Selective Crystallization of Racemic Polymorph via Native Enantiomer Inhibition: dl-Methionine

Crystallization of chiral compounds is dictated by chiral recognition and molecular self-assembly in solution. However, their interplay remains elusive. The reason for the considerably reduced polymorphism in chiral molecules than that of nonchiral molecules remains unclear. Herein, we use a combination of experimental and computational techniques to show that excessive enantiomer functioning, as a native crystallization inhibitor, selectively suppresses the crystallization of racemic polymorphs, affording preferential crystallization of the metastable α polymorph of dl-methionine. Bulk crystallization assays show concomitant crystallization of the α and β polymorphs of racemic dl-methionine in the solution with no enantiomeric excess. However, when the solution contains excessive d-/l-methionine enantiomer, only the metastable α form can be crystallized. Crystal growth experiments, fluoresce confocal microscopy, and atomic force microscope surface topology measurements reveal the growth inhibition of both polymorphs with preferential suppression of the β form by excess native enantiomer. Binding energy calculations and molecular dynamic simulations further demonstrate the preferential adsorption of excessive enantiomers on the (0 0 2) facet of the β form over the α form. Overall, our results uncover a unique chiral self-positioning mechanism where the excess enantiomer solutes serve as a native growth inhibitor to disrupt the kinetics of racemic polymorphic crystallization, affording selective crystallization of only one polymorph of dl-methionine. Our results highlight the important effect of excess enantiomer in a solution on the polymorph occurrence of chiral molecules.