Adding Crystals To Minimize Clogging in Continuous Flow Synthesis

For many carbon–carbon and carbon–nitrogen bond-forming reactions, the stoichiometric formation of inorganic salt crystals limits continuous flow synthesis by causing precipitation, agglomeration, and ultimately clogging of the reactor. We describe a new method of mitigating uncontrolled clogging by adding crystals into the reactant stream. Adding seed crystals of the inorganic salt byproduct shifts the crystallization profile from uncontrolled nucleation to controlled heterogeneous growth. Reactions with the addition of high quality crystals show less agglomeration compared to the unseeded reaction. We realize the formation of high quality seeds using multiple methods including filtration and settling. Modeling enables balancing of the reaction rate and deposition of the salt onto seed crystals to prolong reactor operating times without clogging.