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: 9756891
• 负责人: Jeremy Dale Griffin
• 金额: $ 6.09万
• 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/9756891
• 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.

项目概要/ABSRTACT 本研究项目的主要目标将是开发设计的调解人， 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 从合成的角度来看，这些策略是非常可取的，并且由于潜在的 用于药物的后期衍生化。然而，远程C-H官能化方法一直受到低活性的困扰。 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，深入研究了导致C-H选择性的分子特性， 将进行激活过程。 吡啶N-氧化物及其衍生物将作为一种新的潜在的氧化还原介体（目标1）进行评估。为了 为了将C-H氧化介体的结构和电子性质与选择性相关联，PNO衍生物库 将合成，并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， 提取富含电子的sp3 C-H键。在分子氧的存在下，预期净C-H氧化。PNO 支架提供了构建含有空间/电子结构的广泛变化的衍生物的大型文库所需的模块性。 特性.空间参数，如Sterimol值，预测产生线性自由能关系， 2°和3° C-H键之间的选择性差异，或空间上不同的2° C-H键之间的选择性差异。电子 参数，如键拉伸频率，可以与电子之间的选择性差异相关， 不同的C-H键。这些参数中的每一个对选择性的影响然后可以使用线性组合来组合。 回归算法，以产生数学模型，允许识别特定的中介特征 其控制位点选择性。这种方法的一个关键原则是选择性的所有数据点都将包括在模型中， 因为阴性结果（即差的选择性或对错误的C-H键的选择性）也提供了关于以下的有价值的信息： 位点选择性一个统计学上可靠的选择性模型将允许知情设计新的调解人， 提高了网站的选择性。将评价改良的介质促进位点选择性C-H氧化的能力， 含有空间和电子差异化的C-H键的更广泛种类的底物。 此外，类似的策略将同时采用基于1，4-二氮杂双环[2.2.2]辛烷（DABCO）的 衍生物（目标2）。预期DABCO衍生物相对容易合成，从而提供了DABCO衍生物的一般结构。 产生空间和电子变体的文库。这将允许生成一组不同于 PNO介质获得的那些，从而可以得出更多关于重要结构特征的结论。使用 两种不同的介体支架可以导致开发氧化还原介体的“工具箱”， 选择不同类型的C-H键。