Scale-Up Investigation of the Continuous Phase-Transfer-Catalyzed

Article pubs.acs.org/OPRD

Scale-Up Investigation of the Continuous Phase-Transfer-Catalyzed Hypochlorite Oxidation of Alcohols and Aldehydes Yanjie Zhang, Stephen C. Born, and Klavs F. Jensen* Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States S Supporting Information *

ABSTRACT: The use of bleach to oxidize alcohols with the aid of a phase-transfer catalyst (PTC) offers several benefits over traditional oxidants: low material cost, mild reaction conditions, and no metallic waste. Mass transport limitations often dictate overall reaction rates of such PTC reactions, and continuous-flow reactors with superior mass and heat transport performance are consequently used to enhance their rates. Three PTC hypochlorite oxidation reactions are chosen to illustrate scaling of PTC reactions from microfluidic to mesoscale systems [Corning Low Flow Reactor (LFR) and Advanced Flow Reactor (AFR)]. The successful scaling from microliters per hour in microreactors to intermediate milliliters per minute without sacrificing mass transport performance leads to significant increases in production rate and constitutes an efficient flow reactor scaling approach. The production rate increases up to 700 times in the scaling process from a spiral microreactor to the LFR and then to the AFR.

■

INTRODUCTION Compounds containing ketones and esters are of great importance in the biochemical and fragrance industries, and they are often key intermediates in organic synthesis. Readily available alcohols are able to produce both ketones and esters through oxidation. Common oxidizing agents for oxidation of alcohols include pyridinium chlorochromate (PCC),1−3 Jones reagent, 4−6 pyridinium dichromate (PDC), 7,8 Swern, 9 TEMPO,10−12 TPAP13 and Collins reagent.14 Many of these reagents are either carcinogenic, toxic, or not environmentally friendly. Lee and Freedman15 were the first to use sodium hypochlorite to oxidize alcohols in two phases utilizing a phasetransfer catalyst (PTC). Then Stevens et al.16 found that in the presence of acetic acid, NaOCl is able to oxidize alcohols in the absence of a catalyst. NaOCl offers several advantages: it is inexpensive and is the active agent in bleach and swimming pool chlorine inhibiting microbial growth; it oxidizes primary and secondary alcohols and aldehydes rapidly in high yields; and it avoids the problem of having to dispose of or recycle transition-metal waste because the end products are chloride and the desired products. Scale-up of biphasic oxidation reactions using batch reactors is frequently carried out but can be very challenging. The reaction rate is affected by a number of factors, such as reactor size, shape, and agitation rate. Insufficient agitation may lead to lower yields of the desired products. Moreover, these oxidation reactions are exothermic, and local heat can easily lead to thermal degradation of the oxidizing agent. The possibility of poor mixing and local exotherms also raise safety concerns with scale-up in batch reactors. One approach to mitigating these challenges is to use continuous-flow microreactors (Figure 1a), which are known to provide better mass/heat transfer and offer “numbering-up” scaling strategies.17−21 For mass-transferlimited reactions, microreactors are reported to produce faster mass transfer and higher yields,22−24 but numbering-up of submilliliter volume microreactors is not realistic for production levels because of the complexity of simultaneously controlling © XXXX American Chemical Society

Figure 1. Schematic view of reactors. (a) Spiral design microreactor29 (left) and flow pattern of butanol/water within a spiral reactor (right). (b) Corning LFR set (nine plates). (c) Corning AFR set (seven plates) (left) and flow pattern of hexane/water within an AFR module30 (right).

Special Issue: Continuous Processes 14 Received: May 19, 2014

A

dx.doi.org/10.1021/op500158h | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

flows and temperatures in hundreds of microreactors in parallel. It is preferable to scale the microreactor to a larger size while retaining the heat and mass transfer performance and then to number up a smaller number of flow reactors. In fact, using larger continuous-flow reactors is often preferred over numbering up microscale reactors to make larger amounts of materials.25−28 As examples of the latter approach, we consider two intermediate-scale devices, the Low Flow Reactor (LFR) (internal volume 0.45 mL) and the Advanced Flow Reactor G1 (AFR) (internal volume 8.9 mL) manufactured by Corning (Figure 1b,c).31 The heart-shaped mixing cells and recombination of streams between cells in each LFR and AFR plate force the liquid to split and then recombine, resulting in efficient mixing along the path. In the case of biphasic systems, the organic phase quickly becomes dispersed as small droplets in the aqueous phase, with resulting high mass transfer rates.30 These reactors have proven to have higher mass transfer coefficients for high flow rates of immiscible liquid−liquid flows than those realized in slug flow in a microreactor (see Figure 2).32 Moreover, in these reactor plates the reaction zone is

Scheme 1. Optimized reaction conditions for the oxidation34 of (a) 1-phenylethanol, (b) 3-nitrobenzyl alcohol, and (c) benzaldehyde33

■

RESULTS AND DISCUSSION Oxidation of 1-Phenylethanol. Optimization of 1phenylethanol oxidation was performed in the spiral microreactor. Our goal for this reaction was to find a means to reduce the residence time from 30 min33 down to within 3 min in order to run the process in the number of Corning reactor plates available (nine for the LFR and seven for the AFR) at the recommended flow rate [>2 mL/min (LFR) and >20 mL/min (AFR) for total flow rates]. Preliminary tests showed that out of the various reaction parameters, e.g., solvents and phasetransfer catalysts, the most effective way to accelerate the reaction was to adjust the pH of the aqueous phase to 9.3−9.5 (Figure 3a). Within this pH range, most of the hypochlorite anions were protonated and formed hypochlorous acid, which was then extracted to the organic phase with the hypochlorite anion by the phase-transfer catalyst, resulting in a significant increase in reaction rate.35 pH 9.3−9.5 was readily achieved by saturating the 14.6% sodium hypochlorite solution with sodium bicarbonate, which was found to offer a higher rate than hydrochlorous acid and acetic acid. The saturated bleach had a higher ionic strength, facilitating the extraction of organic salts from the aqueous phase to the organic phase.36 Given the same residence time, the ratio of the aqueous and organic flow rates (QA/QO) also played an important role in controlling the overall reaction rate as a result of the increase in surface to volume ratio and hence higher mass transfer rate with increasing QA/QO37,30 (see Figure 3b). Since the amount of NaOCl was already in large excess at QA/QO = 1:1, the increased rates could be attributed to higher interfacial area, implying that the reaction is within the mass-transfer-limited region. In addition, compared with the spiral reactor, the Corning LFR series had higher productivity because it operated at a much higher flow rate for the same residence time as a consequence of the larger total volume. The optimal flow rate ratio for the spiral reactor was found to be QA/QO = 2.5:1. Once the optimal pH and flow rate ratio were determined, a full factorial design was performed for the oxidation of 1-phenylethanol with two factors (concentration and residence time) and three levels (lowest, medium, and highest). The detailed experimental design and results are

Figure 2. Relationship between residence time in a single plate and mass transfer coefficient (kLa) for liquid−liquid flow obtained through the extraction of succinic acid from 1-butanol with water.32

sandwiched between two glass heat transfer plates, giving short heat transfer paths and resulting in improved heat transfer performance. In an earlier study, Leduc and Jamison33 ran PTC-aided oxidation reactions with bleach in continuous flow on a small scale. Herein we chose three of their reported reactions with high, medium, and low yields (Scheme 1) as examples with the aim of scaling the reactions without sacrificing the yield of the desired products. The first reaction was found to be a simple mass transfer enhancement, while the second brought in the complication of solids clogging the reactors and the third showed increased yield when the reaction solvent was changed and the system was made single-phase. In order to reduce materials consumption, the reaction optimization was done in a spiral design microreactor (Figure 1a), and the reactions were subsequently scaled up to multipleplates-in-series LFR and AFR systems. The reactions are shown to reach completion sooner and to have higher yields in the Corning reactors as a result of the improved mass transfer. Moreover, the yields and conversions obtained with the AFR match well with those from the LFR, indicating that the LFR can serve as a development tool for scale-up to the AFR. B



Article

with corresponding higher mass transfer rates (Figure 2) and larger productivity. Oxidation of 3-Nitrobenzyl Alcohol. In the presence of methanol, 3-nitrobenzyl alcohol can be directly oxidized to its methyl ester without isolation of the aldehyde (Scheme 1).39 During this reaction, the primary alcohol is first oxidized to the corresponding aldehyde, which quickly forms a hemiacetal with methanol40 and is further oxidized to the corresponding methyl ester. This reaction was also pH-dependent, and likewise, the optimal pH was found to be 9−9.5. The optimal aqueous to organic phase ratio in this case was 2:1. Again, a two-factor, three-level full factorial design was carried out for this reaction in order to find the best reaction conditions to give the highest yield (Table 2s and Figure 2s in the Supporting Information). The optimal reaction conditions were determined to be 0.8 M and 1.5 min. This example introduced another complication associated with flow reactors, namely, the potential for clogging by salts and solid products. The product of this reaction is a solid at room temperature, and methanol decreases the solubility of the solutes in both the aqueous phase (inorganic salts) and the organic phase (product) during the mixing. The developing flow in the first couple of mixing cells in the LFR and AFR combined with the high methanol concentration led to solid precipitates under the conditions used in the microreactor. In contrast, the consistent slug flow in the microreactor enabled the solids to remain in solution. The highest concentration of 3nitrobenzyl alcohol that could run smoothly in the Corning reactors was 0.55 M. The high salt content of the aqueous phase could also be a potential source of clogging, so instead of sodium bicarbonate, acetic acid was used to acidify the bleach. The yield of the 3-nitrobenzyl alcohol reaction reached a maximum in 1 min and was slightly better than in the spiral microreactor. With the higher flow rates and short residence time, the productivity was high even with the reduced concentration of alcohol (Table 1). Oxidation of Benzaldehyde. In the presence of methanol, benzaldehyde can be directly oxidized to methyl benzoate without the intermediacy of acid (cf. Scheme 1). However, under the reaction conditions reported by Leduc and Jamison,33 the reaction stopped once the conversion reached 60%, and no more starting material could be consumed afterwards (Figure 5a). It is well-known that electron-rich benzaldehydes are more resistant to oxidation. In view of the biphasic reaction medium, mass-transfer limitations could also be hypothesized as a limiting factor, but the higher mass transfer interfacial area in the microreactor failed to increase the yield (Figure 5b). In addition, variation of the pH, phasetransfer catalyst, and solvent were unsuccessful in driving the reaction to completion (Figure 5a). On the other hand, increasing the methanol content in the starting materials resulted in a conversion higher than 60%. On the basis of this improvement, the solvent (ethyl acetate) was completely replaced with methanol, and the reaction was able to reach completion. With that change, the biphasic reaction became single-phase, and the phase-transfer catalyst would supposedly not be needed. However, the reaction rate was very low in the absence of Bu4NBr, which implied that it served another role other than that of a phase-transfer catalyst. We propose that bromide ion is formed from hypobromite in the presence of bleach and then acts as an oxidant. This assertion is supported by the comparable conversions obtained when another reagent containing bromide ion, KBr, was used instead of Bu4NBr.

Figure 3. (a). Relationship between residence time and conversion of 1-phenylethanol under different reaction conditions in a spiral microreactor (conditions other than those noted were the same for all of the runs; Scheme 1a). (b) Relationship between conversion and flow rate ratio (QA/QO) in the Corning AFR and spiral microreactor for the oxidation of 1-phenylethanol at a residence time of 1 min. The concentration of 1-phenylethanol was 0.8 M, and the concentration of NaOCl was 2 M. Diamonds, microreactor (pH 9, τ = 1 min); squares, Corning LFR (pH 9, τ = 1 min).

shown in the Supporting Information (Table 1s and Figure 1s, respectively). The response surface was defined as yield and was obtained by fitting the data to a second-order model. The optimum conditions for oxidation of 1-phenylethanol in the spiral microreactor were 1.4 M (concentration of 1-phenylethanol) and a residence time of 1.5 min.38 These results provided initial conditions for subsequent experiments in the Corning reactors. The Corning LFR constitutes a smooth transition between the spiral microreactor and the milliscale Corning AFR since the Corning AFR differs from the Corning LFR only in the channel dimensions. For liquid−liquid flows, the Corning LFR has mass transfer characteristics similar to those of the AFR, while both are superior to the spiral microreactor for 2 s < τ < 10 s (Figure 2). With this in mind, a higher concentration of the starting material (2 M) than the optimal concentration was applied in the Corning reactors. As expected from the improved mass transfer in the LFR set, the reaction finished within 1 min. Higher QA/QO ratios (>2.5) were not found to be beneficial. Similar conversion and yield were obtained in the AFR under the same conditions, while the conversion was just 95% in the spiral microreactor (Figure 4a). The residence times in single LFR and AFR plates were 4.66 and 8.16 s, respectively, which are much shorter than that in the spiral microreactor (52.8 s), C



Article

Figure 4. Consumption and yield comparison among the spiral microreactor and the Corning LFR and AFR for oxidation of (a) 1-phenylethanol, (b) 3-nitrobenzyl alcohol, and (c) benzaldehyde. Blue bars, conversion (%); red bars, yield of the desired product (%).

transfer enhancement. For the second reaction, the concentration of the starting material had to be reoptimized in the Corning reactors to circumvent the formation of solids in the early-mixing section. Nevertheless, increased productivity relative to the microreactor again resulted from the increased mass transfer and short residence times of the Corning systems. Replacing ethyl acetate with methanol as the solvent made the oxidation of benzaldehyde become mass-transfer-limited. Overall, the scaling-up process from the spiral microreactor to the LFR and then to the AFR increased the production rate up to 700 times while maintaining good mass and heat transport behavior.

Table 1. Production rate comparison for oxidation reactions among different reactors product acetophenone

methyl 3-nitrobenzoate

methyl benzoate

reactor type

production rate (g/min)

microreactor Corning LFR Corning AFR microreactor Corning LFR Corning AFR microreactor Corning LFR Corning AFR

0.0064 0.37 4.08 0.0063 0.16 1.76 0.0027 0.075 0.85

■

A QA/QO ratio of 2:141 was chosen as the best condition not only because of the improved mass transfer coefficient but also because it was observed to prevent the clogging in the Corning reactors. The oxidation of benzaldehyde went to full conversion in the Corning systems within 2.7 min, whereas the conversion was only 90% after 3 min in the spiral microreactor (Figure 4c).

EXPERIMENTAL METHODS

Materials. 1-Phenylethanol, benzaldehyde, and tetra-nbutylammonium bromide (Bu4NBr) were purchased from Sigma-Aldrich and used as received. 3-Nitrobenzyl alcohol, 14.6% available chlorine bleach (sodium hypochlorite NaOCl and sodium chloride NaCl) were purchased from Alfa Aesar and used as received. All of the products (acetophenone, methyl benzoate, and methyl 3-nitrobenzoate) used to generate standard curves were purchased from Sigma-Aldrich. Starting materials were prepared using the method reported by Leduc and Jamison33 with modifications, and the optimized reaction conditions for each reaction are shown in Scheme 1. The bleach used in this paper was either acidified with acid or

■

CONCLUSION In this work, we have optimized and scaled three oxidation reactions with bleach by first optimizing the performance in a spiral microreactor and then scaling up to Corning LFR and AFR systems. The latter two reactor sets have higher throughput combined with improved mass transport. The oxidation of 1-phenylethanol was shown to be an easy mass D



Article

system volume was 64 mL. The recommended flow rate in the AFR is 10−200 mL/min, and the allowed maximum pressure is 18 bar at room temperature. The reagents were pumped into the AFR via peristaltic pumps (Thermo Scientific Masterflex P/ S 955-0000). In order to get better heat transfer on such a large scale for these exothermic reactions, heat exchange fluid set at 23 °C was pumped into the heat exchange layer using Lauda Integral XT 750 process thermostate.

■

ASSOCIATED CONTENT

S Supporting Information *

HPLC and GC methods and details of the factorial design of experiments. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank Corning Inc. for the use of the LFR and AFR, Dr. Gerhard Penn for his helpful suggestions, and the Novartis− MIT Center for Continuous Manufacturing for financial support.

■

Figure 5. (a) Relationship between residence time and conversion of benzaldehyde under different reaction conditions (pH, PTC catalyst, and solvent) in a spiral microreactor (conditions other than those noted were the same for all of the runs; Scheme 1c). (b). Relationship between conversion of benzaldehyde and flow rate ratio in a spiral microreactor (τ = 2.73 min).

REFERENCES

(1) Ordóñez, M.; Guerrero de la Rosa, V.; Alcudia, F.; Llera, J. M. Diels−Alder Reaction of Optically Active (E)-γ-Keto-α,β-Unsaturated p-Tolylsulfoxides with Cyclopentadiene. Tetrahedron 2004, 60, 871− 875. (2) Hunsen, M. Pyridinium Chlorochromate Catalyzed Oxidation of Alcohols to Aldehydes and Ketones with Periodic Acid. Tetrahedron Lett. 2005, 46, 1651−1653. (3) Corey, E. J.; Boger, D. L. Oxidative Cationic Cyclization Reactions Effected by Pyridinium Chlorochromate. Tetrahedron Lett. 1978, 19, 2461−2464. (4) Lanes, R. M.; Lee, D. G. Chromic Acid Oxidation of Alcohols: A Simple Experiment on Reaction Rates. J. Chem. Educ. 1968, 45, 269. (5) Anantakrishnan, S. V.; Venkatasubramanian, N. Kinetics of Oxidation of Alcohols by Chromic AcidThe Mechanism of the Reaction. Proc. Indian Acad. Sci., Sect. A 1960, 51, 310−318. (6) Westheimer, F. H.; Nicolaides, N. The Kinetics of the Oxidation of 2-Deuteropropanol-2 by Chromic Acid. J. Am. Chem. Soc. 1949, 71, 25−28. (7) Corey, E. J.; Schmidt, G. Useful Procedures for the Oxidation of Alcohols Involving Pyridinium Dichromate in Aprotic Media. Tetrahedron Lett. 1979, 20, 399−402. (8) Cornforth, R. H.; Cornforth, J. W.; Popják, G. Preparation of Rand S-Mevalonolactones. Tetrahedron 1962, 18, 1351−1354. (9) McConnell, J. R.; Hitt, J. E.; Daugs, E. D.; Rey, T. A. The Swern Oxidation: Development of a High-Temperature Semicontinuous Process. Org. Process Res. Dev. 2008, 12, 940−945. (10) Sheldon, R. A.; Arends, I. W. C. E. Organocatalytic Oxidations Mediated by Nitroxyl Radicals. Adv. Synth. Catal. 2004, 346, 1051− 1071. (11) Vogler, T.; Studer, A. Applications of TEMPO in Synthesis. Synthesis 2008, 1979−1993. (12) Ciriminna, R.; Pagliaro, M. Industrial Oxidations with Organocatalyst TEMPO and Its Derivatives. Org. Process Res. Dev. 2010, 14, 245−251. (13) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Tetrapropylammonium Perruthenate, Pr4N+RuO4−, TPAP: A Catalytic Oxidant for Organic Synthesis. Synthesis 1994, 639−666.

sodium bicarbonate or used as received. The acidified bleach was filtered before use.42 Spiral Microreactor. The starting material and the oxidizing agent bleach were separately delivered into the spiral microreactor through syringe pumps. The residence time (min) is defined as the total system volume (250 μL) divided by the flow rate (μL/min). The reaction samples were collected in a vial containing saturated sodium sulfite after five residence times and subsequently analyzed by HPLC or GC-FID. Corning LFR. A total of nine Corning LFR plates were connected in sequence, as depicted in Figure 1b. The volume of each plate was 0.45 mL and the total system volume was 5.8 mL. The flow rate and the pressure limit recommended by the manufacturer for the LFR on the basis of the material of the fittings (perfluoroalkoxy, PFA) are 2−10 mL/min and 18 bar at room temperature, respectively. Consequently, the ideal residence time had to be within 3 min. The aldehyde/alcohol and bleach were delivered to the reactor by two HPLC pumps (Dynamax SD-200 solvent delivery system). A PEEK inline filter was mounted on each inlet to prevent the solids from flowing into the system. Two pressure-relief valves (250 psi backpressure regulator) were set at the inlets of both streams to ensure the safety of the process. The effluent was collected in a vial containing saturated sodium sulfite and then analyzed by HPLC or GC-FID. Corning AFR. Seven Corning AFR plates were connected in series (Figure 1c) to provide a shorter residence time in each plate. The volume of each plate was 8.7 mL, and the total E



Article

(14) Collins, J. C.; Hess, W. W.; Frank, F. J. Dipyridinechromium(VI) Oxide Oxidation of Alcohols in Dichloromethane. Tetrahedron Lett. 1968, 9, 3363−3366. (15) Lee, G. A.; Freedman, H. H. Phase Transfer Catalyzed Oxidations of Alcohols and Amines by Aqueous Hypochlorite. Tetrahedron Lett. 1976, 17, 1641−1644. (16) Stevens, R. V.; Chapman, K. T.; Weller, H. N. Convenient and Inexpensive Procedure for Oxidation of Secondary Alcohols to Ketones. J. Org. Chem. 1980, 45, 2030−2032. (17) Vankayala, B. K.; Löb, P.; Hessel, V.; Menges, G.; Hofmann, C.; Metzke, D.; Krtschil, U.; Kost, H.-J. Scale-Up of Process Intensifying Falling Film Microreactors to Pilot Production Scale. Int. J. Chem. React. Eng. 2007, DOI: 10.2202/1542-6580.1463. (18) De Mas, N.; Günther, A.; Kraus, T.; Schmidt, M. A.; Jensen, K. F. Scaled-Out Multilayer Gas−Liquid Microreactor with Integrated Velocimetry Sensors. Ind. Eng. Chem. Res. 2005, 44, 8997−9013. (19) deMello, A. J. Control and Detection of Chemical Reactions in Microfluidic Systems. Nature 2006, 442, 394−402. (20) Watts, P.; Wiles, C. Recent Advances in Synthetic Micro Reaction Technology. Chem. Commun. 2007, 443−467. (21) Jensen, K. F. Microreaction EngineeringIs Small Better? Chem. Eng. Sci. 2001, 56, 293−303. (22) Haswell, S. J.; O’Sullivan, B.; Styring, P. Kumada−Corriu Reactions in a Pressure-Driven Microflow Reactor. Lab Chip 2001, 1, 164−166. (23) Illg, T.; Hessel, V.; Löb, P.; Schouten, J. C. Continuous Synthesis of tert-Butyl Peroxypivalate Using a Single-Channel Microreactor Equipped with Orifices as Emulsification Units. ChemSusChem 2011, 4, 392−398. (24) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Deciding Whether to Go with the Flow: Evaluating the Merits of Flow Reactors for Synthesis. Angew. Chem., Int. Ed. 2011, 50, 7502−7519. (25) Nagy, K. D.; Shen, B.; Jamison, T. F.; Jensen, K. F. Mixing and Dispersion in Small-Scale Flow Systems. Org. Process Res. Dev. 2012, 16, 976−981. (26) Allian, A. D.; Richter, S. M.; Kallemeyn, J. M.; Robbins, T. A.; Kishore, V. The Development of Continuous Process for Alkene Ozonolysis Based on Combined in Situ FTIR, Calorimetry, and Computational Chemistry. Org. Process Res. Dev. 2011, 15, 91−97. (27) Kockmann, N.; Gottsponer, M.; Roberge, D. M. Scale-Up Concept of Single-Channel Microreactors from Process Development to Industrial Production. Chem. Eng. J. 2011, 167, 718−726. (28) Mendorf, M.; Nachtrodt, H.; Mescher, A.; Ghaini, A.; Agar, D. W. Design and Control Techniques for the Numbering-Up of Capillary Microreactors with Uniform Multiphase Flow Distribution. Ind. Eng. Chem. Res. 2010, 49, 10908−10916. (29) Bedore, M. W.; Zaborenko, N.; Jensen, K. F.; Jamison, T. F. Aminolysis of Epoxides in a Microreactor System: A Continuous Flow Approach to β-Amino Alcohols. Org. Process Res. Dev. 2010, 14, 432− 440. (30) Nieves-Remacha, M. J.; Kulkarni, A. A.; Jensen, K. F. Hydrodynamics of Liquid−Liquid Dispersion in an Advanced-Flow Reactor. Ind. Eng. Chem. Res. 2012, 51, 16251−16262. (31) Calabrese, G. S.; Pissavini, S. From Batch to Continuous Flow Processing in Chemicals Manufacturing. AIChE J. 2011, 57, 828−834. (32) Woitalka, A.; Kuhn, S.; Jensen, K. F. Scalability of Mass Transfer in Liquid−Liquid Flow. Chem. Eng. Sci. 2014, 116, 1−8. (33) Leduc, A. B.; Jamison, T. F. Continuous Flow Oxidation of Alcohols and Aldehydes Utilizing Bleach and Catalytic Tetrabutylammonium Bromide. Org. Process Res. Dev. 2012, 16, 1082−1089. (34) Our goal was to achieve full conversion in one pass in the Corning reactor, but we were limited by the number of plates. Therefore, we had to use a higher concentration of the PTC and NaOCl to speed up the reaction. The amounts of PTC and NaOCl can be reduced when more plates are used. The concentration of NaOCl we are using now is the highest we can find in the market. Although the aqueous phase can be continuously separated and reused, the concentration is lower after the recycle, therefore slowing the reaction.

(35) Abramovici, S.; Neumann, R.; Sasson, Y. Sodium Hypochlorite as Oxidant in Phase Transfer Catalytic Systems: Part I. Oxidation of Aromatic Aldehydes. J. Mol. Catal. 1985, 29, 291−297. (36) Albanese, D. Liquid−Liquid Phase Transfer Catalysis: Basic Principles and Synthetic Applications. Catal. Rev. 2003, 45, 369−395. (37) Jovanović, J.; Rebrov, E. V.; Nijhuis, T. A. (X.); Hessel, V.; Schouten, J. C. Phase-Transfer Catalysis in Segmented Flow in a Microchannel: Fluidic Control of Selectivity and Productivity. Ind. Eng. Chem. Res. 2010, 49, 2681−2687. (38) Each run was repeated a couple times. The conversion and yield increased as either the mass transfer rate or residence time increased since this reaction fell into the mass-transfer-limited region. The impact of the mass transfer rate seems greater than that of the residence time, which could explain why lowest conversion/yield was observed at the middle. (39) McDonald, C. E.; Nice, L. E.; Shaw, A. W.; Nestor, N. B. Calcium Hypochlorite-Mediated Oxidation of Primary Alcohols to Methyl Esters. Tetrahedron Lett. 1993, 34, 2741−2744. (40) Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.; Albizati, K. F. Further Studies on the Utility of Sodium Hypochlorite in Organic Synthesis. Selective Oxidation of Diols and Direct Conversion of Aldehydes to Esters. Tetrahedron Lett. 1982, 23, 4647−4650. (41) The oxidation of benzaldehyde is monophasic, and the flow ratio refers to the different flow rates of bleach and the starting material. (42) We found that once the pH was below 9, chlorine gas formed, which would cause safety and selectivity concerns. The bleach is more stable at pH >9, and therefore, we kept the pH slightly above 9 (9.3− 9.5) for all runs. For future work, we plan to use a safer oxidizing agent, hydrogen peroxide, which will eliminate these concerns.

F


Scale-Up Investigation of the Continuous Phase-Transfer-Catalyzed

Recommend Documents