Proof of Concept: Magnetic Fixation of Dendron-Functionalized Iron

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Proof of Concept: Magnetic Fixation of DendronFunctionalized Iron Oxide Nanoparticles Containing Pd Nanoparticles for Continuous-Flow Suzuki Coupling Reactions Thomas H. Rehm, Anca Bogdan, Christian Hofmann, Patrick Löb, Zinaida Shifrina, David Gene Morgan, and Lyudmila M. Bronstein ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.5b08466 • Publication Date (Web): 19 Nov 2015 Downloaded from http://pubs.acs.org on November 24, 2015

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ACS Applied Materials & Interfaces

Proof of Concept: Magnetic Fixation of DendronFunctionalized Iron Oxide Nanoparticles Containing Pd Nanoparticles for Continuous-Flow Suzuki Coupling Reactions Thomas H. Rehm,*a Anca Bogdan,a Christian Hofmann,a Patrick Löb,a Zinaida B. Shifrina,b David G. Morgan,c and Lyudmila M. Bronsteinc,d a

Fraunhofer ICT-IMM, Continuous Chemical Engineering Department, Carl-Zeiss-Straße 18-20,

55129 Mainz, Germany. b

A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28

Vavilov St., Moscow, Russia. c

Indiana University, Department of Chemistry, 800 E. Kirkwood Av., Bloomington, USA.

d

King Abdulaziz University, Faculty of Science, Department of Physics, Jeddah, Saudi Arabia.

KEYWORDS: magnetic immobilization, continuous-flow microreactor, dendron, palladium nanoparticles, Suzuki coupling.

ACS Paragon Plus Environment

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ABSTRACT: A new concept for the magnetic immobilization of catalytically active material has been developed for continuous-flow Suzuki cross coupling reactions. The reversible immobilization of the magnetic catalyst material inside a novel capillary microreactor has been achieved by utilizing a newly designed reactor housing with 208 small permanent magnets. As a catalyst material, magnetic Fe3O4 nanoparticles decorated with polyphenylenepyridyl dendrons and loaded with Pd nanoparticles have been employed. Both batch and continuous-flow experiments prove the activity of the catalyst and the applicability of this new microreactor concept.

Introduction Transition metal catalyzed carbon-carbon coupling reactions are fundamental synthetic strategies to construct complex organic molecules. Palladium is the most commonly used precious metal to activate precursor molecules prior to the desired coupling steps.1 A large variety of ligand systems allows the delicate control over the activity and selectivity of the noble metal center.2,3 The progress throughout the last decades has made this type of chemical transformation one of the most productive and active research areas, finally awarded with the Nobel Prize in 2010 for the development of palladium catalyzed cross coupling reactions.4 Besides homogenously catalyzed cross coupling reactions with molecular catalysts,5,6 heterogeneous systems have also become a very important branch of scientific research, especially since the development and utilization of nanoparticulate transition metals.7-9 These nanoparticles (NPs) can be used as highly reactive catalysts onto so-called “semi-heterogeneous” supports.10 Due to their inherent tendency to agglomerate it is necessary to stabilize NPs with ligand systems. The stabilization of NPs inside a macroscopic matrix allows the easy separation


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from the reaction solution by filtration and, in consequence, a repetitive use of the same catalyst material.11,12 Common matrices can be made of simple polymer chains with high steric hindrance7, amphiphilic block copolymers13, polyelectrolyte systems14-16, high-molecular weight polymers with rigid cavities17, or metal-organic frameworks18. Dendrimers and dendrimer-based structures are another architecture which can stabilize NPs.19 Due to their controlled synthesis they do not exhibit polydispersity like polymers but show a strict and well-defined structure from the core to the outer rim of the periphery. The possibility to generate and stabilize metal NPs inside or around such a defined host molecule allows the direct control over the NP properties by the molecular characteristics of the host.20 In analogy to the easy separation of the polymeric catalyst from the reaction products, dendrimers can be enhanced with magnetic properties by incorporation of iron oxide NPs (i.e., magnetite, Fe3O4).21-23 Strong rare-earth metal magnets can be used to extract magnetic dendrimers from reaction solutions for washing steps and repetitive use of the catalyst.24 This methodology has been widely applied to various magnetic materials as semi-heterogeneous catalytic systems.25-29 Except for recent examples by Reiser30 and Kim31 using magnetite or cobalt nanomagnets for continuous-flow synthesis on the macro- and microscale, magnetic forces have been solely used for the separation of catalyst materials from small batch vessels. With the advent of continuous-flow synthesis and appropriate lab equipment new approaches for catalysis have become possible.32-34 Microstructured mixers and reactors demonstrate better mixing of liquid reagents or improved gas/liquid contact.35,36 A more efficient heat management allows the use of higher concentrated solutions of starting materials while minimizing hot-spot and by-product formation.37 Increased process safety was achieved by shrinking the reaction volume from a big vessel to a small, but continuously running microreactor. With the


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tremendously decreased volume of the reaction solution temperature, and pressure regimes are feasible which would be irresponsible for a classical batch vessel.38 The overall more efficient utilization of starting materials with a decreased solvent consumption is a strong advantage of a continuous-flow synthesis in the microstructured equipment for sustainable chemical processes.39 But in case of catalyst immobilization, some hurdles have to be overcome. For example, the transfer of a batch process with a powder catalyst into the continuous-flow regime might end up with a high pressure drop in the lab plant due to a clogged microreactor. Immobilization of the powder catalyst is possible on a large surface support like metal or ceramic foam pellets, but requires reactor tubes with diameters on the centimeter scale.40 And again increasing the reaction volume requires a sophisticated heat management. These efforts for catalyst immobilization can abolish the advantages of the continuous-flow synthesis in microreactors. Another approach might be the direct attachment of catalyst materials on the wall of capillaries. In case of glass reactors, it is possible to functionalize the channel surface via commonly used silane chemistry in order to incorporate functional groups for anchoring of catalysts.41,42 But what about stainless steel capillaries featuring for instance longer channels than those in glass microreactors? In addition, any error correction during the functionalization process of the channel wall is hardly possible. One might damage expensive lab equipment due to a simple mistake. To overcome these obstacles, a novel continuous-flow microreactor was developed. With this design we demonstrate the magnetic fixation of solid material inside the reactor microstructures via external magnetic forces. This approach allows the non-covalent, reversible immobilization of catalyst materials onto the walls of the microchannels. The excellent catalytic properties of Pd NPs inside the dendron shell of a magnetite nanoparticle were used to prove the catalyst activity


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for continuous-flow Suzuki cross coupling after magnetic immobilization in proof of concept of this new microreactor design. Materials and Methods Materials. Iron(III) acetylacetonate (Fe(acac)3, 99+%) was purchased from Acros Organics and was used as received. Palladium(II) acetate was purchased from Strem Chemicals and also used as received. Benzyl ether (≥98%) was purchased from Sigma-Aldrich and used without purification. Acetone (99.5%) and chloroform (99.8%) were purchased from MACRON Chemicals and used as received. Phenylboronic acid (≥97%), 4-Bromoanisole (≥99%), and potassium carbonate (≥99%) were purchased from Sigma-Aldrich, while 1,4-dioxane was purchased from Carl Roth GmbH; all these reagents were used without purification. Ultrapure water was obtained from a Millipore Milli-Q Plus Water Purification System. Catalyst preparation and characterization. The synthesis of iron oxide NPs in the presence of second generation dendron 1 (Fig. 1) and subsequent formation of Pd NPs was carried out according to the procedure published by us elsewhere.24 The detailed description is given in the Supporting Information. The sample is denoted Pd-Den-Fe3O4.


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Figure 1. Polyphenylenepyridyl dendron 1 as capping molecule for iron oxide NPs and ligand for Pd complexation. Electron-transparent NP specimens for transmission electron microscopy (TEM) were prepared by placing a drop of a dilute dispersion onto a carbon-coated Cu grid. Images were acquired at an accelerating voltage of 80 kV on a JEOL JEM1010 transmission electron microscope. Images were analyzed with the National Institute of Health developed imageprocessing package ImageJ to estimate NP diameters. Between 150 and 300 NPs were used for this analysis. High resolution TEM (HRTEM) images and scanning TEM (STEM) energy dispersive X-ray spectroscopy (EDS) were acquired at accelerating voltage 300 kV on a JEOL 3200FS transmission electron microscope equipped with an Oxford Instruments INCA EDS system. The same TEM grids were used for both analyses. Reactor design. Two reactor designs were chosen: a glass microreactor for visualizing the magnetic immobilization in the channels (MR Lab Serie LTF-V, Little Things Factory GmbH) and a stainless steel capillary uniformly wrapped around an aluminum body for the detailed experiments (Fig. 2, Table 1). The latter was equipped with an integrated heat exchanger in order to apply necessary thermal energy as close to the capillary as possible.


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Figure 2. Microreactor designs used for magnetic fixation: a glass microreactor for visualization of the immobilized catalyst material (a) and a stainless steel capillary reactor with an integrated heat exchanger for proof of concept studies (b). Pictures of fully assembled reactors are shown in Figure S1 in the Supporting Information. The key part of the concept is the reactor housing which carries the permanent magnets. The housing consists of two PEEK plates each carrying 204 small rare-earth metal permanent magnets (NdFeB cubes coated with Ni, edge length: 5 mm, WebCraft GmbH). Both capillary reactors fit into the base plate and are fixed by screws or held tight by the inlet and outlet of the heat exchanger. The top plate is directed by steel pins from the base plate and fixed by the mutual magnetic interactions between the magnets from both plates. Table 1. Material properties and physical dimensions of the microreactors. Reactor type

Material

Total mL

volume, Inner mm

Glass MR

borosilicate

1.7

1

8

Stainless-steel MR

1.4404

3.0

0.89

200


diameter, Max. applicable pressure, bar

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Magnetic fixation of the catalyst material. Prior to any continuous-flow experiments the catalyst material has to be immobilized inside the microreactor. This procedure was done in several steps and used for both reactors (Fig. 3). At first, the reactor was filled with pure solvent mixture (1,4-dioxane/water, 45/55). The catalyst powder (6 mg) was suspended in the same solvent mixture (2 mL) and treated with ultrasound resulting in a fine brownish suspension. The catalyst suspension was then loaded into a glass syringe and connected to the glass microreactor via PTFE tubing. A second glass syringe was loaded with 0.5 mL of a solvent mixture and connected to the outlet of the reactor. At this point it was absolutely crucial to avoid any air bubbles inside the reactor. The interfacial area between the gas slugs and the liquid phase results in a continuous removal of the catalyst material from the capillary wall. This finding is also the reason why any gas-liquid reactions, like hydrogenations, cannot be performed with this novel immobilization method. The suspension was pumped several times through the microchannel in order to achieve a homogeneous distribution of catalyst particles inside the system. After that the reactor was placed into the bottom housing with 104 magnets. Within approx. 30 seconds the available catalyst material inside the microchannel accumulated along the induction lines of the magnets. Then the solvent was pumped again several times through the reactor at low speed in order to fix the residual catalyst material from the syringes to the magnets. During this procedure the solution was becoming colorless. In the case of the glass microreactor combined only with the bottom plate of the housing, all catalyst material is fixed on one side of the microchannel. This was done only for visualization of the immobilized catalyst. By using the bottom and top plates the catalyst material is fixed on both sides of the microchannel resulting virtually in a double surface coated with the catalyst material.


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Figure 3. Immobilization procedure of the magnetic catalyst: the catalyst suspension in a syringe (a), filling the microchannel (b), and magnetic fixation of the catalyst material along the induction lines of the magnet array (c). Detailed pictures of the microreactor channels are shown in Figure S3 in the Supporting Information. Experimental procedure for Suzuki coupling batch reactions. Due to magnetic properties of the catalyst using a standard magnetic stir bar was unwise as the catalyst was attracted to the latter. A rotary evaporator was used instead for continuous shaking and heating in a water bath (Fig. S2, the Supporting Information). The vial containing the reaction mixture was placed in a 50 mL glass flask and fixed inside with a tissue. The flask was then filled with water to ensure the necessary heat transfer from the water bath to the reaction solution inside the vial. The rotation speed was kept constant at 152 rpm for all experiments. The catalyst powder (6 mg) was suspended in an appropriate solution mixture containing the starting materials and base, and sonicated for 5 min. After the desired reaction time the catalyst was fixed on the glass wall of the vial with a strong FeNdB magnet and a sample was taken for the GC analysis. Experimental procedure for the continuous-flow Suzuki coupling reactions. A lab plant was set up using a standard HPLC pump (Smartline 100, Knauer GmbH), a thermostat (cc304, Huber


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GmbH) and a pressure retention valve (Swagelok). Between the outlet of the reactors and the back pressure valve a transparent FEP capillary was placed close to a magnet (NdFeB cuboid coated with Ni, 50 x 15 x 15 mm, WebCraft GmbH) to check the leaching of the magnetic material from the reactor during the flow experiments (Fig. 4). The reaction solution was pumped through the microreactor with a flow rate of 0.2 mL/min resulting in a residence time of 8 min for the glass reactor or 15 min for the stainless-steel reactor. The thermal treatment was applied via a heating bath for the glass microreactor or via the integrated heat exchanger for the stainless steel microreactor.

Figure 4. (a) Lab plant with the installed glass microreactor in full housing. (b) Strong permanent magnet as a trap for potentially leaching magnetite NPs from the reactor during the experiments. Results and Discussion Catalyst characterization. The magnetic properties of the catalyst material result from the intrinsic magnetic response of Fe3O4 NPs decorated with second generation polyphenylenpyridyl dendron 1 (Fig. 1). The dendron is attached on the iron oxide NP surface via adsorption of a carboxyl group and partially pyridyl and phenylene moieties.24 The pyridyl groups of the


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dendron shell were then used to complex palladium (II) species followed by reduction to Pd metal NPs inside the dendron shell (Figure 5). The TEM image (Fig. 5b) shows that iron oxide NPs aggregate upon interaction with Pd species and Pd NP formation, facilitating magnetic separation.

Figure 5. (a) Schematic representation of complexation of Pd species by pyridyl units in dendron shells and Pd NP formation. (b) TEM image of Pd-Den-Fe3O4 after Pd NP formation in the dendron shells. (c) 15 mg of the catalyst material as reversible glue for sticking a vial upsidedown to a strong magnet. Figure 6 shows a HRTEM image of the catalyst studied. Larger magnetite NPs with a mean diameter of 21.8 ± 3.3 nm are surrounded by small NPs with a mean diameter of 1.7 ± 0.4 nm which were tentatively assigned to Pd species (see red arrows in Figure 6). To demonstrate that these small NPs indeed contain Pd and are located on top of iron oxide NPs, EDS mapping was


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performed. Figure 7 presents the STEM dark field image and EDS maps of Fe and Pd. The superposition of all three images clearly shows that Pd species are located on top of iron oxide NPs.

Figure 6. HRTEM image of Pd-Den-Fe3O4.


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Figure 7. STEM dark-field image (a), EDS Fe (b) and Pd (c) maps and the superposition of all three images (d) for Pd-Den-Fe3O4. Suzuki coupling batch reactions. As a standard benchmark reaction for Suzuki crosscoupling we chose phenylboronic acid and 4-bromoanisole as substrates resulting in paramethoxybiphenyl as a desired product and biphenyl and anisole as by-products via homocoupling and dehalogenation, respectively (Scheme 1).

HO

B

OH

Br

[Pd/DEN] base solvent

O O 2

3

4

Scheme 1. Benchmark reaction for Suzuki coupling with Pd-Den-Fe3O4 as magnetic catalyst.


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Batch tests were first performed in order to obtain insight into the activity and selectivity of Pd-Den-Fe3O4 without fixation and to choose conditions for the continuous-flow experiments. The results of successful Suzuki coupling batch experiments using this catalyst in a batch reactor are presented in Table 2. Table 2. Reaction conditions and conversions of the Suzuki batch reactions. Entry

2*, mM 3*, mM Base / mM

Solvent

T, °C t, min

Conversion, %

1

1.1

1

NaOAc / 2

Ethanol

50

180

11

2

1.1

1

NEt3 / 2

Toluene

50

120

0

3

1.1

1

K2CO3 / 2

1,4-dioxane/ water (45/55)

50

120

48

4

25

20

K2CO3 / 40


70

60

90

5

11

10

K2CO3 / 20


70

30

81

6**

11

10

K2CO3 / 20


70

120

0

*See scheme 1. ** Control experiment was performed with Pd-free catalyst. As is pointed out above, for the catalyst immobilization, liquid phase changes in the microchannel resulting in a two-phase system are not recommended since the interfacial forces between water/oil or gas/liquid slugs minimize the adhesion of the catalyst to the channel walls and might result in continuous stripping of the catalyst. Therefore, only solvent combinations were tested which result in a single liquid phase. In entries 1 and 2 of Table 2 purely organic solvents were used with either a carbonic or amine base. These combinations fail or result in poor conversion. A change to an inorganic base and the use of a mixture of 1,4-dioxane and


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water as a solvent resulted in a conversion of 48% achieved after 120 min (entry 3). With increasing temperature and a higher substrate concentration, a conversion of 90% was obtained after 60 min (entry 4). Finally, a medium concentration in a basic solution allowed a good conversion of 81% at the selectivity of 70% within the shortest time frame of 30 min. It is noteworthy that the time parameter is essential for the comparative continuous-flow experiments, since the residence time of a reaction solution inside a reactor is limited by the reactor volume and the lowest flow rate of the pump. Therefore, it was decided to use the reaction conditions of entry 5 as a starting point for the continuous-flow experiments. A control experiment (entry 6) was also performed with a Pd-free catalyst material. As was expected, no conversion has been observed with this catalyst. Continuous-flow Suzuki coupling reactions. The basic principle of the reactor concept is to immobilize the magnetic catalyst material on the internal wall of a capillary structure by external permanent magnets. The non-covalent functionalization of the capillary wall with the catalytically active material allows heterogeneously catalyzed reactions in a continuous-flow mode by pumping the reaction solution through the capillary. Although the recommended maximum temperature43 of 80 °C for the permanent magnets in the reactor housing was exceeded, no magnetic material was collected outside the reactor. This clearly proves the successful magnetic immobilization of the catalyst based on the Fe3O4 NPs on the walls of the microchannels. After the reaction, the catalyst material is removed from the capillary walls by removing the magnets and flushing the capillary with a solvent. Glass reactor (one-sided immobilization). At first the glass microreactor was tested. The catalyst material was immobilized as is described above only on one side of the microchannel in order to visualize the catalyst behavior during the experiments by the naked eye. Compared to


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the batch test, the composition of the reaction solution was slightly changed to 10 mM of 4bromoanisole, 12 mM of phenylboronic acid, and 36 mM of potassium carbonate in the 1,4dioxane/water (45/55, v/v) mixture. With a temperature of 70 °C at a system pressure of 5 bar a 3.2% conversion was obtained with 41% selectivity for 4-methoxybiphenyl as a desired product. These values are much lower than those for the batch tests, but they can be attributed to two significant differences between the flow and batch tests. First, the residence time is about a third of the reaction time of the batch test (8.5 min vs. 30 min). Second, the way how the same amount of the catalyst interacts with the substrates is strikingly different. In case of the batch synthesis, the catalyst is suspended as a fine solid material in the reaction solution. This suspension has a very large surface allowing great interactions between the catalyst and the substrates. In case of the immobilized catalyst, the active surface which is available for contacting the substrates is decreased to the cross section of the microchannel wall and the magnets. Glass reactor (double-sided immobilization). In order to improve the conversion, the available catalyst surface was doubled by immobilizing the material on both sides of the microchannel. For this approach, the catalyst was unloaded from the reactor by removing the magnet array and purging the microchannel with a pure reaction solvent. The suspension was collected in a glass vial and the catalyst was immobilized with a strong magnet on the wall of the glass vial. Subsequently, the glass microreactor was loaded again with the recycled portion of the catalyst material as is described above, but now bottom and top magnet arrays were used for catalyst immobilization. The reaction solution was pumped through the microreactor under the same conditions as before, resulting in a major improvement of conversion and selectivity to 18% and 55%, respectively (Table 3, entries 1 and 2). The strong increase in the conversion by a factor of ~ 6 cannot be correlated only with doubling of the theoretical catalyst surface. Most likely the


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different magnetic field generated by the mutual interactions of both magnet arrays yields either an even larger surface available for catalysis or a less compressed catalyst material for easier diffusion of the substrates into the catalyst matrix. Stainless-steel reactor (double-sided immobilization). In the next step the metal-based microreactor was employed for temperature-dependent experiments, since this design allows a direct heat transfer from the inside of the reactor body to the stainless-steel capillary. In this case, higher temperatures are possible, as the magnet arrays need not to be immersed in a heating bath.43 A new portion of the same catalyst batch was loaded into the metal microreactor as is described above and immobilized on both sides of the microchannel. Three reaction temperatures were tested with the reactor pressurized at 10 bar (Table 3, entries 3-5). At 23 °C (room temperature) a conversion of 8.3% with a very low selectivity of 5.6% was obtained. Most likely the oxidative addition of the palladium species to 4-bromoanisole has occurred, but the consecutive steps of the catalytic cycle have not been run through. By increasing the temperature to 70 °C, the conversion increased to 14% with selectivity of 47%. These results are lower than those obtained in the glass microreactor with double-sided immobilization at 70 °C (conversion of 18% and selectivity of 55%). This behavior can be explained by the design differences of the two reactors. The metal reactor has a larger volume compared to that of the glass microreactor (3 mL vs. 1.7 mL), which results also in a longer residence time inside the reactor (15 min vs. 8.5 min @ 0.2 mL/min). But one has to keep in mind that the surface inside the reactor carrying the catalytically active material is defined by the area overlap of the channel wall and the magnet surface. Extracting this data from the Computer-Aided Design drawings shows that the glass microreactor has an approx. 8% larger active area (1955 mm2 vs. 1790 mm2). In order to overcome the reduced active area for the metal reactor, temperature was increased to 90 °C,


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resulting in a conversion of 17% and selectivity of 53% which is comparable with those values for the glass reactor. In addition, the same system was used to run a test at atmospheric pressure. In this case, the conversion dropped to 7.5% with a selectivity of 52%. The decrease of more than 50% in conversion might be contributed to a partial evaporation of the solvent inside the capillary resulting in an uneven liquid flow of the reaction solution and a declined contact with the catalytically active surface. A control experiment with the Pd-free catalyst material was not possible in a continuous-flow mode since the magnetic attraction of this catalyst was too low to be immobilized inside the capillary reactor by magnetic forces. As was discussed above, the aggregation of the iron oxide NPs in the catalyst material via complexation with Pd NPs is crucial in order to respond to external magnetic fields.44,45 Table 3. Conversion and selectivity for the Suzuki coupling reaction in continuous-flow microreactors. Entry Reactor type, immobilization

T, °C

P, bar

Conversion, %

Selectivity, %

1

Glass reactor, one-sided

70

5

3.1

41

2

Glass reactor, double-sided

70

5

18

55

3

Stainless-steel sided

reactor,

double- 23

10

8.3

5.6

4


reactor,

double- 70

10

14

47

5


reactor,

double- 90

10

17

53

Leaching of catalytically active Pd species. As is described in literature, the Suzuki coupling reaction is not taking place on the surface of Pd NPs, but with palladium atoms, that have been


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detracted from the NPs by oxidative addition to the aryl halogen. During the catalytic cycle active Pd species can leach from the parent NP.46-50 In order to assess the leaching of Pd species from the catalyst, all samples used for real-time analysis with GC were sealed and re-measured after storing them for one week at room temperature. In case of the batch experiments, no increase of conversion could be detected. In the case of the samples from the continuous-flow experiments, the product formation was observed outside the reactor at room temperature. The amount of the product was considerably higher as verified by GC after one week. Interestingly, there seems to be a temperature-dependent leaching behavior. Samples collected during the experiments performed at room temperature showed a maximum increase in the conversion of more than 177% (Table 4). Experiments at 70 °C gave a smaller increase in conversion of approx. 85%. Finally at 90 °C the lowest product increase of approx. 23% was detected after one week. Table 4. Conversion and selectivity for the Suzuki coupling reaction in the stainless steel continuous-flow microreactor. Entry

T, °C

Conversion, %

Conversion after 1 week, %

Increase of conversion, %

1

23

8.3

23

177

2

70

14

26

85

3

90

17

21

23

Selected samples with a high product increase outside the reactor were analyzed with ICP-OES (see the Supporting Information). It is noteworthy that the amount of Pd was below the detection limit, i.e.,

Proof of Concept: Magnetic Fixation of Dendron-Functionalized Iron

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