Designed Mediators for Selective Electrochemical C H Oxidation

设计用于选择性电化学CH氧化的介体

基本信息

批准号：
9921204
负责人：
Jeremy Dale Griffin
金额：
$ 6.49万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9921204
关键词：
Acidity Address Affect Amines Anodes Benchmarking Binding Cathodes Cations Characteristics Complex Data Descriptor Development Electronics Electrons Environment Enzymes Equilibrium Evaluation Free Energy Frequencies Generations Goals Health Human Hydrogen Bonding Lead Libraries Light Linear Regressions Measures Mediator of activation protein Methodology Modeling Modernization Molecular Molecular Structure Octanes Organic Synthesis Oxidants Oxidation-Reduction Oxides Oxygen Pharmaceutical Preparations Process Property Research Project Grants Series Site Statistical Models Stretching Structure Structure-Activity Relationship System Techniques Variant abstracting base catalyst design drug synthesis improved mathematical model next generation oxidation pyridine regression algorithm scaffold screening small molecule success tertiary amine tool

项目摘要

PROJECT SUMMARY/ABSRTACT The primary goal of this research project will be the development of designed mediators for selective electrochemical oxidation of sp3 C–H bonds, through the use of descriptive statistical modeling. Remote C–H oxidation strategies are highly desirable from a synthetic standpoint and have implications for human health because of the potential for late stage derivatization of drugs. However, remote C–H functionalization methodologies have been plagued with low levels of selectivity, compared to the high levels of selectivity that have become the standard in modern organic synthesis. To address this complex problem, an intensive study into the molecular properties which bring about selectivity for C–H activation processes will be undertaken. Pyridine N-oxide and its derivatives will be evaluated as a new potential class of redox mediators (Aim 1). In order to correlate structural and electronic properties of C–H oxidation mediators with selectivity, a library of PNO derivatives will be synthesized and site-selectivity data (ΔΔG‡) will be collected using model substrates that have varying complexity. Electrochemical oxidation of PNO derivatives would produce highly electrophilic radical intermediates capable of abstracting electron rich sp3 C–H bonds. In the presence of molecular oxygen, a net C–H oxidation is expected. The PNO scaffold provides the modularity required to build a large library of derivatives containing wide variation in steric/electronic properties. Steric parameters, such as Sterimol values, are predicted to produce linear free-energy relationships that correlate to selectivity differences between 2° and 3° C–H bonds, or between sterically differentiated 2° C–H bonds. Electronic parameters, such as bond stretching frequencies, could correlate to selectivity differences between electronically differentiated C–H bonds. The effects of each of these parameters on selectivity can then be combined using linear regression algorithms to produce mathematical models that will allow identification of specific mediator characteristics which control site selectivity. A key tenet of this approach is that all data points for selectivity will be included in the model, because negative results (i.e. poor selectivity or selectivity for the wrong C–H bond) also give valuable information about site-selectivity. A statistically robust model for selectivity will allow for the informed design of new mediators with improved site selectivity. Improved mediators will be evaluated for their ability to facilitate site selective C–H oxidation in a wider variety of substrates containing sterically and electronically differentiated C–H bonds. Additionally, a similar strategy will be concurrently pursued using 1,4-diazabicyclo[2.2.2]octane (DABCO) based derivatives (Aim 2). DABCO derivatives are expected to be relatively easily synthesized, providing a general structure for producing a library of steric and electronic variants. This will allow for the generation of a different set of parameters than those obtained for PNO mediators and thus more conclusions about important structural features can be made. The use of two different mediator scaffolds could lead to the development of a “toolbox” of redox mediators that could be used to select for different types of C–H bonds.

项目概要/摘要该研究项目的主要目标是开发设计的介体，用于选择性通过使用描述性统计模型进行 sp3 C-H 键的电化学氧化。从综合的角度来看，策略是非常可取的，并且由于潜在的潜力而对人类健康产生影响然而，远程C-H功能化方法一直受到低水平的困扰。与已成为现代有机合成标准的高选择性水平相比。为了解决这个复杂的问题，深入研究了 C-H 选择性的分子特性将进行激活过程。 N-氧化物吡啶及其衍生物将被评估为一类新的潜在氧化还原介体（目标 1）。将 C-H 氧化介体的结构和电子特性与选择性关联起来，PNO 衍生物库将使用具有不同复杂性的模型底物来合成并收集位点选择性数据（ΔΔG‡）。 PNO 衍生物的电化学氧化会大量产生亲电自由基中间体，能够在分子氧存在的情况下，预计会发生净 C-H 氧化。脚手架提供了构建包含空间/电子方面广泛变化的大型衍生物库所需的模块化空间参数（例如 Sterimol 值）预计会产生相关的线性自由能关系。 2° 和 3° C-H 键之间的选择性差异，或空间差异的 2° C-H 键之间的选择性差异。键拉伸频率等参数可能与电子之间的选择性差异相关然后可以使用线性组合每个参数对选择性的影响。回归算法可生成数学模型，从而识别特定的中介特征这种方法的一个关键原则是选择性的所有数据点都将包含在模型中，因为负面结果（即选择性差或对错误的 C-H 键的选择性）也提供了有关以下方面的有价值的信息：位点选择性。技术上稳健的选择性模型将允许对新介体进行明智的设计。将评估改进的介体促进位点选择性 C-H 氧化的能力。含有空间和电子差异 C-H 键的更多种基材。此外，将同时采用基于 1,4-二氮杂双环[2.2.2]辛烷 (DABCO) 的类似策略衍生物（目标 2）预计相对容易合成，提供通用结构。生成空间和电子变体库，这将允许生成一组不同的参数。那些为 PNO 介体获得的结果，因此可以得出关于重要结构特征的更多结论。两种不同的介体支架可能会导致氧化还原介体“工具箱”的开发，该工具箱可用于选择不同类型的 C-H 键。