Preferential Enrichment of DL‐Leucine Using Cocrystal Formation With Oxalic Acid Under Nonequilibrium Crystallization Conditions

Abstract

By utilizing the preferential enrichment (PE) technique, we achieved an improved enantiomeric resolution of DL-leucine (Leu) using a 1:1 cocrystal (DL-) of DL-Leu and oxalic acid. The crystal structure analysis of DL- indicated the occurrence of a novel type of phase transition and subsequent preferential redissolution of one enantiomer from the resulting crystals into solution.

A Kinetic/Thermodynamic Origin of Regular Chiral Fluctuation or Symmetry Breaking Unique to Preferential Enrichment

“…[12] Since the discovery of the first compound showingP E, [9] more than twenty analogousf irstgeneration chiral organic compounds including 1-5 were found to exhibit the same PE phenomenon ( Figure 2). [10] Furthermore, quite recently,i th as been revealedt hat PE is applicable to two amino acids (alanine and leucine), [13] the twocomponent cocrystalo fdl-phenylalanine [14] or dl-arginine [15] with fumaric acid, the cocrystal of leucine with oxalic acid, [16] and ketoprofen, [17] which are classifieda saconventional "racemic compound" crystal composed of ar egular packing of pairs of R and S enantiomers or a" racemicm ixed crystal (solid solu- Figure 1. Features of preferential enrichment (PE) of aracemic crystal in case of substantial enrichment of the (+ +)-enantiomer in the mother liquor after the first recrystallizationo fc hiral racemic organic compounds including 1-5. tion)" of ar andom alignment of two enantiomers in the crystals.…”

In Situ Observation of Polymorphic Transition during Crystallization of Organic Compounds Showing Preferential Enrichment By Means Of Temperature-Controlled Video-Microscopy and Time-Resolved X-ray Powder Diffraction

“…[5][6][7][8][9][10] Thus, the mechanism of PE has been interpreted in terms of a nonlinear complexity phenomenon including two unique processes: a solvent assisted solid-to-solid polymorphic transition and subsequent selective redissolution into the mother liquor of the excess one enantiomer from the transformed disordered crystals. [11][12][13][14][15][16][17][18][19][20][21] With respect to the second process, the kinetic and thermodynamic origin has been unveiled in terms of the unique nonlinear solubility properties of the two enantiomers after the occurrence of polymorphic transition under PE crystallization conditions using high supersaturation, together with the ternary phase diagram that is consistent with the mechanism of PE. 22,23 As to the first process, we have judged the occurrence of polymorphic transition during crystallization indirectly by the in situ ATR-FTIR spectroscopy which can detect a change in the hydrogen bonding mode in small particles (< ca.…”

“…By comparing the IR spectrum just before crystallization with that after crystallization, we predicted the occurrence of polymorphic transition. [11][12][13][14][15][16][17][18][19][20][21] However, some compounds showing an excellent PE phenomenon failed to give an appreciable IR spectral change during crystallization, due most likely to a small change in the hydrogen bonding mode upon the polymorphic transition. Therefore, the use of other in situ techniques to observe polymorphic transition directly during crystallization was indispensable.…”

Separation of Chiral Compounds: Enantiomeric and Diastereomeric Mixtures

“…A possible mechanism of the recrystallization of racemate-type enantiomeric mixtures is described by Tamura [24][25][26][27][28].…”