Radical Functionalization of Olefinic Compounds

Radical functionalization of olefinic compounds has emerged as a versatile strategy for the selective construction of carbon–heteroatom and carbon–carbon bonds under mild conditions. The approach harnesses alkyl radicals generated by controlled processes, such as hydrogen atom transfer (HAT), single-electron transfer or photoredox activation, which add across the π-bond of alkenes to form functionalised products with high regiocontrol. Advances in catalyst design, especially with first-row transition metals such as cobalt, iron and nickel, have enabled transformations that were previously unattainable or required harsh reagents. The methods accommodate a broad range of feedstock olefins and complex molecules, allowing late-stage modification of bioactive scaffolds. Key paradigms include Markovnikov- and anti-Markovnikov hydrofunctionalisation, radical-polar crossover cascades for ring assembly, and tandem radical coupling processes that forge quaternary centres. These developments promise streamlined routes to pharmaceuticals, agrochemicals and advanced materials by exploiting the innate reactivity of olefin substrates, whilst addressing sustainability by minimising stoichiometric waste and using benign reaction media.

Research from Nature Portfolio

Recent studies have demonstrated a ligand-promoted cobalt-catalysed radical hydroamination of unactivated alkenes, achieving Markovnikov-selective addition of nitrogen sources with both high regio- and enantioselectivity. The use of tailored tridentate and chiral ligands enables access to hydrazone intermediates that can be converted into chiral amines under mild conditions. A complementary advance introduced a silane- and peroxide-free hydrogen atom transfer hydrogenation in aqueous media using a combined cobalt/photoredox system and ascorbic acid. This protocol offers exceptional functional-group tolerance and sustainability, allowing direct hydrogenation of unprotected sugars and late-stage reduction of drug mimetics. In a further development, an intermolecular oxidative hydroamidation has been realised via a cobalt-catalysed radical pathway, affording α-tertiary amides from terminal alkenes and nitriles in a single step with remarkable chemoselectivity for olefinic substrates over competing functionalities.

Radical Functionalization of Olefinic Compounds publication trend

The graph below shows the total number of articles in radical functionalization of olefinic compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Olefins: Unsaturated hydrocarbons containing at least one carbon–carbon double bond.

Radical functionalization: Chemical transformation involving open-shell intermediates (radicals) that add to or abstract from unsaturated substrates.

Hydrogen atom transfer (HAT): A mechanism in which a metal hydride or photocatalyst transfers a hydrogen atom to generate a carbon-centred radical.

Photoredox catalysis: Use of light-absorbing catalysts to mediate single-electron transfer events under visible-light irradiation.

Markovnikov selectivity: Regioselective addition to the more substituted carbon of an alkene, leading to the thermodynamically favoured radical or carbocation intermediate.

References

1. Photo‐ and Electrochemical Cobalt Catalysed Hydrogen Atom Transfer for the Hydrofunctionalisation of Alkenes. Angewandte Chemie International Edition (2023).
2. Ligand-promoted cobalt-catalyzed radical hydroamination of alkenes. Nature Communications (2020).
3. Silane- and peroxide-free hydrogen atom transfer hydrogenation using ascorbic acid and cobalt-photoredox dual catalysis. Nature Communications (2021).
4. Highly chemoselective synthesis of hindered amides via cobalt-catalyzed intermolecular oxidative hydroamidation. Nature Communications (2021).
5. Photoinduced Cobalt Catalysis for the Reductive Coupling of Pyridines and Dienes Enabled by Paired Single‐Electron Transfer**. Angewandte Chemie International Edition (2023).
6. Reductive Cross-Coupling of Olefins via a Radical Pathway. Journal of the American Chemical Society (2023).
7. Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances. Beilstein Journal of Organic Chemistry (2021).
8. Hydrogen‐Atom‐Transfer‐Initiated Radical/Polar Crossover Annulation Cascade for Expedient Access to Complex Tetralins. Angewandte Chemie International Edition (2023).