Thiol-Ene Click Reaction

Thiol-ene click reaction is a coupling reaction between a thiol and an alkene to form an alkyl sulfide, which has been known since the beginning of 20^th century and the first radical thiol-ene step growth reaction mechanism was suggested in 1938. This reaction is widely used in natural products, bioconjugate chemistry, polymer chemistry, modern materials, and pharmaceuticals due to the formation of carbon-sulfur bonds^[1]. The schematic diagram of the thiol-ene click reaction is shown in scheme 1.

Scheme 1. Schematic diagram of the thiol-ene click reaction.

Essential Characteristics

There are several essential characteristics associated with the thiol-ene click reaction that make it a particularly attractive, facile and versatile reaction^[2].

• Firstly, thiol-ene click reaction can occur under a variety of conditions, including radical pathways, supramolecular catalysis, and catalytic processes mediated by nucleophiles, acids, or bases in highly polar solvents without apparent catalyst additions.
• Secondly, virtually any thiol can be employed, including highly functional species. However, the reactivity is different depending on the strength of S-H bond and reaction mechanism.
• Thirdly, a wide range of alkenes or multiply-substituted alkenes act as suitable substrates. The reactivity, however, varies considerably depending on the reaction mechanism and substitution pattern.
• Finally, thiol-ene click reaction is extremely rapid and can be completed in a matter of seconds (even at ambient temperature and pressure or in the presence of air/oxygen and moisture).

Mechanisms

Thiol-ene click reaction is known to proceed through two mechanisms: the free radical mechanism and the nucleophilic mechanism^[3].

• Free radical mechanism

The free radical mechanism of thiol-ene click reaction is generally photochemical induced or metal catalyzed, which proceeds through a typical chain process with initiation, propagation and termination steps (Scheme 2). The chain initiation step refers to the reaction of a sulfhydryl group and photoinitiator to form a sulfhydryl radical, which reacts with an ene functional group via anti-Markovnikov addition to form a carbon-centered radical. A chain-transfer step removes a hydrogen radical from a thiol, which can subsequently participate in multiple propagation steps.

Scheme 2. Free radical mechanism of the thiol-ene click reaction.

• Nucleophilic mechanism

The thiol-ene click reaction can readily proceed nucleophilic addition of base like triethylamine (NEt₃). Reaction of a thiol with NEt₃ results in the deprotonation of thiol into the corresponding thiolate anion and the formation of triethylammonium cation. Among them, thiolate anion is a powerful nucleophile that can bind to the activated C=C bond to form the intermediate carbon-centered anion (or enolate). This anion picks up a proton (either from a thiol or an ammonium cation) yielding the thiol-ene product (Scheme 3).

Scheme 3. Nucleophilic mechanism of thiol-ene click reaction.

What Can We Do?

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References

1. Fındık, V.; et al. Theoretical investigation of thiol-ene click reactions: a DFT perspective. European Polymer Journal. 2019, 110: 211-220.
2. Lowe, A.B. Thiol-ene "click" reactions and recent applications in polymer and materials synthesis. Polymer Chemistry. 2010, 1: 17-36.
3. Sinha, A.K.; Equbal, D. Thiol-ene reaction as a sharping stone of click chemistry: recent advances in synthetic aspects and mechanistic studies of antiMarkovnikov-selective hydrothiolation of olefins. Asian Journal of Organic Chemistry. 2019, 1(8): 32-47.