NaI-Mediated Electrochemical Cyclization-Desulfurization for the Synthesis of N-Substituted 2-Aminobenzimidazoles.

An electrochemical method for the synthesis of N-substituted 2-aminobenzimidazoles through a NaI-mediated desulfurization-cyclization process is reported. This electrosynthesis method utilizes cost-effective NaI as both a mediator and an electrolyte in a catalytic amount (0.2 equiv), replacing traditional oxidizing reagents. N-Substituted o-phenylenediamines and isothiocyanates undergo a thiourea formation/cyclization/desulfurization process to provide N-substituted 2-aminobenzimidazoles (55 examples, up to 98% yield) in a single reaction vessel. Importantly, this electrochemical methodology is applicable to gram-scale synthesis, maintaining reaction efficiency.

Electrochemical NaI-mediated one-pot synthesis of guanidines from isothiocyanates via tandem addition-guanylation.

In this study, we present an electrochemical approach for the synthesis of guanidines from isothiocyanates and amines in a single reaction vessel. This one-pot operation takes place in aqueous media, utilizing an undivided cell setup with NaI serving as both the electrolyte and mediator. The process involves the in situ generation of thiourea, followed by electrolytic guanylation with amines. Under ambient temperature conditions, we successfully demonstrated the formation of 30 different guanidine compounds, achieving yields ranging from fair to excellent. Furthermore, the synthesis method could be carried out on a gram scale with a good yield. This protocol stands out for its cost-effectiveness, step-economical design, high tolerance towards various functional groups, and environmentally friendly reaction conditions.

Indomethacin-based near-infrared photosensitizer for targeted photodynamic cancer therapy.

Near-IR fluorescent sensitizers based on heptamethine cyanine (Cy820 and Cy820-IMC) were synthesized and their abilities to target and abolish tumor cells via photodynamic therapy (PDT) were explored. Some hepthamethine cyanine dyes can be transported into cancer cells via the organic anion transporting polypeptides (OATPs). In this study, we aimed to enhance the target ability of the sensitizer by conjugation Cy820 with indomethacin, a non-steroidal anti-inflammatory drug (NSAID), to obtain Cy820-IMC that aimed to target cyclooxygenase-2 (COX-2) which overexpresses in cancer cells. The results showed that Cy820-IMC internalized the cancer cells faster than Cy820 which was verified to be related to COX-2 level and OATPs. Based on PDT experiments, Cy820-IMC has higher photocytotoxicity index than Cy820, >7.13 and 4.90, respectively, implying that Cy820-IMC showed better PDT property than Cy820. However, Cy820 exhibits slightly higher normal-to-cancer cell toxicity ratio than Cy820-IMC, 6.58 and 3.63, respectively. Overall, Cy820-IMC has superior cancer targetability and enhanced photocytoxicity. These characteristics can be further improved towards clinically approved sensitizers for PDT.

A Dihydropyridine Derivative as a Highly Selective Fluorometric Probe for Quantification of Au3+ Residue in Gold Nanoparticle Solution.

Novel dihydroquinoline derivatives (DHP and DHP-OH) were synthesized in one pot via a tandem trimerization-cyclization of methylpropiolate. DHP and DHP-OH possess strong blue fluorescence with high quantum efficiencies over 0.70 in aqueous media. DHP-OH displays a remarkable fluorescence quenching selectively to the presence of Au3+ through the oxidation of dihydropyridine to pyridinium ion as confirmed by NMR and HRMS. DHP-OH was used to demonstrate the quantitative analysis of Au3+ in water samples with the limit of detection of 33 ppb and excellent recovery (>95%). This fluorescent probe was also applied for the determination of Au3+ residue in the gold nanoparticle solution and a paper-based sensing strip for the on-site detection of Au3+.

Self-Assembly of 1D Double-Chain and 3D Diamondoid Networks of Lanthanide Coordination Polymers through In Situ-Generated Ligands: High-Pressure CO2 Adsorption and Photoluminescence Properties.

Two new lanthanide-based coordination polymers, [Sm2(bzz)(ben)6(H2O)3]·0.5H2O (1) and [Eu(bbz)(ben)3] (2), were synthesized and characterized. The described products were formed from in situ-generated benzoate (ben) and N'-benzoylbenzohydrazide (bbz) ligands, which were the products of transformation of originally added benzhydrazide (bzz) under hydrothermal conditions. Compound 1 exhibits a one-dimensional (1D) double-chain structure built up from the connection of the central Sm3+ ions with a mixture of bzz and ben ligands. On the other hand, 2 features a 3D network with a 4-connected (66) dia topology constructed from dinuclear [Eu2(ben)6] secondary building units and bbz linkers. High-pressure CO2 sorption studies of activated 1 show that maximum uptake increases to exceptionally high values of 376.7 cm3 g-1 (42.5 wt%) under a pressure of 50 bar at 298 K with good recyclability. Meanwhile, 2 shows a typical red emission in the solid state at room temperature with the decay lifetime of 1.2 ms.

Flavylium-Based Hypoxia-Responsive Probe for Cancer Cell Imaging.

A hypoxia-responsive probe based on a flavylium dye containing an azo group (AZO-Flav) was synthesized to detect hypoxic conditions via a reductase-catalyzed reaction in cancer cells. In in vitro enzymatic investigation, the azo group of AZO-Flav was reduced by a reductase in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) followed by fragmentation to generate a fluorescent molecule, Flav-NH2. The response of AZO-Flav to the reductase was as fast as 2 min with a limit of detection (LOD) of 0.4 µM. Moreover, AZO-Flav displayed high enzyme specificity even in the presence of high concentrations of biological interferences, such as reducing agents and biothiols. Therefore, AZO-Flav was tested to detect hypoxic and normoxic environments in cancer cells (HepG2). Compared to the normal condition, the fluorescence intensity in hypoxic conditions increased about 10-fold after 15 min. Prolonged incubation showed a 26-fold higher fluorescent intensity after 60 min. In addition, the fluorescence signal under hypoxia can be suppressed by an electron transport process inhibitor, diphenyliodonium chloride (DPIC), suggesting that reductases take part in the azo group reduction of AZO-Flav in a hypoxic environment. Therefore, this probe showed great potential application toward in vivo hypoxia detection.

Hydrophilic Truxene Derivative as a Fluorescent off-on Sensor for Copper (II) Ion and Phosphate Species.

A new symmetrical truxene derivative (TP3) containing three dipicolylamino peripheral groups is successfully synthesized in four synthetic steps with an overall yield of 42%. This hydrophilic fluorescent compound exhibits a maximum absorption wavelength at 375 nm, an emission maximum at 474 nm with an outstanding 58% quantum efficiency in THF-HEPES buffer mixture. The compound shows a highly selective fluorescence quenching towards Cu(II) ion with a detection limit of 0.06 ppm. The results from mass spectrometry and Job plot indicate that a 1:1 complex between TP3 and Cu(II) ion is responsible for the signal quenching. Interestingly, this TP3-Cu complex can be used as a turn-on sensor for hydrogen phosphate and nucleoside phosphates. The limit of detection for hydrogen phosphate is estimated at 8.7 nM. The signal restoration involves a displacement of TP3 in the complex by the phosphates which have strong coordination abilities with Cu(II) ion.

Microwave-Enhanced On-Water Amination of 2-Mercaptobenzoxazoles To Prepare 2-Aminobenzoxazoles.

In this work, we developed a catalyst-free amination of 2-mercaptobenzoxazoles on water under microwave irradiation. The product, 2-aminobenzoxazoles, was successfully produced via direct amination with various amines in moderate to high yields. The formal synthesis of Suvorexant, a medication for the treatment of insomnia, was accomplished using a developed amination process. The reaction was completed in an hour at 100-150 °C in a microwave reactor without the use of external catalyst or additive. Key benefits of this process include an on-water reaction, short reaction time, being scalable and catalyst-free, and use of 2-mercaptobenzoxazoles as an inexpensive starting material having low environmental impact in its preparation.

Organocatalytic Visible Light Enabled SNAr of Heterocyclic Thiols: A Metal-Free Approach to 2-Aminobenzoxazoles and 4-Aminoquinazolines.

The direct amination reaction of heterocyclic thiols has been developed in the presence of the nonhazardous photocatalyst Rose Bengal under irradiation of visible light. The reaction provides a straightforward approach to pharmaceutically and synthetically useful 2-aminobenzoxazole and 4-aminoquinazoline derivatives from the corresponding heterocyclic thiols with amines in good to excellent yields. Our photochemical reaction can be successfully adapted into a continuous flow reactor which is applicable for large-scale chemical industry. The key benefits of this reaction include the use of metal-free, low-cost Rose Bengal catalyst and practical operation (ambient temperature, open flask, and undried solvents).

Salicylyl Fluorene Derivatives as Fluorescent Sensors for Cu(II) Ions.

Two derivatives of fluorene containing salicylic acid groups are successfully synthesized by palladium-catalyzed coupling reactions and subsequent hydrolysis of salicylate esters. The compounds are characterized by various spectroscopic methods. In phosphate buffer (pH 8.0) solutions, these compounds are well soluble. They show maximum absorption wavelengths in the range of 304-330 nm and exhibit maximum emission wavelength around 420 and 430 nm with the quantum yields of 2.7 and 4.4 %, respectively. The compound with alkynyl salicylate groups (2) exhibits a selective fluorescence quenching towards Cu(II) and Fe(II) with a relatively similar sensitivity. The selectivity favoring Cu(II) over Fe(II) and other metal ions can be achieved upon the addition of 30 µM Triton X-100. The Cu(II) detection limit in solution phase is 1.47 ppb. The fluorescence signal recovery upon the addition of EDTA indicate a reversible complexation between 2 and Cu(II) ion. Fabrication of 2 on filter paper using a 50 µM solution in THF affords a naked-eye detection for Cu(II) and Fe(II) in aqueous media at picomole level.

Glucopyranosyl-1,4-dihydropyridine as a new fluorescent chemosensor for selective detection of 2,4,6-trinitrophenol.

Glucopyranosyl-1,4-dihydropyridine (Glc-DHP) was synthesized as a new fluorescent chemosensor via cyclotrimerization of the ß-amino acrylate in the presence of TiCl4. This DHP derivative is soluble in aqueous medium and the solution gives a blue fluorescence signal with a quantum yield of 29%. The fluorescence signal of Glc-DHP was selectively quenched by 2,4,6-trinitrophenol (TNP) with a quenching coefficient (Ksv) of 4.47 × 10(4) and at one of the best reported detection limits of 0.94 µM. The quenching mechanism was confirmed to be of the static type at the low concentration region (less than 50 µM) with the significant quenching effect of competitive absorption starting from the concentration of 50 µM. Even in the real sample (seawater and industrial water), the quenching efficiencies of TNP on the fluorescence emission of Glc-DHP were proven to be at the same level with that of the test in pure water, demonstrating the practicability of the detection. Furthermore, a fluorescent paper sensor could be prepared by immersing the paper into the Glc-DHP solution. The fluorescence of the paper sensor disappeared either by writing with TNP solution or by exposure to TNP vapor. This detection could be observed by the naked eye under black light. The pH effect was proven to be a substantial factor in the quenching mechanism, providing an accurate determination of TNP, 2,4-dinitrophenol (DNP) and 4-nitrophenol (4NP) in real mixed-samples.

Dual-mode optical sensing of organic vapors and proteins with polydiacetylene (PDA)-embedded electrospun nanofibers.

Optical sensors capable of colorimetric visualization and/or fluorescence detection have shown tremendous potential for field technicians and emergency responders, owing to the portability and low cost of such devices. Polydiacetylene (PDA)-enhanced nanofibers are particularly promising due to high surface area, facile functionalization, simple construction, and the versatility to empower either colorimetric or fluorescence signaling. We demonstrate here a dual-mode optical sensing with electrospun nanofibers embedded with various PDAs. The solvent-dependent fluorescent transition of nanofibers generated a pattern that successfully distinguished four common organic solvents. The colorimetric and fluorescent sensing of biotin-avidin interactions by embedding biotinylated-PCDA monomers into silica-reinforced nanofiber mats were realized for detection of biomolecules. Finally, a PDA-based nanofiber sensor array consisting of three monomers has been fabricated for the determination and identification of organic amine vapors using colorimetry and principal component analysis (PCA). The combination of PCA and the strategy of probing analytes in two different concentration ranges (ppm and ppth) led to successful analysis of all eight amines.

New water soluble terphenylene diethynylene fluorophores.

Inspired by our earlier works on sensors from dendritic phenyleneethynylenes, two new star-shaped water-soluble fluorophores containing terphenylene diethynylene units and anionic carboxylate peripheries are successfully synthesized. The convergent synthesis relies on Sonogashira cross-coupling reactions between tris-(4-ethynylphenyl)amine and the iodophenyleneethynylene branches. All of the compounds are characterized by (1)H, (13)C NMR, and mass spectrometry. In aqueous solution, the less polar fluorophore 1 shows lower quantum yield than 2 (18 vs 33%) as a result of hydrophobic induced aggregation. One of these anionic water-soluble fluorophores exhibits a selective fluorescence quenching by Fe(3+) ion in phosphate buffer pH 8.

A 5,7-dimethoxyflavone/hydroxypropyl-ß-cyclodextrin inclusion complex with anti-butyrylcholinesterase activity.

This study aimed to improve the water solubility of 5,7-dimethoxyflavone (5,7-DMF) isolated from Kaempferia parviflora by complexation with 2-hydroxypropyl-ß-cyclodextrin (HPß-CD). The phase solubility profile of 5,7-DMF in the presence of HPß-CD was classified as AL-type and indicated a 1:1 mole ratio. Differential scanning colorimetry, X-ray diffraction, NMR and SEM analyses supported the formation of a 5,7-DMF/HPß-CD inclusion complex involving the A ring of 5,7-DMF inside the HPß-CD cavity. This is the first example of CD inclusion with the A ring of non-hydroxyl flavones. The stability and binding constants of the complexes were determined using the phase solubility and UV-vis absorption spectroscopy, respectively. The water solubility of 5,7-DMF was increased 361.8-fold by complexation with HPß-CD and overcame the precipitation problem observed in aqueous buffers, such as during in vitro anti-butyrylcholinesterase activity assays. The 1:1 mole ratio of the 5,7-DMF/HPß-CD complex showed a 2.7-fold higher butyrylcholinesterase inhibitory activity (in terms of the IC50 value) compared to the non-complexed compound.

Cu(II) detection by a fluorometric probe based on thiazoline-amidoquinoline derivative and its application to water and food samples.

Two novel fluorescent probes for Cu2+ detection have been developed based on thiazoline-quinoline conjugates bearing a 4-ethynyl-N,N-dimethylaniline unit (QT1 and QT2). QT2 exhibits instantaneous fluorescence quenching of Cu2+ with an emissive change from bright orange to arctic blue under UV light irradiation (365 nm). The plots of I0/I against Cu2+ concentrations show a good linear relationship that ranges from 0 to 50 µM with a coefficient of determination (R2) = 0.9906 and a limit of detection (LOD) of 76 nM, which is considered low (4.84 ppb). A 1:1 complexation between QT2 and Cu2+ was confirmed by UV-Vis titration, ESI-MS, and SC-XRD. The QT2·Cu2+ complex was dissociated by the addition of EDTA. The fluorescence quenching mechanism involves the ligand-to-metal charge transfer (LMCT) of a paramagnetic Cu2+ complex. The QT2 probe on a paper-based strip was used to determine the amount of Cu2+ in water and food samples (shiitake mushrooms and oysters).

Synthesis, structure and photoluminescence properties of heterometallic-based coordination polymers of trimesic acid.

Reacting trimesic acid (H3TMA, C9H6O6) with CaCl2 and MCl2 at 110 °C under hydrothermal conditions gave the isostructural heterobimetallic coordination polymers (CPs) catena-poly[[tetraaquazinc(II)]-µ-5-carboxybenzene-1,3-dicarboxylato-[tetraaquacalcium(II)]-µ-5-carboxybenzene-1,3-dicarboxylato], [CaZn(HTMA)2(H2O)8]n, 1, and catena-poly[[tetraaquacobalt(II)]-µ-5-carboxybenzene-1,3-dicarboxylato-[tetraaquacalcium(II)]-µ-5-carboxybenzene-1,3-dicarboxylato], [CaCo(HTMA)2(H2O)8]n, 2. Compounds 1 and 2 crystallize in the monoclinic space group C2/c. The solid-state structures consist of eight-coordinate CaII ions and six-coordinate MII ions. These ions are connected by a doubly deprotonated HTMA2- ligand to create a one-dimensional (1D) zigzag chain. Poly[[decaaquabis(µ3-benzene-1,3,5-tricarboxylato)calcium(II)dizinc(II)] dihydrate], {[CaZn2(TMA)2(H2O)10]·2H2O}n, 3, was found incidentally as a minor by-product during the synthesis of 1 at a temperature of 140 °C. It forms crystals in the orthorhombic space group Ccce. The structure of 3 consists of a two-dimensional (2D) layer composed of [Zn(TMA)] chains that are interconnected by CaII ions. The presence of aromatic carboxylic acid ligands and water molecules, which can form numerous hydrogen bonds and π-π interactions, increases the stability of the three-dimensional (3D) supramolecular architecture of these CPs. Compounds 1 and 2 exhibit thermal stability up to 420 °C, as indicated by the thermogravimetric analysis (TGA) curves. The powder X-ray diffraction (PXRD) data reveal the formation of unidentified phases in methanol and dimethyl sulfoxide, while 1 exhibits chemical stability in a wide range of solvents. The luminescence properties of 1 dispersed in various low molecular weight organic solvents was also examined. The results demonstrate excellent selectivity, sensitivity and recyclability for detecting acetone molecules in aqueous media. Additionally, a possible sensing mechanism is also outlined.

A novel "turn-on" fluorescent probe based on thiocarbamoyl-DHP for Hg2+ detection in water samples and living cells.

In this study, two fluorescent sensing probes, dihydropyridine (DHP) derivatives (DHP-CT1 and DHP-CT2) bearing phenoxy thiocarbonyl group, have been developed for Hg2+ detection. The tandem trimerization-cyclization of methylpropiolate with ammonium acetate gave 1.4-DHP and 1,2-DHP derivatives, which were reacted with O-phenylcarbonochloridothioate to produce DHP-CT1 and DHP-CT2, respectively. DHP-CT1 exhibits superior sensitivity and selectivity of fluorescence enhancement towards Hg2+ in aqueous media. The fluorescence intensity shows a good linear relationship with the concentration of Hg2+ in the range of 0-10 µM providing the extremely low LOD of 346 nM (69.4 ppb). The fluorescence enhancement is caused by the Hg2+ promoted hydrolysis of the thioamide bond releasing the fluorescent 1,4-DHP that was confirmed by NMR and HRMS. The quantitative analysis of Hg2+ in water samples using DHP-CT1 probe was demonstrated in aqueous solution and paper-based sensing strips. Furthermore, DHP-CT1 was also applied for monitoring intracellular Hg2+ in living RAW264.7 macrophages through fluorescence cell imaging.

Switchable Metal-Ion Selectivity in Sulfur-Functionalised Pillar[5]arenes and Their Host-Guest Complexes.

Nucleophilic substitution of pertosylated pillar[5]arene (P-OTs) with commercially available sulfur containing nucleophiles (KSCN, KSAc, and thiophenol), yields a series of sulfur-functionalised pillar[5]arenes. DLS results and SEM images imply that these pillararene macrocycles self-assemble in acetonitrile solution, while X-ray crystallographic evidence suggests solvent-dependent assembly in the solid state. The nature of the sulfur substituents decorating the rim of the pillararene controls binding affinities towards organic guest encapsulations within the cavity and dictates metal-ion binding properties through the formation of favorable S-M2+ coordination bonds outside the cavity, as determined by 1 H NMR and fluorescence spectroscopic experiments. Addition of a dinitrile guest containing a bis-triazole benzene spacer (btn) induced formation of pseudorotaxane host-guest complexes. Fluorescence emission signals from these discrete macrocycles were significantly attenuated in the presence of either Hg2+ or Cu2+ in solution. Analogous titrations utilizing the corresponding pseudorotaxanes alter the binding selectivity and improve fluorescence sensing sensitivity. In addition, preliminary liquid-liquid extraction studies indicate that the macrocycles facilitate the transfer of Cu2+ from the aqueous to the organic phase in comparison to extraction without pillar[5]arene ligands.

Poly(N-isopropylacrylamide)-stabilized gold nanoparticles in combination with tricationic branched phenylene-ethynylene fluorophore for protein identification.

Gold nanoparticles stabilized by thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAM-AuNPs) were prepared by surface grafting of thiol-terminated PNIPAM onto citrate-stabilized AuNPs. The color change of the PNIPAM-AuNPs solution from red to blue-purple without precipitation when the solution was heated to 40 °C, above the lower critical solution temperature (LCST) of PNIPAM, indicated the thermoresponsive property of the synthesized AuNPs. PNIPAM-AuNPs were used to detect proteins by chemical nose approach based on fluorescence quenching of fluorophore by AuNPs. An array-based sensing platform for detection of six proteins, namely bovine serum albumin, lysozyme, fibrinogen, concanavalin A, hemoglobin, holo-transferrin human can be successfully developed from the PNIPAM-AuNPs having different molecular weights (4 and 8 kDa) and conformation (varied heat treatment from 25 to 40 °C) in combination with a tricationic branched phenylene-ethynylene fluorophore. From principal component analysis (PCA) followed by linear discriminant analysis (LDA), 100% accuracy of protein classification using a leave-one-out (LOO) approach can be achieved by using only two types of PNIPAM-AuNPs.

Selective copper-catalysed atom transfer radical addition (ATRA) in water under environmentally benign conditions.

Simple and green conditions for copper-catalysed ATRA reactions in water have been developed. Firstly, [Cu(ADPA)(H2O)(ClO4)2] (1b, ADPA = 9-[(2,2'-dipicolylamino)methyl]anthracene) was demonstrated to be capable of selectively catalysing the ATRA of CCl4 to styrene using L-ascorbic acid (AsH2) as a reducing agent in organic solvent mixtures under ambient atmosphere. Mechanistic investigation suggested that our ATRA reaction proceeded via a single-electron transfer (SET) mechanism through an inner-sphere complex, which is consistent with the widely accepted mechanism for copper-catalysed ATRA. To perform the reaction in water as a sole solvent, a biocompatible surfactant (2 wt% Tween 20 or Tween 80) was added to improve solubility and increase the local concentration of organic reagents and the copper catalyst. Without the need for a complicated oxygen-free set-up, the ATRA reaction catalysed by this simple aqueous-dispersed system can be performed at a mild temperature (60 °C) and a relatively short reaction time (6 h) using 1 mol% of the catalyst. Furthermore, this facile protocol is also applicable for other alkene substrates demonstrated in this work, resulting in satisfactory to excellent substrate conversion and product yields.