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

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