Hydrogen Atom Transfer in Organic Synthesis

Hydrogen atom transfer (HAT) has emerged as a central strategy in modern organic synthesis, enabling the selective activation of inert C–H bonds under mild conditions. At its core, HAT involves the homolytic cleavage of a C–H bond to generate a carbon-centred radical alongside a hydrogen-atom acceptor, typically a radical species or excited-state photocatalyst that abstracts the hydrogen atom. This radical pathway circumvents the need for prefunctionalised substrates, streamlining the synthesis of complex molecules and extending the reach of C–H functionalisation to late-stage derivatisation of pharmaceuticals and natural products.

Advances in catalyst design, including the use of photoexcited decatungstate anions, cobaloximes and dual photoredox/transition-metal systems, have broadened the scope of HAT processes. These platforms exploit visible or near-UV irradiation to access reactive radical species selectively at ambient temperature. The interplay between catalyst electronics and substrate structure allows precise control over site-selectivity, enabling transformations such as alkylation, alkenylation, acylation and heteroarylation. The global significance of HAT methodologies lies in their atom economy, environmental benignity and potential to streamline industrial processes ranging from fine-chemical synthesis to hydrogen evolution and dehydrogenation.

Research from Nature Portfolio

Recent studies have demonstrated a catalytic protocol for cross-dehydrogenative heteroarylation that employs in situ generation of chlorine radicals from metal–chloride complexes under photoirradiation. This dual catalytic system features a radical-mediated hydrogen abstraction from alkanes with only three equivalents of substrate, followed by coupling with heteroarenes and catalytic hydrogen evolution for turnover. Operating without external oxidants, it affords diverse alkylated heteroarenes in gram-scale yields, offering a practical route to functionalise strong C–H bonds.

Another breakthrough is the asymmetric benzylic C–H acylation of alkylarenes via nickel and photoredox dual catalysis. A photogenerated bromine radical selectively abstracts a benzylic hydrogen atom to form a stabilised carbon radical that undergoes enantioselective cross-coupling with carboxylic acid derivatives. This mild protocol delivers chiral α-aryl ketones with high enantioselectivity and broad functional-group tolerance, showcasing the power of combining HAT with asymmetric transition-metal catalysis for constructing valuable stereochemical motifs.

Hydrogen Atom Transfer in Organic Synthesis publication trend

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

Technical terms

Hydrogen atom transfer (HAT): A radical mechanism involving the homolytic abstraction of a hydrogen atom from a substrate C–H bond by a radical acceptor to generate a new radical species.

Photoredox catalysis: A process in which light-excited photocatalysts mediate electron transfer events, often initiating radical pathways such as HAT under mild conditions.

Homolytic cleavage: The symmetric breaking of a chemical bond in which each fragment retains one of the shared electrons, forming radical species.

C(sp3)–H bond: A σ-bond between a carbon atom in the sp3 hybridisation state and hydrogen, typically exhibiting high bond dissociation energy and requiring activation.

Radical species: Highly reactive intermediates with one or more unpaired electrons that participate in chain and catalytic processes for bond formation and functionalisation.

References

1. A cross-dehydrogenative C(sp3)−H heteroarylation via photo-induced catalytic chlorine radical generation. Nature Communications (2021).
2. Asymmetric benzylic C(sp3)−H acylation via dual nickel and photoredox catalysis. Nature Communications (2021).
3. Direct Photocatalyzed Hydrogen Atom Transfer (HAT) for Aliphatic C–H Bonds Elaboration. Chemical Reviews (2021).
4. Visible‐Light‐Induced Homolysis of Earth‐Abundant Metal‐Substrate Complexes: A Complementary Activation Strategy in Photoredox Catalysis. Angewandte Chemie International Edition (2021).
5. Iron Photoredox Catalysis–Past, Present, and Future. Journal of the American Chemical Society (2023).