ortholithiation

Ortholithiation, also known as directed ortho-metalation, is a method in organic synthesis for regioselective deprotonation of arenes at the position ortho to a coordinating directing group. The resulting aryllithium species can be transformed into a wide range of ortho-substituted arenes by reaction with electrophiles or subsequent functionalization. The directing group coordinates to lithium, enabling a chelated transition state that favors deprotonation of the adjacent C–H bond over other positions.

Typically, strong organolithium bases are used, such as n-butyllithium, sec- or tert-butyllithium, or lithium diisopropylamide, in a polar aprotic solvent like THF at low temperatures (often around -78 °C). The choice of base and temperature depends on the substrate and directing group. The directing groups are usually bidentate or strongly coordinating, including amides, carbamates, sulfinamides, nitriles, or related functionalities that can hold lithium in the ortho region.

After lithiation, the aryllithium intermediate is trapped with electrophiles to install new substituents at the ortho position. Common transformations include carboxylation with carbon dioxide to form ortho-carboxylated arenes, halogenation, and reaction with carbon electrophiles, aldehydes, ketones, or electrophilic surrogates. The approach enables rapid, regioselective diversification of arenes without prefunctionalization at other positions.

Limitations include the need for an effective directing group and strict control of moisture and temperature, as organolithiums are highly reactive and may induce side reactions or over-lithiation. Substrates lacking compatible directing groups or bearing strongly coordinating functionalities that destabilize the intermediates may be unamenable to ortholithiation. The method is widely used for preparing densely functionalized arenes and as a precursory step in complex molecule synthesis.