Nickel-Catalyzed C–H Functionalization and Cross-Coupling Reactions

Nickel has emerged as a versatile and sustainable catalyst for the direct activation of C–H bonds and subsequent cross-coupling processes. By harnessing the unique redox flexibility of nickel—from zero to high oxidation states—chemists have developed routes that transform inert C–H bonds into C–C and C–heteroatom linkages with high efficiency and selectivity. Directed strategies employ coordinating groups to bring the metal into proximity with a specific C–H bond, while undirected methods exploit innate substrate bias or transient ligand interactions. Mechanistic pathways often invoke oxidative addition of C–H or C–X bonds to nickel, transmetalation steps that transfer aryl or alkyl fragments, and reductive elimination to forge new bonds. Such processes capitalise on nickel’s propensity for single-electron transfer sequences, enabling unconventional bond formations inaccessible to palladium catalysts. Applications span the synthesis of complex pharmaceutical intermediates, agrochemicals and advanced functional materials, underscoring nickel’s capacity to combine cost-effectiveness with broad functional-group tolerance and environmental advantage.

Research from Nature Portfolio

Recent theoretical studies have illuminated the sequence of oxidative addition and C–H cleavage in Ni(II)-catalysed arylation. Calculations reveal that the choice of oxidant dictates whether C–H bond activation precedes or follows oxidative addition, leading to either alkyl-aryl-Ni(IV) intermediates or alternative reaction sequences. Frontier molecular orbital analysis demonstrates that the energy of the antibonding orbital of the oxidant governs the order of these elementary steps. This insight allows chemists to predict and control the mechanism by judicious selection of hypervalent iodine reagents, thereby optimising yields and selectivity in nickel-mediated C–H arylations.

Nickel-Catalyzed C–H Functionalization and Cross-Coupling Reactions publication trend

The graph below shows the total number of articles in nickel-catalyzed c–h functionalization and cross-coupling reactions across all publications each year (not limited to Nature Index journals).

Technical terms

C–H functionalization: Transformation of an unactivated carbon–hydrogen bond into a carbon–X bond, where X may be carbon or a heteroatom.

Cross-coupling reaction: A catalytic process that joins two organic fragments (often one bearing a leaving group) via metal-mediated bond formation.

Oxidative addition: The step in which a metal inserts into a bond (e.g. C–H or C–X), increasing its oxidation state by two units.

Reductive elimination: The reverse of oxidative addition, whereby two ligands on a metal centre combine and detach as a new bond, reducing the metal’s oxidation state.

Transmetalation: Transfer of an organic group from one metal to another, often serving as the bond-forming step in cross-couplings.

References

1. Theoretical study of FMO adjusted C-H cleavage and oxidative addition in nickel catalysed C-H arylation. Communications Chemistry (2019).
2. Recent Advances in the Nickel-Catalyzed Alkylation of C-H Bonds. Molecules (2024).
3. A Redox Transmetalation Step in Nickel-Catalyzed C–C Coupling Reactions. ACS Catalysis (2023).
4. Nickel and Palladium Catalyzed C−H Trifluoromethylation using Trifluoromethyliodide: Investigations into New Reactivity. ChemCatChem (2022).