Multicatalysis combining 3D-printed devices and magnetic

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Cite This: ACS Appl. Mater. Interfaces 2019, 11, 25283−25294

Multicatalysis Combining 3D-Printed Devices and Magnetic Nanoparticles in One-Pot Reactions: Steps Forward in Compartmentation and Recyclability of Catalysts Antonio Sanchez Díaz-Marta,† Susana Yáñez,‡ Carmen R. Tubío,†,# V. Laura Barrio,∇ Yolanda Piñeiro,‡ Rosa Pedrido,∥ José Rivas,‡ Manuel Amorín,§ Francisco Guitián,† and Alberto Coelho*,†,⊥

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Instituto de Cerámica, ‡Instituto NANOMAG, §Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química Orgánica, ∥Departamento de Química Inorgánica, Facultad de Química, and ⊥ Departamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain # BCMaterials, Basque Center for Materials, Applications, and Nanostructures, UPV/EHU, Science Park, 48940 Leioa, Spain ∇ Escuela de Ingeniería, Universidad del País Vasco (UPV/EHU), Plaza Ingeniero Torres Quevedo, 48013, Bilbao, Spain S Supporting Information *

ABSTRACT: A tricatalytic compartmentalized system that immobilizes metallic species to perform one-pot sequential functionalization is described: a three-dimensional (3D)-printed palladium monolith, ferritic copper(I) magnetic nanoparticles, and a 3D-printed polypropylene capsule-containing copper(II) loaded onto polystyrene-supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (PS-TBD) allowed the rapid synthesis of diverse substituted 1-([1,1′-biphenyl]-4-yl)-1H-1,2,3-triazoles. The procedure is based on the Chan−Lam azidation/copper alkyne−azide cycloaddition/Suzuki reaction strategy in the solution phase. This catalytic system enabled the efficient assembly of the final compounds in high yields without the need for special additives or intermediate isolation. The monolithic catalyst-containing immobilized palladium species was synthesized by surface chemical modification of a 3D-printed silica monolith using a soluble polyimide resin as a key reagent, thus creating an extremely robust composite. All three immobilized catalysts described here were easily recovered and reused in numerous cycles. This work exemplifies the role of 3D printing in the design and manufacture of devices for compartmented multicatalytic systems to carry out complex one-pot transformations. KEYWORDS: 3D printing, multicatalysts, compartmentation, monolithic catalyst, magnetic nanoparticles

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INTRODUCTION One of the primary challenges in drug discovery chemistry is the development of fast and sustainable transformation procedures.1 Accelerated molecule production can be addressed by robotization,2 miniaturization,3 and the use of tandem,4,5 multicomponent,6 one-pot reactions,7 and, in general, high-throughput synthesis processes,8 which are all valuable tools. On the other hand, clean and efficient transformations for sustainable chemistry require efficient catalytic reactions instead of stoichiometric ones.9 In fact, 80% of industrial processes are catalytic, and this has become a key priority in efficient chemical engineering procedures.10 In © 2019 American Chemical Society

addition, the use of heterogeneous catalysts for drug synthesis is a key issue due to the strict safety regulations and trials to determine the presence of traces of metals in the final products.10 Specifically, the field is evolving toward the development of transition-metal-catalyzed reactions (TMCRs) for one-pot multicatalytic processes,11cooperative,12 relay, or sequential catalysis13 and multifunctional catalysts14,15with the help of new technological possibilities Received: May 9, 2019 Accepted: June 21, 2019 Published: June 21, 2019 25283

DOI: 10.1021/acsami.9b08119 ACS Appl. Mater. Interfaces 2019, 11, 25283−25294

Research Article

ACS Applied Materials & Interfaces

composed of metal and ceramics).29 For this reason, the incorporation of a catalytic active metal species on the silica surface by chemical or physical processes that do not generate leaching phenomena (under the reaction conditions) is a challenge in the development of this type of monolithic catalyst.32 The chemistry of supported polymers and reagents has been developed significantly in recent years, and this has provided excellent solutions. One example is the development of supported superbases on polymeric supports, many of which are commercially available.33 Therefore, from a practical point of view, it is also interesting to develop one-pot procedures that combine the use of monoliths, magnetic nanoparticles, and supported reagents, thus enabling immobilization, control of catalyst oxidation states, compartmentation, and individual recovery of the precious catalysts. Recently, we have reported the combined use of monoliths in bicatalytic heterogeneous transformations for the synthesis of diverse substituted benzyl-1,2,3-triazoles.27 To the best of our knowledge, there are no previous examples of tricatalytic systems based on immobilized and compartmentalized metal species in supports for practical reuse in one-pot solutionphase chemistry. Besides, the joint use of monoliths and magnetic nanoparticles in tandem or in one-pot transformations has not been reported previously. We describe here a compartmented and reusable triplecatalytic system (Cu2+, Cu1+, Pd0) to perform one-pot reactions based on the Cu(II)-mediated Chan−Lam azidation/copper alkyne−azide cycloaddition (1,3-copper alkyne− azide cycloaddition, CuAAC)/Suzuki reaction. The work also delves into the different aspects in which 3D printing technology can contribute efficiently to the manufacture of catalytic devices. For example, a porous capsule for the entrapment of a Cu2+-supported reagent or a Pd0-monolithic catalyst was produced, along with the joint catalytic evaluation of these systems in the presence of Cu+1-magnetic nanoparticles. The work is divided into the following stages: (1) immobilization of copper(II) species on the superbase 1,5,7triazabicyclo [4.4.0]dec-5-ene-polystyrene [PS-TBD-Cu(II)]; (2) 3D printing of a solvent-permeable capsule and encapsulation of PS-TBD-Cu(II); (3) synthesis of magnetic nanoparticles based on Fe3O4, chitosan, and Cu2O; (4) 3D printing of a monolith-shaped structure based on SiO2, with controlled shape, size, and porosity; (5) surface functionalization of the SiO2 structure with a polyimide resin and Pd(AcO)2; (6) characterization of all three catalytic systems synthesized; and (7) catalytic evaluation of PS-TBD-Cu(II), Fe3O4-Cu2O nanoparticles, and the monolith SiO2-PI-Pd. This evaluation was carried out individually or in a combined way in one-pot azidation/CuAAC/Suzuki transformations.

that have emerged from the use of polymer-supported reagents, particularly at the nanoscale.16 In this regard, metal nanoparticles and, in general, nanoparticles that immobilize metallic species have become well-established and effective tools in heterogeneous catalytic transformations.17,18 However, these materials do have some drawbacks. First, their use requires tedious workup operations such as centrifugation to separate them from the products. Furthermore, their combined use in typical multicatalytic reactions (transformations in which two or more catalysts are present in the reaction medium) suffers from difficult individual recycling and recovery of each individual catalyst since solid−solid separation is a difficult task. In this context, the use of magnetic nanoparticles19,20 can be considered as an alternative that has been frequently explored in different studies for compartmentalization in bicatalytic systems.21 However, individual compartmentalization and catalyst recovery using powdered catalysts in tricatalytic systems are not possible during the workup process on using this kind of material exclusively. Given this scenario, the introduction of 3D devices for effective entrapment of catalytic powders or the use of 3D monolithic catalysts would allow simplification of the individual recovery in an effective way in multicatalytic transformations. This is a powerful argument for the use of such approaches in multicatalysis. The use of monolithic catalysts in liquid batch reactions (especially on a large scale) may suffer from problems related to poor surface properties and limited reaction rates. However, such systems have numerous advantages over packed-bed reactors such as high transport rates of heat and mass per unit pressure drop, small transverse temperature gradients, and ease of scale-up.22 A significant advantage of a monolithic catalyst is related to the easy individual recovery and recycling after a tandem or onepot process, and this avoids the need for filtration or centrifugation, thus offering easier handling and better reusability. Shape and size are important macroscopic aspects in the design of monolithic heterogeneous catalysts.23 3D printing enables the fabrication of monoliths with different cross sections, pore sizes, and wall thicknesses, thus maximizing the catalytic surface. In addition, the manufacturing parameters and postprocessing steps can be tuned to obtain units with excellent mechanical properties. A wide range of 3D printing materials are able to produce tough functional prototypes that look like the final products. The development of 3D printing in the field of chemistry is quite recent.24 Cronin and co-workers demonstrated the utility of this approach in the manufacture of chemical reactionware, particularly reactors for linear drug synthesis, using polypropylene as a 3D printing material.25,26 Other groups recently described the use of several 3D printing techniques to obtain porous monolithic structures with controlled pore size and shape in which different metal species are immobilized, for example, palladium on carbon24 or ceramic supports27 and iron, nickel, or copper on ceramic supports28,29 fabricated by robocasting (direct ink writing)30 and copper in an acrylic support through stereolithography.31 Collectively, these monolithic systems are very suitable materials in the field of catalysis. Particularly desirable are those processes that incorporate metal species only on the monolith surface by simple and inexpensive procedures since this leads to savings in terms of precious metal with respect to those systems in which the metal is also present throughout the structure of the bulky material (3D printing of catalytic inks

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EXPERIMENTAL SECTION

Synthesis of PS-TBD-cu(II): Immobilization of Copper Species on Polystyrene-Supported TBD (PS-TBD). Kimble vials in a PLS (6 × 4) organic synthesizer were used to load PS-TBD. To a solution of Cu(AcO)2 (30 mg) in DMF (12 mL) was added 1.0 g of PS-TBD (2.6 mmol g−1 loading), and the suspension was vigorously stirred under orbital stirring at room temperature for 24 h. The resulting green supported base was filtered through a fritted syringe, washed (MeOH, CH2Cl2, diethyl ether), and dried under vacuum for 5 h at room temperature (Figure S1). 3D Printing of a Polypropylene Capsule. An Ultimaker 2+ 3D printer was used for the construction of the capsule, following the 25284


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ACS Applied Materials & Interfaces fused deposition modeling technique. A filament of polypropylene (2.85 mm diameter) was used as a 3D printing material for the capsule. A polypropylene porous membrane was placed on the base and fixed to the base with a polypropylene film on which the 3D printing was started. Tinkercad and CURA programs were used for the construction of the virtual 3D capsule. The 3D-printed structure was sealed at the bottom by melting the borders of the polypropylene membrane during 3D printing. Once the printing of the capsule had begun (when the process reached 50% progress, the capsule walls had already formed, Figure S2 in the Supporting Information), the impression was paused briefly to fill the capsule with the PS-TBDCu(II) resin. Once the capsule was filled with the PS-TDB-Cu(II) polymer reagent, 3D printing was resumed. In order to avoid melting or swelling of the polypropylene membrane located in the base, the temperature of the platform was maintained at 40 °C. The impression of the capsule was completed in 30 min. Synthesis of Fe3O4-Cu2O Magnetic Nanocomposites. The magnetic chitosan−Fe3O4 (CS-Fe3O4) nanoparticles (NPs) were prepared by adding 70 mL of a FeCl3 solution (0.13 mol L−1 in 0.13 mol L−1 HCl) to a 50 mL chitosan solution (13.8 mg mL−1 in 1% HCl, v/v) under continuous stirring for 1 h. 0.1 M Na2S2O3 solution (30 mL) was then added to the resulting yellow colloidal solution of chitosan, and the color of the mixed solution immediately changed from yellow to red. As soon as the color changed from red to yellow again, 18 mL (28%) of ammonia solution was quickly added under vigorous stirring at room temperature. A black precipitate/suspension appeared immediately. After 15 min, the resulting powders were collected with the aid of a magnet and washed several times with distilled water and isopropanol. Finally, the solid was dispersed in water. For the preparation of the Cu2O/chitosan−Fe3O4 (Cu2O/CSFe3O4) nanocomposites (NCs), 0.5 mmol of Cu(AcO)2·H2O was dissolved in 100 mL of distilled water, and then 10 mL of the CSFe3O4 solution were dispersed under ultrasonication for 30 min followed by mechanical stirring for 2 h. 0.5 M NaOH (20 mL) was added with vigorous stirring. 0.3 M ascorbic acid (15 mL) was added dropwise to the solution. The solution was stirred for 30 min, and the resulting precipitate was collected by centrifugation, washed with distilled water, and then dried at 80 °C for 12 h. 3D-Printed SiO2 Monolith Fabrication (Monolith Support). Monoliths of SiO2 were created using a direct ink writing method (robocasting) described in detail elsewhere.27 Briefly, in this method, a SiO2 ink was loaded into a 3 mL syringe barrel (Nordson EFD, USA) and fitted to a cylindrical nozzle (410 μm diameter, EFD). The monolith was then printed using a robotic deposition apparatus (Model A3200, Aerotech Inc., USA) with an air pressure system (Performus VII with HP7x, EFD). The printed monolith had a cylindrical structure (40 layers, 10 mm diameter) with a bodycentered tetragonal (bct) symmetry. The spacing between filaments was set to 1 mm, whereas the diameter of the filaments was 410 μm. After drying, the monolith was debound at 400 °C for 1 h at a heating rate of 2 °C min−1 and sintered at 1500 °C for 3 h at a heating rate of 5 °C min−1. Surface Modification of SiO2: Synthesis of SiO2-PolyimidePalladium Monolith. A SiO2 monolith (1.3 cm in height × 0.8 cm diameter) was submerged in a solution of polyimide resin (50 mg) (CAS: 43656) and Pd(AcO)2 (15 mg) in 2 mL of anhydrous DMF and heated at 50 °C under orbital stirring for 1 h. The monolith was removed from the flask with tweezers and then placed and heated in an oven at 240 °C for 24 h. This protocol was repeated twice. The resulting dark-brownish monolith was treated with an aqueous sodium borohydride solution (8 mL, 0.05 M, dropwise at 0 °C) and stirred at room temperature for 1 h. The resulting black monolith was washed with distilled water, MeOH, and CH2Cl2 and dried under vacuum for 2 h. Catalyst Characterization. The X-ray diffraction (XRD) patterns of CS-Fe3O4 NPs and Cu2O/CS-Fe3O4 NCs were obtained using a Philips diffractometer with Cu Kα radiation (λ = 1.5406 Å), with a step size of 0.02° and counting time of 2 s per step from 10 to 80 (2θ). Fourier-transform infrared spectra (FT-IR) were recorded on a Varian FT-IR 670 spectrophotometer in the range of 400−4000 cm−1.

The morphology of the sample was characterized by scanning electron microscopy (SEM) using a Zeiss FE-SEM ULTRA Plus (30 kV) microscope and transmission electron microscopy (TEM) using a JEOL JEM-1011 microscope operating at 100 kV. Total Fe and Cu determinations were performed with a NexION 300X ICP-MS system (Perkin-Elmer). The magnetization curve of the products was obtained by using a vibrating sample magnetometer (VSM) with an applied field between −10000 and 10000 Oe at room temperature. The microstructural surface morphology of the 3D-printed SiO2 catalyst was examined by SEM (JEOL 6400, JEOL Corp., Japan). Mapping SEM for C and Pd was performed with a Zeiss FesemUltraplus apparatus. Optical microscopy was performed on an Olympus SZX12 stereomicroscope (Olympus, Japan). Specific surface area measurements of the 3D-printed monoliths were performed according to the Brunauer−Emmett−Teller (BET) nitrogen adsorption method at 77 K in a Gemini 2360 porosimeter (Micromeritics, USA). The chemical composition of the catalysts was evaluated by energy dispersive X-ray spectrometry (AZTEC/ Xact, Oxford, U.K.). Palladium loading in the monolith was determined by inductively coupled plasma optical emission spectroscopy (ICP-OES, Varian Liberty 200). FT-IR was performed on a Varian FT-IR 670 spectrophotometer. The oxidation states of Pd were determined by X-ray photoelectron spectroscopy (XPS) using a Physical Electronics PHI 5700 spectrometer with nonmonochromatic Mg Kα radiation (300 W, 15 kV, 1253.6 eV) as the excitation source. High-resolution spectra were recorded at a 45° take-off angle by a concentric hemispherical energy electron analyzer, operating in the constant pass energy mode at 29.35 eV, using a 720 μm diameter analysis area. Charge referencing was measured against adventitious carbon (C1s at 284.8 eV). Acquisition and analysis of the data were performed by a PHI ACCESS ESCA-V6.0 F software package. Gauss−Lorentz curves (maximum 20% Lorentz) were used for the fitting of the recorded data. Evaluation of the Catalytic Activity. Kimble vials in a PLS (6 × 4) organic synthesizer (Figure S1) were used to perform the azidation, CuAAC, Suzuki, and multicatalytic one-pot reactions. Polystyrene-supported TBD (PS-TBD, 2.6 mmol g−1), 4-iodophenylboronic acid pinacol ester, and the rest of the boronic acids and alkynes were purchased from Sigma-Aldrich. Polyimide resin (CAS: 43656) was purchased from Alfa Aesar. Monitoring of all reactions was performed by TLC with 2.5 mm Merck silica gel GF 254 strips. The final purified compounds showed a single spot. Detection of compounds was performed by UV light and/or iodine vapor. Purification of isolated products was carried out by preparative TLC using silica gel plates. Characterization of the synthesized compounds was performed by spectroscopic and analytical data. The NMR spectra were recorded on Bruker AM 300 MHz (1H) and 75 MHz (13C) and XM500 spectrometers. Chemical shifts are given as δ values against tetramethylsilane as the internal standard. J values are given in hertz. Proton and carbon nuclear magnetic resonance spectra were recorded in CDCl3 or DMSO. EPR experiments were performed on a Bruker EMX spectrometer. Melting points were determined on a Gallenkamp apparatus and are uncorrected. Mass spectra were obtained on a Varian MAT-711 instrument. High-resolution mass spectra (HR-MS) were obtained on an Autospec Micromass spectrometer. General Procedures for Single Catalytic Reactions. Synthesis of Compound 2 by Chan−Lam-Type Azidation. In a coated Kimble vial were dissolved sodium azide (0.55 mmol) and 4-iodophenylboronic acid (1a) or boronate (1b) (0.5 mmol) in MeOH (8 mL). The capsule containing PS-TBD-Cu(II) (100 mg, 0.26 mmol TBD) was added, and the mixture was heated at 70 °C for 3 h. The capsule was removed from the solution with tweezers. 1-Azido-4-iodobenzene was isolated by careful evaporation of the solvent in a rotavapor. Synthesis of Compound 3a by CuAAC. In a coated Kimble vial were dissolved 1-azido-4-iodobenzene (0.5 mmol) and phenylacetylene (0.5 mmol) in MeOH (5 mL). To this solution was added the Cu2O/CS-Fe3O4 NCs (10 mg, 61% Cu w/w). The mixture was orbitally stirred for 4 h at room temperature. The white solid formed in the vessel was dissolved in AcOEt. Cu2O/CS-Fe3O4 NCs 25285


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ACS Applied Materials & Interfaces were retained in the vessel by the application of a magnet on the walls, and Cu2O/CS-Fe3O4 NCs were washed with MeOH before reuse. The organic phase was placed in a flask, washed with water, and dried with anhydrous Na2SO4. The solvent was removed under reduced pressure, and the resulting solid was recrystallized (iPrOH) to give compound 3a as a white solid (95%). Synthesis of Compound 4a by Suzuki Reaction. In a coated Kimble vial, the iodotriazole 3a (0.5 mmol), DIPEA (2.5 mmol), and phenyl boronic acid (0.6 mmol) were dissolved in MeOH (5 mL). The 3D-SiO2-PI-Pd catalyst was added (total Pd content on monolith: 1.6 mg, 3 mol % Pd in the reaction) to this solution. The mixture was heated at 90 °C under orbital stirring for 2 h until the starting material was consumed. The mixture was allowed to cool. Then the vial cap was removed, and the monolithic catalyst was extracted with tweezers and sonicated and washed with EtOH/ CH2Cl2/H2O for reuse. The reaction mixture was washed with H2O. The organic phase was extracted with EtOAc and dried with anhydrous Na2SO4. The solvent was removed in the rotavapor. The resulting solid was purified by recrystallization (iPrOH) to give compound 4a as a colorless solid (92%). General Procedure for One-Pot Chan−Lam Azidation + CuAAC + Suzuki Reaction (Synthesis of Compounds 4a−4f). In a coated Kimble vial (2 cm diameter), sodium azide (0.6 mmol) and 4iodophenylboronic acid or boronate (0.5 mmol) were dissolved in MeOH (8 mL). A capsule containing PS-TBD-Cu(II) (100 mg, mmol) was added to the vial. The mixture was heated at 70 °C for 2 h until the boronic acid was consumed. The capsule was then removed from the solution with tweezers, sonicated and washed with EtOH/ CH2Cl2/H2O, and dried under vacuum for reuse. To the resulting vial containing the in situ 4-iodophenyl azide were added the corresponding alkyne (0.6 mmol) and the magnetic Cu2O/CSFe3O4 NCs (10 mg), and the mixture was stirred at 40 °C for 4−5 h. After checking the reaction course by TLC and once the iodotriazole intermediate formed, the Kimble vial was turned upside down, and the magnetic nanoparticles were recovered by means of a magnet placed externally on top of the Kimble vial. The nanoparticles were adhered to the internal rubber membrane of the Kimble vial and were available for reuse in another reaction. The vial cover was replaced with a clean one, and the last step of the process was carried out, namely, the Suzuki reaction: the corresponding arylboronic acid (1.2 mmol) and DIPEA (2.5 mmol) were added to the solution. A 3DSiO2-PI-Pd (Pd content: 1.6 mg, 3 mol % Pd) monolithic catalyst was added, and the mixture was heated at 90 °C for 2−6 h until the iodotriazole intermediate was consumed. The palladium catalyst was then removed with tweezers; washed in water, methanol, and dichloromethane; and stored in vacuo for reuse. The reaction mixture was washed with water and extracted with EtOAc. The organic phase was dried with anhydrous Na2SO4, the solvent was removed under reduced pressure, and the resulting product was purified by preparative TLC to give compounds 4a−4f.

Figure 1. (a) Photograph of the 3D printing process used to form the capsule for the entrapment of PS-TBD-Cu(II) (green powder). (b) Detailed optical micrograph of PS-TBD-Cu(II) before encapsulation. Tailor-made capsule for a Kimble vial: (c) front view, details of the capsule showing the polypropylene border sealed during the 3D printing process with the polymer PS-TBD-Cu(II) inside. The chemical structure of PS-TBD-Cu(II) is shown. (d) The capsule is shown in the reaction vial (2.5 cm diameter) in the solvent (MeOH).

Cu(AcO)2 in DMF and stirring the mixture overnight. The yellowish polymer takes a marked greenish color (Figure 1). The copper was detected and quantified by XRD, and this indicated the presence of 1.36% Cu (w/w). An EPR experiment showed the characteristic signal of the paramagnetic Cu(II). 3D Printing for Polypropylene Capsule Fabrication. The manufacture of a polypropylene capsule containing a polymersupported reagent is an innovation of the well-known ‘Tea bag method’.35 In this work, we present an innovative, costeffective, simple, and practical porous capsule for the entrapment of the supported reagent PS-TBD-Cu(II). The capsule was designed by CAD and synthesized by 3D printing with the aim of miniaturizing and minimizing the workup operations. The PS-TDB-Cu(II)-loaded capsule was produced by packing 100 mg of an easily synthesized PS-TDB-Cu(II) inside a 3D-printed device (Figure 1), which served as a protective envelope. The 3D printing process for the capsule was carried out using the fused deposition modeling technique. This capsule contained a permeable polypropylene membrane (porous area, Figure 1) that allowed the flow of reagents and solvent and access to a polymeric reagent located inside [PSTBD-Cu(II)] but at the same time preventing its exit. This device has excellent resistance to the conditions of temperature (70−80 °C), reagents, and solvents required for the azidation of boronic acids. In addition, the use of this system facilitates the workup process through extraction by tweezers. As can be seen in Figure 1, the shape and size are adapted to the dimensions of the desired reactor (Kimble vial). The 3D printing of polypropylene in the manufacture of chemical reactionware has been described by Cronin and coworkers.26 This material has considerable advantages, such as its high resistance to attack by chemicals or solvents and its thermal stability.36 However, the preparation of custom pieces using this material is a challenge, mainly due to the high degree of polypropylene crystallinity, which makes this material very

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RESULTS AND DISCUSSION Design, Preparation, and Characterization of the Catalysts. The design of the tricatalytic system described here followed an overall strategy based on the achievement of efficient, robust, practical, and easily recoverable and compartmented heterogeneous multicatalytic systems and their application in drug synthesis and sustainable chemistry. Synthesis of Cu(II)-TBD on Polystyrene. Commercially available polymer-supported bases (on silica or polystyrene supports) show the potential advantages of the use of those incorporating the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) framework (Figure 1). The choice of this superbase was based on the well-documented availability of TBD as well as our experience in using this reagent34 to act as an effective ligand for copper by coordination of Cu(I) and Cu(II) species. This coordination can be carried out easily by adding PS-TBD (TDB on polystyrene, 2.6 mmol g−1) to a solution of 25286


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Figure 2. (a) XRD patterns: Fe3O4 and Cu2O diffraction peaks are labeled as “*” and “+”, respectively. (b) FT-IR spectra. (c) Scanning electron microscopy images. Transmission electron microscopy images of (d) CS-Fe3O4 NPs and (e) Cu2O/CS-Fe3O4 NCs. (f) EDX spectra of Cu2O/CSFe3O4 NCs. (g) Magnetization curves of both samples.

CS-Fe3O4 NPs spectra show the characteristic bands of −NH2 and −OH groups, the C6−O vibration of chitosan, and the Fe−O bond of Fe3O4, thus indicating that Fe3O4 in CS-Fe3O4 NPs was formed in situ. In contrast with CS-Fe3O4 NPs, several peaks were shifted noticeably in the FT-IR spectrum of Cu2O/CS-Fe3O4 NCs, and new peaks at 1591 and 1450 cm−1 indicate that the amino group and the hydroxyl groups were involved in complexation during the preparation of Cu2O/CSFe3O4 NCs.37 Additionally, the peak related to the Cu−O bond was observed, and this indicates that Cu2O was formed successfully. The morphology and size of Cu2O/CS-Fe3O4 NCs were studied by SEM and TEM. An SEM image of the Cu2O/CSFe3O4 NCs is shown in Figure 2c. It was very easy to distinguish between these two kinds of particles in the hybrid material due to their different shapes and sizes. The smaller particles (5−7 nm) belong to the Fe3O4 nanospheres (see Figure 2d), while the larger particles (125 nm) belong to the cubic Cu2O (see Figure 2e). The presence of the elements Fe, Cu, and O was further confirmed by energy-dispersion X-ray spectrometry (EDX) (see Figure 2f). The amounts of Fe3O4 and Cu2O were determined by ICP-MS, and the sample is composed of 39% Fe3O4 and 61% Cu2O. In Figure 2g, the typical hysteresis loops of the as-prepared CS-Fe3O4 NPs and Cu2O/CS-Fe3O4 NCs can be observed. It was concluded that these species were both superparamagnetic owing to their almost zero coercivity and zero remanence in the magnetization curve and also because the saturation magnetization value of Cu2O/CS-Fe3O4 NCs (15.34 emu g−1) was weakened to some extent compared to that of CS-Fe3O4 NPs (27.85 emu g−1). However, the value is high enough for the material to be separated by an external magnet. In the absence of a magnetic field, the Cu2O/CS-Fe3O4 NCs dispersed well in aqueous solution. However, when an external magnet was applied, the particles were attracted quickly to the

prone to the warping phenomenon during the 3D printing process. In addition, polypropylene is very difficult to adhere and fix to the base of the printer. Collectively, these characteristics mean that 3D printing of polypropylene involves a careful choice of 3D printing parameters (temperature, flow, speed, etc.). For this reason, in this work, we made some modifications to the standard printing conditions for polypropylene (see Figure S2). 3D printing of polypropylene enables the construction of capsules containing supported regents, depending on the measurements of the reactor. Thus, it is possible to print capsules with different sizes depending on the quantity of the product required for synthesis, simply by scaling or changing the virtual design. Synthesis of Cu2O/CS-Fe3O4 Magnetic Nanocomposite. We selected a nanocomposite due to its high surface area, and this was composed of the magnetic Fe3O4 cores to ensure a magnetic response and a chitosan shell to provide active functional groups that chelate copper ions and make it a precursor for the synthesis of Cu2O. Ascorbic acid was also added to ensure the stability of Cu2O. The phase structure and crystallinity of as-prepared CSFe3O4 NPs and Cu2O/CS-Fe3O4 NCs were investigated by XRD, and the results are shown in Figure 2a. The XRD pattern of CS-Fe3O4 NPs contained the peaks of the crystalline Fe3O4 phase (JCPDS 79-0417). In addition to the typical peaks of Fe3O4, new peaks were identified in the XRD pattern of Cu2O/ CS-Fe3O4 NCs that were indexed to the Cu2O phase (JCPDS 05-0667). These results reveal that Cu2O particles were formed in situ, and the crystal structures of Fe3O4 and Cu2O remained unchanged in the composites. Moreover, the intensities of the diffraction peaks of Cu2O were much higher than that of Fe3O4 in the XRD pattern of Cu2O/CS-Fe3O4 NCs, possibly due to the high crystallinity of the Cu2O phase and the lower content of Fe3O4, as confirmed by subsequent ICP-MS and EDX analysis. The FT-IR spectra of CS-Fe3O4 NPs and Cu2O/CS-Fe3O4 NCs are shown in Figure 2b. The 25287


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Figure 3. (a) As-prepared woodpile structure of SiO2. Optical images of the 3D-SiO2-Polyimide-Pd structure: (b) top view and (c) side top view images. (d) Cross section of the monolith where functionalization is observed only on the surface of the bars. Mapping of carbon (green) and palladium (red) distribution on the sample surface: (e) low- and (f) high-magnification images. (g) SEM image of the PI-Pd composite on the monolithic silica surface. (h) IR spectra of the monolith surface before and after functionalization. (i) Chemical structure of the polyimide and EDS spectrum for 3D-SiO2-PI-Pd. (j) XPS of the SiO2-PI-Pd monolithic surface after thermal treatment and (k) after NaBH4 treatment.

sintering29 in which the metal species are also inside the mass of the support and therefore not accessible to the reagents and solvents. On the other hand, we designed and carried out a simple and effective procedure for the immobilization of the palladium species on the monolith surface by chemical modification of the silica surface by using a polyimide resin and a palladium source as an effective coating. Therefore, the synthesis of the 3D-SiO2-PI-Pd monolith was carried out in two stages: (1) 3D printing and sintering of the silica support and (2) subsequent surface modification of the sintered silica monolith with a polyimide-palladium (PI/Pd) composite. 3D printing of a silica monolithic support: A SiO2-based ink was extruded to assemble interconnected 3D-monolithic structures with cylindrical symmetry. As in our previous

location of the magnet in a few minutes, and they could be redispersed easily once the magnetic field was removed. Synthesis of the 3D-SiO2-Polyimide-Palladium Monolithic Catalyst. The design and synthesis of a monolithic catalyst by 3D printing was motivated by the convenience of a robust solid catalytic system that is easily separable and reusable. Furthermore, such a system provides the possibility of modulating the shape and size as desired to adapt the catalyst to a particular reactor. We prioritized two important aspects in the design of this catalyst: On the one hand, as previously commented, the presence of catalytic species only on the surface of the monolith minimizes the cost of production and avoids sintering after metalation. Therefore, the strategy carried out here is an alternative to other composite metal− ceramic materials obtained by robocasting and further 25288


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as the metal source. A subsequent thermal treatment (240 °C) fixed the PI-Pd composite to the ceramic surface. The attachment of a PI-Pd composite on the silica surface occurred readily after sinking a sintered silica monolith into a solution of polyimide resin (CAS: 43656) and palladium acetate in anhydrous DMF, with stirring at 50 °C for 1 h. After thermal treatment at 240 °C, the color of the monolith became brown/ black. The use of other solvents (DCM, MeCN) for the attachment of the PI-Pd composite gave poor results. Optical images of the functionalized 3D-SiO2-PI-Pd catalyst after functionalization of the silica support are shown in Figure 3a− d. It can be seen from the figures how the color of the structure changes after functionalization. The dark brown color of the 3D-SiO2-PI-Pd is due to the presence of Pd, which increases after the final aqueous treatment with dilute NaBH4 to promote the formation of Pd(0) species. The SEM image (Figure 3g) shows the PI-Pd composite and the microporosity of the ceramic material. The elemental composition of the structure surface was determined by energy-dispersive spectroscopy (EDS). The results unequivocally confirmed the presence of Pd (Figure 3i) in the sample. The Si and O peaks correspond to the SiO2 support (substrate), and the C peak corresponds to the carbon content of the polyimide. The palladium loadings on the monolith surface were determined by inductively coupled plasma optical emission spectroscopy (ICP-OES), and the value was 1.6 mg of Pd on the 3D-SiO2PI-Pd monolith (average for 5 monolithic samples). As can be seen in Figure 3d, all of the Pd content is exclusively on the surface of the monolith (BET area for monolith: 0.3 m2/g), thus representing the amount of available metal for the catalytic processes. This represents a percentage of 3 mol % Pd present in each catalytic reaction. The mapping images of the 3D-SiO2-PI-Pd monolith cylinder surfaces are shown in Figure 3e−f. These images show the surface distribution of Pd and C on the SiO2 monolith surface. C and Pd were found to be present throughout the sample with an almost homogeneous distribution along the cylinder surface. The FT-IR spectrum was recorded for all steps in the synthesis of the 3D-SiO2-PIPd (Figure 3h). For the ceramic support SiO2, the adsorption peaks at 467, 807, and 1090 cm−1 correspond to the symmetric and antisymmetric stretching vibrations of the Si−O−Si bond. The polyimide resin spectrum contains the aromatic stretching bands at around 2900 cm−1, the characteristic NH stretching band in the region 2800−2900 cm−1, and the amide I, II, and III bands at 1690, 1640, and 1240 cm−1. Deposition of the polyimide resin on the monolith surface was confirmed by the joint appearance of the characteristic polyamide and SiO2 bands. Finally, the IR spectrum of the 3D-SiO2-PI-Pd composite retained the polyamide/monolith main bands, but these were slightly shifted, probably due to the presence of palladium in the material, which was mainly deposited as Pd(0). These IR findings reveal that the application of successive treatments on the polyimide does not alter its integrity, thus confirming the success in synthesizing the 3DSiO2-PI-Pd composite. XPS experiments were carried out to determine the oxidation state of palladium at two stages. The Pd 3d XPS profiles for the SiO2-PI-Pd monolith after thermal treatment and reduction (NaBH4) are compiled in Figure 3j−k. According to the literature,40 two main peaks can be observed: the first one at 335.2 and 340.4 eV was assigned to metallic Pd, while the other doublet at 337.1 and 342.4 eV belongs to the Pd(II) oxidation state. Other elements like Si, N, O, and C

work,25 SiO2 was selected as an ideal material for the support since (in addition to its excellent surface properties) silica can be easily extruded by 3D printing. The printed structures were designed as cylindrical woodpile with the geometry adapted to the dimensions of the Kimble vial in which the reactions were carried out (Figures 3a−d and 4).

Figure 4. General strategy for Cu(II)/Cu(I)/Pd(0) one-pot sequential multicatalysis.

The printed structures were dried and calcined at high temperature (1500 °C). This thermal treatment provides chemical stability and sufficient mechanical strength. Polymers and solvent were removed from the monolithic structure during the sintering process. The structures have suitable mechanical strength allowing numerous catalytic reactions to be performed under orbital stirring. The peaks of the crystalline cristobalite phase of SiO2 are observed in the XRD pattern (JCPDS 89-3434) of the calcined structure at 1500 °C (Figure S3). These images reveal the interconnected pores with a homogeneous periodicity and without defects or cracks. The sintered support resulted in a rod diameter of 307 μm and an inter-rod spacing of 607 μm. It means an open porosity, that is, the distance provided by the gaps in the grid, of ∼50%. Surface chemical modification: The use of polyimide resin (CAS: 43656)38 was our starting point for the substrate modification and formation of a PI-Pd composite coating (Figure 3). Polyimides are extremely stable under harsh conditions (temperature, solvents, reagents) and tend to be deposited as polymeric films. This provides total coverage and maximizes the introduction of organic functionality.39 Furthermore, silica forms stable products with polyimide films. The polyimide resin 43656 is a solid powder that contains an indane moiety. It is fully imidized, thus eliminating the need for high-temperature processing, and is soluble in a variety of solvents. Evaporation of the solvent leaves strong, durable, and tough coating films that have excellent chemical resistance. The methodology described in this work was employed to perform the functionalization of the ceramic surface (SiO2) and the metalation in the same step by impregnation of the monolith using a soluble polyimide resin and palladium acetate 25289


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ICP-MS analysis (on the final isolated products), although the presence of homogeneous copper species was detected during our CuAAC experiments with PS-TBD-Cu(II). These results confirmed the excellent stabilizing profile of this superbase, enabling the copper(II) species to remain fixed on the polymeric solid support. The synthesis of the PS-TBD-Cu(II) is very simple and involves stirring PS-TBD into a solution of Cu(OAc)2 in DMF. The complete coordination of the copper to the polymeric reagent takes place over 10−12 h to give a green resin. Copper loading (1.36%) was quantified by wavelength dispersive X-ray fluorescence spectrometry (WDXRF). Once the synthesis of PS-TDB-Cu(II) was made, the catalytic performance was evaluated in the azidation of boronic acids or boronates as model reactions. On the basis of the results for copper loading, the quantity of superbase was adjusted to the reaction conditions. The catalytic activity of the PS-TBD-Cu(II) is shown in Table 1. MeOH worked well at a

were also detected in the survey XPS spectra. The XPS trace after treatment with dilute NaBH4 is shown in Figure 3k. Almost complete reduction of Pd(II) to Pd(0) species is evident. These changes in the superficial structure suggest that the SiO2-PI-Pd monolith is an active and robust catalyst for the Suzuki reactions as this process is favored by Pd(0). All of the XPS, FT-IR, EDS, and mapping distribution results, together with the absence of palladium leaching, demonstrate that the PI-Pd composite covers the SiO2 monolithic surface. Evaluation of the Performance of the Catalytic System. We describe here the development of efficient and operationally simple transformations that allow the rapid assembly of diverse libraries of biphenyl-1,2,3-triazoles from simple and readily available starting materials. The process involves sequential one-pot reactions that employ three compartmentalized catalytic systems based on transition metals (Cu2+, Cu+1, Pd0) immobilized on three different supports. The general scheme for the synthetic strategy can be seen in Figure 4. The processes exemplify the synergic exploitation of key concepts of modern organic synthesis (e.g., click chemistry, multicatalytic reactions, supported reagents, surface chemical functionalization of solid supports, and catalyst compartmentation). This work was divided into two phases: (i) optimization of the reaction conditions for each catalytic process and (ii) the unification of the optimized conditions in a one-pot process to merge the conditions for three catalytic transformations. First, we evaluated the catalytic efficiency of a device that immobilized copper(II) species to carry out the azidation of boronic acids or boronates (Chan−Lam-type coupling).41 The second process consisted of the design of magnetic nanoparticles that immobilized Cu(I) species and their catalytic evaluation in CuAAC, using the aryl azides formed in the previous step, to obtain 1-(4-iodophenyl)-1H-1,2,3-triazoles 3, in the presence of an alkyne without any other additive (reductant). The conversion of iodo-phenyltriazoles 3 into substituted 1-([1,1′-biphenyl]-4-yl)-1H-1,2,3-triazoles 4a−4f was studied through the Suzuki reaction, using a silica monolith containing palladium species immobilized by polyimide onto a surface. The final stage of the work consisted of the study of the ideal conditions to carry out these transformations in a one-pot version and also the individual recovery of the tricatalytic system. Key aspects such as the compatibility of reagents in solution, different bases, and solvents were evaluated. The azidation of arylboronic acids or boronates is a suitable procedure for the construction of arylazides, which are very valuable substrates to carry out further CuAAC in the presence of alkynes. Organic azides are characterized by their instability and explosive nature under certain conditions. Therefore, procedures that provide in situ azides are in high demand. The Chan−Lam-type azidation uses Cu(II) species as the catalyst and oxidizing environments to favor the course of the reaction. During the optimization process, we tested different supported reagents for the immobilization of Cu(II), including Amberlite IR120 Na+ form (IR-120), p-toluenesulfonic acid (Ps-TsOH), or diethylamine on polystyrene (PS-DIEA). The supported superbase PS-TBD gave the best results (effectiveness and absence of meaningful leaching). The 1,5,7triazabicyclo[4.4.0]dec-5-ene (TBD) framework supporting copper species [TBD-Cu] showed to be an ideal candidate due to the excellent stabilizing profile of guanidine to copper by coordination. No leaching of copper was verified by the

Table 1. Optimization of the Azidation of Boronic Acids or Boronates (Chan−Lam Coupling)

entry

B(OR)2

support

yield (%)a

1 2 3 4 5

B(OH)2 B(OH)2 B(OC3H6)2 B(OC3H6)2 B(OC3H6)2

PS-IR-120-Cu(II) PS-TBD-Cu(II) PS-TBD-Cu(II) PS-TBD-Cu(II)b PS-TBD-Cu(II)b,c

10 95 97 95 92b

a

Isolated yields. All reactions were performed using sodium azide (0.5 mmol), 4-iodophenylboronic acid or 4-iodophenylboronic acidpinacol ester (0.5 mmol), and PS-TBD-Cu(II) (100 mg, 0.26 mmol) in MeOH for 1 h. bYield after 3 h, using a 3D-printed capsule (containing 100 mg PS-TBD-Cu(II), i.e., 1.36 mg of Cu(II)) c Isolated yield with the reused device.

temperature of 70 °C. Interestingly, although PS-TBD has been reported as an effective scavenger for boronic acids,42 we did not detect boronate or boronic acid scavenging by PSTBD-Cu(II) during the azidation reaction, probably due to the fact that the coordination of TBD and copper prevents this entrapment. Once we had verified the effectiveness of PS-TBD-Cu(II) in the azidation reaction, the reactivity was evaluated when the metal species was trapped in the polypropylene capsule. To our satisfaction, significant differences were not observed in terms of catalytic performance (Table 1) with respect to the reagent without the capsule, although a longer reaction time was necessary (3 h) to complete the azidation. The capsule was not deformed, swollen, or fractured by the effect of temperature, solvent, or the reagents studied. The capsule did not allow the exit to the reaction medium of the PS-TBD-Cu(II) inside, and it was easily removed with tweezers from the reaction medium once the azidation was complete. The capsule could also be reused several times. Catalytic Optimization for Single CuAAC and Suzuki. The effectiveness of the magnetic nanoparticles in CuAAC was evaluated. Our efforts were focused on obtaining optimum yields without leaching under simple conditions for CuAAC without any other additive (reducing agent) as well as 25290


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ACS Applied Materials & Interfaces obtaining sufficient magnetism in the ferrite substrate to be able to separate the material in the workup process. Three samples of Cu2O/CS-Fe3O4 NCs with different Cu2O contents were evaluated in CuAAC using 1-azido-4-iodobenzene 2 as the model substrate with terminal alkynes (Table 2). The

Table 3. Catalytic Activity of SiO2-PI-Pd Monolith: Optimization for Suzuki Reactions

Table 2. Catalytic Activity of Fe3O4-Cu2O Nanoparticles: Optimization for CuAAC

a

entry

base

solvent

yield (%)a

1 2 3 4 5 6 7

TEA DIPEA K2CO3 TEA DIPEA DIPEA DIPEA

DMF DMF t-BuOH/H2O t-BuOH/H2O t-BuOH/H2O MeOH MeOH

85 87 70 88 92 92 90b

Isolated yields at 90 °C for 2 h. bYield with reused 3D-SiO2-PI-Pd.

were not observed after two or three cycles and significant leaching did not occur (8 ppb). In addition, fractures and polymer shedding along the surface of the monolith were not observed (SEM) after catalysis, and this shows the stability and robustness of the PI-Pd composite. Collectively, these results demonstrate the efficiency and mechanical resistance of these catalysts in simple reactions under orbital agitation. Having confirmed the efficiency of each catalytic system during the optimization processes described above, we attempted the complete one-pot process (sequential azidation + CuAAC + Suzuki reactions) in MeOH. The results are provided in Table 4. The first process (azidation) occurred very satisfactorily, and the capsule was easily removed from the reaction mixture using tweezers after the consumption of the iodophenyl boronic acid in the first step. The simple extraction of the capsule avoids the presence of Cu(II) species in the second step (CuAAC). When present in significant amounts, the ability of Cu(II) to mediate the Glaser-type alkyne coupling process (during CuAAC) can result in the formation of undesired by-products while impairing triazole formation.43 The addition of magnetic Cu2O/CS-Fe3O4 NCs and an alkyne gave the corresponding 1,2,3-iodotriazoles 3 in high yields as single products in 4−5 h. As shown in Figure 4, the synthetic one-pot strategy proposed here would involve the coexistence of a Cu(I), a boronic acid, and a Pd(0) catalyst in the final step. However, copper is known to insert into the carbon−boron bond,44 which leads to useful coupling reactions when desired,41 but boronic acids have very different stabilities in the presence of Cu(I) and Cu(II). As a consequence, when the Suzuki reaction is carried out in the presence of copper species, the coupling reaction often does not occur efficiently due to deactivation of the boronic acid by boron−copper coordination. For this reason, prior to the Suzuki step, the nanoparticles were scavenged from the reaction medium, thus avoiding the interaction with the boronic acid in the last step and the heating of the nanoparticles at high temperatures, which could eventually have an adverse effect on the particles. An external magnet was used to scavenge the chitosan ferromagnetic nanoparticles (Figure S4), and these were easily recovered. The 3D-SiO2-PI-

a

Isolated yields. All reactions were performed using 1-azido-4iodobenzene (0.5 mmol), alkyne (0.5 mmol), and Cu/CS-Fe3O4 NCs (10 mg) in MeOH (5 mL) at 40 °C. bSample 1 (23% Cu1+) was used. cSample 2 (28% Cu1+) was used. dSample 3 (61% Cu1+) was used. eIsolated yield with reused Cu2O/CS-Fe3O4 NCs (sample 3).

results are shown in Table 2: sample 1, containing Cu(II): 26% (CuO), Cu(I): 23%, and Fe3O4: 51%, sample 2, containing Cu(I): 28% and Fe3O4: 72%, and sample 3: Cu(I): 61% and Fe3O4: 39%. In these studies, equimolar amounts of the reactants were treated with the nanoparticles at different copper loadings. The reactions were subjected to orbital stirring at 40 °C for the required time (4−5 h), and the effect of a range of solvents (MeOH, t-BuOH, DMF) on the reaction outcome was also investigated. The results of this optimization process revealed that the presence of stabilized Cu(I) species is essential for the transformation to take place efficiently. In addition, a magnetite percentage of 39% is sufficient to ensure catalyst recovery after the reaction by applying a neodymium magnet. Therefore, on using sample 3 (Cu2O/CS-Fe3O4 NCs), CuAAC proceeded to give high yields in MeOH. Other solvents such as t-BuOH or H2O also worked well (data not shown). The Suzuki reaction is widely used in the synthesis of biomolecules and is preferred to the Stille reaction, which suffers from the inherent toxicity of tin. Boronic acids are in many aspects ideal partners in TMCRs. The organoboron derivatives frequently exhibit air and water stability at ambient temperature and have low toxicity. The reaction conditions initially studied for the evaluation of the SiO2-PI-Pd monolith in the Suzuki reaction included the use of 2.5 equiv of organic (N3Et, DIPEA) and inorganic (K2CO3) bases as well as solvents that were compatible with the reaction medium and with the transformations previously studied. The model reaction between iodotriazole 3a and phenylboronic acid occurred satisfactorily at 90 °C under orbital agitation (Table 3). A crucial finding in these initial experiments was that changes in the catalytic behavior of the 3D-SiO2-PI-Pd catalyst 25291


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ACS Applied Materials & Interfaces Table 4. Cu(II)/Cu(I)/Pd(0) Multicatalytic Sequential One-Pot Reactions

All reactions were performed in 2.5 × 5 cm coated Kimble vials (Figure 4). bt-BuOH was added in the last step (Suzuki) as the cosolvent.

a

Pd catalyst was subsequently added and the Suzuki transformation proceeded efficiently after 2−6 h. Reusability, Leaching Studies, and Characterization after Catalytic Performance. Recycling studies were carried out using the general procedures for single azidation of boronic acids [PS-TBD-Cu(II)], CuAAC (Cu2O/CS-Fe3O4 NCs), and Suzuki (3D-SiO2-PI-Pd) transformations, with the synthesis of compounds 2, 3a, and 4a as model reactions (runs), respectively. After completing the reactions, each catalyst was easily removed from the reaction mixture. The results of the recycling process are provided in Table S1. The reusability of PS-TBD-Cu(II) was evaluated after washing the capsule containing the polymer with dichloromethane, MeOH, and diethyl ether. Although the polymer changed from green to black, the reused device was effective for at least 10 runs without a significant loss of yield (Table S1). EPR experiments demonstrated that the reduction of Cu(II) species did not occur in the catalytic system. The superimposed EPR spectra obtained for a representative catalyst of the initial (green powder) and final (black powder) samples are shown in Figure 5. These results suggest the prevalence of copper(II) species within the material. In addition, one polypropylene capsule resisted after 10 reactions (Figure S4). Separation of Cu2O/CS-Fe3O4 NCs from the reaction mixture was easily performed by the application of a magnet to the external wall of the vessel. This scavenging can also be performed by applying the magnet to the cap closure of the vial. In this way, the nanoparticles can be easily recovered from the upper part of the vial, adhered to the internal Kimble rubber membrane (Figure S4). The magnetic nanoparticles were washed with MeOH and dichloromethane and reused at least 10 times (see Table S1) in the synthesis without significant changes in physical appearance, magnetic properties, or oxidation states for copper after catalysis. In addition, the percentage of Cu2O in a sample of particles reused 10 times was very similar to that of the initial sample (57% Cu2O and 43% Fe3O4), which indicates that the Cu(I) species are

Figure 5. (a) EPR experiment showing the characteristic signal of the paramagnetic Cu(II) state for PS-TBD-Cu(II) before (top) and after (bottom) catalysis. (b) X-ray powder diffraction spectra of the Cu2O/ CS-Fe3O4 nanocomposite before (bottom) and after (top) catalysis. Significant changes were not observed after the catalytic reactions.

stable without the need for any extra additive during the CuAAC (Figure 5). The 3D-SiO2-PI-Pd catalyst was easily removed from the reaction mixture with tweezers, and it was exhaustively washed with H2O, EtOH, and CH2Cl2. Prior to reuse, the catalyst was dried under vacuum at room temperature. This monolithic catalyst could be recycled and reused at least 10 times in Suzuki transformations without a noticeable drop in the 25292



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product yield or catalytic activity. In the same way, when multicatalytic reactions were performed, 3D-SiO2-PI-Pd could be reused separately in new reaction cycles. The SEM images of 3D-SiO2-PI-Pd did not show significant changes in the morphology of the monolith surface after carrying out several Suzuki reactions (Figure S3). This finding confirms the robustness and good stability of the monolith after reuse. In order to determine whether our catalysts experienced extensive leaching of active metal species during reactions or fast back redeposition of soluble species on the support, which could eventually lead to the loss of catalytic activity, we performed complementary experiments at two levels. First, elemental analysis (ICP) of the filtrates after each model reaction demonstrated that leaching of Cu (in azidation or CuAACs) by the PS-TBD-Cu(II) in the capsule was almost negligible (0.7 ppm). ICP of Cu2O/CS-Fe3O4 NCs also showed that significant leaching did not occur (

Multicatalysis combining 3D-printed devices and magnetic

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