A thioester is an organic compound that contains a carbonyl–sulfur (–C(=O)–S–) linkage, where a carbonyl group (>C=O) is bonded to a sulfur atom (S). Its general formula is R–C(=O)–SR′. ^[1-3]

Thioesters play a central role in both chemistry and biology. A well-known biological example is acetyl-CoA, a high-energy thioester that functions as a key intermediate in cellular metabolism. In synthetic and industrial chemistry, thioesters act as mild acyl-transfer agents and serve as versatile building blocks for various organic synthesis applications. For example, β‐keto dithioesters are useful in constructing complex molecules in medicinal chemistry.

Structure and Bonding ^[7,8]

Structurally, a thioester resembles an ester (R–C(=O)–OR′), but with sulfur replacing the oxygen atom. The C–S bond length in thioesters ranges from approximately 1.810 Å to 1.991 Å, although it can vary depending on the specific molecule and its chemical environment. This bond length is longer than that of the C–O bond in esters (~1.2 Å) because sulfur has a larger atomic radius and its 3p orbitals overlap less effectively with the carbon 2p orbitals, resulting in weaker π-interaction and a longer, weaker bond.

Thioester bonds are considered high-energy because the sulfur atom cannot effectively participate in resonance stabilization, thereby leaving the carbonyl carbon more electrophilic and making thioesters more reactive toward nucleophilic attack than esters.

Synthesis ^[1,2,6]

1. From Acid Chlorides and Thiol Salts

A simple and widely used method is the reaction of an acid chloride (RCOCl) with the alkali metal salt of a thiol (RSNa). This nucleophilic substitution yields the thioester along with sodium chloride:

RSNa + R′COCl  → R′COSR + NaClRSNa

Example: Formation of ethyl thioacetate from acetyl chloride and sodium ethanethiolate.

CH₃COCl + C₂H₅SNa  → CH₃COSC₂H₅ + NaCl

2. From Thiocarboxylic Acid Salts

Thioesters can also be prepared by reacting thiocarboxylate salts (R-C(=O)-S^– M⁺) with alkyl halides (RX).

Example: Potassium thioacetate reacts with an alkyl halide (RX) to yield the corresponding thioacetate ester.

CH₃COSK + RX → CH₃COSR + KX

3. Condensation of Thiols and Carboxylic Acids

Direct condensation of a thiol (RSH) with a carboxylic acid (RCOOH) is possible in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC).

RSH + R’COOH → R’COSR + H₂O

Example: s-Methyl thioacetate is synthesized from methanethiol and acetic acid at room temperature.

CH₃SH + CH₃COOH →  CH₃COSCH₃ + H₂O (using DCC)

Reactions ^[1,2,4,5]

1. Hydrolysis

Thioesters readily undergo hydrolysis to yield a carboxylic acid and a thiol. This reaction is of great biochemical importance, particularly in the metabolism of acetyl-CoA.

RCOSR’ + H₂O  →  RCO₂H + R’SH

Example: Hydrolysis of ethyl thioacetate produces acetic acid and ethanethiol.

CH₃COSC₂H₅ + H₂O → CH₃COOH + C₂H₅SH

2. Amide Formation

The carbonyl carbon of a thioester reacts more readily with amines (RNH_2​) than with oxygen nucleophiles, leading to amide formation:

RCOSR’ + R’NH_2​ → RCONR’ + R’SH

Example: Reaction of ethyl thioacetate with methylamine produces acetamide.

CH₃COSC₂H₅ + CH₃NH₂  → CH₃CONHCH₃ + C₂H₅SH

This reactivity is widely exploited in native chemical ligation, a powerful method for peptide synthesis in which thioesters act as acyl donors to form peptide bonds.

3. Fukuyama Coupling

A distinctive reaction of thioesters is the Fukuyama coupling, where a thioester reacts with an organozinc halide (RZnX) in the presence of a palladium (Pd) catalyst to produce a ketone:

RCOSR’ + R”ZnX →  RCOR”

Example: Benzoyl thioester reacting with ethylzinc halide.

C₆H₅COSPh + C₂H₅ZnBr →  C₆H₅COC₂H₅

Thioesters occupy a unique position at the crossroads of biological and industrial chemistry. This dual importance highlights thioesters as a bridge between fundamental chemistry and the processes that sustain life.