Li Li

Pyridines and related N-heteroarenes are commonly found in pharmaceuticals, agrochemicals and other biologically active compounds^1,2. Site-selective C–H functionalization would provide a direct way of making these medicinally active products^3,4,5. For example, nicotinic acid derivatives could be made by C–H carboxylation, but this remains an elusive transformation^6,7,8. Here we describe the development of an electrochemical strategy for the direct carboxylation of pyridines using CO₂. The choice of the electrolysis setup gives rise to divergent site selectivity: a divided electrochemical cell leads to C5 carboxylation, whereas an undivided cell promotes C4 carboxylation. The undivided-cell reaction is proposed to operate through a paired-electrolysis mechanism^9,10, in which both cathodic and anodic events play critical roles in altering the site selectivity. Specifically, anodically generated iodine preferentially reacts with a key radical anion intermediate in the C4-carboxylation pathway through hydrogen-atom transfer, thus diverting the reaction selectivity by means of the Curtin–Hammett principle¹¹. The scope of the transformation was expanded to a wide range of N-heteroarenes, including bipyridines and terpyridines, pyrimidines, pyrazines and quinolines.