Metalation

Metalation refers to the introduction of a metal atom or metal ion into a molecule to form a metallated species, often an organometallic intermediate. In organic synthesis, metalation typically proceeds by replacing a hydrogen atom with a metal, creating a carbon–metal bond. This can occur via deprotonative metalation, where a strong base removes a C–H proton while the metal (such as lithium, magnesium, or zinc) remains associated with the substrate, or by direct metalation with a metal complex that coordinates and inserts into a substrate.

Directed ortho-metalation is a notable variant in which a directing group on the molecule coordinates to the metal and guides lithiation to the ortho position relative to the directing group. This enables regioselective functionalization after trapping the metallated intermediate with an electrophile. Common metals used for metalation include lithium, magnesium (Grignard-type reagents), and zinc, with reactions typically carried out at low temperatures in dry ether solvents like THF or diethyl ether.

Practical considerations include sensitivity to moisture and air, the need for inert atmospheres, and the influence of substituents and directing groups on regioselectivity. The choice of metal, base strength, and solvent determine the balance between reactivity and selectivity. Metalation can be reversible in some systems and may require careful control to avoid overreaction or side reactions.

In a broader context, metalation also describes the incorporation of metal ions into biological macromolecules, such as metalloproteins and enzymes, where proper metalation is critical for activity and stability. Mis-metalation can impair function.

Applications of metalation include preparation of organolithium and organomagnesium reagents, enabling subsequent nucleophilic substitution and cross-coupling reactions, and serving as a key step in complex molecule synthesis.