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Mild Single-Atom Skeletal Editing to Swap Carbon for Nitrogen
Chemists at ETH Zürich develop a milder, direct method for single-atom skeletal editing that swaps a carbon atom for a nitrogen atom in core organic scaffolds. The method operates under mild conditions using commercially available reagents and is demonstrated for direct interconversion between indoles and benzimidazoles.
Mild Single-Atom Skeletal Editing:
| Dimension | Key Details |
|---|---|
| Core concept | Skeletal editing provides for deleting, inserting, or swapping single atoms inside a pre-existing, fully assembled molecular skeleton without disturbing surrounding functional groups. |
| Traditional approach in drug discovery | Modifying the underlying ring framework of a complex molecule traditionally requires destroying the molecule and synthesizing it again from scratch over multiple step-by-step chemical reactions. |
| Effect of carbon-to-nitrogen swap | Swapping C for N alters a drug molecule's polarity, metabolic stability, solubility, and hydrogen-bonding capabilities, and it often makes the drug more bioavailable or capable of crossing the blood-brain barrier. |
| Operating conditions and reagent set | The protocol operates under mild conditions using a commercially available combination: phenyliodine(III) diacetate (PIDA) as the oxidant, and ammonium carbamate (H4N+H2NCOO) as a mild, safe nitrogen donor. |
| Cascade pathway steps | The mechanism comprises oxidative cleavage that selectively opens the double bond in the core indole ring, oxidative amidation and a Hofmann-type rearrangement that inserts nitrogen while removing a single carbon atom, and recyclization that spontaneously re-closes the ring into a benzimidazole scaffold. |
| Functional group tolerance | The mild protocol tolerates sensitive functional groups across highly complex, late-stage drug molecules, unlike earlier atomic-swap methods requiring harsh reagents such as ozone or hazardous azides. |
| Bio-isostere access | The method provides for direct interconversion between indoles and benzimidazoles. |
| Drug discovery utility | The method enables rapid testing of how adding nitrogen atoms into drug candidates impacts biological efficacy without building new molecules from scratch. |
| Late-stage diversification | The method is demonstrated on complex, drug-like molecules, cutting down research timelines and hazardous chemical waste in pharmaceutical development. |