Guest Binding Research Articles

Halogen Bonding Tripodal Metallo-Receptors for Phosphate Recognition and Sensing in Aqueous-Containing Organic Media.

The anion recognition and electrochemical anion-sensing properties of halogen-bonding (XB) tripodal zinc(II) receptors strategically designed and constructed for tetrahedral anion guest binding are described. The XB tris(iodotriazole)-containing hosts exhibit high affinities and selectivities for inorganic phosphate over other more basic, mono-charged oxoanions such as acetate and the halides in a competitive CD3 CN/D2 O (9 : 1 v/v) aqueous solvent mixture. 1 H NMR anion binding and electrochemical voltammetric anion sensing studies with redox-active ferrocene functionalised metallo-tripodal receptor analogues, reveal each of the XB tripods as superior anion complexants when compared to their tris(prototriazole)-containing, hydrogen bonding (HB) counterparts, not only exemplifying the halogen bond as a strong alternative interaction to the traditional hydrogen bond for molecular recognition but also providing rare evidence of the ability of XB receptors to preferentially bind the "harder" phosphate oxoanion over the "softer" and less hydrated halides in aqueous containing media.

Acceleration and deceleration of chirality inversion speeds in a dynamic helical metallocryptand by alkali metal ion binding

We report that the chirality inversion kinetics of a trinickel(II) cryptand can be controlled by guest recognition in the cryptand cavity. When the guest was absent, the nickel(II) cryptand underwent a dynamic interconversion between the P and M forms in solution, preferring the M form, with a half-life of t 1/2 = 4.99 min. The P / M equilibrium is reversed to P -favored by binding with an alkali metal ion in the cryptand cavity. The timescale of this M→P inversion kinetics was both notably accelerated and decelerated by the guest binding ( t 1/2 = 0.182 min for K + complex; 186 min for Cs + complex); thus, the equilibration rate constants differed by up to 1000-fold depending on the guest metal ions. This acceleration/deceleration can be explained in terms of the virtual binding constants at the transition state of the P / M chirality inversion; K + binding more stabilizes the transition state rather than the P and M forms to result in the acceleration.

Stabilization of Guest Molecules inside Cation-Lidded Cucurbiturils Reveals that Hydration of Receptor Sites Can Impede Binding.

Docking of alkali metal ions to water-soluble macrocyclic receptors generally reduces the affinity of guest molecules due to competitive binding. The idea that solvation water molecules could display a larger steric hindrance towards guest binding than cations has not been considered to date. We show that the docking of large cations to cucurbit[5]uril (CB5) unexpectedly increases (by a factor of 5-8) the binding of hydrophobic guests, methane and ethane. This is due to the removal of water molecules from the carbonyl portals of CB5 during cation binding, which frees up space for hydrophobe encapsulation. In contrast, smaller cations like sodium protrude deeply into the cavity of CB5 and cause the expected decrease in binding, such that the rational selection of alkali cations allows for a variation of up to a factor of 20 in binding of methane and ethane. The statistical analysis of crystallographic data shows that the cavity volume of CB5 can be enlarged by placing large alkali ions (Rb+ and Cs+ ) centro-symmetrically at the portals. The results reveal a hitherto elusive steric hindrance of solvation water molecules near receptor binding sites, which is pertinent for the design of supramolecular catalysts and the understanding of biological receptors.

Stabilization of Guest Molecules inside Cation‐Lidded Cucurbiturils Reveals that Hydration of Receptor Sites Can Impede Binding

AbstractDocking of alkali metal ions to water‐soluble macrocyclic receptors generally reduces the affinity of guest molecules due to competitive binding. The idea that solvation water molecules could display a larger steric hindrance towards guest binding than cations has not been considered to date. We show that the docking of large cations to cucurbit[5]uril (CB5) unexpectedly increases (by a factor of 5–8) the binding of hydrophobic guests, methane and ethane. This is due to the removal of water molecules from the carbonyl portals of CB5 during cation binding, which frees up space for hydrophobe encapsulation. In contrast, smaller cations like sodium protrude deeply into the cavity of CB5 and cause the expected decrease in binding, such that the rational selection of alkali cations allows for a variation of up to a factor of 20 in binding of methane and ethane. The statistical analysis of crystallographic data shows that the cavity volume of CB5 can be enlarged by placing large alkali ions (Rb+ and Cs+) centro‐symmetrically at the portals. The results reveal a hitherto elusive steric hindrance of solvation water molecules near receptor binding sites, which is pertinent for the design of supramolecular catalysts and the understanding of biological receptors.

Comprehensive Evaluation of End-Point Free Energy Techniques in Carboxylated-Pillar[6]arene Host-Guest Binding: IV. The QM Treatment, GB Models and the Multi-Trajectory Extension

Due to the similarity of host–guest complexes and protein–ligand and protein–protein assemblies, computational tools for protein–drug complexes are commonly applied in host–guest binding. One of the methods with the highest popularity is the end-point free energy technique, which estimates the binding affinity with gas-phase and solvation contributions extracted from simplified end-point sampling. Our series papers on a set of carboxylated-pillararene host–guest complexes have proven with solid numerical evidence that standard end-point techniques are practically useless in host–guest binding, but alterations, such as slightly increasing interior dielectric constant in post-processing calculation and shifting to the multi-trajectory realization in conformational sampling, could better the situation and pull the end-point method back to the pool of usable tools. Also, the force-field selection plays a critical role, as it determines the sampled region in the conformational space. In the current work, we continue the efforts to explore potentially promising end-point modifications in host–guest binding and further extend the sampling time to an unprecedent length. Specifically, we comprehensively benchmarked the shift from the original MM description to QM Hamiltonians in post-processing the popular single-trajectory sampling. Two critical settings in the multi-scale QM/GBSA regime are the selections of the QM Hamiltonian and the implicit-solvent model, and a scan of combinations of popular semi-empirical QM Hamiltonians and GB models is performed. The multi-scale QM/GBSA treatment is further combined with the three-trajectory sampling protocol, introducing a further advanced modification. The sampling lengths in the host–guest complex, solvated guest and solvated host ensembles are extended to 500 ns, 500 ns and 12,000 ns. As a result, the sampling quality in end-point calculations is unprecedently high, enabling us to draw conclusive pictures of investigated forms of modified end-point free energy methods. Numerical results suggest that the shift to the QM Hamiltonian does not better the situation in the popular single-trajectory regime, but noticeable improvements are observed in the three-trajectory sampling regime, especially for the DFTB/GBSA parameter combination (either DFTB2 or its third-order extension), the quality metrics of which reach an unprecedently high level and surpass existing predictions (including costly alchemical transformations) on this dataset, hinting on the applicability of the advanced three-trajectory QM/GBSA end-point modification for host–guest complexes.

Applications of macrocycle-based solid-state host-guest chemistry.

Macrocyclic molecules have been used in various fields owing to their guest binding properties. Macrocycle-based host-guest chemistry in solution can allow for precise control of complex formation. Although solution-phase host-guest complexes are easily prepared, their limited stability and processability prevent widespread application. Extending host-guest chemistry from solution to the solid state results in complexes that are generally more robust, enabling easier processing and broadened applications. Macrocyclic compounds in the solid state can encapsulate guests with larger affinities than their soluble counterparts. This is crucial for use in applications such as separation science and devices. In this Review, we summarize recent progress in macrocycle-based solid-state host-guest chemistry and discuss the basic physical chemistry of these complexes. Representative macrocycles and their solid-state complexes are explored, as well as potential applications. Finally, perspectives and challenges are discussed.

Photoresponsive Supramolecular Cages and Macrocycles.

The utilisation of light to achieve precise manipulation and control over the structure and function of supramolecular assemblies has emerged as a highly promising approach in the development of complex, configurable, or multifunctional systems and nanoscopic machine-like entities. In this minireview, we highlight recent examples of self-assembled and covalently bound cages and macrocycles with a focus on the external and internal functionalisation of a structure with a photoswitchable unit or the embedment of a photoswitch into the framework of a structure. Functionalising the interior or exterior of a supramolecular cage or macrocycle with a photoresponsive group enables control over different properties, such as guest binding or assembly in the solid-state, while the overall shape of the assembly often undergoes no significant change. By directly integrating a photoswitchable unit into the framework of a supramolecular structure, the isomerisation can either induce a geometry change, the disassembly, or the disassembly and reassembly of the structure. Historical and recent examples covered in this review are based on azobenzene, diarylethene, stilbene photoswitches, or alkene motors that were incorporated into macrocycles and cages constructed by metal-organic, dynamic covalent, or covalent bonds.

Stoichiometric Control of Guest Recognition of Self-Assembled Palladium(II)-Based Supramolecular Architectures.

We report flexible [Pd(L)2 ]2+ complexes where there is self-recognition, driven by π-π interactions between electron-rich aromatic arms and the cationic regions they are tethered to. This self-recognition hampers the association of these molecules with aromatic molecular targets in solution. In one case, this complex can be reversibly converted to an 'open' [Pd2 (L)2 ]4+ macrocycle through introduction of more metal ion. This is accomplished by the ligand having two bidentate binding sites: a 2-pyridyl-1,2,3-triazole site, and a bis-1,2,3-triazole site. Due to favourable hydrogen bonding, the 2-pyridyl-1,2,3-triazole units reliably coordinate in the [Pd(L)2 ]2+ complex to control speciation: a second equivalent of Pd(II) is required to enforce coordination to bis-triazole sites and form the macrocycle. The macrocycle interacts with a molecular substrate with higher affinity. In this fashion we are able to use stoichiometry to reversibly switch between two different species and regulate guest binding.

Quantifying the Effect of Guest Binding on Host Environment.

The environment around a host-guest complex is defined by intermolecular interactions between the complex, solvent molecules, and counterions. These interactions govern both the solubility of these complexes and the rates of reactions occurring within the host molecules and can be critical to catalytic and separation applications of host-guest systems. However, these interactions are challenging to detect using standard analytical chemistry techniques. Here, we quantify the hydration and ion pairing of a FeII4L4 coordination cage with a set of guest molecules having widely varying physicochemical properties. The impact of guest properties on host ion pairing and hydration was determined through microwave microfluidic measurements paired with principal component analysis (PCA). This analysis showed that introducing guest molecules into solution displaced counterions that were bound to the cage, and that the solvent solubility of the guest has the greatest impact on the solvent and ion-pairing dynamics surrounding the host. Specifically, we found that when we performed PCA of the measured equivalent circuit parameters and the solubility and dipole moment, we observed a high (>90%) explained variance for the first two principal components for each circuit parameter. We also observed that cage-counterion pairing is well-described by a single ion-pairing type, with a one-step reaction model independent of the type of cargo, and that the ion-pairing association constant is reduced for cargo with higher water solubility. Quantifying hydration and cage-counterion interactions is a critical step to building the next generation of design criteria for host-guest chemistries.

Hetero-Diels-Alder Reaction between Singlet Oxygen and Anthracene Drives Integrative Cage Self-Sorting.

A ZnII8L6 pseudocube containing anthracene-centered ligands, a ZnII4L'4 tetrahedron with a similar side length as the cube, and a trigonal prism ZnII6L3L'2 were formed in equilibrium from a common set of subcomponents. Hetero-Diels-Alder reaction with photogenerated singlet oxygen transformed the anthracene-containing "L" ligands into endoperoxide "LO" ones and ultimately drove the integrative self-sorting to form the trigonal prismatic cage ZnII6LO3L'2 exclusively. This ZnII6LO3L'2 structure lost dioxygen in a retro-Diels-Alder reaction after heating, which resulted in reversion to the initial ZnII8L6 + ZnII4L'4 ⇌ 2 × ZnII6L3L'2 equilibrating system. Whereas the ZnII8L6 pseudocube had a cavity too small for guest encapsulation, the ZnII6L3L'2 and ZnII6LO3L'2 trigonal prisms possessed peanut-shaped internal cavities with two isolated compartments divided by bulky anthracene panels. Guest binding was also observed to drive the equilibrating system toward exclusive formation of the ZnII6L3L'2 structure, even in the absence of reaction with singlet oxygen.

Leveraging quantum-chemical in silico techniques to determine guest binding energies for the crystalline sponge method

Leveraging quantum-chemical <i>in silico</i> techniques to determine guest binding energies for the crystalline sponge method

Crossover Sorption of C2H2/CO2 and C2H6/C2H4 in Soft Porous Coordination Networks.

Porous sorbents are materialsutilizedfor various applications, including storage and separation. Typically, the uptake of a single gas by a sorbent decreases with temperature, but the relative affinity for two similar gases does not change. However, herein, we report a rare example of "crossover sorption," in which the uptake capacity and apparent affinity for two similar gases reverse at different temperatures. We synthesized twosoft porous coordination polymers, [Zn2(L1)(L2/L3)2]n(PCP-1/2) (L1 = 4,4'-bis(4-pyridyl)phenyl; L2 = 5-methyl-1,3-di(4-carboxyphenyl)benzene; L3 = 5-methoxy-1,3-di(4-carboxyphenyl)benzene). These PCPsexhibits structural changes upon gas sorption and show the crossover sorption for both C2H2/CO2and C2H6/C2H4, where the apparent affinity reverse with temperature. We used in-situ gas-loading single-crystal X-ray diffraction (SCXRD) analyses to reveal the guest-inclusion structures of PCP-1 at various temperatures.Interestingly, we observed three-step single-crystal-to-single-crystal transformations with the different loading phases under these gases, providing insight into guest-binding positions, nature of host-guest or guest-guest interactions. Combining with theoretical investigation, we have fully elucidated the crossover sorption in the flexible coordination networks, which involves a reversal of apparent affinity and uptake of similar gases at different temperatures. We discovered that this behaviour can be explained by the delicate balance between guest binding and host-guest and guest-guest interactions.

Crossover Sorption of C2H2/CO2 and C2H6/C2H4 in Soft Porous Coordination Networks

AbstractPorous sorbents are materials that are used for various applications, including storage and separation. Typically, the uptake of a single gas by a sorbent decreases with temperature, but the relative affinity for two similar gases does not change. However, in this study, we report a rare example of “crossover sorption,” in which the uptake capacity and apparent affinity for two similar gases reverse at different temperatures. We synthesized two soft porous coordination polymers (PCPs), [Zn2(L1)(L2)2]n (PCP‐1) and [Zn2(L1)(L3)2]n (PCP‐2) (L1= 1,4‐bis(4‐pyridyl)benzene, L2=5‐methyl‐1,3‐di(4‐carboxyphenyl)benzene, and L3=5‐methoxy‐1,3‐di(4‐carboxyphenyl)benzene). These PCPs exhibits structural changes upon gas sorption and show the crossover sorption for both C2H2/CO2 and C2H6/C2H4, in which the apparent affinity reverse with temperature. We used in situ gas‐loading single‐crystal X‐ray diffraction (SCXRD) analysis to reveal the guest inclusion structures of PCP‐1 for C2H2, CO2, C2H6, and C2H4 gases at various temperatures. Interestingly, we observed three‐step single‐crystal to single‐crystal (sc‐sc) transformations with the different loading phases under these gases, providing insight into guest binding positions, nature of host–guest or guest‐guest interactions, and their phase transformations upon exposure to these gases. Combining with theoretical investigation, we have fully elucidated the crossover sorption in the flexible coordination networks, which involves a reversal of apparent affinity and uptake of similar gases at different temperatures. We discovered that this behaviour can be explained by the delicate balance between guest binding and host–guest and guest‐guest interactions.

Application of Heterometallic Supramolecular Cages in Treating Cancer

Supramolecular complexes rely on non-covalent interactions, enabling a host-guest structure. When metal ions are introduced into the skeleton of ‘host’, the valance electron configuration of heteroatoms result in versatile stable structures of complexes. Heterometallic supramolecular cage is a kind of stable form which is able to act as a carrier. Instead of diffusing into circulatory system directly, carriers are used to hold the drug molecule and release it at an aim position. In this case, targeted therapy, which significantly reduce the side effect of drugs, can be achieved. There have been discussions on the potential of supramolecular structures as cytotoxic agents and drug delivery systems for anticancer drugs. Several anticancer, antibacterial, and other pharmacological analogue compounds were used to investigate the guest binding capabilities of the successfully synthesized heterometallic complexes. The stability of these cages in water and when coupled with specific guest molecules was examined. These cages' capacity for cytotoxicity as well as diverse host-guest combinations were investigated.

Selective molecular recognition of amino acids and their derivatives by cucurbiturils in aqueous solution: An MD/3D-RISM study

The three-dimensional reference interaction site model theory was utilized to investigate cucurbituril–guest binding and its corresponding solvation structure. In this study, glycine, tryptophan, phenylalanine and their derivatives were employed as representatives of guest molecules. In the case of aromatic amino acids, phenylalanine shows the most significant binding affinity in cucurbit-7-uril, whereas tryptophan provides the highest binding affinity in cucurbit-8-uril. Although these guest molecules are very similar in molecular volumes, their chemical and physical properties are different. These findings agree well with reports from previous studies. We also found that the substitution of the tert-butyl (–C(CH3)3) group at the para-position in phenylalanine provides the highest binding affinity gain among all derivatives. Moreover, the unbound state of glycine is pointed out.

Structural Switching of a Distorted Trigonal Metal-Organic Cage to a Tetragonal Cage and Singlet Oxygen Mediated Oxidations.

Construction of metal-organic cages with unique architecture and guest binding abilities is highly desirable. Herein, we report the synthesis of a distorted trigonal cage (1) from a twisted tetratopic ligand (L) and a PdII acceptor. Surprisingly, 1 exhibited a complete structural reorganization of its building units in the presence of C70 and C60 to form guest-encapsulated tetragonal cages, (C70 )2 @2 and (C60 )2 @2, respectively. These guest-bound cages were found to be potential 1 O2 generators, with the former effectively catalyzing two different varieties of 1 O2 -mediated oxidation reactions.

Structural Switching of a Distorted Trigonal Metal‐Organic Cage to a Tetragonal Cage and Singlet Oxygen Mediated Oxidations

AbstractConstruction of metal–organic cages with unique architecture and guest binding abilities is highly desirable. Herein, we report the synthesis of a distorted trigonal cage (1) from a twisted tetratopic ligand (L) and a PdII acceptor. Surprisingly, 1 exhibited a complete structural reorganization of its building units in the presence of C70 and C60 to form guest‐encapsulated tetragonal cages, (C70)2@2 and (C60)2@2, respectively. These guest‐bound cages were found to be potential 1O2 generators, with the former effectively catalyzing two different varieties of 1O2‐mediated oxidation reactions.

Cyclization of an Achiral Flipping Panel to Homochiral Tubes Exhibiting Circularly Polarized Luminescence.

Macrocyclization of the bendable 2,7-dimethoxythianthrene with methylene linkages afforded a pair of homochiral macrocycles featuring a hex-nut-like geometry. Their structures were fully characterized by NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction analysis. Their stable planar chirality facilitates efficient resolution of the pair of enantiomers which could be readily derivatized. Installing phenylethynyl groups on their rims leads to luminescent tubular macrocycles exhibiting circularly polarized luminescence with a large dissymmetry value |glum | of 5×10-3 . Supramolecular binding of electron-deficient guests by the tube results in fluorescence quenching, which proved its potential for the future development of switchable chiroptical systems.

Mimicking nature’s stereoselectivity through coordination cages

Emulating biology’s recognition properties is challenging yet critical for unlocking innovative solutions in medicine, biotechnology, and materials science. In this issue of Chem, Jonathan R. Nitschke, Dawei Zhang, and co-workers report a series of tetrahedral cages formed by subcomponent self-assembly, which has proven to be highly effective in recognizing complex chiral molecules with exceptional stereoselectivity. Emulating biology’s recognition properties is challenging yet critical for unlocking innovative solutions in medicine, biotechnology, and materials science. In this issue of Chem, Jonathan R. Nitschke, Dawei Zhang, and co-workers report a series of tetrahedral cages formed by subcomponent self-assembly, which has proven to be highly effective in recognizing complex chiral molecules with exceptional stereoselectivity. Enantiopure FeII4L4 cages bind steroids stereoselectivelyLi et al.ChemApril 12, 2023In BriefThe preparation of new enantiopure tetrahedral cages enables the inclusion of steroids with high stereoselectivities. Subtle differences in cavity structure between cage enantiomers lead to major changes in guest binding affinity and even stoichiometry. Our work thus demonstrates how control over host handedness serves as a useful means to gauge and tune the binding of information-rich guests with complex stereochemistries. It also provides insight into how natural stereoselective receptors work and has implications for designing new cage-mediated asymmetric transformations and chemical purification methods. Full-Text PDF Open Access

Negative Homotropic Cooperativity in Guest Binding of a Trisporphyrin Double Cleft.

Invited for the cover of this issue is the group of Takeharu Haino at Hiroshima University. The image depicts the host-guest complex of a trisporphyrin double cleft with an electron-deficient aromatic molecule, which shows negative cooperativity in guest binding. Read the full text of the article at 10.1002/chem.202300107.