Peters L, Fröhlich R, Boyd A S, Kraft A
Institut für Organische Chemie und Makromolekulare Chemie II, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
J Org Chem. 2001 May 18;66(10):3291-8. doi: 10.1021/jo005632i.
Amidines have long been known to form strong noncovalent complexes with carboxylates and phosphates. However, their interaction with tetrazoles, which are acidic heterocycles and important bioisosteric replacements for carboxylic acids in medicinal chemistry, has remained unexplored so far. The binding of a tetrazole to an N,N'-diethyl-substituted benzamidine has been studied for the first time by X-ray crystallography, solution NMR methods, and electrospray mass spectrometry. The amidinium group of model complex 3 was found to prefer an E,Z configuration in the crystal. Benzamidinium and tetrazolate groups alternate along an infinite chain of hydrogen bonds and salt bridges between the amidine-NH groups and the two tetrazole-N atoms next to the ring carbon. In solution, a 1:1 complex was evident from Job's method of continuous variation, and an association constant of 4.0 x 10(3) +/- 1.6 x 10(3) M(-)(1) (in CDCl(3)/CD(3)CN, 6:1) could be determined by (1)H NMR dilution experiments. Tetrazolate was not only found to be a weaker ligand than carboxylates but, surprisingly, the binding mode also changed with concentration in neat CDCl(3). At low concentrations, the amidine group in complex 3 adapted an E,E configuration as it does in a related carboxylic acid complex 4. With increasing concentration, the E,Z isomer starts to predominate. A free activation enthalpy DeltaG(298)() of 64 +/- 1 kJ mol(-)(1) for the E,E to E,Z isomerization was determined by line shape analysis at different magnetic fields. Binding strength was further probed in a competition experiment between a bisamidine, a carboxylate, and a tetrazolate by electrospray mass spectrometry.
长期以来，人们都知道脒能与羧酸盐和磷酸盐形成强非共价复合物。然而，它们与四氮唑的相互作用，四氮唑是酸性杂环且在药物化学中是羧酸重要的生物电子等排体替代物，到目前为止仍未被研究。首次通过X射线晶体学、溶液核磁共振方法和电喷雾质谱研究了四氮唑与N,N'-二乙基取代苯甲脒的结合。发现模型复合物3的脒鎓基团在晶体中倾向于E,Z构型。苯甲脒鎓基团和四氮唑基团沿着由脒基-NH基团与环碳旁边的两个四氮唑-N原子之间的氢键和盐桥组成的无限链交替排列。在溶液中，从Job连续变化法可明显看出形成了1:1复合物，通过1H NMR稀释实验可确定其缔合常数为4.0×10(3)±1.6×10(3) M(-)(1)（在CDCl(3)/CD(3)CN，6:1中）。发现四氮唑不仅是比羧酸盐弱的配体，而且令人惊讶的是，在纯CDCl(3)中结合模式还随浓度变化。在低浓度下，复合物3中的脒基团采用与相关羧酸复合物4中相同的E,E构型。随着浓度增加，E,Z异构体开始占主导。通过在不同磁场下的线形分析确定了E,E到E,Z异构化的自由活化焓ΔG(298)()为64±1 kJ mol(-)(1)。通过电喷雾质谱在双脒、羧酸盐和四氮唑之间的竞争实验中进一步探究了结合强度。
