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SOLVENT EFFECTS ON AMIDE ROTATION USING 'TWISTED' AMIDES

使用“扭曲”酰胺时溶剂对酰胺旋转的影响

基本信息

批准号：
6448792
负责人：
KATHLEEN M MORGAN
金额：
$ 12.99万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2005-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6448792
关键词：
amides chemical bond chemical models chemical reaction chemical structure function hydrogen bond intermolecular interaction solvents thermodynamics

项目摘要

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.

本研究的目的是评估溶剂对酰胺C-N键旋转势垒的影响。已知几个稳定的酰胺类化合物，它们的结构特征部分或完全阻止了氮上的孤对离域进入羰基圆周率键。其中一些“扭曲”的酰胺将被用来探索溶剂对各种酰胺构象的影响。虽然人们对酰胺旋转势垒对溶剂的依赖知道得很多，但对于反应坐标上溶剂/溶质相互作用的差异最显著以及为什么会存在这些差异，人们知之甚少。旋转势垒降低是因为过渡态稳定，反应物不稳定，还是某种组合？这些能量的绝对大小是多少？它们的来源是什么？氢键如何随着酰胺构象的变化而变化？酰胺的性质高度依赖于C-N键的构象。详细分析酰胺类化合物的构象分布，特别是作为环境的函数，是很重要的，原因有几个。蛋白质采用和保持具有特定生物活性的三维结构的能力取决于酰胺键的旋转性，这一点受介质的影响很大。旋转酰胺更容易被水解，例如被丝氨酸蛋白酶。应变酰胺与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自于模拟旋转酰胺的结构特征。更根本的是，更好地了解酰胺中的结构-能量关系将考验我们的结构和成键理论。本文提出了两个或多个“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。通过量热法测量在各种溶剂中的溶解热，以确定与普通平面叔胺相比，哪些溶剂性质在稳定和破坏旋转酰胺的稳定性方面最重要。此外，还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。