The Conformational Landscape of Nicotinoids: Solving the Conformational Disparity of Anabasine

Abstract

The conformational landscape of the alkaloid anabasine (neonicotine) has been investigated by using rotational spectroscopy and ab initio calculations. The results allow a detailed comparison of the structural properties of the prototype piperidinic and pyrrolidinic nicotinoids (anabasine vs. nicotine). Anabasine adopts two most stable conformations in isolation conditions, for which we determined accurate rotational and nuclear quadrupole coupling parameters. The preferred conformations are characterized by an equatorial pyridine moiety and additional N-H equatorial stereochemistry at the piperidine ring (eq-eq; eq=equatorial). The two rings of anabasine are close to a bisecting arrangement, with the observed conformations differing by an approximately 180 degrees rotation of the pyridine subunit, denoted either syn or anti. The preference of anabasine for the eq-eq-syn conformation has been established by relative intensity measurements (syn/anti approximately 5(2)). The conformational preferences of free anabasine are directed by a weak N...H-C hydrogen bond interaction between the nitrogen lone pair at piperidine and the closest C-H bond in pyridine, with N...H distances ranging from 2.686 (syn) to 2.667 A (anti). Supporting ab initio calculations by using MP2 and the recent M05-2X density functional are provided, evaluating the predictive performance of both methods.

Competing hydrogen bonding in methoxyphenols: The rotational spectrum of o-vanillin

“…The crystal structure of o-vanillin detected only the most stable conformation, offering no information on higher-energy structures. Moreover, crystal structures are dominated by intermolecular interactions, so they do not always correspond to the preferred structures of the molecule [6,30]. Alternatively, rotational spectroscopy offers a detailed molecular description, disentangling the intrinsic factors controlling conformation and structure.…”

Rapid probe of the nicotine spectra by high-resolution rotational spectroscopy

“…13 The electron diffraction pattern was reproduced by assuming a mixture of two distinct conformers of nicotine. Studies of the nicotine analogues 2-phenylpyrrolidine 14 and anabasine 15 have been recently reported. The former has been studied in gas and solution-phase using MW, electronic and NMR spectroscopic techniques.…”

Conformational properties of chiral tobacco alkaloids by DFT calculations and vibrational circular dichroism: (−)-S-anabasine

“…3, reproduce those previously proposed for (−)-S-anabasine in Ref. [35] Cartesian coordinates of the eight conformers (B3PW91/aug-cc-pVTZ, gas phase) are available as supplementary material (Table S3).…”

“…At this point, it is worth to mention that authors in Ref. [35] also suggested that an N. . .H HBi may be responsible for the observed deviation from the ideal pyridine ring orientation in the two main conformers, namely m01 and m02.…”

“…(−)-S-anabasine (one of the minority piperidinic nicotinoids in tobacco leaves, ∼0.5%) has also been reported to have interesting biomedical applications [30] and its molecular structure and spectroscopic properties have been the target of several works [31][32][33][34][35][36].…”