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Keywords:
flow chemistry; method development; reactor design
Organic chemistry has shaped modern society by fulfilling the basic needs for pharmaceuticals, agrochemicals, fragrances, and many more. Implementation of new and innovative technologies has played a vital role in this mission and has contributed to the opening of new research areas and to pushing the frontiers of existing ones. Among these new technologies, continuous flow chemistry has stepped on the stage in the last decades [1]. Originating from the petrochemical industry, where it enabled high productivity and scalability even for the most standard processes of heating, cracking, and refining of crude oil to bulk chemicals [2], it has since entered the production of pharmaceuticals and other fine chemicals. This has again led to improved scalability, higher purity of products, and eventually decreased manufacturing costs.
From the undisputed role of continuous flow chemistry for process chemists, the advent of this technology in academic research laboratories, especially for method development and natural product synthesis programs [3], has revealed some inadequacies, particularly in view of the equipment and procedures available. These limitations have been slowly overcome
with many creative but sometimes highly "academic" solutions.
Thus, recent years witnessed a steady increase in the application of continuous flow technology for academic research, leading to an expansion of synthetic options and generally more sustainable operations. Among the many advantages of performing organic reactions in continuous flow, enhanced heat-, mass- and photon transfer, an improved safety profile, broad scalability, and higher sustainability are the most prevalent ones.
To provide examples and explanation for these claims, "flash chemistry", a term coined by late Yoshida [4] for reactions at the diffusion limit, i.e.. reactions completed within milliseconds with proper mixing, showcases the fast heat- and mass transfer of continuous flow reactors. The generation of organolithium species in the presence of carbonyl compounds and their reaction has been facilitated by the extremely fast mixing of reagents and almost instantaneous heat transfer (i.e.. cooling) in specifically designed microreactors [5].
Analogously, significantly increased photon transfer in flow reactors has been exploited. Where the molar attenuation coefficient is high, such as in many important photoredox catalysts, most of the irradiation is already absorbed within a thin layer of a few millimeters. Thus, in batch reactors the vast volume...