Molecular structure and nicotinic activity of arecoline. A gas electron diffraction study combined with theoretical calculations

The molecular structure of arecoline (methyl 1,2,5,6-tetrahydro-1- methylnicotinate, has been determined by gas electron diffraction. Diffraction patterns were taken at about 370 K. Structural constraints for the data analysis were obtained from MP2/6-31G** calculations. Vibrational mean amplitudes and shrinkage corrections were calculated from the force constants obtained from the gas-phase vibrational frequencies and the B3LYP/6-31G** calculations. The electron diffraction data were well reproduced by assuming the mixture of four conformers. The determined structural parameters (r _g (Å) and ∠α (°)) for the main conformer with 3σ in parentheses are as follows: 〈r _g(N-C _ring)〉=1.456(4); r _g(N-C _methyl)=1.451 (d.p.); r _g(CC)=1.339(9); 〈r _g(C-C)〉=1.512(3); r _g(O-C _methyl)=1.434(5); r _g(C(O)-O)=1.355 (d.p.); r _g(CO)=1.209(4); the out-of-plane angle of the methyl group=50.3(23); ∠C _ringN _ringC _ring=112.8(30); ∠N _ringC _ringC _ring(H ₂)=110.5(16); 〈∠C _ringC _ringC _ring〉=118.4(5); ∠CCC(O)=116.8(7); ∠CCO=127.6(9); ∠CC-O=109.8(8), where the angle brackets denote averaged values and d.p. denotes dependent parameters. Fixing the abundances of the minor conformers, Ax-s-cis and Ax-s-trans, at the theoretical values (13% in total), those of the Eq-s-cis and Eq-s-trans conformers were determined to be 46(16) and 41(16)%, respectively. Here Ax and Eq denote the axial and equatorial directions of the N-CH ₃ bond and s-cis and s-trans show the orientation of the methoxycarbonyl group expressed by the configuration of the CO and CC bonds. The N⋯O _carbonyl distances of the Eq-s-cis and Ax-s-cis conformers are 4.832(13) and 4.874(16) Å, respectively. They are close to the N⋯N distance of the most abundant conformer of nicotine, 4.885(6) Å, suggesting that the Eq-s-cis and Ax-s-cis conformers have nicotinic activity.