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Immobilized Palladium Nanoparticles on Zirconium Carboxy-Aminophosphonates Nanosheets as an Efficient Recoverable Heterogeneous Catalyst for Suzuki–Miyaura and Heck Coupling Vadym Kozell 1 , Tommaso Giannoni 1 , Morena Nocchetti 2 , Riccardo Vivani 2 , Oriana Piermatti 1, * and Luigi Vaccaro 1, * 1 2

*

CEMIN—Dipartimento di Chimica, Biologia e Biotecnologie University of Perugia, Via Elce di Sotto, 8, 06123 Perugia, Italy; [email protected] (V.K.); [email protected] (T.G.) Dipartimento di Scienze Farmaceutiche, University of Perugia,Via del Liceo 1, 06123 Perugia, Italy; [email protected] (M.N.); [email protected] (R.V.) Correspondence: [email protected] (O.P.); [email protected] (L.V.); Tel.: +39-075-585-5559 (O.P.); +39-075-585-5541 (L.V.)

Academic Editor: Stuart H. Taylor Received: 5 May 2017; Accepted: 4 June 2017; Published: 9 June 2017

Abstract: Zirconium phosphate glycine diphosphonate nanosheets (ZPGly) have been used as support for the preparation of solid palladium nanoparticles, namely Pd@ZPGly. Thanks to the presence of carboxy-aminophosponate groups on the layer surface, ZPGly-based materials were able to stabilize a high amount of palladium (up to 22 wt %) also minimizing the amount of metal leached in the final products of representative important cross-coupling processes selected for proving the catalysts’ efficiency. The catalytic systems have been fully characterized and used in low amounts (0.1 mol %) in the Suzuki–Miyaura and Heck cross-couplings. Moreover, the protocols were optimized for the use of recoverable azeotropic mixtures (aq. EtOH 96% or aq. CH3 CN 84%, respectively) and in the flow procedure allowing one to isolate the final pure products, without any purification step, with very low residual palladium content and with a very low waste production. Keywords: zirconium phosphonates; nanosheets; palladium nanoparticles; heterogeneous catalysis; Heck reaction; Suzuki–Miyaura coupling

1. Introduction Palladium-catalyzed cross-coupling reactions of aryl halides with organo-boronic acids (Suzuki–Miyaura) and olefins (Heck) are extremely useful carbon–carbon bond formation tools widely investigated and applied in diverse areas such as natural products, agrochemicals, pharmaceutical intermediates and material science [1–4]. A challenging issue for metal-catalyzed transformation is related to the actual recoverability and reusability of the catalytic system while avoiding the possible loss of the metal especially if as precious and exhaustive as palladium. Over the past few years, considerable interest has been focused on supported palladium metallic nanoparticles (PdNPs) as an effective approach to achieve high catalytic activity, easy recovery, along with high stability [5–9]. However, the stability and durable catalytic efficiency of nanoparticles, which are very much related to the avoidance of their aggregation and/or their minimal metal leaching in the reaction products, are still a challenge [10,11]. A large number of supports have been used to stabilize the PdNPs, such as carbon materials [12–14], inorganic materials [15,16], MOFs [17,18], hybrid materials [19–24] and organic polymers [25–27].

Catalysts 2017, 7, 186; doi:10.3390/catal7060186

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Functionalization of the support surface with appropriate functional groups represents a key approach to obtain a better control of the dimensions, dispersion and stability of NPs [20,22–25]. Besides, layered materials with a high surface area and a large amount of exposed active sites have a great potential in the development of new hybrid materials able to efficiently host palladium nanoparticles [19,20,28]. In particular, layered zirconium phosphates and phosphonates can offer a high chemical and thermal robustness together with a facile tunability of their structural features as demonstrated by the large number of applications [15,29–34]. In this study, we used a layered zirconium phosphate glycine diphosphonate [35] because of its peculiarity that revealed it to be suitable for our tasks. This compound possesses a large number of carboxylic, phosphonic and amino groups on the surface of layers that are not coordinated to structural metal atoms and therefore are available for the coordination of Pd. Furthermore, an easy accessibility of these groups can be achieved by complete exfoliation of the material followed by intercalation of propylamine [19]. Propylamine is also a good complexing agent for Pd, and it contributes, together with the surface groups, to efficiently coordinate Pd atoms, aiding its deposition onto the layer surface. Lately, we have been interested in the development of novel solid metal catalysts to be used in safe reaction media for the design of environmentally-sustainable processes [15,19,34,36–38]. In this paper, we have studied the use of palladium nanoparticles on zirconium phosphate glycine diphosphonate nanosheets in the Suzuki–Miyaura and Heck cross-coupling reactions optimizing the reaction conditions in order to replace classic toxic polar aprotic media by using safer and recoverable azeotropic mixtures of CH3 CN/H2 O 84% and EtOH/H2 O 96%, respectively [39]. In addition, the reaction conditions have been adapted to perform the synthetic methodologies in flow reactors, which offer several advantages, such as the preservation of the physical integrity of the heterogeneous catalyst by mixing efficiently the reagents while avoiding mechanical stirring, facilitating the recovery and reuse of both the catalyst and products, minimizing the solvents needed to isolate the final product and the waste associated with the process [40]. 2. Results and Discussion 2.1. Catalysts Preparation and Characterization Recently, in our research group, a layered zirconium phosphate-phosphonate with the formula Zr2 (PO4 )[(O3 PCH2 )2 NHCH2 COOH]2 ·H2 O (ZPGly) was obtained by the reaction among Zr(IV), phosphoric acid and N,N-bis(phosphonomethyl)glycine [35]. For the reader’s convenience, a brief description of ZPGly is reported. The surface of the hybrid layers is rich in phosphonate, carboxylic and amino groups differently protonated, non-coordinated to structural metal atoms, so giving polar properties to the material. Owing to these groups, which can act both as ion exchangers and as metal ligands, ZPGly showed very interesting ion exchange and intercalation properties. Previous studies showed that ZPGly undergoes a complete exfoliation by treatment with propylamine, generating a colloidal dispersion of a single layer or packets of a few layers [19]. This phenomenon largely enhances the accessibility of the functional groups located at the surface of layers. Easily reducible ions, such as Pd(II), present in solution and eventually coordinated with propylamine, can be easily immobilized on the surface of layers by ion exchange reactions. A subsequent reduction gives rise to nanometric metallic particles whose dimensions are affected from the layer surface morphology and interactions. Taking into account these properties, the colloidal dispersion in propylamine was successful used to immobilize a large amount of palladium nanoparticles. In this work, in order to explore the catalytic activity of the PdNPs supported on ZPGly, different samples were prepared by contacting the white ZPGly dispersion with palladium acetate solutions for 1, 7 and 15 days (named Pd@ZPGly-1, Pd@ZPGly-7, Pd@ZPGly-15) and then recovered by ultracentrifugation as brown solids [19]. The samples were characterized by X-ray powder diffraction (PXRD), inductively-coupled plasma (ICP) and transmission electronic microscopy (TEM), and the

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Catalysts 2017, 7, 186 3 of 20 diffraction (PXRD), inductively-coupled plasma (ICP) and transmission electronic microscopy (TEM), and the collected data are reported in Table 1. The contacting time influenced the color intensity palladium of the three Pd@ZPGly 1) collectedand datathe arecorresponding reported in Table 1. Theloading contacting time influenced the solid colorsamples intensity(Table and the with the maximum of 2.11 mmol of palladium per gram of solid matrix achieved after 15 days. In corresponding palladium loading of the three Pd@ZPGly solid samples (Table 1) with the maximum of Figure 1, aofcomparison of the analyses of the Pd@ZPGly samples and 1, that of ZPGly is 2.11 mmol palladium per gramPXRD of solid matrix achieved after 15 days. In Figure a comparison of reported. After a short contacting time (one day), the interlayer distance of ZPGly increased from the PXRD analyses of the Pd@ZPGly samples and that of ZPGly is reported. After a short contacting 14.8–22.7 duethe to the intercalation of of palladium ions coordinated with propylamine molecules; the time (oneÅ day), interlayer distance ZPGly increased from 14.8–22.7 Å due to the intercalation of lack of metallic Pd reflections suggests that palladium was mainly present as bivalent Pd(II) cations. palladium ions coordinated with propylamine molecules; the lack of metallic Pd reflections suggests In thepalladium PXRD of was samples Pd@ZPGly-7 and Pd@ZPGly-15, some changes the interlayer that mainly present as bivalent Pd(II) cations. In the PXRDoccurred, of samplesand Pd@ZPGly-7 and distance of the palladium phase decreased to 20.3 Å, while the ZPGly phase and the cubic phase of Pd@ZPGly-15, some changes occurred, and the interlayer distance of the palladium phase decreased the Pd(0) appeared. It is possible to assert that long contacting times facilitate the reduction of Pd(II) to 20.3 Å, while the ZPGly phase and the cubic phase of the Pd(0) appeared. It is possible to assert to Pd(0) that thetimes negative sites the of the lamellae recapture the protons that longand contacting facilitate reduction of Pd(II) to Pd(0) and thatregenerating the negative the sitesZPGly of the phase. The IR spectrum of Pd@ZPGly-15 shows the presence of typical bands of carboxylate groups lamellae recapture the protons regenerating the ZPGly phase. The IR spectrum of Pd@ZPGly-15 shows instead of carboxylic observed for pristine ZPGly, of suggesting palladium ions the presence of typicalgroups bands of carboxylate groups instead carboxylicthat groups observed for interact pristine with carboxylates groups (Figure S1). The color change of the samples also reflects the presence of ZPGly, suggesting that palladium ions interact with carboxylates groups (Figure S1). The color change PdNP. Pd@ZPGly-1 and Pd@ZPGly-7, which contain the lower and amount of PdNP, were with of the samples also reflects the presence of PdNP. Pd@ZPGly-1 Pd@ZPGly-7, whichtreated contain the NaBH 4, obtaining Pd@ZPGly-1R and Pd@ZPGly-7R. After reduction, no variation was observed on lower amount of PdNP, were treated with NaBH4 , obtaining Pd@ZPGly-1R and Pd@ZPGly-7R. After the amountno of variation palladium, while as expected NaBH treatment, the color from brown to reduction, was observed on theafter amount of4 palladium, while as turned expected after NaBH 4 black. treatment, the color turned from brown to black.

Table Table 1. 1. Pd Pd content, content, mean mean diameter diameter of of PdNP PdNP in in palladium palladium nanoparticle nanoparticle zirconium zirconium phosphate phosphate glycine glycine diphosphonate diphosphonate nanosheet nanosheet (Pd@ZPGly) (Pd@ZPGly) samples. samples. The Thecolors colorsof of the the collected collected solids solids are are also also reported. reported.

PdNP-Catalyst Pd@ZPGly-1 Pd@ZPGly-1 Pd@ZPGly-7 Pd@ZPGly-7 Pd@ZPGly-15 Pd@ZPGly-15 Pd@ZPGly-1R Pd@ZPGly-1R Pd@ZPGly-7R Pd@ZPGly-7R

PdNP-Catalyst

Pd (mmol/g Support) 1 Mean Diameter (nm) Color Mean Diameter (nm) Color 0.92 2–5 light brown 0.92 1.49 2–5 2–5–20 light brown brown 1.49 2–5–20 brown dark brown 2.11 2.11 2–5–20 2–5–20 dark brown 2 2 0.92 2–10 (aggregates) black 0.92 black 2–10 (aggregates) 2 2 1.49 1.49 black 2–10 (aggregates) 2–10 (aggregates) black

Pd (mmol/g Support) 1

11

2 The 2 The Determined byICP-OES ICP-OES analysis. sample is characterized byaggregates PdNP aggregates in which each Determined by analysis. sample is characterized by PdNP in which each particle has dimensions from 2–10 nm. from 2–10 nm. particle hasranging dimensions ranging

Figure Figure 1. 1. PRXD PRXD of of ZrPGly ZrPGly (a), (a); Pd@ZPGly-1 Pd@ZPGly-1 (b), (b); Pd@ZPGly-7 Pd@ZPGly-7 (c) (c) and and Pd@ZPGly-15 Pd@ZPGly-15 (d). (d). The The indexed indexed reflections are assigned to cubic Pd (International Centre for Diffraction Data—PDF2 database reflections are assigned to cubic Pd (International Centre for Diffraction Data—PDF2 database code code no. no. 46-1043). 46-1043).

Figures and Figure S2 report images high and lowand magnification, respectively, of the samples Figure 22 and S2 TEM report TEM at images at high low magnification, respectively, of the containing Pd. In all of thin sheets of ZPGly by covered a population particles samples containing Pd.the Insamples, all of thethe samples, the thin sheetsare of covered ZPGly are by a of population of 2 nm to metallic Pd.toBeside thisPd. population, bigger particles,bigger with diameters of about particles ofascribable about 2 nm ascribable metallic Beside this population, particles, from with about 5 nm–20 nm, are well visible, number increases with the reaction To have diameters from about 5 nm–20 nm, areand welltheir visible, and their number increases with thetime. reaction time.

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To have deeper information the smaller population, high-resolution TEM(HR-TEM) (HR-TEM) and and STEM deeper information about about the smaller population, high-resolution TEM STEM images of Pd@ZPGly-15 have been collected (Figure S3). It was observed that the nanosheets images of Pd@ZPGly-15 have been collected (Figure S3). It was observed that the nanosheets were were completely covered by PdNPs with a mean diameter of two and with a narrow size distribution. After completely covered by PdNPs with a mean diameter of two and with a narrow size distribution. reduction, the samples (Pd@ZPGly-1R and Pd@ZPGly-7R) show the show formation several aggregates After reduction, the samples (Pd@ZPGly-1R and Pd@ZPGly-7R) the of formation of several of PdNP having an overage dimension of 10 nm and a detriment of the 2-nm population. aggregates of PdNP having an overage dimension of 10 nm and a detriment of the 2-nm population.

Figure 2. TEM images of Pd@ZPGly-1 (a), Pd@ZPGly-1R (b), Pd@ZPGly-7 (c), Pd@ZPGly-7R (d) and Figure 2. TEM images of Pd@ZPGly-1 (a); Pd@ZPGly-1R (b); Pd@ZPGly-7 (c); Pd@ZPGly-7R (d) and Pd@ZPGly-15 (e). Pd@ZPGly-15 (e).

2.2. Catalytic Activity 2.2. Catalytic Activity 2.2.1. Suzuki–Miyaura Suzuki–Miyaura Coupling Coupling Reaction Reaction 2.2.1. Westarted startedour ourstudy studytesting testingthe theactivity activityof ofPd@ZPGly Pd@ZPGly catalysts catalysts in in the the Suzuki–Miyaura Suzuki–Miyaura reaction reaction We of 4-bromotoluene 4-bromotoluene(1a) (1a)and andphenylboronic phenylboronicacid acid(2a) (2a)in inEtOH/H EtOH/H2O (1:1) at 80 °C ◦ for 2 h. of 2 O (1:1) at 80 C for 2 h. All of the catalysts showed high activity, but only with Pd@ZPGly-1 and Pd@ZPGly-15 catalysts All of the catalysts showed high activity, but only with Pd@ZPGly-1 and Pd@ZPGly-15 catalysts a a complete conversion was observed after 2 h and for three consecutive run (Table 2, Entries complete conversion was observed after 2 h and for three consecutive run (Table 2, Entries 1 and 3).1 andeach 3). For eachthe reuse, the catalysts were recovered by centrifugation, washed with EtOH/H 2O (1:1) For reuse, catalysts were recovered by centrifugation, washed with EtOH/H 2 O (1:1) and and reused in the next cycle. Pd@ZPGly-7, Pd@ZPGly-1R and 7R showed a lower activity that also decreased after recovery and reuse (Table 2, Entries 2, 5 and 6). This could be ascribable to the

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21 reused in the next cycle. Pd@ZPGly-7, Pd@ZPGly-1R and 7R showed a lower activity that5 of also decreased after recovery and reuse (Table 2, Entries 2, 5 and 6). This could be ascribable to the distribution of the Pd nanoparticle sizes on the surface of the supports. Indeed, in these samples, the distribution of the Pd nanoparticle sizes on the surface of the supports. Indeed, in these samples, the particles having mean dimensions of 10–20 nm are highly represented, and after reduction, also a particles having mean dimensions of 10–20 nm are highly represented, and after reduction, also a relevant aggregation phenomenon occurred. The ICP-OES analysis of crude products, obtained by relevant aggregation phenomenon occurred. The ICP-OES analysis of crude products, obtained by usual work-up procedure (filtration, extraction with ethyl acetate, distillation of solvent under usual work-up procedure (filtration, extraction with ethyl acetate, distillation of solvent under reduced reduced pressure), showed a high content of palladium (20–31 ppm, Table 2). pressure), showed a high content of palladium (20–31 ppm, Table 2).

Table 2. Comparison of efficiency of different PdNP-catalytic system in the Suzuki reaction of Table 2. Comparison of efficiency of different PdNP-catalytic system in the Suzuki reaction of for 2 h. 4-bromotoluene (1a) and phenylboronic acid (2) in EtOH/H2O (1:1) at 80 °C 4-bromotoluene (1a) and phenylboronic acid (2) in EtOH/H2 O (1:1) at 80 ◦ C for 2 h.

Br

B(OH)2 +

EtOH/H2O (1:1), K2CO3 80 °C, 2 h

CH3 1a

PdNP-catalyst (0.1 mol%) H3C 3a

2a

3 3 Run Conv%%2 2 Pd (ppm) Conv Pd (ppm) 1 Pd@ZPGly-1 1° >99 26 26 1 Pd@ZPGly-1 1◦ >99 ◦ 2° >99 2 >99 3◦ >99 3° >99 ◦ 2 Pd@ZPGly-7 1° 97 29 29 2 Pd@ZPGly-7 1 97 2◦ 98 2° 98 3◦ 96 3° 96 3 Pd@ZPGly-15 1◦ >99 3 Pd@ZPGly-15 1° >99 21 21 2◦ 99 2° 99 3◦ 99 3° 99 5 Pd@ZPGly-1R 1◦ 99 5 Pd@ZPGly-1R 1° 99 2◦ 98 20 ◦ 20 2° 98 3 97 3° 97 6 Pd@ZPGly-7R 1◦ 97 6 Pd@ZPGly-7R 1° 97 2◦ 95 31 3◦ 95 31 2° 95 3° 7 1◦ n.d. Pd/α-ZrPK 4 78955 4 5 7 Pd/α-ZrPK 1° 78 n.d. ◦ 8 Pd/C 10 wt % 1 >99 192 8 Pd/C 10 wt % 1° >99 192 1 Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), K CO (1.2 mmol), catalyst (0.1 mol %), EtOH/H O 1:1 (2.4 mL).

Entry 1 Entry 1

12

PdNP-Catalyst PdNP-Catalyst

Run

2

3

2

Conversion of 1a to 3a is measured by Gas–Liquid remaining is Reaction conditions: 1a (1.0 mmol), 2a (1.2Chromatography mmol), K2CO3(GLC) (1.2 analyses; mmol), the catalyst (0.1 material mol %), unreacted 1a. 3 Determined2 by ICP-OES analysis of crude reaction product. 4 [15]. 5 [19].

EtOH/H2O 1:1 (2.4 mL). Conversion of 1a to 3a is measured by Gas–Liquid Chromatography (GLC) analyses; the remaining material is unreacted 1a. 3 Determined by ICP-OES analysis of crude reaction It is known that both semicrystalline and microcrystalline zirconium phosphate (α-ZrP) undergo product. 4 [15]. 5 [19].

hydrolysis to some extent in basic media, especially at high temperatures [41]. The pH of aqueous K2 CO3 reaction medium is about 12, and therefore, the hydrolysis process of the support could be also It is known that both semicrystalline and microcrystalline zirconium phosphate (α-ZrP) responsible for the high palladium leaching that exceeded the allowed upper limit value [42]. undergo hydrolysis to some extent in basic media, especially at high temperatures [41]. The pH of The efficiency of these novel Pd@ZPGly catalysts has been compared to Pd/α-ZrPK catalyst aqueous K2CO3 reaction medium is about 12, and therefore, the hydrolysis process of the support (palladium nanoparticles on layered potassium zirconium phosphate), a similar catalytic system could be also responsible for the high palladium leaching that exceeded the allowed upper limit recently reported by our group [15] and with Pd/C 10 wt %. By using the same reaction conditions, value [42]. Pd/α-ZrPK showed a significantly lower efficiency (Table 2, Entry 6), while when the reaction was The efficiency of these novel Pd@ZPGly catalysts has been compared to Pd/α-ZrPK catalyst performed in the presence of Pd/C, the catalytic activity was comparable with that of Pd@ZPGly (palladium nanoparticles on layered potassium zirconium phosphate), a similar catalytic system catalysts, but the amount of Pd in the product is extremely high (192 ppm, Table 2, Entry 8). recently reported by our group [15] and with Pd/C 10 wt %. By using the same reaction conditions, In order to simplify the procedure of the work-up and also reduce the leaching of the metal into Pd/α-ZrPK showed a significantly lower efficiency (Table 2, Entry 6), while when the reaction was the product, we investigated the use of the heterogeneous K2 CO3 /aq. EtOH azeotrope (EtOH 96%) performed in the presence of Pd/C, the catalytic activity was comparable with that of Pd@ZPGly system [43]. K2 CO3 is in fact insoluble in aqueous ethanol azeotrope, and therefore, it can be removed catalysts, but the amount of Pd in the product is extremely high (192 ppm, Table 2, Entry 8). In order to simplify the procedure of the work-up and also reduce the leaching of the metal into the product, we investigated the use of the heterogeneous K2CO3/aq. EtOH azeotrope (EtOH 96%) system [43]. K2CO3 is in fact insoluble in aqueous ethanol azeotrope, and therefore, it can be

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removed together with the catalyst by simple filtration making possible the separation of the pure product, after the distillation and recovery of the reaction medium, therefore reducing the waste of together with the catalyst by simple filtration making possible the separation of the pure product, the process. In addition, the heterogeneous conditions can significantly protect the support avoiding after the distillation and recovery of the reaction medium, therefore reducing the waste of the process. its hydrolysis under basic aqueous conditions. In addition, the heterogeneous conditions can significantly protect the support avoiding its hydrolysis Pd@ZPGly catalysts were tested in the Suzuki–Miyaura reaction of 4-bromotoluene (1a) and under basic aqueous conditions. phenylboronic acid (2a) in aq. EtOH azeotrope at 80 °C (Table 3). The reaction time was longer Pd@ZPGly catalysts were tested in the Suzuki–Miyaura reaction of 4-bromotoluene (1a) and (24 vs. 2 h), and high conversion was obtained by◦ using Pd@ZPGly-1, -7, -15 (97–98%, Table 3, phenylboronic acid (2a) in aq. EtOH azeotrope at 80 C (Table 3). The reaction time was longer (24 vs. Entries 1 and 3), while lower conversions were observed with Pd@ZPGly-1R and -7R (78% and 85%, 2 h), and high conversion was obtained by using Pd@ZPGly-1, -7, -15 (97–98%, Table 3, Entries 1 and 3), respectively, Table 3, Entries 4 and 5), again presumably due to the aggregation extent of Pd while lower conversions were observed with Pd@ZPGly-1R and -7R (78% and 85%, respectively, Table 3, nanoparticles. The comparable Pd/α-ZrPK catalyst [15] and Pd/C 10 wt % showed a much lower Entries 4 and 5), again presumably due to the aggregation extent of Pd nanoparticles. The comparable efficiency (Table 3, Entries 6 and 7). Pd/α-ZrPK catalyst [15] and Pd/C 10 wt % showed a much lower efficiency (Table 3, Entries 6 and 7). Table 3. Comparison of the efficiency of different PdNP-catalytic systems in the Suzuki reaction of Table 3. Comparison of the efficiency of different PdNP-catalytic systems in the Suzuki reaction of 4-bromotoluene (1a) and phenylboronic acid (2a) in aq. EtOH azeotrope at 80 ◦°C. 4-bromotoluene (1a) and phenylboronic acid (2a) in aq. EtOH azeotrope at 80 C.

Br

B(OH)2 +

EtOH 96%, K2CO3 80 °C, 24 h

CH3 1a

PdNP-catalyst (0.1 mol%)

2a

H 3C 3a

Entry 1 PdNP-Catalyst PdNP-Catalyst Conv Conv%%2 2 Pd (ppm) 3 Pd (ppm) 3 1 Pd@ZPGly-1 9898 13 1 Pd@ZPGly-1 13 2 Pd@ZPGly-7 9797 15 2 Pd@ZPGly-7 15 3 Pd@ZPGly-15 98 11 3 Pd@ZPGly-15 98 11 4 Pd@ZPGly-1R 78 9 4 Pd@ZPGly-1R 78 9 5 Pd@ZPGly-7R 85 17 5 Pd@ZPGly-7R 85 17 4 6 n.d. Pd/α-ZrPK 38 5 4 5 6 Pd/α-ZrPK 38 82 n.d. 7 Pd/C 10 wt % 184 1 Reaction conditions: 1a7(1.0 mmol), 2aPd/C 10 wt % 82 184 (1.2 mmol), K2 CO3 (1.2 mmol), catalyst (0.1 mol %), EtOH 96% (2.4 mL). Entry 1

12

Conversion of 1a to 3a is1ameasured by GLC the remaining material is unreacted 1a. 3mol Determined by Reaction conditions: (1.0 mmol), 2a analyses; (1.2 mmol), K2CO3 (1.2 mmol), catalyst (0.1 %), EtOH ICP-OES analysis2 of crude reaction product. 4 [15]. 5 [19].

96% (2.4 mL). Conversion of 1a to 3a is measured by GLC analyses; the remaining material is 4 [15]. 5 [19]. ICP-OES analysis of crudethat reaction product. unreacted 1a. 3 Determined The ICP-OES analysis ofby crude products revealed by using the ethanol azeotrope, a much

lower content of palladium was obtained than when EtOH/H2 O (1:1) was used as the reaction The ICP-OES analysis of crude products revealed that by using the ethanol azeotrope, a much medium (9–17 ppm vs. 20–31 ppm). This is consistent with the milder pH conditions achieved when lower content of palladium was obtained than when EtOH/H2O (1:1) was used as the reaction the heterogeneous K2 CO3 /aq. EtOH azeotrope system is used, resulting in higher stability of the medium (9–17 ppm vs. 20–31 ppm). This is consistent with the milder pH conditions achieved when support. When Pd/C 10 wt % was used, a very high level of Pd content in the product was observed the heterogeneous K2CO3/aq. EtOH azeotrope system is used, resulting in higher stability of the again (184 ppm, Table 3, Entry 7). Pd@ZPGly-15 proved to be the best catalyst in terms of activity and support. When Pd/C 10 wt % was used, a very high level of Pd content in the product was observed leaching of palladium (Table 3, Entry 3). again (184 ppm, Table 3, Entry 7). Pd@ZPGly-15 proved to be the best catalyst in terms of activity The kinetics of the Suzuki–Miyaura reaction of 4-bromotoluene (1a) and phenylboronic acid (2a) and leaching of palladium (Table 3, Entry 3). in aq. EtOH azeotrope in the presence of Pd@ZPGly-1, -7, -15 was further studied (Figure 3). After 1 h The kinetics of the Suzuki–Miyaura reaction of 4-bromotoluene (1a) and phenylboronic acid at 80 ◦ C, the difference in reactivity was significant. Pd@ZPGly-1, which mainly contains Pd(II) species, (2a) in aq. EtOH azeotrope in the presence of Pd@ZPGly-1, -7, -15 was further studied (Figure 3). provided a lower conversion (63%) as compared to Pd@ZPGly-7 and -15 (78% and 85%, respectively) After 1 h at 80 °C, the difference in reactivity was significant. Pd@ZPGly-1, which mainly contains that also contained Pd(0) species. During the reaction, the reduction of Pd(II) occurs at the expense of Pd(II) species, provided a lower conversion (63%) as compared to Pd@ZPGly-7 and -15 (78% and EtOH [15,44,45], and after 9 h, the conversion was comparable (93–96%). At the end of the reactions, 85%, respectively) that also contained Pd(0) species. During the reaction, the reduction of Pd(II) all of the recovered catalysts were black, supporting the more complete presence of Pd(0) species. occurs at the expense of EtOH [15,44,45], and after 9 h, the conversion was comparable (93–96%). At Pd@ZPGly-15 showed the highest activity and also the best stability. The Pd content (2.11 mmol/g) the end of the reactions, all of the recovered catalysts were black, supporting the more complete was very high, and also, these features can be useful in view of a large-scale flow protocol, allowing presence of Pd(0) species. Pd@ZPGly-15 showed the highest activity and also the best stability. The the use of the minimal quantity of catalytic material to be packed into a flow reactor. Pd content (2.11 mmol/g) was very high, and also, these features can be useful in view of a large-scale flow protocol, allowing the use of the minimal quantity of catalytic material to be packed into a flow reactor.

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Catalysts Catalysts 2017, 2017, 7, 1867, 186 100 100 95 95 90 90

Pd@ZPGly-15 Pd@ZPGly-15 Pd@ZPGly-7 Pd@ZPGly-7 Pd@ZPGly-1 Pd@ZPGly-1

Conv.% Conv.%

85 85 80 80 75 75 70 70 65 65 60 60

0 0

5 5

10 10

t (h) t (h)

15 15

20 20

25 25

Figure 3. Comparative Suzuki reaction of 4-bromotoluene (1a) (1a) and phenylboronic acidacid (2a) (2a) in aq.inEtOH Figure 3. Comparative Suzuki reaction of 4-bromotoluene and phenylboronic Figure 3. Comparative Suzuki reaction of 4-bromotoluene (1a) and phenylboronic acid (2a) in at 1, ◦ azeotrope at 80azeotrope C catalyzed Pd@ZPGly-7,Pd@ZPGly-7, Pd@ZPGly-15 under batch conditions aq. EtOH at 80 by °CPd@ZPGly-1, catalyzed by Pd@ZPGly-1, Pd@ZPGly-15 under batch aq. EtOH azeotrope at 80 °C catalyzed by Pd@ZPGly-1, Pd@ZPGly-7, Pd@ZPGly-15 under batch conditions at 1, 3, 9, 24 h. 3, 9, 24 h. conditions at 1, 3, 9, 24 h.

To confirm efficiency Pd@ZPGly-15in in combination combination with 3/aq. EtOH azeotrope To confirm the the efficiency of of Pd@ZPGly-15 withthe theK2KCO EtOH azeotrope 2 CO 3 /aq. To confirm the efficiency of Pd@ZPGly-15 in combination with the K2CO 3/aq. EtOH azeotrope system, the protocol has been extended to the reactions of a series of aryl bromides 1a–n with phenyl system, the protocol has been extended to the reactions of a series of aryl bromides 1a–n with phenyl system, the protocol has been extended to the reactions of a series of aryl bromides 1a–n with phenyl boronic acids 2a,b (Table 4).The Thereactions reactions were carried atat8080 °C,◦ C, in in thethe presence of 0.1 mol % of % of boronic acids 2a,b (Table 4). were carried presence of 0.1 mol boronic acids 2a,b (Table 4). The reactions were carried at 80 °C, in the presence of 0.1 mol % of Pd@ZPGly-15, obtaining from high to quantitative conversion of 1 and excellent yields of isolated Pd@ZPGly-15, obtaining from conversionofof 1 and excellent yields of isolated Pd@ZPGly-15, obtaining fromhigh hightotoquantitative quantitative conversion 1 and excellent yields of isolated products 3a–n. Bromobenzene and aryl bromide with electron-donating groups (1a,b,d) showed as products 3a–n. Bromobenzene aryl bromide bromidewith with electron-donating groups (1a,b,d) products 3a–n. Bromobenzeneand and aryl electron-donating groups (1a,b,d) showedshowed as expected a lower reactivity (reaction time 24 h) with respect to 4-substituted aryl bromide with expecteda alower lowerreactivity reactivity (reaction time 2424h)h)with respect to to 4-substituted arylaryl bromide with with as expected (reaction time with respect 4-substituted bromide electron-withdrawing groups (1c,e,f,g,l) (reaction time of 3–9 h), while 2- and 3-CHO aryl bromide electron-withdrawing groups (1c,e,f,g,l) (reaction time 3–9 h), while2-2-and and3-CHO 3-CHOaryl arylbromide bromide electron-withdrawing ofof 3–9 h), (1h,i) reacted in agroups longer(1c,e,f,g,l) reaction (reaction time (24 time h) maybe duewhile to steric hindrance (2-CHO) or (1h,i) (1h,i) reacted in a longer reaction time (24 h) maybe due to steric hindrance (2-CHO) or reacted in a longer reaction time (24 h) maybe due to steric (2-CHO) or non-conjugative non-conjugative meta substitution (3-CHO). 2-CN aryl hindrance bromide reacted with 4-formyl phenyl meta non-conjugative meta substitution (3-CHO). 2-CN aryl bromide reacted with 4-formyl phenyl substitution (3-CHO). 2-CN arylinbromide phenyl acids (2b) to in boronic acids (2b) to furnish very highreacted isolatedwith yield4-formyl the biphenyl 3n, aboronic useful intermediate forfurnish the boronic acids (2b) to furnish in very high isolated yield the biphenyl 3n, a useful intermediate for the of valsartan [46].biphenyl 3n, a useful intermediate for the synthesis of valsartan [46]. very synthesis high isolated yield the synthesis of valsartan [46]. 4. Suzuki reaction betweenaryl aryl bromides bromides 1a–n boronic acids 2a,b2a,b catalyzed by by TableTable 4. Suzuki reaction between 1a–nand andphenyl phenyl boronic acids catalyzed Table 4. Suzuki reaction between aryl bromides 1a–n and phenyl boronic acids 2a,b catalyzed by Pd@ZPGly-15 in aq. EtOH azeotrope at 80 ◦°C. Pd@ZPGly-15 in aq. EtOH azeotrope C. Pd@ZPGly-15 in aq. EtOH azeotropeatat80 80 °C.

Br Br + +

R R 1 1 1 Entry Entry 1 Entry 1 1 1 21 2 32 3 43 4 54 5 6 65 7 6 7 8 87 9 98 10 9 11 10 10 12

1

B(OH)2 B(OH)2 R11 R

Pd@ZPGly-15 Pd@ZPGly-15 (0.1 mol%) (0.1 mol%) EtOH 96%, K2CO3 EtOH 80 °C 96%, K2CO3 80 °C

2 2

RR R 4-CH 3 4-CH 3 4-CH HH 3 H 4-NO 4-NO2 2 2 4-NO 4-OCH 33 4-OCH 4-OCH 4-CN3 4-CN 4-COOH 4-CN 4-COOH 4-CHO 4-COOH 4-CHO 2-CHO 4-CHO 2-CHO 3-CHO 2-CHO 3-CHO 4-COCH3 3-CHO 3 2-CH=CH-CH=CH-3 4-COCH 4-COCH 2-CN 3

1 R R 11 R H H H H H H H H H H H H H H H H H H H H H H H H H H H 4-CHO

tt (h) (h) t (h) 24 24 24 24 24 24 33 3 24 24 24 33 9 93 3 9 3 24 3 24 24 24 24 3 24 39 36

R11 R

R R Product Product Product 3a 3a 3a 3b 3b 3b 3c 3c 3c 3d 3d 3d 3e 3e 3f 3e 3f 3g 3f 3g 3h 3g 3h 3i 3h 3i3l 3i 3m 3l 3l 3n

3 3 Conv (%) 22 Conv (%) Conv (%) 2 >99 >99 >99 97 97 97 >99 >99 94 94 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 95 >99 95 >99 95 99 >99 >99 >99

3 Yield (%) Yield (%)

3

Yield (%) 3 9797 97 9595 95 9898 98 9292 92 9999 9799 97 9897 98 9698 9396 96 9993 93 9799 9899

Reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), K2 CO3 (1.2 mmol), Pd@ZPGly-15 (0.1 mol %), EtOH 96% (2.4 mL). Conversion of 1 to 3 is measured by GLC analyses; the remaining material is unreacted 1. 3 Yield of isolated products 3. 2

Catalysts 2017, 7, 186

11 12

8 of 21

2-CH=CH-CH=CH-3 2-CN

H 4-CHO

9 6

3m 3n

99 >99

97 98

1 Reaction Catalysts 2017, 7, 186 conditions: 1 (1.0 mmol), 2 (1.2 mmol), K2CO3 (1.2 mmol), Pd@ZPGly-15 (0.1 mol %), EtOH 96% 8 of 20

(2.4 mL). 2 Conversion of 1 to 3 is measured by GLC analyses; the remaining material is unreacted 1. 3 Yield of isolated products 3.

Continuing with our project and taking into account the optimized batch protocol, we have investigated the catalytic performance of Pd@ZPGly-15 in the Suzuki–Miyaura coupling of phenyl Continuing with our project and taking into account the optimized batch protocol, we have boronic acid (2a) with 4-bromo benzaldehyde (1g) in a flow protocol to assess the ability of ZPGly investigated the catalytic performance of Pd@ZPGly-15 in the Suzuki–Miyaura coupling of phenyl nanosheets stabilize PdNPs and evaluate the(1g) catalytic activity of the recovered catalyst over time. boronic to acid (2a) with 4-bromo benzaldehyde in a flow protocol to assess the ability of ZPGly The flow approach is also strategic to preserve the physical features of solid catalyst throughout nanosheets to stabilize PdNPs and evaluate the catalytic activity of the recovered catalyst over time. the process its is simple, efficient reproducible recovery reuse. Theand flowallows approach also strategic to and preserve the physical featuresand of solid catalyst throughout the To thisand aim, the reactor system was up as depicted inand Scheme process allows its simple, efficient andset reproducible recovery reuse. 1, where the base K2 CO3 Toand this the aim,catalyst the reactor system was set as depicted in both Scheme 1, where in thesolid base glass K2CO3beads (48 mmol) Pd@ZPGly-15 (0.1up mmol %) were dispersed (48 mmol) and the catalyst Pd@ZPGly-15 (0.1 mmol %) were both dispersed in solid glass beads (1 mm diameter) and respectively charged into two separate glass column. Reactants (40 mmol of (1 mm diameter) and respectively charged into two separate glass column. Reactants (40 mmol of 4-bromo benzaldehyde (1g) and 44 mmol of phenyl boronic acid (2a)) dissolved in aq. EtOH azeotrope 4-bromo benzaldehyde (1g) and 44 mmol of phenyl boronic acid (2a)) dissolved in aq. EtOH (0.33 M) were charged into a third glass column, used as the reservoir. The columns were connected to azeotrope (0.33 M) were charged into a third glass column, used as the reservoir. The columns were a pump by using the appropriate valves and installed into a thermostated box at 70 ◦ C (not shown in connected to a pump by using the appropriate valves and installed into a thermostated box at 70 °C Scheme for clarity). (not1shown in Scheme 1 for clarity).

Scheme Schematic flow flow reactor of 3g. Scheme 1.1.Schematic reactorfor forthe thepreparation preparation of 3g.

reaction mixture waspushed pushedat ataa 1.5-mL/min 1.5-mL/min flow rate through the the basebase and and the catalyst The The reaction mixture was flow rate through the catalyst columns for 10 h until complete conversion was obtained (monitored by Gas–Liquid columns for 10 h until complete conversion was obtained (monitored by Gas–Liquid Chromatography Chromatography (GLC) analyses). After this time and only the removal of the solvent by distillation (GLC) analyses). After this time and only the removal of the solvent by distillation (90% of solvent (90% of 7, solvent recovered), the product 3g was obtained as a white solid (98% yield, Table 5). Catalysts 2017, 186 9 of 21

recovered), the product 3g was obtained as a white solid (98% yield, Table 5).

Table 5. Suzuki reaction between 4-bromo benzaldehyde (1g) and phenylboronic acid (2a) catalyzed Table 5. Suzuki reaction between 4-bromo benzaldehyde (1g) and phenylboronic acid (2a) catalyzed by Pd@ZPGly-15 nanosheets under flow conditions. by Pd@ZPGly-15 nanosheets under flow conditions. Br

B(OH)2

Pd@ZPGly-15 (0.1 mol%)

+

EtOH 96%, K2CO3 70 °C, 10 h

CHO 1g

2a

EntryEntry

run 1

run 1 run 2 run 2 run 3 run 3

OHC 3g

YieldYield (%) (%) Pd Leaching Pd(ppm) Leaching (ppm) 98 98 5 5 98 98 3 3 3 98 98 3

The reusability of the catalyst was investigated, and this process was repeated for three consecutive runs with the same catalyst to obtain always the corresponding product 3g in a 98% yield. Hot filtration test has been performed on the Suzuki reaction in aq. EtOH azeotrope with Pd@ZPGly-15. The reaction mixture was stirred at 80 °C for 20 min (conversion 71%), and the hot

Catalysts 2017, 7, 186

9 of 20

The reusability of the catalyst was investigated, and this process was repeated for three consecutive runs with the same catalyst to obtain always the corresponding product 3g in a 98% yield. Hot filtration test has been performed on the Suzuki reaction in aq. EtOH azeotrope with Pd@ZPGly-15. The reaction mixture was stirred at 80 ◦ C for 20 min (conversion 71%), and the hot filtration was performed. K2 CO3 was added again and the reaction mixture stirred at 80 ◦ C. After a total reaction time of 1 h, the conversion was 74%, and the same conversion was observed after 24 h. This suggests that the homogeneous palladium released in solution (see Table 3, Entry 3) does not effectively promote the process. In agreement, the reaction performed with homogeneous Pd catalyst (Pd(OAc)2 ) did not give a satisfactory result as for Pd@ZPGly-15 (see the Supplementary Materials). When the reactions were performed under flow conditions, although the catalyst and the base were loaded into two separate columns, an excellent catalytic activity was observed. A “release and catch” mechanism has been hypothesized in which soluble active palladium species are released from the solid catalyst during the oxidative addition of the halide and then redeposited on the support as a consequence of the reductive elimination step when the new carbon–carbon bond is formed [43,47]. The catalytic system ultimately operates as an efficient heterogeneous system, and Pd content in the final product, determined by ICP analyses, is very low (3–5 ppm, Table 5), proving that the ZPGly system is able to efficiently re-capture palladium. Moreover, the recovered catalytic system showed the same activity. The flow system, with a separate column for the base K2 CO3 and the catalyst Pd@ZPGly-15, allows optimizing the recovery and reuse of the solid catalyst and keeps its physical and chemical integrity over it use. In fact, the palladium leaching was much lower than that observed in batch conditions (3–5 vs. 11 ppm). The TEM images of recovered Pd@ZPGly-15 after three catalytic cycles show that the ZPGly nanosheets’ structure and the distribution of PdNPs on the layers are maintained (Figure 4). Catalysts 2017, 7, 186

10 of 21

Figure 4. TEM images of Pd@ZPGly-15 after three catalytic runs. Figure 4. TEM images of Pd@ZPGly-15 after three catalytic runs.

Furthermore, to to assess assess the the waste waste minimization minimization for for both both batch batch and and flow flow protocols, protocols, we we calculate calculate Furthermore, the E-factor values. When the reaction was performed in homogeneous K 2 CO 3 /EtOH-H 2 O (1:1), the the the E-factor values. When the reaction was performed in homogeneous K2 CO3 /EtOH-H2 O (1:1), use of the not easily recoverable mixture of solvents and the need for extraction work-up lead to an use of the not easily recoverable mixture of solvents and the need for extraction work-up lead to an E-factor value value of of 76. 76. Using Usingthe theheterogeneous heterogeneousKK2 2CO CO33/aq. /aq. EtOH the sustainability sustainability E-factor EtOH azeotrope azeotrope system, system, the of the batch protocol has been greatly improved since no purification step is needed (E-factor 27.7), of the batch protocol has been greatly improved since no purification step is needed (E-factor 27.7), and this thisvalue valueis is noticeable reduced in a large-scale flow protocol by the of recovery of and noticeable reduced in a large-scale flow protocol process process by the recovery azeotrope azeotrope reaction medium by distillation (E-factor 3.2). reaction medium by distillation (E-factor 3.2). 2.2.2. Heck Reaction The catalytic activity of Pd@ZPGly catalysts has been investigated in the representative Heck reaction between iodobenzene (4a) and methyl acrylate (5a) in aqueous CH3CN azeotrope (aq. CH3CN 84%), an alternative to conventional polar aprotic media, as a safer and easily recoverable reaction medium [15,48]. In the presence of a soluble base, such us triethylamine (TEA), at 120 °C for 3 h, all of the

Figure 4. TEM images of Pd@ZPGly-15 after three catalytic runs.

Furthermore, to assess the waste minimization for both batch and flow protocols, we calculate the E-factor values. When the reaction was performed in homogeneous K2CO3/EtOH-H2O (1:1), the use of the not easily recoverable mixture of solvents and the need for extraction work-up lead to an E-factor Catalysts 2017, 7, 186 value of 76. Using the heterogeneous K2CO3/aq. EtOH azeotrope system, the sustainability of the batch protocol has been greatly improved since no purification step is needed (E-factor 27.7), and this value is noticeable reduced in a large-scale flow protocol process by the recovery of azeotrope reaction medium by distillation (E-factor 3.2).

10 of 20

2.2.2. Heck Reaction

2.2.2. Heck Reaction The catalytic activity of Pd@ZPGly catalysts has been investigated in the representative Heck reaction The catalytic of Pd@ZPGly catalysts hasaqueous been investigated the representative Heck between iodobenzene (4a)activity and methyl acrylate (5a) in CH3 CNinazeotrope (aq. CH 3 CN 84%), an reaction between iodobenzene (4a) and methyl acrylate (5a) in aqueous CH3CN azeotrope alternative to conventional polar aprotic media, as a safer and easily recoverable reaction medium [15,48]. (aq. CH3CN 84%), an alternative to conventional polar aprotic media, as a safer and easily In the presencereaction of a soluble base, such us triethylamine (TEA), at 120 ◦ C for 3 h, all of the recoverable medium [15,48]. Pd@ZPGly catalysts promoted complete conversion (Table(TEA), 6, Entries 1-h reaction In the presence of a the soluble base, such us triethylamine at 120 1–5), °C forbut 3 h,after all ofathe Pd@ZPGly catalysts promoted the complete conversion (Table 6, Entries 1–5), but after a 1-h reaction time, lower conversions were observed in the case of Pd@ZPGly-1R and -7R (Table 6, Entries 4 and 5), time, lower conversions were observed in the case of Pd@ZPGly-1R and -7R (Table 6, Entries 4 and again due to the presence of larger PdNPs aggregates. Pd/α-ZrPK catalyst, already reported by our 5), again due to the presence of larger PdNPs aggregates. Pd/α-ZrPK catalyst, already reported by group [15],our and Pd/C a comparable catalytic (Table 6, Entry group [15], 10 andwt% Pd/C showed 10 wt% showed a comparable catalyticefficiency efficiency (Table 6, Entry 6). 6). Table 6. Comparison of the efficiency of different PdNP-catalytic systemsin inthe the Heck Heck reaction Table 6. Comparison of the efficiency of different PdNP-catalytic systems reaction between ◦ 3CN azeotrope at 120 °C for 3 h. between iodobenzene (4a) and methyl acrylate (5a) in aq. CH iodobenzene (4a) and methyl acrylate (5a) in aq. CH3 CN azeotrope at 120 C for 3 h.

+

4a

Entry 1 1 2 3 4 5 6 7 84 94

OMe

OMe

aq. CH3CN 84% TEA, 120 °C, 3 h

5a

6a

1 2 EntryPdNP-Catalyst PdNP-Catalyst Conv Conv % % (1 (1 h) h) 2 1 Pd@ZPGly-1 88 88 2 Pd@ZPGly-1 Pd@ZPGly-7 78 78 3 Pd@ZPGly-7 Pd@ZPGly-15 80 80 4 Pd@ZPGly-15 Pd@ZPGly-1R 76 76 5 Pd@ZPGly-1R Pd@ZPGly-7R 62 62 6 Pd@ZPGly-7R Pd/α-ZrPK 5 5 -7 Pd/α-ZrPK Pd/C 10 wt %

Pd/C 10 wt % Pd@ZPGly-15 Pd/α-ZrPK 5

O

PdNP-catalyst (0.1 mol%)

O

I

-

ConvConv % (3 h)%2 (3 h) Pd2 (ppm) 3 >99 21 >99 >99 16 >99 >99 13 99 >99 20 99 99 21 99 >99 34 5 98 >99 187

98 >99 >99

Pd (ppm) 3 21 16 13 20 21 34 5 187 2 65

1 Reaction conditions: 4a (1.0 mmol), 5a (1.2 mmol), base (1.2 mmol), catalyst (0.1 mol %), aq. CH CN 84% (1 M, 3 1 mL). 2 Conversion of 4a to 6a is measured by GLC analyses; the remaining material is unreacted 4a. 3 Determined 4 by ICP-OES analysis of crude reaction product. In the presence of polystyrene (PS)-TEA as the base. 5 [15].

A remarkable difference was, however, observed in the Pd content determined by ICP-OES analyses of the crude products obtained by filtration and the usual extraction work-up procedure. In fact, the Pd@ZrPGly catalysts showed a Pd leaching in the products of 13–21 ppm, while in the case of Pd/α-ZrPK, the leaching was higher (34 ppm). Extremely high was the content of Pd in the product obtained by Pd/C catalysis (187 ppm, Table 6, Entry 7). This result is very notable and proves that the presence of glycine groups on the surface of ZPGly nanosheets allows better efficiency in re-capturing palladium. As well as for the Suzuki–Miyaura reaction, the best result in terms of activity and release of Pd was obtained with Pd@ZrPGly15. It is known that a “release and catch” mechanism is operative for a PdNP-catalyzed Heck reaction [15,36,48] and that the required organic base strongly binds the soluble palladium species, facilitating their dissolution from the solid catalyst and consequently the leaching into the products. Besides, the base has the fundamental role of regenerating the active Pd(0) species [49], with the formation of the corresponding ammonium salt. In order to reduce the leaching of Pd and the amount of waste but also simplify the work-up procedure, we investigated the use of diethylaminomethyl-polystyrene (PS-TEA) as the heterogeneous base, which can be removed by simple filtration from the reaction mixture, and therefore, the isolation of the final product can be obtained simply by distillation of the azeotropic reaction medium. Since the polystyrene-bonded amino groups may act as capping agents for the Pd nanoparticles, a significantly reduced Pd leaching is expected [50–53]. As shown in Table 6, when the reaction was performed in the presence of PS-TEA as the base, the catalytic activity of Pd@ZrPGly-15 was unchanged, while the Pd content in the final product was only 2 ppm (Table 6, Entry 8 vs. Entry 3), much below the allowed limit value [42]. The comparable

procedure, we investigated the use of diethylaminomethyl-polystyrene (PS-TEA) as the heterogeneous base, which can be removed by simple filtration from the reaction mixture, and therefore, the isolation of the final product can be obtained simply by distillation of the azeotropic reaction medium. Since the polystyrene-bonded amino groups may act as capping agents for the Pd nanoparticles, a significantly reduced Pd leaching is expected [50–53]. Catalysts 2017, 7, 186 11 of 20 As shown in Table 6, when the reaction was performed in the presence of PS-TEA as the base, the catalytic activity of Pd@ZrPGly-15 was unchanged, while the Pd content in the final product was only 2 ppm (Table 6, Entry 8 vs.a Entry much below the allowed valueTable [42]. The comparable Pd/α-ZrPK catalyst [15] showed lower3),efficiency to recapture Pdlimit (6 ppm, 6, Entry 9), proving Pd/α-ZrPK catalyst [15] showed a lower efficiency to recapture Pd (6 ppm, Table 6, Entry 9), proving that ZrPGly can act as an excellent scavenger for palladium nanoparticles. that ZrPGly can act as an excellent scavenger for palladium nanoparticles. Recycle test was performed in batch, by using homogeneous TEA as the base, to evaluate the Recycle test was performed in batch, by using homogeneous TEA as the base, to evaluate the robustness of Pd@ZPGly-15. For For eacheach cycle, the solid catalyst was was separated by centrifugation, washed robustness of Pd@ZPGly-15. cycle, the solid catalyst separated by centrifugation, with washed aq. CHwith CN azeotrope and used again in the next cycle (Table 7). Pd@ZPGly-15 was used 3 aq. CH3CN azeotrope and used again in the next cycle (Table 7). Pd@ZPGly-15 was six timesused always maintaining the same activity and achieving a TON (turnover number) of ca. 6000 six times always maintaining the same activity and achieving a TON (turnover number) of ca.and a and a TOF (turnover 333ICP-OES h−1. The ICP-OES analyses of crude products showed TOF 6000 (turnover frequency) offrequency) ca. 333 h−of1 .ca. The analyses of crude products showed a stable a stable palladium leaching at each cycle (10–12 ppm). palladium leaching at each cycle (10–12 ppm). 7. Recycling of Pd@ZPGly-15in inthe the Heck Heck reaction iodobenzene (4a) (4a) and and methyl TableTable 7. Recycling testtest of Pd@ZPGly-15 reactionbetween between iodobenzene methyl acrylate (5a) in aq. CH3CN azeotrope at 120 ◦°C for 3 h. acrylate (5a) in aq. CH3 CN azeotrope at 120 C for 3 h.

+

4a

Run 1 1 2 3 4 Catalysts 2017, 7, 186 5 6

Run 1 1 2 3 4 5 6

O

Pd@ZPGly-15 (0.1 mol%)

O

I

OMe

OMe

aq. CH3CN 84% TEA, 120 °C, 3 h

5a

Conv Conv % 2% 2 >99>99 >99>99 >99>99 >99>99 >99>99 >99>99

6a 3 3 Yield (%)(%) Yield 97 97 98 98 97 97 96 96 97 97 97 97

4 Pd (ppm)Pd (ppm) 4 11 11 10 10 11 11 12 12 10 10 11 11

12 of 21

1 First cycle: 4a (6.0 mmol), 5a (7.2 mmol), TEA (7.2 mmol), catalyst (0.1 mol %), aq. CH3CN 84% (1 M, First cycle: 4a (6.0 mmol), 5a (7.2 mmol), TEA (7.2 mmol), catalyst (0.1 mol %), aq. CH3 CN 84% (1 M, 6 mL), 6 mL), 120 °C, 3 h. Successive cycles: the reagents and medium quantities were calculated on the 120 ◦ C, 3 h. Successive cycles: the reagents and medium quantities were calculated on the basis of the amount of 2 Conversion of 4a to 6a is measured by GLC analyses; the basis of the amount of recovered 2 Conversion recovered catalyst. of 4a tocatalyst. 6a is measured by GLC analyses; the remaining material is unreacted 4a. 3 Yield of isolated product. 4 Determined by ICP-OES analysis of 3 Yield remaining 4a.by of isolatedmaterial product.is4unreacted Determined ICP-OES analysis of crude reaction product. crude reaction product.

1

In Figure 5, the TEM images of Pd@ZPGly-15 after six cycles are shown. The sample is almost In Figure 5, the TEM images of Pd@ZPGly-15 after six cycles are shown. The sample is almost unchanged, and the result is constituted by thin lamellae that support PdNPs with dimensions unchanged, and the result is constituted by thin lamellae that support PdNPs with dimensions comparable to those of the fresh prepared comparable to those of the fresh preparedcatalyst. catalyst.

Figure 5. TEM micrographs of Pd@ZPGly-15 after six catalytic cycles.

Figure 5. TEM micrographs of Pd@ZPGly-15 after six catalytic cycles.

To confirm the efficiency of Pd@ZPGly-15 in the Heck coupling reaction, we extended the study

To confirm the efficiency of Pd@ZPGly-15 in the Heck coupling reaction, we extended the study to several aryl iodides 4a–h with methyl acrylate (5a) or with styrene (5b) (Table 8). The reactions of to several aryl iodides 4a–h with methyl acrylate (5a) or withatstyrene 8).presence The reactions the aryl iodides (4a–h) with methyl acrylate (5a) were carried 120 °C (5b) for 3 (Table h, in the of ◦ C for 3 h, in the presence of of the0.1 aryl iodides (4a–h) with methyl acrylate (5a) were carried at 120 mol % of Pd@ZPGly-15 and TEA as the base, obtaining from high to quantitative conversions of 4 0.1 mol of Pd@ZPGly-15 and TEA as the6a–h base,(Table obtaining from1–8). highFor to 4-nitro-iodobenzene quantitative conversions and%excellent yields of isolated products 8, Entries (4b), of 4 and2′-iodoacetophenone excellent yields of(4f) isolated products 6a–h(4h), (Table 8, Entriesthe 1–8). For 4-nitro-iodobenzene and 2-iodothiophene we observed formation of the corresponding (4b), homocoupling products, the2-iodothiophene biphenyls 8b, 8f and 8h,we and therefore,the theformation products 6b, 6h were 20 -iodoacetophenone (4f) and (4h), observed of 6f theand corresponding purified byproducts, column chromatography Entries 2, 6 and 8). homocoupling the biphenyls(Table 8b, 8f8,and 8h, and therefore, the products 6b, 6f and 6h were When styrene (5b) was used with iodobenzene 2-iodothiophene (4h), a longer reaction purified by column chromatography (Table 8, Entries (4a) 2, 6 or and 8). time (4 h) was required to attain quantitative conversion (Table 8, Entries 9 and 10). The formation of the gem-products 7i–l and, also, for 2-iodothiophene (1h), the formation of the biphenyl 8h were observed (Table 8, Entries 9 and 10). Table 8. Heck reaction between aryl iodides 4a–h and methyl acrylate (5a) or styrene (5b) catalyzed by Pd@ZPGly-15 in aq. CH3CN azeotrope at 120 °C.

2′-iodoacetophenone (4f) and 2-iodothiophene (4h), we observed the formation of the homocoupling products, the biphenyls 8b, 8f and 8h, and therefore, the products 6b,corresponding 6f and 6h were homocoupling products, the biphenyls 8b, 8f 8h, and purified by column chromatography (Table 8, and Entries 2, 6 therefore, and 8). the products 6b, 6f and 6h were purified column chromatography 8, Entries(4a) 2, 6 and 8). When by styrene (5b) was used with(Table iodobenzene or 2-iodothiophene (4h), a longer reaction When styrene (5b) was used with iodobenzene (4a) or 2-iodothiophene (4h), a longer reaction time (4 h) was required to attain quantitative conversion (Table 8, Entries 9 and 10). The formation of time (4 h) was required to attain quantitative conversion (Table 8, Entries 9 and 10). The formation of the gem-products 7i–l and, also, for 2-iodothiophene (1h), the formation of the biphenyl 8h were the gem-products 7i–l and, also, for 2-iodothiophene (1h), the formation of the biphenyl 8h were 12 of 20 Catalysts 2017, 7, 186 observed (Table 8, Entries 9 and 10). observed (Table 8, Entries 9 and 10).

Table 8. Heck reaction between aryl iodides 4a–h and methyl acrylate (5a) or styrene (5b) catalyzed

Heck reaction between iodides 4a–hand andmethyl methyl acrylate oror styrene (5b)(5b) catalyzed Table 8.Table Heck8.reaction between arylaryl iodides 4a–h acrylate(5a) (5a) styrene catalyzed by 3CN azeotrope at 120 °C. by by Pd@ZPGly-15 inin aq.aq.CH 3CN azeotrope at 120 °C. Pd@ZPGly-15 CH ◦ Pd@ZPGly-15 in aq. CH3 CN azeotrope at 120 C. Ar ArI I + + 4 4 1 1 Entry Entry 1 Entry 1 1 1 2 2 2 3 3 3 4 44 5 55 6 66 7 7

55

1

R1 R

Ar Ar

aq. aq.CH CH33CN CN84% 84% TEA, TEA,120 120°C, °C,33 hh

1 RR

++

1

++

Ar Ar

ArArArAr

66

77

8 8

Product Product Product 6a 6a 6b 6b 6b 6c 6c 6c 6d 6d 6d 6e 6e6e 6f 6f 6g6f 6g 6g

Conv (%) 2 2 2 Conv Conv(%) (%) >99 >99 >99 99 99 99 99 99 99 99 99 99 99 99 >9999 >99 >99 92

2 2 6/7/8 6/7/8 6/7/8 2 100:0:0 100:0:0 100:0:0 97:0:3 97:0:3 97:0:3 100:0:0 100:0:0 100:0:0 100:0:0 100:0:0 100:0:0 100:0:0 100:0:0 100:0:0 95:0:5 95:0:5 95:0:5 100:0:0

R111 RR CO2Me 2Me CO CO Me 22Me CO2Me CO CO Me 22Me CO2Me CO CO Me 22Me CO CO 2Me CO Me 22Me CO CO 2Me CO Me CO22Me CO 2Me CO Me CO22Me CO CO2Me 2 Me

S

CO CO2Me 2 Me

6h 6h

Ph Ph

CC66HH5 5

6i6i

99 99

93:7:0 93:7:0

96 96

CC66HH5 5

6l6l

98 98

87:10:3 87:10:3

92 924 4

8

10 55 10

Pd@ZPGly-15 Pd@ZPGly-15 (0.1 (0.1mol%) mol%)

ArAr Ar PhPh Ph 2-C6H4 4-NO 4-NO 2-C6H4 4-NO 2 -C63H 4-COCH -C46H4 4-COCH 3-C6H4 4-COCH H44 33-C 66H -C 4-CH -C6H 4-CH3-C 4-CH H464H4 3 36-C 4-OCH -C6H 4-OCH3-C 4-OCH H644H4 3 36-C 2-COCH 2-COCH33-C -C66H 2-COCH H4 2-CH3-C6H44 2-CH33-C66H44 2-CH

Catalysts 88 2017, 7, 186 5 99 5

R1R1

S

CO2Me

S

6h

92 92

100:0:0 100:0:0

>99

87:0:13

>99 >99

87:0:13 87:0:13

Yield (%) 3 3 3 Yield Yield(%) (%) 98 98 4 98 4 94 94 94 4 97 97 97 96 96 96 98 98 95 4 984 4 95 87 4954 4

87 87

74 4

134 4of 21 74 74

2017, 7, conditions: 186 13 of 21 1 Reaction 1Catalysts aryl iodide (1.0 mmol), (1.2 mmol), TEAmmol), (1.2 mmol), catalyst (0.1%), mol Reaction conditions: aryl iodide 4a–h 4a–h (1.0 mmol), 5 (1.2 5mmol), TEA (1.2 catalyst (0.1 mol aq.%), CH3 CN ◦ 2 1 2 3CN 120 84% C, (1 3M, 120 °C,of3 4h.to Conversion of 4 to and 6/7/8 by ratio areand measured byanalyses; GLC the aq. 84% (1 M,CH 1 mL), h.1 mL), Conversion 6 and 6/7/8 ratio are6measured GLC H-NMR

6i (6 + 7). 4 3After 9 5 material is unreacted Ph Cof 6H5 99 93:7:0 96 3 Yield remaining isolated chromatography analyses; the4. remaining materialproducts is unreacted 4. Yieldcolumn of isolated products (6purification. + 7). and 1H-NMR 5 Reaction time 4 h. 4 After column chromatography purification. 5 Reaction time 4 h. 6l 98 87:10:3 92 4 10 5 C6H5

When styrene (5b)S was used with on iodobenzene 2-iodothiophene (4h), athe longer reaction Finally, we focused our attention the definition(4a) of aor flow procedure to optimize isolation 1 timeof (4the h) pure was required to attain quantitative conversion (Table Entries and 10). The%),formation product while minimizing the waste production. Reaction conditions: aryl iodide 4a–h (1.0 mmol), 5 (1.2 mmol), TEA8, (1.2 mmol), 9 catalyst (0.1 mol The catalytic behavior of 120 Pd@ZPGly-15, under of flow was inbythe Heck 3CN 84% (1 M, 1 mL), °C,2-iodothiophene 3 h. 2 Conversion 4(1h), to 6conditions, and ratio arestudied measured GLC aq. CH of the gem-products 7i–l and, also, for the6/7/8 formation of the biphenyl 8h were 1H-NMR analyses; the remaining material is unreacted 4. 3 Yield of isolated products (6 + 7). and reaction of iodobenzene (4a) 10). with methyl acrylate (5a) and styrene (5b) by using aq. CH3CN observed (Table 8, Entries 9 and 4 After column chromatography purification. 5 Reaction time 4 h. azeotrope asfocused the reaction and as the heterogeneous base. to optimize the isolation of Finally, we ourmedium attention onPS-TEA the definition of a flow procedure A mixture of the catalyst Pd@ZPGly-15 (0.1 mol %) and the supported PS-TEAthe (1.5isolation equiv) the pure product while minimizing the waste Finally, we focused our attention on the production. definition of a flow procedurebase to optimize 3CN azeotrope solution of the was charged in a stainless-steel HPLC column, while an aq. CH of the pure product while the waste production. The catalytic behavior ofminimizing Pd@ZPGly-15, under flow conditions, was studied in the Heck reaction reactants (40 mmol behavior iodobenzene (4a) and 60 mmol methyl acrylate (5a)) was studied charged in athe second The catalytic of Pd@ZPGly-15, under flow conditions, Heckas the of iodobenzene (4a) with methyl acrylate (5a) and styrene (5b) by using was aq. CH3 CN in azeotrope glass column, the reservoir (Scheme 2). reaction of iodobenzene (4a) with methyl acrylate (5a) and styrene (5b) by using aq. CH 3CN reaction medium and PS-TEA as the heterogeneous base. azeotrope as the reaction medium and PS-TEA as the heterogeneous base. A mixture of the catalyst Pd@ZPGly-15 (0.1 mol %) and the supported base PS-TEA (1.5 equiv) A mixture of the catalyst Pd@ZPGly-15 (0.1 mol %) and the supported base PS-TEA (1.5 equiv) was charged in a stainless-steel HPLC column, while an aq. CH3 CN azeotrope solution of the reactants was charged in a stainless-steel HPLC column, while an aq. CH3CN azeotrope solution of the (40 mmol iodobenzene and 60 mmol methyl acrylate (5a)) was charged a second column, reactants (40 mmol (4a) iodobenzene (4a) and 60 mmol methyl acrylate (5a)) wasincharged in glass a second the reservoir (Scheme 2). glass column, the reservoir (Scheme 2).

Scheme 2. Schematic flow reactor for the preparation of 6a and 6i.

The columns were connected to a pump and installed into a thermostated box at 120 °C (not shown in Scheme 2 for clarity). The reaction mixture was pumped at a 2.0-mL/min flow rate through the columns for 1.5 h to obtain quantitative conversion of 4a to 6a (monitored by GLC, Table 9, Entry 1). Scheme 2. Schematic flow reactor for the preparation of 6a and 6i. Scheme 2. Schematic flow reactor for the preparation of 6a and 6i. Table 9. Catalytic activity and reusability of Pd@ZPGly-15 in the flow reactor for the Heck reaction of The columns were connected to a pump and installed into a thermostated box at 120 °C (not iodobenzene 4a with methyl acrylate (5a) and styrene (5b).

shown in Scheme 2 for clarity). The reaction mixture was pumped at a 2.0-mL/min flow rate through the columns for 1.5 h to obtain quantitative conversion of 4a to 6a (monitored Rby 1 GLC, Table 9, Pd@ZPGly-15 flow Entry 1). I R1 (0.1 mol%) +

R1

PS-TEA (1.5 eq)

+

Scheme 2. Schematic flow reactor for the preparation of 6a and 6i. Catalysts 2017, 7, 186

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The columns were connected to a pump and installed into a thermostated box at 120 °C (not shown in Scheme 2 for clarity). The reaction mixture was pumped at a 2.0-mL/min flow rate through The columns were connected to a pump and installed into a thermostated box at 120 ◦ C (not shown the columns for 1.5 h to obtain quantitative conversion of 4a to 6a (monitored by GLC, Table 9, in Scheme 2 for clarity). The reaction mixture was pumped at a 2.0-mL/min flow rate through the Entry 1). columns for 1.5 h to obtain quantitative conversion of 4a to 6a (monitored by GLC, Table 9, Entry 1). Table 9. Catalytic activity and reusability of Pd@ZPGly-15 in the flow reactor for the Heck reaction of Table 9. Catalytic activity and reusability of Pd@ZPGly-15 in the flow reactor for the Heck reaction of iodobenzene 4a with methyl acrylate (5a) and styrene (5b). iodobenzene 4a with methyl acrylate (5a) and styrene (5b). I

R1

+

4a

EntryEntry 1 1 2 2 3 3 4 4

5

R1 R1 CO2Me CO2 Me CO2 Me CO2Me CO2 Me CO2Me C6 H5 C6H5 1

Pd@ZPGly-15 (0.1 mol%) PS-TEA (1.5 eq) aq. CH3CN 84% 120 °C, 1.5-2 h

CycleCycle Product Product 6a 6a run 1 run 1 6a 6a run 2 run 2 run 3 6a 6a1 run 3 run 4 6i 6i 1 run 4

flow

R1

R1 +

6

t (h) t (h) Yield (%) Yield (%) 1.5 1.5 87 87 1.5 1.5 87 87 1.5 1.5 85 852 2 86 2 86 2 2

7

Pd (ppm) Pd Leaching Leaching (ppm) 44 44 2 2 2 2

A 5% of product 7i was observed. Yield of isolated products 6i + 7i.

The column that contained both the PS-TEA and catalyst was then washed with aq. CH3 CN azeotrope to clean the apparatus and completely recover the product. Finally, the product 6a was obtained in pure form, after distillation of the reaction medium and without any further purification step, in 87% yield (Table 9, Entry 1). The aqueous CH3 CN azeotrope, recovered by distillation, was pure (GLC analysis), comparable to the starting azeotropic mixture and, therefore, fully reusable. The reusability of the catalyst, in flow conditions, was evaluated for the reaction of iodobenzene (4a) with methyl acrylate (5a). The column that contained both the PS-TEA and catalyst was washed with a solution of TEA in aq. CH3 CN azeotrope to regenerate the supported ammine by removal of hydriodic acid (HI) formed during the Heck reaction and then washed with azeotrope to remove the residual TEA. After this treatment, a second batch of reactants was charged in the reservoir, and quantitative conversion was achieved again in 1.5 h (Table 9, Entry 2). An unchanged catalytic activity was also obtained in the third run (Table 9, Entry 3). After three runs, iodobenzene (4a) and styrene (5b) were charged in the reservoir, and the reaction mixture was pumped through the column, containing the recovered PS-TEA and catalyst, to obtain after 2 h a quantitative conversion of 4a to 6i (86% yield, Table 9, Entry 4). To evaluate the sustainability of the processes, we calculated the E-factor value for both the batch and the flow protocols. When TEA was used as the base in the batch condition, an E-factor value of 70.4 was obtained, mainly due to the need of extraction work-up. Under flow conditions by using PS-TEA as the base, we were able to easily run the process on a larger scale (50 mmol) and to reduce this value to 4.7, since the reaction products can be recovered simply by distillation of the reaction medium that was totally recovered. The ICP analyses of the final products revealed the presence of a very low Pd content of ca. 2–4 ppm, below the allowed limit value [42] (Table 9). The low residual of Pd in the products and the high activity over more runs is in agreement with the aforementioned “release and catch” mechanism [36,48].

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3. Experimental Section 3.1. General Remarks All chemicals were purchased and used without any further purification. 1 H-NMR and 13 C-NMR spectra were recorded at 400 MHz and 100.6 MHz, respectively, on a Bruker DRX-ADVANCE 400 MHz in CDCl3 using TMS as the internal standard. Zr, P and Pd analyses were performed on an ICP Varian Liberty inductively-coupled plasma-optical emission spectrometry (ICP-OES) with axial injection. C, H, N elemental analyses (EA) were performed on a Fisons EA1108CHN. Powder X-ray diffraction patterns (PXRD) of powders were collected with a Philips X’Pert PRO MPD diffractometer operating at 40 kV and 40 mA, with a step size of 0.03341◦ 2theta and a step scan of 40 s, using Cu Kα radiation and an X’Celerator detector. Transmission electron microscopy (TEM) analysis was carried out by a Philips 208 transmission electron microscope, operating at an accelerating voltage of 100 kV. Powders were rapidly diluted in water, then supported on copper grids (200 mesh) precoated with Formvar carbon films and quickly dried. GLC analyses were performed by using the Hewlett-Packard HP 5890A equipped with a capillary column DB-35MS (30 m, 0.53 mm), an FID detector and hydrogen as the gas carrier. Gas Chromatography with Electron Impact Mass Spectrometry (GC-EIMS) analyses were carried out by using a Hewlett-Packard HP 6890N Network GC system/5975 Mass Selective Detector equipped with an electron impact ionizer at 70 eV. Thin layer chromatography analyses were performed with silica gel on aluminum plates (silica gel 60 F254, Fluka). Column chromatography purification was performed with silica gel (230–400 mesh) eluting with hexane or mixture hexane/ethyl acetate (98:2–70:30). Melting points were measured on a Büchi 510. Flow procedures were performed using a Jasco PU-2080 HPLC pump, an Omnifit glass column as the reservoir and a Supelco HPLC column blank as the base/catalyst column. All of the equipment was connected using 1/16’ OD PTFE tubing and stainless steel 1/16 OD × 0.02 ID capillary tubing and Hamilton HPV Plug Valves. The system was placed in a ventilated Plexiglas box equipped with electrical resistance heating. Diethylaminomethyl-polystyrene (PS-TEA) was prepared by reacting Merrifield resin (200–400 mesh, 4.4 mmol/g Cl loading, 2% cross-linked with divinylbenzene) with diethylamine (2.5 equiv) in toluene at 100 ◦ C for 24 h. The resin was then washed with a 0.5 M solution of diethylamine in toluene, then toluene, dichloromethane, water and acetone to remove the excess amine, then dried under vacuum. The loading of amine is calculated by C, H, N elemental analysis (EA) on the element nitrogen, which is not contained in the purified and fully-dried polymeric support. Solid NMR analyses also confirm the absence of free amine. Compounds 3a–n [22,43,46,54] and 6a–l [15] are known. 3.2. Synthesis of Zr2 (PO4 )[(O3 PCH2 )2 NHCH2 COOH]2 ·H2 O The synthesis of ZPGly was achieved as reported in [14]. In particular, 2.37 g (9 mmol) of N,N-bis(phosphonomethyl)glycine (L) were dissolved in 93 mL of deionized water (0.097 M), and then, 6 mL of phosphoric acid 1 M were add to this solution. Then, 1.93 g (6 mmol) of ZrOCl2 ·8H2 O were dissolved in 20.4 mL of HF 2.9 M (59 mmol), molar ratio HF/ZrIV = 10. These two solutions were mixed in a 500-mL Teflon bottle and placed in an oven at 90 ◦ C. After three days, the solid was filtered under vacuum, washed three times with deionized water and dried at 60 ◦ C for 24 h. The empirical formula was Zr2 P5 O21 C8 N2 H19 (Formula weight = 816, ionic exchange capacity = 3.67 mmol/g).

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3.3. Preparation of ZPGly Dispersion One gram of ZPGly (1.23 mmol) was suspended in 108 mL of deionized water, and then 22 mL of n-propylamine 0.1 M (2.2 mmol corresponding to 60% of IEC) were added under vigorous magnetic stirring. A stable dispersion was obtained. 3.4. Preparation of Pd@ZPGly Composites Fourteen milliliters of Pd(CH3 COO)2 0.05 M in acetone (0.7 mmol of PdII ) were added drop by drop to 32.5 mL of the ZPGly dispersion (containing 250 mg of ZPGly) under vigorous stirring. The dispersion was left under magnetic stirring for 1 day (Pd@ZPGly-1). Additional composites were obtained by increasing the reaction time to 7 days (Pd@ZPGly-7) and to 15 days (Pd@ZPGly-15). The solids were recovered by ultracentrifugation (15,000 rpm for 10 min) and washed once with acetone and twice with deionized water. The solids were dried over P2 O5 . 3.5. Preparation of Pd@ZPGly-1R and Pd@ZPGly-7R To a suspension of Pd@ZPGly-1 and Pd@ZPGly-7 (100 mg) in deionized water (10 mL), a solution of NaBH4 (10 equiv) in deionized water (10 mL) was added drop by drop, under magnetic stirring. At the end of the addition, the reaction mixture was left under stirring for one hour. The solids were recovered by ultracentrifugation (hereafter Pd@ZPGly-1R, Pd@ZPGly-7R) washed with deionized water and dried over P2 O5 . 3.6. Determination of Pd Content A weighed amount of the catalyst was first treated with concentrated HF in order to dissolve ZPGly, then with aqua regia to digest the Pd species, and the obtained solution was diluted with deionized water and analyzed by ICP-OES. 3.7. Typical Procedure for the Suzuki Reaction in EtOH/H2 O (1:1) under Batch Conditions In a vial, Pd@ZPGly-15 catalyst (0.47 mg, 2.11 mmol of Pd per g, 0.1 mol %), phenylboronic acid (2a, 134 mg, 1.2 mmol), K2 CO3 (167 mg, 1.10 mmol), 4-bromotoluene (1a, 171 mg, 1 mmol), ethanol (1.2 mL) and water (1.2 mL) were placed. The reaction mixture was stirred at 80 ◦ C; the conversion of the aryl bromide was monitored by GLC analyses. After 2 h, water was added (2 mL) and the mixture extracted with ethyl acetate (3 × 3 mL). The combined organic layers were dried with sodium sulfate and evaporated under reduced pressure. E-factor calculation: E-factor = [0.171 g (4-bromotoluene, 1a) + 0.134 g (phenylboronic acid, 2a) + 0.167 g (K2 CO3 ) + 0.00047 g (Pd@ZPGly-15) + 0.947 g (EtOH) + 3.2 g (water) + 8.1 g (ethyl acetate) − 0.165 g (4-methyl-1,10 -biphenyl (3a), 98% yield)]/0.165 g (4-methyl-1,10 -biphenyl (3a), 98% yield) = 76. 3.8. Typical Procedure for the Suzuki Reaction in aq. EtOH Azeotrope under Batch Conditions In a vial, Pd@ZPGly-15 catalyst (0.47 mg, 2.11 mmol of Pd per g, 0.1 mol %), phenylboronic acid (2a, 134 mg, 1.1 mmol), K2 CO3 (167 mg, 1.10 mmol), 4-bromotoluene (1a, 171 mg, 1 mmol) and ethanol 96% (2.4 mL) were placed. The reaction mixture was stirred at 80 ◦ C; the conversion of the aryl bromide was monitored by GLC analyses. After 24 h, the reaction mixture was filtered and the solid residue washed with ethanol (3 mL). The organic layer was evaporated under reduced pressure. E-factor calculation: E-factor = [0.171 g (4-bromotoluene, 1a) + 0.134 g (phenylboronic acid, 2a) + 0.167 g (K2 CO3 ) + 0.00047 g (Pd@ZPGly-15) + 4.26 g (EtOH) − 0.165 g (4-methyl-1,10 -biphenyl (3a), 98% yield)]/0.165 g (4-methyl-1,10 -biphenyl (3a), 98% yield) = 27.7. 3.9. Typical Procedure for the Suzuki Reaction in aq. EtOH Azeotrope under Flow Conditions A pre-mixed mixture of 4-bromobenzaldehyde (1g, 40 mmol, 7.4 g), phenylboronic acid (2a, 44 mmol, 5.36 g) and ethanol 96% (0.33 M, 121.2 mL) was charged into a glass column functioning

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as a reservoir. Potassium carbonate (48 mmol, 6.7 g), dispersed in 1 mm diameter solid glass beads, was charged in a glass column; the catalyst Pd@ZPGly-15 (18.9 mg, 2.11 mmol of Pd/g, 0.1 mmol %) was also charged in another glass column and dispersed in 1 mm diameter solid glass beads; the equipment was installed into a thermostated box and connected, by using the appropriate valves, to a pump. The reaction mixture was continuously pumped (flow rate 1.5 mL·min−1 ) through the base and catalyst columns at 70 ◦ C for 10 h to reach the complete conversion of reactant to 1,10 -biphenyl-4-carbaldehyde (3g). At this stage, the pump was left to run in order to recover the reaction mixture into the reservoir. To completely recover the product and clean the reactor, ethanol (2 × 8 mL at a 1.5 mL·min−1 ) was cyclically pumped through the base and the catalyst columns for 10 min (each fraction) and then collected into the reservoir to isolate the product in a 98% yield (>99% purity) after removal and recovery of the solvent (90% of solvent recovered) via distillation. E-factor calculation: E-factor = [7.4 g (4-bromobenzaldehyde, 1g) + 5.36 g (phenylboronic acid, 2a) + 6.7 g (K2 CO3 ) + 108.2 g (EtOH) − 7.1 g (1,10 -biphenyl-4-carbaldehyde (3g), 98% yield) − 97.8 g (recovered EtOH)]/7.1 g (1,10 -biphenyl-4-carbaldehyde (3g), 98% yield) = 3.2. 3.10. Typical Procedure for the Heck Reaction under Batch Conditions In a steel reactor, to a solution of the aryl iodide 4a–h (1 mmol) and the alkene 5a–b (1.2 mmol) in aq. CH3 CN 84% (1 M, 1 mL), triethylamine (0.167 mL, 1.2 mmol) and catalyst Pd@ZPGly-15 (0.47 mg, 2.11 mmol of Pd per g, 0.1 mol %) were added. The reaction mixture was stirred at 120 ◦ C for 3 h with methyl acrylate (5a) and for 4 h with styrene (5b); the conversion of the aryl iodide 1a–h was monitored by GLC analyses. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic layers were dried with sodium sulfate and evaporated under reduced pressure. Representative E-factor calculations: E-factor for Heck reaction of iodobenzene (4a) (1 mmol) and methyl acrylate (5a) (1.2 mmol) (98% isolated yield): E-factor = [0.204 g (iodobenzene (1a)) + 0.103 g (methyl acrylate (2)) + 0.121 g (TEA) + 0.818 g (1 mL CH3 CN/H2 O 84:16) + 2 g (water) + 8.1 g (ethyl acetate) − 0.159 g (methyl cinnamate (6a))]/0.159 g (methyl cinnamate (6a)) = 70.4 (catalyst was not considered due to its recovery and recycle). 3.11. Typical Procedure for Recovery and Reuse of Pd@ZPGly-15 in the Heck Reaction under Batch Conditions In a steel reactor, to a solution of iodobenzene (4a, 1.22 g, 6 mmol) and methyl acrylate (5a, 0.62 g, 7.2 mmol) in aq. CH3 CN 84% (1 M, 6 mL), triethylamine (1 mL, 7.2 mmol) and catalyst Pd@ZPGly-15 (2.8 mg, 2.11 mmol of Pd per g, 0.1 mol %) were added. The reaction mixture was stirred at 120 ◦ C for 3 h; the conversion of the iodobenzene (4a) was monitored by GLC analyses. The solid catalyst was separated by centrifugation and then washed with aq. CH3 CN azeotrope (2 × 1 mL), dried at 50 ◦ C for 3 h and reused in a successive cycle. The product was isolated after extraction with ethyl acetate. 3.12. Typical Procedure for the Heck Reaction in the Presence of PS-TEA under Batch Conditions In a steel reactor, to a solution of iodobenzene (4a, 0.204 g, 1 mmol) and methyl acrylate (5a, 0.103 g, 1.2 mmol) in aq. CH3 CN 84% (1 M, 1 mL), diethylaminomethyl-polystyrene (PS-TEA, 0.312 g, 3.84 mmol/g, 1.2 equiv) and catalyst Pd@ZPGly-15 (0.47 mg, 2.11 mmol of Pd per g, 0.1 mol %) were added. The reaction mixture was stirred at 120 ◦ C for 3 h; the conversion of the iodobenzene (4a) was monitored by GLC analyses. The heterogeneous base and catalyst were separated by filtration, washed with aq. CH3 CN azeotrope (1 mL) and the product 6a isolated by distillation of the azeotrope. E-factor calculations: (96% isolated yield): E-factor = [0.204 g (iodobenzene (4a)) + 0.103 g (methyl acrylate (5a)) + 0.312 g (PS-TEA) + 0.00047 g (Pd@ZPGly-15) + 1.64 g (2 mL CH3 CN/H2 O 84:16) − 0.155 g (methyl cinnamate (6a))]/0.155 g (methyl cinnamate (6a)) = 13.6.

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3.13. Heck Reaction of Iodobenzene (4a) and Methyl Acrylate (5a) under Flow Conditions A pre-mixed mixture of iodobenzene (4a, 5.60 mL, 50 mmol) and methyl acrylate (5a, 5.40 mL, 60 mmol) in aq. CH3 CN 84% (50 mL) was charged into a glass column functioning as a reservoir. The supported base PS-TEA (19.5 g, 3.84 mmol/g, 75 mmol) and the catalyst Pd@ZPGly-15 (23.7 mg, 2.11 mmol of Pd per g, 0.1 mol %) were mixed and dispersed in 1 mm diameter solid glass beads and charged in a stainless steel HPLC column; the equipment was connected, by using the appropriate valves, to a pump and installed into a thermostated box. The reaction mixture was continuously pumped (flow rate 2.0 mL/min) through the base-catalyst column at 120 ◦ C until complete conversion of reactants to methyl cinnamate (6a) was achieved (the reaction was monitored by GLC). At this stage, the pump was left to run in order to recover the reaction mixture in the reservoir. To completely recover the product and clean the reactor, aq. CH3 CN azeotrope (3 × 25 mL at a 2 mL/min) was cyclically pumped through the base-catalyst column for 15 min (each fraction) and then collected in the reservoir to isolate the product in 87% yield, after removal and recovery of the azeotrope (95% of which was recovered) via distillation. A solution of TEA (15 mL in 30 mL of aq. CH3 CN azeotrope) was cyclically pumped through the base/catalyst column (2 mL/min, 30 min) to regenerate the diethylaminomethyl-polystyrene. Finally, azeotrope (40 mL) was cyclically pumped through the base/catalyst column in two portions to remove residual TEA. Representative E-factor calculations: (87% isolated yield): E-factor = [10.2 g (iodobenzene (4a)) + 5.16 g (methyl acrylate (5a)) + 102.25 g (CH3 CN/H2 O 84:16) + 19.5 g (PS-TEA) + 0.0275 g (catalyst) − 7.05 g (methyl cinnamate (6a)) − 97.15 g (95% recovered medium)]/7.05 g (methyl cinnamate (6a)) = 4.7. 4. Conclusions The immobilization of palladium nanoparticles on zirconium phosphate glycine diphosphonate nanosheets provided stable catalysts with high Pd content (up to 22 wt %). The prepared materials were used as catalysts in a low amount (0.1 mol %) in the Suzuki–Miyaura and Heck reactions by using the aqueous azeotropic mixture (EtOH 95%, CH3 CN 84%) as a safe and easily recoverable reaction media. Pd@ZPGly-15 was found to be the best catalyst, in terms of activity and release of Pd, both in the Suzuki and Heck reaction. The robustness of the catalyst was tested, and a high reactivity was obtained over more runs. Finally, the waste production (E-factor) and the residual palladium content in the reaction products have been considerably reduced by using the flow technology. Supplementary Materials: The following are available online at www.mdpi.com/2073-4344/7/6/186/s1. Acknowledgments: The University of Perugia is thanked for financial support. R.V. gratefully acknowledges the financial support from “Fondo per il sostegno della Ricerca di Base 2015”, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia. Author Contributions: Oriana Piermatti and Luigi Vaccaro conceived of and designed the experiments. Vadym Kozell and Tommaso Giannoni performed the experiments. Morena Nocchetti and Riccardo Vivani prepared and characterized the catalysts. Oriana Piermatti, Luigi Vaccaro and Morena Nocchetti wrote the paper. Conflicts of Interest: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; nor in the decision to publish the results.

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