Abstract
Mandelic acids are prototypic chiral molecules where the sensitivity of crystallized forms (enantiopure/racemic compound/polymorphs) to both conditions and substituents provides a new insight into the factors that may allow chiral separation by crystallization. The determination of a significant number of single crystal structures allows the analysis of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There are some common phenyl packing motifs between some groups of racemic and enantiopure structures, although they show very different hydrogen-bonding motifs. The computed crystal energy landscape of 3-chloromandelic acid, which has at least two enantiopure and three racemic crystal polymorphs, reveals that there are many more possible structures, some of which are predicted to be thermodynamically more favorable as well as slightly denser than the known forms. Simulations of mandelic acid dimers in isolation, water, and toluene do not differentiate between racemic and enantiopure dimers and also suggest that the phenyl ring interactions play a major role in the crystallization mechanism. The observed crystallization behavior of mandelic acids does not correspond to any simple "crystal engineering rules" as there is a range of thermodynamically feasible structures with no distinction between the enantiopure and racemic forms. Nucleation and crystallization appear to be determined by the kinetics of crystal growth with a statistical bias, but the diversity of the mandelic acid crystallization behavior demonstrates that the factors that influence the kinetics of crystal nucleation and growth are not yet adequately understood.
Highlights
The chirality of biomolecules and their stereospecific recognition by receptors in the human body is linked to fundamental questions about the origins of life and results in our bodies responding differently to molecules that are mirror images of each other
If the experiments lead to the production of long-lived metastable polymorphs of either the racemic or enantiopure crystals, chiral separation by crystallization runs the risk of the late appearance of a thermodynamically more stable form
We have detailed studies of 3ClMA from the exploration of the binary and ternary phase diagrams[10,14] and characterization by powder X-ray diffraction (PXRD) patterns of two racemic and two enantiopure polymorphs,[14] and our work has identified further polymorphs
Summary
The chirality of biomolecules and their stereospecific recognition by receptors in the human body is linked to fundamental questions about the origins of life and results in our bodies responding differently to molecules that are mirror images of each other. The assumption that crystallization will result in only one racemic compound or two separate enantiopure crystal structures (i.e., a conglomerate) seems unlikely given the extent of observed[5,6] and potential[7] polymorphism (multiple crystal structures containing the same chemical constituents) for organic molecules. If the experiments lead to the production of long-lived metastable polymorphs of either the racemic or enantiopure crystals, chiral separation by crystallization runs the risk of the late appearance of a thermodynamically more stable form. This can lead to loss of control of the physical and physiological properties of the process and Received: June 8, 2015 Published: August 5, 2015
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