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 p-bromoanisole reaction with n-BuLi. Moreover...