Study of Chiral Ionic Liquid as Stationary Phases for GC

Due to the synthetic flexibility and special enantioselectivity, chiral ionic liquids (CILs) have heightened interest and an increasing number of CILs has been designed and utilized. In this work, CIL named l-1-butyl-3-(2-propionic-1-ether) imidazolium bromide ([BAlaIM]Br) derived from natural amino acids was synthesized, with chiral center at cation moiety. Chiral stationary phases for gas chromatography were then prepared by mixing the CIL with polymeric ionic liquid ([PSOMIM][NTf₂], homemade) at different ratios (4:1, 2:1, and 1:1). The column efficiency was measured to be about 3,200 plates m⁻¹ (8 m × 0.25 mm i.d.) when the content of [BAlaIM]Br was 50 % (mass percent) in the mixed stationary phase. All columns were coated via the static coating method using 0.30 % (w/v) of stationary phases dissolved in methanol. The results showed that the CIL contributed to the selectivity of stationary phase toward positional isomers dichlorobenzenes, methylnaphthalenes and pinenes, etc. Meanwhile, [BAlaIM]Br showed better selectivity for enantiomers such as carvones, citronellals, limonenes and camphors. The interactions between chiral selector and enantiomers were also discussed.

     

Direct Enantiomeric Separation of Chiral Pesticides by LC on Amylose Tris(3,5-dimethylphenylcarbamate) Stationary Phase under Reversed Phase Conditions

Amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phase was used by liquid chromatography under reversed-phase conditions for the chiral separation of 20 pesticides, of which ten samples were separated directly under suitable conditions. The influence of mobile phase composition and column temperature from 0 to 40 °C on the separation was investigated. The mobile phases were methanol/water or acetonitrile/water at a flow rate of 0.5 mL min^?1 with UV detection at 230 nm. The two enantiomers of fenamiphos, terallethrin, fenoxaprop-ethyl, benalaxyl and lactofen could obtain base separation under optimized conditions, while the enantiomers of quizalofop-ethyl, metalaxyl, napropamide, fluroxypyr-meptyl and 2,4-D-ethylhexyl got partial separation. The retention factors (k) and selectivity factor (α) for the enantiomers of most investigated pesticides decreased with increasing the temperature. The lnα–1/T plots for enantiomers of chiral pesticides were linear at the range of 0–40 °C except for that of metalaxyl, fenoxaprop-ethyl and 2,4-D-ethylhexyl enantiomers in methanol/water. The thermodynamic parameters calculated based on linear Van’t Hoff plots showed the chiral separation was controlled by enthalpy. Better separation was not always at low temperature. The chiral recognition mechanisms were discussed. The elution orders of the eluting enantiomers were determined by a circular dichroism detector.     

Use of chiral amino acid ester‐based ionic liquids as chiral selectors in CE

In this study, the applicability of a chiral ionic liquid (CIL) as the sole chiral selector in CE was investigated for the first time. In particular, five amino acid ester‐based CILs were synthesized and used as additives in the BGE in order to evaluate their chiral recognition ability. The performance of these CILs as the sole chiral selectors was evaluated by using 1,1′‐binaphthyl‐2,2‐diylhydrogenphosphate (BNP) as the analyte and by comparing the resolution values. Different parameters were examined, such as the alkyl group bulkiness and the configuration of the cation, the anion type of the CIL and its concentration, and the pH of the BGE, in order to optimize the separation of the enantiomers and to demonstrate the effect that each parameter has on the chiral‐recognition ability of the CIL. Baseline separation of BNP within 13 min was achieved by using a BGE of 100 mM Tris/10 mM sodium tetraboratedecahydrate (pH 8) and a chiral selector of 60 mM l ‐alanine tert butyl ester lactate. The run‐to‐run and batch‐to‐batch reproducibilities were also evaluated by computing the %RSD values of the EOF and the two enantiomer peaks. In both cases, very good reproducibilities were observed, since all %RSD values were below 1%.     

Separation mechanism of chiral compounds in chiral stationary phase liquid chromatography

In this paper, the concept of reversed- or normal-phase chiral stationary phase liquid chromatography has been put forward according to the polar strength of mobile and stationary phases. The statistical model developed in HPLC has been used to investigate the separation mechanism of D- and L-enantiomer in chiral stationary phase liquid chromatography. It has been observed that the variation of capacity factor of enantiomers with mobile phase composition in both reversed-phase and normal-phase chiral stationary phase liquid chromatography can be described by the fundamental elution equation lnk' = a + blnC_b + _cC_b. The effect of mobile phase composition on the selectivity of enantiomers D and L in normal-phase chiral stationary phase liquid chromatography can be described by the equation lnα = Δa + ΔblnC_b, but in reversed-phase chiral stationary phase liquid chromatography the selectivity is almost independant of the mobile phase composition.     

Chiral separation of amino acids using a chiral crown ether by impregnation on a polymeric support and monoamine modified silica gel

A chiral monoaza-15-crown-5 ether derivative was prepared from l-Leucinol and used as a chiral stationary phase. The new chiral stationary phases CSP-1 and CSP-2 were employed in separating the enantiomers of the sodium and potassium salts of amino acids. The sodium and potassium salt of the d-enantiomers of all amino acids (PhyAlaNa, PhyAlaK and PhyGlyNa, PhyGlyK, and TrpNa, TrpK) show higher selectivity than the l-enantiomers for both CSP-1 and CSP-2.     

Chiral separation of nipecotic acid amides.

1-Decyl-3-(N,N-diethylcarbamoyl)piperidine (1) and alpha,alpha'-bis[3-(N-benzyl-N-methylcarbamoyl)piperidinol]-p-xyle ne (2) represent mono-N-substituted and bis-N-substituted carbamoylpiperidines, or nipecotic acid amides, respectively. Initially, several attempts were made to resolve these compounds using beta-cyclodextrin, cellulose carbamate and Pirkle-type columns. However, the interactions of the stereoisomers of the two compounds with these stationary phases did not differ enough to permit satisfactory separations. Baseline resolution was achieved using an alpha 1-acid glycoprotein (AGP) chiral column. The mobile phase was phosphate buffer (pH 7.0). Tetrabutylammonium (TBA) was used as the cationic modifier and ethanol as the uncharged modifier. Circular dichroism was used to identify the enantiomers. Compound 1 was resolved into positive and negative enantiomers and 2 into positive and negative enantiomers and a meso diastereomer. The influence of pH, buffer ionic strength, cationic and uncharged modifier concentrations on retention, chiral selectivity and resolution were evaluated. Based on the results, it is suggested that both ionic and hydrophobic interactions may be responsible for retention and resolution.     

Cellulose Derivatives Used as Chiral Stationary Phases in Capillary Gas Chromatography

Abstract

In this work, we present the first separation of enantiomers in gas chromatography (GC) using a fused‐silica capillary column containing cellulose triacetate, cellulose triphenylcarbamate, or cellulose tris(3,5‐dimethylphenylcarbamate) as the new chiral stationary phase. The separated solutes included alcohols, amine, ketone, ether, ester, and amino acid. Their column efficiency, polarity, and chiral selectivity were studied. The retention mechanism was discussed. The results showed that those derivatives had relatively high chiral recognition abilities and can be used as the chiral stationary phases in GC.     

手性离子液体和纤维素三(3,5-二甲基苯基氨基甲酸酯)混合气相色谱手性固定相研究

合成了手性离子液体[C7H17NO] [(CF3SO2)2]-和纤维素三(3,5-二甲基苯基氨基甲酸酯),将其混合作为气相色谱固定相。研究结果表明:该混合固定相麦氏常数的平均极性值为760;在容量因子大于2的前提下,新型柱的塔板数可达1680块/m;其对手性化合物、特别是对氨基酸类具有良好的分离效果。有10对氨基酸的分离因子大于1.10,展示了该类色谱柱良好的手性应用前景。     

Editorial

Abstract

Asymmetric syntheses of optically active polymethacrylate, polyacrylate, polyacrylamide, and polyisocyanate with helical conformation and their chiral recognition abilities are described. 1-Phenyldibenzosuberyl methacrylate (PDBSMA) gave a purely onehanded-helical, optically active polymer ([α]₃₆₅ +1670 ～ +1780º) with almost perfectly isotactic structure by anionic polymerization using optically active initiators. Radical polymerizations of PDBSMA using chiral initiators, chain transfer agents, and additives also afforded optically active polymers with a prevailing onehanded helicity. Triphenylmethyl acrylate yielded an optically active, helical polymer ([α]₃₆₅ +102º) having a dyad isotacticity of 70% using an optically active anionic initiator. Although the polyacrylate demonstrated chiral recognition ability as a chiral stationary phase for HPLC, the ability was low mainly because of the low degree of one-handedness. N-(3-Chlorophenyl)-N-phenylacrylamide gave an optically active, helical polymer ([α]_365–343º) in the asymmetric anionic polymerization; the polymer had a dyad tacticity of 77%. Optically active polyisocyanates with a predominantly one-handed helical conformation were prepared in homo-and co-polymerization of optically active phenyl isocyanate derivative. These polyisocyanates showed the ability to discriminate enantiomers in solution.     

Evaluation of novel dendrimer chiral stationary phases using HPLC

Summary The reversed phase chromatographic properties of the [G1]-L-glutamic and ethyl ester-AC-silica (1), [G2]-L-glutamic acid ethyl ester-AC-silica (2) and the [G1]-L-glutamic acidt-butyl ester-AC-silica (3) dendrimer stationary phases were evaluated. Initial studies involved the comparison between these phases with a classic reversed phase (i.e. ODS1) by the separation of a standard reversed phase test mixture composed of dimethylphthalate, nitrobenzene, anisole, diphenylamine and fluorene. Separations were achieved with comparable performance to those obtained with the conventional reversed phase (ODS1). However, it was apparent that the chromatographic selectivity exhibited by the dendrimer stationary phases was different from that of the ODS1 phase. On a per mole basis, the dendrimers exhibited similar (and sometimes greater) affinity for these analytes compared with the ODS1 ligand. Subsequent chromatographic experiments were conducted upon the dendrimer chiral stationary phases using chiral analytes under reversed phase and normal phase conditions. Chiral resolution was not observed.     

Natural terpene derivatives as new structural task‐specific ionic liquids to enhance the enantiorecognition of acidic enantiomers on teicoplanin‐based stationary phase by high‐performance liquid chromatography

We present the specific cooperative effect of a semisynthetic glycopeptide antibiotic teicoplanin and chiral ionic liquids containing the (1R ,2S ,5R )‐(–)‐menthol moiety on the chiral recognition of enantiomers of mandelic acid, vanilmandelic acid, and phenyllactic acid. Experiments were performed chromatographically on an Astec Chirobiotic T chiral stationary phase applying the mobile phase with the addition of the chiral ionic liquids. The stereoselective binding of enantiomers to teicoplanin in presence of new chiral ionic liquids were evaluated applying thermodynamic measurements and the docking simulations. Both the experimental and theoretical methods revealed that the chiral recognition of enantiomers in the presence of new chiral ionic liquids was enthalpy driven. The changes of the teicoplanin conformation occurring upon binding of the chiral ionic liquids are responsible for the differences in the standard changes in Gibbs energy (ΔG ⁰) values obtained for complexes formed by the R and S enantiomers and teicoplanin. Docking simulations revealed the steric adjustment between the chiral ionic liquids cyclohexane ring (chair conformation) and the β‐d ‐glucosamine ring of teicoplanin and additionally hydrophobic interactions between the decanoic aliphatic chain of teicoplanin and the alkyl group of the tested salts. The obtained terpene derivatives can be considered as “structural task‐specific ionic liquids” responsible for enhancing the chiral resolution in synergistic systems with two chiral selectors.     

1-Hexadecyl-3-methylimidazolium Ionic Liquid as a New Cationic Surfactant for Separation of Phenolic Compounds by MEKC

The ionic liquid 1-hexadecyl-3-methylimidazolium bromide ([C₁₆MIm]Br) has been used as a novel cationic surfactant for separation of phenolic compounds, including quinol, phloroglucinol, resorcinol, phenol, p-cresol, and m-nitrophenol, by micellar electrokinetic capillary chromatography (MEKC). The effects of buffer concentration and pH, concentration of [C₁₆MIm]Br, and applied potential were studied. Use of the optimized buffer (25 mmol L^?1 NaH₂PO₄), 10 mmol L^?1 [C₁₆MIm]Br, and an applied potential of ?15 kV enables optimum separation with regard to resolution and migration time. The phenolic compounds were detected at 214 nm. The micelle of this long-alkyl-chain imidazolium ionic liquid acts as a pseudo-stationary phase in this MEKC separation.     

Enantioseparation of mandelic acid enantiomers in ionic liquid aqueous two-phase extraction systems

In the past decade, ionic liquids have received great attention owing to their potential as green solvent alternatives to conventional organic solvents. In this work, hydrophobic achiral ionic liquids (1-butyl-3-methylimidazolium-hexafluorophosphate([bmim][PF₆]), 1-octyl-3-methylimidazolium tetrafluoroborate([omim][BF₄])) were used as solvents in chiral liquid-liquid extraction separation of mandelic acid (MA) enantiomers with β-cyclodextrin (β-CD) derivatives as hydrophilic chiral selectors preferentially forming complexes with (R)-enantiomers. Factors affecting the separation efficiency were optimised, namely the type of the extraction solvents and β-CD derivatives, concentrations of the β-CD derivatives and MA enantiomers, pH, and temperature. Excellent enantioseparation of MA enantiomers was achieved in the ionic liquid aqueous two-phase extraction systems under the optimal conditions of pH 2.5 and temperature of 5°C with the maximum enantioselectivity (α) of 1.74. The experimental results demonstrated that the ionic liquid aqueous two-phase extraction systems with a β-CD derivative as the chiral selector have a strong chiral recognition ability, which might extend the application of ionic liquids in chiral separation.     

Design and synthesis of C-2 substituted chiral imidazolium ionic liquids from amino acid derivatives

[reaction: see text] A series of novel chiral ionic liquids (CILs) has been synthesized and fully characterized. The reaction of 1-methyl-2-imidazolecarboxaldehyde and chiral amino alcohols followed by reduction is key to the design of these new CILs. This is the first time that CILs have been synthesized by introducing chiral scaffolds on the C-2 position of the imidazolium cation of ILs. The simple and straightforward procedure resulted in CILs as colorless oils at room temperature in good yields.     

Cholesteric gratings induced by electric field in mixtures of liquid crystal and novel chiral ionic liquid

Formation of gratings upon alternating electric field in compositions of highly birefringent liquid crystal (LC) with novel chiral ionic liquid (CIL) enclosed in 10-µm-thick cells is studied. The compatibility of two organic components of the mixture is investigated. The grating is formed in 1–5% CIL mixtures and causes significant changes of the transmission of polarised light through the cells. Transmission of polarised λ = 633 nm light through the 5% CIL sample is studied with respect to frequency (1 Hz–3 MHz) and amplitude (up to 10 V) of alternating voltage and the results are used for sketch a voltage–frequency phase diagram. Two possible ways of formation of the gratings with perpendicular orientation to that formed from initial state are presented. Two twisting axes in the molecular alignments of the cholesteric LC gratings with perpendicular directions are proposed. Optical switch based on four different states of LC including two gratings with perpendicular directions is proposed. Moreover, behaviour of the rotation of a grating induced by AC field in hybrid planar-homeotropic cell is studied in two frequency regimes and rotation by more than 90° upon change of the AC field amplitude is observed.     

Simultaneous Chiral Separation of Geometry Isomers and Enantiomers of Nateglinide by Capillary Electrophoresis with Mixture of CD Derivations as Chiral Selector

Abstract

A capillary electrophoresis (CE) method for the simultaneous separation of geometry isomers and enantiomers of nateglinide was built. Several different dyclodextrin (CD) derivatives were tested for the chiral separation of nateglinide, and it was proved that ionic CDs [i.e., carboxymethy-β-CD (CM-β-CD) and sulphonic-β-CD (S-β-CD)] could show better chiral selectivity for both geometry isomers and enantiomers than the neutral CDs. The separation of geometry of both isomers and enantiomers of nateglinide was obtained by CE in a 75-µm i.d. × 60 cm (effective length 45 cm) fused-silica capillary at 11 kV voltage, while 30 mM phosphate (pH = 8.38) acted as running buffer and a mixture of 40 mM S-β-CD + 21 mM CM-β-CD served as chiral selector. The detective wavelength was set at 254 nm.     

Comparison of Separation Efficiency of Macrocyclic Glycopeptide-Based Chiral Stationary Phases for the LC Enantioseparation of β-Amino Acids

Direct reversed-phase high-performance liquid chromatographic methods were developed for the separation of enantiomers of eighteen unnatural β-amino acids, including several β-3-homo-amino acids. The direct separations of the underivatized analytes were performed on chiral stationary phases containing macrocyclic glycopeptide antibiotics such as teicoplanin (Chirobiotic T and T2), teicoplanin aglycone (Chirobiotic TAG), vancomycin (Chirobiotic V and V2), and ristocetin A (Chirobiotic R) as chiral selectors. The effects of the organic modifier, mobile phase composition and pH on the separations were investigated. A comparison of the separation performances of the macrocyclic glycopeptide stationary phases revealed that the Chirobiotic T2 column exhibited better selectivity than the Chirobiotic T column for the separation of β-3-homo-amino acid enantiomers; vancomycin or ristocetin A exhibited lower selectivity. The elution sequence was determined in some cases: the S enantiomers eluted before the R enantiomers, with the exception of the Chirobiotic R column, where the elution sequence R < S was observed.     

Preparation and characterization of phenyl carbamate derivative β-cyclodextrin bonded phase for chiral HPLC

A partially substituted β-cyclodextrin chiral stationary phase was prepared by the reaction of phenyl isocyanate. The enantiomers of a series of O,O-diethyl(p-methylbenzenesulfonamido)-aryl(or alkyl)-methylphosphonates were studied on the prepared phenyl carbamate derivative β-cyclodextrin bonded phase and a commercial (S)-(+)-1–(1-naphthyl) ethylcarbamate derivative β-cyclodextrin bonded phase on normal phase chromatographic condition. Results show that the prepared phenyl carbamate derivative β-cyclodextrin bonded phase has better enantiomeric selectivity to the series of compounds. A chiral recognition mechanism was suggested for the separation of these novel organic phosphorus enantiomers.     

A 3-D open-framework material with intrinsic chiral topology used as a stationary phase in gas chromatography

Compared with liquid chromatography and capillary electrophoresis, the diversity of gas chromatography chiral stationary phases is rather limited. Here, we report the fabrication of Co(d-Cam)_1/2(bdc)_1/2(tmdpy) (d-Cam?=?d-camphoric acid; bdc?=?1,4-benzenedicarboxylate; tmdpy?=?4,4′-trimethylenedipyridine)-coated open tubular columns for high-resolution gas chromatographic separation of compounds. The Co(d-Cam)_1/2(bdc)_1/2(tmdpy) compound possesses a 3-D framework containing enantiopure building blocks embedded in intrinsically chiral topological nets. In this study, two fused-silica open tubular columns with different inner diameters and lengths, including column A (30 m?×?530 μm i.d.) and column B (2 m?×?75 μm i.d.), were prepared by a dynamic coating method using Co-(d-Cam)_1/2(bdc)_1/2(tmdpy) as the stationary phase. The chromatographic properties of the two columns were investigated using n-dodecane as the test compound at 120 °C. The number of theoretical plates (plates/m) of the two metal–organic framework columns was 1,450 and 3,100, respectively. The separation properties were evaluated using racemates, isomers, alkanes, alcohols, and Grob's test mixture. The limit of detection and limit of quantification were found to be 0.125 and 0.417 ng for citronellal enantiomers, respectively. Repeatability (n?=?6) showed lower than 0.25 % relative standard deviation (RSD) for retention times and lower than 2.2 % RSD for corrected peak areas. The experimental results showed that the stationary phase has excellent selectivity and also possesses good recognition ability toward these organic compounds, especially chiral compounds.

A Validated LC Method for Determination of the Enantiomeric Purity of Montelukast Sodium in Bulk Drug Samples and Pharmaceutical Dosage Forms

A new and accurate chiral liquid chromatographic method has been developed for determination of the enantiomeric purity of montelukast sodium (R enantiomer) in bulk drugs and dosage forms. Normal phase chromatographic separation was performed on an immobilized amylose-based chiral stationary phase with n-hexane–ethanol–1,4-dioxane–trifluoroacetic acid–diethylamine 65:25:10:0.3:0.05 (v/v) as mobile phase at a flow rate of 1.0 mL min^?1. The elution time was approximately 15 min. The resolution (R _S) between the enantiomers was >3. The mobile phase additives trifluoroacetic acid and diethylamine played a key role in achieving chromatographic resolution between the enantiomers and also in enhancing chromatographic efficiency. Limits of detection and quantification for the S enantiomer were 0.07 and 0.2 μg, respectively, for a test concentration of montelukast sodium of 1,000 μg mL^?1 and 10 μL injection volume. The linearity of the method for the S enantiomer was excellent (R ² > 0.999) over the range from the LOQ to 0.3%. Recovery of the S enantiomer from bulk drug samples and dosage forms ranged from 97.0 to 103.0%, indicative of the high accuracy of the method. Robustness studies were also conducted. The sample solution stability of montelukast sodium was determined and the compound was found to be stable for a study period of 48 h.