Chiral Molecules Research Articles

Enhanced Chirality Transfer in Self‐Assembled Nanocomposites Powered by A Trace Amount of Chiral Dimeric Molecules

Chiral‐selective self‐assembly has markedly advanced the development of chiral materials. While the Sergeant and Soldiers principle allows for chirality amplification, it necessitates precise shape‐matching between chiral and achiral molecules, leading to a low chirality transfer efficiency—where one chiral molecule influences the chirality of a limited number of achiral molecules. Here, we show that this efficiency can be markedly enhanced by introducing chiral dimeric molecules. In this work, a single chiral molecule can control the chirality of up to 200 achiral molecules and even direct the assembly of inorganic nanoparticles into chiral nanocomposites through a sequential chirality transfer process. Moreover, this approach exhibits remarkable robustness, operating effectively without necessitating a precise match between chiral and achiral molecules. Consequently, using the same chiral molecules at an exceptionally low molar fraction (0.5 mol%) allows for the chiral‐selective assembly of achiral molecules over a broad spectrum, regardless of their packing habits, thus facilitating the creation of otherwise inaccessible chiral materials with modulated chiroptical properties. Last but not least, even a trace amount of chiral molecules can enhance the elastic modulus of the self‐assembled nanocomposites by a factor of eight.

Enhanced Chirality Transfer in Self‐Assembled Nanocomposites Powered by A Trace Amount of Chiral Dimeric Molecules

Chiral‐selective self‐assembly has markedly advanced the development of chiral materials. While the Sergeant and Soldiers principle allows for chirality amplification, it necessitates precise shape‐matching between chiral and achiral molecules, leading to a low chirality transfer efficiency—where one chiral molecule influences the chirality of a limited number of achiral molecules. Here, we show that this efficiency can be markedly enhanced by introducing chiral dimeric molecules. In this work, a single chiral molecule can control the chirality of up to 200 achiral molecules and even direct the assembly of inorganic nanoparticles into chiral nanocomposites through a sequential chirality transfer process. Moreover, this approach exhibits remarkable robustness, operating effectively without necessitating a precise match between chiral and achiral molecules. Consequently, using the same chiral molecules at an exceptionally low molar fraction (0.5 mol%) allows for the chiral‐selective assembly of achiral molecules over a broad spectrum, regardless of their packing habits, thus facilitating the creation of otherwise inaccessible chiral materials with modulated chiroptical properties. Last but not least, even a trace amount of chiral molecules can enhance the elastic modulus of the self‐assembled nanocomposites by a factor of eight.

Macrocyclic Chiral Two‐Dimensional Membranes for Enantiomers Separation

AbstractChiral enantiomers, while typically exhibiting similar physical and chemical properties, often have distinct therapeutic effects. The preparation of pure enantiomers is therefore of significant interest in the food, chemical, and pharmaceutical industries, making the separation of enantiomers highly sought after. Membrane separation technology has garnered widespread attention for its environmental friendliness and scalability. Recently, chiral two‐dimensional (2D) membranes have demonstrated superior separation performance due to their ultrathin nature and orderly transmission channels. Macrocyclic chiral 2D membranes, in particular, combine the inherent cavity structure of macrocyclic molecules with the host‐guest interaction capabilities that specifically recognize chiral molecules. Additionally, they benefit from the excellent chemical stability and adjustable interlayer spacing of 2D materials. This combination allows these membranes to achieve high enantioselectivity while improving flux. By optimizing the trade‐off between flux and enantioselectivity, this strategy offers a promising new approach for developing advanced chiral membranes.

Dual Signature of Chirality Induced Spin Selectivity through Spontaneous Resolution of 2D Metal–Organic Frameworks

AbstractThe Chiral‐Induced Spin Selectivity (CISS) effect has emerged as a fascinating phenomenon within the realm of electron's spin manipulation, showcasing a unique interplay between electron's spin and molecular chirality. Subsequent to its discovery, researchers have been actively involved in exploring the new chiral molecules as effective spin filters. In the realm of observing the CISS effect, the conventional approach has mandated the utilization of two distinct enantiomers of chiral molecules. However, this present study represents a significant advancement by demonstrating the ability to control both spin states of electrons in a single system. In this work, we have demonstrated the preparation of chiral metal–organic frameworks (MOFs) via a “spontaneous resolution” process, obviating the requirement for chiral sources. This resulted in the production of chiral crystals exhibiting opposite handedness (1P and 1M) and these crystals were subsequently employed as a new class of spin filters based on CISS effect. Remarkably, this work signifies the first instance of achieving dual signature of spin selectivity from a single and exclusively achiral system through a spontaneous resolution process. This holds immense potential as it facilitates the production of two distinct spin‐filtering materials from a unified system. Furthermore, we investigated the contact potential differences (CPD) of these chiral crystals and, for the first time, associated it with the preferential spin transport properties. Our findings revealed a correlation between the CPD and the chirality of the crystals, as well as the magnetization orientations of the ferromagnetic substrate, which can be elucidated by the CISS effect. In overall, the significant findings achieved using these robust and easily synthesized MOF crystals without the requirement for chiral medium represent a crucial advancement in enhancing the effectiveness of spin filtering materials to produce spintronic devices.

Surface Magnetic Stabilization and the Photoemission Chiral-Induced Spin-Selectivity Effect.

The spinterface mechanism was suggested as a possible origin for the chirality-induced spin-selectivity (CISS) effect and was used to explain and reproduce, with remarkable accuracy, experimental data from transport experiments showing the CISS effect. Here, we apply the spinterface mechanism to explain the appearance of magnetization at the interface between nonmagnetic metals and chiral molecules, through the stabilization of otherwise fluctuating magnetic moments. We show that the stabilization of surface magnetic moments occurs for a wide range of realistic parameters and is robust against dephasing. Importantly, we show that the direction of the surface magnetic moments is determined by the chiral axis of the chiral molecules. Armed with the concept of stable surface magnetic moments, we then formulated a theory for the photoemission CISS effect. The theory, based on spin-dependent scattering, leads to direct predictions regarding the relation between the photoemission CISS effect, the chiral axis direction, the spinterface "size", and the tilt angle of the detector with respect to the surface. These predictions are within reach of current experimental capabilities and may shed new light on the origin of the CISS effect.

General Alkene 1,2-syn-Cyano-Hydroxylation Procedure Via Electrochemical Activation of Isoxazoline Cycloadducts.

Stereoselective alkene 1,2-difunctionalization is a privileged strategy to access three-dimensional C(sp3)-rich chiral molecules from readily available "flat" carbon feedstocks. State-of-the-art approaches exploit chiral transition metal-catalysts to enable high levels of regio- and stereocontrol. However, this is often achieved at the expense of a limited alkene scope and reduced generality. 1,3-Dipolar cycloadditions are routinely used to form heterocycles from alkenes with high levels of regioselectivity and stereospecificity. Nevertheless, methods for the ring-opening of cycloadducts to reveal synthetically useful functionalities require the use of hazardous reagents or forcing reaction conditions; thus limiting their synthetic applications. Herein, we describe the implementation of a practical, general and selective electrosynthetic strategy for olefin 1,2-syn-difunctionalization, which hinges on the design of novel reagents-consisting of a nitrile oxide 1,3-dipole precursor, equipped with a sulfonyl-handle. These can selectively difunctionalize alkenes via "click" 1,3-dipolar cycloadditions, and then facilitate the telescoped electrochemical single electron transfer activation of the ensuing isoxazoline intermediate. Cathodic reduction of the cycloadduct triggers a radical fragmentation pathway delivering sought-after stereodefined 1,2-syn-hydroxy nitrile derivatives. Our telescoped electrochemical procedure tolerates a wide range of functionalities, and─crucially─enables the difunctionalization of both electron-rich, electron-poor and unactivated olefins, with diverse degree of substitution; thus providing a robust, general and selective metal-free alternative to current alkene difunctionalization strategies. Capitalizing on these features, we employed our electrosynthetic method to enable the late-stage syn-hydroxy-cyanation of natural products and bioactive compounds, and streamline the de novo synthesis of pharmaceutical agents.

Determining the Absolute Configuration of Small Molecules by Diffusion NMR Experiments

AbstractEnantiomers are ubiquitous in many areas of science, such as pharmaceuticals, agriculture, and food. Nuclear magnetic resonance (NMR) alone is not able to differentiate enantiomers as their spectra are identical. However, these can be distinguished using chiral auxiliaries (such as chiral complexing agents) that form diastereomeric complexes, but absolute identification is still troublesome, usually requiring a chemical reaction with a chiral derivatizing agent. Here, we propose a new method that uses a hybrid mixture of solvating agents in a simple comparison of diffusion NMR experiments, which can discriminate enantiomers in both frequency and diffusion domains, dubbed CHIMERA (CHIral Micelle Enantiomer Resolving Agent). The new method was assessed for twenty‐three small chiral molecules using a combination of BINOL and (−)‐DMEB, a chiral surfactant, and initial results indicate that absolute configuration can be obtained from a simple experiment.

Symmetry Breaking in Inorganic Nanostructures: Chirality vs. Optical Activity or Structural vs. Electronic Effects

AbstractThis essay presents the viewpoint of the author on the topic of chirality and optical activity in nanostructures. It particularly focuses on the interaction of chiral molecules with plasmonic and excitonic nanocrystals and on induction of circular dichroism in such achiral nanocrystals. It discusses recent developments in the shape symmetry breaking of achiral metal nanostructures using photochemical processes induced by asymmetric localized plasmonic hot spots excited through circularly polarized light illumination. Finally, it addresses symmetry breaking in intrinsically chiral inorganic nanocrystals using chiral ligands during their formation, leading to 100 % enantiomeric excess in the nanocrystals of TbPO4⋅H2O. These nanocrystals exhibit an interesting nucleation mechanism, which leads to very high chiral amplification (secondary nucleation).

Constraining P and T violating forces with chiral molecules

New sources of parity and time-reversal violation are predicted by well motivated extensions of the Standard Model and can be effectively probed by precision spectroscopy of atoms and molecules. Chiral molecules have distinguished enantiomers which are related by parity transformation. Thus they are promising candidates to search for parity violation at molecular scales, which has yet to be observed. In this work, we show that precision spectroscopy of the hyperfine structure of chiral molecules is sensitive to new physics sources of parity and time-reversal violation. In particular, such a study can be sensitive to regions unexplored by terrestrial experiments of a new chiral spin-1 particle that couples to nucleons. We explore the potential to hunt for time-reversal violation in chiral molecules and show that it can be a complementary measurement to other probes. We assess the feasibility of such hyperfine metrology and project the sensitivity in CHDBrI+. Published by the American Physical Society 2024

Significant Chiral Asymmetry Observed in Neutral Amino Acid Ultraviolet Photolysis.

The origin of homochirality in biological organisms remains an open question. Some suggest that its origin might be extraterrestrial, specifically due to the exposure of chiral molecules to circularly polarized photons in interstellar space, which could cause an initial population imbalance leading to the homochirality observed today. However, this extraterrestrial hypothesis has not been widely accepted, largely due to the belief that molecular optical rotatory dispersion is too insignificant to create the substantial imbalance required for homochirality. Here we report experimental evidence that specific conformers of neutral amino acids exhibit significant asymmetry in the chiral destroying dissociation rate induced by circularly polarized photons. The observed anisotropy factor for the lowest energy conformer of leucine was remarkably large, reaching 0.1─a factor of 13 times larger than observed for zwitterionic leucine in solid films, and nearly 40 times greater than the anisotropy reported in the electronic absorption spectrum of gas-phase leucine ensembles at room temperature. This significant finding indicates that even if reported anisotropy values in the electronic absorption spectrum are low, the dissociation asymmetry of certain conformers can still be substantial. An anisotropy factor of 0.1 could result in an initial enantiomeric excess exceeding 10%, even with a 90% extent of reaction. This discovery suggests that asymmetric photodissociation of amino acids may have been a crucial factor in the emergence of biological homochirality.

Enantioselective Synthesis of Azatricycles via Post-Ugi Cyclizations.

We report a new method to create enantioenriched azatricycles using chiral α-amino acids in a two-step process after an Ugi reaction. Amino acids are great building blocks for making pure chiral molecules. Using chiral natural molecules in multicomponent reactions (MCRs) helps increase their variety by adding new chiral centers. The Ugi reaction, discovered by Ivar Karl Ugi in 1959, is a versatile MCR that helps create complex molecular structures and natural products through additional transformations called post-Ugi modifications. Designing these modifications requires selecting the right amine, acid, aldehyde/ketone, and isocyanide. Amino acids, with their primary amine and carboxylic acid groups and a pre-existing chiral center, are ideal for making diverse and selective post-Ugi modifications. Our method uses ipso-cyclization and aza-Michael cyclization with hypervalent iodine to create various azaspirotricyclic structures with high stereocontrol. This approach works well with different substrates and shows promise for further development in drug discovery.

Using AR to Enhance the Learning of Chirality

This study investigates the use of Augmented Reality (AR) to teach the concept of chirality—a fundamental topic in organic chemistry. Building on Cognitive Load Theory (CLT) and previous research on AR’s educational benefits, we designed an AR learning environment to facilitate students’ understanding of chirality by allowing them to interact with and superimpose virtual and physical models of chiral molecules. An initial pilot study involving 11th-grade students revealed positive student attitudes towards AR, with participants reporting enhanced comprehension of chirality and a preference for AR-based learning over traditional methods. The follow-up study refined the AR lesson based on pilot feedback, extending its scope to introduce, rather than review, the concept of chirality. Results indicated significant learning gains, low extraneous cognitive load, and high acceptance of AR technology among students. These findings underscore the potential of AR to support complex spatial learning in chemistry, though further research, such as value-added studies, is recommended to explore the generalizability and long-term impacts of AR on different student populations.

Self-Assembly of Chiral Ligands on 2D Semiconductor Nanoplatelets for High Circular Dichroism.

Group II-VI semiconductor nanoplatelets (NPLs) with atomically defined thicknesses and extended atomically flat (001) facets are used for ligand binding and chiro-optical effects. In this study, we demonstrate that tartrate ligands, anchored by two carboxylate groups, chelate the (001) facets of NPLs at an average ratio of one tartrate molecule to two cadmium (Cd) surface atoms. This assembly of chiral molecules on inorganic nanocrystals generates a circular dichroism g-factor as high as 1.3 × 10-2 at the first excitonic transition wavelength of NPLs. Tartrate ligands induce an orthorhombic distortion of the initially "cubic" crystal structure, classifying the NPLs within the 222-point group. Unlike spherical nanocrystals, where it is difficult to discern whether chiral ligands affect only the surface atoms or the entire crystal structure, our findings unequivocally show that the crystal structure of NPLs is modified due to their thinness and atomically precise thickness. The in-plane lattice parameters experience compressive and tensile stresses, significantly splitting the heavy-hole and light-hole bands. Additionally, tartrate ligands adopt different conformations on the NPL surface over time, resulting in dynamic changes in the circular dichroism signal, including an inversion of its sign.

Design of Self-Standing Chiral Covalent-Organic Framework Nanochannel Membrane for Enantioselective Sensing.

Nanochannel membranes are promising materials for enantioselective sensing. However, it is difficult to make a compromise between the selectivity and permeability in traditional nanochannel membranes. Therefore, new types of nanochannel membranes with high enantioselectivity and excellent permeability should be explored for chiral analysis. Here, asymmetric catalysis strategy is reported for interfacial polymerization synthesis of chiral covalent-organic framework (cCOF) nanochannel membrane for enantioselective sensing. Chiral phenylethylamine (S/R-PEA) and 2,4,6-triformylphloroglucinol (TP) are used to prepare chiral TP monomer. 4,4',4″-triaminotriphenylamine (TAPA) is then condensed with chiral TP to obtain cCOF nanochannel membrane via a C═N Schiff-base reaction. The molar ratio of TP to S/R-PEA is adjusted so that S/R-PEA is bound to the aldehyde only or both the aldehyde and hydroxyl groups on TP to obtain chiral-induced COF (cCOF-1) or both chiral-induced and modified COF (cCOF-2) nanochannel membrane, respectively. The prepared cCOF-2 nanochannel membrane showed two times more selectivity for limonene enantiomers than cCOF-1 nanochannel membrane. Furthermore, cCOF-2 nanochannel platform exhibited excellent sensing performance for other chiral molecules such as limonene, propanediol, methylbutyric acid, ibuprofen, and naproxen (limits of detection of 19-42ngL-1, enantiomer excess of 63.6-86.3%). This work provides a promising way to develop cCOF-based nanochannel enantioselective sensor.

Supramolecular Control of Helicene Circularly Polarized Luminescence Emitters in Molecular Solids and Bright Nanoparticles

AbstractCircularly polarized luminescence (CPL) from chiral molecules is attracting much attention due to its potential use in optical materials. However, formulation of CPL emitters as molecular solids typically deteriorates photophysical properties in the aggregated state leading to quenching and unpredictable changes in CPL behavior impeding materials development. To circumvent these shortcomings, a supramolecular approach can be used to isolate cationic dyes in a lattice of cyanostar‐anion complexes that suppress aggregation‐caused quenching and which we hypothesize can preserve the synthetically‐crafted chiroptical properties. Herein, we verify that supramolecular assembly of small‐molecule ionic isolation lattices (SMILES) allows translation of molecular ECD and CPL properties to solids. A series of cationic helicenes that display increasing chiroptical response is investigated. Crystal structures of three different packing motifs all show spatial isolation of dyes by the anion complexes. We observe the photophysical and chiroptical properties of all helicenes are seamlessly translated to water soluble nanoparticles by the SMILES method. Also, a DMQA helicene is used as FRET acceptor in SMILES nanoparticles of intensely absorbing rhodamine antennae to generate an 18‐fold boost in CPL brightness. These features offer promise for reliably accessing bright materials with programmable CPL properties.

Polyphenol Tannin‐Induced Protein Precipitation for Drug Target Discovery by Chemical Proteomics

AbstractHigh‐throughput drug discovery is highly dependent on the targets available to accelerate the process of candidate screening. Unbiased drug target identification is of crucial importance to reveal the mechanisms of protein–drug interactions. In recent years, energetics‐based protein conformation methods have become an alternative strategy for protein target discovery of bioactive drugs. In this study, we present a novel tannin protein precipitation method (TAP) for identifying target proteins of small molecules using the effect on protein solubility of tannin. The feasibility of this method was validated using a drug model of methotrexate. It was found that the known target DHFR yields a significant solubility shift. This method was further investigated with Annexin A2, the target protein of protopanaxadiol (PPD)‐S by western blot, and by screening potential target proteins of PPD‐S in K562 cells by quantitative proteomics. Finally, the TAP method was employed to differentiate the target proteins of pair chiral molecules PPD‐S and PPD‐R, which can bring up novel insights into the mechanism of drug–protein interactions. This study not only provides an effective tool for drug research and development but also offers new ideas for understanding the mechanism of action of natural chiral bioactive compounds.

Magnetically Aligned Grains as a Ubiquitous Source of Spin-polarized Electrons and Chiral-symmetry-breaking Agents

The unique biosignature of life on Earth is the homochirality of organic compounds, such as amino acids, proteins, and sugars. High-energy spin-polarized (spinup or spindown) electrons (SPEs) from the β decay of radioactive nuclei have been proposed as a source of symmetry breaking, leading to homochirality; however, their exact role is much debated. Here, we propose magnetically aligned dust grains as a new source of SPEs, due to the photoemission of electrons having aligned spins by the Barnett effect. For the interstellar UV radiation field of strength G UV, we find that the SPE emission rate is ΓpeSPE∼10−14GUV electrons per second per H, the fraction of spin-polarized to total photoelectrons is ∼10%, and the SPE yield (photoelectron number per UV photon) can reach ∼1%, using the modern theory of grain alignment. SPEs emitted from aligned grains could play an important role in chiral-induced spin-selectivity-driven reduction chemistry in the icy grain mantles, producing an enantiomer excess of chiral molecules formed on the grain mantle. Finally, we suggest magnetically aligned grains could directly impact the enantio-selectivity through the chiral-induced spin-selective adsorption effect and exchange interaction. We estimate the disalignment of electron spins and depolarization by elastic scattering using the Mott theory and find that these effects are negligible for low-energy SPEs, so that the spins of SPEs remain well aligned during their journey through dust grains and the gas. Our proposed mechanism might explain the chiral asymmetry of prebiotic molecules detected in numerous comets, asteroids, and meteorites.

Substrate as the primer of relay-race spin-driven self-assembly of chiral molecules

The molecules of chiral N-trifluoroacetylated α-aminoalcohols can self-assemble and form long and thin fiber-like supramolecular structures (strings). The strings effectively grow on the surface of the substrate and the amount of them, as well as their morphology, depend on the properties of the substrate. In particular, self-assembly was not observed on the electroconductive substrates, such as some metals (copper and aluminum) and graphite. The strings were found on the surface of titanium due to the peculiarities of the titanium oxide’s properties. The strings usually emanate from some nucleation zones, where the growth was initiated and then proceeded spontaneously outside these areas. We supposed the relay-race scheme of the transfer of spin polarization, which describes the mechanics and thermodynamics of the observed self-assembly process. The scheme implies the preliminary orientation of two molecules, their mutual polarization accompanied by spin-polarization, and finally the binding of the molecules. We also suppose this mechanism can play a significant role in various self-assembly processes in living cells.

Phenazinium- and Malachite Green-Based Pd(II) Cages: Chiroptical Discrimination of Nucleoside Triphosphates.

Organic chromophores have been successfully implemented into supramolecular systems to bestow them with distinct photophysical properties for various applications, ranging from solar energy conversion, photochemical reactions or as receptors for guest molecules with optical readout. We had previously introduced first members of the large family of coal-tar dyes (methylene blue, crystal violet and rhodamine) as integral components of coordination cages. Here, we add two new chromophores, malachite green (MGP) and a purple phenazinium dye (PHP), serving as backbones of bis-monodentate banana-shaped ligands with pyridine donors. We show the formation of corresponding green and purple coloured Pd2L4 coordination cages and investigate their interaction with chiral guest molecules via UV-Vis and CD spectroscopy. The PHP cage can be used to recognize nucleoside triphosphates, based on chirality transfer from the guests to the structurally flexible helicate. In combination with the already known methylene blue cage MBP we could further differentiate between all four canonical NTPs through characteristic changes in the observed CD signatures.

Deep-Learning Empowered Customized Chiral Metasurface for Calibration-Free Biosensing.

As a 2D metamaterial, metasurfaces offer an unprecedented avenue to facilitate light-matter interactions. The current "one-by-one design" method is hindered by time-consuming, repeated testing within a confined space. However, intelligent design strategies for metasurfaces, limited by data-driven properties, have rarely been explored. To address this gap, a data iterative strategy based on deep learning, coupled with a global optimization network is proposed, to achieve the customized design of chiral metasurfaces. This methodology is applied to precisely identify different chiral molecules in a label-free manner. Fundamentally different from the traditional approach of collecting data purely through simulation, the proposed data generation strategy encompasses the entire design space, which is inaccessible by conventional methods. The dataset quality is significantly improved, with a 21-fold increase in the number of chiral structures exhibiting the desired circular dichroism (CD) response (>0.6). The method's efficacy is validated by a monolayer structure that is easily prepared, demonstrating advanced sensing abilities for enantiomer-specific analysis of bio-samples. These results demonstrate the superior capability of data-driven schemes in photonic design and the potential of chiral metasurface-based platforms for calibration-free biosensing applications. The proposed approach will accelerate the development of complex systems for rapid molecular detection, spectroscopic imaging, and other applications.