Thermal transformation of a chiral,non-racemic epoxide into a conglomerate

Formation of conglomerates is of general interest because they offer the possibility of enantiomeric separation by preferential crystallization. A surprising result was obtained for the chiral epoxide 1a, 2, 7, 7a-tetrahydro-3-methoxynaphth-(2,3b)-oxirene, for which we have shown that the racemate crystals of a non racemic mixture can be easily transformed into a conglomerate by gentle heating and cooling within a defined temperature range. This transformation is not possible with the pure racemic mixture. Thus the enantiomeric excess seems to be the driving force for the conglomerate formation. Experiments have been carried out on analytical and preparative scale. Non racemic mixtures have been characterized by high pressure liquid chromatography on chiral stationary phase and crystal transformation has been monitored with differential scanning calorimetry (DSC) and infrared spectroscopy (IR).     

Chiral symmetry breaking and polymorphism in 1,1'-binaphthyl melt crystallization

We have studied chiral symmetry breaking in the melt crystallization of 1,1'-binaphthyl. We confirm that chiral symmetry breaking can be induced by stirring the melt as it crystallizes. We find an additional process of vapor crystallization to occur alongside the melt crystallization. This complicates the analysis of the enantiomorphism by introducing a further phenomenon: that of polymorphism. Crystallographic studies by X-ray diffraction reveal two polymorphs of 1,1'-binaphthyl that are made up of two different conformers of each of the two enantiomeric forms of the molecule. Crystals from the melt are generally chiral tetragonal crystals (P42(1)2(1)) composed of (R)- or (S)-1,1'-binaphthyl in a transoid conformer, while those from the vapor are racemic monoclinic crystals (C2/c) made up of the cisoid conformer of both (R)- and (S)-1,1'-binaphthyl enantiomers. The main intermolecular interactions in all these crystals are weak aromatic CH/pi hydrogen bonds, which are responsible for the enantiomeric discrimination in the molecular recognition during crystallization. A tendency for whisker crystal formation is notable in 1,1'-binaphthyl. In stirred crystallization, fluid and mechanical forces can break off these whiskers, which provide secondary nuclei for further crystallization. This autocatalytic mechanism induces chiral symmetry breaking during the crystallization.     

Enantioselective crystallization of histidine on chiral self-assembled films of cysteine

In this paper, the preparation and use of chiral surfaces derived from enantiomerically pure crystals of amino acids are described. For this purpose, a self-assembly process to grow thin chiral films of (+)-L- or (-)-D-cysteine on gold surfaces was chosen. These chiral films were utilized as crystallization catalysts in the crystallization of enantiomers from solutions. To demonstrate the chiral discrimination power of the chiral surfaces in crystallization processes, the crystallization of racemic histidine onto the chiral films was investigated. Our study demonstrates the potential application of chiral films to control chirality throughout crystallization, where one enantiomer crystallizes onto the chiral surfaces with relative high enantiomeric excess. In addition, crystallization of pure histidine enantiomers onto chiral films results in strong crystal morphology modification with preferred orientation.     

Disappearing Enantiomorphs: Single Handedness in Racemate Crystals

Although crystallization is the most important method for the separation of enantiomers of chiral molecules in the chemical industry, the chiral recognition involved in this process is poorly understood at the molecular level. We report on the initial steps in the formation of layered racemate crystals from a racemic mixture, as observed by STM at submolecular resolution. Grown on a copper single‐crystal surface, the chiral hydrocarbon heptahelicene formed chiral racemic lattice structures within the first layer. In the second layer, enantiomerically pure domains were observed, underneath which the first layer contained exclusively the other enantiomer. Hence, the system changed from a 2D racemate into a 3D racemate with enantiomerically pure layers after exceeding monolayer‐saturation coverage. A chiral bias in form of a small enantiomeric excess suppressed the crystallization of one double‐layer enantiomorph so that the pure minor enantiomer crystallized only in the second layer.     

Discovery of a solid solution of enantiomers in a racemate-forming system by seeding

A racemic liquid of opposite enantiomers usually crystallizes as a racemic compound (racemate), rarely as a conglomerate, and even more rarely as a solid solution. We discovered a Type II solid solution (mixed crystal) of the enantiomers of the chiral drug tazofelone (TZF) by seeding its racemic liquid with enantiomerically pure crystals (enantiomorphs). Without seeding, the racemic liquid crystallized as a racemic compound. The crystal structure of this solid solution resembles that of the enantiomorph but has static disorder arising from the random substitution of enantiomers. This solid solution is a kinetic product of crystallization made possible by its faster growth rate compared to that of the competing racemate (by 4- to 40-fold between 80 and 146 degrees C). The free energy of the solid solution continuously varies with the enantiomeric composition between those of the conglomerate and the racemates. The existence of the TZF solid solution explains the absence of eutectic melting between crystals of different enantiomeric compositions. The ability of TZF to simultaneously form racemate and solid solution originates from its conformational flexibility. Similar solid solutions of enantiomers may exist in other systems and may be discovered in similar ways. The study demonstrates the use of cross-nucleation for discovering and engineering crystalline materials to optimize physical properties.     

Mechanism of preferential enrichment,an unusual enantiomeric resolution phenomenon caused by polymorphic transition during crystallization of mixed crystals composed of two enantiomers

The mechanism of Preferential Enrichment, an unusual enantiomeric resolution phenomenon observed upon recrystallization of a series of racemic crystals which are classified as a racemic mixed crystal with fairly ordered arrangement of the two enantiomers, has been studied. On the basis of the existence of polymorphs and the occurrence of the resulting polymorphic transition during crystallization from solution, the mechanism has been accounted for in terms of (1) a preferential homochiral molecular association to form one-dimensional chain structures in the supersaturated solution of the racemate or nonracemic sample with a low ee value, (2) a kinetic formation of a metastable crystalline phase retaining the homochiral chain structures in a process of nucleation, (3) a polymorphic transition from the metastable phase to a stable one followed by enantioselective liberation of the excess R (or S) enantiomers from the transformed crystal into solution at the beginning of crystal growth to result in a slight enrichment (up to 10% ee) of the opposite S (or R) enantiomer in the deposited crystals, together with an enantiomeric enrichment of the R (or S) enantiomer in the mother liquor, and (4) a chiral discrimination by the once formed S (or R)-rich stable crystalline phase in a process of the subsequent crystal growth, leading to a considerable enantiomeric enrichment of the R (or S) enantiomer up to 100% ee in the mother liquor. The processes (3) and (4) are considered to be directly responsible for an enrichment of one enantiomer in the mother liquor. The association mode of the two enantiomers in solution has been investigated by means of (i) the solubility measurement and (ii) the number-averaged molecular weight measurement in solution by vapor pressure osmometry, together with (iii) the molecular dynamics simulation of oligomer models. The polymorphic transition during crystallization has been observed visually and by means of the in situ FTIR technique and DSC measurement. Both metastable and stable crystals have been obtained, and their crystal structures have been elucidated by X-ray crystallographic analysis of their single crystals.     

Degree of supersaturation-regulated chiral symmetry breaking in one crystal

This paper aimed at studying chiral symmetry-breaking phenomena in one crystal. Preferential crystallization of racemic asparagines was carried out in nonseeded stagnant solutions through slow cooling. By varying the supersaturation, only one transparent crystal could be obtained at enough low supersaturation of dl-asparagine, and the crystal was not pure enantiomer with crystal enantiomeric excess increasing inversely with the degree of supersaturation. Crystal enantiomeric excess can amount up to 85% in one transparent crystal. Because no secondary nucleation occurred except for stochastic primary nucleation, we suggest that primary nucleation and competition between l- and d-nuclei were considered to be a mechanism for asymmetry amplification. High-performance capillary electrophoresis coupled with laser-induced fluorescence was used to separate and quantify l- and d-asparagine and the enantiomeric excess value can be calculated according to their concentration.     

Chiral soluble polymers and microspheres for enantioselective crystallization

A series of chiral polymers based on poly(N‐acryl) amino acids was synthesized using a convergent synthetic approach. These chiral polymers have been used as chiral additives to induce enantioselective crystallization of racemic or conglomerate amino acids in solutions. These polymeric additives showed strong capabilities to enhance highly enantioselective resolution during the crystallization of amino acids. In addition, these polymers caused unusual modifications of amino acid crystal morphologies. Furthermore, spherical microparticles of those same chiral polymers were also shown active in similar chiral discriminations during amino acid crystallizations occurring on microparticle surfaces. Our study demonstrates the high potential of chiral polymers and microparticles to resolve amino acids throughout crystallization processes. High enantiomeric excesses in one targeted enantiomer of amino acids can also be maximized via time‐dependent kinetic control of crystallizations. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 3009–3017, 2006     

Enantiopure O-substituted phenylphosphonothioic acids: chiral recognition ability during salt crystallization and chiral recognition mechanism

[structure: see text] The chiral recognition ability of enantiopure O-methyl, O-ethyl, O-propyl, and O-phenyl phenylphosphonothioic acids (1a-d) for various kinds of racemic amines during salt crystallization and the chiral recognition mechanism were thoroughly investigated. The chiral recognition abilities of enantiopure 1a-d for a wide variety of racemic amines varied in a range of 6 to >99% enantiomeric selectivity. Deposited less-soluble diastereomeric salts were classified into two categories, prism- and needle-type crystals; the prism-type crystals were composed of a globular molecular cluster, while there existed a 2(1) column in the needle-type crystals. In contrast to a general observation of a similar 2(1) column in the less-soluble diastereomeric salt crystals of chiral primary amines with chiral carboxylic acids, the globular molecular cluster is a very unique hydrogen-bonding motif that has never been constructed in diastereomeric salt crystals. Excellent chiral recognition was always achieved when the less-soluble diastereomeric salts were prism-type crystals. Significant correlations were found between the degree of the chiral recognition with 1a-d, the crystal shape of the less-soluble diastereomeric salts, and the hydrogen-bonding motif (molecular cluster/2(1) column). The chiral recognition mechanisms via the molecular cluster and the 2(1) column formations are discussed in detail on the basis of X-ray crystallographic analyses.     

Kinetic resolution of racemic amines using provisional molecular chirality generated by spontaneous crystallization

N-(2-methoxy-1-naphthoyl)pyrrolidine afforded chiral crystals by spontaneous crystallization. The molecular chirality in the crystal was retained after dissolving the crystals in a cooled solvent. Kinetic resolution of racemic amines was performed using the provisional chiral molecular conformation derived from chiral crystals.     

Chiral Symmetry Breaking of Spiropyrans and Spirooxazines by Dynamic Enantioselective Crystallization

Dynamic enantioselective crystallization enabled the chiral symmetry breaking of two spiropyrans and one spirooxazine. The three spiro compounds afforded racemic conglomerate crystals, and easily racemized in alcoholic solution without irradiation. Optically pure enantiomorphic crystals were obtained by vapor-diffusion crystallization or attrition-enhanced deracemization (Viedma ripening). Their absolute configurations were determined by single-crystal X-ray analysis and each enantiomorphic crystal was correlated with its solid-state circular dichroism (CD) spectrum.     

Chiral symmetry breaking via crystallization of the glycine and α-amino acid system: a mathematical model

We introduce and numerically solve a mathematical model of the experimentally established mechanisms responsible for the symmetry breaking transition observed in the chiral crystallization experiments reported by I. Weissbuch, L. Addadi, L. Leiserowitz and M. Lahav, J. Am. Chem. Soc., 1988, 110, 561-567. The mathematical model is based on five basic processes: (1) the formation of achiral glycine clusters in solution, (2) the nucleation of oriented glycine crystals at the air/water interface in the presence of hydrophobic amino acids, (3) a kinetic orienting effect which inhibits crystal growth, (4) the enantioselective occlusion of the amino acids from solution, and (5) the growth of oriented host glycine crystals at the interface. We translate these processes into differential rate equations. We first study the model with the orienting process (2) without (3) and then combine both allowing us to make detailed comparisons of both orienting effects which actually act in unison in the experiment. Numerical results indicate that the model can yield a high percentage orientation of the mixed crystals at the interface and the consequent resolution of the initially racemic mixture of amino acids in solution. The model thus leads to separation of enantiomeric territories, the generation and amplification of optical activity by enantioselective occlusion of chiral additives through chiral surfaces of glycine crystals.     

Dipolar origin of water etching of amino acid surfaces

The etching induced by water on hydrophobic (001) surfaces of enantiomeric L-, D- and racemic DL-valine crystals has been characterized by means of atomic force microscopy (AFM) at ambient conditions. Well-defined chiral parallelepipedic shallow patterns, one bilayer deep, are observed for the enantiomeric crystals with sides (steps) oriented along low index crystallographic directions. Hence, chirality can be readily identified by visual inspection of an AFM image after etching. The formation of such regular patterns can be rationalized using basic concepts of electrical dipolar interactions. The key factor that determines the relative etching rate for each step and thus defines the shape of the etching patterns is the orientation of the molecular dipoles with respect to the step edge. The simplicity of the approach allows the prediction of the effect of water etching on other amino acid crystals as well as the effect of the interaction of water with amino acid molecules forming part of more complex structures.     

Spontaneous and induced chiral symmetry breaking of stereolabile pillar[5]arene derivatives upon crystallisation

Stereolabile pillar[5]arene (P[5]) derivatives, which are dynamic racemic mixtures in solution on account of their low inversion barriers, were employed as platforms to study chiral symmetry breaking during crystallisation. In the solid state, we showed that crystal enantiomeric excess of a conglomerate-forming P[5] derivative can be obtained by handpicking and Viedma ripening without the intervention of external chiral entities. On the other hand, in the presence of ethyl d/l-lactate as both optically-active solvents and chiral guests, the handedness of P[5] derivative crystals, either forming racemic compounds or conglomerates upon condensation, can be directed and subsequently inverted in a highly controllable manner.

Stereolabile pillar[5]arene derivatives, which are dynamic racemic mixtures in solution on account of their low inversion barriers, were employed as platforms to study chiral symmetry breaking during crystallisation.     

Control of the morphogenesis of barium chromate by using double-hydrophilic block copolymers (DHBCs) as crystal growth modifiers

A systematic morphosynthesis of barium chromate particles has been performed by using double-hydrophilic block copolymers (DHBCs), which consist of a hydrophilic solvating block and a hydrophilic binding block, as crystal growth modifiers to direct the controlled precipitation of barium chromate from aqueous solution. Several kinds of DHBCs with different functional groups -COOH, -PO3H2, -SO3H, -SH as well as PEG-poly(aminoamine) block-dendrimer copolymers were explored for crystallization and morphology control of barium chromate. Well-defined morphologies of BaCrO4 particles can be produced, such as more or less dendritic X-shaped, elongated X-shaped, or rodlike particles, flower-like plates, ellipsoids, spheres, nanofiber bundles, nanofibers, and other more complex morphologies. In the presence of the phosphonated copolymer PEG-b-PMAA-PO3H2 (degree of phosphonation: 21%) at pH 5, large conelike bundles of nanofibers ranging from 10 to 20 nm in diameter with lengths up to 150 microns can be produced at room temperature, whereas replacement of the covalently bound phosphonate groups by the ionic salt analogue dopant fails to produce this structure, indicating the importance of the functional polymer block structures. The time-resolved formation process of the bundles of nanofibres was investigated, showing a remarkable self-similarity. At temperatures higher than 50 degrees C, in plastic flasks or when undergoing continuous stirring, only ellipsoids or nearly spherical particles can be obtained. This shows that the fiber formation relies on heterogeneous nucleation and is in agreement with a recently published mechanism where fiber formation is due to the vectorially directed self-assembly of primary particles. Our results demonstrate that the integration of DHBCs, taking advantage of the experimental conditions such as crystallization sites, temperature, pH, and reactant concentration, will extend the possibilities for controlling the shape, size, and microstructures of the inorganic crystals by means of a simple mineralization process.     

Selective growth and distribution of crystalline enantiomers in hydrogels

The crystallization of sodium chlorate (NaClO3) is a classic example of spontaneous chirality, since it is achiral in solution but adopts a chiral form in the solid state. While crystal growth of NaClO3 from pure aqueous solutions yields a 50:50 statistical distribution of d- and l-crystals, large enantiomeric excesses of either d- and l-crystals can be achieved by crystal growth in agarose gel, a naturally occurring chiral polysaccharide. The influence of gel density (0.1-0.75 wt %), temperature, and the diffusion of cosolvents on crystal distribution was discerned from statistical data obtained from 752 gel-mediated crystallization experiments yielding 12,384 individual crystals. These studies demonstrate that the magnitude and direction of the bias can be selectively engineered toward either d- or l-forms by changing the gelation conditions. Aqueous agarose gels infused with 48 wt % NaClO3 at 6 degrees C, favored the growth of d-NaClO3 crystals, with ee's reaching 22% at the highest gel concentrations. Crystal growth under methanol diffusion favored deposition of the opposite enantiomorph, l-NaClO3. The bias in the crystal distribution is enhanced at higher temperatures. Aqueous gels at 24 degrees C infused with methanol cosolvent favored l-NaClO3, with ee's reaching 53%. The changing magnitude and direction of the enantiomorph bias can be ascribed to differences in the agarose conformation and intermolecular interactions between the gel and crystal surfaces that inhibit the formation of the two enantiomers to different extents.     

A list of organometallic kryptoracemates

The vast majority of racemic solutions of chiral compounds apparently crystallize at room temperature in non‐Sohncke space groups as racemic crystals. However, kryptoracemic crystals composed of nearly enantiomeric pairs occasionally crystallize at room temperature, or appear as low‐temperature phases, in Sohncke space groups. As a complement to the previously published catalog of organic kryptoracemates [Fábián & Brock (2010). Acta Cryst. B 66 , 94–103], 1412 chiral organometallic crystal structures have now been extracted from the Cambridge Structural Database and analyzed. 26 are listed herein as credible kryptoracemates. The possible influence of temperature is discussed, together with some problems in characterizing and classifying these structures.     

Highly Efficient Chiral Resolution of dl‐Arginine by Cocrystal Formation Followed by Recrystallization under Preferential‐Enrichment Conditions

An excellent chiral symmetry‐breaking spontaneous enantiomeric resolution phenomenon, denoted preferential enrichment, was observed on recrystallization of the 1:1 cocrystal of dl ‐arginine and fumaric acid, which is classified as a racemic compound crystal with a high eutectic ee value (>95 %), under non‐equilibrium crystallization conditions. On the basis of temperature‐controlled video microscopy and in situ time‐resolved solid‐state ¹³C NMR spectroscopic studies on the crystallization process, a new mechanism of phase transition that can induce preferential enrichment is proposed.     

Enantiospecific synthesis of vicinal stereogenic tertiary and quaternary centers by combination of configurationally-trapped radical pairs in crystalline solids

[reaction: see text] Photochemical irradiation of crystalline (2R,4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-butanone 1 led to highly efficient decarbonylation reactions. Experiments with optically pure and racemic crystals showed that the intermediate radical pairs undergo a highly diastereo- and enantiospecific radical-radical combination that leads to the formation of two adjacent stereogenic centers in good chemical yield and with high chemical control. Reactions with chiral crystals occurred with quantitative enantiomeric yields and >95% diastereomeric yields.     

Absolute helical arrangement of sulfonamide in the crystal

[reaction: see text] 1,2-Bis(N-benzenesulfonyl-N-methylamino)benzene (2), which has no fixed asymmetric element, was crystallized from ethyl acetate as chiral crystals belonging to space group P4(1)2(1)2 (No. 92) or P4(3)2(1)2 (No. 96). The array of molecules built by the CH-pi interaction along the c-axis forms an enantiomeric helical superstructure in each individual crystal. The absolute configurations of the chiral crystals of 2 were determined by X-ray crystal structure analysis using the Flack parameter method. The solid-state CD spectra of the chiral crystals in KBr were mirror images. The equilibrium between the two enantiomers in solution is fast during crystallization at ambient temperature, and the energy barrier (DeltaG()) is estimated to be 11.7 +/- 0.3 kcal/mol (233 K).