Copper-Catalyzed Cross-Coupling Chemistry

Copper-catalyzed cross-coupling encompasses a family of reactions that form carbon–carbon and carbon–heteroatom bonds by joining two organic fragments under the action of copper catalysts. Traditional Ullmann and Goldberg methodologies have been revitalised through the introduction of tailored ligands, nanoparticle architectures and alternative reaction media, enabling transformations at lower temperatures with improved functional-group tolerance. Mechanistic pathways include oxidative addition, transmetallation and reductive elimination, as well as single-electron processes in photochemical contexts. Innovations such as recyclable heterogeneous catalysts and photochemically activated copper/graphene systems have broadened substrate scope to aryl halides, boronic acids, amines and heterocycles. These advances offer cost-effective, sustainable alternatives to palladium-based protocols, with significant impact on pharmaceutical synthesis, materials development and agrochemical manufacture.

Research from Nature Portfolio

Recent studies have demonstrated the deployment of Cu0 nanoparticles immobilised on nanoporous polymers as highly active, recyclable catalysts for classic Ullmann couplings of aryl halides with amines in aqueous media. These materials exhibit minimal metal leaching, facile recovery and sustained activity over multiple cycles. In parallel, photocatalytic systems based on copper nanoparticles supported on graphene have shown that visible-light irradiation induces plasmonic excitation, driving efficient N-arylation of imidazoles and enabling C–O and C–S bond formation under mild conditions. These approaches illustrate how nanostructured copper catalysts can harness light and solid supports to achieve green and versatile cross-coupling protocols.

Copper-Catalyzed Cross-Coupling Chemistry publication trend

The graph below shows the total number of articles in copper-catalyzed cross-coupling chemistry across all publications each year (not limited to Nature Index journals).

Technical terms

Cross-Coupling Reaction: A catalytic process that joins two organic electrophiles or nucleophiles to form a new bond, typically C–C or C–X (X = N, O, S).

Ullmann Coupling: A copper-mediated reaction that forms C–C or C–N bonds between aryl halides and nucleophiles, traditionally requiring high temperature and stoichiometric copper.

Deep Eutectic Solvent: A mixture of hydrogen-bond donors and acceptors that forms a low-melting-point liquid, serving as an environmentally friendly reaction medium.

N-Heterocyclic Carbene (NHC): A strong σ-donor ligand derived from azolium salts, stabilising metal centres and enhancing catalytic activity.

Photocatalysis: Activation of a catalyst by light absorption, enabling single-electron pathways and lower-energy reaction routes.

References

1. Cu0 Nanoparticles Deposited on Nanoporous Polymers: A Recyclable Heterogeneous Nanocatalyst for Ullmann Coupling of Aryl Halides with Amines in Water. Scientific Reports (2015).
2. Visible-light-driven Photocatalytic N-arylation of Imidazole Derivatives and Arylboronic Acids on Cu/graphene catalyst. Scientific Reports (2015).
3. Reshaping Ullmann Amine Synthesis in Deep Eutectic Solvents: A Mild Approach for Cu-Catalyzed C–N Coupling Reactions With No Additional Ligands. Frontiers in Chemistry (2019).
4. C−X (X = N, O) Cross-Coupling Reactions Catalyzed by Copper-Pincer Bis(N-Heterocyclic Carbene) Complexes. Frontiers in Chemistry (2019).
5. Recent Advancement of Ullmann Condensation Coupling Reaction in the Formation of Aryl-Oxygen (C-O) Bonding by Copper-Mediated Catalyst. Catalysts (2020).