Molecular recognition in water using macrocyclic synthetic receptors constitutes a vibrant and timely research area of supramolecular chemistry. Pioneering examples on the topic date back to the ...1980s. The investigated model systems and the results derived from them are key for furthering our understanding of the remarkable properties exhibited by proteins: high binding affinity, superior binding selectivity, and extreme catalytic performance. Dissecting the different effects contributing to the proteins’ properties is severely limited owing to its complex nature. Molecular recognition in water is also involved in other appreciated areas such as self-assembly, drug discovery, and supramolecular catalysis. The development of all these research areas entails a deep understanding of the molecular recognition events occurring in aqueous media. In this review, we cover the past three decades of molecular recognition studies of neutral and charged, polar and nonpolar organic substrates and ions using selected artificial receptors soluble in water. We briefly discuss the intermolecular forces involved in the reversible binding of the substrates, as well as the hydrophobic and Hofmeister effects operating in aqueous solution. We examine, from an interdisciplinary perspective, the design and development of effective water-soluble synthetic receptors based on cyclic, oligo-cyclic, and concave-shaped architectures. We also include selected examples of self-assembled water-soluble synthetic receptors. The catalytic performance of some of the presented receptors is also described. The latter process also deals with molecular recognition and energetic stabilization, but instead of binding ground-state species, the targets become elusive counterparts: transition states and other high-energy intermediates.
•The binding properties of a series of porphyrin tweezers are reviewed.•Spectroscopic techniques used to probe the host–guest interaction are illustrated.•Porphyrin tweezers are applied to determine ...absolute configuration.•Self-assembled porphyrin tweezers are introduced.
Metallated porphyrins have been widely used as binding sites in covalently linked molecular tweezer receptors. This review describes selected examples of covalently linked porphyrin tweezer receptors extracted from the extensive literature generated in this area during the last 20 years. The binding processes of some porphyrin tweezer receptors with different substrates are discussed on the basis of the stoichiometry of the formed complexes, the magnitudes of their thermodynamic stabilities and the spectroscopic techniques used in the characterization. The physicochemical properties of the porphyrin units allow the use of a wide variety of techniques to probe the interaction of the tweezer receptors with different guests. The relationship that exists between the magnitude of the binding constant of 1:1 complexes involving ditopically bound ligands and the conformational features of the spacers is assessed in detail. The different strengths of the non-covalent forces, mainly metal–ligand coordination bonds and π–π interactions, involved in the formation of the host–guest complexes of the tweezers are also discussed and some of the relevant applications of molecular tweezers are also presented. In particular, the use of several porphyrin tweezers in the assignment of absolute configuration of chiral organic compounds using exciton-coupling circular dichroism spectroscopy is described. Finally, porphyrin tweezer receptors prepared through self-assembly processes are introduced and their binding properties emphasized.
Chemical intuition suggests that anions and π-aromatic systems would repel each other. Typically, we think of cations as being attracted to electron-rich π-systems of aromatic rings, and the cation−π ...interaction, a well-established noncovalent interaction, plays an important role in nature. Therefore the anion−π interaction can be considered the opposite of the cation−π interaction. Computational studies of simple models of anion−π interactions have provided estimates of the factors that govern the binding geometry and the binding energy, leading to a general consensus about the nature of these interactions. In order to attract an anion, the charge distribution of the aromatic system has to be reversed, usually through the decoration of the aromatic systems with strongly electron-withdrawing groups. Researchers have little doubt about the existence of attractive anion−π interactions in the gas phase and in the solid state. The bonding energies assigned to anion−π interactions from quantum chemical calculations and gas phase experiments are significant and compare well with the values obtained for cation−π interactions. In solution, however, there are few examples of attractive anion−π interactions. In this Account, I describe several examples of neutral molecular receptors that bind anions in solution either solely through anion−π interactions or as a combination of anion−π interactions and hydrogen bonding. In the latter cases, the strength of the anion−π interaction is indirectly detected as a modulation of the stronger hydrogen bonding interaction (enforced proximity). The dissection of the energy contribution of the anion−π interaction to the overall binding is complex, which requires the use of appropriate reference systems. This Account gives an overview the experimental efforts to determine the binding energies that can be expected from anion−π interactions in solution with examples that center around the recognition of halides. The studies show that anion−π interactions also exist in solution, and the free energy of binding estimated for these attractive interactions is less than 1 kcal/mol for each substituted phenyl groups. The quantification of anion−π interactions in solution relies on the use of molecular recognition model systems; therefore researchers need to consider how the structure of the model system can alter the magnitude of the observed energy values. In addition, the recognition of anions in solution requires the use of salts (ion pairs) as precursors, which complicates the analysis of the titration data and the corresponding estimate of the binding strength. In solution, the weak binding energies suggest that anion−π interactions are not as significant for the selective or enhanced binding of anions but offer potential applications in catalysis and transport within functional synthetic and biological systems.
Coordination cages containing endohedrally functionalized aromatic cavities are scarce in the literature. Herein, we report the self-assembly of a tetra-cationic super aryl-extended calix4pyrrole ...tetra-pyridyl ligand into a water-soluble Pd(
ii
)-cage featuring two endohedral polar binding sites. They are defined by the four pyrrole NHs of the calix4pyrrole unit and the four inwardly directed α-protons of the coordinated pyridyl groups. The efficient assembly of the Pd(
ii
)-cage requires the inclusion of mono- and ditopic pyridyl
N
-oxide and aliphatic formamide guests. The monotopic guests only partially fill the cage's cavity and require the co-inclusion of a water molecule that is likely hydrogen-bonded to the endohedral α-pyridyl protons. The ditopic guests are able to completely fill the cage's cavity and complement both binding sites. We observed high conformational selectivity in the inclusion of the isomers of α,ω-bis-formamides. We briefly investigate the uptake and release mechanism/kinetics of selected polar guests by the Pd(
ii
)-cage using pair-wise competition experiments.
A tetra-cationic calix4pyrrole tetra-pyridyl ligand self-assembles into a water-soluble Pd(
ii
)-cage featuring two endohedral polar binding sites. The Pd(
ii
)-cage encapsulates pyridyl
N
-oxide and aliphatic formamide guests in water.
We report the synthesis and characterization of two water-soluble container compounds (cavitand hosts) with rigidified open ends. One cavitand uses four (CH2)4’s as spacers to bridge the adjacent ...walls, while another cavitand uses four CH2CH2OCH2CH2’s bridges and features a wider open end. The spacers preorganize the deep cavitands into vase-like, receptive shapes and prevent their unfolding to the unreceptive kite-like conformation. Cycloalkane guests (C6–C8) and small n-alkanes (C5–C7) form 1:1 complexes with the cavitands and move freely in the cavitands’ spaces. Hydrophilic compounds 1,4-dioxane, tetrahydrofuran, tetrahydropyran, pyridine, and 1-methylimidazole also showed good binding affinity to the new cavitands. Longer alkanes (C11–C14) and n-alcohols (C11–C16) are taken up with a −CH3 group fixed at the bottom of the cavity and the groups near the rim in compressed conformations. The methylene bridges appear to divide the cavitand into a narrow hydrophobic compartment and a broader space with exposure to the aqueous medium. Longer alkane guests (C15–C18), N,N-dimethyldioctylammonium, and dioctylamine induce the formation of capsules (2:1 host:guest complexes). The new cavitands showed selectivity for p/m-cresol isomers and xylene isomers. The cavitand with CH2CH2OCH2CH2 bridges bound long-chain α,ω-diols (C13–C15) and diamines in folded, U-shaped conformations with polar functions exposed to the aqueous medium. It was used to separate o-xylene from its isomers by using simple extraction procedures.
We describe the synthesis of unprecedented calix4pyrrole receptors featuring “super aryl extended” (SAE) cavities. We elaborated the aromatic cavity provided by the αααα‐isomer of ...para‐tetraiodo‐meso‐phenyl calix4pyrrole by installing ethynyl‐aryl substituents at its upper rim. We report the binding properties of the prepared SAE‐calix4pyrrole tetraester towards pyridyl‐N‐oxides. The binding data revealed the formation of thermodynamically and kinetically highly stable 1:1 complexes. The complexation‐induced chemical shifts indicated the formation of hydrogen bonds and aromatic interactions with the calix‐core adopting the cone conformation. We quantified the additional interactions established between the four terminal aryl groups and the para‐phenyl substituent of 4‐phenyl pyridine N‐oxide to be in the order of 1 kcal mol−1. The complex formation rate was found to be close to the diffusion control suggesting that the free host adopted a 1,3‐alternate conformation. Finally, we attempted to gain water solubility of SAE‐calix4pyrroles using derivatives that display four ionizable or charged groups at their upper rims.
Super aryl‐extended calix4pyrroles displaying a deep aromatic cavity are reported. The 1:1 inclusion complexes formed with pyridyl‐N‐oxides in chloroform solution are thermodynamically and kinetically highly stable. The incorporation of ionizable and charged groups to gain water solubility is also investigated.
This critical review describes selected examples extracted from the extensive literature generated during the past 42 years on the topic of anion binding in molecular capsules. The goal of including ...anions in molecular capsules emerges from the idea of incorporating the traits exhibited by biological receptors into synthetic ones. At the outset of this research area the capsules were unimolecular. The scaffold of the receptor was designed to covalently link a series of functional groups that could converge into a cavity and to avoid its collapse. The initial examples involved the encapsulation of one monoatomic spherical anion. With time, the cavity size of the receptor was increased and encapsulation of polyatomic anions and co-encapsulation became a reality. Synthetic economy fueled the use of aggregates of self-complementary molecules rather than one large molecule as capsules. The main purpose of this review is to give a general overview of the topic which might be of interest to supramolecular or non supramolecular chemists alike (149 references).
We report on the eligibility of tetraphosphonate resorcinarene cavitands for the molecular recognition of amino acids. We determined the crystal structure of 13 complexes of the tetraphosphonate ...cavitand TiiiiH, CH3, CH3 with amino acids. 1H NMR and 31P NMR experiments and ITC analysis were performed to probe the binding between cavitand TiiiiC3H7, CH3, C2H5 or the water-soluble counterpart TiiiiC3H6Py+Cl‑, CH3, C2H5 and a selection of representative amino acids. The reported studies and results allowed us (i) to highlight the noncovalent interactions involved in the binding event in each case; (ii) to investigate the ability of tetraphosphonate cavitand receptors to discriminate between the different amino acids; (iii) to calculate the K a values of the different complexes formed and evaluate the thermodynamic parameters of the complexation process, dissecting the entropic and enthalpic contributions; and (iv) to determine the solvent influence on the complexation selectivity. By moving from methanol to water, the complexation changed from entropy driven to entropy opposed, leading to a drop of almost three orders in the magnitude of the K a. However, this reduction in binding affinity is associated with a dramatic increase in selectivity, since in aqueous solutions only N-methylated amino acids are effectively recognized. The thermodynamic profile of the binding does not change in PBS solution. The pivotal role played by cation−π interactions is demonstrated by the linear correlation found between the log K a in methanol solution and the depth of +N–CH3 cavity inclusion in the molecular structures. These findings are relevant for the potential use of phosphonate cavitands as synthetic receptors for the detection of epigenetic modifications of histones in physiological media.
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