Deracemization Controlled by Reaction-Induced Nucleation: Viedma Ripening as a Safety Catch for Total Spontaneous Resolution

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. 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 3 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 ...

Section: Discussionmentioning

confidence: 99%

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

Xiouras

Horst

Gerven

et al. 2017

“…1 Crystallization is an efficient way to achieve chiral purification because the crystalline phase can induce a high level of chiral selectivity during crystal growth. [2][3][4][5][6][7] Viedma ripening in particular enables easy, fast and complete deracemization of chiral crystals. [8][9][10] During Viedma ripening, a suspension consisting of conglomerate crystals of both chiral forms is continuously ground.…”

Section: Introductionmentioning

confidence: 99%

Scaling Up Temperature Cycling-Induced Deracemization by Suppressing Nonstereoselective Processes

Steendam

Horst

2018

Self Cite

The scale-up of Temperature Cycling Induced Deracemization (TCID) of sodium bromate is feasible provided that two non-stereoselective processes are suppressed. Both nonstereoselective processes occur as a result of insufficient crystal breakage or attrition. In the absence of crystal breakage or attrition during the temperature cycles, large crystals emerge and the resulting small total crystal surface area is unable to sufficiently consume the supersaturation during cooling, resulting in non-stereoselective nucleation. This nonstereoselective process can be avoided by applying small temperature cycles involving small dissolving solid fractions. However, this leads to a slow deracemization rate. In addition, crystals undergo non-stereoselective agglomeration, which leads to the formation of large racemic agglomerates constructed of both chiral forms. To counteract their formation, secondary nucleation through crystal breakage was found to be a key requirement. At a large scale, a homogenizer was used to induce crystal breakage which, in combination with 2 temperature cycles, led to the removal of racemic agglomerates as well as a significant increase in the deracemization rate. Overusing the homogenizer, however, caused the enantiomeric excess increase to stop. Our experiments show the importance of secondary nucleation in TCID of sodium bromate. However, secondary nucleation is currently not incorporated in the TCID process models. In the presence of a sufficient amount of crystals at the highest temperature and careful use of the homogenizer, TCID leads to complete deracemization in volumes up to 1 L, demonstrating the potential to extend TCID to industrial applications.

“…Long processing times also lead to high energy consumption. Several studies have focused on using alternative methods for optimizing or even replacing grinding in the Viedma ripening process, for example using industrial bead mill 18 , spatial temperature variations 11,19 and temporal temperature variations 20,21 . Ultrasound-enhanced grinding can potentially alleviate some of the practical difficulties inherent to the glass bead-enhanced grinding, although proper design of such a system is necessary to overcome the ultrasound intensity decrease when larger volumes are involved.…”

Section: Introductionmentioning

confidence: 99%

Attrition-Enhanced Deracemization of NaClO₃: Comparison between Ultrasonic and Abrasive Grinding

Xiouras

Aeken

Panis

et al. 2015

Ultrasound-enhanced grinding is a more practical alternative to glass bead-enhanced grinding for performing attrition-enhanced deracemization at large scale or in continuous flow. In this work, both ultrasound-enhanced grinding (41.2 kHz) and glass bead-enhanced grinding were applied to induce Viedma deracemization of sodium chlorate (NaClO 3) crystals in isothermal conditions. The results demonstrate that high intensity, low frequency ultrasound can achieve efficient grinding of enantiomorphous NaClO 3 crystals, producing small crystal size and narrow size distribution, both being highly desirable final product properties. Monitoring the width of the crystal size distribution, reveals its crucial role and offers further insight on the underlying phenomena in the deracemization process. Compared to glass bead-enhanced grinding, ultrasound-enhanced grinding resulted in faster crystal size reduction, and rapid initial deracemization. However, further increase in the enantiomeric excess was hindered after prolonged times of ultrasonication. This ensues probably due to the absence of crystal sizeinduced solubility gradients, owing to the existence of close to monodispersed sized crystals after the initial stage in the ultrasound-enhanced grinding process. We show that this can be overcome by combining: a) ultrasound with glass beads, or b) ultrasound with seeding, both of which led to enantiopurity.