Ring-Opening of 1,3-Imidazole Based Mesoionic Carbenes (iMICs) and Ring-Closing Clicks: Facile Access to iMIC-Compounds.

Herein, ring-opening of mesoionic carbenes (iMICs) (iMIC=[ArC{N(Dipp)}2 C(SiMe3 )C:) (Dipp=2,6-iPr2 C6 H3 , Ar=Ph, 4-Me2 NC6 H4 or 4-PhC6 H4 ) based on an 1,3-imidazole scaffold to yield N-ethynylformimidamide (eFIM) derivatives as crystalline solids (eFIM={(Dipp)N=C(Ar)N(Dipp)}C≡CSiMe3 ) is reported. eFIMs are thermally stable under inert gas atmosphere and show moderate air stability (t1/2= 3 h for Ar=Ph). eFIMs are excellent surrogates of iMICs, which generally have a limited shelf-life, and readily undergo ring-closing click reactions with a variety of main-group as well as transition metal Lewis acids to form hitherto challenging iMIC-compounds in good to excellent yields. In addition to the relevance of eFIMs in the synthesis of iMIC-compounds, quantification of the stereoelectronic properties of a representative iMIC (Ar=Ph) by experimental and theoretical methods suggests remarkably σ-donor property and steric profile of these new ligand sets.

Tunable Macrocyclic Polyparaphenylene Nanolassos via Copper-Free Click Chemistry.

Deriving diverse compound libraries from a single substrate in high yields remains to be a challenge in cycloparaphenylene chemistry. In here, a strategy for the late-stage functionalization of shape-persistent alkyne-containing cycloparaphenylene has been explored using readily available azides. The copper-free [3+2]azide-alkyne cycloaddition provided high yields (>90 %) in a single reaction step. Systematic variation of the azides from electron-rich to -deficient shines light on how peripheral substitution influences the characteristics of the resulting adducts. We find that among the most affected properties are the molecular shape, the oxidation potential, excited state features, and affinities towards different fullerenes. Joint experimental and theoretical results are presented including calculations with the state-of-the-art, artificial intelligence-enhanced quantum mechanical method 1 (AIQM1).

Polyaromatic Hydrocarbon (PAH)-Based Aza-POPOPs: Synthesis, Photophysical Studies, and Nitroanalyte Sensing Abilities.

1,4-Bis(5-phenyl-2-oxazolyl)benzene (POPOP) is a common scintillation fluorescent laser dye. In this manuscript, the synthesis of 2-Ar-5-(4-(4-Ar'-1H-1,2,3-triazol-1-yl)phenyl)-1,3,4-oxadiazoles (Ar, Ar' = Ph, naphtalenyl-2, pyrenyl-1, triphenilenyl-2), as PAH-based aza-analogues of POPOP, by means of Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-Ar-1,3,4-oxadiazole and terminal ethynyl-substituted PAHs is reported. An investigation of the photophysical properties of the obtained products was carried out, and their sensory response to nitroanalytes was evaluated. In the case of pyrenyl-1-substituted aza-POPOP, dramatic fluorescence quenching by nitroanalytes was observed.

(1-(4-(5-Phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-Bisfunctionalized 3- and 4-PEG: Synthesis and Photophysical Studies.

Two new azaheterocycle-based bolas, such as (1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-bisfunctionalized PEGs, were prepared via Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-(aryl)-oxadiazole-1,3,4 and terminal ethynyls derived from PEG-3 and PEG-4. Due to the presence of two heteroaromatic cores and a PEG linker, these bola molecules are considered as promising fluorescent chemosensors for electron-deficient species. As a result of a well-pronounced "turn-off" fluorescence response towards common nitro-explosive components, such as 2,4-dinitrotoluene (DNT) and 2,4,6-trinitrotoluene (TNT), hard-to-detect pentaerythritol tetranitrate (PETN), as well as Hg2+ cation was observed.

Controllable Synthesis of Hybrid Dendrimers Composed of a Carbosilane Core and an Aromatic Shell: Does Size Matter?

The controllable synthesis of novel hybrid dendrimers composed of flexible and rigid components was accomplished via effective Cu-catalyzed azide-alkyne cycloaddition ("click") reaction between azide-functionalized carbosilane cores of two generations and monoethynyl-substituted hexaphenylbenzene dendron. A comprehensive analysis of the thermal and phase behavior of dendrimers allows us to detect a similar performance of dendrimers of both generations which, in our opinion, can be due to the similar ratio of rigid and flexible blocks in the dendrimers regardless the generation of carbosilane cores. The propensity to crystallization and ordering after the annealing procedure was confirmed by DSC and SWAXS. We found that hybrid dendrimers have a tendency to order depending on their constituents of different structures. This is in contrast to homogeneous dendrimers whose propensity to order is determined by the dendrimer molecule as a whole.

Functionalized C3-Symmetric Building Blocks-The Chemistry of Triaminotrimesic Acid.

A series of C3-symmetric fully substituted benzenes were prepared based on alkyl triamino-benzene-tricarboxylates. Starting with a one step-synthesis, the alkyl triamino-benzene-tricarboxylates were synthesized using the corresponding cyanoacetates. The reactivity of these electronically sophisticated compounds was investigated by the formation of azides, the click reaction of the azides and a Sandmeyer-like reaction. Caused by the low stability of triaminobenzenes, direct N-alkylation was rarely reported. The use of the stable alkyl triamino-benzene-tricarboxylates allowed us total N-alkylation under standard alkylation conditions. The molecular structures of the C3-symmetric structures have been corroborated by an X-ray analysis.

Click Synthesis Enabled Sulfur Atom Strategy for Polymerization-Enhanced and Two-Photon Photosensitization.

Facile tailoring of photosensitizers (PSs) with advanced and synergetic properties is highly expected to broaden and deepen photodynamic therapy (PDT) applications. Herein, a catalyst-free thiol-yne click reaction was employed to develop the sulfur atom-based PSs by using the in situ formed sulfur "heavy atom effect" to enhance the intersystem crossing (ISC), while such an effect can be remarkably magnified by the polymerization. The introduction of a tetraphenylpyrazine-based aggregation-induced emission (AIE) unit was also advantageous in PS design by suppressing their non-radiative decay to facilitate the ISC in the aggregated state. Besides, the resulting sulfur atom electron donor, together with a double-bond π bridge and AIE electron acceptor, created a donor-π-acceptor (D-π-A) molecular system with good two-photon excitation properties. Combined with the high singlet oxygen generation efficiency, the fabricated polymer nanoparticles exhibited an excellent in vitro two-photon-excited PDT towards cancer cells, therefore possessing a huge potential for the deep-tissue disease therapy.

Tailoring the Pore Surface of 3D Covalent Organic Frameworks via Post-Synthetic Click Chemistry.

Three-dimensional covalent organic frameworks (3D COFs) have gained increasing attention for their attractive features. However, the development of 3D COFs is strongly restricted, mainly due to their synthetic difficulty and complicated structure determination. Post-synthetic modification, which can avoid these problems by incorporating functional moieties into a predetermined framework, provides an alternative way to construct 3D COFs with specific functions. Herein, we report the designed synthesis and characterization of a series of highly crystalline 3D COFs with different loadings of ethynyl groups. Notably, these alkyne-tagged 3D COFs provide a platform for targeted anchoring various specific groups onto the pore walls via click reactions. Moreover, the pore surface engineering can accordingly change their properties, for example, the obtained click products exhibited higher CO2 /N2 selectivity. We describe a simple but powerful strategy to build functional 3D COFs, which will certainly advance them for a ranging of interesting applications in the future.

Preparation of a Lanthanide-Titanium Oxo Cluster-Polymer Composite by CuI -Catalyzed Click Chemistry.

Incorporating metal clusters within the skeleton of the organic polymers through a click reaction cannot only effectively prepare cluster-polymer composites, but also effectively avoid the cluster aggregation. Herein, an azide-containing lanthanide-titanium oxo cluster of Eu8 Ti10 -N3 (Eu8 Ti10 -N3 =[Eu8 Ti10 (µ3 -O)14 (H2 O)4 (OAc)2 (tbba)30 (paza)4 (THF)2 ]⋅4 THF⋅8 H2 O (1), Htbba=4-tert-butylbenzoic acid, Hpaza=4-azidobenzoate, HOAc=acetic acid, THF=tetrahydrofuran) through an in situ solvothermal reaction of 4-azidobenzoic acid and 4-tert-butylbenzoic acid. Reaction of 1 with PEG (PEG=methoxypoly(ethyleneglycol)alkyne, 2000 g mol-1 ) through CuI -catalyzed click chemistry generates a lanthanide-polymer composite of Eu8 Ti10 -N3 @PEG (2). Investigation with IR, 1 H NMR and ICP-OES of 2 indicates that the structural integrity of 1 is maintained in 2. Study of the luminescent properties of 1 and 2 reveals that the quantum yield of 1 itself basically remains unchanged in 2. Significantly, the formation of 2 cannot only effectively prevent the cluster 1 from aggregation, but also greatly enhance its solubility and adhesion to the substrate. Owing to the solubility and adhesion of luminescent materials being the key to their practical application, present work is thus of great significance for the development of metal cluster-polymer composite luminescent materials.

Thiol-Bromo Click Reaction for One-Pot Synthesis of Star-Shaped Polymers.

Star-shaped polymers have unique physical properties and they are sought after materials in industry. However, the ease of synthesis is essential for translation of these materials into large-scale applications. Herein, a highly efficient synthetic method to prepare star-shaped polymers by combination of Cu-mediated reversible deactivation radical polymerization (Cu-RDRP) and thiol-bromo click reaction is described. Well-defined linear and block polymers with a very high bromine chain end fidelity are obtained via Cu-RDRP and subsequently react with multi-functional thiol compounds. High coupling efficiencies of larger than 90% are obtained owing to the quick and efficient reaction between thiols and alkyl bromides. Moreover, the arms of the obtained star-shaped polymers are linked via thioether bonds to the core, making them susceptible for oxidative degradation.

Synthesis and Structure of the Bis- and Tris-Polyhedral Hybrid Carboranoclathrochelates with Functionalizing Biorelevant Substituents-The Derivatives of Propargylamine Iron(II) Clathrochelates with Terminal Triple C≡C Bond(s).

A synthetic strategy for obtaining structurally flexible hybrid iron(II) carboranoclatrochelates functionalized with biorelevant groups, based on a combination of a 1,3-dipolar cycloaddition reaction with nucleophilic substitution of an appropriate chloroclathrochelate precursor, was developed. In its first stage, a stepwise substitution of the dichloroclathrochelate precursor with amine N-nucleophiles of different natures in various solvents was performed. One of its two chlorine atoms with morpholine or diethylamine in dichloromethane gave reactive monohalogenoclathrochelate complexes functionalized with abiorelevant substituents. Further nucleophilic substitution of their remaining chlorine atoms with propargylamine in DMF led to morpholine- and diethylamine-functionalized monopropargylamine cage complexes, the molecules of which contain the single terminal C≡C bond. Their "click" 1,3-cycloaddition reactions in toluene with ortho-carborane-(1)-methylazide catalyzed by copper(II) acetate gave spacer-containing di- and tritopic iron(II) carboranoclatrochelates formed by a covalent linking between their different polyhedral(cage) fragments. The obtained complexes were characterized using elemental analysis, MALDI-TOF mass, UV-Vis, 1H, 1H{11B}, 11B, 11B{1H}, 19F{1H} and 13C{1H}-NMR spectra, and by a single crystal synchrotron X-ray diffraction experiment for the diethylamine-functionalized iron(II) carboranoclathrochelate. Its encapsulated iron(II) ion is situated almost in the center of the FeN6-coordination polyhedron possessing a geometry intermediate between a trigonal prism and a trigonal antiprism with a distortion angle φ of approximately 28°. Conformation of this hybrid molecule is strongly affected by its intramolecular dihydrogen bonding: a flexibility of the carborane-terminated ribbed substituent allowed the formation of numerous C-H…H-B intramolecular interactions. The H(C) atom of this carborane core also forms the intermolecular C-H…F-B interaction with an adjacent carboranoclathrochelate molecule. The N-H…N intermolecular interaction between the diethylamine group of one hybrid molecule and the heterocyclic five-membered 1H-[1,2,3]-triazolyl fragment of the second molecule of this type caused formation of H-bonded carboranoclathrochelate dimers in the X-rayed crystal.

A RuII Polypyridyl Alkyne Complex Based Metal-Organic Frameworks for Combined Photodynamic/Photothermal/Chemotherapy.

Despite drug delivery nanoplatforms receiving extensive attention, development of a simple, effective, and multifunctional theranostics nanoplatform still remains a challenge. Herein, a versatile nanoplatform based on a zirconium framework (UiO-66-N3 ) was synthesized, which demonstrated a combined photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy (CT) for cancer treatment. A RuII polypyridyl alkyne complex (Ra) as a photosensitizer was modified into a nanoplatform by click reactions for the first time. When exposed to suitable light irradiation, the as-prepared multifunctional nanoplatform (UiO-Ra-DOX-CuS) not only demonstrated efficient 1 O2 generation, but also exhibited excellent photothermal conversion ability. In particular, the nanotherapeutic agent presented a dual-stimuli response; either acidic environment or NIR laser irradiation would trigger the drug release. The synergetic efficacy of UiO-Ra-DOX-CuS combined PDT, PTT, and CT, which was evaluated by cell experiments. Moreover, the design could promote the development of RuII polypyridyl alkyne complexes based multifunctional nanoparticles and multimodal cancer treatment.

Effect of Chain-End Chemistries on the Efficiency of Coupling Antibodies to Polymers Using Unnatural Amino Acids.

Novel conjugates that incorporate strategies for increasing the therapeutic payload, such as targeted polymeric delivery vehicles, have great potential in overcoming limitations of conventional antibody therapies that often exhibit immunogenicity and limited drug loading. Click chemistry has significantly expanded the toolbox of effective strategies for developing hybrid polymer-biomolecule conjugates, however, effective systems require orthogonality between the polymer and biomolecule chemistries to achieve efficient coupling. Here, three cycloaddition-based strategies for antibody conjugation to polymeric carriers are explored and show that a purely radical-based method for polymer synthesis and subsequent biomolecule attachment has a trade-off between coupling efficiency of the antibody and the ability to synthesize polymers with controlled chemical properties. It is shown that careful consideration of both coupling chemistries as well as the potential effect of how this modulates the chemical properties of the polymer nanocarrier should be considered during the development of such systems. The strategies described offer insight into improving conjugate development for therapeutic and theranostic applications. In this system, polymerization using conventional and established reversible addition fragmentation chain transfer (RAFT) agents, followed by multiple post-modification steps, always leads to systems with more defined chemical architectures compared to strategies that utilize alkyne-functional RAFT agents.

The CuAAC: Principles, Homogeneous and Heterogeneous Catalysts, and Novel Developments and Applications.

The copper-catalyzed azide/alkyne cycloaddition reaction (CuAAC) has emerged as the most useful "click" chemistry. Polymer science has profited enormously from CuAAC by its simplicity, ease, scope, applicability and efficiency. Basic principles of the CuAAC are reviewed with a focus on homogeneous and heterogeneous catalysts, ligands, anchimeric assistance, and basic chemical principles. Recent developments of ligand design and acceleration are discussed.

Fluorinated Polymers via Para-Fluoro-Thiol and Thiol-Bromo Click Step Growth Polymerization.

Click reactions are utilized widely to modify chain ends and side groups of polymers while click polymerizations based on step-growth polymerization of bifunctional monomers have recently attracted increased attention of polymer chemists. Herein, the combination of two highly efficient click reactions, namely para-fluoro-thiol click and thiol-bromo substitution reactions, is demonstrated to form fluorinated polymers with tuned hydrophobicity owing to the nature of the dithiol linker compound. The key compound in this study is 2,3,4,5,6-pentafluoro benzyl bromide that provides the combination of thiol click reactions. The thiols used here are 4,4-thiobisbenzenthiol, 2,2'-(ethylenedioxy) diethanethiol, and 1,2-ethanedithiol that allow tuning of the properties of obtained polymers. The step-growth click reaction conditions are optimized by screening the effect of reaction temperature, base, solvent, and stochiometric ratio of the compounds. Thermal properties and hydrophobicity of synthesized polymers are determined via water contact angle, thermogravimetric analysis and differential scanning calorimetry measurements, showing thermal stability up to 300 °C, glass transition temperatures ranging from -25 to 82 °C and water contact angles ranging from 55 to 90 °C.

PEGylation of Fluorescein by Enzyme-Catalyzed "Click" Michael Addition.

This paper reports the first "Click" Michael addition catalyzed by Candida antarctica lipase B (CALB) between fluorescein o-acrylate and thiol-functionalized poly(ethylene glycol)s (HS-PEG-SH, Mn = 1200 g mol-1 , D = 1.14, and Mn = 2200 g mol-1 , D = 1.09). The progress of the reactions is monitored with 1 H-NMR spectroscopy. In the absence of CALB, the reaction does not go to completion even after 18 h but completes in less than 2 min when CALB is added. Similarly, the reaction with HS-PEG-SH having Mn = 2200 g mol-1 and D = 1.09 completes in less than 2 min by CALB catalysis. The structures of the products are also confirmed by 13 C-NMR. This enzyme-catalyzed "Click" Michael addition is found to be a powerful tool to synthesize fluorescein-based polymeric conjugates for a wide variety of applications.

A Facile and Highly Efficient Route to Amphiphilic Star-Like Rod-Coil Block Copolymer via a Combination of Atom Transfer Radical Polymerization with Thiol-Ene Click Chemistry.

With a combination of atom transfer radical polymerization (ATRP), quasi-living Grignard metathesis method, and thiol-ene click reaction, an amphiphilic star-like rod-coil diblock copolymer poly(acrylic acid)-block-poly(3-hexylthiophene) comprising 21-arm inner coil-like PAA blocks and outer rod-like conjugated polymer poly(3-hexylthiophene) (P3HT) blocks with well-defined molecular structures and narrow molecular weight distribution is synthesized. First, the bromide end-groups of 21-arm star-like ATRP coil polymers PtBA-Br are converted successfully into reactive thioacetate end groups by post-functionalization using potassium thioacetate. Subsequently, 21-arm star-like coil polymers PtBA-SCOCH3 react with rod-like vinyl-functionalized P3HT to yield functional star-like rod-coil diblock copolymers PtBA-b-P3HT via thiol-ene click reaction, followed by selective hydrolysis of inner PtBA block into PAA block. The present synthetic approach enables the construction of well-defined star-like conformation with few structural limitations in a facile and highly efficient manner due to the robust and orthogonal nature of the thiol-ene click reaction. It may be extended to produce block copolymers with other topologies, such as cylindrical, hyperbranched, and dendritic structures.

The potential of click reactions for the synthesis of bioactive triterpenes.

Click reactions between alkynes and azides using the privileged scaffold of triterpenes have been of interest for biological chemistry. Many publications deal with the synthesis of novel bioactive molecules; these conjugates have also been used for bioanalytical and diagnostic purposes. As a result, conjugates of better physicochemical properties were obtained; even compounds of improved solubility in water and physiological fluids were made through the introduction of a triazol residue. "Hybrid-structures", i.e. molecules consisting of two independently bioactive subunits linked by a triazole residue were higher bioactive than their parent compounds but not as active as expected, and with a few exceptions the ultimate breakthrough has not yet been achieved. Only in the synthesis of compounds with anti-leishmanial activity some new and promising lead structures were found. As a consequence, triazole modified triterpenes seem to hold their greatest future prospect rather as diagnostic reagents and molecular probes than as drugs.

Recent Developments in the Area of Click-Crosslinked Nanocarriers for Drug Delivery.

Click-crosslinking has been widely used for the fabrication of nanocarriers in recent years. Crosslinking can enhance the stability of nanocarriers that have served as an emerging platform for drug delivery to achieve cancer diagnosis and therapy. In crosslinking methods, click reactions have attracted increasing attention owing to their high reaction specificity and physiologically stable products. These reports on click-crosslinked nanocarriers are divided into four sections (nanogels, nanoparticles, micelles, and capsules) according to the types of nanocarriers. Click-crosslinked nanocarriers enhance the solubility of hydrophobic drugs and improve the efficacy of drug delivery owing to their good stability. Stimuli-responsive and targeted strategies can be introduced into click-crosslinked nanocarriers to enhance drug accumulation in tumors.

Hyperbranched Multicyclic Polymer Built from Tailored Multifunctional Monocyclic Prepolymer.

A simple and efficient method to construct a hyperbranched multicyclic polymer is introduced. First, a tailored trithiocarbonate with two terminal anthracene units and three azide groups is successfully synthesized, and this multifunctional trithiocarbonate is used as chain transfer agent (CTA) to afford anthracene-telechelic polystyrene (PS) via reversible addition-fragmentation chain transfer (RAFT) polymerization. After that, linear PS is irradiated under 365 nm UV light to achieve the cyclization process. The monocyclic polymer further reacts with sym-dibenzo-1,5-cyclooctadiene-3,7-diyne via "A2 +B3 " strategy based on a self-accelerating click reaction to produce hyperbranched multicyclic polymer. The structures and properties of the polymers are characterized by nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), UV-vis spectrophotometry, and triple-detection size-exclusion chromatography (TD-SEC). The number of monocyclic units of the resultant hyperbranched multicyclic polymer reaches about 21 based on multi-angle laser light scattering (MALLS) measurements. The plot of intrinsic viscosity versus molecular weight reveals that the α value of the unique hyperbranched multicyclic polymer is lower than both hyperbranched polymers and cyclic polymers.