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Submillisecond organic synthesis: Outpacing Fries rearrangement through microfluidic rapid mixing

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Science  06 May 2016:
Vol. 352, Issue 6286, pp. 691-694
DOI: 10.1126/science.aaf1389

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Rapid mixing to race past rearrangement

Chemistry relies on encounters between reactive partners. Sometimes one of the partners changes shape during the wait, spoiling the desired outcome. Kim et al. designed a microfluidic device to keep such botched encounters from happening. The device operates at low temperatures to keep individual reactants from isomerizing. It also achieves fast flow rates to maximize encounters between reactants on a microsecond time scale. The authors showcase the device by achieving bimolecular carbon-carbon coupling before one of the reagents can undergo a Fries rearrangement that would shift a neighboring group to the coupling site.

Science, this issue p. 691

Abstract

In chemical synthesis, rapid intramolecular rearrangements often foil attempts at site-selective bimolecular functionalization. We developed a microfluidic technique that outpaces the very rapid anionic Fries rearrangement to chemoselectively functionalize iodophenyl carbamates at the ortho position. Central to the technique is a chip microreactor of our design, which can deliver a reaction time in the submillisecond range even at cryogenic temperatures. The microreactor was applied to the synthesis of afesal, a bioactive molecule exhibiting anthelmintic activity, to demonstrate its potential for practical synthesis and production.

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