Continuous flow chemistry is being used increasingly; however, without detailed knowledge of reaction engineering, it can be difficult to judge whether dispersion and mixing are important factors on reaction outcome. Understanding these effects can result in improved choices of reactor dimensions and give insight for reactor scale-up. We provide an overview of both dispersive and mixing effects in flow systems and present simple relationships for determining whether mixing or dispersion is important for a given flow system. These results are summarized in convenient charts to enable the experimentalist to identify conditions with potential mixing or dispersion problems. The information also expedites design changes, such as inclusion or changes of mixers and changes in reaction tube diameters. As a case study, application of the principles to a glycosylation reaction results in increased throughput and cleaner product profiles compared to previously reported results.
The synthesis of 5-substituted tetrazoles in flow (see scheme) is safe, efficient, scalable, requires no metal promoter, and uses a near-equimolar amount of NaN3, yet nonetheless displays a broad substrate scope. The hazards associated with HN3 are essentially eliminated, shock-sensitive metal azides such as Zn(N3)2 are avoided, and residual NaN3 is quenched in-line with NaNO2.
Nucleosides in flow: A general, scalable method of Brønsted acid-catalyzed nucleoside formation is described. Because of the high reaction temperatures readily available to the flow reaction format, mild Brønsted acids, particularly pyridinium triflates, can be used. A one-flow multistep synthesis of unprotected nucleosides is also reported (see scheme).
A convenient and efficient flow method for Ullmann condensations, Sonogashira couplings, and decarboxylation reactions using a commercially available copper tube flow reactor (CTFR) is described. The heated CTFR effects these transformations without added metals (e.g., Pd), ligands, or reagents, and in greater than 90% yield in most cases examined.
Using continuous flow techniques for multi-step synthesis enables multiple reaction steps to be combined into a single continuous operation. In this mini-review we discuss the current state of the art in this field and highlight recent progress and current challenges facing this emerging area.
The use of a continuous flow microreactor for β-amino alcohol formation by epoxide aminolysis is evaluated. Comparison to microwave batch reactions reveals that conditions obtainable in the microreactor can match or improve yields in many cases. By increasing the pressure of the system, maximum temperatures can also exceed those accessible using a microwave unit. The use of a microreactor for epoxide aminolysis reactions in the synthesis of two pharmaceutical relevant compounds is described.