Flow reaction reduces aryl diazonium safety risk

The Balz-Schiemann reaction is a versatile means for synthesizing aryl fluorides from anilines. But there’s a catch: The procedure involves preparing and isolating intermediate aryl diazonium salts or generating them in situ under batch conditions. Both routes present a safety hazard because diazonium salts have the potential to spontaneously undergo violent decomposition, which has limited the scalability and utility of the reaction. Nathaniel H. Park, Timothy J. Senter, and Stephen L. Buchwald of Massachusetts Institute of Technology have addressed this problem by devising a continuous-flow process to prepare aryl diazonium salts that eliminates the need to handle them directly (Angew. Chem. Int. Ed. 2016, DOI: 10.1002/anie.201606601). The researchers were challenged to find reagents and conditions for their flow reactor that avoid side reactions that sometimes plague the Balz-Schiemann reaction and still lead to the desired aryl diazonium salts. Using the streamlined diazonium preparation shown, they fed the intermediate into a stirred batch reactor for the final dediazotization step to prevent precipitated salt from clogging the reactor channel. The approach enabled the MIT team to quickly and safely produce gram amounts of aryl and heteroaryl fluorides.