Viedma Ripening and Temperature Cycling: Two Robust Deracemization Methods

  • Webinar
  • 19 March 2020, Online

About the webinar

Routes to enantiomerically pure compounds starting from racemic mixtures of chiral molecules are of paramount importance, especially for the pharmaceutical industry as pharmaceutical products often must be registered in enantiomerically pure form. Also, in the agrochemical industry, in case a chiral product is more active in one of the enantiomeric forms, an enantiomerically pure form can reduce the amount of pesticides needed for crop protection. In this light, crystallization offers an attractive method for the separation of chiral molecules. Although the difference in solubility of diastereomeric salts is commonly exploited for that, for racemic conglomerate forming compounds there are also techniques to obtain crystals of single chirality by preferential crystallization using seeding or tailor-made additives. Although the enantiomeric excess values obtained with these techniques can be quite high, the yield is limited to 50% at most. 

In the group from Radboud University Nijmegen, The Netherlands, we developed a technique, based on seminal work by Cristobal Viedma, who used intense grinding of a slurry of racemic conglomerate crystals of (achiral) NaClO3 in contact with the saturated solution, to arrive at the surprising result of a complete conversion of the solids to one of the two enantiomorphs. Wim Noorduin, in our group, extended the method to chiral molecules by adding a racemization reaction in the solution, to deracemize a racemic mixture of a chiral compound, leading to an enantiomeric excess of 100 % and a quantitative yield in the solid phase. The method can be easily scaled up using industrial mills. The mechanism behind this process is the competition between crystal growth as a result of Ostwald ripening and secondary nucleation due to abrasive grinding in the slurry.

More recently an alternative method was developed in the groups of Gérard Coquerel and Adrian Flood, for which the grinding is replaced by simply cycling the slurry between two temperatures.

For both methods the enantiomeric excess in the solids increases in time with an auto-amplifying trend, offering a robust method because nucleation of the counter enantiomer is avoided by the very low supersaturations applied in the methods.

In this webinar, were discussed the pros and cons of these methods, discussing in particular how to speed up the deracemization process, ways to apply it also to chiral molecules forming racemic compounds and combining  the method with synthesis reactions to arrive at a one-pot production of enantiomerically pure crystals starting from achiral reactants.


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