Radical Activation Strategies in Organic Synthesis

Radical activation has emerged as a versatile paradigm in organic synthesis, enabling the selective construction and deconstruction of bonds under mild conditions. Central to this approach are methods that generate carbon- or oxygen-centred radicals through photoredox, electrochemical or redox dual-catalysed processes. These techniques facilitate diverse transformations, including cross-dehydrogenative coupling, remote C–H functionalisation and radical fragmentations, without the need for stoichiometric reagents or harsh conditions. The ability to harness visible light, base metals and proton-coupled electron transfer for radical initiation has broadened substrate scope, improved functional-group tolerance and driven late-stage diversification of complex molecules. Together, these advances underscore the global significance of radical activation strategies in streamlining synthetic routes, enabling sustainable catalysis and opening new vistas for the rapid assembly of pharmaceuticals, agrochemicals and materials.

Research from Nature Portfolio

Recent studies have demonstrated a metal-free, photoinduced cross-dehydrogenative coupling that constructs α-tertiary amino acid derivatives directly from C(sp3)–H substrates. A bench-stable N-alkoxyphtalimide generates a highly electrophilic trifluoroethoxy radical, which abstracts hydrogen atoms with high regioselectivity and delivers α-tertiary centres under additive-free, mild conditions. The protocol tolerates diverse functional groups and is applicable to late-stage modifications of complex scaffolds.

Complementing this, a photoinduced β-fragmentation strategy employs N-alkoxyphthalimides derived from aliphatic alcohols to form unnatural amino acids and peptide analogues. Visible-light activation triggers alkoxyl radical generation and β-scission, enabling rapid deconstruction of natural product frameworks into novel bioactive scaffolds. The method offers concise access to unique molecular architectures with potential antifungal activity.

Building on bioinspired desaturation, a dual-catalysed photoredox and cobaloxime system achieves acceptorless dehydrogenation of cyclic and linear alcohols. Proton-coupled electron transfer activates the O–H bond to form transient alkoxyl radicals, which undergo C–C cleavage and subsequent radical recombination to yield olefins. This mild protocol extends to aromatic substrates and functionalised natural products, illustrating precise, remote desaturation guided by bond-dissociation energies.

Radical Activation Strategies in Organic Synthesis publication trend

The graph below shows the total number of articles in radical activation strategies in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Photoredox catalysis: Use of light-activated catalysts to mediate single-electron transfer and generate radical intermediates.

Hydrogen atom transfer (HAT): Radical-mediated abstraction of a hydrogen atom from a substrate, forming a new radical centre.

Proton-coupled electron transfer (PCET): Concerted transfer of a proton and an electron in one elementary step, facilitating radical generation.

Decarboxylative cross-coupling: Radical C–C bond formation via loss of CO₂ from a carboxylate precursor.

Alkoxy radical: Oxygen-centred radical generated from alcohol derivatives, capable of HAT or β-fragmentation.

References

1. Metal-free photoinduced C(sp3)–H/C(sp3)–H cross-coupling to access α‑tertiary amino acid derivatives. Nature Communications (2023).
2. Photoinduced β-fragmentation of aliphatic alcohol derivatives for forging C–C bonds. Nature Communications (2022).
3. Bioinspired desaturation of alcohols enabled by photoredox proton-coupled electron transfer and cobalt dual catalysis. Nature Communications (2022).
4. Decarboxylative Cross-Coupling Enabled by Fe and Ni Metallaphotoredox Catalysis. Journal of the American Chemical Society (2024).
5. Diversified Fluoroalkylation of Alkenes Using Quaternary Fluoroalkyl Alcohols as the Fluoroalkylating Reagents. Advanced Science (2024).
6. Catalytic generation of alkoxy radicals from unfunctionalized alcohols. Chemical Science (2020).