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

• Published in: Journal of molecular structure Vol. 841; no. 1; pp. 13 - 21
• Main Authors: Takeshima, Tsuguhide, Takeuchi, Hiroshi, Egawa, Toru, Konaka, Shigehiro
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 30.09.2007
• Subjects: Cotinine; Gas electron diffraction; Molecular structure; Nicotinic activity; Theoretical calculations; Nicotinic activity; Gas electron diffraction; Molecular structure; Cotinine; Theoretical calculations
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2006.11.041

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, 3 σ. 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, Δ G, where x is the abundance of the conformer. The resultant abundances of (ax, sc), (ax, ap), (eq, sp) and (eq, ap) conformers are 34(6)%, 21% (d.p.), 28% (d.p.), and 17% (d.p.), respectively, where d.p. represents dependent parameters. The determined structural parameters ( r g (Å) and ∠ α (°)) of the most abundant conformer, (ax, sc), are as follows: r(N C) pyrrol = 1.463(5); r(N C methyl) = 1.457(←); r(N C( O)) = 1.384(12); r(C O) = 1.219(5); 〈 r(C C) pyrrol〉 = 1.541(3); r(C pyrrol C pyrid) = 1.521(←); 〈 r(C C) pyrid〉 = 1.396(2); 〈 r(C N) pyrid〉 = 1.343(←); ∠(CNC) pyrrol = 113.9(11); ∠CCC pyrrol(−C pyrid) = 103.6(←); ∠NCO = 124.1(13); ∠NC pyrrolC pyrid = 113.1(12); ∠C pyrrolC pyrrolC pyrid = 113.3(←); ∠(CNC) pyrid = 117.1(2); 〈∠(NCC) pyrid〉 = 124.4(←); ∠C methylNC( O) = ∠C methylNC(−C pyrid) = 122.8(d.p.); ∠NC( O)C = 107.1(d.p.); ∠NC pyrrol(−C pyrid)C pyrrol = 103.0(d.p.) and ∠CCC( O) = 105.2(d.p.), where ← in the parentheses means that the parameter is bound to the preceding one and 〈 〉 denote average values. The puckering angle, α, of the pyrrolidinone ring is 26(3)°. 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.