MOLECULAR BUILDING USING N-METHYLBENZANILIDES AS A MOLECULAR SPRINT

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The amide moiety has conformational and electronic characteristics which often determine the physicochemical or biological properties of a molecule, and it plays role in a variety of molecular recognition events. Most compounds having a secondary amide bond, which has a proton on the nitrogen atom, exist trans (Z) form. We found in the course of investigations on various biologically active substances that N-methylation of aromatic secondary amides or ureas causes a dramatic loss of the biological activity due to conformational change of the amide or urea structre. The importance of trans/cis stereochemistry is clear, for example in the biochemistry of immunosuppressants.Conformation of benzanilide, N-methylbenzanilide and those with a methyl group (s) ortho to the amide bond in solution and in the crystal have been studied. N-Methylbenzanilide exists in cis-amide (E) form in the crystal. In CDCl_3 solution, cis-amide form is also predominant (99%), whele benzanilide exists in trans-am … More ide (Z) form in the crystal and in solution. In the crystal, all the methyl-substituted benzanilides exists in trans-amide conformation and the introduction of an ortho-methyl group (s) makes the interplanar angle of the aromatic rings and the amide group (Ar-amide) larger. N-Methylbenzanilides exist in cis form in the crystal except the compound (26) which has four methyl groups ortho to the amide bond. For the N-methylbenzanilides, the effects of introduction of one or two ortho-methyl group on the dihedral angles of Ar-amide are smaller than that of the secondary benzanilides. In solution, benzanilides exist exclusively in trans conformation except for the compound (12) which has a minor cis conformer (3%) in CDDl_3, whereas N-methylbenzanilides exist in equilibrium between the major cis-form and the minortrans-from. The tetramethyl derivative exists in trans conformation in solution as observed in the crystal. For, N-metylbenzanilides, an introduction of a methyl group (s) ortho to the amide bond seems to destabilize the cis-amide conformation in solution, resulting in an increased ratio of the trans-amide conformation. Less