Inorganic chemistry,thioesters areorganosulfur compounds with the molecular structureR−C(=O)−S−R'. They are analogous tocarboxylate esters (R−C(=O)−O−R') with the sulfur in the thioester replacing oxygen in the carboxylate ester, as implied by thethio- prefix. They are the product ofesterification of acarboxylic acid (R−C(=O)−O−H) with athiol (R'−S−H). Inbiochemistry, the best-known thioesters are derivatives ofcoenzyme A, e.g.,acetyl-CoA.[1] The R and R' representorganyl groups, orH in the case of R.
One route to thioesters involves the reaction of anacid chloride with analkali metal salt of a thiol:[1]
Another common route entails the displacement ofhalides by the alkali metal salt of athiocarboxylic acid. (The analogous alkylation of a carboxylate salt is rarely practiced.) For example, thioacetate esters are commonly prepared byalkylation ofpotassium thioacetate:[1]
The alkylation can be conducted usingMannich bases and the thiocarboxylic acid:
Thioesters can be prepared by condensation of thiols and carboxylic acids in the presence ofdehydrating agents:[2][3]
A typical dehydration agent isDCC.[4] Efforts to improve the sustainability of thioester synthesis have also been reported utilising safer coupling reagentT3P and greener solventcyclopentanone.[5]Acid anhydrides and somelactones also give thioesters upon treatment with thiols in the presence of a base.
Thioesters can be conveniently prepared from alcohols by theMitsunobu reaction, usingthioacetic acid.[6]
They also arise viacarbonylation ofalkynes andalkenes in the presence of thiols.[7]
Thioesters hydrolyze to thiols and the carboxylic acid:
The carbonyl center in thioesters is more reactive toward amine than oxygen nucleophiles, givingamides:
This reaction is exploited innative chemical ligation, a protocol forpeptide synthesis.[8]
In a related reaction, thioesters can be converted into esters.[9] 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:[10]
Thioestersenolize easily as the sulfur atom stabilizes the enol. But the enols are less nucleophilic than ketene acetals, andcarbonyl α-substitution reactions occur more slowly.[1]: 728–729
A reaction unique to thioesters is theFukuyama coupling, in which the thioester is coupled with anorganozinc halide by a palladium catalyst to give a ketone.
Thioesters are commonintermediates in many biosynthetic reactions, including the formation and degradation offatty acids andmevalonate, precursor to steroids. Examples includemalonyl-CoA,acetoacetyl-CoA,propionyl-CoA,cinnamoyl-CoA, andacyl carrier protein (ACP) thioesters.Acetogenesis proceeds via the formation ofacetyl-CoA. The biosynthesis oflignin, which comprises a large fraction of the Earth's land biomass, proceeds via a thioester derivative ofcaffeic acid.[11] 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 withubiquitin, which tags the protein for degradation.
Oxidation of the sulfur atom in thioesters (thiolactones) is postulated in the bioactivation of the antithrombotic prodrugsticlopidine,clopidogrel, andprasugrel.[12][13]
As posited in a "Thioester World", thioesters are possible precursors to life.[14] AsChristian de Duve explains:
It is revealing that thioesters are obligatory intermediates in several key processes in whichATP is either used or regenerated. Thioesters are involved in the synthesis of allesters, including those found in complexlipids. They also participate in the synthesis of a number of other cellular components, includingpeptides,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 betweenphosphate 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.[15]
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 thethioacyl chloride with an alcohol.[16]
They can also be made by the reaction ofLawesson's reagent with esters or by treatingpinner salts withhydrogen sulfide.
Various thionoesters may be prepared through thetransesterification of an existing methyl thionoester with an alcohol under base-catalyzed conditions.[17]
Xanthates[18] andthioamides[19] can be transformed to thionoesters under metal-catalyzed cross-coupling conditions.