Catalyst-Free C–N Coupling under Ambient Conditions via High-Throughput Microdroplet Reactions

Carbon–nitrogen (C–N) coupling is essential in organic synthesis, as it underpins the construction of many complex molecules with a wide range of applications. However, well-established C–N coupling methods, such as the Buchwald–Hartwig coupling, often require metal catalysts and heating. This study describes microdroplet-based, catalyst-free C(sp2)–N coupling under ambient conditions with broad substrate scope for both amines and aromatic halides. The reaction was performed using high-throughput desorption electrospray ionization, allowing for the creation of reactive microdroplets in which coupling occurs during their millisecond flight time. Experimental and computational studies of the mechanism suggest that this reaction proceeds via aromatic nucleophilic substitution driven by the superacidic nature of the gas-liquid microdroplet interface. This work highlights the potential of high-throughput microdroplet reactions for efficient and environmentally friendly C–N coupling, offering a promising new tool for synthetic chemistry.