Thiol-yne Reaction Research Articles

Application of a novel small scale UV LED photochemical batch reactor for the thiol-yne reaction

The application of a novel small scale UV LED photochemical batch reactor for the thiol-yne click reaction was investigated.

High refractive index hyperbranched polymers with different naphthalene contents prepared through thiol-yne click reaction using di-substituted asymmetric bulky alkynes

In the present study, different aromatic moieties, naphthalene and benzene, were introduced into alkynes to constitute 1,3,5-tris(naphthylethynyl)benzene as B3 monomer. This monomer could be reacted with different ratios of hexane-1,6-dithiol (A2 monomer) via mono-selective Thiol-Yne reaction (TYR) to form hyperbranched polymers PI. TYR yielded in both, model reactions and polymerizations, mono-adducts with high regioselectivity and proved the absence of any bis-adducts. Polymers of very high molecular weights of up to 625,000 g/mol could be achieved without any sign of gel formation. All the polymers exhibit high transparency in the visible wavelength range and also show high refractive indices of up to 1.745 at 589.7 nm due to the high incorporation of naphthalene and phenyl groups. Besides, all polymers prove excellent solubility and processability together with excellent thermal properties.

Convenient synthesis of functionalized bis-ureidopyrimidinones based on thiol-yne reaction.

The preparation of functionalized bis-ureidopyrimidinones (Bis-UPy) through the thiol-yne reaction is described. Various Bis-UPys with different functional groups were synthesized by using the readily available functionalized alkynes and UPy-thiol to affirm the simplicity and versatility of the methodology.

Site-specific immobilization of DNA on silicon surfaces by using the thiol-yne reaction.

Covalent immobilization of ssDNA fragments onto silicon-based materials was performed using the thiol-yne reaction. Chemical functionalization provided alkyne groups on the surface where the thiol-modified oligonucleotide probes can be easily photoattached as microarrays, reaching an immobilization density around 30 pmol cm-2. The developed method presents the advantages of spatially controlled probe anchoring (by using a photomask), direct attachment without using cross-linkers, and short irradiation times (20 min). Hybridization efficiencies up to 70%, with full complementary strands, were reached. The approach was evaluated by scoring single nucleotide polymorphisms with a discrimination ratio around 15. Moreover, the potential applicability of the proposed methodology is demonstrated through the specific detection of 20 nM of a genomic target of bacterial Escherichia coli.

Radical Thiol‐yne Chemistry on Diphenylacetylene: Selective and Quantitative Addition Enabling the Synthesis of Hyperbranched Poly(vinyl sulfide)s

A powerful variation of traditional radical thiol-yne reaction with diphenylacetylene (DPA)-based starting materials leading to the quantitative and selective formation of the corresponding vinyl sulfides is reported. A variety of different thiols are shown to undergo reaction with DPA and the influence of their structure on reactivity is studied. The results obtained from the model reactions are then used to guide the efficient synthesis of hyperbranched poly(vinyl sulfide) (hb-PVS) systems by employing a dithiol and a trialkyne in an A2 + B3 approach. The polymers obtained show excellent solubility in common organic solvents and exhibit high refractive indices (e.g., 1.70 at 589 nm). The combined ease of processability and potential for cross-linking make these materials very interesting for applications, such as coatings for optical devices. The selective mono-addition thiol-yne reaction on DPA serves not only as a synthetic method for the preparation of PVS but could also be applied to the general modification of acetylene-containing materials.

Modular Design of Redox-Responsive Stabilizers for Nanocrystals

Many potent drugs are difficult to administer intravenously due to poor aqueous solubility. A common approach for addressing this issue is to process them into colloidal dispersions known as "nanocrystals" (NCs). However, NCs possess high-energy surfaces that must be stabilized with surfactants to prevent aggregation. An optimal surfactant should have high affinity for the nanocrystal's surface to stabilize it, but may also include a trigger mechanism that could offer the possibility of altering size distribution and uptake of the NC. This study presents a modular and systematic strategy for optimizing the affinity of polymeric stabilizers for drug nanocrystals both before and after oxidation (i.e., the selected trigger), thus allowing for the optimal responsiveness for a given application to be identified. A library of 10 redox-responsive polymer stabilizers was prepared by postpolymerization modification, using the thiol-yne reaction, of two parent block copolymers. The stabilizing potential of these polymers for paclitaxel NCs is presented as well as the influence of oxidation on size and dissolution following exposure to reactive oxygen species (ROS), which are strongly associated with chronic inflammation and cancer. Owing to the versatility of postpolymerization modification, this contribution provides general tools for preparing triggered-sheddable stabilizing coatings for nanoparticles.

Poly(d-glucose carbonate) Block Copolymers: A Platform for Natural Product-Based Nanomaterials with Solvothermatic Characteristics

A natural product-based polymer platform, having the characteristics of being derived from renewable materials and capable of breaking down, ultimately, into natural byproducts, has been prepared through the ring-opening polymerization (ROP) of a glucose-based bicyclic carbonate monomer. ROP was carried out via chain extension of a polyphosphoester (PPE) macroinitiator in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) organocatalyst to afford the PPE-b-poly(D-glucose carbonate) (PDGC) block copolymer. This new copolymer represents a functional architecture that can be rapidly transformed through thiol-yne reactions along the PPE segment into a diverse variety of amphiphilic polymers, which interestingly display stimuli-sensitive phase behavior in the form of a lower critical solution temperature (LCST). Below the LCST, they undergo self-assembly to form spherical core-shell nanostructures that display a poorly defined core-shell morphology. It is expected that hydrophobic patches are exposed within the micellar corona, reminiscent of the surface complexity of proteins, making these materials of interest for triggered and reversible assembly disassembly processes.

Experimental and Theoretical Studies of Selective Thiol–Ene and Thiol–Yne Click Reactions Involving N-Substituted Maleimides

A combination of experimental and computational methods has been used to understand the reactivity and selectivity of orthogonal thiol-ene and thiol-yne ″click″ reactions involving N-allyl maleimide (1) and N-propargyl maleimide (2). Representative thiols methyl-3-mercaptopropionate and β-mercaptoethanol are shown to add exclusively and quantitatively to the electron poor maleimide alkene of 1 and 2 under base (Et3N) initiated thiol-Michael conditions. Subsequent radical-mediated thiol-ene or thiol-yne reactions can be carried out to further functionalize the remaining allyl or propargyl moieties in near quantitative yields (>95%). Selectivity, however, can only be achieved when base-initiated thiol-Michael reactions are carried out first, as radical-mediated reactions between equimolar amounts of thiol and N-substituted maleimides give complex mixtures of products. CBS-QB3 calculations have been used to investigate the energetics and kinetics of reactions between a representative thiol (methyl mercaptan) with N-allyl and N-propargyl maleimide under both base-initiated and radical-mediated conditions. Calculations help elucidate the factors that underlie the selective base-initiated and nonselective radical-mediated thiol-ene/yne reactions. The results provide additional insights into how to design selective radical-mediated thiol-ene/yne reactions.

Thiol-yne Reaction of Alkyne-derivatized Fatty Acids

Thiol-yne Reaction of Alkyne-derivatized Fatty Acids

Thiol-yne click polymerization

The research on using thiol-ene click reaction to synthesize sulfur-containing polymers with topological structures and advanced functional properties is a hot topic. However, the application of the thiol-yne reaction in the functional polymer preparation is limited and the thiol-yne click polymerization is to be further developed. In this review, we summarized recent research efforts on using thiol-yne click polymerization to synthesize polymers with topological structures. The sulfur-containing polymers were facilely prepared by photo-and thermo-initiated, amine-mediated, and transition-metal-catalyzed thiol-yne click polymerizations. These polymers are promising to be used as drug-delivery vehicles, high refractive index optical materials, photovoltaic materials, and biomaterials etc.

Nanoparticles under the Light: Click Functionalization by Photochemical Thiol‐yne Reaction, Towards Double Click Functionalization

A light click away: The first application of the thiol-yne reaction to nanoparticle functionalization is described (see figure). This metal-free click chemistry approach is compatible with the addition of various molecules at the surface and can be combined with CuAAC methodology to perform chemoselective double functionalization.

Coupling reaction with thiols as the efficient method of functionalization of ‘‘clickable” polylactide

The effectiveness of coupling reactions with thiols proceeding under different conditions is compared as the method of polylactide functionalization. Metal-free syntheses of polylactides (PLAs) fitted at one chain end with unsaturated (allyl, propargyl or acrylate) groups were performed by applying acid catalyzed activated monomer polymerization of lactide using allyl and propargyl alcohols or hydroxyethyl acrylate as initiators. Functional PLAs were used for thiol-ene and thiol-yne reactions proceeding according to radical as well as nucleophilic addition. The coupling efficiency for thiols containing carboxyl groups (in comparison with model benzyl thiol) was investigated by MALDI TOF method.

Rapid and versatile construction of diverse and functional nanostructures derived from a polyphosphoester-based biomimetic block copolymer system.

A rapid and efficient approach for the preparation and modification of a versatile class of functional polymer nanoparticles has been developed, for which the entire engineering process from small molecules to polymers to nanoparticles bypasses typical slow and inefficient procedures and rather employs a series of steps that capture fully the "click" chemistry concepts that have greatly facilitated the preparation of complex polymer materials over the past decade. The construction of various nanoparticles with functional complexity from a versatile platform is a challenging aim to provide materials for fundamental studies and also optimization toward a diverse range of applications. In this paper, we demonstrate the rapid and facile preparation of a family of nanoparticles with different surface charges and functionalities based on a biodegradable polyphosphoester block copolymer system. From a retrosynthetic point of view, the nonionic, anionic, cationic, and zwitterionic micelles with hydrodynamic diameters between 13 and 21 nm and great size uniformity were quickly formed by suspending, independently, four amphiphilic diblock polyphosphoesters into water, which were functionalized from the same parental hydrophobic-functional AB diblock polyphosphoester by click-type thiol-yne reactions. The well-defined (PDI < 1.2) hydrophobic-functional AB diblock polyphosphoester was synthesized by an ultrafast (<5 min) organocatalyzed ring-opening polymerization in a two-step, one-pot manner with the quantitative conversions of two kinds of cyclic phospholane monomers. The whole programmable process starting from small molecules to nanoparticles could be completed within 6 h, as the most rapid approach for the anionic and nonionic nanoparticles, although the cationic and zwitterionic nanoparticles required ca. 2 days due to purification by dialysis. The micelles showed high biocompatibility, with even the cationic micelles exhibiting a 6-fold lower cytotoxicity toward RAW 264.7 mouse macrophage cells, as compared to the commercial transfection agent Lipofectamine.

Using hyperbranched oligomer functionalized glass fillers to reduce shrinkage stress

ObjectiveFillers are widely utilized to enhance the mechanical properties of polymer resins. However, polymerization stress has the potential to increase due to the higher elastic modulus achieved upon filler addition. Here, we demonstrate a hyperbranched oligomer functionalized glass filler UV curable resin composite which is able to reduce the shrinkage stress without sacrificing mechanical properties. MethodsA 16-functional alkene-terminated hyperbranched oligomer is synthesized by thiol-acrylate and thiol-yne reactions and the product structure is analyzed by 1H NMR, mass spectroscopy, and gel permeation chromatography. Surface functionalization of the glass filler is measured by thermogravimetric analysis. Reaction kinetics, mechanical properties and shrinkage stress are studied via Fourier transform infrared spectroscopy, dynamic mechanical analysis and a tensometer, respectively. ResultsSilica nanoparticles are functionalized with a flexible 16-functional alkene-terminated hyperbranched oligomer which is synthesized by multistage thiol-ene/yne reactions. 93% of the particle surface was covered by this oligomer and an interfacial layer ranging from 0.7nm to 4.5nm thickness is generated. A composite system with these functionalized silica nanoparticles incorporated into the thiol–yne–methacrylate resin demonstrates 30% reduction of shrinkage stress (from 0.9MPa to 0.6MPa) without sacrificing the modulus (3100±300MPa) or glass transition temperature (62±3°C). Moreover, the shrinkage stress of the composite system builds up at much later stages of the polymerization as compared to the control system. SignificanceDue to the capability of reducing shrinkage stress without sacrificing mechanical properties, this composite system will be a great candidate for dental composite applications.

Preventing Thiol-Yne Addition Improves the Specificity of Strain-Promoted Azide–Alkyne Cycloaddition

The 1,3-dipolar cycloaddition of azides with ring-strained alkynes is one of the few bioorthogonal reactions suitable for specific biomolecule labeling in complex biological systems. Nevertheless, azide-independent labeling of proteins by strained alkynes can occur to a varying extent, thereby limiting the sensitivity of assays based on strain-promoted azide-alkyne cycloaddition (SPAAC). In this study, a subset of three cyclooctynes, dibenzocyclooctyne (DIBO), azadibenzocyclooctyne (DIBAC), and bicyclo[6.1.0]nonyne (BCN), was used to evaluate the azide-independent labeling of proteins in vitro. For all three cyclooctynes, we show that thiol-yne addition with reduced peptidylcysteines is responsible for most of the azide-independent polypeptide labeling. The identity of the reaction product was confirmed by LC-MS and NMR analysis. Moreover, we show that undesired thiol-yne reactions can be prevented by alkylating peptidylcysteine thiols with iodoacetamide (IAM). Since IAM is compatible with SPAAC, a more specific azide-dependent labeling is achieved by preincubating proteins containing reduced cysteines with IAM.

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.

Facile Synthesis of Clickable, Water-soluble and Degradable Polyphosphoesters.

"Click" chemistry is a library of efficient and reliable reactions, which have been used to functionalize various classes of bio- and synthetic macromolecular systems for the incorporation of designed properties and functions. In this report, azide-alkyne Huisgen cycloaddition and thiol-yne reactions, two classical "click" chemistries, were employed to functionalize biodegradable, clickable polyphosphoester homopolymers and their water-soluble copolymers. A stable alkyne-functionalized phospholane monomer was synthesized, its organocatalyzed polymerization kinetics were evaluated, and the resulting (co)polymers were utilized to develop this facile method that provides the synthesis of clickable, water-soluble and degradable polyphosphoesters, which can be adapted for various applications.

Thiol–yne reaction of alkyne-derivatized fatty acids: biobased polyols and cytocompatibility of derived polyurethanes

With the goal of obtaining renewable diols and polyols for polyurethane (PU) technology, the thiol–yne coupling reaction was applied to alkyne-derivatized fatty acids derived from naturally occurring oleic and 10-undecenoic acids. The resulting monomers were then polymerized with 4,4′-methylenebis(phenylisocyanate) to produce the corresponding PUs. The chemical structures and thermal and mechanical properties of the synthesized PUs have been evaluated by FTIR and NMR spectroscopy, DSC, TGA and tensile tests respectively. Moreover, the biocompatibilities of the synthesized PUs with human osteoblast-like cell line (MG63) have also been evaluated for tissue engineering purposes.

Synthesis of multifunctional polymer brush surfaces via sequential and orthogonal thiol-click reactions

Fabrication of multifunctional surfaces with complexity approaching that found in nature requires the application of a modular approach to surface engineering. We describe a versatile post-polymerization modification strategy to synthesize multifunctional polymer brush surfaces via combination of surface-initiated photopolymerization (SIP) and orthogonal thiol-click reactions. Specifically, we demonstrate two routes to multifunctional brush surfaces: in the first approach, alkyne-functionalized homopolymer brushes are modified with multiple thiolsvia a statistical, radical-mediated thiol-yne co-click reaction; and in the second approach, statistical copolymer brushes carrying two distinctly-addressable reactive moieties are sequentially modified via orthogonal base-catalyzed thiol-X (where X represents an isocyanate, epoxy, or α-bromoester) and radical-mediated thiol-yne reactions. In both cases, we show that surface properties, in the form of wettability, can be easily tuned over a wide range by judicious choice of brush composition and thiol functionality.

Thiol-yne Reaction on Boron-Doped Diamond Electrodes: Application for the Electrochemical Detection of DNA–DNA Hybridization Events

Boron-doped diamond (BDD) interfaces were chemically functionalized through the catalyst free thiol-yne reaction. Different thiolated precursors (e.g., perfluorodecanethiol, 6-(ferrocenyl)-hexanethiol, DNA) were successfully "clicked" to alkynyl-terminated BDD by irradiating the interface at 365 nm for 30 min. Thiolated oligonucleotide strands were immobilized using the optimized reaction conditions, and the surface concentration was tuned to obtain a surface coverage of 3.1 × 10(12) molecules cm(-2). Electrochemical impedance spectroscopy (EIS) was employed to follow the kinetics of hybridization and dehybridization events. The sensitivity of the oligonucleotide modified BDD interface was assayed, and a detection limit of 1 nM was obtained.