Protection of Alcohols

Organic compounds often contain more than one functional group. In such molecules, a protecting group makes the more reactive group inert to a given set of conditions.

An analogous illustration is a pipe with multiple openings. A liquid would flow out through the lowest outlet because of gravity. However, using a cap to block the lower outlet allows the liquid to be obtained from the higher outlet.

For instance, organolithium alkylation of a halide in the presence of alcohol does not occur due to the acidity of the hydroxyl group. However, protecting the alcohol allows the alkylation of the halide.

While designing a protecting group, the fundamental principle is its stability to one set of conditions and susceptibility to another. For instance, the tetrahydropyranyl group is a common protecting group for alcohols from strong bases. While the acetal formed is stable in such conditions, it is susceptible to acid hydrolysis.

After the intended reaction, easy removal of the cap without damaging the pipe is also necessary to return the system to its native state. This process of removing the protecting group is known as deprotection.

Popular protecting groups for alcohols from nucleophiles or carbon and nitrogen bases include the trialkylsilyl family. Here, a trialkylsilyl derivative interacts with the alcohol in the presence of a weak base like imidazole that reacts as a nucleophilic catalyst to generate a trialkylsilyl ether.

These trialkylsilyl groups are then removed from alcohols using fluoride salts that are soluble in organic solvents, like tetra-n-butylammonium fluoride, or TBAF. Consequently, the re-protonation of the oxygen regenerates the native alcohol.

In addition to the reaction conditions, the reactivity of the molecule to be protected must be considered when identifying a suitable protecting group.

For instance, among alcohols, methyl ethers are suitable protecting groups only for phenols because phenoxides are good leaving groups under the deprotection conditions, while alkoxides are poor leaving groups under these conditions.