Highly Selective Anion Template Effect in the Synthesis of Constrained Pseudopeptidic Macrocyclic Cyclophanes.

Herein, we report the synthesis of a novel family of constrained pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo[3,4-f]isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Although the increase in the number of steps involved in the macrocyclization could lead to a larger number of possible side products, the optimization of the methodology and the study of the driving forces have made it possible to obtain the desired macrocycles in excellent yields. A thorough computational study has been carried out to understand the macrocyclization process, and the results obtained nicely agree with experimental data. Moreover, the bromide anion had a clear catalytic template effect in the macrocyclization reaction, and surprisingly, the chloride anion had a negative template effect in opposition to the results obtained for analogous macrocycles. The parameters responsible for the specific kinetic template effect observed have been studied in detail.

Rose Bengal Immobilized on Supported Ionic-Liquid-like Phases: An Efficient Photocatalyst for Batch and Flow Processes.

The catalytic activity of Rose Bengal (RB) immobilized on supported ionic liquid (IL)-like phases was evaluated as a polymer-supported photocatalyst. In these systems, the polymer was designed to play a pivotal role. The polymeric backbone adequately modified with IL-like moieties (supported IL-like phases, SILLPs) was not just an inert support for the dye but controlled the accessibility of reagents/substrates to the active sites and provided specific microenvironments for the reaction. The structure of SILLPs could be finetuned to adjust the catalytic efficiency of the RB-SILLP composites, achieving systems that were more active and stable than the related systems in the absence of IL-like units.

Chiral catalysts immobilized on achiral polymers: effect of the polymer support on the performance of the catalyst.

Positive effects of the polymeric support on the performance of supported chiral catalysts, in terms of activity, stability and selectivity-enantioselectivity, have been reported when the support is properly selected and optimized opening the way to the design of more efficient catalytic systems.

New porous monolithic membranes based on supported ionic liquid-like phases for oil/water separation and homogenous catalyst immobilisation.

Porous monolithic advanced functional materials based on supported ionic liquid-like phase (SILLP) systems were used for the preparation of oleophilic and hydrophobic cylindrical membranes and successfully tested as eco-friendly and safe systems for oil/water separation and for the continuous integration of catalytic and separation processes in an aqueous-organic biphasic reaction system.

The interaction of amino acids with macrocyclic pH probes of pseudopeptidic nature.

The fluorescence quenching, by a series of amino acids, of pseudopeptidic compounds acting as probes for cellular acidity has been investigated. It has been found that amino acids containing electron-rich aromatic side chains like Trp or Tyr, as well as Met quench the emission of the probes mainly via a collisional mechanism, with Stern-Volmer constants in the 7-43 M-1 range, while other amino acids such as His, Val or Phe did not cause deactivation of the fluorescence. Only a minor contribution of a static quenching due to the formation of ground-state complexes has been found for Trp and Tyr, with association constants in the 9-24 M-1 range. For these ground-state complexes, a comparison between the macrocyclic probes and an open chain analogue reveals the existence of a moderate macrocyclic effect due to the preorganization of the probes in the more rigid structure.

Cu2+ recognition by N,N'-benzylated bis(amino amides).

Two new C2-symmetric N,N'-benzylated bis(amino amides) have been synthesised and their interaction with different transition metals studied using a variety of techniques including UV-Vis and CD spectroscopy or ESI-MS. The determination of the corresponding stability constants with Cu2+ has been possible, in H2O/CH3CN 7/3 v/v, for one of these ligands (4) using potentiometric titrations. The results obtained reveal that N-benzylation affords significant changes to their properties and is accompanied by an appreciable decrease in the corresponding complexation stability constants. However, this, along with the low kinetics associated to Ni2+, facilitates the recognition of Cu2+ by 4 that can be followed by the naked-eye up to the submillimolar range. Very interestingly, the chiral nature of this ligand provides an intense and well defined CD curve for the corresponding Cu2+ complex, very sensitive to the coordination geometry, facilitating the analysis of this interaction even at the µM range. The formation by both ligands (3 and 4) of square planar complexes with Cu2+ and Ni2+ displaying a 1 : 1 stoichiometry was confirmed by their X-ray crystal structures.

Influence of polymer composition on the sensitivity towards nitrite and nitric oxide of colorimetric disposable test strips.

The influence of polymer composition on the sensitivity towards nitrite (NO2-) and nitric oxide (NO) of a series of 19 polymeric hydrogel films has been studied. The polymers, based on the hydrophilic monomer 2-hydroxyethylmethacrylate (HEMA), are able to encapsulate the colorimetric indicator 1,2-diaminoanthraquinone (DAQ) and to respond to NO2- and NO by visual changes. In the case of nitrite, the calculated limits of detection (LOD) for two of the polymeric sensors (10 µM) are very close to the sensitivity estimated for free DAQ in solution (LOD 5 µM), but with the advantage of a solid supported sensor with the format of a disposable test-strip made with affordable starting chemicals. The results are interpreted taking into account the nature and proportions of monomers and cross-linkers used for the synthesis of polymers. Key factors for obtaining sensitive materials are the hydrophilic character of the film along with the utilization of low levels of cross-linker and the use of an acidic monomer, like acrylic acid, as a building block.

Mechanistic implications of the enantioselective addition of alkylzinc reagents to aldehydes catalyzed by nickel complexes with α-amino amide ligands.

The enantioselective alkylation of aldehydes catalysed by nickel(ii)-complexes derived from α-amino amides was studied by means of density functional theory (DFT) and ONIOM (B3LYP:UFF) calculations. A mechanism was proposed in order to investigate the origin of enantioselectivity. The chirality-determining step for the alkylation was the formation of the intermediate complexes with the involvement of a 5/4/4-fused tricyclic transition state. The predominant products predicted theoretically were of (S)-configuration, in good agreement with experimental observations. The scope of the reaction was examined and high yields and enantioselectivities were observed for the enantioselective addition of Et2Zn and Me2Zn to aromatic and aliphatic aldehydes.

Cu(2+), Zn(2+), and Ni(2+) Complexes of C2-Symmetric Pseudopeptides with an Aromatic Central Spacer.

Two new tetradentate C2-symmetric pseudopeptidic ligands derived from Val and Phe containing two amino and two amido groups and a central o-substituted aromatic spacer have been prepared. Their complexes with Cu(2+), Zn(2+), and Ni(2+) have been studied by potentiometry, UV-vis spectrophotometry, FT-IR, and ESI-MS. The presence of the aromatic spacer provides Cu(2+) complexes with stability constants several orders of magnitude higher than those observed for related ligands containing aliphatic central spacers. Besides, the formation of [MH-2L] complex species is favored. Crystal structures for the corresponding Cu(2+) and Ni(2+) have been obtained, revealing the metal atom in an essentially square-planar geometry, although, in several instances, the oxygen atom of an amide carbonyl of a second complex species can act as a fifth coordination site. In the case of Zn(2+), the only crystal structure obtained displays a square-pyramidal arrangement of the metal center. Finally, preliminary experiments show the catalytic activity of some of these complexes, in particular, Zn(2+) complexes, for epoxide ring-opening with using aniline as the nucleophile in a ligand accelerated process.

Macrocycle Synthesis by Chloride-Templated Amide Bond Formation.

A new family of pseudopeptidic macrocyclic compounds has been prepared involving an anion-templated amide bond formation reaction at the macrocyclization step. Chloride anion was found to be the most efficient template in the macrocyclization process, producing improved macrocyclization yields with regard to the nontemplated reaction. The data suggest a kinetic effect of the chloride template, providing an appropriate folded conformation of the open-chain precursor and reducing the energy barrier for the formation of the macrocyclic product.

The synthesis of new fluorescent bichromophoric compounds as ratiometric pH probes for intracellular measurements.

Three different bichromophoric compounds (1-3) containing an aminomethyl anthracene moiety linked to a second chromophore (pyrene, 4-nitrobenzo-2-oxa-1,3-diazole (NBD) and dansyl) through a valine-derived pseudopeptidic spacer have been prepared and their fluorescent properties studied. The results obtained show that upon irradiation the photophysical behavior of these probes involves electronic energy transfer from the excited anthracene to the second chromophore and also intramolecular photoinduced electron transfer. The X-ray structure obtained for 3 reveals that the folding associated with the pseudopeptidic spacer favours a close proximity of the two chromophores. The emissive response of 3 is clearly dependent on the pH of the medium, hence this bichromophoric compound was shown to be an excellent ratiometric pH fluorescent sensor. The emission intensity due to the anthracene moiety exhibits a decrease at neutral-basic pH values that is concomitant with an increase in the intensity arising from the dansyl fluorophore. These properties make this compound a good candidate for biological pH sensing as has been confirmed by preliminary studies with RAW 264.7 macrophage cells imaged by means of confocal fluorescence microscopy with an average pH estimation of 5.4-5.8 for acidic organelles.

Application of optically active chiral bis(imidazolium) salts as potential receptors of chiral dicarboxylate salts of biological relevance.

A family of chiral bis(imidazolium) salts derived from natural amino acids has been synthesized by a simple synthetic approach and the corresponding bis(trifluoromethylsulfonyl)imide salts have been shown to be room temperature chiral ionic liquids (RTCILs). The structures and self-assembling properties of the resulting salts have been studied by (1)HNMR, ATR-FTIR, DSC, SEM and theoretical calculations. Moreover, these receptors have been applied to the enantiomeric recognition of dicarboxylic amino acids. The supramolecular complexes formed have been studied by (1)HNMR titration experiments, ATR-FTIR and DSC.

Recognition of free tryptophan in water by synthetic pseudopeptides: fluorescence and thermodynamic studies.

Pseudopeptidic receptors containing an acridine unit have been prepared and their fluorescence response to a series of amino acids was measured in water. Free amino acids, not protected either at the C or the N terminus, were used for this purpose. The prepared receptors display a selective response to tryptophan (Trp) versus the other assayed amino acids under acidic conditions. The macrocyclic nature of the receptor is important as the fluorescence quenching is higher for the macrocyclic compound than for the related open-chain receptor. Notably, under the experimental acidic conditions used, both the receptor and guest are fully protonated and positively charged; thus, the experimental results suggest the formation of supramolecular species that contain two positively charged organic molecular components in proximity stabilized through aromatic-aromatic interactions and a complex set of cation-anion-cation interactions. The selectivity towards Trp seems to be based on the existence of a strong association between the indole ring of the monocharged amino acid and the acridinium fragment of the triprotonated form of the receptor, which is established to be assisted by the interaction of the cationic moieties with hydrogen sulfate anions.

Tight and selective caging of chloride ions by a pseudopeptidic host.

The selective molecular recognition of chloride versus similar anions is a continuous challenge in supramolecular chemistry. We have designed and prepared a simple pseudopeptidic cage (1 a) that defines a cavity suitable for the tight encapsulation of chloride. The interaction of the protonated form of 1 a with different inorganic anions was studied in solution by (1)H NMR spectroscopy and ESI-MS, and in the solid state by X-ray diffraction. The solution binding data showed that the association constants of 1 a to chloride are more than two orders of magnitude higher than to any other tested inorganic anion. Remarkably, 1 a displayed a high selectivity for chloride over other closely related halides such as bromide (selectivity=111), iodide (selectivity=719), and fluoride (selectivity >1000). Binding experiments ((1)H NMR spectroscopy and ESI-MS) suggested that 1 a has a high-affinity (inner) binding site and an additional low-affinity (external) binding site. The supramolecular complexes with F(-), Cl(-), and Br(-) have been also characterized by the X-ray diffraction of the corresponding [1 a⋅nHX] crystalline salts. The structural data show that the chloride anion is tightly encapsulated within the host, in a binding site defined by a very symmetric array of electrostatic H-bonds. For the fluoride salt, the size of the cage cavity is too large and is occupied by a water molecule, which fits inside the cage efficiently competing with F(-). In the case of the bigger bromide, the mismatch of the anion inside the cage caused a geometrical distortion of the host and thus a large energetic penalty for the interaction. This minimalistic pseudopeptidic host represents a unique example of the construction of a simple well-defined binding pocket that allows the highly selective molecular recognition of a challenging substrate.

Turn-on fluorescent probes for nitric oxide sensing based on the ortho-hydroxyamino structure showing no interference with dehydroascorbic acid.

A new family of fluorescent synthetic molecular probes for nitric oxide sensing based on ortho-hydroxyamino-triarylpyrylium salts is presented.

The role of the amino acid-derived side chain in the preorganization of C2-symmetric pseudopeptides: effect on S(N)2 macrocyclization reactions.

A family of pseudopeptidic macrocycles containing non-natural amino acids have been synthesized. The macrocyclization reaction has been studied experimentally and computationally, demonstrating the key role of both the amino acid side chain and the catalytic bromide anion. The bromide anion acts as an external template assisting the folding of the open-chain precursor in a proper conformation. Computations revealed that in the presence of the anion, the effect of the side chain on the energy barrier for the macrocyclization is very small. However, the effect on the conformational equilibria of the open-chain precursors is very important. Overall, the stabilization of those conformation(s) in which the two reactive ends of the open-chain intermediate are located at short distances from each other with the correct orientation is the critical parameter defining the success of the macrocyclization. The best yield was found for the compound containing cyclohexylalanine, for which the computationally-predicted most stable conformer in the presence of Br(-) has a proper preorganization for cyclization. The remarkable agreement obtained between experiments and theory reveals that the computational approach here considered can be of great utility for the prediction of the behavior of other related systems and for the design of appropriate synthetic routes to new macrocyclic compounds.

Singlet oxygen generation by photoactive polymeric microparticles with enhanced aqueous compatibility.

Two new photoactive materials compatible with environmentally friendly solvents (water and methanol) have been synthesized and characterized. They are comprised of a porous matrix of polystyrene and divinylbenzene with bound Rose Bengal and additional pendant groups added to increase the hydrophilicity (ethylenediamine and γ-gluconolactone). The new polymers are efficient photocatalysts capable of generating singlet oxygen after irradiation with visible light. Photochemical oxygenations of 9,10-anthracenedipropionic acid and 2-furoic acid have been carried out. The measured conversions indicate that the new supported photosensitizers are more effective than the parent hydrophobic polymer.

Fluorescent macrocyclic probes with pendant functional groups as markers of acidic organelles within live cells.

A new family of acidity sensitive fluorescent macrocycles has been synthesized and fully characterized. Their photophysical properties including emission quantum yield and fluorescence lifetime have been determined. The acid-base properties of the new molecules can be tuned by the incorporation of pendant functional groups. The nature of such functional groups (carboxylic acid or ester) influences dramatically the pKa of the probes, two compounds of which exhibit low values. Preliminary intracellular studies using confocal microscopy together with emission spectra of the probes from the cellular environment have shown that the synthesized fluorescent macrocycles mark the acidic organelles of RAW 264.7 macrophage cells.

New advances in dual stereocontrol for asymmetric reactions.

Achieving dual stereocontrol in asymmetric reactions using a single enantiomer for the building of the chiral catalyst or auxiliary is a very important goal in enantioselective synthesis as it eliminates the need for having available the two enantiomers of the auxiliary or catalyst designed. Recent strategies and advances towards this goal during the last four years will be discussed throughout this review.