Chiral Differentiation Research Articles

Chiral differentiation of limonene in chiral nematic liquid crystals.

Chirality is of great importance in physical and biological systems. It helps differentiate chemical reactions and physical processes. It was reported that the diffusion of mesogenic chiral guests in chiral nematic liquid crystal hosts profoundly depends on the chirality of the guest and host molecules. When the guest and host molecules have the same handedness, the diffusion is much faster than that when the guest and host molecules have the opposite handedness. In this paper, we report the discovery that chiral differentiation also exists in the diffusion of limonene, which is non-mesogenic in chiral nematic liquid crystals. The diffusion of l-limonene (right-handed) in chiral nematic liquid crystals with a right handed helical structure is faster than that of d-limonene (left-handed). This result might be important in understanding the effects of chirality on physical processes that take place in biological systems. In addition, this effect could be utilized for enantiomer separation in the pharmaceutical industry.

Exploring the Self-Assembled Tacticity in Aurophilic Polymeric Arrangements of Diphosphanegold(I) Fluorothiolates.

Despite the recurrence of aurophilic interactions in the solid-state structures of gold(I) compounds, its rational control, modulation, and application in the generation of functional supramolecular structures is an area that requires further development. The ligand effects over the aurophilic-based supramolecular structures need to be better understood. This paper presents the supramolecular structural diversity of a series of new 1,3-bis(diphenylphosphane)propane (dppp) gold(I) fluorinated thiolates with the general formula [Au2(SRF)2(μ-dppp)] (SRF = SC6F5 (1); SC6HF4-4 (2); SC6H3(CF3)2-3,5 (3); SC6H4CF3-2 (4); SC6H4CF3-4 (5); SC6H3F2-3,4 (6); SC6H3F2-3,5 (7); SC6H4F-2 (8); SC6H4F-3 (9); SC6H4F-4 (10)). These compounds were synthesized and characterized, and six of their solid-state crystalline structures were determined using single-crystal X-ray diffraction. In the crystalline arrangement, they form aurophilic-bridged polymers. In these systems, the changes in the fluorination patterns of the thiolate ligands tune the aurophilic-induced self-assembly of the compounds causing tacticity and chiral differentiation of the monomers. This is an example of the use of ligand effects on the tune of the supramolecular association of gold complexes.

Chiral Differentiation of Non-Covalent Diastereomers Based on Multichannel Dissociation Induced by 213-nm Ultraviolet Photodissociation.

Here we present the implementation of 213-nm ultraviolet photodissociation (UVPD) in a FT-ICR mass spectrometer for chiral differentiation in the gas phase. The L/D amino acid-substituted serine octamer ions were selected as examples of diastereoisomers for chiral analysis. Several kinds of fragment ions were observed in these experiments, including fragment ions that are similar to the ones observed in corresponding collision-activated dissociation (CAD) experiments, fragment ions generated with different protonation sites by only destroying non-covalent bonds, and unique non-covalent cluster radical ions. The latter two kinds of fragment ions are found to be more sensitive to the chirality of the substituted units. Further experiments suggest that the formation of radical ions is mainly affected by chromophores on side chains of the substituted units and micro surroundings of the characterized non-covalent diastereoisomers. A comparing experiment performed by only changing the wavelength of UV laser to 266nm shows that the 213-nm UV laser has the priority in the diversity of fragmentation pathways and potential of further application in chiral differentiation experiments.

Chirality Discrimination at the Single Molecule Level by Using a Cationic Supermolecule Quasi-Gated Organic Field Effect Transistor.

Achieving rapid and highly sensitive small molecule chiral discrimination is a great challenge in modern-day analytical sciences. Herein, an organic field effect transistors (OFET) is developed by employing an imidazolium 3,5-dimethylphenylcabamoylated-β-cyclodextrin (Im+-Ph-β-CD) as both the recognition unit and a quasi gate, which induces a secondary accumulation channel of electrons in the n-type transistor to achieve the signal transduction and amplification via field effect. The charge of the imidazolium group is partially shielded due to its self-inclusion in the CD cavity, and this shielding effect is reduced at varying degrees in the existence of isomers due to the competitive inclusion. Consequently, the different weak intermolecular interactions related to the target-induced CD-enantiomer complexation with different geometry and stabilization energy for each isomer can be transformed to electronic signals based on the variety of Im+-Ph-β-CD's effective charge rather than the intrinsic charge of analytes, hence leading to chiral differentiation, and the hydrogen-bonding network of Im+-Ph-β-CD membrane further magnifies the signal. This working strategy even allows chiral discrimination of electrically neutral analytes. The as-prepared sensor affords rapid and real-time discrimination to small molecule enantiomers at single molecule level with a limit of detection of 8.1 × 10-19 M in a 200 μL volume (about 100 small molecules). Moreover, we prove the great potential of the chiral organic field effect transistor in quantitative analysis of commercial medicines.

Direct differentiation of stereoisomers of ezetimibe/ambrisentan/atorvastatin and their mechanism study by electrospray ionization quadrupole time-of-flight mass spectrometry.

A mass spectrometric method is introduced for rapid and accurate chiral quantification by examining a trimeric metal complex into which a chiral reference is incorporated with the analyte. Several metal ions (CuII , NiII , MgII , MnII , CoII , and ZnII ) were selected as the central metal ion, and chiral drugs ezetimibe (EZM) and ambrisentan (AMB) were used as the reference to each other for isomeric differentiation by using electrospray ionization quadrupole time-of-flight mass spectrometry. Doubly charged trimeric cluster ions instead of the singly charged clusters were applied in this study. Kinetic method (KM) and chiral recognition (CR) method were used for construction of a calibration curve for chiral quantitation. The results from the two methods were found to be complementary to each other, which improved quantitative analysis of stereoisomers for EZM. Furthermore, we have successfully used S-AMB as reference for the chiral differentiation of enantiomeric atorvastatin (ATO), which is frequently combined with EZM as a codrug. Experimental results showed that the binary mixture of EZM and ATO enantiomers can be determined simultaneously without prior separation steps. The direct measurement of chiral purity within 5% was demonstrated. This mass spectrometric method represents an effective alternative to commonly used chromatographic techniques as means of chiral purity determination and is of potential use in rapid screening experiments.

Simultaneous chiral impurity analysis of methamphetamine and its precursors by supercritical fluid chromatography–tandem mass spectrometry

Impurity profiling of seized illicit methamphetamine (MA) provides information on MA manufacturing methods in clandestine laboratories, and this drug intelligence supports formulation of strategies to control MA abuse. In the present study, we developed a simultaneous chiral analysis method for MA and its precursors using supercritical fluid chromatography–tandem mass spectrometry equipped with an enantioselective stationary phase. Chromatographic conditions were optimized by systematic investigation of the flow rate, temperature, back pressure, co-solvent, additive, and mobile phase composition. The ability of the developed method was evaluated using standard and authentic illicit MA. The use of a chiral selector in the stationary phase allowed for simultaneous chiral differentiation of MA and its precursors including ephedrine, norephedrine, chloropseudoephedrine, methylephedrine, dimethylamphetamine, and amphetamine. Sufficient limit of detection, repeatability of retention time, and linearity were achieved. A switching valve interfacing a chromatograph and a mass spectrometer enabled analyzing large amounts of MA directly. The application to the authentic illicit MA samples was achieved and revealed the existence of impurities, which was not detected by conventional gas chromatography–mass spectrometry. The developed supercritical fluid chromatography–tandem mass spectrometry method could be a powerful analytical tool for MA impurity profiling.

Molecular recognition of flunarizine dihydrochloride and \u03b2-cyclodextrin inclusion complex by NMR and computational approaches

BackgroundFlunarizine dihydrochloride (FLN) is used in the prophylactic treatment of migraine, vertigo, occlusive peripheral vascular disease and epilepsy. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocycles known for their inner hydrophobic and outer hydrophilic site. They form complexes with hydrophobic drug molecules and enhance the solubility and bioavailability of such compounds by enhancing drug permeability through mucosal tissues. NMR spectroscopy and computational docking have been recognized as an important tool for the interaction study of CDs-drug inclusion complexes in solution state.ResultsThe structural assignments of FLN and β-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, β-CD and their mixtures confirmed the formation of β-CD-FLN inclusion complex in solution. 1H NMR titration data for β-CD-FLN inclusion complex showed 1:1 stoichiometry, an association constant of Ka = 157 M−1 and change in Gibbs free energy of ∆G = − 12.65 kJ mol−1. The binding constant of the β-CD inclusion complex with two nearly similar structures, FLN and cetirizine dihydrochloride, were compared. Two-dimensional 1H-1H ROESY spectral data and molecular docking studies showed the modes of penetration of the aromatic rings from the wider rim side into the β-CD cavity. The possible geometrical structures of the β-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the β-CD truncated cone.ConclusionNMR spectroscopic studies of FLN, β-CD and FLN:β-CD mixtures confirmed the formation of 1:1 inclusion complex in solution at room temperature. Two-dimensional 1H-1H ROESY together with molecular docking study confirmed that the F-substituted aromatic ring of FLN penetrates into β-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of β-CD. The splitting of aromatic signals of FLN in the presence of β-CD suggests chiral differentiation of the guest FLN by β-CD.

Polarity tuned perphenylcarbamoylated cyclodextrin separation materials for achiral and chiral differentiation

Phenylcarbamoyls are known to remarkably accentuate cyclodextrin's enantioselectivities. In this work, by inducing electron-donating methoxyl or electron-withdrawing bromine/trifluoromethyl moieties, three novel cyclodextrin enantioseparation materials including per(4-trifluoromethoxy) phenylcarbamoylated-β-CD CSP (CSP1), per(4-bromo)phenylcarbamoylated-β-CD CSP (CSP2) and per(4-methoxy)phenylcarbamoylated-β-CD CSP (CSP3) were prepared via thiol-ene click chemistry. The polarity tuning decorations are found to significantly influence the CSPs’ achiral and chiral separation performance. The three CSPs can easily separate toluene, 1,2-xylene and 1,3,5-trimethylbenzene with the strongest retention on CSP3. In reversed-phase mode, the three CSPs exhibited completely different enantioseparation ability towards specific isoxazolines and flavonoids. 4′-hydroxyflavanone was separated on CSP1 with a resolution of 9.24 while 6-methoxyflavanone was best separated on CSP2 (Rs = 9.98). CSP3 exhibited the strongest differentiation ability towards 4NPh-2Py (Rs = 9.69). The comparison study may provide some insight into the design of functional cyclodextrin materials.

Cyclodextrin functionalized reduced graphene oxide for electrochemical chiral differentiation of tartaric acid

Tartaric acid (2,3-dihydroxybutanedioic acid, TA) is one of the major organic acids with a wide range of applications in industry and life.

Chiral differentiation of d- and l-isoleucine using permethylated β-cyclodextrin: infrared multiple photon dissociation spectroscopy, ion-mobility mass spectrometry, and DFT calculations.

Chiral differentiation of protonated isoleucine (Ile) using permethylated β-cyclodextrin (perCD) in the gas-phase was studied using infrared multiple photon dissociation (IRMPD) spectroscopy, ion-mobility, and density functional theory (DFT) calculations. The gaseous protonated non-covalent complexes of perCD and d-Ile or l-Ile produced by electrospray ionization were interrogated by laser pulses in the wavenumber region of 2650 to 3800 cm-1. The IRMPD spectra showed remarkably different IR spectral features for the d-Ile or l-Ile and perCD non-covalent complexes. However, drift-tube ion-mobility experiments provided only a small difference in their collision cross-sections, and thus a limited separation of the d- and l-Ile complexes. DFT calculations revealed that the chiral distinction of the d- and l-complexes by IRMPD spectroscopy resulted from local interactions of the protonated Ile with perCD. Furthermore, the theoretical results showed that the IR absorption spectra of higher energy conformers (by ∼13.7 kcal mol-1) matched best with the experimentally observed IRMPD spectra. These conformers are speculated to be formed from kinetic-trapping of the solution-phase conformers. This study demonstrated that IRMPD spectroscopy provides an excellent platform for differentiating the subtle chiral difference of a small amino acid in a cyclodextrin-complexation environment; however, drift-tube ion-mobility did not have sufficient resolution to distinguish the chiral difference.

Sulfated cyclodextrins as water-soluble chiral NMR solvating agents for cationic compounds

The utility of a series of sulfated cyclodextrins as water-soluble chiral NMR solvating agents for cationic substrates is described. Sulfated α-, β- and γ-cyclodextrin with degrees of substitution of 12, 13 and 14, respectively, a sulfated β-cyclodextrin with a degree of substitution of 9 and a sulfobutyl ether β-cyclodextrin with a degree of substitution of 6.3 are examined. Results with 33 water-soluble cationic organic salts are reported. Chiral differentiation with the sulfated cyclodextrins is compared to prior results obtained with anionic carboxymethylated and phosphated cyclodextrins. The highly sulfated cyclodextrins are often more effective at causing enantiomeric differentiation in 1H NMR spectra than the sulfobutyl ether, carboxymethylated and phosphated cyclodextrins, and are recommended as the first choice of a chiral solvating agent for the analysis of chiral cationic organic salts in aqueous solution.

Chiral differentiation of amino acids through binuclear copper bound tetramers by ion mobility mass spectrometry

In this study, travelling wave ion mobility mass spectrometry has been used to investigate chiral differentiation of common chiral amino acids, through separation of binuclear copper bound tetrameric ions formed with chiral selector tryptophan, proline, tyrosine, phenylalanine or histidine. Significant chiral recognition was observed for amino acids with aromatic rings or long and active side chains, with peak-to-peak resolutions up to 1.826. Tryptophan and histidine offered better enantioselectivity, compared to other chiral selectors. The results suggested that the mechanism for chiral recognition in ion mobility mass spectrometry might be significantly different from that in tandem mass spectrometry. Linear calibration curves were also established to allow determination of enantiomeric excess of the analytes by the approach. This study showed that higher assembly of chiral analyte and chiral selector might enable better chiral discrimination and ion mobility mass spectrometry could be a powerful technique for provide qualitative, quantitative and structural information of chiral analysis.

Layer-by-layer self-assembly of gold nanoparticles/thiols β-cyclodextrin coating as the stationary phase for enhanced chiral differentiation in open tubular capillary electrochromatography

The popularity of capillary electrochromatography (CEC) has led to an increasing number of studies on the development and evaluation of enantioselective CEC systems. Herein, a novel, simple, and economical method for the preparation of chiral stationary phases for enantioselective open tubular capillary electrochromatography (OTCEC) was reported for the first time. This novel capillary column was fabricated through layer-by-layer self-assembly of GNPs on a 3-mercaptopropyl-trimethoxysilane (MPTMS)-modified fused-silica capillary and subsequent surface functionalization of the GNPs through self-assembly of thiols β-cyclodextrin (SH-β-CD). With this method, monolayer and multilayer GNPs film capillary columns were prepared and evaluated using meptazinol and its three intermediate enantiomers as templates. Consequently, the three-layer GNPs capillary column was found to exhibit favorable enantioseparation performance. Factors that influence the chiral separation resolution were examined. Under the optimized conditions, enantioselectivity was obtained for meptazinol and its three intermediate enantiomers (intermediates Ⅱ, Ⅲ and Ⅳ) in less than 20min with resolutions of 2.05, 0.36, 1.67, 1.53, respectively. The proposed column revealed adequate repeatability concerning run-to-run and day-to-day. In brief, these results confirmed the use of GNPs as the electrochromatographic support can enhance the phase ratio of OTC column in capillary electrochromatography (CEC). Then, this proposed method was well validated with good linearity (≥0.999), recovery (92.0–94.5%) and repeatability, and was successfully used for enantioseparation of meptazinol in spiked urine samples, which indicated the new column's potential usage in biological analysis.

Phosphated cyclodextrins as water-soluble chiral NMR solvating agents for cationic compounds.

The utility of phosphated α-, β- and γ-cyclodextrins as water-soluble chiral NMR solvating agents for cationic substrates is described. Two sets of phosphated cyclodextrins, one with degrees of substitution in the 2–6 range, the other with degrees of substitution in the 6–10 range, are examined. Results with 33 water-soluble cationic substrates are reported. We also explored the possibility that the addition of paramagnetic lanthanide ions such as praseodymium(III) and ytterbium(III) further enhances the enantiomeric differentiation in the NMR spectra. The chiral differentiation with the phosphated cyclodextrins is compared to prior results obtained with anionic carboxymethylated cyclodextrins. There are a number of examples where a larger differentiation is observed with the phosphated cyclodextrins.

Chiral differentiation of d- and l-alanine by permethylated β-cyclodextrin: IRMPD spectroscopy and DFT methods.

The gaseous chiral differentiation of alanine by permethylated β-cyclodextrin was studied using IRMPD spectroscopy and density functional theory calculations. The protonated non-covalent complexes of permethylated β-cyclodextrin and d- or l-alanine were mass-selected and investigated by IR laser pulses in the wavelength region of 2650-3800 cm-1. The remarkably different features of the IRMPD spectra for d- and l-alanine are described, and their origin is elucidated by quantum chemical calculations. We show that the differentiation of the experimentally observed spectral features is the result of different local interactions of d- and l-alanine with permethylated β-cyclodextrin. We also assign the extremely high-frequency (>3700 cm-1) bands in the observed spectra to the stretch motions of completely isolated alanine -OH groups.

Investigation of l/d-threonine substituted l-serine octamer ions by mass spectrometry and infrared photodissociation spectroscopy

Threonine-substituted serine octamer ions were generated by electrospray ionization (ESI) and investigated by mass spectrometry and infrared photodissociation (IRPD) spectroscopy. IRPD spectra of [L-Ser7+L/D-Thr1]H+ and [L-Ser6+L/D-Thr2]H+ were obtained in the range of 2700–3600cm−1. Chiral differentiation was achieved by comparing their IRPD spectra. The main difference located in the range of 3300–3500cm−1. And the results indicate the substitution of L-Ser by D-Thr could weaken the intermolecular H-bonds and loosen the original structures of serine octamers.

Exploration of the Chiral Recognition of Sugar-Based Diindolylmethane Receptors: Anion and Receptor Structures.

In this study, we have conducted a systematic investigation of the chiral recognition of carboxylic anions by D-glucuronic acid/diindolylmethane receptors. We investigate the influence of the anion structure on chiral recognition in the diindolylmethane/glucuronic acid-based receptor 1 a. We found that presence of an additional hydrogen-bond donor at the α position to the carboxylic function is essential for effective chiral differentiation in these systems. Furthermore, we present a synthetic procedure that allows for the synthesis of sugar-decorated receptors that possess a modified substituent at the anomeric position. Four new receptors 1 b-e have been synthesized, and their chiral-discrimination ability toward model carboxylates is studied. The obtained results show that the chiral recognition of these receptors can be fine-tuned by incorporation of a proper substituent into the receptor structure.

Scalemic and racemic imprinting with a chiral crosslinker

The development of molecularly imprinted chiral stationary phases has traditionally been limited by the need for a chiral pure template. Paradoxically, availability of a chiral pure template largely defeats the purpose of developing a chiral stationary phase. To solve this paradox, imprinting of scalemic and racemic template mixtures was investigated using both chiral (N-α-bismethacryloyl-l-alanine) and achiral (N,O-bisacrylamide ethanolamine) crosslinkers. Imprinting of scalemic mixtures provided polymers capable of partial separation of Boc-tyrosine enantiomers with virtually the same results when using either the chiral or achiral crosslinker. However, the chiral crosslinker was required for chiral differentiation by the racemic imprinted polymers which were evaluated in both batch rebinding and chromatographic modes. Batch rebinding analysis revealed intersecting binding isotherms for the L- and D-Boc-tyrosine, indicating bias for the D or L enantiomer is concentration dependent. Partial chromatographic separation was achieved by the racemic imprinted polymers providing variable D or L bias in equal probability over multiple replicates of polymer synthesis. Correlation of enantiomer bias with the batch rebinding results and optimization of HPLC parameters are discussed.

ChemInform Abstract: Calixarenes and Calix[4]resorcinarenes as Chiral NMR Solvating Agents

AbstractReview: 51 refs.

‘Click’ preparation of a novel ‘native-phenylcarbamoylated’ bilayer cyclodextrin stationary phase for enhanced chiral differentiation

This paper reports an effective approach for the fabrication of a novel hybrid bilayer cyclodextrin (CD) chiral stationary phase (CSP), where native and perphenylcarbamoylated-β-CD were successively immobilized onto silica surface via a two-step click approach to form a bilayer CD structure. By decorating the bulky phenylcarbamoylated CD onto the unmodified CD silica, the CSP can provide multiple interaction sites such as H-bonding (OH, CO, NH), steric effects, π–π, dipole–dipole and inclusion complexation interactions, which help to broaden the CSP's enantioselectivity profile and enhance the enantioselectivity to some specific analytes. A group of enantiomer pairs such as isoxazolines, bendroflumethiazide, indoprofen, diperodon, fenoterol, atropine, styrene oxide and dansyl amino acids can be baseline or partially separated on the current CSP under reversed phase high performance liquid chromatography (RP-HPLC). The selectivity and resolution of 4NPh-OPr reached 5.25 and 13.97, which is an exciting achievement for the enantioseparations by CD CSPs.