MOLECULAR BUILDING USING N-METHYLBENZANILIDES AS A MOLECULAR SPRINT

酰胺部分具有构象和电子特征，这些特征往往决定了分子的物理化学或生物特性，并在各种分子识别事件中发挥作用。大多数具有酰胺二级键的化合物，在氮原子上有一个质子，存在反式(Z)形式。我们在对各种生物活性物质的研究过程中发现，芳香仲酰胺或尿素的n -甲基化由于酰胺或尿素结构的构象变化而导致生物活性的急剧丧失。反式/顺式立体化学的重要性是显而易见的，例如在免疫抑制剂的生物化学中。研究了苯甲苯胺、n -甲基苯甲苯胺和酰胺键邻甲基苯甲苯胺在溶液和晶体中的构象。n -甲基苄基苯胺在晶体中以顺酰胺(E)形式存在。在CDCl_3溶液中，以顺酰胺形式存在较多（99%），而苯并苯胺在晶体和溶液中以反式和多酰(Z)形式存在。在晶体中，所有甲基取代的苯甲苯胺都以反酰胺构象存在，邻甲基的引入使芳环与酰胺基团（ar -酰胺）的面夹角变大。n -甲基苄基苯胺在晶体中以顺式存在，除了化合物（26）有四个甲基与酰胺键邻位。对于n -甲基苄基苯胺，引入一个或两个邻甲基对ar酰胺二面角的影响小于引入仲苯基苯胺的影响。在溶液中，除了化合物（12）在CDDl_3中有一个次要的顺式构象（3%）外，苯甲苯胺只以反式构象存在，而n -甲基苯甲苯胺则在主顺式和次反式构象之间平衡存在。在晶体中观察到四甲基衍生物在溶液中以反式构象存在。对于n -甲基苄基苯胺，在酰胺键上引入一个邻位甲基似乎会破坏溶液中顺酰胺构象的稳定性，导致反式酰胺构象的比例增加。少

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