Editing Hemiacetal

{{Short description|Organic compound of the form >C(OH)O–}}
[[File:Hemiacetal and Hemiketal structure.png|thumb|The general structure of a hemiacetal (left) and hemiketal (right).]]
In [[organic chemistry]], a '''hemiacetal''' is a [[functional group]] the general formula {{chem2|R^{1}R^{2}C(OH)OR}}, where {{chem2|R^{1}, R^{2}|}} is a [[hydrogen]] atom or an organic [[substituent]]. They generally result from the nucleophilic [[Addition reaction|addition]] of an [[Alcohol (chemistry)|alcohol]] (a compound with at least one [[hydroxy group]]) to an [[aldehyde]] ({{chem2|R\sCH\dO}}) or a [[ketone]] ({{chem2|R2C\dO}}) 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 [[Monosaccharide|monosaccharides]]. Hemiacetals have use as a protecting group and in synthesizing oxygenated heterocycles like [[Tetrahydrofuran|tetrahydrofurans]].

==Nomenclature==
According to the [[IUPAC]] definition of a hemiacetal, the R<sup>1</sup> and R<sup>2</sup> 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.<ref>{{GoldBookRef | file = H02776 | title = hemiketals}}</ref> The prefix ''hemi,'' meaning half, refers to the one alcohol added to the [[carbonyl group]]. This is half of the required alcohols to form [[acetal|acetals]] or [[ketal|ketals]].<ref name=":0">{{Cite book|url=https://books.google.com/books?id=xx_uIP5LgO8C&pg=PA590|title=Organic Chemistry|last=Fox|first=Marye Anne|last2=Whitesell|first2=James K.|date=2004|publisher=Jones & Bartlett Learning|isbn=9780763721978|pages=590|language=en}}</ref> Cyclic hemiacetals can sometimes be referred to as [[lactol]]s.<ref>IUPAC Gold Book [http://goldbook.iupac.org/L03438.html lactols]</ref>
==Formation ==
{{Multiple image
| direction         = horizontal
| total_width       = 600
| image1            = Formation of hemiacetals.png
| alt1              = Formation of hemiacetals
| caption1          = Formation of hemiacetals
| image2            = Hemiketal formation.png
| alt2              = Formation of hemiketals
| caption2          = Formation of hemiketals
| align             = center
}}
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.<ref>{{Cite journal |last=Azofra |first=Luis Miguel |last2=Alkorta |first2=Ibon |last3=Elguero |first3=José |last4=Toro-Labbé |first4=Alejandro |date=2012-08-09 |title=Mechanisms of Formation of Hemiacetals: Intrinsic Reactivity Analysis |url=https://pubs.acs.org/doi/10.1021/jp304495f |journal=The Journal of Physical Chemistry A |language=en |volume=116 |issue=31 |pages=8250–8259 |doi=10.1021/jp304495f |issn=1089-5639|hdl=10553/74807 |hdl-access=free }}</ref> A subsequent nucleophilic attack of the hemiacetal by the alcohol results in an [[acetal]].<ref name=":0" /> 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.<ref name="Patai">{{cite book |doi=10.1002/9780470771075.ch7|chapter=Acetals and Hemiacetals|title=The Ether Linkage (PATAI'S Chemistry of Functional Groups)|year=1967|last1=Schmitz|first1=Ernst|last2=Eichhorn|first2=Inge|pages=309–351|isbn=9780470771075}}</ref>
{| class="wikitable"|center|
|+ 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 reaction|intramolecular cyclization reaction]].<ref name=":1">{{Cite book |last=Solomons |first=Thomas W. Graham |title=Solomons' organic chemistry |last2=Fryhle |first2=Craig B. |last3=Snyder |first3=Scott A. |date=2016 |publisher=John Wiley & Sons, Inc |isbn=978-1-119-24897-2 |edition=12th, global |location=Hoboken, New Jersey}}</ref>[[File:Lactol equilibrium.png|center|thumb|442x442px|Formation of a general cyclic hemiacetal]]
[[File:RobustHemiacetals.svg|thumb|center|600 px|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]].<ref>{{cite journal |doi=10.1021/cr00058a002|title=Cyclopropanone Hemiacetals|year=1983|last1=Salaun|first1=Jacques|journal=Chemical Reviews|volume=83|issue=6|pages=619–632}}</ref> The two cases on the right illustrate the effect of ring-closure.<ref name= Patai/>]]

===Hemiacetals in nature===
{{Multiple image
| direction         = horizontal
| total_width       = 300
| image1            = Alpha-D-Glucopyranose.svg
| alt1              = Left, glucose, a cyclic hemiacetal.
| caption1          = Left: glucose, a cyclic hemiacetal.
| image2            = Beta-D-Fructopyranose.svg
| alt2              = Right, a lactol of fructose, a cyclic hemiketal.
| caption2          = Right: a lactol of fructose, a cyclic hemiketal.
| align             = right
}}

Hemiacetals commonly exist in nature as [[Aldose|aldoses]] such as [[glucose]], and hemiketals commonly exist in nature as [[Ketose|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.<ref>{{Cite web |date=2018-08-10 |title=10.3: Hemiacetals, Hemiketals, and Hydrates |url=https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Book:_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/10:_Nucleophilic_Carbonyl_Addition_Reactions/10.03:_Hemiacetals_Hemiketals_and_Hydrates#:~:text=When%20an%20alcohol%20adds%20to,resulting%20product%20is%20a%20hemiketal. |access-date=2024-11-30 |website=Chemistry LibreTexts |language=en}}</ref>


== Usage ==
[[Tetrahydrofuran|Tetrahydrofurans]] can be synthesized from nucleophilic addition to hemiacetals with high stereoselectivity, which can be further used to form polymers such as [[Lignan|lignans]].<ref>{{Citation |last=Rainier |first=Jon D. |title=Synthesis of Substituted Tetrahydrofurans |date=2014 |work=Synthesis of Saturated Oxygenated Heterocycles I |volume=35 |pages=1–41 |editor-last=Cossy |editor-first=Janine |url=https://link.springer.com/10.1007/978-3-642-41473-2_1 |access-date=2024-11-30 |place=Berlin, Heidelberg |publisher=Springer Berlin Heidelberg |language=en |doi=10.1007/978-3-642-41473-2_1 |isbn=978-3-642-41472-5}}</ref>

Hemiacetals can also undergo acid-catalyzed [[Spiro compound|spirocyclization]] or metal-catalyzed addition/elimination to afford spiroacetals. These reactions are moderately stereoselective, although the thermodynamically-favoured isomer is often produced.<ref>{{Citation |last=Brimble |first=Margaret A. |title=Synthesis of 5,6- and 6,6-Spirocyclic Compounds |date=2014 |work=Synthesis of Saturated Oxygenated Heterocycles I |volume=35 |pages=189–267 |editor-last=Cossy |editor-first=Janine |url=https://link.springer.com/10.1007/978-3-642-41473-2_5 |access-date=2024-11-30 |place=Berlin, Heidelberg |publisher=Springer Berlin Heidelberg |language=en |doi=10.1007/978-3-642-41473-2_5 |isbn=978-3-642-41472-5 |last2=Stubbing |first2=Louise A.}}</ref> [[Drug discovery]] programs synthesize spiroacetal scaffolds to generate libraries of spiroacetal-containing molecules. These spiroacetal derivatives have potential use in treating diseases such as [[Leukemia|CLL leukemia]].<ref>{{Citation |last=Lenci |first=Elena |title=Chapter 8 - Synthesis and biological properties of spiroacetal-containing small molecules |date=2020-01-01 |work=Small Molecule Drug Discovery |pages=225–245 |editor-last=Trabocchi |editor-first=Andrea |url=https://linkinghub.elsevier.com/retrieve/pii/B978012818349600008X |publisher=Elsevier |doi=10.1016/b978-0-12-818349-6.00008-x |isbn=978-0-12-818349-6 |editor2-last=Lenci |editor2-first=Elena}}</ref>

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 acid|carboxylic acids.]]<ref>{{Cite journal |last=Boucher |first=David |last2=Laviéville |first2=Sidonie |last3=Ladmiral |first3=Vincent |last4=Negrell |first4=Claire |last5=Leclerc |first5=Eric |date=2024-02-13 |title=Hemiacetal Esters: Synthesis, Properties, and Applications of a Versatile Functional Group |url=https://pubs.acs.org/doi/10.1021/acs.macromol.3c01250 |journal=Macromolecules |volume=57 |issue=3 |pages=810–829 |doi=10.1021/acs.macromol.3c01250 |issn=0024-9297}}</ref>

== References ==

<references/>

[[Category:Functional groups]]
[[Category:Hemiacetals]]