Abstract

The formation of multiple and remote C–C bonds remains highly challenging owing to difficulties in reactivity and selectivity control. Herein, we report a nickel-catalyzed twofold conjunctive cross-electrophile coupling that employs an alkene and a 1,3-enyne as conjunctive platforms and alkyl and aryl halides as coupling partners. Through a philicity-alternating radical relay followed by selective radical capture, the reaction enables the formation of three or more C–C bonds. Combined experimental and theoretical investigations provide a rationale for the sequential radical additions to the π systems and the selective capture of a radical intermediate by the nickel catalyst. Furthermore, a five-component coupling showcases the sequential and controlled addition of alkyl and aryl moieties across three conjunctive units, demonstrating the synthetic versatility of the twofold conjunctive coupling.

A joint research team from UNIST and DGIST has developed a new chemical synthesis method that links four different compounds together in a single reaction step, offering a faster and more controllable route to building complex molecules vital for pharmaceuticals and advanced materials.

The study, led by Professors Sung You Hong and Jan-Uwe Rohde from the Department of Chemistry, in collaboration with Professors Sangwon Seo and Byunghyuck Jung from DGIST, introduces the first nickel-catalyzed twofold conjunctive cross-electrophile coupling system capable of connecting four distinct chemical building blocks through one controlled reaction sequence.

Modern chemical synthesis typically excels at connecting two or three molecular components at a time. Extending those reactions to four or more components has remained difficult because reactive intermediates tend to generate unwanted byproducts or trigger uncontrolled polymerization.

The research team addressed this challenge through a carefully engineered radical relay mechanism. In the reaction, highly reactive radical intermediates alternately shift between electrophilic and nucleophilic states, guiding molecules to connect in a precise order and at defined positions. The process functions much like a relay race, with each reaction intermediate triggering the next step in sequence.

Nickel catalysts play a central role by generating the initial radical species and selectively capturing intermediates at the final stage, preventing side reactions and maintaining control throughout the synthesis.

The method enables sequential coupling among alkyl halides, alkenes, 1,3-enynes, and aryl halides to form multiple carbon-carbon bonds in a single operation. Under modified reaction conditions, the system can even be extended to five-component coupling reactions.

The study was co-authored by Ji Hwan Jeon and Da Hye Kim of UNIST as first authors. Beyond the technical advance itself, the researchers say the work opens a new middle ground between traditional small-molecule synthesis used in pharmaceuticals and polymer synthesis used in plastics and materials manufacturing.

“This study presents a new strategy for connecting multiple molecular components sequentially within a single reaction system,” the research team explained. “It offers a conceptual bridge between precision organic synthesis and macromolecular chemistry.”

Professor Hong said the approach could become a foundational technology for designing complex organic molecules and next-generation functional materials. “The method provides a versatile platform for constructing sophisticated molecular architectures with greater efficiency and control,” he said.

The findings of this research were published in Advanced Science  on April 9, 2026. The study has been supported by the Ministry of Science and ICT (MSIT) and the National Research Foundation of Korea (NRF) through the ERC program (Engineering Research Center for Microplastic through Bio/Chemical engineering Convergence Process). 

Journal Reference

Ji Hwan Jeon, Da Hye Kim, Gun Ha Kim, et al ., “Nickel-Catalyzed Twofold Conjunctive Coupling via Philicity-Alternating Radical Relay,” (2026).