Editing Thioester

{{short description|1=Organosulfur compounds of the form R–SC(=O)–R’}}

{{Redirect|Thioate|the ion class|thiocarboxylic acid}}
[[Image:Thioester-2D-A.svg|thumb|class=skin-invert-image|right|150px|General structure of a thioester, where R and R' are [[organyl]] groups, or [[Hydrogen|H]] in the case of R.]]
In [[organic chemistry]],  '''thioesters''' are [[organosulfur compounds]] with the molecular structure {{chem2|R\sC(\dO)\sS\sR’}}. They are analogous to [[carboxylate ester]]s ({{chem2|R\sC(\dO)\sO\sR’}}) with the sulfur in the thioester replacing oxygen in the carboxylate ester, as implied by the [[thio-]] prefix. They are the product of [[esterification]] of a [[carboxylic acid]] ({{chem2|R\sC(\dO)\sO\sH}}) with a [[thiol]] ({{chem2|R'\sS\sH}}). In [[biochemistry]], the best-known thioesters are derivatives of [[coenzyme A]], e.g., [[acetyl-CoA]].<ref name=PATAI>Matthys J. Janssen "Carboxylic Acids and Esters" in PATAI's Chemistry of Functional Groups: Carboxylic Acids and Esters, Saul Patai, Ed. John Wiley, 1969, New York: pp. 705–764.  {{doi|10.1002/9780470771099.ch15}}</ref> The R and R' represent [[organyl]] groups, or [[Hydrogen|H]] in the case of R.

==Synthesis==
One route to thioesters involves the reaction of an [[acid chloride]] with an [[alkali metal]] salt of a thiol:<ref name=PATAI/>
:{{chem2|RSNa + R'COCl -> R'COSR + NaCl}}
Another common route entails the displacement of [[halide]]s by the alkali metal salt of a [[thiocarboxylic acid]]. For example, thioacetate esters are commonly prepared by [[alkylation]] of [[potassium thioacetate]]:<ref name=PATAI/>
:{{chem2|CH3COSK + RX -> CH3COSR + KX}}
The analogous alkylation of an acetate salt is rarely practiced. The alkylation can be conducted using [[Mannich base]]s and the thiocarboxylic acid:
:{{chem2|CH3COSH + R'2NCH2OH -> CH3COSCH2NR'2 + H2O}}

Thioesters can be prepared by condensation of thiols and carboxylic acids in the presence of [[Desiccant|dehydrating agent]]s:<ref>{{cite book | last1 = Fujiwara | first1 = S. | last2 = Kambe | first2 = N. | chapter = Thio-, Seleno-, and Telluro-Carboxylic Acid Esters | title = Topics in Current Chemistry | year = 2005 | volume = 251 | pages = 87–140 | publisher = Springer | location = Berlin / Heidelberg | doi = 10.1007/b101007 | isbn = 978-3-540-23012-0 }}</ref><ref>{{cite web | url = https://www.organic-chemistry.org/synthesis/C1S/thioesters.shtm | title = Synthesis of thioesters | publisher = Organic Chemistry Portal }}</ref>
:{{chem2|RSH + R'CO2H -> RSC(O)R' + H2O}}
A typical dehydration agent is [[N,N'-Dicyclohexylcarbodiimide|DCC]].<ref>{{OrgSynth | last1 = Mori | first1 = Y. | last2 = Seki | first2 = M. | year = 2007 | title = Synthesis of Multifunctionalized Ketones Through the Fukuyama Coupling Reaction Catalyzed by Pearlman's Catalyst: Preparation of Ethyl 6-oxotridecanoate | volume = 84 | pages = 285 | collvol = 11 | collvolpages = 281 | prep = V84P0285 }}</ref> Efforts to improve the sustainability of thioester synthesis have also been reported utilising safer coupling reagent [[Propanephosphonic acid anhydride|T3P]] and greener solvent [[cyclopentanone]].<ref>{{cite journal |last1=Jordan |first1=Andrew |last2=Sneddon |first2=Helen F. |title=Development of a solvent-reagent selection guide for the formation of thioesters |journal=Green Chemistry |date=2019 |volume=21 |issue=8 |pages=1900–1906 |doi=10.1039/C9GC00355J|s2cid=107391323 }}</ref> [[Acid anhydride]]s and some [[lactone]]s also give thioesters upon treatment with thiols in the presence of a base.

Thioesters can be conveniently prepared from alcohols by the [[Mitsunobu reaction]], using [[thioacetic acid]].<ref>{{cite journal | last = Volante | first = R. | title = A new, highly efficient method for the conversion of alcohols to thiolesters and thiols | journal = [[Tetrahedron Letters]] | year = 1981 | volume = 22 | issue = 33 | pages = 3119–3122 | doi = 10.1016/S0040-4039(01)81842-6}}</ref>

They also arise via [[carbonylation]] of [[alkyne]]s and [[alkene]]s in the presence of thiols.<ref>{{ Ullmann | author = Bertleff, W. | author2 = Roeper, M. | author3 = Sava, X. | title = Carbonylation | doi = 10.1002/14356007.a05_217.pub2}}</ref>

==Reactions==
Thioesters hydrolyze to thiols and the carboxylic acid:
:{{chem2|RC(O)SR'  +  H2O  ->  RCO2H  +  RSH}}
The carbonyl center in thioesters is more reactive toward amine than oxygen nucleophiles, giving [[amide]]s:
:[[File:FormationofAmides.png|class=skin-invert-image|500px|Formation of amides from thioesters]]
[[Image:NCL mechanism.pdf|thumb|class=skin-invert-image|300px|right|Thioesters are components of the [[native chemical ligation]] method for peptide synthesis.]]
This reaction is exploited in [[native chemical ligation]], a protocol for [[peptide synthesis]].<ref>{{Cite journal |last1=McGrath |first1=N. A. |last2=Raines |first2=R. T. |title=Chemoselectivity in chemical biology: Acyl transfer reactions with sulfur and selenium |journal=Acc. Chem. Res. |year=2011 |volume=44 |pmid=21639109 |pmc=3242736 |pages=752–761 |doi=10.1021/ar200081s |issue=9}}</ref>

In a related reaction, thioesters can be converted into esters.<ref>{{cite journal|journal=Organic Syntheses|volume=61|page=48|year=1983|title=Preparation of O-esters From The Corresponding Thiol Esters: Tert-butyl Cyclohexanecarboxylate|author=Wan Kit Chan|author2=S. Masamune|author3=Gary O. Spessard|doi=10.15227/orgsyn.061.0048}}</ref>  Thioacetate esters can also be cleaved with methanethiol in the presence of stoichiometric base, as illustrated in the preparation of pent-4-yne-1-thiol:<ref>{{cite journal|title=4-Pentyne-1-thiol|author=Matteo Minozzi |author2=Daniele Nanni |author3=Piero Spagnolo |year=2008|doi=10.1002/047084289X.rn00855|journal=EEROS|isbn=978-0-471-93623-7 }}</ref>
:{{chem2|H3C(CH2)3OMs + KSAc -> H3C(CH2)3SAc  + KOMs}}
:{{chem2|H3C(CH2)3SAc + HSMe -> H3C(CH2)3SH  + MeSAc}}

A reaction unique to thioesters is the [[Fukuyama coupling]], in which the thioester is coupled with an [[organozinc halide]] by a palladium catalyst to give a ketone.
:[[Image:FukuyamaCoupling.svg|class=skin-invert-image|Fukuyama coupling]]

==Biochemistry==
{{Category see also|Thioesters of coenzyme A}}
[[Image:Acetyl-CoA-2D.svg|thumb|class=skin-invert-image|320 px|left|Structure of [[Acetyl-CoA|acetyl coenzyme A]], a thioester that is a key intermediate in the biosynthesis of many biomolecules.]]
Thioesters are common [[Reaction intermediate|intermediates]] in many biosynthetic reactions, including the formation and degradation of [[fatty acid]]s and [[mevalonate]], precursor to steroids.  Examples include [[malonyl-CoA]], [[acetoacetyl-CoA]], [[propionyl-CoA]], [[cinnamoyl-CoA]], and [[acyl carrier protein]] (ACP) thioesters.  [[Acetogenesis]] proceeds via the formation of [[acetyl-CoA]]. The biosynthesis of [[lignin]], which comprises a large fraction of the Earth's land biomass, proceeds via a thioester derivative of [[caffeic acid]].<ref>{{cite book | author1 = Lehninger, A. L. | author2 = Nelson, D. L. | author3 = Cox, M. M. | title = Principles of Biochemistry | edition = 3rd | publisher = Worth Publishing | location = New York | year = 2000 | isbn = 1-57259-153-6 | url-access = registration | url = https://archive.org/details/lehningerprincip01lehn}}</ref> These thioesters arise analogously to those prepared synthetically, the difference being that the dehydration agent is ATP. In addition, thioesters play an important role in the tagging of proteins with [[ubiquitin]], which tags the protein for degradation.

Oxidation of the sulfur atom in thioesters ([[thiolactone]]s) is postulated in the bioactivation of the antithrombotic prodrugs [[ticlopidine]], [[clopidogrel]], and [[prasugrel]].<ref>{{cite journal |author1=Mansuy, D. |author2=Dansette, P. M. | title = Sulfenic acids as reactive intermediates in xenobiotic metabolism | journal = [[Archives of Biochemistry and Biophysics]] | year = 2011 | volume = 507 | issue = 1 | pages = 174–185 | doi = 10.1016/j.abb.2010.09.015 | pmid=20869346|url=https://zenodo.org/record/898058}}</ref><ref>{{ cite journal |author1=Dansette, P. M. |author2=Rosi, J. |author3=Debernardi, J. |author4=Bertho, G. |author5=Mansuy, D. | title = Metabolic Activation of Prasugrel: Nature of the Two Competitive Pathways Resulting in the Opening of Its Thiophene Ring | journal = [[Chemical Research in Toxicology]] | year = 2012 | volume = 25 | issue = 5 | pages = 1058–1065 | doi = 10.1021/tx3000279 |pmid=22482514 }}</ref>

===Thioesters and the origin of life===
As posited in a "Thioester World", thioesters are possible precursors to life.<ref>{{ cite journal | author = de Duve, C. | year = 1995 | volume = 83 | issue = 5 | title = The Beginnings of Life on Earth | journal = American Scientist | pages = 428–437 | jstor = 29775520 | url = https://www.jstor.org/stable/29775520 }}</ref> As [[Christian de Duve]] explains:
<blockquote>It is revealing that thioesters are obligatory intermediates in several key processes in which [[Adenosine triphosphate|ATP]] is either used or regenerated. Thioesters are involved in the synthesis of all [[esters]], including those found in complex [[lipid]]s. They also participate in the synthesis of a number of other cellular components, including [[peptide]]s, [[fatty acid]]s, [[sterol]]s, [[terpene]]s, [[porphyrin]]s, and others. In addition, thioesters are formed as key intermediates in several particularly ancient processes that result in the assembly of ATP. In both these instances, the thioester is closer than ATP to the process that uses or yields energy. In other words, thioesters could have actually played the role of ATP in a "thioester world" initially devoid of ATP. Eventually, [these] thioesters could have served to usher in ATP through its ability to support the formation of bonds between [[phosphate group]]s.</blockquote>

However, due to the high free energy change of thioester's hydrolysis and correspondingly their low equilibrium constants, it is unlikely that these compounds could have accumulated abiotically to any significant extent especially in hydrothermal vent conditions.<ref>{{cite journal|last1=Chandru|first1=Kuhan|last2=Gilbert|first2=Alexis|last3=Butch|first3=Christopher|last4=Aono|first4=Masashi|last5=Cleaves|first5=Henderson James II|title=The Abiotic Chemistry of Thiolated Acetate Derivatives and the Origin of Life|journal=Scientific Reports|date=21 July 2016|volume=6|issue=29883|pages=29883|doi=10.1038/srep29883|pmid=27443234|pmc=4956751|bibcode=2016NatSR...629883C}}</ref>

==Thionoesters==
[[Image:Thionoester general structure.png|thumb|class=skin-invert-image|right|150px|General structure of a thionoester, where R and R' are [[organyl]] groups, or [[Hydrogen|H]] in the case of R]]
[[Image:Methyl-thionobenzoate-2D-skeletal.png|thumb|class=skin-invert-image|right|150px|[[Skeletal formula]] of methyl thionobenzoate]]
'''Thionoesters''' are isomeric with thioesters.  In a thionoester, sulfur replaces the carbonyl oxygen in an ester. Methyl thionobenzoate is C<sub>6</sub>H<sub>5</sub>C(S)OCH<sub>3</sub>. Such compounds are typically prepared by the reaction of the [[thioacyl chloride]] with an alcohol.<ref>{{cite book | author = Cremlyn, R. J. | title = An Introduction to Organosulfur Chemistry | publisher = John Wiley and Sons | location = Chichester | year = 1996 | isbn = 0-471-95512-4 }}</ref>

[[Image:Thionoester-from-thioacyl-chloride-2D-skeletal.png|center|class=skin-invert-image|380 px]]

They can also be made by the reaction of [[Lawesson's reagent]] with esters or by treating [[pinner salt]]s with [[hydrogen sulfide]].

Various thionoesters may be prepared through the [[transesterification]] of an existing methyl thionoester with an alcohol under base-catalyzed conditions.<ref>{{cite journal |last1=Newton |first1=Josiah J. |last2=Britton |first2=Robert |last3=Friesen |first3=Chadron M. |title=Base-Catalyzed Transesterification of Thionoesters |journal=The Journal of Organic Chemistry |volume=83 |issue=20 |pages=12784–12792 |date=4 October 2018 |doi=10.1021/acs.joc.8b02260|pmid=30235418|s2cid=52309850 }}</ref>

[[Image:Transesterification of Thionoesters.png|center|class=skin-invert-image|380px]][[Xanthate]]s<ref>{{Cite journal |last1=Monteith |first1=John J. |last2=Scotchburn |first2=Katerina |last3=Mills |first3=L. Reginald |last4=Rousseaux |first4=Sophie A. L. |date=2022 |title=Ni-Catalyzed Synthesis of Thiocarboxylic Acid Derivatives |url=https://doi.org/10.1021/acs.orglett.1c04074 |journal=Organic Letters |volume=24 |issue=2 |pages=619–624|doi=10.1021/acs.orglett.1c04074 |pmid=34978834 |s2cid=245669904 |url-access=subscription }}</ref> and [[thioamide]]s<ref>{{Cite journal |last1=Liu |first1=Yinbo |last2=Mo |first2=Xiaofeng |last3=Majeed |first3=Irfan |last4=Zhang |first4=Mei |last5=Wang |first5=Hui |last6=Zeng |first6=Zhuo |date=2022 |title=An efficient and straightforward approach for accessing thionoesters ''via'' palladium-catalyzed C–N cleavage of thioamides |url=http://dx.doi.org/10.1039/d1ob02349g |journal=Organic & Biomolecular Chemistry |volume=20 |issue=7 |pages=1532–1537 |doi=10.1039/d1ob02349g |pmid=35129563 |s2cid=246418140 |issn=1477-0520|url-access=subscription }}</ref> can be transformed to thionoesters under metal-catalyzed cross-coupling conditions.

==See also==
* [[Thiocarboxylic acid]]
* [[Thiocarbonate]]
* [[Liebeskind–Srogl coupling]]
* [[2,2'-Dipyridyldisulfide|Aldrithiol-2]]

==References==
{{reflist}}

{{Functional group}}

[[Category:Functional groups]]
[[Category:Origin of life]]
[[Category:Thioesters| ]]