Organic Solvent Nanofiltration as a Tool for Separation of Quinine

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Organic solvent nanofiltration as a tool for separation of quinine-based organocatalysts Thomas Fahrenwaldt, Julia Grosseheilmann, Friedrich Erben, and Udo Kragl Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op400037h • Publication Date (Web): 21 Aug 2013 Downloaded from http://pubs.acs.org on September 2, 2013

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Organic Process Research & Development

Organic solvent nanofiltration as a tool for separation of quinine-based organocatalysts. Thomas Fahrenwaldt, Julia Großeheilmann, Friedrich Erben† and Udo Kragl* Institute of Chemistry, University of Rostock, Technische Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany † Leibniz Institute for Catalysis (LIKAT Rostock), Albert-Einstein-Str. 29a, 18059 Rostock, Germany *AUTHOR EMAIL ADDRESS: [email protected] KEYWORDS Catalyst recycling, Henry reaction, membranes, nanofiltration, organocatalysis ABSTRACT Organic solvent nanofiltration (OSN) promises to be a versatile tool for a mild and energy saving downstream processing. In this case study the use of modern solvent resistant membranes to separate organocatalysts from reaction media was investigated. Commercially available membranes with molecular weight cut-offs (MWCO) between 150 to 500 g mol-1 were used. They showed high retentions for native catalysts up to 99 % in THF. The enantioselective Henry

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reaction of ethyl pyruvate and nitromethane catalyzed by benzoyl cupreine was used to demonstrate the potential of this technique for preparative use. 1. INTRODUCTION In recent years organocatalysis, which has the characteristics of biocatalysis and transition metal catalysis, has been introduced for stereoselective synthesis1-3. A huge and steadily rising number of transformations were developed in the last two decades. In many fields of synthetic chemistry organocatalytic transformations offer effective alternatives to common procedures1. Often there is no need for inert conditions with respect to water or oxygen. Other advantages are low toxicities or good catalyst stabilities to name only a few. Also the large variety of catalytically active structures starting from simple amino acids like L-proline over some chiral alcohols to complex thiourea derivates is amazing2, 4, 5. Cinchona alkaloids as another very important group of organocatalytic structures show a versatile range for applications and are used in many transformations such as C-C bond-forming reactions, C-X bond-forming reactions or kinetic resolutions6, 7. Organocatalysts are defined as metal free organic substances used in substoichiometric amounts to accelerate chemical reactions2. Substoichiometric amounts often mean concentrations between 5 and 20 mol%. Therefore the substrate to catalyst ratio or the total turnover number, respectively, is often lower for organocatalysts compared to organometallic or biocatalysts. To overcome this drawback an efficient catalyst recycling is necessary for a successful process development. There are many existing strategies also known from other catalytic processes like phase transfer catalysis (PTC) where catalysts and products are in different phases or with immobilisation on insoluble supports like resins to recover the catalysts by simple filtration8-11.


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Organic solvent nanofiltration (OSN) is another approach for separation and recycling of all types of homogenous catalysts12, 13. After catalytic transformation the post-reaction mixture is filtered over a solvent stable membrane. The catalyst is retained while the product molecules can permeate through the membrane. One of the great advantages is the eco-friendly lower energy consumption in comparison to conventional methods like distillation or crystallization14. Thermal degradation of product and catalyst is minimized by working at ambient temperatures and without phase transitions. OSN has been applied for many different separation processes, for example for purification of pharmaceuticals,15 concentration of natural product extracts16, 17 or recycling of ionic liquids18. It was also used for separation of different unmodified transition metal catalysts like Ru-BINAP for hydrogenation19, Pd-complexes for Heck reaction20 or enlarged catalysts for various reactions21,

22

. The Review from Janssen et al. gives a good

overview about the actual progress13. For separations of organocatalysts there are only a few examples described in literature. One of the first case studies was the reduction of ketones by oxazaborolidines in a membrane reactor23. Giffels et al. showed the possibility to recycle a polymer bound molecular weight enlarged catalyst for enantioselective ketone reduction. Wöltinger et al. transferred this concept to an asymmetric ring opening of meso-anhydrides24. They used the commercially available (DHQD)2AQN catalyst with a linear polystyrene support in high molar ratio of 100 mol% to lower the reaction time. Siew et al. developed a 2-step membrane process with an improved solvent recycling for an asymmetric Michael addition with quinidine-based organocatalysts25. In 2002 Tsogoeva et al. first tested the industrial application of organocatalysis in a chemzyme membrane reactor26. A molecularly enlarged oligo(L-leucine) catalyst with a soluble polymer was used for the Julia-Colonna epoxidation.


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In this study the enantioselective Henry reaction catalyzed by benzoyl cupreine (BzCPN) developed by Li and coworkers27 was used to demonstrate the potential of organic solvent nanofiltration to separate the catalyst from product after the reaction is finished. The Henry reaction is a C-C bond-forming reaction providing access to small, but highly functionalised building blocks. Ethyl pyruvate and nitromethane are readily available educts and the products are valuable starting materials for synthesis of aziridines and β-lactams as key intermediates for pharmaceuticals. The quinine based organocatalysts without coupling them to a soluble support are characterised with respect to their filtration behaviour. For this purpose a number of novel commercially available nanofiltration membranes made of polyimide from the DuraMem Series (DM) with low molecular weight cut-offs (MWCO) between 150 - 500 g mol-1 were tested.

OMe

OH

6´

6´

N 9

N 9

OH

OH

N

N

QN: MW = 324,4 g mol-1

OMe

CPN: MW = 310,4 g mol-1

OH

6´

6´

N 9

N 9

O

O

N

O

O

N

BzQN: MW = 428,5 g mol-1

BzCPN: MW = 414,5 g mol-1

Chart 1. Structures, abbreviations and molecular weights of quinine and derived catalysts.


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2. RESULTS AND DISCUSSIONS 2.1 Membrane Screening Prior to the filtration of the post-reaction mixture, screening experiments with different membranes from DuraMem (DM) Series (Evonik MET Ltd, UK) were made. Quinine (QN) in THF was chosen as a test system for a typical organocatalyst due to its easy availability. Filtration results of membranes with different MWCOs between 150 g mol-1 up to 500 g mol-1 are shown in Figure 1. The numbers adjacent to the abbreviation “DM” are the MWCOs provided by the manufacturer as a 90% rejection for polystyrene oligomeres when acetone is used as solvent.

100

QN

90 Rejection / %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


80 70 60 50

DM 150 DM 200 DM 300 DM 500 Membrane

Figure 1. Screening results for different membranes (Conditions: 0.01 M QN in THF, 30 bar pressure (DM 500: 20 bar), stirred cell, 20 °C).

The membranes DM 150 and DM 200 showed high retentions with 97 % and 93 % respectively, for QN with a molecular weight of 324 g mol-1. A rejection of 90 % was obtained by using the DM 300 membrane. The manufacturer’s cut-off seems to be a good guidance also


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for THF as filtration media. With nearly 80 % rejection the high MWCO of 500 g mol-1 for the DM 500 was verified by the experimental data. However, the membrane seems not to be useable for an efficient catalyst recycling in this molecular weight range. For further investigations only membranes DM 150, DM 200 and DM 300 were used.

100 90 Rejection / %

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80 70 60 50

QN

BzQN

BzCPN

Catalyst

Figure 2. Screening results for different catalysts with DM 300 membrane (Conditions: 0.01 M catalyst in THF, 30 bar pressure, stirred cell, 20 °C).

In order to achieve better retentions the C9-OH group of QN was transformed to C9-OBz to give BzQN. This step was done by esterification with benzoyl chloride according to the literature procedure25, 27. The catalyst was also modified to the corresponding cuprein by ether cleavage in the C6’-OMe position (BzCPN), a well-known organocatalyst for various transformations like the Henry reaction and the Michael reaction7. Structures and abbreviations are shown in Chart 1. Filtration experiments with DM 300 membrane indeed provided an increased rejection for the different catalyst species (Figure 2). BzQN with a molar weight of 428.5 g mol-1 gave the highest retention with 97.1 %. The corresponding cuprein BzCPN (414.5 g mol-1) gave also a good


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rejection of 96.7 %; about 6.7 % points higher than the unsubstituted quinine with around 90 % and not significantly lower than BzQN.

2.2 Henry reaction The Henry reaction of ethyl pyruvate 1 with nitromethane catalyzed by BzCPN in THF was chosen as an example for the separation of an organocatalyst from the post-reaction mixture (Scheme 1). In accordance to literature procedure27 the Henry reaction was first tested in dichloromethane. Due to the lack of stability of most OSN membranes in chlorinated solvents, CH2Cl2 was replaced by THF. Nitromethane was used in large excess in comparison to the pyruvate derivative to ensure complete conversion of the pyruvate derivative. After filtration unreacted nitromethane and solvent could be easily separated from the product under reduced pressure. The temperature was increased from -18 °C to room temperature (20 °C) to get an energy efficient and easy controllable reaction. The achieved results for yield and enantiomeric excess are shown in Table 1. Yield and ee decreased from 93-92 or 91 % respectively to 90 % for THF and room temperature. In general, no large deviation was observed.

O O O

CH3NO2 (10 eq.) 10 mol% BzCPN THF, 20 °C,12 h

OH ∗

O2 N

1

O O 2

Scheme 1. Enantioselective Henry reaction.


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Table 1. Influence of solvent and temperature.

Entry solvent

T Yield ee a (°C) (%) (%)b 1 CH2Cl2 -18 93 91 2 CH2Cl2 25 92 87 3 THF -18 90 94 4 THF 25 90 90 General conditions: 1 M ethyl pyruvate, 10 eq. CH3NO2, 10 mol% BzCPN, 20°C, 12 h; aYield determined by HPLC measurements, based on ethyl pyruvate; bee determined by HPLC measurements. 2.3 Catalyst filtration The molecular weight difference between 2 (M = 177.06 g/mol) and BzCPN (M = 414.19 g/mol) is about a factor of two and seems to be adequate for selective separation of catalyst and product by nanofiltration. According to the screening results (Fig. 1) with different membranes and the simple quinine system, the DM 150, 200, 300 membranes were chosen for filtration experiments with the BzCPN. By lowering the MWCO to 200 g mol-1 or 150 g mol-1 respectively, a rise in retention of the used catalyst BzCPN could be expected. BzCPN

Product 2

100 90 Rejection / %

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80 70 n.d. 60 50

DM 150

DM 200

DM 300

Membrane

Figure 3. Filtration results for different membranes (Conditions: 0.01 M BzCPN in THF, 30 bar pressure, stirred cell, 20 °C, n.d. = not determined).


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The filtration results shown in Figure 3 confirm the expected behaviour. The rejection rose from 96.7 % for DM 300 to 99.6 % for the DM 200 or to 99.9 % for the DM 150 membrane, respectively. The differences seem to be small, but are important for repeated filtration steps or a continuously operated process. In addition to the rejection of the catalyst, the rejection of the product plays an important role for a selective isolation. DM 200 and DM 300 showed a very similar behaviour with 86.5 % and 86.0 % rejection for product 2. The results and the small differences are reliable as all experiments were repeated at least once. For an efficient process development it is also important to monitor the flux during the filtration (Table 2). However, for practical purposes the membrane area can be enlarged to reduce filtration time or to increase volumetric productivity.

Table 2. Flux (J) measurements for BzCPN in THF and 30 bar pressure. JSb JPc Membrane JCa (L h-1 m-2) (L h-1 m-2) (L h-1 m-2) DM 150 13.5 9.1 n.d. DM 200 51.4 46.4 20.3 DM 300 49.6 25.7 n.d. a Filtration conditions: stirred filtration cell, 20 °C; JC = permeate flux during conditioning of membrane with pure THF; bJS = permeate flux for filtration of 0.01 M BzCPN solution in THF; c JP = permeate flux for filtration with the post-reaction mixture. n.d. = not determined.


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DM 150 demonstrated the lowest flux for the screening with catalysts with 9.1 L h-1 m-2 and during the conditioning with pure THF with 14 L h-1 m-2. During the conditioning of the membranes DM 300 and DM 200, a flux of about 50 L h-1 m-2 was achieved for both of the membranes. As compared to DM 300 with 26 L h-1 m-2, DM 200 showed the highest flux during filtration of 0.01 M BzCPN with 46 L h-1 m-2. Combining results from rejection and flux experiments, the membrane DM 200 with a good rejection for the catalyst and the highest flux was chosen for further investigations for catalyst and product separation from post-reaction mixtures.

2.4 Catalyst and product separation from post-reaction mixture Figure 4 shows the standard set-up for the separation experiments with post-reaction mixture. Ethyl pyruvate (25 mmol), BzCPN (10 mol%) and nitromethane (13.4 mL) were dissolved in THF and stirred in a reaction vessel. After 12 h a sample was analysed by HPLC and UV-Vis spectrometry to determine yield and ee of reaction mixture and the exact catalyst starting concentration. The feed solution was diluted with 150 mL of THF and transferred into the filtration cell (batch I). Up to four discontinous diafiltration steps were performed and the feed solution was concentrated to the initial volume of 50 mL. After every step samples were taken from permeate and retentate fractions and analysed. Figure 5 shows the process steps in the stirred filtration cell and figure 6 the amount of substance of product 2 during the reaction/filtration cycles. At the end of the diafiltration, less than 10 % of the synthesized product was left in the cell. More than 90 % of the formed product 2 was flushed out with the permeate stream. Between batches I to IV the catalyst was not isolated. To investigate the catalyst´s activity after the filtration steps, fresh substrates were added to the solution and stirred


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again for 12 h. The results for yield and enantioselectivity are compiled in Table 3, the flux is included in Table 2.

Figure 4. Reaction and filtration set-up for the enantioselective Henry reaction.

The analysis of the reaction product yield, ee and purity was done by HPLC on a chiral stationary phase. After diafiltration, the permeate fractions were evaporated under reduced pressure. The residue was weighed to determine the isolated yield and analysed by NMR without further purification. 1H-NMR confirmed that the residue was the target product, but some signals indicated small impurities from the permeating catalyst. This result was in good agreement with the purity of 94 % determined by the HPLC measurements.


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(3)

Postreactionmixture

fresh substrates

pressure

fresh solvent

(1)

(1a)

(2)

(1b)

product 2 + solvent catalyst

substrate 1

product 2

Figure 5. Process scheme for the diafiltration/reaction cycle in the stirred filtration cell (step (1) discontinuous diafiltration of the diluted post-reaction mixture (1st batch from reaction vessel); step (1a) repeated filtration; step (1b) repeated dilution; step (2) adding fresh substrates; step (3) subsequent reaction. Product 2 Amount of substance / [mmol]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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I diafiltration

II diafiltration III diafiltration IV diafil.

20

15

10

5

0

Process step

Figure 6. Amount of product 2 in the filtration cell during different reaction batches and diafiltration steps (I-IV number of reaction batches).


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Based on the yields and the enantioselectivities measured for the subsequent batches it can be concluded that the catalyst was still fully active and can be easily reused after the nanofiltration steps. The decrease in product yield from batch I with 81 % to 38 % in batch IV mainly depends on the loss of catalyst during the diafiltration steps and retentate sampling. The concentration of BzCPN lowers from 48 mmol/L to 9 mmol/L. A decrease in the retention of product and catalyst was also observed during the consecutive filtration steps, possibly caused by a change of membrane material. Table 3. Separation results for Henry reaction. Yielda Yield isol.b R(P)c R(C)d c(C)e eea (%) (%) (%) (%) (%) (mol/L) I 87 81 76 61.2 99.6 0.048 II 88 80 76 56.0 98.9 0.037 III 88 71 66 64.3 98.4 0.022 IV 89 38 37 25.0 96.4 0.009 a b General Conditions: determined by HPLC measurements, isol. yield after diafiltration steps and solvent removal under reduced pressure, determined by weighing; cRetention of Product 2; dRetention of BzCPN as catalyst; eConcentration of BzCPN as catalyst in the repeated batch reactions, determined by UV-Vis. Batch

3. CONCLUSION OSN has been introduced as an eco-friendly alternative to existing methods for product and catalyst separation for reactions using organocatalysts. Compared to attempts published more than a decade ago modern membranes offer much lower MWCO’s and better defined ranges13. Coupling of the catalyst to polymers or dendrimers is no longer necessary20, 25. The retention of catalyst can be improved by some simple transformations such as esterification of available


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hydroxyl groups. This might even improve the enantioselectivity of the reaction, whereas the coupling to soluble or insoluble polymers often leads to reduced enantioselectivity28. Based on the simplicity of the filtration step OSN is also a technique to be easily integrated into existing laboratory procedures. The high retention rates >96 % verified the possibility for an efficient process design with novel OSN membranes. After the filtration step the product can be isolated in high purity after evaporation of the solvent. No further purification steps are necessary. At the same time the high catalyst’s retention up to 99.6 % allows the separation of homogeneously soluble organocatalysts from the reaction mixtures without any loss of activity. The greatest opportunity is to perform the reactions at very high catalyst loadings, which will yield improved reaction efficiency. Moreover, by decoupling the residence time of catalysts and reactants an improved turnover number will be achieved. However, the largest challenge is the availability of membranes, which are stable against the solvent and reactive reagents. Also the batch to batch reproducibility of both, membrane stability and retention rate sometimes yields problems. During solvent, catalyst and membrane screening and further investigations with other systems DM 200 membranes from one batch were used. Furthermore, membrane stability is still a limiting parameter since within this study a second batch of DM 200 membranes exhibited a significant loss of long term stability in THF. Despite this, OSN has shown tremendous advantages within downstream processing and catalyst recycling and proved its significance within the chemist's toolbox.


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4. EXPERIMENTAL SECTION 4.1 General Moisture sensitive catalyst syntheses were carried out under standard Schlenk conditions. All chemicals and starting materials were obtained from Sigma-Aldrich, Acros Organics and Merck KGaA and were used without further purification unless noted. Solvents for filtration experiments were distilled prior to use. For catalyst screenings and separation experiments THF HPLC grade was used without further purification. NMR spectra are recorded on a Bruker AVANCE 250 II and a Bruker AVANCE 300 III. Catalyst QN was purchased from Acros Organics. Catalysts BzQN and BzCPN were prepared according to the reported literature procedures27, 29.

4.2 Nanofiltration conditions All described filtration experiments were carried out in a modified stainless-steel filtration cell from Berghof (Eningen, Germany) with a volume of 200 mL. Flat-sheet DuraMem membranes (DM) from Evonik MET Ltd, UK were used. Membrane conditioning: The membrane was cut to a size of 44 cm2 and placed in the filtration cell. Each membrane sample was conditioned with the process solvent THF at 30 bar prior to the experiment to flush out any preserving agents e.g. polyethylene glycol. According to the manufacturer a minimum of 40 L solvent per m2 of membrane (176 mL per 44 cm2) was used. The flux during conditioning was monitored by determination of permeate volume over time and calculated by the following equation:


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Flux (J) = (permeate volume)/(membrane area×time) Screening: 0.01 M solution of catalyst or 2 in THF was filled into the filtration cell after membrane conditioning. Filtration was performed with a pressure of 30 bar at room temperature (20°C) unless stated otherwise. Samples of permeate and retentate were taken and analysed. Flux was monitored. 4.3 Measurement of catalyst retention To determine the retention of the different catalysts, samples from filtration were evaporated under argon atmosphere and the residue was dissolved in 0.1 M HCl and diluted. Concentration analysis was done by UV –Vis spectrometry at a wavelength of λ = 370 nm for quinine, BzQN and λ = 380 nm for BzCPN at 25 °C. Retention was calculated by following equation: Retention = (1 - cpermeate/cretentate) 100 %

4.4 Characterisation of Henry Product (2) Yield, ee and purity determination: Yield, ee and purity were determined by HPLC measurements

with

chiral

stationary

phase

consisting

of

amylose

tris(5-chloro-2-

methylphenylcarbamate) (Lux 5u Amylose-2, 250 x 4.6 mm provided by Phenomenex, USA). Eluent: IPA/ Hexane 30/70, 1.0 mL/min, λ = 215 nm, t (major) = 7.97 min, t (minor) = 6.95 min. Isolated yield was determined from permeate after filtration by removing solvent under reduced pressure and weighing the residue. The residue was identified by NMR. 1H-NMR (250 MHz, CDCl3): δ = 4.84 (d, 2J = 13.9 Hz, 1H), 4.55 (d, 2J = 13.9 Hz, 1H), 4.40-4.26 (m, 2H, CH2), 3.73


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(s, 1H, OH), 1.45 (s, 3H, CH3), 1.32 ppm (t, J = 7.1, 3H, CH3); 13C NMR (250 MHz, CDCl3): δ = 173.4, 81.0, 72.4, 63.1, 23.9, 14.0 ppm.

4.5 Catalyst separation from post-reaction mixture For catalyst separation experiments, (1) (2.9 g), 10 mol% BzCPN and 10 eq. nitromethane (13.39 mL) were mixed in a glass vessel. THF was added to a total volume of 50 mL. The solution was stirred at 20 °C for 12 h. Samples were taken and analysed by HPLC to monitor the progress of the reaction. The solution was transferred to the filtration equipment with a NF membrane which had been conditioned before. 150 mL THF were added and the nanofiltration was performed by applying a pressure of 30 bar. After 150 mL of permeate had been collected, the pressure was released and 150 mL of fresh THF were added. Filtration cycles with fresh solvent were repeated until the percentage of formed product in the retentate was lower than 10 %. The cell was refilled with fresh educts and stirred again for 12 h (batch II-IV). For product analysis samples (0.5 mL) from batch, retentate or permeate solution were taken and passed through a plug of silica gel for removal of solids and catalyst. Ethyl acetate was used as eluent. The solvent was removed by heating under argon flow. The residue was dissolved in IPA and analysed by HPLC. Catalyst rejection was calculated as mentioned before. For recovery of pure catalyst after literature procedure, solvent of reaction mixture was evaporated and the residue was filtered through a small silica column27. The column was flushed with ethyl acetate and the catalyst was recovered nearly quantitative after washing the column with MeOH. NMR analysis showed no changes.


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ACKNOWLEDGMENT The authors acknowledge a stipend from Landesgraduiertenförderung (MV, Germany) for T.F.. Special thanks go to Mr. Peter Kumm and Mr. Martin Riedel for technical support concerning the filtration systems and to Mr. Jan von Langermann. ABBREVIATIONS OSN, Organic solvent nanofiltration; MWCO, molecular weight cut-off; PTC phase transfer catalysis; BzCPN, 9-O-benzoyl cuprein; QN, quinine; BzQN, 9-O-benzoyl quinine; DM, DuraMem; J, Flux (L h-1 m-2);R, Retention; IPA, 2-propanol. REFERENCES (1)

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TOC Picture:

Product + Solvent

Post-reaction mixture

Product Catalyst Membrane


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Organic Solvent Nanofiltration as a Tool for Separation of Quinine

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