Palladium-Catalyzed Cross-Coupling Reactions of Terminal Alkynes

Palladium-catalysed cross-coupling of terminal alkynes with aryl or vinyl halides—commonly known as the Sonogashira reaction—represents a cornerstone of modern synthetic chemistry, enabling the efficient construction of C(sp²)–C(sp) bonds. The traditional protocol employs a Pd(0)/Pd(II) catalytic cycle in combination with a copper cocatalyst and a base to promote oxidative addition, transmetallation and reductive elimination. Advances in ligand design and mechanistic understanding have yielded copper-free variants, dual-Pd systems and single-atom heterogeneous catalysts, broadening functional-group tolerance and enabling greener, scalable processes. These methodologies underpin the synthesis of pharmaceuticals, natural products, conjugated materials and complex molecular architectures, with continuous-flow and biomass-derived supports further enhancing sustainability and metal economy.

Research from Nature Portfolio

Recent kinetic analyses have dissected the monometallic process into two intertwined palladium cycles, each comprising elementary oxidative addition, transmetallation and reductive elimination steps, thus pinpointing the rate-determining carbopalladation event and informing catalyst design for balanced kinetics. Further mechanistic work has clarified the long-standing copper-free Sonogashira paradigm, revealing a tandem Pd/Pd cycle linked by multistep transmetallation analogous to Pd/Cu co-catalysis and identifying phosphine dissociation as the critical initiation step. These studies collectively refine our understanding of active species, catalytic resting states and transition-state energetics, paving the way to more efficient, ligand-tuned protocols.

Palladium-Catalyzed Cross-Coupling Reactions of Terminal Alkynes publication trend

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

Technical terms

Oxidative addition: Insertion of a low-valent palladium species into an aryl–halide bond, increasing the metal's oxidation state.

Transmetallation: Transfer of an alkynyl fragment from one metal centre to another, forming a new Pd–C bond.

Reductive elimination: Coupling of two ligated fragments on palladium to release the desired carbon–carbon bond and regenerate the active Pd(0) species.

Sonogashira coupling: A palladium-catalysed cross-coupling between a terminal alkyne and an aryl or vinyl halide, typically in the presence of a copper cocatalyst or its copper-free variants.

Terminal alkyne: An alkyne with the triple bond at the end of the carbon chain, bearing an acidic hydrogen atom.

References

1. Reaction Environment Design for Multigram Synthesis via Sonogashira Coupling over Heterogeneous Palladium Single-Atom Catalysts. ACS Sustainable Chemistry & Engineering (2023).
2. Elucidating the reaction mechanism of a palladium-palladium dual catalytic process through kinetic studies of proposed elementary steps. Communications Chemistry (2023).
3. Mechanism of copper-free Sonogashira reaction operates through palladium-palladium transmetallation. Nature Communications (2018).
4. Biomass Waste-Derived Pd–PiNe Catalyst for the Continuous-Flow Copper-Free Sonogashira Reaction in a CPME–Water Azeotropic Mixture. ACS Sustainable Chemistry & Engineering (2021).
5. New Mechanistic Insights into the Copper-Free Heck–Cassar–Sonogashira Cross-Coupling Reaction. ACS Catalysis (2023).