Expanding the Structural Portfolio of Hydantoin Derivatives with Spiro Frameworks Bearing π-Functionalities

The hydantoin ring is a key structural feature in many pharmaceutically active compounds and blockbuster drugs, especially those targeting disorders of the central nervous system. In an effort to expand the molecular diversity of hydrophobic hydantoin derivatives, we synthesized a series of compounds in which the hydantoin ring is tethered to a tetralin unit in a spiro fashion, followed by the introduction of a 4-substituted benzyl group (X = H, Cl, NO2, or CN). These compounds exhibit not only a diversity in conformational flexibility but also sufficient variation in intermolecular interactions to rationalize the relationship between the molecular and crystal structures. This allowed us to evaluate effects of attaching the hydantoin ring to different positions of the tetralin ring system, as well as the number and substitution of the benzyl group on the molecular conformation and the crystal packing. The resulting crystal structures are dominated by hydrogen bonding motifs, forming either discrete R22(8) ring dimers or infinite chains. However, medium to weak interactions are decisive in constructing continuous supramolecular architectures. Even in the situation when there are no strong hydrogen bonds due to the introduction of an additional 4-chlorobenzyl group, these interactions lead to interesting assemblies. Advanced computational methods were employed to evaluate interaction energies, while molecular electrostatic potential (MEP) surfaces were used to elucidate the hierarchy and competition of hydrogen bonds involving different acceptor sites. These insights are valuable for understanding the design principles underlying supramolecular assemblies of potential pharmaceutical relevance.