28 November 2009

Grinding Induced Attrition

Angewandte has just published a mini-review, "From Ostwald Ripening to Single Chirality" which explains that,

"Ostwald ripening, is thought to be involved in a recently discovered method in which grinding-induced attrition is used to transform racemic conglomerates virtually quantitatively into a single enantiomer."

The process is illustrated by mixing the conglomerate racemate solid with sufficient solvent to partly dissolve it, with glass beads, a racemisation agent and a chiral seed. Presumably the conditions are such that the chiral seeds grow larger by inducing further crystallisation from that particular enantiomer. The solution is maintained as a racemic mixture by the racemisation agent while the racemic solid will dissolve in preference to the chiral solid since it has a greater solubility due to conglomerate nature of the species. The attrition aspect will be necessary in order to ensure that there are a constant supply of chiral seeds within the system (Attrition-Enhanced Deracemization in the Synthesis of Clopidogrel - A Practical Application of a New Discovery).

The method is illustrated in the diagram, below ...

Diagram from Chiral Separation.

Also, see Complete Deracemization by Attrition-Enhanced Ostwald Ripening Elucidated.

The technique looks to be a more sophisticated form of resolution by entrainment as described in "Enantiomers, Racemates, and Resolutions" by Jaques, Collet and Wilen p 223, which explains that the process was first described in 1886 by Genez, a student of Pasteur. He wrote in a letter to Pasteur,

"I have observed that a supersaturated solution of levorotatory double salt sodium ammonium tartrate does not crystallize in the presence of a fragment of this salt which is hemihedric in the dextrorotatory sense; and vice versa, the supersaturated solution of the dextrorotatory salt yields no crystals when seeded with the levorotatory salt.

This fact led me to study the inactive solution of the double salt sodium ammonium racemate. I prepared a solution of this salt from the racemic acid. ... When seeded by a particle of dextrorotatory salt, it yielded only dextrorotatory crystals. A portion of the the same liquid in contact of levorotatory crystal produced a deposit of levorotatory salt. Here then is a simple means for separating at will one or the other of the two salts which constitute the double salt sodium ammonium racemate.

Over one hundred and forty years later ... we have an improved process.

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