Heterochiral Dimers Research Articles

Enantioselective interactions of aminonitrile dimers.

Enantioenrichment of amino acids is essential during the early chemical evolution leading to the origin of life. However, the detailed molecular mechanisms remain unsolved. Dimerization of enantiomers is the first molecular process in the nucleation of deposition and crystallization, which are both essential for enantioenrichment. Here, we report the enantioselective interactions of dimers of chiral intermediates, i.e., aminonitriles, in both gas and water environments based on density functional theory (DFT) and more accurate coupled-cluster (CC) calculations. We show that all the aminonitriles stabilize the homochiral dimer preferentially to the heterochiral dimer in the gas phase, while this trend was not observed in water. The energies of the enantioselective interactions in aminonitriles are substantially lower compared to those in amino acids, especially isovaline. These results suggest that prebiotic enhancements of enantiomeric excess are more likely to occur in amino acids than in the aminonitrile intermediates.

Protein-based 2D Nanoarchitectures Constructed by Heterochiral π-Stacking Dimerization of Helical Foldamers.

In this study, we focus on the designability and controllability of the interaction interface between secondary structures, and discover an important interface interaction between helical secondary structures by non-covalent synthesis along the helical axis. The formation of discrete heterochiral dimers consisting of left-handed helix and right-handed helix not only helps to discover nonclassical supramolecular chirality phenomena, but also enables controllable protein assembly. Highly ordered nanostructures were thus constructed using p-stacking dimerization of helical foldamers to control tetrameric avidin proteins. The designable and modifiable primitives of artificial folded molecules enable the modification of secondary structure interfaces through non-covalent interactions, leading to the generation of unique structures and functions. These findings are of fundamental importance to the understanding of the precise assembly process of helical foldamers and can provide insights to facilitate the rational design of abiotic protein-like tertiary structures and further functionalization.

Molecular Structures and Microwave Spectra of the Gas-Phase Homodimers of 3-Fluoro-1,2-epoxypropane and 3,3-Difluoro-1,2-epoxypropane.

Molecular structures for the heterochiral and homochiral gas-phase homodimers of 3-fluoro-1,2-epoxypropane and 3,3-difluoro-1,2-epoxypropane are investigated using both ab initio and density functional quantum chemistry calculations. Although microwave spectra for the heterochiral dimers are not observed as the lowest-energy isomers lack an electric dipole moment and others are presumably too high in energy, rotational spectra are observed for the homochiral dimers of each molecule that are consistent with the lowest-energy isomers of each. The presence of hydrogen atoms in the fluoromethyl groups makes it possible for these groups to participate in the intermolecular interactions that stabilize these dimers, resulting in a distinctly different bonding motif than is observed in the homodimers of 3,3,3-trifluoro-1,2-epoxypropane where the lack of a hydrogen atom prevents this possibility. The rotational spectra and energy ordering of the dimers are sufficiently well predicted with modest calculational methods to enable straightforward assignment of the observed spectra and to identify the molecular carrier of an assigned spectrum.

Turning Enantiomeric Relationships into Diastereomeric Ones: Self-Resolving α-Ureidophosphonates and Their Organocatalytic Enantioselective Synthesis

Controlling chiral recognition and chiral information transfer has major implications in areas ranging from drug design and asymmetric catalysis to supra- and macromolecular chemistry. Especially intriguing are phenomena associated with chiral self-recognition. The design of systems that show self-induced recognition of enantiomers, i.e., involving homochiral versus heterochiral dimers, is particularly challenging. Here, we report the chiral self-recognition of α-ureidophosphonates and its application as both a powerful analytical tool for enantiomeric ratio determination by NMR and as a convenient way to increase their enantiomeric purity by simple achiral column chromatography or fractional precipitation. A combination of NMR, X-ray, and DFT studies indicates that the formation of homo- and heterochiral dimers involving self-complementary intermolecular hydrogen bonds is responsible for their self-resolving properties. It is also shown that these often unnoticed chiral recognition phenomena can facilitate the stereochemical analysis during the development of new asymmetric transformations. As a proof of concept, the enantioselective organocatalytic hydrophosphonylation of alkylidene ureas toward self-resolving α-ureidophosphonates is presented, which also led us to the discovery of the largest family of self-resolving compounds reported to date.

Torsional chirality and molecular recognition: the homo and heterochiral dimers of thenyl and furfuryl alcohol.

Furfuryl alcohol and thenyl alcohol contain a labile torsional chiral center, producing transiently chiral enantiomers interconverting in the nanosecond time-scale. We explored chiral molecular recognition using the weakly-bound intermolecular dimers of both alcohols, freezing stereomutation. Supersonic jet broadband microwave spectroscopy revealed homo and heterochiral diastereoisomers for each alcohol dimer and the structural characteristics of the clusters. All dimers are primarily stabilized by a moderately intense O-H⋯O hydrogen bond, but differ in the secondary interactions, which introduce additional hydrogen bonds either to the ring oxygen in furfuryl alcohol or to the π ring system in thenyl alcohol. Density-functional calculations (B2PLYP-D3(BJ)/def2-TZVP) show no clear preferences for a particular stereochemistry in the dimers, with relative energies of the order 1-2 kJ mol-1. The study suggests opportunities for the investigation of chiral recognition in molecules with torsional barriers in between transient and permanent interconversion regimes.

Vibrational Spectroscopy of Homo- and Heterochiral Amino Acid Dimers: Conformational Landscapes.

The homo- and heterochiral protonated dimers of asparagine with serine and with valine were investigated using infrared multiple-photon dissociation (IRMPD) spectroscopy. Extensive quantum-chemical calculations were used in a three-tiered strategy to screen the conformational spaces of all four dimer species. The resulting binary structures were further grouped into five different types based on their intermolecular binding topologies and subunit configurations. For each dimer species, there are eight to fourteen final conformational geometries within a 10 kJ mol−1 window of the global minimum structure for each species. The comparison between the experimental IRMPD spectra and the simulated harmonic IR features allowed us to clearly identify the types of structures responsible for the observation. The monomeric subunits of the observed homo- and heterochiral dimers are compared to the corresponding protonated/neutral amino acid monomers observed experimentally in previous IRMDP/rotational spectroscopic studies. Possible chirality and kinetic influences on the experimental IRMPD spectra are discussed.

Absence of Non‐Linear Effects Despite Evidence for Catalyst Aggregation

AbstractAn in‐depth study of the catalytic system, consisting of the enantioselective addition of ZnEt2 to benzaldehyde with (1R,2S)‐(−)‐N‐Methylephedrine (NME) as chiral ligand, suggests the presence of dimeric and trimeric aggregates, as deduced from product ee vs. catalyst loading and NMR investigations (1H, DOSY). Formation of catalyst aggregation was excluded in earlier studies as this system displays a linear product ee vs. ligand ee‐correlation, which is usually taken as an indication for the absence of catalyst aggregation. A subsequent theoretical study, using the monomer‐dimer competition model, which we have recently developed, highlights the possible parameter configurations leading to linear product ee vs. ligand ee plots – despite the presence of catalyst dimers. It shows that, while the Kagan and Noyori models allow linearity in very specific cases only, a multitude of scenarios may lead to linearity here, especially if heterochiral dimers are catalytically active.

Dynamic chiral self-recognition in aromatic dimers of styrene oxide revealed by rotational spectroscopy

Chiral molecular recognition is a pivotal phenomenon in biomolecular science, governed by subtle balances of intermolecular forces that are difficult to quantify. Non-covalent interactions involving aromatic moieties are particularly important in this realm, as recurring motifs in biomolecular aggregation. In this work, we use high-resolution broadband rotational spectroscopy to probe the dynamic conformational landscape enclosing the self-pairing topologies of styrene oxide, a chiral aromatic system. We reach a definite assignment of four homochiral and two heterochiral dimers using auxiliary quantum chemistry calculations as well as structure-solving methods based on experimental isotopic information. A complete picture of the dimer conformational space is obtained, and plausible routes for conformational relaxation are derived. Molecular structures are discussed in terms of conformational flexibility, the concerted effort of weak intermolecular interactions, and their role in the expression of the molecular fit.

Efficient Amplification in Soai's Asymmetric Autocatalysis by a Transient Stereodynamic Catalyst.

Mechanisms leading to a molecular evolution and the formation of homochirality in nature are interconnected and a key to the underlying principles that led to the emergence of life. So far proposed mechanisms leading to a non-linear reaction behavior are based mainly on the formation of homochiral and heterochiral dimers. Since homochiral and heterochiral dimers are diastereomers of each other, the minor enantiomer is shifted out of equilibrium with the major enantiomer by dimer formation and thus a reaction or catalysis can be dominated by the remaining molecules of the major enantiomer. In this article a mechanism is shown that leads to homochirality by the formation of a highly catalytically active transient intermediate in a stereodynamically controlled reaction. This is demonstrated by Soai's asymmetric autocatalysis, in which aldehydes are transformed into the corresponding alcohols by addition of dialkylzinc reagents. The mechanism of chirogenesis proposed here shows that an apparently inefficient reaction is the best prerequisite for a selection mechanism. In addition, stereodynamic control offers the advantage that the minor diastereomeric intermediate can be interconverted into the major diastereomer and thus be stereoeconomically efficient. This is supported by computer simulation of reaction kinetics.

Ab Initio Study of Chiral Discrimination in the Glycidol Dimer.

Chiral discrimination, the ability of a chiral molecule to exhibit different weak intermolecular interactions than its mirror image, is investigated for dimers of oxiranemethanol (glycidol). In this regard, high-level ab initio calculations were performed to study the chiral recognition effects in the homochiral and heterochiral dimers of glycidol. Fourteen dimer structures, seven homochiral and seven heterochiral, were studied: they all feature two intermolecular O-H···O hydrogen bonds. These structures have been determined with the second-order Møller-Plesset perturbation theory (MP2) using the aug-cc-pVTZ basis set and verified to pertain to actual local minima. The benchmark interaction energy values were computed using MP2 extrapolated from the aug-cc-pVQZ and aug-cc-pV5Z bases with a higher-level correction from a coupled-cluster calculation in the aug-cc-pVTZ basis. The global minimum structure is a homochiral one, with the two hydrogen bonds forming a part of a ring with eight heavy atoms. A similar heterochiral structure has a binding energy smaller by about 0.6 kcal/mol. The largest diastereomeric energy difference is about 1.0 kcal/mol. Further insight into the origins of chiral discrimination was provided by symmetry-adapted perturbation theory (SAPT) and a functional-group SAPT (F-SAPT) difference analysis to investigate the direct and indirect effects of two -H/-CH2OH substitutions leading from an achiral ethylene oxide dimer to the chiral glycidol dimer. Last but not least, harmonic frequency shifts relative to a noninteracting glycidol molecule were calculated and analyzed for all conformations to get insight into the origins of chiral discrimination. It is found that the largest frequency shifts are related to the effect of hydrogen bonding on the O-H stretch mode, the stability of the ring involving both hydrogen bonds, and the transition between two nonequivalent minima of the glycidol molecule.

Structural Elucidation of Enantiopure and Racemic 2-Bromo-3-Methylbutyric Acid

Halogenated carboxylic acids have been important compounds in chemical synthesis and indispensable research tools in biochemical studies for decades. Nevertheless, the number of structurally characterized simple α-brominated monocarboxylic acids is still limited. We herein report the crystallization and structural elucidation of (R)- and rac-2-bromo-3-methylbutyric acid (2-bromo-3-methylbutanoic acid, 1) to shed light on intermolecular interactions, in particular hydrogen bonding motifs, packing modes and preferred conformations in the solid-state. The crystal structures of (R)- and rac-1 are revealed by X-ray crystallography. Both compounds crystallize in the triclinic crystal system with Z = 2; (R)-1 exhibits two crystallographically distinct molecules. In the crystal, (R)-1 forms homochiral O–H···O hydrogen-bonded carboxylic acid dimers with approximate non-crystallographic C2 symmetry. In contrast, rac-1 features centrosymmetric heterochiral dimers with the same carboxy syn···syn homosynthon. The crystal packing of centrosymmetric rac-1 is denser than that of its enantiopure counterpart (R)-1. The molecules in both crystal structures adopt a virtually identical staggered conformation, despite different crystal environments, which indicates a preferred molecular structure of 1. Intermolecular interactions apart from classical O–H···O hydrogen bonds do not appear to have a crucial bearing on the solid-state structures of (R)- and rac-1.

Mechanism Change of (+)-Nonlinear Effect in a Phase Separation System in a CuII-Catalyzed Asymmetric Friedel-Crafts Reaction Using a C2-Chiral Dioxolane-Containing-Bisamidine Ligand, Naph-diPIM-dioxo-iPr

Abstract A CuII complex of bisamidine ligand LS, chirally modified naphtho[1,2-b:7,8-b′]dipyrroloimidazole (Naph-diPIM), catalyzes the enantioselective Friedel-Crafts (FC) reaction of indole (1a) with ethyl trifluoropyruvate (2) to give quantitatively the FC adduct 3a with a 98:2 S/R enantiomer ratio (er). The reaction shows no nonlinear effect (NLE) under the standard conditions of [1a] = [2] = 100 mM; [Cu(OTf)2] = [LS + LR] = 0.10 mM; CPME; and 0 °C irrespective of the catalyst aging temperature. A five-fold increase in the catalyst concentration (0.50 mM) changes the situation, leading to a strong (+)-NLE with phase separation of a white solid. The NLE is expressed by the Noyori-type mechanism: Aggregate of heterochiral dimer CuLSCuLR is separated from the reaction system (Khetero > 1 > Khomo). Furthermore, a strong (+)-NLE is observed via a purple solid liberation even with [CuII] = 0.10 mM after the catalyst aging at 100 °C in the presence of an excess amount of chiral ligand. A mechanistic study has revealed i) that the sterically disfavored homochiral 1:2 complex CuLSLS is more stabilized by an intramolecular n-π* interaction than the sterically favored heterochiral 1:2 complex CuLSLR and ii) that the (+)-NLE originates from the phase separation of heterochirally interacted (CuLSLSCuLRLR).

Heterochiral Dimer Formation of α-l- and α-d-Polyalanine Molecules on Surfaces

The self-assembly process of racemic mixtures of right(L)- and left(D)-handed α-polyalanine molecules (DL-PA) with a length of 4 nm (27 alanine units) and a helix pitch of λ=0.54 nm on HOPG was inv...

Theoretical studies of infrared signatures of proton-bound amino acid dimers with homochiral and heterochiral moieties.

Proton-bound homochiral and heterochiral dimers, X-H+ -X, of five amino acids (X = Ser, Ala, Thr, Phe, and Arg) are investigated theoretically using quantum chemical density functional theory (DFT) calculations and molecular dynamics simulations with the aim to unveil diastereomer-specific mid-infrared (mid-IR) absorption bands in the spectral range of 1000 to 1800 cm-1 . The theoretical calculations performed in this work imply that all systems, except Ala2 H+ , have distinct mid-IR absorption bands in homochiral and heterochiral configurations, which make them appropriate systems to be studied experimentally with mid-IR spectroscopy. We show that intermolecular interaction with the side chain, in the form of hydrogen bonding or cation-π interaction, is necessary for chiral effects to be present in the mid-IR spectra of proton-bound dimers of amino acids. We also report new conformers for Ala2 H+ , Thr2 H+ , Phe2 H+ , and Arg2 H+ , which were not found in earlier studies of these dimers.

Understanding benzyl alcohol aggregation by chiral modification: the pairing step

A combination of linear infrared and Raman spectroscopy in supersonic slit jet expansions is used to clarify the conformational preferences in the dimer of the transiently chiral benzyl alcohol (phenylmethanol) under vacuum isolation. By experimentally exploring close analogies with the permanently chiral 1-phenylethanol, which is conformationally locked in the jet through intramolecular chirality induction, and by computational analysis of their conformational energy landscapes, several conclusions are drawn. The lowest energy dimer is confirmed to be cooperatively OHOHπ-bonded and shown to be homochiral. Its heterochiral counterpart is slightly higher in energy and can be spectrally assigned as a minor constituent. A metastable heterochiral OHπ/OHπ structure with weakly coupled hydrogen bonds is efficiently trapped behind a Ci symmetry-enhanced barrier and can be assigned by IR/Raman mutual exclusion. Its homochiral counterpart is kinetically less stable but might be addressed by rotational spectroscopy. Ratings of standard density functionals with a standard basis set in terms of reproducing these experimental chirality synchronization benchmarks are presented.

Optical purity, enantiomeric excess and the Horeau effect

The optical purity of an enantiomeric mixture deduced from specific rotation measurements was found by Horeau to be different from its enantiomeric excess, which came to be known as the Horeau effect. This observation had important implications in the practical use of specific rotations and has led to investigations on homochiral and heterochiral aggregation processes. In this review, dedicated to the Horeau principle, the theoretical basis for the observance of the Horeau effect and a survey of the specific rotation studies investigating the Horeau effect are provided, and possible future investigations are suggested.

Theoretical investigation of the self-association of antitumor drug imexon

The dimers resulting from self-association of oxo-imino, oxo-amino, and hydroxyl-imino tautomers of imexon, that present two hydrogen bonds, were fully optimized with the density functional methods B3LYP, M06-2X in conjunction with 6-311++G(d,p) basis set. Additionally, second-order Moller-Plesset (MP2) level in combination with 6-311++G(d,p) basis set was employed for comparison purpose. The thermodynamic stability of the self assembled structures in gaseous phase has been obtained according to the analyses of total electronic energies and hydrogen bonding interactions. The bulk water environment has been simulated using the universal solvation model based on solute electron density (SMD). Stability and structure of homochiral and heterochiral imexon dimers resulting from the three imexon tautomers have been carried out to investigate the chiral discrimination. The imexon dimer with heterochiral configuration resulting from self-assembling oxo-amino tautomer is found to be thermodynamically most stable in both gas and aqueous phases. The interaction energies for these self assembled structures were further evaluated with the basis set superposition error corrections. The so-called seven-point interaction energy which includes corrections for BSSE and deformation was calculated. The intermolecular interactions of the selected dimers have been analyzed by calculation of electron density (ρ) and Laplacian (∇2ρ) at the bond critical points (BCPs) using atoms-in-molecule (AIM) theory.

Synthesis of Tungsten Oxo Alkylidene Biphenolate Complexes and Ring-Opening Metathesis Polymerization of Norbornenes and Norbornadienes

We have synthesized and characterized tungsten oxo alkylidene biphenolate complexes with the formulas W(O)(CHR)(rac-biphenolate)(PPhMe2) and (R,S)-[W(μ-O)(CHR)(biphenolate)]2 (R = CMe2Ph; biphenolate = L1 or L2 in the text). They behave as initiators for the stereoselective (cis,isotactic) polymerization of 2,3-dicarbomethoxy-5-norbornadiene and eight enantiomerically pure 5-substituted norbornenes with a cis,isotactic precision of 95–98% in most cases. The active initiators are 14e W(O)(CHR)(biphenolate) complexes, which are formed through either dissociation of PPhMe2 from the phosphine adducts or scission of the heterochiral dimer. Addition of B(C6F5)3 (one per W) to (R,S)-[W(μ-O)(CHR)(L1)]2 led to formation of what we propose to be monomeric W[OB(C6F5)3](CHR)(L1) in equilibrium with B(C6F5)3 and (R,S)-[W(μ-O)(CHR)(L1)]2. This mixture decomposed over a period of 1–2 h, was much slower to initiate polymerization than (R,S)-[W(μ-O)(CHR)(L1)]2, and was much less stereoselective. Polymerization of five of the monomers with the imido alkyidene initiator, W(N-2,6-Me2C6H3)(CHCMe2Ph)(rac-L1), gave virtually identical results compared to the results obtained with oxo complexes.

Thalidomide-type teratogenicity: structure-activity relationships for congeners.

Unravelling the molecular basis of thalidomide embryotoxicity, which is remarkably species-specific, is challenging in view of its low toxicity in the mature animal. Employing data derived solely from proven sensitive primate species or susceptible strains of rabbit, the structure-activity relationship of over 50 compounds which are, arguably, congeners of thalidomide has been reviewed. The molecular requirement for 'thalidomide-type' teratogenicity was highly structure dependent. Both the phthalimide and glutarimide groups were essential for embryopathic activity, although minor substitutions in either or both rings could be tolerated without a loss of toxicity. An α-linkage between the two cyclic structures was essential; a β-link resulted in a complete loss of embryopathic activity. Crucially, this α-configuration provided a centre of asymmetry enabling the existence of stereoisomers. The thalidomide molecule is not a static entity and under physiological conditions it undergoes a number of intra- and inter-molecular reactions. Besides irreversible hydrolysis, its keto-enol tautomerism, base-assisted proton transfer and glutarimide ring rotation lead to rapid interconversion of the thalidomide enantiomers. These enantiomers form equilibria between themselves and also between both homochiral and heterochiral dimers. It is proposed that the more energetically favourable and stable heterochiral dimer of thalidomide is an active agent that possesses the structural features of the paired nucleotides of the double-stranded DNA. Its capacity to enter into hydrogen bonding interactions affects DNA expression in a chaotic manner without causing permanent mutations. This disruption may well be concentrated at nucleotide sites known to be involved in specific promoter regions of the genome.

Mineral-Induced Enantioenrichment of Tartaric Acid

Interaction of mixtures of <sc>d</sc>- and <sc>l</sc>-tartrates with dissolved gibbsite minerals produces homochiral and heterochiral dimers in a stochastic manner, providing a mechanism for enantioenrichment given a small initial imbalance. This work offers the first suggestion for a path towards the emergence of homochirality in prebiotic metabolism via the glyoxylate scenario.