DFT‐Aided Vibrational Circular Dichroism Spectroscopy Study of (−)‐S‐cotinine

Abstract

The implementation of a strategy comprising the use of vibrational circular dichroism spectroscopy and DFT calculations allows determination of the solution-state conformational distribution in (-)-S-cotinine, giving further proof of the extra conformer-discriminating potential of this experimental technique, which may offer unique molecular fingerprints of subtly dissimilar molecular conformers of chiral samples. Natural bond orbital electronic structure calculations of the rotational barrier height between the two main conformers of the species indicate that hyperconjugative effects are the key force governing the conformational equilibrium. The negligible effect of the solvent's polarity over both structure and conformational energy profile supports this result.

Structural Studies of Nicotinoids: Cotinine versus Nicotine

“…The results presented herein offer the chance to study the effect of this modification on the behavior of this nicotinoid. Finally,i ti sn oteworthy that in previous studies aboutc otinine, [6,10] the same four conformations as calculated herein were described as envelope-type structures. The cotinine five-membered ring takes on am ore planar configuration than that in nicotine (shownb yalower value of the puckering amplitude in Figure S2).…”

“…cotininer educes the energy difference between axial and equatorial conformations. Finally,i ti sn oteworthy that in previous studies aboutc otinine, [6,10] the same four conformations as calculated herein were described as envelope-type structures.…”

“…Xiu and co-workers explained the interaction between nicotinea nd nAChR in terms of as trong cation···p interaction between the protonated nicotine and an aromatic residue of at ryptophan residue. [10] However,i ntra-and intermolecular interactions can be masked by solvent and crystal-packing forces, so these data are not alwaysc onclusive for the free molecule. [6] Accurate structurali nformation on nicotinoids is thus required to model binding to receptor proteins and to define structure-activity biochemical relationships.…”

“…Av ibrationalc irculard ichroism (VCD) analysisi ns olution and in the solid phase suggestedt hat four conformationscould be responsible for the vibrational spectra. [10] However,i ntra-and intermolecular interactions can be masked by solvent and crystal-packing forces, so these data are not alwaysc onclusive for the free molecule. A gas phase electron diffraction (GED) [6] also pointed to the coexistence of four different conformations, but this technique is not appropriate to resolve small structural differencesi nc on-formationally complex mixtures.I nt his work we present as tructural studyo fc otinineu sing ac ombination of rotational spectroscopy and supersonic jet expansions.T his techniquei s ideal for structuralc haracterization due to its unparalleled high resolution and sensitivity.O ther nicotinoids such as nicotine [11] or anabasine [12] (3,S cheme 1) have been previously studied with this method.…”

“…No previous high‐resolution spectroscopic studies of cotinine can be found in the literature. A vibrational circular dichroism (VCD) analysis in solution and in the solid phase suggested that four conformations could be responsible for the vibrational spectra . However, intra‐ and intermolecular interactions can be masked by solvent and crystal‐packing forces, so these data are not always conclusive for the free molecule.…”