Price, Louise S; Price, Sarah L; (2022) Packing Preferences of Chalcones: A Model Conjugated Pharmaceutical Scaffold. Crystal Growth and Design , 22 (3) pp. 1801-1816. 10.1021/acs.cgd.1c01381.

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Abstract

We sought the crystal packing preferences of the chalcone scaffold by analyzing 232 single-component crystal structures of chalcones with a small (six or fewer non-hydrogen atoms) substituent on either or both rings, including the unsubstituted molecule. This covers 216 molecules, as some are polymorphic, and 277 independent molecular conformations, as 16% of the crystal structures have more than one symmetry independent molecule. Quantum mechanical conformational profiles of the unsubstituted molecule and the almost 5000 crystal structures within 20 kJ mol–1 of the global minimum generated in a crystal structure prediction (CSP) study have been used to complement this analysis. Although π conjugation would be expected to favor a planar molecule, there are a significant number of crystal structures containing nonplanar molecules with an approximately 50° angle between the aromatic rings. The relative orientations of the molecules in the inversion-related dimers and translation-related dimers in the experimental crystal structures show the same trends as in the CSP-generated structures for the unsubstituted molecule, allowing for the substituent making the side-to-side distances larger. There is no type of dimer geometry associated with particularly favorable lattice energies for the chalcone core. Less than a third of the experimental structures show a face-to-face contact associated with π···π stacking. Analysis of the experimental crystal structures with XPac and Mercury finds various pairs of isostructural crystals, but the largest isostructural set had only 15 structures, with all substituents (mainly halogens) in the para position. The most common one-dimensional motif, found in half of the experimental crystal structures, is a translation-related side-to-side packing, which can be adopted by all the observed conformations. This close-packed motif can be adopted by chalcones with a particularly wide variety of substituents as the substituents are at the periphery. Thus, although the crystal structures of the substituted chalcones show thermodynamically plausible packings of the chalcone scaffold, there is little evidence for any crystal engineering principle of preferred chalcone scaffold packing beyond close packing of the specific molecule.

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