Thiol-ene Reaction Research Articles

One pot synthesis of thiol-functional nanoparticles

Polysorbate 80 (PS80) was reacted with 3-mercaptopropyl trimethoxysilane (SiSH) via a photoinitiated thiol-ene reaction. The resulting conjugate was co-condensed with SiSH to form stable aqueous solutions of thiol-functional nanoparticles (TFNs).

Organosilica nanoparticles containing sodium borocaptate (BSH) provide new prospects for boron neutron capture therapy (BNCT): efficient cellular uptake and enhanced BNCT efficacy.

Boron neutron capture therapy (BNCT), a method based on the fission of boron-10 upon neutron irradiation, has emerged as an attractive option for radiation therapy. To date, the main drugs used in BNCT are 4-boronophenylalanine (BPA) and sodium borocaptate (BSH). While BPA has been extensively tested in clinical trials, the use of BSH has been limited, mainly due to its poor cellular uptake. Here, we describe a novel type of mesoporous silica-based nanoparticle containing BSH covalently attached to a nanocarrier. Synthesis and characterization of these nanoparticles (BSH-BPMO) are presented. The synthetic strategy involves a click thiol-ene reaction with the boron cluster, providing hydrolytically stable linkage with the BSH in four steps. The BSH-BPMO nanoparticles were efficiently taken up into cancer cells and accumulated in the perinuclear region. Inductively coupled plasma (ICP) measurements of boron uptake in cells highlight the important role of the nanocarrier in the enhancement of boron internalization. BSH-BPMO nanoparticles were also taken up and distributed throughout tumour spheroids. BNCT efficacy was examined by the neutron exposure of the tumour spheroids. BSH-BPMO loaded spheroids were completely destroyed upon neutron irradiation. In contrast, neutron irradiation of tumour spheroids loaded with BSH or BPA resulted in significantly less spheroid shrinkage. The significant difference in BNCT efficacy of the BSH-BPMO was correlated with the improved boron uptake via the nanocarrier. Overall, these results demonstrate the critical role of the nanocarrier in BSH internalization and the enhanced BNCT efficacy of the BSH-BPMO compared with BSH and BPA, two drugs used in BNCT clinical trials.

3D-bioprinted, phototunable hydrogel models for studying adventitial fibroblast activation in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature, characterized by elevated pulmonary blood pressure, remodeling of the pulmonary arteries, and ultimately right ventricular failure. Therapeutic interventions for PAH are limited in part by the lack of in vitro screening platforms that accurately reproduce dynamic arterial wall mechanical properties. Here we present a 3D-bioprinted model of the pulmonary arterial adventitia comprised of a phototunable poly(ethylene glycol) alpha methacrylate (PEG-αMA)-based hydrogel and primary human pulmonary artery adventitia fibroblasts (HPAAFs). This unique biomaterial emulates PAH pathogenesis in vitro through a two-step polymerization reaction. First, PEG-αMA macromer was crosslinked off-stoichiometry by 3D bioprinting an acidic bioink solution into a basic gelatin support bath initiating a base-catalyzed thiol-ene reaction with synthetic and biodegradable crosslinkers. Then, matrix stiffening was induced by photoinitiated homopolymerization of unreacted αMA end groups. A design of experiments approach produced a hydrogel platform that exhibited an initial elastic modulus (E) within the range of healthy pulmonary arterial tissue (E = 4.7 ± 0.09 kPa) that was stiffened to the pathologic range of hypertensive tissue (E = 12.8 ± 0.47 kPa) and supported cellular proliferation over time. A higher percentage of HPAAFs cultured in stiffened hydrogels expressed the fibrotic marker alpha-smooth muscle actin than cells in soft hydrogels (88 ± 2% versus 65 ± 4%). Likewise, a greater percentage of HPAAFs were positive for the proliferation marker 5-ethynyl-2ʹ-deoxyuridine (EdU) in stiffened models (66 ± 6%) compared to soft (39 ± 6%). These results demonstrate that 3D-bioprinted, phototunable models of pulmonary artery adventitia are a tool that enable investigation of fibrotic pathogenesis in vitro.

Sustainable approach for coating production: Room temperature curing of diglycidyl furfuryl amine and itaconic acid with UV-induced thiol-ene surface post-functionalization

In this work, diglycidyl furfuryl amine (DGFA) is synthesized towards the production of a functional coating. With the aim to reduce the energy consumption during processing, a room temperature (RT) curing of the epoxy monomer is performed in presence of bio-based itaconic acid (IA). The RT curing process was demonstrated by means of DSC, rheology, and real-time ATR FTIR and the thermo-mechanical properties were investigated by DMTA. As last step, the properties of the coating surface were modified via an UV-induced thiol-ene reaction between the CC double bonds from itaconic acid moieties and fluorine-based monomers. The surface functionalization was investigated by contact angle measurements and XPS analysis.

Triblock Elastomeric Vitrimers: Preparation, Morphology, Rheology, and Applications

Vitrimer chemistry of boronic transesterification was introduced into a triblock thermoplastic elastomer to allow associative bond exchange in its highly ordered nanoscale domains. The purpose of this localized dynamic cross-linking is to enable reprocessing while also improving creep resistance. Triblock poly(styrene-b-butadiene-b-styrene) (SBS) was used as an elastomeric vitrimer precursor to gain understanding of fundamental structure–property effects of localized dynamical cross-linking. The occurrence of the UV-induced thiol–ene reaction was corroborated by Fourier transform infrared (FTIR) spectroscopy and swelling experiments. Transmission electron microscopy (TEM) images and small-angle X-ray scattering (SAXS) profiles demonstrate a prominently lamellar morphology with domain spacings that decline with the increase of cross-linking degree. Short and long relaxation modes of triblock SBS vitrimers (vSBSs) were found to have opposite temperature dependence, which caused thermorheological complexity in linear viscoelasticity. As compared to its random analog, vSBS shows much slower stress relaxation and higher activation energy, as well as superior resistance to creep under a steady load. The enhanced rheological properties are attributed to the high concentration of localized cross-links in the soft phase and to additional constraints that hinder network strand diffusion in the microphase-separated structure. The mechanical properties of vSBSs at low strain were substantially enhanced by the associative dynamic cross-links between the soft segments, increasing the maximum stress to 7.5 MPa at 100% strain. Its Young’s modulus of 88.1 MPa is about 2.8 times that of neat SBS. Applications of vSBSs as hot-melt adhesives were explored, showing excellent lap shear strength on iron plates. Due to the dynamic exchange of boronic ester bonds, adhesive joints can efficiently rebind at least three times and the lap shear strength remains almost unchanged.

Syntheses, Properties, and Aggregation Behavior of Novel Carboxylate-Based Silicone Surfactants.

Two new anionic silicone surfactants were synthesized for the first time from dichloromethylvinylsilane or trichlorovinylsilane through hydrolysis-condensation and then thiol-ene reactions. Their structures were characterized by FT-IR, 1 H NMR and ESI-MS. The surface tension (γ), critical aggregate concentration (CAC), surface pressure at CAC ( ) and minimum surface area per surfactant molecule ( ) were studied by surface tension and electrical conductivity, demonstrating their high surface activity at the gas/liquid interface. Transmission electron microscopy measurements showed that uniform spherical aggregates former in aqueous solution for both surfactants. Moreover, the size of the aggregates was determined to be in the range from 50 to 300 nm by dynamic light scattering.

Thiol-divinylbenzene: A thiol-ene system with high storage stability

Based on a number of advantages, thiol-ene polymerization is of great significance in photopolymerization, especially in emerging industries such as biomedical materials and optoelectronic materials. However, the research is limited by its poor storage stability. Meanwhile the spontaneous reaction mechanism of thiol-ene is unclear. In this study, ene with different structures were explored to determine the storage stability and the mechanism of spontaneous reaction, it was found that structure of ene led to different effects on storage stability. Thiol-divinylbenzene (DVB) was found to be stable both at normal and high temperatures, which was due to the moderate electron cloud density and conjugated structure. Besides, the Spontaneous reaction mechanism of thiol-DVB was explored mainly as free radical-initiated thiol-ene reaction. It is worth mentioning that in addition to good storage stability, thiol-DVB also has excellent photopolymerization efficiency and a higher sulfur content in the network compared to the thiol-acrylate system. It is showed the significant potential and value of the thiol-DVB system for applications.

Efficient exfoliation of covalent organic frameworks by a facile thiol-ene reaction

Exfoliating insoluble bulk covalent organic frameworks (COFs) into covalent organic nanosheets (CONs) is an attractive way to improve their processability and the application performance. Herein, we report an efficient thiol-ene-induced exfoliation of oligo (phenylene vinylene) (OPV) based 2D COF-935 into CONs, which exhibits an obvious improvement in the reversible charge/discharge capacity as electrode materials for energy storage devices. The presence of vinylene groups in OPV units allows the addition of thiols under UV irradiation, which weaken the interlayer interactions for exfoliation by breaking the planarity of the layers in COFs. Furthermore, the degree of modification can be quantitatively controlled by varying the feeding ratio to obtain CONs with reasonable π-conjugation and short lithium-ion transfer distance. Specifically, the CON-UV-1 offers a nearly 90 % higher excellent cycle performance of 494 mA·h·g−1 at 1 A·g−1 after 500 cycles and outstanding rechargeability. This research thus provides a promising strategy for the chemical exfoliation of covalent organic frameworks into nanosheets and promotes their potential applications in energy storage.

Tuning the hydrophobicity of bio-based waterborne polyurethane by leveraging a diol derived from oleic acid

Vegetable oils containing long aliphatic chains are widely used to obtain polyols and further produce eco-friendly bio-based waterborne polyurethanes (BWPU). However, the effect of the long aliphatic chains on the properties of BWPU, especially hydrophobicity, has been awfully neglected in previous works. Here, we have successfully prepared a series of linear anionic BWPU by incorporating an oleic-based primary glycol (OPG) with long aliphatic chains into polytetrahydrofuran ether glycol (PTMG) in different proportions. Firstly, the optimized reaction conditions for efficient synthesis of OPG via the thiol-ene photo-click reaction are: 2 wt% photoinitiator 1173, molar ratio of -SH to -CC- of 2:1, and reaction time of 1 h. Then, the effect of incorporating OPG on BWPU’s properties, especially the intrinsic hydrophobicity, was extensively investigated. Specifically, due to the long hydrophobic aliphatic chain, the particle size of the BWPU dispersions increased with the increase of OPG content, and correspondingly the absolute value of zeta potential decreased. Additionally, the water contact angle of the BWPU films increased from 60.8° to 90.3°, and their water absorption decreased from 7.88% to 3.21%, exhibiting enhanced hydrophobicity and water resistance. This work demonstrates the designed and synthesized vegetable oil-based diol with a long aliphatic chain plays a positive role in tailoring the hydrophobicity of bio-based WPU, which holds great promises for applications in waterproof and self-cleaning coatings.

A facile preparation method of UV rapid curing fluorosilicone coatings with good hydrophobicity and excellent corrosion resistance based on thiol-ene click reaction

As reported herein, UV rapid curing fluorosilicone coatings with good hydrophobicity and corrosion resistance were developed with a novel fluorosilicone polymer possessing thiol functional groups (PTFPMS-SH) and a series of fluorosilicone polymers having different vinyl content (PTFPMS-Vi). The chemical structures of the prepared polymers (PTFPMS-Vi and PTFPMS-SH) were first characterized by FT-IR (fourier infrared transform spectroscopy) and 1H NMR (nuclear magnetic resonance), confirming the successful synthesis of expected polymers. Subsequently, the curing process, basic properties, thermal properties and surface properties of the UV cured fluorosilicone coatings were investigated. Moreover, the application of the fluorosilicone coatings as anti-corrosion coatings in the field of circuit boards were also preliminarily explored. The results show that the photocuring reaction based on the thiol-ene reaction for the preparation of fluorosilicone coatings is very effective because the conversion rate of carbon‐carbon double bonds can reach more than 95 % within 5 s under UV irradiation. These obtained fluorosilicone coatings exhibit transparency higher than 90 %. The contact angle of the obtained coatings ranges from 100° to 110°, showing their excellent hydrophobicity. Furthermore, the fluorosilicone coatings with outstanding corrosion resistance show their potential application worth as protective coatings for electronic devices.

Application of "Click" Chemistry in Biomedical Hydrogels.

Since “click” chemistry was first reported in 2001, it has remained a popular research topic in the field of chemistry due to its high yield without byproducts, fast reaction rate, simple reaction, and biocompatibility. It has achieved good applications in various fields, especially for the preparation of hydrogels. The development of biomedicine presents new challenges and opportunities for hydrogels, and “click” chemistry provides a library of chemical tools for the preparation of various innovative hydrogels, including cell culture, 3D bioprinting, and drug release. This article summarizes several common “click” reactions, including copper-catalyzed azide–alkyne cycloaddition reactions, strain-promoted azide–alkyne cycloaddition (SPAAC) reaction, thiol–ene reaction, the Diels–Alder reaction, and the inverse electron demand Diels–Alder (IEDDA) reaction. We introduce the “click” reaction in the nucleic acid field to expand the concept of “click” chemistry. This article focuses on the application of “click” chemistry for preparing various types of biomedical hydrogels and highlights the advantages of “click” reactions for cross-linking to obtain hydrogels. This review also discusses applications of “click” chemistry outside the field of hydrogels, such as drug synthesis, targeted delivery, and surface modification, hydrogels have great application potential in these fields in the future and hopefully inspire other applications of hydrogels.

Click chemistry functionalization of self-assembling peptide hydrogels.

Self-assembling peptide (SAP) hydrogels provide a fibrous microenvironment to cells while also giving users control of biochemical and mechanical cues. Previously, biochemical cues were introduced by physically mixing them with SAPs prior to hydrogel assembly, or by incorporating them into the SAP sequence during peptide synthesis, which limited flexibility and increased costs. To circumvent these limitations, we developed "Click SAPs," a novel formulation that can be easily functionalized via click chemistry thiol-ene reaction. Due to its high cytocompatibility, the thiol-ene click reaction is currently used to crosslink and functionalize other types of polymeric hydrogels. In this study, we developed a click chemistry compatible SAP platform by addition of a modified lysine (lysine-alloc) to the SAP sequence, enabling effective coupling of thiol-containing molecules to the SAP hydrogel network. We demonstrate the flexibility of this approach by incorporating a fluorescent dye, a cellular adhesion peptide, and a matrix metalloproteinase-sensitive biosensor using the thiol-ene reaction in 3D Click SAPs. Using atomic force microscopy, we demonstrate that Click SAPs retain the ability to self-assemble into fibers, similar to previous systems. Additionally, a range of physiologically relevant stiffnesses can be achieved by adjusting SAP concentration. Encapsulated cells maintain high viability in Click SAPs and can interact with adhesion peptides and a matrix metalloproteinase biosensor, demonstrating that incorporated molecules retain their biological activity. The Click SAP platform supports easier functionalization with a wider array of bioactive molecules and enables new investigations with temporal and spatial control of the cellular microenvironment.

Efficient synthesis of S-protected thiolated polysaccharide xylan

Since thiolated polysaccharides are valuable reactive carriers for thiol-ene reaction and thiol-disulfide exchange, we investigated a sophisticated method that avoids the crosslinking of thiols during polymer modification. Hydroxyl groups of xylan were activated by forming the phenylcarbonates and exploit as coupling group. The reactive xylan phenylcarbonates were allowed to react with the aminium chloride group under base addition to form the corresponding carbamate bond. The pKb of the base used was crucial for the successful synthesis. A pyridyl disulfide was applied as terminal functional moiety, which is not only a S-protected- but also an activated thiol for the synthesis of functional polysaccharide disulfides. The deprotected thiol, obtained by reduction of the disulfide, could be converted with a functional thiol. On the one hand, we have developed a valuable method to make disulfide chemistry easily accessible for the modification of neutral polysaccharides. On the other hand, the novel cationic polysaccharide derivative, where the functional group is bound by a reduction-sensitive disulfide bond, is an appealing product suitable for gene delivery applications.

Preparation of Photocoated Polysiloxane Nanoparticles from 3-Mercaptopropyl Trimethoxysilane with Furan Substitues by the Photoinitiated Thiol-Ene Reaction

Preparation of Photocoated Polysiloxane Nanoparticles from 3-Mercaptopropyl Trimethoxysilane with Furan Substitues by the Photoinitiated Thiol-Ene Reaction

Thiol-ene biobased networks: Furan allyl derivatives for green coating applications

Biomass feedstocks are playing a crucial role toward the development of new sustainable materials with the aim to replace the fossil-based ones limiting the emissions and waste. Among the other, cellulose, and hemicellulose are gaining interest as a source of new bio-based building blocks such as furan derivatives. In this study, two furan derivatives were selected as bio-based monomers to design four innovative UV-curable coatings. Specifically, 2,5-Furandimethanol (FDM), and cis-cyclobutane-1,2-dicarboxylic acid (CBDA-2) derived from Furylacrylic acid were modified by allylation of their respective OH groups. The bis allyl derivatives were combined with commercial tris- and tetra-functional thiols compounds and cured by means of UV-light through a thiol-ene reaction. The UV-curing was deeply investigated by means of real-time FT-IR, photo-DSC and photorheology. Successively, the bio-based thermosets were characterized by DMTA and tensile test to examine the thermal-mechanical behavior. The results indicated comparable properties with previous studied bio-based thiol-ene thermoset raising the possibility to use the studied material for coating applications.

Radical Mediated Rapid In Vitro Formation of c-Type Cytochrome.

A cytochrome c552 mutant from Thermus thermophilus HB8 (rC552 C14A) was reported, where the polypeptide with replaced Cys14 by alanine, overexpressed in the cytosol of E. coli. The apo-form of the C14A mutant (apo-C14A) without the original prosthetic group was obtained by simple chemical treatments that retained compact conformation amenable to reconstitution with heme b and zinc(II)-protoporphyrin(IX), gradually followed by spontaneous formation of a covalent bond between the polypeptide and porphyrin ring in the reconstituted apo-C14A. Further analysis suggested that the residual Cys11 and vinyl group of the porphyrin ring linked through the thiol-ene reaction promoted by light under ambient conditions. In this study, we describe the kinetic improvement of the covalent bond formation in accordance with the mechanism of the photoinduced thiol-ene reaction, which involves a thiyl radical as a reaction intermediate. Adding a radical generator to the reconstituted C14A mutant with either heme-b or zinc(II) porphyrin accelerated the bond-forming reaction, which supported the involvement of a radical species in the reaction. Partial observation of the reconstituted C14A in a dimer form and detection of sulfuryl radical by EPR spectroscopy indicated a thiyl radical on Cys11, a unique cysteinyl residue in rC552 C14A. The covalent bond forming mediated by the radical generator was also adaptable to the reconstituted apo-C14A with manganese(II)-protoporphyrin(IX), which also exhibits light-mediated covalent linkage formation. Therefore, the radical generator extends the versatility of producing c-type-like cytochrome starting from a metallo-protoporphyrin(IX) and the apo-C14A instantaneously.

Thermal and UV Curable Formulations of Poly(propylene glycol)-Poly(hydroxyurethane) Elastomers toward Nozzle-Based 3D Photoprinting.

In this work, isocyanate-free formulations for poly(propylene glycol) polyurethane elastomers are studied. These formulations are based on poly(propylene glycol) end-capped by CO2-sourced cyclic carbonate (bisCC PPG) macromonomers able to react with amines leading to poly(hydroxyurethane)s. In order to obtain covalent networks, two curing approaches are studied. First, the direct thermally activated cross-linking of bisCC PPG with a mixture of various aliphatic or aromatic diamines and a triamine is investigated, and in particular the nature of the diamine on the mechanical properties. In the second approach, UV-activated formulations are developed by reacting bisCC PPG with allylamine followed by the addition of a trithiol by photoactivated thiol-ene reaction. The swelling tests show that both systems provide highly cross-linked polymer networks and complementary characterizations highlighted excellent mechanical properties. Thanks to the fast curing and adapted viscosity of the developed photoactive formulation, the latter was found suitable for use as a photoresin for 3D printing as demonstrated by printing a vaginal ring by a nozzle-based photoprinter.

Synthesis and characterization of terpene-derived cationic bolaamphiphiles

Terpenes represent an abundant and sustainable feedstock for the construction of functional organic materials. Utilizing either trans-β-farnesene or myrcene as starting materials, we have developed a three-step synthetic sequence leading to a new class of terpene-containing cationic bolaamphiphiles. Two of the synthetic steps are devoid of solvent and proceed in reasonably high yield. The final step, a photochemical thiol-ene reaction, transforms a wholly hydrophobic precursor into a segmented amphiphilic molecule. The implementation of a late-stage thiol-ene reaction creates new opportunities for the introduction of chemical diversity into terpene-containing compounds and assemblies. The ease of synthesis combined with the versatility of the thiol-ene late stage functionalization opens-up a large design space and creates opportunities in a wide variety of areas including gene delivery, surfactants, and antimicrobials.

Thiol-Ene Reaction of Heparin Allyl Ester, Heparin 4-Vinylbenzyl Ester and Enoxaparin

Heparin allyl ester and heparin 4-vinylbenzyl ester were prepared and examined for their potential for thiol-ene reaction using both free radical initiators and photochemistry. While both undergo reaction with mercaptoacetic acid, the allyl ester adduct proved to be somewhat more labile. Several more examples of adducts from heparin 4-vinylbenzyl ester are reported. Similar reactions on enoxaparin, where the reaction site is solely at the non-reducing end of the molecule, are also reported. These reactions may show promise as a strategy in the development of drug conjugates.

Facile construction of fluorescent C70-COOH nanoparticles with advanced antibacterial and anti-biofilm photodynamic activity.

Photodynamic antibacterial therapy has been considered as one of the most promising treatments to alleviate the spread of multidrug resistant bacterial pathogens. Given the hypoxic environment of infectious tissues, photosensitizers with reduced oxygen-demand could exhibit superiority upon irradiation. Herein reported is a novel C70-based photosensitizers synthesized by the facile one-step thiol-ene reaction. Various characterization techniques were employed to confirm the structural, photoluminescent properties, photostability and biocompatibility of the as-synthesized C70-COOH nanoparticles. Furthermore, they were capable of efficiently producing reactive oxygen species following both the type I and II mechanistic pathways, thus still generating adequate free radicals under hypoxic condition. Therefore, they could approach and destroy the bacterial cell membrane in the presence of visible light, thereby causing cytoplasmic leakage and eventually achieving broad-spectrum inactivation of four representative bacterial strains. Especially, methicillin-resistant Staphylococcus aureus (MRSA) were completely eliminated after merely 10 minutes irradiation, and the formation of its corresponding biofilm were also greatly inhibited by C70-COOH nanoparticles. These results provide new insights and opportunities for the development of hypoxia-tolerant fullerene-based photosensitizers to combat multidrug resistant bacterial and related infections.