SOLVENT EFFECTS ON AMIDE ROTATION USING 'TWISTED' AMIDES

本研究的目的是评估溶剂对酰胺C-N键旋转势垒的影响。已知有几种稳定的酰胺，其结构特征部分或完全阻止氮上的孤对离域进入羰基键。其中一些“扭曲”的酰胺将用于探索溶剂对各种酰胺构象的影响。虽然我们对酰胺旋转势垒对溶剂的依赖性了解甚多，但对反应坐标上溶剂/溶质相互作用的差异最显著的位置以及存在这些差异的原因知之甚少。转动势垒降低是因为过渡态稳定，反应物不稳定，还是两者兼而有之？这些能量的绝对值是多少，它们的起源是什么？氢键如何随酰胺构象变化？酰胺的性质高度依赖于C-N键的构象。由于几个原因，详细分析酰胺的构象分布，特别是作为环境的函数，是很重要的。蛋白质采用和维持具有特定生物活性的三维结构的能力取决于酰胺键旋转的难易程度，受到介质的高度影响。旋转酰胺更容易被水解，例如被丝氨酸蛋白酶水解。菌株酰胺与β -内酰胺类抗生素的生物活性密切相关，免疫抑制剂FK-506和雷帕霉素的活性来源于模拟旋转酰胺的结构特征。更根本的是，更好地了解酰胺的结构-能量关系将检验我们的结构和成键理论。本文提出了两种或两种以上的“扭曲”酰胺的研究，它们代表了C- N旋转势能曲线上的不同点。将用量热法在各种溶剂中测量溶液焓，以确定与普通平面叔酰胺相比，哪种溶剂性质对稳定和破坏旋转酰胺最重要。此外，将使用已知的模拟方法计算扭曲酰胺的溶剂化自由能，并将其与实验结果进行比较。

The goal of this investigation is to evaluate the influence of solvent on the barrier to rotate the amide C-N bond. Several stable amides are known in which structural features partially or completely prevent the lone pair on nitrogen from delocalizing into the carbonyl pi bond. Some of these "twisted" amides will be used to explore solvent effects on a variety of amide conformations. While much is known about the solvent dependence on the amide rotational barrier, little is known about where on the reaction coordinate the differences in solvent/solute interactions are most significant, and why these differences exist. Is a rotational barrier lowered because the transition state is stabilized, the reactant is destabilized, or some combination? What are the absolute magnitudes of these energies, and what are the origins? How does hydrogen bonding change with amide conformation? The properties of an amide are highly dependent on the conformation of the C-N bond. A detailed analysis of the conformational profile in amides, especially as a function of environment, is important for several reasons. The ability of a protein to adopt and maintain a three-dimensional structure with specific biological activity is dependent on the ease of rotation of the amide bonds, highly influenced by medium. Rotated amides are more susceptible to hydrolysis, for example by serine proteases. Strained amides are intimately involved in the biological activity beta-lactam antibiotics, and the immunosuppressants FK-506 and rapamycin derive their activity from structural features which mimic a rotated amide. More fundamentally, better knowledge of structure - energy relationships in amides will test our theories of structure and bonding. Study of two or more "twisted" amides is proposed herein, representing different points on the potential energy curve to C- N rotation. Enthalpies of solution will be measured in a variety of solvents by calorimetry to determine which solvent properties are most important in stabilizing and destabilizing the rotated amides, compared to normal planar tertiary amides. Also, free energies of solvation for the twisted amides will be calculated using known simulation methods and will be compared to experimental results.