Heterochiral Preference Research Articles

Symmetry breaking and chiral amplification in prebiotic ligation reactions.

The single chirality of biological molecules is a signature of life. Yet, rationalizing how single chirality emerged remains a challenging goal1. Research has commonly focused on initial symmetry breaking and subsequent enantioenrichment of monomer building blocks-sugars and amino acids-that compose the genetic polymers RNAand DNA as well as peptides. If these building blocks are only partially enantioenriched, however, stalling of chain growth may occur, whimsically termed in the case of nucleic acids as "the problem of original syn"2. Here, in studying a new prebiotically plausible route to proteinogenic peptides3-5, we discovered that the reaction favours heterochiral ligation (that is, the ligation of L monomers with D monomers). Although this finding seems problematic for the prebiotic emergence of homochiral L-peptides, we demonstrate, paradoxically, that this heterochiral preference provides a mechanism for enantioenrichment in homochiral chains. Symmetry breaking, chiral amplification and chirality transfer processes occur for all reactants and products in multicomponent competitive reactions even when only one of the molecules in the complex mixture exhibits an imbalance in enantiomer concentrations (non-racemic). Solubility considerations rationalizefurther chemical purification and enhanced chiral amplification. Experimental data and kinetic modelling support this prebiotically plausible mechanism for the emergence of homochiral biological polymers.

Homochiral vs. heterochiral preference in chiral self-recognition of cyclic diols.

The structure and clustering propensity of a chiral derivative of cis-1,2-cyclohexanediol, namely, 1-phenyl-cis-1,2-cyclohexanediol (cis-PCD), has been studied under supersonic expansion conditions by combining laser spectroscopy with quantum chemistry calculations. The presence of the phenyl substituent induces conformational locking relative to cis-1,2-cyclohexanediol (cis-CD), and only one conformer of the bare molecule is observed by both Raman and IR-UV double resonance spectroscopy. The homochiral preference inferred for the dimer formation at low enough temperature is in line with the formation of a conglomerate in the solid state. The change in clustering propensity in cis-PCD relative to trans-1,2-cyclohexanediol (trans-CD), which shows heterochiral preference, is explained by the presence of the phenyl substituent rather than the effect of cis-trans isomerism. Indeed the transiently chiral cis-CD also forms preferentially heterodimers, whose structure is very close to that of the corresponding trans-CD dimer.

Sodium-ion-induced reversal of chiral preference observed in proline clusters in the gas phase

Enantioselective self-assembly can be observed in some amino acid cluster ions in the gas phase. Some interesting characters have been previously observed for proline, such as the formation of homochiral dodecamers and chiral preference oscillations of small-sized clusters. However, how alkali metal ions affect the formation and stability of the related homochiral and heterochiral proline clusters is unknown. Herein, the subtle effects of sodium ions on the chiral preference of proline clusters were studied in the gas phase. For the clusters of [Pro10,11+2H]2+ with strong heterochiral preference, the substitution of one proton with one sodium ion reverses their chiral preference, making the ions of [Pro10,11+H + Na]2+ characterized by the homochiral preference. However, the second substitution of sodium ion can reverse the preference once again. The reversal of chiral preference was found to be both cluster-size and alkali metal ion sensitive. Since sodium ions are involved in a wide variety of biological processes and usually inevitably exist in laboratory experiments, the results may have an important impact on the assembly of large-sized proline-related clusters.

Alternating Heterochiral Supramolecular Copolymerization

In stacking-based supramolecular polymerization, chiral hydrogen bonding (H-bonding) monomers often prefer to adapt a homochiral monomer sequence. Herein, we investigated the polymerization of a chiral thiophene-fused cyclooctatetraene (COT) as a novel nonplanar-core monomer and found the first example of the formation of an alternating heterochiral supramolecular copolymer. Although single enantiomer (-) or (+)-COT alone did not polymerize, when (-) and (+)-COT were mixed together, supramolecular polymerization took place to give a stereochemically alternating copolymer. By means of the microcrystal electron crystallography of a shorter side-chained COT analogue, we found that the resulting heterochiral supramolecular copolymer adapted an alternating arrangement of H-bonded and polar π-stacked parts. A computational study using density-functional theory (DFT) suggested that such an alternating heterochiral preference occurs because it allows two thiophene amide moieties facing each other to effectively cancel their in-plane dipole moments.

Lattice and thermodynamic characteristics of N-stearoyl-allo-threonine monolayers.

The effect of the second chiral center of diastereomeric N-alkanoyl-allo-threonine on the main monolayer characteristics has been investigated. The characteristic features of the enantiomeric and racemic forms of N-stearoyl-allo-threonine monolayers are studied on a thermodynamic basis and molecular scale. The π-A curves of the enantiomeric and racemic allo-forms show similar features to those of N-stearoyl-threonine. The compression curves are always located above the corresponding decompression curves and the decompression curves can be used as equilibrium isotherms for both the enantiomeric and racemic N-stearoyl-allo-threonine. The absolute T0-values (disappearance of the LE/LC-transition) are 4-5 K larger compared with the corresponding N-stearoyl-threonines, but the ΔT0 between the enantiomeric (d) and the racemic (dl) forms is only slightly larger than that of N-stearoyl-threonine. The difference in the critical temperatures Tc, above which the monolayer cannot be compressed into the condensed state, between the enantiomeric and the racemic forms, is quite small (ΔTc = 0.8 K) and is smaller compared to that of the corresponding threonines (ΔTc = 1.8 K). This is consistent with the dominance of the van der Waals interactions between the alkyl chains reducing the influence of chirality on the thermodynamic parameters. GIXD studies of N-stearoyl-allo-threonine monolayers provide information about the lattice structure of condensed monolayer phases on the Angstrom scale and stipulate the homochiral or heterochiral preference in the condensed phases. Comparable to N-stearoyl-threonine, the enantiomers exhibit an oblique lattice structure, whereas the racemates form a NNN tilted orthorhombic structure demonstrating the dominance of heterochiral interactions in the racemates independent of the diasteomeric structure change of the polar head group. The A0 values are characteristic for rotator phases. The smaller A0 value obtained for the racemic monolayers indicates their tighter packing caused by heterochiral interactions. The program Hardpack was used to predict the geometric parameters of possible 2-dimensional packings. For comparison with the experimental GIXD data, the two-dimensional lattice parameters and characteristic features of the enantiomeric and racemic diastereomeric stearoyl-threonine monolayers were calculated and are in reasonable agreement with the experimental GIXD data.

Unusual H‐Bond Topology and Bifurcated H‐bonds in the 2‐Fluoroethanol Trimer

AbstractBy using a combination of rotational spectroscopy and ab initio calculations, an unusual H‐bond topology was revealed for the 2‐fluoroethanol trimer. The trimer exhibits a strong heterochiral preference and adopts an open OH⋅⋅⋅OH H‐bond topology while utilizing two types of bifurcated H‐bonds involving organic fluorine. This is in stark contrast to the cyclic OH⋅⋅⋅OH H‐bond topology adopted by trimers of water and other simple alcohols. The strengths of different H‐bonds in the trimer were analyzed by using the quantum theory of atoms in molecules. The study showcases a remarkable example of a chirality‐induced switch in H‐bond topology in a simple transient chiral fluoroalcohol. It provides important insight into the H‐bond topologies of small fluoroalcohol aggregates, which are proposed to play a key role in protein folding and in enantioselective reactions and separations where fluoroalcohols serve as a (co)solvent.

Unusual H-Bond Topology and Bifurcated H-bonds in the 2-Fluoroethanol Trimer.

By using a combination of rotational spectroscopy and ab initio calculations, an unusual H-bond topology was revealed for the 2-fluoroethanol trimer. The trimer exhibits a strong heterochiral preference and adopts an open OH⋅⋅⋅OH H-bond topology while utilizing two types of bifurcated H-bonds involving organic fluorine. This is in stark contrast to the cyclic OH⋅⋅⋅OH H-bond topology adopted by trimers of water and other simple alcohols. The strengths of different H-bonds in the trimer were analyzed by using the quantum theory of atoms in molecules. The study showcases a remarkable example of a chirality-induced switch in H-bond topology in a simple transient chiral fluoroalcohol. It provides important insight into the H-bond topologies of small fluoroalcohol aggregates, which are proposed to play a key role in protein folding and in enantioselective reactions and separations where fluoroalcohols serve as a (co)solvent.

Chirality and Packing in Small Proline Clusters

The chiral composition of amino acid clusters may be related to the origin of chirality in biological systems. Here, we use ion mobility/mass spectrometry techniques to investigate the gas phase structures of singly charged proline clusters containing two to six monomers. Using deuterated L-proline (L(D7)) and different electrospray solution compositions varying from enantiopure (50:50 L:L(D7)) to racemic (50:50 L(D7):D), it is possible to study collision cross sections of L-, D-, and mixed xL:xD-proline clusters (where x refers to the number of monomers). These results show that [2Pro+H](+) and [3Pro+H](+) clusters, previously shown (Holliday et al. J. Phys. Chem. A 2012, DOI: 10.1021/jp302677n) to have a very small heterochiral preference, have similar collision cross sections for homochiral and heterochiral proline assemblies. The [4Pro+H](+) and [6Pro+H](+) clusters that exhibit homochiral preference have smaller collision cross sections for homochiral clusters and larger collision cross sections for heterochiral clusters. The [5Pro+H](+) cluster with heterochiral preference has a smaller collision cross section for its heterochiral compositions than for its homochiral compositions. These results suggest that the packing efficiency of subunits within each cluster influences the stability and prevalence of proline multimers as either homochiral or mixed L- and D- clusters.

Chiral Discrimination in Stearoyl Amine Glycerol Monolayers

Chiral discrimination in Langmuir monolayers of amphiphilic 1-stearylamine-glycerol is studied using the hybrid quantum mechanical/molecular mechanical method. Using the experimental information about the lattice structure [D. Vollhardt, U. Gehlert, J. Phys. Chem. B. 2002, 106, 4419], the intermolecular interaction profiles for enantiomeric and racemic pair are studied as a function of mutual tilt and azimuth for different values of intermolecular separation. The present study reveals that, at shorter separation, the interaction profile of the racemic pair has deeper minima than the enantiomeric pair, whereas at larger separation the minimum of the enantiomeric pair is deeper. Thus, the theoretical studies reveal an interesting crossover from heterochiral preference to homochiral preference in 1-stearylamine-glycerol monolayers, with the increase in the intermolecular separation corresponding to a larger area per molecule in the monolayer. This predicts that, with gradual compression, the interactions between racemic pair dominate the experimental features, whereas, under nonequilibrium conditions at the beginning of the formation of the condensed phase, the experimental characteristics of homochirality are observable. The study conclusively shows that the chiral structure of the molecule and the lattice packing drive the chiral preference at the mesoscopic level.

Alkali Metal-Cationized Serine Clusters Studied by Sonic Spray Ionization Tandem Mass Spectrometry

Serine solutions containing salts of alkali metals yield magic number clusters of the type (Ser(4)+C)(+), (Ser(8)+C)(+), (Ser(12)+C)(+), and (Ser(17)+2C)(+2) (where C = Li(+), Na(+), K(+), Rb(+), or Cs(+)), in relative abundances which are strongly dependent on the cation size. Strong selectivity for homochirality is involved in the formation of serine tetramers cationized by K(+), Rb(+), and Cs(+). This is also the case for the octamers cationized by the smaller alkalis but there is a strong preference for heterochirality in the octamers cationized by the larger alkali cations. Tandem mass spectrometry shows that the octamers and dodecamers cationized by K(+), Rb(+), and Cs(+) dissociate mainly by the loss of Ser(4) units, suggesting that the neutral tetramers are the stable building blocks of the observed larger aggregates, (Ser(8)+C)(+) and (Ser(12)+C)(+). Remarkably, although the Ser(4) units are formed with a strong preference for homochirality, they aggregate further regardless of their handedness and, therefore, with a preference for the nominally racemic 4D:4L structure and an overall strong heterochiral preference. The octamers cationized by K(+), Rb(+), or Cs(+) therefore represent a new type of cluster ion that is homochiral in its internal subunits, which then assemble in a random fashion to form octamers. We tentatively interpret the homochirality of these tetramers as a consequence of assembly of the serine molecules around a central metal ion. The data provide additional evidence that the neutral serine octamer is homochiral and is readily cationized by smaller ions.

Chiral discrimination in hydrogen‐bonded complexes of hydrogen peroxide with methyl hydroperoxide: Theoretical study

AbstractFor the first time, the discrimination of different chiral forms of 1:1 complexes with hydrogen peroxide and methyl hydroperoxide have been investigated using density functional theory (DFT) and Møller–Plesset type 2 (MP2) methods at varied basis set levels from 6‐31+G(d,p) to 6‐31++G(2d,2p). Three pairs of chiral enantiomers were considered. The optimized geometric parameters, interaction energies, and chirodiastatic energies for various isomers at different levels are estimated. To take into account the water solvation effect, the polarized continuum model (PCM) method has been used to evaluate the ΔGsolv. The gas phase results show that the heterochiral six‐membered ring complex (structure I) and homochiral five‐membered ring complexes (structures IV and V) are preferred configurations for the three pairs of chiral enantiomers. The solvation effect on six‐membered ring complexes (structures I and II) shows nonsignificant changes in the configurations preferred, but on five‐membered ring complexes, the homo‐/heterochiral preference is found to be inverse in the polar solvent. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006

Tailor-made aggregates of α-hydroxy esters in supersonic jets

Hydrogen-bonded clusters of methyl glycolate and methyl α-hydroxyisobutyrate are investigated by ragout-jet FTIR-spectroscopy to elucidate the influence of α-C hydrogens on the unusual aggregation of α-hydroxy esters. Highly structured OH-stretching spectra, stagnation pressure studies, and argon coating experiments show that two α-C hydrogens enable the formation of small oligomers such as trimers and tetramers, whereas the lack of α-C hydrogens stops selective aggregation beyond dimers. Methyl lactate with a single chiral α-C hydrogen is suggested to be intermediate in its clustering behavior, with a homochiral preference for trimers and a strong heterochiral preference for tetramers.

Chiral Discrimination Effects in Langmuir Monolayers of 1-O-Hexadecyl Glycerol

Chiral discrimination effects in the monolayer of 1-O-hexadecyl glycerol (3-hexadecyl-oxy-propane-1,2-diol) amphiphile are theoretically investigated on the basis of a detailed coarse-grained molecular model. The theory uses experimentally obtained information for the average tilt and azimuthal orientation of a reference molecule and minimizes the energy of neighboring molecules using a theoretical framework developed previously. On the basis of the effective pair potential (EPP) of a neighboring pair of molecules, the mutual orientation at the minimum of EPP is obtained. The predicted curvature of the domains composed of enantiomeric amphiphiles based on the mutual orientation obtained from the EPP theory agrees with the experimentally observed handedness based on results from optical studies such as Brewster angle microscopy and fluorescence microscopy. The study revealed, for the first time, interesting crossover from heterochiral preference to homochiral preference of hexadecyl glycerol amphiphile. Th...

Chiral discrimination in liquid 1,1,1-trifluoropropan-2-ol: A molecular dynamics study

The structural and thermodynamical properties of the R and S enantiomers of 1,1,1trifluoropropan-2-ol (TFIP) have been investigated by molecular-dynamics simulations. In particular, the chiral discrimination (Ch.D.) between the two enantiomers in a racemic solution has been analyzed in detail. Differences in density and enthalpy of vaporization between the pure enantiomeric liquid and the racemic mixture have been found. The comparison of the radial distribution functions and the distribution of the reciprocal orientations of TFIP molecules have shown the presence of a slightly different packing organization in the aforementioned solutions explaining the difference in density and enthalpy of vaporization. Furthermore, the structural analysis of the racemic mixture has shown a strong dependence of the homo- and heterochiral preference by the nature of the functional groups present in the molecule. At 298 K, in the case of CH3, CF3, and hydroxy groups, the homochiral interaction is followed by a heterochiral one in the order: OH≫CH3≫CF3. The effect of pressure and temperature on the Ch.D. has been also analyzed. As general trend, the Ch.D. is more effective at lower temperatures and decrease as the temperature is raised. At high pressure (1000 bars) the Ch.D. is still present for the OH and CH3 groups while is negligible for the CF3 group. The Ch.D. has been also quantified by calculating the differential free energy of solvation of the R and S enantiomer in a solution of TFIP(R) molecules, at 298 K and 1 bar pressure. A value equal to −1.7±0.7 kJ mol−1 has been found, indicating a slight immiscibility of the two enantiomers. As a general result, the balance between the first neighbor interactions, affecting the geometrical packing and the 2nd–3rd shell organizations, results in different structural and thermodynamical properties (i.e., density and enthalpy of vaporization) between the racemic TFIP mixture and the pure enantiomers.

Heterochirality in Langmuir monolayers and antiferromagnetic Blume–Emery–Griffiths model

Chirality is quite a common property in organic molecules. Chiral molecules exist in two forms (called enantiomers) which cannot be superimposed by rotations and translations and may have very different biochemical properties. Experiments on Langmuir monolayers made up of chiral amphiphiles have shown that, in most cases, heterochiral interactions dominate, implying the formation of a racemic compound. It has been shown that a monolayer mixture of two enantiomers can be simply described by a two-dimensional (2-D) spin-1 lattice gas [Blume–Emery–Griffiths (BEG) model], where the heterochiral preference is represented by an effective antiferromagnetic coupling. By now just mean field calculations have been performed on this model. Here we present a revisitation of the tripod amphiphile model, proposed by Andelman and de Gennes [D. Andelman and P.-G. de Gennes, Compt. Rend. Acad. Sci. (Paris) 307, 233 (1988)], together with a rigorous proof of the heterochiral preference shown by the model in the hypothesis of van der Waals interactions. Moreover, a cluster variation analysis of the antiferromagnetic BEG model on a triangular lattice is performed and possible interpretations in terms of surface pressure–concentration phase diagrams for monolayer mixtures of enantiomers are discussed. The choice of a triangular lattice has been suggested by the triangularlike structure of condensed phases of Langmuir monolayers, shown by x-ray diffraction experiments.

Temperature Dependence of Chiral Discrimination in Langmuir Monolayers of N-Acyl Amino Acids As Inferred from Π/A Measurements and Infrared Reflection−Absorption Spectroscopy

N-Hexadecanoylalanine monolayers were investigated on pure aqueous subphases and in the presence of 1 mM solutions of CaCl2 and ZnCl2, respectively, in the temperature range between 293 and 308 K using Langmuir trough measurements and IR reflection−absorption spectroscopy (IRRAS). The overwhelming importance of the temperature for chiral recognition processes was particularly clearly shown in the presence of Zn2+ in the subphase, where a change from homo- to heterochiral preference was observed by IRRAS measurements within a temperature range of 5 deg only. This change was not reflected by corresponding changes in Langmuir curves. This result implies that chiral interactions on a molecular scale inferred from IRRAS and on a macroscopic scale (Langmuir curves) may be at variance because of a different importance of hydrogen bond and complex formation at these scales. Calcium ions exert strong expanding effects, thus weakening the homochiral effect on the macroscopic level and even inducing a heterochiral effect on the molecular level at 293 K. A comparison between the results obtained in the presence of N-hexadecanoylalanine and its methyl ester, respectively, supports the hypothesis that hydrogen bond formation via the carboxyl group also plays an important role for chiral recognition.