Hemiacetal

Last updated December 01, 2024

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

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

Formation of hemiacetals

Formation of hemiketals

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]

Acetalization of aldehydes and ketones
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]

Structures of some readily isolable hemiacetals and hemiketals. Chloral and ethyl glyoxalate illustrate the stabilizing influence of electron-withdrawing groups. The cyclopropanone case illustrates the effect of ring-strain. The two cases on the right illustrate the effect of ring-closure. RobustHemiacetals.svg — Structures of some readily isolable hemiacetals and hemiketals. Chloral and ethyl glyoxalate illustrate the stabilizing influence of electron-withdrawing groups. The cyclopropanone case illustrates the effect of ring-strain. The two cases on the right illustrate the effect of ring-closure.

Hemiacetals in nature

Left: glucose, a cyclic hemiacetal.

Right: a lactol of fructose, a cyclic hemiketal.

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

Hemiacetals can be strategically used as a protecting group for carbonyls in organic synthesis to prevent unwanted reactions from occurring.^[6] A carbonyl can be converted to its hemiacetal form to decrease its reactivity. The desired reaction with the target functional group can then be carried out, and the hemiacetal can later be converted back to a carbonyl via hydrolysis.

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]

Related Research Articles

<span class="mw-page-title-main">Ether</span> Organic compounds made of alkyl/aryl groups bound to oxygen (R–O–R)

In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom bonded to two organyl groups. They have the general formula R−O−R′, where R and R′ represent the organyl groups. Ethers can again be classified into two varieties: if the organyl groups are the same on both sides of the oxygen atom, then it is a simple or symmetrical ether, whereas if they are different, the ethers are called mixed or unsymmetrical ethers. A typical example of the first group is the solvent and anaesthetic diethyl ether, commonly referred to simply as "ether". Ethers are common in organic chemistry and even more prevalent in biochemistry, as they are common linkages in carbohydrates and lignin.

<span class="mw-page-title-main">Ester</span> Compound derived from an acid

In chemistry, an ester is a compound derived from an acid in which the hydrogen atom (H) of at least one acidic hydroxyl group of that acid is replaced by an organyl group. These compounds contain a distinctive functional group. Analogues derived from oxygen replaced by other chalcogens belong to the ester category as well. According to some authors, organyl derivatives of acidic hydrogen of other acids are esters as well, but not according to the IUPAC.

<span class="mw-page-title-main">Ketone</span> Organic compounds of the form >C=O

In organic chemistry, a ketone is an organic compound with the structure R−C(=O)−R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group −C(=O)−. The simplest ketone is acetone, with the formula (CH₃)₂CO. Many ketones are of great importance in biology and industry. Examples include many sugars (ketoses), many steroids, and the solvent acetone.

In organic chemistry, an aldehyde is an organic compound containing a functional group with the structure R−CH=O. The functional group itself can be referred to as an aldehyde but can also be classified as a formyl group. Aldehydes are a common motif in many chemicals important in technology and biology.

In organic chemistry, an acetal is a functional group with the connectivity R₂C(OR')₂. Here, the R groups can be organic fragments or hydrogen, while the R' groups must be organic fragments not hydrogen. The two R' groups can be equivalent to each other or not. Acetals are formed from and convertible to aldehydes or ketones and have the same oxidation state at the central carbon, but have substantially different chemical stability and reactivity as compared to the analogous carbonyl compounds. The central carbon atom has four bonds to it, and is therefore saturated and has tetrahedral geometry.

The following outline is provided as an overview of and topical guide to organic chemistry:

An aldol condensation is a condensation reaction in organic chemistry in which two carbonyl moieties react to form a β-hydroxyaldehyde or β-hydroxyketone, and this is then followed by dehydration to give a conjugated enone.

<span class="mw-page-title-main">Protecting group</span> Group of atoms introduced into a compound to prevent subsequent reactions

A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis.

A tetrahedral intermediate is a reaction intermediate in which the bond arrangement around an initially double-bonded carbon atom has been transformed from trigonal to tetrahedral. Tetrahedral intermediates result from nucleophilic addition to a carbonyl group. The stability of tetrahedral intermediate depends on the ability of the groups attached to the new tetrahedral carbon atom to leave with the negative charge. Tetrahedral intermediates are very significant in organic syntheses and biological systems as a key intermediate in esterification, transesterification, ester hydrolysis, formation and hydrolysis of amides and peptides, hydride reductions, and other chemical reactions.

The Cannizzaro reaction, named after its discoverer Stanislao Cannizzaro, is a chemical reaction which involves the base-induced disproportionation of two molecules of a non-enolizable aldehyde to give a primary alcohol and a carboxylic acid.

Dioxolane is a heterocyclic acetal with the chemical formula (CH₂)₂O₂CH₂. It is related to tetrahydrofuran (THF) by replacement of the methylene group (CH₂) at the 2-position with an oxygen atom. The corresponding saturated 6-membered C₄O₂ rings are called dioxanes. The isomeric 1,2-dioxolane (wherein the two oxygen centers are adjacent) is a peroxide. 1,3-dioxolane is used as a solvent and as a comonomer in polyacetals.

<span class="mw-page-title-main">Carbonyl condensation</span> Organic reaction of carbonyl compounds with amines to imines

In organic chemistry, alkylimino-de-oxo-bisubstitution is the organic reaction of carbonyl compounds with amines to imines. The reaction name is based on the IUPAC Nomenclature for Transformations. The reaction is acid catalyzed and the reaction type is nucleophilic addition of the amine to the carbonyl compound followed by transfer of a proton from nitrogen to oxygen to a stable hemiaminal or carbinolamine. With primary amines, water is lost in an elimination reaction to an imine. With aryl amines, especially stable Schiff bases are formed.

The Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996 two years after the first two efforts described in the Holton Taxol total synthesis and the Nicolaou Taxol total synthesis. Combined they provide a good insight in the application of organic chemistry in total synthesis.

The Dakin oxidation (or Dakin reaction) is an organic redox reaction in which an ortho- or para-hydroxylated phenyl aldehyde (2-hydroxybenzaldehyde or 4-hydroxybenzaldehyde) or ketone reacts with hydrogen peroxide (H₂O₂) in base to form a benzenediol and a carboxylate. Overall, the carbonyl group is oxidised, whereas the H₂O₂ is reduced.

The Prins reaction is an organic reaction consisting of an electrophilic addition of an aldehyde or ketone to an alkene or alkyne followed by capture of a nucleophile or elimination of an H⁺ ion. The outcome of the reaction depends on reaction conditions. With water and a protic acid such as sulfuric acid as the reaction medium and formaldehyde the reaction product is a 1,3-diol (3). When water is absent, the cationic intermediate loses a proton to give an allylic alcohol (4). With an excess of formaldehyde and a low reaction temperature the reaction product is a dioxane (5). When water is replaced by acetic acid the corresponding esters are formed.

<span class="mw-page-title-main">Sodium cyanoborohydride</span> Chemical compound

Sodium cyanoborohydride is a chemical compound with the formula Na[BH₃(CN)]. It is a colourless salt used in organic synthesis for chemical reduction including that of imines and carbonyls. Sodium cyanoborohydride is a milder reductant than other conventional reducing agents.

Selenoxide elimination is a method for the chemical synthesis of alkenes from selenoxides. It is most commonly used to synthesize α,β-unsaturated carbonyl compounds from the corresponding saturated analogues. It is mechanistically related to the Cope reaction.

In organic chemistry, a lactol is a functional group which is the cyclic equivalent of a hemiacetal or a hemiketal . The compound is formed by the intramolecular, nucleophilic addition of a hydroxyl group to the carbonyl group of an aldehyde or a ketone.

Oxidation with chromium(VI) complexes involves the conversion of alcohols to carbonyl compounds or more highly oxidized products through the action of molecular chromium(VI) oxides and salts. The principal reagents are Collins reagent, PDC, and PCC. These reagents represent improvements over inorganic chromium(VI) reagents such as Jones reagent.

In organic chemistry, carbonyl reduction is the conversion of any carbonyl group, usually to an alcohol. It is a common transformation that is practiced in many ways. Ketones, aldehydes, carboxylic acids, esters, amides, and acid halides - some of the most pervasive functional groups, -comprise carbonyl compounds. Carboxylic acids, esters, and acid halides can be reduced to either aldehydes or a step further to primary alcohols, depending on the strength of the reducing agent. Aldehydes and ketones can be reduced respectively to primary and secondary alcohols. In deoxygenation, the alcohol group can be further reduced and removed altogether by replacement with H.

References

↑ IUPAC , Compendium of Chemical Terminology , 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) " hemiketals ". doi : 10.1351/goldbook.H02776
1 2 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. ISSN 1089-5639.
1 2 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.
1 2 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.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.

[1] IUPAC , Compendium of Chemical Terminology , 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) " hemiketals ". doi : 10.1351/goldbook.H02776

[:0-2] 1 2 Fox, Marye Anne; Whitesell, James K. (2004). Organic Chemistry. Jones & Bartlett Learning. p. 590. ISBN 9780763721978.

[3] IUPAC Gold Book lactols

[4] 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. ISSN 1089-5639.

[Patai-5] 1 2 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.

[:1-6] 1 2 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.

[7] Salaun, Jacques (1983). "Cyclopropanone Hemiacetals". Chemical Reviews. 83 (6): 619–632. doi:10.1021/cr00058a002.

[8] "10.3: Hemiacetals, Hemiketals, and Hydrates". Chemistry LibreTexts. 2018-08-10. Retrieved 2024-11-30.

[9] 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

[10] 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

[11] 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

[12] 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.

[1]

[2]

[3]

[4]

[5]

[6]

[8]

[9]

[10]

[11]

[12]