Molecular structure of cotinine studied by gas electron diffraction combined with theoretical calculations

Abstract

The molecular structure of cotinine ((S)-1-methyl-5-(3-pyridinyl)-2-pyrrolidinone), the major metabolite of nicotine, has been determined at about 182˚C by gas electron diffraction combined with MP2 and DFT calculations. The diffraction data are consistent with the existence of the (ax, sc), (ax, ap), (eq, sp) and (eq, ap) conformers, where ax and eq indicate the configuration of the pyrrolidinone ring by means of the position (axial and equatorial) of the pyridine ring, and sc, sp and ap distinguish the isomers arising from the internal rotation around the bond connecting the two rings.The (CH 3 )NCCC(N) dihedral angles, φ, of the (ax, sc) and (eq, sp) conformers were determined independently to be 158(12)° and 129(13)°, respectively, where the numbers in parentheses are three times the standard errors, 3σ. According to the MP2 calculations, the corresponding dihedral angles for the (ax, ap) and (eq, ap) conformers were assumed to differ by 180° from their syn counterparts. The ratios x(ax, sc) / x(ax, ap) and x(eq, sp) / x(eq, ap) were taken from the theoretically estimated free energy differences, ΔG, where x is the abundance of the conformer. The resultant abundances of (ax, sc), (ax, ap), (eq, sp) and (eq, ap) conformers are 34 ( The N … N distances of the (ax, sc) and (eq, sp) conformers, which are 4.844(5) and 4.740(5) Å, respectively, are close to that of the most stable conformer of nicotine, 4.885(6) Å and the corresponding one of arecoline, 4.832(13) Å. It is concluded that the weak nicotinic activity of cotinine cannot be ascribed to such a small difference in the N … N distances.

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).…”

“…Cotinine (1-methyl-5-(3-pyrinidyl)-2-pyrrolidinone, 2)i st he predominanto xidative metabolite of nicotine, [4] differing only in the addition of ac arbonyl group to the pyrrolidine ring. [6] Accurate structurali nformation on nicotinoids is thus required to model binding to receptor proteins and to define structure-activity biochemical relationships. 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.…”

“…[5] In other nicotinoids the N···N distance could modulate the intensity of their biological activity.A dditionally,t he partial charge on the pyrrole Na tom might influence the tendency to protonation and hence the biological activity.Apossible CÀH···O=Ci ntramolecular interaction is also suggested as an explanation for the lower affinity of cotinine to the receptor. 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. Pharmacological uses of cotinine have been reviewed.…”

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

“…Despite the important biological role that this and other structurally related compounds may play, the number of studies focused on the structural characterization of (−)‐ S ‐cotinine is relatively scarce. Indeed, it has been the subject of several works mainly focused on its molecular structure and conformational distribution in the gas phase,25, 34 its basicity equilibrium constants35 and its analytical determination 36. 37 Nevertheless, the conformer distribution of the species in solution as well as the mechanisms controlling its conformational equilibrium (both in the gas phase and in solution) still remain unclear.…”

Magnetic Dextran Nanoparticles That Bear Hydrophilic Porphyrin Derivatives: Bimodal Agents for Potential Application in Photodynamic Therapy

“…Based on geometrical grounds, the authors of Ref. 34 also mention the possible occurrence of an intramolecular hydrogen bond (Hbi) linking the carbonyl group and the H atom of the NCH 3 group. Supporting their proposal, the results of our NBO analyses (MP2/6‐31+G*) suggest the incidence of a weak CO12⋅⋅⋅H contact.…”