Chiral Separation Process Research Articles

Axially Chiral Multiple Resonance Thermally Activated Delayed Fluorescence Enantiomers for Efficient Circularly Polarized Electroluminescence

AbstractThe chiral materials and circularly polarized organic light‐emitting diodes (CP‐OLEDs) have potential applications in 3D display due to the generation of circularly polarized luminescence (CPL). However, achieving a combination of chirality, high efficiency, and narrowband emission for thermally activated delayed fluorescence (TADF) materials has proven to be a challenging endeavor, often involving complicated synthesis and chiral separation processes. In this study, a simple design approach is introduced by direct connection of the multiple resonance (MR) skeleton and chiral (R/S)‐1,1′‐binaphthyl units, obtaining two pairs of chiral MR‐TADF enantiomers (R/S)‐DtCzB‐OBN and (R/S)‐DtCzB‐BN without chiral resolution. These enantiomers exhibit blue‐green emissions with photoluminescence quantum efficiencies of up to 98% in doped films and full‐width at half‐maximum of 22 nm both in toluene and in the device. Furthermore, (R/S)‐DtCzB‐OBN and (R/S)‐DtCzB‐BN display symmetric CPL spectra with dissymmetry factors (gPL) of + 3.86( ± 0.317) × 10−4/‐3.37( ± 0.317) × 10−4 and + 7.09( ± 0.233) × 10−4/‐7.74(± 0.233) × 10−4, respectively. The CP‐OLEDs based on (R/S)‐DtCzB‐OBN and (R/S)‐DtCzB‐BN exhibit impressive maximum external quantum efficiencies of 30.0% and 33.9%, as well as gEL factors of +3.40( ± 0.362) × 10−4/‐3.11( ± 0.362) × 10−4 and + 7.99( ± 0.391) × 10−4/‐8.19( ± 0.391) × 10−4, respectively. This research proposes a strategy for directly constructing chiral MR‐TADF materials for high‐performance CP‐OLEDs, avoiding complicated chiral separation.

Continuous chiral separation process for high-speed countercurrent chromatography established and scaled up: A case of Voriconazole enantioseparation.

An efficient method for the continuous separation of Voriconazole enantiomers was developed using sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as a chiral selector in high-speed countercurrent chromatography (HSCCC) with different types. The separation was performed using a two-phase solvent system consisting of n-hexane/ethyl acetate/100mmol/L phosphate buffer solution (pH=3.0, containing 50mmol/L SBE-β-CD) (1.5:0.5:2, v/v/v). A fast and predictable scale-up process was achieved using an analytical DE HSCCC instrument. The optimized parameters were subsequently applied to a preparative Tauto HSCCC instrument, resulting in consistent separation time and enantiomeric purity, with throughput boosted by a remarkable 11-fold. Preparative HSCCC successfully separated 506mg of the racemate, delivering enantiomers exceeding 99% purity as confirmed by high-performance liquid chromatography analysis. This investigation presents an effective methodology for forecasting the HSCCC scale-up process and attaining continuous separation of chiral drugs.

Enantiomeric separation of tryptophan via novel chiral polyamide composite membrane.

The separation of chiral drugs continues to pose a significant challenge. However, in recent years, the emergence of membrane-based chiral separation has shown promising effectiveness due to its environmentally friendly, energy-efficient, and cost-effective characteristics. In this study, we prepared chiral composite membrane via interfacial polymerization (IP), utilizing β-cyclodextrin (β-CD) and piperazine (PIP) as mixed monomers in the aqueous phase. The chiral separation process was facilitated by β-CD, serving as a chiral selective agent. The resulting membrane were characterized using SEM, FT-IR, and XPS. Subsequently, the chiral separation performance of the membrane for DL-tryptophan (Trp) was investigated. Lastly, the water flux, dye rejection, and stability of the membrane were also examined. The results showed that the optimized chiral PIP0.5β-CD0.5 membrane achieved an enantiomeric excess percentage (ee%) of 43.0% for D-Trp, with a solute flux of 66.18 nmol·cm-2·h-1, and maintained a good chiral separation stability. Additionally, the membrane demonstrated positive performance in the selective separation of mixed dyes, allowing for steady operation over a long period of time. This study offers fresh insights into membrane-based chiral separations.

The role of deep eutectic solvents in chiral capillary electrokinetic chromatography: A comparative study based on α-cyclodextrin chiral selector

• The first investigation of the effect of HBAs of DESs on chiral EKC. • The comparison of the performance of chiral and achiral DESs in chiral EKC. • The comparison of the performance of DESs and ILs as additives in chiral EKC. • The objective evaluation of the feasibility of DESs as additives in chiral EKC. Deep eutectic solvents (DESs) are emerging as potential candidates as additives/modifiers in chiral electrokinetic chromatography (EKC). However, the true role of DESs in the chiral separation process is far from being fully elucidated. Since most previous studies have been restricted to using choline chloride as the hydrogen-bond acceptor (HBA) in DESs, here we first evaluated the effect of five types of DESs (containing different HBAs) on the enantioseparation performance of an α-CD-based EKC system. The results demonstrate that these DESs are capable of moderately improving the enantioresolutions of several model drugs. A series of comparative experiments indicate that the improvement is mainly due to the contribution of the HBAs, rather than the selected hydrogen-bond donors (HBDs). Considering that most of these DESs are achiral, we further prepared five chiral DESs, aiming to investigate whether there is a synergistic effect between α-cyclodextrin and chiral DESs. However, these chiral DESs did not show obvious superiority compared with achiral DESs. This conclusion is different from the use of achiral or chiral ionic liquids (ILs) as additives in chiral EKC, in which chiral ILs usually exhibit significantly better enantioseparation performance than achiral ILs. Another important conclusion of this work is that there seems to be no significant difference between using DESs and their individual components, which is also different from the performance of most previously reported ILs. This conclusion indicates that the DESs may be virtually completely dissociated into their initial components (HBAs + HBDs) in the separation medium due to the destruction of their hydrogen-bond network. Therefore, a question which deserves particular attention of researchers in this field is raised here: whether it is absolutely necessary to use DESs in chiral EKC since adding HBAs and HBDs separately seems to have the same function?

Using Molecular Simulations to Facilitate Design and Operation of Membrane-Based and Chiral Separation Processes

Using Molecular Simulations to Facilitate Design and Operation of Membrane-Based and Chiral Separation Processes

Chiral resolution of racemic amines in µ-reactor-crystallizer

• A semi-continuous microfluidic platform for the chiral separation process is developed. • The crystal is formed in µ-Crystallizer ∼ 33 times faster than the batch process. • The obtained diastereomeric salt from µ-Crystallizer is purer than the batch process. • A parametric map with concentration and flow rate is presented for the desired crystal. • The microfluidic process demonstrated here can be adopted for industrial application. The production of pure chiral drugs in a continuous manner is one of the major issues for pharmaceutical industries. A micro continuous process is developed for chiral separation of racemic molecules exploiting a “classical” method of diastereomer formation and subsequent crystallization. A flexible µ-reactor and µ-crystallizer are fabricated for the continuous production of diastereomer salt crystals from racemic α-phenylethylamine (I) where optically active L-(+)-tartaric acid (II) is used as a resolving agent. CD spectroscopy, UV–Vis spectroscopy, and other characterizations confirm that the diastereomeric salt obtained from the micro-continuous process is similar in quality if not better than that obtained from a conventional batch process. The process described here is capable to produce crystals at ∼ 33 times faster than the batch process at identical feed concentrations. The better control over crystals and faster resolution in this low-cost micro-continuous process offer industries a potential route for production through very-large-scale integration (VLSI).

Recyclable aqueous two-phase system formed by two temperature-responsive polymers for the chiral resolution of mandelic acid enantiomers

Aqueous two-phase systems (ATPSs) have been used in the chiral resolution of various enantiomers in recent years. However, it is difficult to recycle and reuse the phase-forming components and chiral selectors in these applications. Therefore, a completely recyclable ATPS that is based on two temperature-responsive polymers, viz., poly(MAH-β-CD-co-NIPAAm-DMAEMA-BMA) (PNDB-CD) and poly(NVCL-AM) (PVAm), was employed for the chiral separation of mandelic acid (MA) enantiomers. The two polymers can be recovered by simply adjusting the temperature; meanwhile, the polymer PNDB-CD can be used as a chiral selector. The factors that affect the chiral resolution process were also investigated. A maximum separation factor (α) of 1.49 was achieved via a one-step extraction under the following conditions: PVAm concentration of 14.0 wt%, PNDB-CD concentration of 9.0 wt%, MA concentration of 5.0 mg/g, and system pH of 4.0. Moreover, the two polymers can be easily recycled after the chiral separation process. The recyclable ATPS used for enantioseparation in the current study can provide new ideas for other applications by using enantioselective liquid–liquid extraction (ELLE).

In situ Assembly of Functionalized Single-Walled Carbon Nanotube with partially reduced Graphene oxide Nanocomposite Membrane for Chiral Separation of β-substituted-α-amino acids

• Fabrication of a tunable pillar of rGO-FSWCNT based nanocomposite membrane. • The nancomposite membrane selectively separated the racemic mixture. • A maximum of 88–99.4 % of ee (L)–isomer was obtained for each racemic mixture. • Synergistic assembly of FSWCNT within the graphene sheets acts as chiral probe. The usage of functionalized nanoporous materials with a high aspect ratio, excellent selectivity, good thermal and chemical robustness and easy aqueous processability can significantly influence the membrane-based chiral separation process. In the present study, we have reported a tunable pillar of rGO-FSWCNT based nanocomposite membrane for the chiral separation of β-substituted-α-amino acids. The nanocomposite membranes were prepared via Interfacial Polymerization (IP) method between partially rGO-FSWCNT composite and trimesoylchloride over the surface of polysulfone support. The membrane permeation experiment investigated the influence of physicochemical factors such as permeation time, operating pressure, and feed concentration on the separation performance. Nanocomposite membranes containing D-tryptophan as the chiral probe preferentially adsorbed the D-isomer of the racemic mixture while allowing the passage of the L-isomer to the permeate side. A maximum of 88–99.4 % of ee (L)–isomer was obtained for each racemic mixture separated under optimal experimental parameters such as feed concentration of the racemic mixture of 10 mmol.L -1 , an applied pressure of 3.5 bar, a flow rate of 25 mL.min −1 and a temperature of 25 °C. The pillaring effect exhibited by vertically aligned CNT within graphene planes possesses desirable L-isomer transport and provide excellent mechanical properties to retentate the D-isomer over nanocomposite membrane. This effect has proven that the synergistic assembly of FSWCNT acts as chiral probe to successfully fabricate the pillared tunnel for better enantioseparation of chiral molecules.

Enantioselective liquid-liquid extraction of tryptophan enantiomers by a recyclable aqueous biphasic system based on stimuli-responsive polymers

The hydrophobic organic solvents/water biphasic system had been always used in the traditional enantioselective liquid-liquid extraction (ELLE). In recent years, aqueous biphasic systems (ABSs) are considered as a promising method used in the ELLE. In the present work, a recyclable ABS composed of a temperature-responsive polymer poly(MAH-β-CD-co-NIPAAm) (PN-CD) and a pH-responsive polymer poly(AA-DMAEMA-BMA) (PADB) was employed in the enantioseparation of tryptophan enantiomers. The polymer PN-CD acted as not only the phase-forming component but also the chiral selector, which can be recycled by changing the temperature. The polymer PADB can be used as the phase-forming component, which can also be recycled by adjusting the pH. The phase behaviors of this PN-CD/PADB ABS had been studied. The influencing parameters were studied for this chiral separation process, including the polymer concentration, initial tryptophan concentration, extraction temperature, and system pH. The maximum separation factor (α) of 1.42 was obtained by one-step extraction under the optimal conditions. Meanwhile, the distribution coefficients of L-tryptophan (L-Trp) and D-tryptophan (D-Trp) were 2.79 and 1.96, respectively. This study develops a green and sustainable strategy for enantioseparation by using the ELLE.

Enantioseparation of lysine derivatives on amylose tris (3, 5-dimethylphenylcarbamate) as chiral stationary phase with high separation factor

Enantioseparation of lysine derivatives by chiral high-performance liquid chromatography (HPLC) was accomplished using two chiral stationary phases (CSPs, Chiralpak IA and Chiralpak IC) based on polysaccharides under normal phase (NP) conditions. All analytes were completely separated. The impacts of polar modifiers, analyte structure and column temperature on chiral separation were discussed. Moreover, the relationship between structure and retention was investigated. The van't Hoff equation was employed to evaluate the thermodynamic parameters of the chiral separation process. The data suggest that the chiral separation process was enthalpy-driven. Surprisingly, two uncommon phenomena were observed: (1) high separation factors on Chiralpak IA and (2) different binding mechanisms with CSP and the two enantiomers.

Analytical separation of four stereoisomers of luliconazole using supercritical fluid chromatography: Thermodynamic aspects and simulation study with chiral stationary phase

The work describes a novel supercritical fluid chromatography method for the separation of four stereoisomers, RZ(+), SZ(-), RE(+) and SE(-) of luliconazole, an antifungal agent on amylose tris[(S)-α-methylbenzyl carbamate] based Chiralpak IH column. The effect of organic modifiers (methanol, ethanol and isopropanol), column temperature and back pressure were evaluated for their selective separation. A consistent elution order, RZ(+) > SZ(-) > RE(+) > SE(-) was observed in all the modifiers. Amongst the three modifiers, the best result in terms of selectivity, resolution and analysis time was obtained with isopropanol. Analytical separation (Rs > 1.5) of RZ(+) and SZ(-) & RE(+) and SE(-) pairs was achieved with a mobile phase consisting of CO2: isopropanol (80: 20, v/v) within 5.0 min. The retention of isomers increased with increase in temperature and decreased with increase in pressure, which was more prominent for RE(+) and SE(-) isomers. The van't Hoff plots revealed that the chiral separation process was essentially entropy driven. Molecular docking was performed to understand the type of chiral recognition between the stereoisomers and the chiral stationary phase and to understand their elution orders under optimized conditions. The results suggested hydrogen bonding and π–π interactions, as the dominant interaction modes. The elution order and binding energy of the interactions were in good agreement with the experimental results. Quantitative studies of RE(+) luliconazole the pharmacologically active isomer was also performed using a marketed formulation.

Resolution of alkaloid racemate: a novel microbial approach for the production of enantiopure lupanine via industrial wastewater valorization

BackgroundLupanine is a plant toxin contained in the wastewater of lupine bean processing industries, which could be used for semi-synthesis of various novel high added-value compounds. This paper introduces an environmental friendly process for microbial production of enantiopure lupanine.ResultsPreviously isolated P. putida LPK411, R. rhodochrous LPK211 and Rhodococcus sp. LPK311, holding the capacity to utilize lupanine as single carbon source, were employed as biocatalysts for resolution of racemic lupanine. All strains achieved high enantiomeric excess (ee) of L-(−)-lupanine (> 95%), while with the use of LPK411 53% of the initial racemate content was not removed. LPK411 fed with lupanine enantiomers as single substrates achieved 92% of D-(+)-lupanine biodegradation, whereas L-(−)-lupanine was not metabolized. Monitoring the transcriptional kinetics of the luh gene in cultures supplemented with the racemate as well as each of the enantiomers supported the enantioselectivity of LPK411 for D-(+)-lupanine biotransformation, while (trans)-6-oxooctahydro-1H-quinolizine-3-carboxylic acid was detected as final biodegradation product from D-(+)-lupanine use. Ecotoxicological assessment demonstrated that lupanine enantiomers were less toxic to A. fischeri compared to the racemate exhibiting synergistic interaction.ConclusionsThe biological chiral separation process of lupanine presented here constitutes an eco-friendly and low-cost alternative to widely used chemical methods for chiral separation.

Deracemization in a Complex Quaternary System with a Second-Order Asymmetric Transformation by Using Phase Diagram Studies.

A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H2 O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second-order asymmetric transformation was achieved with up to 97 % ee. Furthermore, this methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any of the typical limitations of deracemization, although application is still limited to conglomerate-forming systems. We anticipate that this present study will serve as a fundamental model for the design of sophisticated chiral separation processes.

Accurate lattice energies of organic molecular crystals from periodic turbomole calculations.

Accurate lattice energies of organic crystals are important i.e. for the pharmaceutical industry. Periodic DFT calculations with atom-centered Gaussian basis functions with the Turbomole program are used to calculate lattice energies for several non-covalently bound organic molecular crystals. The accuracy and convergence of results with basis set size and k-space sampling from periodic calculations is evaluated for the two reference molecules benzoic acid and naphthalene. For the X23 benchmark set of small molecular crystals accurate lattice energies are obtained using the PBE-D3 functional. In particular for hydrogen-bonded systems, a sufficiently large basis set is required. The calculated lattice energy differences between enantiopure and racemic crystal forms for a prototype set of chiral molecules are in good agreement with experimental results and allow the rationalization and computer-aided design of chiral separation processes. © 2018 Wiley Periodicals, Inc.

Influence of Flexibility on the Separation of Chiral Isomers in STW-Type Zeolite.

Molecular simulation, through the computation of adsorption isotherms, is a useful predictive tool for the selective capacity of nanoporous materials. Generally, adsorbents are modelled as rigid frameworks, as opposed to allowing for vibrations of the lattice, and this approximation is assumed to have negligible impact on adsorption. In this work, this approach was tested in an especially challenging system by computing the adsorption of the chiral molecules 2-pentanol, 2-methylbutanol and 3-methyl-2-butanol in the all-silica and germanosilicate chiral zeolites STW and studying their lattice vibrations upon adsorption. The analysis of single- and multicomponent adsorption isotherms showed the suitability of STW-type zeolites as molecular sieves for chiral separation processes, which pose a challenging task in the chemical and pharmaceutical industries. Moreover, new experimental adsorption data validate the force field employed. The results reveal that the lattice vibrations of the all-silica framework are sorbate-independent, while those of germanosilicate STW show host-guest coupling modulated by uptake and sorbate type that disrupts the chiral recognition sites. This study indicates that the effects of intrinsic flexibility on the selective capacity of nanoporous materials may range from low to high impact, and some of them could not have been foreseen even after examination of the structural dynamics of an empty framework.

Highly efficient chiral separation of amlodipine enantiomers via triple recognition hollow fiber membrane extraction

In this study, a triple recognition chiral extraction process has been developed to separate (S)-amlodipine from racemic raw medicine, based on the combination of molecularly imprinted hollow fiber membrane and cross-flow biphasic recognition extraction. The chiral separation process was operated in a dismountable hollow fiber module coated with molecularly imprinted polymer, and the cross-flow extraction was applied with d-tartaric acid in feed phase and sulfobutyl ether-β-cyclodextrin in stripping phase. The synergistic effect of molecularly imprinted polymer and dual chiral additives was investigated, and excellent enantioseparation ability with a selectivity factor of 1.98 was obtained. Mathematical model of S/R=0.598e0.150NTU for racemic amlodipine separation by molecularly imprinted hollow fiber membrane extraction was established. The optical purity for amlodipine is up to 90% when 4 hollow fiber membrane modules of 25cm in length in series are used. The triple recognition process strongly enhanced the separation selectivity; therefore it may bring about the potentially application for large-scale production of pure enantiomeric compound.

Nanocellulose Derivative/Silica Hybrid Core-Shell Chiral Stationary Phase: Preparation and Enantioseparation Performance.

Core-shell silica microspheres with a nanocellulose derivative in the hybrid shell were successfully prepared as a chiral stationary phase by a layer-by-layer self-assembly method. The hybrid shell assembled on the silica core was formed using a surfactant as template by the copolymerization reaction of tetraethyl orthosilicate and the nanocellulose derivative bearing triethoxysilyl and 3,5-dimethylphenyl groups. The resulting nanocellulose hybrid core-shell chiral packing materials (CPMs) were characterized and packed into columns, and their enantioseparation performance was evaluated by high performance liquid chromatography. The results showed that CPMs exhibited uniform surface morphology and core-shell structures. Various types of chiral compounds were efficiently separated under normal and reversed phase mode. Moreover, chloroform and tetrahydrofuran as mobile phase additives could obviously improve the resolution during the chiral separation processes. CPMs still have good chiral separation property when eluted with solvent systems with a high content of tetrahydrofuran and chloroform, which proved the high solvent resistance of this new material.

Enantiomeric separation of oxybutynin by recycling high-speed counter-current chromatography with hydroxypropyl-β-cyclodextrin as chiral selector.

Recycling high-speed counter-current chromatography was successfully applied to the preparative separation of oxybutynin enantiomers. The two-phase solvent system consisted of n-hexane, methyl tert-butyl ether, and 0.1 mol/L phosphate buffer solution (pH = 5.0) with the volume ratio of 6:4:10. Hydroxypropyl-β-cyclodextrin was employed as the chiral selector. The influence of factors on the chiral separation process, including the concentration of chiral selector, the equilibrium temperature, the pH value of the aqueous phase were investigated. Under optimum separation conditions, 15 mg of oxybutynin racemate was separated with the purities of both the enantiomers over 96.5% determined by high-performance liquid chromatography. Recovery for the target compounds reached 80-82% yielding 6.00 mg of (R)-oxybutynin and 6.15 mg of (S)-oxybutynin. Technical details for recycling elution mode were discussed.

Preparation and chromatographic characteristics of a novel 2,6-dimethyl-β-CD bonded HPLC chiral stationary phase

Abstract A novel 2,6-dimethyl-β-CD bonded and silica based HPLC chiral stationary phase (CSP) was prepared. The diphenylmethane diisocyanate (MDI) was applied for the first time in the immobilization of 2,6-dimethyl-β-CD onto the surface of aminized silica gel under mild conditions. The composite materials obtained were used as the CSP for chiral separation processes and this kind of CSP exhibits good enantioselectivity for a variety of chiral compounds under reversed-phase conditions.

Synthesis of a nano-sized chiral imprinted polymer and its use as an (S)-atenolol carrier in the bulk liquid membrane.

In this work, nanosized chiral imprinted polymers containing (S)-atenolol ((S)-ATN) selective sites were synthesized by using suspension polymerization in silicon oil. (S)-ATN, methacrylic acid, and ethylene glycol dimethacrylate were used as enantiomerically pure template, functional monomer, and cross-linker, respectively. The prepared chiral imprinted polymers were used as the carrier elements in a bulk liquid membrane (BLM). (S)-ATN transport capability of the chiral imprinted polymers was compared with that of the nonimprinted polymer. It was shown that chiral imprinted polymers could transport (S)-ATN through the BLM more effectively than (R)-ATN, whereas no difference in the facilitated transport was observed between (R)-ATN and (S)-ATN when using nonimprinted polymer particles as the carrier element in the BLM. A kinetic model was proposed for the transportation of (S)-ATN through the chiral imprinted polymers based BLM. It was found that the extraction of ATN from the source to the membrane controls the chiral separation process. It was also found that the pH of source and receiving phases as well as the racemic ATN concentration in source phase had very crucial effect on the chiral separation efficiency.