion was monitored to check that the catalytic species was still present in the mixture ( Figure 2). The results show that the reaction without the solid catalyst afforded only 1% of conversion after 17 h, indicating that the catalytically active Pd species were effectively removed.
It is worth noting that the leaching test and filtration test alone cannot univocally establish the real nature of the active catalyst (i.e., heterogeneous or homogeneous), as the support can catch the leached Pd so fast that it may not be revealed by the leaching or hot filtration test [43,53]. However, the ability of the PVPy resin to coordinate palladium active species formed in carbon-carbon coupling reactions was previously described [54,55].  Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the  Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions (Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH 2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4-methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).    Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions ( Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).    Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions ( Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).   Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions ( Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).   Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions ( Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).   Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions ( Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).   Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions ( Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).   Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions ( Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).   Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions ( Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).   Table 1 for experimental conditions).
From the data described above, the Pd/PVPy system has the requisites to be transferred into industrial applications. Indeed, from an applicative point of view, the Pd/PVPy catalyst can effectively reduce the issue of the metal contamination in products prepared via the Suzuki-Miyaura cross-coupling reaction (e.g., for the synthesis of active pharmaceutical intermediates), avoiding the time-consuming and expensive cleaning steps needed in order to remove the Pd residue.
In order to further investigate the applicability of the Pd/PVPy catalyst, we extended the substrate scope by creating a library of suitable aryl halide and boronic acid investigated under the optimized reaction conditions ( Table 2). Deactivated aryl iodides as well as activated and deactivated aryl bromides were completely converted with a yield of the corresponding isolated products ranging from 58 to 99%. The reaction exhibited good diversity with both electron withdrawing and donating groups. For the deactivated aryl halides sterically hindered, both bromides and iodides, a satisfactory yield could be obtained increasing the reaction time (entries [11][12][13][14]. Interestingly, both protic free groups (i.e., NH2 and OH) were well-tolerated in the reaction (entries [16][17][18]. Furthermore, aryl chlorides (entry 19) were converted with low yield into the product even after a longer reaction time because of their low reactivity, as a consequence of their reluctance to oxidatively add to Pd(0). Regarding aryl boronic acids, the coupling reaction of electron-rich aryl boronic acid (e.g., 4methoxyphenylboronic acid, (2b)) proceeded more efficiently when compared with non-substituted phenylboronic acid (2a). Noteworthy, the reaction with aryl boronic acid sterically hindered such as 2-methoxyphenylboronic acid (2c) led to the corresponding product in moderate yield (48%) in conjunction with the product of homocoupling (entry 15).

Catalyst Reusability
We investigated the lifetime of the Pd/PVPy catalyst and its level of reusability in consecutive Suzuki-Miyaura reactions using both an electron-poor aryl bromide (e.g., 4-bromonitrobenzene, 1a) and an electron-rich aryl bromide (e.g., 4-bromotoluene, 1b) in combination with the phenylboronic acid (2a) (Figure 3). After each cycle, the catalyst was recovered by filtration and afterward washed with water and acetone and then dried under vacuum. The solid catalyst was then reused without further activation. As a result, the catalyst showed a comparable performance for five consecutive runs, showing a slight decrease of the efficiency only during the fifth catalytic cycle. TEM analysis of a Pd/PVPy sample recovered after the first catalytic run (Figure 4, right side) confirmed only a slight increase in the particle size (dm = 3.5 nm) with respect to the freshly prepared sample.

Catalyst Reusability
We investigated the lifetime of the Pd/PVPy catalyst and its level of reusability in consecutive Suzuki-Miyaura reactions using both an electron-poor aryl bromide (e.g., 4-bromonitrobenzene, 1a) and an electron-rich aryl bromide (e.g., 4-bromotoluene, 1b) in combination with the phenylboronic acid (2a) (Figure 3). After each cycle, the catalyst was recovered by filtration and afterward washed with water and acetone and then dried under vacuum. The solid catalyst was then reused without further activation. As a result, the catalyst showed a comparable performance for five consecutive runs, showing a slight decrease of the efficiency only during the fifth catalytic cycle. TEM analysis of a Pd/PVPy sample recovered after the first catalytic run (Figure 4, right side) confirmed only a slight increase in the particle size (dm = 3.5 nm) with respect to the freshly prepared sample.

Catalyst Reusability
We investigated the lifetime of the Pd/PVPy catalyst and its level of reusability in consecutive Suzuki-Miyaura reactions using both an electron-poor aryl bromide (e.g., 4-bromonitrobenzene, 1a) and an electron-rich aryl bromide (e.g., 4-bromotoluene, 1b) in combination with the phenylboronic acid (2a) (Figure 3). After each cycle, the catalyst was recovered by filtration and afterward washed with water and acetone and then dried under vacuum. The solid catalyst was then reused without further activation. As a result, the catalyst showed a comparable performance for five consecutive runs, showing a slight decrease of the efficiency only during the fifth catalytic cycle. TEM analysis of a Pd/PVPy sample recovered after the first catalytic run (Figure 4, right side) confirmed only a slight increase in the particle size (dm = 3.5 nm) with respect to the freshly prepared sample.

Catalyst Reusability
We investigated the lifetime of the Pd/PVPy catalyst and its level of reusability in consecutive Suzuki-Miyaura reactions using both an electron-poor aryl bromide (e.g., 4-bromonitrobenzene, 1a) and an electron-rich aryl bromide (e.g., 4-bromotoluene, 1b) in combination with the phenylboronic acid (2a) (Figure 3). After each cycle, the catalyst was recovered by filtration and afterward washed with water and acetone and then dried under vacuum. The solid catalyst was then reused without further activation. As a result, the catalyst showed a comparable performance for five consecutive runs, showing a slight decrease of the efficiency only during the fifth catalytic cycle. TEM analysis of a Pd/PVPy sample recovered after the first catalytic run (Figure 4, right side) confirmed only a slight increase in the particle size (d m = 3.5 nm) with respect to the freshly prepared sample.
We investigated the lifetime of the Pd/PVPy catalyst and its level of reusability in consecutive Suzuki-Miyaura reactions using both an electron-poor aryl bromide (e.g., 4-bromonitrobenzene, 1a) and an electron-rich aryl bromide (e.g., 4-bromotoluene, 1b) in combination with the phenylboronic acid (2a) (Figure 3). After each cycle, the catalyst was recovered by filtration and afterward washed with water and acetone and then dried under vacuum. The solid catalyst was then reused without further activation. As a result, the catalyst showed a comparable performance for five consecutive runs, showing a slight decrease of the efficiency only during the fifth catalytic cycle. TEM analysis of a Pd/PVPy sample recovered after the first catalytic run (Figure 4, right side) confirmed only a slight increase in the particle size (dm = 3.5 nm) with respect to the freshly prepared sample.  Table 2 for experimental conditions).  Table 2 for experimental conditions).
We investigated the lifetime of the Pd/PVPy catalyst and its level of reusability in consecutive Suzuki-Miyaura reactions using both an electron-poor aryl bromide (e.g., 4-bromonitrobenzene, 1a) and an electron-rich aryl bromide (e.g., 4-bromotoluene, 1b) in combination with the phenylboronic acid (2a) (Figure 3). After each cycle, the catalyst was recovered by filtration and afterward washed with water and acetone and then dried under vacuum. The solid catalyst was then reused without further activation. As a result, the catalyst showed a comparable performance for five consecutive runs, showing a slight decrease of the efficiency only during the fifth catalytic cycle. TEM analysis of a Pd/PVPy sample recovered after the first catalytic run (Figure 4, right side) confirmed only a slight increase in the particle size (dm = 3.5 nm) with respect to the freshly prepared sample.  Table 2 for experimental conditions).

Comparison with Commercially Available Pd-Based Catalysts
The catalytic performances of the Pd/PVPy system used in the reaction of 4-bromonitrobenzene (1a) with phenylboronic acid (2a) was compared with other commercially available heterogeneous catalysts such as Pd/C and palladium acetate microencapsulated in polyurea matrix (Pd EnCat ® 40) ( Table 3). The results showed that Pd/PVPy led to the best results in terms of selectivity (99.9%), without the formation of the homocoupling side-product. Moreover, the presented system provides a lower Pd leaching (1.3 Pd wt % of the initial Pd content) than the other commercially available systems examined (2.2-2.6 Pd wt % of the initial Pd content).

Suzuki-Miyaura Reactions
Aryl halides (2.0 mmol), aryl boronic acid (2.5 mmol), K 3 PO 4 ·12H 2 O (6.0 mmol), Pd/PVPy (32 mg, 3.0 × 10 −3 mmol Pd), and DMA:H 2 O 4:1 (4 mL) were introduced into a 25 mL round-bottomed, two-necked flask equipped with a stirring magnetic bar, a condenser, and a silicon stopper. The reaction mixture was stirred at 125 • C. For GLC analysis, the samples were treated with 0.5 M aqueous HCl. The organic products were then extracted with diethyl ether, and dried over anhydrous sodium sulfate. The coupling products were purified by column medium-pressure chromatography (silica, solvent mixture). The reaction was stopped at the time reported in Table 2. All the products were characterized by using mass spectrometry (see Supplementary Materials).

Recycling Tests
The coupling reaction of aryl bromide (1a and 1b) with phenylboronic acid (2a) was carried out as described in the general procedure of Suzuki-Miyaura cross-coupling reactions (4.2.1.). After filtering off the product, the catalyst was washed with H 2 O (3 × 10 mL), acetone (3 × 5 mL), and Et 2 O (3 × 5 mL), respectively, and dried under vacuum for 12 h. Then, the recovered catalyst was used in a further coupling experiment.

Conclusions
In conclusion, the Pd/PVPy catalytic system synthesized by the MVS approach is an effective catalyst for the Suzuki-Miyaura coupling reaction under aerobic conditions. This catalyst remarkably expands the scope of palladium supported catalysts by enabling the possibility of using various arylboronic acids for the coupling of aryl bromides. The catalytic system exhibits high recyclability, with coupling yields preserved over five catalytic cycles, and a very low Pd leaching (i.e., product contamination). Further applications of the reported system can be foreseen due to the high versatility of this catalyst.
Funding: This research was funded by the Italian Ministry of University and Scientific Research (MIUR), grant number "RBFR10BF5V".

Conflicts of Interest:
The authors declare no conflict of interest.