Azide Chemistry in Organic Synthesis

Organic azides have long been prized for their unique reactivity and versatility in constructing complex molecular architectures. The azido group (–N3) serves as a robust precursor to a range of nitrogen-containing functionalities, enabling the formation of C–N bonds via both nucleophilic and radical pathways. Pivotal applications include click chemistry, wherein azides undergo copper-catalysed azide–alkyne cycloaddition to yield 1,2,3-triazoles, and diazidation reactions that afford geminal or vicinal diazides for further transformation into diamines, aziridines or heterocycles. Recent advances have expanded the repertoire of azide chemistry to encompass mild photochemical and electrochemical methods, earth-abundant metal catalysis, and sustainable flow processes. Catalytic systems now allow selective hydroazidation of unactivated C=C and C–H bonds under ambient conditions, while redox-active strategies harness ligand-to-metal charge transfer and radical ligand transfer to achieve difunctionalisation of olefins. Such methodologies have broad implications across pharmaceuticals, materials science and chemical biology, offering streamlined access to bioactive compounds, functional materials and probes for biomolecular labelling.

Research from Nature Portfolio

Innovative catalytic approaches have realised the synthesis of geminal diazides via 1,1-diazidation of alkenes using redox-active selenium catalysis under mild conditions. This protocol delivers monoalkyl and dialkyl geminal diazides that are readily converted into diverse functional motifs and exhibit favourable safety profiles. Complementing this, ligand-to-metal charge transfer activation with iron salts has enabled practical 1,2-diazidation of alkenes, utilising trimethylsilyl azide as an azide source and obviating strong oxidants. The cooperative ligand-to-metal homolysis mechanism generates electrophilic azidyl radicals that add across C=C bonds, followed by radical capture to furnish vicinal diazides in high functional-group tolerance. These developments underscore the potential of earth-abundant metals and photochemical activation to transform simple alkenes into valuable nitrogen-rich building blocks.

Azide Chemistry in Organic Synthesis publication trend

The graph below shows the total number of articles in azide chemistry in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Azidyl radical: A nitrogen-centred radical species (·N3) that adds to unsaturated bonds in radical addition reactions.

Ligand-to-metal charge transfer (LMCT): A photochemical process in which an electron is excited from a ligand orbital to a metal centre, initiating bond homolysis.

Radical ligand transfer (RLT): A mechanism in which a ligand radical generated at a metal centre is transferred to a substrate to form a new bond.

Geminal diazide: A compound bearing two azide groups on the same carbon atom, enabling successive transformations into diamines or heterocycles.

Vicinal diazide: A molecule with two adjacent azide substituents on a carbon–carbon bond, serving as precursors to vicinal diamines and related motifs.

References

1. Catalytic 1,1-diazidation of alkenes. Nature Communications (2024).
2. Iron-mediated ligand-to-metal charge transfer enables 1,2-diazidation of alkenes. Nature Communications (2022).
3. Photochemical diazidation of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer. Nature Communications (2022).
4. Iron-Mediated Photochemical Anti-Markovnikov Hydroazidation of Unactivated Olefins. Journal of the American Chemical Society (2023).
5. Azido-alkynylation of alkenes through radical-polar crossover. Chemical Science (2023).
6. POLITAG-M-F as Heterogeneous Organocatalyst for the Waste-Minimized Synthesis of β‑Azido Carbonyl Compounds in Batch and under Flow Conditions. ACS Sustainable Chemistry & Engineering (2023).