This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: A research team has developed a new molecular editing strategy that can directly convert pyridine compounds into their positional isomers. Instead of moving individual substituents around the molecule, the method relocates the nitrogen atom within the pyridine ring itself, allowing existing molecular structures to be reorganized while preserving their substituents.
The work is published in the journal Nature. Pyridine, a six-membered aromatic ring containing five carbon atoms and one nitrogen atom, is one of the most common structural motifs in pharmaceutical compounds. Even when two pyridine molecules contain exactly the same substituents, changing where those substituents are positioned relative to the nitrogen atom can substantially alter properties such as solubility, metabolic stability and interactions with biological targets.
For this reason, medicinal chemists routinely compare different positional isomers when investigating structure–activity relationships. Obtaining these isomers, however, has traditionally required separate starting materials and independently designed synthetic routes. Attempts to move substituents directly are also difficult to generalize because different functional groups can require different reaction conditions.
The team, led by Hong Sungwoo, associate director of the Center for Catalytic Hydrocarbon Functionalizations within the Institute for Basic Science (IBS) and a professor at the Korea Advanced Institute of Science and Technology (KAIST), approached the problem from a different direction—rather than moving the substituents, they moved the nitrogen atom that defines their positions. Because positions around a pyridine ring are defined relative to its nitrogen atom, relocating the nitrogen changes the positional relationship of the substituents even though the substituents themselves remain attached to the same carbon atoms. Carrying out this idea required selectively removing the original nitrogen atom from the highly stable pyridine ring while inserting a new nitrogen atom at another position, without disrupting the surrounding carbon framework or functional groups.
The researchers accomplished this through a sequence of nitrogen insertion and deletion. A new nitrogen atom is first introduced into the pyridine framework, temporarily generating an expanded nitrogen-containing intermediate. The original pyridine nitrogen is then removed, while the externally supplied nitrogen remains in the reconstructed ring.
A key feature of the reaction is that the original nitrogen ultimately leaves as nitrogen gas (N₂), an exceptionally stable molecule. This provides a strong thermodynamic driving force for the transformation. Because the intermediates involved are too short-lived to isolate directly, the researchers used isotope-labeling experiments to determine how the atoms move during the reaction.
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