Article pubs.acs.org/OPRD
On the Potential of Organic Solvent Nanofiltration in Continuous Heck Coupling Reactions Ludmila Peeva, Jannine Arbour, and Andrew Livingston* Department of Chemical Engineering, Imperial College London, London SW7 2AZ, U.K. ABSTRACT: Active pharmaceutical ingredients are often synthesized by multiple reactions involving organometallic catalysts, and it is necessary for substrates to pass through several reaction and separation steps during processing. Flow chemistry is an attractive solution for multistep synthesis, but between reactions, streams require workup and purification using techniques such as liquid−liquid extraction, gas−liquid separation, distillation, and others. Organic solvent nanofiltration (OSN) is an emerging technology for performing membrane separation/purification processes in organic solvents which offers major advantages for performing catalyst separation in a continuous process without phase transition or biphasic operations. The main challenges faced by in situ continuous separation of catalysts by OSN are the compatibility of membranes with the reaction conditions (high temperature, aggressive solvents, and often high concentrations of acid/base). This work demonstrates, for the first time, a onepot, long-term continuous Heck coupling reaction performed in DMF at 80 °C and organic base concentrations >0.9 mol·L−1, where the Pd catalyst is retained by a polymeric OSN membrane. The process achieved stable performance for more than 1000 h at conversion rates higher than 85%. The average product contamination in the continuous process integrated with membrane separation was 20 times lower than in a simple batch process utilising the same catalyst loading.
1. INTRODUCTION Continuous flow techniques can often provide better mixing and heat transfer, precise control over concentrated or hazardous reaction streams, reduced solvent waste, and synthetic shortcuts together with rapid process optimisation of synthetic steps on a small scale.1 In most of the continuous flow case studies the catalyst is immobilised on an insoluble inorganic,2−4 polymeric,5−7 or composite8 support. Simple purification of the products and easy recyclability of the catalysts are major advantages of heterogenization of transition metals. The major drawbacks associated with catalyst leaching, mass-transfer limitations, swelling of certain polymer supports, deposition of products and byproducts, and the necessity to periodically replace the cartridges, limit the practicality of these systems.9 Several unit operations have been developed in order to achieve separation and purification in a continuous reaction: a single-step liquid−liquid microextraction,9,10 a microfluidic distillation,11 a multistep synthesis combining multiple reactions, and liquid−liquid and gas−liquid separations.12 However, in all these cases, a biphasic process is involved, typically with associated mass-transfer limitations. Organic solvent nanofiltration (OSN) is an emerging technology for performing membrane separation/purification processes in organic solvents and has been successfully applied for organometallic catalyst recovery.13−22 One major advantage of OSN separation is that it does not require any phase transition or biphasic operation. Thus, the development of continuous catalytic process combined with continuous catalyst recovery by OSN can potentially offer major economic and process efficiency advantages over the conventional batch-based system and/or biphasic operation processes. A continuous hydrogenation hybrid process that combines nanofiltration with homogeneous catalysis using Rh-EtDUPHOS and Ru-BINAP catalysts has been demonstrated by De Smet, et al.14 The total catalyst turnover numbers (TON, © 2013 American Chemical Society
defined as total mols of product produced per mol of catalyst added) for the hydrogenation with Ru-BINAP and RhEtDUPHOS respectively were 1950 and 930, with the reactions performed in methanol at a mild temperature 30−40 °C. Brinkmann et al.23 reported a continuously operating membrane reactor for an allylic substitution reaction performed using an enlarged dendritic palladium catalyst with MW of 10,212 g·mol−1. The reaction was performed at 25 °C in dichloromethane, achieving a moderate catalyst TON of 95. Nair, et al. demonstrated a semicontinuous nanofiltrationcoupled Heck-reaction of styrene and iodobenzene to form trans-stilbene, where five consecutive reaction nanofiltration cycles were performed giving a total catalyst TON of 1200.13 Three solvent mixtures were investigated as a reaction media, (1) a 50:50 mixture of ethyl acetate and acetone (17.7 mL), H2O (1.49 mL); (2) a 40:60 mixture of methyl-tert-butyl ether and acetone (18.6 mL) and H2O (0.54 mL); and (3) tetrahydrofuran (18.1 mL) and H2O (1.08 mL). The reaction was performed in a glass reactor at 60 ± 10 °C until 95−100% conversion was reached. The reactor was then cooled to 20 °C and the postreaction mixture transferred from the reactor to the nanofiltration cell for catalyst separation and recycle. Despite the success of the above process, it was necessary to perform the reaction and the separation in separate vessels under different conditions due to membrane incompatibility with the Heck reaction conditions. In addition, when THF was used as a solvent, it was necessary to replace the membrane after each run, since lower retentions occurred during the subsequent filtration. The work cited above, illustrates some of the major issues associated with the implementation of OSN in catalytic processes. The existing polymeric OSN membranes are Received: March 21, 2013 Published: June 11, 2013 967
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bath was replaced frequently until neutral pH was reached, to remove the traces of acidic solvent from the bulk of the membrane. 2.2. Experimental Procedures. 2.2.1. Experimental Procedure to Determine the Effect of Temperature on the Reaction Rate. In a reaction carousel (Radleys, U.K.) a series of batch experiments were performed at two different temperatures: 110 °C25,26 and 80 °C (temperature selected as a trade-off between reaction rate and the boiling points of MA (80 °C) and the NEt3 base 88.8 °C). In a carousel tube under N2 5.4 mg (0.024 mmol) of Pd(OAc)2 and 19.8 mg (0.048 mmol) of dppp were dissolved in DMF (2 mL) under continuous stirring at room temperature for 15 min. IB (0.273 mL, 2.45 mmol), MA (0.264 mL, 2.93 mmol), NEt3 (0.5 mL, 3.58 mmol), and DMF (1 mL) were then added, and the solution was stirred throughout the experiment. In the experiments performed with catalyst preactivation, the same amount of Pd(OAc)2 and dppp were added to 2 mL of DMF, and the mixture was stirred for an additional 30 min at 80 °C. IB (0.273 mL, 2.45 mmol), MA (0.264 mL, 2.93 mmol), NEt3 (0.5 mL, 3.58 mmol), and DMF (1 mL) were then added, and the solution was continuously stirred throughout the experiment. Samples of 0.1 mL were taken for analysis. 2.2.2. Experimental Procedure to Determine the Effect of Membrane Material on the Heck Coupling Reaction Rate. The reactions were performed in the reaction carousel as described above in section 2.2.1. To each carousel tube was added ∼30 mm2 of membrane or backing material (membrane support only) cut into small pieces. 2.2.3. Experimental Procedure for Continuous Runs. A membrane disk was placed into the reactor/separator which was clamped and purged with nitrogen for ∼30 min. DMF solution (50 mL) containing 0.1375 g Pd(OAc)2 and 0.505 g dppp (for the 1 mol % catalyst loading experiments) or 0.275 g Pd(OAc)2 and 1.01g dppp (for the 2 mol % catalyst loading experiments) were initially quickly pumped (10 mL·min−1) into the cell chamber and stirred for ∼1h at 80 °C (for preactivation). To ensure the catalytic complex was fully formed, more time for catalyst preactivation was allowed than in the batch experiment. The continuous run was then started by pumping a feed stream through the cell with the following composition per 100 mL of the feed solution: −65.2 mL of anhydrous DMF; 6.8 mL of iodobenzene (0.061 mol, final concentration of 0.6 mol·L−1); 10 mL (0.11 mol) of methyl acrylate, and 18 mL (0.129 mol) of triethylamine. The flask containing feed was kept under a N2 blanket (∼0.5 bar overpressure). The concentrations of methyl acrylate and triethylamine were deliberately kept higher than in the batch experiment to compensate for the losses (due to their volatility) through the nitrogen stream in the feed flask. 2.3. Analysis. 2.3.1. Conversion. An Agilent 6890 series II gas chromatograph, equipped with a HP-1 column (30 m × 0.318 mm × 0.25 μm) and a flame ionization detector (FID), was used to determine the conversion of the limiting substrate, iodobenzene, to product by comparing the area of the individual characteristic peaks (conversion = area product/ (area product + area substrate)). The programme ran from 40 °C (1 min hold) to 200 °C with a ramp of 15°·min−1. 2.3.2. Palladium Analysis. Permeate (0.5 mL) and retentate samples were heated on a flat plate heater at 90 °C. After complete drying, 1.5 mL of aqua regia (nitric acid and hydrochloric acid 1:3 v/v) was added to each dried sample to digest the organic content (digestion within ∼24 h). Each
restricted to operations/separations at moderate temperatures in a limited number of solvents and are not recommended for operations under high concentrations of acids and bases. For example, according to the membrane supplier, the polymeric OSN membranes from the DuraMem series, which are widely used at present, are restricted to maximum temperature of 50 °C, and their use is not recommended when there is a presence of strong amines.24 To the best of our knowledge there is a lack of published work on the long-term, continuous Heck coupling reaction performed at elevated temperature (∼100 °C) in polar aprotic solvent in the presence of base, where the catalyst is retained in situ using a polymeric membrane. The work described in this contribution demonstrates, for the first time, a one-pot, continuous Heck coupling reaction performed in DMF at 80 °C and with organic base concentrations >0.9 mol·L−1 where Pd catalyst is retained by a polymeric OSN membrane. The process showed stable performance for more than 1000 h with an estimated average Pd rejection of ∼93%.
2. EXPERIMENTAL SECTION 2.1. Materials. 2.1.1. Chemicals. Analytical grade palladium(II) acetate (Pd(OAc)2), 1,3-bis(diphenylphosphino)propane (dppp), iodobenzene (IB), methyl acrylate (MA), anhydrous N,N-dimethylformamide (DMF), triethylamine (NEt3), fuming nitric acid (100%), and hydrochloric acid (37%) were supplied by Sigma-Aldrich. The styrene oligomer standards used for molecular weight characterisation studies of the membranes contained a mixture of PS580, PS1000, PS1300 (purchased from Agilent Technologies Deutschland GmbH, Germany), and α-methylstyrene dimer (purchased from Sigma-Aldrich, UK). Poly(ether ether ketone) (PEEK, Vestakeep 4000P) was kindly provided by Evonik Degussa GmbH, Germany. Methane sulfonic acid and sulphuric acid were purchased from SigmaAldrich, UK. 2.1.2. Membranes. The membranes used for this investigation were prepared in our laboratory. The membranes were of asymmetric type, cast from a polymer dope solution on a polypropylene nonwoven support and vitrified by the wetphase inversion. The membranes are denoted as follows: crosslinked PBI membrane (prepared from polybenzimidazole and cross-linked with dibromobutane); APTS cross-linked PI membrane with a mixed matrix (organic−inorganic) structure (prepared from polyimide and cross-linked using aminopropyltrimethoxysilane); PEEK membranes M1 and M2 (prepared from poly(ether ether ketone)). Duramem 300 was purchased from Evonik-Membrane Extraction Technology, UK. The Duramem 300 membrane is based on cross-linked polyimide (PI) and has a molecular weight cutoff (MWCO) of 300 g·mol−1 according to the supplier. 2.1.3. Preparation of PEEK Membranes. The dope solution was prepared by dissolving PEEK powder in a mixture of methane sulphonic acid and sulphuric acid (3:1 by weight) for 5 h at ambient temperature. The homogeneous dark-yellow solution that formed (6 wt % polymer (M1); 12 wt % polymer (M2)) was then degassed under vacuum for 2 h and cast on a nonwoven polypropylene fabric (Novatex 2471, Freudenberg, Germany) using an automatic film applicator (Braive Instruments, Belgium). The thickness of the membrane was set by adjusting the casting knife to 250 μm. After casting, the membrane was immediately transferred to a deionised (DI) water bath for phase inversion. The water in the 968
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Figure 1. (A) Flow-through reactor/membrane separator cell assembly; (B) Schematic representation of the process scheme for the continuous Heck reaction with in situ membrane separation of the catalyst.
3. RESULTS AND DISCUSSION 3.1. The Heck Coupling Reaction. Since the aim of this study is proof of concept, we selected a simple Heck reaction that would proceed regioselectivitly and form a stable productthe reaction between iodobenzene 1 (MW 204) and methyl acrylate 2 (MW 86) to form (E)-methyl cinnamate 3 (MW 162) (Scheme 1).
sample was then diluted in 10 mL centrifuge tubes with distilled water and mixed (the small amount of residual organic matter was found not to interfere with the analysis). The samples were analysed using inductively coupled plasma optical emission spectrometry (ICP-OES) on a Perkin-Elmer Optima 2000DV spectrometer and compared against a calibration curve of 2 ppm, 5 ppm, and 10 ppm palladium standard samples. The Pd rejection was calculated as
Scheme 1. Heck coupling reaction to form 3
⎛ Pd concentration in permeate ⎞ ⎟ rejection (%) = ⎜1 − ⎝ Pd concentration in retentate ⎠ × 100%
2.4. Experimental Setup. A flow-through nanofiltration cell27 with working volume of ∼60 mL and membrane area of ∼51 cm2 was used as a reaction and separation vessel. The cell operated in a bottom-to-top permeation mode. The stainless steel cell comprised a ∼60 mL compartment containing a magnetic stirrer bar to provide effective stirring of the reaction media. Six ports surrounding the compartment were used as inlet (feed) and outlet (permeate) ports, or connected to a thermocouple and a pressure gauge for temperature and pressure monitoring and control. A 51 cm2 disk of desired membrane was fitted into the stainless steel cell with the membrane active side facing towards the reaction mixture. A stainless steel sintered plate was placed on top of the membrane to provide it with mechanical support during the filtration. Finally the cell was closed by clamping the cell base against the body with a set of high pressure clamps (Figure 1A). A schematic representation of the process scheme for the continuous Heck reaction is shown in Figure 1B. The reactor/ separator cell was maintained at 80 °C via the heating/stirring plate. Fresh feed was added continuously to the cell (at 0.5 mL·min−1 or 0.2 mL·min−1 flow rate), while the cell contents were continuously filtered through the membrane at a filtration rate equal to the feed supply flow rate.
To optimise the conditions the reaction was first carried out under batch mode in a reaction carousel. Initially the experiments were performed at 110 °C, where 98% conversion was reached after 40 min (Figure 2). The reaction kinetics were also investigated at 80 °C. There are two reasons for selecting this particular temperature. First, the boiling points of MA and the NEt3 base used in this study are 80 and 88.8 °C, respectively, and a lower reaction temperature will reduce reagent losses. Second, the polymeric membranes (e.g., PI) in the OSN suffer severe flux reduction at elevated temperatures (particularly above 100 °C).28 At 80 °C, 99.5% conversion was achieved within 2 h (Figure 2). The conversion rate was initially slow, but increased significantly after 100 min, which indicates that formation of the in situ catalytic complex is likely to be the rate-limiting step. When the catalyst was initially preactivated by stirring Pd(OAc)2 and dppp together in DMF for 30 min at 80 °C (catalyst preactivation period in Figure 2) and the remaining reagents were introduced thereafter, the reaction proceeded to full conversion in 50 min. This mechanism provides an interesting case for the continuous reaction/OSN separation process, where the catalyst can be 969
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Figure 2. Conversion over time of the Heck reaction shown in Scheme 1 at 80 and 110 °C. The reaction was performed under batch conditions in a reaction carousel.
preactivated in the nanofiltration cell and then eventually retained in its active state while continuously adding the fresh reagents. 3.2. Membrane Selection Procedure. 3.2.1. Temperature Stability of Membranes. Three membranes prepared in our laboratory were identified as potential candidates for the relatively high-temperature Heck coupling reaction, namely APTS cross-linked PI membrane, cross-linked PBI membrane, and PEEK membrane. PBI and PEEK were selected because of the exceptional chemical and thermal stability of the membrane material.29,30The APTS cross-linked PI membrane was selected since it potentially achieves temperature stability due to the mixed organic−inorganic network. The membrane separation performance was characterised by performing a standard rejection characterisation test described elsewhere31 with a DMF solution of styrene oligomers. The initial screening suggested that the APTS-cross-linked membrane retains its separation properties at up to 100 °C (Figure 3) with a stable MWCO of ∼260 g·mol−1 (molecular weight cutoff (MWCO), the MW of a polystyrene rejected 90% by a membrane). The solvent flux was increasing with temperature, probably due to increased permeability of the membrane material and/or lower solution viscosity. Interestingly, the flux increase could be well interpolated with exponential temperature dependence, but more detailed investigation is needed in order to derive any defined correlation. The cross-linked PBI membrane was also investigated by using a polystyrene mixture in DMF but only at 80 °C. The membrane separation performance, although stable, was worse than the APTS cross-linked PI membrane with max rejection achieved of ∼70% (Figure 4). Finally the PEEK membranes M1 and M2 were investigated at 80 °C, showing stable performance and MWCO of ∼480 g·mol−1 and ∼395 g·mol−1, respectively (Figure 5). 3.2.2. Effect of Membrane Material on the Heck Coupling Reaction Kinetics. Apart from membrane stability under the reaction conditions, another important issue which is often neglected in the membrane studies is the effect of the membrane material on the reaction kinetics. This could possibly be a crucial factor for a continuous process, and it was therefore decided to investigate whether any material used for the membranes described above has an inhibitory effect on
Figure 3. Flux (A) and rejection (B) data (DMF solution of polystyrenes) for APTS cross-linked PI membrane at three different temperatures, 50, 80, and 100 °C and 30 bar pressure.
Figure 4. Polystyrenes rejection data (DMF solution of polystyrenes) for cross-linked PBI membrane at 80 °C, 8 bar pressure, and flux of ∼2 L·m−2·h−1 (the conditions were chosen to simulate the continuous Heck reaction conditions).
the Pd catalyst. The experiments were performed in a carousel in batch mode by adding a piece of membrane into the reaction solution at the beginning of the reaction. PBI, APTS crosslinked PI, and PEEK membranes were investigated. A separate 970
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the “inertness” of PEEK toward Pd catalyst. On the basis of this result together with PEEK’s excellent acid and base stability,33 we propose that PEEK is a good membrane candidate for the Heck coupling reactions.
3.3. Continuous Heck Coupling Reaction Combined with OSN Membrane Separation. For the two membranes that seem compatible with the Heck coupling reaction, namely APTS cross-linked PI membrane and PEEK, the first test was performed with the APTS cross-linked PI membrane (run 1). Pd catalyst, 50 mL of 2 mol % (catalyst mol % was calculated relative to substrate concentration in the feed) was added into the reactor/separator cell and preactivated for 60 min at 80 °C. It was unclear what the catalyst rejection level by the membrane would be at this stage; furthermore the batch experiments described earlier suggested that the APTS cross-linked PI membrane may partially inhibit the catalyst, and thus, catalyst loading higher than that in the batch process was used. At the end of the preactivation period the continuous run was started. Feed solution (0.61 mol·L−1) of IB in DMF containing respective equivalent amounts of MA and NEt3 was pumped through the reactor/separator cell at a flow rate of 0.5 mL·min−1 (residence time ∼120 min). It was expected that, since the catalyst has already been preactivated, the reaction rate would be high. However, the conversion after 2 h was only ∼10% (Figure 6). The flow rate was reduced to 0.2 mL·min−1 (residence time of ∼300 min), but the conversion did not improve and remained ∼13% for a further 3 h. After 5 h the reaction rate increased considerably, and conversion quickly reached 53% and further to 78% after 7 h. The lag phase for this reaction appeared to be longer at larger scale (∼60 mL) than at a small scale of 2−3 mL, or the concentration of reagents (substrates) in the cell at the beginning of the continuous process was too low to provide a sufficient reaction rate. Nevertheless, this fact makes it even more attractive for a continuous process since the long nonproductive preactivation periods preceding each batch will be avoided. Unfortunately, the membrane exhibited poor performance during these experiments. The pressure in the cell had initially increased to 10 bar for a few minutes, followed by a sudden drop to 0 bar which suggested the membrane had ruptured.
Figure 5. Polystyrenes rejection data (DMF solution of polystyrenes) for PEEK membrane M2 at 80 °C, 30 bar pressure, and flux of ∼2 L·m−2·h−1 (the conditions were chosen to simulate the continuous Heck reaction conditions). The rejection data for M1 (not shown) followed a similar pattern with MWCO of ∼480 g·mol−1.
experiment was also performed to investigate the effect of the polypropylene membrane backing material alone. A blank experiment using no membrane in the carousel tube was run in parallel. The average results of two runs are summarised in Table 1. These results showed that the use of APTS crosslinked PI membrane reduced the reaction rate, while the PBI membrane seemed to completely inhibit the reaction (most likely via catalyst inhibition). Literature data32 suggest that PBI tends to form complexes with Pd, and this may have caused catalyst deactivation. The inhibitory effect of PBI could be due to the chelating properties of the nitrogen present in the imidazolium ring (PBI monomer unit structure presented below).
In contrast, the PEEK membrane appeared to have no effect on the reaction rate. The lack of a strong chelating group within the PEEK structure (presented below) may be responsible for
Table 1. Effect of membrane material on the Heck reaction rate, expressed as conversion over time for the tests performed as batch in a reaction carousela experiment I (average of 2 runs)
a
experiment II (average of 2 runs)
time (min)
conversion % blank
conversion % PEEK membrane
conversion % backing
time (min)
conversion % blank
conversion % APTS cross-linked
conversion % PBI cross-linked
15 30 45 60 75 90 10 12 180 240 330
61.5 (±4.5) 76.5 (±1.5) 88.6 (±1.2) 93 (±0.3) 95.3 (±0.5) 96.8 (±0) 97.6 (±0.3) 98.4 (±0.4) 99 (±0.2) 99.3 (±0.3) 99.6 (±0.4)
68.9 (±5.1) 84.5 (±0.4) 93.1 (±0.7) 95.5 (±0) 97.3 (±0.3) 97.7 (±0.3) 98.7 (±0.3) 99.2 (±0.2) 99.5 (±0.1) 99.8 (±0.2) 100 (±0)
53.9 (±4.9) 68.8 (±5.2) 77.1 (±0.6) 84.9 (±0.9) 88.8 (±0.2) 90.7 (±0.2) 92.8 (±0.3) 94.3 (±0.3) 96.6 (±0.2) 97.3 (±0.7) 97 (±4.5)
10 20 30 40 60 80 120 180 240
3 (±1) 8 (±5) 78.5 (±12) 95.6 (±3) 98.3 (±1) 99.2 (±0.1) 99.8 (±0.1)
29.4 (±15) 59.2 (±10) 66.3 (±2) 74.7 (±2) 83.5 (±2) 87 (±7) 91.4 (±1) 94.3 (±1) 96.7 (±0.1)
0 0 0 0 0 0 0 0 0
30 min pre-activation time was applied; 1 mol % catalyst loading. 971
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Figure 6. Conversion over time during the continuous Heck coupling reaction experiment using APTS cross-linked PI membrane (run 1), Duramem 300 (run 2), and a blank experiment with no membrane in the cell (run 3). (A) APTS membrane after use in the continuous Heck reaction (run 1); (B) Duramem 300 membrane after use in the continuous Heck reaction (run 2).
Figure 7. Conversion over time for the continuous Heck coupling reaction (run 4) using PEEK membrane M1. (Residence time 300 min; total catalyst amount 0.61 mmol. The feed supply was stopped during laboratory downtime.)
After the run, the membrane which was removed from the cell was swollen with creases at the edge, suggesting poor membrane compatibility with the reaction conditions (Figure 6A). Since similar phenomena were not observed during the temperature stability tests of the membrane and it proved stable up to 100 °C in DMF (see section 3.2.1), this was attributed to a chemical attack from the reagents used in the Heck coupling reaction on the membrane material, in particular the triethylamine base present at high concentration (>0.9 mol·L−1). To test this hypothesis, we performed further a similar experiment (run 2) using a commercial membrane Duramem 300 which is made of cross-linked PI. The results demonstrated a very similar pattern. After the pressure initially increased to approximately 10 bar, it suddenly dropped to 0 bar, suggesting membrane rupture. When the membrane was removed from the cell at the end of the experiment, the top layer was swollen, soft, and peeling off easily (Figure 6B). The reaction conversion followed the same pattern as with the APTS cross-linked PI
membrane (Figure 6). Nevertheless, the experiment produced encouraging results, since we were able to perform a continuous process over 400 min. To evaluate whether the prolonged lag phase is due to the presence of the membrane in the reaction cell, we performed a separate experiment and placed an impermeable Teflon sheet in the cell instead of a membrane (run 3). The outlet stream was collected through the back-pressure regulator (relief valve) adjusted at 20 bar relief pressure. The pattern of reaction conversion over time (Figure 6) was relatively similar to the results achieved when a membrane was present, suggesting that the adverse effect is not due to the membrane−catalyst interactions. Finally the PEEK membrane performance was evaluated in the continuous Heck coupling reaction. An experiment was performed using the PEEK membrane denoted as M1 (run 4). Pd catalyst (50 mL of 1 mol %, 0.61 mmol) was added into the reactor/separator cell and 972
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Figure 8. Pd concentration in the permeate stream (measured) and the retentate stream (estimated), for the continuous Heck reaction (run 4) performed using PEEK membrane M1. (The feed supply was stopped during laboratory downtime.)
Figure 9. Conversion over time for the continuous Heck coupling reaction (run 5) using PEEK nanofiltration membrane M2. (Residence time 300 min; total catalyst amount 0.61 mmol.) The feed supply was stopped overnight and over the weekends and restored at the next day. (A) PEEK membrane M2 after ∼1000 h use in the continuous Heck coupling reaction (run 5).
preactivated for 60 min at 80 °C. Having verified already that the PEEK material does not inhibit the Pd catalyst, the same catalyst concentration as in a batch experiment was used. During the continuous run, IB solution (0.61 mol·L−1) in DMF containing the corresponding equivalent amounts of MA and NEt3 was pumped through the reactor/separator cell at a flow rate of ∼0.2 mL·min−1 (residence time ∼300 min). The conversion (Figure 7) increased slowly, and after 19 h reached 64% and remained stable within the 64−70% range for
197 h. The feed supply was stopped during laboratory downtime; however, when the feed supply was restored, the conversion was quickly reinstated to ∼70%. After 215 h the conversion dropped considerably to 26% and continued to decrease; at that point the experiment was halted. The deteriorating performance was attributed to Pd washout from the system, and this was confirmed by the Pd ICP analysis. Nevertheless, the overall yield was ∼0.21 mol product, and the estimated catalyst TON of ∼344 achieved was encouraging. 973
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Figure 10. Pd concentration in the permeate stream over time for the continuous Heck coupling reaction (run 5) using PEEK nanofiltration membrane M2. (Residence time 300 min; total catalyst amount 0.61 mmol.) The feed supply was stopped overnight and over the weekends and restored at the next day.
The Pd concentration was measured in the permeate samples and the final retentate sample and used to estimate the Pd rejection (Figure 8). More than ∼10 reactor volumes were passed through the system over the run. After 10 reactor volumes at 0% rejection, the expected Pd concentration in the retentate is ∼0.04 mg·L−1, while the actually measured one was ∼8 mg·L−1, corresponding to an average Pd rejection of ∼51% throughout the run. There was no obvious damage to the PEEK membrane when it was removed from the cell; the surface seemed clean and shiny with no cracks or wrinkles. This result suggests that the PEEK membrane is a good candidate for this application. A follow-up experiment (run 5) was performed using a membrane from the PEEK series which has tighter separation characteristics (M2, MWCO of ∼395 g·mol−1, Figure 5). The experiment was performed in exactly the same manner as before. Pd catalyst (50 mL, 1 mol %, 0.61 mmol) was added into the reactor/separator cell and preactivated for 60 min at 80 °C. After that, the reagents’ solution was pumped through with a flow rate of ∼0.2 mL·min−1 (residence time ∼300 min). For the first 30 h of the reaction, the conversion remained relatively low, below 60%. During the analysis it was noticed that the amount of base (triethyl amine) in the feed solution decreases over time due to the nitrogen purging of the feed. Once the amount of triethylamine in the feed was restored, the conversion increased above 85% and remained stable for the rest of the run. Due to the absence of an automatic control of the system and for safety reasons, the feed supply was stopped overnight and then restored at the next day. Nevertheless, the system performance still remained stable (Figure 9). The experiment ran for nearly 1000 h (∼190 h effective feed supply time, the feed flow was stopped overnight) utilising ∼35 reactor volumes (Figure 9). The Pd concentration was measured in the permeate samples and in the final retentate sample and used to estimate the Pd rejection (Figures 10, 11). A repeatable pattern was observed. Specifically at the beginning of the run the Pd concentration in the permeate is relatively high, and decreases over the run. When the feed supply is interrupted overnight, the Pd concentration in the permeate is high at the beginning of the feed supply and then decreases soon after. This observation is
Figure 11. Estimated Pd content in the reactor vs reactor volumes of feed supplied at different Pd rejections; measured Pd content in the reactor at the end of the continuous runs (runs 4, 5) using PEEK membranes M1 (∼51% rejection) and M2 (∼93% rejection).
not uncommon for membrane processes and suggests the existence of reversible membrane compaction. The Pd rejection estimated on the basis of the final Pd concentration in the reactor was ∼93% (see Figure 11). It should be acknowledged that this value is indicative since it is based on only a single measurement. For comparison, the estimated Pd content in the reactor for rejections of 51% (as for the PEEK M1 membrane run) and 0% rejection are also shown. The Pd mass-balance was closed within 2.5% error. The experiment was stopped after ∼1000 h, producing ∼1.081 mol of product and utilising 0.61 mmol catalyst equivalent to catalyst TON of ∼1772. The Pd catalyst, once preactivated in the beginning of the run, seemed to remain active throughout the whole experimental period. There were no obvious changes to the PEEK membrane which retained its integrity and separation properties under the harsh operating conditions of Heck coupling reaction −80 °C; solvent DMF; ∼1 mol·L−1 NEt3. In spite of the fluctuations during the beginning of the feed supply, the average Pd concentration in permeate was ∼42 mg·L−1. The average product contamination 974
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is 317 mg Pd·kg product−1, a value which is too high to be of significant interest for the pharmaceutical industry. However, the same catalyst loading (1 mol %) used in a batch process without membrane separation resulted in a 20 times higher product contamination of 6569 mg Pd·kg product−1. An improvement in the separation properties of membranes and further process optimisation are essential to advance process feasibility and will require further research and validation. These initial results have clearly demonstrated the potential of OSN in continuous catalytic reactions. It is possible to couple together several catalytic stages in a membrane cascade where each catalyst will be retained at a separate stage of the cascade. Furthermore, additional membrane separation/purification units could be incorporated, if necessary, between the catalytic stages.
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4. CONCLUSIONS A continuous Heck coupling reaction was successfully performed in a flow-through nanofiltration membrane reactor/separator unit. The unit was operated continuously for more than 1000 h at conversion rates higher than 85%. Approximately 1.081 mol of product was produced equivalent to catalyst TON of ∼1772. The average product contamination in the continuous process integrated with membrane separation was 20 times lower than in a simple batch process utilising the same catalyst loading. The PEEK membranes exploited retained their integrity and separation performance throughout the run. This result demonstrates clearly the potential of OSN in continuous catalytic processes applications.
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AUTHOR INFORMATION
Corresponding Author
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[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was funded by the Novartis Pharma AG, Massachusetts Institute of Technology Subaward Agreement No. 5710002924. We acknowledge also the financial support from the U.K. Engineering and Physical Sciences Research Council (EPSRC) Grant No EP/G070172/1 - ELSEP and the EC FP7 Ares(2011)1042335 - MEMTIDE.
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dx.doi.org/10.1021/op400073p | Org. Process Res. Dev. 2013, 17, 967−975
