Halogen–Lithium Exchange Reaction Using an Integrated Glass Microfluidic Device: An Optimized Synthetic Approach

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 p-bromoanisole and n-BuLi, followed by its reaction with water. In the first stage, p-methoxyphenyllithium was synthesized and consumed immediately in the second stage. For this purpose, an integrated glass microfluidic device was fabricated using laser ablation followed by the 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 p-bromoanisole does not react with n-BuLi in pure n-hexane, the existence of a small amount of THF (or 2-MeTHF) in n-hexane facilitates pbromoanisole reaction with n-BuLi. Moreover, the reaction is complete within 1 s 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 a 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.

Process Development of a Second Generation β-Amyloid-Cleaving Enzyme Inhibitor—Improving the Robustness of a Halogen-Metal Exchange Using Continuous Stirred-Tank Reactors

“…It is noteworthy that THF also acts as a coordinating solvent to enhance the reactivity by dissociating n-BuLi hexamers in hexane to form more reactive tetramers and dimers. 7 Conversely, the significantly increased amount of THF has a deleterious effect on the reaction kinetics, and this necessitated a superstoichiometric amount of BF 3 •OEt 2 . Overall, the use of THF as a cosolvent was a good trade-off by allowing the reaction to be operable on scale by eliminating the gelling concern.…”

“…THF complexes with BF 3 competitively, hence breaking up the gelling. It is noteworthy that THF also acts as a coordinating solvent to enhance the reactivity by dissociating n -BuLi hexamers in hexane to form more reactive tetramers and dimers . Conversely, the significantly increased amount of THF has a deleterious effect on the reaction kinetics, and this necessitated a superstoichiometric amount of BF 3 ·OEt 2 .…”

Carbon‐Based Nanomaterials and Sensing Tools for Wearable Health Monitoring Devices

“…[305][306][307][308][309][310][311] Furthermore, microfluidic devices provide a high surface-tovolume ratio, leading to high mass and heat transfer rates. [312] To date, microfluidic devices have several applications in various research fields, including protein engineering, [313] immunoassays, [314] DNA research. [315] Given their intrinsic features, microfluidic devices have been used in wearable applications to enhance accuracy and reliability through precise sample gathering, analyzing, and data transferring.…”

Continuous synthesis of 1‐ethoxy‐2,3‐difluoro‐4‐iodo‐benzene in a microreactor system and the Gaussian and computational fluid dynamics simulations

“…Recently, microreactor systems have been regarded as potential replacements to batch processes [14][15][16][17][18] and have been reported to be useful for some ortho-and halogen-lithiation reactions. 19,20 However, few studies have been conducted on the large-scale synthesis of P in a microreactor system, which has great potential to overcome the shortcomings of conventional methods. First, the continuous operation of the microreactor system can lead to higher production efficiency and make the process controllable, safe, and sustainable.…”

“…Recently, microreactor systems have been regarded as potential replacements to batch processes 14‐18 and have been reported to be useful for some ortho‐ and halogen‐lithiation reactions 19,20 . However, few studies have been conducted on the large‐scale synthesis of P in a microreactor system, which has great potential to overcome the shortcomings of conventional methods.…”