Towards understanding intermolecular interactions in hydantoin derivatives: the case of cycloalkane-5-spirohydantoins tethered with a halogenated benzyl moiety

Abstract

A series of cycloalkane-5-spirohydantoins bearing a halogeno substituted benzyl group (X = Cl and Br) in position 3 has been synthesized and their structures (1-6) have been determined by single crystal X-ray diffraction method. These compounds have multiple functional groups, which allow a greater competition and/or cooperation among the different intermolecular interactions in formation of their crystal structures. The molecules are linked together by paired N-H•••O hydrogen bonds in R2 2 (8) rings, while the C-H•••O interactions lead to their further association into double chains. The contribution of the cycloalkyl ring depends on its conformational flexibility and the multiple C-H donor implications. In the case of compounds 1-4 bearing the cyclopentyl or the cyclohexil ring, halogen bonding (X•••O) interactions give rise to a supramolecular pseudo-hexagonal network. In addition, the C-H•••X interactions with a higher degree of multifurcation at the halogen acceptor have an important role in formation of the crystal structure. Regarding compounds 5 and 6 with the cycloheptane ring, the X•••O interaction is absent and, along with the C-H•••X interactions, these compounds realize an alternative crystal structure with emphasis on the X•••π interactions. The lattice energies of all these crystal structures, as well as intermolecular pair energies, have been calculated using PIXEL and further partitioned into coulombic, dispersive, polarization and repulsive factors. The crystal structures have also been subjected to Hirshfeld surface analysis which reveals that approximately 75% of the close contacts correspond to relatively weak interactions. The application of both concepts has provided a new insight into relationships between molecular and crystal structure of the hydantoin derivatives.

Synthesis, structural characterization, DFT calculations and antiproliferative evaluation of novel spirohydantoin derivatives containing a substituted benzyl moiety

“…The selected bond lengths, angles and torsion angles for both compounds are listed in Table 2. The values are similar with analogous bond lengths, angles and torsion angles found in related hydantoin derivatives [22,36,37].…”

“…8), the molecules of 2a are connected into centrosymmetric dimmers parallel to the b-axis. The formation of the centrosymmetric dimmers are not rare for this type of compounds and they are found in similar systems [22,36,37]. The crystal packing of 2a is stabilized by the C-H•••O interactions (Table 3), while additional weak C-H•••π interactions (H•••Cg distance is 2.940 Å) between H16 atom from one phenyl ring and the π-system of the adjacent phenyl ring (Fig.…”

Substituent Effects on the Patterns of Intermolecular Interactions of 3-Alkyl and 3-Cycloalkyl Derivatives of Phenytoin: A Crystallographic and Quantum-Chemical Study

“…The geometric parameters are very close to those of hydantoin derivatives described previously. [32][33][34][35][36] The hydantoin ring is nearly planar. The π-conjugation within the imide fragments results in the length of the N1-C2 and N3-C4 bonds falling in the shortest ones (average 1.34 and 1.37 Å, respectively).…”

Chromatographic and in silico assessment of logP measures for new spirohydantoin derivatives with anticancer activity

“…The intermolecular interactions of halogenated benzyl cycloalkane‐5‐spirohydantoins in crystal form were previously analyzed . In addition, the effect of the substituent on the absorption UV‐Vis spectra of cyclopentanespiro‐5‐hydantoins was studied .…”