HalogenâLithium Exchange Reaction Using an Integrated Glass

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Halogen-lithium exchange reaction using an integrated glass microfluidic device: an optimized synthetic approach Saeedreza Zeibi Shirejini, and Aliasghar Mohammadi Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00307 • Publication Date (Web): 27 Feb 2017 Downloaded from http://pubs.acs.org on February 27, 2017

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Organic Process Research & Development

Halogen-lithium exchange reaction using an integrated glass microfluidic device: an optimized synthetic approach Saeedreza Zeibi Shirejini and Aliasghar Mohammadi* Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran

*Corresponding author: [email protected] 1 ACS Paragon Plus Environment


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For Table of Contents Only

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Abstract A telescoped approach was developed for the efficient synthesis of methoxybenzene through the generation of an unstable intermediate reagent, based on the Br-Li exchange reaction of pbromoanisole and n-BuLi, followed by its reaction with water. In the first stage, pmethoxyphenyllithium was synthesized and consumed immediately in the second stage. For this purpose, an integrated glass microfluidic device was fabricated using laser ablation followed by thermal fusion bonding method. The impact of various parameters, including solvent, reaction time, molar ratio, concentration of reagents, and flow rates were investigated to achieve the highest yield of the desired product, leading to an optimized condition for the synthetic approach. It was found that the yield varies significantly with change in solvent composition. While pbromoanisole does not react with n-BuLi in pure n-hexane, existence of a small amount of THF (or 2-MeTHF) in n-hexane facilitates p-bromoanisole reaction with n-BuLi. Moreover, the reaction is complete within 1 second by the yield of 95% using the microfluidic device whereas in a batch system, the best result is obtained in 1 min by the yield of 49%. In addition, the optimal molar ratio of n-BuLi to p-bromoanisole was found to be 1.2. Furthermore, the higher flow rates of the reagents result in higher yield of the desired product. Finally, under the optimized condition, the generated p-methoxyphenyllithium, by the Br-Li exchange reaction of p-bromoanisole and n-BuLi, was reacted with various electrophiles using the microfluidic device.

Keywords: microfluidics; integrated glass microfluidic device; halogen-lithium exchange reaction; methoxybenzene; organometallic compound; butyllithium



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1.

Introduction

Organolithium compounds, such as aryllithiums, are powerful tools in organic synthesis mainly due to their high reactivity1-3. Such compounds are often unstable in room and higher temperatures, and are generated at low temperatures in conventional batch systems using halogen-lithium exchange reaction4-10. Furthermore, the compounds react with various electrophiles in a very fast and exothermic manner. Therefore, exposure rate of reagents must be carefully controlled to avoid heat and by-products generation11. However, even under highly controlled conditions, side reactions, including deprotonation, decomposing, and coupling do not allow to achieve appropriate yield of desired products4, 7, 8. Thus, considering such difficulties, the halogen-lithium exchange reaction remains in laboratories for small-scale organic synthesis. According to the fact that, producing aromatic organic compounds in industrial scale is highly interested, there is still a need for finding a green, feasible, and simple method for conducting the halogen-lithium exchange reaction to produce aromatic compounds in large scales. Recently, microflow systems have been introduced as an alternative to batch processing12-19. Microfluidic or lab-on-a-chip devices, as helpful tools for microflow systems, have increasingly come into focus due to their wide range of applications for biological, chemical, and medical purposes20-26. Microreactors as a functional component of microfluidic devices, designed for mixing and reaction of two or more reagents, have many advantages compared to batch reactors, including short reaction time, low cost, portability, reduced reagent consumption, and high surface-to-volume ratio27. In particular, the high surface-to-volume ratio improves heat-transfer rate during highly endothermic or exothermic reactions by avoiding formation of large temperature-gradients28,

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. In microreactors, residence time can be adjusted in the range of 4 ACS Paragon Plus Environment

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milliseconds to minutes by changing either dimensions of the microchannels or flow rates. For instance, Deng et al.30 investigated the effect of the inner diameter of a stainless-steel Tmicromixer and tube microreactor on the conversion of the Grignard exchange reaction. They observed that the conversion decreases with increase in the inner diameter, arising from the decreased mixing rate. Lately, many researchers have focused on performing competitive reactions in microflow systems31, 32. There are two prevailing concepts in controlling reactions using either microflow or conventional batch systems. Under conditions at which the reaction is faster than mixing, the reaction takes place before the homogeneity of the solution is obtained. This usually occurs in conventional batch reactors, such as flasks. In such cases, product selectivity is not controlled by the kinetics but by the mixing rate, called disguised chemical selectivity33,

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. To obtain high

selectivity of desired products in fast reactions, which suffer from disguised chemical selectivity, the mixing rate should be increased. This can be achieved through performing the reactions in microflow systems. In this vein, in an experimental attempt, Bourne and kozicki35 explored the effect of mixing rate on the selectivity of the monobromination product to the dibromination product in the bromination of 1,3,5-trimethoxybenzene using a batch system. They found that the selectivity increases with increasing the mixing rate. In parallel, in an experimental attempt, Hecht et al.36 investigated the effect of various micromixers (Swagelok T-shaped, IMVT cyclone, LTF serpentine, and Bohlender T-shaped mixers) on the selectivity in the same bromination reaction. They showed that the selectivity depends on the total flow rate of reagents so that high selectivity occurred at higher flow rates. In addition, when an effective micromixer, such as IMVT cyclone mixer was used, the highest selectivity was achieved. Comparison of the two studies indicates 5 ACS Paragon Plus Environment


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that the mixing rate was lower in the batch system and, therefore, the reaction was suffering from the problem of disguised chemical selectivity. Also, the results demonstrated that microreactors were providing an environment in which fast mixing was occurred and the reaction was controlled by kinetics. Bearing this information in mind, microreactors are a safe environment for performing halogen-lithium exchange reactions, by providing a condition at which short residence time occurs. In the halogen-lithium exchange reaction of aryl halides, which produce highly unstable reagents, high selectivity and yield of desired products can be achieved using microreactors through precise controlling of temperature and residence time37, 38. In particular, halogen-lithium (X-Li) exchange reaction of aryl halides (ArX) with n-BuLi, as an efficient method for synthesizing aryllithium compounds (ArLi), results in formation of alkyl halides (n-BuX). ArLi reacts with the produced n-BuX if the subsequent reaction is slow, and undesired products are generated. In microreactors, reagents are well-mixed and the residence time and temperature can be precisely controlled. Therefore, organolithium intermediates can be rapidly produced and quenched with an electrophile compound and there cannot be enough time for highly reactive intermediates to decompose and produce undesired products. For instance, Yoshida and co-workers38 showed that the Br-Li exchange reaction of pdibromobenzene with n-BuLi, followed by reaction with MeOH in a batch system, should be carried out at temperatures less than −48 ℃ within 5-60 min. At higher temperatures and reaction times, the produced highly reactive intermediate, p-bromophenyllithium, decomposes significantly and the major by-product, p-bromobutylbenzene, can be formed from the reaction of p-bromophenyllithium with 1-bromobutane. In the same study, they showed that the reaction can be conducted even at 20 ℃ with the reaction time of few seconds, by using microflow 6 ACS Paragon Plus Environment

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systems, consisting of stainless-steel T-shaped micromixers and microreactors, with higher yields compared with those for batch systems. In another experimental attempt, Yoshida and coworkers

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performed halogen-lithium exchange reaction of 2,2’-dibromobiphenyl to investigate

the effect of the reaction time on the yield of the reaction. They found that the yield of 85% is obtained with the reaction time of 0.057 s using a microflow system at 24 ℃. On the other hand, the yield of the same reaction with the reaction time of 60 min is 76% using a batch system. The comparison of results revealed the importance of precise control of the reaction time in halogenlithium exchange reaction. In addition, according to the results obtained from microflow system, after the mentioned time, the yield of the desired product decreases, demonstrating that highly reactive intermediate decomposes if the reaction is not quenched with appropriate electrophiles. Nevertheless, microflow systems have limited throughput to be, at first glance, considerable for industrial scale. In spite of this fact, for increased throughput, required in industrial-scale, a number of microfluidic devices can be utilized in parallel for continuous production of various products40. This scale-out, or number-up, makes it possible to produce large amount of products without changing the chemistry of the reaction and encountering with difficulties associated with conventional scale-up modifications. For instance, an industrial company, in Japan, conducts halogen-lithium exchange reaction of aryl bromide with butyllithium using microflow systems. The generated intermediate product is reacted with various electrophiles to produce approximately 1000 kg year of desired products41. However, in spite of such experimental efforts, less work has been reported on the investigation of various parameters, including solvent, reaction time, molar ratio, concentration and flow rates of reagents, modulating the halogen-lithium exchange reaction of p-bromoanisole and n-BuLi to achieve high yield and selectivity of desired products using microflow systems. A 7 ACS Paragon Plus Environment


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thorough understanding of the impact of the experimentally controllable parameters on selectivity and yield of the halogen-lithium exchange reaction can help to improve the industrial application of microflow systems for organic syntheses3,

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systematic studies to develop a more comprehensive understanding of how the experimentally controllable parameters alter the progress of the halogen-lithium exchange reaction. For this purpose, we are aimed, in this paper, to find an optimized condition for the reaction between p-bromoanisole and n-BuLi, based on the Br-Li exchange reaction, followed by reaction with H2O to achieve high yield of the desired product, methoxybenzene, using an integrated glass microfluidic device. In this vein, first, the method for fabricating the glass microfluidic device is presented. To ensure about the efficiency of the fabrication method, video and atomicforce microscopies are employed. A plexiglass holder was built to introduce organic reagents into the microfluidic device. Wide range of parameters, including solvent, reaction time, molar ratio, reagents’ concentration, and flow rates of reagents have been investigated. Finally, under the optimized condition, the reaction of p-methoxyphenyllithium with various electrophiles using the microfluidic device is examined. 2. 2.1

Experimental setup and procedures Materials

Methoxybenzene was synthesized using p-bromoanisole (Merck, ≥ 98%) and n-BuLi (Acros, 1.6 M in hexane) according to the reactions, shown in scheme 1, where freshly prepared doubledistilled water, with the conductivity of 1.5 μS/cm, was used for all the experiments. In our experiments, tetrahydrofuran (THF, Ameretat Shimi, dry, water content ≤ 500 ppm), 2methyltetrahydrofuran (2-MeTHF, VWR, GPR RECTAPUR for synthesis, water content max. 0.03 wt. %), toluene (Ameretat Shimi, dry, water content ≤ 50 ppm), ethyl acetate (Ameretat 8 ACS Paragon Plus Environment

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Shimi, dry, water content ≤ 500 ppm), and n-hexane (Merck, dry, water content ≤ 40 ppm) were exploited as embedding medium (solvent). Organolithium compounds are highly reactive compounds with special sensitivity to oxygen and moisture. Thus, the solvents used for the Br-Li exchange reaction must be completely dried. For this purpose, all mentioned solvents except THF were purchased with dried quality, and were used without further purification. For the purpose of drying THF, at the beginning, THF was predried by adding 10 g of magnesium sulfate to 200 mL of THF. The resulting mixture was refluxed at 66 ℃ for 48 h. Then, the mixture was filtered to remove suspending magnesium sulfate. Next, 5 g of sodium-metal pieces, which were dipped in petroleum ether, rinsed with nhexane to be cleaned from any traces of petroleum ether. The rinsed sodium-metal pieces were cut into small slices, and mixed with the filtered THF. Then, 1 g of benzophenone was added to the resulting mixture. The resulting mixture was refluxed at 66 ℃ until the mixture turned blue in color. Finally, THF was distilled off from the mixture, and collected into a container. To keep the solvent dried for longer time, we kept it under 4A molecular sieve. The solutions were prepared under argon atmosphere using a glove box to isolate the solutions from air and moisture, which are detrimental for organometallic compounds. Specifically, n-BuLi solutions were prepared by adding an appropriate amount of n-BuLi from the commercially available n-BuLi solution (1.6 M in hexane) into a vial, with a desired volume of n-hexane, in the glove box. Then, the vial, while was in the glove box, was sealed carefully using a septum stopper and parafilm against moisture and air contamination, and stored in a fridge, until it was being used for performing experiments. The stored vial was monitored before each experiment to make sure of limited presence of solids in the solution. Unless there were



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large amounts of solids in the vial, we uptaked solutions from the upper part of the solution within the vial, which had lower amount of solids. However, in addition, we performed other syntheses according to scheme 1, where E was an electrophile, including methyl trifluoromethansulfonate (MeOTf, Sigma-Aldrich, ≥ 98%), ethyl trifluoromethansulfonate (EtOTf, Sigma-Aldrich, 99%), iodomethane (MeI, Merck, for synthesis), and iodoethane (EtI, Merck, 99% with 1% Ethanol). Also, benzophenone, acetophenone, and benzaldehyde, used as electrophiles, were purchased from commercially available resources. 2.2

Microfluidic device fabrication

In this paper, laser ablation and thermal bonding as a low cost, feasible, and low-turnaround-time method for fabricating glass microfluidic device was utilized. One of the important advantages of direct-write micromachining is that it does not need any mask to change the design of the microchannels structure. Consequently, new channel design can be changed immediately during the prototyping process. Soda-lime glass slides (250 × 120 × 4 ) were used as substrate for laser ablation process. Because the presence of any contaminants on the substrate surface results in a significant reduction in the surface quality of the ablated substrates, the substrates were initially washed with soap and tap water and, then, sonicated in double-distilled water and, subsequently, dried at 100 ℃, to remove any residual water, in an oven. Finally, the substrates were cooled to room temperature. In the following step, a laser ablation device was used for patterning on the glass substrate. The used CO2 laser setup had maximum output power of 100 W, output beam diameter at exit of 3.5 mm, a beam divergence of 3 mrad, and the wavelength of 10.6 m. The beam scanning velocity was programmable and could be adjusted over the range of 1 − 100 mm s . The laser 10 ACS Paragon Plus Environment

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system was placed on a 90 × 60 cm" X-Y platform driven by a DC servo control system. The microfluidic device pattern, depicted in figure 1, was then transmitted to laser scriber to accomplish direct micromachining pattern on the substrate surface. It is noteworthy that various parameters affect the cross-sectional shape of etched microchannels, such as scanning speed, laser power, shape of the laser beam, and thermal diffusivity of substrate material. The smallest microchannel width, which is achievable by the current method, mainly depends on focusing power of aperture. In our experiments, the minimum available width was ~100 m. After ablation process on the glass substrate, again, both glass substrate and cover plate, which had holes on its surface, were cleaned using soap and tap water and, then, sonicated in double-distilled water. The two glass pieces were then carefully aligned and stick to each other by small amount of glue. The glued glasses were placed in a furnace and temperature increased from room temperature to 670 ℃ with a ramp rate of 6.5 ℃ min. Having reached the furnace temperature to 670 ℃, the sample was then maintained at the temperature for 90 min. Subsequently, the sample was allowed to cool to room temperature in 12 h. Finally, a sealed microfluidic device was constructed after bonding procedure of the two glass pieces. No permeation around the channel was observed by filling dye and, also, organic solvents, such as THF and n-hexane, into the device after a long time of exposure. 2.2.1

Video microscopy

In thermal bonding process for fabricating microfluidic devices, because the bonding temperature is close to the glass transient temperature of soda-lime glass, there is a concern that the channels might be sagged during the bonding process or the depth of channels be different before and after bonding process. Microscopic images were used to explore this fact. Figure 2 shows the cross-sectional shape of a microchannel, demonstrating little deformation of the 11 ACS Paragon Plus Environment


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channel features after using thermal bonding method. There is no observable change in the depth of the microchannel after using thermal bonding method. The thermal bonding method causes negligible change in the depth of fabricated microchannels if proper temperature and holding time are utilized. Our experiences indicate that temperatures less than 670 ℃ result in incomplete bonding even when two glass substrates remain for a long period of time. In addition, higher temperatures fail the bonding method and lead to collapse of microchannels. 2.2.2

Atomic force microscopy

In microfluidic devices surface roughness and utilizing proper etching technique to engrave microchannels are important factors that affect device efficiency and fluid motion. Figure 3 depicts an atomic force microscopic (AFM) graph as a quantitative inspection of an ablated microchannel’s surface roughness after thermal annealing. Also, in the figure, the AFM graph of a glass substrate without laser ablation but after thermal annealing is shown. Note that the scanned areas for the AFM graphs were 2 × 2 μm" , and surface roughness was obtained by three times of measurements at different positions and the average value is reported. The results show that the surface roughness of engraved glass is 465 nm (RMS) and the average surface roughness (Ra) is 398 nm, indicating a smooth profile of the engraved glass surface after thermal annealing. The roughness of glass surface before machining and after thermal annealing is 50.7 nm (RMS) and the average surface roughness (Ra) is 43.9 nm. Our results illustrate that laser ablation method followed by thermal annealing provides excellent etching quality and a smooth etched surface can be obtained.


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2.3

Fabricated microfluidic device

A photograph of our fabricated integrated glass microfluidic device is shown in figure 4. The device consists of two Y-shaped micromixers and two microreactors. The specifications of the microreactors are listed in table 1. In order to introduce solutions into the device, we built a plexiglass holder. In our experiments, glass microfluidic device was placed in the custom-built holder. Using the holder, solutions can be easily injected into the microchannels. As it is obvious from figure 4, the holder consists of three rectangular blocks. The chip was placed between blocks, which are assembled by means of a screw at each corner. Punctured steel screws were used at the inlet and outlet sections. Copper tube with the inner diameter of 2 mm and the outer diameter of 2.5 mm was soldered to the steel screw. In order to seal the interface of chip and the copper tube, at inlet and outlet sections, O-rings were used. Figure 5 shows the experimental setup. In whole parts of experiments, reagents were injected into the device using two syringe pumps (NE-1600, New Era Pumps, and HSP1000, Fanavaran Nano-Meghyas), and syringes along with PTFE tubing. To inspect the efficiency of the fabricated device, various solvents, including n-hexane, toluene, and THF were introduced into the device and no fluid leaking problem through the inlet and outlet sections was observed after a long time of exposure using different flow rates. Also, solutions containing green and red dyes were introduced into the device. The results delineate that after 3 h of exposure no leaking problem was occurred. Furthermore, the device portrays high optical transparency where the channels can be clearly seen. Optical transparency feature of the fabricated device can be helpful in Br-Li exchange reaction at which there is possibility of clogging the microchannels. In this vein, note that, a frequently encountered issue with Br-Li exchange reaction is the presence of solids in the reagent, n-BuLi. Such solids limit the operation of the reaction in 13 ACS Paragon Plus Environment


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microfluidic devices. In general, the techniques that can be applied to alleviate the issue fall into one of two categories: active or passive methods43-45. In active methods, external means, such as ultrasound, are employed to prevent microchannel clogging. In passive methods, the most used means to prevent clogging rely on increasing the fluid velocity. However, in our microfluidic devices, we employed the passive method to alleviate the issues with the presence of solids in the reaction media. The applied flow rates in our microfluidic devices were high enough to impose large drag forces on solids in order to flow from the entrance to the exit of the microfluidic device without deposition on the device walls. 2.4

Operating procedures

We performed the Br-Li exchange reaction using our experimental setup shown in figure 5. For this purpose, air was initially pumped into the fabricated microfluidic device to ensure that the microchannels were dried. Then, p-bromoanisole (0.02-0.125 M, flow rate of 450-1800 μl min) in various solvents (such as toluene, n-hexane, THF, mixtures of THF and n-hexane, 2-MeTHF, and mixtures of 2-MeTHF and n-hexane) and n-BuLi in n-hexane (0.1-0.6 M, flow rate of 112.5-450 μl min) were introduced into microreactor 1 (20-80 cm length, 400 μm width, and approximately 170 μm depth). The resulting mixture was passed through microreactor 2 (80 cm length, 800 μm width, and approximately 170 μm depth) and was mixed with double-distilled water. The product solution was collected for 60 s after achieving steady state. Crude product mixture was treated with double-distilled water and extracted by ethyl acetate for three times and organic phase was dried over Na" SO* and analyzed by GC-MS. The reaction conditions were optimized by changing various parameters, including residence time, molar ratio of n-BuLi to p-bromoanisole, flow rates and concentrations of n-BuLi and pbromoanisole, and solvent. Previous studies38,

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reveal that adjusting the flow rate of p-


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bromoanisole 4-5 times greater than that of n-BuLi results in higher mixing rate. Therefore, in whole parts of our experiments, except section 3.3, the flow rate of p-bromoanisole was set 4 times that of n-BuLi. In order to examine the reaction of p-methoxyphenyllithium with various electrophiles, solutions of p-bromoanisole (0.1 M, flow rate of 1800 μl min) in a mixture of THF and nhexane with the volume ratio of 1 to 15 and n-BuLi in n-hexane (0.48 M, flow rate of 450 μl min) were introduced into microreactor 1 (length of 80 cm). The generated pmethoxyphenyllithium was introduced into microreactor 2, where a solution of electrophile in THF (0.2 M, flow rate of 1800 μl min) was also injected. After steady state was achieved, the product solution was collected for 60 s. Crude product mixture was treated with double-distilled water and extracted by ethyl acetate for three times. Then, organic phase was dried over Na" SO* and analyzed by GC-MS. 2.5

Characterization methods

GC-MS analysis was performed using an Agilent 7890A gas chromatograph (GC) coupled with an Agilent 5975C mass spectrometer (MS). GC separation was achieved by a DB-1MS fusedsilica capillary column of 15 m length × 0.25 mm i.d. × 0.1 μm film thickness. GC oven temperature was initially set 40 ℃ and then increased to 250 ℃ with a ramp rate of 15 ℃ min . The products were identified by matching the generated spectra from the MS with the National Institute of Standards and Technology (NIST) and Wiley spectral libraries using manufacturersupplied software. Furthermore, we used area-percent method for analyzing data. In this method, to calculate area percent, the chromatographic peak area of an analyte was divided by the sum of the areas for all peaks. This value was representing the percentage of an analyte in the sample.



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However, the area-percent method was assuming that the GC-MS responds identically to all our compounds. To examine how reliable this assumption is for our samples, we prepared samples with known concentrations of, at least, one of our analytes (standard samples) and injected into the GC-MS. Then, we examined whether the chromatographic peak area percent of the analyte is equal to the analyte percentage in the standard samples. In our study, the standard samples were chosen to be 0, 0.00125, 0.0025, 0.00375, and 0.005 M solutions of methoxybenzene (Merck, ≥ 99%) in n-hexane. The obtained chromatographic peak area percent for methoxybenzene was completely comparable with the methoxybenzene percentage in our standard samples. 3.

Results and discussion

In what follows, the results are reported and discussed on the impact of various experimentally controllable parameters, including embedding medium (solvent), reaction time, molar ratio of reagents, and concentration and flow rates of reagents on the progress of the reaction between pbromoanisole and n-BuLi followed by reaction with H2O. To examine the importance of such parameters, first, the results on the modulation of the Br-Li exchange reaction by solvent type is examined (section 3.1). Then, considering the reaction as a competitive consecutive reaction, the reaction time is another modulating parameter examined in the following section (section 3.2). Afterwards, the importance of ratio of excess reagent to limiting reagent, called molar ratio, is investigated (section 3.3). Furthermore, the other important parameter is the concentration of reagents, which is studied in section 3.4. In addition, the effect of the flow rates of reagents on the mixing efficiency and, consequently, on the yield of the reaction is explored (section 3.5). Finally, the introduction of various electrophiles to the anisole ring is presented in section 3.6.


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3.1

Effect of solvent

Solvents act a crucial role in the progress of halogen-lithium exchange reactions. The choice of solvent can minimize or maximize the degree of aggregation of organolithium compounds, which depends on the solvent, temperature, concentration, and chelating ligands or additives. For instance, using aromatic solvents leads to the reduction of the degree of aggregation. It is generally accepted that the lower the degree of aggregation, the higher is organolithium compounds reactivity. Organolithium compounds in solutions exist as hexamer, tetramer, dimer, and monomer49. In particular, it is well-known that n-BuLi is a hexameric aggregate in hydrocarbons50, a tetrameric aggregate in diethyl ether51, and a temperature-dependent equilibrium mixture of dimeric and tetrameric aggregates in THF52. In recent years, many investigations have focused on the reactivity of organolithium compounds in various solvents. For instance, while McGarrity et al.52 found dimers as the most reactive species when n-BuLi is utilized, Waack and Doran53 asserted that monomers are the most reactive. Bearing this information in mind, the nature of organolithium compounds in solvents has modulating impact on their reactivity with substrates, such as p-bromoanisole. Due to the broad use of aryl halides in pharmaceutical and fine chemical industry, it is imperative to evaluate the effect of solvents for Br-Li exchange reactions. In such reactions, the yield of reaction remarkably changes by using different solvents54. Diethyl ether is not an industrially-interested solvent due to its physical hazards, including high volatility and low flash points55. On the other hand, although the use of hydrocarbons alleviates the mentioned issues, the reactivity of organolithium compounds reduce in hydrocarbon media. We performed experiments using neat solvents and co-solvents systems including n-hexane-THF and n-hexane17 ACS Paragon Plus Environment


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2-MeTHF to examine the role of solvents in the Br-Li exchange reaction of p-bromoanisole and n-BuLi followed by reaction with H2O. In this vein, the results, presented in table 2, are associated with the reactivity of n-BuLi in various solvents. It is observed that using toluene as embedding medium does not result in measurable reaction progress. Furthermore, a very limited reaction progress is observed in nhexane. Ostensibly, n-BuLi tolerates hexameric aggregate, which results in limited reaction with p-bromoanisole, so that 98% of p-bromoanisole remains unchanged after reaction with n-BuLi in pure n-hexane. Nevertheless, the presence of small amount of THF or 2-MeTHF in n-hexane leads to a high yield of methoxybenzene (Table 2, entries 3 and 7) and small amount of the byproduct, p-butylanisole, produced through the reaction of p-methoxyphenyllithium with generated 1-bromobutane (see scheme 1). However, at higher concentration of THF or 2-MeTHF in n-hexane, the more by-product, p-butylanisole, is produced. Using neat THF and 2-MeTHF results in 63% and 74% yield of the desired product and 36% and 24% yield of the by-product, respectively. The optimal volume ratio of n-hexane to THF or 2-MeTHF was found to be 15:1. This result mainly arises from the fact that n-BuLi exists as a hexamer in n-hexane and addition of a coordinating solvent, such as THF or 2-MeTHF, enhances the reactivity of n-BuLi through dissociating hexamers and formation of more reactive tetramers and dimers. However, although THF or 2-MeTHF increases dissociation, it also reacts with organolithium reagents according to the reaction shown scheme 256-58. The reaction results in consumption of n-BuLi existing in reaction media and, therefore, more equivalent of n-BuLi is needed to compensate the consumed amounts of n-BuLi.


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In this vein, note that, based on the results shown in table 2, using THF or 2-MeTHF has almost the same impact on the progress of the reaction between p-bromoanisole and n-BuLi. This observation arises from the fact that the mechanism of the organometallic reactions is similar in both THF and 2-MeTHF57. Our results are in agreement with previous studies54, 57, 59. However, additives, such as tertiary amines60, can be employed for conducting halogenlithium exchange reactions, causing remarkable increase in the reactivity of Li-C bond. The additives, such as N, N, N’, N’-tetramethylethylenediamine, which are simple Lewis bases, form complexes with organolithium compounds, increasing the reactivity of the Li-C bond60. Thus, it would be interesting to investigate the effect of such additives using our microfluidic device, which will be undertaken in our future studies. 3.2

Effect of reaction time

The residence time is another important factor, which affects the yield, selectivity, and conversion of reagents. When the residence time is too short, reagents leave the microreactor before the reaction is complete and remain unreacted. Under such condition, the conversion and yield of the reaction would be small. On the other hand, when the residence time is too long, reagents pointlessly flow inside the microreactor. In Br-Li exchange reactions, unstable intermediate products decompose during such excessive time and produce undesired products. Thus, the residence time must be precisely tuned to achieve the highest yield of desired products. The residence time can be controlled by varying either flow rates or dimensions of microreactors. However, changing flow rates modifies the mixing rate. Accordingly, we changed the residence time with varying dimensions of microreactors. To make comparison between the impact of residence time in batch and microflow systems, the Br-Li exchange reaction of p-bromoanisole with n-BuLi followed by reaction with H2O was 19 ACS Paragon Plus Environment


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carried out in both cases. For this purpose, at the beginning, a conventional batch reactor was used to perform the Br-Li exchange reaction of p-bromoanisole with 1.2 molar equivalents of nBuLi. A solution of n-BuLi in n-hexane (0.48 M, 0.5 mL) was added dropwise in 1 min to a solution of p-bromoanisole in a mixture of THF and n-hexane with the volume ratio of 1 to 15 (0.1 M, 2 mL) in a round-bottom flask, while the flask was being stirred with a magnetic stirrer to generate p-methoxyphenyllithium. After this step, double-distilled water was added dropwise in 1 min to quench the reaction. Crude product mixture was treated with double-distilled water and extracted by ethyl acetate for three times. Then, the organic phase was analyzed by GC-MS to determine the yield of methoxybenzene. According to the results, presented in table 3, p-methoxyphenyllithium can survive for 1 min and decomposes remarkably in 5 and 15 min. The major by-product was pbutylanisole, the product from the SN2 reaction of p-methoxyphenyllithium and 1-bromobutane. The same reaction was carried out using integrated glass microfluidic devices to examine the impact of residence time. For this purpose, two other microfluidic devices were fabricated. The only difference between two latter devices and the reference device was in the length of microreactor 1 (see table 1). In this vein, a 0.48 M solution of n-BuLi in n-hexane (flow rate of 450 μl min, 0.216 mmol min) and a 0.1 M solution of p-bromoanisole in a mixture of THF and n-hexane with the volume ratio of 1 to 15 (flow rate of 1800 μl min , 0.18 mmol min ) were introduced to each device using syringe pumps. The mixture was passed through microreactor 1 of each device and the exit stream was introduced to microreactor 2 of the corresponding device, which was simultaneously fed with double-distilled water (flow rate of 1800 μl min). The residence time was adjusted by the length of microreactor 1 of each device


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since the flow rates were the same. After a steady state was attained, the product solution was collected for 60 s. The amount of methoxybenzene was determined by GC-MS. Based on the results reported in table 4, high yield and selectivities are obtained. The results illustrate that although in the batch system, the maximum yield of the desired product is 49%, the maximum yield of the desired product is 95% using the microflow system. The yield of 95% indicates that rapid mixing in the microflow system prevents side reactions from proceeding. The presented results are in agreement with those, reported by Yoshida and coworkers38, 39, 48, 61, for the Br-Li exchange reaction with various substrates. 3.3

Effect of molar ratio

In chemical reactions, especially in organic synthesis reactions, reagents would not be used in exact stoichiometric amounts. In such cases, one reagent would be the first to be completely consumed if a desired reaction were to proceed to completion. That reagent is called limiting reagent, and all other reagents are called excess reagents. The molar ratio of excess reagent to limiting reagent has modulating impact on the progress of the reaction. In organic synthesis usually one of reagents is used in excess amount to consume all the limiting reagent. The key point is to utilize the appropriate amount of excess reagent. If the two reagents are mixed in exact stoichiometric proportions, usually the conversion of the reaction would be low. On the other hand, if excess reagent added to the reaction exceeds reasonable values, some undesirable side reactions may occur and the selectivity of the desired product would be lower. Thus, there is a need to find an appropriate molar ratio of excess reagent to limiting reagent.



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To find the optimal molar ratio of n-BuLi to p-bromoanisole, we can change either initial concentration or flow rate of each reagent. With respect to the fact that changing the initial concentration of reagents modulates the rate of reaction, the molar ratio was varied by changing the flow rates of reagents rather than initial concentrations. Moreover, to keep the mixing rate constant at whole experiments, total flow rate maintained at 2250 μL min . To adjust a specified molar ratio, flow rates of each reagent was calculated using -C/ F/ = C2 F2 , with F3 + F2 = 2250 μl min, where - is the molar ratio of n-BuLi to p-bromoanisole, C/ and F/ (= Q" ) are concentration and flow rate of p-bromoanisole, respectively, and C2 and F2 (= Q ) are concentration and flow rate of n-BuLi, respectively. The concentrations of n-BuLi and pbromoanisole were (C2 =) 0.48 and (C3 =) 0.1 M, respectively. In this vein, different molar ratios implemented in our experiments are reported in table 5. It is observed that conversion of p-bromoanisole is 60% when 1.0 equivalent of n-BuLi is used (entry 1). Furthermore, as the molar ratio increases, the conversion increases (entries 2, 3, and 4). When 1.2 or more equivalents of n-BuLi is used, conversion is 100%. Although both 1.2 and 1.5 equivalents of n-BuLi give the same results, the optimal molar ratio is selected to be 1.2 equivalents to maintain atom-economy. Note that 2 equivalents of n-BuLi results in blocking of the microchannels, stemming from the fact that the excess n-BuLi, which remains unreacted in microreactor 1, causes LiOH to precipitate in microreactor 2. In addition, the results demonstrate that 1.2 equivalents of n-BuLi gives the best yield of the methoxybenzene product.


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3.4

Effect of concentration of reagents

Concentration of reagents is an important parameter, which modulates the rate of reactions and, thus, changes the yield of desired products. The reaction rate usually increases with increasing the concentration of reagents. Although using higher reagents concentrations is an efficient way to improve the rate and yield of reactions and, also, saving solvents in industrial scales, this may result in higher viscosity of solutions, which requires higher applied pressures to drive solutions through microchannels. Higher flow rates and pressure drop across microchannels result in higher power consumption of syringe pumps, which is not feasible due to the power restrictions of used syringe pumps. Another problem, which appears in higher concentrations, is that at such concentrations, higher flow rates are required to achieve complete mixing. Therefore, at high concentrations of reagents, part of n-BuLi remains unreacted at the exit of microreactor 1 due to incomplete mixing. Then, remaining n-BuLi reacts with water in microreactor 2, and produces LiOH precipitates, which results in blocking of microchannels. Considering the potential for LiOH salt to precipitate from the solution and block microchannels, we performed experiments to find the proper concentrations of reagents (table 6). For this purpose, the flow rates of n-BuLi and p-bromoanisole were set 450 and 1800 μl min, respectively. In addition, the molar ratio of n-BuLi to p-bromoanisole was set ~ 1.2. Combining 0.02 M solution of p-bromoanisole with 0.1 M solution of n-BuLi results in formation of the desired product, methoxybenzene, without blockage of the microchannels (table 6, entry 1). The reaction carried out well up to 0.1 M concentration of p-bromoanisole. Above 0.1 M concentration of p-bromoanisole, a layer of precipitates was observed in microfluidic device and, therefore, pumping was terminated. It was found that at concentrations of 0.1, 0.2, 0.3, and 0.48 M for n-BuLi solution, the conversion of the Br-Li exchange reaction was the same.



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3.5

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Effect of flow rate

The flow rate is a very important factor in conducting our reactions using the integrated microfluidic devices, modulating the yield of the Br-Li exchange reaction. To keep the reaction time fixed, our three different microfluidic devices with dimensions listed in table 1 were used to investigate the effect of the flow rate. Table 7 shows that the best result is obtained with the flow rate of 1800 μl min for p-bromoanisole. In addition, the yield of the desired product, methoxybenzene, increases as the flow rates increase even at the high temperature compared with that required in conventional batch systems due to fast mixing in microreactors. In microfluidic devices, mixing efficiency strongly depends on flow rates so that higher flow rates result in faster mixing62. Thus, in our reactions, it is necessary to apply high flow rates to achieve high yields. However, our results are in agreement with previous studies38, 63. 3.6

Br-Li exchange reaction quenched with electrophile

Under the optimized condition (0.48 M solution of n-BuLi in n-hexane with the flow rate of 450 μl min, a 0.1 M solution of p-bromoanisole in a mixture of THF and n-hexane with the volume ratio of 1 to 15 at the flow rate of 1800 μl min), the reaction of pmethoxyphenyllithium with various electrophiles in THF (0.2 M, flow rate of 1800 μl min), using microfluidic device no. 3 was conducted. Iodomethane, iodoethane, methyl trifluoromethansulfonate, ethyl trifluoromethansulfonate, benzophenone, acetophenone, and benzaldehyde were used as electrophiles and the corresponding products were obtained in high yield. In all cases, the conversion of p-bromoanisole was almost 100%. From table 8, the results demonstrate that the microflow system serves as a fast and useful method for conducting the BrLi exchange reaction of p-bromoanisole with n-BuLi followed by reaction with various electrophiles. 24 ACS Paragon Plus Environment

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4.

Conclusions

An integrated microfluidic device was fabricated for the multistep synthesis of methoxybenzene, based on the Br-Li exchange reaction of p-bromoanisole and n-BuLi, followed by reaction with water. For this purpose, the microfluidic device pattern was ablated on a soda-lime glass substrate using laser and thermally bonded to another glass substrate with drilled holes, as inlet and outlet sections. The yield and selectivity of the desired product, methoxybenzene, by changing various parameters, including solvent, reaction time, molar ratio, and concentration and flow rates of reagents were investigated. It was observed that the composition of solvent affects considerably the yield so that employing a mixture of n-hexane and THF (or 2-MeTHF) by the volume ratio of 1 to 15, the highest yield was obtained. Also, in the microflow system, the reaction was carried out in 1 second by the yield of 95%, whereas in a batch system, the reaction time increased to 1 min with the maximum yield of 49%. The optimal molar ratio of n-BuLi to p-bromoanisole was found to be 1.2 to achieve the highest yield. Moreover, the yield increased with increasing the concentration of the reagents, indicating to the higher reaction rate at higher concentrations. The upper bound for the concentration of the reagents was limited by the power restrictions of the used syringe pumps through injecting more viscous solutions at higher concentrations of reagents. Furthermore, higher flow rates of the reagents resulted in higher yields. In addition, under an optimized condition, the generated p-methoxyphenyllithium, by the Br-Li exchange reaction of p-bromoanisole and n-BuLi, was reacted with various electrophiles using the microfluidic device, resulting in the introduction of various electrophiles to the anisole ring. Although chemistry in microflow and conventional batch systems is the same, selectivity was



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observed to be disguised in batch systems due to limited mass transfer, which is released in microflow systems by providing an environment in which the diffusion length is short. However, it was found that the fabricated microfluidic device enables performing the Br-Li exchange reaction at ambient temperature, which is much higher than that required in conventional batch systems, through controlling residence time; this fact is of considerable importance for industrial applications due to less energy consumption and lower operating cost6466

. Finally, note that this study is a preliminary study for developing integrated microfluidic

devices for synthesis, separation, and purification of aromatic compounds based on halogenlithium exchange reactions, where this paper provides a basis for further experimental investigations. Acknowledgments A.M. gratefully acknowledges supports from the Sharif University of Technology Research Council.

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Table 1. The specifications of the microreactors of three different integrated glass microfluidic devices that we tested in our experiments for examining the influence of the reaction time and flow rates. Microreactor 2 for all three microfluidic devices had the same dimensions. We refer to geometry 3 as the reference device, which was used for all our other experiments.

Microfluidic

Microreactor 1

Microreactor 2



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device no.

length (cm)

width (μm)

depth (μm)

length (cm)

width (μm)

depth (μm)

1

20

400

170

80

800

170

2

50

400

170

80

800

170

3

80

400

170

80

800

170

Table 2. Br-Li exchange reaction of p-bromoanisole with n-BuLi in various solvents followed by reaction with H2O using microfluidic device no. 3 (see table 1).[a]

Entry 1

solvent Toluene

Yield [%][b]

Conversion [%]

methoxybenzene

p-butylanisole

0

0


0

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2 3

4

n-hexane n-hexane-THF (15:1 by vol) n-hexane-THF (13:3 by vol) n-hexane-THF

5

(1:1 by vol)

6

THF n-hexane-2-MeTHF

7

(15:1 by vol) n-hexane-2-MeTHF

8

(13:3 by vol) n-hexane-2-MeTHF

9

(1:1 by vol)

10

2-MeTHF

2

0

2

95

4

100

89

6

100

88

8

100

63

36

100

96

3

100

89

6

100

88

6

100

74

24

100

[a] Solutions of n-BuLi in n-hexane (0.48 M, 450 μl min ) and p-bromoanisole in mentioned solvents (0.1 M, 1800 μl min ) were injected in microreactor 1 of microfluidic device no. 3. Flow rate of double-distilled water, Q3, was 1800 μl min . Note that the molar ratio of n-BuLi to p-bromoanisole was 1.2, and the flow rate of p-bromoanisole solution was 4 times that of n-BuLi solution. [b] Yields were determined by GC-MS.

Table 3. Br-Li exchange reaction of p-bromoanisole with n-BuLi followed by reaction with H2O using a batch system.[a]

Yield [%][b] Entry

Reaction time (min)

Conversion [%] methoxybenzene p-butylanisole



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1

1

49

17

80

2

5

35

21

78

3

15

11

40

73

[a] A solution of n-BuLi in n-hexane (0.48 M, 0.5 mL) was added dropwise over a period of mentioned times to a solution of p-bromoanisole in a mixture of THF and n-hexane with the volume ratio of 1 to 15 (0.1 M, 2 mL) in a flask, while the flask was being stirred. After stirring, double-distilled water (2 mL) was added dropwise in 1 min. Note that the molar ratio of n-BuLi to p-bromoanisole was 1.2. [b] Yields were determined by GC-MS.

Table 4. Br-Li exchange reaction of p-bromoanisole with n-BuLi followed by reaction with H2O using three different integrated glass microfluidic devices (see table 1).[a]

Length of Microfluidic microreactor device no. 1 (cm)

Residence time in microreactor 1 (sec)

Yield [%][b]

methoxybenzene


pbutylanisole

Conversion [%]

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1

20

0.25

54

0

54

2

50

0.62

77

0

77

3

80

1

95

3

100

[a] Solutions of n-BuLi in n-hexane (0.48 M, 450 μl min ) and p-bromoanisole in a mixture of THF and n-hexane with the volume ratio of 1 to 15 (0.1 M, 1800 μl min ) were injected in microreactor 1 of each microfluidic device. The flow rate of double-distilled water was 1800 μl min. Note that the molar ratio of n-BuLi to p-bromoanisole was 1.2, and the flow rate of p-bromoanisole solution was 4 times that of n-BuLi solution. [b] Yields were determined by GC-MS.

Table 5. Br-Li exchange reaction of p-bromoanisole with n-BuLi at various molar ratios followed by reaction with H2O using microfluidic device no. 3 (see table 1).[a]

Entry

Flow rate Flow rate of Molar ratio Yield [%][b] pof n-BuLi to of n-BuLi p(μl min ) bromoanisole pbromoanisole (μl min) methoxybenzene butylanisole


Conversion [%]


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 34 of 44

1

1

388

1862

60

0

60

2

1.1

420

1830

79

1

81

3

1.2

450

1800

95

3

100

4

1.5

536

1714

94

4

100

5

2

662

1588

Clogging

Clogging

Clogging

[a] Solutions of n-BuLi in n-hexane (0.48 M) and p-bromoanisole in a mixture of THF and n-hexane with the volume ratio of 1 to 15 (0.1 M) were injected in microreactor 1 of microfluidic device no. 3 at mentioned flow rates. The flow rate of double-distilled water, Q3, was equal to that of p-bromoanisole. [b] Yields were determined by GC-MS.

Table 6. Br-Li exchange reaction of p-bromoanisole with n-BuLi followed by reaction with H2O at various concentrations of reagents using microfluidic device no. 3 (see table 1). [a]

Entry

n-BuLi concentration (M)

pbromoanisole concentration (M)

Yield [%][b] Conversion [%] methoxybenzene


p-butylanisole

Page 35 of 44


1 2 3 4 1 0.1 0.02 78 10 100 5 6 7 8 2 0.2 0.042 81 8 100 9 10 11 12 3 0.3 0.062 89 7 100 13 14 15 16 4 0.48 0.1 95 3 100 17 18 19 5 0.6 0.125 Clogging Clogging Clogging 20 21 22 23 [a] Solutions of n-BuLi in n-hexane (450 μl min ) and p-bromoanisole in a mixture of THF and n-hexane with the 24 25 volume ratio of 1 to 15 (1800 μl min ) were injected in microreactor 1 of microfluidic device no. 3. The flow rate 26 27 of double-distilled water was 1800 μl min . Note that the molar ratio of n-BuLi to p-bromoanisole was ~1.2, and 28 29 the flow rate of p-bromoanisole solution was 4 times that of n-BuLi solution. 30 31 [b] Yields were determined by GC-MS. 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Table 7. Br-Li exchange reaction of p-bromoanisole and n-BuLi followed by reaction with H2O at different flow 46 47 rates using three different microfluidic devices listed in table 1.[a] 48 49 50 p51 Yield [%][b] n-BuLi H2O flow Length of 52 Microfluidic bromoanisole Conversion rate microreactor flow rate 53 device no. flow rate [%] p1 (cm) (μl min) (μl min) methoxybenzene 54 (μl min ) butylanisole 55 56 57 58 59 35 60 ACS Paragon Plus Environment


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1

Page 36 of 44

20

112.5

450

450

36

7

74

2

50

281.2

1124.8

1124.8

77

4

83

3

80

450

1800

1800

95

3

100

[a] Solutions of n-BuLi in n-hexane (0.48 M) and p-bromoanisole in a mixture of THF and n-hexane with the volume ratio of 1 to 15 (0.1 M) were injected in microreactor 1 of the indicated microfluidic devices. The flow rate of double-distilled water was equal to that of p-bromoanisole. Note that the molar ratio of n-BuLi to p-bromoanisole was 1.2. [b] Yields were determined by GC-MS.

Table 8. Br-Li exchange reaction of p-bromoanisole with n-BuLi followed by reaction with indicated electrophiles using microfluidic device no. 3 (see table 1).[a]

entry

electrophile

1

MeI

product

Yield (%)[b] 90


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2

EtI

66

3

MeOTf

92

4

EtOTf

78

5

Ph2CO

92

6

PhCHO

89

7

PhAc

88

[a] Solutions of n-BuLi in n-hexane (0.48 M, 450 μl min ) and p-bromoanisole in a mixture of THF and n-hexane with the volume ratio of 1 to 15 (0.1 M, 1800 μl min ) were injected in microreactor 1 of microfluidic device no.3. The resulting mixture and indicated electrophiles (0.2 M, 1800 μl min ) were injected simultaneously into microreactor 2. Note that the molar ratio of n-BuLi to p-bromoanisole was 1.2, and the flow rate of p-bromoanisole solution was 4 times that of n-BuLi solution. [b] The yields were determined by GC-MS.



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Figure 1. Pattern of our glass microfluidic device. Indicated dimensions are in mm.


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Figure 2. Cross-sectional shape of a microchannel before (left) and after (right) thermal bonding. Images were processed and analyzed using ImageJ software for determining the depth of the microchannels.



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Figure 3. AFM graphs of an ablated microchannel (left) and a glass substrate (right) after thermal annealing.


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Figure 4. A photograph of our fabricated integrated glass microfluidic device and chip holder.



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Figure 5. The experimental setup consisting of two syringe pumps and the microfluidic device. Solutions of n-BuLi in n-hexane and p-bromoanisole in various solvents were injected into microreactor 1 through, respectively, inlets 1 and 2, with double-distilled water or various electrophiles injected into microreactor 2 through inlet 3. The injected flow rates were Q1, Q2, and Q3 through inlets, respectively, 1, 2, and 3.


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OMe

OMe

n-BuBr

n-BuLi

Li

Br

n-BuBr

H2O or Electrophile (E) OMe

OMe

H (E)

Bu

desired product

by-product

Scheme 1. The Br-Li exchange reaction of p-bromoanisole and n-BuLi followed by reaction with H2O or an electrophile (E).



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Scheme 2. The reaction of THF with n-BuLi.


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HalogenâLithium Exchange Reaction Using an Integrated Glass

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