Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA 19104, USA.
Phys Chem Chem Phys. 2013 Jul 28;15(28):11883-92. doi: 10.1039/c3cp50353d.
We examine the conformational preferences of the furan- and thiophene-based arylamides, N-methylfuran-2-carboxamide (3) and N-methylthiophene-2-carboxamide (4), using a combination of computational methods and NMR experiments. The compound choice stems from their use as foldamer building blocks. We quantify the differences in the conformational rigidity of the two compounds, which governs corresponding foldamer conformations. Specifically, we demonstrate the effects of intramolecular hydrogen bonding (H-bonding), geometrical patterns and solvent polarity on arylamide conformations by comparing 3, 4 and previously studied ortho-methoxy N-methylbenzamide (1) and ortho-methylthio N-methylbenzamide (2). The study reveals that compound 3, despite its non-optimal S(5)-type H-bond geometry, retains a large portion of the H-bonded (eclipsed) conformation even in polar protic solvents. This behaviour is consistent with the quantum mechanical (QM) torsional energy profile. The percentages of H-bonded conformers that 3 retains are just slightly smaller than those of 1, which has a stronger S(6)-type H-bond. As for 2 and 4, the replacement of the O atom in 1 by an S atom in 2 results in a 70–90% loss of the H-bonded conformer in solution. However, the equivalent O to S replacement in 3 (leading to 4) causes only 15–30% loss of the eclipsed conformers in 4. Therefore, conformational preferences of 4 are very different from 2, in contrast to the similarity between 3 and 1. This study shows how the interplay of several forces modulates the conformational flexibility of arylamides. It also attests the strategy we are developing, which leads to accurate prediction of foldamer structure. The vital component of this strategy is the re-parameterization of critical force field parameters based on QM potential energy profiles, as well as validation of these parameters using experimental data in solution.
我们使用计算方法和 NMR 实验相结合，研究了呋喃基和噻吩基芳酰胺，N-甲基呋喃-2-甲酰胺（3）和 N-甲基噻吩-2-甲酰胺（4）的构象偏好。化合物的选择源于它们作为折叠体构建块的用途。我们量化了这两种化合物的构象刚性差异，这种差异决定了相应的折叠体构象。具体来说，我们通过比较 3、4 和之前研究过的邻甲氧基-N-甲基苯甲酰胺（1）和邻甲基硫代-N-甲基苯甲酰胺（2），展示了分子内氢键（H 键）、几何形状和溶剂极性对芳酰胺构象的影响。研究表明，尽管 3 的非最佳 S(5)-型 H 键几何形状，但即使在极性质子溶剂中，它仍保留了大部分氢键（重叠）构象。这种行为与量子力学（QM）扭转能谱一致。3 保留的氢键构象的百分比仅略小于具有更强 S(6)-型 H 键的 1。对于 2 和 4，1 中 O 原子被 2 中的 S 原子取代，导致溶液中氢键构象的损失率为 70-90%。然而，3 中 O 到 S 的等效取代（导致 4）仅导致 4 中重叠构象的损失率为 15-30%。因此，4 的构象偏好与 2 非常不同，与 3 和 1 的相似性相反。本研究表明了几种力的相互作用如何调节芳酰胺的构象灵活性。它还证明了我们正在开发的策略，可以准确预测折叠体结构。该策略的关键组成部分是基于 QM 势能谱重新参数化关键力场参数，并使用溶液中的实验数据验证这些参数。
