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 groups, or 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 esters ({{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.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}} The R and R' represent organyl groups, or 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:
:{{chem2|RSNa + R'COCl -> R'COSR + NaCl}}
Another common route entails the displacement of halides by the alkali metal salt of a thiocarboxylic acid. For example, thioacetate esters are commonly prepared by alkylation of potassium thioacetate:
:{{chem2|CH3COSK + RX -> CH3COSR + KX}}
The analogous alkylation of an acetate salt is rarely practiced. The alkylation can be conducted using Mannich bases 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 dehydrating agents:{{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 }}{{cite web | url = https://www.organic-chemistry.org/synthesis/C1S/thioesters.shtm | title = Synthesis of thioesters | publisher = Organic Chemistry Portal }}
:{{chem2|RSH + R'CO2H -> RSC(O)R' + H2O}}
A typical dehydration agent is DCC.{{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 }} Efforts to improve the sustainability of thioester synthesis have also been reported utilising safer coupling reagent T3P and greener solvent cyclopentanone.{{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 }} Acid anhydrides and some lactones 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.{{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}}
They also arise via carbonylation of alkynes and alkenes in the presence of thiols.{{ Ullmann | author = Bertleff, W. | author2 = Roeper, M. | author3 = Sava, X. | title = Carbonylation | doi = 10.1002/14356007.a05_217.pub2}}
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 amides:
Image:NCL mechanism.pdf method for peptide synthesis.]]
This reaction is exploited in native chemical ligation, a protocol for peptide synthesis.{{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}}
In a related reaction, thioesters can be converted into esters.{{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}} 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:{{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 }}
:{{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.
Biochemistry
{{Category see also|Thioesters of coenzyme A}}
Image:Acetyl-CoA-2D.svg, a thioester that is a key intermediate in the biosynthesis of many biomolecules.]]
Thioesters are common intermediates in many biosynthetic reactions, including the formation and degradation of fatty acids 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.{{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}} 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 (thiolactones) is postulated in the bioactivation of the antithrombotic prodrugs ticlopidine, clopidogrel, and prasugrel.{{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}}{{ 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 }}
=Thioesters and the origin of life=
As posited in a "Thioester World", thioesters are possible precursors to life.{{ 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 }} As Christian de Duve explains:
It is revealing that thioesters are obligatory intermediates in several key processes in which ATP is either used or regenerated. Thioesters are involved in the synthesis of all esters, including those found in complex lipids. They also participate in the synthesis of a number of other cellular components, including peptides, fatty acids, sterols, terpenes, porphyrins, 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 groups.
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.{{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}}
Thionoesters
Image:Thionoester general structure.png groups, or H in the case of R]]
Image:Methyl-thionobenzoate-2D-skeletal.png of methyl thionobenzoate]]
Thionoesters are isomeric with thioesters. In a thionoester, sulfur replaces the carbonyl oxygen in an ester. Methyl thionobenzoate is C6H5C(S)OCH3. Such compounds are typically prepared by the reaction of the thioacyl chloride with an alcohol.{{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 }}
Image:Thionoester-from-thioacyl-chloride-2D-skeletal.png
They can also be made by the reaction of Lawesson's reagent with esters or by treating pinner salts with hydrogen sulfide.
Various thionoesters may be prepared through the transesterification of an existing methyl thionoester with an alcohol under base-catalyzed conditions.{{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 }}
Image:Transesterification of Thionoesters.pngXanthates{{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 }} and thioamides{{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}} can be transformed to thionoesters under metal-catalyzed cross-coupling conditions.
