Tuning organic crystal chirality by enantiomer-specific oriented attachment†

Jingren Li^ab, Yanbo Liu^ab, Zhiqiang Guo^c, Dandan Han*^ab and Junbo Gong^ab
aSchool of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin, 300072, P. R. China. E-mail: handandan@tju.edu.cn
^bHaihe Laboratory of Sustainable Chemical Transformations, Tianjin, 300192, P.R. China
^cJewim Pharmaceutical (Shandong) Co., Ltd., Shandong, 271000, P.R. China

First published on 6th August 2024

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Introduction

Chirality is a constant topic and the fundamental property of nature. A typical example is the presence of symmetry breaking in living organisms, mainly L-amino acids and D-sugars.¹ For chiral compounds, different configurations generally have different physiological and pharmacological functions, some enantiomers are even harmful to humans, so the preparation of pure chiral substances (i.e., single enantiomers) has always been a thriving area of chemical research in today's chemical and pharmaceutical industries.^2–4 For the separation and purification of chiral molecules, there are various methods including chiral chromatography, kinetic resolution of racemates, chiral pool synthesis, chiral asymmetric synthesis, and chiral symmetry breaking in solution crystallization and the latest dynamic crystal bounce applied to chiral separation,^5–10 among which the most practical and simple process is solution crystallization, which has been widely used in the chiral separation of various crystal products and materials. In addition, unlike conventional crystallization, since Viedma's first preparation of the single enantiomer of sodium chlorate by frictional de-racemization of glass beads (Viedma ripening),¹¹ spontaneous separation of achiral molecules and conglomerates has become an effective and promising approach for enantiomer purification and chiral amplification.^12–14 During Viedma ripening, what can be viewed as a friction-induced Gibbs–Thomson effect leads to an increase in the solubility of the crystals, which in turn achieves enantiomer-specific oriented attachment under the dual effect of Ostwald ripening and recognition of identical chiral aggregates, thus leads to the amplification of the homochiral crystal cluster.^15–20 This non-classical chiral separation is an unprecedented technique that can greatly expand the field of chiral separation.

An early non-classical crystallization route was proposed by Liesegang in 1911, suggesting that crystal growth may not only occur by Ostwald ripening (i.e., smaller crystals in solution dissolve into individual molecules to be used as feedstock for larger crystals to grow), but also involves larger-scale crystal aggregation, where two or more small, undissolved crystals in solution are adhered to a larger crystal through the adhesion surface of intermediary dissolved material.²¹ This nonclassical crystallization of nano- or micrometers through oriented attachment to form single-crystal aggregates has been extensively studied over the last two decades,^22–26 and what was then known as oriented attachment (OA). In 2013, Cristóbal Viedma extended this concept to the crystallization process of chiral crystals, transferring it from the micro- and nanoscale to the mesoscale.²⁷ Using NaBrO₃ and NaClO₃ as models for the study, a large number of very small mixed racemic crystals suspended in their respective saturated solutions were boiling or shaking under heat, respectively, and the crystals eventually formed dozens of large aggregates through dissolution and aggregation. Most of these aggregates exhibit chiral symmetry breaking by optical examination (aggregates held between polarization filters uncrossed by a few degrees in opposite directions), even to the extent of pure chirality of a single enantiomer. Under the scanning electron microscope (SEM), it can be clearly observed that the aggregates are formed by the adhesion of individual crystals, confirming the formation of enantiomer-specific oriented attachment. It is noteworthy that for threonine, a conglomerate whose own molecule carries chirality, the aggregates macroscopically displays left- and right-handed helical textures. Subsequently in 2016, Sivakumar subjected the guanidine carbonate aggregates obtained from boiling and shaking experiments to SEM tests and observed that the single crystals in the aggregates were exposed with the (0 0 1) and (0 1 2) crystal faces relatively parallel to each other and detected chiral enrichment of the aggregates by constructing standard curves of circular dichroism spectra in specific bands, which strongly supporting the hypothesis of the enantiomer-specific oriented attachment.²⁸ In the same year, Viedma also reported on the directional attachment of gypsum crystals (CaSO₄·2H₂O) in the presence of stirring. Gypsum crystals can be formed from millimeter-scale needle crystals adhering to larger-scale aggregates by directional attachment in orthorhombic orientation. Observations by crossed polarizers show that all aggregates formed with orthogonal orientation have almost the same optical phenomena, indicating homochiral aggregation. It is also found that the attachment of these aggregates has a distinctive feature: the crystals of the same chirality are basically attached in the (−1 1 1) face, while the crystals of opposite chirality are attached in the (0 1 0) face.²⁹ In recent years, research on oriented attachment has continued. In 2021, Wan et al. were able to select the preferred formation of a single enantiomer directly from the racemic solutions by introducing a customized polymer additive, and caused the enantiomer to undergo oriented attachment to form macroscopic aggregates with helical structures. This polymer additive-induced strategy not only switches the chirality on both chiral molecular and macroscopic levels, but also expands the extended racemate. This serves as a meaningful guide for the construction of multilevel structural materials with a single chirality as well as for chiral identification.³⁰

Here, we report in detail the ESOA of N-benzoylglycine crystals (Fig. S1†) that occurs during boiling experiments, resulting in the formation of large aggregates, based on our existing research experience. Similarly, N-benzoylglycine is a achiral molecule and can form chiral conglomerate crystals in the P2₁2₁2₁ chiral space group,^14,31,32 which makes it possible for the chiral separated by frictional de-racemization, as is the case for sodium chlorate, sodium bromate and guanidine carbonate. As for the conglomerates, ESOA is currently only achieved in DL-threonine, and in order to verify the stability of this mechanism, we used the racemic N-succinopyridine (Fig. S2†) synthesized from maleic acid and pyridine via the aza-Michael addition reaction as a model substance for boiling experiments. N-succinopyridine crystallizes as a conglomerate in the chiral space group of P2₁2₁2₁,^33,34 and is a derivative of aspartic acid, which can be converted to aspartic acid,³⁵ as well as being a useful second-order nonlinear optical material.³⁶ In addition, we also make a final attempt to explore the application of the ESOA method to racemic compounds systems (namely, isoleucine, leucine, and valine (Fig. S3†)).

Results and discussion

Achiral molecules

The chiral analysis of N-benzoylglycine crystals can be performed by solid-state circular dichroism. Pure N-benzoylglycine enantiomers can be prepared by Viedma ripening. The two different enantiomers have (+) CD signal and (−) CD signal by circular dichroism detection (Fig. 1a), respectively. During Viedma ripening, the enantiomeric excess of the solids in the slurry increased as time continued, and samples were taken at 12-hour intervals until the peaks of the CD signals were almost constant on two adjacent occasions, so that we considered that pure N-benzoylglycine enantiomers were obtained by Viedma ripening. Samples with enantiomeric excess changes were prepared by mixing appropriate proportions of levo- and dextro-crystallized powders while keeping the total weight constant. The CD signals of these samples at the specified wavelengths were subsequently measured (Fig. 1b), and the peaks were plotted against the enantiomeric excess of the standards to generate a calibration curve (Fig. 1c). Multiple replicate preparations of each standard were used to measure the average CD signal with the standard deviation determined. After the calibration curve is constructed, the enantiomeric excess (% ee) of the different crystal aggregates can be determined from the CD signal at the specified wavelength.

Once a calibration curve was available, boiling experiments on N-benzoylglycine crystals in saturated solution were initiated to investigate enantiomer-specific oriented attachment. By boiling a conglomerate of many small N-benzoylglycines suspended in saturated aqueous solution at 180 °C through a round-bottomed flask, the tendency to form aggregates began after 6–10 h, and larger aggregates were formed after 20–24 h. This is because the crystals would first grow through Ostwald ripening, and only when they have grown to a suitable size will they begin to aggregate to form larger aggregates.²⁷ The appearance and morphology of all the aggregates is spherical or elliptical, and a few undeveloped crystal aggregates are irregularly flattened (Fig. 2).^27,28

The chiral purity of the aggregates was determined by solid circular dichroism after grinding them. Two sets of experiments, 8 hours and 24 hours, were selected and 20 chiral aggregates were detected in each set of experiments, of which 12 (−) aggregates and 8 (+) aggregates were detected (Fig. 1d). From the assay results, the enantiomeric excess was higher than the starting commercial grade material (commercial grade N-benzoylglycine is powdered crystals with an enantiomeric excess of 10% [CD(−)260 nm]), both for the 8-hour just-beginning aggregates and for the 24-hour fully-formed aggregates. More intuitively, the symmetry breaking of the fully formed aggregates is greater with time, and some aggregates are even able to reach full monochiral purity.

Previous hypotheses on enantiomer-specific oriented attachment suggest that the aggregation of individual crystals into aggregates is a result of the linkage of certain specific crystallographic surfaces, while that the unconnected crystallographic surfaces appear nearly parallel to each other in the aggregates, and these have been confirmed in both NaBrO₃ and guanidine carbonate. Here the N-benzoylglycine aggregates were analyzed by scanning electron microscopy (Fig. 3a), indicating the exposed unconnected crystal faces in the aggregates do remain relatively parallel to some extent (Fig. 3b), which strongly supports the hypothesis about the enantiomer-specific oriented attachment of N-benzoylglycine.

Conglomerates

After the synthesis of N-succinopyridine (Fig. S4†), its single crystals were obtained from saturated aqueous solution by slow evaporation of water vapor. With the aid of a stereomicroscope, we were able to clearly observe the single crystals of two different enantiomers (Fig. S5†). Immediately by circular dichroism detection, two single crystal powders with different chirality were detected by circular dichroism spectroscopy with the (+) CD signal and (−) CD signal (Fig. 4a), and the spectra were approximately symmetric in appearance. This suggests that we were able to determine the enantiomeric excess of N-succinopyridine roughly by circular dichroism spectroscopy.

In the same manner, N-succinopyridine crystals in saturated aqueous solution were subjected to boiling experiments in a round-bottomed flask. The target temperature was set at 160 °C (Fig. S6†), and huge aggregates of crystals formed at the bottom of the flask after about 15–24 hours. These aggregates appeared as large irregular flakes, and careful observation showed that one side of the aggregates had a smooth appearance, while the other side had a rough surface with uneven heights, which seemed to be able to continue to grow by adsorption (Fig. 4b). The images acquired by SEM show that the smooth side of the crystal is adsorbed through specific crystal faces, weaving a network of crystals parallel to each other, and then randomly adsorbing crystals on the other side of the cluster through specific faces, which results in the gradual growth of the cluster to become larger and thicker (Fig. 4c and d). This suggests that the formation of aggregates may be a step-by-step process, in which a certain number of crystals first oriented attachment to shape the crystal aggregates, and then the rest of the crystals grow on the basis of this morphology. We also observed that there are many small crystal connections between the large crystals, and these cluster connection bridges can be clearly seen as layers of flocculent by magnification (Fig. 4e and f). These flocculent crystal defects may be the ones that play an important role in enantiomer-specific oriented attachment. Finally, we examined the chiral purity of the chiral aggregates, and the enantiomeric excess of the aggregates could reach about 75% ee, which is consistent with the chiral amplification of DL-threonine.²⁷

For the ESOA of achiral molecules and conglomerates, we can summarize that crystals of different sizes are boiled in their saturated aqueous solutions, where Ostwald ripening occurs on one side and aggregation between crystals takes place on the other side, resulting in the formation of aggregates. The difference between the two types of molecules is only that achiral molecules undergo “chiral amnesia” during solid–liquid equilibration (Fig. 5).³⁷ After the success of experiments with N-benzoylglycine and N-succinopyridine, model substances with melting points higher than the temperature capable of causing water to boil at atmospheric pressure, we then try to use this method to experiment on racemic compounds.

Racemic compounds

Viedma ripening and temperature cycling have been shown to be promising methods for chiral de-racemization over the past two decades,^1,11,38–41 but for the most part are only applicable to the system of conglomerates. Whereas in nature about less than 10% of chiral compounds crystallize to form conglomerates, and about 90% of chiral molecules form racemic compounds, even for the twenty amino acids that constitute the most fundamental part of life, only two are capable of forming conglomerates (asparagine and threonine).⁴² Therefore, there is an exact need to devise separation methods to apply to racemic compounds. Here, we set out to explore whether the ESOA method can be applied to racemic compounds.

We chose three branched-chain amino acids, isoleucine, leucine and valine. This is because in 2020, Viedma demonstrated that mechanochemical milling in the presence of Zn or ZnO causes the conversion of isoleucine, leucine, and valine from racemic compounds to conglomerates.⁴³ This is in line with the conditions of our aforementioned experiments to realize the chiral enrichment of ESOA. In view of this, we set out to see if we could achieve enantiomer-specific oriented attachment based on the addition of ZnO.

Take isoleucine as an example, DL-isoleucine and a certain amount of ZnO powder were added to a flask, and then the volume ratio of 60% ethanol aqueous solution (V_EtOH:V_Water = 3:2) is added, so that the solid powder existed in the form of suspension. Afterwards, the temperature was raised to 120 °C, accompanied by condensation reflux during the heating process. In the experiment, the solid powders were able to mix well in the boiling state. In this system, around 6 hours, it is clearly noticed that large particles of aggregates are formed in the flask (Fig. 6). After removing the aggregates again for rinsing and drying, they were tested for powder XRD diffraction (PXRD), and from the results (Fig. 7a), the XRD diffraction peaks of the aggregates were quite deviated from those of DL-isoleucine, but consistent with those of L-isoleucine. This indicates that the isoleucine molecule has changed inside the crystal cell. In order to be more certain whether symmetry breaking had occurred in DL-isoleucine, we dissolved the aggregates in water after grinding them and examined them by liquid chromatography. Unfortunately, according to the results of liquid chromatography, the cluster did not undergo chiral enrichment, and L-isoleucine and D-isoleucine still existed in the form of 1:1 (Fig. 7b), but only transformed from the original racemic compounds to conglomerates under the action of ZnO, that is, the interactions between the heterochiral crystals were weakened while the homochiral crystals were adsorbed onto each other, and the independent crystal aggregates of D and L were formed on the ZnO, respectively. Since DL-isoleucine has been transformed into a conglomerate, another attempt was made to split it into pure enantiomers by adding crystal seeds of L-isoleucine during the experiments, which was detected by liquid chromatography, and even though DL-isoleucine: L-isoleucine = 2:1 (ee = 33.33%), the final ee of the aggregates was only 5–8%. This indicates that most of the L-isoleucine is dissolved in solution, while only a small portion is adsorbed onto the DL-isoleucine aggregates. All indications are that ZnO somehow has an extremely strong stabilizing effect on the conglomerate form of DL-isoleucine. Leucine and valine also showed the same phenomenon (Fig. S7–S9†).

Regarding the verification of ZnO's ability to stabilize the conversion of DL-isoleucine to conglomerate, thermodynamic properties were analyzed by thermogravimetric analyses (TGA) and differential scanning calorimeter (DSC). From the analysis of both results, the cluster formed by L-isoleucine and ZnO started to decompose at a temperature of 319.17 K, which is much higher than the decomposition temperatures of DL-isoleucine and L-isoleucine (Fig. 7c), and the melting point of the cluster as measured by the DSC of 328.83 K is also higher than that of the other two substances (Fig. 7d), which proves that ZnO can indeed play a role in the conglomerate of DL-isoleucine. It is no wonder that even the addition of excessive amounts of L-isoleucine crystal seeds did not achieve the symmetry breaking, as was the case for DL-leucine and DL-valine (Fig. S10†). The most stable form of these amino acids in nature is racemic, which is surprising. For the formation of racemic compounds, the interaction between heterochiral molecules are greater than between homochirals, but there may also be competition between the two.⁴⁴ During the boiling stage, as the saturated solution evaporates and condenses, the amino acid undergoes homochiral reorganization through sublimation crystallization, resulting in a degree of separation of L and D. This was previously demonstrated by Viedma's conversion of valine to a conglomerate through high temperature sublimation.⁴⁵ This homochiral recombination of sublimation is similar to enantiomer-specific oriented attachment. In solution, ZnO may provide some active sites for L or D amino acid fragmentation while preventing heterochiral interactions, preserving this unstable structure, but this is only our initial guess and there is no clear evidence to confirm this conclusion.⁴⁶ Overall, at this stage, we built on Viedma's work,⁴² which enabled the conversion of the three total racemic compounds of amino acids mentioned above into conglomerates by means of ESOA method (Fig. 8). This approach is able to process these amino acid in large quantities, and is expected to be useful in the future for other specific complex chiral drugs. Moreover, the formed conglomerates counter-confirm that most of the conditions for the success of ESOA are that the chiral substrates are conglomerates, except that the existing regrets are still not able to separate the formed conglomerates. Meanwhile, because ZnO has a strong stabilizing effect on the formation of conglomerate of three amino acids, and ZnO is an amphoteric oxide, the commonly used acid-catalyzed or base-catalyzed racemization methods cannot be applied, so even if we want to enhance the process by means of racemization, it is still very difficult to do so.

Conclusions

Overall, we clearly validate the application of ESOA in chiral separation. In this case, for achiral molecules, we chose N-benzoylglycine, which is soluble in water and has a high melting point, and boiling in saturated aqueous solution enabled the formation of large aggregates of particles and quantified the degree of N-benzoylglycine attachment using circular dichroism. Experiments show that the chirality purity of the aggregates is closer to that of pure products with the increase of boiling time at constant temperature. For the conglomerate, experiments were carried out on the racemic N-succinopyridine synthesized by the aza-Michael addition reaction, and the SEM morphology of the resulting large flake-like aggregates was analyzed by SEM image collection, and it is reasonable to assume that the aggregates proceeded in divisions of formation, that is, the crystals were oriented to attach first to form a smooth crystal network with crystals relatively parallel to each other. Subsequently, the cluster is thickened by different degrees of re-attachment on the other side. The chirality of the formed aggregates is also amplified to a certain extent. For the first two types of chiral substances, although the ESOA mechanism is not able to guarantee that each cluster will become completely monochiral, it is still worthwhile to recognize the advantage of a large chiral enrichment of the crystals in only a small amount of time. We hereby hope that more cases of enantiomer-specific oriented attachment of achiral molecules and conglomerates will be reported in the future.

Turn the attention to racemic compounds, it appears that by ESOA we have discovered a method capable of preparing conglomerates of DL-isoleucine, DL-leucine, and DL-valine on a large scale, something that Viedma had previously hoped to investigate further in his related studies.⁴³ Although we attempted to enhance the process by means of adding pure enantiomeric crystal seeds as well as increasing the racemization agent, we were ultimately unsuccessful. However, from the results of this experiment, it is more than certain that most of the conditions for the success of the ESOA mechanism are that the chiral substrate is a conglomerate. Although there is a lot of regret, we are still optimistic and believe that in the future, if we can find a substance like ZnO, which can make the racemic compounds into conglomerates and at the same time be acidic or basic, then we believe that with the powerful effect of the ESOA method, we will be able to obtain a pure single chirality. This is the next step for us to carry out in detail.

Data availability

The data will be made available on request.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the Major Science and Technology Project of Hebei Province (22282801Z), National Natural Science Foundation of China Youth Foundation (22208236), Natural Science Foundation of Shandong (ZR202105230005) and the financial support of Haihe Laboratory of Sustainable Chemical Transformations.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4ce00546e

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