Terminal Alkyne Groups Research Articles

Synthesis of furoquinolinones/pyranones/coumarins via a copper-catalyzed heteroannulation of oxime acetates and 1,3-cyclic dicarbonyls

A divergent copper-mediated cyclization between oxime acetates and distinct 1,3-cyclic dicarbonyl compounds such as 4-hydroxyquinolinones/pyranones/coumarins was developed. Using the same reaction conditions, an array of furan-fused heterocycles such as furoquinolinones/pyranones/coumarins were prepared in good to high yields. The products possess a less common substitution pattern than those in previous syntheses. The mildness of the protocol enables a broad scope without affecting sensitive functionalities such as azido, alcohol, terminal alkyne, alkyl ester, and alkyl halide groups. Mechanistic investigations infer a purely organometallic pathway, excluding the participation of radical intermediates. Ultimately, the heteroannulation was exploited as the key step in a short and high-yielding synthesis of the phytoestrogen coumestrol.

Template Assisted Synthesis of Linear [5]Catenane by Post-Functionalization of Templated [2]Catenane and Using Click Reaction.

Polymers with all mechanically interlocked rings, such as linear [n]catenanes, have great potential as functional materials due to possible higher degrees of freedom that may contribute to their flexibility but remain elusive. All the synthetic methods used to prepare such a polymer yield mixtures of products. In the absence of higher molecular weight linear [n]catenanes, emphasis on synthesizing low molecular weight oligomers is being pursued. Here, we have described the synthesis of a linear [5]catenane by post-functionalizing a Co(III) templated [2]catenane having a pyridine-diamide unit free for further metal ion coordination. Two molecules were synthesized with suitable threading groups: one, two terminal azide groups, and two, with two terminal alkyne groups to form two [3]pseudorotaxane utilizing Co(III) coordination. These units were then joined, forming a macrocycle, using click reaction, giving the desired metalated linear [5]catenane in 40 % yield. Removal of metal ions leads to linear [5]catenane. In addition, the formation of linear [3] and [2]catenane are also observed. All synthesized structures have been isolated by column chromatographic technique and characterized by 1H-NMR, 13C-NMR, and mass spectroscopy.

Introducing terminal alkyne groups at the reducing end of cellulose nanocrystals by aldimine condensation for further click reaction

In recent years, click reactions with cellulose nanocrystals (CNC) participation have gradually become a research hotspot. Carboxylamine condensation is the most used method to introduce terminal alkyne groups at the reducing end of CNC as reaction sites for click reactions. However, hydroxyl groups on CNC surface would be slightly oxidized during the carboxyamine condensation process, inducing the potential positions of introduced alkynes would be not only at the reducing end but also on CNC surface. Here, aldimine condensation was proposed to introduce terminal alkyne groups just at the reducing end of CNC, and a systematic comparison analysis was conducted with carboxylamine condensation. Firstly, the selectivity and extent of alkynylation were characterized by XPS and EA. Secondly, the end aldehyde content in these CNC samples was measured by the BCA method, which quantitatively explained the grafting efficiency of aldimine condensation and further verified its feasibility. Thirdly, the clickability of the modified CNC samples was confirmed through XPS analysis of the products after a pre-designed click reaction. In sum, aldimine condensation was proven to be a simple and effective strategy for introducing terminal alkyne groups at the reducing end of CNC, which could be used as reaction sites for further click reactions.

Tridentate Lewis Acids Based on Tribenzotriquinacene Chalices.

Chalice-shaped tridentate poly-Lewis acids (PLA) based on the tribenzotriquinacene (TBTQ) scaffold have been synthesised. Stannylation of the alkyne units, attached via phenyl-spacers to the benzhydrylic positions to the TBTQ scaffold, with Me2NSnMe3 afforded the trimethyltin substituted TBTQ derivative. Replacement of these tin functions with other elements resulted in rigid boron- and aluminium-functionalised PLAs. More flexible PLAs were obtained by hydrometallation reactions of the terminal alkyne groups of 4b,8b,12b-tris((ethynyl)phenyl)tribenzotriquinacene. The resulting poly-Lewis acids were tested for their acceptor abilities in host-guest experiments with suitable bases. Preliminary tests with pyridine led to the synthesis of a large tridentate base with three pyridyl groups attached to a TBTQ backbone. Complexation of this Lewis base with the PLAs resulted in the formation of aggregates, which were studied in solution in more detail by 1H DOSY NMR experiments regarding their size. Further experiments were performed with the tridentate bases 1,4,7-trimethyl-1,4,7-triazacyclononane and tris((dimethylphosphino)methyl)phenylsilane.

Using Poly(N‐isopropylacrylamide) and Poly(ethyleneglycol) Grafted Polycarbodiimides as Unique Nanocarriers for Hydrophobic Form of the Doxorubicin (DOX)

AbstractAmphiphilic helical polycarbodiimides bearing side chains with terminal alkyne groups provide a unique platform for construction of polymeric micelles. Incorporation of propargyl pendants into polyguanidine backbone allowed post‐polymerization modification with azide terminated, random coil, poly(N‐isopropylacrylamide), PNIPAM15K and poly(ethyleneglycol), PEG2K moieties using copper‐catalyzed click reaction (CuAAC). Thus, four new amphiphilic brush copolymers with varying grafting density were synthesized and their self‐assembly behavior in aqueous medium was studied by combination of TEM, SEM, AFM, and optical microscopy techniques. It was shown the formation of micellar structures at critical micelle concentration (CMC) ranging from 1.58 × 10−5 to 1.05 × 10−3mg mL−1. A hydrophobic drug doxorubicin (DOX) was then encapsulated successfully into these micellar structures with encapsulation efficiency (EE) falling in the range from 16% to 27%. Further, the cellular uptake studies were carried out by using HeLa cells and the cytotoxic activity of DOX‐loaded micelles was determined to be less than 65% of cell viability at a concentration of 0.250 mg mL−1. Fluorescence microscopy imaging revealed importing the micelles into the cells by endocytosis and internalization of the DOX into nucleus of the HeLa cells.

Edge Functionalization of Bulk γ-Graphyne Facilitates Mechanical Exfoliation and Modulates the Mode of Sheet Stacking.

We have successfully achieved selective and efficient functionalization of sheet edges in microcrystalline multilayer γ-graphyne through two methods: cross-coupling with residual bromide edge groups and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with edge terminal alkyne groups. This modification significantly enhances the ease of mechanical exfoliation and dispersibility of the sheets of γ-graphyne. Specifically, C18-grafted γ-graphyne forms stable dispersions in compatible organic solvents, allowing for the imaging of atomically thin layers of γ-graphyne for the first time. Additionally, we have discovered that phenylacetylide edge groups alter the preferred stacking mode of γ-graphyne sheets. Few-layer flakes of Ph-edge γ-graphyne exhibit a preference for the R3m space group, contrasting with the aperiodic stacking of Br-edge γ-graphyne. These results open the door for scalable exfoliation of few-layer flakes of γ-graphyne with a high aspect ratio, enabling potential applications in carbon electronics.

Metal Phthalocyanine Sensitized Photoelectrochemical Cell Assembling with Azide‐Functionalized Reduced Graphene and Quaternary Metal Chalcogenide Composites

AbstractHere, photoelectrodes of photoelectrochemical (PEC) cells consisting of azide functionalized reduced graphene oxide (GO‐N3) and quaternary metal chalcogenide (CdZnNiSSe) composites sensitized with metal phthalocyanines (MPc, M: Co, Zn, Ti) are developed and then tested in hydrogen evolution reaction (HER). CdZnNiSSe/RGO‐N3 composite is deposited on an indium tin oxide (ITO) electrode through a facile electrodeposition technique and ITO/CdZnNiSSe/RGO‐N3 photoelectrode is constructed. Then, MPcs bearing terminal alkyne groups are connected to RGO‐N3 via the copper(I)‐catalyzed azide‐alkyne cycloaddition (click chemistry) technique to produce ITO/CdZnNiSSe/RGO‐N3‐MPc structures. Decoration of ITO/CdZnNiSSe/RGO‐N3 with MPcs is proposed to improve the charge transfer capability of the photoelectrode due to wide light absorption of MPcs from UV toward the IR region of the light spectrum. PECHER responses indicate that among the photoanodes bearing ZnPc, CoPc, and TiOPc, ITO/CdZnNiSSe/RGO‐N3‐ZnPc electrode exhibits the highest PECHER performance owing to the suitability of band structure of ZnPc. Sensitizing ITO/CdZnNiSSe/RGO‐N3 with ZnPc increases the photocurrent density from 5.0 to 7.3 mA cm−2 at 0.8 V vs. RHE and the applied bias photon to current efficiency (ABPE) enhances from 3.18 % to 3.87 %. This study provides a new approach for increasing the performance of photoanodes via sensitization with MPcs in photoelectrochemical hydrogen evolution processes for future applications.

Clicked BODIPY-Fullerene-Peptide Assemblies: Studies of Electron Transfer Processes in Self-Assembled Monolayers on Gold Surfaces.

Two BODIPY-C60-peptide assemblies were synthesized by CuAAC reactions of BODIPY-C60 dyads and a helical peptide functionalized with a terminal alkyne group and an azide group, respectively. The helical peptide within these assemblies was functionalized at its other end by a disulfide group, allowing formation of self-assembled monolayers (SAMs) on gold surfaces. Characterizations of these SAMs, as well as those of reference molecules (BODIPY-C60-alkyl, C60-peptide and BODIPY-peptide), were carried out by PM-IRRAS and cyclic voltammetry. BODIPY-C60-peptide SAMs are more densely packed than BODIPY-C60-alkyl and BODIPY-peptide based SAMs. These findings were attributed to the rigid peptide helical conformation along with peptide-peptide and C60-C60 interactions within the monolayers. However, less dense monolayers were obtained with the target assemblies compared to the C60-peptide, as the BODIPY entity likely disrupts organization within the monolayers. Finally, electron transfer kinetics measurements by ultra-fast electrochemistry experiments demonstrated that the helical peptide is a better electron mediator in comparison to alkyl chains. This property was exploited along with those of the BODIPY-C60 dyads in a photo-current generation experiment by converting the resulting excited and/or charge separated states from photo-illumination of the dyad into electrical energy.

1,3-Butadiynyl sulfide-based compact trialkyne platform molecule for sequential assembly of three azides.

A compact trialkyne platform with a silyl-protected 1,3-butadiynyl sulfide moiety and a terminal alkyne group has been developed for sequential regioselective transition metal-catalyzed triazole formation reactions with three azides. This method enabled the facile construction of a low-molecular-weight triazole library and the synthesis of middle-molecular-weight trifunctional probes for protein modification.

Synthesis, Crystal structure, Anticancer evaluation and Hirshfeld surface analysis of novel antipyrine gathered bis-triazoles as breast adenocarcinoma inhibitors

A series of novel substituted antipyrine attached bis-triazoles 7(a-h) were synthesized via coupling followed by click chemistry reaction. Their structure was established by means of physico-chemical spectral studies and a single-crystal X-ray diffraction analysis (7c and 7f). X-ray diffraction results exhibited that 7c and 7f were crystallized in triclinic space group P¯1 where a=9.352 (3), b=11.002 (3), c=14.616 (4) Å and also revealed that the bis-triazole ring formed by two terminal alkyne groups joined with substituted azides (6a-h). The Hirshfeld surface analysis of the crystal surface shows that the most contributions for H…H/H…H, C… H/H …C, N…H / H…N, O…H/H…O, and C …C interactions. Breast adenocarcinoma cell line used test the compounds anticancer effects by MTT assay. Compound 7f was found to be most promising scaffold, exhibiting a anticancer effect near to standard imatinib (IC50 at 25.03±0.01 mg). The results exhibited that these analogues could be lead compounds in search for new effective anticancer agents.

Removing Perfluoro Pollutants PFOA and PFOS by Two-Pronged Design of a Ni8-Pyrazolate Porous Framework.

Inspired by the practical need to remove persistent perfluoro pollutants from the environment, we leverage cutting-edge crystal engineering approaches. For this, we set our eyes on a recent porous coordination framework system based on the Ni8-oxo cluster and pyrazolate linkers as it is known for its stability to bases and other harsh environmental conditions. Our designer linker molecule here features (1) pyrazole donors masked by t-butyloxycarbonyl and (2) ethynyl side units protected by triisopropylsilyl groups. The former solvothermally demasks to assemble the Ni8-pyrazolate framework, in which the triisopropylsilyl groups can be post-synthetically cleaved by guest fluoride ions to unveil the terminal alkyne group (-CCH). The ethynyl groups of the framework solid offer versatile reactions for functionalization, as with perfluorophenyl azide (via a click reaction) to afford the two prongs of the 1,2,3-triazole base unit and the perfluoro unit. Together, these two functions make for an effective adsorbent for the topical acid pollutants of perfluorooctanoic acid and perfluorooctanesulfonic acid, with a high apparent rate constant (kobs) of 0.99 g mg-1 h-1 and large maximum uptake capacity (qmax) of 268.5 mg g-1 for perfluorooctanoic acid and kobs of 0.77 g mg-1 h-1 and qmax of 142.1 mg g-1 for perfluorooctanesulfonic acid.

Substituents role in highly symmetrical 1,2,3-triazoles derivatives toward self-assembly of soft liquid crystals

Triazole bent-core mesogens based on symmetrical bent-shaped of two 1,2,3-triazole ring arms were synthesized and characterized. The the thermail stability of those new synthesised mesogens from the embient temperature to 215 °C giving mesogenic phase transitions over a wide temperature range is investigated. A study of different substituents located on the rigid bentcore was carried out for compact supramolecular innovated architectures which were produced by self-assembly of many triazoles soft crystals with a liquid crystals behaviour. The synthetic procedures, characterizations and polymorphism of four novel bent-core mesogens comprising symmetrical 1,2,3-triazole arms were demonstrated. The preparation process was carried out through‘‘click chemistry’’ via Cu-catalyzed azide-alkyne cycloaddition of nitro- and alkyl-substituted aromatic azides with aromatic compounds, comprising terminal alkyne groups and long alkyl or alkoxy side-chains. The triazole derivatives were fully characterized by 1H/13C NMR, Fourier-transform infrared spectroscopy (FTIR) and elemental analysis. The mesophases and textures were examined by employing polarizing optical microscope (POM), differential scanning calorimetry (DSC) and X-ray Diffraction (XRD). The analogues with shorter alkoxy terminal substituents displayed higher mesomorphic properties with wide mesomorphic temperature ranges compared to analogues with shorter alkoxy terminals. The morphological characteristics of the self-assembled triazoles were investigated by scanning electron microscopy (SEM) which demonstrated arrangement of highly ordered columnar architectures. These orders were driven by layer to next layer adjacent influences and π-π stacking. The effect of 1,2,3-triazole ring and length of terminal aliphatic chains on the liquid crystalline performance were discussed. Through an appropriate choice of lateral structures employing “click chemistry’’, both transition temperature and mesophases ranging from isotropic to columnar or B1/B4-like supramolecular liquid crystalline aggregates can be tuned.

New calix[4]resorcinol rccc diastereoisomer with terminal triple bonds: Synthesis, structural features and reactions

One-pot acid-catalyzed cyclocondensation of 2-methyl-resorcinol with 4-(propargyloxy)benzaldehyde in CHCl3/CF3CO2H media affords all-cis (rccc) and/or cis-trans-trans (rctt) calix[4]resorcinol diastereomers bearing four terminal alkyne groups at aromatic substituents, the isomer ratio and yield being dependent on the CHCl3/CF3CO2H ratio. The rctt isomer (kinetic control product) can be converted to thermodynamically more stable rccc isomer at prolonged refluxing in CHCl3/CF3CO2H mixture. The rccc diastereomer was subjected to additional propargylation followed by the click reactions with benzylic azides to afford new highly triazolated calix[4]resorcinols.

Self-Healable, Stretchable, and Super-Soft Bottlebrush Polyester Elastomers for Highly Sensitive Flexible Sensors

While much effort has been devoted to the creation of super-soft elastomers, there is a dearth of research aimed at self-healable and super-soft renewable elastomers. Herein, self-healing and super-soft renewable elastomers are developed based on bottlebrush architecture design and dynamic associative transesterification. The bottlebrush polymer precursors are generated by ring-opening metathesis polymerization (ROMP) of the norbornene-terminated macromonomer poly(ε-caprolactone-co-l-lactide) (PCLLA) (NB-PCLLA). After introducing alkyne groups onto the end of PCLLA side chains, the bottlebrush polymers are cross-linked to achieve elastomer networks via a UV-induced “click” thiol-yne reaction between the terminal alkyne groups and the dithiothreitol (DTT) additive. The resulting materials exhibit a shear modulus as low as 17 kPa, high stretchability with breaking strains as large as 315%, and a self-healing efficiency of 95.6% at an elevated temperature of 80 °C. Taking the super-softness advantage, flexible sensor devices are assembled based on the prepared elastomer, which are highly sensitive to deformation with a gauge factor of 0.347. This work demonstrates that high-performance biodegradable materials with unique properties that conventional linear polymers impossibly possess can be easily constructed by molecular architecture design using bottlebrush polymers as building blocks.

Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine.

Nirmatrelvir (PF-07321332) is a nitrile-bearing small-molecule inhibitor that, in combination with ritonavir, is used to treat infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nirmatrelvir interrupts the viral life cycle by inhibiting the SARS-CoV-2 main protease (Mpro), which is essential for processing viral polyproteins into functional nonstructural proteins. We report studies which reveal that derivatives of nirmatrelvir and other Mpro inhibitors with a nonactivated terminal alkyne group positioned similarly to the electrophilic nitrile of nirmatrelvir can efficiently inhibit isolated Mpro and SARS-CoV-2 replication in cells. Mass spectrometric and crystallographic evidence shows that the alkyne derivatives inhibit Mpro by apparent irreversible covalent reactions with the active site cysteine (Cys145), while the analogous nitriles react reversibly. The results highlight the potential for irreversible covalent inhibition of Mpro and other nucleophilic cysteine proteases by alkynes, which, in contrast to nitriles, can be functionalized at their terminal position to optimize inhibition and selectivity, as well as pharmacodynamic and pharmacokinetic properties.

Frequency Changes in Terminal Alkynes Provide Strong, Sensitive, and Solvatochromic Raman Probes of Biochemical Environments.

The C≡C stretching frequencies of terminal alkynes appear in the "clear" window of vibrational spectra, so they are attractive and increasingly popular as site-specific probes in complicated biological systems like proteins, cells, and tissues. In this work, we collected infrared (IR) absorption and Raman scattering spectra of model compounds, artificial amino acids, and model proteins that contain terminal alkyne groups, and we used our results to draw conclusions about the signal strength and sensitivity to the local environment of both aliphatic and aromatic terminal alkyne C≡C stretching bands. While the IR bands of alkynyl model compounds displayed surprisingly broad solvatochromism, their absorptions were weak enough that alkynes can be ruled out as effective IR probes. The same solvatochromism was observed in model compounds' Raman spectra, and comparisons to published empirical solvent scales (including a linear regression against four meta-aggregated solvent parameters) suggested that the alkyne C≡C stretching frequency mainly reports on local electronic interactions (i.e., short-range electron donor-acceptor interactions) with solvent molecules and neighboring functional groups. The strong solvatochromism observed here for alkyne stretching bands introduces an important consideration for Raman imaging studies based on these signals. Raman signals for alkynes (especially those that are π-conjugated) can be exceptionally strong and should permit alkynyl Raman signals to function as probes at very low concentrations, as compared to other widely used vibrational probe groups like azides and nitriles. We incorporated homopropargyl glycine into a transmembrane helical peptide via peptide synthesis, and we installed p-ethynylphenylalanine into the interior of the Escherichia coli fatty acid acyl carrier protein using a genetic code expansion technique. The Raman spectra from each of these test systems indicate that alkynyl C≡C bands can act as effective and unique probes of their local biomolecular environments. We provide guidance for the best possible future uses of alkynes as solvatochromic Raman probes, and while empirical explanations of the alkyne solvatochromism are offered, open questions about its physical basis are enunciated.

Synthesis of Cy5-Labelled C5-Alkynyl-modified cytidine triphosphates via Sonogashira coupling for DNA labelling

New applications of palladium-catalyzed Sonogashira-type cross-coupling reaction between C5-halogenated 2′-deoxycytidine-5′-monophosphate and novel cyanine dyes with a terminal alkyne group have been developed. The present methodology allows to synthesize of fluorescently labeled C5-nucleoside triphosphates with different acetylene linkers between the fluorophore and pyrimidine base in good to excellent yields under mild reaction conditions. Modified 2′-deoxycytidine-5′-triphosphates were shown to be good substrates for DNA polymerases and were incorporated into the DNA by polymerase chain reaction.

Preparation of radiolabeled erlotinib analogues and analysis of the effect of linkers

Erlotinib is a first generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) which was granted Food and Drug administration (FDA) approval for treatment of patients with locally advanced or metastatic NSCLC. The present study aimed at development of radiolabeled erlotinib variants as tyrosine kinase inhibitors. Three DOTA-erlotinib conjugates were prepared for radiolabeling with 177Lu. The terminal alkyne group of erlotinib was modified by performing Cu-catalyzed click chemistry and three different linkers were introduced which were then conjugated to the chelator, DOTA. The DOTA-erlotinib conjugates were characterized by 1H NMR and ESI-MS. 177Lu-DOTA-erlotinib complexes were characterized using natLu-DOTA-erlotinib conjugates. The 177Lu-complexes exhibited high in vitro stability in human serum up to 48 h. They were highly hydrophilic in nature as observed from their log Po/w values (177Lu-DOTA-propyl-Er: −2.5 ± 0.1; 177Lu-DOTA-PEG3-Er: −3.0 ± 0.1; 177Lu-DOTA-PEG6-Er: −3.3 ± 0.1). The MTT assay in A431 human epidermoid carcinoma cell lines indicates that the chemical modification at the terminal alkyne group of the erlotinib molecule does not have significant effect on its TKI property. Biodistribution studies in normal Swiss mice demonstrated fast clearance and excretion of 177Lu-labeled erlotinib complexes. These studies indicate that erlotinib variants with hydrophobic pharmacokinetic modifiers/chelators may enhance the retention of 177Lu-labeled complexes in blood thereby increasing the probability to reach EGFR-expressing tumor.

Detachable all-carbon-linked 3D covalent organic framework films for semiconductor/COF heterojunctions by continuous flow synthesis

Detachable all-carbon-linked 3D covalent organic framework films for semiconductor/COF heterojunctions by continuous flow synthesis

Synthesis of Xylan-Click-Quaternized Chitosan via Click Chemistry and Its Application in the Preparation of Nanometal Materials.

For the high-valued utilization of hemicelluloses and for realizing the controllable synthesis of NPs, this paper’s aim is to combine xylan, chitosan and nanometal materials at the same time. In this research study, firstly, propargyl xylan was synthesized via nucleophilic substitution reaction between xylan and propargyl bromide in NaOH solution. On the other hand, a tosyl group was introduced onto the 6th position of synthesized quaternized chitosan (QCS), and the azide group replaced the tosyl group to obtain 6-amido-QCS (QCS-N3). The synthesis conditions of the above reactions were optimized. Subsequently, the novel xylan-click-QCS polymer was obtained via click reaction between terminal alkyne groups on the xylan chains and azide groups on QCS. Then, AgNPs and AuNPs were synthesized by adopting the xylan-click-QCS polymer as the reducing and stabilizing agent, and the reaction conditions were optimized to obtain well-dispersed and highly stable nanoparticles. There were two kinds of Ag nanomaterials, with diameters of 10~20 nm and 2~5 nm, respectively, indicating the formation of Ag nanoclusters, except for Ag nanoparticles, in this reaction. The diameter of the synthesized AuNPs was 20~30 nm, which possessed a more uniform size distribution. The Ag nanoclusters with a smaller size (2~5 nm) could inhibit MCF-7 cell proliferation effectively, indicating their application potential in cancer therapy. The study gives a new approach to the high-value utilization of biopolymers.