Aziridine scaffolds for the detection and quantification of hydrogen-bonding interactions through transition-state stabilization.
Aziridine scaffolds for the detection and quantification of hydrogen-bonding interactions through transition-state stabilization.
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氮丙啶支架用于通过过渡态稳定检测和定量氢键相互作用。
DOI：
10.1002/anie.201005580
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Giordano L
中科院分区：
文献类型：
--
作者：
Giordano L
准确量化非共价相互作用的强度、距离和角度依赖性对于理解生物学和医学以及超分子和合成化学的许多方面至关重要。[1]然而，特定的弱相互作用往往难以量化。已知的方法[1，2]包括计算建模，信息学和各种实验技术。在后者中，最值得注意的是内部运动仅限于两种构象的系统，通过键旋转可互换。[2]例如，Wilcox等人开发的“分子扭转天平”，通过确定这两种构象异构体的平衡数量，成功地量化了一系列弱相互作用。[2b-d在这里，我们演示了如何在氮杂环丙烷的锥体反转的形式的分子运动可用于检测和评估单个H-键的强度。使用氮丙啶支架测量非共价相互作用背后的关键概念总结在方案1中。假设氮丙啶1受益于基态（GS）取代基X和Y之间有利的非共价相互作用;相对于缺乏这种相互作用的氮丙啶3，N转化的速率将降低（假设N转化需要X··· Y解离）。一旦考虑到次级相互作用（见下文），情况1和情况3之间吉布斯自由能势垒的差异（ΔΔG）应该可以直接测量1中的X··· Y相互作用强度。或者，假设X和Y仅在过渡态（TS）中相互作用。2的反转势垒将通过TS稳定而降低，因此N反转的速率将相对于3增加。同样，ΔΔ G将与X··· Y相互作用强度相关。在任何特定的系统中，通过将X和Y连接到氮丙啶支架的接头对X和Y施加的几何约束将决定X和Y是否可以在GS或TS中有效地相互作用，从而调节N转化的速率。基于氮丙啶的支架赋予许多属性，使得它们非常适合于这种应用。其中包括：1）相对于其他系统有利的合成可及性;[2c，d] 2）可以通过动态NMR光谱准确量化的转化率;[3] 3）在可预测的、明确定义的方向上对环取代基的空间控制; 4）氮丙啶氮原子的相对弱的碱性（不太可能与X··· Y相互作用竞争）;和5）适合从头计算的系统尺寸。为了探索这种新方法的潜力，一个简单的和众所周知的分子内相互作用，寻求在第一个实例中，与一个单一的H-键之间的邻位取代的吡啶和仲酰胺拟合这些标准。[4]因此，化合物4与对照化合物5-8一起沿着合成（方案2）。4、5和8中的H-键通过1H NMR光谱（298 K，约100 ° C）探测。10 mm）。有趣的是，与化合物5和8相比，在[D2]四氯乙烷中仅观察到4的酰胺NH信号的小的低场位移（4：δ= 6.94和6.25 ppm; 5：δ= 6.34和5.90 ppm; 8：δ= 6.31和5.90 ppm），这最多表明GS中仅存在非常弱的分子内相互作用。[5]这与文献中相关化合物的数据形成对比[4 b，c]
Accurately quantifying the strength, distance, and angular dependence of noncovalent interactions is central to understanding numerous aspects of biology and medicine, as well as supramolecular and synthetic chemistry.[1] However, specific weak interactions are often difficult to quantify. Known approaches [1, 2] include computational modeling, informatics, and a variety of experimental techniques. Of the latter, most notable are systems in which internal motions are restricted to two conformations, interchangeable through bond rotation.[2] For example, the “molecular torsion balance”, developed by Wilcox et al., has successfully quantified a range of weak interactions by determining the equilibrium population of these two conformers.[2b–d, g, h] Here, we demonstrate how molecular motion in the form of pyramidal inversion in aziridines may be used for detecting and assessing the strength of an individual H-bond. The key concepts behind the use of aziridine scaffolds for measuring noncovalent interactions are summarized in Scheme1. Suppose aziridine 1 benefits from a favorable noncovalent interaction between substituents X and Y in the ground state (GS); the rate of Ninversion will decrease relative to aziridine 3 lacking this interaction (provided X··· Y dissociation is required for N inversion). The difference in Gibbs free energy barrier between cases 1 and 3 (ΔΔG) should provide a direct measure of the X··· Y interaction strength in 1, once secondary interactions (see below) are accounted for. Alternatively, suppose X and Y interact only in the transition state (TS). The inversion barrier for 2 will then be lowered by TS stabilization and hence the rate of N inversion will increase relative to 3. Again, ΔΔGwill correlate with the X··· Y interaction strength. Geometric constraints placed on X and Y by linkers attaching them to the aziridine scaffold in any specific system will dictate whether X and Y can interact effectively in either the GS or TS and hence modulate the rate of N inversion. Aziridine based scaffolds confer a number of attributes making them well-suited for this application. These include: 1) favorable synthetic accessibility with respect to other systems;[2c, d] 2) inversion rates that can be accurately quantified by dynamic NMR spectroscopy;[3] 3) spatial control of ring substituents in predictable, well-defined orientations; 4) the relatively weak basicity of the aziridine nitrogen atom (less likely to compete with X··· Y interactions); and 5) system sizes that are amenable to ab initio calculations. To explore the potential of this new approach, a simple and well known intramolecular interaction was sought in the first instance, with a single H-bond between an orthosubstituted pyridine and a secondary amide fitting these criteria.[4] Compound 4 was accordingly synthesized, along with control compounds 5–8 (Scheme 2). H-bonding in 4, 5, and 8 was probed by 1H NMR spectroscopy (298 K, ca. 10 mm). Interestingly, only small downfield shifts for the amide NH signals of 4 in [D2] tetrachloroethane were observed compared to those for compounds 5 and 8 (4: δ= 6.94 and 6.25 ppm; 5: δ= 6.34 and 5.90 ppm; 8: δ= 6.31 and 5.90 ppm) indicating at best only a very weak intramolecular interaction in the GS.[5] This contrasts with data for related compounds in the literature [4b, c]
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