Experimental (NMR) and Computational (MD) Studies on the Inclusion Complexes of 1-Bromoadamantane with alpha-, beta-, and gamma-Cyclodextrin

The inclusion complexes between the most commonly used cyclodextrins (alpha-, beta-, and gamma-CD) and 1-bromoadamantane were prepared and studied experimentally by NMR methods and by molecular dynamics simulations (AMBER force field) with solvation. The NMR results suggest host/guest ratios of 2:1, 1:1, and 1:1 for the complexes with alpha-, beta-, and gamma-cyclodextrin, respectively, as well as defined geometries for the complexes. Averaged geometrical data from the molecular dynamics simulations agree with the complexation geometries deduced experimentally.     

Micellar behavior of aqueous solutions of dodecyldimethylethylammonium bromide, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride in the presence of alpha-, beta-, HPbeta- and gamma-cyclodextrins

Conductivity, static fluorescence and (1)H NMR measurements have been carried out to study the micellar behavior of aqueous solutions of dodecyldimethylethylammonium bromide (DDAB), dodecyltrimethylammonium chloride (DTAC) and tetradecyltrimethylammonium chloride (TDAC) in absence and presence of alpha-cyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HPbeta-CD) and gamma-cyclodextrin (gamma-CD). The conductivity measurements were carried out at 298.15 K. The influence of cyclodextrins on the micellar parameters, such as cmc* (apparent critical micellar concentration), beta (degree of ionization) have been analyzed. Thermodynamics of the systems was discussed in terms of the change in standard free energy of micellization, DeltaG(m)(0). Micellization was found to be less spontaneous in presence of cyclodextrins. The fluorescence intensity of the surfactant solutions is enhanced by the addition of cyclodextrins. The association constants obtained from conductivity and fluorescence data suggest the binding of gamma-CD with the surfactants to be strongest among all the cyclodextrins used. (1)H NMR chemical shift changes provide powerful means for probing the cyclodextrin-micellar interactions and inclusion of surfactant is shown by the change in the chemical shift of some of the guest and host protons in comparison with the chemical shifts of the same protons in the free compounds.     

Rapid adsorption and entrapment of benzoic acid molecules onto mesoporous silica (FSM-16)

Changes in the molecular state of benzoic acid (BA) in the presence of folded sheet mesoporous material (FSM-16), which has uniformly sized cylindrical mesopores and a large surface area, were assessed with several analyses. When BA was blended with FSM-16 for 5 min (BA content=30%), the X-ray diffraction peaks of BA crystals disappeared, suggesting an amorphous state. Fluorescence analysis of the mixture showed a new fluorescence emission peak for BA at 386 nm after mixing with FSM-16. Fluorescence lifetime analysis of the BA component in the mixture at 386 nm showed a longer lifetime in comparison with that of BA crystals. The solid-state (13)C CP/MAS and PST/MAS NMR spectra of the mixture with FSM-16 showed a significantly different spectral pattern from the mixture with nonporous glass, whose NMR spectra were identical to those of BA crystals. These results indicate that BA molecules disperse quickly into the hexagonal channels of FSM-16 by a simple blending procedure and adsorbed BA molecules had clearly different physicochemical properties to BA crystals.     

Enantiomeric discrimination of 1,1'-binaphthol by room temperature phosphorimetry using gamma-cyclodextrin as chiral selector

In the presence of a small amount of 1,2-dibromopropane (1,2-DBP), 1,1'-binaphthol (BINOL) displays strong room temperature phosphorescence in gamma-cyclodextrin (gamma-CD) solution without deoxygenation. The phosphorescence intensity as well as the phosphorescence lifetime of (S)-BINOL is greater than that of (R)-BINOL, indicating a distinct chiral discrimination of gamma-CD toward this pair of enantiomers. Both (R)-BINOL and (S)-BINOL exhibit a double exponential phosphorescence decay with lifetimes of 5.89 ms and 17.3 ms for (R)-BINOL and 7.58 ms and 23.6 ms for (S)-BINOL, respectively. The association constant obtained for (S)-BINOL/gamma-CD/1,2-DBP ternary complex is larger than that for (R)-BINOL/gamma-CD/1,2-DBP complex. Thus, the observation of RTP lifetime differences between (R)-BINOL and (S)-BINOL can be attributed to their different ability to form complexes with chiral gamma-CD, which is further supported by an analysis of the proton NMR chemical shift differences between (R)-BINOL and (S)-BINOL.     

Mechanistic study of enantiomeric recognition with native gamma-cyclodextrin by capillary electrophoresis,reversed-phase liquid chromatography,nuclear magnetic resonance spectroscopy,electrospray mass spectrometry and circular dichroism techniques

The possible mechanisms for the chiral recognition of 2(S)-(3,5-bis-trifluoromethyl-phenyl)-2-[3(S)-(4-fluorophenyl)-4-(1H-[1,2,4]triazol-3-ylmethyl)-morpholin-2(R)-yloxy]-ethanol (compound A) and its enantiomer with native gamma-cyclodextrin (gamma-CD) were investigated using capillary electrophoresis (CE), reversed-phase liquid chromatography (RPLC), proton (1H), fluorine (19F) and carbon (13C) nuclear magnetic resonance spectroscopy (NMR), electrospray mass spectrometry (ESI-MS) and circular dichroism (CD). All experiments provided clear evidence of the formation of diastereomeric complexes between the enantiomers and gamma-CD. Proton, fluorine and carbon NMR spectra suggested that both aromatic rings, with mono-fluoro and bis-tri-fluoro functional groups, on the guest molecule were partially included into the cavity of the gamma-CD. ESI-MS spectra indicated that the diastereomeric complexes have a 1:1 stoichiometric ratio. The binding constants of the diastereomeric complexes obtained by CE, RPLC and CD were compared. The effects of the gamma-CD concentration, organic modifiers and temperature on the CE-chiral separation were also investigated.     

Solubilization of steviolbioside and steviolmonoside with gamma-cyclodextrin and its application to selective syntheses of better sweet glycosides from stevioside and rubusoside

1,4-alpha-Glucosylation at the 13-O-glycosyl moiety of stevioside (S) and rubusoside (RU) results in a significant increase of sweetness. Saponification of the 19-COO-beta-glucosyl linkage of S and RU yielded steviolbioside (SB) (= 13-O-beta-sophorosyl-steviol) and steviolmonoside (SM) (= 13-O-beta-glucosyl-steviol), respectively, both of which are poorly soluble in an acetate buffer. It was found that the solubilities of SM and SB in the buffer solution were remarkably increased in the presence of gamma-cyclodextrin (gamma-CD). SB was solubilized in the buffer solution with the aid of gamma-CD, and the solution was subjected to 1,4-alpha-transglucosylation by using a cyclodextrin glucanotransferase-starch system to give a mixture of products which were glucosylated at the 13-O-glycosyl moiety. This mixture was acetylated, and the acetate was subjected to chemical beta-glucosylation of 19-COOH followed by deacetylation to afford compounds which have superior sweetness to S. In the same way, derivatives with superior sweetness were selectively prepared from RU through SM.     

Theoretical studies on hydrogen bonding, NMR chemical shifts and electron density topography in alpha, beta and gamma-cyclodextrin conformers

Hydrogen-bonded interactions in alpha-, beta-, and gamma-CD conformers are investigated from the molecular electron density topography and chemical shift in the nuclear magnetic resonance (NMR) spectra calculated by using the Gauge Invariant Atomic Orbital (GIAO) method within the framework of density functional theory. For the lowest-energy CD conformers in the gas phase, the O3-H...O2' hydrogen-bonding interactions are present. Calculated 1H NMR chemical shifts (delta H) correlate well with the hydrogen-bond distance as well as electron density at the bond critical point in the molecular electron density (MED) topography. The conformers of beta- and gamma-CD comprised of relatively strong secondary hydroxyl interactions are stabilized by solvation from polar solvents.     

Investigation on gamma-cyclodextrin nanotube induced by N,N'-diphenylbenzidine molecule

Dynamic light scattering (DLS) measurement provides an effective way to investigate the formation of nanotube of gamma-cyclodextrin (gamma-CD) induced by N,N'-diphenylbenzidine (DPB) in water. With the combination of steady-state fluorescence and fluorescence anisotropy experiments, it was found that for alpha- and beta-CD, only 1:2 (guest:host) inclusion complexes were formed and for gamma-CD, cyclodextrin nanotube was formed involving 16 gamma-CD units at maximum. The pH effect studies with both DLS and fluorescence anisotropy measurements indicated that the hydrogen bonding between neighboring CDs was necessary to the formation of cyclodextrin nanotube. In the temperature experiment, we found that the nanotube of DPB-gamma-CD could exist stably at relatively high temperatures and the transition point for structural collapse was estimated to be around 54 degrees C. The aggregation states of both gamma-CD itself and DPB-gamma-CD nanotube were observed with TEM.     

Effect of peracetylation on the conformation of gamma-cyclodextrin

The well-known, fourfold symmetry of the gamma-CD molecule in its solid inclusion complexes is lost on peracetylation, which yields a highly distorted host molecule in which self-inclusion of acetyl residues divides the macrocyclic cavity into two distinct sub-cavities that accommodate solvent molecules.     

A spectroscopic study of the inclusion of azulene by beta- and gamma-cyclodextrins

The inclusion of azulene (AZ) inside the cavities of beta-cyclodextrin (beta-CD) and gamma-cyclodextrin (gamma-CD) was studied using absorption, fluorescence and induced-circular dichroism spectroscopy. The inclusion of AZ into the cavity of beta-CD has a stoichiometry of 1:1, whereas that of AZ/gamma-CD complex is 1:2. The equilibrium constants for the formation of the two complexes were calculated to be 780+/-150 M(-1) for AZ:beta-CD and (4.5+/-0.86)x10(5) M(-2) for AZ:(gamma-CD)(2). The latter is due to a stepwise equilibrium mechanism in which a 1:1 complex is formed with a binding constant of 775 M(-1), followed by the formation of a 1:2 complex with a binding constant of 580 M(-1). The difference between the two binding constant values is slight, indicating an almost equal contribution from each of the gamma-CD molecules to the overall binding in AZ:(gamma-CD)(2). From the induced-circular dichroism spectra, the inclusion of AZ was found to be axial in AZ:beta-CD and nearly axial in AZ:(gamma-CD)(2).     

External electrostatic interaction versus internal encapsulation between cationic dendrimers and negatively charged drugs: which contributes more to solubility enhancement of the drugs?

Relationships of electrostatic interaction and encapsulation between poly(amidoamine) (PAMAM) dendrimers and negatively charged drug molecules have been investigated by aqueous solubility and NMR ( (1)H NMR and two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY)) studies. PAMAM dendrimers significantly increased the solubilities of phenobarbital and sulfamethoxazole, but scarcely influenced those of primidone and trimethoprim. Moreover, (1)H NMR and 2D-NOESY measurements indicated that few phenobarbital or sulfamethoxazole molecules were entrapped in the cavities of low-generation dendrimers (generation 3, G3). These results suggest that external electrostatic interaction contributes more to the solubility enhancement of drugs than internal encapsulation.     

Supramolecular enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate mediated by capped gamma-cyclodextrins: critical control of enantioselectivity by cap rigidity

A series of gamma-cyclodextrins (CDs) modified with capping and noncapping aromatic group(s) were synthesized to mediate the enantiodifferentiating [4 + 4] photocyclodimerization of 2-anthracenecarboxylic acid (AC). The complexation behavior of these gamma-CDs with AC was studied by circular dichroism, UV-vis, and NMR spectroscopy to reveal the formation of stable 1:2 host-guest complexes in all cases. The capped gamma-CD with a biphenyl group bridging the A and D glucose units was shown to confine the included AC molecules most strictly among the capped and noncapped gamma-CDs examined. Photocyclodimerization of AC mediated by capped gamma-CDs considerably improved the yield and enantiomeric excess (ee) of the head-to-head photodimer 3. The ee and the absolute configuration of syn-head-to-tail photodimer 2 critically depended on the rigidity of capping. Thus, the flexibly capped and rim-substituted gamma-CDs afforded 2 in moderate ee's of around 40%, whereas gamma-CD with a rigid biphenyl cap gave the antipodal 2 in -58% ee. Interestingly, the ee of 2 mediated by flexibly capped gamma-CDs was highly sensitive to the temperature variation as a consequence of large differential entropy changes in the enantiodifferentiation process. In contrast, the entropy effect does not appear to play a significant role in the photocyclodimerization of AC with rigidly capped gamma-CDs. The differential enthalpy and entropy changes obtained for the enantiodifferentiating photocyclodimerization mediated by native and most of the modified gamma-CDs gave an excellent enthalpy-entropy compensation plot with an exception of the biphenyl-capped gamma-CD, indicating the operation of significantly different enantiodifferentiation mechanism within the rigidly capped cyclodextrin cavity.     

Molecular electrostatic potentials and hydrogen bonding in alpha-, beta-, and gamma-cyclodextrins

Cyclodextrins (CDs) are cyclic oligomers of glucose having the toroid of sugars elaborating a central cavity of varying size depending on the number of glucoses. The central hydrophobic cavity of CD shows a binding affinity toward different guest molecules, which include small substituted benzenes to long chain surfactant molecules leading to a variety of inclusion complexes when the size and shape complementarity of host and guest are compatible. Further, interaction of guest molecules with the outer surface of alpha-CD has also been observed. Primarily it is the electrostatic interactions that essentially constitute a driving force for the formation of inclusion complexes. To gain insights for these interactions, the electronic structure and the molecular electrostatic potentials in alpha-, beta-, and gamma-CDs are derived using the hybrid density functional theory employing the three-parameter exchange correlation functional due to Becke, Lee, Yang, and Parr (B3LYP). The present work demonstrates how the topography of the molecular electrostatic potential (MESP) provides a measure of the cavity dimensions and understanding of the hydrogen-bonded interactions involving primary and secondary hydroxyl groups. In alpha-CD, hydrogen-bonded interactions between primary -OH groups engender a "cone-like" structure, while in beta- or gamma-CD the interactions from the primary -OH with ether oxygen in glucose ring facilitates a "barrel-like" structure. Further, the strength of hydrogen-bonded interactions of primary -OH groups follows the rank order alpha-CD > beta-CD > gamma-CD, while the secondary hydrogen-bonded interactions exhibit a reverse trend. Thus weak hydrogen-bonded interactions prevalent in gamma-CD manifest in shallow MESP minima near hydroxyl oxygens compared to those in alpha- or beta-CD. Furthermore, electrostatic potential topography reveals that the guest molecule tends to penetrate inside the cavity forming the inclusion complex in beta- or gamma-CD.     

SiO2固载咪唑基手性硫醚钯(ll)催化剂的合成及其在Suzuki反应中的应用

以L-缬氨酸、L-亮氨酸和L-苯丙氨酸为原料合成了未见报道的4种咪唑基手性硫醚化合物,并将咪唑基硫醚固载到SiO2上制备了二氧化硅固载咪唑基手性硫醚配体,用元素分析、热重等手段进行了表征;进而与PdCl2反应得到二氧化硅固载咪唑基手性硫醚-钯(Ⅱ)催化剂,用XPS等方法对其进行了表征.考察了该催化剂在Suzuki反应中的催化性能.结果表明,在以溴苯与苯硼酸为底物的Suzuki反应中,该催化剂用量为底物的0.75％、反应时间为5h、温度为80℃时,溴苯的转化率可达95％.     

Energetically favorable interactions between diclofenac sodium and cyclodextrin molecules in aqueous media

The effect of the addition of cyclodextrins (CD) viz., alpha-, beta-, HPbeta- and gamma-CD to the aqueous solutions of the most widely prescribed anti-inflammatory drug, diclofenac sodium (DS), has been fully investigated by means of spectroscopic (UV-vis, steady-state fluorescence, (1)H NMR and ROESY) and thermodynamic (conductivity) techniques. The global picture of the results indicates that diclofenac sodium penetrates the CD cavity. The apparent association constants for all the inclusion complexes were estimated from fluorescence data. Conductivity measurements of aqueous solutions of diclofenac sodium were performed both as a function of DS concentration and CD concentration, at different temperatures ranging from 15 to 40 degrees C. Results suggested the existence of 1:1 complex between DS and CD. The thermodynamics of the system was discussed in terms of change in Gibbs free energy. Free energy of the DS/W system was found to decrease on addition of cyclodextrin, which points towards the energetically favorable interactions between drug and cyclodextrin molecules in solution phase. (1)H NMR chemical shift changes and ROESY spectra provide powerful means for probing CD:DS interactions.     

Mesomorphic phase transitions and electro-optical properties of benzyl fluoroalkyl thioether liquid crystalline compounds

Four series of liquid crystalline (LC) compounds containing benzyl perfluoroalkyl thioether groups (BFT), 4-n-alkoxyphenylbenzyl perfluoroalkyl thioethers (nO-BBFT-FmF), 4-n-alkoxyphenylbenzyl perfluoroisoalkyl thioethers (nO-BBFT-FmIF), 4-n-propylcyclohexylbenzyl perfluoroalkyl thioethers (3-C1BFT-FmF) and 4-ethylcyclohexyl-3'-fluorobenzyl perfluoroalkyl thioethers (2-C1FBFT-FmF), were synthesized and their mesomorphic phase transitions and electro-optical properties investigated. nO-BBFT-FmF and nO-BBFT-FmIF have SmA, SmB and CrE phases, while 3-C1BFT-FmF and 2-C1FBFT-FmF showed a SmB phase. It was found that the appearance of a LC phase and the thermal stability were closely connected with the chemical structures of the rigid core part and the terminal groups. The electrooptical properties were investigated for BFT using ZLI-1132 as nematic solvent. Some of the BFT compounds have a good solubility of 15 wt % in ZLI-1132 and can be used as a component for lowering the refractive anisotropy (Delta n) of the host ZLI-1132 solvent.     

Mesomorphic phase transitions and electro-optical properties of benzyl fluoroalkyl thioether liquid crystalline compounds

Four series of liquid crystalline (LC) compounds containing benzyl perfluoroalkyl thioether groups (BFT), 4-n-alkoxyphenylbenzyl perfluoroalkyl thioethers (nO-BBFT-FmF), 4-n-alkoxyphenylbenzyl perfluoroisoalkyl thioethers (nO-BBFT-FmIF), 4-n-propylcyclohexylbenzyl perfluoroalkyl thioethers (3-C1BFT-FmF) and 4-ethylcyclohexyl-3'-fluorobenzyl perfluoroalkyl thioethers (2-C1FBFT-FmF), were synthesized and their mesomorphic phase transitions and electro-optical properties investigated. nO-BBFT-FmF and nO-BBFT-FmIF have SmA, SmB and CrE phases, while 3-C1BFT-FmF and 2-C1FBFT-FmF showed a SmB phase. It was found that the appearance of a LC phase and the thermal stability were closely connected with the chemical structures of the rigid core part and the terminal groups. The electrooptical properties were investigated for BFT using ZLI-1132 as nematic solvent. Some of the BFT compounds have a good solubility of 15 wt % in ZLI-1132 and can be used as a component for lowering the refractive anisotropy (Delta n) of the host ZLI-1132 solvent.     

Effects of alcohols on CE enantioseparation of basic drugs with native gamma-CD as chiral selector

The effects of alcohol on the CE enantioseparation of selected basic drugs with gamma-CD as the chiral selector was investigated. The enantioseparation behavior of the analytes with gamma-CD in the absence and presence of different alcohols specifically methanol, ethanol, 2-propanol (IPA), and 2-methyl-2-propanol (TBA), the relationship of enantiomeric resolution (R(s)) values with either hydrophobicity or bulkiness of the alcohols, as well as the effect of these alcohols on interaction of the analytes with gamma-CD were studied. Results showed that hydrophobicity and/or bulkiness of alcohols have an influence on the enantioresolution of most of the analytes based on the relatively high correlation coefficients (R) obtained between R(s) versus log P and between R(s) versus ovality (i.e., parameter to indicate bulkiness of a molecule). Comparison of the values of the average binding constants obtained for each enantiomeric pair in the presence and absence of 5% IPA showed that alcohols can increase, decrease, or give a minimal effect on the analyte-gamma-CD interaction depending on the analyte. Furthermore, the significant enhancement in the enantioresolution of both propranolol and pindolol in the presence of either IPA or TBA led to the baseline enantioresolution of both drugs using 35 mM gamma-CD.     

Separation of some chiral flavanones by micellar electrokinetic chromatography

Micellar electrokinetic chromatography (MEKC) was applied for enantioseparation of selected flavanones, including naringin, hesperidin, neohesperidin, naringenin, hesperetin, pinostrobin, isosakuranetin, eriodictyol, and homoeriodictyol. gamma-Cyclodextrin (gamma-CD) and sodium cholate (SCh) were used as chiral modifiers inducing enantioselectivity to the background electrolyte. From among many investigated selectors only these two appeared to possess the best enantioselective properties in respect to studied flavanones. The mechanisms of their action are a little different; SCh used above critical micelle point concentration forms chiral micelles itself while gamma-CD is deprived of this property and requires addition of surfactants as, e.g., sodium dodecyl sulfate. It was found that SCh enables separation of flavanone glycosides diastereomers while separation of enantiomers of flavanone aglycones may be achieved with gamma-CD. Consideration of structural relation led to the suggestion that interaction of sugar moiety of glycosides with SCh micelles give rise to chiral recognition. MEKC appeared to be a suitable and efficient analytical tool to follow enantiomeric composition of flavanones.     

Can the anomalous aqueous solubility of beta-cyclodextrin be explained by its hydration free energy alone?

The well-documented anomalous solubility of beta-cyclodextrin (beta-CD), relative to alpha- and gamma-CD, has been examined by Naidoo et al. (J. Phys. Chem. B, 2004, 108, 4236-4238.) from the perspective of water organization and internal motion of the macrocyclic rings. Whether modulation in the hydration patterns and in the rigidity of the molecular scaffold can be reconciled with the hydration free energy of beta-CD to rationalize its notorious low solubility remains open to further investigation. In this contribution, multi-nanosecond molecular dynamics (MD) simulations have been carried out to investigate the hydration process of alpha-, beta- and gamma-CD. The distribution of water molecules involved in this process and the linearity of intramolecular hydrogen bonds have been analyzed. The results reported here demonstrate that the anomalous solubility for beta-CD can be essentially rationalized by its greater rigidity conferred by the participating intramolecular hydrogen bonds and the higher density of water molecules of lesser mobility. The hydration free energy of alpha-, beta- and gamma-CD was computed using the free energy perturbation method. This quantity is shown to increase with the number of glucose units, thereby suggesting that the anomalous solubility of beta-CD cannot be explained by its free energy of hydration alone.