Thiol-ene Coupling Reaction Research Articles

Characterizing the effects of heparin gel stiffness on function of primary hepatocytes.

In the liver, hepatocytes are exposed to a large array of stimuli that shape hepatic phenotype. This in vivo microenvironment is lost when hepatocytes are cultured in standard cell cultureware, making it challenging to maintain hepatocyte function in vitro. Our article focused on one of the least studied inducers of the hepatic phenotype-the mechanical properties of the underlying substrate. Gel layers comprised of thiolated heparin (Hep-SH) and diacrylated poly(ethylene glycol) (PEG-DA) were formed on glass substrates via a radical mediated thiol-ene coupling reaction. The substrate stiffness varied from 10 to 110 kPa by changing the concentration of the precursor solution. ELISA analysis revealed that after 5 days, hepatocytes cultured on a softer heparin gel were synthesizing five times higher levels of albumin compared to those on a stiffer heparin gel. Immunofluorescent staining for hepatic markers, albumin and E-cadherin, confirmed that softer gels promoted better maintenance of the hepatic phenotype. Our findings point to the importance of substrate mechanical properties on hepatocyte function.

Access to nonisocyanate poly(thio)urethanes: A comparative study

ABSTRACTThis article describes the synthesis of new cyclic compounds able to react with amines to get nonisocyanate polyurethanes (NIPUs). The contribution of the most studied five‐membered cyclic carbonate was compared to five‐membered cyclic dithiocarbonate analogous and to a six‐membered cyclic carbonate. Difunctional reactive species were obtained by a simple substitution reaction or an efficient thiol–ene coupling reaction. The products, obtained with high yields, were characterized by 1H NMR, 13C NMR, and Fourier tansform infrared spectroscopy analysis. The dicyclocarbonates were then used to synthesize NIPUs by step growth polymerization with several diamines. These materials exhibited glass transition temperatures from 19 to −29 °C, molar mass from 1800 to 20,400 g mol−1, and a 20% mass loss temperature (Td = 20%) between 249 and 296 °C. Such materials are interesting candidates for coating applications. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3284–3296

Synthesis of Carbohydrate‐Functionalised Sequence‐Defined Oligo(amidoamine)s by Photochemical ThiolEne Coupling in a Continuous Flow Reactor

Poly/oligo(amidoamine)s (PAAs) have recently been recognised for their potential as well-defined scaffolds for multiple carbohydrate presentation and as multivalent ligands. Herein, we report two complimentary strategies for the preparation of such sequence-defined carbohydrate-functionalised PAAs that use photochemical thiol-ene coupling (TEC) as an alternative to the established azide-alkyne cycloaddition ("click") reaction. In the first approach, PAAs that contained multiple olefins were synthesised on a solid support from a new building block and subsequent conjugation with unprotected thio-carbohydrates. Alternatively, a pre-functionalised building block was prepared by using TEC and assembled on a solid support to provide a carbohydrate-functionalised PAA. Both methods rely on the use of a continuous flow photoreactor for the TEC reactions. This system is highly efficient, owing to its short path length, and requires no additional radical initiator. Performing the reactions at 254 nm in Teflon AF-2400 tubing provides a highly efficient TEC procedure for carbohydrate conjugation, as demonstrated in the reactions of O-allyl glycosides with thiols. This method allowed the complete functionalisation of all of the reactive sites on the PAA backbone in a single step, thereby obtaining a defined homogeneous sequence. Furthermore, reaction at 366 nm in FEP tubing in the flow reactor enabled the large-scale synthesis of an fluorenylmethyloxycarbonyl (Fmoc)-protected glycosylated building block, which was shown to be suitable for solid-phase synthesis and will also allow heterogeneous sequence control of different carbohydrates along the oligomeric backbone. These developments enable the synthesis of sequence-defined carbohydrate-functionalised PAAs with potential biological applications.

Synthesis and self-assembly of amphiphilic polymers based on polyoxazoline and vegetable oil derivatives

The synthesis and self-assembly of amphiphilic polymers based on unsaturated vegetable oils and poly(2-methyl-2-oxazoline) (POx) are reported. Two architectures of lipopolymers were explored starting from fatty methyl esters and raw vegetable oils. The latter were converted into macroinitiators for cationic ring-opening polymerization (CROP) of 2-methyl-2-oxazoline. Firstly, a thiol–ene coupling reaction in the presence of mercaptoethanol under UV irradiation was performed to introduce hydroxyl groups that were further transformed into initiating species used for cationic polymerization. According to this strategy, various lipopoly(2-methyl-2-oxazoline)s (LipoPOxs) with different lipidic/POx ratios were successfully obtained and characterized by 1H NMR, SEC and MALDI-TOF analyses. Finally, the self-organization of the LipoPOx was studied using dynamic light scattering (DLS). Well-shaped nanoparticles were obtained with characteristic radii of 4.3 and 10.2 nm for the fatty ester- and triglyceride-based lipopolymers, respectively. The latter value is about twice the former one due to the higher lipidic fraction of the triglyceride-based polymer that promotes hydrophobic interactions. The relaxation time distributions of both systems were found to be monomodal, indicating monodisperse colloidal suspensions.

Synthesis of end-functionalized phosphate and phosphonate-polypeptides by ring-opening polymerization of their corresponding N-carboxyanhydride

Phosphopolypeptides provide an interesting biomimetic analog for phosphorylated proteins that are involved in biomineralization. We have developed a high yielding synthesis of cysteine-based phosphate and phosphonate N-carboxyanhydride (NCA) by using the thiol–ene coupling reaction. These phosphate and phosphonate NCA monomers underwent polymerization using simple primary amine initiators to form well defined homophosphopolypeptides. Using a bifunctional initiator we were able to install a “clickable” alkyne or azide group at the end of the polypeptide chain. We were also able to successfully synthesize fully water-soluble phosphonate based polypeptides by hydrolysis of the corresponding phosphonate ester groups in the polypeptide. These water-soluble phosphopolypeptides adopt a random coil conformation at physiological pH.

Systematic study on free radical hydrothiolation of unsaturated monosaccharide derivatives with exo- and endocyclic double bonds

Exo- and endocyclic double bonds of glycals and terminal double bonds of enoses were reacted with various thiols by irradiation with UV light in the presence of a cleavable photoinitiator. The photoinduced radical-mediated hydrothiolation reactions showed highly varying overall conversions depending not only on the substitution pattern and electron-density of the double bond but also on the nature and substitution pattern of the thiol partner. Out of the applied thiols thiophenol, producing the highly stabilized thiyl radical, exhibited the lowest reactivity toward each type of alkene. In most cases, the hydrothiolations took place with full regio- and stereoselectivities. Successful addition of 1,2 : 3,4-di-O-isopropylidene-6-thio-α-d-galactopyranose to a 2,3-unsaturated N-acetylneuraminic acid derivative, providing a (3 → 6)-S-linked pseudodisaccharide, demonstrated that the endocyclic double bond of Neu5Ac-2-ene, bearing an electron-withdrawing substituent, shows sufficient reactivity in the photoinduced thiol-ene coupling reaction.

Synthesis of antibacterial amphiphilic elastomer based on polystyrene-block-polyisoprene-block-polystyrene via thiol-ene addition

A new type of amphiphilic antibacterial elastomer has been described. Thermoplastic elastomer, polystyrene–block-polyisoprene–block-polystyrene (PS–b-PI–b-PS) triblock copolymer was functionalized in toluene solution by free radical mercaptan addition in order to obtain an amphiphilic antibacterial elastomer. Thiol terminated PEG was grafted through the double bonds of PS–b-PI–b-PS via free radical thiol-ene coupling reaction. The antibacterial properties of the amphiphilic graft copolymers were observed. The original and the modified polymers were used to create microfibers in an electro-spinning process. Topology of the electrospun micro/nanofibers were studied by using scanning electron microscopy (SEM). The chemical structures of the amphiphilic comb type graft copolymers were elucidated by the combination of elemental analysis, 1H NMR, 13C NMR, GPC and FTIR.

Sequential interpenetrating poly(ethylene glycol) hydrogels prepared by UV‐initiated thiol–ene coupling chemistry

AbstractPoly(ethylene glycol) (PEG)‐diallyls, ranging from 2 to 8 kDa, were successfully reacted with a trifunctional thiol crosslinker via thiol–ene coupling reaction to construct four different primary PEG hydrogels. These systems were used as scaffolds for the preparation of a library of sequential interpenetrating networks (SeqIPNs). The solid content of the secondary networks varied between 21 and 34% and was dependent on the length of the absorbing PEGs. The gel fractions for the IPNs were above 85%. Additionally, the lowest degree of swelling was found for the IPN based on 2‐kDa PEG (315%), whereas the 8‐kDa PEG IPN exhibited a value of 810%. The SeqIPN strategy facilitated hydrogel systems that cover a larger domain of tensile modulus (192–889 kPa) when compared with single hydrogel networks (175–555 kPa). © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013

Modification of polysaccharides via thiol‐ene chemistry: A versatile route to functional biomaterials

AbstractWe present herein a mild and rapid method for the modular functionalization of polysaccharides. Several ene‐functional charged and neutral polysaccharides, that is, hyaluronic acid and dextran, were prepared by esterification of the hydroxyl groups with pentenoic anhydride. The modified polysaccharides were then reacted with six model mercaptans under UV light, leading to linear polymers modified with hydrophobic groups, peptides, or oligosaccharides as well as chemical hydrogels. The thiol‐ene coupling reactions were found to proceed with high efficiency in short reaction times and with nearly no degradation of the polysaccharide backbone. Moreover, they were carried out in aqueous media, without the use of any metal catalysts, enhancing the attractive nature of this process. Notably, we investigated whether it is feasible to prepare cell‐responsive hydrogels by sequential bioconjugation and cross‐linking of the polysaccharide backbone with a bioactive peptide and poly(ethylene glycol)‐dithiol, respectively. All together, these results highlight the potential of this coupling strategy for the modular functionalization of polysaccharides under click chemistry‐like conditions. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

High Refractive Index Polymers Based on Thiol–Ene Cross-Linking Using Polarizable Inorganic/Organic Monomers

The self-initiation of the thiol–ene coupling reaction of tetravinyl monomers containing main group elements and trivinyl heterocycles with alkyl and aryl dithiols resulted in the formation of highly cross-linked prepolymer gels which upon final curing at 120 °C yielded hard, monolithic polymeric materials. Because of the presence of highly polarizable main group elements such as Si, Ge, Sn, and S and the relative absence of highly electronegative elements, the resulting polymers exhibited high refractive indices ranging from 1.590 to 1.703 and Abbe numbers between 24.3 and 45.0. All of the polymers were highly transparent over the UV–vis region of the spectrum. Moreover, due to the high cross-linked density achievable in specific compositions, very hard materials capable of being ground and polished could be produced. The range of compositions produced yields important structure–property relationships, indicating the effect of monomer structure on mechanical and optical properties.

Synthesis of Novel Hexathiolated Squalene and Its Thiol-Ene Photopolymerization with Unsaturated Monomers

In this work is described the synthesis of a multifunctional thiolated squalene. Thiol-ene coupling reactions were employed to functionalize the six double bonds of squalene, using thiolacetic acid. Hydrolysis of the resulting thioacetates, rendered the corresponding hexathiolated squalene SQ6SH. This compound was further photopolymerized separately with triallyl cyanurate, pentaerythritol triacrylate and diethyleneglycol divinyl ether. Real Time FTIR kinetics revealed that homopolymerization of the ene monomers took place in addition to the thiol-ene photopolymerization. Flexible films were obtained when SQ6SH was photopolymerized in bulk with the above mentioned unsaturated monomers.

Polystyrene-supported organocatalysts for α-selenenylation and Michael reactions

Abstract Three different resin-supported catalysts have been prepared by using the well established post-modification approach by means of thiol-ene coupling reaction. Two catalysts were tested for the first time in the asymmetric α-selenenylation of propanal, while the third catalyst was used in the Michael addition reaction. While the preliminary results are not encouraging in the case of supported Jorgensen’ catalyst, interesting data have been collected with both for the supported MacMillan and prolyl-prolinol catalysts. In fact, these catalysts displayed good activity and selectivity. A reversed enantioselectivity in the α-selenenylation was observed by changing the polarity of the solvent. Finally, these materials were easily recovered, and used four and five times, respectively.

Exhaustive glycosylation, PEGylation, and glutathionylation of a [G4]-ene(48) dendrimer via photoinduced thiol-ene coupling.

We report in this paper the use of free-radical thiol-ene coupling (TEC) for the introduction of carbohydrate, poly(ethylene glycol), and peptide fragments at the periphery of an alkene functional dendrimer. Four different sugar thiols including glucose, mannose, lactose and sialic acid, two PEGylated thiols and the natural tripeptide glutathione were reacted with a fourth generation alkene functional dendrimer [G4]-ene(48) upon irradiation at λ(max) 365 nm. In all cases, the (1)H NMR spectra of the crude reaction mixture revealed the complete disappearance of alkene proton signals indicating the quantitative conversion of all 48 alkene groups of the dendrimer. With one exception only, all dendrimer conjugates were isolated in high yields (70-94%), validating the high efficiency of multiple TEC reactions on a single substrate. All isolated and purified compounds were analyzed by MALDI-TOF spectrometry and gave spectra consistent with the assigned structure.

Synthesis and use of a new alkene-functionalized SG1-based alkoxyamine

A new alkene-functionalized SG1-based alkoxyamine was synthesized and used to prepare well-defined functional polymers by nitroxide mediated polymerization. The latter were characterized by NMR, SEC and MALDI-TOF mass spectrometry. Livingness was assessed by chain extension toward AB-type block copolymer. The alkene functionality located at the α-chain-end allowed the post-modification of the polymer by thiol–ene coupling reaction.

Low loss photopatternable matrix materials for LWIR-metamaterial applications

Transparent matrix materials with low-loss and low-permittivity are an important component of integrated optical devices including filters, lenses, and novel metamaterials. Many of the structural matrix materials that are currently utilized at visible and near-infrared wavelengths, such as solution deposited, high-k dielectrics and commercial photoresists, exhibit vibrational absorption bands in the 8–12 μm spectral range which represents a significant challenge to developing transmissive, three-dimensional (3D) metamaterials operating in the long wavelength infrared (LWIR) spectral region. In this paper, we present new, low loss photopatternable polymer dielectrics as well-suited matrix materials for fabricating LWIR-metamaterials. These materials are synthesized by partially hydrogenating polynorbornene to varying degrees followed by a thiol-ene coupling reaction to cross-link the remaining olefin groups. After cross-linking, the olefin LWIR-absorption band is minimized and the glass transition temperature (Tg) of the material increases. Thick layers of the polymer (>3 μm), which acts as a negative photoresist, can be deposited easily using a spin coating technique to develop planarizing layers with photopatternable vias. A demonstration on the low loss nature of the polymer dielectrics was carried out by incorporating the polymer into an all-dielectric, infrared metamaterial. Thus, the material is ideal for both lithography and fabrication of 3D metamaterial structures operating in the LWIR spectral region.

Synthesis and characterization of poly(aryl ether ketone) ionomers with sulfonic acid groups on pendant aliphatic chains for proton-exchange membrane fuel cells

A series of parent poly(aryl ether ketone)s bearing different content of unsaturated pendant propenyl groups were synthesized via nucleophilic substitution polymerization from 3,3′-diallyl-4,4′-dihydroxybiphenyl, 9,9′-bis(4-hydroxyphenyl) fluorene and 4,4′-difluorobenzophenone. The polymers with pendant aliphatic sulfonic acid groups were further synthesized by free radical thiol-ene coupling reactions between 3-mercapto-1-propanesulfonic sodium and the parent propenyl functional copolymers. The resulting sulfonated polymers with high inherent viscosity (1.83–4.69 dL/g) were soluble in polar organic solvents and can form flexible and transparent membranes by casting from their solutions. The copolymers with different ion exchange capacity could be conveniently synthesized by varying the monomers ratios. Transmission electron microscopy (TEM) was used to examine the microstructures of the membrane and the results revealed that significant hydrophilic/hydrophobic microphase separation with spherical, uniform-sized (5–10 nm) and well-dispersed hydrophilic domains was afforded. The proton conductivities of the as-prepared membranes and the state-of-the-art Nafion 117 membrane in fully hydrated state were investigated. The results revealed that the proton conductivity of the synthesized membranes increased more remarkably than that of Nafion 117 membrane with increasing temperature. The membrane with 1.69 mequiv/g of IEC had a conductivity of 2.5 × 10 −2 Scm −1 at 100 °C. The membranes also possessed excellent mechanical properties, good thermal, oxidative, hydrolytic and dimensional stabilities.

Block Copolymers Containing Intrinsically Proton-Conducting Blocks Tethered with Benzimidazole Units

ABA triblock copolymers having benzimidazole-tethered end blocks have been prepared and characterized with respect to their intrinsically proton conducting properties. The copolymers were synthesized by using a linear poly(ethylene oxide) (PEO) as a difunctional macroinitiator for the anionic ring-opening polymerization of allyl glycidyl ether. The pendent allyl groups of the end blocks were subsequently linked with 2-(2-benzimidazolyl)ethanethiol via a free radical thiol-ene coupling reaction. Thermogravimetry showed that the final materials were stable up to 210 C under a nitrogen atmosphere. The benzimidazole units of the copolymers were found to crystallize from solution but not from the melt. After heating the materials above the melting point of benzimidazole units, the copolymers displayed single glass transitions temperatures (Tg's). Moreover, the crystallization of the PEO blocks was depressed which may indicate a high degree of interaction between the dissimilar blocks. The proton conductivity was found to be promoted by a high benzimidazole concentration and a high segmental mobility, that is, low Tg's of the copolymers. Increased concentrations of benzimidazole raised the Tg, and the resulting conductivity thus depended on a balance between the charge carrier density and the mobility. Conductivities close to 80 μS/cm were reached at 160 C by these materials under completely anhydrous conditions. (Less)

Intrinsically proton-conducting comb-like copolymers with benzimidazole tethered to the side chains

Intrinsically proton-conducting comb-like copolymers having side chains tethered with benzimidazole units have been prepared and characterized with respect to their thermal properties and proton conductivity. In the first step of the preparation, poly(4-hydroxystyrene) was synthesized by polymerization of tert-butoxystyrene followed by hydrolysis of the butoxy groups. In the next step, poly(allyl glycidyl ether) side chains were grafted from the polyhydroxystyrene (PHSt) backbone. Finally, benzimidazole units were tethered via free radical thiol-ene coupling between 2-(2-benzimidazolyl)ethanethiol and the pendant allyl groups of the side chains. The efficiency of the thiol-ene coupling reaction was found to decrease with increasing length of the side chains, which was attributed to sterical effects. The materials were thermally crosslinkable, most probably via the residual allyl groups. Calorimetry showed that the benzimidazole-tethered copolymers had glass transition temperatures of 50– 60 °C, partly a consequence of the strong hydrogen bonds between the benzimidazole units. The proton conductivity of the fully polymeric materials exhibited a non-Arrhenius behavior and a maximum conductivity of 6.6 μS/cm was reached at 160 °C under anhydrous conditions.

Polysulfones tethered with benzimidazole

Benzimidazole units have been grafted onto a polysulfone (PSU) backbone via long alkyl thio–ether chains using a two-step procedure. In the first step, lithiated PSU was reacted with 10-undecenoyl chloride to graft PSU with undecenoyl side chains. The second step involved a free-radical thiol–ene coupling reaction between the C C bonds of the pendant undecenoyl chains and 2-(2-benzimidazolyl)ethanethiol. In this reaction, all the C C bonds were converted into thio–ether linkages without any detectable structural degradation, as confirmed by 1H NMR spectroscopy and size-exclusion chromatography. The procedure constitutes a convenient and general pathway to attach functional or mesogenic groups to PSU via long flexible spacers. Thermogravimetry showed that the benzimidazole-functionalized polymers were stable up to 250 °C under nitrogen atmosphere, and that the first degradation step was attributed to the cleavage of the thio–ether bond. While the grafting of the undecenoyl side chains was found to significantly decrease the glass transition temperature ( T g), the subsequent tethering of the benzimidazole only slightly increased the T g of the grafted PSU backbone. The concentration of benzimidazole was probably too low for the formation of a percolating benzimidazole domain. This explains the quite modest proton conductivity measured under completely dry conditions, e.g. 34 nS/cm at 180 °C for a polymer functionalized with 1.7 benzimidazole units per repeating unit of PSU.

Thiol–ene coupling reaction of fatty acid monomers

AbstractThe reactivities and reaction rates of the thiol–ene coupling reaction of 2‐ethyl‐(hydroxymethyl)‐1,3‐propanediol trimercapto acetate and 2‐ethyl‐(hydroxymethyl)‐1,3‐propanediol trimercapto propionate with two common unsaturated fatty acid methyl esters (methyl oleate and methyl linoleate) were evaluated. The reactions were monitored with real‐time IR and 1H NMR, which both showed that the mercapto acetate was more reactive than the mercapto propionate. Both thiols were more prone to add to the monounsaturated methyl oleate than to methyl linoleate, which contained two unconjugated double bonds. According to bond energy calculations, the thiol hydrogen of mercapto acetate was somewhat more difficult to abstract than the hydrogen of mercapto propionate. Consequently, the formed SC bond in the acetate case was stronger than in the propionate case, and so the equilibrium was more shifted toward the addition products. The real‐time IR measurements also showed that the cis unsaturation in methyl oleate isomerized much more quickly than that in methyl linoleate, and this also had an impact on the overall addition rate of the thiols because a trans unsaturation was more reactive than a cis unsaturation. The higher isomerization rates in the oleate systems, compared with those of the linoleate systems, was suggested to be due to a more restricted rotation along the CC bond of the reacted unsaturation in linoleate. This study showed the importance of trans unsaturations in obtaining reasonable reaction rates in thiol–ene reactions with fatty acid derivatives. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 6346–6352, 2004