Flow Chemistry for Safer and More Efficient Diazotization: Recent Advances and Future Prospects

Abstract Diazotization is a cornerstone synthetic methodology for the construction of carbon–carbon and carbon–heteroatom bonds, enabling versatile applications in pharmaceuticals, agrochemicals, and dye chemistry. However, the inherent thermal instability and explosive risk of diazonium species make safe scaleup via conventional batch processing a significant challenge. Moreover, “passive-defence” measures, including cryogenic operation and extensive dilution, are frequently neither cost-inefficient nor ideally safe. In this review, we summarize recent advances in applying continuous flow technology to diazotization. We examine how continuous flow microreactors, taking advantage of high surface-to-volume ratios and precise residence-time control, enable the in situ generation and immediate consumption of high-risk aliphatic diazo compounds (e.g., diazomethane and diazoacetonitrile). Furthermore, we highlight their superior mass- and heat-transfer characteristics in aromatic diazotization systems such as the Balz–Schiemann, Sandmeyer, and Meerwein reactions. We further discuss emerging reactor designs for diazotization, emphasizing the unique ability of continuous flow systems to simultaneously improve process safety, increase space–time yields, and expedite industrial translation.