A new copper-catalysed reaction could give chemists a powerful way to create chiral molecules from some of the most difficult intermediates in organic chemistry: highly reactive, unstabilized alkyl radicals. Reported by Chen, Fan, Wang and colleagues in Nature Catalysis, the method uses a specially designed chiral ligand to control how short-lived carbon radicals approach a cyanation reagent. The result is an enantioselective transformation that can convert unactivated alkenes and otherwise inert sp³ carbon–hydrogen bonds into valuable chiral nitriles.
The advance addresses a long-standing problem in radical chemistry. Radicals are molecules or molecular fragments containing an unpaired electron, which makes them highly reactive and useful for building chemical bonds under relatively mild conditions. Their reactivity, however, also makes them difficult to control. In particular, unstabilized alkyl radicals lack adjacent groups capable of spreading out or “resonance-stabilizing” the unpaired electron. They therefore tend to react rapidly and indiscriminately, often before a catalyst can impose a preferred three-dimensional orientation.
Many successful asymmetric radical reactions have focused on resonance-stabilized species, including radicals adjacent to aromatic rings, carbonyl groups or other π systems. These intermediates are sufficiently persistent for a chiral catalyst to influence their fate. Unstabilized alkyl radicals behave differently. Once formed, they can undergo nearly barrierless coupling with another reactive partner. Because the radical–radical or radical–metal bond-forming event may require little additional activation energy, even a subtle difference between two possible approaches can be difficult for a catalyst to amplify into high enantioselectivity.
The researchers’ solution is a ligand-mediated radical orientation strategy. At the centre of the process is copper, coordinated by a chiral Box^OH ligand. Box ligands, or bis(oxazoline) ligands, are widely used in asymmetric catalysis because their rigid architecture can create a well-defined chiral environment around a metal centre. The Box^OH ligand adds another feature: a strategically positioned hydroxyl group capable of forming hydrogen bonds with functional groups located on the radical precursor or the developing radical intermediate.
Hydrogen bonding is commonly associated with stabilizing molecules or organizing substrates, but in this reaction it serves a more dynamic purpose. The ligand can interact with remote functional groups on the reacting carbon framework, even when those groups are not directly attached to the radical centre. These temporary interactions help position the substrate within the copper catalyst’s chiral pocket. Rather than simply making one pathway lower in energy at the final bond-forming step, the ligand reshapes the sequence of intermediate structures and transition states leading to that step.
This distinction is crucial for controlling an unstabilized radical. The radical itself remains highly reactive, but its surroundings are no longer random. Through reversible hydrogen bonding, the Box^OH ligand can guide the radical into a preferred orientation relative to the copper-bound cyanide component. The catalyst effectively turns a fleeting and difficult-to-direct intermediate into one that encounters its reaction partner from one dominant face. That facial preference determines whether the newly formed stereocentre adopts one configuration or its mirror-image alternative.
The key chemical event is asymmetric cyanation, the introduction of a cyano group into an organic molecule while simultaneously creating a stereogenic carbon centre. Nitriles are especially useful functional groups in synthesis because the carbon–nitrogen triple bond can be transformed into amides, carboxylic acids, amines and other nitrogen-containing structures. A method that installs a nitrile with high enantiocontrol can therefore provide a direct route to chiral building blocks for pharmaceuticals, agrochemicals and advanced materials.
According to the study, the reaction can be applied directly to unactivated alkenes. These carbon–carbon double bonds are abundant in commercial chemicals and synthetic feedstocks but generally lack the electronic features that make asymmetric radical reactions easier. The copper catalyst first enables the alkene to participate in radical generation and subsequent cyanation, while the chiral ligand controls the geometry of the carbon–carbon and carbon–nitrogen bond-forming sequence. In this way, a relatively simple alkene can be converted into a more complex chiral nitrile in a single functionalization operation.
The researchers also extend the strategy to inert sp³ C–H bonds. Carbon–hydrogen bonds in ordinary alkyl groups are among the least reactive bonds in organic molecules, particularly when they are not activated by nearby aromatic rings, carbonyl groups or heteroatoms. Selectively replacing one of these hydrogen atoms with a cyano group is already challenging; doing so while distinguishing between two enantiomeric outcomes is considerably more demanding. The reported approach shows that remote molecular features can become handles for stereochemical control, allowing the ligand to influence a reaction centre that may be several bonds away.
The broader significance of the work lies in its attempt to move asymmetric radical chemistry beyond the relatively comfortable territory of stabilized intermediates. Radical reactions are attractive because they can rapidly assemble molecular complexity, tolerate many functional groups and access bond constructions that are difficult through conventional ionic pathways. Yet their speed and energetic accessibility have often worked against precise stereochemical control. By using ligand–substrate interactions to orient rather than simply stabilize the radical, the copper system offers a conceptual framework for managing these unstable species.
The strategy may also point toward a broader design principle for catalyst development. In many catalytic reactions, the groups closest to the reacting bond receive most of the attention. The Box^OH ligand demonstrates that remote functional groups can play an equally important role if they are positioned to form temporary, directional interactions inside the catalytic assembly. Such interactions could help control other radical transformations in which a metal centre alone cannot discriminate effectively between competing approaches.
Although the chemistry remains a specialised laboratory technique, its potential relevance reaches beyond a single reaction. Unactivated alkenes and sp³ C–H bonds are plentiful in petrochemical feedstocks, commodity chemicals and complex natural-product frameworks. Directly transforming these motifs can reduce the number of prefunctionalization steps required in synthesis, making routes shorter and potentially more efficient. If related ligand designs can be developed for other bond-forming reactions, the same orientation concept could eventually influence asymmetric carbon–carbon, carbon–oxygen, carbon–nitrogen or carbon–sulfur bond construction.
The work does not eliminate the intrinsic reactivity of unstabilized radicals; instead, it harnesses that reactivity within a carefully organized catalytic environment. Copper supplies a relatively accessible platform for radical generation and cyanide transfer, while the chiral Box^OH ligand supplies the molecular choreography needed to produce one enantiomer preferentially. Together, these components show how dynamic noncovalent interactions can impose order on a reaction that would otherwise proceed too quickly for conventional stereocontrol.
By combining radical chemistry, transition-metal catalysis and hydrogen-bond-directed molecular recognition, the researchers have created a route to chiral nitriles from simple chemical starting points. The study suggests that the future of asymmetric radical synthesis may depend less on making radicals behave like stable intermediates and more on learning how to guide them during the brief moments before they react. That shift could open new possibilities for converting abundant, unremarkable molecules into structurally sophisticated compounds with the precision demanded by modern medicinal and materials chemistry.
Subject of Research: Enantioselective copper-catalysed cyanation of unstabilized alkyl radicals generated from unactivated alkenes and inert sp³ C–H bonds.
Article Title: Ligand-mediated radical orientation enables asymmetric cyanation of unstabilized alkyl C-radicals.
Article References: Chen, X., Fan, W., Wang, J. et al. “Ligand-mediated radical orientation enables asymmetric cyanation of unstabilized alkyl C-radicals.” Nature Catalysis 9, 773–781 (2026). https://doi.org/10.1038/s41929-026-01573-0
Image Credits: AI Generated
DOI: 10.1038/s41929-026-01573-0
Keywords: asymmetric catalysis, radical chemistry, copper catalysis, cyanation, unstabilized alkyl radicals, chiral BoxOH ligand, hydrogen bonding, unactivated alkenes, C–H functionalization, enantioselective synthesis
