Chromatographic and Spectroscopic Studies on β-Cyclodextrin Functionalized Ionic Liquid as Chiral Stationary Phase: Enantioseparation of Flavonoids

In this study, β-cyclodextrin functionalized ionic liquid was prepared by adding 1-benzylimidazole onto 6-monotosyl-6-deoxy-β-cyclodextrin (β-CDOTs) to obtain β-CD-BIMOTs. β-CD-BIMOTs were then bonded onto the modified silica to produce chiral stationary phases (β-CD-BIMOTs-CSP). The performance of β-CD-BIMOTs-CSP was evaluated by observing the enantioseparation of flavonoids. The performance of β-CD-BIMOTs stationary phase was also compared with native β-CD stationary phase. For the selected flavonoids, flavanone and hesperetin obtained a high resolution factor in reverse phase mode. Meanwhile, naringenin and eriodictyol attained partial enantioseparation in polar organic mode. In order to understand the mechanism of separation, the interaction of selected flavonoids and β-CD-BIMOTs was studied using spectroscopic methods (¹H NMR, NOESY and UV–Vis spectrophotometry). The enantioseparated flavanone and hesperetin were found to form an inclusion complex with β-CD-BIMOTs. However, naringenin and eriodictyol were not enantioseparated due to the formation of hydrogen bonding at exterior torus of β-CD-BIMOTs.

     

Comparison of enantioseparation of amino acid derivatives in aqueous and mixed aqueous-organic media by capillary zone electrophoresis

The chiral separation of dansyl-amino acids has been performed by capillary zone electrophoresis using ¶β-cyclodextrin as a chiral selector, urea as an additive and 2-propanol and methanol as organic modifiers. The enantiomeric separations of dansyl-amino acids were investigated in aqueous medium and compared with the separation in mixed aqueous-organic medium as background electrolytes. The separation conditions, (concentration of buffer, β-cyclodextrin, methanol, urea and the pH value of buffer) were optimized. In the absence of organic modifier, only five pairs of 8 separated dansyl-amino acids were resolved when run separately. A mixture of up to eight chiral amino acids can be baseline resolved in less than 19 min by β-cyclodextrin-modified capillary zone electrophoresis with a buffer of 60 mmol L^–1 H₃BO₃-KCl/40 mmol L^–1 NaOH (pH 9.0), 4 mol L^–1 urea, 100 mmol L^–1β-cyclodextrin and 10% (v/v) methanol.     

Enantioseparation of Methyl 2-Hydroxypropionate with Two Peracylated β-Cyclodextrin Derivatives as CGC Chiral Stationary Phases

Two peracylated β-cyclodextrin derivatives, 2,3,6-tri-O-valeryl-β-cyclodextrin and 2,3,6-tri-O-octanoyl-β-cyclodextrin, were synthesized and used as capillary gas chromatography (CGC) chiral stationary phases. The two peracylated β-cyclodextrin derivatives showed enantioseparation abilities to some chiral compounds tested, such as enantiomers of methyl 2-chloropropionate, 5-hydroxy-4, 4-dimethyl-dihydrofuran-2-one, and methyl 2-hydroxypropionate. As CGC chiral stationary phases, the two peracylated β-cyclodextrin derivatives showed excellent enantioseparation abilities to methyl 2-hydroxypropionate (i.e., methyl lactate). On 2,3,6-tri-O-valeryl-β-cyclodextrin, the enantiomer separation factor and resolution of methyl lactate were 1.21 and 6.08, respectively, and on 2,3,6-tri-O-octanoyl-β-cyclodextrin, 1.22 and 5.49, respectively. The enantioseparation results of methyl lactate on the two peracylated β-cyclodextrin derivatives were better than on most reported β-cyclodextrin derivatives, including a commercial chiral column of permethylated β-cyclodextrin tested in this study. Results suggest that CGC methods using 2,3,6-tri-O-valeryl-β-cyclodextrin or 2,3,6-tri-O-octanoyl-β-cyclodextrin as chiral stationary phase could be used for enantioseparation and evaluating the enantiomeric optical purity of methyl lactate.     

Arylcarbamoylated allylcarbamido-β-cyclodextrin: synthesis and immobilization on nonfunctionalized silica gel as a chiral stationary phase

Four new chiral stationary phases based on mono-(6^A-allylcarbamido-6^A-deoxy)-arylcarbamoylated β-cyclodextrin were synthesized. The chiral stationary phase of phenylcarbamoylated β-cyclodextrin exhibited excellent separation capability for a variety of chiral compounds. Compared with the previous work, it was found that the spacer remained on the surface of the silica gel and decreased the enantioseparation capability.     

Preparation and chiral resolution properties of bridged bis(cyclodextrin)s hybrid spheres for high performance liquid chromatography

Selenium-bridged bis(β-cyclodextrin)s organic–inorganic hybrid silica material with regular spherical shape as new type of chiral stationary phase was directly synthesized under the one-pot hydrothermal synthesis method, and the chiral stationary phase was further characterized by infrared spectroscopy, scanning electron microscopy, thermogravimetry, and elemental analysis. The results of chiral separation showed that eight chiral compounds including various types of chiral alcohols and flavanone were successfully separated in the reversed-phase separation mode by high performance liquid chromatography, which showed the better chiral resolution effect than that on the C2 position of single β-cyclodextrin. The mechanism of chiral separation was likely due to multiple interactions such as inclusion, hydrogen bonding, electrostatic interaction, dipole–dipole interaction, and the synergistic effect of two cyclodextrins during the chiral resolution process. The synergy of the two cyclodextrins has great potential for development in chiral resolution.     

Investigation of the synergistic effect with chiral D-penicillamine functionalized gold nanoparticle as an additive for enantiomeric separation in capillary electrophoresis

The authors describe a synergistic system for nanoparticle based chiral separation. It is based on the use of a conventional chiral selector hydroxyproyl-β-cyclodextrin and a kind of gold nanoparticle functionalized with D-penicillamine as an additive. This nanomaterial displays a synergistic effect on the efficiency of the enantioseparation of the chiral drugs amlodipine, tropicamide, and ofloxacin. A comparative study on the enantioseparation capability of three separation systems, viz. (a) single hydroxyproyl-β-cyclodextrin system, (b) achiral citrate capped gold nanoparticle/ hydroxyproyl-β-cyclodextrin system, and (c) chiral D-penicillamine functionalized gold nanoparticle/ hydroxyproyl-β-cyclodextrin system was performed. The results show that the D-penicillamine functionalized gold nanoparticle/hydroxyproyl-β-cyclodextrin synergistic system has remarkable superiority. The effects of concentrations of D-penicillamine functionalized gold nanoparticle and hydroxyproyl-β-cyclodextrin, of buffer pH value and concentration, and of applied voltage on the performance of enantioseparation were investigated.     

Enantioselective separation in capillary electrophoresis using a novel mono-6-propylammonium-β-cyclodextrin as chiral selector

The chiral resolving ability of a novel single-isomer cationic β-cyclodextrin (CD), mono-6^A-propylammonium-6^A-deoxy-β-cyclodextrin chloride (PrAMCD), as a chiral selector in capillary electrophoresis (CE) is reported in this work for the enantioseparation of hydroxy, carboxylic acids and amphoteric analytes. The effect of chiral selector concentration on the resolution was studied. Good resolutions were achieved for hydroxy acids. Optimum resolutions were obtained even at 3.5 mM CD concentration for carboxylic acids. The electrophoretic method showed good linearity and reproducibility in terms of migration times and peak areas, which should make it suitable for routine analysis. In addition, baseline chiral separation of a six-acid mixture was achieved within 20 min. PrAMCD proved to be an effective chiral selector for acidic analytes.     

Dendrimer-Like Chiral Stationary Phases Derived from (1R, 2R)-(+)-1,2-Diphenylethylenediamine and 1,3,5-Benzenetricarbonyl Trichloride

Three dendrimers were synthesized directly on aminated silica gel using (1R, 2R)-(+)-1,2-diphenylethylenediamine and 1,3,5-benzenetricarbonyl trichloride as building blocks. The chiral stationary phases were obtained by modification of these dendrimers with phenyl isocyanate. All derivatives prepared on silica gel were characterized by FTIR spectrum, solid-state ¹H NMR and elemental analysis. The enantioseparation ability of the chiral stationary phases was preliminarily evaluated by high-performance liquid chromatography. The chiral stationary phase of one-generation dendrimer exhibited best enantioseparation ability.     

Preparation and chromatographic evaluation of a chiral stationary phase based on carboxymethyl-β-cyclodextrin for high-performance liquid chromatography

A novel chiral stationary phase (CSP) was prepared by chemically bonding carboxymethyl-β-cyclodextrin (CM-β-CD) onto 3-aminopropyl silica gel and showed excellent enantioseparation abilities for a broad range of chiral compounds and drugs.     

LC Enantioseparation of β-Lactam Stereoisomers through the Use of β-Cyclodextrin-Based Chiral Stationary Phases

Direct liquid chromatographic methods were developed to investigate the enantioseparation of 19 β-lactams on three cyclodextrin-bonded chiral stationary phases: permethyl-β-cyclodextrin, β-cyclodextrin and R,S-hydroxypropyl-β-cyclodextrin, prepared by a novel synthetic route. 17 of the 19 β-lactam stereoisomers were partially or baseline-separated on at least one of the tested chiral stationary phases. The influence of the structures of the β-lactams (the positions and types of the substituents, the size of the attached rings) on the enantiomer separation is discussed. The permethylated β-cyclodextrin selector proved to be the most effective one for the tested analytes.     

Enantioseparation of Hydrobenzoin and Structurally Related Compounds on <Emphasis Type="Italic">β</Emphasis>-Cyclodextrin and Hydroxypropyl-<Emphasis Type="Italic">β</Emphasis>-cyclodextrin Bonded Chiral Stationary Phases

A β-cyclodextrin (β-CD) and a hydroxypropyl-β-cyclodextrin (HP-β-CD) bonded chiral stationary phase (CSP) were prepared. Comparative evaluations of these two CSPs for the enantioseparation of hydrobenzoin, benzoin and α-phenethyl alcohol by reversed-phase liquid chromatography were presented. The effects of buffer composition in the mobile phase on the retention and enantioseparation were investigated. The borate buffer had a significant influence on the retention and enantioseparation of hydrobenzoin. Linear solvent strength retention model was used to fit the chromatographic data. Good linearity existed between the logarithm of retention factor (k) and the volume fraction of organic modifier (φ). Another retention model, stoichiometric displacement theory for retention, was also tried to fit the chromatographic data. The results showed that not only acetonitrile, but also water molecules participated in the displacing process of the solute.     

Cationic cyclodextrins chemically-bonded chiral stationary phases for high-performance liquid chromatography

Two covalently bonded cationic β-CD chiral stationary phases (CSPs) prepared by graft polymerization of 6^A-(3-vinylimidazolium)-6-deoxyperphenylcarbamate-β-cyclodextrin chloride or 6^A-(N,N-allylmethylammonium)-6-deoxyperphenylcarbamoyl-β-cyclodextrin chloride onto silica gel were successfully applied in high-performance liquid chromatography (HPLC). Their enantioseparation capability was examined with 12 racemic pharmaceuticals and 6 carboxylic acids. The results indicated that imidazolium-containing β-CD CSP afforded more favorable enantioseparations than that containing ammonium moiety under normal-phase HPLC. The cationic moiety on β-CD CSPs could form strong hydrogen bonding with analytes in normal-phase liquid chromatography (NPLC) to enhance the analytes’ retention and enantioseparations. In reversed-phase liquid chromatography (RPLC), the analytes exhibited their maximum retention when the pH of mobile phase was close to their pK_a value. Inclusion complexation with CD cavity and columbic/ionic interactions with cationic substituent on the CD rim would afford accentuated retention and enantioseparations of the analytes.     

Mono(6-N-allylamino-6-deoxy)perphenylcarbamoylated β-cyclodextrin: synthesis and application as a chiral stationary phase for HPLC

A novel cyclodextrin derivative: mono(6^A-N-allylamino-6^A-deoxy)perphenylcarbamoylated β-cyclodextrin was synthesized. Hydrosilylation with (EtO)₃SiH and then reaction of the reactive siloxane with pristine silica gel afforded a facile entry into a durable, structurally well-defined chiral stationary phase capable of enantioseparation of a variety of racemic drugs.     

Chiral Separation of Duloxetine and Its R-Enantiomer by LC

The direct enantioseparation of duloxetine and its R-enantiomer was achieved by HPLC using hydroxypropyl-β-cyclodextrin (HP-β-CD) as a chiral selector and a vancomycin chiral stationary phase (Chirobiotic V). Operational parameters, such as the concentration of HP-β-CD, buffer pH, organic modifiers, temperature and flow rate, were varied in order to achieve the desired retention time and resolution. These two enantioseparation methods developed gave a baseline resolution of the enantiomers. Finally, the HPLC-CSP method was selected to determine the enantiomeric purity of duloxetine drug substance due to its much shorter analysis time and better resolution. The limit of detection of this method was 0.06 μg mL⁻¹.     

Click chemistry for facile immobilization of cyclodextrin derivatives onto silica as chiral stationary phases

Click chemistry was applied to immobilize mono-azido-β-cyclodextrin derivatives onto the surface of silica to give novel chiral stationary phases (CSPs). The desired CSPs showed high stability and excellent enantioseparation effects in capillary electrochromatography (CEC).     

Preparation of Cyclodextrin Type Stationary Phase Based on Graphene Oxide and Its Application in Enantioseparation and Hydrophilic Interaction Chromatography

Graphene oxide (GO) was covalently coupled to the surface of amino silica gel by amide bond. β-cyclodextrin (β-CD) was further chemically bonded with GO to prepare a novel chiral stationary phase. The resulting material was characterized by Fourier transform-infrared (FT-IR) spectra, scanning electron microscopy (SEM), transmission electron microscopy (TEM), elemental analysis and thermogravimetric analysis (TGA). The separation of seven enantiomers was improved in varying degrees. Meanwhile, the stationary phase showed typical characteristics of hydrophilic interaction chromatography (HILIC), and four small nucleoside molecules were separated with the mobile phase of methanol-acetonitrile-water (45:45:10, V/V) in the HILIC mode. In addition, the separation mechanism of the stationary phase was further explored by studying the effects of mobile phase composition, temperature and pH value on the analyte retention. The low temperature was conducive to the separation of analytes at 20–60 °C. The addition of protonated solvent methanol significantly decreased the retention time of the four analytes. The change of pH affected the degree of protonation of the analyte, the interaction between analytes and the stationary phase, and retention time of analytes. The results showed that GO and β-CD played a synergistic effect in the chiral resolution of the chromatographic stationary phase. The retention of analytes in HILIC was attributed to their mixed-mode retention mechanisms including hydrophilic interaction, electrostatic interaction, hydrogen bonding, π-π stacking and so on.     

Development of Vancomycin-Capped β-CD-Bonded Silica Particles as Chiral Stationary Phase for LC

Vancomycin-capped (3-(2-O-β-cyclodextrin)-2-hydroxypropoxy)-propylsilyl-appended silica particles (VCD-HPS), a new type of substituted β-cyclodextrin-bonded chiral stationary phase (CSP) for liquid chromatography (LC), have been synthesized by treatment of bromoacetate-substituted-(3-(2-O-β-cyclodextrin)-2-hydroxypropoxy)-propylsilyl-appended silica particles (BACD-HPS) with vancomycin in anhydrous methanol. The stationary phase is characterized by elemental analysis. This new CSP has a chiral selector with two recognition sites: vancomycin and β-cyclodextrin (β-CD), which can provide multiple interactions with the solutes. The chromatographic performance of VCD-HPS was studied with several disubstituted benzenes and some chiral drug compounds as solutes in reversed-phase LC. The results show that VCD-HPS has excellent selectivity for the separation of aromatic positional isomers and enantiomers of chiral compounds.     

A convenient synthesis of a permethyl-substituted β-cyclodextrin-containing polysiloxane stationary phase using an amide linking group

A novel amide-linked permethyl-substituted β-cyclodextrin-bound polysiloxane stationary phase was prepared in only four steps. First, mono(6-O-toluenesulfonyl)-β-cyclodextrin was treated with sodium azide. Second, the resulting azide derivative was treated with methyl iodide and base followed by reduction with hydrogen to give amine-substituted permethylcyclodextrin 3 . Third, cyclodextrin 3 was treated with p-(allyloxy)benzoyl chloride to form 6^A-(p-allyloxybenzamido)-substituted permethyl-β-cyclodextrin 4 . Lastly, β-cyclodextrin 4 was hydrosilylated onto a polysiloxane backbone containing hydrogen, methyl, and p-tolyl substituents. This new phase separated the enantiomers of certain chiral lactones and alcohols in capillary supercritical fluid chromatography.     

Stereoisomeric flavor compounds,part LXI: Enantioselective analysis of aroma-relevant dihydrofuranones

The odor impression of the pure enantiomers of various chiral dihydrofuranones which are important flavor compounds has been evaluated by sniffing the well separated optical antipodes in the GC eluate from heptakis(2,3-di-O-methyl-6-TBDMS)-β-cyclodextrin as the chiral phase for capillary gas chromato-graphic separation. Liquid chromatographic separation has been achieved by the use of bonded β-cyclodextrin as the chiral stationary phase and methanol–water as eluent. Enantiomer separation in the latter was improved by addition of triethylammonium acetate to the eluent.     

Stereoisomeric flavor compounds. Part LXV: Preparative resolution of the enantiomers of chiral dihydrofuranones by recycling chromatography

Preparative resolution of the enantiomers of several chiral dihydrofuranones, known to be important flavor compounds, has been achieved by combining the use of bonded β-cyclo-dextrin as chiral stationary phase with closed-loop recycling chromatography. The purity of the separated enantiomers has been determined by chirospecific capillary GC analysis, using heptakis(2,3-di-O-methyl-6-TBDMS)-β-cyclodextrin as the chiral stationary phase.