Fluorometric and NMR Studies of the Naproxen–Cyclodextrin Inclusion Complexes in Aqueous Solutions

Inclusion complexation processesinvolving four cyclodextrins and naproxen have beenstudied for the protonated and unprotonated forms ofthe guest molecule. The association constants havebeen evaluated from changes in the fluorescenceintensity of naproxen following addition of acyclodextrin to an aqueous naproxen solution. ¹HNMR NOESY and ROESY spectra have shown that twoorientations of the guest molecule relative to-cyclodextrin are possible.     

H-Nuclear Magnetic Resonance and Phase Solubility Studies of the Stoichiometries in 2,4-D: α- and β-Cyclodextrins Inclusion Complexes

The interaction in solution between2,4-dichlorophenoxyacetic acid with - and-cyclodextrins was evaluated by phasesolubility studies. Association constants werecalculated by this technique. The stoichiometries were1 : 2 and 1 : 1 for the - and -cyclodextrincomplexes, respectively. In order to corroborate thecomplexation and the knowledge of structural aspectsof the host : guest interaction, proton nuclearmagnetic resonance (¹H-NMR) spectroscopy wasemployed. The application of the continuous variationtechnique corroborated the calculated complexstoichiometries by solubility assays. ComplementaryNOE studies were applied in order to corroborate theproposed complex structures.     

Inclusion Complex of β-cyclodextrin with CTAB in Aqueous Solution

Cetyltrimethylammonium bromide (CTAB)/potassium bromide (KBr) micellar system has been used as a viscosity probe to study the inclusion complexation between β-cyclodextrin (β-CD) and CTAB. Viscosity measurements show that the inclusion complexation between β-CD and CTAB may cause the breakdown of CTAB/KBr wormlike micelles, resulting in the decrease of the solution viscosity. The viscosity minimum at C_β-CD/C_CTAB=2 indicate the molecular ratio of host molecule to guest molecule is 2:1 in the β-CD/CTAB inclusion complex.     

Complexation of Aliphatic Alcohols by α- and β-Cyclodextrins and their Partial Methylated Derivatives in Aqueous Solution

The complexation of aliphatic alcohols by α- and β-cyclodextrins and their partially methylated derivatives has been studied by means of calorimetric titrations in aqueous solution. The methyl substituents have no pronounced influence upon the complex formation. α-Cyclodextrin and the partially methylated derivative form with only few exceptions more stable than β-cyclodextrin. With increasing chain length of the alcohols the values of the stability constants and reaction enthalpies increase in case of the complex formation with α-cyclodextrin and partially methylated α-cyclodextrin. In contrast the complex formation becomes disfavoured by the reaction entropy with an increasing number of methylene groups. The values of the reaction enthalpies with the β-cyclodextrins are close to zero. Thus the complexation is only favoured by entropic contributions. This revised version was published online in July 2006 with corrections to the Cover Date.     

Inclusion Complexes of Atrazine with α-, β- and γ-Cyclodextrins. Evidence by Polarographic Kinetic Currents

The reduction of atrazine in acidic aqueous media on mercury electrodes proceeds only after the protonation reaction. In fact, the efficiency of the reduction process is very low at pHs greater than 4. However, the addition of cyclodextrins (CDs) to neutral aqueous solutions of atrazine yields a kinetically controlled polarographic reduction wave, whose limiting current depends on the size of the CD cavity, and increases with the concentration of the CD itself. In particular, the size of the increase follows the order -CD < -CD < -CD for the same CD concentration. The half-wave potential shifts toward more negative values when the concentration of CDs increases. These findings lead to the conclusion that atrazine and CDs form an inclusion complex, whose stability constant we have estimated, and also that atrazine undergoes protonation facilitated by complexation with CDs. The stability constants of 1:1 complexes evaluated from polarographic data in 0.1M-KCl and at neutral pH for -CD, -CD and -CD are 4900, 1970 and 19000, respectively. The formation of the inclusion complex was indirectly confirmed by UV-Vis measurements in the presence of methylred and phenolphthalein, which both compete with atrazine in the formation of the corresponding inclusion compounds with CDs.     

Studies on Inclusion Complexes of Felodipine with β-Cyclodextrin

The inclusion behaviour of -cyclodextrin(-CD) with felodipine (FL) as a guest moleculewas studied. Inclusion complexes were obtained by thekneading method in a binary or ternary system with anaddition of polyethylene glycol 6000. Formation ofinclusion complexes was studied by IR spectroscopy,differential scanning calorimetry (DSC), and¹³C-NMR. It has been shown that an aromaticphenyl ring was involved in the process ofcomplexation, and that in the solid clathrates thesolubility of FL increased two fold when compared tothe physical mixture, while it increased 10 fold inliquid three-component complexes. Moreover, thephotochemical stability of felodipine was studied inits crystalline form and in the inclusion complexeswith -CD. Quantitative assessment of thefelodipine photochemical decomposition was made on thebasis of the rate constants of decomposition (k) inthe first order kinetic reaction, half life time(t_0.5) and the time of decomposition of 10% of thecompound (t_0.1). It was shown that complexationof FL with -CD causes a two fold increase ofthe rate of the photodegradation process.     

NMR Study of the Inclusion Complexes of Carboxy-Phenoxathiin Derivatives with β-Cyclodextrin

The inclusion complexes of the carboxylate forms of 3-carboxy-(I) and 2-carboxy-phenoxathiin (II) with -cyclodextrin were studied by bothone- and two-dimensional NMR spectroscopy. The analysis of the induced chemical shifts of theguests in the presence of different amounts of the host indicates the formation of complexes with 1:1stoichiometry and association averaged pK values of 3.75 (I) and 4.4 (II). Thequalitative analysis of cross peaks in the ROESY spectra support the inclusion of the guests in the cavitywith the substituted phenyl ring, the COO^- group being in the proximity of the primary rim.     

Studies on Water-soluble α-, β- or γ-Cyclodextrin Prepolymer Inclusion Complexes with C60

Treatment of water-soluble -,- and -cyclodextrin-epichlorohydrin prepolymer (CDP) with C60 by kneading leads to the formation of six distinct water-soluble inclusion complexes: -CDP/C60 (1 : 1), -CDP/C60 (1 : 1), -CDP/C60 (1 : 1), -CDP(2 : 1), -CDP(2 : 1) and -CDP(2 : 1). Their formation and structures have been examined by X-ray powder diffraction (XRD), differential scanning calorimeter (DSC) and UV-vis spectrosocopy. The effect of side chains of the CDPs has also been studied.     

Thermodynamic Data for the Complex Formation of Alkylamines and Their Hydrochlorides with α-Cyclodextrin in Aqueous Solution

The formation of complexes between α-cyclodextrin and n-alkylamines and their hydrochlorides has been studied in aqueous solution using calorimetric titrations. All alkylamines form stronger complexes than the corresponding hydrochlorides. The values of the reaction enthalpies are smaller for the alkylamine hydrochlorides compared with the alkylamines. By increasing the number of methylene groups, these differences become smaller. In addition, the reaction enthalpies for protonation of the alkylamines and their complexes with α-cyclodextrin have been measured. The heat of protonation of these complexes is always smaller compared with the alkylamines. Due to the protonation and the formation of a strong solvation shell around the ammonium group the interactions with α-cyclodextrins are weakened. From a thermodynamic cycle using all measured reactions, it can be concluded that the aggregation of the alkylamines with long alkyl chains (heptyl-, octyl-, and nonylamine) has an influence on the values of the reaction enthalpies and entropies for the protonated form only.This revised version was published online in July 2005 with a corrected issue number.     

Structure of the β-Cyclodextrin·p-Hydroxybenzaldehyde Inclusion Complex in Aqueous Solution and in the Crystalline State

-Cyclodextrin (-CD) and p-hydroxybenzaldehyde (p-HB) were studied by ¹H-NMR in deuterated aqueous solution and the stoichiometry of the resulting complex (1:1) was determined by the continuous variation method. Inclusion of p-HB in -CD was confirmed by the observation of NMR shifts for the inside H5 protons of the -CD cavity. In the solid state X-ray analysis was carried out and revealed the detailed structure of the inclusion complex. Two -CDs cocrystallize with four p-HB and 9.45 water molecules[2(C₆H₁₀O₅)^7·4C₇H₆O_2·9.45H₂O] in the triclinic space group P1 with unit cell parameters: a = 15.262(2), b = 15.728(1), c = 16.350(1) Å, = 92.67(1)°, = 96.97(1)°, = 103.31(1)°. The anisotropic refinement of 1973 atomic parameters converged at an R-factor = 0.066 for 10157 data with F_o ² > 2 (F_o ²). The 2:4 stoichiometry for the -CD inclusion complex with p-HB in the crystalline state is different from that obtained in solution. -CD forms dimers stabilized by direct O2(m)₁O3(m)₁·O2(n)₂O3(n)₂ hydrogen bonds (intradimer) and by indirect O6(m)₁·O6(n)₂ hydrogen bonds with one or two bridging water molecules joined in between (interdimer). These dimers are stacked like coins in a roll constructing infinite channels where the p-HB molecules are included. The p-HB molecules direct their polar CHO and OH groups into the nonpolar -CD cavities and are hydrogen bonded to each other, yielding infinite, antiparallel chains. In addition, crystals of the complex were also investigated with thermogravimetry, vibrational spectroscopy (FTIR), and ¹³C CP-MAS NMR spectroscopy. The results obtained enabled us to structurally characterize the -CD inclusion complex with p-HB.     

Surface Tension and 1H NMR Studies on Inclusion Complexes of β-Cyclodextrin with Sodium Alkyl Sulfonate

The inclusion complexes of -CD with sodium octylsulfonate (C8As), sodium dodecyl sulfonate (C12As), andsodium hexadecyl sulfonate (C16As) in aqueous solutions havebeen studied by surface tension measurement at the air/water interfaceand 1H NMR spectroscopy at 323 K.At fixed concentrations of the surfactants, the surface tensions firstincrease with the increase of -CD concentrations,then they attain a maximum. The surface tension curves of the surfactantsin the presence of -CD are higher than those in the absence of-CD. The values increase with increasing -CD concentrations foreach surfactant. The apparent critical micelle concentrations (CMC) of thesurfactants vary linearly with -CD concentrations.A 1H NMR study shows that the signals of theinner H-3 and H-5 of -CDshift upfield upon addition of the surfactants.The magnitude of the chemicalshift changes (= CD obs)varies as a functionof the concentrations of the surfactants. From therelationships between the chemicalshift changes of H-3 or H-5 inside the -CD cavityand guest/host molar ratios, a 1:1 stoichiometry foreach inclusion complex is assumed. The associationconstants of the inclusion complexes have beendetermined by 1H NMR spectroscopy.     

Cucurbituril and α- and β-Cyclodextrins as Ligands for the Complexation of Nonionic Surfactants and Polyethyleneglycols in Aqueous Solutions

The complexation of nonionicsurfactants and polyethylene glycols by the ligandscucurbituril, - and -cyclodextrin wasstudied in aqueous solution. All the examined guestmolecules form complexes with these ligands.Calorimetric titrations were performed to determinedirectly the stability constants and reactionenthalpies. The presence of an aromatic part innonionic surfactants leads to more stable complexeswith -cyclodextrin than with the other ligands.If the surfactants contain no benzene group, theinteractions with -cyclodextrin are strongercompared to other ligands. The chain length of thepolyethylene glycols has only an influence upon thevalues of the reaction enthalpy in the case of-cyclodextrin.     

Inclusion of Enantiomeric Carvones in β-Cyclodextrin: a Variable Temperature 1H NMR Study in Aqueous Solution

In aqueous solution, the apparent association constant at room temperature for the 1 : 1 inclusion of S-(+)-carvone in - cyclodextrin is double of that for R-(-)-carvone, whereas, at 45 °C, both enantiomers have association constants two orders of magnitude smaller, with the S-(+) inclusion being then slightly weaker than the R-(-) encapsulation. Calculations carried out at the molecular mechanics, AM1 and STO-3G levels confirm the preferential inclusion of the S-enantiomer and provide important clues for understanding chiral discrimination by -cyclodextrin.     

Complexation of Monosulfonated Triphenylphosphine with Chemically Modified β-Cyclodextrins: Effect of Substituents on the Stability of Inclusion Complexes

Interactions between the meta-substituted monosulfonated triphenylphosphine and chemically modified β-cyclodextrins were investigated in aqueous solution by NMR and UV–vis spectroscopy. Titration and continuous variation plots obtained from ³¹P NMR data indicate that the monosulfonated triphenylphosphine forms 1:1 inclusion complexes with the 2-hydroxypropylated β-cyclodextrin, the methylated β-cyclodextrin and the (2-hydroxy-3-trimethylammoniopropyl)-β-cyclodextrin chloride. These inclusion complexes are more stable that those formed with native β-cyclodextrin, confirming that poisoning of the chemically modified β-cyclodextrins by the hydrosoluble phosphine occurs when modified cyclodextrins are used as mass transfer promoters in aqueous-phase organometallic catalysis.This revised version was published online in July 2005 with a corrected issue number.     

Inclusion Complexation of Carbaryl and β-Cyclodextrin in Solution and in the Solid State

This study was carried out with the aim ofinvestigating the interactions between-cyclodextrin and carbaryl, a carbamatepesticide, and their effect on some physico-chemicalproperties of carbaryl, such as aqueous solubility andlipophilicity. The interactions between carbaryl and-cyclodextrin were thoroughly investigated bothin solution and in the solid state. The effect of-cyclodextrin on the aqueous solubility ofcarbaryl was evaluated by the phase solubility method.The amount of carbaryl dissolved increased linearlywith the addition of -cyclodextrin according toan A_L type plot and without precipitation of thecomplex. The apparent stability constant of thecomplex was 289 ± 21 M^-1, assuming a 1 : 1stoichiometry; this value was confirmed by a methodbased on circular dichroism measurements.Equimolar carbaryl/-cyclodextrin solid systemswere prepared by physical-mixing and freeze-drying,and fully characterised by Differential ScanningCalorimetry, X-ray powder diffractometry and FourierTransform Infra-Red analysis. The results of the solidstate study demonstrated that the freeze-drying methodyields a system with a high degree of amorphisationand yields an inclusion complex.The dissolution profile of the pesticide was affectedby the physico-chemical properties of each solidsystem, the freeze-dried form dissolving more rapidly. However, the physical association of-cyclodextrin and carbaryl enhanced the aqueoussolubility of the insecticide as well.     

Bi-directional Inclusion Complexation of Methylalkyl Viologens with β-Cyclodextrin and Naphthyl group-Tethered β-Cyclodextrins

Inclusion complexation of methylalkyl viologens(C₁C_nV²⁺; n = 7–10, 12) withmono-6-O-(2-sulfonato-6-naphthyl)-β-CD (1)and mono-6-O-(2-naphthyl)-β-CD (2) werestudied by steady-state and time-resolved fluorescencespectroscopies and compared with the binding of theviologens with native β-CD investigated by induced circulardichroism. The viologens form bimodal complexes with1 and 2, in which the bipyridinium group of theviologens is placed on the primary side (type I complex) andsecondary side (type II complex) of β-CD cavity, while thegroup is predominantly on the secondary side in complexeswith native β-CD. The microscopic binding constantsK_I and K _II were calculated from theanalysis of fluorescence data. The formation of the type Icomplexes with 1 and 2 appears to be largely dueto the charge–transfer interaction between the bipyridinium andnaphthyl groups in the complexes. This work shows thatthe location of the bipyridinium group in β-CDcomplexes and in the type II complexes of the viologens with1 and 2 depends little on the length of alkyl chainof the viologens.     

Aqueous Solution Inclusion of the Nonionic Surfactant C 12 E 4 in β-Cyclodextrin: Implications of Micellization in Stoichiometry Determination and Model Calculations

The inclusion of -n-dodecyl--hydroxytetra(oxyethylene), C₁₂E₄, in -cyclodextrin (CD) has been studied in aqueous solution. Guest encapsulation is recognized by the upfield variations in the chemical shifts of the H3 and H5 inner protons of CD, and the chemical shift differences of the H5 protons are used for determining the complex stoichiometry (2CD : 1C₁₂E₄) by the continuous variation method. Self-association (micellization) of the surfactant molecules is considered, and the relative amount of surfactant involved in micellar systems at the stoichiometric point estimated. A two-layered integrated molecular orbital and molecular mechanics approach with the PM3 and UFF model chemistries for the guest and host, respectively, was used to perform full geometry optimizations and frequency calculations on the host-guest systems. Energies for the optimized structures were subsequently obtained by single point calculations at the Hartree–Fock level using the STO-3G basis set. These calculations showed that one C₁₂E₄ molecule encapsulated by a head-to-head CD dimer is a stable model system in consonance with the experimentally determined stoichiometry, and that the 1 : 1 complex is not stable with respect to dissociation. In the stable 2 : 1 model system, the guest molecule is appreciably tilted with respect to the CD dimer axis and presents a gradually bent alkylic chain in clear manifestation of conformational flexibility. Model calculations for CD inclusion complexes of other oligo(oxyethylene) molecules further indicate that the number and strength of HH intermolecular close contacts reflect the position and conformational flexibility of the guest hydrophobic chain inside CD.     

Inclusion Behavior of α-Cyclodextrin with 2-Methylnaphthalene in Aqueous Solutions

By means of absorption and fluorescence spectroscopy, 2-methylnaphthalene (2MN) was found to be incorporated into the cavity of -cyclodextrin (-CD) to form a 1 : 1 inclusion complex. The 1 : 1 inclusion complex further associated with another -CD molecule, resulting in the formation of a 2 : 1 -CD-2MN inclusion complex. The equilibrium constants for the formation of the 1 : 1 and 2 : 1 inclusion complexes were estimated to be 44.6 and 376 mol-1 dm3, respectively, on the basis of a simulation of the observed 2MN fluorescence intensities. The induced circular dichroism spectra suggested that 2MN, buried within the -CD inclusion complexes, resided in a different orientation relative to the CD symmetry axis, as compared to 2MN within a -CD inclusion complex.     

Thermodynamic Data for the Formation of 1:1 and 2:1 Complexes of α,ω-Diamino Dihydrochlorides with 18-Crown-6 in Aqueous Solution

Calorimetric titrations are used to study the interactions between the crown ether 18-crown-6 and several α,ω-diamino dihydrochlorides in aqueous solution. These complexes are formed by ion-dipole interactions between the positively charged nitrogen atoms and the oxygen donor atoms of the crown ether. Depending on the experimental conditions, the formation of 1:1 or 2:1 complexes (ligand:diamines) can be studied. The solvation of the ligand and the amines are responsible for the observed thermodynamic values. The number of water molecules released during the reaction were calculated from the determined reaction entropies. Formation of 1:1 complexes distorts the solvation shell around the molecules. As a result, the number of solvent molecules released during the formation of the 2:1 complexes is slightly smaller than the number released from formation of the 1:1 complex. No experimental evidence is observed for the formation of complexes between one crown ether and two protonated amino groups.