Chiral Selector Research Articles

An extended model for chirality selection in single-walled carbon nanotubes.

The chirality selective production of single-walled carbon nanotubes (SWCNTs) continues to represent one of the most important technological challenges. In this study, an extended model which considers all steps of the SWCNT growth process, including adsorption, decomposition, diffusion, and incorporation, is applied, for the first time, to obtain chirality selection in the SWCNT populations. We show that the dependence of the population distribution on chirality, defined as a product of the nucleation probability and the growth rate, has a volcano-shape. The model is in good agreement with the reported experimental studies and supports the results which show the surplus of near armchair or near zigzag SWCNTs. The present work emphasizes the role of the catalyst in chirality selection via optimization of chemisorption strength between the carbon species and the catalyst surface needed to achieve stable nucleation and fast growth rates. The obtained results can be used in catalyst designs to define the pathways towards the growth of SWCNTs with specific chiralities exhibiting distinguished electronic properties.

Chiral selectivity vs. noise in spontaneous mirror symmetry breaking.

Mirror symmetry breaking bifurcations, that occur in nonlinear chemical systems leading to final chiral states with very large enantiomeric excess, can be exploited as an efficient chiral signal selector for even the smallest chiral polarizations. This effect of the chiral polarization requires the system's capacity for overcoming thermal noise, which is manifested as fluctuating reaction rate constants. Therefore, we investigate the chiral selectivity across a range of tiny parity-violating energy differences (PVED) in the presence of inevitable non-equilibrium temperature fluctuations. We use a stochastic differential equation simulation methodology (Ito process) that serves as a valuable tool in open systems for identifying the thresholds at which the chiral force induces chiral selectivity in the presence of non-equilibrium temperature fluctuations. This approach enables us to include and analyze chiral selectivity in the presence of other types of fluctuations, such as perturbations in the rate of fluid flow into and out of the reactor and in the clamped input concentrations. These concepts may be of practical interest (i.e., spontaneous deracemizations) but are also useful for a better understanding of the general principles governing the emergence of biological homochirality.

Evaluation of kasugamycin as a chiral selector in capillary electrophoresis.

The discovery of novel chiral selectors always fascinates us. This work describes the chiral separation performances of a new chiral selector (kasugamycin, KAS) in capillary electrophoresis (CE) for six pairs of stereoisomers, including ephedrine and pseudoephedrine, quinine and quinidine, cinchonine and cinchonidine, and amlodipine, promethazine and ofloxacin enantiomers. Kasugamycin, an aminoglycoside antibiotic in agriculture, shows significant biological activity against rice blast with low toxicity. As it turns out, this new chiral selector possesses good CE compatibility and stereoselectivity towards model analytes. In this work, we systematically investigated several separation parameters including kasugamycin concentration, buffer pH, separation voltage and the composition of the buffer solution. A detailed discussion about the chiral recognition mechanism was made based on Statistical Product and Service Solution (SPSS) analysis, NMR experiments (1D and 2D) and molecular modeling. This is the first time that kasugamycin is utilized as a chiral selector in CE, and the development of new chiral selectors from agricultural or veterinary antibiotics deserves more attention.

Novel approaches to the formation of coatings based on gold nanoparticles and albumin for chiral separation in capillary electrophoresis

Combination of properties of gold nanoparticles and bovine serum albumin is promising for the formation of chiral stationary phases enabling high enantioselectivity due to developed surface of coatings and increased chiral selector concentration on the capillary walls. In this work we proposed and compared two approaches to the formation of physically adsorbed multilayer coatings based on citrate-stabilized gold nanoparticles (cGNP) and bovine serum albumin (BSA) for the chiral separation in capillary electrophoresis. In the first approach pre-synthesized cGNP modified with BSA were immobilized on the capillary coated by poly(diallyldimethylammonium chloride) (PDADMAC). PDADMAC polymer was used as a binding layer promoting sorption of the nanoparticles on the capillary surface. It was shown that cGNP-BSA was poorly adsorbed on the capillary surface due to low zeta potential and could not be used for the formation of dense coatings. The second approach included sequential layer-by-layer deposition of PDAMAC and cGNP, resulting in the formation of a dense layer of nanoparticles. The main stage included in-capillary functionalization of cGNP with BSA. Scanning electron microscopy confirmed that the layer-by-layer deposition of modifiers ensured the formation of dense layer of nanoparticles on the capillary surface. The coating was stable in the entire range of pH studied (2–10). The application of such coating allowed reduction of BSA concentration (to 5 μM) in the background electrolyte required for the tryptophan enantiomers separation. It confirms the prospectiveness of combining nanoparticles and chiral selectors for the increase of specific surface area of the capillary inner walls.

Surface modified nanoparticles and their applications for enantioselective detection, analysis, and separation of various chiral compounds.

The development of efficient enantioselective detection, analysis, and separation relies significantly on molecular interaction. In the scale of molecular interaction, nanomaterials have a significant influence on the performance of enantioselective recognitions. The use of nanomaterials for enantioselective recognition involved synthesizing new materials and immobilization techniques to produce various surface-modified nanoparticles that are either encapsulated or attached to surfaces, as well as layers and coatings. The combination of surface-modified nanomaterials and chiral selectors can improve enantioselective recognition. This review aims to offer engagement insights into the production and application of surface-modified nanomaterials to achieve sensitive and selective detection, better chiral analysis, and separation of numerous chiral compounds.

A paper-based chemical tongue based on the charge transfer complex of ninhydrin with an array of metal-doped carbon dots discriminates natural amino acids and several of their enantiomers.

Simultaneous detection of multiple amino acids (AAs) instead of individual AAs is inherently worthwhile for improving diagnostic accuracy in clinical applications. Here, a facile and reliable colorimetric microfluidic paper-based analytical device (μPAD) using carbon dots doped with transition metals (Cr3+, Mn2+, Fe3+, Co2+, Ni2+, Cu2+, and Zn2+) has been provided to detect and discriminate 20 natural amino acids. To make the colourless metal-doped carbon dots suitable for colorimetric assays, they were mixed with ninhydrin to form a charge transfer complex. This optical tongue system, which was constructed by dropping mixtures of ninhydrin with a series of metal-doped carbon dots on a paper substrate in an array format, represented obvious but different colorimetric signatures for every examined amino acid. Since bovine serum albumin was used as a chiral selector reagent for synthesizing the CDs, the sensor device represented excellent selectivity to identify enantiomeric species of AAs. This is the first optical array device that can simultaneously discriminate AAs and several of their enantiomers. We employed various statistical and chemometric methods to analyze the digital data library collected by Image J software, including principal component analysis (PCA), linear discriminant analysis (LDA), and hierarchical cluster analysis (HCA). Twenty AAs could be well distinguished at various concentrations (10.00, 5.00, 2.50, and 1.25 mM). The colorimetric patterns were highly repeatable and were characteristic of individual AAs. Besides qualitative analysis, the designed μPAD-based optical tongue represented quantitative analysis ability, e.g., for lysine in the concentration ranges of 0.005-20.0 mM with a detection limit of 1.0 × 10-6 M and for arginine in the concentration range of 0.12-20.00 mM with a detection limit of 80.0 × 10-6 M. In addition, the binary, ternary, and quaternary mixtures of AAs could also be well recognized with this sensor.

Mechanism of low-temperature helical streamer discharge driven by pulsed electromagnetic field

Under the condition of specific pulsed discharge parameters, the discharge mode conversion of the low-temperature plasma jet discharge channel that originally propagates along a straight line will occur, forming a three-dimensional helical plasma channel. Unlike the traditional helical wave discharge, there are no factors such as an external constant magnetic field that destroys the poloidal symmetry of the dielectric tube, and the chiral direction of the helical streamer will change with the discharge parameters. In order to understand in depth the electromagnetic mechanism of the helical structure in the plasma jet, and the source and influencing factors of the poloidal electric field that leads to the helical shape and determines the chirality in this new type of discharge, we analyze the complex characteristics and electromagnetic mechanism of the helical streamer, such as the chiral direction, pitch, branching, by establishing a self-consistent plasma theoretical model. It is found that the phase of the poloidal wave mode has an effect on the chiral selection of the helical streamer, that the electron density has an influence on the pitch of the streamer, and that the repetition frequency has an effect on the bifurcation point. The above discharge characteristics and their influencing factors are of scientific significance in exploring the interaction mechanism of electromagnetic wave and plasma, and also in providing experimental and theoretical support for the chiral application of low-temperature plasma.

DNA methylation induces subtle mechanical alteration but significant chiral selectivity.

DNA methylation is a major epigenetic modification that is closely related to human health. Many experimental techniques as well as theoretical methods have been used to detect the modified nucleotides and identify their effects on molecular binding. It remains challenging to resolve the effect of few methylations of nucleic acids. Using super-resolution force spectroscopy, we firstly revealed that single cytosine methylation increases the mechanical stability of the DNA duplex by 1.9 ± 0.3 pN. Methylation also induces significant chiral selectivity towards drug molecules such as d,l-tetrahydropalmatine. Our results precisely quantify the mechanical effect of methylation and suggest that drug design should take methylation into consideration for enhanced selectivity.

Chiral implications on Fmoc-dipeptide self-assembly and catalytic kinetics of thermolysin

It is well known that the diverse biocatalysis in living systems are chirality-dependent, but so far, the principle has not been fully revealed. Hence, series of fluorenylmethoxycarbonyl-dipeptide (Fmoc-dipeptide) substrates are designed and varied in sequence and amino acid chirality to further explore the chiral catalytic kinetics of thermolysin. The results demonstrate that the chirality features of the constituent amino acids of Fmoc-dipeptides have significant effect on their supramolecular morphology and chirality. In the thermolysin-catalyzed reaction, the enzyme shows stereoselectivity and preferably screens out the dipeptide substrates consisting solely of l-amino acids to perform catalytic action. The presence of d-amino acids at either end of the target peptide bond will significantly resistant to the catalysis by thermolysin, leading to the catalytic efficiency reduced from 63.8 %-100 % to less than 9.6 %. This is well explained by the molecular docking results that the binding distance for the d-amino acid-containing group is found to be 1.8, 1.4 and 1.7-folds than the corresponding group composed entirely of l-amino acids, respectively. This study is helpful to better understand the specific chiral selection mechanism for enzyme catalysis in biological process, and may have some guidelines for biocatalysis. Furthermore, our findings may provide meaningful insights into understanding the occurrence of the diseases associated with the accumulation of d-amino acids in human body.

Selective growth of metallic single-walled carbon nanotubes via the application of high magnetic fields of 10 T

The structure of carbon materials can be controlled using a magnetic field, enhancing their functional properties. Most of the magnetic-field effects on carbon material growth were found to originate from the magnetic-field orientation. However, we observed that the magnetic-field orientation did not affect the growth of single-walled carbon nanotubes (SWCNTs); instead, under a magnetic field of 10 T, the preferential growth of metallic SWCNTs (1-nm diameter) was observed using chemical vapor deposition and liquid decomposition, suggesting chirality selectivity. Raman and X-ray photoelectron spectra showed that the defect structure and oxygen content of SWCNTs increased with increasing magnetic-field intensity. Therefore, thin metallic nanotubes can be selectively grown by applying a high magnetic field in environments where nanotubes are relatively difficult to form.

Microspherical polystyrene-divinylbenzene particles hybridized with eremomycin stabilized gold nanoparticles as a stationary phase for chiral liquid chromatography

A novel enantioselective adsorbent was obtained by hybridization of microspherical polystyrene-divinylbenzene (PS-DVB) macroporous particles with eremomycin-stabilized gold nanoparticles (GNPs). Macrocyclic antibiotic eremomycin was used as a stabilization agent to obtain GNPs which were then characterized by transmission electron microscope. The average diameter of obtained nanoparticles is about 16.6 nm. Eremomycin-stabilized nanoparticles were successfully embedded into the porous polymer structure with a resulting chiral selector content of 37.5 pmol/g. The obtained PS-DVB composite containing GNPs with immobilized eremomycin was studied by scanning electron microscopy and diffuse reflectance spectroscopy. The values of the specific surface area (500 m2/g) and porosity of the adsorbent (0.39 cm3/g) are measured using nitrogen adsorption at low temperatures. The obtained composite material was used as a chiral stationary phase of liquid chromatography. A good separation enantio-selectivity to amino acids, their derivatives and beta-blockers under RPC (reversed-phase) and HILIC (Hidrophilic Interaction Liquid Chromatography) mode is demonstrated. The results obtained revealed that the prepared Eremo@GNP@PS-DVB composite is promising for use as a stationary phase in HPLC.

Recognition of d-Glucose in Water with Excellent Sensitivity, Selectivity, and Chiral Selectivity Using γ-Cyclodextrin and Fluorescent Boronic Acid Inclusion Complexes Having a Pseudo-diboronic Acid Moiety.

Fluorescence recognition of d-glucose in water with excellent sensitivity, selectivity, and chiral selectivity is desired because d-glucose is an essential component in biological and pathological processes. We report an innovative approach that exploits the 1:2 stoichiometric inclusion complexes of γ-cyclodextrin (γ-CyD) with two molecules of fluorescent monoboronic acid-based receptors, which form a pseudo-diboronic acid moiety as the recognition site for d-glucose in water. Two monoboronic acids (1F and 2N) were easily synthesized without heating or column purification. The 1:2 stoichiometric inclusion complexes (1F/γ-CyD and 2N/γ-CyD) were prepared in a mixture of dimethyl sulfoxide/water (2/98 in v/v) by mixing γ-CyD and the corresponding monoboronic acids. Both 1F/γ-CyD and 2N/γ-CyD exhibited strong turn-on response to d-glucose with excellent selectivity over nine other saccharides in the water-rich solvent at pH 7.4 owing to the ditopic recognition of d-glucose by the pseudo-diboronic acid moieties. The limits of detection of 1F/γ-CyD and 2N/γ-CyD for d-glucose were 1.1 and 1.8 μM, respectively, indicating the remarkable sensitivity for the detection of d-glucose at μM levels. 1F/γ-CyD and 2N/γ-CyD also demonstrated chiral-selective recognition of d-glucose, which is apparent from the 2.0- and 6.3-fold enhancement of fluorescence by the addition of d-glucose relative to l-glucose addition, owing to the chiral pseudo-diboronic acid moieties produced by the chiral γ-CyD cavity. To the best of our knowledge, 2N/γ-CyD has the highest d/l selectivity among hitherto reported fluorescent diboronic acid-based receptors.

Use of chiral ionic liquid as additive for synergistic enantioseparation of basic drugs in capillary electrophoresis

This work presents a synergistic system for enantioseparation in capillary electrophoresis (CE) with a chiral ionic liquid (CIL) based on D-10-camphorsulfonic acid as additive and carboxymethyl-β-cyclodextrin (CM-β-CD) as the chiral selector. The proposed method showed excellent enantioseparation performance towards sixteen chiral drugs. In contrast to the single CM-β-CD system, the notably improved resolution (Rs) and selectivity factor (α) of model drugs were observed in synergistic system. Several key parameters such as CIL concentration, CM-β-CD concentration, buffer pH and separation voltage were investigated, after which Statistical Product and Service Solutions (SPSS) was used to prove the potential synergistic effect. The nuclear magnetic resonance (NMR) results further demonstrated the function of the CIL and the superiority of synergistic system. Finally, chiral impurity determination of chlorpheniramine maleate sample was successfully carried out using the established method.

Simultaneous Determination of Escitalopram Impurities including the R-enantiomer on a Cellulose tris(3,5-Dimethylphenylcarbamate)-Based Chiral Column in Reversed-Phase Mode.

A high-performance liquid chromatographic method was developed for the simultaneous determination of the related substances-three potential synthesis-related chemical impurities and the distomer-of escitalopram. The separation capacity of seven different polysaccharide-type chiral columns, including three amylose-based (Lux Amylose-1, Lux i-Amylose-1, Lux Amylose-2) and four cellulose-based columns (Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3, and Lux Cellulose-4) were screened in the polar organic and reversed-phase modes. Lux Cellulose-1, based on cellulose tris(3,5-dimethylphenylcarbamate) as the chiral selector with an acetonitrile-water mixture containing 0.1% diethylamine was identified as the most promising separation system. Using the "one factor at a time" optimization approach, the effect of column temperature, flow rate, and mobile phase constituents on separation performance was evaluated, and the critical resolution values were determined. A U-shaped retention pattern was obtained when plotting the retention factors of the citalopram enantiomers versus the water content of the binary mobile phases on the Lux Cellulose-1 column. A thermodynamic analysis revealed enthalpy-driven enantioseparation in both the polar organic and reversed-phase modes. For further method optimizations, an L9 orthogonal array table was employed. Using the optimized parameters (Lux Cellulose-1 column with 0.1% (v/v) diethylamine in water/acetonitrile 55/45 (v/v); 0.8 mL/min flow rate at 25 °C), baseline separations were achieved between all compounds. Our newly developed HPLC method was validated according to the ICH guidelines and its application was tested with a commercially available pharmaceutical formulation. The method proved to be suitable for routine quality control of related substances and the enantiomeric purity of escitalopram.

Method Development, Optimization, and Validation of the Separation of Ketamine Enantiomers by Capillary Electrophoresis Using Design of Experiments

Capillary electrophoresis was chosen as cost-effective and robust method to separate ketamine enantiomers. For the method development, first different native and modified cyclodextrins were tested. The most promising chiral selector was α-cyclodextrin. A design of experiments (DoE) was carried out, which started with the screening of relevant factors. Based on these results, the method was optimized according to the significant factors (buffer, cyclodextrin concentration, pH value, voltage, temperature) of the screening based on the response resolution and migration time of the later migrating enantiomer. The optimized conditions consisted of a background electrolyte with 275 mM TRIS, adjusted with 85% phosphoric acid to a pH of 2.50, and 50 mM α-cyclodextrin, at a temperature of 15 °C, an applied voltage of 30 kV and an injection pressure of 1.0 psi for 10 s. A fused-silica capillary with a total length of 70 cm and an effective length to the detector of 60 cm was used. The method was validated according to ICH guideline Q2 R(1). The limit of quantification was 3.51 µg mL−1 for S-ketamine and 3.98 µg mL−1 for R-ketamine. The method showed good linearity for racemic ketamine with R2 of 0.9995 for S-ketamine and 0.9994 for R-ketamine. The lowest quantifiable content of S-ketamine found in R-ketamine was 0.45%.

Development of a capillary electrophoretic method for determination of ketorolac enantiomers in human plasma using cationic β-cyclodextrin derivative as a chiral selector.

A novel approach for the separation of ketorolac enantiomers by capillary electrophoresis is presented. A cationic β-cyclodextrin derivative based on imidazole was synthesized and used as a chiral selector in the background electrolyte. The influence of pH and ionic strength of background electrolyte, as well as cationic β-cyclodextrin derivative concentration on the resolution of ketorolac enantiomers, was investigated. The highest value of the resolution for ketorolac enantiomers was 1.46 when the background electrolyte consisted of 25mM NaH2 PO4 (pH 6.4) with 1mM 1-butyl-3-β-cyclodextrinimidazolium tosylate. Additionally, the possibilities of cationic derivatives for the separation of ketoprofen enantiomers were shown (peak resolution 1.06). The two-step preconcentration mode was developed to reduce the limit of detection of individual enantiomers. The proposed approach was successfully applied to determine ketorolac enantiomers in tablet "Ketorol express" and human plasma. The calibration range of ketorolac enantiomers for plasma samples was 0.25-2.50μg/ml with coefficients of determination ≥ 0.99. The relative standard deviation both of the peak area and migration time was less than 15%, as well as the accuracy ranged from 90.1% to 110.2% for both analytes. The limits of detection were 44 and 55ng/ml for R- and S-ketorolac. The quantity of ketorolac in plasma was verified with high-performance liquid chromatography.

Poly(carboxyethyl acrylate-co-ethylene glycol dimethacrylate) precursor monolith with bonded (S)-(-)-1-(2-naphthyl) ethylamine ligands for use in chiral and achiral separations by capillary electrochromatography

In this research report, the previously developed poly(carboxyethyl acrylate-co-ethylene glycol dimethacrylate) precursor monolith (referred to as carboxy monolith) is further exploited in the preparation of a chiral stationary phase for enantiomeric separations. The carboxy monolith precursor was subjected to post polymerization functionalization (PPF) with the chiral selector (S)-(-)-1-(2-naphthyl) ethylamine (NAS) at room temperature in the presence of N, N´-dicyclohexylcarbodiimide (DCC) in chloroform. The DCC, which is an organic soluble carbodiimide, permits the linkage for the amine functionality of the chiral ligand NAS to the carboxy group of the monolithic surface forming a stable amide linkage. The NAS column thus obtained allowed not only enantiomeric separations in the RP mode via its chiral site but also the separation of nonpolar species via its achiral functionality offering both hydrophobic and π-π interactions for aromatic compounds such toluene derivatives and polyaromatic hydrocarbons. The dual interaction sites (e.g., chiral, and achiral) of the NAS present a convenient column for the separations of slightly polar and nonpolar chiral and achiral solutes in the RP mode.

Enantioselective CE-MS analysis of ketamine metabolites in urine.

The chiral drug ketamine has long-lasting antidepressant effects with a fast onset and is also suitable to treat patients with therapy-resistant depression. The metabolite hydroxynorketamine (HNK) plays an important role in the antidepressant mechanism of action. Hydroxylation at the cyclohexanone ring occurs at positions 4, 5, and 6 and produces a total of 12 stereoisomers. Among those, the four 6HNK stereoisomers have the strongest antidepressant effects. Capillary electrophoresis with highly sulfated γ-cyclodextrin (CD) as a chiral selector in combination with mass spectrometry (MS) was used to develop a method for the enantioselective analysis of HNK stereoisomers with a special focus on the 6HNK stereoisomers. The partial filling approach was applied in order to avoid contamination of the MS with the chiral selector. Concentration of the chiral selector and the length of the separation zone were optimized. With 5% highly sulfated γ-CD in 20mM ammonium formate with 10% formic acid and a 75% filling the four 6HNK stereoisomers could be separated with a resolution between 0.79 and 3.17. The method was applied to analyze fractionated equine urine collected after a ketamine infusion and to screen the fractions as well as unfractionated urine for the parent drug ketamine and other metabolites, including norketamine and dehydronorketamine.

Chiral Separations of Pyrethroic Acids Using Cyclodextrin Selectors.

Pyrethroid insecticides are broadly used. They have low toxicity for warm-blooded living creatures, but high toxicity for both insects and fish. Therefore, it is important to reduce the environmental impact of pyrethroids. Pyrethroic acids are chiral compounds. An effective way to decrease pollution is to use enantio-pure insecticide products instead of their racemic mixtures. Enantiomer-pure products require enantiomer selective synthesis and analysis. The chiral selective analysis of pyrethroic acids (an intermediate of pyrethroids) is also important in terms of process control and from the point of view of their degradation metabolism in the environment. This study used various enantiomeric selective chromatographic methods for the separation of different pyrethroic acids, including gas chromatography, supercritical fluid chromatography and capillary electrophoresis. Systematic experiments were conducted to find the optimum conditions for their chiral separation. The employed enantio-selective agents were cyclodextrin derivatives with different ring sizes and substitution patterns. The β-cyclodextrin proved to be excellent for the chiral separation of these acids. The different chiral recognition mechanisms were established using different ring-sized cyclodextrins. The results of these systematic studies demonstrated the correlations of the chiral selectivity features of selectors and the structures of analytes.

Chirality logic gates.

The ever-growing demand for faster and more efficient data transfer and processing has brought optical computation strategies to the forefront of research in next-generation computing. Here, we report a universal computing approach with the chirality degree of freedom. By exploiting the crystal symmetry-enabled well-known chiral selection rules, we demonstrate the viability of the concept in bulk silica crystals and atomically thin semiconductors and create ultrafast (<100-fs) all-optical chirality logic gates (XNOR, NOR, AND, XOR, OR, and NAND) and a half adder. We also validate the unique advantages of chirality gates by realizing multiple gates with simultaneous operation in a single device and electrical control. Our first demonstrations of logic gates using chiral selection rules suggest that optical chirality could provide a powerful degree of freedom for future optical computing.