Microfluidic Thread-Based Analytical Platform for Reaction Screening Enabled by In Situ Thread Spray Mass Spectrometry

This study describes a microfluidic thread-based analytical device (μTAD) capable of in situ mass spectrometric analysis for continuous flow reaction monitoring. Organic reaction screening is foundational to drug discovery. Microfluidic devices are of special interest here because they provide continuous reaction monitoring with advantages such as the use of smaller reagent volumes and short analysis times. We created a μTAD platform from cellulose thread and a microscope glass slide in a Y-shaped format, which enabled multiple reactants to be introduced through individual channels/reservoirs. The naturally corrugated and intertwined subfibers within cellulose thread substrates serve as serpentine mixing medium, requiring no special preparation. The capillary action behind the flow of the reactants in the thread substrate leads to controlled solvent evaporation, which is found to accelerate the chemical reactions. When performed in front of a mass spectrometer, the μTAD platform provides a facile approach to directly characterize the reaction products formed on the thread substrate. We have used the μTAD mass spectrometry platform to monitor (1) Katritzky chemistry for the synthesis of pyridinium species, (2) aza-Michael addition for uncatalyzed formation of C-N bonds, and (3) Mannich reaction, which is a three-component condensation reaction that affords β-amino carbonyl compounds. Similar reactions were screened using nanoelectrospray ionization, which suggested limited reactivity in charged microdroplets. Therefore, the main factors observed to influence reactivity on the μTAD platform were identified to include effective mixing and solvent evaporation, leading to reagent concentration in the resultant thin films. The μTAD proved to be a rapid, efficient, and low-cost platform for organic reaction monitoring, which has the potential to act as an alternative to the traditional batch screening method.