Thermodynamic analysis of receptors based on guanidinium/boronic acid groups for the complexation of carboxylates, alpha-hydroxycarboxylates, and diols: driving force for binding and cooperativity

The thermodynamics of guanidinium and boronic acid interactions with carboxylates, alpha-hydroxycarboxylates, and diols were studied by determination of the binding constants of a variety of different guests to four different hosts (7-10). Each host contains a different combination of guanidinium groups and boronic acids. The guests included molecules with carboxylate and/or diol moieties, such as citrate, tartrate, and fructose, among others. The Gibbs free energies of binding were determined by UV/Vis absorption spectroscopy, by use of indicator displacement assays. The receptor based on three guanidinium groups (7) was selective for the tricarboxylate guest. The receptors that incorporated boronic acids (8-10) had higher affinities for guests that included alpha-hydroxycarboxylate and catechol moieties over guests containing only carboxylates or alkanediols. Isothermal titration calorimetry revealed the enthalpic and entropic contributions to the Gibbs free energies of binding. The binding of citrate and tartrate was investigated with hosts 7-10, for which all the binding events were exothermic, with positive entropy. Because of the selectivity of hosts 8-10, a simple boronic acid (14) was also investigated and determined to be selective for alpha-hydroxycarboxylates and catechols over amino acids and alkanediols. Further, the cooperativity of 8 and 9 in binding tartrate was also investigated, revealing little or no cooperativity with 8, but negative cooperativity with 9. A linear entropy/enthalpy compensation relationship for all the hosts 7-10, 14, and the carboxylate-/diol-containing guests was also obtained. This relationship indicates that increasing enthalpy of binding is offset by similar losses in entropy for molecular recognition involving guanidinium and boronic acid groups.     

β-环糊精及其衍生物对脂肪族手性对映体及有机染料的分子识别研究

在25℃用荧光和紫外光谱滴定法分别测定了β-环糊精(β-CD)、2,3,6-三[氧-(2-羟基丙基)]-β-环糊精(HP-β-CD)及2,3,6-三(甲氧基)-β-环糊精(MO-β-CD)与6种脂肪族手性客体和4种染料分子形成超分子配合物的稳定常数.结果表明,多种弱相互作用协同贡献于主-客体的包结配位过程.环糊精衍生物中取代基的疏水性和链长影响主体的配位能力,客体与环糊精间的尺寸适合及疏水相互作用决定其配合物的稳定性.在配位过程中,氢键作用也是影响主体环糊精键合行为的重要因素.     

Binding propensity and selectivity of cationic,anionic, and neutral guests with model hydrophobic hosts: A first principles study

Computations play a critical role in deciphering the nature of host–guest interactions both at qualitative and quantitative levels. Reliable quantum chemical computations were employed to assess the nature, binding strength, and selectivity of ionic, and neutral guests with benzenoid hosts. Optimized complex structures reveal that alkali and ammonium ions are found to be in the hydrophobic cavity, while halide ions are outside, while both complexes elicit substantial binding energy. The origin of the selectivity of host toward the guest has been traced to the interaction and deformation energies, and the nature of associated interactions is quantified using energy decomposition and the Quantum Theory of Atoms in Molecules analyses. While the larger hosts lead to loosely bound complexes, as assessed by the longer intermolecular distances, the binding strengths are proportional to the size of the host systems. The binding of cationic complexes is electrostatic or polarization driven while exchange term dominates the anionic complexes. In contrast, dispersion contribution is a key in neutral complexes and plays a pivotal role in stabilizing the polyatomic complexes.     

Modeling competitive guest binding to beta-cyclodextrin molecular printboards

Anchoring of functionalized guest molecules to self-assembled monolayers (SAMs) is key to the development of molecular printboards for nanopatterning. One very promising system involves guest binding to immobilized beta-cyclodextrin (beta-CD) hosts, with guest:host recognition facilitated by a hydrophobic interaction between uncharged anchor groups on the guest molecule and beta-CD hosts self-assembled at gold surfaces. We use molecular dynamics free energy (MDFE) simulations to describe the specificity of guest:beta-CD association. We find good agreement with experimental thermodynamic measurements for binding enthalpy differences between three commonly used phenyl guests: benzene, toluene, and t-butylbenzene. van der Waals interaction with the inside of the host cavity accounts for almost all of the net stabilization of the larger phenyl guests in beta-CD. Partial and full methylation of the secondary rim of beta-CD decreases host rigidity and significantly impairs binding of both phenyl and larger adamantane guest molecules. The beta-CD cavity is also very intolerant of guest charging, penalizing the oxidized state of ferrocene by at least 7 kcal/mol. beta-CD hence expresses moderate specificity toward uncharged organic guest molecules by van der Waals recognition, with a much higher specificity calculated for electrostatic recognition of organometallic guests.     

Synthesis, computational study and binding properties of some structurally rigid glycoluril-derived molecular clips

Several new clip-shaped molecules, with different degrees of steric hindrance around their cavities as well as more rigidity on their glycoluril scaffold, have been synthesized and the molecular geometry of their most stable structures has been investigated and optimized with density functional theory (DFT) at the B3LYP level of theory using 6-311G basis set. The affinity of these molecular clips for some dihydroxybenzene derivatives (guests) has been computationally and experimentally studied. The clips having dimethyl-substituted aromatic side walls, showed the best interaction energies towards the mentioned guests. Also, the computational results revealed that the more electron-deficient guest interacts more strongly with the clips (hosts).     

Caged oxoanions

The association between azacryptand hosts and oxoanion guests is reviewed. Positively charged hosts are the most effective; we focus on protonated azacryptands. Assessment of quantitative data suggests an anion cryptate effect and provides clear evidence for charge-based selectivity. Crystal structures show both cavity and cleft binding sites for anions within the series of cryptands studied. These two binding modes exhibit different pH dependence offering the possibility for design of monitoring/clean-up strategies based on a variation of appropriate host(s) and pH conditions.     

Crystalline complexes of N,N'-ditritylurea (DTU) and N-tritylurea (NTU) hosts with molecular guests

This paper reports crystalline complexes of the new hosts N,N'-ditritylurea (DTU) and N-tritylurea (NTU) with various uncharged molecular guests. The crystal structures of the following complexes were elucidated by single crystal X-ray diffraction analysis at 115^oK: (I) 1:1 DTU-propanamide — space group C2/c, a=15.839Å, b=9.088Å, c=24.584Å, =111.05^o, Z=4; (II) 1:1 DTU-ethyl N-acetylglycinate — space group P1, a=9.010Å, b=10.800Å, c=19.810 Å, =105.29^o =94.33^o, =93.03^o, Z=2; (III) 2:1 NTU-N, N-dimethylformamide — space group Cc, a=29.614Å, b=8.906Å, c=16.127Å, =121.04^o, Z=4. The three crystal structures are stabilized mainly by a cooperative effect of hydrogen bonding between amide fragments displaced along the shortest axis of each crystal. This interaction occurs between host and guest in complexes I and II, and between host and host in complex III. The latter also represents a cage-type clathrate in which the guest molecules are accommodated in voids between the hydrophobic fragments of four neighboring NTU hosts. On the other hand, complexes of DTU are characterized by a more specific interaction between the two components, each guest molecule being inserted between two adjacent hosts (related by translation) and strongly bound to them via hydrogen bridges. These results illustrate a useful concept in the design of molecular species which can be potential hosts upon crystallization with neutral molecular guests. Supplementary Data relating to this article are deposited with the British Library as Supplementary Publication No. SUP 82022 (7 pages).     

Dynamic analyses on induced-fit gaseous guest binding to organic crystals with a quartz-crystal microbalance

The inclusion behavior of gaseous guest molecules in a solid apohost, an orthogonal anthracene-bis(resorcinol)tetraol (1), was investigated with a quartz-crystal microbalance (QCM). Compound 1 forms crystals composed of molecular sheets bound together by an extensive hydrogen-bonded network. An apohost of 1 was cast onto a QCM and the binding of gaseous guest molecules was followed as a function of time by observing the decrease in the oscillation frequency, which is directly related to the increase in mass. Ethyl acetate and methyl ethyl ketone were significantly included into the apohost, whereas benzene and cyclohexane were simply adsorbed onto the surface of the solid; all these guests have similar vapor pressures at 25 degrees C. On the other hand, a host analogue 2, a tetramethoxy derivative of 1, barely included these guest molecules. The inclusion amount and the rate of inclusion of ethyl acetate or methyl ethyl ketone showed a drastic increase above a threshold concentration of guests in the gas phase. Thus, the structure of the apohost changed cooperatively in order to bind guest molecules above the threshold guest concentration. This cooperativity of the binding behavior was kinetically analyzed.     

Guest binding and orientation within open nanoscale hosts

The synthesis of three different nanoscale molecular hosts is reported. These cavitands each possess a highly preorganized cavity with an open portal (nearly 1 nm wide), by which guests can enter and egress the cavity. Additionally, these hosts are deep-functionalized with a crown of weakly acidic benzal C-H groups which can form a variety of noncovalent interactions with guest molecules residing within the cavity. Thirty-one guests were examined for their propensity to form complexes with the hosts. Guests that possess halogen atoms were the strongest binders, suggesting the formation of polydentate C-H triplebond X-R hydrogen bonds with the deep crown of benzal hydrogens. Exchange rates between the free and bound states were noted to be dependent on the size of the guest and the solvent used to study complexation. In general, stronger binding and slower exchange were noted for complexations carried out in DMSO with highly complementary guests. The orientation of each guest within the cavity was determined using either EXSY NMR spectroscopy or (1)H NMR shift data. Cumulatively these results showed that the principal factors directing orientation were interactions with the benzal groups and the type of solvent. Van't Hoff analyses of selected complexations were also carried out. As well as revealing that all complexations were entropically unfavorable, these experiments provided support for guest orientation determinations, and gave an estimation that the formation of a C-H triplebond I-R hydrogen bond releases between 1 and 1.5 kcal mol(-1).     

Hetero-Coencapsulation within a Supramolecular Cage: Moving away from the Statistical Distribution of Different Guests

Beside sensing and delivery, another peculiar property arising from confinement in discrete molecular hosts comes from the possibility to have in close proximity, and in defined position, two different molecules (hetero-coencapsulation). This phenomenon can be tuned considering steric and electronic properties of the guests. In this work, a study on the parameters affecting homo- and hetero-coencapsulation processes within a supramolecular cage is reported. In particular, different benzoate guests were bound within a supramolecular cage containing two metal-binding sites and the experimental binding thermodynamics measured. Unexpectedly, from competition experiments it was observed that the maximum concentration of hetero-coencapsulation is achieved if a weakly binding guest is used to partially displace a strongly binding guest.     

Complexation of Neutral Molecules by Cyclophane Hosts

Since the discovery of the crown ethers by Pedersen twenty years ago, the chemistry of synthetic hosts for the selective complexation of organic and inorganic guests has seen an extraordinarily rapid development. This article discusses in particular the contributions provided by synthetic cyclophanes as hosts to the understanding of molecular complexation of neutral organic guest molecules in aqueous and organic solvents. In aqueous solution, cyclophanes form stoichiometric complexes with neutral aromatic guests which can approach enzyme-substrate complexes in their stability. Efficient molecular complexation is also observed in organic environments. Here, as a result of large solvation effects, the strength of complexation is strongly dependent on the nature of the organic solvent. Electron donor-acceptor interactions can contribute significantly to the stability of complexes formed between cyclophane hosts and aromatic guests. Force-field calculations together with computer graphics are powerful tools in the design of water-soluble, optically active hosts for chiral recognition of complexed racemic guests. Simple and selective functionalization of the cyclophane framework leads to stable, bioorganic catalysts. Like enzymes, these catalysts bind their substrates in a rapid equilibrium prior to the reaction steps. As a perspective, some fascinating research objectives in the field of molecular recognition and catalysis which can be targeted with designed cyclophane hosts are shown.     

Recent Advances in the Applications of Water-soluble Resorcinarene-based Deep Cavitands

We review here the use of container molecules known as cavitands for performing organic reactions in water. Central to these endeavors are binding forces found in water, and among the strongest of these is the hydrophobic effect. We describe how the hydrophobic effect can be used to drive organic molecule guests into the confined space of cavitand hosts. Other forces participating in guest binding include cation−π interactions, chalcogen bonding and even hydrogen bonding to water involved in the host structure. The reactions of guests take advantage of their contortions in the limited space of the cavitands which enhance macrocyclic and site-selective processes. The cavitands are applied to the removal of organic pollutants from water and to the separation of isomeric guests. Progress is described on maneuvering the containers from stoichiometric participation to roles as catalysts.     

Influence of dimensionality and charge on anion binding in amide-based macrocyclic receptors

The influence of dimensionality and charge on anion binding and structure is explored for a selected series of amide-based macrocyclic receptors. Monocyclic, bicyclic and tricyclic hosts are described in terms of affinities towards simple oxo anions (including acetate) and halides. Binding propensities tend to vary, although some selectivity patterns emerge for similar ligand frameworks. Some anions also exert a template influence the cyclization reactions during the synthesis of host precursors. Structurally sandwich complexes are often formed in the monocycles, while bicycles tend to encapsulate their guests. Multiple anions plus water molecules are often found in the larger bicycles. Added charge via quaternization or protonation tends to enhance binding by one or two orders of magnitude while maintaining the same selectivity patterns.     

A Comparative Study of Complexation of β-Cyclodextrin,Calix[4]arenesulfonate and Cucurbit[7]uril with Dye Guests: Fluorescence Behavior and Binding Ability

The complexation behaviors of acridine red (AR), neutral red (NR) and rhodamine B (RhB) dye guest molecules by three kinds of supramolecular hosts, including β-cyclodextrin (β-CD), calix[4]arene tetrasulfonate (C4AS) and cucurbit[7]uril (CB[7]), have been investigated by means of fluorescence spectra in aqueous citrate buffer solution (pH 6.0). The results obtained show that the three hosts, possessing different types of cavity, lead to various complexation-induced fluorescence of dye guests, and present different binding ability and molecular selectivity. The complexation stability constants decrease in the order of NR > AR > RhB for C4AS and CB[7] hosts, while in the order of RhB > AR > NR for β-CD host. Particularly, CB[7] displays the strongest binding ability with NR (K _S = 33300 M^? 1), and provides the molecular selectivity of 4.8 for NR/AR pairs. Although the binding ability of C4AS for present dye guests is weaker than CB[7], but the molecular selectivity of the two hosts are nearly equivalent. β-CD shows stronger binding ability with RhB (K _S = 5880 M^? 1) as comparison with CB[7] and C4AS. Furthermore, the solvent effects and salt effects during the course of complexation have also been investigated.     

Selectivity in supramolecular host-guest complexes

The background of possible selectivity-affinity correlations and their limitations is reviewed, with typical crown ether and cryptand complexes, ionic associations, hydrogen bonded complexes and complexes driven by van der Waals, stacking or hydrophobic interactions, with some additional topics including associations based on metal coordination as supplementary material. This tutorial review is addressed to students and researchers interested in molecular recognition, and relates to the design of sensors, of discriminators for separation processes, of supramolecular devices and of drug compounds. A theoretical analysis of selectivity in supramolecular host-guest complexes, defined as a difference in binding free energies for structurally related guests, as a function of total binding free energy shows that for certain types of intermolecular interactions one may observe a correlation between selectivity and affinity. Such correlation fails however if the selectivity is due to additional interactions at a secondary binding sites, which is expected in complexes with anisotropic guest molecules. Several clear examples of theoretically expected selectivity-affinity correlations are found. The influence of reaction conditions on the experimentally observed selectivity, defined as a difference in complexation degrees with different guests in the presence of added receptor, is illustrated. The importance of often neglected solvent effects on selectivity is exemplified with ionophore and hydrogen bonded complexes.     

Highly emissive supramolecular oligo(p-phenylene vinylene) dendrimers

pi-Conjugated oligo(p-phenylene vinylene) (OPV) guest molecules for interaction with dendritic hosts were synthesized and fully characterized by NMR spectroscopy, MALDI-TOF-MS, elemental analysis and optical measurements. The binding properties of the five different OPV guests to a N,N-bis[(3-adamantyl ureido) propyl] methylamine host have been investigated. The guests that contained an aryl urea glycine spacer were bound with the highest association constant. Subsequently, an adamantyl urea modified fifth generation poly(propylene imine) dendrimer was synthesized as a multivalent host which contains 32 N,N-bis[(3-adamantyl ureido) propyl] amine binding sites. Size exclusion chromatography showed that 32 of the OPV guests strongly bind to the fifth generation adamantyl functionalized dendritic host. In the case of the supramolecular dendritic host/guest system smooth homogeneous thin films could be obtained by spin coating. The dendritic guest-host complexes showed a significantly higher emission upon binding then that of the individual molecules due to the three-dimensional orientation of the OPV guest molecules. In the solid state, this enhancement in luminescence was a factor of 10. The pi-conjugated oligomers are less aggregated in the supramolecular assemblies presumably because of a shielding effect of the bulky adamantyl units present in the hosts.     

Inclusion of Carboxyl Function Inside of Cucurbiturils and its Use in Molecular Switches

We have prepared organic guest molecules in which two pyridinium rings are connected through an aromatic/aliphatic bridge bearing a carboxyl group. The supramolecular interactions between these guests and macrocyclic hosts cucurbit[7]uril ( CB7 ) and cucurbit[8]uril ( CB8 ) has been studied. We have demonstrated that the binding modes of the complexes depend on the type of central bridge present in the guest molecules and the size of the macrocycle. We have also showed that the binding mode between cucurbiturils and guests with aromatic bridges is pH independent. On the other hand, a guest containing an aliphatic bridge and CB7 formed a pseudorotaxane, which behaved as a pH‐driven molecular switch.     

Highly organized spherical hosts that bind organic guests in aqueous solution with micromolar affinity: microcalorimetry studies

Two novel closed-shell hemicarcerand-like hosts with spherical cavities of 11 A diameter that are soluble in aqueous solution were constructed. The binding of xylenes, aryl ethers, polyaromatic compounds, ferrocene derivatives, and bicyclic aliphatic compounds were examined by NMR spectroscopy and microcalorimetry. NMR binding studies indicated that binding depended upon guest hydrophobicity and shape. No binding was detected for guests in which a charge must be desolvated as part of inclusion or for guests that can not fit within the cavity of the host. Three complexes 2.naphthalene, 2.p-xylene, and 2.ferrocene were isolated and found to be indefinitely stable in the solid phase and in aqueous solution. The binding constants for these complexes are estimated to be greater than 10(8) M-1. Thirteen guests were examined by microcalorimetry with binding constants ranging between 10(7) and 10(3) M-1. A comparison of results obtained here with those from previous work with beta-cyclodextrin and cyclophane hosts, along with analysis of the entropy-enthalpy compensation data, indicate that there is a higher degree of guest desolvation with this host structure than with open-shell hosts. This accounts at least partially for the increase in affinity observed with these closed-shell hosts. Replacing a hydroxy group in the host portal with a hydrogen atom does not affect the binding constant, a finding consistent with the guest residing deeply buried within the host cavity. It was observed that aromatic guests are bound with higher affinity than aliphatic ones in agreement with results that point to the importance of London dispersion forces in the association of aromatic components in face-to-edge orientations. The correlation of changes in NMR chemical shift with microcalorimetry data supports a model in which increased CH-pi interactions strengthen association between host and guest due to the dominant role of van der Waals dispersion forces. Remarkably, the binding constant for the 1,4 isomer of dimethoxybenzene is 32 times higher than for the 1,2 isomer, and even greater discrimination is observed between the xylene guests since the binding constant for p-xylene is 80 times greater than that for o-xylene. This discrimination between isomeric guests by a rigid host indicates that changes in specific hydrophobic interactions have substantial effects upon binding affinity.     

Predicting conformations and orientations of guests within a water soluble host: a molecular docking approach

In this study we have examined conformations and orientations of guests within a water-soluble host known by the trivial name Octa Acid (OA). Docking program Vina, which was originally developed for screening drug-like molecules, has been used to identify binding modes and affinities of select guest molecules with OA. Hydrophobic guests were encapsulated into the nonpolar cavity of OA capsule owing to solvophobic interactions. Amphiphilic guests were bound by keeping the nonpolar part within the cavity of OA, while pointing the polar anionic group out of the cavity. All these results obtained from the docking study were in accord with experimental findings. The post-complexation attributes of the guests were regulated by available free space and the specific interactions between guest–OA pair, which led to unusual conformations and orientations. This study showed that scoring function available with Vina, which was derived from protein–ligand data set, could successfully predict post-complexed structural features of guests within OA, thus opening opportunities to modulate physical and chemical behavior of guest molecules.     

Novel permethylated beta-cyclodextrin derivatives appended with chromophores as efficient fluorescent sensors for the molecular recognition of bile salts

Two novel permethylated beta-cyclodextrin (PM-beta-CD) derivatives, i.e., 6I-O-(1-naphtholxy)-2I,31-di-O-methylhexakis(2II-VII,3II-VII,6II-VII-tri-O-methyl)-beta-cyclodextrin (1) and 6I-O-(8-hydroxyquinoline)-2I,31-di-O-methylhexakis(2II-VII,3II-VII,6II-VII- tri-O-methyl)-beta-cyclodextrin (2), were synthesized in satisfactory yields, and their inclusion modes, complex-induced fluorescent behaviors, binding ability, and selectivity for bile salts of biological relevance (cholic acid sodium salt, CA; deoxycholic acid sodium salt, DCA; glycochoic acid sodium salt, GCA; taurocholic acid sodium salt, TCA) were investigated by the circular dichroism, 2D NMR, steady-state, and time-resolved fluorescent spectra. The results obtained from induced circular dichroism and ROESY spectra show that the chromophore groups of 1 and 2 reside in the central cavity of PM-beta-CD, and are expelled to the region of narrow torus rim upon complexation with bile guests, which presents the binding mode of cooperative inclusion. The transfer of the chromophore groups from the central cavity to the more hydrophobic torus rim leads to the remarkable increase of fluorescent intensities and longer fluorescent lifetimes of hosts 1 and 2 upon gradual addition of bile salts, which is importantly distinct from the molecular recognition of the chromophore-modified beta-CD species with bile salts. Interestingly, hosts 1 and 2 present much stronger binding ability for bile guests than PM-beta-CD. Differing from native beta-CD, all the PM-beta-CDs are more prone to include bile salts with longer tails, such as GCA and TCA. Their corresponding binding ability and molecular selectivity are closely discussed from the viewpoints of difference of cavity size/shape between beta-CD and PM-beta-CD, effect of substituent groups, and structures of bile guests, respectively.