Development of a two-phase flow reaction system for DNA-encoded amide coupling

Abstract

Synthesis platforms are of particular interest to DNA-encoded library (DEL) technologies to facilitate chemistry development, building block validation, and high-throughput library synthesis. A liquid–liquid two-phase flow reactor was designed that enables parallel conduction of reactions on DNA-coupled substrates. The dispersed phase in capillary slug flow contained the DNA reaction mixture and allowed for spatially separated batch experiments in a microchannel. A coiled flow inverter (CFI) tubular reactor with a 3D-printed internal structure on which a capillary is coiled was used for improved mixing and compact setup. An inert continuous phase was introduced, which generated slug flow and prevented backmixing of the individual reactants. In order to enable parallelized reactions, slugs containing a variety of different carboxylic acids were successfully generated to act as individual reaction compartments representing single batch experiments. As a widely used exemplary DEL reaction, the amide coupling reaction was successfully transferred to the tailored flow reaction system and DNA was recovered.