A pyridine reaction that moves the nitrogen instead of the substituents
A Nature paper reports direct positional isomerisation of pyridines by nitrogen insertion and deletion, turning what were separate syntheses for each isomer into one starting material.
The Scientist · Science desk
What happened
- A research team developed a molecular editing strategy that directly converts pyridine compounds into their positional isomers by relocating the nitrogen atom within the pyridine ring rather than moving individual substituents, preserving the substituents.
- The team was 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).
- The paper is cited as Choi, W., Ju, H., Park, J. et al., 'Positional isomerisation of pyridine via nitrogen transposition', Nature (2026), DOI 10.1038/s41586-026-11006-4.
- Pyridine is a six-membered aromatic ring containing five carbon atoms and one nitrogen atom, and 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 sit relative to the nitrogen atom can substantially alter properties such as solubility, metabolic stability and interactions with biological targets.
Why it matters
A group led by Hong Sungwoo, associate director of the Institute for Basic Science's Center for Catalytic Hydrocarbon Functionalizations and a professor at KAIST, has reported a reaction that converts a pyridine directly into its positional isomers by relocating the ring nitrogen rather than shifting the groups attached to the ring [1][21]. The work, published in Nature by Choi, Ju, Park and co-authors, matters because the isomers medicinal chemists compare during structure-activity work have until now each required their own starting material and their own route [22][4][5].
The logic is a change of reference point. A pyridine is a six-membered aromatic ring with five carbons and one nitrogen, and it is one of the most common motifs in drug molecules [2]. Positions on that ring are defined relative to the nitrogen, so moving the nitrogen changes the positional relationship of every substituent even though each substituent stays bonded to the same carbon [6]. That relationship is not cosmetic: with identical substituents, changing where they sit relative to the nitrogen can substantially alter solubility, metabolic stability and interactions with biological targets [3]. Trying to move the substituents themselves has been hard to generalise, because different functional groups want different conditions [7].
Mechanically, the team inserts a new nitrogen into the pyridine framework to make an expanded intermediate, then deletes the original nitrogen, leaving the externally supplied one in the rebuilt ring [8]. The original nitrogen departs as N2, which supplies a strong thermodynamic driving force [9]. Because the intermediates are too short-lived to isolate, the mechanism rests on labelling: nitrogen-15 reagents showed the nitrogen in the new position came from the external reagent [10][11], the original ring nitrogen was confirmed to leave as part of N2 [12], and carbon-13 labelling showed the ring carbons kept their original positions [13]. That combination is what distinguishes genuine transposition from a wholesale skeletal rearrangement [14].
Two practical details stand out. Solvent choice steers the outcome: toluene strongly favoured one positional arrangement, while more polar solvents gave different isomer mixtures, so the same substrate can be pushed toward different products [15]. And because the substituents do not have to participate in the reaction, several can change their positional relationship at once while keeping their identities and relative arrangement [16]. The reported scope covers mono-, di- and multisubstituted pyridines with a range of functional groups common in medicinal chemistry [17][18], demonstrated on complex substrates derived from menthol, sulindac, paracetamol, flurbiprofen, indomethacin and tedizolid, among others [19][23].
What the publicly visible material does not give is numbers. Neither the Nature abstract nor the release reports yields or isomer ratios [25], and the supplementary information includes a section on positional isomers and unsuccessful substrates alongside the mechanistic studies, DFT-computed mechanism and an X-ray structure for one compound [24][26]. The authors' own framing is that substitution pattern becomes a mutable variable in retrosynthetic design [20]; whether that holds depends on how narrow the unsuccessful set turns out to be.
Watch the substrate table and the regioselectivity section when the supplementary data is read in detail: the questions for a planning chemist are which isomer ratios are achievable in toluene versus polar solvent, what the nitrogen source costs at scale, and whether basic nitrogens elsewhere in a drug-like molecule survive the insertion step.
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What the record supports and how the coverage leans. The claims behind it follow.
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- [1]
A research team developed a molecular editing strategy that directly converts pyridine compounds into their positional isomers by relocating the nitrogen atom within the pyridine ring rather than moving individual substituents, preserving the substituents.
- [2]
Pyridine is a six-membered aromatic ring containing five carbon atoms and one nitrogen atom, and is one of the most common structural motifs in pharmaceutical compounds.
- [3]
Even when two pyridine molecules contain exactly the same substituents, changing where those substituents sit relative to the nitrogen atom can substantially alter properties such as solubility, metabolic stability and interactions with biological targets.
- [4]
Medicinal chemists routinely compare different positional isomers when investigating structure-activity relationships, but obtaining these isomers has traditionally required separate starting materials and independently designed synthetic routes.
- [5]
According to the Nature abstract, direct interconversion of pyridine positional isomers remains largely inaccessible, so each isomer is typically prepared through an independent synthesis.
- [6]
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 remain attached to the same carbon atoms.
- [7]
Attempts to move substituents directly are difficult to generalise because different functional groups can require different reaction conditions.
- [8]
The transformation proceeds by a sequence of nitrogen insertion and deletion: a new nitrogen atom is introduced into the pyridine framework, temporarily generating an expanded nitrogen-containing intermediate, and the original pyridine nitrogen is then removed while the externally supplied nitrogen remains in the reconstructed ring.
- [9]
The original nitrogen ultimately leaves as nitrogen gas (N2), an exceptionally stable molecule, providing a strong thermodynamic driving force for the transformation.
- [10]
The intermediates involved are too short-lived to isolate directly, so the researchers used isotope-labelling experiments to determine how the atoms move during the reaction.
- [11]
Reagents containing the heavier nitrogen isotope 15N showed that the nitrogen occupying the new position in the final pyridine came from the external reagent.
- [12]
Additional experiments confirmed that the original pyridine nitrogen was expelled as part of nitrogen gas.
- [13]
13C labelling showed that the carbon atoms of the ring retained their original positions.
- [14]
Together the labelling results demonstrated that the reaction proceeds through genuine nitrogen transposition rather than wholesale rearrangement of the molecular framework.
- [15]
Changing the solvent could influence which positional isomer was formed: toluene strongly favoured one positional arrangement, while more polar solvents produced different mixtures of isomers, providing an additional means of accessing different structures from the same starting material.
- [16]
Because the substituents themselves do not need to participate directly in the reaction, several groups can effectively change their positional relationship at the same time while their identities and relative arrangement remain intact.
- [17]
The method worked across mono-, di- and multisubstituted pyridines and tolerated a wide range of functional groups commonly encountered in medicinal chemistry.
- [18]
The Nature abstract states the method is broadly applicable to mono-, di- and multisubstituted pyridines and operates across structurally complex molecular environments, allowing predictable translocation of preinstalled substituents without altering substituent identity.
- [19]
The researchers demonstrated the method on structurally complex molecules derived from compounds including menthol, sulindac, paracetamol, flurbiprofen, indomethacin and tedizolid.
- [20]
The Nature abstract states that the work establishes positional isomerization as a practical synthetic transformation, defining pyridine substitution patterns as mutable variables in retrosynthetic design.
- [21]
The team was 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).
- [22]
The paper is cited as Choi, W., Ju, H., Park, J. et al., 'Positional isomerisation of pyridine via nitrogen transposition', Nature (2026), DOI 10.1038/s41586-026-11006-4.
- [23]
The source lists at least six named drug- or natural-product-derived substrates, and the list is truncated, so the demonstrated set is at least that large.
- [24]
The paper's supplementary information contains sections on reaction optimization, substrate scope, investigation of positional isomerization regioselectivity, investigation of positional isomers and unsuccessful substrates, mechanistic studies, a computed proposed reaction mechanism and DFT calculation data.
- [25]
Neither the Nature abstract nor the phys.org account of the work reports reaction yields or isomer ratios.
- [26]
The supplementary material includes crystallographic information and an IUCr CheckCIF validation report for the X-ray structure of compound 7bc.
Sources
2 independent publishers whose own reporting we read for this story.
- nature.comPositional isomerisation of pyridine via nitrogen transposition
1 article · August 16, 2026
- phys.orgMoving nitrogen within pyridine opens a new path for molecular editing
1 article · August 18, 2026
Topics and entities
Topics
- Heterocyclic chemistry
- Skeletal and molecular editing
- Mechanistic study by isotope labelling and DFT
- Medicinal chemistry and structure-activity relationships
- Late-stage functionalisation of drugs
Entities
- Abiraterone acetate
- KAIST
- Institute for Basic Science
- Positional isomerisation of pyridine via nitrogen transposition
- Center for Catalytic Hydrocarbon Functionalizations
- Nature