Controlling the Catalyst’s First Move: Nickel Catalysis Overcomes a Long-Standing Challenge in Alkyl–Alkynyl Coupling
Professors Won Jun Jang and Seungwoo Hong
Department of Chemistry and Nanoscience
Researchers at Ewha Womans University have developed a nickel-catalyzed method that directly joins unactivated alkyl halides with alkynyl halides, two classes of electrophiles whose pronounced reactivity mismatch has long made selective coupling difficult. Rather than attempting to equalize the intrinsic reaction rates of the two partners, the team used a tridentate ligand to control the order in which the nickel catalyst activates them. The study, led by Professors Won Jun Jang and Seungwoo Hong of the Department of Chemistry and Nanoscience, with Nayeong Kim and Hyeri Jeon as co-first authors, was recently published in Nature Communications.
Cross-electrophile coupling (XEC) connects two electrophiles directly under reductive conditions, avoiding the need to prepare sensitive organometallic nucleophiles in advance. However, alkyl–alkynyl XEC has remained underdeveloped because activation of the alkynyl partner can outpace generation of the alkyl intermediate, favoring alkynyl–alkynyl homocoupling that produces undesired 1,3-diynes instead of the cross-coupled product. Previous approaches largely relied on specially activated alkyl precursors, which require additional synthetic steps and preclude the direct use of readily available, unactivated alkyl halides.
The Ewha team overcame this limitation by introducing a tridentate ligand that enforces an unusual "alkyl-first" activation sequence. In direct kinetic measurements, the ligand-bound Ni(0) complex reacted with the alkyl halide approximately 20 times faster than with the alkynyl bromide. The catalyst therefore forms an alkyl–nickel intermediate before engaging the alkynyl partner, suppressing competing homocoupling and enabling selective formation of C(sp³)–C(sp) bonds. Spectroscopic, kinetic, and computational studies support this sequential pathway and the involvement of Ni(I) and Ni(III) intermediates.
The reaction tolerates a broad range of functional groups and is applicable to unactivated primary, secondary, and sterically hindered tertiary alkyl electrophiles. According to the researchers, this constitutes the first reductive coupling of an unactivated tertiary alkyl electrophile with an alkynyl partner. The method was also applied to the late-stage functionalization of complex molecules derived from estrone, cholesterol, α-tocopherol, and nootkatone, including the direct coupling of two bulky fragments derived from α-tocopherol and estrone.
By establishing the sequence of substrate activation as a controllable element of catalyst design, this work offers a new strategy for forming carbon–carbon bonds between electrophiles with strongly mismatched reactivities. The concept may facilitate the development of more efficient methods for the synthesis and late-stage modification of structurally complex organic molecules.
Paper: "Ligand-controlled sequential activation enables nickel-catalysed alkyl–alkynyl coupling," Nature Communications (2026). DOI: 10.1038/s41467-026-74943-8