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.
Nomenclature
[edit]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]
Formation
[edit]
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]
| Carbonyl compound | alcohol solvent | %hemiacetal |
|---|---|---|
| acetaldehyde | methanol | 97 |
| acetaldehyde | ethanol | 91 |
| propionaldehyde | methanol | 95 |
| bromoacetone | methanol | 47 |
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 in nature
[edit]
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]
Usage
[edit]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]
References
[edit]- ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "hemiketals". doi:10.1351/goldbook.H02776
- ^ a b Fox, Marye Anne; Whitesell, James K. (2004). Organic Chemistry. Jones & Bartlett Learning. p. 590. ISBN 9780763721978.
- ^ IUPAC Gold Book lactols
- ^ Azofra, Luis Miguel; Alkorta, Ibon; Elguero, José; Toro-Labbé, Alejandro (2012-08-09). "Mechanisms of Formation of Hemiacetals: Intrinsic Reactivity Analysis". The Journal of Physical Chemistry A. 116 (31): 8250–8259. doi:10.1021/jp304495f. hdl:10553/74807. ISSN 1089-5639.
- ^ a b Schmitz, Ernst; Eichhorn, Inge (1967). "Acetals and Hemiacetals". The Ether Linkage (PATAI'S Chemistry of Functional Groups). pp. 309–351. doi:10.1002/9780470771075.ch7. ISBN 9780470771075.
- ^ Solomons, Thomas W. Graham; Fryhle, Craig B.; Snyder, Scott A. (2016). Solomons' organic chemistry (12th, global ed.). Hoboken, New Jersey: John Wiley & Sons, Inc. ISBN 978-1-119-24897-2.
- ^ Salaun, Jacques (1983). "Cyclopropanone Hemiacetals". Chemical Reviews. 83 (6): 619–632. doi:10.1021/cr00058a002.
- ^ "10.3: Hemiacetals, Hemiketals, and Hydrates". Chemistry LibreTexts. 2018-08-10. Retrieved 2024-11-30.
- ^ Rainier, Jon D. (2014), Cossy, Janine (ed.), "Synthesis of Substituted Tetrahydrofurans", Synthesis of Saturated Oxygenated Heterocycles I, vol. 35, Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 1–41, doi:10.1007/978-3-642-41473-2_1, ISBN 978-3-642-41472-5, retrieved 2024-11-30
- ^ Brimble, Margaret A.; Stubbing, Louise A. (2014), Cossy, Janine (ed.), "Synthesis of 5,6- and 6,6-Spirocyclic Compounds", Synthesis of Saturated Oxygenated Heterocycles I, vol. 35, Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 189–267, doi:10.1007/978-3-642-41473-2_5, ISBN 978-3-642-41472-5, retrieved 2024-11-30
- ^ Lenci, Elena (2020-01-01), Trabocchi, Andrea; Lenci, Elena (eds.), "Chapter 8 - Synthesis and biological properties of spiroacetal-containing small molecules", Small Molecule Drug Discovery, Elsevier, pp. 225–245, doi:10.1016/b978-0-12-818349-6.00008-x, ISBN 978-0-12-818349-6
- ^ Boucher, David; Laviéville, Sidonie; Ladmiral, Vincent; Negrell, Claire; Leclerc, Eric (2024-02-13). "Hemiacetal Esters: Synthesis, Properties, and Applications of a Versatile Functional Group". Macromolecules. 57 (3): 810–829. doi:10.1021/acs.macromol.3c01250. ISSN 0024-9297.