Chemists Program Alkenes With Switchable Radical and Organometallic Sorting

Chemists at Wuhan University have unveiled a nickel-catalysed reaction that can build an impressive range of alkene architectures from the same simple set of starting materials, simply by changing the ligand on the catalyst. The work, published in Nature Chemistry, addresses one of the most stubborn challenges in synthetic chemistry: how to access regioisomers, stereoisomers and homologues of complex alkene skeletons in a programmable, divergent fashion rather than through separate, substrate-specific campaigns. Because the precise arrangement of substituents around a carbon-carbon double bond profoundly influences how a molecule functions, whether as a drug candidate, a natural product fragment or an electronic material, the ability to dial in a desired alkene geometry on demand represents a significant advance for the field.

The new method, developed by Chengmi Huang, Dong Wu, Shiyang Wang, Yangyang Li and Guoyin Yin in the laboratory of Guoyin Yin, with computational contributions from Shuang Deng and Xiaotian Qi, is a sequential three-component coupling of alkynes, organohalides and a diboron reagent. Alkynes are attractive building blocks because they are flat, linear and readily available, and their conversion into substituted alkenes by adding two different groups across the triple bond, a process known as difunctionalization, is a powerful way to generate molecular complexity in a single operation. The difficulty has always been control: which group adds to which end of the alkyne, and whether the two groups end up on the same side or opposite sides of the resulting double bond.

Traditional approaches to alkyne difunctionalization typically rely on predesigned substrates bearing directing groups, or on rigid, single-pathway reaction mechanisms that lock in one regiochemical and stereochemical outcome. That rigidity restricts structural diversity, forcing chemists to redesign substrates and conditions every time a different isomer is needed. The Wuhan team’s solution is conceptually different. Instead of fixing the pathway, they exploit the fact that nickel catalysts can operate through two fundamentally different reactive intermediates, organometallic species on one hand and free radicals on the other, and they show that the choice of ligand determines which of these pathways dominates.

Mechanistic studies, combining experiments with density functional theory calculations, revealed the heart of the switch. The electronic properties of the ligand regulate whether the nickel catalyst generates an organometallic intermediate or a radical intermediate after oxidative addition of the organohalide. When the organometallic pathway prevails, the reaction proceeds through a well-defined nickel-carbon bond and delivers one set of alkene products; when radical generation dominates, the reaction follows an entirely different trajectory. Remarkably, the team found that the intrinsic metal-binding ability of the various radicals further modulates their reactivity, providing a second layer of selectivity control that governs how the radical interacts with the nickel-bound alkyne.

This dual-control architecture allows the researchers to access alkene products that are otherwise difficult to make. Under one set of conditions, the coupling delivers uncommon 1,2-trans alkenes, in which the two newly installed groups sit on opposite carbons of the double bond and point away from each other. Under another set of conditions, the same three components combine to give 2,1-cis alkenes, with the groups on adjacent carbons and on the same face. Achieving both regioselectivity and unique stereoselectivity simultaneously in a single catalytic operation is rare, and the fact that the outcome can be toggled by ligand choice rather than by rebuilding the substrate is what makes the system genuinely programmable.

The programmability extends beyond stereochemistry into molecular homologation. By controlling the incorporation of two alkyne units into the product, the team accomplished the divergent synthesis of conjugated diene homologues, molecules that differ by the number of conjugated alkene units in their backbone. Conjugated dienes are ubiquitous structural motifs: they appear in natural products such as the sorbicillinoid family, in agrochemicals including neonicotinoid insecticides, and in functional materials where the extent of conjugation dictates optical and electronic properties. Being able to prepare two different conjugated diene homologues from the same reaction setup, choosing between them with the catalyst rather than with new starting materials, offers a modular route to libraries of these valuable compounds.

The concept of radical sorting has been gaining momentum in catalysis research in recent years. Landmark studies from the MacMillan group on alkene dialkylation by triple radical sorting, and from other laboratories on cross-couplings enabled by bimolecular homolytic substitution, have shown that selectively channelling different radical species through a catalytic cycle can enable transformations that would otherwise be hopelessly scrambled. The Wuhan work pushes this idea further by sorting not just among radicals but between radical and organometallic regimes, effectively giving the chemist a switch that selects the reactive personality of the catalyst. The authors’ computational analysis, including average local ionization energy mapping of nickel(I) intermediates and buried-volume steric maps of the ligand environment, provided a quantitative picture of how ligand electronics and sterics steer the competition between pathways.

Detailed mechanistic experiments underpinned the proposal. The team examined how different ligands altered the fate of the alkenyl-nickel and alkenyl-radical intermediates that arise after the first addition across the alkyne, and their calculations compared the competing pathways for two distinct ligand frameworks, designated L4 and L6, at a high level of theory in solvents matching the experimental conditions. The results showed that chemoselectivity, whether the intermediate continues down the productive coupling channel or diverts into an unproductive one, is dictated by the interplay of ligand electronics and the radical’s affinity for the metal centre. This mechanistic clarity is valuable in its own right, because it converts what could have been an empirical observation into a set of design principles that other laboratories can apply to their own catalytic problems.

The practical scope of the method was demonstrated across a broad collection of substrates, with crystallographic data for seven representative products deposited at the Cambridge Crystallographic Data Centre to confirm the assigned structures unambiguously. The authors also showcased synthetic applications, including downstream transformations of the borylated alkene products and an application to the synthesis of histamine H3 receptor inverse agonists, a class of pharmacologically active compounds, illustrating how the reaction could feed directly into medicinal chemistry workflows. Because the products carry a boronate handle, they are primed for further diversification through well-established organoboron chemistry, multiplying the value of each coupling event.

The work was supported by the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, the Shenzhen Science and Technology Program and institutional funds from Wuhan University, and it was peer reviewed by experts including Javier Corpas, Albert Poater and Qiuling Song. Beyond its immediate synthetic utility, the study signals a broader shift in how chemists think about selectivity. Rather than accepting the selectivity dictated by a substrate’s inherent bias, catalysts can now be engineered to override that bias and impose an outcome chosen by the operator. As switchable catalysis matures, the prospect of running a single reaction flask and extracting whichever molecular isomer a drug discovery or materials program requires, simply by swapping a ligand, moves from aspiration toward routine practice, and this nickel-catalysed alkene construction provides a compelling demonstration of that future.

Subject of Research: Ligand-switchable nickel catalysis for programmable regio-, stereo- and homologation-divergent construction of alkene skeletons from alkynes, organohalides and diboron reagents.

Article Title: Programmable alkene skeleton construction via switchable radical and organometallic sorting

Article References: Huang, C., Deng, S., Wu, D., Wang, S., Li, Y., Qi, X., & Yin, G. (2026). Programmable alkene skeleton construction via switchable radical and organometallic sorting. Nature Chemistry. https://doi.org/10.1038/s41557-026-02242-2

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02242-2

Keywords: nickel catalysis, alkyne difunctionalization, radical sorting, organometallic chemistry, alkene synthesis, conjugated dienes, stereoselectivity, regioselectivity, ligand control, diboron reagent, homologation, synthetic methodology