16.4: Acetal Formation

3. Acetal formation – acetal is like a gem-diol except the alcohols are ethers:

This reaction is only acid-catalyzed. The forward direction is acetal formation (protection) and the reverse direction is hydrolysis (driven by entropy).

In the acid-catalyzed acetal formation, the H⁺ functioned to lower the LUMO of the carbonyl but also to protonate the hemiacetal and make H₂O a good leaving group. The reason this reaction cannot be catalyzed by base is because this reaction would stop at formation of the hemiacetal (there is no way to remove the hydroxyl group).

When would we want to use an acetal in synthesis? As a protecting group! A protecting group is a way to convert one functional group to another temporarily, so that its reactivity is removed and other transformations can occur. The protecting group is then easily removed to regenerate the original functional group. Consider the example below:

Note that we need to reduce the carboxylic acid without reducing the ketone. If we were to treat this molecule with LAH (more reactive, less selective), both the ketone AND carboxylic acid would be reduced to the alcohol. But, if we make an acetal first, LAH will only react with the carboxylic acid functional group. The acetal will remain inert, and then you can remove the acetal (hydrolysis) to regenerate the ketone. This is known as a protection/deprotection scheme.

Another example of acetal use in synthesis is in the use of Grignard reagents in the presence of either carbonyls or alcohols. If we treated the starting material below with Mg metal, the resulting Grignard reagent would be destroyed by the alcohol groups’ protons. So, we must protect these alcohols as the acetal first.

The most interesting example of acetals is in the chemistry of sugars, or carbohydrate chemistry. Sugars have both alcohol and aldehyde functional groups, but normally exist as cyclic hemiacetals. Compared to acyclic hemiacetals, which we’ve said are unstable, cyclic hemiacetals are completely stable.