Designed Mediators for Selective Electrochemical C H Oxidation

设计用于选择性电化学CH氧化的介体

• 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
• 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

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 这项研究项目的主要目标将是为选择性地开发设计的调解器 SP3 C-H键的电化学氧化，通过使用描述性统计建模。远程C-H氧化 从综合的角度来看，战略是非常可取的，并对人类健康具有影响，因为 用于药物的后期衍生化。然而，远程C-H功能化方法一直存在低 与现代有机合成中已成为标准的高选择性水平相比，选择性水平更高。 为了解决这个复杂的问题，深入研究了导致C-H选择性的分子性质 将进行激活过程。 吡啶氮氧化物及其衍生物将被评为一类新的潜在的氧化还原介体(目标1)。按顺序 为了将C-H氧化介体的结构和电子性质与选择性相关联，建立了PNO衍生物的文库 将被合成，并将使用具有不同复杂性的模型底物收集站点选择性数据(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，能够 提取富电子的SP3C-C-H键。在分子氧存在的情况下，预计会发生净的C-H氧化。PNO 支架提供了所需的模块化，以建立包含大量空间/电子变化的衍生物库 属性。空间参数，如斯特里摩尔值，被预测为产生线性自由能关系 2°C-H键和3°C-H键之间的选择性差异，或立体分化的2°C-H键之间的选择性差异。电子学 参数，如键伸展频率，可能与电子之间的选择性差异相关 差异化的C-H键。然后，这些参数中的每一个对选择性的影响可以使用线性组合 回归算法，以生成数学模型，以识别特定的介体特征 它控制着位置的选择性。该方法的关键原则是选择性的所有数据点都将包括在模型中， 因为负结果(即，对错误的C-H键的选择性较差)也提供了关于 站点选择性。一个统计稳健的选择性模型将允许在知情的情况下设计新的介体 改进了站点选择性。将评估改进的介体促进C-H选择性氧化的能力 更多种类的底物，含有空间和电子差异的C-H键。 此外，还将同时采用基于1，4-二氮杂双环[2.2.2]辛烷(DABCO)的类似战略 衍生品(目标2)。DABCO衍生物预计相对容易合成，为以下化合物提供一般结构 产生了一个立体和电子变异体的文库。这将允许生成一组不同于 对于PNO中介体，可以得出更多关于重要结构特征的结论。对.的使用 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，可以用来 为不同类型的C-H键选择。