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Anti-Markovnikov addition! How does the Thiol-ene reaction change the rules of the game in organic chemistry?
The reaction results in the anti-Markovnikov addition of thiols to alkenes, a synthetically useful reaction that may support future applications in materials and biomedical sciences.
Reaction Mechanism
Free Radical Addition
Thiol-ene addition is known to occur via two mechanisms: free radical addition and catalytic Michael addition. Free radical addition can be initiated by light, heat, or a free radical initiator to form a thiol radical. The free radical then reacts with the ene functional group through anti-Markovnikov addition to form a carbon-centered free radical. One chain propagation step removes a hydrogen radical from the thiol, which can further participate in multiple propagation steps.
Thiol-ene free radical addition has advantages in chemical synthesis because it can effectively form a uniform polymer network.
Michael Bonus
Thiol-ene reactions can also proceed via the Michael addition pathway, which is catalyzed by bases or nucleophiles and ultimately produces anti-Markovnikov addition products similar to free radical additions.
Dynamics
Click chemistry is known for its high efficiency and fast reaction rate, but the actual reaction rate is significantly affected by the functional group of the olefin. To better understand the kinetics of thiol-ene reactions, calculations and experiments on transition states and reaction enthalpies were performed for multiple olefins and their radical intermediates.
The study showed that the reactivity and structure of the olefin determine whether the reaction follows a step-growth or chain-growth pathway.
Electron-rich olefins (such as vinyl ethers or allyl ethers) and nobenzenes are more reactive, while conjugated and electron-deficient olefins (such as butadiene and methoxyethylene) are less reactive. Lower. The behavior of the reaction rate is affected by the structure of the olefin, which determines whether the reaction is rate-limiting by propagation or chain transfer.
Synthetically useful Thiol-ene reactions
Initiation of cascade cyclization
Thiol-ene reactions are widely used to generate reaction intermediates of unsaturated substrates and promote cyclization. Free radical hydrosulfidation of unsaturated functional groups indirectly generates carbon-centered radicals, which can undergo ring internalization reactions.
Internal Bond Thiol-ene Reaction
Internal bond thiol-ene reactions can be used to create sulfur-containing heterocycles. The advantage of this reaction is that it can synthesize four- to eight-membered ring structures as well as macrocyclic molecules. Although free radical thiol-ene reactions prefer Markovnikov-resistant products, the stereochemistry of the cycloaddition depends on substituent effects and reaction conditions.
Cis-trans isomerization
Based on the reversibility of thiol-ene radical addition, this reaction can promote cis-trans isomerization. When the reaction is reversed, the direction of hydrogen addition determines whether the product is cis or trans. Therefore, the composition of the products depends on the conformational stability of the carbon-centered free radical intermediate.
Potential ApplicationsDendrimer Synthesis
Dendrimers have potential in medicine, biomaterials and nanoengineering. Due to the characteristics of click chemistry, thiol-ene addition is very useful in the branched synthesis of dendrimers, such as hydrophilic molecules, polysulfide dendrimers, and organosilicon sulfide dendrimers. The application of this reaction facilitates the synthesis of dendrimers, thus expanding their application prospects.
Polymer Synthesis
Multifunctional thiols such as pentaerythritol tetrakis(3-mercaptopropionate) can be photopolymerized with multifunctional olefins such as sled-base olefins to form a cross-linked polymer network.
Surface patterning
Thiol-ene functionalized surfaces have been extensively studied in materials science and biotechnology. Polymers can be constructed by attaching molecules with sterically accessible olefin or thiol functional groups to solid surfaces. This provides enhanced spatial specificity for surface functionalization, allowing for the generation of reaction products with different structures.
Moreover, thiol-ene can also be used as an electron beam resist to form nanostructures for direct functionalization of proteins. The potential application of this reaction is wide-ranging, from dendrimers to polymer synthesis and even the design of nanomaterials. Can it trigger more scientific research changes?
