Conglomerate Crystals Research Articles

Pasteur made simple - mechanochemical transformation of racemic amino acid crystals into racemic conglomerate crystals.

Conglomerate crystallization is required for many deracemization or enantioenrichment protocols. Here, we report the metal-mediated mechanochemical transformation of racemic compounds of some proteinogenic amino acids - valine, leucine and isoleucine - into their corresponding conglomerates. Specifically, ZnO has the ability to promote and stabilize the conglomerate phase of these amino acids to an extent where the racemic compound is not observed.

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.

Retraction of “A Population Balance Model for Temperature Cycling-Enhanced Deracemization”

It has been recently observed that a suspension of conglomerate crystals of both chiralities in contact with a solution where racemization takes place can undergo symmetry breaking due to periodic fluctuations in temperature. The interplay between the mechanisms behind this process is still a matter of debate, although there is consensus that growth/dissolution of crystals and racemization in the solution phase play a crucial role. In this work, we present a population balance model (PBM), based on temperature-size dependent solubility, which simulates a system of enantiomeric crystals of both chiralities subjected to Ostwald ripening under periodic temperature fluctuations, in the presence of a liquid-phase racemization reaction. Our simulations reveal that for a racemic system with small initial size asymmetries between the enantiomers complete deracemization is achieved due to temperature fluctuations, whereas isothermal Ostwald ripening only leads to partial enantiomeric enrichment. This implies that ...

A Population Balance Model for Temperature Cycling-Enhanced Deracemization

It has been recently observed that a suspension of conglomerate crystals of both chiralities in contact with a solution where racemization takes place can undergo symmetry breaking due to periodic fluctuations in temperature. The interplay between the mechanisms behind this process is still a matter of debate, although there is consensus that growth/dissolution of crystals and racemization in the solution phase play a crucial role. In this work, we present a population balance model (PBM), based on temperature-size dependent solubility, which simulates a system of enantiomeric crystals of both chiralities subjected to Ostwald ripening under periodic temperature fluctuations, in the presence of a liquid-phase racemization reaction. Our simulations reveal that for a racemic system with small initial size asymmetries between the enantiomers complete deracemization is achieved due to temperature fluctuations, whereas isothermal Ostwald ripening only leads to partial enantiomeric enrichment. This implies that size-temperature dependence of solubility is an essential mechanism in temperature cycling-enhanced deracemization. Although enantiopurity is achieved with only growth, dissolution and temperature cycling, other mechanisms, such as breakage, could also be included. While our model qualitatively reproduces many of the experimental observations in temperature cycling-enhanced deracemization, the autocatalytic nature of the process is not captured and, similarly to Viedma ripening, some sort of chiral feedback mechanism (e.g., agglomeration or secondary nucleation) seems to be required to fully describe the process dynamics. The results presented here offer further insight into temperature cycling-enhanced deracemization and help pinpoint the influence of the various mechanisms in the process.

Asymmetric Diels–Alder Reaction Involving Dynamic Enantioselective Crystallization

Asymmetric Diels-Alder reaction was achieved under achiral conditions. Reaction of prochiral 2-methylfuran and N-phenylmaleimide in heptane or hexane solution at 80 °C efficiently gave a conglomerate crystal of exo-type Diels-Alder adduct selectively, and continuous suspension of the reaction mixture with glass beads promoted attrition-enhanced deracemization, leading to an optically active exo-adduct in 90% ee.

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.

Biomineralization of Calcium Oxalate Crystals in Leaves of (L.) Schott (Araceae) in Colocasia esculenta Response to Herbivory and Water Regime

Calcium oxalate crystals are common constituents of plant tissues and are believed to play a role in protection against herbivory, calcium regulation and even heavy metal sequestration. In this study, calcium oxalate crystals in leaves of Colocasia esculenta were studied in order to elucidate the biomineralization process of these inorganic components in response to herbivory and different water regimes. Different crystal types occurring in the leaves of C. esculenta were identified, described and quantified in terms of density and distribution. Two general types of calcium oxalate crystals were found, namely: the raphides and druses. The raphides were of two types, the defensive and non- defensive, and both occurred as bundles of elongated crystals enclosed in specialized cells called idioblasts. Druses were spherical conglomerate crystals extensively distributed throughout the leaf. Although degree of herbivory did not significantly affect overall density of calcium oxalate crystals, there was a highly significant interaction effect between herbivory and crystal type. With increasing degree of herbivory from 10% to 30%, the density of druses and non-defensive raphides decreased significantly but that of the defensive type increased. Water availability had a highly significant effect on overall crystal density. Interaction effect between water regime and crystal type was also highly significant. Density of druses significantly increased under waterlogged than non-waterlogged conditions while those of the defensive and non-defensive raphides were unaffected.

有機結晶のキラリティーを利用した不斉合成法の開発

Asymmetric synthesis from achiral starting materials using only crystal chirality under absolutely achiral conditions-that is, absolute asymmetric synthesis-has been investigated by many methods, including solid-state photochemical reactions, asymmetric reactions using frozen chirality, and dynamic crystallization (total spontaneous resolution). Dynamic crystallization using racemic conglomerate crystals involved that an enantiomerically enriched solid state could be achieved through crystallization from a solution in which chiral molecules could rapidly racemize. Many such examples resulted in total optical resolution by deracemization, selectively leading to single-handed molecules. Furthermore, a combined methodology for generating a chiral center from achiral materials, involving dynamic crystallization or attrition-enhanced deracemization, was recently developed. These examples demonstrate the high potential of this new category of absolute asymmetric synthesis.

Towards Deracemization in the Absence of Grinding through Crystal Transformation, Ripening, and Racemization

New insights into the obscure mechanisms of solid-state deracemization phenomena are obtained by crystal ripening experiments that, contrary to standard techniques, exclude attrition enhancement (grinding). The results point out that small particles and an initial size imbalance between the two enantiomeric crystal populations can intensify the rate of solid-state enantiomeric enrichment even in the absence of intermediate actions (e.g., grinding or thermal cycling). On this ground, a new process that creates such initial conditions is designed and exemplified for the proteinogenic glutamic acid. As a first step, racemic compound solvate (dl-glutamic acid monohydrate) crystals are completely converted to small-sized conglomerate anhydrate crystals, in the presence of larger seeds of a single chirality. After the transformation is complete and the racemization catalyst is added, the suspension contains an equal number of small-sized conglomerate crystals of both enantiomers together with the larger seeds o...

Directing the Viedma ripening of ethylenediammonium sulfate using "Tailor-made" chiral additives.

Both enantiomers of trans-cyclohexane-1,2-diammonium sulfate and trans-1,2-diphenylethylenediammonium sulfate were used as "tailor-made" additives to direct the mirror-symmetry breaking in the attrition-enhanced deracemization (i.e. Viedma ripening) of conglomerate crystals of ethylenediammonium sulfate (EDS). Isothermal titration calorimetry (ITC) shows chiral recognition of (1R,2R)- and (1S,2S)-1,2-diphenylethylenediamine to EDS crystals where the enthalpy of adsorption of the (1R,2R)-isomer on l-EDS crystals is higher in comparison to that on d-EDS crystals. These results are consistent with a "rule of reversal" mechanism driving the chiral outcome of the Viedma ripening of EDS.

Homochiral crystal generation via sequential dehydration and Viedma ripening

1,2-Bis(N-benzoyl-N-methylamino)benzene (2) forms centrosymmetric hydrate crystals (2·xH2O) and non-centrosymmetric anhydrous crystals. Dehydration of this hydrate (30 min at 140 °C) resulted in the formation of chiral crystals (i.e. a physical racemate of the conglomerate crystals) as verified using solid-state circular dichroism and powder X-ray diffraction. Subsequent attrition-enhanced deracemization, also known as Viedma ripening, was used to obtain homochiral crystals of 2 within 5 h.

Evaluation of Calcium Regulating Roles of Guttation and Calcium Oxalate Crystals in Leaf Blades and Petioles of HydroponicallyGrown Eddo

We investigated the involvement of guttation and calcium oxalate crystals in the maintenance of calcium homeostasis in leaf blades and petioles of eddo in hydroponic solution containing calcium at different concentrations. Under scanning electron microscopy, two types of crystals were observed in leaf blades and petioles: raphides (bundles of needle-shaped crystals) and druses (multifaceted conglomerate crystals). The number and size of crystals of leaf blades and petioles in 1 mMcalcium treatment (control) were smaller than that in 15 mM calcium treatments and larger than that in 0 mM calcium treatment. Calcium contents of leaf blades, petioles and whole plants increased with the increase of calcium concentration in the treatment solution. In addition, calcium-mapping images demonstrated a positive correlation between the amount of calcium in crystal idioblasts and concentration of calcium in treatment solutions. On the other hand, the weight percentage of calcium per mesophyll cell (spongy cell and palisade cell) of leaf blades and per normal parenchyma cell of petioles was stable irrespective of calcium treatment conditions. These results suggest that calcium accumulates in crystals under calcium-excessive conditions and is released from crystals under calcium-deficient conditions to stabilize calcium levels in leaf tissues other than the idioblasts. A positive correlation was observed between the calcium concentration of guttation fluid (μg mL−1), the total amount of calcium in guttation fluid (μg leaf−1night−1) and the calcium concentration of treatment solutions. These results suggest that guttation eliminates excess calcium and would be involved in maintaining calcium ion homeostasis in eddo.

Enantiopure isoindolinones through Viedma ripening.

Here we demonstrate that deracemization of isoindolinones using Viedma ripening is possible starting from a racemic mixture of conglomerate crystals. Crystals of the enantiopure isoindolinones lose their chiral identity upon dissolution even without the need for a catalyst. This enabled complete deracemization of the reported isoindolinones without a catalyst.

Anion Effect on the Binary and Ternary Phase Diagrams of Chiral Medetomidine Salts and Conglomerate Crystal Formation

The binary phase diagrams of hydrogen halides salts of medetomidine (Med.HX, X:Br,I) and hydrogen oxalate salt of medetomidine (Med.Ox) were determined based on thermogravimetric/differential thermal analysis (TGA/DTA) and their crystal structure behavior was confirmed by comparison of the X-ray diffractometry and FT-IR spectroscopy of the racemate and pure enantiomer. All hydrogen halide salts presented racemic compound behavior. Heat of fusion of halides salt of (rac)-medetomidine decreased with ionic radius increase. Eutectic points for Med.HCl (previously reported), Med.HBr, and Med.HI rest were unchanged approximately. The solubility of different enantiomeric mixtures of Med.HBr and Med.HI were measured at 10, 20, and 30°C in 2-propanol showing a solubility increase with ionic radius. A binary phase diagram of Med.Ox shows a racemic conglomerate behavior. The solubility of enantiomeric mixtures of Med.Ox were measured at 10, 20, 30, and 40°C. The ternary phase diagram of Med.Ox in ethanol conforms to a conglomerate crystal forming system, favoring its enantiomeric purification by preferential crystallization.

Viedma Ripening of Conglomerate Crystals of Achiral Molecules Monitored Using Solid-State Circular Dichroism

Viedma ripening is the attrition-induced spontaneous chiral amplification of a conglomerate crystal mixture. To demonstrate the general nature of this deracemization process, we have extended attrition-enhanced chiral amplification to 10 achiral organic molecules that form conglomerate chiral crystals: benzil (1), diphenyl disulfide (2), benzophenone (3), tetraphenylethylene (4), guanidine carbonate (5), butylated hydroxytoluene (6), hippuric acid (7), ninhydrin (8), cytosine (9), and adeninium dinitrate (10). In these experiments the time required to reach homochirality was as low as 3 h and typically ranged from 25 to 50 h. In most cases amplification to homochirality of both enantiomers was observed in repeat experiments, although often in a nonstochastic fashion, reflecting the scalemic nature of the starting material. We have also demonstrated the utility of quantitative circular dichroism (CD) to determine enantiomeric excess in systems where chirality exists only in the solid-state.

A computational investigation of attrition-enhanced chiral symmetry breaking in conglomerate crystals

Attrition-enhanced chiral symmetry breaking in crystals, also known as Viedma ripening, is a remarkable phenomenon from a variety of perspectives. By providing a direct route to solid-phase homochirality in a controllable manner, it is of inherent interest to those who study chiral symmetry-breaking/amplification mechanisms. When applied to intrinsically chiral molecules, Viedma ripening may have implications for the origin of biological homochirality, as well as applications in chiral drug resolution. Despite an abundance of research, the mechanistic details underlying this phenomenon have not been unambiguously elucidated. We employ a Monte Carlo algorithm to study this driven system, in order to gain further insights into the mechanisms capable of reproducing key experimental signatures. We provide a comprehensive numerical investigation of how the model parameters (attrition rate, liquid-phase racemization kinetics, and the relative rates of growth and dissolution kinetics) impact the system's overall behavior. It is shown that size-dependent crystal solubility alone is insufficient to reproduce most of the experimental signatures of Viedma ripening, and that some form of a solid-phase chiral feedback mechanism must be invoked in order to reproduce experimentally observed behavior. In this work, such feedback mechanisms can take the form of agglomeration, or of artificial modification of the size dependent growth kinetics.

Formation of conglomerate crystals: A closer look at helical pitches and unit cell volumes of P- and M-helical copper(II) coordination polymers

Conglomerate crystals of tubular helical coordination polymers, P- and M-[CuCl2(L)(S)]·S′ (L=dimethylbis(4-pyridyl)silane; S=Me2SO, HCONMe2; S′=Me2SO, 1/2Et2O), have been obtained in high yields. Their helical pitches and unit cell volumes are sensitive to the molecular size of ligand, co-ligand, and solvate molecules. Both crystals evaporate solvate molecules at around 100°C, and then calcination at 600°C finally produces micro-sized chaotic surface materials consisting of copper(II) oxide/silicon(IV) oxide composite with evolving burned organics.

Enantiomer Resolution by Pressure Increase: Inferences from Experimental and Topological Results for the Binary Enantiomer System (R)- and (S)-Mandelic Acid

In pharmacy, racemic compounds are often problematic, because generally only one of the enantiomers possesses therapeutic activity and it is often difficult to separate them. Even though this problem is likely as old as the pharmaceutical industry, one thermodynamically obvious way of separating racemic crystals has never been studied experimentally, which is by using pressure. Data have been obtained on the equilibria of the (R)- and (S)-mandelic acid system as a function of pressure and temperature. With the use of thermodynamic arguments including the Clapeyron, Schröder, and Prigogine-Defay equations, it has been demonstrated that the conglomerate (crystals of separated enantiomers) becomes more stable than the racemic compound at approximately 0.64 GPa and 460 K. Even though this pressure is still higher than at the bottom of the Mariana Trench, there are no technical obstacles to produce such conditions, making pressure a viable option for separating enantiomers.

Homo- and Heterochiral Aggregations of Samarium(III) Complexes with Acetate and Tripod Ligand Containing Three Imidazole Groups

Abstract Three SmIII complexes with tripod heptadentate N7 ligands containing three imidazole groups, [Sm(H3L2-Me)(ac)](ClO4)2·2MeOH·H2O (1), [Sm(H3L2-Me)(ac)](ClO4)2·2EtOH (2), and [Sm(H3L4-Me)(ac)](ClO4)2·MeOH (3), were synthesized and the crystal structures were determined, where H3L2-Me and H3L4-Me are the 1:3 condensation products of tris(2-aminoethyl)amine and either 2-methyl-4-formylimidazole and 4-methyl-5-formylimidazole, respectively, and ac denotes acetate ion. Each SmIII ion is coordinated by a tripod heptadentate N7 ligand and two oxygen atoms of the acetate ion. Due to the screw coordination arrangement of the achiral tripod ligand to the SmIII ion, the complex-cation [SmIII(H3L2- or 4-Me)(ac)]2+ gives Δ- and Λ-enantiomorphs. In compounds 1 and 2, two adjacent [Sm(H3L2-Me)(ac)]2+ species with the same chirality are linked by an intermolecular imidazole···acetate hydrogen bond to form a homochiral 1D chain structure. Adjacent chains with the same chirality are stacked to give a conglomerate crystal in 1, while adjacent chains with opposite chiralities are stacked to give a racemic crystal in 2. In compound 3, two adjacent [Sm(H3L4-Me)(ac)]2+ species with the opposite chiralities are doubly bridged by two intermolecular imidazole···acetate hydrogen bonds to form a heterochiral dimer and the adjacent dimers are connected by ClO4− ion through the hydrogen bonds to form a racemic crystal.

Kinetics and Thermodynamics of Efficient Chiral Symmetry Breaking in Nearly Racemic Mixtures of Conglomerate Crystals

The remarkable evolution of homochirality in Viedma-type conversions, which typically start from racemic or nearly racemic mixtures of d and l conglomerate crystals, is examined using dispersive kinetic models. One such model for nucleation rate-limited phase transformations is found to describe well the sigmoidal (“S”-shaped) conversion transients of those processes better than both the classical first-order (simple exponential) mechanism proposed in the current literature and the JMAEK (“Avrami”) equation traditionally used to model nucleation-and-growth processes. That finding is discussed in light of the secondary nucleation observed in similar, Kondepudi-type conversions as well as the recently proposed mechanisms of attrition-enhanced Ostwald ripening and solution phase racemization.