The fine chemicals and pharmaceutical industries are transforming how their products are manufactured, where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chemistry on all scales-from the laboratory to full production. This Review discusses the relative merits of batch and micro flow reactors for performing synthetic chemistry in the laboratory.

Microchemical systems have evolved rapidly over the last decade with extensive chemistry applications. Such systems enable discovery and development of synthetic routes while simultaneously providing increased understanding of underlying pathways and kinetics. We review basic trends and aspects of microsystems as they relate to continuous-flow microchemical synthesis. Key literature reviews are summarized and principles governing different microchemical operations discussed. Current trends and limitations of microfabrication, micromixing, chemical synthesis in microreactors, continuous-flow separations, multi-step synthesis, and integration of analytics are delineated. We conclude by summarizing the major challenges and outlook related to these topics.

We investigate the mechanisms that govern plugging in microreactors during Pd-catalyzed amination reactions. Both bridging and constriction were shown to be important mechanisms that lead to clogging in our system and greatly limited the utility of microsystems for this class of reactions. On the basis of these observations, several approaches were engineered to overcome the challenge of plugging and to enable the continuous-flow synthesis of a biarylamine. Bridging could be eliminated with acoustic irradiation while constriction was managed via fluid velocity and the prediction of growth rates.

The management of solid compounds is a major challenge facing the upstream, continuous processing of pharmaceuticals and fine chemicals. Many reactions relevant to fine chemical production either react with or form insoluble materials, which become problematic in continuous flow microreactors. The deposition, growth, or bridging of compounds can limit fluid flow from the micro-to the mesoscale, and thereby render continuous reactors inoperable. A comprehensive approach for managing solids consists of solids identification, the development of the root failure mechanism(s), and the application of active and passive techniques for the prevention and remediation. This review examines the basic principles of microreactor design for reactions that involve solids, toward the goal of performing the continuous flow processing of fine chemicals.