Biphasic Catalytic Hydrogen Peroxide Oxidation of Alcohols inFlow: Scale-up and ExtractionMaryam 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

*S Supporting Information

ABSTRACT: We report continuous solvent-free biphasic alcohol oxidation with hydrogen peroxide and in-line separation of thetungsten polyoxometalate catalyst and phase transfer catalyst from the product. Zinc-substituted polyoxotungstate incombination 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 reactionconditions for each substrate and selection of the phase transfer catalyst. Scaling of the production rate (up to 650 times) isachieved with a Corning low flow reactor (LFR) and an advanced flow reactor (AFR). New scaled-up, in-line membrane-basedliquid−liquid extraction units at the reactor outlet first separate the tungsten polyoxometalate catalyst with the aqueous wastestream from the organic product stream. A three-stage countercurrent liquid−liquid extraction then removes more than 90% ofthe phase transfer catalyst from the desired organic effluent stream while reducing the amount of extraction solvent required.

■ INTRODUCTION

Oxidation is one of the major techniques for transformation ofalcohols to value-added products and intermediates, includingaldehydes and ketones.1,2 However, oxidation is also consideredto be a challenging reaction as it often involves the use of heavymetals or organic stoichiometric oxidants, which are potentiallytoxic and expensive. Hence, the use of available and environ-mentally friendly oxidants such as pure oxygen, air, andhydrogen peroxide is attractive.1,3 Relatively low selectivity andsafety concerns have limited the use of aerobic oxidation chem-istry in fine chemicals and pharmaceuticals industry.2 Hydrogenperoxide offers several advantages in terms of product purityand atom efficiency while reducing waste generation, especiallyfor smaller scale operations.3

Both homogeneous and heterogeneous catalysts have beenemployed for efficient and selective oxidation of alcohols.4−8

Tungsten-based complexes were found to be most effective forhydrogen peroxide alcohol oxidation owing to their low activityfor the decomposition of the peroxide.9−11 Noyori et al. used acommercially available tungsten catalyst, Na2WO4, in combi-nation with a phase transfer catalyst (PTC) to oxidize severalalcohols in batch mode.3 Polyoxometalates (POMs), a family ofanionic metal−oxygen clusters possessing superior activity andselectivity for alcohol oxidation, have attracted significantattention.12−17 In addition to advantages similar to thoseoffered by commercial tungsten-based catalysts, sandwich-typePOMs display enhanced oxidative and solvolytic stability.9

Water-soluble POMs can be easily separated and recoveredfrom the biphasic reaction mixture by either filtration orextraction.14,15

Conventionally, liquid-phase oxidation is performed in batchor semibatch reactors, but these processes can suffer from lowmass and heat transfer due to small surface to volume ratios.2

The rate of mass transfer is important in biphasic systemswhere the overall reaction rate is affected by the rate of transfer

of active species between the two phases. Continuous flowreactors have the potential to mitigate safety challengesassociated with using batch reactors.2,18,19 Advantages offeredby flow reactors have led to the growing interest in employingsuch systems for liquid phase/biphasic alcohol oxidation withhomogeneous and heterogeneous catalysts.2,20−22

In this study, we perform continuous PTC-assistedNaZnPOM-catalyzed biphasic alcohol oxidation using hydro-gen peroxide oxidant. The reaction conditions are optimizedquickly using a minimum amount of reagents by using a spiralsilicon Pyrex microreactor. In order to demonstrate the widescope of the continuous catalytic process, a range of alcoholsare explored. While biphasic oxidations involving POM−PTCtypically need between one to few hours to reach quantita-tive conversion in batch mode,3 quantitative conversion andyield are achieved within a few minutes of residence time(5−10 min) in the microreactor. Working at elevated pressuresallows for safe operation at high temperatures (100 °C) withoutevaporating the oxidant (H2O2). The reaction is scaled up inincreasing volumes using first a Corning low flow reactor(LFR) (internal volume of each plate 0.45 mL) and then aCorning advanced flow reactor G1 (AFR) (internal volume ofeach plate 8.9 mL).23 The heart-shaped static mixer designs inthe channels in these reactors enables enhanced mixing andimproved mass transfer through successive splitting andrecombination of the immiscible liquid streams.19,24 Theproduction rate increases by a factor of 30 and 650 by carryingout the oxidation reaction in the LFR and AFR, respectively,with a similar conversion and yield.Homogeneous transition metal catalysts can be separated

from the product by scavenging or using liquid−liquid biphasicconditions.25,26 We implement the latter method because the

Received: July 8, 2016Published: August 9, 2016

Article

pubs.acs.org/OPRD

© 2016 American Chemical Society 1677 DOI: 10.1021/acs.oprd.6b00234Org. Process Res. Dev. 2016, 20, 1677−1685

Dow

nloa

ded

via

BU

RA

PHA

UN

IV o

n Ja

nuar

y 11

, 202

1 at

03:

28:0

3 (U

TC

).Se

e ht

tps:

//pub

s.ac

s.or

g/sh

arin

ggui

delin

es f

or o

ptio

ns o

n ho

w to

legi

timat

ely

shar

e pu

blis

hed

artic

les.

reaction effluent is biphasic. The POM catalyst is dissolved in theaqueous phase and can be readily separated from the product,which is the organic phase after the oxidation. The removal ofthe PTC is more challenging, and it requires an additional step.Several methods of separation of PTC from the reaction mixturehave been studied, including column chromatography, extraction,distillation, and adsorption to an insoluble support.27,28 Extractionis the most common for the separation of water-soluble PTCowing to its high efficiency, easy setup, less heat-intensive oper-ation, which a high temperature could cause PTC decomposition,and simple downstream processing for recovery and recycle.29,30

In this work, we present continuous PTC extraction of fullyintegrated with continuous synthesis. To our knowledge, therehave not been examples on continuous extraction of PTCfrom the reaction mixtures containing aldehydes and ketones.Instead of gravity-based techniques, the phase separation isaccomplished using a membrane with selective wettability. Thisapproach not only avoids lengthy batch-wise process due to thesmall density differences between the two phases, but also itenables for scale-up and cascading of separation units, whichimproves the PTC extraction efficiency while minimizing theamount of solvents required and waste produced.

■ RESULTS AND DISCUSSIONOxidation in the Microreactor. The spiral microreactor

served to assess reaction conditions and screen PTCs foroxidation of different substrates (S). Two quaternary ammo-nium salts with different molecular composition, hydrocarbonchain lengths, and counterions (Cl− and HSO4

−), Aliquat 336and tributylammonium hydrogen sulfate (TBAHS), served asPTCs in the biphasic oxidation reactions. The initial tests atflow rate of 15 μL/min (residence time of 10.6 min) showed astrong dependence of conversion on the amount of PTC andtemperature. At a fixed residence time and PTC and catalyst(C) quantity (10.6 min, molar ratio: PTC/C: 12 and S/C:500), benzyl alcohol conversion increased with temperaturefrom 25 to 100 °C, with almost 100% selectivity towardbenzaldehyde (Figure 1a). The molar ratio of PTC to catalystwas chosen to be 12 in the initial experiment based on thenumber of negative charges on each catalyst molecule ([WZn3-(ZnW9O34)2]

12−) that are available to attach to ammoniumcounterions. TBAHS displayed better performance at all tem-peratures owing to the less bulky hydrocarbon chains andbetter solubility in water, allowing for faster transport betweenthe two phases and easier formation of the PTC−POM com-plex, consistent with previous findings.31 The amount of PTChad a substantial effect on the reaction conversion, as well. Inthe absence of PTC, the conversion is as low as 30 mol % evenat high temperatures (e.g., 90 °C). Increasing the PTC/Cmolar ratio to 6 resulted in more than doubling of the con-version (Figure 1b). On the basis of the preliminary results atdifferent conditions and to minimize the use of PTC, weselected a PTC/C ratio of 6 for the future experiments (unlessotherwise mentioned).Given the same residence time, a flow rate ratio of 1.1 for aque-

ous to organic phase (FA/FO) results in the high conversionand maximum yield (Figure 2a). At high temperatures (100 °C),doubling the amount of catalyst has a negligible impact on theconversion (Figure 2b). This observation, along with the signif-icant increase in the conversion by incorporating more PTC,shows the important role of the PTC in determining the overallreaction rate. The PTC catalyzed reactions involve multiplesteps. The formation of active peroxo species happens in the

aqueous phase followed by the cation exchange at theinterface.3 The quaternary ammonium cation of the PTC aidsto transfer the active species (peroxo anion) into the organicphase, where the reaction takes place. By increasing the PTC/Cratio (Figure 1b), we gradually approach and exceed thestoichiometric amount of PTC required for complexation withall of the catalysts present in the aqueous phase. Increasing thePTC beyond this value does not enhance the overall reactionrate, and it is the more beneficial to enhance the exchange rateat the interface by more efficient mixing or boosting thereaction kinetic by working at higher temperatures.28,32

Figure 1. (a) Conversion vs reaction temperature for PTC/C = 12and (b) conversion versus PTC/C ratio at T = 90 °C for benzylalcohol oxidation in the microreactor. Substrate to catalyst ratio(S/C) = 500, residence time = 10.6 min.

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 versusresidence time, for benzyl alcohol oxidation in the microreactor(PTC/C = 12).

Organic Process Research & Development Article

DOI: 10.1021/acs.oprd.6b00234Org. Process Res. Dev. 2016, 20, 1677−1685

1678

The biphasic oxidation reaction in the spiral microreactor forreactive alcohols reaches quantitative conversion and yieldwithin 5−6 min at S/C and PTC/C ratios of 500 and 6,respectively. We also performed benzyl alcohol oxidation usingcommercial sodium tungstate catalyst in the spiral microreactorand found out much higher molar concentration (S/C = 80) isrequired to achieve similar conversion (83 mol %), within thesame time frame (5.3 min). Thus, the zinc-substitutedpolyoxotungstate offers higher molar-based oxidation activitycompared to sodium tungstate. Additionally, the contactingsegmented flow pattern in the microchannels of the spiralreactor increases the interfacial area between the organic andaqueous phases and facilitates the transfer of active species.Consequently, the reaction time decreases to 5 min for benzylalcohol and 1-phenyl ethanol; considerably shorter comparedto the batch procedure (1 h for 1-phenyl ethanol and 3−5 h forbenzyl alcohol) using sodium tungstate as the catalyst andmethyl-trioctylammonium hydrogensulfate as PTC.3 Moreover,the PTC utilized in this study (TBAHS) is less expensivecompared to the previously used methyltrioctylammoniumhydrogen sulfate.

In order to expand the scope of the presented methodology,we attempted the continuous oxidation of various secondaryaliphatic alcohols, substituted benzylic alcohols, and diols atidentical conditions (Table 1). Secondary alcohols such as2-pentanol (entry 4, Table 1) are selectively oxidized toketones. Moreover, the secondary alcohol moiety in 2-ethyl-1,3-hexanediol oxidation is selectively oxidized and gives 2-ethyl-1-hydroxy-3-hexanone with 100% selectivity (entry 5, Table 1).Similar observations are reported in previous studies.3,10 Again,the reaction rate was enhanced significantly using the micro-reactor compared to batch systems, as the result of enhancedtransfer at the interface.The low conversion of 3-pyridine methanol (entry 8, Table 1)

is attributed to the electron-withdrawing effect of nitrogensubstitution as reported in the literature for different oxidantsand catalysts.33−35

The role of the PTC/C ratio is as significant as the effectof catalyst concentration (comparing entries 1, 3, and 5 inTable S1). Conversion of 2-pentanol increases to ∼64 mol %either by decreasing the S/C ratio to 250 or increasing thePTC/C to 12. It is possible to reach higher conversion through

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

Organic Process Research & Development Article

DOI: 10.1021/acs.oprd.6b00234Org. Process Res. Dev. 2016, 20, 1677−1685

1679

increasing both PTC/C and residence time (entry 6), but theflow rate of oxidant (hydrogen peroxide) needs to be adjustedcarefully in order to avoid overoxidation and loss in selectivity(entries 7 and 8 in Table S1).Consistent with previous results, we found that TBAHS acts

more efficiently than Aliquat 336, in transferring the activespecies between the two phases (Table S2). Selective oxidationof the secondary alcohol functionality in 2-ethyl-1,3-hexanediolis well-promoted (83.1 mol % conversion) in the microreactorutilizing 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), butwe observe significant loss in the selectivity due to overoxidation.At high PTC concentration, the presence of excess catalyticallyactive species and faster kinetic of the second oxidation stepto 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 andother aliphatic alcohols.36

Increasing the amount of catalyst (decreasing S/C ratio)does not always result in higher conversion (as observed for1-phenyl-2-ethanol, entries 2 and 3 in Table S4). However,keeping the S/C ratio constant and increasing the amount ofPTC (higher PTC/C ratio) lead to higher conversions(compare entries 2 and 4 in Table S4). Doubling the PTC/Cratio is more effective than increasing the catalyst loading,which underscores the significance of adjusting the PTCamount for each specific alcohol to maximize the overall rate. Itis an indirect observation of the critical role of the active speciestransfer rate at the aqueous−organic interface through theformation of PTC−POM adducts. This effect is more pro-nounced at longer residence times when the mass transfercoefficient is smaller and the optimum amount of PTC requiredis higher. The lower mass transfer coefficient at longer resi-dence times have been previously reported and attributed tothe change in the flow pattern and the contacting geometrybetween the two phases due to the variation in flow rate.19

Reaction Scale-up. Two intermediate sized systems, theCorning low flow reactor (LFR) and advanced flow reactor(AFR) served to scale up the biphasic oxidation reaction. Thesereactors have high mass transfer coefficients at high flow ratesof two immiscible liquids.19,24,37 Additionally, each plate inthese reactors is sandwiched between two glass heat transferplates, allowing for fast and improved heat transfer. Con-sequently, we were able to scale up the continuous oxidationwithout sacrificing conversion and yield. Table 2 summarizesthe conversion results for five different substrates in the LFRalong with the corresponding values obtained in the spiralmicroreactor. 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 theeffective exchange of the active species owing to the enhancedmixing in the LFR. The organic phase flow rate is 0.55 mL/minin the LFR raising the production level by a factor of ∼38 ascompared to the microreactor.We evaluated the oxidation performance of three of the

substrates in the Corning AFR in order to further scale up theproduction rate and confirm the improved mass transferbetween the two phases in this reactor (Table 2). We fixed theresidence time in AFR at 5 min, slightly shorter than that ofthe microreactor. Nevertheless, the obtained conversions werehigher for all three alcohols in the AFR, further evidencing the

efficient mixing and highly facilitated mass transfer in thisreactor configuration. The estimated Damkohler number for1-phenyl ethanol oxidation (assuming first-order reaction) inboth LFR and AFR is 0.04, indicating the absence of masstransfer limitations at the reaction condition in these reactors.The production rate was scaled up by a factor of ∼660 utilizingthe AFR.In the case of alcohols with slower kinetic and lower conver-

sion such as 3-phenyl-1-propanol, a longer residence time isrequired to achieve acceptable conversion and yield. The AFRsystem has a total volume of 100 mL, and the flow rate wasadjusted at 20 mL/min based on the recommended flow ratesfor the system as well as targeted residence time (5 min). Thelimited number of plates available in our AFR restricted themaximum achievable residence time. As an alternative, we usedPFA tube as a longer residence time reactor and increased theresidence time to 10 min, keeping the total flow rate constant,and achieved 32.6 mol % conversion. Quantitative conversioncould presumably be achieved by using even longer tubing andpacking or in-line static mixers in the tube reactor.The turnover frequency (TOF) calculated from the data pre-

sented by Noyori3 for batch 1-phenyl ethanol oxidation usingsodium tungstate as catalyst and 1 h reaction time, equals to479 h−1. In the current study, for 1-phenyl ethanol oxidation atS/C = 500, PTC/C = 6, T = 100 °C, and P = 100 psi in thecontinuous reactor systems, the TOF is estimated to be 972 h−1

and 6012 h−1, for commercial sodium tungstate and synthesizedPOM catalyst, respectively. The TOF values demonstrate theimproved performance of the biphasic reaction offered byenhanced mixing in the continuous flow reactor systems. Thereported TOF values are all estimated based on the totalnumber of moles of catalysts used. If the basis were the numberof tungsten atoms in the catalyst molecule, the synthesizedcatalyst would have a TOF of 316 h−1.

Continuous Separation of Biphasic Reaction Stream.The data presented in Tables 1 and S1−S4 suggest that,although the employed flow microreactor and POM−PTCcombination is an effective platform for fast and solvent-freeoxidation of numerous alcohols, the amount of PTC needs to

Table 2. Conversion Data for Different Substrates inCorning LFR, AFR, and Spiral Microreactor at T = 100 °C,P = 100 psi, S/C = 500, and PTC/C = 6

Organic Process Research & Development Article

DOI: 10.1021/acs.oprd.6b00234Org. Process Res. Dev. 2016, 20, 1677−1685

1680

be tuned for each specific substrate to achieve acceptable con-version within short residence times (5−10 min). For lessreactive alcohols such as aliphatic and primary alcohols, theamount of PTC dissolved in the organic substrate must beincreased by a factor of at least 2 to complete the reaction.Although the PTC used in this study is relatively inexpensive,the addition of excess PTC necessitates its extraction from theproduct (organic phase) in-line and downstream from thereactor.Traditionally, the phase separation of a biphasic reaction

mixture is performed using gravity. However, for the currentsystem, although a sharp interface formed quickly within10 min, the density difference between the organic and aqueousphases was small enough to keep emulsion stable. The topphase remained visibly turbid for a long period of time (Figure 3).

The densities of the organic and aqueous phases at 15 °C areabout 1.05 and 0.99 g/cm3. This agrees with the referencedshake flask characteristics that the dispersion tends to form forthe system with the density difference of 0.05 g/cm3 orsmaller.38

To address this issue, we employed liquid−liquid extractionin laminar slug flow, followed by microporous membrane-basedphase separation. This method allowed mass transfer of the keycomponents between the two immiscible phases to happenwithout any droplet breakup and coalescence. The two phaseswere subsequently separated based on their wettability char-acteristics, instead of density. The organic phase preferentiallywets the hydrophobic porous Teflon membrane, which facil-itated drop separation39 and removed the organic productphase 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 demonstratethe continuous workup procedure. After the completed alcoholoxidation in Corning LFR and AFR, the biphasic reactionstream was flowed into PFA tubing to allow sufficient times forinterphase equilibrium. Then, the membrane-based separatorwas used to remove the aqueous phase from the flow system.At this stage of separation, significant amount of catalyst wasremoved with the aqueous phase (as confirmed by analyzingthe aqueous phase using LC-MS). However, most of the PTCstill 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 inextracting the product into organic phase while removing thePCT 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. Thissolvent ratio was a compromise between maximized removal ofPTC and minimized amount of solvent consumption. With thisratio, 77% of PTC was removed after a significantly long mixingand settling time, driven by gravity (>20 h) at 20 °C. Assumingequilibrium between the two phases, this result provided abenchmark for assessing continuous separation performanceas well as a determination of a distribution coefficient of PTCbetween the organic and aqueous phases KPTC.Three assumptions were made to simplify the analysis,

particularly when employed for different types of cascades dis-cussed later in this section.

• The distribution coefficient for the PTC, KPTC, isconstant.

• The benzaldehyde stream, which is the effluent from theprevious separation step, is completely miscible withtoluene but immiscible with water. The volumetric flowrate of the benzaldehyde, toluene, and water are F, FT,and FW, respectively.

• Extraction generates mutually insoluble organic raffinateand aqueous extract phases.

The last two assumptions imply that the flow rates ofraffinate and extract phases are equal to FT + F and FW,respectively. The concentrations of the PTC in thebenzaldehyde, the raffinate, and the extract streams are CPTC

benz,CPTCraf , and CPTC

ext , respectively. The material balance for PTCaround a single stage of extraction is written as follows:

+ × + × = + +C F F F C F F C F0 0 ( )PTCbenz

T W PTCraf

T PTCext

W(1)

The concentrations and flow rates have units of mg/mL andmL/min. Rearrangement gives the fraction of PTC that is notextracted out with the aqueous phase:

=+

CC E

11

PTCraf

PTCorg

(2)

CPTCorg is the concentration of PTC in the organic phase entering

the extraction step, i.e., the resulting stream of the mixingbetween the benzaldehyde phase and toluene, given by

=+( )

CC

1 FF

PTCorg PTC

benz

T

(3)

The extraction factor then takes the form:

=+

=⎛⎝⎜

⎞⎠⎟E K

FF F

KCC

withPTCW

TPTC

PTCext

PTCraf

(4)

Table 3 lists similar expressions derived for crosscurrent andcountercurrent cascades. Using eqs 2−4 and the experimentalvalue of 77% PTC removed in one-stage batch experiment,KPTC was calculated to be 10.04. We thus used this value topredict theoretically the fraction of PTC removed in differenttypes of configurations and number of stages, using the set ofexpressions in Table 3.As shown in Figure 4, more than 92% removal of PTC could

be potentially achieved by simply adding another stage ofextraction. The plot also demonstrates that the countercurrentcascade performed more efficiently compared to the cross-current cascade, i.e., a higher degree of extraction for a givenamount of solvent and number of stages.

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

Organic Process Research & Development Article

DOI: 10.1021/acs.oprd.6b00234Org. Process Res. Dev. 2016, 20, 1677−1685

1681

Continuous Extraction of PTC and Scale-up. Theprevious section prompted an implementation of membrane-based separators into the multistage countercurrent cascade.For the LFR system, each stage accommodated a residencetime of 52.5 s for mixing. According to Table 4, this length of

time was sufficient for the mass transfer to reach equilibrium, asindicated by close agreement between the benchmark (L1) andthe single-stage continuous extraction (L2) results.

The membrane-based separators were assembled in a three-stage countercurrent cascade (Figure 5). The mixing in eachstage happened in cocurrent slug flow, but the arrangement ofmultiple stages was countercurrent such that the overallaqueous and organic phases flowed in the opposite directions.The aqueous phase was delivered from stage i to i−1 byperistaltic pumping while the organic phase flowed from stage ito i+1 by the pressure drop of the system.The three-stage countercurrent cascading (L4) resulted in

92% extraction of PTC, with only 0.3 wt % PTC in the finalstream of benzaldehyde. As shown previously, the counter-current cascade is, theoretically, more efficient than the cross-current cascade. Experimentally, the two-stage crosscurrentcascade (L3) required twice as much extraction solvents as thethree-stage countercurrent cascade (L4) to achieve the samedegree of purification, i.e. 92% extraction of PTC (Table 4).The PTC extraction was scaled up to the throughput of the

AFR system. The membrane-based separator was scaled20 times by increasing the membrane area and the size of theintegrated pressure control element (Figure 6). A preliminarytest with toluene and water demonstrated complete separationat 10−100 mL/min in flow rates (Table S6).

The large-scale membrane separators were assembled intothe three-stage countercurrent extraction, similar to the setup inthe LFR system; each stage had the PFA tubing to allow forcomplete mass transfer before the separator. We used tubingwith the same diameter as the LFR system (1/8″ O.D. and1/16″ I.D.) but with a shorter length, i.e., shorter mixing time.At this scale, the short residence time (15 s) was sufficient forthe mass transfer completion owing to enhanced mixing at highflow velocity. This was verified by similar percent extractionsobtained from the shake-flask test (A1) and the continuous

Table 3. Expressions of PTC Remaining in the RaffinateStream and Extraction Factor (E)

configuration expression for CC

PTCraf

PTCorg expression for E

single stage + E1

1=

+

⎛⎝⎜

⎞⎠⎟E K

FF FPTC

W

T

N-stage crosscurrenta + E1

(1 )N =+

⎛⎝⎜

⎞⎠⎟E K

FFN FPTC

W

T

N-stage countercurrent ∑ = E1

nN n

0=

+

⎛⎝⎜

⎞⎠⎟E K

FF FPTC

W

T

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

Figure 4. Percent extractions of PTC that are theoretically calculatedusing Table 3 (FT:FW:F = 2:1:1, KPTC = 10.04).

Table 4. Results of the PTC Extraction Experiments atDifferent Conditions for the LFR System

experiment conditions% PTCextraction

PTC wt % in theproduct

L1 batch (shake-flask) 77 0.86

L2 continuous single stage 75 0.94

L3 continuous two-stage crosscurrent 92 0.3

L4 continuous three-stage countercurrent 92 0.3

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

Figure 6. Two sizes of the membrane-based separators used in thepost-reaction purification steps. The small and large separators wereimplemented for the LFR and AFR systems, respectively.

Organic Process Research & Development Article

DOI: 10.1021/acs.oprd.6b00234Org. Process Res. Dev. 2016, 20, 1677−1685

1682

single-stage extraction (A2), as shown in Table 5. The three-stage countercurrent cascade (A3) gave about 89% extractionof PTC. The similar extraction efficiencies obtained for LFRand AFR systems demonstrate the ability to scale themembrane separation technology.

■ CONCLUSIONWe performed continuous biphasic oxidation of differentalcohols using zinc-substituted polyoxotungstate assisted bya phase transfer catalyst (TBAHS). Oxidation of 1-phenylethanol and benzyl alcohol reached quantitative conversionwithin 5 min at the optimized reaction condition in a spiralmicroreactor. Reaction conditions including S/C and PTC/Cratio required further adjustment in order to reach similarconversions for less reactive alcohols. Increasing the PTC/Cratio was found to be most effective in enhancing the reactionrate through improving the rate of the active species exchangeat the interface. The reaction was scaled up using Corning LFRand AFR systems without sacrificing mass and heat transfer,increasing the productivity by a factor of 650 in the case of theAFR. We successfully performed continuous extraction down-stream the reactors using PTFE membranes, to separate theexcess PTC from the organic phase and purify the product.Membrane modules having two different sizes were employedto scale up the extraction process, and in both cases highextraction extent (>90%) was achieved using three-stagecounter-current configuration, leaving as low as 0.3 wt % ofPTC in the product and consuming less solvent compared toother extraction modes. The fully continuous integratedreaction−separation procedure used for production andpurification could be applied to other multiphase reactions.

■ EXPERIMENTAL METHODSMaterials. All of 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 Sigma-Aldrich andutilized as the two main PTCs. Sodium tungstate dihydrate(≥99%, Sigma-Aldrich) was used as the commercial catalyst forcomparison purpose. All of reaction products to generatestandard calibration curves using GC and HPLC were obtainedfrom 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 ofan aqueous solution of sodium tungstate dihydrate (31.75 g,0.095 mol) was treated with 6.25 mL (0.087 mol) of 14 Mnitric acid, while being heated at 85 °C and vigorously stirred.The stirring was continued until the precipitate formed duringthe addition of nitric acid was completely dissolved. This stepwas followed by dropwise 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 asyringe pump so that the solution remains clear during thisstep. Then the solution was slowly cooled to 50 °C, and half ofthe solvent was evaporated using a rotary evaporator at 50 °C.Then the solution was kept unstirred for 2−3 days at 50 °Cfor crystallization to occur. The white needle-like crystals of thecatalyst were filtered and washed several times using excessamount of water and dried in an oven overnight at 70 °C.Elemental analysis, FTIR spectroscopy, and X-ray diffractionpattern results for the synthesized catalyst are presented inTable S5 and Figure S1, respectively.

Oxidation Procedure and the Reactors. We preparedthe starting feed solutions by dissolving the catalyst and PTC inhydrogen peroxide solution and substrate, respectively. In atypical reaction for benzyl alcohol oxidation in the micro-reactor, 63 mg of PTC (TBAHS) was dissolved in 1.66 g alco-hol. In a separate beaker 185 mg of the synthesized catalyst wasdissolved 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, hydrogenperoxide/substrate = 1.1). When necessary, we increased theamount of prepared solutions by a factor of 15−30 in order torun 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 performthe initial experiments and optimize the reaction condition. Weutilized two syringe pumps (Harvard Apparatus, PHD 2000) todeliver the organic and aqueous phases into the reactor. Theresidence time is defined as the reactor volume (μL) divided bythe total flow rate (μL/min). The microreactor consists of twodistinct zones, mixing and reaction zone. A custom-made back-pressure regulator or BPR (Figure S5) set at 100 psi was placeddownstream the reactor to minimize the ineffective decom-position of hydrogen peroxide. The total flow rate was set to30 μL/min, resulting in a residence time of 5.3 min, unlessotherwise mentioned.The Corning LFR consists of nine plates connected in

sequence. Each plate holds an internal volume of 0.45 mL, andthe total volume of the reaction system is 5.8 mL.18 Theorganic and aqueous phases were conveyed to the reactor usinga HPLC pump (Rainin Dynamax SD-200) and a high pressureISCO pump (Teledyne ISCO, 500D), respectively. We set twocheck valves and two pressure-relief valves (250 psi) at theinlets of the reagents to guarantee the process safety. By settingthe total flow rate at 1.15 mL/min, we realized the residencetime of 5 min in the LFR. Further reaction scale-up was accom-plished in the Corning AFR. The total system volume was100 mL with the recommended flow rate of 10−200 mL/min.The same pumps used for the LFR system supplied the feedstreams to the reactor. Similar to the LFR system, each inletline was equipped with a check valve and a relief valve. Weadjusted the total flow rate at 20 mL/min in order to fix theresidence time at 5 min. The reaction temperature in both cases(LFR and AFR) was controlled using a Lauda Integral XT 750heating system circulating the heat exchange fluid into the heatexchange layers of the reactor plates. The reaction samples werecollected after 3−5 residence times, and the organic andaqueous phases were analyzed using GC-FID or HPLC.

Membrane Phase Separation and PTC Extraction.There are two post-reactor steps for purification of the productfrom POM−PTC: (a) aqueous portion removal and (b) PTCextraction (Figure 7). For the aqueous portion removal step,the biphasic reaction stream was first separated using a

Table 5. Results of the PTC Extraction Experiment atDifferent Conditions for the AFR System

experiment conditions% PTCextraction

PTC wt % in theproduct

A1 batch (shake-flask) 63 1.4A2 continuous single stage 67 1.2A3 continuous three-stage

countercurrent89 0.4

Organic Process Research & Development Article

DOI: 10.1021/acs.oprd.6b00234Org. Process Res. Dev. 2016, 20, 1677−1685

1683

membrane-based separator. Similar to the previous designreported in Adamo et al.,39 the separator consisted of a PallZeflour 0.5 μm hydrophobic PTFE membrane and the inte-grated pressure control element. The wetted structure of theseparator was made of ultrahigh molecular-weight polyethylene(UHMW), which provided excellent chemical compatibility,and was embedded in an aluminum shell for enhancedmechanical support (Figure S2a). The current design of theseparator accommodates the total flow rate between 1 and20 mL/min. We also designed a scaled-up version of theseparator (Figure S2c) to be applied with the reaction streamfrom the AFR.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) andcascading configurations for the liquid−liquid extraction werestudied (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 settingtime served as a benchmark for equilibrium extraction. All ofthe experiments were carried out at room temperature (20 °C).The purification of benzaldehyde, which is the product ofbenzyl alcohol oxidation, was selected as a case study for these

extraction experiments. Both organic and aqueous outgoingstreams were collected after 3−5 residence times and analyzedusing LC-MS.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.oprd.6b00234.

Complete details of the analytical methods (GC, HPLC,and LC-MS), catalyst characterization (elemental anal-ysis, FTIR, and XRD), and the setup designs for themultistage extraction and the back pressure regulator(PDF)

■ AUTHOR INFORMATIONCorresponding Author*E-mail: kfjensen@mit.edu.Author Contributions†M.P. and N.W. contributed equally to this work.NotesThe authors declare no competing financial interest.Present Address#(Y.Z.) NanoBio Systems Inc., 141 Innovation Dr., Elyria,OH 44035, United States.

■ ACKNOWLEDGMENTSThe authors gratefully acknowledge the financial support fromNovartis-MIT Centre for Continuous Manufacturing. We alsothank Corning Inc. for the LFR and AFR reactors. We thankEleanor Rose from Imperial College London for assistance withthe extraction experiment.

■ REFERENCES(1) Mizuno, N. Modern Heterogeneous Oxidation Catalysis: Design,Reactions and Characterization; Wiley-VCH Verlag GmbH & Co.KgaA: Weinheim, 2009.(2) Gemoets, H. P. L.; Su, Y.; Shang, M.; Hessel, V.; Luque, R.; Noel,T. Chem. Soc. Rev. 2016, 45, 83−117.(3) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977−1986.(4) Ryland, B. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2014, 53, 8824−8838.(5) Mannel, D. S.; Stahl, S. S.; Root, T. W. Org. Process Res. Dev.2014, 18, 1503−1508.(6) Powell, A. B.; Stahl, S. S. Org. Lett. 2013, 15, 5072−5075.(7) Zhu, J.; Wang, P. C.; Lu, M. RSC Adv. 2012, 2, 8265−8268.(8) Singh, S.; Narkhede, N.; Patel, A. RSC Adv. 2015, 5, 36270−36278.(9) Ingle, R. H.; Kala raj, N. K.; Manikandan, P. J. Mol. Catal. A:Chem. 2007, 262, 52−58.

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

Table 6. Various Conditions and Configurations for the PTCExtraction Experiment for the LFR and AFR System

experiment FTa FW

a S/Fb Nctype of

extractiond cascadinge

Low Flow Reactor (LFR) ExperimentL1 2 1 3:1 1 batchL2 2 1 3:1 1 continuousL3 4 2 6:1 2 continuous crosscurrentL4 2 1 3:1 3 continuous countercurrent

Advanced Flow Reactor (AFR) ExperimentA1 20 10 3:1 1 batchA2 20 10 3:1 1 continuousA3 20 10 3:1 3 continuous countercurrent

aFT and Fw: volumetric flow rates of toluene and water, respectively, inmL/min. bS/F: The solvent-to-benzaldehyde phase ratio is defined asthe sum of water and toluene volumetric flow rates divided by the flowrate of the organic stream from the previous step. cNumber ofextraction stages. dBatch refers to the gravity-based extraction (i.e.,shake-flask), whereas the continuous extraction refers to the use ofsegmented flow inside the small-diameter tubing, followed by themembrane-based separation. eDetails of crosscurrent and counter-current setups are in the Supporting Information.

Organic Process Research & Development Article

DOI: 10.1021/acs.oprd.6b00234Org. Process Res. Dev. 2016, 20, 1677−1685

1684

(10) Sloboda-Rozner, D.; Witte, P.; Alsters, P. L.; Neumann, R. Adv.Synth. Catal. 2004, 346, 339−345.(11) Shang, M.; Noel, T.; Wang, Q.; Hessel, V. Chem. Eng. Technol.2013, 36, 1001−1009.(12) Kozhevnikov, I. V. Chem. Rev. 1998, 98, 171−198.(13) Vazylyev, M.; Sloboda-Rozner, D.; Haimov, A.; Maayan, G.;Neumann, R. Top. Catal. 2005, 34, 93−99.(14) Chen, L.; Zhu, K.; Bi, L. H.; Suchopar, A.; Reicke, M.; Mathys,G.; Jaensch, H.; Kortz, U.; Richards, R. M. Inorg. Chem. 2007, 46,8457−8459.(15) Sousa, J. L. C.; Santos, I. C. M. S.; Simoes, M. M. Q.; Cavaleiro,J. A. S.; Nogueira, H. I. S.; Cavaleiro, A. M. V. Catal. Commun. 2011,12, 459−463.(16) Ma, B.; Zhao, W.; Zhang, F.; Zhang, Y.; Wu, S.; Ding, Y. RSCAdv. 2014, 4, 32054−32062.(17) Zhang, Z.; Zhu, Q.; Ding, Y. Synth. Commun. 2013, 43, 1211−1218.(18) Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem., Int. Ed.2015, 54, 6688−6729.(19) Woitalka, A.; Kuhn, S.; Jensen, K. F. Chem. Eng. Sci. 2014, 116,1−8.(20) Zhang, Y.; Born, S. C.; Jensen, K. F. Org. Process Res. Dev. 2014,18, 1476−1481.(21) Zotova, N.; Hellgardt, K.; Kelsall, G. H.; Jessiman, A. S.; Hii, K.K. Green Chem. 2010, 12, 2157−2163.(22) Leduc, A. B.; Jamison, T. F. Org. Process Res. Dev. 2012, 16,1082−1089.(23) Calabrese, G. S.; Pissavini, S. AIChE J. 2011, 57, 828−834.(24) Nieves Remacha, M. J.; Kulkarni, A. A.; Jensen, K. F. Ind. Eng.Chem. Res. 2012, 51, 16251−16262.(25) Gursel, I. V.; Aldiansyah, F.; Wang, Q.; Noel, T.; Hessel, V.Chem. Eng. J. 2015, 270, 468−475.(26) Gursel, I. V.; Noel, T.; Wang, Q.; Hessel, V. Green Chem. 2015,17, 2012−2026.(27) Zaidman, B.; Sasson, Y.; Neumann, R. Ind. Eng. Chem. Prod. Res.Dev. 1985, 24, 390−393.(28) Starks, C M.; Liotta, C. L.; Halpern, M. Phase-Transfer Catalysis:Fundamentals, Applications, and Industrial Perspectives; Chapman &Hall: Dordrecht, 1994.(29) Berris, B. C. Phase transfer catalyst recovery. U.S. Patent5,030,757, 1991.(30) Wang, D. H.; Weng, H. S. Chem. Eng. Sci. 1988, 43, 2019−2024.(31) Sato, K.; Aoki, M.; Takagi, J.; Zimmermann, K.; Noyori, R. Bull.Chem. Soc. Jpn. 1999, 72, 2287−2306.(32) Jovanovic, J.; Rebrov, E. V.; Nijhuis, T. A.; Hessel, V.; Schouten,J. C. Ind. Eng. Chem. Res. 2010, 49, 2681−2687.(33) Cao, Q.; Dornan, L. M.; Rogan, L.; Hughes, N. L.; Muldoon, M.J. Chem. Commun. 2014, 50, 4524−4543.(34) Liu, R.; Liang, X.; Dong, C.; Hu, X. J. Am. Chem. Soc. 2004, 126,4112−4113.(35) Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901−16910.(36) Kondo, T.; Kimura, Y.; Kanda, T.; Takagi, D.; Wada, K.;Toshimitsu, A. Green Sustainable Chem. 2011, 1, 149−154.(37) Nieves Remacha, M. J.; Jensen, K. F. J. Flow Chem. 2015, 5,160−165.(38) Green, D. W.; Perry, R. H. Perry’s Chemical Engineers’ Handbook,8th ed.; McGraw-Hill Education, 2007.(39) Adamo, A.; Heider, P. L.; Weeranoppanant, N.; Jensen, K. F.Ind. Eng. Chem. Res. 2013, 52, 10802−10808.(40) Tourne, C. M.; Tourne, G. F.; Zonnevijlle, F. J. Chem. Soc.,Dalton Trans. 1991, 1, 143−155.(41) Bedore, M. W.; Zaborenko, N.; Jensen, K. F.; Jamison, T. F. Org.Process Res. Dev. 2010, 14, 432−440.

Organic Process Research & Development Article

DOI: 10.1021/acs.oprd.6b00234Org. Process Res. Dev. 2016, 20, 1677−1685

1685