Characteristic Hydrogen Bonding Observed in the Crystals of Aromatic Sulfonamides: 1D Chain Assembly of Molecules and Chiral Discrimination on Crystallization

Abstract

N-Phenylbenzenesulfonamides exist preferentially in (+)-or (−)-synclinal conformations, which place the aromatic rings at both ends in the same direction with a twist. We have systematically analyzed the crystal structure of secondary aromatic sulfonamides bearing methyl, ethyl, and/ or methoxy groups on the benzene rings. Intermolecular hydrogen bonding between the sulfonamide protons and sulfonyl oxygens was observed in 81 out of 85 crystals. The intermolecular hydrogen-bonding patterns could be classified into four types, i.e. Dimeric, Zigzag, Helical, and Straight patterns, with retention of the synclinal conformation of the sulfonamide moiety. We investigated the relationship between the hydrogen-bonding pattern and the proportion of the compounds that show chiral crystallization. On the basis of our classification of the intermolecular hydrogen bonds of aromatic sulfonamides, the crystals with Dimeric and Zigzag patterns, which both have enantiomeric synclinal conformers, intrinsically become achiral, except for kryptoracemates. In contrast, a high proportion of compounds with Helical or Straight patterns in the crystals showed chiral crystallization. Our classification is useful for discussion regarding the chirality of molecular assemblies, on the basis of the conformational chirality of the molecules in the crystal.

Spectroscopic, X-ray Diffraction and Density Functional Theory Study of Intra- and Intermolecular Hydrogen Bonds in Ortho-(4-tolylsulfonamido)benzamides

“…Interest in sulfonamides is not only limited to drug development, but also exists in terms of their conformations and crystalline structures [ 3 , 4 , 5 ]. This scaffold provides a versatile template to explore hydrogen bonding interactions, control molecular conformations and improve the physicochemical properties of the drug molecules [ 6 , 7 ]. The sulfonamide group generally adopts tetrahedral geometry, and the oxygen atoms of this group easily form hydrogen bonds in higher dimensions than amides do.…”

“…The sulfonamide group generally adopts tetrahedral geometry, and the oxygen atoms of this group easily form hydrogen bonds in higher dimensions than amides do. Aromatic sulfonamides have been found to display conformational chirality emanating from the synclinal conformation [ 6 ]. The N -phenylbenzenesulfonamides, for example, exist preferentially in (+)- or (−)-synclinal conformations with a twist in the same direction of the aromatic rings at both ends.…”

“…The hydrogen atom of the sulfonamide group was found to be involved in an intermolecular hydrogen bonding interaction with the O atom of the sulfonyl group of another, which is generally stronger than the other intermolecular interactions, such as CH–π, CH–lone pair, aromatic–aromatic, and other hydrogen bonding interactions. Kikkawa et al classified the intermolecular hydrogen-bonding patterns of aromatic sulfonamides into four types, namely, dimeric, zigzag, helical, and straight patterns, all retaining the synclinal conformation of the sulfonamide functionality [ 6 ]. Integrating intramolecular hydrogen bonding formation in drug design has become an exciting challenge for medicinal chemistry, as this noncovalent force results in conformational restriction of small drug molecules, leading to increased lipophilicity, membrane permeability and pharmacological activity [ 8 ].…”

Synthesis, Structural and Biological Properties of the Ring-A Sulfonamido Substituted Chalcones: A Review

“…The twisting of the sulfonamide moiety from coplanarity of the conjugated carbon framework has also been observed in the crystal structures of the analogous N -(2-acetyl-4-(styryl)phenyl)sulfonamides [ 34 ] and the corresponding 5-styryl-2-sulfonamidochalcone hybrids [ 26 ]. The distorted tetrahedral geometry of the sulfonamide moiety, on the other hand, makes its oxygen atoms to engage in several hydrogen bonding interactions [ 17 ]. As a result, this moiety represents a versatile template to explore hydrogen bonding interactions, control molecular conformations and improve the physicochemical properties of the drug molecules [ 16 , 17 ].…”

“…The distorted tetrahedral geometry of the sulfonamide moiety, on the other hand, makes its oxygen atoms to engage in several hydrogen bonding interactions [ 17 ]. As a result, this moiety represents a versatile template to explore hydrogen bonding interactions, control molecular conformations and improve the physicochemical properties of the drug molecules [ 16 , 17 ]. The Hirshfeld surface analyses and molecular potential maps of sulfonamidochalcones confirm the preponderance of intermolecular interactions of the type C–H···O and N–H···O which stabilize the crystal packing.…”