Enantioselective Molecular Recognition Research Articles

Two-Dimensional Crystal Transition from Radialene to Cumulene on Ag(111) via Retro-[2 + 1] Cycloaddition.

Two-dimensional (2D) crystal-to-crystal transition is an important method in crystal engineering because of its ability to directly create diverse crystal materials from one crystal. However, steering a 2D single-layer crystal-to-crystal transition on surfaces with high chemo- and stereoselectivity under ultra-high vacuum conditions is a great challenge because the transition is a complex dynamic process. Here, we report a highly chemoselective 2D crystal transition from radialene to cumulene with retention of stereoselectivity on Ag(111) via retro-[2 + 1] cycloaddition of three-membered carbon rings and directly visualize the transition process involving a stepwise epitaxial growth mechanism by the combination of scanning tunneling microscopy and non-contact atomic force microscopy. Using progression annealing, we found that isocyanides on Ag(111) at a low annealing temperature underwent sequential [1 + 1 + 1] cycloaddition and enantioselective molecular recognition based on C-H···Cl hydrogen bonding interactions to form 2D triaza[3]radialene crystals. In contrast, a higher annealing temperature induced the transformation of triaza[3]radialenes to generate trans-diaza[3]cumulenes, which were further assembled into 2D cumulene-based crystals through twofold N-Ag-N coordination and C-H···Cl hydrogen bonding interactions. By combining the observed distinct transient intermediates and density functional theory calculations, we demonstrate that the retro-[2 + 1] cycloaddition reaction proceeds via the ring opening of a three-membered carbon ring, sequential dechlorination/hydrogen passivation, and deisocyanation. Our findings provide new insights into the growth mechanism and dynamics of 2D crystals and have implications for controllable crystal engineering.

Enantioselective Molecular Recognition in a Flexible Self-Folding Cavitand.

We report a chiral deep cavitand receptor based on calix[5]arene stabilized by a cooperative network of hydrogen bonds and having a highly flexible structure. The cavitand displays enantioselective molecular recognition with a series of chiral quaternary ammonium salts, providing unprecedented stability ratios between the corresponding diastereomeric host-guest complexes. Molecular dynamics simulations corroborate the higher flexibility of the new host and the emergence of superior induced-fit behavior with regards to resorcin[4]arene derived self-folding cavitands.

Preferential molecular recognition of heterochiral guests within a cyclophane receptor

The discrimination of enantiomers by natural receptors is a well-established phenomenon. In contrast the number of synthetic receptors with the capability for enantioselective molecular recognition of chiral substrates is scarce and for chiral cyclophanes indicative for a preferential binding of homochiral guests. Here we introduce a cyclophane composed of two homochiral core-twisted perylene bisimide (PBI) units connected by p-xylylene spacers and demonstrate its preference for the complexation of [5]helicene of opposite helicity compared to the PBI units of the host. The pronounced enantio-differentiation of this molecular receptor for heterochiral guests can be utilized for the enrichment of the P-PBI-M-helicene-P-PBI epimeric bimolecular complex. Our experimental results are supported by DFT calculations, which reveal that the sterically demanding bay substituents attached to the PBI chromophores disturb the helical shape match of the perylene core and homochiral substrates and thereby enforce the formation of syndiotactic host-guest complex structures. Hence, the most efficient substrate binding is observed for those aromatic guests, e. g. perylene, [4]helicene, phenanthrene and biphenyl, that can easily adapt in non-planar axially chiral conformations due to their inherent conformational flexibility. In all cases the induced chirality for the guest is opposed to those of the embedding PBI units, leading to heterochiral host-guest structures.

Evolution of Br⋯Br contacts in enantioselective molecular recognition during chiral 2D crystallization

Halogen-mediated interactions play an important role in molecular recognition and crystallization in many chemical and biological systems, whereas their effect on homochiral versus heterochiral recognition and crystallization has rarely been explored. Here we demonstrate the evolution of Br⋯Br contacts in chiral recognition during 2D crystallization. On Ag(100), type I contacts prevail at low coverage and lead to homochiral recognition and the formation of 2D conglomerates; whereas type II contacts mediating heterochiral recognition are suppressed at medium coverage and appear in the racemates induced by structural transitions at high coverage. On Ag(111), type I contacts dominate the 2D crystallization and generate 2D conglomerates exclusively. DFT calculations suggest that the energy difference between type I and type II contacts is reversed upon adsorption due to the substrate induced mismatch energy penalty. This result provides fundamental understanding of halogen-mediated interactions in molecular recognition and crystallization on surface.

Enantioselective Recognition of Helicenes by a Tailored Chiral Benzo[ghi]perylene Trisimide π-Scaffold.

Enantioselective molecular recognition of chiral molecules that lack specific interaction sites for hydrogen bonding or Lewis acid–base interactions remains challenging. Here we introduce the concept of tailored chiral π‐surfaces toward the maximization of shape complementarity. As we demonstrate for helicenes it is indeed possible by pure van‐der‐Waals interactions (π–π interactions and CH–π interactions) to accomplish enantioselective binding. This is shown for a novel benzo[ghi]perylene trisimide (BPTI) receptor whose π‐scaffold is contorted into a chiral plane by functionalization with 1,1′‐bi‐2‐naphthol (BINOL). Complexation experiments of enantiopure (P)‐BPTI with (P)‐ and (M)‐[6]helicene afforded binding constants of 10 700 M−1 and 550 M−1, respectively, thereby demonstrating the pronounced enantiodifferentiation by the homochiral π‐scaffold of the BPTI host. The enantioselective recognition is even observable by the naked eye due to a specific exciplex‐type emission originating from the interacting homochiral π‐scaffolds of electron‐rich [6]helicene and electron‐poor BPTI.

Enantiomeric recognition of α-amino acid derivatives by chiral uranyl–salen receptors

Enantioselective molecular recognition of α-amino acid derivatives by two chiral uranyl–salen hosts was investigated by NMR data. The receptors differ for the presence of two tert-butyl groups in the salen backbone. The uranyl hosts have shown high binding constant values and excellent enantioselectivities for the selected guests (up to 100 for the tryptophan derivative).

Enantioselective Molecular Recognition of Chiral Organic Ammonium Ions and Amino Acids Using Cavitand–Salen‐Based Receptors

AbstractTwo new receptors, a cavitand–salen (2) and a uranyl–cavitand–salen (3), for the selective molecular recognition of chiral ammonium ion pairs, where the amino acid is the countercation or counteranion of the ion pair, were designed and synthesized. UV/Vis measurements indicate the formation of 1:1 host–guest complexes with high association constants and good to excellent enantiomeric discriminations. NMR spectroscopic experiments confirmed cation–π interactions between the organic cations and the π‐electron‐rich cavity, leading to the stability of the complexes, as well as the coordination of the amino acid carboxylate anion to the uranyl metal center. Extraction experiments showed that a racemic mixture of (R,S)‐α‐methylbenzyltrimethylammonium iodides undergoes chiral resolution by 2 with high selectivity.

ESI‐MS investigation of solvent effects on the chiral recognition capacity of tartar emetic towards neutral side‐chain amino acids

The effect of solvent systems on previously-reported ESI-MS based proton-assisted enantioselective molecular recognition phenomena of tartar emetic, L-antimony(III)-tartrate, was evaluated. This was achieved by carrying out a series of competitive binding experiments using chiral selectors, bis(sodium) D- and -L-antimony(III)-tartrates with chiral selectands, neutral side-chain amino acid enantiomeric isotopomers of alanine (Ala), valine (Val), leucine (Leu) and phenylalanine (Phe), in three different solvent systems, ACN/H(2)O (75/25 v/v), H(2)O (100%) and H(2)O/MeOH (25/75 v/v). Observations from these experiments suggest that the effect of solvent systems on previously reported proton-assisted chiral recognition capacity of D,L-antimony(III)-tartrates is small, but not negligible. It was observed that an ACN/H(2)O (75/25 v/v) solvent system facilitates and enhances the chiral discrimination capacity of protonated {[D,L-Sb(2)-tar(2)][H]}(-) ionic species. Further, amino acid enantiomers showed a general trend of increasing selectivity order, Val ≤ Ala < Leu ≈ Phe towards the protonated {[D,L-Sb(2)-tar(2)][H]}(-) ionic species which was independent of the solvent system employed. The lack of enantioselective binding for {[D,L-Sb(2)-tar(2)]}(2-) ionic species was consistently recorded in respective mass spectra from all performed experiments, which suggests that ESI-friendly solvent systems have no effect and do not influence this phenomenon.

Antimony(III)- D, L-Tartrates Exhibit Proton-Assisted Enantioselective Binding in Solution and in the Gas Phase

The negative ion mode ESI mass spectral analysis of antimony(III)-D- and -L-tartrate ("tartar emetic"), in association with leucine enantiomeric isotopomers, revealed remarkable proton-assisted enantioselective molecular recognition phenomena. The current study infers that recognition of amino acids by antimony(III)-D,L-tartrate complexes requires that the chiral selector associate a proton to become enantioselective. The dianionic selector itself failed to show enantiomeric discrimination capacity. This observation was shown to be consistent both in solution-phase targeting full scan and gas-phase targeting collision threshold dissociation (CTD) experiments. Importantly, this disparity in enantioselective binding capacity between the dianionic and the protonated monoanionic representatives of antimony(III)-D- and -L-tartrates could only be clearly revealed by ESI-MS and tandem mass spectrometry experiments as described herein. This finding urges a more in-depth study of mechanisms associated with exhibited enantiomeric resolving capacity of antimony tartrates in HPLC and CE applications, as well as in former ESI-MS association studies.

Exploring enantioselective molecular recognition mechanisms with chemoinformatic techniques

A comprehensive review of chemoinformatic techniques and studies applied to the field of enantioselective molecular recognition is presented. Several approaches such as enantiophores/pharmacophore modelling, QSPRs, CoMFA and other insightful data mining procedures are discussed. The review focuses on the central role of chemoinformatic approaches on the establishment of connections between available experimental data, mainly HPLC separation data, and these algorithms that describe properties of chiral molecules. The general overview of the aforementioned calculations account for a use of these techniques as a valuable strategy to achieve reliable prediction systems, infer the mechanisms of chiral recognition, generate insight for the conception of new chiral receptors and corroborate and assist experimental techniques such as chiral LC. Moreover, it is pointed out that computer methods in this field promise a wide range of applications for both academia and industry, ranging from enantioselective reactions, drug discovery and analysis of high-throughput screenings, to analytical and semi-preparative separations or large-scale production of enantiopure compounds.

Investigation of Monovalent and Bivalent Enantioselective Molecular Recognition by Electrospray Ionization-Mass Spectrometry and Tandem Mass Spectrometry

In this work is described the investigation of bivalent versus monovalent enantioselective molecular recognition in the context of enantioselective separations. Electrospray ionization-mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS) are used for evaluating enantioselective systems through the measurement of (1) relative solution-phase binding constants via titration and (2) relative gas-phase binding via collision threshold dissociation. In HPLC, a cinchonane-type chiral stationary phase (CSP) based on tert.-butylcarbamoylquinine provides vastly increased retention and enantioselectivity for separation of bivalent versus monovalent alkoxy-benzoyl-N-blocked leucine enantiomers. The bivalent enantiomers are able to span and simultaneously interact with multiple interaction sites on the CSP surface, leading to enhanced separation. ESI-MS titration measurements also show an increased avidity for binding between bivalent selector and bivalent selectand, compared with the monovalent system. However, enhanced enantioselectivities measured in HPLC for the bivalent system cannot be reproduced by MS due to inherent mechanistic differences. Assumed discrepancies in relative response factors also give rise to systematic errors which are discussed. The results of MS/MS gas-phase experiments show that enantioselectivity is essentially lost in the absence of solvation, but that dissociation thresholds can provide a measure of relative dissociation energy in the bivalent interaction system compared to the monovalent counterpart. Such measurements may prove useful and efficient in better understanding multivalent interactions, in line with current theoretical considerations of effective concentrations and ion trap effects. This is the first application of mass spectrometric methods for assessing increased avidity of binding in multivalent enantioselective molecular recognition.

Enantioselective recognition of 2,3-benzodiazepin-4-one derivatives with anticonvulsant activity on several polysaccharide chiral stationary phases

The retention behaviour of racemic 1-(4-aminophenyl)-1,2,3,5-tetrahydro-7,8-methylendioxy-4H-2,3-benzodiazepin-4-one derivatives with anticonvulsant activity on several chiral stationary phases was investigated. The selective performances of six polysaccharide phases, namely, Chiralcel OA, OD, OF, OG, OJ and Chiralpak AD were studied and normal phase HPLC methods were optimized to separate the enantiomeric forms of this class of compounds. The chiral recognition mechanism between the analytes and the chiral selectors was discussed. A molecular modeling study was carried out with the aim to explore the enantioselective molecular recognition process with the Chiralcel OG stationary phase.

A highly enantioselective abiotic receptor for malate dianion in aqueous solution

The highly enantioselective molecular recognition of the malate dianion by a synthetic receptor in aqueous solution has been studied by potentiometric titrations, mass spectrometry (ESI-MS), diffusion measurements (PGSE NMR) and molecular modeling.

Optically Pure Calix[6]tris-ammoniums: Syntheses and Host−Guest Properties toward Neutral Guests

[reaction: see text] Optically pure calix[6]arenes bearing chiral amino arms 4, 7, and 10 have been synthesized in high yields from the known symmetrically 1,3,5-trismethylated calix[6]arene. For both compounds 7 and 10, the key step consists of an efficient selective alkylation on the narrow rim of the calix[6]arene with Ba(OH)2 as the base. All of these chiral calix[6]tris-amines possess a similar flattened cone conformation with the cavity occupied by the methoxy groups. In contrast to 4 and 7, upon protonation, the enantiopure calix[6]arene 10 can switch to the opposite flattened cone conformation through self-assembly of its ammonium arms in an ion-paired cap which closes the cavity. As shown by NMR host-guest studies and an X-ray structure, the obtained polarized host (10 x 3H+) behaves as a remarkable endo-receptor for small polar neutral molecules. Thanks to the tris-cationic chiral binding site of 10 x 3H+, it was shown that the guests experience a chiral environment upon inclusion. Finally, the first example of enantioselective molecular recognition inside the cavity of a calix[6]arene has been evidenced with a racemic 1,2-diol guest.

Enantioselective molecular recognition between beta-sheets.

This communication asks whether homochiral or heterochiral interaction is preferred between enantiomeric beta-sheets and finds that homochiral pairing is strongly preferred. Interactions between beta-sheets occur widely among proteins through pairing of the hydrogen-bonding edges. Although the hydrogen-bonding edges of both l- and d-beta-sheets put forth the same pattern of hydrogen-bond donor and acceptor groups, the side chains point in opposite directions. Homochiral pairing of beta-sheets generates structures in which the pleats and side chains of adjacent beta-strands are parallel to each other, while heterochiral pairing of beta-sheets generates structures in which the pleats and side chains are antiparallel. To test which pairing is preferred, we have prepared and studied the interactions of beta-sheets 1a-d, which comprise all l-amino acids, and beta-sheets 2a-c, which comprise all d-amino acids. Previous studies in our laboratory have established that these compounds form well-defined dimers in organic solvents. In the current study, 1H NMR experiments establish that when the l-beta-sheets (1) are mixed with the enantiomeric d-beta-sheets (2), homochiral beta-sheet dimers predominate, and only small quantities of heterochiral beta-sheet dimers form. Ratios of homochiral and heterochiral dimers ranging from 95.8:4.2 to 98.5:1.5 are measured in CDCl3 at 253 K, which correspond to statistically corrected free-energy differences of 3.1-4.2 kcal/mol (0.6-0.8 kcal/mol per interacting residue). Possible explanations for the high enantioselectivity of molecular recognition between beta-sheets include favorable nonbonded contacts between the adjacent beta-strands of the homochiral beta-sheets and poor fit of the heterochiral beta-strands, which should twist in opposite directions.

ChemInform Abstract: Geometrical Optimization of 1,1′‐Binaphthalene Receptors for Enantioselective Molecular Recognition of Excitatory Amino Acid Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Geometrical optimisation of 1,1′-binaphthalene receptors for enantioselective molecular recognition of excitatory amino acid derivatives

A series of optically active 1,1′-binaphthalene-derived receptors with N-(pyridine-2,6-diyl)acetamide [CONH(py)] H-bonding sites in the 6,6′-positions has been prepared for the enantioselective complexation of the N-carbobenzyloxy (Cbz)-protected excitatory amino acids aspartic (Asp) and glutamic (Glu) acid via two COOH· · ·CONH(py) H-bonding arrays and additional secondary bonding interactions. The conformational homogeneity of the receptors is enhanced by locking the dihedral angle θ about the chirality axis through the C(1)–C(1′) bond of the 1,1′-binaphthalene moiety either by bridging the 2,2′-positions or by attaching bulky substituents to these centres. Computer modelling has shown that bridging is more efficient in locking this dihedral angle than the introduction of bulky substituents, and these predictions have been confirmed by 1H NMR binding studies in CDCl3 and in CDCl3–CD3OD 99.8∶0.2. Plots of the enantioselectivity Δ(ΔG°) (difference in stability between diastereoisomeric complexes) in the recognition by the bridged receptors as a function of the enforced dihedral angle θ are peak-shaped, and the highest values have been measured in CDCl3 (300 K) for the complexation of the enantiomers of N-Cbz-Asp [Δ(ΔG°) = 6.9 kJ mol–1] and N-Cbz-Glu [Δ(ΔG°) = 5.2 kJ mol–1] by (R)-21 (θ = 86 ± 4°). The more stable diastereoisomeric complexes are highly structured, and tight host–guest bonding has been confirmed by the observation of up to five intermolecular NOEs. Enforcing the conformational homogeneity by bridging represents a new general principle for improving the chiral recognition potential of 1,1′-binaphthalene receptors.

クロモジェニックレセプター：カチオン認識から不斉認識へ

This article describes our recent achievements in developing synthetic chromogenic receptors which are characterized by combined “recognition” and “optical sensing” functions. The focus is on preparation and some intriguing properties of several kinds of azomethine-derived calixarenes : this work is extended in two related directions, the incorporation of indoaniline-type chromophores as an appropriate optical sensory group into calixarenes bearing a guest-binding site produced new types of receptors for optical sensing against cations. Second, a chiral calix [4] crown containing an optically active 1, 1' -binaphthyl subunit and two indophenol chromophores was synthesized as a molecular sensor which is capable of translating an enantioselective molecular recognition event into a discernible color change. A simple monitoring system for biologically and/or chemically important species is discussed.

Colorimetric chiral recognition by a molecular sensor

ONE of the most pressing challenges in the design of molecular sensors1–7 is to achieve visual discrimination between enantiomers. A simple monitoring system for distinguishing between the left- and right-handed forms of chiral drugs would be extremely useful in pharmacology8. A molecular sensor that achieves this would have to translate an enantioselective molecular recognition event into a discernible colour change. Here we describe a system of this sort, in which a proton transfer and conformational change in a chiral calixarene-based receptor brought about by recognition of a chiral substrate cause spectral shifts in two chromophores attached to the binding cavity of the calixarene. Because the spectral shift in one chromophore is greater for one enantiomer of the substrate than for the other, binding is accompanied by a colour change that can be observed visually.

Recent developments in the synthesis and functionalization of conducting poly(thiophenes)

AbstractThe mechanism of the electropolymerization of thiophene derivatives has been investigated by varying the electrosynthesis conditions and the monomer structure. The results of these analyses led to the definition of optimized electrosynthesis conditions allowing the control of the electrical and electrochemical properties of poly(thiophenes). On the basis of these results, the properties of these polymers have been modified by means of a new one‐step electrosynthesis of conducting composite materials and by the direct electropolymerization of tailor‐made functionalized monomers. For this purpose, the steric conditions associated to the various possibilities of covalent derivatization have been analyzed, leading to the definition of a “functionalization space”, compatible with the preservation of high conductivity and electrochemical reversibility in the resulting polymers. This concept has been applied to the synthesis of highly conducting chiral poly(thiophenes) on which an effect of enantioselective molecular recognition has been demonstrated for the first time.