Decoding Hierarchical Crystal Packing in Phenprocoumon and Related 4-Hydroxycoumarins

Abstract

Polymorphism in flexible molecular systems arises from the interplay between molecular conformation, strong intermolecular interactions, and crystal packing. Here, a combined experimental and computational study of RS-phenprocoumon, encompassing multiple newly characterized solid forms, reveals a hierarchical organization of its crystal structures in which a conserved heterochiral dimer acts as a persistent supramolecular construct, while structural diversity emerges at successive higher levels. At the one-dimensional level, the orientation of the enolic OH group governs hydrogen-bond propagation symmetry and consequently the chirality of the resulting β-chains. At the two-dimensional level, alternative relative arrangements of equivalent β-chains generate the distinct packing organizations observed experimentally. Crystal structure prediction (CSP) identifies all experimentally observed polymorphs as low-energy structures on the landscape, which is populated by a remarkably limited set of recurrent conformational and packing symmetry combinations. Comparison with related 4-hydroxycoumarin derivatives in the Cambridge Structural Database shows that the same hierarchical structural relationships extend beyond RS-phenprocoumon and consistently describe crystal packing across the scaffold. Together, these results suggest that the crystal energy landscape of RS-phenprocoumon can provide useful insights into the solid-state behavior of structurally related compounds, providing a framework for understanding packing preferences across the 3-substituted 4-hydroxycoumarin scaffold.