Twisted perylene stereodimers reveal chiral molecular assembly codes

Unique perylene diastereomeric linear and cyclic dimers were synthesized from twisted perylene monomers, revealing that pi-stacking stereoisomerism imparted specific intermolecular self-assembly and intramolecular folding. Only the homochiral twisted tetrachloroperylene monomers cyclized via a cooperative reaction, forming the homochiral diastereomers. The heterochiral tetrachloroperylene monomers proceeded through a stepwise reaction and yielded a linear heterochiral dimer, which equilibrated with the linear homochiral dimers. The linear homochiral dimers cyclized to produce the same cyclic homochiral diastereomers. These results demonstrated that homochiral and heterochiral self-assemblies were two distinct molecular codes, directing two specific chemical pathways. The homochiral cyclic dimers remain isomerically pure at -20 degrees C but can be interconverted to the heterochiral cyclic dimer meso compound at room temperature. The diastereomers were readily separated by HPLC. While driven by solvophobic forces, foldable linear dimers synthesized from the same twisted monomers using phosphoramidite chemistry folded into homodimer and heterodimer, confirming the inherent molecular codes, which were dictated by the perylene chirality, ultimately gauged the weak pi-stack forces, and directed self-assembly and folding.     

Mechanism of the Asymmetric Autocatalytic Soai Reaction Studied by Density Functional Theory

The mechanism of the Soai reaction has been thoroughly investigated at the M05‐2X/6‐31G(d) level of theory, by considering ten energetically distinct paths. The study indicates the fully enantioselective catalytic cycle of the homochiral dimers to be the dominant mechanism. Two other catalytic cycles are shown to both be important for correct understanding of the Soai reaction. These are the catalytic cycle of the heterochiral dimer and the non‐enantioselective catalytic cycle of the homochiral dimers. The former has been proved to be not really competitive with the principal cycle, as required for the Soai reaction to manifest chiral amplification, whereas the latter, which is only slightly competitive with the principal one, nicely explains the experimental enantioselectivity observed in the reaction of 2‐methylpyrimidine‐5‐carbaldehyde. The study has also evidenced the inadequacy of the B3LYP functional for mechanistic investigations of the Soai reaction.     

Homochiral versus Heterochiral Dimeric Helical Foldamer Bundles: Chlorinated-Solvent-Dependent Self-Sorting

Aromatic oligoamide sequences programmed to fold into stable helical conformations were designed to display a linear array of hydrogen-bond donors and acceptors at their surface. Sequences were prepared by solid-phase synthesis. Solution ¹H NMR spectroscopic studies and solid-state crystallographic structures demonstrated the formation of stable hydrogen-bond-mediated dimeric helix bundles that could be either heterochiral (with a P and an M helix) or homochiral (with two P or two M helices). Formation of the hetero- or homochiral dimers could be driven quantitatively using different chlorinated solvents—exemplifying a remarkable case of either social or narcissistic chiral self-sorting or upon imposing absolute handedness to the helices to forbid PM species.     

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.     

The Effects of Substituents on the Geometry of π–π Interactions

We have designed and utilized a simple molecular recognition system to study the substituent effects in aromatic interactions. Recently, we showed that 3‐ and 3,5‐disubstituted benzoyl leucine diethyl amides with aromatic rings of varying electronic character organized into homochiral dimers in the solid state through a parallel displaced π–π interaction and two hydrogen bonds, but no such homochiral dimerization was observed for the unsubstituted case. This phenomenon supports the hypothesis that substituents stabilize π–π interactions regardless of their electronic character. To further investigate the origin of substituent effects for π–π interactions, we synthesized and crystallized a series of 4‐substituted benzoyl leucine diethyl amides. Surprisingly, only two of the 4‐substituted compounds formed homochiral dimers. A comparison among the 4‐substituted compounds that crystallized as homochiral dimers and their 3‐substituted counterparts revealed that there are differences in regard to the geometry of the aromatic rings with respect to each other, which depend on the electronic nature and location of the substituent. The crystal structures of the homochiral dimers that showed evidence of direct, local interactions between the substituents on the aromatic rings also displayed nonequivalent dihedral angles in the individual monomers. The crystallographic data suggests that such “flexing” may be the result of the individual molecules orienting themselves to maximize the local dipole interactions on the respective aromatic rings. The results presented here can potentially have broad applicability towards the development of molecular recognition systems that involve aromatic interactions.     

Chiral recognition in cyclic alpha-hydroxy carbonyl compounds: a theoretical study

A theoretical study (DFT and MP2) of the self-association of homochiral (RR or SS) and heterochiral (RS or SR) dimers of three series of cyclic alpha-hydroxy-carbonyl derivatives has been carried out. The solvation effect on the parent derivative dimers has been explored, showing nonsignificant changes in the configurations preferred but altering in some cases the homo/heterochiral preference of the dimers. The results in the gas phase of the systems with different substituents show a preference for the heterochiral dimers. The energetic results have been analyzed with the NBO and AIM methodologies. Optical rotatory power calculations of the monomers and homochiral dimers show large variations of this parameter depending on the substituents and the complexation.     

Mass spectrometric and quantum-chemical study on the structure, stability, and chirality of protonated serine dimers

Stability and structure of homo- and heterochiral protonated serine (Ser) dimers were investigated by a combination of mass spectrometry and ab initio quantum chemical calculations. This established that the energy difference between the most stable homo- and heterochiral forms is very small: tandem mass spectrometry with Cooks' kinetic method yielded a negligible difference in Gibbs free energy (0.2+/-0.2 kJ mol(-1)). The various isomeric forms of (Ser)2 H+ and their energetics were determined by extensive electronic-structure calculations, which yielded homo- and heterochiral forms of the isomers with distinctly different relative energies. The most stable homochiral isomer is stabilized by two hydrogen bonds and is far more stable than any other homochiral isomer. The most stable heterochiral isomer has completely different features, and it is characterized by a salt-bridge structure. This clearly shows that salt-bridge structures do exist in the gas phase even in comparatively small molecules and in the absence of particularly basic or acidic functional groups.     

The role of weak hydrogen bonds in chiral recognition

Chiral recognition has been studied in neutral or ionic weakly bound complexes isolated in the gas phase by combining laser spectroscopy and quantum chemical calculations. Neutral complexes of the two enantiomers of lactic ester derivatives with chiral chromophores have been formed in a supersonic expansion. Their structure has been elucidated by means of IR-UV double resonance spectroscopy in the 3 μm region. In both systems described here, the main interaction ensuring the cohesion of the complex is a strong hydrogen bond between the chromophore and methyl-lactate. However, an additional hydrogen bond of much weaker strength plays a discriminative role between the two enantiomers. For example, the 1:1 heterochiral complex between R-(+)-2-naphthyl-ethanol and S-(+) methyl-lactate is observed, in contrast with the 1:1 homochiral complex which lacks this additional hydrogen bond. On the other hand, the same kind of insertion structures is formed for the complex between S-(±)-cis-1-amino-indan-2-ol and the two enantiomers of methyl-lactate, but an additional addition complex is formed for R-methyl-lactate only. This selectivity rests on the formation of a weak CHπ interaction which is not possible for the other enantiomer. The protonated dimers of Cinchona alkaloids, namely quinine, quinidine, cinchonine and cinchonidine, have been isolated in an ion trap and studied by IRMPD spectroscopy in the region of the ν(OH) and ν(NH) stretch modes. The protonation site is located on the alkaloid nitrogen which acts as a strong hydrogen bond donor in all the dimers studied. While the nature of the intermolecular hydrogen bond is similar in the homochiral and heterochiral complexes, the heterochiral complex displays an additional weak CHO hydrogen bond located on its neutral part, which results in slightly different spectroscopic fingerprints in the ν(OH) stretch region. This first spectroscopic evidence of chiral recognition in protonated dimers opens the way to the study of the complexes of Cinchona alkaloids involved in enantioselective catalysis. These examples show how secondary hydrogen bonds controlled by stereochemical factors govern molecular recognition processes.     

Chiral recognition in self-complexes of tetrahydroimidazo[4,5-d]imidazole derivatives: from dimers to heptamers

The chiral discrimination in the self-association of chiral 1,3a,4,6a-tetrahydroimidazo[4,5-d]imidazoles has been studied using density functional theory methods. Clusters from dimers to heptamers have been considered. The heterochiral dimers (RR:SS or SS:RR) are more stable than the homochiral ones (RR:RR or SS:SS) with energy differences up to 17.5 kJ/mol. Besides, in larger clusters the presence of two adjacent homochiral molecules impose an energetic penalty when compared to alternated chiral systems (RR:SS:RR:SS...). The differences in interaction energy within the dimers of the different derivatives have been analyzed based on the atomic energy partition carried out within the atoms in molecules framework. The mechanism of proton transfer in the homo- and heterochiral dimers shows large transition-state barriers except in those cases in which a third additional molecule is involved in the transfer. The optical rotatory power of several clusters of the parent compound have been calculated and rationalized based on the number of homochiral interactions and the number of monomers of each enantiomer within the complexes.     

A simple chiral recognition system to investigate substituent effects on π-π interactions

We have used a simple molecular recognition system to study substituent effects in aromatic interactions. A series of substituted benzoylleucine diethyl amides with aromatic rings of varying electronic character were crystallized. All of the substituted dimers organized into homochiral dimers in the solid state but with pronounced differences in regard to the orientation of the aromatic rings with respect to each other. However, no homochiral dimerization was observed in the unsubstituted case.     

Chiral monomeric and homochiral dimeric copper(II) complexes of a new chiral ligand, N-(1,2-bis(2-pyridyl)ethyl)pyridine-2-carboxamide: an example of molecular self-recognition

Reaction of Cu(ClO(4))(2) x 6H(2)O with a racemic mixture of the novel chiral ligand N-(1,2-bis(2-pyridyl)ethyl)pyridine-2-carboxamide (PEAH) affords only the homochiral dimeric copper(II) complexes [Cu(2)((R)()PEA)(2)](ClO(4))(2) and [Cu(2)((S)()PEA)(2)](ClO(4))(2) in a 1:1 ratio. The phenomenon of molecular self-recognition is also observed when a racemic mixture of the monomeric copper(II) complex [Cu((R(S))()PEA)(Cl)(H(2)O)] is converted into the homochiral dimeric species [Cu(2)((R(S))()PEA)(2)](ClO(4))(2) via reaction with Ag(+) ion. This is the first report of direct conversion of a racemic mixture of a chiral monomeric copper(II) complex to a mixture of the homochiral dimers.     

Reversible enolization of beta-amino carboxamides by lithium hexamethyldisilazide

The enolization of beta-amino carboxamides by lithium hexamethyldisilazide (LiHMDS) in THF/toluene and subsequent diastereoselective alkylation with CH(3)I are reported. In situ IR spectroscopic studies reveal that beta-amino carboxamides coordinate to LiHMDS at -78 degrees C before enolization. Comparison with structurally similar carboxamides suggests that the beta-amino group promotes the enolization. IR spectroscopic studies also show that the enolization is reversible. Efficient trapping of the enolate by CH(3)I affords full conversion to products. (6)Li and (15)N NMR spectroscopic studies reveal that lithium enolate-LiHMDS mixed dimers and trimers as well as a homoaggregated enolate are formed during the reaction. At ambient temperature, racemization of the beta-position through a putative reversible Michael addition was observed.     

Valine sulfonamidecinnamic acid asymmetric crystal reactions

Racemic and homochiral valine sulfonamidecinnamic acids crystallize with components aligned by use of the complementary features of hydrogen bonds and molecular topology to give supramolecular dimers. These discrete motifs effectively organize adjacent olefins for UV initiated single-crystal-to-single-crystal [2+2] photodimerization reactions. The racemic crystals produce inversion related cyclobutane products, while the desymmetrized crystalline architectures of the homochiral phase promote asymmetric photodimerization with 90% conversion.     

Homo- and heterochiral alkylzinc fencholates: linear or nonlinear effects in dialkylzinc additions to benzaldehyde

Scalemic mixtures of chiral anisyl fenchols with different ortho-substituents (X) in the anisyl moieties [X = H (1), Me (2), SiMe3 (3) and tBu (4)] are employed as pre-catalysts in enantioselective additions of diethylzinc to benzaldehyde. While a remarkable asymmetric depletion is apparent for X = H and Me, a linear relationship between the enantiomeric purity of the chiral source and the product 1-phenylpropanol is observed for X = SiMe3 and tBu. X-ray single crystal analyses show that racemic methylzinc fencholates obtained from 1 (X = H) and 2 (X = Me) yield homochiral dimeric complexes, while for 3 (X = SiMe3) and 4 (X = tBu) the heterochiral dimeric alkylzinc structures are formed. The enantiopure fenchols 1-4 all yield homochiral dimeric methylzinc complexes. Computed relative energies of homo- and heterochiral fencholate dimers with X = H and Me reveal an intrinsic preference for the formation of the homochiral dimers, consistent with the observed negative NLE. In contrast, similar stabilities are computed for homo- and heterochiral complexes of ligands 3 (X = SiMe3) and 4 (X = tBu), in agreement with the absence of a nonlinear effect for bulky ortho-subsituents.     

Self-discrimination of enantiomers in hydrogen-bonded dimers

The homochiral and heterochiral hydrogen-bonded (HB) dimers of a set of small model molecules (alpha-amino alcohols) have been studied by means of ab initio methods. The gas-phase calculations have been carried out with the hybrid HF/DFT B3LYP method and the 6-311++G** basis set. The electron density of the complexes has been analyzed using the atoms in molecules (AIM) methodology, which allows characterization of the HB interactions and additional intermolecular contacts. To take into account the water solvation effect, the polarized continuum model (PCM) method has been used to evaluate the Delta G(solv). The gas-phase results show that the heterochiral dimers are the most stable ones for each case studied, while in solution for several cases, the relative stability is reversed and the homochiral dimers become more stable. The AIM analysis shows the typical bond critical points characteristic of the HB and additional bond critical points denoting, in this case, destabilization of intermolecular interaction as CF(3)...F(3)C and CH(3)...H(3)C contacts.     

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.     

A kinetic study on Rh/binap-catalyzed 1,4-addition of phenylboronic acid to enones: negative nonlinear effect caused by predominant homochiral dimer contribution

A kinetic study on the Rh/binap-catalyzed 1,4-addition of phenylboronic acid using reaction calorimetry revealed that the catalytically inactive dimeric hydroxorhodium complex [Rh(OH)((R)-binap)]2 (RR-4) is the resting state. A negative NLE in eeprod and an amplified reaction rate were predicted and observed in the present reaction system characterized by the preferential formation of homochiral dimer.     

Molecular recognition of chiral conformers: a rotational study of the dimers of glycidol

Two homochiral dimers of glycidol, deriving from two different conformers, have been characterized by rotational spectroscopy in a supersonic expansion.     

Dicatechol cis-dioxomolybdenum(VI): a building block for a lithium cation templated monomer-dimer equilibrium

Dinuclear helicate-type complexes form from 3-carbonyl catechol derivatives and MoO2 units. The two monomeric subunits are non-covalently bound through templating Li+ ions. The monomeric and dimeric complexes as well as a hydrolysis product have been investigated in the solid state by X-ray crystallography, in solution by NMR experiments, and in the gas phase by ESI mass spectrometry. Dimerization constants can easily be extracted from NMR experiments. A particular property of these complexes is the mutual homochiral recognition between the two halves of the dimers which only occurs between homochiral monomers.     

Evidence for Kinetic Nucleation in Helical Nanofiber Formation Directed by Chiral Solvent for a Perylene Bisimide Organogelator

The self‐assembly behavior of an achiral perylene bisimide (PBI) organogelator that bears two 3,4,5‐tridodecyloxybenzoylaminoethyl substituents at the imide positions has been investigated in chiral solvents (R)‐ and (S)‐limonene in great detail by circular dichroism (CD) spectroscopy and atomic force microscopy (AFM). CD spectroscopic studies on dilute solutions revealed a preferential population of one‐handed helical assemblies in chiral solvent with an enantiomeric excess close to 100 %, whereas AFM images of more than 100 nanofibers of the organogel obtained from more concentrated solutions were found to consist of both handed helices with an enantiomeric excess of only 20 %. This discrepancy is attributed to the fast gelation process at high dye concentration that evidently proceeds through non‐equilibrated nuclei in a kinetic rather than thermodynamic self‐assembly process. Under these conditions the chiral induction from the homochiral solvent may not be adequate in effectively populating only one‐handed helices.