Chiral Discrimination Research Articles

Enantioseparation on helical poly(diphenylacetylene)s bearing optically-active pendants: Effects of differences in higher-order structures of kinetically-trapped and thermodynamically-stable states on chiral recognition ability

An optically-active poly(diphenylacetylene) (PDPA) bearing carboxy pendant groups with left-handed helicity memory (M-h-poly-1), synthesized using the noncovalent helicity-induction-and-memory strategy, was converted into a PDPA bearing optically-active pendant groups through an amide bonding (M-hKT-poly-2S), while maintaining the left-handed helicity memory, by reaction with (S)-1-phenylethylamine ((S)-2) using a condensing reagent at room temperature. Its chiral recognition ability was investigated as a chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC). M-hKT-poly-2S exhibited significantly different chiral recognition ability towards racemates compared to the previously reported corresponding helical PDPA bearing the same optically-active pendant groups (M-hTS-poly-2S) (prepared by the reaction of an optically-inactive PDPA bearing carboxy pendants with (S)-2, followed by thermal annealing, to induce a left-handed helical structure in the polymer main chain). Although the main chains of both M-hKT-poly-2S and M-hTS-poly-2S formed almost completely left-handed helical structures, their higher-order structures varied slightly, as confirmed by various spectroscopic methods (UV-Vis, circular dichroism (CD), IR, and vibrational CD). M-hKT-TS-poly-2S, the PDPA formed on the thermal annealing of M-hKT-poly-2S, exhibited the same higher-order structure and chiral discrimination ability as M-hTS-poly-2S. Therefore, slight differences in the higher-order structures of the kinetically-trapped metastable state (M-hKT-poly-2S) and the thermodynamically-stable state (M-hTS-poly-2S), due to differences in synthetic procedures, significantly impact their chiral recognition abilities as CSPs, even with identical primary structures and helix-sense of the polymer main chain.

Side Group of Hydrophobic Amino Acids Controls Chiral Discrimination among Chiral Counterions and Metal–Organic Cages

The self-assembly of chiral Pd12L24 metal-organic cages (MOCs) based on hydrophobic amino acids, including alanine (Ala), valine (Val), and leucine (Leu), into single-layered hollow spherical blackberry-type structures is triggered by nitrates through counterion-mediated attraction. In addition to nitrates, anionic N-(tert-butoxycarbonyl) (Boc)-protected Ala, Val, and Leu were used as chiral counterions during the self-assembly of d-MOCs. Previously, we showed that l-Ala suppresses the self-assembly process of d-Pd12Ala24 but has no effect on l-Pd12Ala24, i.e., chiral discrimination. Here, we indicate when the amino acid used as the chiral counterion has a bulkier side group than the amino acid in the MOC structure, no chiral discrimination exists; otherwise, chiral discrimination exists. For example, Ala can induce chiral discrimination in all chiral MOCs, whereas Leu can induce chiral discrimination only in Pd12Leu24. Moreover, chiral anionic d- and l-alanine-based surfactants have no chiral discrimination, indicating that bulkier chiral counterions with more hydropohobic side groups can erase chiral discrimination.

Functional metal-based 3D-printed electronics engineering: Tunability and bio-recognition

3D-printing technology has brought light to the large-scale and sustainable production of a wide range of low-cost electronic devices with custom forms on-demand. Despite the current availability of mainstream carbon-based nanocomposite filaments, 3D-printing of noble metals is nowadays a challenge. Herein, a one-step functionalization approach has been devised for the straightforward and cost-effective manufacturing of functional metal-based 3D-printed electronics by galvanically replacing Cu-based 3D-printed (3D-Cu) electrodes with nobler metal counterparts, viz. Ag and Au. As a first demonstration of applicability, two appealing bio-electroanalytical approaches, such as the chiral discrimination of amino acids and the supramolecular determination of uranium have been considered —by taking advantage of the capability of noble metals to physically/chemically accommodate several molecular components—, reaching enhanced performances when compared with the pristine 3D-Cu counterpart. Consequently, this alchemy-inspired approach, which combines (i) 3D-Cu electrodes as sacrificial platforms with (ii) noble metals via a galvanic exchange reaction, provides a robust pathway to harbor molecular components in order to exploit metal-based 3D-printed electronics in real tasks.

Chiral separation study of atenolol and carvedilol β-blocker drugs by DFT calculations

In the present work, we perform a theoretical study to understand the chiral recognition process of polysaccharide-derived stationary phases with two β-blocker drugs: atenolol and carvedilol. According to the main results, the structural and thermodynamic parameters obtained by DFT calculations pointed out the chiral discrimination, as well as the enantiomeric elution order of both β-blockers, thus explaining at the molecular level the HPLC experimental data previously obtained. Finally, the relative stability of distinct diastereoisomeric complexes was explained by the hydrogen bonds and π-π stacking interactions formed between β-blockers enantiomers and their respective chiral selectors.

Clay Column Chromatography for Optical Resolution: A Series of Derivatized Amino Acids

Abstract Chromatographic resolution of a series of derivatized amino acids was attempted on a column packed with an ion-exchange adduct of Δ-[Ru(phen)3]2+ (phen = 1,10-phenanthroline) and synthetic hectorite. An amino acid was modified to N-3, 5-dinitrobenzoyl amino acid methyl ester (denoted by DNB-aa-me). For aa = Ala, Phe, Leu, Ile, Ser, Val, Thr, Tyr, Asp and Glu, racemic DNB-aa-me was resolved nearly to baseline separation on being eluted with methanol. For aa = Trp and His, racemic DNB-aa-me was resolved partially. No resolution was achieved for Pro and Lys. The mechanism of chiral discrimination was investigated by means of solid-state vibrational circular dichroism spectroscopy.

ON/OFF receptor-like enantioseparation of planar chiral 1,2-ferrocenes on an amylose-based chiral stationary phase: The role played by 2-propanol

A set of nine planar chiral 1,2-ferrocenes was analyzed by high-performance liquid chromatography (HPLC) on the amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phase. The enantioseparations were carried out using neat methanol, ethanol, 1-propanol, and 2- propanol as well as mixtures of n-hexane-2-propanol as mobile phases. The differences in retention times between the second eluted (Rp)-enantiomers and the first eluted (Sp)-enantiomers were significantly influenced by elution modes and the steric hindrance of substituents at the aromatic rings of the ferrocene backbone. It has been demonstrated an ON/OFF switching of receptor-like chiral discrimination through the employment of different alcohols as mobile phases. In particular, the presence of pure 2-propanol triggers exceptional conditions of enantioselectivity that for some ferrocenes result in values of the enantioseparation factor higher than 80.

Chiral Recognition R- and RS- of New Antifungal: Complexation/Solubilization/Dissolution Thermodynamics and Permeability Assay

Novel potential antifungal of 1,2,4-triazole class have been synthesized as pure enantiomer (R-98) and racemic (RS-186). The effect of 2-hydroxypropyl-β-cyclodextrin (CD) on the solubility and permeability of RS-186 and R-98 in terms of chiral recognition was investigated. Phase solubility studies were carried out at 4 temperatures in 0–0.05 M CD concentration range for pH 2.0 and pH 7.4. - and -type phase-solubility profiles were obtained for both compounds in pH 2.0 and pH 7.4. The racemic formed more stable complexes with CD as compared to R-isomer. Disclosing of chiral discrimination was facilitated using the approach based on the complex consideration of the derived complexation/solubilization/inherent dissolution thermodynamic functions, including the differential parameters between the racemic compound and R-enantiomer. The differences in the thermodynamic parameters determined by the chirality were discussed in terms of the driving forces of the processes and the main interactions of the compounds with CD in solution. The membrane permeability of both samples in the presence of CD was accessed in order to evaluate the specificity of enantioselective transport through the lipophilic membrane. The solubility/permeability interrelation was disclosed. The investigated compounds were classified as medium permeable in pure buffers and low permeable in the presence of 0.01 M CD. The obtained results can be useful for the design of pharmaceutical products in the form of liquid formulations based on the investigated substances.

Reversed-phase chromatography as an effective tool for the chiral separation of anionic and zwitterionic carboranes using polysaccharide-based chiral selectors

The aspect of the different spatial arrangement of anionic cobalt bis(dicarbollides) and dicarba-nido-undecaboranes remains grossly overlooked despite increased scientific interest. Regarding their growing potential, which does not limit only to medicinal chemistry, suitable enantioseparation methods are needed. The presented paper explores the possibilities of chiral separations of anionic cobalt bis(dicarbollide) and dicarba-7,8-nido-undecaborane derivatives on four polysaccharide-based columns under reversed-phase conditions. The chromatographic behavior of anionic derivatives was evaluated and compared with that of zwitterionic clusters. The isocratic procedure for HPLC method development was suggested. The main parameters for the optimization of separations were described. Successful chiral separations were critically compared to previously reported results in normal phase and polar-organic mode. Reversed-phase separations are superior in resolution, lower consumption of organic solvents, and flexibility during the method development. Moreover, the first chiral discrimination of some hydroxyalkyl derivatives of anionic cobalt bis(dicarbollides) is reported. The outcomes of this work may be used for method development in any area, where the chirality of these interesting molecules is of concern.

Chiral Discrimination via Shortcuts to Adiabaticity and Optimal Control

AbstractA protocol to distinguish chiral molecules with the help of a cyclic three‐level structure is proposed. Non‐resonant microwave pules are applied to drive the transition of chiral molecules from their ground states to dressed‐states with different eigenenergies, which induce a large energy split in the levels of left‐handed molecules. This dynamics helps to realize a chirality‐selective transition, where only the right‐handed molecules can be excited to the higher levels. By utilizing the SU(2)‐transformation‐based shortcuts to adiabaticity method and the systematic‐error‐sensitivity nullified optimal control method, systematic‐error‐resistant control pulses to realize maximal population difference between molecules with different chirality are designed. Numerical simulations show that the protocol is also insensitive to random noise and energy relaxation. Therefore, the protocol may provide a promising approach for rapid and robust chiral discrimination.

Synthesis of Chiral Au Nanocrystals with Precise Homochiral Facets for Enantioselective Surface Chemistry.

Metal surfaces with intrinsic chirality play an irreplaceable role in many significant enantioselective chemical processes such as enantioselective catalysis, sensing, and separation. Nonetheless, current methods for the precise preparation of such chiral surfaces suffer with issues of unscalable production and low surface areas. Herein, we report the synthesis of chiral Au nanoparticles with precisely determined homochiral facets. Though a scalable wet chemical method, {125̅8}R and {85̅12}S high-Miller-index facets are obtained with the l- and d-chiral Au nanocrystals, respectively. The growth process of these homochiral facets is investigated, and a new nanocrystal growth pathway is revealed. More importantly, the remarkable enantioselective recognition properties of these homochiral surfaces are demonstrated and enable an efficient electrochemical method for chiral discrimination of l-/d-tryptophan. These results provide a foundation of fundamental studies of heterogeneous enantioselective processes and may pave way for the development of nanocatalysts for enantioselective chemistry.

Chirality Gearing in an Achiral Cage through Adaptive Binding.

Herein we report an adaptive, achiral trithiourea molecular cage and its conformational and stereodynamics toward tricarboxylate anion binding. The cage was readily synthesized in four steps with a 44% yield for the irreversible cage-forming reaction. It possesses a flexible conformation and strongly binds 1,3,5-benzene tricarboxylate by forming a sandwich-like inclusion complex, with an affinity up to 106 M-1 in acetonitrile. Upon binding, the cage is locked in a twisted helical conformation. By incorporation of three chiral arms on the guest, a gear-like complex dominant in one given helical sense was produced. Due to the steric crowding in the helical grooves, a small change of methyl to ethyl on guest caused a striking difference on binding and chiral induction. The system thus represents a rare example of chiral induction on a flexible, achiral host and provides a decoupled model that the generation of a racemate and following chiral discrimination can be individually probed.

Arrow of Time, Entropy, and Protein Folding: Holistic View on Biochirality.

Chirality is a universal phenomenon, embracing the space–time domains of non-organic and organic nature. The biological time arrow, evident in the aging of proteins and organisms, should be linked to the prevalent biomolecular chirality. This hypothesis drives our exploration of protein aging, in relation to the biological aging of an organism. Recent advances in the chirality discrimination methods and theoretical considerations of the non-equilibrium thermodynamics clarify the fundamental issues, concerning the biphasic, alternative, and stepwise changes in the conformational entropy associated with protein folding. Living cells represent open, non-equilibrium, self-organizing, and dissipative systems. The non-equilibrium thermodynamics of cell biology are determined by utilizing the energy stored, transferred, and released, via adenosine triphosphate (ATP). At the protein level, the synthesis of a homochiral polypeptide chain of L-amino acids (L-AAs) represents the first state in the evolution of the dynamic non-equilibrium state of the system. At the next step the non-equilibrium state of a protein-centric system is supported and amended by a broad set of posttranslational modifications (PTMs). The enzymatic phosphorylation, being the most abundant and ATP-driven form of PTMs, illustrates the principal significance of the energy-coupling, in maintaining and reshaping the system. However, the physiological functions of phosphorylation are under the permanent risk of being compromised by spontaneous racemization. Therefore, the major distinct steps in protein-centric aging include the biosynthesis of a polypeptide chain, protein folding assisted by the system of PTMs, and age-dependent spontaneous protein racemization and degradation. To the best of our knowledge, we are the first to pay attention to the biphasic, alternative, and stepwise changes in the conformational entropy of protein folding. The broader view on protein folding, including the impact of spontaneous racemization, will help in the goal-oriented experimental design in the field of chiral proteomics.

Highly enantioselective electrochemical sensing based on helicoid Au nanoparticles with intrinsic chirality

Chiral discrimination has played significant roles in food science, pharmaceutical science, medical science, and biology. As such, design of electrochemical chiral sensors with high enantiomeric discrimination ability and service life is highly desirable. Herein, helicoid Au nanoparticles with intrinsic chirality were synthesized and utilized to construct an electrochemical chiral sensor for the first time. Notably, nearly 6 times difference of peak currents was observed for tyrosine (Tyr) enantiomers by differential pulse voltammetry (DPV) method. To the best of our knowledge, it is the best result reported so far in electrochemical enantiomers detection, which is sufficient to enable an accurate determination of the enantiomeric purity and composition of the Tyr analytes. The obtained chiral electrodes were also applied to determine the L-Tyr contents in L-Tyr capsules, beer and milk. These results highlight the tremendous potential of using Au nanoparticles with intrinsic chirality to build chiral recognition interface for enantiomers recognition and offer the promise of practical application of electrochemical chiral sensors.

Chiral discrimination by polarization singularities of a metal sphere

The practical applications of chiral discrimination are usually limited by the weak chiral response of enantiomers and the high complexity of detection methods. Here, we propose to use the C lines (i.e., lines of polarization singularities) emerged in light scattering by a metal sphere to detect small chiral particles. Using full-wave numerical simulations and analytical multipole expansions, we determined the absorption dissymmetry of deep-subwavelength helices (i.e., chiral particles) at different positions on the C lines. We find that the absorption dissymmetry can be much larger than that induced by circularly polarized plane wave excitation, and it can be attributed to the asymmetric absorption of the induced electric and magnetic dipoles. We also show that the absorption dissymmetry strongly depends on the anisotropy of the helices. The results may find applications in optical manipulations, optical sensing, and chiral quantum optics.

Enantioselectivity of Pentedrone and Methylone on Metabolic Profiling in 2D and 3D Human Hepatocyte-like Cells.

Pentedrone and methylone can express stereoselectivity in toxicokinetic and toxicodynamic processes. Similarly, their chiral discrimination in metabolism, which was not yet evaluated, can result in different metabolic profiles and subsequent hepatotoxic effects. Therefore, the aim of this work was to assess, for the first time, both the hepatic cytotoxic and metabolic profile of pentedrone and methylone enantiomers using physiologically relevant in vitro models. The hepatotoxicity of these compounds was observed in a concentration-dependent manner in human stem-cell-derived hepatocyte-like cells (HLCs) cultured under 3D (3D-HLCs) and 2D (2D-HLCs) conditions. Enantioselectivity, on the other hand, was only shown for pentedrone (1 mM) in 3D-HLCs, being R-(−)-pentedrone the most cytotoxic. Furthermore, the metabolic profile was initially evaluated in human liver microsomes (HLM) and further demonstrated in 3D-HLCs and 2D-HLCs applying a gas chromatography coupled to a mass spectrometer (GC–MS) technique. Methylone and pentedrone showed distinct and preferential metabolic routes for their enantiomers, resulting in the production of differentiated metabolites; R-(+)-methylone and R-(−)-pentedrone are the most metabolized enantiomers. In conclusion, the results demonstrated enantioselectivity for pentedrone and methylone in the metabolic processes, with enantioselectivity in cytotoxicity for pentedrone.

Beyond energetic and scalar measures: Next generation quantum theory of atoms in molecules

AbstractNext generation quantum theory of atoms in molecules (NG‐QTAIM) is currently the only vector‐based quantum chemical theory as all other quantum chemical theories are scalar‐based. NG‐QTAIM can, for instance, be used to distinguish enantiomers, isotopomers undergoing normal modes of vibration, predict ring‐opening reaction products, ground and excited states at a conical intersection and predict reaction pathways of permutation‐inversion isomers. As a consequence, NG‐QTAIM can uniquely be used to investigate iso‐energetic phenomena where the reliance on differences in geometric measures is removed. NG‐QTAIM has already been used to determine molecular chirality consistent with the Cahn–Ingold–Prelog (CIP) classifications for chiral molecules in addition to the reactant and product of a chiral SN2 reaction. The CIP classifications however, cannot quantify the chirality of intermediate reaction structures due to their formally achiral nature. We identify the presence of chirality by quantifying a helical response of the bond electrons consistent with photoexcitation circular dichroism experiments that utilize the helical motion of the bound electrons for chiral discrimination. NG‐QTAIM can also be used to provide nongeometric based reasoning as to why there are stronger hydrogen‐bonds in cyclic water clusters compared with compact water clusters. Additionally, the effects of electric‐fields and laser irradiation in conditions not amenable to explanation using scalar measures are quantified. The QuantVec software is introduced, which coordinates external programs and efficiently computes the NG‐QTAIM analyses using the wavefunctions from a wide range of ground and excited states computed with DFT, coupled‐cluster, complete active space SCF, configuration interaction, or quantum dynamics methods.This article is categorized under: Structure and Mechanism > Molecular Structures Structure and Mechanism > Reaction Mechanisms and Catalysis Software > Quantum Chemistry

An X-ray investigation of stereoselectivity in the interactions of [Co(en)3]3+ with [Co(ox)3]3- (en is ethane-1,2-diamine and ox is oxalate).

The X-ray structure of racemic tris(ethane-1,2-diamine-κ2N,N')cobalt(III) tris(oxalato-κ2O1,O2)cobaltate(III) pentahydrate, [Co(C2H8N2)3][Co(C2O4)3]·5H2O or [Co(en)3][Co(ox)3]·5H2O, has been determined. Hydrogen-bonding interactions along the C3-axis of the [Co(en)3]3+ cation with the [Co(ox)3]3- anion are heterochiral, while those perpendicular to this axis are homochiral. Implications for the interpretation of chiral discriminations and induction in electron-transfer reactions in solution are discussed.

Rapid determination of cysteine and chiral discrimination of D-/L-cysteine via the aggregation-induced emission enhancement of gold nanoclusters by Ag.

Cysteine (Cys) plays vital roles in various physiological and pathological functions. Either a deficiency or excess of Cys could lead to severe ailments in human. The identification and determination of Cys are the key issues for the early diagnosis of relevant diseases. This contribution has presented a promising potential of fluorescent gold nanoclusters (AuNCs) for Cys determination and D-/L-Cys enantiomer discrimination. Cys determination and discrimination are involved three steps. First, as a reducing and capping ligand, glutathione was applied to fabricate weak fluorescent AuNCs. Second, Ag+ was introduced to lead the aggregation-induced emission (AIE) to form well-dispersed aggregates. The fluorescence intensity of AuNCs was monitored at excitation/emission wavelengths of 396/620nm. Third, Cys was found to quickly bind with Ag+ to form a grid network to light up the system via aggregation-induced emission enhancement (AIEE). A novel sensor for a sensitive and a visually selective detection of Cys was established on the basis of the AIEE mechanism. Rapid quantitative determination of Cys was achieved in 2min via AIEE within the range of 0.5-100μmol L-1 and a detection limit of 0.365μmol L-1. Moreover, due to the specific interactions of D-/L-Cys with mandelic acid and tartaric acid, the visual discrimination of D-/L-Cys enantiomers with naked eyes was realized by replacing the organic acid buffer.

Controlling the length of porphyrin supramolecular polymers via coupled equilibria and dilution-induced supramolecular polymerization

Multi-component systems often display convoluted behavior, pathway complexity and coupled equilibria. In recent years, several ways to control complex systems by manipulating the subtle balances of interaction energies between the individual components have been explored and thereby shifting the equilibrium between different aggregate states. Here we show the enantioselective chain-capping and dilution-induced supramolecular polymerization with a Zn2+-porphyrin-based supramolecular system when going from long, highly cooperative supramolecular polymers to short, disordered aggregates by adding a monotopic Mn3+-porphyrin monomer. When mixing the zinc and manganese centered monomers, the Mn3+-porphyrins act as chain-cappers for Zn2+-porphyrin supramolecular polymers, effectively hindering growth of the copolymer and reducing the length. Upon dilution, the interaction between chain-capper and monomers weakens as the equilibria shift and long supramolecular polymers form again. This dynamic modulation of aggregate morphology and length is achieved through enantioselectivity in the aggregation pathways and concentration-sensitive equilibria. All-atom and coarse-grained molecular simulations provide further insights into the mixing of the species and their exchange dynamics. Our combined experimental and theoretical approach allows for precise control of molecular self-assembly and chiral discrimination in complex systems.

Effect of pendant stereostructure on backbone conformation and enantioseparation ability of helical polyacetylene-based chiral stationary phases.

Six proline-derived acetylene monomers bearing either two stereocenters (S-mR, S-mS, R-mS, Rac-mS and S-mRac) or one stereocenter (S-mBn) were obtained from commercially available N-(tert-butoxycarbonyl)-prolinal. Under the catalysis of Rh-diene complex, they were converted to the corresponding optically active helical polymers, S-pR, S-pS, R-pS, Rac-pS, S-pRac, and S-pBn. The correlations between configuration and position of stereocenters in pendants with the polymer conformation as well as chiral resolution performance were systematically explored by a combination of nuclear magnetic resonance (NMR), Raman, UV-Vis absorption, electronic/vibration circular dichroism spectroscopies, high-performance liquid chromatography (HPLC), and computational simulation. The configuration of the stereocenter adjacent to polymer mainchain determined the sense of helical conformation and the elution order of analytes, while that of the remote one affected the arrangement of pendants and the scope of analytes that could be discriminated. Among 18 aromatic analytes selected, S-pR could discriminate 10, while S-pS recognized 12. The racemization of adjacent or remote stereocenters greatly reduced the scope of analytes that could be resolved. Based on computer simulations, S-pS had larger recognition space than S-pR, favoring the steric fit with the racemates containing axial chirality. The strength and number of intermolecular hydrogen bondings between enantiomers and CSPs predominantly determined the chiral discrimination.