Chiral separation of α-cyclohexylmandelic acid enantiomers using ionic liquid/salt aqueous two-phase system

In this paper, an ionic liquid-based aqueous two-phase system (ILATPS) was applied to the chiral separation of α-cyclohexylmandelic acid (α-CHMA) enantiomers with hydroxypropyl-β-cyclodextrin (HP-β-CD) as the chiral selector. Several influencing parameters were investigated including the types and concentration of ionic liquids, the amount of phase-forming salt, temperature, mixing time, pH, and the content of HP-β-CD. The results showed that not all ILATPS had the ability to chirally recognise the selected enantiomers and that [C₄mim]BF₄/(NH₄)₂SO₄-based ATPS possessed the best enantioseparation ability of the investigated ILATPSs. Under optimal conditions, the separation factor (α) attained 1.59 in a single-step extraction. ILATPS is much “greener” than other liquid-liquid extraction systems, showing its potential for application to the chiral separation.     

Biphasic recognition chiral extraction — novel way of separating pantoprazole enantiomers

This paper presents a biphasic recognition chiral extraction system developed as a new chiral separation technology for the separation of pantoprazole enantiomers, combining a hydrophilic β-CD derivative in the aqueous phase and a hydrophobic tartaric acid in the organic phase which preferentially recognise the (R)-enantiomer and (S)-enantiomer, respectively. In this study, a number of factors which influence the efficiency of the extraction were investigated including types of organic solvents, β-CD and tartaric acid esters and their concentrations, pH and temperature. As a result, enantioselectivity for pantoprazole enantiomers can be improved up to 1.42 under optimised conditions; in addition, it is clear that the combined action of β-CD and tartaric acid esters leads to formation of the biphasic chiral extraction system with a stronger separation capacity than a monophasic chiral extraction system.     

Enantioselective resolution of chiral aromatic acids by biphasic recognition chiral extraction

This paper reports a new chiral separation technology—biphasic recognition chiral extraction for the separation of aromatic acid enantiomers such as α-cyclohexyl-mandelic acid (CHMA) and naproxen (NAP). The biphasic recognition chiral extraction system was established by adding hydrophobic d(l)-isobutyl tartrate in 1,2-dichloroethane organic phase and hydrophilic β-cyclodextrin (β-CD) derivative in aqueous phase, which preferentially recognize the (R)-enantiomer and (S)-enantiomer, respectively. These studies involve an enantioselective extraction in a biphasic system, where aromatic acid enantiomers form complexes with the β-cyclodextrin derivative in the aqueous phase and d(l)-isobutyl tartrate in the organic phase, respectively. Factors affecting the extraction mechanism are analyzed, namely the influence of the concentrations of the extractants and aromatic acid enantiomers, the types of the extractants, pH, and temperature. The experimental results show that the biphasic recognition chiral extraction is of much stronger chiral separation ability than the monophasic recognition chiral extraction, which utilizes the cooperations of the forces of the tartrate and the β-CD derivative. Hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxyethyl-β-cyclodextrin (HE-β-CD), and methyl-β-cyclodextrin (ME-β-CD) have stronger recognition abilities for the (S)-aromatic acid enantiomers than those for (R)-aromatic acid enantiomers, among which HP-β-CD has the strongest ability. d-Isobutyl tartrate preferentially recognizes (R)-CHMA and (S)-NAP, while l-isobutyl tartrate preferentially recognizes (S)-CHMA and (R)-NAP. The maximum enantioselectivities of CHMA and NAP are 2.49 and 1.65, under conditions at which the pH values of the aqueous phases are 2.7 and 2.5, at the ratio of 2:1 of [isobutyl tartrate] to [HP-β-CD].     

Enantioselective Extraction System Containing Binary Chiral Selectors and Chromatographic Enantioseparation Method for Determination of the Absolute Configuration of Enantiomers of Cyclopentolate

The distribution coefficients and enantioseparation of cyclopentolate were studied in an extraction system containing d-tartaric acid ditertbutyl ester in organic phase and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous phase. Various parameters involved in the enantioseparation such as the type and the concentration of chiral selectors, pH value and a wide range of organic solvents were investigated. The maximum enantioselectivity (α = 2.13) and optimum distribution coefficients (K _R = 0.85, K _S = 0.40) were obtained under the following conditions: 0.10 mol/L HP-β-CD in aqueous phase and 0.20 mol/L d-tartaric acid ditertbutyl ester in decanol as organic phase. Cyclopentolate is present as a racemic mixture to the aqueous phase. The potentially different biological activities of cyclopentolate enantiomers have not been examined yet. Two chiral liquid chromatography methods have been developed for the direct separation of the enantiomers of cyclopentolate. First method was used for the quantification analysis of cyclopentolate enantiomers in aqueous phase. Second method used two chiroptical detectors: electronic circular dichroism (ECD) and optical rotation (OR) for the identification of individual cyclopentolate enantiomers from the organic phase enriched with (R)-enantiomer. The absolute stereochemistry was determined by means of the comparison of the experimental and computed ECD spectra and signs of OR. The ECD spectra of chiral analytes were measured on-line using HPLC-ECD technique.     

Room temperature ionic liquid as a novel medium for liquid/liquid extraction of metal ions

Room temperature ionic liquids (RTILs) have been used as novel solvents to replace traditional volatile organic solvents in organic synthesis, solvent extraction, and electrochemistry. The hydrophobic character and water immiscibility of certain ionic liquids allow their use in solvent extraction of hydrophobic compounds. In this work, a typical room temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate [C₄mim][PF₆], was used as an alternative solvent to study liquid/liquid extraction of heavy metal ions. Dithizone was employed as a metal chelator to form neutral metal-dithizone complexes with heavy metal ions to extract metal ions from aqueous solution into [C₄mim][PF₆]. This extraction is possible due to the high distribution ratios of the metal complexes between [C₄mim][PF₆] and aqueous phase. Since the distribution ratios of metal dithiozonates between [C₄mim][PF₆] and aqueous phase are strongly pH dependent, the extraction efficiencies of metal complexes can be manipulated by tailoring the pH value of the extraction system. Hence, the extraction, separation, and preconcentraction of heavy metal ions with the biphasic system of [C₄mim][PF₆] and aqueous phase can be achieved by controlling the pH value of the extraction system. Preliminary results indicate that the use of [C₄mim][PF₆] as an alternate solvent to replace traditional organic solvents in liquid/liquid extraction of heavy metal ions is very promising.     

Enantioseparation of mandelic acid and α-cyclohexylmandelic acid using an alcohol/salt-based aqueous two-phase system

An alcohol/salt-based aqueous two-phase system (ATPS) was employed for enantioseparation of (R,S)-mandelic acid (MA) and (R,S)-α-cyclohexylmandelic acid (α-CHMA). Sulfonated β-cyclodextrin (Sf-β-CD) with different degrees of substitution (DS) was considered as the chiral selector. The ethanol/(NH₄)₂SO₄ system showed the optimal chiral recognition ability for MA. To optimize the experimental conditions, Sf-β-CD concentration, ethanol and salt concentration, temperature, and pH were studied. The recognition ability of enantiomers was mainly dependent on the type of the chiral selector but the ethanol and (NH₄)₂SO₄ concentrations also had significant influence on the enantiomeric recognition. The maximum values of α and ee ^up of 1.69 and 16.3 % were obtained, respectively, for MA under the optimal conditions. A potential application of this alcohol/salt ATPS is the scale-up of chiral separation of MA.     

Equilibrium studies on reactive extraction of naproxen enantiomers using hydrophilic ��-cyclodetrin derivatives extractants

A simple and low-cost method using liquid?Cliquid extraction coupled with complexation reactive technique has been developed for enantioselective separation of naproxen enantiomers. Three kinds of modified ??-cyclodextrins including methyl-??-cyclodextrin (Me-??-CD), hydroxyethyl-??-cyclodextrin (HE-??-CD) and hydroxypropyl-??-cyclodextrin (HP-??-CD), were selected as hydrophilic chiral selectors for extraction naproxen from organic phase to aqueous phase. A systematic study of the factors affecting chiral separation performance were investigated. The experiment results obtained show that, HP-??-CD, HE-??-CD and Me-??-CD has stronger recognition abilities for S-naproxen than those for R-naproxen. Among the ??-CD derivatives studied, HP-??-CD has the strongest ability for chiral recognition and separation. Excellent enantioselectivity (a) of 1.59 is obtained under the optimal conditions of pH of 2.5 and temperature of 5 °C.     

Resolution of α-cyclohexyl-mandelic acid enantiomers by two-phase (O/W) recognition chiral extraction

This paper presents a new chiral separation technology: two-phase (O/W) recognition chiral extraction. Distribution behavior of α-cyclohexyl-mandelic acid enantiomers was studied in the extraction system with D(L)-isobutyl tartrate in 1,2-dichloroethane organic phase and β-CD derivatives in aqueous phase, and the influence of the kind and concentration of extractant and pH on extraction performance was investigated. The experimental results indicate that two-phase (O/W) recognition chiral extraction is of strong chiral separation ability. HP-β-CD, HE-β-CD and Me-β-CD have higher recognition ability for S-CHMA than that for R-CHMA, among which HP-β-CD has the strongest ability; whereas, D-isobutyl tartrate has reversed recognition ability for them. In the extraction system containing HP-β-CD and D-isobutyl tartrate, e.e.% of S-CHMA in aqueous phase reached 27.6% by one stage extraction, and the distribution ratio for R-CHMA(k _R ) and for S-CHMA(k _s ) and separation factor (α) are 2.44, 0.89 and 2.49, respectively. Meanwhile, pH and concentration of extractant have great effects on chiral separation ability. Two-phase (O/W) recognition chiral extraction has great significance for preparative separation of racemic compounds.     

Enantioselective Extraction System Containing Binary Chiral Selectors and Chromatographic Enantioseparation Method for Determination of the Absolute Configuration of Enantiomers of Cyclopentolate

The distribution coefficients and enantioseparation of cyclopentolate were studied in an extraction system containing d-tartaric acid ditertbutyl ester in organic phase and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous phase. Various parameters involved in the enantioseparation such as the type and the concentration of chiral selectors, pH value and a wide range of organic solvents were investigated. The maximum enantioselectivity (α = 2.13) and optimum distribution coefficients (K _R = 0.85, K _S = 0.40) were obtained under the following conditions: 0.10 mol/L HP-β-CD in aqueous phase and 0.20 mol/L d-tartaric acid ditertbutyl ester in decanol as organic phase. Cyclopentolate is present as a racemic mixture to the aqueous phase. The potentially different biological activities of cyclopentolate enantiomers have not been examined yet. Two chiral liquid chromatography methods have been developed for the direct separation of the enantiomers of cyclopentolate. First method was used for the quantification analysis of cyclopentolate enantiomers in aqueous phase. Second method used two chiroptical detectors: electronic circular dichroism (ECD) and optical rotation (OR) for the identification of individual cyclopentolate enantiomers from the organic phase enriched with (R)-enantiomer. The absolute stereochemistry was determined by means of the comparison of the experimental and computed ECD spectra and signs of OR. The ECD spectra of chiral analytes were measured on-line using HPLC-ECD technique.

     

Effect of anionic structure on the phase formation and hydrophobicity of amino acid ionic liquids aqueous two-phase systems

Compared with the conventional ionic liquids, amino acid ionic liquids are more biodegradable and biocompatible, and can enhance stability of biomaterials. In this work, amino acid ionic liquids 1-butyl-3-methylimidazolium L-serine ([C(4)mim][Ser]), 1-butyl-3-methylimidazolium glycine ([C(4)mim][Gly]), 1-butyl-3-methylimidazolium L-alanine ([C(4)mim][Ala]) and 1-butyl-3-methylimidazolium L-leucine ([C(4)mim][Leu]) have been synthesized. These ionic liquids are found to form aqueous two-phase systems (ATPSs) by the salted-out of K(3)PO(4) in aqueous solutions. Phase diagram of the ATPSs and the Gibbs energies of transfer of methylene group from the bottom salt-rich phase to the top ionic liquid-rich phase have been determined at 298.15K and pH 14, and the effect of anionic structure of the ionic liquids on phase formation of the ATPSs and the relative hydrophobicity between the top and the bottom phases are then examined. In order to understand the effect of relative hydrophobicity of the phases in equilibrium in the ATPSs on the extraction/separation capability of biomolecules, the partition coefficients of cytochrome-c (as a model biomolecule) in the ATPSs are measured by spectrophotometry. It is suggested that hydrophobic interactions are mainly responsible for the higher partition coefficients of cytochrome-c in aqueous two-phase systems at pH 14, and the extraction and separation capacity of biomolecules can be improved by the modulation of the relative hydrophobicity of the phases and/or the pH of the system.     

Studies on Liquid/liquid Extraction of Copper Ion with Room Temperature Ionic Liquid

Room temperature ionic liquids are regarded as “Green solvents” for their nonvolatile and thermally stable properties. They are employed to replace traditional volatile organic solvents in organic synthesis, solvent extraction, and electrochemistry. In this work, a water immiscible room temperature ionic liquid, 1‐butyl‐3‐methylimidazolium hexafluorophosphate [C₄mim][PF₆], was used as an alternative solvent for liquid/liquid extraction of copper ions. Metal chelators, including dithizone, 8‐hydroxyquinoline, and 1‐(2‐pyridylazo)‐2‐naphthol, were employed to form neutral metal‐chelate complexes with copper ions so that copper ions were extracted from aqueous solution into [C₄mim][PF₆]. The parameters that affect the extraction of copper ions with this biphasic system were investigated. The extraction behavior in this novel biphasic system is shown to be consistent with that of traditional solvents. For example, the extraction with this biphasic system is strongly pH dependent. So, the extraction efficiency of coppers ion from an aqueous phase can be manipulated by tailoring the pH value of the extraction system. Hence, the extraction, separation and preconcentraction of copper ions can be accomplished by controlling the pH value of the extraction system. It appears that the use of ionic liquid as an alternate solvent system in liquid/liquid extraction of copper ions is very promising.     

Synthesis and application of a chiral ionic liquid functionalized β‐cyclodextrin as a chiral selector in capillary electrophoresis

A novel chiral ionic liquid functionalized β‐cyclodextrin, 6‐O‐2‐hydroxpropyltrimethylammonium‐β‐cyclodextrin tetrafluoroborate ([HPTMA‐β‐CD][BF₄]), was synthesized and used as a chiral selector in capillary electrophoresis. [HPTMA‐β‐CD][BF₄] not only increased the solubility in aqueous buffer in comparison with the parent compound, but also provided a stable reversal electroosmotic flow, and the enantioseparation of eight chiral drugs was examined in phosphate buffer containing [HPTMA‐β‐CD][BF₄] as the chiral selector. The effects of the [HPTMA‐β‐CD][BF₄] concentration and the background electrolyte pH were studied. Moreover, the chiral separation abilities of β‐CD and [HPTMA‐β‐CD][BF₄] were compared and possible mechanisms for the chiral recognition of [HPTMA‐β‐CD][BF₄] are discussed. Copyright © 2013 John Wiley & Sons, Ltd.     

Enantioselective extraction of terbutaline enantiomers with <Emphasis Type="Italic">β</Emphasis>-cyclodextrin derivatives as hydrophilic selectors

Hydrophilic β-cyclodextrin (β-CD) and its derivatives are not soluble in organic liquids but they are highly soluble in water and can interact with enantiomers selectively to form diastereomeric complexes which enable their use as chiral selectors in chiral solvent extraction. In this paper, terbutaline enantiomers were extracted by hydrophilic β-CD derivatives in an aqueous/organic biphasic solvent system with racemic terbutaline in the organic phase and β-CD in the aqueous phase. Five β-CD derivatives, namely: methyl-β-cyclodextrin (Me-β-CD), hydroxyethyl-β-cyclodextrin (HE-β-CD), 2-hydroxyethyl-β-cyclodextrin (2-HE-β-CD), (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and (4-sulfobutylether)-β-cyclodextrin (SBE-β-CD) were used as hydrophilic selectors, respectively. Process variables affecting extraction efficiency were investigated, namely influence of the type of organic solvents and β-CD derivatives, concentrations of selectors and terbutaline enantiomers, pH, and temperature. Experimental results show that the efficiency of extraction depends, often strongly, on process variables. All five β-CD derivatives studied preferentially extract the more biologically active (R)-terbutaline from the organic phase; HP-β-CD has the strongest recognition ability. The maximum enantioselectivity (α) of 1.42 was achieved under optimal conditions: pH 7.0 and temperature of 5°C. Utilization of the extraction method for separation of terbutaline enantiomers is expected to be cheap and easy to scale up to commercial scale.     

Homogeneous ionic liquid microextraction of the active constituents from fruits of Schisandra chinensis and Schisandra sphenanthera

Homogeneous ionic liquid microextraction (HILME) was developed for the extraction of schizandrin, schisantherin A and deoxyschizandrin from Schisandra chinensis and Schisandra sphenanthera. 1-Butyl-3-methylimidazolium tetrafluoroborate ([C₄MIM][BF₄]) aqueous solution was used as extraction solvent, and ammonium hexafluorophosphate ([NH₄][PF₆]) was used as ion-pairing agent. 1-Butyl-3-methylimidazolium hexafluorophosphate ([C₄MIM][PF₆]), which is barely soluble in water, was formed in situ, and was used as sample solution. High-performance liquid chromatography (HPLC) was employed for separation and determination of the analytes. The calibration curve showed good linear relationship (r > 0.9998). The recoveries were between 69.71% and 88.33% with RSDs lower than 4.86%. External standard method was adopted in the proposed method, and internal standard method was applied for the evaluation of the proposed method. The two methods were compared and the results indicated that the proposed method was acceptable and simple. The HILME is free of volatile organic solvents, and represents lower expenditures of sample, extraction time and solvent, compared with ultrasonic and Soxhlet extraction. There was no obvious difference in the extraction yields of active constitutions obtained by the three extraction methods.     

Kinetic study on reactive extraction for chiral separation of phenylsuccinic acid enantiomers

The kinetics of the extraction of phenylsuccinic acid (PSA) enantiomers by hydroxypropyl-β-cyclodextrin (HP-β-CD) in a modified Lewis cell was studied, in which HP-β-CD dissolved in 0.1 mol L^?1 NaH₂PO₄/H₃PO₄ buffer solution (pH = 2.5) was selected as the chiral extractant. PSA enantiomers were extracted from organic phase to aqueous phase in the extraction module. The theory of extraction accompanied by a chemical reaction has been used to obtain the intrinsic kinetics of this extraction module. The different parameters affecting the extraction rate such as agitation speed, interfacial area, initial concentration of PSA enantiomers in organic phase as well as HP-β-CD concentration in aqueous phase were separately studied. The experimental results demonstrate that the extraction reactions are fast. The reactions were found to be first order with respect to PSA and second order with respect to HP-β-CD with forward rate constants of 3.4 × 10^?2 m⁶ mol^?2 s^?1 for R-PSA and 9.96 × 10^?3 m⁶ mol^?2 s^?1 for S-PSA. These data will be useful in the design of extraction processes.     

Separation of benzene and hexane by solvent extraction with 1-alkyl-3-methylimidazolium bis{(trifluoromethyl)sulfonyl}amide ionic liquids: effect of the alkyl-substituent length

The influence of the alkyl-substituent chain in 1-alkyl-3-methylimidazolium bis{(trifluoromethyl)sulfonyl}amide ionic liquids ([C(n)mim][NTf(2)], where n is the length of a linear alkyl chain) as solvents for the separation of benzene and hexane by liquid extraction was investigated. The liquid-liquid equilibrium (LLE) at 25 degrees C for the ternary systems ([C(n)mim][NTf(2)] + hexane + benzene), with n taking the values 4, 8, 10, and 12, were determined. These data were analyzed and compared to those previously reported for the system ([C(2)mim][NTf(2)] + hexane + benzene). The results show that short alkyl chains on the imidazolium cation of the ionic liquid lead to a better extractive separation of benzene and hexane, and reveal the influence of the relative degree of ordering in the ionic liquids on the extraction parameters.     

(Liquid + liquid) equilibria for (acetate-based ionic liquids + inorganic salts) aqueous two-phase systems

In the present work, (liquid + liquid) equilibrium data have been determined experimentally for aqueous two-phase systems formed by the imidazolium ionic liquids of [C_nmim][CH₃COO] (n = 4, 6, 8) and inorganic salts of K₃PO₄, K₂HPO₄, and K₂CO₃ at T = 298.15 K. Combined with available data in the literature, the effect of alkyl chain length of cations, type of anions of the ionic liquids, and nature of the inorganic salts were examined on the binodal curves of the systems. Then the binodal curves were fitted to a four-parameter empirical equation, and the tie-lines were described by the Othmer–Tobias and Bancroft equations. In addition, the extraction capacity of the {[C_nmim][CH₃COO] (n = 4, 6, 8) + K₃PO₄} aqueous two-phase systems was evaluated through their application to the extraction of l-tryptophan. The high extraction efficiency suggests that these aqueous two-phase systems are feasible to be used in the extraction and separation process.     

Extraction and high performance liquid chromatographic determination of 3-indole butyric acid in pea plants by using imidazolium-based ionic liquids as extractant

In this paper, imidazolium-based ionic liquids [C₄mim][PF₆], [C₆mim][PF₆], [C₈mim][PF₆], [C₆mim][BF₄] and [C₈mim][BF₄] were tested as extracting solvents for removal of 3-indole butyric acid (IBA) from aqueous media with subsequent determination using HPLC. Percent extraction of IBA was strongly affected by pH of aqueous phases and the chemical structures of ionic liquids (ILs). Extraction of IBA was quantitative in the pH values lower than pK_a of IBA. Considering both extraction and stripping efficiencies of IBA, [C₄mim][PF₆] was found to act more efficient than other studied ILs. Capacity of [C₄mim][PF₆] was 17.6 × 10⁻⁴ mmol IBA per 1.0 mL of IL. Ionic strength of aqueous phase and temperature had shown no serious effects on extraction efficiency of IBA. A preconcentration factor of 100 and a relative standard deviation of 1.16% were obtained. It was found that ionic liquid phase was reusable almost five times for extraction/stripping purposes. 3-Indole acetic acid showed interferential effect in the extraction step. In order to assess the applicability of the method, extraction and stripping of IBA from pea plants and some other samples were studied.     

Relative hydrophobicity of equilibrium phases in biphasic systems (ionic liquid + water)

Partition coefficients for a series of dinitrophenylated (DNP) amino acids in biphasic systems composed of hydrophobic ionic liquids and water were experimentally determined. The ionic liquids used were three 1-alkyl-3-methylimidazolium tetrafluoroborates, [C_nmim][BF₄], with alkyl chain substituents hexyl, octyl, and decyl. The liquid–liquid phase diagram for the system ([C₁₀mim][BF₄] + water) was experimentally determined. DNP amino acids distribute preferentially to the IL-rich phase and ([C₁₀mim][BF₄] + water) was found to be the system with the lowest partition coefficients for the solutes studied. The experimental partition coefficients decrease as the size of the alkyl side chain in the ionic liquids increases. The free energy of transfer of a methylene group between phases was calculated through the partition coefficients, which provides a measure of the relative hydrophobicity of the equilibrium phases. It was found that the system ([C₁₀mim][BF₄] + water) presents a lower free energy (and thus a lower relative hydrophobicity) than the system ([C₈mim][BF₄] + water). In order to better understand this result, the micellar behavior of the three ionic liquids was studied. Electrical conductivities of several aqueous solutions of the ionic liquids were measured to determine the critical micelle concentration (CMC) and the degree of micelle ionization, α, of the three ionic liquids. From these two properties it was possible to obtain the free energy of micellization, ΔG_mic, for the ionic liquids.