Racemic Crystals Research Articles

Solid-State Deracemization via Temperature Cycles in Continuous Operation: Model-Based Process Design.

Solid-state deracemization via temperature cycles converts a racemic crystal mixture into an enantiopure product by periodic cycling of the temperature in the presence of a racemization catalyst. A continuous counterpart of this conventional batch-operated process is proposed that can be performed in mixed suspension mixed product removal crystallizers (MSMPRCs). More specifically, three different configurations are described to perform periodic forcing via temperature cycles, which differ from each other in the type of the feed and in the withdrawal system. We have developed a model by extending our recent population balance equation model of batch solid-state deracemization via temperature cycles, and we exploit this tool to analyze the start-up and periodic steady-state behavior. Moreover, we compare the performance of the different configurations based on the selected key performance indicators, namely, average periodic steady-state enantiomeric excess and productivity. The process with solution feed yields pure enantiomers, while the solid and suspension-fed process alternatives result in highly enantiomerically enriched crystals. We further design an MSMPRC cascade to overcome this purity limitation. This work discusses guidelines on how to transform the batch process of temperature cycles into a continuous operation, which enables stable, unattended operation and chiral crystal production with consistent product quality.

Racemic Porous Organic Cage Crystal with Selective Gas Adsorption Behaviors

AbstractA mixture containing the reactions solution between 3,3′′,5,5′′‐tetraformyl‐4,4′′‐[1,1′:4′,1′′‐terphenyl]diol (TTD) and two enantiomers of cyclohexanediamine, respectively, affords porous racemic molecular crystal (1). Two kinds of homochiral [3+6] porous organic cage molecules 1 have been clearly disclosed by single crystal X‐ray diffraction analysis, forming one‐dimensional porous supramolecular channels with the narrowest size of 3.5 Å. The intercrossing channels of 1 enable the permanent porosity as well as the selective gas adsorption of acetylene and carbon dioxide over methane.

Controllable spontaneous resolution in ultrasmall Cu-Ag bimetallic cluster ion pairs from achiral components.

Bimetallic cluster ion pairs containing a quaternary phosphonium and an ultrasmall Cu2Ag3 anionic cluster protected by thiolates: (PPh3R'')[Cu2Ag3(SR')6] (R'SH = cyclohexylthiol (CySH), R'' = Ph, 1; Me, 2; Et, 3; Pr, 4; R'SH = tert-butylthiol (tBuSH) and R'' = Ph, 5) were reported. Without any chiral source, 1 crystallizes as conglomerate crystals with homochiral packings and spontaneous resolution occurs, while four other clusters 2-5 crystallize as racemic crystals with heterochiral packings. These results indicate that racemic and homochiral crystallization in the cluster system could be controlled through fine-tuning internal achiral structural components.

Spontaneous chiral resolution of pentahelicene molecules on Cd(0001).

Chiral resolution is of fundamental importance to conglomerate or racemate crystallization. Here we demonstrate that the spontaneous chiral resolution of pentahelicene racemates occurred in the monolayer domains. When deposited on a Cd(0001) surface, pentahelicene molecules crystallize into a commensurate (6 × 6)R0° structure built mainly from homochiral trimers. Spontaneous chirality separation takes place in the form of opposite mirror domains, where 2D enantiomorphism is not expressed by the oblique adlattice, but by the supramolecular chirality of the pentahelicene trimers. Furthermore, annealing the sample or extreme close-packing lead to the presence of lattice handedness through the formation of a porous network structure or an edge-on phase. These results provide valuable insight for 2D conglomerate crystallization and stereochemical recognition.

Pre-Nucleation Clusters Predict Crystal Structures in Models of Chiral Molecules.

Kinetics can play an important role in the crystallization of molecules and can give rise to polymorphism, the tendency of molecules to form more than one crystal structure. Current computational methods of crystal structure prediction, however, focus almost exclusively on identifying the thermodynamically stable polymorph. Kinetic factors of nucleation and growth are often neglected because the underlying microscopic processes can be complex and accurate rate calculations are numerically cumbersome. In this work, we use molecular dynamics computer simulations to study simple molecular models that reproduce the crystallization behavior of real chiral molecules, including the formation of enantiopure and racemic crystals, as well as polymorphism. A significant fraction of these molecules forms crystals that do not have the lowest free energy. We demonstrate that at high supersaturation crystal formation can be accurately predicted by considering the similarities between oligomeric species in solution and molecular motifs in the crystal structure. For the case of racemic mixtures, we even find that knowledge of crystal free energies is not necessary and kinetic considerations are sufficient to determine if the system will undergo spontaneous chiral separation. Our results suggest conceptually simple ways of improving current crystal structure prediction methods.

Memory Effect and Crystallization of (R, S)-2-Chloromandelic Acid Glass.

(R, S)-2-Chloromandelic acid, which can crystallize in racemic crystals (forms α and β) or a conglomerate (form γ), has been studied for its glass-forming behavior. Below the glass transition temperature, samples of the title compound crack into pieces. Correlation plots of DSC results have been used to investigate what determines the cracking and its occurrence temperature. We found that the latter is influenced by the polymorph from which the melt state has been obtained, showing that a certain memory of the previous crystalline phase persists in the undercooled melt. Moreover, this residual structure could be eliminated by elongating the annealing period or increasing the annealing temperature. Investigation using broadband dielectric spectroscopy confirmed such a memory effect. Finally, we studied the role of cracking in the control of the crystallization. In contrast with previous literature on other glass-forming molecular systems, we verified that the crystallization upon reheating is not impacted by the occurrence of cracks in the glassy state. This observation challenges the current views on polymorphic crystallization from organic glasses.

Chiral Resolution via Cocrystallization with Inorganic Salts

AbstractThe coordination mode to lithium, magnesium, calcium and zinc cations of racemic vs. enantiopure amino acids and racetam APIs is analysed and its effect on chiral selection critically reviewed. It is shown that chiral resolution in the solid state can be obtained via cocrystallization of racemic compounds with an achiral inorganic salt coformer, such as LiX (X=Cl, Br, I) or ZnCl2, which favour tetrahedral coordination in the solid state. The chiral selection may take the form of conglomerate crystal formation or of selective homochiral aggregation in racemic crystals. When cocrystallization involves alkaline earth metal cations, such as Ca2+ and Mg2+, which favour octahedral coordination, heterochiral complexation is observed in most cases, with formation of racemic crystals.

Access to Enantiomeric Organic Compounds with Potential for Synthesis via Racemic Conglomerates: Inositol Derivatives as a Case in Point

The crystal structure database was used to identify inositol derivatives that could be crystallizing as racemic conglomerates. Among the six racemic inositol derivatives identified, racemic 4-O-tosyl-6-O-benzyl-myo-inositol-1,3,5-orthoformate (A) was found to be a true conglomerate and was resolved on the multigram scale by the preferential crystallization technique. This resolution procedure does not require the use of any enantiomeric resolving agent. The resolved enantiomers of A are useful for the synthesis of natural and unnatural enantiomeric derivatives of inositol, since they carry orthogonal hydroxy protecting groups. Racemic 4-O-methanesulfonyl-myo-inositol-1,3,5-orthoformate (B) on crystallization from common organic solvents generally yielded racemic twin crystals, while in the presence of structural analogs as additives, they yielded true racemic crystals. A comparison of the crystal structures of the true racemate, twinned crystal and crystal of one of the enantiomers of B, revealed the reasons for the formation of polymorphic (twin) crystals. Such instances are relatively rarely encountered but nevertheless shed light on our understanding of polymorphism and twinning of crystals.

Hybridization of Biomolecular Crystals and Low-Dimensional Materials.

In cellular environments, metabolites, peptides, proteins, and other biomolecules can self-assemble into planar and fibrilar molecular crystals. We use atomistic molecular dynamics simulations to show that such biomolecular crystals coupled with low-dimensional materials can form stable hybrid superstructures. We discuss enantiopure and racemic TRP and PHE amino acid crystals adsorbed on or intercalated between graphene, phosphorene, and carbon nanotubes. While racemic biomolecular crystals tend to stay straight in solutions and when adsorbed on flat and cylindrical nanosurfaces, enantiopure crystals undergo twisting. Mixed material properties of these hybrid superstructures can be attractive in many applications.

Metal-Binding Q-Proline Macrocycles.

We introduce the efficient Fmoc-SPPS and peptoid synthesis of Q-proline-based, metal-binding macrocycles (QPMs), which bind metal cations and display nine functional groups. Metal-free QPMs are disordered, evidenced by NMR and a crystal structure of QPM-3 obtained through racemic crystallization. Upon addition of metal cations, QPMs adopt ordered structures. Notably, the addition of a second functional group at the hydantoin amide position (R2) converts the proline ring from Cγ-endo to Cγ-exo, due to steric interactions.

Construction of Aromatic Multilayered Structures Based on the Conformational Properties of N,N'-Dimethylated Squaramide.

Squaramide is a highly rigid four-membered ring system bearing two carbonyl and two amino groups, and its derivatives have found applications in many fields. We synthesized several N,N'-dimethylated oligosquaramides linked via phenyl groups, and investigated their structures in the crystalline state and in solution. Compounds 1, 2 (bissquaramides), and 13 (trissquaramide) exist as folded structures in the crystalline state, in which the aromatic rings are located in a face-to-face position. In their multilayered structures, the benzene rings are more nearly parallel and are closer to each other, compared with those in N,N'-dimethylated oligoureas. Individual molecules of meta-connected compounds 2 and 13 show a helical structure with all-R or all-S axis chirality, but afford only racemic crystals. The NMR spectra indicated that these compounds retain well-ordered folded structures in solution. The unique steric and electronic properties of N,N'-dimethylated squaramide can provide access to novel functional aromatic multilayered and helical foldamers.

Nucleation behaviour of racemic and enantiopure histidine

Small non-centrosymmetric domains are observed in the racemic crystal, due to the low nucleation activation energy of the conglomerate.

Creating porosity in a trianglimine macrocycle by heterochiral pairing.

Macrocycles are usually non-porous or barely porous in the solid-state because of their small intrinsic cavity sizes and tendency to close-pack. Here, we use a heterochiral pairing strategy to introduce porosity in a trianglimine macrocycle, by co-crystallising two macrocycles with opposing chiralities. The stable racemic trianglimine crystal contains an interconnected pore network that has a Brunauer-Emmett-Teller (BET) surface area of 355 m2 g-1.

Theoretical study on the molecular stacking interactions and charge transport properties of triazasumanene crystals - from explanation to prediction.

Computational analyses of the solid-state properties of triazasumanene (TAS), a C3-symmetric nitrogen-doped sumanene derivative, were carried out in this work. The present studies are mainly divided into two parts. In the first part, we demonstrated the differences in the interactions of the crystal packing between the racemic and the homochiral structures: the former having perpendicular columnar packing and the latter forming slipped helical packing. Two geometries of the TAS monomer, a theoretically optimized structure under vacuum and an X-ray crystal structure in experiment, were compared. It can be found that it is not the total interaction energy, but the local interactions (mainly the electrostatic interactions) of the molecular dimer that dominate the columnar stacking conformation. The second part involves the investigation of the potential charge transport properties of the crystals according to the semiclassical Marcus theory with the hopping mechanism using the simple dimer model. The charge transfer integrals of the two sets of dimers, racemic and homochiral dimer models, were compared as well. The calculation results show that the TAS racemic crystal was predicted to have an advantage of hole transport properties. The perpendicular columnar stacking of the homochiral conformation should essentially have better charge transport properties than the racemic conformation. It is reasonable to employ the simple dimer model built using optimized monomers under vacuum for the purpose of the prediction of the molecular packing conformation by IES calculation and the charge transport properties of the perpendicular columnar-stacking crystal. Our work provides a simple approach to the deep understanding of the structure-property relationship of bowl-shaped molecular systems in theory. It can help to facilitate the design and preparation of heteroatom-doped sumanene derivatives with perpendicular columnar stacking crystals as novel organic semiconductor materials.

Supramolecular chirality in the crystals of mononuclear and polymeric cobalt(ii) complexes with enantiopure and racemic N-thiophosphorylated thioureas

The control of stereochemistry in Co(ii) complexes was provided by additional pyridine and pyrazine ligands. 1D and 2D supramolecular homochiral arrangements in racemic crystals of mononuclear complexes are transferred to their polymeric counterparts.

Persistent room temperature blue phosphorescence from racemic crystals of 1,1-diphenylmethanol derivatives

Among the six alkyldiphenylmethanol derivatives assessed in this study, five showed persistent room temperature phosphorescence (pRTP), whereas the original diphenylmethanol (DPhHOH) did not. pRTP is a unique luminescence phenomenon that appears only in the crystalline state and is different from the luminescence produced by dispersed molecules, such as those in a glassy solvent matrix at 77 K or a polymeric matrix. The data also suggest that pRTP appears in conjunction with a specific crystal structure. The present work demonstrates that various crystal structures show pRTP regardless of the presence or absence of weak hydrogen bonds. However, nonradiative deactivation is suppressed by both intermolecular interactions and steric regulation in the crystal, such that the emission quantum yield is dependent on the crystal structure. In addition, although the molecular structure in the crystalline state necessary for the appearance of pRTP was not fully elucidated, intermolecular interactions between face-to-face and face-to-edge benzene rings appear to play a major role. Density functional theory calculations indicate that intersystem crossing is promoted in the crystalline state because the number of paths that allow this intersystem crossing is greater in a structure having weak interactions between molecules as compared to a dispersed state. DPhHOH did not show pRTP and is considered to have a structure based on the column-like stacking of multiple molecules. In contrast, the crystals that exhibited pRTP had pseudo racemic conformation in their crystals even though each molecule was achiral. In these racemic crystals, the interactions between pairs of molecules were important to the generation of pRTP.

Heterogeneous Interactions Promote Crystallization and Spontaneous Resolution of Chiral Molecules.

Predicting the crystallization of chiral molecules from solution is a major challenge in the chemical sciences. In this paper, we use molecular dynamics computer simulations to study the crystallization of a family of coarse-grained models of chiral molecules with a broad range of molecular shapes and interactions. Our simulations reproduce the experimental crystallization behavior of real chiral molecules, including racemic and enantiopure crystals, as well as amorphous solids. Using efficient algorithms for the packing of shapes, we enumerate millions of low-energy crystal structures for each model and analyze the thermodynamic landscape of polymorphs. In agreement with recent conjectures, our analysis shows that the ease of crystallization is largely determined by the number of competing polymorphs with low free energy. We find that this number and, hence, crystallization outcomes depend on molecular interactions in a simple way: Strongly heterogeneous interactions across molecules promote crystallization and favor the spontaneous resolution of racemic mixtures. Our results help rationalize a number of experimental observations and can provide guidance for the design of molecules and experimental conditions for desired crystallization outcomes.

Precise Evaluation of the Effects of a Small Amount of D-histidine in L-histidine Crystal Form B Using High-Frequency-Accurate Terahertz Spectroscopy

The effects of small amounts of enantiomeric impurities on the vibrational modes of polycrystalline L-histidine (His) were examined using high-frequency-accurate terahertz (THz) spectroscopy. Samples of polycrystalline L-His in its monoclinic form (form B) were grown from an ethanol-rich solvent. D-histidine, ranging from 0.05 to 10.0% in content, was added to the L-His/ethanol-rich solution prior to recrystallization. The crystal forms of all recrystallized samples were first confirmed by high-frequency-accurate THz spectra recorded at 70 K and room-temperature powder X-ray diffraction spectra. A detailed analysis of two spectral features (1.54 and 1.80 THz) measured at 10 K showed that the absorption lines had a narrow linewidth, as well as broad spectral components that could be fitted by Gaussian curves corresponding to defects within the crystals. The shifts in peak frequency with varying amounts of D-His additive in the polycrystalline L-His samples were examined in detail. It was observed that the peak frequency shifted to lower frequencies when small amounts of D-histidine were present and then to higher frequencies when relatively large amounts were present. At low concentrations, D-His molecules are thought to act as impurities that disturb the normal mode vibrations of L-His crystals; however, above certain concentrations, D-His contributes to the formation of a DL racemic crystal. Although the effects of small amounts of D-His molecules in L-His crystals were detectable, quantitative determination of trace amounts of impurity was limited by the complex crystallography of L-His, which includes defects and racemic compounds.

Phospho-rescent mono- and diiridium(III) complexes cyclo-metalated by fluorenyl- or phenyl-pyridino ligands with bulky substituents, as prospective OLED dopants.

The crystal structures of tris-[9,9-dihexyl-2-(5-meth-oxy-pyridin-2-yl-κN)-9H-fluoren-3-yl-κC 3]iridium pentane monosolvate, [Ir(C31H38NO)3]·C5H12, (I), di-μ2-chlorido-bis-{bis-[2-(5-fluoro-pyridin-2-yl)-9,9-dihexyl-9H-fluoren-3-yl]iridium} pentane 0.3-solvate, [Ir2(C30H35FN)4Cl2]·0.3C5H12, (II), di-μ2-cyanato-bis-{bis-[9,9-dihexyl-2-(5-meth-oxy-pyridin-2-yl)-9H-fluoren-1-yl]iridium} pentane monosolvate, [Ir2(C31H38NO)4(NCO)2(NCO)2]·C5H12, (III), and {μ-N,N'-bis-[3,5-bis-(tri-fluoro-meth-yl)phen-yl]oxamidato}bis(bis{2-[4-(2,4,6-trimethylphenyl)pyridin-2-yl]phenyl-κ2 C 1,N'}iridium)-chloro-benzene-pentane (1/2.3/0.4), [Ir2(C20H19N)4(C18H6F12N2O2)]·2.3C6H5Cl·0.4C5H12, (IV), synthesized in the quest for organic light-emitting devices, were determined. The bis-μ2-chloro and bis-μ2-cyanato complexes have ΔΔ and ΛΛ configurations of the distorted octa-hedral Ir centres in racemic crystals, whereas the oxamido complex has a centrosymmetric (meso) structure with the ΔΛ configuration. The bridging oxamido moiety has a nearly planar anti geometry. All structures show substantial disorder of both host mol-ecules and solvents of crystallization.

Chiroptical Spectroscopic Studies on Lanthanide Complexes with Valinamide Derivatives in Solution.

Ligands based on 2,2'-bipyridine and valinamide moieties induce circularly polarized luminescence in their europium complexes. Both the R and S enantiomers of the complexes were successfully obtained. Single-crystal X-ray analysis of the racemic crystal confirmed that the ligand is coordinated to the europium ion in a tetradentate fashion. The π-electronic system of the ligand is co-planar with the valinamide moiety, and acts as an efficient photoantenna to sensitize europium luminescence by UV excitation. The luminescence quantum yield (QY) of europium in the valinamide-containing complex was 44 % in acetonitrile. The glum value to evaluate the circularly polarized luminescence was relatively high at |0.13| estimated from their magnetic dipole transitions around 593 nm. For comparison, we prepared hexadentate europium complexes in the S- and R-forms derived from two bipyridine moieties linked by ethylenediamines. The determined QYs were 18 % (S) and 16 % (R), and the glum value |0.12| for the hexadentate complexes. The photophysical properties of the gadolinium complexes of the ligands were also evaluated.