Tuning CH Hydrogen Bond-Based Receptors toward Picomolar Anion Affinity via the Inductive Effect of Distant Substituents.

Inspired by nature, artificial hydrogen bond-based anion receptors have been developed to achieve high anion selectivity; however, their binding affinity is usually low. The potency of these receptors is usually increased by the introduction of aryl substituents, which withdraw electrons from their binding site through the resonance effect. Here, we show that the polarization of the C(sp3 )-H binding site of bambusuril receptors, and thus their potency to bind anions, can be modulated by the inductive effect. The presence of electron-withdrawing groups on benzyl substituents of bambusurils significantly increases their binding affinities to halides, resulting in the strongest iodide receptor reported to date with an association constant greater than 1013  M-1 in acetonitrile. A Hammett plot showed that while the bambusuril affinity toward halides linearly increases with the electron-withdrawing power of their substituents, their binding selectivity remains essentially unchanged.

Synthesis of Enantiomerically Pure Bambus[6]urils Utilizing Orthogonal Protection of Glycolurils.

A general strategy for the synthesis of 2N,4N'-disubstituted glycoluril enantiomers on a multigram scale using orthogonal protection is reported. The use of these glycolurils is demonstrated in the synthesis of enantiomerically pure bambus[6]uril macrocycles. Moreover, the deprotection of (S)-1-phenylethyl substituents on the macrocycle was achieved, opening access to various chiral bambus[6]urils via post-macrocyclization modification strategy.

Monomerization of Phthalocyanines in Water via Their Supramolecular Interactions with Cucurbiturils.

Aggregation of phthalocyanines (Pcs) represents a problematic feature that decreases the potential of these macrocycles in a number of applications. In this work, we present a supramolecular approach based on the interaction of aminoadamantyl-substituted Pcs with bulky and hydrophilic cucurbit[7]uril (CB[7]) to increase the levels of Pc monomers in water. A series of zinc(II) Pcs substituted at positions α or ß by an aminoadamantyl substituent (with a different level of alkylation of nitrogen) were prepared from the corresponding phthalonitriles. A 1H nuclear magnetic resonance study of the interaction of phthalonitriles with CB[7] in water confirmed the formation of an inclusion complex with an aminoadamantyl moiety with Ka values of ∼1012 M-1. The interaction of CB[7] with Pcs in water substantially weakened H-type aggregation and improved both fluorescence and singlet oxygen production, confirming that this approach is efficient for the monomerization of Pcs. In vitro evaluation of the photodynamic activity of prepared Pcs led to EC50 values in the submicromolar range on HeLa and SK-MEL-28 cells. However, the activity decreased for at least an order of magnitude after host-guest interaction with CB[7] despite better photophysical properties. This was attributed to a much lower uptake by cells due to the very bulky and hydrophilic character of the Pc-CB[7] assembly.

Monofunctionalized Fluorinated Bambusurils and Their Conjugates for Anion Transport and Extraction.

Bambusurils are macrocyclic molecules that are known for their high binding affinity and selectivity toward anions. Here, we present the preparation of two bambusurils bearing fluorinated substituents and one carboxylic function. These monofunctionalized bambusurils were conjugated with crown ether and cholesterol units. The resulting conjugates were successfully tested in liquid-liquid extraction of inorganic salts and chloride/bicarbonate transport across lipid bilayers.

Highly Efficient and Selective Recognition of Dicyanoaurate(I) by a Bambusuril Macrocycle in Water.

Dicyanoaurate(I) anion, [Au(CN)2 ]- , plays a central role in the current industrial production of gold, as its extraction from crude ore samples represents the most money-consuming step. Herein, we present the strongest host-guest recognition of dicyanoaurate anion using the bambusuril receptor in water, a highly competitive solvent. The micromolar stability of such a complex facilitated the up to date most efficient supramolecular stripping of dicyanoaurate from activated carbon at ambient temperature. Thermodynamic characteristics of bambusuril binding with [Au(CN)2 ]- differing from binding of other inorganic chaotropic anions are rationalized, as well as the bambusuril selectivity for [Au(CN)2 ]- over [Ag(CN)2 ]- .

Bambusuril Macrocycles as Mediators of Supramolecular Interactions: Application to the Europium Cage Helicate.

Herein, it is shown how bambusurils can be used for tuning and/or characterizing supramolecular systems. Indeed, the addition of bambusurils as anion scavengers to metal-mediated self-assemblies allows manipulation of the subtle equilibria in the given system. This is demonstrated for the case of the tetranuclear europium helical cage, which is well suited to different applications. Among the reported results, experimental evidence is provided showing that perchlorate and triflate anions act as a molecular template for the cage assembly. The complexation of inorganic anions with neutral bambusurils resulted in bulky non-coordinating counterions that may trigger the self-assembly process or stimulate specific interactions between components. Moreover, bambusuril was able to selectively remove coordinating nitrates from the mixture with non-coordinating anions, enabling the regeneration of the helical cage.

Transmembrane Transport of Bicarbonate Unravelled.

Invited for the cover of this issue are Dr. Stephen Butler, Dr. Hennie Valkenier and co-workers at Université Libre de Bruxelles, Loughborough University, Masaryk University, and the University of Bristol. The image depicts the transport of bicarbonate anions versus the spontaneous diffusion of CO2 across the lipid bilayer of a liposome. Read the full text of the article at 10.1002/chem.202100491.

Transmembrane Transport of Bicarbonate Unravelled*.

Anion receptors can be used to transport ions across lipid bilayers, which has potential for therapeutic applications. Synthetic bicarbonate transporters are of particular interest, as defects in transmembrane transport of bicarbonate are associated with various diseases. However, no convenient method exists to directly observe bicarbonate transport and study the mechanisms involved. Here, an assay is presented that allows the kinetics of bicarbonate transport into liposomes to be monitored directly and with great sensitivity. The assay utilises an encapsulated europium(III) complex, which exhibits a large increase in emission intensity upon binding bicarbonate. Mechanisms involving CO2 diffusion and the dissipation of a pH gradient are shown to be able to lead to an increase in bicarbonate concentration within liposomes, without transport of the anion occurring at all. By distinguishing these alternative mechanisms from actual bicarbonate transport, this assay will inform the future development of bicarbonate transporters.

Conformationally Mobile Acyclic Cucurbit[n]uril-Type Receptors Derived from an S-shaped Methylene Bridged Glycoluril Pentamer.

We report the synthesis of the conformationally mobile S-shaped glycoluril pentamer building block 3a and two new acyclic CB[n]-type receptors P1 and P2. P1 (9 mM) and P2 (11 mM) have moderate aqueous solubility but their host•guest complexes are poorly soluble. Host P1 does not undergo intermolecular self-association whereas P2 does (Ks = 189±27 M-1). 1H NMR titrations show that P1 and P2 are poor hosts toward hydrophobic (di)cations 6 - 11 (P1: Ka = 375-1400 M-1; P2: Ka = 1950-19800 M-1) compared to Tet1 and Tet2 (Tet1: Ka = 3.09 × 106 to 4.69 × 108 M-1; Tet2: Ka = 4.59 × 108 to 1.30 × 1010 M-1). Molecular modelling shows that P1 and P2 exist as a mixture of three different conformers due to the two S-shaped methylene bridged glycoluril dimer subunits that each possess two different conformations. The lowest energy conformers of P1 and P2 do not feature a well-defined central cavity. In the presence of guests, P2 adapts its conformation to form 1:1 P2•guest complexes; the binding free energy pays the energetic price of conformer selection. This energetically unfavorable conformer selection results in significantly decreased Ka values of P1 and P2 compared to Tet1 and Tet2.

Dynamic Interactions in Synthetic Receptors: A Guest Exchange Saturation Transfer Study.

The accumulated knowledge regarding molecular architectures is based on established, reliable, and accessible analytical tools that provide robust structural and functional information on assemblies. However, both the dynamicity and low population of noncovalently interacting moieties within studied molecular systems limit the efficiency and accuracy of traditional methods. Herein, the use of a saturation transfer-based NMR approach to study the dynamic binding characteristics of an anion to a series of synthetic receptors derived from bambusuril macrocycles is demonstrated. The exchange rates of BF4 - are mediated by the side chains on the receptor (100 s-1

Bambusurils as a mechanistic tool for probing anion effects.

Bambusuril macrocycles have high affinity towards anions (X-) such as PF6- and SbF6- or BF4- and ClO4-. Therefore, addition of bambusurils to reaction mixtures containing these anions effectively removes the free anions from the reaction process. Hence, comparing reactions with and without addition of bambusurils can demonstrate whether the anions actively participate in the reaction mechanism or not. We show this approach for gold(i) mediated addition of methanol to an alkyne. The reaction mechanism can proceed via monoaurated intermediates (e.g., in catalysis with [(IPr)AuX]) or via diaurated intermediates (e.g., in catalysis with [(PPh3)AuX]). We show that anions X- slightly affect the reaction rates, however the effect stays almost the same even after their encapsulation in the cavity of bambusurils. We also demonstrate that X- affects the overall reaction rate in the very same way as the reaction rate of the protodeauration step. All results are consistent with the indirect effect of X- by the acidity of the conjugated acid HX on the rate-determining step. There is no evidence that a direct involvement of X- would affect the reaction rate.

Hypervalent Iodine Based Reversible Covalent Bond in Rotaxane Synthesis.

Reversible covalent bonds play a significant role in achieving the high-yielding synthesis of mechanically interlocked molecules. Still, only a handful of such bonds have been successfully employed in synthetic procedures. Herein, we introduce a novel approach for the fast and simple preparation of interlocked molecules, combining the dynamic bond character of bis(acyloxy)iodate(I) anions with macrocyclic bambusuril anion receptors. The proof of principle was demonstrated on rotaxane synthesis, with near-quantitative yields observed in both the classical and "in situ" approach. The rotaxane formation was confirmed in the solid-state and solution by the X-ray and NMR studies. Our novel approach could be utilized in the fields of dynamic combinatorial chemistry, supramolecular polymers, or molecular machines, as well inspire further research on molecules that exhibit dynamic behavior, but owing to their high reactivity, have not been considered as constituents of more elaborate supramolecular structures.

Bambusuril analogs based on alternating glycoluril and xylylene units.

The glycoluril monomer is a popular building block in supramolecular chemistry as it is used for the synthesis of versatile host molecules which can interact with cationic, anionic or neutral guest molecules. Here we present the design and synthesis of a new hybrid macrocycle containing glycoluril and aromatic units. The reaction afforded a mixture of macrocyclic homologues from which a two-membered macrocycle was isolated as the main product. Two disastereomers of the macrocycle were separated and characterized by means of NMR spectroscopy and X-ray crystallography. Conformational changes of these diastereomers were investigated using DFT models and variable-temperature NMR.

Chiral Bambusurils for Enantioselective Recognition of Carboxylate Anion Guests.

Synthesis of the first enantiomerically pure chiral bambusurils is reported. The bambusurils were prepared on the gram scale without using any chromatography techniques. The bambusurils formed supramolecular complexes with all tested chiral carboxylates including amino acids and drug molecules with the enantioselectivity ranging from 1.1 to 3.2.

Thermodynamics of Halide Binding to a Neutral Bambusuril in Water and Organic Solvents.

Driving forces of anion binding in water in contrast to nonpolar environments are of high interest because of their relevance to biology and medicine. Here we report a neutral bambusuril macrocycle (1), soluble in both water and nonpolar solvents due to decoration with 12 polyethylene glycol-based substituents. The new bambusuril has the highest affinity for I- in pure water ever reported for a synthetic macrocycle relying on hydrogen bonding interactions rather than metal coordination or Coulombic forces. Isothermal titration calorimetry (ITC) experiments in nine different solvents, ranging from polar water to nonpolar carbon tetrachloride, provided insight into the forces responsible for halide binding by bambusurils. The different importance of anion solvation and solvent expulsion from the cavity of the macrocycle in various solvents is illustrated by the fact that halide binding in water and chloroform is exclusively driven by favorable enthalpy with an entropic penalty, while in alcohols and nonpolar solvents, both favorable enthalpy and entropy contribute to anion encapsulation. DFT calculations and correlation of thermodynamic data with the solvent Swain acity parameter further underscore the importance of solvent effects on anion binding by bambusurils.

Bambusuril as a One-Electron Donor for Photoinduced Electron Transfer to Methyl Viologen in Mixed Crystals.

Methyl viologen hexafluorophosphate (MV2+·2PF6-) and dodecamethylbambus[6]uril (BU6) form crystals in which the layers of viologen dications alternate with those of a 1:2 supramolecular complex of BU6 and PF6-. This arrangement allows for a one-electron reduction of MV2+ ions upon UV irradiation to form MV+• radical cations within the crystal structure with half-lives of several hours in air. The mechanism of this photoinduced electron transfer in the solid state and the origin of the long-lived charge-separated state were studied by steady-state and transient spectroscopies, cyclic voltammetry, and electron paramagnetic resonance spectroscopy. Our experiments are supported by quantum-chemical calculations showing that BU6 acts as a reductant. In addition, analogous photochemical behavior is also demonstrated on other MV2+/BU6 crystals containing either BF4- or Br- counterions.

Modulation of Bambusuril Anion Affinity in Water.

Neutral and negatively charged anion receptors functioning in pure water are rare in supramolecular chemistry. Moreover, studies on adjusting the affinity of such receptors toward anions in water are absent from the literature. Two new bambusurils, 1 a and 2 a, were prepared to demonstrate that the affinity of bambusurils towards anions can be altered by the length of carboxyalkyl groups attached to the macrocycles. The stability of the bambusuril complexes was further controlled by the pH value. The crystal structure of bambusuril 1 a was described, in which two carboxyalkyl arms fold into the macrocycle cavity, thus forming the intramolecular self-inclusion complex.

Supramolecular Storage and Controlled Photorelease of an Oxidizing Agent using a Bambusuril Macrocycle.

The oxidizing ability of peroxodisulfate upon complexation inside the Bambusuril macrocycle cavity is inhibited. This dianionic agent can be released on demand from its stable 1:1 complex in water (log Ka =6.9 m-1 ) by addition of a more strongly bound anion, such as iodide (log Ka =7.1 m-1 ), which can also be delivered in situ upon irradiation from a 4-hydroxyphenacyl iodide derivative with spatial and temporal precision. The oxidizing properties of peroxodisulfate ions liberated from the complex recover and can take part in subsequent chemical transformations.

pH Control on the Sequential Uptake and Release of Organic Cations by Cucurbit[7]uril.

Cucurbit[7]uril (CB7) is a macrocycle with the ability to form the most stable supramolecular complexes in water ever reported for an artificial receptor. Its use for the design of advanced functional materials is, however, very limited because there is no example of a fully reversible CB7 based supramolecular complex enabling repetitious dissociation/association controlled by external stimuli. We report the synthesis of a new ferrocene amino acid that forms with CB7 a 1:1 inclusion complex that is stable in submicromolar concentration at low pH but dissociates at high pH. This reversible process was used for the sequential uptake and release of bispyridinium and antraquinone guests by CB7, which is controlled by adjusting the pH of the solution.

Glycoluril-Derived Molecular Clips are Potent and Selective Receptors for Cationic Dyes in Water.

Molecular clip 1 remains monomeric in water and engages in host-guest recognition processes with suitable guests. We report the Ka values for 32 1⋅guest complexes measured by 1 H NMR, UV/Vis, and fluorescence titrations. The cavity of 1 is shaped by aromatic surfaces of negative electrostatic potential and therefore displays high affinity and selectivity for planar and cationic aromatic guests that distinguishes it from CB[n] receptors that prefer aliphatic over aromatic guests. Electrostatic effects play a dominant role in the recognition process whereby ion-dipole interactions may occur between ammonium ions and the C=O groups of 1, between the SO3- groups of 1 and pendant cationic groups on the guest, and within the cavity of 1 by cation-π interactions. Host 1 displays a high affinity toward dicationic guests with large planar aromatic surfaces (e.g. naphthalene diimide NDI+ and perylene diimide PDI+) and cationic dyes derived from acridine (e.g. methylene blue and azure A). The critical importance of cation-π interactions was ascertained by a comparison of analogous neutral and cationic guests (e.g. methylene violet vs. methylene blue; quinoline vs. N-methylquinolinium; acridine vs. N-methylacridinium; neutral red vs. neutral red H+ ) the affinities of which differ by up to 380-fold. We demonstrate that the high affinity of 1 toward methylene blue (Ka =3.92×107 m-1 ; Kd =25 nm) allows for the selective sequestration and destaining of U87 cells stained with methylene blue.