orthocarboxylation

Orthocarboxylation is a chemical transformation in which a carboxyl group is installed at the ortho position relative to a pre-existing substituent on an aromatic ring, yielding ortho-carboxylated arenes. The term covers both classical directed metalation approaches and modern catalytic C–H activation methods that use carbon dioxide as the carbon source.

Classical routes rely on directed ortho-metalation, where a substrate bearing a coordinating group directs metallation at the ortho position. The resulting organometallic intermediate is then exposed to CO2 to trap a carboxylate, and aqueous workup furnishes the o-carboxylated acid. Catalytic methods use transition-metal catalysts (such as palladium, rhodium, or copper) in the presence of a directing group and CO2, enabling direct orthocarboxylation under milder conditions and sometimes without stoichiometric organolithium reagents.

Substrates typically include arenes bearing directing groups such as amides, carbamates, or oxazolines, as well as certain heteroaromatics. The directing group or other activating features promote regioselective formation of the ortho carboxylate, which can be further elaborated.

Mechanistically, many orthocarboxylation processes involve C–H activation to form a metallated arene, followed by CO2 insertion to give a metal carboxylate; subsequent protonolysis or reductive elimination releases the o-carboxylated product and regenerates the catalyst or metal species.

Applications include access to o-carboxylated benzoic acids and derivatives, which are valuable intermediates in pharmaceutical synthesis and natural product chemistry. Limitations include the need for directing groups, substrate tolerance considerations, and sometimes CO2 pressure requirements. See also carboxylation and C–H activation.