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.