CONFORMATIONAL-ANALYSIS OF 1,2,3,4-TETRAHYDROISOQUINOLINES

Ring and nitrogen inversion account for the conformational equilibria of 3-phenyl-1,2,3,4-tetrahydroisoquinolines. In order to quantitate th e relative contribution of each conformer to the equilibrium, we under -took a molecular mechanics study on several substituted 3-phenyl-1,2, 3,4-tetrahydroisoquinolines. Predictions from calculations were checke d against cmr chemical shift data. No boat conformation contributed si gnificantly to the equilibrium. A general result of our calculations i s that in all cases the 3-phenyl group in the equatorial position is s trongly favored (by at least 2.50 kcal/mole). For 3-phenyl-1,2,3,4-tet rahydroisoquinolines without substitution at nitrogen, N-H in equatori al position is preferred over the axial conformer, although the energy difference between both is always small (0.30-1.10 kcal/mole). For th e cis-1,3-disubstituted compounds the 1e'3e conformers are the only sp ecies present (at least 99.8%). The calculated energy differences betw een the 1a'3a conformer and the 1e'3e conformer are always large (3.80 -6.10 kcal/mole for the NHe conformers and 3.60-3.80 kcal/mole for the NHa conformers). The lack of a gamma(1a) upfield shift at C3 also poi nts to the preference for the pseudoequatorial-equatorial conformer. F or N-methyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline a preference for t he NMe group in the equatorial position is predicted (0.60-2.00 kcal/m ole). The small downfield shift at C4 (gamma(Na) = 0.5 ppm) is consist ent with the equatorial NMe preference. For the cis-1,2,3-trisubstitut ed compounds no significant yl, effect at C3 (gamma(1a) = -0.2 and 1.0 ppm) or gamma(Na) effect at C4 (gamma(Na) = 0.1 and 0.4 ppm) is obser ved. For these compounds, deformations due to steric congestion are ev idenced by the deviation from the values of the C4a-C8a-C1-N and C4a-C 4-C3-N torsional angles, as compared to less crowded 3-phenyl-1,2,3,4- tetrahydroisoquinolines Here the heterocyclic ring adopts a distorted half-chair conformation.