Observation of Efficient Preferential Enrichment Phenomenon for a Cocrystal of (dl)-Phenylalanine and Fumaric Acid under Nonequilibrium Crystallization Conditions

Abstract

Described is a new strategy using cocrystallization, one of the crystal engineering techniques, to convert a racemic compound crystal into a racemic mixed crystal which can show preferential enrichment, a symmetry-breaking spontaneous enantiomeric resolution phenomenon observed upon recrystallization of a certain kind of racemic mixed crystal with a fairly ordered arrangement of the two enantiomers under nonequilibrium conditions. The 1:1 cocrystal (2) of (DL)-phenylalanine (Phe) and fumaric acid satisfied the requirements proposed for the occurrence of preferential enrichment, such as (i) a sufficient solubility difference (racemic crystal , enantiomeric crystal), (ii) the occurrence of polymorphic transition during crystallization, and (iii) the deposition of nonracemic mixed crystals with a unique crystal structure, and thus successfully showed preferential enrichment. In contrast, a racemic compound (DL)-Phe itself failed to show a polymorphic transition during crystallization and thereby preferential enrichment. These results indicate that (a) crystal engineering principles based on a high potential of two-component crystals to show a polymorphism and induce a polymorphic transition during crystallization can significantly contribute to the occurrence of preferential enrichment and (b) the proposed requirements described above for the occurrence of preferential enrichment are mandatory.

Highly Efficient Chiral Resolution of dl‐Arginine by Cocrystal Formation Followed by Recrystallization under Preferential‐Enrichment Conditions

“…The crystal structure of the newly synthesized cocrystal dl ‐ 1 (Figure 3 a) is quite different from that of the 1:1 cocrystal of dl ‐phenylalanine and fumaric acid, which showed PE 14. In dl ‐ 1 , unit‐cell‐translated Arg molecules are linked along the b axis by NH ⋅⋅⋅ O hydrogen bonds (N4 ⋅⋅⋅ O1 2.92 Å) to form a homochiral 1D chain.…”

“…This difference can be correlated with the molecular organization in dl ‐ 2 and dl ‐ 3 ; thus, an undesired robust crystal structure without a planar 2D sheet should prevent the selective redissolution of homochiral chains during the crystallization process (3 b, c and Supporting Information Figure S1b, S1c). We emphasize that the first generation of chiral organic compounds10 and other racemic compounds14, 15 that were found to exhibit good to excellent PE all have the space group P ${\bar 1}$ . Thus, the absence of mirror/glide symmetry constraints for the redissolution of the homochiral chains may be important for PE.…”

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

“…On the basis of these experimental results and the elucidated or proposed mechanism of PE with respect to the cocrystals of DL ‐Phe or DL ‐Arg with fumaric acid, the observed PE phenomenon of cocrystal 1 can be interpreted in terms of the following successive processes in the case of a slightly L ‐rich sample: 1) preferential formation of homochiral 1D D and L chains of Leu through the intermediary of oxalic acid in the slightly L ‐rich supersaturated solution, which is similar to Fig. a and 2) direct nucleation (phase transition) from the slightly L ‐rich cluster to give the stable, slightly L ‐rich mixed crystalline phase composed of 2D D and L sheets (Figs.…”

“…3c). Meanwhile, semi-oxalate molecules directly connect with each other by O-H···O hydrogen bond (O3···O6: 2.63Å) forming a 1D chain structure along the a-axis [graph set: C 1 1 (5)] to contribute to the formation of DL-sheet pair structure. This crystal structure is quite different from those of racemic crystals that thus far showed PE; the latter consisted of heterochiral cyclic DL dimer chains as well as homochiral 1D D chains and L chains to form a heterochiral 2D sheet structure.…”

“…Meanwhile, we reported that respective cocrystals of racemic compound DL ‐phenylalanine (Phe) and DL ‐arginine (Arg) with fumaric acid show excellent PE under nonequilibrium crystallization conditions starting from the racemic supersaturated solution (0% ee ), whereas PE is not feasible in the cases of free DL ‐Phe and DL ‐Arg. These results indicate that the two‐component crystal formation based on the crystal engineering principles greatly contribute to produce the requisite molecular arrangement, which can induce appropriate phase transition during crystallization to result in the occurrence of excellent PE.…”