In organic chemistry, thioesters are compounds that contain sulfur. Their structure is made up of atoms connected as R−C(=O)−S−R'. Thioesters are similar to carboxylate esters, which have the structure R−C(=O)−O−R', but sulfur replaces oxygen in thioesters, as shown by the "thio-" part of their name. Thioesters form when a carboxylic acid (R−C(=O)−O−H) reacts with a thiol (R'−S−H). In biochemistry, thioesters are commonly found in molecules like acetyl-CoA, which is a type of coenzyme A derivative. The letters R and R' represent groups of atoms attached to the molecule. In some cases, R can be a single hydrogen atom.

Synthesis

One way to make thioesters is through a reaction between an acid chloride and a salt made from an alkali metal and a thiol.

Another method uses a salt made from an alkali metal and a thiocarboxylic acid to replace halides in a chemical compound. (A similar process using carboxylate salts is rarely used.) For example, thioacetate esters are often made by reacting potassium thioacetate with other chemicals.

This reaction can also involve Mannich bases and thiocarboxylic acids.

Thioesters can be formed when thiols and carboxylic acids combine in the presence of a substance that removes water, such as DCC. Scientists have also explored using safer chemicals like T3P and greener solvents like cyclopentanone to make thioester synthesis more sustainable. Acid anhydrides and some lactones can also create thioesters when they react with thiols in the presence of a base.

Thioesters can be made from alcohols using a process called the Mitsunobu reaction, which involves thioacetic acid.

They can also form when alkynes or alkenes react with thiols during a process called carbonylation.

Reactions

Thioesters break down into thiols and carboxylic acids when water is involved.

The carbonyl group in thioesters reacts more readily with amines than with oxygen-based nucleophiles, forming amides.

This reaction is used in a method called native chemical ligation, which helps create peptides.

In a similar process, thioesters can be changed into esters. Thioacetate esters can also be broken down using methanethiol and a base, as shown in the preparation of pent-4-yne-1-thiol.

Thioesters form enol structures easily because the sulfur atom stabilizes these structures. However, enols are less reactive than ketene acetals, and reactions involving substitution at the carbonyl α-position occur more slowly.

A reaction that only happens with thioesters is the Fukuyama coupling. In this process, a thioester combines with an organozinc halide in the presence of a palladium catalyst to produce a ketone.

Biochemistry

Thioesters are common chemical compounds in many biological processes, such as the creation and breakdown of fatty acids and mevalonate, a substance used to make steroids. Examples include malonyl-CoA, acetoacetyl-CoA, propionyl-CoA, cinnamoyl-CoA, and acyl carrier protein (ACP) thioesters. Acetogenesis is a process that forms acetyl-CoA. The production of lignin, a major component of plant matter on Earth, involves a thioester linked to caffeic acid. These thioesters form in a way similar to how they are made in labs, with the difference being that ATP acts as the dehydration agent. Additionally, thioesters are important in marking proteins with ubiquitin, which signals the protein to be broken down.

The oxidation of sulfur in thioesters (thiolactones) is believed to be involved in activating antithrombotic drugs like ticlopidine, clopidogrel, and prasugrel.

According to the "Thioester World" theory, thioesters may have been early building blocks for life. As Christian de Duve explains:

Thioesters are essential in several key processes where ATP is either used or created. They are involved in making all esters, including those in complex lipids. They also help form other cellular components, such as peptides, fatty acids, sterols, terpenes, porphyrins, and others. Additionally, thioesters are key intermediates in ancient processes that lead to ATP formation. In both these cases, thioesters are closer to energy-related processes than ATP itself. This suggests thioesters might have acted like ATP in an early "thioester world" before ATP existed. Over time, thioesters could have helped create ATP by supporting phosphate bond formation.

However, because the breakdown of thioesters releases a large amount of energy and has very low equilibrium constants, it is unlikely they could have formed in significant amounts naturally, especially in hydrothermal vent environments.

Thionoesters

Thionoesters are similar to thioesters but have a different arrangement of atoms. In a thionoester, sulfur replaces the oxygen atom in the carbonyl group of an ester. Methyl thionobenzoate has the chemical formula C6H5C(S)OCH3. These compounds are usually made by reacting thioacyl chloride with an alcohol.

They can also be created by reacting Lawesson's reagent with esters or by treating Pinner salts with hydrogen sulfide.

Various thionoesters can be made by changing the alcohol part of an existing methyl thionoester through a process called transesterification, which occurs under base-catalyzed conditions.

Xanthates and thioamides can be converted into thionoesters using metal-catalyzed cross-coupling reactions.