A LIS investigation of analogues of amiodarone containing the 3-benzoyl-2-butylbenzofuran system has been performed, utilizing the pseudo-contact shifts of all the proton and carbon nuclei in the molecules. The 13C diamagnetic shifts were removed by use of La(fod), and the pseudo-contact shifts were analysed to obtain the conformations in solution of these molecules.
In 3-(2,6-dibromobenzoyl)-2-butylbenzofuran (l), the ortho bromo substituents produce sufficient steric hindrance so as to enable the separate 0-trans and 0-cis conformers to be observed at room temperature.
Thus the LIS analysis was performed on both conformers separately. In each case good solutions (R, < 5%) were obtained for the conformations in which the benzofuran and carbonyl groups are coplanar and the phenyl group orthogonal to this plane. This was achieved using an unsymmetrical model of the lanthanide complexation to the carbonyl group in which the different spatial environment of the oxygen lone pairs is allowed for in the refinement procedure.
In 3-(3,5-diiodobenzoyl)-2-butylbenzofuran (2), in which there is no evidence of conformation isomerism in the NMR spectrum down to -100 OC, the analysis of the LIS data on the basis of a rapidly interconverting mixture of conformers analogous to those of 1 did not produce a satisfactory result. In contrast, analysis on the basis of a single conformation in which the phenyl group is coplanar with the carbonyl group and the benzofuran moiety is twisted out of this plane gave a satisfactory solution for an angle of twist of ca 90". Owing to the long time scale of the NMR experiment, the LIS results are also consistent with a rapidly interconverting equilibrium between two non-planar conformations in which the average angle of twist of the benzofuran group is ca 90'. This intriguing result can be rationalized by steric considerations and molecular mechanics calculations which indicate that, in the absence of any abutting ortho substituents on the phenyl group, coplanarity of the carbonyl group and the 2-alkylbenzofuran moiety is less favoured energetically than coplanarity of the carbonyl and the phenyl groups. The slightly greater intrinsic torsional barrier of the carbonyl and benzofuran parts is more than compensated for by the increased steric interactions of the carbonyl with the 2-alkyl and 4-hydrogen groups of the benzofuran in the planar form.