Hemiacetal

In organic chemistry, a hemiacetal is a functional group the general formula R¹R²C(OH)OR, where R¹, R² is a hydrogen atom or an organic substituent. They generally result from the nucleophilic addition of an alcohol (a compound with at least one hydroxy group) to an aldehyde ( R−CH=O) or a ketone ( R₂C=O) under acidic conditions. The addition of an alcohol to a ketone is more commonly referred to as a hemiketal. Common examples of hemiacetals include cyclic monosaccharides. Hemiacetals have use as a protecting group and in synthesizing oxygenated heterocycles like tetrahydrofurans.

According to the IUPAC definition of a hemiacetal, the R¹ and R² groups may or may not be hydrogen. In a hemiketal, both of these R-groups must not be hydrogen. Thus, hemiketals are regarded as a subclass of hemiacetals.^[1] The prefix hemi, meaning half, refers to the one alcohol added to the carbonyl group. This is half of the required alcohols to form acetals or ketals.^[2] Cyclic hemiacetals can sometimes be referred to as lactols.^[3]

Hemiacetals form in the reaction between alcohols and aldehydes or ketones. Using an acid catalyst, the reaction proceeds via nucleophilic attack of the carbonyl group by the alcohol.^[4] A subsequent nucleophilic attack of the hemiacetal by the alcohol results in an acetal.^[2] Solutions of simple aldehydes in alcohols mainly consist of the hemiacetal. The equilibrium is dynamic and can be easily reversed via hydrolysis. The equilibrium is sensitive to steric effects.^[5]

Cyclic hemiacetals often form readily, especially when they are 5- and 6-membered rings. In this case, a hydroxy group reacts with a carbonyl group within the same molecule to undergo an intramolecular cyclization reaction.^[6]

Hemiacetals commonly exist in nature as aldoses such as glucose, and hemiketals commonly exist in nature as ketoses such as fructose. The favorability of the formation of a strain-free six-membered ring and the electrophilicity of an aldehyde combine to strongly favor the acetal form.^[8]

Tetrahydrofurans can be synthesized from nucleophilic addition to hemiacetals with high stereoselectivity, which can be further used to form polymers such as lignans.^[9]

Hemiacetals can also undergo acid-catalyzed spirocyclization or metal-catalyzed addition/elimination to afford spiroacetals. These reactions are moderately stereoselective, although the thermodynamically-favoured isomer is often produced.^[10] Drug discovery programs synthesize spiroacetal scaffolds to generate libraries of spiroacetal-containing molecules. These spiroacetal derivatives have potential use in treating diseases such as CLL leukemia.^[11]

One method of producing linear hemiacetal esters is through the condensation of stabilized hemiacetals by anhydrides; this creates a stable hemiketal intermediate that subsequently undergoes acetylation into the hemiacetal ester. Hemiacetal esters are primarily used in polymer chemistry as a polymerization initiator and as a protecting group for carboxylic acids.^[12]