Crown Ether Receptors Research Articles

Proximity Effects on the Reactivity of a Nonheme Iron (IV) Oxo Complex in C-H Oxidation.

Precise control of substrate positioning and orientation (its proximity to the reactive unit) is often invoked to rationalize the superior enzymatic reaction rates and selectivities when compared to synthetic models. Artificial nonheme iron (IV) oxo (Fe(IV)=O) complexes react with C(sp3)-H bonds via a biomimetic Hydrogen Atom Transfer/Hydroxyl Rebound mechanism, but rates, site-selectivity and even hydroxyl rebound efficiency (ligand rebound versus substrate radical diffusion) are smaller than in oxygenases. Herein, we quantitatively analyze how substrate binding modulates nonheme Fe(IV)=O reactivity by comparing rates and outcomes of C-H oxidation by a pair of Fe(IV)=O complexes that share the same first coordination sphere but only one contains a crown ether receptor that recognizes the substrate. Substrate binding makes the reaction intramolecular, exhibiting Michaelis-Menten kinetics and increased reaction rates. In addition, C-H oxidation occurs with high site selectivity for remote sites. Analysis of Effective Molarity reveals that the system operates at its maximal theoretical capability for the oxidation of these remote sites. Remarkably, substrate positioning also affects Hydroxyl Rebound, whose efficiency only increases on the sites placed in proximity by recognition. Overall, these observations provide evidence that supramolecular control of substrate positioning can effectively modulate the reactivity of oxygenases and its models.

Proximity Effects on the Reactivity of a Nonheme Iron (IV) Oxo Complex in C−H Oxidation

AbstractPrecise control of substrate positioning and orientation (its proximity to the reactive unit) is often invoked to rationalize the superior enzymatic reaction rates and selectivities when compared to synthetic models. Artificial nonheme iron (IV) oxo (Fe(IV)=O) complexes react with C(sp3)−H bonds via a biomimetic Hydrogen Atom Transfer/Hydroxyl Rebound mechanism, but rates, site‐selectivity and even hydroxyl rebound efficiency (ligand rebound versus substrate radical diffusion) are smaller than in oxygenases. Herein, we quantitatively analyze how substrate binding modulates nonheme Fe(IV)=O reactivity by comparing rates and outcomes of C−H oxidation by a pair of Fe(IV)=O complexes that share the same first coordination sphere but only one contains a crown ether receptor that recognizes the substrate. Substrate binding makes the reaction intramolecular, exhibiting Michaelis–Menten kinetics and increased reaction rates. In addition, C−H oxidation occurs with high site selectivity for remote sites. Analysis of Effective Molarity reveals that the system operates at its maximal theoretical capability for the oxidation of these remote sites. Remarkably, substrate positioning also affects Hydroxyl Rebound, whose efficiency only increases on the sites placed in proximity by recognition. Overall, these observations provide evidence that supramolecular control of substrate positioning can effectively modulate the reactivity of oxygenases and its models.

A Doubly Dissipative System Driven by Chemical and Radiative Stimuli.

The operation of a dissipative network composed of two or three different crown-ether receptors and an alkali metal cation can be temporally driven by the use (combined or not) of two orthogonal stimuli of a different nature. More specifically, irradiation with light at a proper wavelength and/or addition of an activated carboxylic acid, are used to modulate the binding capability of the above crown-ethers towards the metal ion, allowing to control over time the occupancy of the metal cation in the crown-ether moiety of a given ligand. Thus, application of either or both of the stimuli to an initially equilibrated system, where the metal cation is distributed among the crown-ether receptors depending on the different affinities, causes a programmable change in the receptor occupancies. Consequently, the system is induced to evolve to one or more out-of-equilibrium states with different distributions of the metal cation among the different receptors. When the fuel is exhausted or/and the irradiation interrupted, the system reversibly and autonomously goes back to the initial equilibrium state. Such results may contribute to the achievement of new dissipative systems that, taking advantage of multiple and orthogonal stimuli, are featured with more sophisticated operating mechanisms and time programmability.

Site-selective methylene C-H oxidation of an alkyl diamine enabled by supramolecular recognition using a bioinspired manganese catalyst.

Site-selective oxidation of aliphatic C-H bonds is a powerful synthetic tool because it enables rapid build-up of product complexity and diversity from simple precursors. Besides the poor reactivity of alkyl C-H bonds, the main challenge in this reaction consists in differentiating between the multiple similar sites present in most organic molecules. Herein, a manganese oxidation catalyst equipped with two 18-benzo-6-crown ether receptors has been employed in the oxidation of the long chain tetradecane-1,14-diamine. 1H-NMR studies evidence simultaneous binding of the two protonated amine moieties to the crown ether receptors. This recognition has been used to pursue site-selective oxidation of a methylenic site, using hydrogen peroxide as oxidant in the presence of carboxylic acids as co-ligands. Excellent site-selectivity towards the central methylenic sites (C6 and C7) is observed, overcoming selectivity parameters derived from polar deactivation by simple amine protonation and selectivity observed in the oxidation of related monoprotonated amines.

Concurrent base and silver(I) catalysis pulsed by fuel acid.

Treatment of a crown-ether receptor and a silver(I)-loaded cyclam derivative (NetState-I) with a fuel acid reversibly afforded the protonated cyclam and the silver(I)-loaded crown ether (NetState-II). While NetState-I was catalytically OFF, a base-catalysed Michael addition and a silver(I)-catalysed oxime cyclisation reaction was pulsed under dissipative conditions in NetState-II.

Whither Second-Sphere Coordination?

Whither Second-Sphere Coordination?

One-step double emulsion via amphiphilic Se[sbnd]N supramolecular interactions: Towards porous multi-cavity beads for efficient recovery lithium from brine

Efficient recovery lithium ions (Li+) from brine is a recognized challenge with potential strategic and economic implications. In this work, one-step double emulsion reactors, based on amphiphilic SeN supramolecular interactions between phenyl selenium bromide (PhSeBr) and polystyrene-b-polyvinylpyridine (PS-b-P4VP), was constructed to prepare porous multi-cavity beads (PMCB). After immobilizing aminoethyl benzo-12-crown-4 (B12C4-NH2) through post-interface modification strategy, the resultant sorbents (PMCB-B12C4) were adopted for selective separation and enrichment Li+ from brine. PMCB-B12C4 possessed surface pores, multiple interconnected chambers, and abundant crown ether receptors, and the dynamic and adjustable mechanism between structure and turning the volume fraction was also studied. Li+ adsorption in PMCB-B12C4 is best approximated by Langmuir and Hill isotherms showing the homogeneous adsorption on the heterogeneous surface, and the calculated maximum monolayer adsorption capacities are 61.35 mg g−1 and 59.53 mg g−1, respectively. Kinetic study reveals good agreement by pseudo-second order, and chemical adsorption mainly dominates the adsorption process. The mass transfer study depicts that both membrane and inter-particle diffusion are involved in a diffusion inhibition rate process. PMCB-B12C4 can selectively recovery Li+ from simulated samples with the selectivity coefficient (α) and relative selectivity coefficient (αr) as high as >5.0 and 6.0, respectively. PMCB-B12C4 still retains significant Li+ uptake capacity in brine owing to the specific “size matching” effect of crown ether. Moreover, PMCB-B12C4 is regenerated in mild acid and exhibits nearly consistent adsorption capacity after five reuse cycles. Thus, this work not only reports a new clue to fabricate porous sorbent beads via droplet reactor, but also provides a novel platform for Li+ extraction.

A dual-fluorophore sensor approach for ratiometric fluorescence imaging of potassium in living cells.

Potassium is the most abundant intracellular metal in the body, playing vital roles in regulating intracellular fluid volume, nutrient transport, and cell-to-cell communication through nerve and muscle contraction. On the other hand, aberrant alterations in K+ homeostasis contribute to a diverse array of diseases spanning cardiovascular and neurological disorders to diabetes to kidney disease to cancer. There is an unmet need for studies of K+ physiology and pathology owing to the large differences in intracellular versus extracellular K+ concentrations ([K+]intra = 150 mM, [K+]extra = 3–5 mM). With a relative dearth of methods to reliably measure dynamic changes in intracellular K+ in biological specimens that meet the dual challenges of low affinity and high selectivity for K+, particularly over Na+, currently available fluorescent K+ sensors are largely optimized with high-affinity receptors that are more amenable for extracellular K+ detection. We report the design, synthesis, and biological evaluation of Ratiometric Potassium Sensor 1 (RPS-1), a dual-fluorophore sensor that enables ratiometric fluorescence imaging of intracellular potassium in living systems. RPS-1 links a potassium-responsive fluorescent sensor fragment (PS525) with a low-affinity, high-selectivity crown ether receptor for K+ to a potassium-insensitive reference fluorophore (Coumarin 343) as an internal calibration standard through ester bonds. Upon intracellular delivery, esterase-directed cleavage splits these two dyes into separate fragments to enable ratiometric detection of K+. RPS-1 responds to K+ in aqueous buffer with high selectivity over competing metal ions and is sensitive to potassium ions at steady-state intracellular levels and can respond to decreases or increases from that basal set point. Moreover, RPS-1 was applied for comparative screening of K+ pools across a panel of different cancer cell lines, revealing elevations in basal intracellular K+ in metastatic breast cancer cell lines vs. normal breast cells. This work provides a unique chemical tool for the study of intracellular potassium dynamics and a starting point for the design of other ratiometric fluorescent sensors based on two-fluorophore approaches that do not rely on FRET or related energy transfer designs.

Bright far-red emitting BODIPYs via extension with conjugated fluorene and carbazole motifs

Six new BODIPY dyes have been synthesized exhibiting fluorescence emission in the far red part of the electromagnetic spectrum. The compounds were prepared via an acid catalyzed reaction of rigidified pyrroles with benzaldehyde derivatives. This reaction tolerates a variety of aldehydes and therefore analyte responsive parts can be easily introduced. As an example, indicators with a crown ether receptor, sensitive for potassium, and a pH sensitive group for the determination of CO2, were obtained via modification of a BODIPY bearing a carbazole motif. Apart from the bathochromic shift of the absorption and emission spectra (about 130–200 nm compared to 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene) most of the new dyes possess excellent photophysical properties, such as high molar absorption coefficients (130 000–230 000 M−1 cm−1), sharp absorption and emission bands as well as high quantum yields (0.48–0.95). In case of the potassium fluoroionophore both fluorescence intensity and decay time are enhanced in presence of the analyte making it potentially suitable for the self-referenced read-out.

Crown Ether Ditopic Receptors for Ammonium Salts with High Affinity for Amino Acid Ester Salts

Two bis crown ether receptors were synthesized and tested as host molecules for protonated forms of alkyl amines and amino acid esters. Molecular recognition studies were conducted in CH2Cl2:MeOH (92:8) by spectrophotometric UV/Vis titrations andby spectrometric 1H NMR titrations in CDCl3. The calculated binding constants are in the range 102-105 M-1. A high affinity for L-amino acid methyl ester derivatives was found. A theoretical study at the DFT level of the synthesized receptor and some analog ligands with three different ammonium ions helps to rationalize the experimentally found trends.

Mix-&-Read Determination of Mercury(II) at Trace Levels with Hybrid Mesoporous Silica Materials Incorporating Fluorescent Probes by a Simple Mix-&-Load Technique.

The synthesis, characterization, and application of mesoporous materials containing boron–dipyrromethene (BODIPY) moieties that allow the sensitive and selective detection of HgII in aqueous environments by fluorescence enhancement is reported. For this purpose, BODIPY dye I containing a thia‐aza crown ether receptor as the fluorescent probe for the detection of HgII in aqueous environments is encapsulated into mesoporous materials to avoid self‐quenching or aggregation in water. Determination of HgII is accomplished within a few seconds with high selectivity and sensitivity, reaching a limit of detection of 12 ppt. The determination of trace amounts of HgII in natural waters and in fish extracts is demonstrated by using our sensing material. The incorporation of the material into several μ‐PAD strips yields a portable, cheap, quick, and easy‐to‐handle tool for trace HgII analysis in water.

Multivalent Crown Ether Receptors Enable Allosteric Regulation of Anion Exchange in an Fe4L6 Tetrahedron

AbstractWe report a strategy for regulating the rate of internally bound anion exchange within an Fe4L6 metal–organic tetrahedron through external coordination of tripodal tris(alkylammonium) cations. The cage features three flexible 18‐crown‐6 receptors at each of its FeII vertices, facilitating strong tritopic interactions with tris(ammonium) cations to “cap” the vertices of the tetrahedron. This capping mechanism restricts the flexibility of the cage framework, thereby reducing the rate of anion exchange within its central cavity by 20‐fold. Thus, we demonstrate the first use of an externally bound multivalent effector to allosterically control internal guest binding in a molecular cage.

Cation Molecular Exchanger Based on a Conformational Hinge.

A cation molecular exchanger has been developed that consists of the bipyridine and crown ether receptor subunits. It has been shown that binding of the zinc(II) cation to the bipyridine subunit induces the conformational switching of the crown ether subunits, which results in a release of the potassium cation. Two conformational states of the cation exchanger have been supported by the results from solution- and solid-state studies. It has been demonstrated that the cation exchanger is able to communicate with a cation sensor induced by a chemical stimulus.

Mix-&-Read Determination of Mercury(II) at Trace Levels with Hybrid Mesoporous Silica Materials Incorporating Fluorescent Probes by a Simple Mix-&-Load Technique.

The synthesis, characterization, and application of mesoporous materials containing boron–dipyrromethene (BODIPY) moieties that allow the sensitive and selective detection of HgII in aqueous environments by fluorescence enhancement is reported. For this purpose, BODIPY dye I containing a thia‐aza crown ether receptor as the fluorescent probe for the detection of HgII in aqueous environments is encapsulated into mesoporous materials to avoid self‐quenching or aggregation in water. Determination of HgII is accomplished within a few seconds with high selectivity and sensitivity, reaching a limit of detection of 12 ppt. The determination of trace amounts of HgII in natural waters and in fish extracts is demonstrated by using our sensing material. The incorporation of the material into several μ‐PAD strips yields a portable, cheap, quick, and easy‐to‐handle tool for trace HgII analysis in water.

Ion-pair recognition based on halogen bonding: a case of the crown-ether receptor with iodo-trizole moiety

The development of halogen-bond-based ditopic receptors capable of binding simultaneously both a cation and an anion has attracted recent research interest. In this work, the crown-ether receptor 1, which consists of an iodo-trizole moiety for anion recognition through halogen bonding and a Lewis-basic center for cation binding, was investigated using density functional theory calculations. The structural and energetic features for the complexes of 1 with single cations, single halide anions, and ion pairs were explored. Intermolecular interactions in these complexes were systematically analyzed by the atoms in molecules and noncovalent interaction index methods. The presence of the coordinated cation significantly increases the anion-binding affinity, while the binding of halide anions has a slight influence on the cation-binding affinity. Anti-cooperative effects were found in the ion-pair recognition of 1, due to the strong attraction between the two counterions in the complexes. The solvent weakens the interaction strength considerably, and anti-cooperativity becomes very small in solvent. The results reported in this work are of fundamental importance in the design of ion-pair receptors based on halogen bonding.

Amplified fluorescence emission of bolaamphiphilic perylene-azacrown ether derivatives directed towards molecular recognition events.

Long-term creative approaches have been considered in the design of molecular probes to overcome the quenching effect of important dyes in an aqueous medium. Using the rational donor-acceptor based design principle, we demonstrate herein the different fluorescence states of a non-conjugated symmetrical perylene-azacrown ether system in a solution, from the molecular to the aggregated states. The ethylene-spacer is exceptionally capable of fluorescence enhancement, even in the aggregated state (organic nanoparticle, ONPs, 44 nm), overcoming the quenching effect on changing the solvent from tetrahydrofuran to water. The ONPs with crown ether receptors at the surface show colloidal stability in an aqueous solution. Furthermore, an improved fluorescent state is developed via ONPs-polymer (protamine, Pro) hybridization. Supramolecular interactions between the crown ring and the guanidinium group in Pro play an important role in the ONPs-Pro hybrid formation. The decorated fluorescent hybrid state is finally used as a nano-probe for sensing heparin via the turn-OFF mechanism. The decoration method is further generalized by recognition of the nucleotides. Herein, we detail the bottom-up approach to the molecular design and development of the different fluorescent states of a useful probe. Most excitingly, this new approach is very general and adaptive to facile detection.

Magnetic solid-phase extraction of strontium using core–shell structured magnetic microspheres impregnated with crown ether receptors: a response surface optimization

A new kind of core–shell structured magnetic microspheres impregnated with di-tert-butyl cyclohexano-18-crown-6 (DtBuCH18C6) receptors in the encapsulation layer was developed in this study, and was utilized for selective removal of strontium in strong HNO3 solutions via magnetic solid-phase extraction (MSPE). The magnetic microspheres, labelled as Fe3O4@SiO2@DtBuCH18C6, exhibited good magnetism (M s = 52.2 emu g−1), fast response under applied magnetic field and easy redispersion ability due to the superparamagnetic nature. Adsorption behaviors and mechanism were comprehensively studied, showing that the adsorption of Sr(II) by Fe3O4@SiO2@DtBuCH18C6 was most likely to be a monolayer chemisorption process via forming complexation between the crown ether receptors and Sr(II) (i.e. Langmuir model). More importantly, central composite design based on response surface methodology was utilized for optimizing the operational conditions of the adsorption process. A quadratic model was obtained to describe the relationship between adsorption capacity and the independent factors such as initial Sr(II) concentration, HNO3 concentration etc. The simulated model well predicted the optimum HNO3 concentration (~1.7 mol L−1) to achieve the best Sr(II) adsorption capacity. On this basis, a conceptual MSPE process was proposed for an effective separation of strontium in simulated high level liquid wastes.

Cation-dependent spectral properties of fluorescent complexon based on 1,8-naphthalimide with PET mechanism of optical response

Complexation of 4-amino-1,8-naphthalimide derivative containing an aza-15-crown-5 ether receptor unit in the N-aryl substituent at the imide nitrogen atom of the naphthalimide core with alkaline earth metal cations was studied using optical and NMR spectroscopy. The binding of the cations with crown ether receptors was accompanied by signifacant fluorescence enhancement of naphthalimide moiety caused by the inhibition of the photoinduced electron transfer (PET) process. An increase in the cation radii on going from Mg2+ to Ca2+ to Ba2+ leads to a decrease in the complex stability and an increase in the quantum yield of its fluorescence.

Negative Cooperativity in the Binding of Imidazolium and Viologen Ions to a Pillar[5]arene-Crown Ether Fused Host.

A pillar[5]arene-crown ether fused bicyclic host 1 was found to be able to recognize an imidazolium ion G1 by its pillar[5]arene subunit and a viologen ion G2 by its crown ether receptor discriminatively. The simultaneous binding of G1 and G2 by 1 resulted in the formation of a three-component host-guest complex G1⊂1⊃G2. Negative heterotropic cooperative effects were displayed by G1 and G2 in their binding to 1 and were investigated by stepwise bindings of G1 and G2 to 1.

Metal‐Atom Impact on the Self‐Assembly of Cup‐and‐Ball Metalloporphyrin–Fullerene Conjugates

AbstractA fullerene ammonium derivative has been combined with different metalloporphyrin–crown ether receptors to generate very stable supramolecules. The combination of fullerene–porphyrin and ammonium–crown ether interactions leads to a strong chelate effect as evidenced by a high effective molarity (3.16 M). The different parameters influencing the stability of the supramolecular ensembles, in particular the nature of the metal in the porphyrin moiety, have been rationalized with the help of theoretical calculations thus providing new insights into fullerene–porphyrin interactions.