Chiral Separation Ability Research Articles

Enantioselective Partitioning of Racemic Ibuprofen in a Biphasic Recognition Chiral Extraction System

AbstractEnantioselective partitioning of ibuprofen enantiomers in a biphasic recognition chiral extraction system was studied. A combination of hydrophobic L‐isobutyl tartrate in organic phase and hydrophilic β‐cyclodextrin derivative in aqueous phase is necessary to establish a biphasic recognition chiral extraction system. The studies performed involve an enantioselective extraction in a biphasic system, where ibuprofen enantiomers form four complexes with the β‐cyclodextrin derivative in aqueous phase and the D(L)‐isobutyl tartrate in organic phase, respectively. In these biphasic resolutions, the types and the concentrations of the extractants, pH and temperature all exert a considerable influence on the biphasic recognition process. Good enantioselectivities for ibuprofen enantiomers were obtained at pH≦2.5 and a ratio of 2:1 of [L‐isobutyl tartrate] to [HP‐β‐CD]. Biphasic recognition chiral extraction is of strong chiral separation ability, and may be very helpful to optimize the extraction systems and realize the large‐scale production of enantiomers.

Chiral separation abilities: Aspartic acid block copolymer-imprinted mesoporous silica

Herein we report on the synthesis of chiral mesoporous silica (CMS) that can be used for chiral separation from a racemic mixture of two enantiomers. The CMS with a pore size of 3–5 nm and a high surface area of 725 m 2 g −1 was synthesized by templating chiral block copolymers (CBCs) of polyethylene oxide (PEG) and D/L-aspartic acid (D/L-AspA), [PEO 45-b-(D/L-AspA) 10]. The chiral mesopores were characterized by HRTEM, small angle XRD and BET. The chiral resolution abilities and the chiral separation kinetics of the copolymer-extracted CMS were investigated using a racemic mixture of valine by circular dichroism (CD) and optical polarimetry. The chiral resolution of the CMS was further verified with a racemic mixture of alanine. A chiral selectivity factor of 7.52 was found for the specific enantiomer which is adsorbed preferably. These results allow a new approach towards enantiomeric separation and other enantiomeric applications of novel CMS.

Enantioselective separation of R,S-phenylsuccinic acid by biphasic recognition chiral extraction

A new process has been developed to separate phenylsuccinic acid (H2A) enantiomers, based on the oppositely preferential recognition of hydrophobic and hydrophilic chiral selectors in organic and aqueous phases, respectively, which is named as biphasic recognition chiral extraction (BRCE). BRCE system is established by adding hydrophobic l-iso-butyl tartrate in organic phase and hydrophilic β-cyclodextrin (β-CD) derivative in aqueous phase, which preferentially recognize S-H2A and R-H2A, respectively. The studies performed involve two enantioselective extractions in a biphasic system, where H2A enantiomers form four complexes with β-CD derivative in aqueous phase and l-iso-butyl tartrate in organic phase, respectively. Here it is shown that the efficiency of the extraction depends, often strongly, on a number of process variables, including the types of organic solvents and β-CD derivatives, iso-butyl tartrate configurations, the concentrations of the extractants and H2A enantiomers, pH and temperature. Phase-equilibria in BRCE systems is governed by the complex chemical equilibria in both the organic and aqueous phases. By changing the monophasic recognition chiral extraction (MRCE) system into BRCE system, the enantioselectivity increases from 1.501 to 2.862. The maximum enantioselectivity for H2A enantiomers is obtained at pH≤2.5 and the ratio of 2:1 of [l-(+)-iso-butyl tartrate] to [HP-β-CD]. The experimental results show that BRCE is of much stronger chiral separation ability than MRCE, which is due to utilization of the separation abilities of both tartrate and β-CD derivative. It may be very helpful to optimize the extraction systems and realize the large-scale production of pure enantiomers.

Molecularly imprinted organic–inorganic hybrid membranes for selective separation of phenylalanine isomers and its analogue

A novel kind of molecularly imprinted organic–inorganic hybrid membrane, using sodium alginate (SA) and 3-aminopropyltriethoxysilane (APTES) as the organic and inorganic phase, respectively, was prepared and investigated for the optical resolution of chiral isomers. The hybrid membrane was prepared in an aqueous environment with the presence of d-phenylalanine ( d-Phe) as imprinting templates, and the silica phase was introduced in the alginate matrix by sol–gel process of APTES. It was found by FT-IR and SEM–EDX characterizations that strong covalent bonds were formed between the organic and inorganic phases, and silica was homogenously distributed in the matrix. These molecularly imprinted SA–APTES hybrid membranes showed chiral separation ability towards the d, l-Phe isomers with a maximum selectivity ( α D/ L ) of 1.8 at 40% APTES content. The recognition mechanism was tentatively analyzed and discussed based on permeation and binding experiments. The separation ability of the above hybrid membranes toward d-Phe and its analogue, d-tyrosine ( d-Tyr), was also investigated, and a separation factor of up to 2.9 was achieved.

Chiral polyamides consisting of N‐α‐benzoyl‐L‐glutamic acid as a diacid component

AbstractNovel polyamide with chiral environment was obtained from aromatic diamine, 4,4′‐diaminodiphenylmethane (DADPM), and N‐α‐protected L‐glutamic acid, N‐α‐benzoyl‐L‐glutamic acid (Benzoyl‐L‐Glu‐OH). The optical rotation ([α]D) of the polyamide was determined to be 3.6° (c = 1.00 g/dL in DMF), implying that the optically active polyamide was obtained. The present polyamide gave a durable self‐standing membrane. The membrane selectively incorporated the D‐isomer of Ac‐Trp from racemic mixture of Ac‐Trp. The adsorption selectivity toward Ac‐D‐Trp was determined to be 1.95. It showed chiral separation ability by adopting potential difference as a driving force for membrane transport. The permselectivity was dependent on the potential difference, and at the applied potential difference of 3.0 V, the membrane selectively transported Ac‐D‐Trp and the permselectivity toward Ac‐D‐Trp was determined to be 1.84, which was close to the adsorption selectivity of 1.95. Contrary to this, the membrane showed opposite permselectivity at the applied potential difference of 2.0 V and the permselectivity toward the L‐isomer reached 2.48. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2530–2538, 2009

Enantiomeric Separation of Several Oxirane Derivatives by High Performance Liquid Chromatography on Polysaccharide-Based Chiral Stationary Phases

Five polysaccharide based chiral stationary phases have been used for separation of enantiomers of fourteen heterocyclic oxiranes. The polysaccharide based chiral stationary phases used in this study are Chiralak AD, Chiralpak AS, Chiralcel OD, Chiralcel OG, and Chiralcel OJ. From the chiral separation results, the chiral separation ability for the selected compounds show the order of Chiralpak AD > Chiralcel OD > Chiralcel OJ > Chiralcel OG > Chiralpak AS. Chiralcel OD appears to be quite versatile, since 8 out of 11 oxiranes with π-aromatic system were successfully resolved, yet no resolution was obtained for those oxirane derivatives, which lacks the π-aromatic system. Although Chiralcel OD is also versatile, it was not as effective; since the separation factors (α) are much smaller. The results indicate that dipole interactions have a strong impact on the retention mechanism, and extended π systems are essential. The spatial arrangement of the substituent groups around the analyte stereogenic center plays an important role in enantiomeric separations. The closer a group is to the chiral center, the more likely is the chiral recognition and enantioselectivity.

Optical resolution of racemic amino acid derivatives with molecularly imprinted membranes from tetrapetide consisting of glycinyl residues

Molecularly imprinted polymeric membranes were prepared from polystyrene resin bearing tetrapeptide of glycine. The tetrapeptide was converted into a chiral recognition site by using the d- or l-isomer of N-α- tert-butoxycarbonyltryptophan (Boc-Trp) as a print molecule. The d-isomer was incorporated into the membrane imprinted by Boc- d-Trp in preference to the corresponding l-isomer and vice versa. Those molecularly imprinted membranes showed chiral separation ability. In the enantioselective electrodialysis, the observed permselectivity corresponded to the adsorption selectivity of ca. 2.3 at the optimum potential difference of 2.0 V.

Biphasic recognition chiral extraction: A novel method for separation of mandelic acid enantiomers

This article reports a new chiral separation method-biphasic recognition chiral extraction for the separation of mandelic acid enantiomers. Distribution behavior of mandelic acid enantiomers was studied in the extraction system with O,O'-di-benzoyl-(2S,3S)-4-toluoyl-tartaric acid (D-(+)-DTTA) in organic phase and beta-CD derivatives in aqueous phase, and the influence of the types and concentrations of extractants and pH on extraction efficiency was investigated. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD), hydroxyethyl-beta-cyclodextrin (HE-beta-CD), and methyl-beta-cyclodextrin (Me-beta-CD) have stronger recognition abilities for S-mandelic acid than those for R-mandelic acid, among which HP-beta-CD has the strongest ability. D-(+)-DTTA preferentially recognizes R-mandelic acid. pH and the concentrations of extractants have great effects on chiral separation ability. A high enantioseparation efficiency with a maximum enantioselectivity of 1.527 is obtained at pH of 2.7 and the ratio of 2:1 of [D-(+)-DTTA] to [HP-beta-CD]. The obtained results indicate that the biphasic recognition chiral extraction is of stronger chiral separation ability than the monophasic recognition chiral extraction. It may be very helpful to optimize the extraction systems and realize the large-scale production of pure enantiomers.

Resolution of Zopiclone enantiomers by biphasic recognition chiral extraction

This paper reports a new chiral separation technology—biphasic recognition chiral extraction for the racemic separation of zopiclone, which was selected, as a case study, due to its enantiomers diverse properties. The studies performed involve an enantioselective extraction in a biphasic system, where zopiclone complexes with β-cyclodextrin derivative in aqueous phase and complexes with d( l)-tartaric acid esters present in organic phase, respectively. Factors affecting the extraction mechanism were analysed, namely the influence of the concentrations of the extractants and zopiclone enantiomers, the types of the extractants, pH and temperature. Experimental results show that, in the biphasic recognition chiral extraction system containing hydroxypropyl-β-cyclodextrin and l-isobutyl tartrate, the maximum enantioselectivity is 1.51, which is larger than that in the monophasic recognition chiral extraction system containing only l-isobutyl tartrate in organic phase. Biphasic recognition chiral extraction is of strong chiral separation ability, and has great significance for preparative separation of racemic compounds. It may also be very helpful to optimize the extraction systems and realize the large-scale production of enantiomer.

Separation of phenylalanine racemates using d-phenylalanine imprinted microbeads as HPLC stationary phase

A successful enantioseparation of d, l-phenylalanine (Phe) was achieved for the first time by using d-Phe imprinted P(MAA-co-EGDMA) microbeads as HPLC stationary phase. The d-Phe imprinted microbeads were prepared by a novel modified suspension polymerization method without derivatization of the water-soluble template molecule. This preparation method was employed in order to capture template molecules in organic phase droplets during polymerization. The prepared d-Phe imprinted P(MAA-co-EGDMA) microbeads were packed into an empty stainless steel column, which was used for the separation of the Phe enantiomers. The selection of a suitable mobile phase, mobile phase composition, pH and flow rate were investigated for determining the best resolution of the Phe enantiomers. Baseline separation was achieved using an organic–aqueous buffer (EtOH–acetate buffer) solution as a mobile phase. Separation factors of more than 2.56, with a resolution of 1.38, were obtained with a mobile phase containing 9–18% (v/v) EtOH in a 0.030 M acetate buffer solution. d-Phe imprinted microbeads were superior to the majority of the reported molecularly imprinted polymers with respect to chiral separation abilities. The column backpressure was less than 300 psi.

Preparation and Evaluation of a Novel Cellulose Tris(N‐3,5‐dimethylphenylcarbamate) Chiral Stationary Phase

AbstractA novel cellulose tris(N‐3,5‐dimethylphenylcarbamate) (CDMPC) chiral stationary phase (CSP) was prepared by coating CDMPC on TiO2/SiO2, which was prepared by coating titania nanoparticles on silica through a self‐assemble technique. At first, 2‐hydroxyl‐phenyl acetonitrile and α‐phenylethanol were separated on this new CSP to evaluate the chiral separation ability. Then, two pesticides, matalaxyl and diclofop‐methyl were separated. The influence of the mobile phase composition on the enantioselectivity was discussed, and the repeatability and stability of the CSP were studied too.

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.

Cyclodextrin Complexes: Chiral Recognition and Complexation Behaviour

Cyclodextrins are well known in supramolecular chemistry as host molecules capable of engulfing molecules in their hydrophobic cavity via noncovalent interactions. Although cyclodextrins are frequently used for chiral separation of racemates, the mechanism of chiral recognition has not yet been fully characterised. The current investigation was aimed at examining chiral recognition mechanism in order to construct an in silico method for prediction of chiral recognition. Amino acids were selected as model guest, whereas alphaCD was used as model host. The results of molecular docking and molecular dynamic calculations were compared to results of stability constant determination and capillary electrophoresis measurements of enantioseparations. Positive correlation between binding strength and chiral separation ability was found. However, the small energy differences between interaction energy of each enantiomer with alphaCD fell into the range of standard error of molecular docking calculations limiting its applicability for in silico prediction. Examining the stability of complex geometry during molecular dynamics simulation revealed that stable complex geometry is likely to be a prerequisite for chiral recognition. This hypothesis was tested on methylderivatized tryptophan. Indeed, chiral separation of beta-methyl-tryptophans by alphaCD could be successfully predicted by examining the complex geometries during molecular dynamic simulation.

Preparation of novel β-cyclodextrin chiral stationary phase based on click chemistry

A facile strategy based on click chemistry for preparation of the structurally well-defined native β-cyclodextrin (β-CD) based chiral stationary phase (CSP) was proposed. The β-CD CSP was evaluated by enatioseparation of benzoin, trans-stilbene oxide, Troger's base, bendroflumethiazide, ketoprofen, chlorthalidone, three flavanone compounds and two β-adrenergic blocking agents under reversed phase high performance liquid chromatography. The chromatographic results demonstrate the chiral separation ability of click β-CD CSP and illustrate the usefulness of click chemistry in the preparation of β-CD based CSP.

Optical Resolution of Racemic Amino Acids through DNA-Poly(4-vinylbenzyl)trimethylammonium Polyion Complex Membranes

Novel polyion complex membranes were prepared from DNA-Na and poly(4-vinylbenzyl)trimethylammonium chloride (PVBTMAC). The newly prepared DNA-PVBTMA polyion complex membranes showed a chiral separation ability toward racemic lysine (Lys) mixtures. The membranes transported D-Lys in preference to the corresponding L-isomer of Lys. The permselectivity toward the D-isomer reached 1.26. From transport experiments and adsorption studies, it was revealed that the permselectivity was mainly determined by diffusivity selectivity.

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].

Chiral Separation of Racemic Amino Acids through DNA‐Polydiallyldimethylammonium Polyion Complex Membranes

AbstractNovel polyion complex membrane was prepared from DNA‐Na and polydiallyldimethylammonium chloride (PDADMAC). The newly prepared DNA‐PDADMA polyion complex membrane showed a chiral separation ability, which was measured by using various racemic amino acids as model racemic mixtures. The membrane transported the L‐isomer of Trp or Phe in preference to the corresponding D‐isomer and permselectivities toward the L‐isomer were determined to be 1.26 for L‐Trp and 1.25 for L‐Phe, respectively. From adsorption experiments, it was revealed that the permselectivity was mainly governed by adsorption selectivity.

Characterization of Chiral Interactions Using Fluorescence Anisotropy

This work details a study whereby the characterization of chiral selectors and identification of optimal separation conditions is evaluated by steady-state fluorescence anisotropy measurements. Earlier studies in our laboratory have shown fluorescence anisotropy to be an effective tool in evaluating chiral recognition, and in this study, the feasibility of characterizing chiral separation systems by the technique is evaluated. Four chiral selectors were examined under various conditions to explore correlation between chiral separation ability and differences in the steady-state fluorescence anisotropy of the enantiomers measured under similar conditions. A good correlation between the fluorescence anisotropy data and separation data was observed with R2 values ranging from 0.9279 to 0.9959. The fluorescence anisotropy measurements were examined under conditions that mimicked chiral separation conditions and the feasibility of a priori optimization of chiral separations is discussed.

Preparation of CS/GPTMS hybrid molecularly imprinted membrane for efficient chiral resolution of phenylalanine isomers

An enantioselective chitosan (CS)/γ-glycidoxypropyltrimethoxysilane (GPTMS) hybrid membrane was prepared in aqueous phase by a modified sol–gel process using CS as bulk polymer, l-phenylalanine ( l-Phe) as imprinting molecules and GPTMS as crosslinking agent. SEM-EDX characterization reveals the dense structure of the membrane and homogeneous distribution of silica in chitosan matrix. The chiral separation ability of CS/GPTMS hybrid molecularly imprinted membranes towards the underivatized d, l-Phe aqueous mixture was evaluated by permeation and binding experiments. Significantly improved selectivity with a separation factor α d/ l up to 4.5 has been achieved.

Enantioselective extraction of d,l-tryptophan by a new chiral selector: Complex formation with di(2-ethylhexyl)phosphoric acid and O,O′-dibenzoyl-(2 R,3 R)-tartaric acid

The paper presents a new complex chiral selector of di(2-ethylhexyl)phosphoric acid (D2EHPA) and O,O′-dibenzoyl-(2 R,3 R)-tartaric acid ((−)-DBTA) and its enantioselectivity on d,l-tryptophan (Trp). The influence of the initial concentration of d,l-Trp, (−)-DBTA, D2EHPA were studied. Both the distribution ratio and enantioselectivity of d,l-Trp are greatly improved with the complex extractant instead of (−)-DBTA individually. It was also found that the enantioselectivity of the complex extractant was changed by the D2EHPA content, although pure D2EHPA has no chiral separation ability. By adjusting the equilibrium pH in the aqueous phase, a high chiral separation efficiency with a maximum enantioselectivity of 5.3 and an enantiomeric excess (e.e.) of up to 57% in aqueous phase were reached at PI point. Finally, the most reasonable extraction mechanisms of the complex to Trp enantiomers have been suggested.