Click Coupling Reaction Research Articles

Cinnamyl-Modified Polyglycidol/Poly(ε-Caprolactone) Block Copolymer Nanocarriers for Enhanced Encapsulation and Prolonged Release of Cannabidiol.

The present study describes the development of novel block copolymer nanocarriers of the phytocannabinoid cannabidiol (CBD), designed to enhance the solubility of the drug in water while achieving high encapsulation efficiency and prolonged drug release. Firstly, a well-defined amphiphilic block copolymer consisting of two outer hydrophilic polyglycidol (PG) blocks and a middle hydrophobic block of poly(ε-caprolactone) bearing pendant cinnamyl moieties (P(CyCL-co-CL)) were synthesized by the click coupling reaction of PG-monoalkyne and P(CyCL-co-CL)-diazide functional macroreagents. A non-modified polyglycidol/poly(ε-caprolactone) amphiphilic block copolymer was obtained as a referent system. Micellar carriers based on the two block copolymers were formed via the solvent evaporation method and loaded with CBD following two different protocols-loading during micelle formation and loading into preformed micelles. The key parameters/characteristics of blank and CBD-loaded micelles such as size, size distribution, zeta potential, molar mass, critical micelle concentration, morphology, and encapsulation efficiency were determined by using dynamic and static multiangle and electrophoretic light scattering, transmission electron microscopy, and atomic force microscopy. Embedding CBD into the micellar carriers affected their hydrodynamic radii to some extent, while the spherical morphology of particles was not changed. The nanoformulation based on the copolymer bearing cinnamyl moieties possessed significantly higher encapsulation efficiency and a slower rate of drug release than the non-modified copolymer. The comparative assessment of the antiproliferative effect of micellar CBD vs. the free drug against the acute myeloid leukemia-derived HL-60 cell line and Sezary Syndrome HUT-78 demonstrated that the newly developed systems have pronounced antitumor activity.

From speciation study to removal of Pb2+ from natural waters by a carnosine-based polyacrylamide/azlactone copolymer

A deep speciation study on L-carnosine (CAR) and Pb2+ system was performed in aqueous solution with the aim to assess its potential use as a sequestering agent of metal cation. To determine the best conditions for Pb2+ complexation, potentiometric measurements were carried out over a wide range of ionic strength (0.15 ≤ I/≤ 1 mol/L) and temperature (15 ≤ T/°C ≤ 37), and thermodynamic interaction parameters (logβ, ΔH, ΔG and TΔS) were determined. The speciation studies allowed us to simulate sequestration ability of CAR toward Pb2+ under different conditions of pH, ionic strength and temperature and to establish a priori the conditions for the best removal performance, i.e., pH > 7 and I = 001 mol/L. This preliminary investigation was very useful in optimizing removal procedures and limiting subsequent experimental measurements for adsorption tests. Therefore, to exploit the binding ability of CAR for Pb2+ removal from aqueous solutions, CAR was covalently grafted on an azlactone-activated beaded-polyacrylamide resin (AZ) using an efficient click coupling reaction (78.3% of coupling efficiency). The carnosine-based resin (AZCAR) was analyzed by ThermoGravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC) and Differential Thermal Analysis (DTA). Morphology, surface area and pore size distribution were studied through a combination of Scanning Electron Microscope (SEM) and adsorption/desorption of N2 analyses according to the Brunauer-Emmett-Teller (BET) and Barret-Johner-Halenda (BJH) approaches. The adsorption capacity of AZCAR toward Pb2+ was investigated under conditions simulating the ionic strength and pH of different natural waters. The time needed to reach equilibrium in the adsorption process was 24 h, and the best performance was obtained at pH > 7, typical of most natural waters, with removal efficiency ranging from 90.8% (at I = 0.7 mol/L) to 99.0 (at I = 0.001 mol/L).

Direct mechanocatalysis by resonant acoustic mixing (RAM).

We demonstrate the use of a metal surface to directly catalyse copper-catalysed alkyne-azide click-coupling (CuAAC) reactions under the conditions of Resonant Acoustic Mixing (RAM) - a recently introduced and scalable mechanochemical methodology that uniquely eliminates the need for bulk solvent, as well as milling media. By using a simple copper coil as a catalyst, this work shows that direct mechanocatalysis can occur in an impact-free environment, relying solely on high-speed mixing of reagents against a metal surface, without the need for specially designed milling containers and media. By introducing an experimental setup that enables real-time Raman spectroscopy monitoring of RAM processes, we demonstrate 0th-order reaction kinetics for several selected CuAAC reactions, supporting surface-based catalysis. The herein presented RAM-based direct mechanocatalysis methodology is simple, enables the effective one-pot, two-step synthesis of triazoles via a combination of benzyl azide formation and CuAAC reactions on a wide scope of reagents, provides control over reaction stoichiometry that is herein shown to be superior to that seen in solution or by using more conventional CuCl catalyst, and is applied for simple gram-scale synthesis of the anticonvulsant drug Rufinamide.

Preparation of pH-responsive solanesol-based poly (glutamic acid) micellar carrier for doxorubicin delivery

This study focuses on the development of a new preparation method of solanesol derivatives for their effective use as drug carriers. The current preparation methods for solanesol derivatives generally suffer from poor accessibility and low yields of the target products, which affect the further development of their products. To address this issue, a solanesol-based poly (glutamic acid) (Sol-PEG-PGA) was first designed on the basis of the click reaction between alkynyl-functionalized solanesol and amino-polyethylene glycol (PEG)-azide, followed by a coupling reaction with poly (glutamic acid). The introduced polyethylene glycol and poly (glutamic acid) conferred amphipathic properties on solanesol. Sol-PEG-PGA possessed a suitable lipid-water partition coefficient of 1.01 and water contact angle of 55° and could self-assemble into spherical micelles with an average diameter of 74.0 ± 3.5 nm to load doxorubicin (DOX) via hydrophobic interaction, with a loading capacity of 27.7 ± 1.2%. Besides, Sol-PEG-PGA micelle exhibited excellent stability before and after loading DOX under the dilution of 1000 times and could be stored stably at room temperature for 15 days. The DOX loaded into Sol-PEG-PGA could be released by acid induction, with a cumulative release of 84.8 ± 2.5% at pH 5.0. Furthermore, in vitro cytotoxicity assay, the normal cells NIH/3T3 treated with Sol-PEG-PGA maintained relatively high viability of 95.0% compared to that of free DOX at 320 µg/mL, verifying its good biocompatibility. The DOX loaded into Sol-PEG-PGA possessed a high-efficiency anticancer activity compared to free DOX, with an inhibition rate of 99.2 ± 1.6% against tumor cells 4T1, suggesting the potentials of Sol-PEG-PGA for drug delivery applications. This new preparation method is expected to provide a new strategy for constructing various functional carriers from solanesol derivatives. • A novel pH-responsive solanesol-based poly (glutamic acid) micellar carrier was synthesized based on click reaction and coupling reaction. • Solanesol-based poly (glutamic acid) (Sol-PEG-PGA) micellar carrier achieved enhanced DOX-loading capacity of 27.7 ±1.2%. • DOX loaded into Sol-PEG-PGA micelle can exert more effective inhibition on tumor 4T1 cells. • A new strategy is provided for the construction of various functional solanesol derivatives.

Synthesis of N-Fused Triazole-Piperazine-Quinazolinones via One-Pot Tandem Click Reaction and Cross-Dehydrogenative Coupling.

Herein, a one-pot protocol to synthesize tetracyclic triazole-piperazine-quinazolinone-fused N-heterocyclic scaffolds is reported. In this strategy, a tandem approach of two highly efficient synthetic reactions, click and cross-dehydrogentive coupling reactions, with high atom economy were employed to obtain the target N-fused scaffolds. Being highly functional group tolerable, this method has broad substrate scope. Interestingly, some of these derivatives showed strong white solid-state fluorescence.

Chemoadaptive Polymeric Assemblies by Integrated Chemical Feedback in Self-Assembled Synthetic Protocells.

The design and chemical synthesis of artificial material objects which can mimic the functions of living cells is an important ongoing scientific endeavor. A key challenge necessary for fulfilling the criteria for a system to be living currently regards evolution, which is derived from adaptivity. Integrated chemical loops capable of feedback control are required to achieve chemical systems which exhibit adaptivity. To explore this, we present an integrated, two-component orthogonal chemical process involving reversible addition–fragmentation chain transfer (RAFT) based polymerization-induced self-assembly (PISA) and a copper-catalyzed azide–alkyne click (CuAAC) coupling reaction. The chemical processes are linked through electron transfer from the activated chain-transfer agent (CTA) to the dormant Cu(II) precatalyst. We show that combining these complementary chemistries in a single reaction pot resulted in two primary outcomes: (i) simplification of the PISA process to synthesize the macro-CTA in situ from available nonamphiphilic components and (ii) routes to complexity and adaptation involving population dynamics, morphologies, and dissipative phenomena observed during in situ microscopy analysis.

Assembly of amphiphilic nucleic acid-polymer conjugates into complex superaggregates: Preparation, properties, and in vitro performance

Nucleic acid-polymer conjugates (NAPCs) are obtained by click coupling reactions of appropriately functionalized oligonucleotides with synthetic polymer chains of different chemical nature, composition, and properties, namely, polyethers such as poly(ethoxyethyl glycidyl ether) and polyesters such as poly(ε-caprolactone). The resulting NAPCs are amphiphilic and form stable aggregates in aqueous solution. The aggregates are thoroughly investigated by a variety of techniques – static, dynamic, and electrophoretic light scattering, transmission electron microscopy, and atomic force microscopy. The size and molar masses of the particles as well as other parameters such as aggregation number and number of oligonucleotide strands per particle are significantly larger than those, reported for metal-free spherical nucleic acids. Formation of superaggregates of smaller individual micelles or non-micellar assemblies by hydrophobic interactions between the synthetic polymer chains and “sticky” interactions between oligonucleotides such as base pairing, π-stacking, hydrogen bonding is anticipated. The “sticky” interactions are counterbalanced by repulsion between the negatively charged oligonucleotide strands thus providing colloidal stability of the structures. The surface density of the oligonucleotide strands in the shell implies that the latter are in a random coil (mushroom) conformation rather than in a fully extended, brush regime. The hallmark properties of the prototypical spherical nucleic acids – non-toxicity and biocompatibility, increased cellular uptake without the need of transfection agents, enhanced nuclease stability – are also exhibited by the novel constructs despite of the differences in size, morphology, and structure.

Synthesis of an amphiphilic spiro‐multiblock copolymer via thiol‐ene click chemistry

ABSTRACTA multiblock [poly(ethylene oxide)‐b‐spiro‐polystyrene] ([(PEO‐b‐spiro‐PS)]) copolymer with a topologically novel architecture was synthesized using thiol‐ene step‐growth polymerization reaction. Spiro‐PS with dimercapto groups as the hard segment was synthesized in three main steps: (a) preparation of tetra‐arm PS by atom transfer radical polymerization and the conversion of the chain‐end group to azide functionality, (b) alkyne‐azide click coupling reaction to synthesize a tricyclic PS, and (c) tactical ring opening of the tricyclic PS through disulfide/thiol redox reaction. The PEO soft segment was obtained as chain‐ends modified with norbornene groups. Finally, the hydrothiolation of the highly reactive norbornene chain‐ends of polyethylene glycol with the dimercapto groups of spiro‐PS produced the multiblock ([(PEO‐b‐spiro‐PS)]) copolymer in quantitative yield. The multiblock copolymer was characterized using size‐exclusion chromatography, proton nuclear magnetic resonance spectroscopy, Fourier‐transform infrared spectroscopy, X‐ray photoelectron spectroscopy, and Raman spectroscopy. © 2019 Wiley Periodicals, Inc. J. Polym. Sci. 2020, 58, 132–138

Modification of Supramolecular Membranes with 3D Hydrophilic Slide-Rings for the Improvement of Antifouling Properties and Effective Separation.

A three-dimensional (3D) strategy for the fabrication of ethylene vinyl alcohol (EVAL) membranes with a dynamic surface was developed based on sliding supramolecular polymer brushes (SSPBs). The SSPBs with a 3D hydrophilic structure were introduced into the alkyne-EVAL membrane matrix via an azide-alkyne click coupling reaction. The self-mobile hydrophilic slide-rings in the SSPB provided a proactive exclusion system. This resulted in reduced direct contact of the membrane surface with multiple pollutants such as bovine serum albumin (BSA) and oil droplets. The EVAL-SSPB membrane demonstrated increased surface hydrophilicity, underwater oleophobicity, and antifouling properties. More importantly, the abundant hydrophilic rings in the membrane matrix result in supramolecular assembly and efficient hydrophilic sliding channels. This resulted in a dramatic increase in the water flux [2000 L/(m2 h)] while retaining a 96% rejection of BSA and oil/water emulsions. The results of the study indicate that three effects of the cyclodextrins rings, i.e., the hydrophilic effect, the exclusion effect, and the sliding effect, enabled the improved membrane performance. The demonstrated 3D fabrication strategy is versatile, facile, and scalable, which allows for its application to various other membranes. The fabricated materials possess excellent permeability and separation efficiencies, which make them attractive candidates for use as separation membranes with novel functions.

Click Coupling Reactions on Flat and Nanostructured Hydrogen‐Passivated Silicon Surfaces

Dialkynes are grafted onto hydrogen‐passivated silicon wafers, porous silicon, and silicon nanowires via thermally induced hydrosilylation followed by surface functionalization via azide alkyne cycloaddition. The surfaces are characterized with Fourier transform infrared spectroscopy (FTIR) and electrochemical measurements that indicate a correlation between the quality of the organic layer and the morphology of the substrate. After the initial hydrosilylation reaction, the amount of accessible surface bonded alkynes is observed to be substantially lower on porous, irregular surfaces compared to flat wafers and well‐defined vertically aligned silicon nanowire arrays, thus precluding an effective subsequent azide‐alkyne cycloaddition on porous silicon.

Functionalization of Bambusurils by a Thiol–Ene Click Reaction and a Facile Method for the Preparation of Anion‐Free Bambus[6]urils

Sulfide-functionalized bambus[4]urils ((RS)8 BU[4]) and bambus[6]urils ((RS)12 BU[6]) were synthesized through thiol-ene click coupling reactions (TEC) of allylbambus[n]urils. Thiosugars were grafted to BU[4] and BU[6]. Synthesis of BU[6] derivatives always requires the use of a template anion (iodide, chloride, or bromide), which is enclosed in the cavity of BU[6]. We show that this anion influences the reactivity of bambus[6]urils. An encapsulated iodide makes allyl functions of allyl12 BU[6] less reactive towards TEC and hydrogenation reactions in comparison to the corresponding chloride or bromide inclusion complexes. This is critical for the chemical reactivity of BU[6] and even more to determine their anion-binding properties. We report a new, facile and fast method using AgSbF6 to prepare anion-free BU[6]. NMR spectroscopic methods were used to estimate association constants of these new empty BU[6] with different anions. Quantum chemical calculations were employed to rationalize the observed results. These new functionalized bambusuril scaffolds in alternate conformations could find applications as multivalent binders.

Exclusive Synthesis of Poly(3-hexylthiophene) with an Ethynyl Group at Only One End for Effective Block Copolymerization.

Well-controlled synthesis of ethynyl-functionalized poly(3-hexylthiophene) (P3HT) is crucial for preparation of block copolymers containing the P3HT segment by means of click coupling reaction. A well-known chain end modification method, in which Kumada-Tamao catalyst-transfer polymerization is quenched with ethynylmagnesium chloride, under various conditions is re-examined, but in all cases not only P3HT with an ethynyl group at one end but also P3HT di-ethynylated at both ends is obtained. Accordingly, Sonogashira coupling reaction of P3HT having H/Br ends with trimethylsilylacetylene is tried, followed by removal of the trimethylsilyl group, and it is found that this protocol affords exclusively P3HT with an ethynyl group at one end. This post end-modification method is applied to the synthesis of an amphiphilic diblock copolymer of P3HT and poly(2-ethyl-2-oxazoline) (PEtOx) by means of click reaction between ethynylated P3HT and PEtOx with an azide group at one end, and the product is confirmed to be free from contamination with triblock copolymer. Micellization of this block copolymer is confirmed in tetrahydrofuran (THF)/water and THF/methanol mixtures.

Synthesis of new triazole based imidazo[1,2-a]pyrazine-benzimidazole conjugates: H-bonding assisted FRET efficient ratiometric detection of pyrophosphate

Abstract Triazole tethered imidazo[1,2- a ]pyrazine-benzimidazole conjugates 13-38 has been synthesized by click and Suzuki-Miyaura cross coupling reactions at C-8 and C-6 positions, respectively. The research findings clearly predicted that by modification of electronic structure of the receptor, the sensitivity of the recognition process could be modified. Compound 24 with hydroxyphenyl substituent, showed stronger binding to the pyrophosphate than other compounds. Compound 24 has been used as selective probe for ratiometric detection of pyrophosphate amongst the other anions. The binding event of compound 24 toward PPi has been successfully evaluated by absorption and emission spectroscopy as well as NMR titration method. The compound 24 showed H-bonding assisted facilitation of FRET phenomenon in the presence of PPi.

Synthesis and Characterization of Multiwalled Carbon Nanotubes/Poly(HEMA-co-MMA) by Utilizing Click Chemistry.

The hybrid material consisting of multi walled carbon nanotubes (MWNTs) and poly(2-hydroxyethylmethacrylate-co-methylmethacrylate) [poly(HEMA-co-MMA)] was synthesized by a combination of RAFT and Click chemistry. In the primary stage, the copolymer poly(HEMA-co-MMA) was prepared by applying RAFT technique. Alkynyl side groups were incorporated onto the poly(HEMA-co-MMA) backbone by esterification reaction. Then, MWNTs-N3 was prepared by treating MWNTs with 4-azidobutylamine. The click coupling reaction between azide-functionalized MWNTs (MWNTs-N3) and the alkyne-functionalized random copolymer ((HEMA-co-MMA)-Alkyne) with the Cu(I)-catalyzed [3+2] Huisgen cycloaddition afforded the hybrid compound. The structure and properties of poly(MMA-co-HEMA)-g-MWNTs were investigated by FT-IR, EDX and TGA measurements. The copolymer brushes were observed to be immobilized onto the functionalized MWNTs by SEM and TEM analysis.

Nanoporous poly(3-hexylthiophene) thin films based on “click” prepared degradable diblock copolymers

A facile approach to control the nanostructured organization of conjugated polymer platforms is proposed, based on the synthesis and characterization of copolymers containing a cleavable group inside the chain. This is illustrated by copolymerization of electroconjugated units representing regioregular poly(3-hexylthiophene) obtained by Grignard metathesis polymerization with a terminal alkynyl group and a sacrificial unit of poly(ethylene oxide) with a functionalized end azide group. The diblock copolymers were successfully synthesized via a click coupling reaction between blocks, where an acid degradable acetal group was incorporated. The strategy for formation of thin porous poly(3-hexylthiophene) films includes acid treatment of diblock copolymers, accompanied by the degradation of the acetal linker and easy removal of the poly(ethylene oxide) block. The study displays an appropriate strategy to convert nanoporous poly(3-hexylthiophene) thin films into suitable high surface area matrices, which, after successful filling with electron acceptor material, could create novel nanostructures for organic photovoltaics.

The use of azide–alkyne click chemistry in recent syntheses and applications of polytriazole-based nanostructured polymers

The rapid development of efficient organic click coupling reactions has significantly facilitated the construction of synthetic polymers with sophisticated branched nanostructures. This Feature Article summarizes the recent progress in the application of efficient copper-catalyzed and copper-free azide-alkyne cycloaddition (CuAAC and CuFAAC) reactions in the syntheses of dendrimers, hyperbranched polymers, star polymers, graft polymers, molecular brushes, and cyclic graft polymers. Literature reports on the interesting properties and functions of these polytriazole-based nanostructured polymers are also discussed to illustrate their potential applications as self-healing polymers, adhesives, polymer catalysts, opto-electronic polymer materials and polymer carriers for drug and imaging molecules.

Chelating magnetic copolymer composite modified by click reaction for removal of heavy metal ions from aqueous solution

Novel chelating magnetic copolymer beads in micron-size range were prepared by suspension polymerization and click reaction. The click chemistry was proposed as a tool for tuning the surface functionality of magnetic poly(vinylbenzyl chloride-co-styrene-co-divinyl benzene), M-PVBC, by a covalent attachment with propargyl alcohol via triazole formation. After click-coupling reaction, the changes in surface morphology and chemical functionality were examined by SEM–EDX and FT-IR, respectively. Adsorption characteristics for heavy metal were investigated by a batch adsorption in an aqueous system under different experimental conditions. The adsorption process was pH, concentration and time dependent. The maximum adsorption capacities of the chelating magnetic copolymer, M10-PVBC-C, for Zn(II), Cu(II) and Ni(II) in 500ppm solutions were 67.29, 61.20 and 57.18mg/g, respectively. Adsorption of Cu(II) ion, the model heavy metal ion, was well fitted to the Langmuir isotherm model. The magnetic chelating beads could be rapidly recovered from aqueous solution by an external magnetic field, regenerated and reused for 5 cycles without significant lost in adsorption capacity. The results of this work indicated that the surface functionalization by click reaction could be a simple and suitable method for the preparation of polymeric adsorbents for an effective removal of metal ions from aqueous solution.

The Synthesis of Poly(ethylene glycol) (PEG) Containing Polymers via Step-Growth Click Coupling Reaction for CO2Separation

The synthesis of step-growth polymers via a step-growth click coupling reaction of diazides based on poly(ethylene glycol) (PEG) and dialkynes based on aromatics is reported. The polymers are characterized by proton nuclear magnetic resonance spectroscopy (1H-NMR), carbon-13 nuclear magnetic resonance spectroscopy (13C-NMR), Fourier transform infrared spectroscopy (FT-IR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Gas transport properties of one polymer are measured by the time lag (constant volume, variable pressure) method. Low gas permeabilities are a consequence of the rather high glass transition temperature. The rather high selectivities in separation of CO2/N2 and CO2/CH4 result from the CO2-philic groups such as PEG, triazole, and benzoxazine. According to the gas permeation measurements, the membrane is stable in the temperature range from 30 to 90 °C.

A concise and simple click reaction catalyzed by immobilized Cu(I) in an ionic liquid leading to the synthesis of β-hydroxy triazoles

This study describes an ecocompatible, concise, and practically reliable approach for the regioselective synthesis of β-hydroxy triazoles via Huisgen's click coupling reaction among varied epoxides, NaN 3 , and suitable acetylenes catalysed by immobilized Cu(I) in ionic liquid (IL). This one-pot, atom-economic, efficient, and highly regioselective green protocol ensures higher yield of β-hydroxy triazole scaffolds (85–95%). To make the process ecofriendly, this study emphasizes on the catalyst immobilization technique along with its possible recycling that gave a high reaction yield in up to three runs. The structures of all synthesized compounds have been characterized by comparing 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass spectroscopic data with those reported in the literature.

Quantitative fluorine NMR to determine carbohydrate density on glyconanomaterials synthesized from perfluorophenyl azide-functionalized silica nanoparticles by click reaction.

A quantitative fluorine NMR ((19)F qNMR) method was developed to determine the carbohydrate density on glyconanomaterials. Mannose (Man)- and galactose (Gal)-conjugated silica nanoparticles (SNPs) were synthesized from perfluorophenyl azide (PFPA)-functionalized SNPs and propargylated Man or Gal by copper-catalyzed azide-alkyne cycloaddition (click reaction). After treating PFPA-SNPs or Man-SNPs with hydrofluoric acid followed by lyophilization, the remaining residues were directly subjected to (19)F NMR analysis. The density of PFPA on PFPA-SNP was determined to be 7.7 ± 0.2 × 10(-16) nmol/nm(2) and Man on Man-SNP to be 6.4 ± 0.2 × 10(-16) nmol/nm(2) giving a yield of ∼83% for the click coupling reaction. The apparent dissociation constant (Kd) of Man-SNPs with fluorescein isothiocyanate (FITC)-concanavalin A (Con A) was determined using a fluorescence competition assay to be 0.289 ± 0.003 μM, which represents more than 3 orders of magnitude affinity increase compared to free Man with Con A.