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The present study describes representative examples of supramolecular arrangement of 5-phenylhydantoins achieved through various N–H⋯O hydrogen-bonding patterns. Four derivatives, 5-ethyl-5-(4-methylphenyl)hydantoin (1) and three 5-methyl-5-(3- or 4-substituted phenyl)hydantoins (2–4), were synthesized by the Bucherer–Bergs reaction and their crystal structures were determined by the single crystal X-ray diffraction method. A racemate, racemic hydrate and conglomerate as outcomes of crystallization from racemic solutions were found here. The crystal structures were firstly subjected to Hirshfeld surfaces analysis. The development of hydrogen bonding driven two-dimensional assemblies such as tapes, ribbons and sheets was further analysed using DFT calculations in terms of contribution of dimeric motifs as building blocks, which are associated with the presence of intermolecular interactions. To explore qualitative correlations between intermolecular interactions determining the crystal structures of the investigated compounds and those underlying their biological activity, we performed a docking study on the neuronal voltage gated sodium channels, matrix metalloproteinase 12 and aldose reductase. The supramolecular profiles of the investigated compounds are also maintained in biological systems and as such are responsible for differences in their biological activities. [ABSTRACT FROM AUTHOR]

A racemic spirohydantoin derivative with two aromatic substituents, a tetralin and a 4‐methoxybenzyl unit, was synthesized and its crystal structure was determined. To define the relationship between molecular stereochemistry and spatial association modes, development of the crystal packing was analyzed through cooperativity of intermolecular interactions. Homo and heterochiral dimeric motifs were stabilized by intermolecular N−H⋅⋅⋅O, C−H⋅⋅⋅O, C−H⋅⋅⋅π interactions and parallel interactions at large offsets (PILO), thus forming alternating double layers. The greatest contribution to the total stabilization came from a motif of opposite enantiomers linked by N−H⋅⋅⋅O bonds (interaction energy=−13.72 kcal/mol), followed by a homochiral motif where the 4‐methoxybenzyl units allowed C−H⋅⋅⋅π, C−H⋅⋅⋅O interactions and PILO (interaction energy=−11.56 kcal/mol). The number of the contact fragments in the environment of the tetralin unit was larger, but the 4‐methoxybenzyl unit had greater contribution to the total stabilization. The statistical analysis of the data from the Cambridge Structural Database (CSD) showed that this is a general trend. The compound is a potential inhibitor of kinase enzymes and antigen protein‐coupled receptors. A correlation between the docking study and the results of the CSD analysis can be drawn. Due to a greater flexibility, the 4‐methoxybenzyl unit is more adaptable for interactions with the biological targets than the tetralin unit. [ABSTRACT FROM AUTHOR]

Ten 5‐(substituted phenylazo)‐3‐cyano‐1‐ethyl‐6‐hydroxy‐4‐methyl‐2‐pyridones were studied (five new compounds) to provide insight into the electronic effects of diverse substituents located at different positions in their phenyl moieties. The structural features of these dyes were examined by combining experimental and theoretical approaches. The crystal structures of two derivatives were revealed by X‐ray crystallography and diverse packing modes owing to different intermolecular interactions (π–π stacking and lone pair–π interactions, as well as hydrogen bonds) were found. A study on lattice energy and energy related to the molecular pairs obtained from their crystal packing was performed. The tautomerism and ionisation of the dyes in ethanol or N,N ‐dimethylformamide solution were rationalised in terms of diazo component substitution pattern. [ABSTRACT FROM AUTHOR]

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 a single crystal X-ray diffraction method. These compounds have multiple functional groups, which allow greater competition and/or cooperation among the different intermolecular interactions in the formation of their crystal structures. The molecules are linked together by paired N–H…O hydrogen bonds in R22(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 cyclohexyl 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 the 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 an emphasis on the X…π interactions. The lattice energies of all these crystal structures, as well as the 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 the relationship between the molecular interactions and crystal structures of the hydantoin derivatives. [ABSTRACT FROM AUTHOR]

• A new spirohydantoin was synthesized and characterized. • A bilayer structure is formed via hydrogen bonds, C–H∙∙∙π, lp∙∙∙π and π∙∙∙π interactions. • The highest stabilization comes from the motif with the paired N–H∙∙∙O hydrogen bonds. • HOMO is mainly over the hydantoin and cyclohexyl rings; LUMO is on the benzoyl group. • The global reactivity descriptors indicate the soft nature of the molecule. Providing structural information on drug-like compounds is a significant step in efforts to develop innovative drugs with balanced solubility, cell permeability and target binding. In this paper, a new cyclohexane-5-spirohydantoin tethered with a 4‑tert-butylbenzoyl group was synthesized and its crystal structure was determined using the single crystal X-ray diffraction. The Hirshfeld surface analysis was used to gain a preliminary insight into the proportion and nature of the intermolecular interactions in the crystal structure, while their quantitative description is further presented in terms of a systematic analysis of dimeric motifs representing different recognition modes. A combination of N–H∙∙∙O and C(sp3)–H∙∙∙O hydrogen bonds, C(sp3)–H∙∙∙π, lone-pair∙∙∙π and π∙∙∙π stacking interactions links the molecules into a bilayer having two carbonyl O atoms exposed to the exterior. Further stacking of the bilayers occurs through C(sp3)–H∙∙∙O hydrogen bonds involving these O atoms as acceptors, C(sp3)–H∙∙∙π and π∙∙∙π stacking interactions between the phenyl groups. The molecular electrostatic potential surface map reveals that the carbonyl O atoms of the hydantoin ring and the phenyl ring are electrophilic centers, while the N1–H1 group is a nucleophilic center. The calculated HOMO and LUMO energies were used to semiquantitatively estimate the global reactivity descriptors suggesting the soft nature of the molecule. [Display omitted] [ABSTRACT FROM AUTHOR]

• Hydrated zwitterionic crystals of pyridone derivatives have been obtained. • Water and zwitterions interlocked into crystal packing through an interplay of interactions. • By coupling the experimental and calculated data of crystal structure, packing is elucidated. • The architecture depends on the number of water molecules and the nature of interactions. Two pyridone derivatives, bearing the pyridinium moiety (1), or dimethylpyridinium moiety (2), have been synthesized and their crystal structures have been determined. The compounds crystalize in hydrated zwitterionic forms with either two (1·2H 2 O) or four (2·4H 2 O) water molecules. The zwitterionic networks contain different types of water clusters, generated into channels, incorporating them into the network by sandwiching. The type of channel depends on the crystal lattice and the nature of non-covalent interactions established between zwitterions as well as the number of water molecules incorporated into the architecture. 1 affords tubes filled in with water channels formed by water tetramers, contrary to 2 , which affords a layered network altering the zwitterionic layer and the layer formed by water tetramers and hexamers. A detailed study of intermolecular interactions of both crystal structures and a quantification of interaction energies has been performed using PIXEL lattice energy calculations, giving an insight to a quantitative evaluation of interactions through Coulombic, disperse, repulsion and polarization energies. The strongest pairwise, in both structures, is found to be a dipole–dipole interaction between oppositely charged heterocyclic rings. The differences in the crystal packings of these hydrates have been elucidated by the fingerplot analysis. The comparative studies between experimental and calculated (DFT) data of molecules 1·H 2 O and 2·4H 2 O for systems of different complexity are performed. Furthermore, correlations of experimental and calculated bond lengths and the simulation of compound solvation with the CPCM model are done. [Display omitted] [ABSTRACT FROM AUTHOR]