3-Ethynyltriimidazo[1,2-a:1',2'-c:1″,2″-e][1,3,5]triazine Dual Short- and Long-Lived Emissions with Crystallization-Enhanced Feature: Role of Hydrogen Bonds and π-π Interactions.

Organic room temperature phosphorescent (ORTP) materials with stimuli-responsive, multicomponent emissive behaviour are extremely desirable for various applications. The derivative of cyclic triimidazole (TT) functionalized with an ethynyl group, TT-CCH, is isolated and investigated. The compound possesses crystallization-enhanced emission (CEE) comprising dual fluorescence and dual phosphorescence of both molecular and supramolecular origin with aggregation-induced components highly sensitive to grinding. The mechanisms involved in the emissions have been disclosed thanks to combined structural, spectroscopic and computational investigations. In particular, strong CH⋯N hydrogen bonds are deemed responsible, for the first time in the TT family, together with frequently observed π⋯π stacking interactions, for the aggregated fluorescence and phosphorescence.

Direct Decarboxylative C-2 Alkylation of Azoles through Minisci-Type Coupling.

This note discusses the application of a Minisci-type reaction for the direct alkylation of azoles with carboxylic acids as radical precursors. Different reaction conditions were investigated to achieve high yield of the desired products, focusing on acid strength and solvent screening. Moreover, the reactivity of imidazoles with various carboxylic acids was investigated, showing good yield for most cases. The study reveals the potential of this approach for late-stage functionalization in drug discovery.

Ligandless Palladium-Catalyzed Direct C-5 Arylation of Azoles Promoted by Benzoic Acid in Anisole.

The palladium-catalyzed direct arylation of azoles with (hetero)aryl halides is nowadays one of the most versatile and efficient procedures for the selective synthesis of heterobiaryls. Although this procedure is, due to its characteristics, also of great interest in the industrial field, the wide use of a reaction medium such as DMF or DMA, two polar aprotic solvents coded as dangerous according to environmental, health, safety (EHS) parameters, strongly limits its actual use. In contrast, the use of aromatic solvents as the reaction medium for direct arylations, although some of them show good EHS values, is poorly reported, probably due to their low solvent power against reagents and their potential involvement in undesired side reactions. In this paper we report an unprecedented selective C-5 arylation procedure involving anisole as an EHS green reaction solvent. In addition, the beneficial role of benzoic acid as an additive was also highlighted, a role that had never been previously described.

Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug.

Water-soluble amphiphilic random copolymers composed of tri(ethylene glycol) methacrylate (TEGMA) or poly(ethylene glycol) methyl ether methacrylate (PEGMA) and perfluorohexylethyl acrylate (FA) were synthesized by ARGET-ATRP, and their self-assembling and thermoresponsive behavior in water was studied by dynamic light scattering (DLS) and UV-vis spectroscopy. The copolymer ability to self-fold in single-chain nano-sized structures (unimer micelles) in aqueous solutions was exploited to encapsulate Combretastatin A-4 (CA-4), which is a very hydrophobic anticancer drug. The cloud point temperature (Tcp) was found to linearly decrease with increasing drug concentration in the drug/copolymer system. Moreover, while CA-4 was preferentially incorporated into the unimer micelles of TEGMA-ran-FA, the drug was found to induce multi-chain, submicro-sized aggregation of PEGMA-ran-FA. Anyway, the encapsulation efficiency was very high (≥81%) for both copolymers. The drug release was evaluated in PBS aqueous solutions both below and above Tcp for TEGMA-ran-FA copolymer and below Tcp, but at two different drug loadings, for PEGMA-ran-FA copolymer. In any case, the release kinetics presented similar profiles, characterized by linear trends up to ≈10-13 h and ≈7 h for TEGMA-ran-FA and PEGMA-ran-FA, respectively. Then, the release rate decreased, reaching a plateau. The release from TEGMA-ran-FA was moderately faster above Tcp than below Tcp, suggesting that copolymer thermoresponsiveness increased the release rate, which occurred anyway by diffusion below Tcp. Cytotoxicity tests were carried out on copolymer solutions in a wide concentration range (5-60 mg/mL) at 37 °C by using Balb/3T3 clone A31 cells. Interestingly, it was found that the concentration-dependent micro-sized aggregation of the amphiphilic random copolymers above Tcp caused a sort of "cellular asphyxiation" with a loss of cell viability clearly visible for TEGMA-ran-FA solutions (Tcp below 37 °C) with higher copolymer concentrations. On the other hand, cells in contact with the analogous PEGMA-ran-FA (Tcp above 37 °C) presented a very good viability (≥75%) with respect to the control at any given concentration.

Ligand-free Pd/Ag-mediated dehydrogenative alkynylation of imidazole derivatives.

A variety of 2-alkynyl(benzo)imidazoles have been synthesized by dehydrogenative alkynylation of (benzo)imidazoles with terminal alkyne in NMP under air in the presence of Ag2CO3 as the oxidant and Pd(OAc)2 as the catalyst precursor. The data obtained in this study support a reaction mechanism involving a non-concerted metalation deprotonation (n-CMD) pathway.

Aggregation Effects on Pigment Coatings: Pigment Red 179 as a Case Study.

Here, we have studied, with a combined experimental and computational approach, the effect of the crystal environment and aggregation on the electronic properties of Pigment Red 179, which affect both its color and optical energy gap. Spectra acquired in the near-infrared and visible range of energies suggest that this molecule is indeed a "cool" dye, which can be employed as a red pigment that provides effective color coverage to different substrates without contributing to their heating during light irradiation. Spectra acquired on different polymer mixtures at different pigment concentrations (i.e., 2.5-10 wt %) suggest that absorption features depend on chromophoric arrangements promoted by the strong intermolecular π-π interactions. Calculations, performed at the time-dependent density functional theory level, allowed to both attribute the nature of the electronic transitions causing the observed spectra involved and understand the effect of the environment. Indeed, the visible spectra of the pigment is dominated by two localized transitions, with negligible charge transfer for both a dye monomer and dimer either in vacuum or acetonitrile solution. Instead, models including the crystal environment of the pigment show the presence of a high-wavelength S1 ← S0 charge transfer transition between two adjacent molecules, in quantitative agreement with the experimental absorption energy of the crystal pigment.

Stereoselectivity of Aldose Reductase in the Reduction of Glutathionyl-Hydroxynonanal Adduct.

The formation of the adduct between the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) and glutathione, which leads to the generation of 3-glutathionyl-4-hydroxynonane (GSHNE), is one of the main routes of HNE detoxification. The aldo-keto reductase AKR1B1 is involved in the reduction of the aldehydic group of both HNE and GSHNE. In the present study, the effect of chirality on the recognition by aldose reductase of HNE and GSHNE was evaluated. AKR1B1 discriminates very modestly between the two possible enantiomers of HNE as substrates. Conversely, a combined kinetic analysis of the glutathionyl adducts obtained starting from either 4R- or 4S-HNE and mass spectrometry analysis of GSHNE products obtained from racemic HNE revealed that AKR1B1 possesses a marked preference toward the 3S,4R-GSHNE diastereoisomer. Density functional theory and molecular modeling studies revealed that this diastereoisomer, besides having a higher tendency to be in an open aldehydic form (the one recognized by AKR1B1) in solution than other GSHNE diastereoisomers, is further stabilized in its open form by a specific interaction with the enzyme active site. The relevance of this stereospecificity to the final metabolic fate of GSHNE is discussed.

Anticancer effects of novel resveratrol analogues on human ovarian cancer cells.

Resveratrol, a naturally occurring phytoalexin, has long been known to play an important regulatory role in key functions in cell physiology. This multifunctional role of resveratrol is explained by its ability to interact with several targets of various cell pathways. In the recent past, synthetic chemical modifications have been made in an attempt to enhance the biological effects of resveratrol, including its anti-cancer properties. In this study, we investigated the molecular mechanisms of action of novel trans-restricted analogues of resveratrol in which the C-C double bond of the natural derivative has been replaced by diaryl-substituted imidazole analogues. In ovarian cancer models, the results of in vitro screening revealed that the resveratrol analogues exhibited enhanced anti-proliferative properties compared with resveratrol. We found that the resveratrol analogues also significantly inhibited Akt and MAPK signalling and reduced the migration of IL-6 and EGF-treated cells. Finally, in ascite-derived cancer cells, we demonstrated that the resveratrol analogues reduced the expression of epithelial mesenchymal transition (EMT) markers. Collectively, these findings indicate the enhanced anti-cancer properties of the resveratrol analogues.

Integrating computational and chemical biology tools in the discovery of antiangiogenic small molecule ligands of FGF2 derived from endogenous inhibitors.

The FGFs/FGFRs system is a recognized actionable target for therapeutic approaches aimed at inhibiting tumor growth, angiogenesis, metastasis, and resistance to therapy. We previously identified a non-peptidic compound (SM27) that retains the structural and functional properties of the FGF2-binding sequence of thrombospondin-1 (TSP-1), a major endogenous inhibitor of angiogenesis. Here we identified new small molecule inhibitors of FGF2 based on the initial lead. A similarity-based screening of small molecule libraries, followed by docking calculations and experimental studies, allowed selecting 7 bi-naphthalenic compounds that bound FGF2 inhibiting its binding to both heparan sulfate proteoglycans and FGFR-1. The compounds inhibit FGF2 activity in in vitro and ex vivo models of angiogenesis, with improved potency over SM27. Comparative analysis of the selected hits, complemented by NMR and biochemical analysis of 4 newly synthesized functionalized phenylamino-substituted naphthalenes, allowed identifying the minimal stereochemical requirements to improve the design of naphthalene sulfonates as FGF2 inhibitors.

Tuning of dye optical properties by environmental effects: a QM/MM and experimental study.

The present work is aimed at a deeper investigation of two recently synthesized heteroaromatic fluorophores by means of a computational multilayer approach, integrating quantum mechanics (QM) and molecular mechanics (MM). In particular, dispersion of the title dyes in a polymer matrix is studied in connection with potential applications as photoactive species in luminescent solar concentrators (LSCs). Molecular dynamics simulations, based on accurate QM-derived force fields, reveal increased stiffness of these organic dyes when going from CHCl3 solution to the polymer matrix. QM/MM computations of UV spectra for snapshots extracted from MD simulations show that this different flexibility permits explaining the different spectral shapes obtained experimentally for the two different environments. Moreover, the general spectroscopic trends are reproduced well by static computations employing a polarizable continuum description of environmental effects.

Structural, thermal and photo-physical data of azo-aromatic TEMPO derivatives before and after their grafting to polyolefins.

The data reported in this paper are complementary to the characterization of 4-(phenylazo)-benzoyl-2,2,6,6-tetramethylpiperidine-1-oxyl radical (AzO-TEMPO) and of the 4-(2-thienylazo)-benzoyl-2,2,6,6-tetramethylpiperidine-1-oxyl radical (ThiO-TEMPO) before and after their grafting to two polyethylene matrices (a copolymer ethylene/α-olefin (co-EO) and a high density polyethylene (HDPE)). Particularly the data reported in this paper confirm the structure (FT-IR analysis), the thermal (TGA and EPR) and the photo-physical (UV-vis) properties of the RO-TEMPO derivatives before and after their grafting. Herein, the FT-IR spectrum and TGA thermogram of ThiO-TEMPO were compared with those of AzO-TEMPO. Moreover, the superimposition of UV-vis spectra collected during the irradiation under 366 or 254 nm emitting lamp of AzO-TEMPO and ThiO-TEMPO in acetonitrile solution are reported. Finally, a complete DSC characterization of the functionalized POs is shown. DOI of original article: 〈http://dx.doi.org/10.1016/j.polymer.2015.11.018〉 [1].

A New 1,3,4-Oxadiazole-Based Hole-Transport Material for Efficient CH3 NH3 PbBr3 Perovskite Solar Cells.

A new hole-transport material (HTM) based on the 1,3,4-oxadiazole moiety (H1) was prepared through a single-step synthetic pathway starting from commercially available products. Thanks to a deep HOMO level, H1 was used as HTM in CH3 NH3 PbBr3 perovskite solar cells yielding an efficiency of 5.8%. The reference HTM (Spiro-OMeTAD), under the same testing conditions, furnished a lower efficiency of 5.1%. Steady-state and time-resolved photoluminescence of the thin films showed good charge-extraction dynamics for H1 devices. In addition, H1 shows a large thermal stability and completely amorphous behavior (as evaluated by thermal gravimetric analysis and differential scanning calorimetry).

Toward the design of alkynylimidazole fluorophores: computational and experimental characterization of spectroscopic features in solution and in poly(methyl methacrylate).

The possibilities offered by organic fluorophores in the preparation of advanced plastic materials have been increased by designing novel alkynylimidazole dyes, featuring different push and pull groups. This new family of fluorescent dyes was synthesized by means of a one-pot sequential bromination-alkynylation of the heteroaromatic core, and their optical properties were investigated in tetrahydrofuran and in poly(methyl methacrylate). An efficient in silico pre-screening scheme was devised as consisting of a step-by-step procedure employing computational methodologies by simulation of electronic spectra within simple vertical energy and more sophisticated vibronic approaches. Such an approach was also extended to efficiently simulate one-photon absorption and emission spectra of the dyes in the polymer environment for their potential application in luminescent solar concentrators. Besides the specific applications of this novel material, the integration of computational and experimental techniques reported here provides an efficient protocol that can be applied to make a selection among similar dye candidates, which constitute the essential responsive part of those fluorescent plastic materials.

Synthesis and Optical Properties of Imidazole-Based Fluorophores having High Quantum Yields.

A series of 1,4-phenylene-spaced bis-imidazoles with fluorescence quantum yields up to 0.90 and large Stokes shifts have been designed and synthesized using recently developed regioselective direct CH arylation protocols. All the fluorophores show a bright blue-green emission that is well retained in the solid state. DFT calculations attributed their excellent luminescence properties to the significant planarization of the molecules in the equilibrium structures of their excited electronic states.

Computational design, synthesis, and mechanochromic properties of new thiophene-based π-conjugated chromophores.

The possibility of exploiting supramolecular architectures for the preparation of innovative mechanochromic devices has been extended by designing novel thienyl-substituted 1,4-bis(ethynyl)benzene dyes, which are characterized by a conjugated, rigid, rodlike core structure. This new family of chromophores was synthesized according to a simple two-step sequential cross-coupling reaction, and the optical properties were investigated in solution and in a polymeric matrix. To tune the mechanochromic performances in smart polymer materials, a virtual screening was set up that was able to select a derivative with optimal spectral features. The effective combination of experimental and computational investigations allowed us to spot those homologues with already potential anisotropic and aggregachromic features and characterized by the best spectral properties and luminescent response. The best candidate was synthesized and dispersed into a polyethylene matrix, indeed achieving an "in silico designed" mechanochromic material. Besides the specific applications of this novel material, the integration of computational and experimental techniques reported here defines an efficient protocol that can be applied to make a selection among similar dye candidates, which constitute the essential responsive part of such supramolecular devices.

Light-Responsive Polystyrene Films Doped with Tailored Heteroaromatic-Based Fluorophores.

We describe a simple but effective strategy for imparting light-responsive peculiarity to polystyrene films. A pH-sensitive fluorescent dye having the electron-poor pyridine nucleus as a key structural feature was synthesized and dispersed at low loadings (0.2-0.5 wt %) in a PS matrix. Once light irradiation in the near-UV range was sent to PS/dye films, PS photooxidation likely occurred at the film surface with the formation of carboxylic compounds. These species locally promoted dye protonation, thus, yielding a clear change of the film emission from blue to green. This study opens the door to a wide range of light-responsive materials from easily accessible polymers, enabling the use of UV light as an effective trigger for smart materials and devices.

Chiral ionic liquid-mediated photochirogenesis. Enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid.

Enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid (AC-H) and its lithium salt (AC-Li) in chiral ionic liquid (CIL), (R)-1-(2,3-dihydroxypropyl)-3-methylimidazolium acetate {[(R)-GLYMI][AcO]}, gave a mixture of two head-to-tail (HT) and two head-to-head (HH) cyclodimers in HT/HH ratios of 1.3-1.7 (for AC-H) and 2.2-4.3 (for AC-Li) with low enantiomeric excesses (ee) of 0-3% for chiral syn-HT and anti-HH dimers. In contrast, irradiation of AC-H in an aqueous solution, containing cucurbit[8]uril (CB[8]) as a host and [(R)-GLYMI][AcO] or [(R)-GLYMI][Tf(2)N] as a modifier of CB portals, afforded the HH dimers in 91-99% selectivity, although the anti-HH dimer was totally racemic. Interestingly, irradiation of AC-H in a dichloromethane solution, containing [(R)-GLYMI][AcO] as a chiral template, led to the formation of the HH-dimers in 98% selectivity with chiral anti-HH dimer in -14% ee, presumably by the dual ligation of two ACs to a CIL through electrostatic and hydrogen-bonding interactions.

The Heck reaction in ionic liquids: progress and challenges.

As the interest for environmental increases and environmental laws become more stringent, the need to replace existing processes with new more sustainable technologies becomes a primary objective. The use of ionic liquids to replace organic solvents in metal catalyzed reactions has recently gained much attention and great progress has been accomplished in this area in the last years. This paper reviews the recent developments in the application of ionic liquids and related systems (supported ionic liquids, ionic polymers, and so on) in the Heck reaction. Merits and achievements of ionic liquids were analyzed and discussed considering the possibility of increasing the effectiveness of industrial processes.

Photochirogenesis in chiral ionic liquid: enantiodifferentiating [4+4] photocyclodimerization of 2-anthracenecarboxylic acid in (R)-1-methyl-3-(2,3-dihydroxypropyl)imidazolium bistriflimide.

Enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid and its alkali metal salts performed in a chiral ionic liquid gave chiral cyclodimers in good enantiomeric excesses of up to 41%, which is the highest ever reported for a photochirogenic reaction in chiral media.

Novel (glycerol)borate-based ionic liquids: an experimental and theoretical study.

A series of newly designed (glycerol)borate based ionic liquids were synthesized and characterized. The synthesis of these ionic liquids involves, first, the preparation of the bis(glycerol)boric acid(s) followed by neutralization with the appropriate base, [cat]OH. Ionic liquids bearing inorganic (Li(+), Na(+), K(+)) or organic cations have been prepared and characterized. The ability of the bis(glycerol)borate anions to undergo dissociation reaction in the presence of water, depending on cation nature, was investigated by NMR. Theoretical calculations were also performed to evaluate the relative stability of the possible bis(glycerol)borate isomers as nude ions or as ion pairs with Li(+), Na(+), and H(+). Important information about the structural features of H[Gly(2)B] useful to rationalize the chemical behavior have been obtained.