Inclusion Complex of 4-Hydroxycoumarin with Cyclodextrins and Its Characterization in Aqueous Solution

The physicochemical properties of 4-hydroxy-7-methoxy-3-phenyl-2H-chromen-2-one (4HC) and β-cyclodextrins (CDs) inclusion complexes were investigated. The phase solubility profile of 4HC with β-cyclodextrin derivatives was classified as A_L-type. Stability constants for complexes with 1:1 molar ratios were calculated from the phase solubility diagrams and indicate the following trend: DMβCD>HPβCD>βCD. The highest value of the binding constant was for 4HC-DMβCD; the binding association constant (K _a) for this complex was determined at different temperatures and the thermodynamic data indicate that 4HC-DMβCD association is mainly an entropically driven process. ¹H NMR and ROESY were carried out, revealing that 4HC is embedded in the apolar cavity of DMβCD with the 4OH group buried in the cyclodextrin cavity with the phenyl group outside, near the primary rim. These results are in agreement with ORAC_FL values; the decrease in the antioxidant activity of 4HC-DMβCD is explained by the effective protection of the hydroxyl group due to complexation.     

Study on inclusion complexes of meso-tetrakis(2-thienyl)porphyrin and Cu-meso-tetrakis(2-thienyl)porphyrin with cyclodextrins by spectroscopy method

In phosphate buffer solution of pH5.4, the interaction of meso-tetrakis(2-thienyl)porphyrin(H₂TTP) and Cu-meso-tetrakis(2-thienyl)porphyrin(Cu-TTP) with α-cyclodextrin(α-CD), β-CD, γ-CD, heptakis(2,3,6-tri-O-methyl)-β-CD(TM-β-CD) has been studied by means of UV-vis, fluorescence and ¹HNMR spectroscopy, respectively. The H₂TTP and Cu-TTP can form 1:2 inclusion complexes with TM-β-CD and 1:1 inclusion complexes with the other three cyclodextrins. In this paper, the inclusion constants (K) of H₂TTP and Cu-TTP for the formation of the inclusion complexes have been estimated from the changes of absorbance and fluorescence intensity in phosphate buffer solution. The inclusive capabilities of different kinds of cyclodextrins are compared. The result shows that the inclusion ability of α-CD with H₂TTP and Cu-TTP is the strongest among the three native CDs. The inclusion ability of modified β-CD with H₂TTP and Cu-TTP is stronger, compared to the native β-CD, which indicates that the capacity matching plays a crucial role in the inclusion procedure except for the hydrophobic effect. In addition ¹HNMR spectra supports the inclusion conformation of the TM-β-CD-Cu-TTP inclusion complex, indicating the interaction mechanism of inclusion processes.     

Ethylenediaminetetraacetic acid (EDTA) as an auxiliary tool in the electrospray ionization mass spectrometry analysis of native and derivatized β-cyclodextrins,maltoses, and fructans contaminated with Ca and/or Mg

The effect of Ca²⁺ (and Mg²⁺) and the disodium salt of ethylenediaminetetraacetic acid (EDTA), a well known Ca²⁺ (and Mg²⁺) chelating agent, on the volatilization/ionization of carbohydrates by using electrospray ionization mass spectrometry has been studied. Model compounds such as maltoses (maltose to maltoheptaose), β-cyclodextrins (β-cyclodextrin, methyl-β-cyclodextrin, heptakis(2,6-di-O-methyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, and 2-hydroxypropyl-β-cyclodextrin) and fructans (sucrose, 1-ketose, nystose, and 1F-fructofuranosylnystose) were used.     

Mechanistic studies on cationic ring-opening polymerisation of cyclodextrin derivatives using various Lewis acids

In order to investigate the potential of cyclodextrins for the preparation of block-like substituted polysaccharides, we submitted mixtures of heptakis[2,3,6-tri-O-methyl]-β-cyclodextrin (Me₂₁-β-CD, 1) and heptakis[2,3,6-tri-O-methyl-d ₃]-β-cyclodextrin ((Me-d ₃)₂₁-β-CD, 2) to cationic ring-opening polymerisation (CROP). Reactions were performed with BF₃·OEt₂, methyl triflate (MeOTf), and Et₃OSbCl₆. Products were compared with respect to their degree of polymerisation (DP) and the average block length (BL). Highest DP was observed with BF₃·OEt₂, while Et₃OSbCl₆ was the most active initiator. Average block length decreased from 14 in the early stage of product formation to about 2 due to competing chain transfer reaction. ¹H NMR spectroscopy, GLC, GLC–MS, ESI-MS and MALDI-TOF-MS were applied for detailed investigations of side reactions. During incubation with BF₃·OEt₂, a stereroisomeric β-CD with one β-glucosidic linkage (Me₂₁-β-CD_6α1β, 3a (Me-d ₃)₂₁-β-CD_{6α 1β}, 3b) is formed as an intermediate, while linear Me₂₁- and (Me-d ₃)₂₁-maltoheptaose (4a/b) was detected in the early stage of the reaction promoted by MeOTf. In the case of Et₃OSbCl₆, both intermediates (3a/b, 4a/b) can be observed during the lag phase of polymerisation, but to a very low degree. End group analysis by GLC reveals that some alkyl exchange occurs at position 3 and 6 in the presence of Et₃OSbCl₆, and that polymerisation is also initiated by protons. Copolymerisation of heptakis[2,3,6-tri-O-benzyl]-β-cyclodextrin (Bn₂₁-β-CD, 5) and Me₂₁-β-CD (1) and subsequent debenzylation yielded a polymer of only 1,4-glcp-Me₃- and 1,4-glcp-residues. Reactivity of Bn₂₁-β-CD was significantly lower than of Me₂₁-β-CD, resulting in higher average block length of 1,4-glcp-Me₃-units.     

Differential Effects of Substituent and Pressure on Induced Inclusion Complexation of 6-O-α-D-Glucosyl-β-Cyclodextrin with 4-Substituted Phenols

The inclusion complexation of 6-O-α-D-glucosyl-β-cyclodextrin (G-β-CD), in which the glucosyl side chain is introduced to β-CD, with various kinds of phenols was studied spectrophotometrically at high pressures. The characteristic effects of substituent and pressure were found for the inclusion complexation of G-β-CD. The association constants K for the G-β-CD inclusion complexation increased with an increase in the bulkiness of the 4-substituent groups in phenols. As the external pressure increases, the inclusion constants for the G-β-CD complexation increased and the reaction volumes were estimated to be −3.8 to −19.4 cm³ mol⁻¹ from their pressure dependences. From analysis of the effect of pressure on the inclusion complexation with G-β-CD, the number of water molecules included in the G-β-CD cavity in water was estimated. The number of water molecules repelled from the CD cavity plays an important role in the change in volume upon inclusion. In addition, the structures of the inclusion complexes of G-β-CD with phenols have been established by 1D and 2D NMR measurements. Based on the results, we suggested that the ability of the G-β-CD inclusion complexation is enhanced by the interaction between guest molecules and the glucosyl side chain of G-β-CD.     

Thermodynamic Study of the Inclusion Interaction between Gemini Surfactants and Cyclodextrins by Isothermal Titration Microcalorimetry

The inclusion complexes of a series of bis-quarternary ammonium surfactants, (C _n N)₂Cl₂ (where n = 12, 14, 16) and sodium bis(2-ethylhexyl) sulfosuccinae (AOT), with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) in aqueous solutions were investigated by using isothermal titration calorimetry (ITC) at 298.15 K. The stability constants, stoichiometry, and formation enthalpies, entropies and Gibbs energies for the complexes in aqueous solutions have been derived from the calorimetric data. The values of the binding constant, K ^∘ _i , are very large, which indicates that these complexes are quite stable in their aqueous solutions. The enthalpy changes (ΔH ^∘) for all of the inclusion processes are negative, showing that the complex process is enthalpy driven. The entropy effect (TΔS ^∘) is negative, so the inclusion process is entropically unfavorable. The large negative Gibbs energy changes indicate that formation of host-guest inclusion complexes is generally a spontaneous process. The thermodynamic parameters are discussed in the light of the different structures of the host and guest molecules.     

A quartz crystal microbalance study of β-cyclodextrin self assembly on gold and complexation of immobilized β-cyclodextrin with adamantane derivatives

Quartz crystal microbalance (QCM) was used to study the self-assembly of per-6-thio-β-cyclodextrin (t₇-βCD) on gold surfaces, and the subsequent inclusion interactions of immobilized βCD with adamantane-poly(ethylene glycol) (5,000 MW, AD-PEG), 1-adamantanecarboxylic acid (AD-C) and 1-adamantylamine (AD-A). From a 50 μM solution of t₇-βCD in 60:40 DMSO:H₂O, a t₇-βCD layer was formed on gold with surface density of 71.7 ± 2.7 pmol/cm², corresponding to 80 ± 3% of close-packed monolayer coverage. Gold sensors with immobilized t₇-βCD were then exposed alternately to six different concentrations of AD-PEG, 500 μM AD-C or 500 μM AD-A aqueous solutions for association, and water for dissociation. Association of AD-PEG conformed to a Langmuir isotherm, with a best fit equilibrium constant K = 125,000 ± 18,000 M⁻¹. For AD-C and AD-A, association (k _a ) and dissociation (k _d ) rate constants were extracted from kinetic profiles by fitting to the Langmuir model, and equilibrium constants were calculated. The parameters for AD-C were found to be: k _a = 100 ± 5 M⁻¹ s⁻¹, k _d = 110 (±18) × 10⁻⁴ s⁻¹, and K = 9,400 ± 1,700 M⁻¹. For AD-A, k _a = 58 ± 6 M⁻¹ s⁻¹, k _d = 154 (±7) × 10⁻⁴ s⁻¹, and K = 3,800 ± 400 M⁻¹. The results demonstrate the utility of QCM as a tool for studying small molecule surface adsorption and guest–host interactions on surfaces. More specifically, the kinetic and thermodynamic data of AD-C, AD-A, and AD-PEG inclusion with immobilized t₇-βCD form a basis for further surface association studies of AD-X conjugates to advance surface sensory and coupling applications.     

Spectroscopic investigation of β-cyclodextrin -metoprolol tartrate inclusion complexes

Aqueous-solution complexes of β-cyclodextrin (β-CD) with metoprolol tartrate (MET) have been analysed with ¹H NMR and UV–vis spectroscopy. With ¹H NMR a [1:1] stoichiometry could be established for the β-CD-MET complex while its stability constant was determined with UV–vis spectroscopy. Powder diffraction data of a polycrystalline sample of the β-CD-MET complex show that a novel product has been formed, likely to be a β-CD-MET [1:1] inclusion complex. Also Hyperchem MM+ molecular-dynamics results suggest an inclusion complex and from ¹H NMR data it is inferred that probably the MET is docked in the CD with the formers methoxyethyl-benzene moiety in front. Mihaela Toma is Socrates/Erasmus student at UNED Madrid     

How does β-cyclodextrin affect the aggregation of sodium perfluoroheptanoate in aqueous solution: a 19F NMR study

¹H and ¹⁹F NMR spectra were recorded for D₂O solutions of sodium perfluoroheptanoate with defined concentrations up to 200 mM, in the absence and presence of β-cyclodextrin (15 mM). Analysis of ¹H chemical shift data obtained by the method of continuous variations (Job’s method) confirms the formation of 1:1 inclusion complexes for the perfluoroheptanote anion in β-cyclodextrin and leads to an estimate for the apparent inclusion constant (≥10⁴ M⁻¹). In addition, analysis of ¹⁹F chemical shift data based on two simplifying assumptions (monodisperse perfluoroheptanoate solutions below the critical micellar concentration (CMC), and a single self-associated state after the CMC) enables to interpret all the experimental chemical shift data and allows to determine CMC values for the absence and presence of β-cyclodextrin (104 and 116 mM). It is shown that the self-association of perfluoroheptanoate and its inclusion in β-cyclodextrin lead to shielding and deshielding of the fluorine atoms, respectively.     

Complexation of [2.2]paracyclophane with β- and γ-cyclodextrins studied by HPLC and NMR

The NMR spectra of [2.2]paracyclophane with β- or γ-cyclodextrin in DMF-d₇ at room temperature do not show significant complexation, while HPLC of the complexes in mixed H₂O:alcohol solvents demonstrate complexation with different stoichiometries. At 243 K in DMF solution the H3 and H5 NMR signals of γ-cyclodextrin (but not β) exhibit complexation-induced chemical shifts denoting complex formation. According to HPLC, at room temperature the [2.2]paracyclophane complex with β-cyclodextrin in 20% H₂O:EtOH exhibits 1:2 stoichiometry with K ₁ = 1×10² ± 2, K ₂ = 9.0×10⁴ ± 2×10³ (K = 9×10⁶) while that with γ-cyclodextrin in 50% H₂O:MeOH exhibits 1:1 stoichiometry with K ₁ = 4×10³ ± 150 M⁻¹. Thermodynamic parameters for both complexes have been estimated from the retention time temperature dependence. For the β-cyclodextrin complexation at 25°C ΔG ⁰ _CD is −39.7 kJ mol⁻¹ while ΔH ⁰ _CD and ΔS ⁰ _CD are −88.2 kJ mol⁻¹ and −0.16 kJ mol⁻¹ K⁻¹. For γ-cyclodextrin, the corresponding values are ΔG ⁰ _CD = −20.5 kJ mol⁻¹, ΔH ⁰ _CD = −33.5 kJ mol⁻¹ and ΔS ⁰ _CD = −0.04 kJ mol⁻¹ K⁻¹.      

Enhancement of aqueous solubility of tricyclic acyclovir derivatives by their complexation with hydroxypropyl-β-cyclodextrin

Solubilities of tricyclic acyclovir derivatives in buffered aqueous solutions of hydroxypropyl-β-cyclodextrin (HP-β-CD) at pH 5.5 and 7.0 were determined at 25 and 37 °C. Complexation of these compounds with HP-β-CD resulted in a noticeable increase of their solubility; nevertheless it was limited to tricyclic derivatives of acyclovir carrying an aryl substituent. Combination of ¹H NMR and DSC techniques demonstrated the existence of inclusion complexes between acyclovir derivatives and HP-β-CD. The stability constants, estimated using the Higuchi–Connors method, were found in the range of 10–100 M⁻¹. Additionally, the pK _a values at 25 °C and molar extinction coefficients in aqueous buffered solutions were also determined for all studied compounds.     

Self-assembly behavior of phenyl modified β-cyclodextrins

The self-assembly behavior of mono(6-phenolic-6-deoxy)-β-cyclodextrin (1) both in solution and the solid state is comparatively studied by X-ray crystallography and ¹H NMR spectroscopy. The results obtained show that the phenolic groups in the crystal 1 can successively penetrate into the adjacent β-cyclodextrin cavities from the secondary side to form head-to-tail linear polymeric supramolecule with a 2-fold screw axis. The self-assembly behavior also can be determined in D₂O solution, giving a self-association constant of 240 mol⁻¹·L. Using the present and previous structures reported for the relevant β-cyclodextrin derivatives, i.e., mono(6-anilino-6-deoxy)-β-cyclodextrin (2), mono(6-phenylselenyl-6-deoxy)-β-cyclodextrin (3), and mono(6-phenylthio-6-deoxy)-β-cyclodextrin (4), we further reveal the factors governing the formations of supramolecular assemblies.     

Effect of Solvents and pH on <Emphasis Type="Italic">β</Emphasis>-Cyclodextrin Inclusion Complexation of 2,4-Dihydroxyazobenzene and 4-Hydroxyazobenzene

The spectral characteristics of 2,4-dihydroxyazobenzene (DHAB, sudan orange G) and 4-hydroxyazobenzene (HAB) have been studied in various solvents, different hydrogen ion and β-cyclodextrin (β-CD) concentrations, and are compared with azobenzene (AB). The inclusion complexes of the above molecules with β-CD were analyzed by UV-vis spectrometry, flourometry, FT-IR, ¹H NMR, SEM and DFT methods. The solvent study shows that only the azo form is present in DHAB and HAB molecules. The unusually large red shift observed in acidic solutions indicates both molecules exhibit azo-hydrazo tautomerization. In the β-CD solutions, the increase in fluorescence intensity and large bathochromic shift in the S₁ state indicates that DHAB and HAB form 2:2 inclusion complexes, whereas AB forms a 1:1 inclusion complex.     

Inclusion Complexes of Cyclodextrins with Galangin: a Thermodynamic and Reactivity Study

The formation of the complexes of galangin (GAL) with native β-cyclodextrin (βCD), and with its substituted counterparts such as dimethyl-βCD (DMβCD) and hydroxypropyl-βCD (HPβCD), was studied by fluorescence spectra in aqueous medium. The binding association constants (K _a) of the complexes were determined at different temperatures. The formation constants obtained have the following trend upon complex formation at the three temperatures studied: HPβCD > DMβCD > βCD. The thermodynamic data for the inclusion of GAL in DMβCD and HPβCD indicated that is mainly enthalpy driven whereas for βCD it is an entropy-driven process.     

Triangular ruthenium acetate clusters containing the bis(pyridyl)propane ligand and their inclusion chemistry with β-cyclodextrin

The triruthenium carboxylate cluster [Ru₃O(OAc)₆(py)₂(bpp)]⁺ (OAc = acetate) containing the bridging 1,3-bis(4-pyridyl)propane (bpp) ligand, and its dimeric species [{Ru₃O(OAc)₆(py₂)}₂(μ-bpp)]²⁺ were synthesized in order to investigate their inclusion compounds with β-cyclodextrin (β-CD). Characterization of the complexes was carried out based on spectroscopic, electrochemical and spectroelectrochemical techniques, while the formation of inclusion complexes was evaluated using ¹H NMR/NOESY spectroscopy. Since bpp is a flexible ligand, a DFT study was carried out in order to characterize its conformational isomers and their possible role in the host–guest chemistry with β-CD. Instead of observing the formation of inclusion compounds with different stoichiometries, we observed the formation of 1:1 bpp/β-CD compounds in which the bpp ligand assumes different conformations. The assembly of polymetallic rotaxane species was successfully demonstrated by monitoring the ¹H NMR spectra of the monomeric cluster species in the presence of aquapentacyanoferrate(II) ions and β-CD.     

Study of the chromatographic behavior and inclusion constants of new fluorescence agents by use of cyclodextrin additives under conditions of steady- and dynamic-state equilibrium and with fluorescence detection

Summary We report four new derivatization agents, acridone-N-acetic acid (ARC), carbazole-9-ylacetic acid (CRA), carbazole-9-ylpropionic acid (CRP), and 2-methyl-2-carbazole-9-ylacetic acid (MCRA), with strong fluorescence emission which has low dependence on solvent polarity. The emission maxima for ARC, CRA, CRP, and MCRA were 430 nm (λ_ex 404 nm), 368 nm (λ_ex 335 nm), 356 nm (λ_ex 340 nm) and 360 nm (λ_ex 330 nm), respectively. The effects of mobile-phase composition, pH, and temperature on the liquid chromatographic retention behavior of the four fluorescence agents were investigated. An experimental model was established for calculating the inclusion constants of cyclodextrin (CD) complexes in the dynamic state, using β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) as examples, and different mobilephase compositions. On the basis of the model, the inclusion constants of the solutes in pure water (K _fw) were determined by extrapolation. The thermodynamic parameters (ΔH ^o and ΔS ^o) and dissociation constantsK _am for the solutes in this chromatographic system were obtained by means of capacity factor (k) values using a corresponding model formulation.     

Spectral Characteristics of Bicalutamide Drug in Different Solvents and β-Cyclodextrin

Absorption and fluorescence spectra of bicalutamide (BCA) in different solvents and aqueous β-cyclodextrin (β-CD) solutions are reported. The solid inclusion complex of BCA with β-CD is prepared and investigated by FT-IR, ¹H NMR, differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The Stokes shift of BCA is correlated with various solvent polarity scales like E _T(30), BK and f(D,n). β-CD studies show that (i) the absorption and emission maxima of BCA are shifted to red, (ii) the absorbance is slightly decreased whereas emission intensity is increased largely with an increasing β-CD concentration, (iii) BCA forms 1:1 inclusion complex with β-CD and (iv) intramolecular charge transfer (ICT) emission is present in the excited state.     

Experimental Analysis of Complex Formation of Niflumic Acid with β-Cyclodextrins

Complex formation of niflumic acid with β-, hydroxypropyl-β- and methyl-β-cyclodextrins in aqueous solution (pH 7.4) were studied by calorimetry of solution, ¹H NMR spectroscopy and solubility method. The enhancement of niflumic acid solubility in the presence of hydroxypropyl-β-cyclodextrin was detected. This effect is explained on the basis of ¹H NMR data confirming the inclusion of hydrophobic trifluoromethylphenyl residue of niflumic acid molecule into the macrocyclic cavity. The thermodynamic parameters of 1:1 binding were derived from the data of␣calorimetry and solubility measurements. It was obtained, that complex formation of niflumic acid with β-cyclodextrin and both its derivatives is enthalpy driven. Substitutes surrounding the macrocyclic cavity slightly influence the thermodynamics of complex formation resulting in decrease of stability of the complexes formed.     

Host–Guest Interaction Study of Resveratrol With Natural and Modified Cyclodextrins

The aim of this work is to increase the stability and water solubility of resveratrol by complexation with different cyclodextrins. Furthermore, physical–chemical properties of each inclusion compound were investigated. Complexes of resveratrol with cyclodextrins both native (α, β, γ) and modified (2-hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin) were obtained by using the suspension method. An inclusion complex with β-cyclodextrin was also prepared by using the microwave. Solid state characterization of the products was carried out using Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (DRX); solution studies were performed by UV–Vis spectrophotometry and ¹H-NMR spectroscopy. Phase solubility profiles with all cyclodextrins employed were classified as A_N type, indicating the formation of 1:1 stoichiometric inclusion complexes. Stability constants (K _c) from the phase solubility diagrams were calculated. Stability studies in the solid state and in solution were performed; the photodegradation by UV–Vis spectrophotometry was monitored. The isomerization rate trans to cis, in ethanol solution, decreased with inclusion. The dissolution studies revealed that resveratrol dissolution rate was improved by the formation of inclusion complexes.     

Thermodynamic study on inclusion complex formation of riboflavin with hydroxypropyl-β-cyclodextrin in water

The inclusion complex formation of riboflavin (RF) with hydroxypropyl-β-cyclodextrin (HP-β-CD) in water was investigated by ¹H NMR, UV-vis spectroscopy, and solubility methods. A 1:1 stoichiometry and thermodynamic parameters of complex formation (K, Δ_c G ⁰, Δ_c H ⁰, and Δ_c S ⁰) were determined. Complexation was characterized by negative enthalpy and entropy changes due to prevalence of van der Waals interactions and hydrogen bonding between polar groups of the solutes. A partial insertion of RF into macrocyclic cavity was revealed on the basis of ¹H NMR data and molecular mechanics calculation. Location of benzene ring of RF molecule inside the hydrophobic cavity of HP-β-CD results in an increase of aqueous solubility of the former.