Conformational polymorphism in organic crystals

Abstract

Polymorphs are different crystalline modifications of the same chemical substance. When different conformers of the same molecule occur in different crystal forms, the phenomenon is termed conformational polymorphism. Occasionally, more than one conformer is present in the same crystal structure. The influence of molecular conformation changes on the formation and stability of polymorphs is the focus of this Account. X-ray crystal structures of conformational polymorphs were analyzed to understand the interplay of intramolecular (conformer) and intermolecular (lattice) energy in the crystallization and stability of polymorphs. Polymorphic structures stabilized by strong O-H···O/N-H···O hydrogen bonds, weak C-H···O interactions, and close packing were considered. 4,4-Diphenyl-2,5-cyclohexadienone (1) and bis(p-tolyl) ketone p-tosylhydrazone (3) are prototypes of C-H···O and N-H···O hydrogen-bonded structures. Distance-angle scatter plots of O-H···O and C-H···O hydrogen bonds extracted from the Cambridge Structural Database indicate that polymorphs with a larger number of symmetry-independent molecules (high Z') generally have better interactions when compared with the polymorphs with lower Z' values, with the implication that these symmetry-independent molecules have different conformations. Since molecular conformer (E_conf) and crystal lattice (U_latt) energy differences are of the same magnitude in organic crystals (typically <5 kcal mol^-1), situations wherein these two factors compensate or cancel one another are illustrative. Calculation of conformer and lattice energies using Gaussian 03 and Cerius² in 23 recently published polymorph sets shows that a strained conformer (higher E_conf) is stabilized by stronger interactions or better crystal packing (lower U_latt) in two-thirds of the cases, whereas there is no energy balance in the remaining structures. Organic molecules with flexible torsions and low-energy conformers have a greater likelihood of exhibiting polymorphism because (1) different conformations lead to new hydrogen -bonding and close-packing modes and (2) the tradeoff reduces the total energy difference between alternative crystal structures. As a test case, polymorph promiscuity in fuchsones (6) is related to the conformational diversity at the exo-methylene phenyl rings and the small energy difference computed for dimethyl fuchsone polymorphs. These ideas find application in the design of putative pharmaceutical polymorphs and crystal structure prediction.