Continuous-flow harnesses the synergy of nitrogen dioxide and ozone for safe, catalyst-free and ultrafast arene nitration

Green and scalable nitration of aromatic compounds remains a challenge in chemical synthesis. While acid-free nitration using simple nitrogen oxides is highly attractive, it is often plagued by poor controllability, low efficiency, and safety hazards in conventional batch reactors. Building on the classical Kyodai nitration, we report a continuous-flow protocol that harnesses the synergy of nitrogen dioxide and ozone for the safe, acid-free, catalyst-free, and ultrafast nitration of arenes within seconds. This method demonstrates broad functional group tolerance and substrate scope, enabling the high-yield synthesis of diverse nitroarenes, encompassing the preparation of drug molecules, key pharmaceutical intermediates, and the late-stage functionalization of complex drugs. The protocol is readily scalable to the gram-scale and exhibits a significantly improved environmental performance over the batch process, as quantified by a substantially lower Process Mass Intensity (PMI). Kinetic studies support an electrophilic aromatic substitution (S E Ar) mechanism. This work establishes a robust and scalable platform for green nitration, offering a compelling solution to a long-standing synthetic challenge. A safe, efficient, and scalable continuous-flow platform harnessing the NO 2 -O 3 synergy for catalyst-free green nitration of arenes.