Crystallization Of Enantiomers Research Articles

Unraveling the Structural and Property Differences between Highly Similar Chiral and Racemic Crystals Composed of Analogous Molecules

The structural differences between chiral and racemic crystals of enantiomers have piqued interest, as exemplified by classical Wallach’s rule. However, the mechanical and thermal disparities between these materials have not been thoroughly investigated. This study reports the structural and mechanical differences between chiral and racemic crystals of two analogous molecules. The similarity of molecular and crystal structures between the two analogues was validated through comparison with known chiral–racemic crystal pairs. Young’s moduli of the four crystals revealed larger values for racemic crystals than their chiral counterparts, consistent with the intermolecular interaction energies projected along the loading direction. The thermal response of crystals plays a significant role in their elastic behavior, and the temperature dependence of interaction energies along the [001] direction was found to agree with the temperature dependence of lattice dynamics for all four crystals.

Molecular Origins of Chiral Amplification on an Achiral Surface: 2D Monolayers of Aspartic Acid on Cu(111).

Recent experiments have demonstrated an intriguing phenomenon in which adsorption of a nonracemic mixture of aspartic acid (Asp) enantiomers onto an achiral Cu(111) metal surface leads to autoamplification of surface enantiomeric excess, ees, to values well above those of the impinging gas mixtures, eeg. This is particularly interesting because it demonstrates that a slightly nonracemic mixture of enantiomers can be further purified simply by adsorption onto an achiral surface. In this work, we seek a deeper understanding of this phenomena and apply scanning tunneling microscopy to image the overlayer structures formed by mixed monolayers of d- and l-Asp on Cu(111) over the full range of surface enantiomeric excess; ees = -1 (pure l-Asp) through ees = 0 (racemic dl-Asp) to ees = 1 (pure d-Asp). Both enantiomers of three chiral monolayer structures are observed. One is a conglomerate (enantiomerically pure), another is a racemate (equimolar mixture of d- and l-Asp); however, the third structure accommodates both enantiomers in a 2:1 ratio. Such solid phases of enantiomer mixtures with nonracemic composition are rare in 3D crystals of enantiomers. We argue that, in 2D, the formation of chiral defects in a lattice of one enantiomer is easier than in 3D, simply because the stress associated with the chiral defect in a 2D monolayer of the opposite enantiomer can be dissipated by strain into the space above the surface.

Chiral Symmetry Breaking of Monoacylated Anhydroerythritols and meso‐1,2‐Diols through Crystallization‐Induced Deracemization

AbstractWe developed a chiral symmetry breaking method for monoacylated meso diols. The X‐ray crystal structure analysis of monoacylated 1,4‐anhydroerythritols, meso cyclic diols with a cis configuration, revealed that the O‐(p‐anisoyl) derivative crystallized as a racemic conglomerate of the P212121 crystal system. It was confirmed that the substrate racemized by intramolecular transfer of the acyl group in the presence of a catalytic amount of base. Evaporating the solvent gradually from the solution or Viedma ripening to promote crystallization‐induced deracemization efficiently led to enantiomer crystals. These results provide the first successful example of asymmetric expression and amplification by deracemization of sugar derivatives without an external chemical chiral source. Furthermore, we applied this methodology to acyclic meso‐1,2‐diols. Three O‐monoacylated substrates were successfully deracemized to 99 % ee by Viedma ripening. We also developed asymmetric desymmetrization of meso‐1,2‐diols by combining acylation and crystallization‐induced deracemization.

Chiral Symmetry Breaking of Monoacylated Anhydroerythritols and meso-1,2-Diols through Crystallization-Induced Deracemization.

We developed a chiral symmetry breaking method for monoacylated meso diols. The X-ray crystal structure analysis of monoacylated 1,4-anhydroerythritols, meso cyclic diols with a cis configuration, revealed that the O-(p-anisoyl) derivative crystallized as a racemic conglomerate of the P21 21 21 crystal system. It was confirmed that the substrate racemized by intramolecular transfer of the acyl group in the presence of a catalytic amount of base. Evaporating the solvent gradually from the solution or Viedma ripening to promote crystallization-induced deracemization efficiently led to enantiomer crystals. These results provide the first successful example of asymmetric expression and amplification by deracemization of sugar derivatives without an external chemical chiral source. Furthermore, we applied this methodology to acyclic meso-1,2-diols. Three O-monoacylated substrates were successfully deracemized to 99 % ee by Viedma ripening. We also developed asymmetric desymmetrization of meso-1,2-diols by combining acylation and crystallization-induced deracemization.

Effect of the Enantiomeric Ratio of Eutectics on the Results and Products of the Reactions Proceeding with the Participation of Enantiomers and Enantiomeric Mixtures

This perspective is focused on the main parameters determining the results of crystallization of enantiomers or enantiomeric mixtures. It was shown that the ratio of supramolecular and helical associations depends on the eutectic composition of the corresponding enantiomeric mixture. The M and P ratios together with the self-disproportionation (SDE) of enantiomers define the reaction of the racemic compound with the resolving agent. Eventually, each chiral molecule reacts with at least two conformers with different degrees of M and P helicity. The combined effect of the configuration, charge distribution, constituent atoms, bonds, flexibility, and asymmetry of the molecules influencing their behavior was also summarized.

High-throughput on demand access of single enantiomers by a continuous flow crystallization process

A novel continuous flow reactive crystallization process for the in situ on-demand access of single enantiomer crystals is reported and exemplified for a chiral pharmaceutical intermediate that crystallizes as a racemic conglomerate.

Control design for a 2 ⊗ 2 hyperbolic system with application to preferential crystallization

AbstractThis paper deals with a mathematical model of the preferential crystallization of enantiomers. The dynamics is governed by two first‐order partial differential equations with controls appearing in the coefficients and in the boundary conditions. We study the problem of stabilizing the equilibrium of this system by a one‐dimensional input. For this purpose we construct a Lyapunov functional in the integral form whose density is defined through solutions of auxiliary ordinary differential equations. It is shown that the time derivative of this functional along the trajectories of the closed‐loop system is negative semidefinite. We also discuss some extensions of these results for the construction of a strict Lyapunov functional.

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

It has been recently observed that coupling Viedma ripening with a seeded in situ metastable racemic crystal to conglomerate transformation leads to accelerated and complete deracemization: crystal transformation–enhanced deracemization. By means of a simple kinetic model, we show that the mechanistic pathway of this new process depends profoundly on the interplay between the crystal transformation and racemization processes, which in turn influence the nucleation process of the counter enantiomer. If the nucleation of the counter enantiomer is suppressed (e.g., by sufficiently fast racemization, low amount of racemic compound or gradual feed, low relative solubility between racemic compound and conglomerate), deracemization proceeds via a second order asymmetric transformation (SOAT) and is limited primarily by the dissolution rate of the racemic crystals and the growth rate of the preferred enantiomer crystals. Breakage and agglomeration accelerate the process, but contrary to conventional Viedma ripening, they are not essential ingredients to explain the observed enantiomeric enrichment. If the nucleation process of the counter enantiomer is not sufficiently suppressed, deracemization is initially controlled by the dissolution rate of the racemic crystals, but Viedma ripening is subsequently required to convert the conglomerate crystals of the counter enantiomer formed by nucleation, resulting in slower deracemization kinetics. In both cases, the combined process leads to faster deracemization kinetics compared to conventional Viedma ripening, while it autocorrects for the main disadvantage of SOAT, i.e., the accidental nucleation of the counter enantiomer. In addition, crystal transformation–enhanced deracemization extends the range of applicability of solid-state deracemization processes to compounds that form metastable racemic crystals.

Chiral (2-cyanophenoxy)methyl-15-crown-5 in diastereomeric discrimination of amino acid esters according to the data of electrospray ionization mass spectrometry

The ability of [(2-cyanophenoxy)methyl]-15-crown-5 lariat ether enantiomers to diastereomeric discrimination with respect to hydrochlorides of 1-phenylethylamine and methyl esters of alanine, phenylalanine, and phenylglycine was studied by electrospray ionization mass spectrometry. The mentioned crown ether is available in non-racemic form owing to the procedure of preferential crystallization of enantiomers of its precursor. The quantitative estimation of the differences in the formation of diastereomeric complexes between the crown ether and the guests was performed by two independent methods: application of the guests with isotopic markers and using an additive of achiral amine-displacer. Both approaches indicate the existence of a moderate chiral discrimination: The (S)-enantiomer of the crown ether binds prevailingly the (S)-enantiomer of the guest, and vice versa.

Absolute refinement of crystal structures by X-ray phase measurements.

A pair of enantiomer crystals is used to demonstrate how X-ray phase measurements provide reliable information for absolute identification and improvement of atomic model structures. Reliable phase measurements are possible thanks to the existence of intervals of phase values that are clearly distinguishable beyond instrumental effects. Because of the high susceptibility of phase values to structural details, accurate model structures were necessary for succeeding with this demonstration. It shows a route for exploiting physical phase measurements in the crystallography of more complex crystals.

Localized crystallization of enantiomeric organic compounds on chiral micro-patterns from various organic solutions.

The controlled crystallization of enantiomers of an organic compound (a cyclic phosphoric acid derivative) on templated micro-patterned functionalised surfaces is demonstrated. Areas where a complementary chiral thiol has been located were effective heterogeneous nucleation centres when a solution of the compound is evaporated slowly. Various organic solvents were employed, which present a challenge with respect to other examples when water is used. The solvent and the crystallization method have an important influence on the crystal growth of these compounds. When chloroform was employed, well-defined crystals grow away from the surface, whereas crystals grow in the plane from solutions in isopropanol. In both cases, nucleation is confined to the polar patterned regions of the surface, and for isopropanol growth is largely limited within the pattern, which shows the importance of surface chemistry for nucleation and growth. The apparent dependence on the enantiomer used in the latter case could imply stereo-differentiation as a result of short-range interactions (the templating monolayer is disordered, even at the nanometre scale). The size of the pattern of chiral monolayer also determines the outcome of the crystallization; 5 μm dots are most effective. Despite the low surface tension of the samples (relative to the high surface tension of water), differential solvation of the polar and hydrophobic layers of the solvents allows crystallization in the polar regions of the monolayer, therefore the polarity of the regions in which heterogeneous nucleation takes place is indeed very important. Despite the complex nature of the crystallization process, these results are an important step towards to the use of patterned surfaces for heterogeneous selective nucleation of enantiomers.

Non-superimposable mirror image crystals of enantiomers by spontaneous resolution and the chiral discrimination mechanism

Abstract Non-superimposable mirror image crystals of both enantiomers ( S / R ) of cyclic γ -alkenyl alcohol ( 2 ) have been recognized and remarkably identified by the naked eye. More interestingly, both crystals are an outcome of most astonishingly H-bond and intermolecular σ/π–π interactions. They accounted for the relatively rare and less predictable spontaneous resolution with optical purity >99% ee from the racemic mixture. The chiral discrimination mechanism of this spontaneous resolution has also been proposed.

Solutions to inversion problems in preferential crystallization of enantiomers—Part II: Batch crystallization in two coupled vessels

In this series of two papers, we investigate inversion techniques for models describing the crystallization of conglomerate forming enantiomers, with application for preferential crystallization. In Part I, population balance and moment model equations for crystallization in a single vessel were analyzed and inverted. Here, in Part II, a configuration consisting of two crystallizers coupled by the exchange of crystal-free liquid is considered. A main problem addressed in this series concerns the use of previous results on orbital flatness of a model for single substance crystallization. An analysis presented in Part I for the single crystallizer moment model, which is a single-input system, is extended in this paper to show that also the moment model for the coupled crystallizer configuration, which is a multi-input system, is not orbitally flat. Despite the absence of orbital flatness, it is possible to obtain inversion results for the simultaneous realization of crystal size distributions (CSDs) in both vessels. The techniques we use build on a time transformation introduced in previous work. We also investigate the effect of idealizations, which are motivated by the design principles of the coupled crystallizer configuration. In combination with idealizing assumptions that were introduced in Part I, solutions to inversion problems are greatly simplified. In particular, the resulting idealized systems are orbitally flat. We extend a numerical example presented in Part I to the coupled crystallizer configuration. In this example we compare the exact and simplified solution techniques and demonstrate how the idealizing assumptions can be justified a posteriori.

Solutions to inversion problems in preferential crystallization of enantiomers—part I: Batch crystallization in a single vessel

In this series of two papers, we investigate inversion techniques for models describing the crystallization of conglomerate forming enantiomers, with application for preferential crystallization. Here, in Part I, a simple batch process in one vessel is considered. In Part II, the results will be extended to a technically important setup consisting of two coupled crystallizers. The research presented here builds on prior work on the use of orbital flatness concepts for trajectory planning and control of single-substance crystallization. Based on a known necessary condition for flatness, we show that moment models for crystallization of enantiomers typically do not exhibit the orbital flatness property. However, we show that a scaling of time introduced in our prior work is still useful. We present inversion results for the realization of prescribed final-time crystal size distributions (CSDs). Due to the lack of orbital flatness, these results involve integration of a zero dynamics. A number of idealizations of the process model are investigated and shown to be suitable for appropriate problem settings. We present a numerical example which demonstrates the exact as well as the simplified inversion procedures, and also justifies application of the simplified techniques.

1-D Selenidoindates {[In2Se5]}∞ Directed by Chiral Metal Complex Cations of 1,10-Phenanthroline

Two 1-D selenidoindates {[M(phen)(3)]In(2)Se(5)·H(2)O}(n) (M = Ni, Fe) were synthesized by a solvothermal method. The 1-D {[In(2)Se(5)](2-)}(n) anion is a new type of single 1-D structure constituted by an alternately fused four-membered In(2)Se(2) ring and five-membered In(2)Se(3) ring. The chalcogenoindates were separated as mechanical racemic mixtures of single enantiomer crystals, in which the R-helix of 1-D InSe anion is directed by the related clockwise (Δ) cations of [M(phen)(3)](2+) or the L-helix of 1-D anion is directed by the related anticlockwise (Λ) cation. The π···π, C···Se, and C-H···Se oriented interactions of metal complex cations with selenidoindate anions play an important role in the formation of the chiral crystals. The embedded [M(phen)(3)](2+) cations improve the optical absorption of the 1-D semiconductor materials.

Parameterization of population balance models for polythermal auto seeded preferential crystallization of enantiomers

For analysis, design and model-based control of crystallization processes typically population balance models or reduced models derived therefrom are used. Usually the kinetic parameters in these models are determined analyzing measured concentration trajectories and/or particle size distributions using parameter estimation procedures. In the case of preferential crystallization of enantiomers the analysis of experiments is complex since there are two “competing” crystal populations. In this field often batch processes are performed using seeds of the desired enantiomer. Currently, it is in particular challenging to quantify and optimize a new concept: e.g. the so-called “ auto seeded programmed polythermal preferential crystallization” (“as3pc” [Coquerel, G., Petit, M.-N., Bouaziz, R., 2000. Method of resolution of two enantiomers by crystallization. United States Patent, Patent number: 6,022,409]). In order to design and optimize this process the temperature dependent kinetic constants for crystal growth, nucleation and dissolution have to be known. In this work a reduced model for this auto seeded process is presented. The general identifiability of the model parameters is investigated along with some suggestions on how to reparameterize the kinetic terms involved. The values of the identified key parameters are estimated using conventional least square optimization using experimental data determined for the model system threonine/water. Parameter confidence and cross correlation are discussed and finally the model is validated using experiments not used for parameter estimation.

Primary Nucleation of Threonine Crystals from Ternary Solutions

Primary nucleation of desired threonine enantiomer crystals occurred by changing solution compositions in a d-threonine/l-threonine/water ternary solution, and nucleation mechanisms of threonine enantiomer crystals are discussed using the ternary phase diagram for a d-threonine/l-threonine/water system. When an l-threonine mother crystal was immersed in a dl-threonine solution, the l-threonine mother crystal surfaces were dissolved, and the supersaturation in the solution with respect to d-threonine increased. Consequently, heterogeneous nucleation of d-threonine crystals occurred, and combined crystals of l- and d-threonine were formed. When an l-threonine supersaturated solution was injected into a dl-threonine supersaturated solution, the supersaturation with l-threonine in the solution became higher by mixing the two solutions, and consequently homogeneous nucleation of l-threonine crystals occurred. Controlling nucleation of desired enantiomer crystals was expected to be applied to a formation of combined crystals and preferential crystallization.

Separation of Racemate from Excess Enantiomer of Chiral Nonracemic Compounds via Density Gradient Ultracentrifugation

In this study, it is shown that preparative density gradient ultracentrifugation can be applied to separate racemate crystals from excess enantiomer crystals. This was demonstrated for alanine crystals separated in a 50 wt % Nycodenz gradient. The recovery rates of the pure enantiomers from the mixtures were good (70−90%), and the separation method showed accuracy in the third digit of the density. As such density differences between racemate and enantiomers can be found for a wide range of crystalline chiral compounds, the presented separation method should be applicable to a large variety of substances on a preparative scale.

Simultaneous preferential crystallization in a coupled, batch operation mode—Part I: Theoretical analysis and optimization

The intention of this paper is the theoretical analysis and optimization of preferential crystallization of enantiomers performed simultaneously in two batch crystallizers which are coupled. An exchange of the liquid phases may increase the overall crystallization kinetics and that might lead to a higher productivity. In this study, the amino acid threonine dissolved in water was used as a model system. Taking experimentally estimated parameters describing the crystallization thermodynamics as well as kinetics into consideration, a simplified mathematical description based on population balance model was established for the simulation of the time changes of liquid phase composition during the preferential crystallization process. Based on this simplified model the above mentioned crystallizer configurations has been optimized and investigated concerning the maximum attainable productivity.

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.