Racemic Solution Research Articles

Chiral Electrokinetic Phenomena in Single Nanopores

AbstractThe arrangement of solvent molecules and ions at solid–liquid interfaces determines electrochemical properties that are important in separations platforms, sensing technologies, and energy‐storage systems. Here we show that single glass and polymer pores in contact with propylene carbonate (PC) solutions of LiClO4 exhibit an effective surface potential that is modulated by the enantiomeric excess of the solvent. In particular, electrochemical and electrokinetic measurements of ionic transport through glass pipettes and polymer pores reveal that the effective surface potential is significantly lower in solutions prepared using enantiomerically pure PC than in solutions prepared using racemic PC. Both pore systems became positively charged in all racemic solutions examined in the range of LiClO4 concentrations between 1 mM and 100 mM, whereas solutions in (R)‐(+)‐PC induced a positive surface potential only at concentrations above ~5 mM. The effective surface potential is quantified through asymmetry in current–voltage curves and zeta‐potential measurements. Vibrational sum‐frequency‐generation experiments on LiClO4 solutions in racemic and enantiomerically pure PC indicate that the surface lipid‐bilayer‐like region in the former is more strongly organized than in the latter, dictating the favorable positions for lithium and perchlorate ions in each case. The more ordered molecular packing in the racemic liquid leads to accumulation of lithium ions on the outside of the bilayer, creating a higher effective positive charge. Our results highlight the extreme sensitivity of the interfacial potential on molecular organization of the solvent, and the relatively unexplored role that chirality can play in electrokinetic phenomena.

Computational design for enantioselective CO2 capture: asymmetric frustrated Lewis pairs in epoxide transformations.

Carbon capture and utilisation (CCU) technologies offer a compelling strategy to mitigate rising atmospheric carbon dioxide levels. Despite extensive research on the CO2 insertion into epoxides to form cyclic carbonates, the stereochemical implications of this reaction have been largely overlooked, despite the prevalence of racemic epoxide solutions. This study introduces an in silico approach to design asymmetric frustrated Lewis pairs (FLPs) aimed at controlling reaction stereochemistry. Four FLP scaffolds, incorporating diverse Lewis acids (LA), Lewis bases (LB), and substituents, were assessed via volcano plot analysis to identify the most promising catalysts. By strategically modifying LB substituents to induce asymmetry, a stereoselective catalytic scaffold was developed, favouring one enantiomer from both epoxide enantiomers. This work advances the in silico design of FLPs, highlighting their potential as asymmetric CCU catalysts with implications for optimising catalyst efficiency and selectivity in sustainable chemistry applications.

Escherichia coli-based biorefining process yields optically pure lactic acid from fermented second-generation feedstocks

Within the circular bioeconomy the production of optically pure LA from 2nd generation feedstocks would be ideal but it is very challenging. In this paper genetically engineered Escherichia coli strains were created to resolve racemic LA solutions synthesised and produced from the fermentation of organic waste or ensiled grass. Refining LA racemic mixtures into either a D- or L-LA was achieved by cells being able to consume one LA isomer as a sole carbon and energy source while not being able to consume the other. A D-LA refining strain JSP0005 was grown on fermented source-sorted organic household waste and different grass silage leachates, which are 2nd generation feedstocks containing up to 33 g/L lactic acid racemate. In all growth experiments, L-LA was completely removed leaving D-LA as the only LA stereoisomer, i.e. resulting in optically pure D-LA, which also increased by as much as 248.6 % from its starting concentration, corresponding to 38 g/L. The strains resulting from this study are a promising first step towards a microbial based LA biorefining process.

Wireless Hollow Miniaturized Objects for Electroassisted Chiral Resolution.

Chiral resolution plays a crucial role in the field of drug development, especially for a better understanding of biochemical processes. In such a context, classic separation methods have been used for decades due to their versatility and easy scale-up. Among the many attempts proposed for enantioselective separation, electroassisted methods are presented as an interesting alternative. Herein, we present the use of wirelessly activated hollow tubular systems for the effective, simple, and tunable separation of racemic and enantioenriched mixtures. These double-layered tubular objects consist of an external polypyrrole chassis, a polymer with good electromechanical properties, functionalized in its inner part with an inherently chiral oligomer. The synergy between the electromechanical pumping process of the outer layer and the enantioselective affinity of the inner part induces the system to behave as a miniaturized chiral column. These hybrid objects are able to separate racemic and enantioenriched solutions of chiral model analytes into the corresponding enantiomers in high enantiomeric purity. Finally, these electromechanical systems can resolve mixtures formed by chiral probes with completely uncorrelated molecular structures injected simultaneously into the single antipodes.

Enantioselective adsorption of ibuprofen enantiomers using chiral-active carbon nanoparticles induced S-α-methylbenzylamine.

The chiral media is crucial to the chiral recognition and separation of enantiomers. In this study, we report the preparation of novel chiral carbon nanoparticles (CCNPs) via surface passivation using glucose as the carbon source and S-(-)-α-methylbenzylamine as the chiral ligand. The structures of the obtained CCNPs are characterized via FT-IR, Raman spectroscopy, DLS, XPS, XRD, TEM, and zeta potential analysis. These CCNPs could be employed as the chiral adsorbent and used for the enantioselective adsorption of the ibuprofen enantiomers. The results demonstrated that the CCNPs could selectively adsorb R-enantiomer from ibuprofen racemate solution and give an enantiomeric excess (e.e.) of about 50% under an optimal adsorption condition. Moreover, the regeneration efficiency of the CCNPs remained above e.e. of 43% after the fifth cycle. The present work confirmed that the prepared CCNPs show great potential in the enantioselective separation of ibuprofen racemate.

The central dogma of biological homochirality: How does chiral information propagate in a prebiotic network?

Biological systems are homochiral, raising the question of how a racemic mixture of prebiotically synthesized biomolecules could attain a homochiral state at the network level. Based on our recent results, we aim to address a related question of how chiral information might have flowed in a prebiotic network. Utilizing the crystallization properties of the central ribonucleic acid (RNA) precursor known as ribose-aminooxazoline (RAO), we showed that its homochiral crystals can be obtained from its fully racemic solution on a magnetic mineral surface due to the chiral-induced spin selectivity (CISS) effect [Ozturk et al., arXiv:2303.01394 (2023)]. Moreover, we uncovered a mechanism facilitated by the CISS effect through which chiral molecules, such as RAO, can uniformly magnetize such surfaces in a variety of planetary environments in a persistent manner [Ozturk et al., arXiv:2304.09095 (2023)]. All this is very tantalizing because recent experiments with tRNA analogs demonstrate high stereoselectivity in the attachment of L-amino acids to D-ribonucleotides, enabling the transfer of homochirality from RNA to peptides [Wu et al., J. Am. Chem. Soc. 143, 11836 (2021)]. Therefore, the biological homochirality problem may be reduced to ensuring that a single common RNA precursor (e.g., RAO) can be made homochiral. The emergence of homochirality at RAO then allows for the chiral information to propagate through RNA, then to peptides, and ultimately through enantioselective catalysis to metabolites. This directionality of the chiral information flow parallels that of the central dogma of molecular biology-the unidirectional transfer of genetic information from nucleic acids to proteins [F. H. Crick, in Symposia of the Society for Experimental Biology, Number XII: The Biological Replication of Macromolecules, edited by F. K. Sanders (Cambridge University Press, Cambridge, 1958), pp. 138-163; and F. Crick, Nature 227, 561 (1970)].

Diastereomer salt crystallization: Comprehensive process modeling and DoE-driven comparison of custom-coded and user-friendly simulators

Process modeling is gaining attention in the pharmaceutical industry due to the promise of exploring the design space with less experimentation. However, the associated numerical apparatus can be prohibitive for many, undermining the attainable benefits. This study aims to demonstrate the readiness of modeling by guiding the reader through the essential steps of model development, from experimentation to kinetic model identification and in-silico DoE execution, implemented and executed in a user-friendly but restrictive simulator and a highly technical, custom-coded environment. The crystallization of (S)-pregabalin l-tartrate from a racemic aqueous solution is applied as a surrogate system, involving secondary nucleation, growth, and agglomeration. The distomer may act as an impurity. This process is sufficiently complex to be representative but straightforward enough to be familiar to a broad audience. Despite their differences, both modeling environments resulted in the same kinetic model structure and fitted the measurements well. The models are compared based on the in-silico DoE outcomes rather than the goodness of fit. The analysis revealed that the key conclusions are identical, which validates the utilization of the user-friendly simulator in time-constrained applications.

Spontaneous Chirality Induction in the Assembly of a Single Layer 2-D Network with Switchable Pores.

Although two dimensional (2-D) chiral sheet structures are attractive because of unique chemical and physical properties, single layer 2-D chiral network structures with switchable pore interior remain elusive. Here we report spontaneous chirality induction in a single layer 2-D network structure formed from the self-assembly of tetrapod azobenzene molecules. The chirality induction arises from multiple sublayers slipped in a preferred direction in which the sublayer consists of unidentical molecular arrangements in in-plane a and b directions, breaking both plane of symmetry and inversion symmetry. The protruded azobenzene units in the pore interior can be selectively isomerized upon UV irradiation, resulting in a reversible deformation of the chiral pores while maintaining 2-D frameworks. The chiral network can thus selectively entrap one enantiomer from a racemic solution with near perfect enantioselectivity, and then release upon UV irradiation.

Spontaneous Chirality Induction in the Assembly of a Single Layer 2D Network with Switchable Pores

AbstractAlthough two‐dimensional (2D) chiral sheet structures are attractive because of their unique chemical and physical properties, single layer 2D chiral network structures with switchable pore interior remain elusive. Here we report spontaneous chirality induction in a single layer 2D network structure formed from the self‐assembly of tetrapod azobenzene molecules. The chirality induction arises from multiple sublayers slipped in a preferred direction in which the sublayer consists of unidentical molecular arrangements in the in‐plane a and b directions, breaking both the plane of symmetry and inversion symmetry. The protruded azobenzene units in the pore interior can be selectively isomerized upon UV irradiation, resulting in a reversible deformation of the chiral pores while maintaining the 2D frameworks. The chiral network can thus selectively entrap one enantiomer from a racemic solution with near perfect enantioselectivity, and then release it upon UV irradiation.

Enantiomeric Resolution and Enantiomer Isolation of H2 TPPS4 J-Aggregate from Aqueous Solution Is Enabled by Vortexes.

Protonated achiral H2 TPPS4 spontaneously self-arranges at acids pH and high ionic strength to build mesoscopic J-aggregates that are intrinsically chiral. According to the symmetry rule aggregation leads to a racemate that, however, can be unbalanced by chemical (chiral pollutants) or physical stimuli (as vortexing the solution). Vortexing the title racemate, in principle, might either induce chiral separation or chiral enrichment. Indeed, herein it is shown that vortices enable the resolution of this racemic solution exploiting the tendency to deposit, onto the quartz cuvette walls, of the enantiomer favored by the stirring sense. Simultaneously, over time, it was found that the opposite chiral conformation becomes prevalent in solution realizing a significant enantiomeric resolution. Therefore, after removing all stirring-favored chiral J-aggregate from the solution, the recovering and isolating of the desired enantiomers from the cuvette walls was successfully obtained without complex procedures. In this sense, it has been demonstrated that the stirring forces are executively able to fulfil the chiral separation in H2 TPPS4 J-aggregates, employed as model of a self-assembled system in aqueous solution.

Visualization of enantioselective recognition and separation of chiral acids by aggregation‐induced emission chiral diamine

AbstractEnantioselective recognition and separation are the most important issues in the fields of chemistry, pharmacy, agrochemical, and food science. Here, we developed two optically active diamines showing aggregation‐induced emission (AIE) that can discriminate 5 kinds of chiral acids with high enantioselectivity. Especially, a very high fluorescence intensity ratio (Il/Id) of 281 for (±)‐Dibenzoyl‐d/l‐tartaric acid was obtained through the collection of fluorescence change after interaction with chiral AIE‐active diamine. By virtue of AIE property and intermolecular acid‐base interaction, enantioselective separation was facilely realized by simple filtration of the precipitates formed by chiral AIE luminogen (AIEgen) and one enantiomer in the racemic solution. The chiral HPLC data indicated that the precipitates of AIEgen/chiral acid possessed 82% l‐analyte (the enantiomeric excess value was assessed to be 64% ee). Therefore, this method can serve as a simple, convenient, and low‐cost tool for chiral detection and separation.

Conglomerate Aggregation of 7,12,17‐Trioxa[11]helicene into Homochiral Two‐Dimensional Crystals on the Cu(100) Surface

AbstractDespite the vast development of stereochemistry it remains a great challenge to predict the fate of homochiral or heterochiral recognition in crystallization from racemic solution or melt. Using the well‐defined model system of racemic trioxaundecahelicene on a Cu(100) surface in ultrahigh vacuum, the chiral recognition of this heterohelicene has been investigated by means of state‐of‐the‐art scanning probe microscopy. The combination of scanning tunneling microscopy and tuning fork‐based non‐contact atomic force microscopy allowed assignment of the absolute configuration of single 7,12,17‐trioxa[11]helicene molecules in their two‐dimensional assemblies. At very low coverages, homochiral van der Waals‐bonded tetramers are observed. These also constitute the building blocks of the completely filled monolayer, which is a 2D conglomerate of homochiral domains. The interpretation of the adsorption geometries was supported by density‐functional theory calculations and molecular dynamics simulations, predicting a stronger interaction energy for homochiral structures over the heterochiral assembly. The striking similarity to heptahelicene on the same surface suggests that chiral recognition is dominated by the footprint interaction of the molecules with the metallic substrate.

The Intestinal and Biliary Metabolites of Ibuprofen in the Rat with Experimental Hyperglycemia.

Hyperglycemia is reported to be associated with oxidative stress. It can result in changes in the activities of drug-metabolizing enzymes and membrane-integrated transporters, which can modify the fate of drugs and other xenobiotics; furthermore, it can result in the formation of non-enzyme catalyzed oxidative metabolites. The present work aimed to investigate how experimental hyperglycemia affects the intestinal and biliary appearance of the oxidative and Phase II metabolites of ibuprofen in rats. In vivo studies were performed by luminal perfusion of 250 μM racemic ibuprofen solution in control and streptozotocin-treated (hyperglycemic) rats. Analysis of the collected intestinal perfusate and bile samples was performed by HPLC-UV and HPLC-MS. No oxidative metabolites could be detected in the perfusate samples. The biliary appearance of ibuprofen, 2-hydroxyibuprofen, ibuprofen glucuronide, hydroxylated ibuprofen glucuronide, and ibuprofen taurate was depressed in the hyperglycemic animals. However, no specific non-enzymatic (hydroxyl radical initiated) hydroxylation product could be detected. Instead, the depression of biliary excretion of ibuprofen and ibuprofen metabolites turned out to be the indicative marker of hyperglycemia. The observed changes impact the pharmacokinetics of drugs administered in hyperglycemic individuals.

Separation of Etiracetam Enantiomers Using Enantiospecific Cocrystallization with 2-Chloromandelic Acid.

Chirality plays an important role in the pharmaceutical industry since the two enantiomers of a drug molecule usually display significantly different bioactivities, and hence, most products are produced as pure enantiomers. However, many drug precursors are synthesized as racemates, and hence, enantioseparation has become a significant process in the industry. Cocrystallization is one of the attractive crystallization approaches to obtain the desired enantiomer from racemic compounds. In this work, we propose a chiral resolution route for an antiepileptic drug, S-etiracetam (S-ETI), via enantiospecific cocrystallization with S-2-chloro-S-mandelic acid (CLMA) as a coformer. The experiments indicate that the system is highly enantiospecific; S-2CLMA cocrystallizes only with S-ETI but not with R-ETI or RS-ETI. Therefore, the chiral purification of S-ETI can be achieved efficiently with a 69.1% yield and close to 100% enantiopurity from the racemic solution. Additionally, structural simulations of the S-ETI:S-2CLMA cocrystal reveal that the cocrystal structure has higher thermodynamic stability than that of R-ETI:S-2CLMA by about 5.5 kcal/mol (per cocrystal formula unit), which helps to confirm the favorability of the enantiospecification in this system.

Anomalous Viscosity of a Racemate: A Simple Experiment Demonstrating Chirally Induced Spin Selectivity.

It has been known for over a century that racemic solutions of hydrogen-bonded compounds are less viscous than their component enantiomers, but this fact has so far remained unexplained. Here we confirm it using enantiomers of lactic acid and compare it to molecular dynamics (MD) simulations of lactic acid viscosity. The effect is absent in classical MD. We suggest that the anomalous viscosity of racemates may be due to a recently discovered magnetic intermolecular force due to spin-dependent charge reorganization.

Homochiral or Heterochiral: A Systematic Study of Threonine Clusters Using a FT ICR Mass Spectrometer

The strong chiral preferences of some magic clusters of amino acids have attracted continually increasing interests due to their unique structures, properties and possible roles in homochirogenesis. However, how chirality can influence the generation and stability of cluster ions in a wild range of cluster sizes is still unknown for most amino acids. In this study, the preference for threonine clusters to form homochiral and heterochiral complex ions has been investigated by electrospray ionization (ESI) mass spectrometry. Abundant cluster [Thrn+mH]m+ ions (7 ≤ n ≤ 78, 1 ≤ m ≤ 5) have been observed for both samples of enantiopure (100% L) and racemic (50:50 L:D) threonine solutions. Further analyses of the spectra show that the [Thr14+2H]2+ ion is characterized by its most outstanding homochiral preference, and [Thr7+H]+ and [Thr8+H]+ ions also clearly exhibit their homochiral preferences. Although most of the triply charged clusters (20 ≤ n ≤ 36) are characterized by heterochiral preferences, the quadruply charged [Thrn+4H]4+ ions (40 ≤ n ≤ 59) have no obvious chiral preference in general. On the other hand, a weak homochiral preference exists for most of the quintuply charged ions observed in the experiment.

Tuning organic crystal chirality by the molar masses of tailored polymeric additives

Hierarchically ordered chiral crystals have attracted intense research efforts for their huge potential in optical devices, asymmetric catalysis and pharmaceutical crystal engineering. Major barriers to the application have been the use of costly enantiomerically pure building blocks and the difficulty in precise control of chirality transfer from molecular to macroscopic level. Herein, we describe a strategy that offers not only the preferred formation of one enantiomorph from racemic solution but also the subsequent enantiomer-specific oriented attachment of this enantiomorph by balancing stereoselective and non-stereoselective interactions. It is demonstrated by on-demand switching the sign of fan-shaped crystal aggregates and the configuration of their components only by changing the molar mass of tailored polymeric additives. Owing to the simplicity and wide scope of application, this methodology opens an immediate opportunity for facile and efficient fabrication of one-handed macroscopic aggregates of homochiral organic crystals from racemic starting materials.

Bovine serum albumin-coated titanium dioxide modified electrochemical interface for enantioselective discrimination of D/L-aspartic acid.

Due to the similar physicochemical properties, the discrimination of chiral isomers faces huge challenges in drug production and biochemical analysis. Herein, the bovine serum albumin-coated titanium dioxide (bovine serum albumin [BSA]/TiO2 ) was modified as a novel electrochemical interface for efficient, simple, and enantioselective discrimination of aspartic acid enantiomers (D/L-Asp) based on the electrochemical impedance spectroscopy (EIS). Utilizing the structural characteristics of large cavity and high specific surface area, TiO2 material provided sufficient space for adequate loading of BSA. The BSA/TiO2 electrochemical interface was successfully fabricated to support abundant chiral recognition sites. The enantioselective discrimination of D/L-Asp was achieved on the interface with a good linear relationship against the impedance difference in the concentration range from 1 to 1000 nM with the detection limit of 0.37 nM for L-Asp and 0.94 nM for D-Asp, reaching the identification coefficient (Ic = KL /KD ) of 1.85. The proposed interface is easy to form with a stable formation of BSA in TiO2 microporous architecture, which maintained the desired stability and reproducibility. For the unknown racemic solution, Ic levels of different enantio-ratios of D/L-Asp were effectively obtained to evaluate the chiral percentage of racemic sample. The possible mechanism of chiral recognition by density function theory (DFT) was confirmed with a stronger adsorption to L-Asp in accordance with our experiment results, reinforcing the validity of our presented interface. The BSA/TiO2 electrochemical interface with robust enantioselective discrimination of D/L-Asp has great potential for the practical application in pharmaceutical surveillance and food security.

Energetics of Competing Chiral Supramolecular Polymers.

Chirality can have unexpected consequences including on properties other than spectroscopic. We show herein that a racemic mixture of bis-urea stereoisomers forms thermodynamically stable supramolecular polymers that result in a more viscous solution than for the pure stereoisomer. The origin of this macroscopic property was probed by characterizing the structure and stability of the assemblies. Both racemic and non-racemic bis-urea stereoisomers form two competing helical supramolecular polymers in solution: a double and a single helical structure at low and high temperature, respectively. The transition temperature between these assemblies, as probed by spectroscopic and calorimetric analyses, is strongly influenced by the composition (by up to 70 °C). A simple model that accounts for the thermodynamics of this system, indicates that the stereochemical defects (chiral mismatches and helix reversals) affect much more the stability of single helices. Therefore, the heterochiral double helical structure predominates over the single helical structure (whilst the opposite holds for the homochiral structures), which explains the aforementioned higher viscosity of the racemic bis-urea solution. This rationale constitutes a new basis to tune the macroscopic properties of the increasing number of supramolecular polymers reported to exhibit competing chiral nanostructures.

Simultaneous High-Purity Enantiomeric Resolution of Conglomerates Using Magnetic Substrates

Applying magnetic substrates, magnetized perpendicular to the surface, we were able to crystallize from racemic solution pure conglomerates of several molecules. The resolution is based on the spin-dependent charge reorganization (SDCR) effect. By having two surfaces with opposite magnetization, it was possible to simultaneously crystallize on each surface a different enantiomer. The method does not require any seeding or chemical modification and is generally employable to any conglomerate. A system is presented for performing the separation, while the racemic mixture flows between the two magnetic surfaces.