Metal-free Click Reaction Research Articles

Introducing Carborane Clusters into Crystalline Frameworks via Thiol-Yne Click Chemistry for Energetic Materials.

Crystalline frameworks represent a cutting-edge frontier in material science, and recently, there has been a surge of interest in energetic crystalline frameworks. However, the well-established porosity often leads to diminished output energy, necessitating a novel approach for performance enhancement. Thiol-yne coupling, a versatile metal-free click reaction, has been underutilized in crystalline frameworks. As a proof of concept, we herein demonstrate the potential of this approach by introducing the energy-rich, size-matched, and reductive 1,2-dicarbadodecaborane-1-thiol (CB-SH) into an acetylene-functionalized framework, Zn(AIm)2, via thiol-yne click reaction. This innovative decoration strategy resulted in a remarkable 46.6 % increase in energy density, a six-fold reduction in ignition delay time (4 ms) with red fuming nitric acid as the oxidizer, and impressive enhancement of stability. Density functional theory calculations were employed to elucidate the mechanism by which CB-SH promotes hypergolic ignition. The thiol-yne click modification strategy presented here permits engineering of crystalline frameworks for the design of advanced energetic materials.

Metal-free click and bioorthogonal reactions of aggregation-induced emission probes for lighting up living systems.

In 2002, two transformative research paradigms emerged: 'click chemistry' and 'aggregation-induced emission (AIE),' both leaving significant impacts on early 21st-century academia. Click chemistry, which describes the straightforward and reliable reactions for linking two building blocks, has simplified complex molecular syntheses and functionalization, propelling advancements in polymer, material, and life science. In particular, nontoxic, metal-free click reactions involving abiotic functional groups have matured into bioorthogonal reactions. These are organic ligations capable of selective and efficient operations even in congested living systems, therefore enabling in vitro to in vivo biomolecular labelling. Concurrently, AIE, a fluorogenic phenomenon of twisted π-conjugated compounds upon aggregation, has offered profound insight into solid-state photophysics and promoted the creation of aggregate materials. The inherent fluorogenicity and aggregate-emission properties of AIE luminogens have found extensive application in biological imaging, characterized by their high-contrast and photostable fluorescent signals. As such, the convergence of these two domains to yield efficient labelling with excellent fluorescence images is an anticipated progression in recent life science research. In this review, we intend to showcase the synergetic applications of AIE probes and metal-free click or bioorthogonal reactions, highlighting both the achievements and the unexplored avenues in this promising field.

Thermal and mechanical properties of thiol-ene photocured thermosets containing DOPO-based liquid reactive flame retardant synthesized by metal-free azide-alkyne click reaction

The use of metal-free click reactions for the design and synthesis of novel flame retardant reactive monomers for thiol-ene photopolymerization is an intriguing area of research. In this study, we have prepared a new, 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO)-based, P- and N-containing reactive flame retardant via the metal-free azide-alkyne click reaction. For this purpose, first, azide-functionalized DOPO (DOPO-N3) has been synthesized via Atherton–Todd reaction, and then this compound has been reacted with acetylene dicarboxylic acid diallyl ester (ACDAE) to give the flame retardant monomer, namely DOPO-triazole diallyl ester (DTDAE). As prepared flame retardant monomer was characterized by nuclear magnetic resonance (NMR) and Fourier-transform infrared spectroscopy (FTIR) spectroscopies. Thermoset materials prepared by using DTDAE displayed over 90% gel content values. Polar triazole and phosphorous units rendered the surface of the thermosets hydrophilic. The thermal stability of the networks was enhanced, char yields increased and the glass transition temperatures (Tgs) were increased. The limiting oxygen index (LOI) values of the crosslinked materials increased up to 27.8% as the DTDAE content was increased in the formulations. The synthetic method described in this study provides a practical approach for the synthesis of a P- and N-containing flame retardant through a metal-free azide-alkyne click reaction Also, the fact that DTDAE is in a liquid state makes this study valuable as it indicates that it can be easily dispersed. It is also believed this promising compound can be used in different polymer structures and formulations to develop new flame retardants in future studies to be applied in industrial applications.

Multicomponent encapsulation into fully degradable protein nanocarriers via interfacial azide-alkyne click reaction in miniemulsion allows the co-delivery of immunotherapeutics.

Encapsulation of multiple adjuvants along with antigens into nanocarriers allows a co-delivery to antigen-presenting cells for the synergistic induction of robust immune responses. However, loading cargoes of different molar masses, polarities, and solubilities in high efficiencies remains a challenge. Therefore, we developed a strategy to encapsulate a triple combination of the so-called adjuvants, i.e. with Resiquimod (R848), muramyl dipeptide (MDP) and polyinosinic-polycytidylic acid (Poly(I : C)) into human serum albumin (HSA) nanocarriers. The loading is conducted in situ while the nanocarrier is formed by an orthogonal and metal-free click reaction at the interface of an inverse miniemulsion. By this unique approach, high encapsulation efficiency without harming the cargo during the nanocarrier formation process and regardless of their physical properties is achieved, thus keeping their bioactivity. Furthermore, we demonstrated high control over the encapsulation efficiency and varying the amount of each cargo did not influence the efficiency of multicomponent encapsulation. Azide-modified HSA was crosslinked with hexanediol dipropiolate (HDDP) at the interface of a water-in-oil miniemulsion. Varying the crosslinker amount allowed us to tailor the density and degradation rates of the protein shell. Additional installation of disulfide bonds into the crosslinker created redox-responsive nanocarriers, which degraded both by protease and under reducing conditions with dithiothreitol. The prepared HSA nanocarriers were efficiently taken up by dendritic cells and exhibited an additive cell activation and maturation, exceeding the nanocarriers loaded with only a single drug. This general protocol allows the orthogonal and metal-free encapsulation of various drugs or adjuvants at defined concentrations into the protein nanocarriers.

Metal-free bioorthogonal click chemistry in cancer theranostics.

Bioorthogonal chemistry is a powerful tool to site-specifically activate drugs in living systems. Bioorthogonal reactions between a pair of biologically reactive groups can rapidly and specifically take place in a mild physiological milieu without perturbing inherent biochemical processes. Attributed to their high selectivity and efficiency, bioorthogonal reactions can significantly decrease background signals in bioimaging. Compared with metal-catalyzed bioorthogonal click reactions, metal-free click reactions are more biocompatible without the metal catalyst-induced cytotoxicity. Although a great number of bioorthogonal chemistry-based strategies have been reported for cancer theranostics, a comprehensive review is scarce to highlight the advantages of these strategies. In this review, recent progress in cancer theranostics guided by metal-free bioorthogonal click chemistry will be depicted in detail. The elaborate design as well as the advantages of bioorthogonal chemistry in tumor theranostics are summarized and future prospects in this emerging field are emphasized.

Mechanistic investigation of enolate/stabilized vinylogous carbanion-mediated organocatalytic azide (3 + 2) cycloaddition reactions for the synthesis of 1,2,3-triazoles.

Herein, we report a fully detailed mechanistic study involving an organocatalyzed 1,3-dipolar cycloaddition via enolate or stabilized vinylogous carbanion intermediates and azide for the synthesis of 1,2,3-triazoles. A detailed investigation of the elementary steps, intermediates, and transition states of the two organocatalyzed metal-free click reactions is supported by DFT calculations and 1H NMR monitoring experiments, providing detailed profiles for both reaction mechanisms. Distortion-interaction activation-strain (DIAS) analysis was also employed to further elucidate the regioselectivity in both reactions.

Molecularly Engineered Aptamers Targeting Tumor Tissue and Cancer Cells for Efficient in Vivo Recognition and Enrichment

Molecularly Engineered Aptamers Targeting Tumor Tissue and Cancer Cells for Efficient in Vivo Recognition and Enrichment

All in one: The preparation of polyester/silica hybrid nanocomposites via three different metal-free click reactions

The development of innovative routes for the preparation of hybrid polymer nanocomposites is an active area of research for engineering applications. In this study, we have utilized three different click chemistry reactions; aza-Michael, thiol-Michael, and metal-free azide-alkyne cycloaddition reactions, and prepared hybrid nanocomposites through the reactions between electron-deficient alkyne-containing polyester and modified silica nanoparticles bearing either azide, thiol, or amine groups. The modification of the silica nanoparticles was characterized by Fourier transform infrared spectroscopy and thermogravimetric analysis. The formation of the hybrid nanocomposites was verified by measuring their gel contents. The mechanical, thermal, and optical properties of the hybrid nanocomposites were also determined. The gel content of the prepared hybrid nanocomposites reached almost 88%. Modified silica nanoparticles showed a much uniform dispersion in the polymer matrix when compared to neat silica nanoparticles. A dramatic increase both in modulus and Tg values was observed for the hybrid nanocomposites.

Fucosylated ubiquitin and orthogonally glycosylated mutant A28C: conceptually new ligands for Burkholderia ambifaria lectin (BambL).

Two orthogonal, metal free click reactions, enabled to glycosylate ubiquitin and its mutant A28C forming two protein scaffolds with high affinity for BambL, a lectin from the human pathogen Burkholderia ambifaria. A new fucoside analogue, with high affinity with BambL, firstly synthetized and co-crystallized with the protein target, provided the insights for sugar determinants grafting onto ubiquitin. Three ubiquitin-based glycosides were thus assembled. Fuc-Ub, presented several copies of the fucoside analogue, with proper geometry for multivalent effect; Rha-A28C, displayed one thio-rhamnose, known for its ability to tuning the immunological response; finally, Fuc-Rha-A28C, included both multiple fucoside analogs and the rhamnose residue. Fuc-Ub and Fuc-Rha-A28C ligands proved high affinity for BambL and unprecedented immune modulatory properties towards macrophages activation.

Facile fabrication of thermosensitive hydrogel microspheres based on a combination of metal-free click chemistry and spray drying

The preparation of hydrogel microspheres continues to be a hot research topic in materials science. In this study, thermosensitive hydrogel microspheres were fabricated by green, one-step spray drying, in which crosslinking points were formed in situ via a metal-free 1,3-dipolar cycloaddition click reaction. First, terpolymers were synthesized by the free radical copolymerization of hydroxyethyl methacrylate, N-isopropyl acrylamide, and N,N-dimethylacrylamide in a solution of 1,4-dioxane with 2,2-azobis(2-methylpropionitrile) as an initiator. Second, polymeric dipoles and polymeric dipolarophiles were prepared by modifying the as-prepared terpolymers with azidoacetic acid and N-maleoyl alanine, respectively. Finally, the hydrogel microspheres were produced by spray drying after dissolving polymeric dipoles and polymeric dipolarophiles in water under optimized conditions, such as solution concentration, inlet temperature, and feeding speed. Swelling experiments indicated that the hydrogel microspheres possess thermosensitivity, in that their swelling ratios decreased with an increase in temperature and their response to temperature was reversible and repeatable. The strategy described here holds great promise for the preparation of hydrogel microspheres since spray drying is an established industrial process with rapid, cost-effective, continuous features, and the in situ formation of crosslinking points was based on the metal-free click reaction without the involvement of organic solvents or catalyzers.

Bio-orthogonal AIE Dots Based on Polyyne-Bridged Red-emissive AIEgen for Tumor Metabolic Labeling and Targeted Imaging.

In this work, we aim to develop cancer cell-targeting AIE dots based on a polyyne-bridged red-emissive AIEgen, 2TPE-4E, through the combination of metabolic engineering and bio-orthogonal reactions. Azide groups on a tumor were efficiently produced by intravenous injection of Ac4ManNAz and glycol-metabolic engineering. These bio-orthogonal azide groups could facilitate the specific targeting of DBCO-AIE dots to the tumor cells undergoing metal-free click reaction in vivo. The efficiency of this targeting strategy could be further improved with the development of new bio-orthogonal chemical groups with higher reactivity and a large amount of AIEgens could be delivered to the tumor for diagnosis.

Ultrathin Covalently Bound Organic Layers on Mica: Formation of Atomically Flat Biofunctionalizable Surfaces.

Mica is the substrate of choice for microscopic visualization of a wide variety of intricate nanostructures. Unfortunately, the lack of a facile strategy for its modification has prevented the on‐mica assembly of nanostructures. Herein, we disclose a convenient catechol‐based linker that enables various surface‐bound metal‐free click reactions, and an easy modification of mica with DNA nanostructures and a horseradish peroxidase mimicking hemin/G‐quadruplex DNAzyme.

External electric field control: driving the reactivity of metal-free azide-alkyne click reactions.

Recent reports have suggested that an external electric field (EEF) can assist and even control product selectivity. In this work, we have shown that the barrier for the Huisgen reaction between alkyl (aryl) azide and cyclooctyne(biflurocyclooctyne) is reduced by ∼3-4 kcal mol-1 when an oriented EEF is applied along the reaction axis. As a consequence of their inherently polar transition-states (TSs), a parallel orientation of the EEF results in enhancement of the charge transfer (CT) between the fragments and concomitant increase in the dipole moment along the reaction axes. This leads to an increase in the reaction rate for moderate EEFs in the range of 0.3-0.5 V Å-1. Since highly polar and directional environments are omnipresent in biological environments, metal-free click reactions can be further accelerated for non-invasive imaging of live-cells. Conceptually, electric field control appears to be a novel tool (catalyst) to drive, and possibly even tune, the reactivity of organic molecules.

Preparation of Lanthanide-Polymer Composite Material via Click Chemistry.

Covalently attaching lanthanide complexes to the polymer backbone can effectively reduce the clustering of lanthanides and thus become an important strategy to fully unleash their potential. In this Communication, a metal-free click reaction is used for the first time to link a lanthanide complex to the polymer matrix. A diene-bearing copolymer with anthracenylmethyl methacrylate as a monomer and a dienophile-bearing lanthanide complex with 5-maleimido-1,10-phenanthroline as the second ligand are synthesized and coupled together through a Diels-Alder cycloaddition (DA). A comparative investigation demonstrates that the composite material prepared by DA click reaction shows the highest quantum yields in the same lanthanide concentration as compared to materials prepared by widely used "directly doping" and "in situ coordinating lanthanide ions with macromolecular ligand" approaches. This work suggests that the "metal-free" DA click reaction can be a promising tool in the synthesis of high efficient lanthanide functionalized polymeric materials.

Cytocompatible in situ forming chitosan/hyaluronan hydrogels via a metal-free click chemistry for soft tissue engineering

Injectable hydrogels are important cell scaffolding materials for tissue engineering and regenerative medicine. Here, we report a new class of biocompatible and biodegradable polysaccharide hydrogels derived from chitosan and hyaluronan via a metal-free click chemistry, without the addition of copper catalyst. For the metal-free click reaction, chitosan and hyaluronan were modified with oxanorbornadiene (OB) and 11-azido-3,6,9-trioxaundecan-1-amine (AA), respectively. The gelation is attributed to the triazole ring formation between OB and azido groups of polysaccharide derivatives. The molecular structures were verified by FT–IR spectroscopy and elemental analysis, giving substitution degrees of 58% and 47% for chitosan-OB and hyaluronan-AA, respectively. The in vitro gelation, morphologies, equilibrium swelling, compressive modulus and degradation of the composite hydrogels were examined. The potential of the metal-free hydrogel as a cell scaffold was demonstrated by encapsulation of human adipose-derived stem cells (ASCs) within the gel matrix in vitro. Cell culture showed that this metal-free hydrogel could support survival and proliferation of ASCs. A preliminary in vivo study demonstrated the usefulness of the hydrogel as an injectable scaffold for adipose tissue engineering. These characteristics provide a potential opportunity to use the metal-free click chemistry in preparation of biocompatible hydrogels for soft tissue engineering applications.

Amphiphilic thermoset elastomers from metal-free, click crosslinking of PEG-grafted silicone surfactants

The hydrophobicity of silicone elastomers can compromise their utility in some biomaterials applications. Few effective processes exist to introduce hydrophilic groups onto a polysiloxane backbone and subsequently crosslink the material into elastomers. This problem can be overcome through the utilization of metal-free click reactions between azidoalkylsilicones and alkynyl-modified silicones and/or PEGs to both functionalize and crosslink silicone elastomers. Alkynyl-functional PEG was clicked onto a fraction of the available azido groups of a functional polysiloxane, yielding azido reactive PDMS-g-PEG rake surfactants. The reactive polymers were then used to crosslink alkynyl-terminated PDMS of different molecular weights. Using simple starting materials, this generic yet versatile method permits the preparation and characterization of a library of amphiphilic thermoset elastomers that vary in their composition, crosslink density, elasticity, hydrogel formation, and wettability. An appropriate balance of PEG length and crosslink density leads to a permanently highly wettable silicone elastomer that demonstrated very low levels of protein adsorption. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 1082–1093

Synthesis and selective recognition toward zinc ion of chiral poly(imine-triazole)

A novel AB type of clickable monomer, (S)-2-[(2-azido-1-phenylethylimino)methyl]-5-propargyloxyphenol (AMPP) was designed and polymerized to yield a class of main-chain chiral poly(imine-triazole)s through the metal-free click reaction. With the thermally induced polymerization, the desired polytriazoles can be easily prepared in high yields by a stepwise heating-up process and have the number-average molecular masses ranging from 5.1 × 103 to 58.1 × 103 (polydispersity indices = 1.38−1.68). The polymers were characterized by Fourier Transform Infrared spectroscopy (FTIR), 1H Nuclear Magnetic Resonance (NMR), and gel permeation chromatography, and their optical properties were studied by fluorescence and circular dichroism (CD) spectroscopies. As a chemosensor, these polymers exhibited a selective “turn-on” fluorescence enhancement response toward Zn2+ ion over other cations such as Na+, K+, Mg2+, Ca2+, Ag+, Pb2+, Cd2+, Hg2+, Mn2+, and Ni2+ in dimethyl sulfoxide. However, the Zn2+-induced fluorescence signal was subject to serious interference by Al3+, Cu2+, Cr3+, and Fe3+ ions. Interestingly, the chiral polymer showed distinctive changes in the CD spectra on complexation with Zn2+, which allowed for the discrimination of this ion in the presence of other species tested including those interfering ions observed in the fluorescent detection. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2248–2257

Synthesis and Characterization of a Novel Linear Benzoxazine-Containing Polytriazole via Metal-Free Click Reaction and its Self-Crosslinking Behavior

A novel linear benzoxazine-containing polytriazole was successfully synthesized via metal-free click reaction. Benefited from the advantages of click reaction, the synthesis procedure was easily and efficiently. The linear polymer could be transformed into crosslinked structure after ring-opening polymerization of oxazine induced by the increasing temperature. The FT-IR characterization verified the structure transformation between linear and crosslinked polymer. Moreover, the thermal properties and thermal degradation behaviors of linear polymer and the corresponding crosslinked polymer were studied by DSC and TGA. The novel polytriazole was proved to be a kind of thermal stable polymers with high thermal decomposition temperature (Td5over 300°C).

Copper-Free Click Biofunctionalization of Silicon Nitride Surfaces via Strain-Promoted Alkyne–Azide Cycloaddition Reactions

Cu-free "click" chemistry is explored on silicon nitride (Si(3)N(4)) surfaces as an effective way for oriented immobilization of biomolecules. An ω-unsaturated ester was grafted onto Si(3)N(4) using UV irradiation. Hydrolysis followed by carbodiimide-mediated activation yielded surface-bound active succinimidyl and pentafluorophenyl ester groups. These reactive surfaces were employed for the attachment of bicyclononyne with an amine spacer, which subsequently enabled room temperature strain-promoted azide-alkyne cycloaddition (SPAAC). This stepwise approach was characterized by means of static water contact angle, X-ray photoelectron spectroscopy, and fluorescence microscopy. The surface-bound SPAAC reaction was studied with both a fluorine-tagged azide and an azide-linked lactose, yielding hydrophobic and bioactive surfaces for which the presence of trace amounts of Cu ions would have been problematic. Additionally, patterning of the Si(3)N(4) surface using this metal-free click reaction with a fluorescent azide is shown. These results demonstrate the ability of the SPAAC as a generic tool for anchoring complex molecules onto a surface under extremely mild, namely ambient and metal-free, conditions in a clean and relatively fast manner.

Generic, Metal-Free Cross-Linking and Modification of Silicone Elastomers Using Click Ligation

Silicone elastomers are widely used in a variety of biomaterials applications. Their high hydrophobicity can, in some cases, compromise their utility. There exist few convenient, efficient and metal-free processes to introduce hydrophilic groups onto the elastomer surface. We describe the utilization of the metal-free click reaction between azido- and alkynyl-modified silicones to both cross-link and functionalize silicone elastomers. Initial cross-linking at, optionally, reduced or elevated temperatures depending on the alkyne used, results in elastomers whose moduli and tackiness can be controlled by manipulation of cross-link density through use of different chain length constituents: the systematic capping of azides on the azide-rich partner provides a level of control of both cross-linking and residual functionality after cross-linking. The residual azides or alkynes resulting from nonstoichiometric mixing of the starting materials can be used for sequential functionalization of the elastomer as shown through the improved wettability that results from the grafting of alkyne-functional PEG to azide-rich silicone elastomers: contact angles decrease from ∼105° for the pure silicone elastomers to 85° for the azide-rich silicone elastomer, and to as low as 41° for the PEG-modified product. It is possible to modify the entire elastomer body or only the surface by judicious choice of the solvent used for the hydrophilic modification.