Dependence of selective enclathration on types of cholic acid crystals

Competitive recrystallizations of cholic acid (CA) from 1:1 binary mixtures of seven mono-substituted benzenes are demonstrated. The order of preference for guests to be incorporated into the cholic acid crystals are as follows: benzene, toluene > n-amylbenzene, n-hexylbenzene > ethylbenzene, n-propylbenzene, n-butylbenzene. These seven compounds afford bilayer type inclusion crystals that are classified into four types based on the host frameworks and host-guest stoichiometries. The order of selective enclathration corresponds to the four types as follows: 1:1 alpha G > 2:1 alpha G > 1:1 beta T or 2:1 alpha T. The preference for the alpha G type was also confirmed by investigating the host frameworks of the crystals obtained from binary mixtures. The dependence of the selectivity on the different types of CA crystals can be understood in terms of the fit of the guest molecule in the host cavity.     

Fluorescence study of inclusion complexes between star-shaped cholic acid derivatives and polycyclic aromatic fluorescent probes and the size effects of host and guest molecules

Star-shaped host molecules containing two, three, and four cholic acid moieties have been used to form inclusion complexes with polycyclic aromatic hydrocarbon probes (guests) varying in size from four (pyrene) to five (benzo(e)pyrene) and seven aromatic rings (coronene) and investigated by steady-state fluorescence measurements and fluorescence lifetime techniques. The results indicated that these hydrophobic guest probes prefer to locate in the hydrophobic cavities formed by the host molecules in an aqueous solution. Further studies showed that the stoichiometric ratios of the complexes depended on the relative size of both the host and the guest. The complexes of 1:1 ratio (guest:host) were formed between pyrene and the host molecules of different sizes, while the complexes of 1:2 ratio (guest:host) were found for coronene in all cases. For benzo(e)pyrene with an intermediate size, the complexes with 1:1 and 1:2 ratios (guest:host) were formed depending on the relative sizes of the host molecules. The stability of the inclusion complexes was observed to change with the solvent polarity, indicative of an adaptation of the hydrophobicity of the host pockets to the polarity of the solvent. The formation of the complexes was driven by the solvophobic interactions.     

Inclusion of cyclic carbonates by a cholic acid host: structure and enantioselection

The optical resolution of some model monosubstituted cyclic carbonates, by inclusion in cholic acid, is described. The X-ray analysis of the host–guest crystal structures provide a rationale for molecular recognition.     

Lipophilic Complexes with Cholic Acid-Based Cleft Compounds Including an Allosteric System

The complexation properties of the three cleft compounds 2, 3 and 4 with two, three and four cholic acid arms coupled to a benzene core were studied in water with four fluorescence dyes F1 to F4 as guest structures, and compared with the parent mono-cholic acid derivative 1. The cholic acid derivatives showed no aggregation or micellation behavior at up to mM concentrations. The coupling of three cholic acid arms to a trene unit yields an allosteric host 5, which shows complexation of some aromatic fluorescence dyes as guest molecules only after addition of Zn(II) salts.     

Host–guest Complex of a Water-soluble Cucurbit[6]uril Derivative with the Hydrochloride Salt of 3-amino-5-phenylpyrazole

Interaction between tetramethylcucurbit[6]uril and 3-amino-5-phenylpyrazole hydrochloride in aqueous solution has been investigated by using ¹H NMR spectroscopy, electronic absorption spectroscopy and fluorescence spectroscopy, as well as by a single crystal X-ray diffraction determination. The ¹H NMR spectra analysis established a basic interaction model in which an inclusion complex with a host:guest ratio of 1:1 forms, in which the host selectively binds the phenyl moiety of the guest. Absorption spectrophotometric and fluorescence spectroscopic analysis in aqueous solution defined the stability of the host–guest inclusion complexes quantitatively as 6.8 × 10⁵ mol^? 1 L at pH 2.6; the interaction is pH dependent, decreasing as pH rises. The single crystal X-ray structure of the isolated inclusion complex shows the phenyl moiety of the guest inserted into the host cavity, which supports particularly the ¹H NMR spectroscopic study in solution. In the crystal structure of the inclusion complex, the host–guest interaction involves both inter- and intra-complex hydrogen bonding, forming 2:2 dimers that stack in one dimension as supramolecular tubes.     

Importance of packing coefficients of host cavities in the isomerization of open host frameworks: guest-size-dependent isomerization in cholic acid inclusion crystals with monosubstituted benzenes

The crystal structures of inclusion compounds of cholic acid (CA) with 28 monosubstituted benzenes have been systematically investigated. All of the crystals belong to the monoclinic space group P2(1) and have bilayer structures with one-dimensional molecular channels that can include guest compounds. They are classified into four types of host frameworks that depend on the conformations and stacking modes of the host compound. The host frameworks and the host-guest ratios depend primarily on the molecular volumes of the guest compounds. The packing coefficient of the host cavity (PCcavity), which is the volume ratio of the guest compound to the host cavity, is used to clarify the relationship between the guest volume and isomerization of the host frameworks. The value of PCcavity, for stable inclusion compounds lies in the range of 55-70%. Compounds out of this range induce isomerization of the host frameworks. The packing coefficients of other host-guest compounds, in which the guest components are included in the host cavities through steric dimensions and van der Waals forces, are also in this range. These results indicate that PCcavity is a useful parameter correlation for guest recognition and isomerization of the host frameworks.     

Inclusion Compounds of Nitrosobenzenes with Cholic Acid and Deoxycholic Acid

The crystalline inclusion compounds of cholic acid (CA) and deoxycholic acid (DCA) with several nitrosobenzenes were prepared. The IR spectra and crystal structures of these compounds confirmed inclusion of the monomeric form of the C-nitroso compounds. The DCA compounds have 2 : 1 host:guest stoichiometry and P2₁ symmetry. Guest molecules are enclosed in channels and disordered. In the CA-nitrobenzene inclusion compound (1·CA) the host:guest stoichiometry is 1 : 1. The host molecules form typical CA bilayer aggregates and guest molecules are accommodated in helicoidal channels. The guest nitroso group is not coplanar with the phenyl ring; the torsion angle on the C–N bond is 8.6(8)°. The solid-state circular dichroism spectrum of 1·CA shows the negative Cotton effect at 780 nm corresponding to the n–^* electronic transition that can be associated with the P helicity of the guest molecule. The extremely weak magnitude of the Cotton effects exhibited by the DCA complexes points to a nearly planar arrangement of the NO group and the phenyl ring in the guest molecules.     

八元瓜环与二(2-亚甲基-1,2,3,4-四氢异喹啉)的自组装模式

以用1,2,3,4-四氢喹啉和二溴乙烷合成的二(2-亚甲基-1,2,3,4-四氢异喹啉)的溴化氢酸盐为客体, 八元瓜环为主体, 利用1H NMR技术, 单晶X射线衍射方法以及理论计算等方法, 考察了两者的自组装模式. 1H NMR分析结果表明, 在溶液状态条件下, 不仅每一个八元瓜环分子同时与两个客体分子的芳环部分相互作用, 而且每一个客体分子两端的芳环部分同时与两个八元瓜环分子相互作用, 从而形成一维的自组装超分子链; 而在固体状态下, 每一个八元瓜环也可同时包结两个客体的芳环部分而形成三元的自组装结构, 但八元瓜环包结两个客体形成一独立的三元自组装结构. 利用晶体结构建立模型的计算结果说明, 模拟溶液状态比固体状态条件下的主客体包结更有利于体系能量的降低, 与主客体在溶液中1H NMR实验结果相符.     

Organic anion recognition of naphthalenesulfonates by steroid-modified beta-cyclodextrins: enhanced molecular binding ability and molecular selectivity

Two beta-cyclodextrin (beta-CD) derivatives bearing steroid groups (1 and 2) were synthesized by the condensation of mono(6-aminoethylamino-6-deoxy)-beta-CD with cholic acid and deoxycholic acid, respectively, and their original conformations and binding behavior to the organic anion of naphthalenesulfonate derivatives were investigated by using 1H NMR spectroscopy and spectrofluorometric titration in combination with computational methods. The 2D NMR experiments reveal that the steroid groups attached to the beta-CD rim could be deeply embedded in the beta-CD cavity to form the intramolecular (for 1) or intermolecular (for 2) inclusion complexes in aqueous solution. Upon complexation with naphthalenesulfonate derivatives, modified beta-CDs display two obviously different binding modes, that is, the competitive inclusion mode and the induced-fit inclusion mode, which is consistent with the results of molecular modeling study. The two modes and the strict size/shape fitting relationship between the hosts and guests reasonably explain the different binding behaviors and molecular selectivity of host beta-CDs 1 and 2 toward the naphthalenesulfonate guests. Therefore, the cholic acid- or deoxycholic acid-modified beta-CDs could effectively recognize the size/shape of guest molecules as compared with the parent beta-CD, giving good molecular selectivity up to 24.9 for the disodium 2,6-naphthalenedisulfonate/disodium 1,5-naphthalenedisulfonate pair by the host 1.     

Host–guest complexes of some cucurbit[n]urils with the hydrochloride salts of some imidazole derivatives

Interaction between the normal cucurbit[n]urils (n = 6,7,8; Q[6], Q[7], Q[8]) and a sym-tetramethyl-substituted cucurbit[6]uril derivative (TMeQ[6]) with the hydrochloride salts of some imidazole derivatives N-(4-hydroxylphenyl)imidazole (g1), N-(4-aminophenyl)imidazole (g2), 2-phenylimidazole (g3) in aqueous solution was investigated by using ¹H NMR spectroscopy, electronic absorption spectroscopy and fluorescence spectroscopy, as well as by using a single crystal X-ray diffraction determination. The ¹H NMR spectra analysis established a basic interaction model in which inclusion complexes with a host:guest ratio of 1:1 forms for the Q[6]s and Q[7] cases, while with a host:guest ratio of 1:2 form for the Q[8] cases. It was common that the hosts selectively bound the phenyl moiety of the guests. Absorption spectrophotometric and fluorescence spectroscopic analysis in aqueous solution defined the stability of the host–guest inclusion complexes at pH 5.8 with a host:guest ratio of 1:1 form quantitatively as logK values between 4 and 5 for the smaller hosts Q[6 or 7]s, while with a host:guest ratio of 1:2 form quantitatively as logK values between 11 and 12 for the host Q[8]. Two single crystal X-ray structures of the inclusion complexes TMeQ[6]-g2 · HCl and TMeQ[6]-g3 · HCl showed the phenyl moiety of these two guests inserted into the host cavity, which supported particularly the ¹H NMR spectroscopic study in solution.     

Inclusion of the Niflumic Acid Anion in β-cyclodextrin: A Solution NMR and X-ray Structural Investigation

We report parallel solution and solid state studies of the inclusion of the anionic form of the non-steroidal anti-inflammatory drug niflumic acid (2-[[3-(trifluoromethyl)phenyl]-amino]-3-pyridinecarboxylic acid) in the host g -cyclodextrin ( g -CD). 1 H NMR data for the interaction between host and guest in aqueous solution recorded at 300 MHz indicated a strong preference for insertion of the trifluoromethylphenyl residue, rather than the pyridinecarboxylate moiety, in the host cavity. A 1:1 complex stoichiometry was determined by the continuous variation method utilising chemical shifts of both host and guest protons. Analysis of the data using a new flexible program developed for this purpose yielded an overall association constant K of 336 M m 1 at 298 K. The NMR data indicate a dynamic equilibrium between complexed and uncomplexed species but do not distinguish guest entry from the primary and secondary sides of the host. Reaction between the Cs + salt of niflumic acid and g -CD yielded the crystalline complex ( g -CD) 2 ·(Cs + niflumate m ) 4 ·22H 2 O whose single crystal X-ray structure was determined. A novel inclusion mode for this host, namely entry of guest trifluoromethylphenyl residues from both the primary and secondary sides, was revealed by the X-ray analysis.     

Remarkable Stabilization of the α‐Helix Structure by an Intramolecular Host‐Guest Bridge in a Cyclodextrin‐Peptide Hybrid

A cyclodextrin‐peptide hybrid (CD‐peptide) bearing three units of γ‐cyclodextrin, cholic acid, and a dansyl fluorophore in the side chain has been prepared. In this novel CD‐peptide, the cholic acid unit acts as an internal guest and forms an intramolecular inclusion complex with γ‐cyclodextrin in the CD‐peptide. This intramolecular complex works as a host‐guest bridge in the CD‐peptide and remarkably stabilizes the α‐helix structure of the CD‐peptide.     

Host–guest complexes of various cucurbit[n]urils with the hydrochloride salt of 2,4-diaminoazobenzene

The interaction products of normal cucurbit[n]urils (n = 7, 8; Q[7] Q[8]) and a sym- tetramethyl-substituted cucurbit[6]uril derivative (TMeQ[6]) with the hydrochloride salts of 2,4-diaminoazobenzene (g·HCl) were investigated in aqueous solution using ¹H NMR spectroscopy, electronic absorption spectroscopy, as well as single crystal X-ray diffraction. The ¹H NMR spectra analysis established a basic interaction model in which inclusion complexes with a host:guest ratio of 1:1 form for the TMeQ[6] and Q[7] cases, while they form with a host:guest ratio of 1:2 for the Q[8] case. Commonly, the hosts selectively bound to the phenyl moieties of the guests. Absorption spectrophotometric analysis in aqueous solution defined the stability of the host–guest inclusion complexes at pH 3.2. Quantitatively, at this pH, complexes with a host:guest ratio of 1:1—those with smaller hosts TMeQ[6] and Q[7]—formed with logK values between 6 and 7. That with host Q[8] and a host:guest ratio of 1:2 formed with a logK value of 10.8. Single crystal X-ray structures of the inclusion complexes TMeQ[6]–g·HCl and Q[8]–g·HCl showed the phenyl moiety of the guest inserted into the host cavity. This result supports the solution-based ¹H NMR spectroscopic study.     

Peculiarities of inclusion complex formation in the 1,4-benzodiazepine-benzene system

5-Phenyl-1-methyl-7-bromo-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one and its 5-(o-chloro)-phenyl analog form 2:1 (host:guest) inclusion compounds with benzene. The crystal structures of the compounds were studied by the single-crystal XRD method and were interpreted as host (H) (benzodiazepine) — guest (G) (benzene solvent molecule) complexes. The studied structures, revealing H-H and H-G interactions as both typical hydrogen bonds and π-π, C-H?π weak interactions, may serve as models for ligand-receptor binding.     

Supramolecular Tilt Chirality Derived from Symmetrical Benzene Molecules: Handedness of the 21 Helical Assembly

Achiral molecules can form aggregates with chirality. This depends on the relative position of the molecules, in other words, the tilt of the molecules (so‐called supramolecular tilt chirality). In this paper, we describe supramolecular chirality appearing in a 2₁ column composed of symmetrical benzene molecules, which is formed in the host cavity of inclusion crystals of cholic acid. Moreover, we determined the handedness, that is, right or left, of the 2₁ helical column of benzene on the basis of the molecular tilt. Determination of the 2₁ helical handedness was performed on assemblies of other benzene derivatives in cholic acid crystals and benzene assemblies in other host frameworks selected from the Cambridge Structural Database. Finally, we demonstrated complementarity of the handedness between the 2₁ symmetrical host framework of cholic acid and the benzene column.     

A New Functional Cyclophane Host. Synthesis, Complex Formation and Crystal Structures of Three Inclusion Compounds

A new macrocyclic host compound 2 having an octamethylsubstituted cyclophane structure with two intra-annular carboxylic acid functions has beensynthesized. The properties of crystalline inclusion formation are studied and X-ray crystalstructures of three inclusion complexes including acetic acid, propionic acid and acetone asthe guest molecules are reported. Inter-host channel formation with complexed guest moleculesaccommodated into the channels are typical features of the acetic acid and acetone 1 : 4 (host : guest) stoichiometric complexes being also hydrated species, while the propionicacid 1 : 2 complex is of the close packing type containing no additional water molecules.Systems of hydrogen bonds involving the host and guest functional groups are common toall structures. In the case of the acetic acid inclusion compound, a complex supramolecularhydrogen-bonded array comprising a bordering tricyclic assembly of eight molecular species exists.     

Why a hexabromodiquinoline host preferentially includes small aromatic hydrocarbon guests

The preparation and properties of the new hexabromodiquinoline derivative 4 are described. This lattice inclusion host shows a strong preference for trapping small aromatic hydrocarbons. The X-ray crystal structures of the benzene, toluene, o-xylene, and p-xylene compounds are reported, and are analysed from a crystal engineering perspective. Crystallisation of 4 from the dual-nature solvent trifluoromethylbenzene yields the solvent-free material. Comparison of the parent crystal structure with those of its inclusion compounds reveals why inclusion of aromatic hydrocarbon guests is such a favoured process. The high concentration of Br...Br interactions in the structure of pure 4 is diluted and increasingly replaced by aromatic offset face-face (OFF) and aromatic edge-face (EF) interactions in the inclusion compounds, and this results in better lattice packing energies. For toluene, o-xylene, and p-xylene the host-guest ratio is 1:1. Inclusion of the smaller benzene molecule results in a change to 2:3 stoichiometry. This increase in guest content is assisted by replacement of host-host OFF and EF motifs with host-host pi-halogen dimer (PHD) interactions, which provide space for inclusion of the additional guest molecules. These changes result in the most efficient lattice packing of the series for compound (4)2.(benzene)3.     

Controlled expansion of a molecular cavity in a steroid host compound.

Expansion of a molecular cavity is described by using elongation of the side chain of a bile acid host compound. Bishomocholic acid (2), which has a side chain that is longer by two methylene unit than cholic acid (1), includes many organic substances at 1:1 host:guest ratios. X-ray crystallographic studies revealed that 2 has two types of open host frameworks: a bilayer type and a crossing type. Both of them are isostructural to those of 1, indicating that they are robust against the elongation of the side chain. In the former type, the increment of the width of the host channel corresponds to that of the length of the molecular structures. Larger aromatic guest components such as 1-methylnaphthalene and 1-tetralone, are included in 2, but not in 1.     

New Cyclophanes as Initiator Cores for the Construction of Dendritic Receptors: Host-guest complexation in aqueous solutions and structures of solid-state inclusion compounds

Cyclophanes 3 and 4 were prepared as initiator cores for the construction of dendrophanes (dendritic cydophanes) 1 and 2 , respectively, which mimic recognition sites buried in globular proteins. The tetra-oxy[6.1.6.1]paracyclophane 3 was prepared by a short three-step route (Scheme 1) and possesses a cavity binding site shaped by two diphenylmethane units suitable for the inclusion of flat aromatic substrates such as benzene and naphthalene derivatives as was shown by ¹H-NMR binding titrations in basic D₂O phosphate buffer (Table 1). The larger cyclophane 4 , shaped by two wider naphthyl(phenyl)methane spacers, was prepared in a longer, ten-step synthesis (Scheme 2) which included as a key intermediate the tetrabromocyclophane 5 . ¹H-NMR Binding studies in basic borate buffer in D₂O/CD₃OD demonstrated that 4 is an efficient steroid receptor. In a series of steroids (Table 1), complexation strength decreased with increasing substrate polarity and increasing number of polar substituents; in addition, electrostatic repulsion between carboxylate residues of host and guest also affected the binding affinity strongly. The conformationally flexible tetrabromocyclophane 5 displayed a pronounced tendency to form solid-state inclusion compounds of defined stoichiometry, which were analyzed by X-ray crystallography (Fig. 2). 1,2-Dichloroethane formed a cavity inclusion complex 5a with 1:1 stoichiometry, while in the 1:3 inclusion compound 5b with benzene, one guest is fully buried in the macrocyclic cavity and two others are positioned in channels between the Cyclophanes in the crystal lattice. In the 1:2 inclusion compound 5c , two toluene molecules penetrate with their aromatic rings the macrocyclic cavity from opposite sides in an antiparallel fashion. On the other hand, p-xylene (= 1,4-dimethylbenzene) in the 1:1 compound 5d is sandwiched between the cyclophane molecules with its two Me groups penetrating the cavities of the two macrocycles. In the 1:2 inclusion compound 5e with tetralin (= 1,2,3,4-tetrahydronaphthalene), both host and guest are statically disordered. The shape of the macrocycle in 5a – e depends strongly on the nature of the guest (Fig. 4). Characteristic for these compounds is the pronounced tendency of 5 to undergo regular stacking and to form channels for guest inclusion; these channels can infinitely extend across the macrocyclic cavities (Fig. 6) or in the crystal lattice between neighboring cyclophane stacks (Fig. 5). Also, the crystal lattice of 5c displays a remarkable zig-zag pattern of short Br…?O contacts between neighboring macrocycles (Fig. 7).     

Double-Diamond Inclusion Compounds of 2,6-Dimethylydeneadamantane-1,3,5,7-tetracarboxylic Acid

The crystal structures of four inclusion compounds of 2,6-dimethylideneadamantane-1,3,5,7-tetracarboxylic acid ( 4 ) are described, which involve the following guest species: (a) a mixture of 4-methylpent-3-en-2-one, 2,6-dimethylhepta-2,5-dien-4-one, and mesitylene (condensation products of acetone); (b) mesitylene; (c) a mixture of 4-methylpent-3-en-2-one and mesitylene; (d) (tert-butyl)benzene. In all four cases, the host architectures consist of two interpenetrating super-diamond networks built up by the tetra-acid molecules via pairwise H-bonds between the tetrahedrally directed COOH groups. In the first three cases (tetragonal crystal symmetry), the two diamond-like host lattices interpenetrate symmetrically, in the fourth case (monoclinic) asymmetrically. This asymmetry is brought about by the increased steric bulk of the (tert-butyl)benzene guest molecules. Attempts to enforce an inclusion compound of 4 with a single, extremely hollow diamond-like host lattice by offering still bulkier guest molecules have as yet not been met with success. The generally very high propensity of 4 to form inclusion compounds was envisaged and designed beforehand by appropriate evaluation and modulation of the crystal structure of the parent adamantane-1,3,5,7-tetracarboxylic acid, which represents a fivefold diamond-like self-inclusion compound. Crystals of the free, uncomplexed 4 appear to be extremely unstable and could so far not be obtained. On the other hand, from aqueous solution a very stable monohydrate of 4 may be crystallized ( 4 -H₂O), which was also subjected to X-ray analysis. The (triclinic) crystal structure of 4 ·H₂O involves an interesting dichotomy inasmuch its pattern of H-bonding may be rationalized either in terms of a double, cross-linked super-zincblende (sphalerite) architecture, or as a system of porous, puckered 4-connected sheets, which interpenetrate each other pairwise and are cross-linked by the H₂O molecules. Various structure and (space group) symmetry characteristics of the supramolecular solid-state complexes reported here are highlighted by pointing out analogies with comparable structures retrieved from the literature.