Biphasic Catalytic Hydrogen Peroxide Oxidation of Alcohols in Flow

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Biphasic catalytic hydrogen peroxide oxidation of alcohols in flow: Scale up and extraction Maryam Peer, Nopphon Weeranoppanant, Andrea Adamo, Yanjie Zhang, and Klavs F. Jensen Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00234 • Publication Date (Web): 09 Aug 2016 Downloaded from http://pubs.acs.org on August 10, 2016

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Organic Process Research & Development

Biphasic catalytic hydrogen peroxide oxidation of alcohols in flow: Scale up and extraction Maryam Peer‡, Nopphon Weeranoppanant‡, Andrea Adamo, Yanjie Zhang and Klavs F. Jensen* Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States ‡

These authors contributed equally to this work.

ACS Paragon Plus Environment

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TABLE OF CONTENT:


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ABSTRACT:

We report continuous solvent-free biphasic alcohol oxidation with hydrogen peroxide and in-line separation of the tungsten polyoxometalate catalyst and phase transfer catalyst from the product. Zinc-substituted polyoxotungstate in combination with the selected phase transfer catalyst drives the oxidation reaction to completion within a short residence time (5-10 min) in a silicon-pyrex microreactor. This continuous and small-scale reactor allows for fast optimization of reaction conditions for each substrate and selection of the phase transfer catalyst. Scaling of the production rate (up to 650 times) is achieved with a Corning Low Flow Reactor (LFR) and an Advanced Flow Reactor (AFR). New scaled-up, in-line membrane-based liquid-liquid extraction units at the reactor outlet first separate the tungsten polyoxometalate catalyst with the aqueous waste stream from the organic product stream. A three-stage counter-current liquid-liquid extraction then removes more than 90% of the phase transfer from the desired organic effluent stream, while reducing the amount of extraction solvent required.

KEYWORDS: Alcohol oxidation; Polyoxometalate; Microreactor; Membrane separation; Continuous liquidliquid extraction; Phase-transfer catalyst


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INTRODUCTION Oxidation is one of the major techniques for transformation of alcohols to value-added products and intermediates, including aldehydes and ketones.1,2 However, oxidation is also considered to be a challenging reaction as it often involves the use of heavy metals or organic stoichiometric oxidants, which are potentially toxic and expensive. Hence, use of available and environmentally friendly oxidants such as pure oxygen, air and hydrogen peroxide is attractive.1,3 Relatively low selectivity and safety concerns have limited the use of aerobic oxidation chemistry in fine chemicals and pharmaceuticals industry.2 Hydrogen peroxide offers several advantages in terms of product purity and atom efficiency while reducing waste generation, especially for smaller scale operations.3 Both homogeneous and heterogeneous catalysts have been employed for efficient and selective oxidation of alcohols.4-8 Tungsten based complexes were found to be most effective for hydrogen peroxide alcohol oxidation owing to their low activity for decomposition of the peroxide.9-11 Noyori et al. used a commercially available tungsten catalyst, Na2WO4, in combination with a phase transfer catalyst (PTC) to oxidize several alcohols in batch mode.3 Polyoxometalates (POMs), a family of anionic metal-oxygen clusters possessing superior activity and selectivity for alcohol oxidation, have attracted significant attention.12-17 In addition to advantages similar to those offered by commercial tungsten-based catalysts, sandwich-type POMs display enhanced oxidative and solvolytic stability.9 Water-soluble POMs can be easily separated and recovered from the biphasic reaction mixture by either filtration or extraction.14,15 Conventionally, liquid phase oxidation is performed in batch or semi-batch reactors, but these processes can suffer from low mass and heat transfer due to small surface to volume ratios.2 The rate of mass transfer is important in biphasic systems where the overall reaction rate is affected


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by the rate of transfer of active species between the two phases. Continuous flow reactors have the potential to mitigate safety challenges associated with using batch reactors.2,18,19 Advantages offered by flow reactors, have led to the growing interest in employing such systems for liquid phase/biphasic alcohol oxidation with homogeneous and heterogeneous catalysts.2,20-22 In this study, we perform continuous PTC-assisted NaZnPOM-catalyzed biphasic alcohol oxidation using hydrogen peroxide oxidant. The reaction conditions are optimized quickly using minimum amount of reagents by using a spiral silicon-pyrex microreactor. In order to demonstrate the wide scope of the continuous catalytic process, a range of alcohols are explored. While biphasic oxidations involving POM-PTC, typically need between one to few hours to reach quantitative conversion in batch mode,3 quantitative conversion and yield are achieved within few minutes of residence time (5-10 min) in the microreactor. Working at elevated pressures allows for safe operation at high temperatures (100 °C) without evaporating the oxidant (H2O2). The reaction is scaled up in increasing volumes using first a Corning Low Flow Reactor (LFR) (internal volume of each plate 0.45 mL) and then a Corning Advanced Flow Reactor G1 (AFR) (internal volume of each plate 8.9 mL).23 The heart-shaped static mixer designs in the channels in these reactors enables enhanced mixing and improved mass transfer through successive splitting and recombination of the immiscible liquid streams.19,24 The production rate increases by a factor of 30 and 650 by carrying out the oxidation reaction in the LFR and AFR, respectively, with similar conversion and yield. Homogeneous transition metal catalysts can be separated from the product by scavenging or using liquid-liquid biphasic conditions.25,26 We implement the latter method because the reaction effluent is biphasic. The POM catalyst is dissolved in the aqueous phase, and can be readily separated from the product, which is the organic phase after the oxidation. The removal of the


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PTC is more challenging, and it requires an additional step. Several methods of separation of PTC from the reaction mixture have been studied, including column chromatography, extraction, distillation, adsorption to an insoluble support.27,28 Extraction is the most common for the separation of water-soluble PTC owing to its high efficiency, easy setup, less heat-intensive operation, which could cause PTC decomposition, and simple downstream processing for recovery and recycle.29,30 In this work, we present continuous PTC extraction of fully integrated with continuous synthesis. To our knowledge, there have not been examples on continuous extraction of PTC from the reaction mixtures containing aldehydes and ketones. Instead of gravity-based techniques, the phase separation is accomplished using a membrane with selective wettability. This approach not only avoids lengthy batch-wise process due to the small density differences between the two phases, but also it enables for scale-up and cascading of separation units, which improves the PTC extraction efficiency while minimizing the amount of solvents required and waste produced.

RESULTS AND DISCUSSION Oxidation in the Microreactor. The spiral microreactor served to assess reaction conditions and screen PTCs for oxidation of different substrates (S). Two quaternary ammonium salts with different molecular composition, hydrocarbon chain lengths, and counter ions ( ), Aliquat 336 and tributylammonium hydrogensulfate (TBAHS), served as PTCs in the biphasic oxidation reactions. The initial tests at flow rate of 15 µL/min (residence time of 10.6 min) showed strong dependence of conversion on the amount of PTC and temperature. At a fixed residence time, PTC and catalyst (C) quantity (10.6 min, molar ratio: PTC/C: 12 and S/C: 500),


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benzyl alcohol conversion increased with temperature from 25 to 100 °C, with almost 100% selectivity towards benzaldehyde (Figure 1a). The molar ratio of PTC to catalyst was chosen to be 12 in the initial experiment based on the number of negative charges on each catalyst molecule ([WZn3(ZnW9O34)2]12-) that are available to attach to ammonium counter ions. TBAHS displayed better performance at all temperatures owing to the less bulky hydrocarbon chains and better solubility in water, allowing for faster transport between the two phases and easier formation of the PTC-POM complex, consistent with previous findings.31 The amount of PTC had a substantial effect on the reaction conversion, as well. In the absence of PTC, the conversion is as low as 30 mol% even at high temperatures (e.g. 90°C). Increasing the PTC/C molar ratio to 6 resulted in more than doubling of the conversion (Figure 1b). Based on the preliminary results at different condition and to minimize the use of PTC, we selected a PTC/C ratio of 6 for the future experiments (unless otherwise mentioned).

100 Conversion (mol%)

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(a) 80 60 40 Aliquat 336 TBAHS

20 0 20

40 60 80 100 Temperature (oC)

120


7


100 Conversion (mol%)

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(b)

80 60 40 Aliquat336

20

TBAHS 0 0

10

20

30

PTC/C Figure 1. (a) Conversion vs. reaction temperature for PTC/C=12, and (b) conversion versus PTC/C ratio at T=90 °C for benzyl alcohol oxidation in the microreactor. Substrate to catalyst ratio(S/C) = 500, residence time = 10.6 min. Given the same residence time, a flow rate ratio of 1.1 for aqueous to organic phase (FA/FO) results in the maximum conversion and yield (Figure 2a). At high temperatures (100°C), doubling the amount of catalyst has negligible impact on the conversion (Figure 2b). This observation along with the significant increase in the conversion by incorporating more PTC, shows the important role of the PTC in determining the overall reaction rate. The PTC catalyzed reactions involve multiple steps. Formation of active peroxo species happens in the aqueous phase followed by the cation exchange at the interface.3 The quaternary ammonium cation of the PTC aids to transfer the active species (peroxo anion) into the organic phase, where the reaction takes place. By increasing the PTC/C ratio (Figure 1b) we gradually approach and exceed the stoichiometric amount of PTC required for complexation with all the catalyst present in the aqueous phase. Increasing the PTC beyond this value does not enhance the overall reaction rate


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and it is the more beneficial to enhance the exchange rate at the interface by more efficient

Conversion and Yield (mol %)

mixing or boosting the reaction kinetic by working at higher temperatures.28,32

100 (a) 80 60 40

Conversion

20

Yield

0 0

1

FA/FO

2

3

100 (b) Conversion (mol%)

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 60

S/C=500, T=100 C

40

S/C=500, T=90 C

20

S/C=250, T=90 C S/C=250, T=100 C

0 0

5 10 Residence Time (min)

15

Figure 2. (a) Conversion as a function of FA/FO at S/C=500, T=100 °C and residence time =10.6 min, and (b) conversion versus residence time, for benzyl alcohol oxidation in the microreactor (PTC/C=12).


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The biphasic oxidation reaction in the spiral microreactor for reactive alcohols reaches quantitative conversion and yield within 5-6 minutes at S/C and PTC/C ratios of 500 and 6, respectively. We also performed benzyl alcohol oxidation using commercial sodium tungstate catalyst in the spiral microreactor and found out much higher molar concentration (S/C=80) is required to achieve similar conversion (83 mol%), within the same time frame (5.3 min). Thus, the zinc-substituted polyoxotungstate offers higher molar-based oxidation activity compared to sodium tungstate. Additionally, the contacting segmented flow pattern in the microchannels of the spiral reactor increases the interfacial area between the organic and aqueous phases and facilitates the transfer of active species. Consequently, the reaction time decreases to 5 minutes for benzyl alcohol and 1-phenyl ethanol; considerably shorter compared to the batch procedure (1 h for 1-phenyl ethanol and 3-5 h for benzyl alcohol) using sodium tungstate as the catalyst and methyl-trioctylammonium hydrogensulfate as PTC.3 Moreover, the PTC utilized in this study (TBAHS) is less expensive compared to the previously used methyltrioctylammonium hydrogen sulfate. In order to expand the scope of the presented methodology, we attempted the continuous oxidation of various secondary aliphatic alcohols, substituted benzylic alcohols and diols at the identical condition (Table 1). Secondary alcohols such as 2-pentanol (entry 4, Table 1) are selectively oxidized to ketones. Moreover, the secondary alcohol moiety in 2-ethyl-1,3hexanediol oxidation is selectively oxidized and gives 2-ethyl-1-hydroxy-3-hexanone with 100% selectivity (entry 5, Table 1). Similar observation are reported in previous studies.3,10 Again, the reaction rate was enhanced significantly using the microreactor compared to batch systems, as the result of enhanced transfer at the interface.


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The low conversion of 3-pyridine methanol (entry 8, Table 1) is attributed to the electron withdrawing effect of nitrogen substitution as reported in the literature for different oxidants and catalysts.33-35 The role of the PTC/C ratio is as significant as the effect of catalyst concentration (comparing entries 1, 3 and 5 in Table S1). Conversion of 2-pentanol increases to ~64 mol% either by decreasing the S/C ratio to 250 or increasing the PTC/C to 12. It is possible to reach higher conversion through increasing both PTC/C and residence time (entry 6), but the flow rate of oxidant (hydrogen peroxide) needs to be adjusted carefully in order to avoid over-oxidation and loss in selectivity (entries 7 and 8 in Table S1).

Table 1. Results of continuous oxidation of different substrates in the spiral microreactor at S/C=500, PTC/C=6, T=100°C, P=100 psi and 5.3 min residence time. Entry

Substrate

Conversion (mol%)

Product

Selectivity (%)

1

83

94

2

98.8

100

3

79

100

4

53.2

100

5

66

100


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6

15.7

100

7

10.8

100

8

1

100

9

52.7

100

10

100

100

11

23.6

60

Consistent with previous results, we found that TBAHS acts more efficiently than Aliquat 336, in transferring the active species between the two phases (Table S2). Selective oxidation of the secondary alcohol functionality in 2-ethyl-1,3-hexanediol is well promoted (83.1 mol% conversion) in the microreactor utilizing TBAHS and 10.6 min of residence time. For oxidation of cyclohexanemethanol, the conversion increases at longer residence times or larger PTC/C ratios (Table S3), but we observe significant loss in the selectivity due to overoxidation. At high PTC concentration, the presence of excess catalytically active species and faster kinetic of the second oxidation step to carboxylic acid, results in lower overall yield of aldehyde (entry 3). Similar results (low yield of intermediate aldehyde) has been reported for oxidation of cylcohexanemethanol and other aliphatic alcohols.36


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Increasing the amount of catalyst (decreasing S/C ratio) does not always result in higher conversion (as observed for 1-phenyl-2-ethanol, entries 2 and 3 in Table S4). However, keeping the S/C ratio constant and increasing the amount of PTC (higher PTC/C ratio) lead to higher conversions (compare entries 2 and 4 in Table S4). Doubling the PTC/C ratio is more effective than increasing the catalyst loading, which underscores the significance of adjusting the PTC amount for each specific alcohol to maximize the overall rate. It is an indirect observation of the critical role of the active species transfer rate at the aqueous-organic interface through the formation of PTC-POM adducts. This effect is more pronounced at longer residence times when the mass transfer coefficient is smaller and the optimum amount of PTC required is higher. The lower mass transfer coefficient at longer residence times have been previously reported and attributed to the change in the flow pattern and the contacting geometry between the two phases due to the variation in flow rate.19 Reaction scale-up. Two intermediate sized systems, the Corning Low Flow Reactor (LFR) and Advanced Flow Reactor (AFR) served to scale up the biphasic oxidation reaction. These reactors have high mass transfer coefficients at high flow rates of two immiscible liquids.19,24,37 Additionally, each plate in these reactors is sandwiched between two glass heat transfer plates, allowing for fast and improved heat transfer. Consequently, we were able to scale up the continuous oxidation without sacrificing conversion and yield. Table 2 summarizes the conversion results for five different substrates in the LFR along with the corresponding values obtained in the spiral microreactor. The residence time in the LFR was set to 5 min, slightly shorter than the residence time in the microreactor (5.3 min). Despite the shorter residence time in the LFR, similar values for conversion were obtained implying the effective exchange of the active species owing to the enhanced mixing in the LFR. The organic phase flow rate is 0.55


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ml/min in the LFR raising the production level by a factor of ~38 as compared to the microreactor. We evaluated the oxidation performance of three of the substrates in the Corning AFR in order to further scale up the production rate and confirm the improved mass transfer between the two phases in this reactor (Table 2). We fixed the residence time in AFR at 5 min, slightly shorter than that of the microreactor. Nevertheless, the obtained conversions were higher for all three alcohols in the AFR, further evidencing the efficient mixing and highly facilitated mass transfer in this reactor configuration. The estimated Damköhler number for 1-phenyl ethanol oxidation (assuming first order reaction) in both LFR and AFR is 0.04, indicating the absence of mass transfer limitations at the reaction condition in these reactors. The production rate was scaled up by a factor of ~660 utilizing the AFR. In the case of alcohols with slower kinetic and lower conversion such as 3-phenyl-1-propanol, longer residence time is required to achieve acceptable conversion and yield. The AFR system has a total volume of 100 mL and the flow rate was adjusted at 20 mL/min based on the recommended flow rates for the system as well as targeted residence time (5 min). The limited number of plates available in our AFR, restricted the maximum achievable residence time. As an alternative, we used PFA tube as a longer residence time reactor and increased the residence time to 10 minutes, keeping the total flow rate constant, and achieved 32.6 mol% conversion. Quantitative conversion could presumably be achieved by using even longer tubing and packing or in-line static mixers in the tube reactor. The turnover frequency (TOF) calculated from the data presented by Noyori3 for batch 1phenyl ethanol oxidation using sodium tungstate as catalyst and 1 h reaction time, equals to 479 h-1. In the current study, for 1-phenyl ethanol oxidation at S/C=500, PTC/C=6, T=100°C and


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P=100 psi in the continuous reactor systems, the TOF is estimated to be 972 h-1 and 6012 h-1, for commercial sodium tungstate and synthesized POM catalyst, respectively. The TOF values demonstrate the improved performance of the biphasic reaction offered by enhanced mixing in the continuous flow reactor systems. The reported TOF values are all estimated based on the total number of moles of catalysts used. If the basis were the number of tungsten atoms in the catalyst molecule, the synthesized catalyst would have a TOF of 316 h-1.

Table 2. Conversion data for different substrates in Corning LFR, AFR and spiral microreactor at T=100°C, P=100 psi, S/C=500 and PTC/C=6. Substrate

Microreactor (mol%)

LFR (mol%)

AFR (mol%)

83

81.5

87

98.8

95

100

79

78

83

10.8

10.2

NA

15.7

15.8

NA


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Continuous separation of biphasic reaction stream. The data presented in Tables 1, and S1S4 suggest that although the employed flow microreactor and POM-PTC combination is an effective platform for fast and solvent-free oxidation of numerous alcohols, the amount of PTC needs to be tuned for each specific substrate to achieve acceptable conversion within short residence times (5-10 minutes). For less reactive alcohols such as aliphatic and primary alcohols, the amount of PTC dissolved in the organic substrate must be increased by a factor of at least two to complete the reaction. Although the PTC used in this study is relatively inexpensive, the addition of excess PTC necessitates its extraction from the product (organic phase) in-line and downstream from the reactor. Traditionally, the phase separation of a biphasic reaction mixture is performed using gravity. However, for the current system, although a sharp interface formed quickly within 10 minutes, the density difference between the organic and aqueous phases was small enough to keep emulsion stable. The top phase remained visibly turbid for a long period of time (Figure 3). The densities of the organic and aqueous phases at 15 ˚C are about 1.05 and 0.99 g/cm3. This agrees with the referenced shake flask characteristics that the dispersion tends to form for the system with the density difference of 0.05 g/cm3 or smaller. 38

Figure 3. PTC extraction in batch requiring long phase separation time due to slow droplet coalescence.


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To address this issue, we employed liquid-liquid extraction in laminar slug flow, followed by microporous membrane-based phase separation. This method allowed mass transfer of the key components between the two immiscible phases to happen without any droplet breakup and coalescence. The two phases were subsequently separated based on their wettability characteristics, instead of density. The organic phase preferentially wets the hydrophobic porous Teflon membrane, which facilitated drop separation39 and removed the organic product phase from the aqueous phase containing the POM. The oxidation of benzyl alcohol into benzaldehyde using the synthesized catalyst was selected as a case study to demonstrate the continuous workup procedure. After the completed alcohol oxidation in Corning® LFR and AFR, the biphasic reaction stream was flowed into PFA tubing to allow sufficient times for interphase equilibrium. Then, the membrane-based separator was used to remove the aqueous phase from the flow system. At this stage of separation, significant amount of catalyst was removed with the aqueous phase (as confirmed by analyzing the aqueous phase using LC-MS). However, most of the PTC still remained in the benzaldehyde phase, i.e. 3.4-3.6 mg/mL. High extraction of PTC with multistage cascading. Toluene and water were found to be effective solvents in extracting the product into organic phase while removing the PCT into the aqueous phase. In a batch test using a shake-flask (L1), one portion of the benzaldehyde phase was combined with two portions of toluene and one portion of water. This solvent ratio was a compromise between maximized removal of PTC and minimized amount of solvent consumption. With this ratio, 77% of PTC was removed after a significantly long mixing and settling time, driven by gravity (> 20 hrs) at 20 ˚C. Assuming equilibrium between the two phases, this result provided a benchmark for assessing continuous separation performance as


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well as a determination of a distribution coefficient of PTC between the organic and aqueous phases K PTC . Three assumptions were made to simplify the analysis, particularly when employed for different types of cascades discussed later in this section. •

The distribution coefficient for the PTC, KPTC, is constant.

•

The benzaldehyde stream, which is the effluent from the previous separation step, is completely miscible with toluene but immiscible with water. The volumetric flow rate of the benzaldehyde, toluene and water are F , FT , and FW , respectively.

•

Extraction generates mutually insoluble organic raffinate and aqueous extract phases.

The last two assumptions imply that the flow rates of raffinate and extract phases are equal to FT + F and FW , respectively. The concentrations of the PTC in the benzaldehyde, the raffinate, benz raf ext and the extract streams are CPTC , CPTC , and CPTC , respectively. The material balance for PTC

around a single stage of extraction is written as follows: benz raf ext C PTC ⋅ F + 0 ⋅ FT + 0 ⋅ FW = C PTC ⋅ (F + FT ) + C PTC ⋅ FW

(1)

The concentrations and flow rates have units of mg/mL and mL/min. Rearrangement gives the fraction of PTC that is not extracted out with the aqueous phase: raf C PTC

C

org PTC

=

(2)

1 1+ E

org is the concentration of PTC in the organic phase entering the extraction step, i.e., the CPTC

resulting stream of the mixing between the benzaldehyde phase and toluene, given by:


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org CPTC =

(3)

benz CPTC FT   1 +  F  

The extraction factor then takes the form: (4)

 F  C ext E = K PTC ⋅  W  with K PTC = PTC raf CPTC  F + FT 

Table 3 lists similar expressions derived for crosscurrent and countercurrent cascades. Using Equations 2-4 and the experimental value of 77% PTC removed in one-stage batch experiment, K PTC was calculated to be 10.04. We thus used this value to predict theoretically the fraction of PTC removed in different types of configurations and number of stages, using the set of expressions in Table 3.

Table 3. Expressions of PTC remaining in the raffinate stream and extraction factor (E) Configurations

raf Expression for CPTC org

Expression for E

Single stage

1 1+ E

 F  E = K PTC ⋅  W   F + FT 

N-stage crosscurrenta

1 (1 + E ) N

  FW E = K PTC ⋅    F ⋅ N + FT 

CPTC

1

N-stage countercurrent

N

∑ En n =0

 F  E = K PTC ⋅  W   F + FT 

a

Based on the assumption that the water and toluene flow rates, FW and FT, are divided into equal portions that are sent to each stage.


19


As shown in Figure 4, more than 92% removal of PTC could be potentially achieved by simply adding another stage of extraction. The plot also demonstrates that the countercurrent cascade performed more efficiently compared to the crosscurrent cascade, i.e. a higher degree of extraction for a given amount of solvent and number of stages. 100%

Percent extraction of PTC

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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98% 96% 94% countercurrent crosscurrent

92% 90% 2

3 4 Number of stages

5

Figure 4. Percent extractions of PTC that are theoretically calculated using Table 3 (FT: FW : F = 2:1:1, KPTC = 10.04). Continuous extraction of PTC and scale-up. The previous section prompted an implementation of membrane-based separators into the multistage countercurrent cascade. For the LFR system, each stage accommodated a residence time of 52.5 seconds for mixing. According to Table 4, this length of time was sufficient for the mass transfer to reach equilibrium, as indicated by close agreement between the benchmark (L1) and the single-stage continuous extraction (L2) results. The membrane-based separators were assembled in a 3-stage countercurrent cascade (Figure 5). The mixing in each stage happened in cocurrent slug flow, but the arrangement of multiple stages was countercurrent such that the overall aqueous and organic phases flowed in the


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opposite directions. The aqueous phase was delivered from stage i to i-1 by peristaltic pumping while the organic phase flowed from stage i to i+1 by the pressure drop of the system.

Figure 5. The scheme of the 3-stage countercurrent extraction depicts the overall flows of aqueous and organic phases through the setup in the opposite directions. (Dot line: cocurrent slug flow, solid line: single-phase flow, blue line: organic phase, red line: aqueous phase).

The 3-stage countercurrent cascading (L4) resulted in 92% extraction of PTC, with only 0.3 wt% PTC in the final stream of benzaldehyde. As shown previously, the countercurrent cascade is, theoretically, more efficient than the crosscurrent cascade. Experimentally, the 2-stage crosscurrent cascade (L3) required twice as much extraction solvents as the 3-stage countercurrent cascade (L4) to achieve the same degree of purification, i.e. 92% extraction of PTC (Table 4).


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Table 4. Results of the PTC extraction experiments at different conditions for LFR system Experiment

Conditions

% PTC extraction

PTC wt.% in the product

L1

Batch (shake-flask)

77

0.86

L2

Continuous single stage

75

0.94

L3

Continuous 2 stage crosscurrent

92

0.3

L4

Continuous 3 stage countercurrent

92

0.3

The PTC extraction was scaled up to the throughput of the AFR system. The membrane-based separator was scaled 20 times by increasing the membrane area and the size of the integrated pressure control element (Figure 6). Preliminary test with toluene and water demonstrated complete separation at 10-100 mL/min in flow rates (Table S6).

Figure 6. The two sizes of the membrane-based separators used in the post-reaction purification steps. The small and large separators were implemented for the LFR and AFR systems, respectively. The large-scale membrane separators were assembled into the 3-stage countercurrent extraction, similar to the setup in the LFR system; each stage had the PFA tubing to allow for complete mass transfer before the separator. We used tubing with the same diameter as the LFR system (1/8” O.D. and 1/16” I.D.) but with a shorter length, i.e. shorter mixing time. At this


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scale, the short residence time (15 seconds) was sufficient for the mass transfer completion owing to enhanced mixing at high flow velocity. This was verified by similar percent extractions obtained from the shake-flask test (A1) and the continuous single-stage extraction (A2), as shown in Table 5. The 3-stage countercurrent cascade (A3) gave about 89% extraction of PTC. The similar extraction efficiencies obtained for LFR and AFR systems demonstrate the ability to scale the membrane separation technology. Table 5. Results of the PTC extraction experiment at different conditions for the AFR system. Experiment

Conditions

% PTC extraction

PTC wt.% in the product

A1

Batch (shake-flask)

63

1.4

A2

Continuous single stage

67

1.2

A3

Continuous 3 stage countercurrent

89

0.4

CONCLUSION We performed continuous biphasic oxidation of different alcohols using zinc-substituted polyoxotungstate assisted by a phase transfer catalyst, (TBAHS). Oxidation of 1-phenyl ethanol and benzyl alcohol reached quantitative conversion within 5 minutes at the optimized reaction condition in a spiral microreactor. Reaction conditions including S/C and PTC/C ratio required further adjustment in order to reach similar conversions for less reactive alcohols. Increasing PTC/C ratio was found to be most effective in enhancing the reaction rate through improving the rate of the active species exchange at the interface. The reaction was scaled up using Corning LFR and AFR systems without sacrificing mass and heat transfer, increasing the productivity by a factor of 650 in the case of the AFR. We successfully performed continuous extraction downstream the reactors using PTFE membranes, to separate the excess PTC from the organic


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phase and purify the product. Membrane modules having two different sizes were employed to scale up the extraction process, and in both cases high extraction extent (>90%) was achieved using three-stage counter-current configuration, leaving as low as 0.3 wt% of PTC in the product and consuming less solvent compared to other extraction modes. The fully continuous integrated reaction-separation procedure used for production and purification could be applied to other multiphase reactions.

EXPERIMENTAL METHODS Materials. All the substrates were purchased from Sigma-Aldrich. Hydrogen peroxide solution

(35 wt.%, Sigma-Aldrich) served as the oxidant. Methyltrioctylammonium chloride (Aliquat 336) and tetrabutylammonium hydrogen sulfate (97%) (TBAHS) were purchased from SigmaAldrich and utilized as the two main PTCs. Sodium tungstate dihydrate (≥99%, Sigma-Aldrich) was used as the commercial catalyst for comparison purpose.

All of reaction products to

generate standard calibration curves using GC and HPLC, were obtained from Sigma-Aldrich. We adapted the procedure developed by Tourne et al.40 to synthesize zinc-substituted sandwich-type polyoxotungstate (Na12[WZn3(ZnW9O34)2]). In a typical synthesis 87.5 ml of an aqueous solution of sodium tungstate dihydrate (31.75 g, 0.095 mol) was treated with 6.25 ml (0.087 mol) of 14 M nitric acid, while heated at 85 °C and vigorously stirred. The stirring was continued until the precipitate formed during the addition of nitric acid was completely dissolved. This step was followed by drop wise addition of zinc nitrate hexahydrate (7.45 g, 0.025 mol) solution in water (25 ml) while heating at 95°C and stirring. The rate of the addition was adjusted using a syringe pump so that the solution remains clear during this step. Then the solution was slowly cooled to 50°C and half of the solvent was evaporated using a rotary evaporator at 50°C. Then the solution was kept unstirred for 2-3 days at 50°C for crystallization


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to occur. The white needle-like crystals of the catalyst were filtered and washed several times using excess amount of water and dried in oven overnight at 70°C. Elemental analysis, FTIR spectroscopy and X-ray diffraction pattern results for the synthesized catalyst are presented in Table S5 and Figure S1, respectively. Oxidation Procedure and the Reactors. We prepared the starting feed solutions by dissolving the catalyst and PTC in hydrogen peroxide solution and substrate, respectively. In a typical reaction for benzyl alcohol oxidation in the microreactor, 63 mg of PTC (TBAHS) was dissolved in 1.66 g alcohol. In a separate beaker 185 mg of the synthesized catalyst was dissolved in 1.63 g of 35 wt.% hydrogen peroxide solution (molar ratio: Phase Transfer Catalysts/Oxidation Catalyst=PTC/C=6 and Substrate/Oxidation Catalyst =S/C=500, Hydrogen peroxide/Substrate=1.1). When necessary, we increased the amount of prepared solutions by a factor of 15-30 in order to run the scaled up experiments in the LFR and AFR. We used a spiral microreactor41 having the total internal volume of 160 µL and channel size of 4.27×10-4 m to perform the initial experiments and optimize the reaction condition. We utilized two syringe pumps (Harvard Apparatus, PHD 2000) to deliver the organic and aqueous phases into the reactor. The residence time is defined as the reactor volume (µL) divided by the total flow rate (µL/min). The microreactor consists of two distinct zones, mixing and reaction zone. A custom-made back- pressure regulator or BPR (Figure S5) set at 100 psi was placed downstream the reactor to minimize the ineffective decomposition of hydrogen peroxide. The total flow rate was set to 30 µL/min, resulting in a residence time of 5.3 min, unless otherwise mentioned. The Corning LFR consists of nine plates connected in sequence. Each plate holds an internal volume of 0.45 mL and the total volume of the reaction system is 5.8 mL.18 The organic and aqueous phases were conveyed to the reactor using a HPLC pump (Rainin Dynamax SD-200)


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and a high pressure ISCO pump (Teledyne ISCO, 500D), respectively. We set two check valves and two pressure-relief valves (250 psi) at the inlets of the reagents to guarantee the process safety. By setting the total flow rate at 1.15 mL/min, we realized the residence time of 5 min in the LFR. Further reaction scale-up was accomplished in the Corning AFR. The total system volume was 100 mL with the recommended flow rate of 10-200 mL/min. The same pumps used for the LFR system supplied the feed streams to the reactor. Similar to the LFR system, each inlet line was equipped with a check valve and a relief valve. We adjusted the total flow rate at 20 mL/min in order to fix the residence time at 5 min. The reaction temperature in both cases (LFR and AFR) was controlled using a Lauda Integral XT 750 heating system circulating the heat exchange fluid into the heat exchange layers of the reactor plates. The reaction samples were collected after 3-5 residence times and the organic and aqueous phases were analyzed using GC-FID or HPLC. Membrane Phase Separation and PTC Extraction. There are two post-reactor steps for purification of the product from POM-PTC: a) aqueous portion removal and b) PTC extraction (Figure 7). For the aqueous portion removal step, the biphasic reaction stream was first separated using a membrane-based separator. Similar to the previous design reported in Adamo et al.,39 the separator consisted of a Pall ZeflourTM 0.5 µm hydrophobic PTFE membrane and the integrated pressure control element. The wetted structure of the separator was made of ultra-high molecular-weight polyethylene (UHMW), which provided excellent chemical compatibility, and embedded in an aluminium shell for enhanced mechanical support (Figure S2-a). The current design of the separator accommodates the total flow rate between 1-20 mL/min. We also designed a scaled-up version of the separator (Figure S2-c) to be applied with the reaction stream from the AFR.


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Next, for the PTC extraction, the separated organic stream was mixed with extraction solvents, toluene and Milli-Q water. Different operational conditions (e.g., solvent-to-feed ratio) and cascading configurations for the liquid-liquid extraction were studied (Table 6). Each extraction stage required the sufficient length of tubing before the phase separation in the membrane-based separator to allow complete mass transfer of the solute (PTC). Batch extraction using rigorous mixing and long setting time served as a benchmark for equilibrium extraction. All the experiments were carried out at room temperature (20˚C). The purification of benzaldehyde, which is the product of benzyl alcohol oxidation, was selected as a case study for these extraction experiments. Both organic and aqueous outgoing streams were collected after 3-5 residence times, and analyzed using LC-MS.

Figure 7. Block diagram of the three main steps for the fully–continuous oxidation of alcohols (dotted line: biphasic stream, solid line: single-phase stream).


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Table 6. Various conditions and configurations for the PTC extraction experiment for LFR and AFR system.

Low-flow reactor (LFR) experiment Experiment FTa

FWa

S/Fb

Nc

Type of extractiond

Cascadinge

L1

2

1

3:1

1

Batch

-

L2

2

1

3:1

1

Continuous

-

L3

4

2

6:1

2

Continuous

Crosscurrent

L4

2

1

3:1

3

Continuous

Countercurrent

Advanced-flow reactor (AFR) experiment

a

A1

20

10

3:1

1

Batch

-

A2

20

10

3:1

1

Continuous

-

A3

20

10

3:1

3

Continuous

Countercurrent

FT and Fw: volumetric flow rates of toluene and water, respectively, in mL/min.

b

S/F: Solvent-to-benzaldehyde phase ratio is defined as the sum of water and toluene volumetric flow rates divided by the flow rate of the organic stream from the previous step. c

Number of extraction stages

d

Batch refers to the gravity-based extraction (i.e. shake-flask) whereas the continuous extraction refers to the use of segmented flow inside the small-diameter tubing, followed by the membrane-based separation. e

Details of crosscurrent and countercurrent setups are in the Supplementary Information.


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ASSOCIATED CONTENT

Supporting Information. Complete details of the analytical methods (GC, HPLC and LC-MS), catalyst characterization (elemental analysis, FTIR, and XRD), the setup designs for the multistage extraction and the back pressure regulator. This material is available free of charge via the internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected]. Author Contributions ‡

M.P. and N.W. contributed equally to this work.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

The authors gratefully acknowledge the financial support from Novartis-MIT Centre for Continuous Manufacturing. We also thank Corning Inc. for the LFR and AFR reactors. We thank Eleanor Rose from Imperial College London for assistance with the extraction experiment.

REFERENCES

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Biphasic Catalytic Hydrogen Peroxide Oxidation of Alcohols in Flow

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