Thiol–Ene Click Chemistry

Following Sharpless′ visionary characterization of several idealized reactions as click reactions, the materials science and synthetic chemistry communities have pursued numerous routes toward the identification and implementation of these click reactions. Herein, we review the radical‐mediated thiol–ene reaction as one such click reaction. This reaction has all the desirable features of a click reaction, being highly efficient, simple to execute with no side products and proceeding rapidly to high yield. Further, the thiol–ene reaction is most frequently photoinitiated, particularly for photopolymerizations resulting in highly uniform polymer networks, promoting unique capabilities related to spatial and temporal control of the click reaction. The reaction mechanism and its implementation in various synthetic methodologies, biofunctionalization, surface and polymer modification, and polymerization are all reviewed.     

Covalently Binding of Bovine Serum Albumin to Unsaturated Poly(Globalide‐Co‐ε‐Caprolactone) Nanoparticles by Thiol‐Ene Reactions

When nanoparticles (NPs) are introduced to a biological fluid, different proteins (and other biomolecules) rapidly get adsorbed onto their surface, forming a protein corona capable of giving to the NPs a new “identity” and determine their biological fate. Protein–nanoparticle conjugation can be used in order to promote specific interactions between living systems and nanocarriers. Non‐covalent conjugates are less stable and more susceptible to desorption in biological media, which makes the development of engineered nanoparticle surfaces by covalent attachment an interesting topic. In this work, the surface of poly(globalide‐co‐ε‐caprolactone) (PGlCL) nanoparticles containing double bonds in the main polymer chain is covalently functionalized with bovine serum albumin (BSA) by thiol‐ene chemistry, producing conjugates which are resistant to dissociation. The successful formation of the covalent conjugates is confirmed by flow cytometry (FC) and fluorescence correlation spectroscopy (FCS). Transmission electron microscopy (TEM) allows the visualization of the conjugate formation, and the presence of a protein layer surrounding the NPs can be observed. After conjugation with BSA, NPs present reduced cell uptake by HeLa and macrophage RAW264.7 cells, in comparison to uncoated NP. These results demonstrate that it is possible to produce stable conjugates by covalently binding BSA to PGlCL NP through thiol‐ene reaction.     

A Thiol–Ene Coupling Approach to Native Peptide Stapling and Macrocyclization

We report the discovery of a peptide stapling and macrocyclization method using thiol–ene reactions between two cysteine residues and an α,ω‐diene in high yields. This new approach enabled us to selectively modify cysteine residues in native, unprotected peptides with a variety of stapling modifications for helix stabilization or general macrocyclization. We synthesized stapled Axin mimetic analogues and demonstrated increased alpha helicity upon peptide stapling. We then synthesized stapled p53 mimetic analogues using pure hydrocarbon linkers and demonstrated their abilities to block the p53‐MDM2 interaction and selectively kill p53 wild‐type colorectal carcinoma HCT‐116 cells but not p53 null cells. In summary, we demonstrated a robust and versatile peptide stapling method that could be potentially applied to both synthetic and expressed peptides.     

On the Orthogonality of Two Thiol‐Based Modular Ligations

The chemoselectivity of two thiol‐based modular ligations operating under mild conditions is assessed. For this purpose, a macromolecular scaffold possessing allyl and pentafluorophenyl groups in two distinct parts is employed, which enables facile characterization by NMR spectroscopy (¹H and ¹⁹F) and size‐exclusion chromatography. By using appropriate triggers (introduction of a base or light irradiation), it is possible to direct thiols to an arbitrarily chosen part of the scaffold, without any change to the other part and with no involvement of protecting group chemistry. Dual functionalization experiments are achieved by applying these triggers consecutively with no consideration of the reaction sequence order, evidencing full bidirectionality. A set of one‐pot, purification‐free procedures that enable near‐quantitative to full dual functionalization in (very) short reaction times (17–180 min) is also presented.     

Divinyl‐End‐Functionalized Polyethylenes: Ready Access to a Range of Telechelic Polyethylenes through Thiol–Ene Reactions

Telechelic α,ω‐iodo‐vinyl‐polyethylenes (Vin‐PE‐I) were obtained by catalytic ethylene polymerization in the presence of [(C₅Me₅)₂NdCl₂Li(OEt₂)₂] in combination with a functionalized chain‐transfer agent, namely, di(10‐undecenyl)magnesium, followed by treatment of the resulting di(vinylpolyethylenyl)magnesium compounds ((vinyl‐PE)₂Mg) with I₂. The iodo‐functionalized vinylpolyethylenes (Vin‐PE‐I) were transformed into unique divinyl‐functionalized polyethylenes (Vin‐PE‐Vin) by simple treatment with tBuOK in toluene at 95 °C. Thiol–ene reactions were then successfully performed on Vin‐PE‐Vin with functionalized thiols in the presence of AIBN. A range of homobifunctional telechelic polyethylenes were obtained on which a hydroxy, diol, carboxylic acid, amine, ammonium chloride, trimethoxysilyl, chloro, or fluoroalkyl group was installed quantitatively at each chain end.     

An Efficient Thiol‐Ene Chemistry for the Preparation of Amphiphilic PHA‐Based Graft Copolymers

We present a straightforward method to prepare amphiphilic graft copolymers consisting of hydrophobic poly(3‐hydroxyalkanoates) (PHAs) backbone and hydrophilic α‐amino‐ω‐methoxy poly(oxyethylene‐co‐oxypropylene) (Jeffamine®) units. Poly(3‐hydroxyoctanoate)‐co‐(3‐hydroxyundecenoate) (PHOU) was first methanolyzed to obtain the desired molar mass. The amino end groups of Jeffamine were converted into thiol by a reaction with N‐acetylhomocysteine thiolactone and subsequently photografted. This “one‐pot” functionalization prevents from arduous and time‐consuming functionalization of the hydrophilic precursor or tedious modifications of PHAs, thus simplifying the process. The amphiphilic nature of modified PHAs leads to water‐soluble copolymers exhibiting thermoresponsive behavior.     

Polysiloxane‐Based Autonomic Self‐Healing Elastomers Obtained through Dynamic Boronic Ester Bonds Prepared by Thiol–Ene “Click” Chemistry

Cross‐linked silicone elastomers constructed with dynamic‐covalent boronic esters are first synthesized by photoinitiated radical thiol−ene “click” chemistry. The resultant samples can be cut with a sharp knife into two pieces and then healed via the reversibility of the boronic ester cross‐linkages to restore the original silicone sample within 30 min. Regulation of luminescent properties is achieved by incorporating organic dye into the elastomers through a “one‐pot” thiol–ene reaction. The proposed synthesis procedure demonstrates a new strategy to produce boronic acid silicone materials capable of self‐healing without external forces.

     

Thiol–enes: Chemistry of the past with promise for the future

The photopolymerization of mixtures of multifunctional thiols and enes is an efficient method for the rapid production of films and thermoset plastics with unprecedented physical and mechanical properties. One of the major obstacles in traditional free‐radical photopolymerization is essentially eliminated in thiol–ene polymerizations because the polymerization occurs in air almost as rapidly as in an inert atmosphere. Virtually any type of ene will participate in a free‐radical polymerization process with a multifunctional thiol. Hence, it is possible to tailor materials with virtually any combination of properties required for a particular application. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 5301–5338, 2004     

Visible‐Light‐Mediated Thiol‐Ene Hydrogelation Using Eosin‐Y as the Only Photoinitiator

The utility of visible‐light‐mediated polymerization in tissue engineering has been limited due to the necessary use of potentially cytotoxic coinitiator and comonomer. Here, we report a visible‐light‐mediated thiol‐ene hydrogelation scheme using eosin‐Y as the only photoinitiator. Under visible light exposure, rapid and highly tunable step‐growth gelation is achieved using PEG‐norbornene and a model cross‐linker dithiothreitol. In addition to investigating the gelation kinetics and properties of thiol‐ene hydrogels formed by this new gelation scheme, we also report high cytocompatibility of these hydrogels using human mesenchymal stem cells (hMSCs) and pancreatic MIN6 β‐cells.     

From NMP to RAFT and Thiol‐Ene Chemistry by In Situ Functionalization of Nitroxide Chain Ends

A straightforward, novel strategy based on the in situ functionalization of polymers prepared by nitroxide‐mediated polymerization (NMP), for the use as an extension toward block copolymers and post‐polymerization modifications, has been investigated. The nitroxide end group is exchanged for a thiocarbonylthio end group by a rapid transfer reaction with bis(thiobenzoyl) disulfide to generate in situ reversible addition–fragmentation chain transfer (RAFT) macroinitiators. Moreover, not only have these macroinitiators been used in chain extension and block copolymerization experiments by the RAFT process but also a thiol‐terminated polymer is synthesized by aminolysis of the RAFT end group and subsequently reacted with dodecyl vinyl ether by thiol‐ene chemistry.     

Polythioethers by Thiol‐Ene Click Polyaddition of α,ω‐Alkylene Thiols

The straightforward synthesis of a series of poly(thioether)s by photoinduced thiol‐ene click polyaddition of α,ω‐alkylene thiols is reported. It is found that linear and telechelic poly(thioether)s can be directly obtained from α,ω‐alkylene thiols with, for example, alkyl chain length of m = 1,2,3, and 9. The reaction proceeds without additives such as (radical) initiators or metal compounds and can simply be carried out by UV‐irradiation of the bulk monomer or monomer solution. Ex situ kinetic studies reveal that the reaction proceeds by a typical a step‐growth polyaddition mechanism. As the homologue series of poly(thioether)s are now synthetically accessible, new direct pathways to tailored poly(alkyl sulphoxide)s and poly(alkyl sulfone)s are now possible.

     

Dual Sulfide–Disulfide Crosslinked Networks with Rapid and Room Temperature Self‐Healability

Polymer‐based crosslinked networks with intrinsic self‐repairing ability have emerged due to their built‐in ability to repair physical damages. Here, novel dual sulfide–disulfide crosslinked networks (s‐ssPxNs) are reported exhibiting rapid and room temperature self‐healability within seconds to minutes, with no extra healing agents and no change under any environmental conditions. The method to synthesize these self‐healable networks utilizes a combination of well‐known crosslinking chemistry: photoinduced thiol‐ene click‐type radical addition, generating lightly sulfide‐crosslinked polysulfide‐based networks with excess thiols, and their oxidation, creating dynamic disulfide crosslinkages to yield the dual s‐ssPxNs. The resulting s‐ssPxN networks show rapid self‐healing within 30 s to 30 min at room temperature, as well as self‐healing elasticity with reversible viscoelastic properties. These results, combined with tunable self‐healing kinetics, demonstrate the versatility of the method as a new means to synthesize smart multifunctional polymeric materials.

     

Facile and Efficient Fabrication of Photoresponsive Microgels via Thiol–Michael Addition

A photoresponsive microgel is designed by the combination of a noncovalent assembly strategy with a covalent cross‐linking method. End‐functionalized poly(ethylene glycol) with azobenzene [(PEG‐(Azo)₂)] was mixed with acrylate‐modified β‐CD (β‐CD‐MAA) to form photoresponsive inclusion complex through host–guest interaction. The above photoresponsive complex was cross‐linked by thiol‐functionalized PEG (PEG‐dithiol) via Michael addition click reaction. The photoreversibility of resulted microgel was studied by TEM, UV–Vis spectroscopy, and ¹H NMR measurements. The characterization results indicated that the reversible size changes of the microgel could be achieved by alternative UV–Vis irradiations with good repeatability.     

Kinetics of thiol–ene and thiol–acrylate photopolymerizations with real‐time fourier transform infrared

We used real‐time Fourier transform infrared to monitor the conversion of both thiol and ene (vinyl) functional groups independently during photoinduced thiol–ene photopolymerizations. From these results, the stoichiometry of various thiol–ene and thiol–acrylate polymerizations was determined. For thiol–ene polymerizations, the conversion of ene functional groups was up to 15% greater than the conversion of thiol functional groups. For stoichiometric thiol–acrylate polymerizations, the conversion of the acrylate functional groups was roughly twice that of the thiol functional groups. With kinetic expressions for thiol–acrylate polymerizations, the acrylate propagation kinetic constant was found to be 1.5 times greater than the rate constant for hydrogen abstraction from the thiol. Conversions of thiol–acrylate systems of various initial stoichiometries were successfully predicted with this ratio of propagation and chain‐transfer kinetic constants. Thiol–acrylate systems with different initial stoichiometries exhibited diverse network properties. Thiol–ene systems were initiated with benzophenone and 2,2‐dimethoxy‐2‐phenylacetophenone as initiators and were also polymerized without a photoinitiator. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3311–3319, 2001     

Preparation of Reactive Three‐Dimensional Microstructures via Direct Laser Writing and Thiol‐ene Chemistry

Three‐dimensional microstructures are fabricated employing the direct laser writing process and radical thiol‐ene polymerization. The resin system consists of a two‐photon photoinitiator and multifunctional thiols and olefins. Woodpile photonic crystals with 22 layers and a rod distance of 2 μm are fabricated. The structures are characterized via scanning electron microscopy and focused ion beam milling. The thiol‐ene polymerization during fabrication is verified via infrared spectroscopy. The structures are grafted in a subsequent thiol‐Michael addition reaction with different functional maleimides. The success of the grafting reaction is evaluated via laser scanning microscopy and X‐ray photoelectron spectroscopy. The grafting density is calculated to be close to 200 molecules μm⁻².