Tube-in-tube flow reactors are emerging as efficient flow chemistry strategies for a wide range of gas-liquid reactions due to their unique properties, such as high specific interface area, enhanced mass transfer and mixing, reduced material consumption, and safe handling of toxic and flammable gases. In this paper, we discuss the latest advances in basic and applied research on high-pressure gas-liquid reactions of carbon monoxide, hydrogen, and syngas using tube-in-tube flow reactors. In addition, we provide an outlook for potential future directions for tube-in-tube flow reactors, such as scale-up and enhanced robustness.
In modern synthesis laboratories, the use of chemicals of hazardous nature (e.g., reactive gases) is restricted or often avoided due to their toxicity, flammability, and the expensive specialized equipment and extensive safety precautions required for proper process control and fluid handling. However, many of these hazardous materials can be used as building blocks for value-added chemicals, such as polymers, crop improvement additives, active pharmaceutical ingredients (APIs), and advanced materials. As a result, there is a lot of concern (especially at the laboratory scale) about safe methods that can easily use these hazardous chemicals to produce the desired products at low cost. Recently, flow reactors have been used to carry out chemical reactions that handle hazardous precursors due to their enhanced safety, inherently high heat and mass transfer (process intensification), the possibility of automating the whole process, and low cost. While tube-in-tube structures have been successfully used to study several gas-liquid reactions, such as aerobic oxidation, methoxycarbonylation, hydrogenation, and carbonylation, this mini-review focuses on reactions involving carbon monoxide and hydrogen using Teflon AF2400 vents in a flow chemistry platform. (Fulin Plastic ** Teflon AF2400 degassing tube).
Figure 1 illustrates a schematic of the configuration of a tube-in-tube flow reactor, either with the gas flow on the outside of the ring and the liquid flow on the inside (Figure 1a) or the reverse arrangement (Figure 1b), i.e., in reverse.
Figure 1Schematic diagram of the (a) normal and (b) reverse configuration of a tube-in-tube flow reactor for basic and applied studies of gas-liquid reactions such as hydrogenation, carbonylation, and hydroformylation.
In gas-liquid reactions, the interfacial area a (m m) plays a key role for efficient mass transfer. Conventional batch reactors offer a much smaller interface area compared to flow reactors. Table 1 summarizes the reported values for the interfacial area and mass transfer coefficient for different types of reactors. It can be seen that the tube-in-tube flow reactor provides an extremely high specific interface area compared to other reactors that carry out gas-liquid reactions.
Table 1Mass transfer parameters in different gas-liquid reactors.
A tube-in-tube microreactor consists primarily of a breathable inner tube and an impermeable shell (Figure 1). Stainless steel and PTFE can be used for airtight outer tubes. The inner tube is primarily made of highly permeable PTFE AF-2400, an amorphous fluoropolymer. The robust components of tube-in-tube flow reactors are a key factor in the safe and long-term operation of this promising flow chemistry strategy for high-pressure gas-liquid reactions. Figure 2 illustrates the traditional fluid connection of a tube-in-tube flow reactor via a "T" joint, where the connections of the inner flow and outer ring are separated. As shown, the internal vent tube passes through a "T" joint and is connected to an airtight tube (typically perfluoroalkoxyalkane or fluorinated ethylene propylene tubing) for the internal flow feed. The outer flow feed is connected to the second port of the "T" joint (perpendicular to the inner feed stream). (Fulin Plastic ** Teflon AF2400 degassing tube).
Figure 2Schematic diagram of the fluid connections used in a tube-in-tube flow reactor.
In the traditional configuration (normal) of a tube-in-tube flow reactor, the liquid and gas phases of the reaction pass through the inner tube and shell side of the reactor, respectively (Figure 3A). In the opposite configuration (reverse), the gas phase flows through the inner tube and the liquid flows through the annulus, Figure 3b. In both configurations, reactive gas molecules permeate through a gas permeation tube, dissolve into the liquid phase, and react with reagents and/or catalysts present in the liquid phase.
Figure 3Schematic diagram of the forward (a) and reverse (b) configurations of the tube-in-tube reactor and the physical and chemical characteristics.
Quantitative mass transfer studies of gas-liquid reactions in tube-in-tube flow reactors are reported, and the physical (mass transfer rate) and chemical (kinetics, conversion, and yield) properties of forward and reverse flow configurations at the same flow rate are compared, as shown in Figures 3a and b, respectively. The higher gas concentration values in the reverse configuration are due to the larger cross-sectional area of the shell side flowing through the solvent, resulting in longer gas-liquid contact times and thus improved mass transfer.
In a recent study, in order to reduce material consumption, a material-efficient tube-in-tube flow reactor was developed using a single microliter volume of reaction droplets during gas-liquid reaction screening and optimization. In the compact flow reactor shown in Figure 4a, droplets containing the reaction mixture are oscillated back and forth in the inner tube using pressurized nitrogen. In addition to all of the above benefits of a continuous tube-in-tube flow reactor, the single-drop flow chemistry strategy provides a rapid screening method without any residence time limitations. As a result, a wide range of reaction times (seconds to hours) can be accommodated in a relatively small reactor footprint.
Teflon AF-2400 is a copolymer of tetrafluoroethylene and perfluorodimethyldioxane and is primarily used as a substrate for tubular permeable membranes in tube-in-tube flow reactors. Compared to inert gases such as nitrogen (N2), Teflon AF-2400 has relatively high permeability to reactive gases such as carbon monoxide (CO), hydrogen (H2), and carbon dioxide (CO2). In addition, relatively small gas molecules have higher permeability to Teflon AF-2400 compared to larger condensable gas molecules. In contrast to gases, Teflon AF-2400 does not permeate non-fluorinated liquids. This is due to its chemical resistance, mechanical strength, and microporous and amorphous structure. Teflon AF-2400 is used as a tubular vent membrane for gas-liquid reactions for the ozone decomposition of a range of olefins, and subsequently for other flowing gas-liquid reactions, including methoxycarbonylation and hydrogenation. (Fulin Plastic ** Teflon AF2400 degassing tube).
The breathability of a polymer is highly dependent on the free volume of the polymer. The free volume fraction (FFV) is used as a metric to compare the free volume of polymers and is defined as the free volume (cm3) of the polymer volume (cm3). The Teflon AF2400 has a high FFV value (032) is the highest reported value in perfluoropolymers, which has significantly high permeability to permanent gases compared to conventional glassy polymers. Table 2 shows a significant difference in the gas permeability of Teflon AF2400 and PTFE for commonly used reactive and inert gases.
Table 2Permeability of Teflon AF2400 and PTFE to different gases.
Carbon monoxide in a tube-in-tube flow reactor
Carbon monoxide (CO) is a toxic and highly flammable gas with limited solubility in most organic solvents. However, due to its low cost and versatility, it has been continuously used in different industrial processes, such as Fischer-Tropsch, carbonylation, and hydroformylation. These reactions are safer and more efficient than traditional batch reactors. The small size of the reactor minimizes the volume of active gas, which reduces the safety risk of using CO. A tube-in-tube flow reactor using Teflon AF-2400 (Figure 5A) was used for palladium-catalyzed methoxycarbonylation of aryl, heteroaromatic, vinyl iodine, and aryl bromide. Different aryl iodides, aryl bromide, and vinyl iodides were tested, with yields of 62-93% in all 14 instances. In addition, in-situ Fourier transform infrared spectroscopy (FTIR) is used to monitor CO concentrations in real time to find the optimal pressure that results in the highest CO concentration in the stream. (Fulin Plastic ** Teflon AF2400 degassing tube).
Figure 5Schematic diagram of a flow chemistry platform for (a) methoxycarbonylation, (b) aryl iodide carbonylation, (c) aminocarbonylation, and (d) ectopic CO generation using a tube-in-tube flow reactor.
In another study, the price was 05 mol% palladium acetate was used as a catalyst to carbonylation of several aryl iodides in a reverse tube inflow reactor and to produce alkoxy carbonylation products (91-99% conversion in 8 examples) (Figure 5b). Heating the stainless steel housing to 120 increased the conversion of the aryl iodide studied.
A novel low-pressure carbonylation reactor in which CO is generated ectopically by a Morgan reaction followed by HECK aminocarbonylation by flowing through a Teflon AF-2400-based tube-in-tube flow reactor, as shown in Figure 5C. As a result, such reactions can avoid the use of carbon dioxide cylinders and produce carbon dioxide ex situ and thus further improve the safety of these reactions.
A cylinder-free carbonylation platform was developed, as shown in Figure 5D. In this study, oxalyl chloride was hydrolyzed with a sodium hydroxide solution, CO was generated in an external stream, which was then passed through a Teflon AF-2400 tube, enriching the reacting stream in the inner stream and being consumed in the internal stream. This cylinder-free strategy was subsequently successfully applied to the study of alkoxy and amino carbonylation reactions. This strategy can be used to generate CO in situ as long as it is compatible with the reaction conditions. Tube-in-tube flow reactors have also been successfully used to perform palladium-catalyzed carbonylation of aryl iodides and bromides, coupled to a range of hydroxyl, alkoxy, and aminophiles. The results show that this flow chemistry platform can be further extended by introducing a second tube-in-tube flow reactor with the introduction of gaseous amine nucleophiles for aminocarbonylation of selected aryl iodides. Therefore, tube-in-tube microreactors can provide a safer alternative to traditional batch reactors for studying gas-liquid reactions of carbon dioxide, which is considered one of the main components of many synthetic products.
Hydrogen is also another important syngas, which is highly flammable and extremely susceptible. Since most hydrogenation reactions tend to be carried out at high pressures, the use of hydrogen for such reactions in research laboratories poses additional risks. Tube-in-tube flow reactors, similar to the CO example above, can provide greater safety for chemical reactions that require hydrogen and gas-liquid contact.
Tube-in-tube flow reactors can be used to achieve process intensification for high-pressure catalytic hydrogenation reactions. The flow chemistry platform requires a low amount of pressurized gas, which increases process safety. In a recent study, a tube-in-tube flow reactor was used to use a Crabtree catalyst (component 2,0001 equivalent) homogeneous hydrogenation of ethyl cinnamate (component 1) in dichloromethane. A conversion rate of 48% was achieved at a liquid flow rate of 2 ml min and a hydrogen pressure of 20 bar. A detailed flow chemistry platform is shown in Figure 6a. By increasing the residence time in the tube-in-tube microreactor and increasing the reactor length, the conversion rate was continuously increased and finally stabilized at about 70% at 150 seconds residence time. By increasing the pressure to 30 bar, the conversion rate was further improved. For heterogeneous catalytic hydrogenation, the same flow chemistry platform was integrated with the Omnifit glass column (filled with 250 mg of 10 mg palladium-carbon catalyst, 77mol substrate) placed between the tube-in-tube flow reactor and the back pressure regulator, as shown in Figure 6b. In this unit, after 290 minutes, the outlet stream is recirculated back to the reactor at a hydrogen pressure of 15 bar, resulting in a complete conversion.
Figure 6A flow chemistry platform for (a) homogeneous and (b) heterogeneous catalytic hydrogenation, (c) continuous flow hydrogenation, and (d) asymmetric hydrogenation of trisubstituted olefins using a tube-in-tube flow configuration.
A flow chemistry platform with tube-in-tube flow reactors has also been used for continuous asymmetric hydrogenation of trisubstituted olefins using chiral iridium and rhodium-based catalysts. This flow reactor is easy to operate and assemble, and enables high-throughput screening of the effects of different chiral iridium and rhodium-based catalysts, as well as the effects of process parameters such as pressure, temperature, catalyst loading, and solvents on hydrogenation reactions. Among the catalysts studied, ubaphox exhibited the highest selectivity and reactivity.
The best results were obtained by connecting two tube-in-tube flow reactors and a micromixer chip in series, as shown in Figure 6d. In this unit, a second flow reactor is added to supplement the hydrogen after the reaction, and the micromixer chip provides a rapid chaotic mixing of substrate and catalyst, resulting in an improved conversion rate.
A mixture of CO and H2, usually with a 1:1 volume ratio, is often referred to as syngas. Syngas is widely used in the formation of carbon-carbon bonds in hydroformylation reactions to produce a variety of aldehydes. The regioselectivity of the product is often of great industrial importance, with aromatic olefins and vinyl ethers typically producing mainly branched-chain (B) aldehydes, while aliphatic olefins mainly produce linear (L) products.
Hydroformylation of functionalized styrene in tube-in-tube flow reactors is reported. A schematic diagram of the commercially available flow chemistry platform used in these studies is shown in Figure 7. The developed flow chemistry platform was then utilized to evaluate the performance of three different catalysts and four phosphorus ligands. The optimal catalyst ligand pair was determined as Rh(Co)2(ACAC) pH3P with a loading of 3 mol%. The process parameters of 65 °C and 25 bar were also shown to achieve high conversion and selectivity, with an aldehyde regioselectivity of 92:8 b l and a conversion rate of 57%. The study also showed that using a 1:1 methanol-toluene mixture as the reaction solvent and running it in a 35 ml coil reactor with a residence time of 58 minutes increased the conversion rate to 93% and the selectivity to 94:6 l . A library of different styrene substrates was tested and reported under these reaction conditions. In addition, a synthetic strategy for the flow preparation of functionalized styrene by palladium-catalyzed cross-coupling of aryl iodide with ethylene gas has been developed. The system was proven to operate in tandem with a continuous flow hydroformylation module. In a recent study, an automated microscale flow chemistry platform was developed to study homogeneous hydroformylation of olefins. The flow chemistry platform was developed with a computer-controlled liquid handler for custom formulation and injection of reagents, internal standards, and quenching solutions. The developed flow chemistry platform prepared 11 l of sample and injected it into a horseshoe-in-tube flow reactor. The reaction plug is then shaken for the set reaction time while being exposed to syngas through a permeable inner tube wall (Teflon AF-2400). The oscillatory motion of the reaction plug decouples the residence time and flow rate, which allows the mixing and mass transfer properties to be maintained while varying the reaction time. The effect of reaction time on the yield and regioselectivity of the hydroformylation reaction was investigated using a [rhh(co)(pph3)3] catalyst ligand. At a temperature of 90 and a pressure of 6 bar, a maximum conversion rate of 90% was obtained at 20 min, with a selectivity of 12。The study also showed that the isomerization of 1-octene had a significantly faster pathway and that the regioselectivity of the reaction stabilized after 4 minutes. It was found that excessive ligands would affect the coordination equilibrium of the catalyst and inhibit the isomerization of the substrate. In addition, the addition of H2 to the catalyst has been reported to be a rate-determining step. It is found that the reaction rate is of the first order with respect to the partial pressure of hydrogen. Methyl and methoxy substitutions of phosphine ligands have been observed to have higher selectivity for branching products compared to triphenylphosphine.
Figure 7Schematic diagram of the process chemistry platform for styrene hydroformylation.
Over the past decade, tubular casing flow reactors in different configurations using Teflon AF2400 vents have been used in laboratory-scale studies of a variety of gas-liquid reactions. Despite some success with laboratory-scale demonstrations of industrially relevant gas-liquid reactions in tube-in-tube flow reactors, this promising flow reactor requires further reactor engineering to transition to pilot-scale and large-scale organic synthesis. Large-scale continuous flow synthesis using parallel flow reactors (scale-out) or flat plate membranes needs to be evaluated in detail to characterize mixing and mass transfer properties at larger production scales. It should be noted that in this work, we considered only from an engineering point of view the potential future development of breathable tubes for carrying out gas-liquid reactions.
Minimizing the possibility of any failure, such as tube rupture, is essential to ensure large-scale adoption of tube-in-tube flow reactors in the chemical industry. The minimum thickness of the pipe made of Teflon AF-2400 is 25 m. This makes the tube very fragile and special care should be taken to avoid potential rupture. In the case of pipes, due to the higher external pressure of the pipes, ruptures are most likely to occur in areas where the pipes are thinner. Since the inside and outside of the tubes in a tube-in-tube reactor are isolated, the pressure on both sides must be carefully monitored or controlled to ensure a reliable start-up and shutdown step to ensure an extended service life of the tube. It should also be noted that the difference in pressure drop between the gas side and the liquid side can become large in longer reactors, which may play a role in reactor failure.
Increasing reactor throughput simply by using longer vented tubing can be very expensive, and while most of the important characteristics of a tube-in-tube flow reactor (i.e., enhanced gas-liquid interface area and mass transfer) are maintained, the likelihood of failure is also high. In a relatively long tube-in-tube flow reactor, failure at any one point can lead to failure of the entire reactor. One already proven strategy to solve this problem is by connecting multiple smaller tube-in-tube flow reactors (number-in-tube strategy), where the failure of one reactor does not destroy the entire reactor. However, this scale-out tube-in-tube flow reactor requires a precise fluid distribution module, especially for the liquid phase. In addition to the tubular geometry of the Teflon AF-2400, other flow reactor and porous reactor geometries can be considered to improve reactor operational reliability and minimize failures in long-term reaction runs. In order to develop alternative platforms, several transport characteristics such as gas permeability, interfacial area, and mixing should be studied in depth.
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