Patterned Hydrophilization of Nanoporous 1,2‐PB by Thiol‐ene Photochemistry

We present an efficient method for functionalizing the large polymer–air interface of a gyroid nanoporous polymer. The hydrophilicity of nanoporous cross‐linked 1,2‐polybutadiene is tuned by thiol‐ene photo‐grafting of mercaptosuccinic acid or sodium 2‐mercaptoethanesulfonate. The reaction is monitored by FT‐IR, UV–Vis, contact angle, and gravimetry. Overall quantum yields are calculated for the two thiol‐ene “click” reactions in nano‐confinement, neatly revealing their chain‐like nature. Top–down photolithographic patterning is demonstrated, realizing hydrophilic nanoporous “corridors” exclusively hosting water. The presented approach can be relevant for many applications where, e.g., high control and contrast in hydrophilicity, chemical functionality or refractive index are needed.

     

Reactive Polymer Coatings: A General Route to Thiol‐ene and Thiol‐yne Click Reactions

Reactive polymer coatings were synthesized via chemical vapor deposition (CVD) polymerization process. These coatings decouple surface design from bulk properties of underlying materials and provide a facile and general route to support thiol‐ene and thiol‐yne reactions on a variety of substrate materials. Through the reported technique, surface functions can be activated through a simple design of thiol‐terminated molecules such as polyethylene glycols (PEGs) or peptides (GRGDYC), and the according biological functions were demonstrated in controlled and low‐fouling protein adsorptions as well as accurately manipulated cell attachments.     

Cysteine‐Functional Polymers via Thiol‐ene Conjugation

A thiofunctional thiazolidine is introduced as a new low‐molar‐mass building block for the introduction of cysteine residues via a thiol‐ene reaction. Allyl‐functional polyglycidol (PG) is used as a model polymer to demonstrate polymer‐analogue functionalization through reaction with the unsaturated side‐chains. A modified trinitrobenzenesulfonic acid (TNBSA) assay is used for the redox‐insensitive quantification and a precise final cysteine content can be predetermined at the polymerization stage. Native chemical ligation at cysteine‐functional PG is performed as a model reaction for a chemoselective peptide modification of this polymer. The three‐step synthesis of the thiofunctional thiazolidine reactant, together with the standard thiol‐ene coupling and the robust quantification assay, broadens the toolbox for thiol‐ene chemistry and offers a generic and straightforward approach to cysteine‐functional materials.

     

Thiol–ene polymerizations using imide‐based monomers

New diene and dithiol monomers, based on aromatic imides such as benzophenone‐3,3′,4,4′‐tetracarboxylic diimide were synthesized and used in thiol‐ene polymerizations which yield poly(imide‐co‐thioether)s. These linear polymers exhibit limited solubility in various organic solvents. The molecular weights of the polymers were found to decrease with increasing imide content. The glass transition temperature (T_g) of these polymers is dependent on imide content, with T_g values ranging from ?55 °C (with no imide) up to 13 °C (with 70% imide). These thermal property improvements are due to the H‐bonding and rigidity of the aromatic imide moieties. Thermal degradation, as studied by thermogravimetric analysis, was not significantly different to the nonimide containing thiol‐ene polymers made using trimethyloylpropane diallyl ether and 3,5‐dioxa‐1,8‐dithiooctane. It is expected that such monomers may lead to increased glass transition temperatures in other thiol‐ene polymer systems as these normally exhibit low glass transition temperatures. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 4637–4642     

Thiol‐ene photopolymerization for efficient curing of vinyl esters

Monomers for radical photopolymerization based on vinyl esters (VEs) have recently been identified as suitable alternatives to (meth)acrylates on account of their low irritancy and cytotoxicity. The drawback of most VEs with abstractable hydrogens is their relatively low reactivity compared with (meth)acrylates. Within this article, we proved by photo‐differential scanning calorimetry measurements and real‐time Fourier transform infrared spectroscopy that the thiol‐ene concept is able to improve the photoreactivity of these VEs to a large extent to a level between those of acrylates and methacrylates. Other VEs have now a reactivity of at least the level of similar acrylates. Mechanical properties as determined by Dynamic Mechanical Analysis and Charpy impact tests showed significant toughening of these materials. Furthermore, we were able to confirm low toxicity of all components by osteoblast cell culture experiments. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

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.     

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.     

Redox‐Responsive Resilin‐Like Hydrogels for Tissue Engineering and Drug Delivery Applications

Resilin, a protein found in insect cuticles, is renowned for its outstanding elastomeric properties. The authors' laboratory previously developed a recombinant protein, which consisted of consensus resilin‐like repeats from Anopheles gambiae, and demonstrated its potential in cartilage and vascular engineering. To broaden the versatility of the resilin‐like protein, this study utilizes a cleavable crosslinker, which contains a disulfide bond, to develop smart resilin‐like hydrogels that are redox‐responsive. The hydrogels exhibit a porous structure and a stable storage modulus (G′) of ≈3 kPa. NIH/3T3 fibroblasts cultured on hydrogels for 24 h have a high viability (>95%). In addition, the redox‐responsive hydrogels show significant degradation in a reducing environment (10 mm glutathione (GSH)). The release profiles of fluorescently labeled dextrans encapsulated within the hydrogels are assessed in vitro. For dextran that is estimated to be larger than the mesh size of the gel, faster release is observed in the presence of reducing agents due to degradation of the hydrogel networks. These studies thus demonstrate the potential of using these smart hydrogels in a variety of applications ranging from scaffolds for tissue engineering to drug delivery systems that target the intracellular reductive environments of tumors.     

Synthesis and Spatiotemporal Modification of Biocompatible and Stimuli‐Responsive Carboxymethyl Cellulose Hydrogels Using Thiol‐Norbornene Chemistry

Carboxymethyl cellulose (CMC) is functionalized with norbornene groups to undergo thiol‐norbornene cross‐linking reactions. Hydrogels synthesized from a single norbornene‐modified carboxymethyl cellulose (NorCMC) via a light‐initiated thiol‐ene cross‐linking reaction with a variety of dithiol cross‐linkers yield hydrogels with a tunable compression modulus ranging from 1.7 to 103 kPa. Additionally, thermoresponsiveness is spatiotemporally imparted to NorCMC hydrogels by photopatterning a dithiol‐terminated poly(N‐isopropyl acrylamide) cross‐linker, enabling swelling and topological control of the hydrogels as a function of incubation temperature. NorCMC hydrogels are cytocompatible as the viability of encapsulated human mesenchymal stem cells (hMSCs) is greater than 85% after 21 d while using a variety of cross‐linkers. Moreover, hMSCs can remodel, adhere, and spread in the NorCMC matrix cross‐linked with a matrix metalloproteinase‐degradable peptide, further demonstrating the utility of these materials as a tunable biomaterial.     

Fatty Acid Derived Monomers and Related Polymers Via Thiol‐ene (Click) Additions

Thiol‐ene additions of methyl 10‐undecenoate, a castor oil derived renewable platform chemical, were studied with the goal of preparing a set of renewable monomers. Good to excellent yields were obtained for these solvent and initiator free thiol‐ene additions. The resulting monomers were then polymerized using TBD as a catalyst, to linear as well as hyperbranched polyesters that also contain thio‐ether linkages. All thus prepared polymers were fully characterized (NMR, GPC, DSC, and TGA) and the results of these investigations will be discussed within this contribution. The thermal analysis of these polymers revealed melting points in the range from 50 to 71 °C. Moreover, no significant weight loss was observed below 300 °C.

     

Characterization of well‐defined poly(ethylene glycol) hydrogels prepared by thiol‐ene chemistry

Considering the large number of applications for hydrogels, a better understanding of the relation between molecular structure and mechanical properties for well‐defined hydrogel is essential. A new library has been compiled of poly(ethylene glycol) polymers (PEG) of different length end functionalized with diallyl, dithiol, and dimethacrylate, and crosslinked with complementary trifunctional crosslinkers. In this study, the hydrogels were initially analyzed by FT‐Raman and NMR to study the conversion ratio of the functional groups. The effects of solvent type, solid content concentration, curing time and length of the PEG chains on the final leaching, swelling and tensile properties of the hydrogels were studied. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Thiol‐ene click derived structurally well‐defined per(3,5‐dimethyl)phenylcarbamoylated cationic cyclodextrin separation material for achiral and chiral chromatography

In this work, a novel single sulfoether‐bridged cationic per(3,5‐dimethyl)phenylcarbamoylated‐β‐cyclodextrin separation material was prepared by thiol‐ene click chemistry and characterized by using FTIR spectroscopy, solid‐state ¹³C NMR spectroscopy and elemental analysis, which confirmed the correct structure. The separation material exhibited a good achiral separation performance for benzene homologues and phenylamine analogs, especially o‐xylene and m‐xylene, and m‐phenylenediamine and o‐phenylenediamine can be discriminated by the (3,5‐dimethyl)phenylcarbamoyl cyclodextrins. The chiral resolving ability of the separation material was evaluated by discriminating various isoxazolines, flavonoids, and β‐blockers in reversed‐phase high‐performance liquid chromatography. For isoxazolines, the material showed the best chiral discrimination toward 3‐aryl‐5‐(2‐oxopyrrolidin‐1‐yl)‐isoxazolines, where the resolution for 3ClPh‐OPr  reached 6.03. For flavonoids, it exhibited more efficient separation to the ones with more hydrophobic substituents, with a resolution of 5.93 for 6‐hydroxyflavanone. β‐Blockers were also enantioseparated satisfactorily on the material. The as‐prepared separation material is a good member of the thiol‐ene click derived cyclodextrin stationary phase family.     

Photopolymerization of thiol‐ene systems based on oligomeric thiols

Thiol oligomers were copolymerized with a triallyl ether by a photoinduced polymerization process. These oligomeric thiol‐ene systems comprise the same components as a photopolymerized thiol‐ene‐acrylate ternary system, yet the photopolymerized networks have much lower glass transition temperatures. An investigation into the effect of oligomeric thiol design on network formation was conducted by analyzing the reaction kinetics and thermal/mechanical properties of the thiol‐ene networks. Real‐time FTIR analysis shows that total conversion is >90% for all thiols investigated. Photo‐DSC analysis shows that the maximum exotherm rate is roughly equivalent for all of the thiols when the equivalent weight of the thiol is taken into account. As would be expected, the glass transition temperature and tensile strength increase with thiol functionality and lower thiol equivalent weight for thiols with functionality from 2 to 4. Films made using the oligomeric thiols have essentially the same glass transition temperatures and tensile modulus values regardless of thiol design. These results distinguish the method for generation of networks consisting of an initial Michael reaction of thiols and acrylates followed by a photoinitiated copolymerization with a multifunctional ene from the traditional photolysis of the corresponding thiol‐ene‐acrylate ternary systems with no Michael reaction. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 14–24, 2009     

The power of thiol‐ene chemistry

As a tribute to Professor Charlie Hoyle, we take the opportunity to review the impact of thiol‐ene chemistry on polymer and materials science over the past 5 years. During this time, a renaissance in thiol‐ene chemistry has occurred with recent progress demonstrating its unique advantages when compared with traditional coupling and functionalization strategies. Additionally, the robust nature of thiol‐ene chemistry allows for the preparation of well‐defined materials with few structural limitations and synthetic requirements. To illustrate these features, the utility of thiol‐ene reactions for network formation, polymer functionalization, dendrimer synthesis, and the decoration of three‐dimensional objects is discussed. Also, the development of the closely related thiol‐yne chemistry is described. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 743–750, 2010     

Designing Visible Light‐Cured Thiol‐Acrylate Hydrogels for Studying the HIPPO Pathway Activation in Hepatocellular Carcinoma Cells

Various polymerization mechanisms have been developed to prepare peptide‐immobilized poly(ethylene glycol) (PEG) hydrogels, a class of biomaterials suitable for studying cell biology in vitro. Here, a visible light mediated thiol‐acrylate photopolymerization scheme is reported to synthesize dually degradable PEG‐peptide hydrogels with controllable crosslinking and degradability. The influence of immobilized monothiol pendant peptide is systematically evaluated on the crosslinking of these hydrogels. Further, methods are proposed to modulate hydrogel crosslinking, including adjusting concentration of comonomer or altering the design of multifunctional peptide crosslinker. Due to the formation of thioether ester bonds, these hydrogels are hydrolytically degradable. If the dithiol peptide linkers used are susceptible to protease cleavage, these thiol‐acrylate hydrogels can be designed to undergo partial proteolysis. The differences between linear and multiarm PEG‐acrylate (i.e., PEGDA vs PEG4A) are also evaluated. Finally, the use of the mixed‐mode thiol‐acrylate PEG4A‐peptide hydrogels is explored for in situ encapsulation of hepatocellular carcinoma cells (Huh7). The effects of matrix stiffness and integrin binding motif (e.g., RGDS) on Huh7 cell growth and HIPPO pathway activation are studied using PEG4A‐peptide hydrogels. This visible light poly­merized thiol‐acrylate hydrogel system represents an alternative to existing light‐cured hydrogel platforms and shall be useful in many biomedical applications.     

A Green Approach for the Synthesis and Thiol‐ene Modification of Alkene Functio1489lized Poly(2‐oxazoline)s

The bulk polymerization of 2‐(dec‐9‐enyl)‐2‐oxazoline ( DecEnOx ), a fatty acid‐based monomer for the cationic ring‐opening polymerization, is reported. Furthermore, under optimal conditions, namely microwave heating at 100 °C, the bulk copolymerization with 2‐ethyl‐2‐oxazoline yielded well‐defined copolymers. Due to its pendant alkene groups DecEnOx ‐based polymers possess the potential to be modified in efficient thiol‐ene reactions. The functionalization with thiols, e.g., dodecanethiol and 2,3,4,6‐tetra‐O‐acetyl‐1‐thio‐β‐D ‐glycopyranose in “green” solvents is demonstrated.

     

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.