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

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

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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.

项目摘要/absrtact 该研究项目的主要目标是开发选择性的设计调解人通过使用描述性统计建模，SP3 C – H键的电化学氧化。远程C – H氧化从综合的角度来看，策略是非常可取的，并且对人类健康具有影响用于药物的晚期衍生化。但是，远程C – H功能化方法已经困扰与高水平的选择性相比，选择性水平已成为现代有机合成的标准。为了解决这个复杂的问题，一项对分子特性的深入研究，该研究带来了C – H的选择性将进行激活过程。吡啶N-氧化物及其衍生物将被评估为一种新的潜在氧化还原介质类别（AIM 1）。为了将C – H氧化介质的结构和电子特性与选择性相关联（PNO衍生物库）将使用具有不同复杂性的模型底物收集位点选择性数据（ΔΔG‡）。 PNO衍生物的电化学氧化将产生高度亲电的自由基中间体抽象富含电子SP3 C – H键。在存在分子氧的情况下，预期净C – H氧化。 pno 脚手架提供了建造大型衍生品库所需的模块化，该衍生物包含宽度/电子的宽度变化特性。预测的空间参数（例如固醇值）被预测会产生线性的自由能关系在2°和3°C – H键之间或在空间分化的2°C – H键之间的选择性差异。电子的参数（例如键拉伸频率）可能与电子方式之间的选择性差异相关分化的C – H键。然后可以使用线性将这些参数中的每个参数的影响组合在一起回归算法生成数学模型，以识别特定的介体特征哪个控制站点的选择性。这种方法的关键宗旨是，所有选择性数据点都将包括在模型中，因为负面结果（即错误的C – H键的选择性差或选择性差）也提供了有关的宝贵信息现场选择性。选择性的统计坚固模型将允许使用新调解人的知情设计提高了现场选择性。将评估改进的介体的能力，以促进现场选择性C – H氧化各种包含空间和电子分化的C – H键的底物。此外，将使用基于1,4-二氮杂的辛烷（DABCO）同时采用类似的策略衍生物（AIM 2）。预计DABCO衍生物将相对容易合成，为产生一个空间和电子变体的库。这将允许生成一组不同的参数可以为PNO介体获得的那些，因此可以得出有关重要结构特征的更多结论。使用两个不同的调解人脚手架可能会导致开发氧化还原介体的“工具箱”，可用于选择不同类型的C – H键。