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.     

The complexation of two different ammonium ions with resorcarenes in protic solvent medium investigated by electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry

The complexations of two ammonium ions (guests) with two resorcarenes (hosts) were investigated using electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry. Although the two guests and the two hosts were noticeably similar, the quantity of the corresponding supramolecular complexes formed varied significantly due to the differences in host conformations and guest ability to form non-covalent interactions.     

Equilibrium isotope effects on noncovalent interactions in a supramolecular host-guest system

The self-assembled supramolecular complex [Ga(4)L(6)](12-) (1; L = 1,5-bis[2,3-dihydroxybenzamido]naphthalene) can act as a molecular host in aqueous solution and bind cationic guest molecules to its highly charged exterior surface or within its hydrophobic interior cavity. The distinct internal cavity of host 1 modifies the physical properties and reactivity of bound guest molecules and can be used to catalyze a variety of chemical transformations. Noncovalent host-guest interactions in large part control guest binding, molecular recognition and the chemical reactivity of bound guests. Herein we examine equilibrium isotope effects (EIEs) on both exterior and interior guest binding to host 1 and use these effects to probe the details of noncovalent host-guest interactions. For both interior and exterior binding of a benzylphosphonium guest in aqueous solution, protiated guests are found to bind more strongly to host 1 (K(H)/K(D) > 1) and the preferred association of protiated guests is driven by enthalpy and opposed by entropy. Deuteration of guest methyl and benzyl C-H bonds results in a larger EIE than deuteration of guest aromatic C-H bonds. The observed EIEs can be well explained by considering changes in guest vibrational force constants and zero-point energies. DFT calculations further confirm the origins of these EIEs and suggest that changes in low-frequency guest C-H/D vibrational motions (bends, wags, etc.) are primarily responsible for the observed EIEs.     

Chiral Encapsulation by Directional Interactions

The complexation of chiral guests in the cavity of dimeric self‐assembled chiral capsule 1 ₂ was studied by using NMR spectroscopy and X‐ray crystallography. Capsule 1 ₂ has walls composed of amino acid backbones forming numerous directional binding sites that are arranged in a chiral manner. The polar character of the interior dictates the encapsulation preferences towards hydrophilic guests and the ability of the capsule to extract guests from water into an organic phase. Chiral discrimination towards hydroxy acids was evaluated by using association constants and competition experiments, and moderate de values were observed (up to 59 %). Complexes with one or two guest molecules in the cavity were formed. For 1:1 complexes, solvent molecules are coencapsulated; this influences guest dynamics and makes the chiral recognition solvent dependent. Reversal of the preferences can be induced by coencapsulation of a nonchiral solvent in the chiral internal environment. For complexes with two guests, filling of the capsule’s internal space can be very effective and packing coefficients of up to 70 % can be reached. The X‐ray crystal structure of complex 1 ₂?((S) ‐6 )₂ with well‐resolved guest molecules reveals a recognition motif that is based on an extensive system of hydrogen bonds. The optimal arrangement of interactions with the alternating positively and negatively charged groups of the capsule’s walls is fulfilled by the guest carboxylic groups acting simultaneously as hydrogen‐bond donors and acceptors. An additional guest molecule interacting externally with the capsule reveals a possible entrance mechanism involving a polar gate. In solution, the structural features and dynamic behavior of the D₄‐symmetric homochiral capsule were analyzed by variable‐temperature NMR spectroscopy and the results were compared with those for the S₈‐symmetric heterochiral capsule.     

水溶性六元瓜环衍生物与1,ω-亚烷基吡啶主客体配合物的^1HNMR及晶体结构

利用^1HNMR技术以及单晶X衍射技术考察对称四甲基取代六元瓜环（TMeQ[6]）与几种1,ω-亚烷基吡啶阳离子（ω=2,4,6,8,10）客体的相互作用．在这些包结配合物中,TMeQ[6]的端口效应以及空腔效应同时存在,其主客体作用模式随着客体亚烷基碳链长短不一而各不相同．对于客体1,2-二乙基吡啶（Edpy）,TMeQ[6]包结Edpy的带正电荷的吡啶环部分,形成一不对称的包结配合物;对于客体1,4-二丁基吡啶（Bdpy）,TMeQ[6]选择性包结Bdpy的吡啶环部分或烷基部分存在竞争作用和快速交换;而具有较长碳链的客体1,6-二己基吡啶（Hdpy）和1,8-二丁庚基吡啶（Odpy）与TMeQ[6]通过空腔的疏水作用以及外部的离子-偶极作用形成稳定的类轮烷包结配合物;客体1,10-二癸基吡啶（Ddpy）的两个吡啶环分别被两个TMeQ[6]包结形成哑铃型的包结配合物．     

Guest encapsulation and self-assembly of a cavitand-based coordination capsule

The synthesis and spectroscopic characterization of a cavitand-based coordination capsule 14 BF4 of nanometer dimensions is described. Encapsulation studies of large aromatic guests as well as aliphatic guests were performed by using 1H NMR spectroscopy in [D1]chloroform. In addition to the computational analysis of the shape and geometry of the capsule, an experimental approach to estimate the interior size of the cavity is discussed. The cavity provides a highly rigid binding space in which molecules with lengths of approximately 14 A can be selectively accommodated. The rigid cavity distinguished slight structural differences in the flexible alkyl-chain guests as well as the rigid aromatic guests. The detailed thermodynamic studies revealed that not only CH-pi interactions between the methyl groups on the guest termini and the aromatic cavity walls, but also desolvation of the inner cavity play a key role in the guest encapsulation. The cavity preferentially selected the hydrogen-bonded heterodimers of a mixture of two or three carboxylic acids 18-20. The chiral capsule encapsulated a chiral guest to show diastereoselection.     

Crown ether-based cryptand/tropylium cation inclusion complexes

Host–guest complexation between crown ether-based cryptand hosts and a carbonium ion, tropylium hexafluorophosphate was studied. ¹H NMR, NOESY NMR, and electrospray ionization mass spectrometry were employed to characterize these inclusion complexes. The contrast tests of ¹H NMR and association constants indicated that cryptands are much better hosts for tropylium hexafluorophosphate than the corresponding simple crown ethers. C–H?O hydrogen bonding, face-to-face π-stacking interactions, and charge-transfer interactions are thought to be the main driving forces for the formation of these host–guest complexes. These multiple non-covalent interactions may jointly contribute to the complex formation and considerably reinforce the complex stability. Moreover, the complexation between dibenzo-24-crown-8-based cryptand 4 and tropylium hexafluorophosphate 7 can be reversibly controlled by adding KPF₆ and then DB18C6 in 1:1 acetonitrile/chloroform, providing a new cation-responsive host–guest recognition motif for supramolecular chemistry.     

Designed Synthesis of a Highly Conjugated Hexaethynylbenzene‐Based Host for Supramolecular Architectures

The construction of efficient synthetic functional receptors with tunable cavities, and the self‐organization of guest molecules within these cavities through noncovalent interactions can be challenging. Here we have prepared a double‐cavity molecular cup based on hexaethynylbenzene that possesses a highly π‐conjugated interior for the binding of electron‐rich guests. X‐ray crystallography, NMR spectroscopy, UV/Vis spectroscopy, fluorescent spectroscopy, cyclic voltammetry, and SEM were used to investigate the structures and the binding behaviors. The results indicated that the binding of a guest in one cavity would affect the binding of the same or another guest in the other cavity. The effect of electron transfer in this system suggests ample opportunities for tuning the optical and electronic properties of the molecular cup and the encapsulated guest. The encapsulation of different guests would also lead to different aggregate nanostructures, which is a new way to tune their supramolecular architectures.     

Guest-induced supramolecular isomerism in inclusion complexes of T-shaped host 4,4-bis(4'-hydroxyphenyl)cyclohexanone

The T-shaped host molecule 4,4-bis(4'-hydroxyphenyl)cyclohexanone (1) has an equatorial phenol group and a cyclohexanone group along the arms and an axial phenol ring as the stem. The equatorial phenyl ring adopts a "shut" or "open" conformation, like a windowpane, depending on the size of the guest (phenol or o/m-cresol), for the rectangular voids of the hydrogen-bonded ladder host framework. The adaptable cavity of host 1 expands to 11x15-18 A through the inclusion of water with the larger cresol and halophenol guests (o-cresol, m-cresol, o-chlorophenol, and m-bromophenol) compared with a size of 10x13 A for phenol and aniline inclusion. The ladder host framework of 1 is chiral (P2(1)) with phenol, whereas the inclusion of isosteric o- and m-fluorophenol results in a novel polar brick-wall assembly (7x11 A voids) as a result of auxiliary C-H...F interactions. The conformational flexibility of strong O-H...O hydrogen-bonding groups (host 1, phenol guest), the role of guest size (phenol versus cresol), and weak but specific intermolecular interactions (herringbone T-motif, C-H...F interactions) drive the crystallization of T-host 1 towards 1D ladder and 2D brick-wall structures, that is, supramolecular isomerism. Host 1 exhibits selectivity for the inclusion of aniline in preference to phenol as confirmed by X-ray diffraction, 1H NMR spectroscopy, and thermogravimetry-infrared (TG-IR) analysis. The T(onset) value (140 degrees C) of aniline in the TGA is higher than those of phenol and the higher-boiling cresol guests (T(onset)=90-110 degrees C) because the former structure has more O-H...N/N-H...O hydrogen bonds than the clathrate of 1 with phenol which has O-H...O hydrogen bonds. Guest-binding selectivity for same-sized phenol/aniline molecules as a result of differences in hydrogen-bonding motifs is a notable property of host 1. Host-guest clathrates of 1 provide an example of spontaneous chirality evolution during crystallization and a two-in-one host-guest crystal (phenol and aniline), and show how weak C-H...F interactions (o- and m-fluorophenol) can change the molecular arrangement in strongly hydrogen-bonded crystal structures.     

Recognition of N‐Alkyl and N‐Aryl Acetamides by N‐Alkyl Ammonium Resorcinarene Chlorides

N‐Alkyl ammonium resorcinarene chlorides are stabilized by an intricate array of intra‐ and intermolecular hydrogen bonds that leads to cavitand‐like structures. Depending on the upper‐rim substituents, self‐inclusion was observed in solution and in the solid state. The self‐inclusion can be disrupted at higher temperatures, whereas in the presence of small guests the self‐included dimers spontaneously reorganize to 1:1 host–guest complexes. These host compounds show an interesting ability to bind a series of N‐alkyl acetamide guests through intermolecular hydrogen bonds involving the carbonyl oxygen (C?O) atoms and the amide (NH) groups of the guests, the chloride anions (Cl^?) and ammonium (NH₂⁺) cations of the hosts, and also through CH ??? π interactions between the hosts and guests. The self‐included and host–guest complexes were studied by single‐crystal X‐ray diffraction, NMR titration, and mass spectrometry.     

A Dynamic Hydrogen‐Bonded Azo‐Macrocycle for Precisely Photo‐Controlled Molecular Encapsulation and Release

A light‐responsive system constructed from hydrogen‐bonded azo‐macrocycles demonstrates precisely controlled propensity in molecular encapsulation and release process. A significant decrease in the size of the cavity is observed in the course of the E→Z photoisomerization based on the results from DFT calculations and traveling wave ion mobility mass spectrometry. These macrocyclic hosts exhibit a rare 2:1 host–guest stoichiometry and guest‐dependent slow or fast exchange on the NMR timescale. With the slow host–guest exchange and switchable shape change of the cavity, quantitative release and capture of bipyridinium guests is achieved with the maximum release of 68 %. This work underscores the importance of slow host–guest exchange on realizing accurate release of organic cations in a stepwise manner under light irradiation. The light‐responsive system established here could advance further design of novel photoresponsive molecular switches and mechanically interlocked molecules.     

Scope and mechanism of the C-H bond activation reactivity within a supramolecular host by an iridium guest: a stepwise ion pair guest dissociation mechanism

A chiral self-assembled supramolecular M(4)L(6) assembly has been shown to be a suitable host for a series of reactive monocationic half-sandwich iridium guests 1, 3, and 4 that are capable of activating C-H bonds. Upon encapsulation, selective C-H bond activation of organic substrates occurs. Precise size and shape selectivity are observed in the C-H bond activation of aldehydes and ether substrates. The reactions exhibit significant kinetic diastereoselectivities. Thermodynamic studies have shown that the iridium starting materials and products are bound strongly by the host assembly. The encapsulation process is largely entropy-driven. Kinetic investigations with water-soluble phosphine traps and added salts have provided evidence for a unique stepwise mechanism of guest dissociation for [4 subset Ga(4)L(6)]. Iridium guest 4 first dissociates from the host cavity to form an ion pair with the host exterior. This species then fully dissociates from the host exterior into the bulk solution. Model ion pair intermediates were characterized directly with (1)H NMR NOESY techniques. The rate of iridium guest dissociation is slower than the rate observed for the C-H bond activation processes, indicating that the selective C-H bond activation reactivity occurs within the cavity of the supramolecular host.     

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.     

Orientational isomerism and binding ability of nonsymmetrical guests encapsulated in a self-assembling heterodimeric capsule

The ability of a guest to induce the assembly of tetracarboxyl-cavitand 1 and tetra(3-pyridyl)-cavitand 2 into a heterodimeric capsule 12, and the orientational isomerism of nonsymmetrical p-disubstituted-benzene guests encapsulated in 12, are described. For example, the ability of a guest to induce the assembly of guest subset(12) increases in the order p-iodoaniline< or =p-chloroanisole < p-bromoanisole < N-methyl-p-iodoaniline < p-iodoanisole. For these five guests encapsulated in 12, the halogen atoms are specifically oriented with respect to the cavity of the 2 unit. By contrast, the orientational isomeric selectivities of p-chloroiodobenzene, p-bromoiodobenzene, and p-methylanisole encapsulated in 12 are quite low, in the range of 1:1.7 to 1:1. The ortho-fluoro derivatives of these three guests, however, are encapsulated in 12 with a highly selective orientation, in which the substituent next to the fluorine atom greatly prefers the cavity of the 2 unit to that of the 1 unit.     

Ternary β-Cyclodextrin Complexes as Models of Allosteric Effects

Two guests reacting with cyclodextrins (CDs) may form ternary complexes, in addition to the common competition of 1:1 complexes. One of the guests can really be included into the cavity of the CD, while the second guest molecule is either inserted close to the first one or attached to the outer surface of the supramolecule by H-bonding. There is a further possibility when the included guest bears a substituent outside the cavity and the second guest can interact with it. The properties of the ternary species formed are highly influenced by the solely (or primarily) included guest. The changes are attributed to the altered properties of the hydrophilic domain of the CD. The phenomena can be proved by NMR data obtained for some binary systems of -CD inclusion complexes and acetic acid and by the stability constants of the ternary complexes formed. Allosteric effects as well as coenzyme/apoenzyme/substrate interactions could be well modelled by these types of CD complexes.     

Recognition of carboxylate and dicarboxylates by azophenol–thiourea derivatives: a theoretical host–guest investigation

Geometries of azophenol–thiourea derivative complexes with acetate, oxalate, malonate, succinate, glutarate, adipate, pimelate, suberate and azelate were carried out using the integrated MO:MO method. The binding and complexation energies of these complexes were derived from the ONIOM(B3LYP/6-31G(d):AM1) calculations. The relative stabilities of the complexes of azophenol–thiourea derivatives with carboxylate guests are reported. The binding interactions of the azophenol–thiourea receptor 1, 2 and carboxylate guests are described as multipoints hydrogen bonding, where the amine and phenolic hydrogen atoms of receptors act as hydrogen bond donors in complex with acetate and all amine-hydrogen and phenolic hydrogen atoms act as hydrogen bond donors in complex with dicarboxylate guests. Thermodynamic properties of binding interactions between receptors 1, 2 and their preorganizations and complexations are also reported.     

Characterization of second coordination shell ionophore–siderophore host–guest assemblies and binding selectivities in binary and complex mixtures by electrospray ionization mass spectrometry

An ESI-MS method for the determination of host–guest association constants and binding selectivities for systems of binary and complex mixtures, respectively, is presented in an effort to quantitatively study the strength of host–guest interactions, while accounting for the different ESI-MS spray efficiencies of each component. Association constants were obtained for host–guest complexes formed between a series of crown ether and linear ionophore hosts and various guests, including protonated amines, and an apo- and ferri-siderophore, ferrioxamine B.     

Host-guest complexes of a water soluble cucurbit[6]uril derivative with some dications of 1,ω-alkyldipyridines: <Superscript>1</Superscript>H NMR and X-ray structures

Interactions between a symmetrical tetramethyl-substituted cucurbit[6]uril (host: TMeQ[6]) and 1,ω-alkylenedipyridine (ω = 2, 4, 6, 8, 10) dicationic guests were investigated using ¹H NMR spectroscopy and single crystal X-ray crystallography. In these inclusion complexes, combined cavity and portal binding in TMeQ[6] were observed, and the length of the bridged alkylene was found to play an important role not only in balancing the overall hydrophilic/hydrophobic interaction between the host and the guest, but also in defining the structure of the resulting inclusion complexes. For the guest 1,2-ethylenedipyridine (Edpy), TMeQ[6] includes a positively charged pyridine ring of Edpy to form an unsymmetrical inclusion complex; for the guest 1,4-butylenedipyridine (Bdpy), TMeQ[6] includes a positively charged pyridine ring of Bdpy, but the different competitive interactions in and between the related inclusion complexes could lead to a fast exchange between the hosts and guests. For the guests with longer bridge chains, such as 1,6-hexamethylenedipyridine (Hdpy) or 1,8-octylenedipyridine (Odpy), a stable pseudorotaxane inclusion complex is formed by combining the hydrophobic cavity and the outer portal dipole-ion interactions. However, for 1,10-decatylenedipyridine (Ddpy), the two TMeQ[6] host molecules include the two end pyridine rings of Ddpy and form a dumbbell inclusion complex. Supported by the National Natural Science Foundation of China (Grant Nos. 20662003 & 20767001), the International Collaborative Project of Guizhou Province (Grant No. 2007400108), the Science Technology Fund of Guizhou Province (Grant No. J-2008-2012) and the Natural Science Youth Foundation of Guizhou University (Grant No. 2007-005)     

Host-guest complexes of cucubit[8]uril with phenanthrolines and some methyl derivatives

Cucurbituril a molecular container (or host) has a rigid hollow interior cavity which is large enough to accommodate, one or more, smaller molecules (or guests). The cavity is accessible through two carbonyl portal openings. Molecules or guests enter the …     

Synthesis and properties of new thiourea-functionalized poly(propylene imine) dendrimers and their role as hosts for urea functionalized guests

Five generations of poly(propylene imine) dendrimers have been modified by palmityl and adamantyl endgroups via a thiourea linkage. The synthesis of the thiourea dendrimers DAB-dendr-(NHCSNHAd)(n) and DAB-dendr-(NHCSNHC(16)H(33))(n) (n = 4, 8, 16, 32, 64) proceeds smoothly via the amino-terminated DAB dendrimer and the adamantyl and palmityl isothiocyanates, respectively. The properties of the thiourea dendrimers have been studied by IR and (1)H NMR, including relaxation (T1, T2) measurements. The thiourea dendrimers are used as multivalent hosts for a number of guest molecules containing a terminal urea-glycine unit in organic solvents. The host-guest interactions have been investigated using 1D- and NOESY-NMR. These investigations show that the guest molecules bind to the dendritic host via thiourea (host)-urea (guest) hydrogen bonding, and ionic bonding between the terminal guest carboxylate moiety and the outer shell tertiary amines of the dendrimer. The ability to bind guest molecules of the adamantyl- and palmitylthiourea dendrimers has been compared with their respective urea containing dendrimer analogues, by NMR-titration, and competition experiments. Upon complexation, the thiourea dendrimer hosts show a larger downfield NH shift than the corresponding urea dendrimer hosts, indicative of stronger hydrogen bonding in the complexed state. Furthermore, microcalorimetry has been used to determine binding constants for formation of the host-guest complexes; the binding constants are typically in the order of 10(4) M(-1). Both NMR and microcalorimetric studies show that the thiourea dendrimers bind the urea containing guests with somewhat higher affinity than the corresponding urea dendrimers.