Ortho-Metalation Reactions in Aromatic Chemistry

Ortho-metalation denotes the selective activation of a C–H bond adjacent to a directing group on an aromatic ring, enabling the installation of a metal atom at the ortho position. This approach underpins a variety of synthetic strategies for constructing complex molecules, from biaryl frameworks to heterocycles. Central to its success is the use of chelation-assisted directing groups, which coordinate to the metal catalyst and guide site-selective C–H cleavage. Commonly employed metals include lithium, magnesium, aluminium, palladium and iridium, each offering distinct reactivity profiles. Recent advances have focused on enantioselective variants, turn-key catalytic systems and the replacement of stoichiometric organometallic reagents by catalytic C–H functionalisation protocols. The practical importance spans agrochemicals, pharmaceuticals and materials science, where rapid access to functionalised arenes can streamline lead generation and property tuning. Key challenges remain in broadening substrate scope, improving regioselectivity in multifunctional molecules and developing sustainable metal catalysts that operate under mild conditions. Emerging strategies integrate cooperative bimetallic catalysis, transient directing groups and photochemical activation to address these challenges and further extend the reach of ortho-metalation in complex settings.

Research from Nature Portfolio

Recent studies have introduced a chiral-amide-directed palladium catalyst that achieves enantioselective ortho-metalation, furnishing axially chiral biaryl scaffolds with high enantiomeric excess. Another report has demonstrated an iridium-catalysed borylation protocol that proceeds via reversible ortho-metalation, enabling regioselective installation of boronate esters under ambient conditions and in the absence of additional directing-group prefunctionalisation. These advances illustrate the potential for catalytic C–H activation to replace classical organolithium methodologies and highlight design principles for ligand-enabled control of regiochemistry and stereochemistry in aromatic functionalisation.

Ortho-Metalation Reactions in Aromatic Chemistry publication trend

The graph below shows the total number of articles in ortho-metalation reactions in aromatic chemistry across all publications each year (not limited to Nature Index journals).

Technical terms

Ortho-metalation: Site-selective replacement of an ortho C–H bond on an aromatic ring with a metal atom.

Directed ortho-metalation (DoM): Use of a coordinating functional group to guide metal insertion at the ortho position.

C–H activation: Catalytic cleavage of a carbon–hydrogen bond to form a new bond or intermediate.

Transient directing group: A removable moiety that temporarily coordinates to the metal catalyst to achieve selectivity.

Bimetallic catalysis: Cooperative use of two metal centres to enhance reactivity or selectivity in a transformation.

Enantioselectivity: Preferential formation of one enantiomer over another in a chiral product.

Borylation: Introduction of a boronate ester group via metal-catalysed C–H functionalisation.

Photochemical activation: Use of light energy to induce or accelerate chemical reactions, often enabling unique pathways.

References

1. Cationic cobalt-catalyzed [1,3]-rearrangement of N-alkoxycarbonyloxyanilines. Beilstein Journal of Organic Chemistry (2018).