CONFORMATIONAL-ANALYSIS - 50 - C-METHYL-1,2,3,4-TETRAHYDROISOQUINOLINES

Conformational equilibria in 1-, 3-, and 4-methyl-1,2,3,4-tetrahydrois oquinolines (THIQs) and the diastereomeric pairs of their 1,3- and 1,4 -dimethyl homologs have been determined by measurement of H-3/H-4(tran s) coupling constants and have been confirmed by molecular mechanics [ MMP2(85]) calculations. The experimental -Delta G degrees values (a -- > e) for the monomethyl compounds (computed values in parentheses) in kcal mol(-1) are Me-1, 0.56 (0.46); Me-3, 1.63 (1.53); and Me-4, -0.32 (-0.22). Agreement of experimental and calculated values is very goad as is the additivity of values for the dimethyl compounds (Table 1). Values for the corresponding hydrochlorides are Me-1, 0.19 (-0.34); Me -3, 1.15 (1.46); and Me-4, 0.35 (0.10) kcal mol(-1). The less than sat isfactory agreement of experimental with computed data here is probabl y due to neglect of solvation. The very small or negative Delta G degr ees values for Me-1 and Me-4 were ascribed not only to the pseudoaxial (rather than axial) nature of Me(ax) and the absence of a syn-axial h ydrogen on the side of the benzene ring but also to a peri interaction with H(8) and H(5), respectively, destabilizing equatorial methyl at positions 1 and 4. This was confirmed by comparing computed conformati onal energy values with values at corresponding positions in Delta(3,4 )-tetrahydropyridines (THPs). While Delta G degrees in the two series is the same for Me-3 (THIQ numbering), that for Me-1 and Me-4 is consi derably smaller in the THIQ than in the THP series which latter is dev oid of peri hydrogens.