Transition Metal-Catalyzed Carbon-Halogen Bond Formation

Transition metal-catalysed carbon–halogen bond formation underpins numerous advances in organic synthesis, enabling the construction of aryl, vinyl and alkyl halides with precision and efficiency. These protocols exploit fundamental steps—oxidative addition of a carbon–halogen σ bond to a metal centre, migratory insertion or C–H activation, transmetalation and reductive elimination—to forge new C–X linkages under mild conditions. Key achievements include palladium-, copper- and nickel-catalysed halogenation reactions, photoredox-enabled radical pathways and dual catalytic systems that combine light activation with traditional cross-coupling. The ability to introduce halogen handles site-selectively is central to drug discovery, agrochemical development and late-stage functionalisation of complex molecules. Contemporary research seeks to enhance selectivity, broaden substrate scope and establish sustainable catalysts that operate at ambient temperature and in environmentally benign media.

Research from Nature Portfolio

Recent studies have harnessed photoredox catalysis to achieve atom-economical halogenation of unactivated substrates via radical processes. In one approach, mild, redox-neutral conditions couple halopyridine units with alkenes, exploiting acid-promoted oxidative quenching to generate halopyridyl radicals that add selectively to the carbon–carbon double bond. This strategy avoids β-hydride elimination and preserves the carbon–halogen bond for subsequent transformations. Mechanistic investigations and computational analysis support a radical–polar crossover pathway and demonstrate the utility of retaining C–X functionality for downstream elaborations in complex molecule synthesis.

Transition Metal-Catalyzed Carbon-Halogen Bond Formation publication trend

The graph below shows the total number of articles in transition metal-catalyzed carbon-halogen bond formation across all publications each year (not limited to Nature Index journals).

Technical terms

Oxidative addition: A fundamental step in which a substrate bond adds to a metal centre, increasing its oxidation state and forming two new metal–ligand bonds.

Reductive elimination: The coupling of two ligands on a metal centre to form a new bond, reducing the metal oxidation state by two units and completing the catalytic cycle.

Transmetalation: Transfer of a ligand (typically carbon or halide) from one metal centre to another, enabling the assembly of new bonds within a catalytic sequence.

Photoredox catalysis: Use of light-activated catalysts to mediate single-electron transfer events, generating radical intermediates for bond construction under mild conditions.

Catellani reaction: A palladium/norbornene-mediated cascade which combines oxidative addition, C–H activation and reductive elimination to achieve ortho-functionalisation of aryl halides.

References

1. Photo-induced catalytic halopyridylation of alkenes. Nature Communications (2021).
2. Closing the Cycle as It Begins: Synthesis of ortho‐Iodobiaryls via Catellani Reaction. Angewandte Chemie International Edition (2023).
3. Closing the Cycle as It Begins: Synthesis of ortho‐Iodobiaryls via Catellani Reaction. Angewandte Chemie (2023).
4. Aggregation‐enabled alkene insertion into carbon–halogen bonds. Aggregate (2023).
5. Mechanistic insights on the Pd-catalyzed addition of C–X bonds across alkynes – a combined experimental and computational study. Chemical Science (2017).