Microfabricated Multiphase Reactors for the Selective Direct

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Ind. Eng. Chem. Res. 2003, 42, 698-710

Microfabricated Multiphase Reactors for the Selective Direct Fluorination of Aromatics Nuria de Mas,† Axel Gu 1 nther,† Martin A. Schmidt,‡ and Klavs F. Jensen*,† Department of Chemical Engineering and Microsystems Technology Laboratories, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

We describe a microchemical reactor built by silicon processing and metal deposition techniques that enables efficient and safe direct fluorination of toluene, a highly exothermic process difficult to implement conventionally on a macroscopic scale. Gas and liquid reagents were contacted cocurrently at room temperature in the microfabricated reactor, and gas-liquid distribution patterns were characterized. A flow regime map, containing slug and annular-dry flows, was obtained for liquid velocities relevant to gas-liquid reactions in microchemical systems. During annular-dry flow operation, the substrate conversion and product distribution were studied as a function of the operating conditions: toluene concentration, fluorine-to-toluene molar ratio, solvent type, and quenching conditions. Among the solvents tested, including acetonitrile, methanol, 1,1,2-trichloro-1,2,2-trifluoroethane, and octafluorotoluene, the highest selectivities toward ring fluorination were obtained in acetonitrile. At toluene conversions of 58%, a combined selectivity of ortho-, meta-, and para-fluorotoluenes of up to 24% was obtained. Introduction Aromatic molecules containing one or two fluorine ring substituents are important precursors used in the synthesis of pharmaceuticals and crop-protection agents, which owe their bioactivity to the presence of fluorine.1 There is, consequently, much interest in developing synthetic methods to selectively introduce fluorine into aromatic molecules. A potential one-step process to fluorinate a wide range of aromatics is reaction of the aromatic with elemental fluorine in an appropriate solvent. Mechanistic studies in benchtop systems at low temperatures (e.g., below -40 °C) and low substrate conversions (e.g., 0.01%)2-5 have shown that the direct fluorination of several activated and deactivated aromatics proceeds via a combination of polar electrophilic substitution and radical reactions. In general, reaction conditions that minimize free-radical processes and enhance the electrophilic attack on the ring are desirable to achieve selective fluorination.6 For example, polar and acidic solvents have recently been shown to promote the electrophilic mechanism.7,8 The direct fluorination of aromatics, however, is rarely practiced on a preparative scale because of the difficulties in controlling the large heat of reaction (∆H°298 ) -473 kJ/mol, ignoring the heat of solution of the reaction byproduct, hydrogen fluoride)9 and the selectivity of the process.7 Because of the low solubility of fluorine in commonly used solvents, reactions proceed at the gas-liquid interface.3,10 Consequently, localized hot spots are likely to form in large-scale systems and can then enhance the formation of fluorine radicals (D°F-F,298 ) 159 kJ/mol),9 nonselective free-radical side reactions, and substrate degradation.6,7 Much effort has been devoted to the development of selective fluorination methods. Commercially, ring* Corresponding author. E-mail: [email protected]. Fax: (617) 258-8224. † Department of Chemical Engineering. ‡ Microsystems Technology Laboratories.

fluorinated aromatics are synthesized by indirect methods that distribute the heat of reaction over several synthetic steps.1,11 These fluorination methods are based on diazotization reactions (e.g., Balz-Schiemann process) and chlorine/fluorine exchange with alkali metal fluorides (“Halex” process). In the Balz-Schiemann process, anilines are diazotized into diazonium tetrafluoroborates, which subsequently undergo thermal decomposition to yield the desired fluorinated aromatic. The main drawback of these methods is their low overall yield, which, for the Balz-Schiemann process, ranges from 20 to 27% of one single fluorinated isomer.12 Recently, direct fluorinations have been demonstrated in reactors with submillimeter feature sizes.13,14 The reduction in reactor size greatly improves the control of fast exothermic reactions by preventing flow maldistributions and localized hot spots. As a result, direct fluorination can be performed in microreactors using more aggressive reaction conditions than in benchtop systems, thereby improving conversion while maintaining good temperature control. These microreactors were micromachined into nickel13 or built using a combination of fabrication techniques such as nickel electroplating using ultraviolet-LIGA (German acronym for lithography, electroplating, and molding), stainless steel wet chemical etching, and stainless steel microelectrodischarge machining.14 Chambers et al. demonstrated the fluorination of 1,3-dicarbonyl and 2,4-substituted aromatics at temperatures ranging between 0 °C and room temperature, whereas Ja¨hnisch et al. fluorinated toluene at -16 °C. These studies, however, did not provide a detailed characterization of the operating gas-liquid flows and did not relate flows and reaction conditions to reactor performance. For commercial application, microreactors would ideally be fully standalone systems with integrated sensing and supporting control capabilities. Metal micromachining is useful for making a small number of reactor prototypes but might not be economical for replicating reactor units to increase productivities by interconnect-

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ing multiple reactors in parallel. The microfabrication techniques used in the microelectronics industry, which have recently expanded to the development of microelectromechanical systems and microchemical reactors, show great promise toward the realization of integrated microchemical systems. Over the past decade, a number of novel microfabricated chemical reactors have been developed using well-established silicon bulk micromachining techniques.15,16 Silicon micromachining enables the deposition and patterning of a variety of thin filmsssilicon oxide, silicon nitride, and metalssas protective coatings,17 structural materials, temperature sensors, and heaters;18 the integration of chemical detection19,20 and feedback control systems; as well as the design of novel multiphase reactors.21 In addition, microfabrication allows reliable batch replication of microreactor units. Herein, we describe the design, fabrication, and characterization of a microfabricated reactor for direct fluorination reactions. We used silicon and Pyrex as structural materials and thin silicon oxide and nickel films as corrosion-protective coatings. Gas-liquid contacting patterns in the microchannels were systematically characterized by flow visualization, and the direct fluorination of toluene was investigated at room temperature as a function of the operating conditions. Experimental Section Fluorine Delivery System. A 25 vol % mixture of fluorine in nitrogen was used as supplied (Spectra Gases, fluorine purity 99.0%, connected to a Monel pressure regulator) and diluted with research-grade nitrogen as appropriate. All piping used in the fluorine delivery system was made of electropolished stainless steel. Degreased welded and welded-VCR fittings were used for sealed connections (Swagelok fittings are not recommended for use with fluorine). A Monel pressure gauge was installed on the gas line to detect any significant changes in pressure drop that might result from a reactor failure. Before exposure to fluorine, the entire gas manifold system was pressurized with nitrogen and leak-tested. When used for the first time, the system was passivated by slowly increasing the fluorineto-nitrogen flow rate ratio until the concentration reached operating conditions. To maximize the durability of the lines and other equipment, the system was maintained under dry nitrogen when not in use to minimize the formation of HF from water. Microreactor Packaging and Flow Visualization. Two types of packaging schemes were implemented to interface the microreactor chip with the macroscale gas and liquid manifolds. For reaction studies, we used the packaging scheme shown in Figure 1A. The silicon chip was compressed between a plexiglass plate, to allow viewing of the reactor chip, and a Kalrez (DuPont perfluoroelastomer, 0.8 mm thick) or a hybrid Kalrez/graphite (Ameraflex, 0.8 mm thick) gasket with punched holes matching the inlet and outlet ports of the microreactor chip to form a fluidic seal on a stainless steel base. Stainless steel fittings (Valco Instruments, TX) and fluidic lines (1/16-in. o.d.) machined into the stainless steel base were used to deliver the reactants. Stainless steel or Teflon (Valco Instruments) tubing from the microreactor base was used to collect the products. The toluene solution was metered at the desired flow rate by a syringe pump (Harvard Apparatus PHD2000). The fluorine mixture was delivered

to the microreactor by a mass flow controller (Unit Instruments). The temperature of the silicon chip was monitored using thermocouples (0.25 mm, type K, Omega) inserted between the plexiglass and the stainless steel base and in contact with the silicon chip. Heat removal from the reactor was facilitated by heat conduction through the packaging assembly, which was heat sunk to a metallic holder via the silicon substrate, the gasket material, and the stainless steel base. In addition to the two reactant inlets, a third inlet was machined into the stainless steel base to permit in situ reaction quenching experiments. Reaction quenching was accomplished by introducing nitrogen into the stream exiting the reactor chip. Gas-liquid flows were visualized using an alternative packaging scheme to allow optical access to the microchannels. Instead of a plexiglass-plate compression seal, PEEK tubing (Upchurch Scientific, 1/16-in. o.d.) and front ferrules (Swagelok, 1/16-in. o.d.) were directly attached with epoxy to the fluidic ports on the back side of a microreactor chip bonded to uncoated Pyrex. An inverted fluorescence microscope (Zeiss Axiovert 200) equipped with a full-frame CCD camera (9 fps, 1280 × 1024 pixels) was used for image acquisition. Two light sources were employed. A 100-W mercury lamp (continuous wave) was used to observe drying of the Pyrex wall in the annular flow regime. The time resolution of images taken using this lamp is determined by the electronic camera shutter speed and is limited to 1 ms. To observe transient flows and obtain sharp and distortion-free images in the other flow regimes, this camera shutter speed is insufficient. Instead, a frequencydoubled Nd:YAG laser (BigSky Ultra) emitting 30 mJ during a 7-ns pulse of green light (532 nm) was used, and the microscope was operated in fluorescence mode. The liquid phase was seeded with 0.5-µm-diameter fluorescent polystyrene microspheres (Interfacial Dynamics) that were excited at the laser wavelength, and a Rhodamine filter set was used to extract the red fluorescent light. Toluene Fluorination. Starting materials were obtained commercially (Sigma-Aldrich, Fluorochem) and used as received unless otherwise specified. Liquid solutions were dried with molecular sieves. Prior to the fluorination experiments, the microreactor assembly and attached tubing were primed with dry nitrogen and anhydrous solvent to remove air and moisture. Under a flow of dry nitrogen, the entire reactor was filled with the liquid solution. The liquid solution and the fluorine mixture were then passed through the reactor at the prescribed flow rates, and the system was allowed to reach steady state (∼20 min for the flow rates used). Once steady state had been reached, liquid products were collected in an ice-cooled round-bottom glass flask (15 mL) containing sodium fluoride, which trapped the byproduct HF in the form of NaHF2.22 The flask was connected to a cooling water West condenser to maximize the recovery of solvent and product vapors from the gas effluent. Samples were typically collected for 1 h. Waste gases were scrubbed in an aqueous 15% potassium hydroxide solution before being exhausted.22 The workup steps included sample degassing with dry nitrogen and filtration through a syringe filter (GHP Acrodisc, 0.45 µm). The reaction products were then identified by GC-MS (Hewlett-Packard 6890 GC equipped with an HP 5973 mass-selective detector) and quantified by a flame ionization detector (FID). An HP-INNOWax

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Figure 1. (A) Packaging scheme of the reactor chip used for carrying out fluorinations. Pressure-driven flow of gas and liquid is employed. The gray areas indicate the flow path. Nitrogen can be introduced into the stream exiting the reactor chip to quench the reaction in situ. (B) Schematic configuration of the microfabricated reactor. Liquid and gas reactants are introduced at inlet location a and flow cocurrently through two channels with triangular cross sections formed in silicon and bonded to a Pyrex cap (Pyrex not drawn). The three locations in the streamwise direction considered for flow visualization are indicated (a-c). Locations b and c correspond to the center and outflow regions, respectively. (C) Cross-sectional scanning electron micrograph of the microchannels at the center region (b). The sample was placed on a 45° stage; vertical dimensions appear a factor of 1.41 smaller than indicated by the horizontal scale bar. (D) Schematic representation of the gas-liquid contacting front in the gas inlet region.

column (0.25-µm film thickness, 0.25 mm × 30 m) was used. Identification was based on a comparison of retention times and mass spectra with those obtained from commercial standards. Product conversions and yields were calculated from the integrated areas of the FID chromatograms and the response factor of each compound with respect to octafluorotoluene, which was added to the initial toluene solution and used as an internal standard. The concentration of octafluorotoluene used was at least an order of magnitude lower than that of toluene. Octafluorotoluene showed good GC separation from acetonitrile, toluene, and product peaks, as well as a linear area-concentration response. Octafluorotoluene was found to be inert within a (1.7% experimental error attributed to the manual sample injection (calculated from a series of nine replicate manual injections of a standard solution for a 95% Student-t confidence interval) when used in up to 1.0 M toluene solutions in acetonitrile. Reactor Design and Fabrication. The reaction channels were formed in a silicon wafer by potassium hydroxide etching, silicon oxide was thermally grown

over the silicon, nickel thin films were evaporated over the wetted areas to protect them from corrosion, and Pyrex was bonded to the silicon to cap the device. Corrosion-resistant coatings are necessary because silicon reacts readily with fluorine at ambient conditions and forms silicon tetrafluoride.1 Silicon oxide is attacked by the reaction subproduct hydrogen fluoride;23 however, we have observed that silicon oxide is compatible with mixtures of fluorine in nitrogen (at least up to 25 vol %) at room temperature under scrupulously dry conditions. The microreactor, schematically represented in Figure 1B, consists of two reaction channels with a triangular cross section, 435 µm wide, 305 µm deep, and 2 cm long. The channel hydraulic diameter dh (4 times the crosssectional area divided by the wetted perimeter) is 224 µm, and the volume of the reactor is 2.7 µL. A scanning electron micrograph channel cross section is shown in Figure 1C. Microchannels with sloped walls etched in potassium hydroxide (sidewalls form a 54.7° angle with respect to the plane of the wafer)24 were chosen to facilitate the step coverage of the evaporated nickel


Figure 2. Schematic representation of the microfabrication sequence for the direct fluorination microreactor: (A) channel cross section and (B) gas inlets cross section.

films.25 Potassium hydroxide etching of (100) silicon is a simple and low-cost method for etching silicon anisotropically to form channels with trapezoidal or triangular cross sections. The inlet region consists of one single liquid inlet and two gas ports, which are located 3 mm downstream from the liquid inlet. The upstream end of the interchannel wall is located about 500 µm from the gas ports. Figure 1D is a schematic representation of the gas-liquid contacting front in the gas inlet region. The outlet region is geometrically equal to the inlet region; the two channels merge into a single channel, and the fluids exit the reactor through a single port. The dual-channel reactor can operate continuously at ambient conditions without requiring external cooling for heat loads of up to 0.3 W, calculated by considering heat conduction through a series of heat-transfer resistances in series in the packaging assembly. The two channels per reactor facilitate an increased productivity per device and a high area-to-volume ratio (1.8 × 104 m2/m3) to enhance the contacting area between the substrate solution and fluorine. In addition, a dualchannel reactor is a first step toward the development of a “scaled-out” reactor, i.e., a reactor consisting of a large number (∼100) of channels with common inlet and outlet ports operating in parallel. By characterizing the flow patterns in the dual-channel reactor, design criteria for obtaining uniform flow distribution in the multichannel device can be obtained. The fabrication process involved several photolithographic steps, silicon etching in potassium hydroxide,

wet silicon oxidation, nickel evaporation, and anodic bonding. Three photolithographic masks were used: a mask to pattern the reaction channels on the front side of the silicon wafer, a mask to pattern the inlet and outlet ports on the back side, and a shadow mask to allow deposition of nickel pads on the areas wetted by the reaction mixture. All photolithographic masks were fabricated by printing the desired features onto a transparency, via a high-resolution printer, and photolithographically patterning a chromium-coated quartz plate (suitable for feature sizes equal to or greater than 20 µm).26 The microfabrication sequence is schematically illustrated in Figure 2. Low-stress silicon nitride (minimum of 50 nm thick) was first deposited by low-pressure chemical vapor deposition (LPCVD) on the front and back sides of a double-polished (100) silicon wafer (100 mm in diameter, 525 µm thick) for use as a masking material during the potassium hydroxide etch. The front side of the silicon wafer was photolithographically patterned to define the reaction channels. The exposed silicon nitride (i.e., not protected by photoresist) was etched using a standard dry etch (CF4 and O2 plasma). The inlet and outlet ports to the reaction channels were patterned on the back side in a similar manner. The reaction channels and ports were then simultaneously etched in an aqueous solution of potassium hydroxide (20 wt %, 80 °C). The silicon nitride mask was then removed using a dry or wet (hot phosphoric acid) etch. Prior to metallization, an intermediate layer of silicon

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dioxide (200-500 nm thick) was conformally grown over the silicon channels by wet oxidation. The wetted channel areas on the front side of the silicon and Pyrex (7740, 100 mm in diameter, 510 µm thick) were then metallized with nickel (minimum of 200 nm thick) on an adhesion layer of chromium (10 nm thick) by electron-beam evaporation. The shadow mask covered the nonwetted areas of the silicon and Pyrex during evaporation, as the subsequent anodic bonding required uncoated silicon and Pyrex. The shadow mask is a silicon wafer (100 mm in diameter) with rectangular openings approximately 200 µm larger per side than the exterior edges of the reactor channels; it was fabricated in a similar manner by etching through the wafer in potassium hydroxide. The ports on the back side were then coated with a blanket layer of nickel. The fabrication process was completed by capping the channels formed in the silicon wafer via an anodic bond onto the Pyrex wafer (500 °C, 800 V). A total of 12 reactors were made from a 100-mm-diameter silicon wafer. The scanning electron micrograph channel cross section in Figure 1C shows that the metal pads (200nm-thick nickel) did not interfere with the bonding process. In addition, chromium was not detected on the metallized areas by X-ray photoelectron spectroscopy, indicating that nickel remained on the surface after bonding. Reactors coated with 200 nm of silicon oxide and 200 nm of nickel have routinely been operated for periods of hours without signs of corrosion. Results and Discussion Gas-Liquid Flows. Because the rates of mass and heat transfer strongly depend on the gas-liquid contacting patterns and specific interfacial area, a systematic characterization of the gas-liquid flows in the microchannels is required to understand the performance of the reactor. Pressure drop measurements are also necessary to design microfluidic networks with even flow distributions. In contrast to single-phase flows, the characterization of gas-liquid flows relies on experimental studies and is not yet documented in microchannels at the flow conditions relevant to gas-liquid reactions in microchemical systems.13,14 These systems are operated at liquid superficial velocities much lower than the gas velocities to match the molar flow rates of liquid and gas reactants and provide sufficient residence times for mass transfer to take place in the liquid phase. Liquid superficial velocities below 0.01 m/s are typically used. We first describe the gas-liquid contacting patterns observed in our dual-channel reactor and then relate these flow patterns to flow regimes obtained in a single channel of identical cross section. Several gas-liquid contacting patterns were obtained in our dual-channel reactor using nitrogen and acetonitrile as working fluids. Instantaneous fluorescence images of the gas-liquid distributions for the three streamwise positions indicated in Figure 1B are shown in Figure 3. Because the mercury lamp was used as the light source, the time resolution of the images is limited to 1 ms. Conditions I-III are plotted in Figure 4 as a function of the superficial gas (jG) and liquid (jL) velocities

jG )

VG VL and jL ) nA nA

(1)

where VG and VL are, respectively, the gas and liquid

volumetric flow rates entering the reactor; A is the crosssectional area of one channel (6.6 × 10-8 m2); and n ) 2 is the number of channels. It was observed that the formation of a liquid film on the channel walls was strongly influenced by the gas velocity. At the liquid velocity used in the fluorination studies, jL ) 5.6 × 10-3 m/s, and gas velocities below jG ) 0.8 m/s, channeling occurred (I); annular-dry flow (in which liquid wets the walls except for the Pyrex wall and gas flows in the channel core) was obtained in one channel, while the other one remained filled with liquid. Channeling also occurred at lower liquid velocities. With increasing jG (II), the flow distribution equalized, and annular-dry flow was obtained in both channels. As jG was further increased (III), the drying of the Pyrex wall increased. It is important to note that a substantial amount of liquid is carried through the menisici as a result of the effect of capillary forces acting on the microchannel vertices. In addition, the Pyrex wall and the upstream end of the interchannel wall dried out at the gas inlet region under conditions II and III. It was observed that the distribution of the liquid flow was strongly influenced by the position of the gas inlets (Figure 1D). Initially, the upstream end of the interchannel wall was dry, and liquid accumulated on the outer edges of the microchannels. The liquid, however, slowly redistributed on the inner channel walls along the entire channel length, which indicated that the liquid film was connected through the bottom wall. At the downstream end of the interchannel wall, the liquid menisci appeared equally distributed over the inner and outer channel walls. The location of the gas inlets partly caused the drying of the Pyrex. Evaporation of acetonitrile represents only a small contribution to the drying effects. For example, at jL ) 5.6 × 10-3 m/s and jG ) 1.4 m/s and ambient conditions (used in the fluorination studies), the amount of acetonitrile necessary to saturate the nitrogen stream is 5% of the amount initially fed into the microchannel. The gas-liquid contacting patterns in our dualchannel reactor were compared with flow regime diagrams obtained in single channels (n ) 1), where channeling cannot occur. As in regime diagrams for gas-liquid flows through macroscopic pipes or channels, the jG-jL plane was chosen to characterize regime transitions. For flows in microchannels, where capillary forces become influential, the location of the flow transition lines can vary as a function of the liquid surface tension, solid wettability, channel hydraulic diameter, and channel cross section. We minimized the influence of these variables by employing the same fluids and a channel of identical cross section and comparable surface properties. We distinguish between annular, churn, wavy annular, slug, bubbly, and annular-dry flows. Annular and wavy annular flows are defined by a gas core in the center of the channel and a liquid film wetting the walls (the gas-liquid interface is wavy in the wavy annular flow). Churn flow occurs at very high jG and jL and is characterized by an irregular gas-liquid interface. Slug flow in microchannels is characterized by discrete gas plugs with a characteristic width on the order of the channel width and any plug length, whereas in bubbly flow, the width of the gas plug is much lower than the channel width. On the microscale, in contrast to channels with hydraulic diameters greater than several millimeters, gas entrainment in the liquid phase does not occur at the


Figure 3. Fluorescence images of the gas-liquid flow distribution for the three superficial gas velocities represented in Figure 4 (I-III) at the three streamwise positions shown in Figure 1B: (a) inlet, (b) center, and (c) outlet. Images were recorded using the continuouswave lamp. The bright areas correspond to the liquid phase (L), which is seeded with fluorescent microspheres. The gas phase (G) and the interchannel wall appear dark. The slightly asymmetric shape of the end corners of the interchannel wall is an effect of the potassium hydroxide etching process.

slug tail, and gas bubbles with diameters comparable to the channel hydraulic diameter are stable. As previously mentioned, annular-dry flow differs from annular flow in that partial drying of the Pyrex wall occurs. Region 1 in Figure 4 presents gas-liquid flow regimes from previously published studies for air-water systems in single triangular channels (dh ) 1.097,27 0.866 mm28). These studies were performed in conventionally manufactured microchannels at relatively large superficial liquid velocities (jL > 0.01 m/s). Such conditions are relevant for compact heat-exchanger applications, where single-component gas-liquid flow frequently occurs.27 Region 2 is the preferred operating window for gasliquid reactions in microchemical systems. The three

distribution patterns of our dual-channel reactor (n ) 2, 224 µm) along with the flow conditions of previous fluorination studies in a rectangular-channel device (n ) 32, 150 µm)14 and a rectangular channel (n ) 1, 500 µm)13 are shown. Because flow regime studies have previously been limited to region 1 and have been documented for different cross-sectional areas, a detailed flow regime map for nitrogen and acetonitrile was obtained in a 40-mm-long single triangular channel (224 µm). The channel was fabricated in silicon and Pyrex in the same way as the dual-channel reactor. The silicon was coated with 500 nm of thermal silicon oxide; however, nickel was not deposited on the silicon oxide to minimize internal reflections and thus facilitate flow

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Figure 4. Gas-liquid flow regime map in microchannels. Flow regimes are annular, churn, wavy annular (WA), wavy annulardry (WAD), slug, bubbly, and annular-dry (AD) flows. Transition lines for nitrogen-acetonitrile flows in a triangular channel with dh ) 224 µm are shown (s). Region 1 contains transition lines for air-water flows in triangular channels with dh ) 1.097 (- - -)27 and 0.866 mm (- - -).28 Region 2 presents flow conditions in the dual-channel reactor (b) with the acetonitrile-nitrogen system between the limits of channeling (low jG, I) and partially dried walls (high jG, III). Flow conditions of previous fluorination studies in rectangular channels are represented for a 32-channel reactor with dh ) 150 µm (1)14 and a single channel with dh ) 500 µm (2).13

visualization, in particular, visualization of the dry Pyrex wall. The surface free energies of the various surfaces (Pyrex and silicon coated with silicon oxide, nickel, or nickel fluoride) in contact with acetonitrile are expected to be comparable. Contact angles of acetonitrile in air were measured on Pyrex and unpatterned silicon coated with 500 nm of silicon oxide. Contact angles were also measured on the same substrates coated with 10 nm of Cr and 200 nm of Ni and unpatterned nickelcoated substrates passivated by exposure to fluorine. In all cases, acetonitrile wetted the surfaces with advancing contact angles of less than 15°. Figure 4 shows that the slug-annular transition line previously reported in region 1 could be extended into region 2. However, for jG exceeding the slug transition line and jL below ∼0.01 m/s, the Pyrex cap dried out, i.e., annular-dry flows were observed, consistent with the visualization studies in our dual-channel reactor. The degree of drying increased as the ratio jG/jL increased, as expected. Figure 5 shows example images of slug flows obtained in region 2. When the pulsed laser is used, the gas-liquid interfaces appear sharp. In contrast, when the mercury lamp is employed, interference fringes are observed on the Pyrex wall, i.e., the Pyrex is wetted (fringes form because of the slight variation of the thickness of the liquid film). The dry Pyrex wall is best visualized using the lamp and is clearly indicated by the absence of interference fringes between menisci (Figure 7A). In the annular-dry region, the flow does not fully develop, and the contacting pattern depends on the order in which gas and liquid are introduced. For example, when the gas is introduced first at jL ) 5.6 × 10-3 m/s and jG ) 1.4 m/s, a completely dry Pyrex wall is obtained. From the regime flow map in Figure 4, we conclude that the onset of channeling in our system is due to the slug-annular regime transition. The slug frequency is low near the transition line and increases as the gas

Figure 5. Slug flow in a single channel with dh ) 224 µm at jG ) 0.50 m/s for nitrogen and jL ) 5.0 × 10-3 m/s for acetonitrile. The pulsed laser resolves the slug flow (left), and interference fringes are observed on the Pyrex, i.e., the Pyrex is wetted, when the mercury lamp is used (right). FOV ) 435 µm × 1.3 mm (left). FOV ) 435 µm × 875 µm (right).

velocity decreases. Gas and liquid are fed to each channel through common gas and liquid inlets (about 400-µm-square cross section) with negligible pressure drop, and therefore, channels can cross talk. Slug flow results in dynamic variations in pressure. Such a transient gas-liquid flow leads then to unequal pressure drops across the channels and unequal flow rates. Eventually, the flow becomes unstable, and channeling occurs. When the flow resistance of the liquid relative to that of the gas increases, slug flow can be obtained in both channels. Figure 6 shows representative images of such flow at jL ) 0.025 m/s and jG ) 0.7 m/s, with a slug frequency in either channel of approximately 1.5 Hz. To operate the reactor in any slug regime, gas and liquid should be introduced through individual inlet channels that present a pressure drop significantly higher than that across the reaction channels. This principle is also applicable to achieving even flow distribution in a multichannel reactor consisting of a much higher number of parallel reaction channels with common inlet and outlet ports. The previous fluorination studies reported slug flow according to our definitions,14 as well as slug and annular flow regimes,13 for a given range of liquid velocities (the slug-annular transition was not determined), in agreement with our flow regime map. However, annular-dry flow was not previously reported. A representative image of the annular-dry gas-liquid flow at the operating conditions used for our fluorination studies (jG ) 1.4 m/s, jL ) 5.6 × 10-3 m/s) is shown in Figure 7A, along with a schematic of the gas-liquid distribution in one channel cross section. Under these conditions, the interior channel walls at the upstream end of the interchannel wall or the Pyrex wall were not covered by a liquid film. Figure 7A shows two sharp menisci (in focus along the channel depth) on either side


Figure 6. Slug flows in the dual-channel device. The nitrogen and acetonitrile superficial velocities are jG ) 0.69 m/s and jL ) 0.025 m/s, respectively. The laser was used as the light source. FOV ) 1.0 mm × 1.3 mm.

Figure 7. (A) Gas (G)-liquid (L) flow distribution representative of the fluorination studies in the channel center region, location b in Figure 1B. Sharp menisci are observed on the side walls. The gas flow rate is 10 sccm for nitrogen (jG ) 1.4 m/s), and the liquid flow rate is 45 µL/min for acetonitrile (jL ) 5.6 × 10-3 m/s). The mercury lamp was used as the light source. FOV ) 435 µm × 485 µm. Below, a sketch of the gas-liquid distribution in the channel cross section. (B) Radial distribution of the gas and liquid velocities calculated in a tube of hydraulic diameter 224 µm for flows of 10 sccm for nitrogen and 45 µL/min for acetonitrile equally distributed over two tubes. The dashed line represents the gas-liquid interface.

of the microchannel for flow in the single microchannel. Even though the Pyrex cap of each channel was partially dry, all walls were wetted at the outflow end, position c in Figure 1B. The fluorescence images in Figure 8,

obtained with the pulsed laser with a time separation of approximately 1 s, show annular flow at the outflow end and the periodic motion of the liquid leaving and accumulating on the interchannel wall. The accumula-

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Figure 8. Two fluorescence images of the gas (G)-liquid (L) annular flow at the end of the interchannel wall, location c in Figure 1B, with a temporal separation of approximately 1 s. The nitrogen flow rate was 10 sccm (jG ) 1.37 m/s), and the acetonitrile flow rate was 45 µL/min (jL ) 5.6 × 10-3 m/s), representative of the fluorination conditions. The laser was used as the light source. The images show the liquid film accumulating on the interchannel wall and periodically being washed away to the outer walls. The darker region in the center is the interchannel wall. FOV ) 1.0 mm × 1.3 mm.

tion of liquid on the interchannel wall and the shedding motion, with a frequency of approximately 0.5 Hz, creates a mechanism for the liquid to wet the Pyrex wall. Given jG and jL, the liquid film thickness and the pressure drop in the annular regime were estimated by solving a force balance on the fluids in a tube with a diameter equal to the hydraulic diameter, 224 µm, i.e., the presence of menisci was ignored. A model schematic is shown in the lower part of Figure 7B. We assume the annular flow to be axisymmetric, laminar, and fully developed. Using a constant pressure gradient in the gas and liquid phases along the streamwise direction, the flow satisfies the equations

-

(

)

dP 1 d dvz,g r )0 + Fgg + µg dz r dr dr

( )

1 d dvz,l dP + Flg + µl r )0 dz r dr dr

(gas)

(2)

(liquid)

(3)

with the boundary conditions

vz,l(R) ) 0, vz,l(δ) ) vz,g(δ), µl

dvz,g (0) ) 0 dr

(wall)

dvz,l dvz,g (δ) ) µg (δ) dr dr

(4)

(interface) (5)

where P, µ, g, vz, δ, and R are the pressure, fluid viscosity, acceleration of gravity, axial velocity, radial position of the gas-liquid interface, and radius of the tube, respectively. The subscripts g and l indicate gas and liquid, respectively. A simple analytical solution

exists,29 and expressions for the gas and liquid volumetric flow rates are obtained by integrating the velocities over the appropriate cross-sectional area. For 10 sccm nitrogen and 45 µL/min acetonitrile flowing horizontally and evenly distributed over two identical tubes, the liquid film was calculated to be 14 µm thick with a pressure drop of 860 Pa for a 2-cm-long channel. The calculated gas and liquid velocity profiles are shown in Figure 7B. Because of the capillary forces acting on the channel vertices, the gas-liquid interface is located about 85 µm from the channel sidewall (Figure 7A), and the calculated pressure drop compares well with the pressure drop measured in a single channel, 595 Pa. Reaction Studies. The direct fluorination of toluene at room temperature was selected as model chemistry to characterize the performance of the microreactor because both mechanistic and preparative studies have been reported at lower temperatures (-40 and -16 °C).3,14 Several model solvents were tested, as solvent effects are expected to play an important role in the selectivity of the fluorination at room temperature.7 Acetonitrile and methanol each provided a polar medium to encourage the electrophilic aromatic substitution mechanism;6 however, they react with fluorine even at well below room temperature.2,10 Octafluorotoluene and 1,1,2-trichloro-1,2,2-trifluoroethane were explored as alternative solvents because they are presumably more inert toward fluorine and should present higher fluorine solubilities.10 Octafluorotoluene has been reported in mechanistic studies at 40 °C,3 whereas 1,1,2trichloro-1,2,2-trifluoroethane has been used in preparative direct fluorinations of several aromatic molecules (e.g., substituted pyridines) at temperatures of -25 °C.30 The toluene conversion (X), the combined selectivity of ortho-, meta-, and para-fluorotoluene isomers (S), and


the yield (Y) were determined as functions of the reaction conditions. These parameters are defined as follows

X)1-

S)

Ctol,f/CIS,f Ctol,i/CIS,i

CmF,f/CIS,f (Ctol,i/CIS,i - Ctol,f/CIS,f) Y ) XS

(8a)

(8b) (8c)

where Ctol,i and Ctol,f are the molar concentrations of toluene in the initial and final solutions, respectively; CIS,i and CIS,f are the molar concentrations of the internal standard (IS), octafluorotoluene, in the initial and final solutions, respectively; and cmF,f is the sum of the molar concentrations of the ortho-, meta-, and parafluorotoluene isomers in the final solution. Octafluorotoluene was not used to determine final concentrations for reactions performed in methanol because peaks of products due to the methanol-fluorine reaction coeluted with octafluorotoluene. In addition, no internal standard was used for reactions carried out in octafluorotoluene. To demonstrate the capabilities of the microfabricated reactor, a 0.1 M toluene solution in acetonitrile was fluorinated at room temperature in the annular-dry flow regime (jG ) 1.4 m/s, jL ) 5.6 × 10-3 m/s) with varying numbers of fluorine equivalents (i.e., the ratio between the fluorine and toluene molar flow rates). In all experiments, the gas and liquid flow rates were kept constant to maintain the system hydrodynamics, so only the concentration of fluorine in the gas phase was changed. To compensate for the fraction of fluorine that could be lost in side reactions (with the solvent and fluorinated products), the number of fluorine equivalents was varied from 1 to 5. Aromatic direct fluorinations are fast gas-liquid reactions. The reaction occurs essentially at the gasliquid interface, and at steady state, the rate of reaction is expected to be strongly dominated by the rate of mass transfer of reactants from the liquid phase to the gasliquid interface. The ratio between the concentrations of fluorine and toluene in the liquid phase is used to estimate the location of the reaction plane relative to the thickness of the liquid film. Fluorine solubilities in several solvents have been reported at various temperatures, albeit reaction with the solvent was observed in some cases.10 From these studies, the Henry’s constant of fluorine at room temperature is estimated to range between 104 and 105 Pa‚m3/mol, which is typical of slightly soluble gases. Assuming HF2 ) 104 Pa‚m3/ mol and using partial pressures of fluorine (PF2) of up to 5 × 103 Pa (the maximum initial concentration of fluorine used was 5 vol %, and the reactor was operated at nearly atmospheric pressure) and 0.1 M (i.e., 100 mol/ m3) toluene solutions, the concentration of fluorine in the liquid phase, calculated as PF2/HF2, is 0.5 mol/m3. Conversion and selectivity must be considered to maximize the reaction yield. Flows in the microchannels are laminar (the liquid Reynolds number is on the order of 1, and the gas Reynolds number is on the order of 10). To achieve full conversion of toluene, the liquid residence time should be comparable to or larger than the characteristic diffusion time of toluene across the liquid film thickness. In addition, fluorine is likely to become the limiting reactant as a result of side reac-

Figure 9. Chromatogram of reaction products showing the substitution pattern (3.3:1.0:1.9) of the ortho-, meta-, and parafluorotoluenes. The reaction conditions were 0.1 M toluene solution in acetonitrile and 1.0 equiv of fluorine.

tions; thus, excess fluorine is supplied. Excess fluorine, however, might lead to increased side reactions, i.e., lower selectivities. Thin liquid films provide short diffusion distances as well good heat-transfer characteristics out of the reaction zone into the silicon substrate. On the basis of the flow visualization studies, the liquid velocity was estimated to be 4.0 × 10-2 m/s, with a liquid residence time of 0.5 s and an average characteristic diffusion time of 0.5 s, assuming an average liquid thickness of 30 µm and a toluene diffusion coefficient in the liquid phase (Dtol,l) of 1.7 × 10-9 m2/s. The surface instabilities observed at the outlet region of the channel (Figure 8) are expected to enhance the mass transport in the liquid phase. Therefore, masstransfer limitations in the liquid phase should not be strongly limiting the conversion of toluene. The substitution pattern and the range of selectivities measured in acetonitrile are comparable to the results of previous fluorination studies conducted in micromachined metallic reactors at much lower temperatures (-16 °C).14 The ortho-, para-, and meta-fluorotoluene isomers were the main products identified from a mixture of fluorinated toluenes at lower than 5 equiv of fluorine. A reaction chromatogram section showing the fluorotoluenes obtained using a 0.1 M toluene solution in acetonitrile and 1.0 equiv of fluorine is presented in Figure 9. A standard for benzyl fluoride was not available; however, according to the mass spectrum, elution time, and elution temperature, small amounts of fluoromethylbenzene (comparable to the amount of meta-fluorotoluene, assuming equal response factors) also formed. The formation of benzyl fluoride has been reported in mechanistic studies at much lower temperatures (-40 °C) and conversions (0.01%) than used in the study presented here.3 Small amounts of difluorotoluenes, trifluorotoluenes, and other unidentified high-boiling compounds were also detected, which is expected from the fluorination of monosubstituted precursors such as toluene.6 The substitution pattern, defined as the ratio of the molar concentrations of the ortho-, meta-, and parafluorotoluene isomers, was 4:1:2 and did not change significantly with the number of fluorine equivalents (Table 1). The observed substitution pattern was consistent with the electrophilic aromatic substitution mechanism (ortho substitution is statistically favored twice as much as para substitution, except for steric

708


Table 1. Reaction Results from Toluene Direct Fluorination in the Dual-Channel Microfabricated Reactor for Various Solvents and Reactant Concentrationsa toluene concentration (M)

solvent

0.1

CH3CN CH3OH

1.0 a

C7F8 CH3CN

fluorine concentration (vol %)

number of fluorine equivalents

conversion (%)

yield (%)

selectivity (%)

substitution pattern

1.0 2.5 5.0 2.5 5.0 1.0 10.0

1.0 2.5 5.0 2.5 5.0 1.0 1.0

33 58 96 48 77 41 34

12 14 10 11 12 7 11

36 24 11 24 15 16 32

3.3:1.0:1.9 3.8:1.0:2.1 3.2:1.0:1.8 5.3:1.0:2.4 5.6:1.0:2.4 3.5:1.0:2.1 3.7:1.0:2.1

Gas flow rate ) 10 sccm (jG ) 1.4 m/s), liquid flow rate ) 45 µL/min (jL ) 5.6 × 10-3 m/s), room temperature.

Figure 11. Product chromatogram showing the influence of the number of fluorine equivalents on product distribution. Products eluting before and after the fluorotoluene isomers correspond to multifluorinated toluenes, including di- and trifluorotoluenes. The proportion of multifluorinated toluenes increases with the number of fluorine equivalents. The asymmetric shape of the 3-fluorotoluene peak at 5.0 equiv of fluorine is due to the coelution of a small fraction of a compound with a mass-to-charge ratio (m/z) equal to 146 (trifluorotoluene).

Figure 10. Conversion, selectivity, and yield showing the influence of the number of fluorine equivalents (0.1 M toluene in acetonitrile).

effects).31 However, the measured selectivities clearly indicate that other reaction pathways, in addition to ring substitution, were accessed (Figure 10). The observed tradeoff between conversion and selectivity as the number of fluorine equivalents increased was partly due to the increased formation of reaction byproducts such as multifluorinated toluenes, as shown in Figure 11. Selectivities of up to 36% were achieved at 33% conversion (0.1 M). The overall selectivity considering multisubstituted toluenes and chain-fluorinated toluenes is estimated to be 49% at 1.0 equiv of fluorine (the same response factor as for ortho-fluorotoluene was assumed). The remainder of the toluene converted is lost in other side reactions. Higher-molecular-weight compounds were detected but not quantified. Full toluene conversion in acetonitrile was achieved using 5 equiv of fluorine; however, the excess fluorine led to increased multifluorination and decreased selectivity. The highest yield, 14%, was found at 2.5 equiv of fluorine and 58% conversion; for these reaction conditions, no significant changes in conversion or yield were observed upon in situ quenching of the reaction by dilution of the exiting

gas stream with nitrogen up to a factor of 3. The fluorination was thus confined to the microreactor channels because of the high reactivity of fluorine, and excess fluorine neutralization was not necessary. Quantitative data from direct fluorinations carried out in methanol and octafluorotoluene (0.1 M) are shown in Table 1. Fluorination of 1.0 M toluene solutions in acetonitrile at room temperature was also successful. The general product distribution previously described for the dilute case in acetonitrile was not significantly affected by the solvent or toluene concentration used. The substitution pattern varied from 4:1:2 for solutions prepared in octafluorotoluene to 5:1:2 for solutions prepared in methanol. The highest yields were obtained using acetonitrile (Table 1). Methanol showed selectivities comparable to those obtained in acetonitrile but lower conversion levels. For example, a 48% conversion was observed operating at 2.5 equiv in methanol (10% lower than in acetonitrile). In contrast, reactions carried out in octafluorotoluene led to slightly higher conversions than those carried out in acetonitrile but showed increased chain fluorination linked to free-radical reactions31 and thus poorer selectivity toward ring fluorination. It was not possible to maintain a steady flow through the microreactor for longer than 20 min for reactions carried out in 1,1,2-trichloro-1,2,2-trifluoroethane (0.1 M, 1.0 equiv). The formation of a white powder at the gas inlet ports suggested that the presence of fluorine radicals induced the radical polymeri-


zation of 1,1,2-trichloro-1,2,2-trifluoroethane; the powder, however, was not identified. It is also important to consider the heat effects associated with fluorination and their influence on the selectivity of the reaction. Heat removal from the reaction zone relies on heat transfer across the liquid film. Given the rate of reaction and the rate of heat removal across the liquid layer at the inlet conditions, one can estimate the maximum temperature rise at the gas-liquid interface. For the reaction conditions presented in this study, mass transport of toluene across the liquid is dominant, assuming that the solvent and reaction products are inert to fluorine. For extremely fast reaction kinetics, a lower-bound, order-of-magnitude estimate for the reaction rate is given by the rate of mass transfer of toluene in the liquid phase. Assuming fully developed flow, the rate of mass transfer of toluene in the liquid phase under laminar flow conditions can be estimated as32

R (mol/m3‚s) )

DF2,l Dtol,l Ctol,i a DF2,l δl

(9)

where DF2,l is the diffusion coefficient of fluorine in the liquid phase, Ctol,i is the initial molar toluene concentration (100 mol/m3), δl is the average liquid film thickness (30 µm), and a is the interfacial area per unit volume of reactor (m2/m3). Using the rate of mass transfer, the temperature rise at the gas-liquid interface can be estimated from33

∆T (°C) )

R(-∆H°298) aκl/δl

(10)

where κl is the thermal conductivity of the liquid (0.2 W/m‚°C). Equation 4 neglects the amount of heat removed by convection in the gas stream. A reaction rate of 85 mol/m3‚s (using a ≈ 1.5 × 104 m2/m3) and a maximum temperature rise at the gas-liquid interface of ∆T ) 0.4 °C were estimated. Uncertainties include the reactivity of fluorine toward the solvent and reaction byproducts. The experimental results indicated that fluorine was highly reactive and multiple side reactions occurred. Therefore, consumption rates of fluorine are significantly higher and the rate of heat generation is larger than determined exclusively by mass transfer of toluene in the liquid phase. Fluorination of 1.0 M toluene solutions in acetonitrile provided ring-fluorination selectivities comparable to those obtained using 0.1 M solutions, i.e., the reaction mechanism was not appreciably affected, even though the heat load increased by a factor of 10. Conclusions In conclusion, we have demonstrated the direct fluorination of toluene in a microfabricated reactor constructed of silicon and Pyrex and coated with nickel/ silicon oxide thin films. Gas and liquid contacting patterns were systematically characterized in the microreactor, and a flow regime map was obtained for liquid velocities relevant to gas-liquid microchemical systems. It was possible to control the reaction at room temperature using aggressive reaction conditions (up to 10 vol % fluorine) and useful preparative yields (up to 14%). Toluene ring fluorination was most effective in polar solvents that enhanced the electrophilic mecha-

nism, such as acetonitrile and methanol. Perfluorinated solvents, although more inert toward fluorine, enhanced radical reactions and chain fluorination. Fluorotoluene selectivities of up to 33% were obtained in acetonitrile (0.1 and 1.0 M solutions). The highest yield of fluorotoluenes was found operating with 2.5 equiv of fluorine in acetonitrile, and it was shown that the reaction was confined to the microchannels. Further increasing the number of fluorine equivalents led to increased formation of reaction byproducts, including multifluorination of toluene and reaction with the solvent. The unique performance advantages offered by microfabrication technology pave a promising path for the commercialization of direct fluorination processes in the near future. A benchtop microreactor array system consisting of a few number of multichannel reactor units operating in parallel is a promising discovery tool for fluorinated aromatics. According to our results, a reactor system consisting of 200 channels (i.e., a total reactor volume of only ∼0.25 mL) could produce up to 0.4 g/h. Acknowledgment The authors thank Dr. S. A. Vitale and Prof. H. H. Sawin (Department of Chemical Engineering, MIT) for assistance in designing and constructing the fluorine delivery system. Dr. R. J. Jackman and the personnel of the MIT Microsystems Technology Laboratories provided guidance with the microfabrication. Helpful discussions with Prof. T. F. Jamison (Department of Chemistry, MIT) and Dr. T. M. Vettiger (Syngenta Crop Protection A.G.) are gratefully acknowledged. This research was funded by the Novartis Research Foundation and the MIT Microchemical Systems Technology Center. Literature Cited (1) Kirk-Othmer Encyclopedia of Chemical Technology, 4th ed.; Wiley: New York, 1994. (2) Grakauskas, V. Direct Liquid-Phase Fluorination of Aromatic Compounds. J. Org. Chem. 1970, 35 (3), 723-728. (3) Cacace, F.; Giacomello, P.; Wolf, A. P. Substrate Selectivity and Orientation in Aromatic Substitution by Molecular Fluorine. J. Am. Chem. Soc. 1980, 102 (10), 3511-3515. (4) Conte, L.; Gambaretto, G. P.; Napoli, M.; Fraccaro, C.; Legnaro, E. Liquid-Phase Fluorination of Aromatic Compounds by Elemental Fluorine. J. Fluorine Chem. 1995, 70 (2), 175-179. (5) Misaki, S. Direct Fluorination of Phenol and Cresols. J. Fluorine Chem. 1981, 17, 159-171. (6) Hutchinson, J.; Sandford, G. Elemental Fluorine in Organic Chemistry. Top. Curr. Chem. 1997, 193, 1-43. (7) Lagow, R. J. Direct Fluorination: A “New” Approach to Fluorine Chemistry. Prog. Inorg. Chem. 1979, 26, 161-210. (8) Chambers, R. D.; Hutchinson, J.; Sandford, G. Recent Studies at Durham on Direct Fluorination. J. Fluorine Chem. 1999, 100 (1-2), 63-73. (9) CRC Handbook of Chemistry and Physics, 78th ed.; CRC Press: Boca Raton, FL, 1997. (10) Gambaretto, G. P.; Conte, L.; Napoli, M.; Legnaro, E.; Carlini, F. M. Determination of the Solubility of Fluorine in Various Solvents. J. Fluorine Chem. 1993, 60 (1), 19-25. (11) Carpenter, K. J. Chemical Reaction Engineering Aspects of Fine Chemicals Manufacture. Chem. Eng. Sci. 2001, 56 (2), 305-322. (12) Ehrfeld, W.; Hessel, V.; Lo¨we, H. Microreactors; WileyVCH: Weinheim, Germany, 2000. (13) Chambers, R. D.; Holling, D.; Spink, R. C. H.; Sandford, G. Elemental Fluorine. Part 13. Gas-Liquid Thin Film Microreactors for Selective Direct Fluorination. Lab on a Chip 2001, 1 (2), 132-137. (14) Ja¨hnisch, K.; Baerns, M.; Hessel, V.; Ehrfeld, W.; Haverkamp, V.; Lo¨we, H.; Wille, C.; Guber, A. Direct Fluorination of

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Received for review September 13, 2002 Revised manuscript received December 16, 2002 Accepted December 16, 2002 IE020717Q

Microfabricated Multiphase Reactors for the Selective Direct

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