Electrophoretic Separations for Continuous Flow Synthesis

The continuous-flow synthesis field has grown considerably in the last several decades. Converting a reaction from its batch synthesis to a continuous-flow alternative offers a long list of potential improvements. The latest advances make it possible for reactions to take place “on the chip’, where microscopic channels are used to propagate and mix different reactants. Continuously propagating discrete volumes of reactants inside a small capillary has the advantage of improved mass and heat transfers. These transport phenomena directly affect the kinetics and thermodynamics of the reaction, two factors that influence reaction yield over time. Having higher yields means that more product is made in a similar or lesser time frame, which can potentially lower the production cost of a pharmaceutical product, resulting in a monetary advantage for the early adopter. Another positive aspect of continuous flow chemistry is safety. By miniaturizing a reactor, we gain another level of control over the system. Since flow-reactor volumes are microscopic, the enthalpy of exothermic reactions can be easily dissipated. This is extremely important when reactions of interest possess high enthalpic contribution, especially if they are self-accelerating decomposition reactions. Since no reaction can ever achieve a hundred percent yield, a product purification mechanism is required at the end of each synthesis step. It runs naturally that a continuous-flow synthesis system should feed into a continuous-flow separation compliment without breaking the fundamental continuity concept. Up to this day, this remains the most problematic area of continuous-flow chemistry. Available continuous separation methods are either pseudo-continuous (simulated moving bed chromatography, SMBC) or severely limited in the number of concurrently separated analytes (Continuous liquid-liquid extraction, CLLE). The real solution to this problem are molecular stream separation (MSS) platforms. MSS approach allows for multiple analytes to be separated and analyzed simultaneously without disturbing the synthesis platform's continuous nature. Only two major MSS branches exist today, continuous-flow electrophoresis (CFE) and continuous annular chromatography (CAC). Although CAC has always been developed with the organic synthesis in mind, CFE has historically been reserved for water-soluble biological analytes such as DNA or proteins. By adapting CFE to the world of organic chemistry, we open the door to the field of electrophoretic separations for continuous-flow synthesis. The following manuscript will touch on the subject of fundamental engineering challenges imposed by the project and will serve to summarize our latest efforts at transforming CFE into a simple yet comprehensive platform for continuous chemistry separations.