Phenylsuccinic Acid Enantiomers Research Articles

Enantioseparation of Phenylsuccinic Acid Enantiomers by Solvent Sublation with Collaborative Selectors

A new solvent sublation (SS) system for chiral separation is introduced by using phenylsuccinic acid (H2A) as the model enantiomers. The experiments were carried out in a traditional SS apparatus but with collaborative chiral selectors: dibenzoyl-L-tartaric acid (L-DBTA) in the organic phase and hydroxypropyl-β-cyclodextrin (HP-β-CD) in the aqueous phase. The chiral recognition abilities of the two selectors are opposite for the H2A enantiomers. Several important parameters were investigated. The results demonstrate that enantioselective sublation and partitioning behavior are mainly dependent on the pH of the solution, the concentrations of chiral selectors and H2A. Furthermore, the flow rate of air and flotation time also have some effects on the enantioseparation. Under the optimized conditions, the enantioselectivity expressed by the separation factor (β) and enantiomer excess (e.e.%) are 2.47 and 29.50%, and the yields of R-H2A and S-H2A are 0.23 and 0.13 g·L−1, respectively. Compared with the SS system with the single selector HP-β-CD in the aqueous phase (or L-DBTA in the organic phase), the increased values of β and e.e.% in the new SS system with collaborative selectors are 1.31 (or 1.38) and 5.90% (or 13.82%), respectively.

Efficient enantioseparation of phenylsuccinic acid enantiomers by aqueous two-phase system-based biphasic recognition chiral extraction: Phase behaviors and distribution experiments

A novel method of aqueous two-phase system (ATPS)-based biphasic recognition chiral extraction has been developed to separate phenylsuccinic acid (PSA) enantiomers. The phase behaviors of ethanol/ammonium sulfate ATPS including phase diagrams, phase volume ratios and phase compositions were studied thoroughly. Based on crucial phase transition points, a modified phase diagram was established experimentally. It was found the phase volume ratios of the system change curves in two parts of ATPS area showed opposite trends, and ideal region with appropriate phase volume ratios and high stability was selected for enantioseparation process. Furthermore, the optimum phase composition for improved enantioseparation was obtained based on two different chiral selector-oriented recognition regions. Then the main system parameters including pH, types of chiral selectors, operational temperature, as well as the PSA enantiomers concentration were also investigated. The maximum separation factor of 4.06 was obtained under the optimized experimental conditions with l-(+)-Tartaric acid diisopropyl ester and Hydroxypropyl-β-cyclodextrin as the biphasic chiral selectors. It is foreseeable that the ATPS-based biphasic recognition chiral extraction could be beneficial to developing efficient enantioseparation methodologies for other racemic compounds.

Enantioseparation of phenylsuccinic acid enantiomers based on aqueous two-phase system with ethanol/ammonium sulfate: phase diagrams optimization and partitioning experiments

In the study herein we focused on enantioseparation of phenylsuccinic acid (PSA) enantiomers using an aqueous two-phase system (ATPS) composed of ethanol and ammonium sulfate. Based on phase-forming points and salting-out points, a modified phase diagram of ethanol/ammonium sulfate system with three distinct phase areas, including homogeneous area, ATPS area and salting-out area, has been constructed experimentally. The ATPS optimization and evaluation of chiral separation efficiency for PSA enantiomers have been investigated thoroughly. A hydrophilic chiral selector, hydroxypropyl-β-cyclodextrin (HP-β-CD), which has good chiral recognition ability for R-PSA, was added into bottom phase. The chiral separation efficiencies, namely distribution coefficients and separation factor, were affected by various process variables, including phase compositions of ATPS, concentrations of HP-β-CD and PSA enantiomers, pH value and operational temperature. Under the optimum conditions, separation factor could reach 1.42 after just one step extraction. This environmentally benign chiral separation technique opens up new possibilities for preparative separation of other racemic compounds at a large-scale.

Separation of phenylsuccinic acid enantiomers using biphasic chiral recognition high-speed countercurrent chromatography.

High-speed countercurrent chromatography (HSCCC) combined with biphasic chiral recognition was successfully applied to the resolution of phenylsuccinic acid enantiomers. D-Isobutyl tartrate and hydroxypropyl-β-cyclodextrin were employed as lipophilic and hydrophilic selectors dissolved in the organic stationary phase and aqueous mobile phase, respectively. The two-phase solvent system was made up of n-hexane/methyl tert-butyl ether/water (0.5:1.5:2, v/v/v). Impacts of the type and concentration of chiral selectors, the pH value of the aqueous phase solution as well as the temperature on the separation efficiency were investigated. By means of preparative HSCCC, pure enantiomer was obtained by separating 810 mg of racemate with a purity >99.5% and a recovery rate between 82 and 85%. The experimental results indicate that biphasic recognition HSCCC provide a promising means for efficient separation of racemates.

Enantioseparation of Phenylsuccinic Acid Enantiomers Using Aqueous Two-Phase Flotation and Their Determination by HPLC and UV Detection

Aqueous two-phase flotation (ATPF) is especially applicable to bioseparation. However, there is no previous work reporting on its application in enantioseparation. Using phenylsuccinic acid (H2A) as the model enantiomers, ATPF was first introduced into the field of chiral separation. The contributions of a series of ATPF systems to the enantioseparation were investigated. The results indicated that an appropriate increase in the amount of phase-forming components and a decrease in pH values (from 5.5 to 2) are both beneficial for the enantioseparation. Enantioselective flotation and partitioning behavior are mainly dependent on pH values of the solutions, types, and concentrations of chiral selectors. Furthermore, salt, PEG, flow rates of air, and flotation time also have some effects on the enantioseparation. Under the optimal conditions, the enantioselectivity was calculated in terms of the separation factor (α) and enantiomer excess (e.e. %) as 1.99 and 23.49 %, respectively. Finally, the most reasonable mechanisms for H2A enantioseparation in ATPF system have been proposed. An ATPF system composed of PEG2000/(NH4)2SO4 was proved to have the best ability for the separation of H2A enantiomers. The explorations in our study will further enrich the enantioseparation methods and pave the way for the application of ATPF in the enantioseparation field.

Experimental and Simulation on Enantioselective Extraction in Centrifugal Contactor Separators

The increasing demand for optically pure compounds stimulates the development of new chiral separation processes on an industrial scale. The enantioselective liquid–liquid extraction (ELLE) of phenylsuccinic acid (PSA) enantiomers using hydrophilic hydroxyphenyl‐β‐CD as extractant (C) was studied experimentally in a countercurrent cascade of 10 centrifugal contactor separators at 293 K. Based on a single‐stage equilibrium model and the law of conservation of mass, a multistage equilibrium model of ELLE was developed to investigate the influence of changes in the process parameterssuch as phase ratios and concentrations on extraction efficiency. The multistage equilibrium model was verified experimentally with a good agreement. The model was applied to predict the symmetrical separation of PSA enantiomers. By modeling, optimal process parameters for the symmetrical separation of PSA enantiomers can beachieved. The minimum number of stages was determined at 22 and 24 for eeeq>98% and eeeq>99%, respectively. © 2013 American Institute of Chemical Engineers AIChE J, 59: 2594–2602, 2013

Determination of Kinetics in Biphasic Recognition Chiral Extraction for Separation of Phenylsuccinic Acid Enantiomers

This paper reports on the determination of the intrinsic kinetics in biphasic recognition chiral extraction of phenylsuccinic acid enantiomers (H2A) by L-IBTA and HP-β-CD in a modified Lewis cell. The two-phase homogeneous reaction model was selected, because there is a finite physical solubility of phenylsuccinic acid enantiomers in both the aqueous phase and the organic phase. The regime analysis was split up in three parts: a regime analysis on the aqueous phase reaction in the absence of organic phase reaction, a regime analysis of the organic phase reaction in the absence of the aqueous phase reaction, and a regime analysis of reactions in both phases. The reactions have been found to be first order with respect to H2A and second order with respect to L-IBTA and HP-β-CD. Competitive extraction of H2A enantiomers with HP-β-CD and L-IBTA has great influence on the extraction process. With increase of HP-β-CD concentration, high enantioselectivity was obtained, but the extraction rate decreases.

Equilibrium Studies on Liquid-Liquid Reactive Extraction of Phenylsuccinic Acid Enantiomers Using Hydrophilic β-CD Derivatives Extractants

This paper deals with the enantioseparation of phenylsuccinic acid (H 2A) enantiomers by liquid-liquid reactive extraction using β-CD derivatives as aqueous selectors. Cyclodextrin and its derivatives can interact with guest molecules selectively to form complexes with different stabilities. Cyclodextrin derivatives are not soluble in organic liquids, but highly soluble in water. In this work, hydroxypropyl- β-cyclodextrin (HP- β-CD), hydroxyethyl- β-cyclodextrin (HE- β-CD) and methyl- β-cyclodextrin (Me- β-CD) were selected as chiral selectors in aqueous phase for the reactive extraction of phenylsuccinic acid enantiomers from organic phase to aqueous phase. The results show 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, the concentrations of the extractants and H 2A enantiomers, pH and temperature. HP- β-CD, HE- β-CD and Me- β-CD have stronger recognition abilities for R-phenylsuccinic acid than for S-phenylsuccinic acid. Among the three kinds of β-CD derivatives, HP- β-CD has the strongest separation ability. Excellent enantioseparation was achieved under the optimal conditions of pH of 2.5 and temperature of 5°C with a maximum enantioselectivity ( a) of 2.38. Reactive extraction of enantiomers with hydrophilic β-CD derivatives is of strong chiral separation ability and can be hopeful for separations of various enantiomers at a large-scale.

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.

Enantiomeric separation of phenylsuccinic acid by cyclodextrin-modified reversed phase high-performance liquid chromatography

The chiral separation of phenylsuccinic acid (PSA) was studied by reversed phase high-performance liquid chromatography (RP-HPLC) with cyclodextrins (CDs) as chiral mobile phase additives. The effects of types of CDs, concentration of hydroxypropyl-β-cyclodextrin (HP-β-CD), percentage of organic modifier, pH value and column temperature on enantioselective separation were investigated. The quantification property of the developed RP-HPLC method was examined. The chiral recognition mechanism of PSA was also discussed. The results show that a baseline separation of PSA enantiomers is achieved on a Lichrospher C18 column (4.6 mm (inner diameter)×250 mm, 5 μm) with HP-β-CD as chiral mobile phase additive. The capacity factors of R-PSA and S-PSA are 3.94 and 4.80, respectively. The separation factor and resolution are respectively 1.22 and 8.03. The mobile phase is a mixture of acetonitrile and deionized water (20:80, volume ratio) containing 10 mmol/L HP-β-CD and 0.05% trifluoroacetic acid (pH 2.5, adjusted with triethylamine) with a flow rate of 1.0 mL/min. The ultraviolet (UV) detector is set at 254 nm. The likely roles are inclusion interaction, induction and hydrogen bonding between HP-β-CD and PSA enantiomers.