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

Themolecular 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 (rg (A° ) and :a (8)) for the main conformer with 3s in parentheses are as follows: hrg(N–Cring)iZ1.456(4); rg(N–Cmethyl)Z1.451 (d.p.); rg(CaC)Z1.339(9); hrg(C–C)iZ1.512(3); rg(O– Cmethyl)Z1.434(5); rg(C(O)–O)Z1.355 (d.p.); rg(CaO)Z1.209(4); the out-of-plane angle of the methyl groupZ50.3(23); :CringNring- CringZ112.8(30); :NringCringCring(H2)Z110.5(16); h:CringCringCringiZ118.4(5); :CaCC(O)Z116.8(7); :CCaOZ127.6(9); :CC– OZ109.8(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–CH3 bond and s-cis and s-trans show the orientation of the methoxycarbonyl group expressed by the configuration of the CaO and CaC bonds. The N/Ocarbonyl distances of the Eq-s-cis and Ax-s-cis conformers are 4.832(13) and 4.874(16) A ° , respectively. They are close to the N/N distance of the most abundant conformer of nicotine, 4.885(6) A ° , suggesting that the Eq-s-cis and Ax-s-cis conformers have nicotinic activity. q 2004 Elsevier B.V. All rights reserved.