Thiol-ene reaction

In organosulfur chemistry, the thiol-ene reaction (also alkene hydrothiolation) is an organic reaction between a thiol (R−SH) and an alkene (R2C=CR2) to form a thioether (R−S−R'). This reaction was first reported in 1905, but it gained prominence in the late 1990s and early 2000s for its feasibility and wide range of applications. This reaction is accepted as a click chemistry reaction given the reactions' high yield, stereoselectivity, high rate, and thermodynamic driving force.

The reaction results in an anti-Markovnikov addition of a thiol compound to an alkene. Given the stereoselectivity, high rate and yields, this synthetically useful reaction may underpin future applications in material and biomedical sciences.

Mechanisms

Radical addition Thiol-ene additions are known to proceed through two mechanisms: free-radical additions and catalyzed Michael additions. Free-radical additions can be initiated by light, heat or radical initiators, which form a thiyl radical species. The radical then propagates with an ene functional group via an 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. Thiol-ene radical additions are advantageous for chemical synthesis because the step growth (propagation and chain-transfer steps) and chain growth (homopolymerization) processes can be effectively used to form homogeneous polymer networks. Photopolymerization is a useful radical-based reaction for applications within the nanotechnology, biomaterial, and material sciences, but these reactions are hindered by the inhibitory capabilities of oxygen. The thiol-ene radical addition combines the benefits of photopolymerization reactions with the aforementioned advantages of click chemistry reactions. This reaction is useful to the field of radical-based photopolymerization because it quantitatively and rapidly proceeds through a simple mechanism under ambient atmospheric conditions. The carbon-centered radical can undergo chain-growth polymerization depending on the thiol and ene functional groups. This free-radical polymerization can be useful in the synthesis of uniform polymer networks.

Michael addition Thiol-ene reactions are known to proceed through a Michael addition pathway. These reactions are catalyzed by either a base or a nucleophile, resulting in a similar anti-Markovnikov addition product as the thiol-ene radical addition.

Kinetics Click chemistry reactions are known to be high efficiency and have fast reaction rates, yet there is considerable variability in the overall reaction rate depending on the functionality of the alkene. To better understand the kinetics of thiol-ene reactions, calculations and experiments of transition-state and reaction enthalpies were conducted for a number of alkenes and their radical intermediates. It was shown that the reactivity and structure of the alkene determines whether the reaction will follow a step-growth or chain-growth pathway. It was also shown that the thiol-ene polymerization can be tuned by enhancing intermolecular interactions between the thiol and alkene functional groups. A currently accepted trend is that electron-rich alkenes (such as vinyl ether or allyl ether) and norbornene are highly reactive compared to conjugated and electron-poor alkenes (butadiene and methoxyethene). In the case of norbornene and vinyl ether only step-growth is observed, no homopolymerization occurs after the formation of the carbon centered radical.

Due to the complex kinetics of this two-step cyclic reaction, the rate-determining step was difficult to delineate. Given that the rates of both steps must be equal, the concentration of the radical species is determined by the rate constant of the slower of the reaction steps. Thus the overall reaction rate (RP) can be modeled by the ratio of the propagation rate (kP) to the chain-transfer rate (kCT).The behavior of the reaction rate is outlined by the relationship below. In all cases the reaction is first order, when kP ≫ kCT [Eq. 1] the reaction rate is determined by the thiol concentration and the rate limiting step is chain-transfer, when kP ≪ kCT [Eq. 2] the reaction rate is determined by the alkene concentration and the rate limiting step is the propagation, and finally when kP ≈ kCT [Eq. 3] the reaction is half order with respect to both the alkene and thiol concentrations. The functional groups on the thiol and alkene compounds can affect the reactivity of the radical species and their respective rate constants. The structure of the alkene determines whether the reaction will be propagation or chain-transfer limited, and therefore first order with respect to alkene or thiol concentration respectively. In the case of reactive alkenes, such as allyl ether, chain-transfer is the rate-limiting step, while in the case of less reactive alkenes, such as vinyl silazanes, propagation is the rate-limiting step. The thiol's hydrogen affinity also affects the rate-limiting step. Alkyl thiols have less abstractable protons and therefore the chain-transfer step has a lower reaction rate than the propagation step.

Most time the quasi-first-order reaction yields a kinetic rate equation following the exponential decay function for the reactants and products.

[normalized thiol-ene product] = 1 − e − k t {\displaystyle 1-e^{-kt}}

where k is an effective rate constant and t is time. However, when the radical generation becomes the rate-limiting step, an induction period is often observed at the early stage of the reaction, for example, for photoinitiated reaction under weak light condition. The kinetic curve deviates from the exponential decay function for a common first-order reaction by having a slow growth period. The kinetic model has to include the radical generation step to explain this induction period (right figure). The final expression has a Gaussian-like shape.

[normalized thiol-ene product] = 1 − e − 1 2 k t 2 {\displaystyle 1-e^{-{\frac {1}{2}}kt^{2}}}

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