(Radio)Fluorination and Other Nucleophilic Functionalizations Enabled by Photocatalytic Radical-Polar Crossover

光催化自由基-极性交叉实现的（放射性）氟化和其他亲核官能化

• 批准号: 2102266
• 负责人: Abigail Doyle
• 金额: $ 50万
• 依托单位: University of California-Los Angeles
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2102266&HistoricalAwards=false
• 关键词: Radio; Fluorination; Other; Nucleophilic; Functionalizations

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Abigail Doyle of University of California, Los Angeles is developing new chemical reactions that will enable the synthesis of organofluorine compounds; namely those that contain a C-F bond. Such bond constructions are in high demand as C-F bonds are found in next-generation medicines, agrochemicals, and biomedical imaging agents. The chemical reactions under development here use a catalyst that can harness the energy in visible light to generate a high-energy reactive intermediate, a carbocation, that is most often only accessible under harsh (thermal or strongly acidic or Lewis-acidic) conditions. Because the strategy being pursued by Professor Doyle and her students accesses this intermediate under the mild conditions associated with visible light irradiation, reactions are being developed that generate chemical structures that were previously challenging to access, starting from abundant and inexpensive reagents. The researchers will use a variety of tools to help them understand how the reactions work at the molecular level such that this knowledge can be used to discover new processes and design improved reactions. Students conducting these research activities will have the opportunity to develop a broad skill set, both scientific in nature and with respect to communication, mentorship, leadership, and also with respect to embracing and building diversity, equity, inclusion and belonging, that will help them become leaders in their independent careers. Broader impacts of this work also include the development of activities directed at recruitment and retention of students from underrepresented groups to science, technology, engineering, and mathematics (STEM). For example, the program includes the development of undergraduate teaching material to highlight scientific contributions from researchers of diverse backgrounds, experiences and perspectives and the design of workshops for entering graduate students on topics such as citation bias, conflict management, and micro-aggression.Carbocations are reactive intermediates in a broad range of synthetic transformations because they undergo reaction with abundant and stable nucleophiles like water, alcohols, halides, amines, and olefins. Nevertheless, the generation of carbocation intermediates typically requires harsh reaction conditions and requires use of pre-oxidized precursors such as alkyl halides. These limitations preclude applications in more complex settings, such as in the synthesis of bioactive compounds or radiolabelling, and access to desirable products. This program seeks to address these challenges by using a photocatalyst and light to convert abundant and stable C(sp3)–OH, –NH2 and –H precursors to radicals and then to carbocations (a so-called radical-polar crossover). A focus of these efforts will be to use fluoride to trap the carbocation intermediates in order to generate organofluorine products that are useful in the pharmaceutical and agrochemical industries. Mechanistic studies will accompany these synthetic efforts and the most efficient strategies will also be adapted for the synthesis of 18-fluorine-radiolabelled small molecules for use in positron emission tomography (PET), an important diagnostic tool for detecting disease. This research will provide a rigorous and multi-disciplinary training environment for a diverse group of graduate and undergraduate students and postdoctoral fellows.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系化学合成 (SYN) 项目的支持下，洛杉矶加利福尼亚大学的 Abigail Doyle 教授正在开发新的化学反应，能够合成有机氟化合物，即含有 C-F 键的化合物。由于在下一代药物、农用化学品和生物医学成像剂中发现了 C-F 键，因此对这种结构的需求量很大。这里正在开发的化学反应使用可以利用可见光能量来产生光的催化剂。高能中间体活性物质，一种碳正离子，通常只能在恶劣（热或强酸性或路易斯酸性）条件下才能获得，因为多伊尔教授和她的学生所追求的策略是在与可见光相关的温和条件下获得这种中间体。在光照射下，正在开发的反应可以产生以前难以获得的化学结构，研究人员将使用各种工具来帮助他们了解反应如何在分子水平上进行，以便这些知识能够实现。用来发现新的进行这些研究活动的学生将有机会发展广泛的技能，包括科学本质和沟通、指导、领导力，以及拥抱和建立多样性、公平、包容性和包容性。这项工作的更广泛影响还包括开展旨在招募和留住弱势群体学生的活动，例如科学、技术、工程和数学 (STEM)。该计划包括开发本科教材以突出科学性来自不同背景、经验和观点的研究人员的贡献，以及为进入研究生设计的研讨会，主题涉及引用偏差、冲突管理和微攻击等。碳阳离子是各种合成转化中的反应性中间体，因为它们与丰富且稳定的亲核试剂，如水、醇、卤化物、胺和烯烃，然而，碳阳离子中间体的生成通常需要苛刻的反应条件，并且需要使用预氧化的前体，如烷基。这些限制阻碍了在更复杂的环境中的应用，例如生物活性化合物的合成或放射性标记，以及获得所需产品的方法，该计划旨在通过使用光催化剂和光来转化丰富且稳定的 C(sp3) 来解决这些挑战。 -OH、-NH2 和 -H 是自由基的前体，然后是配位（所谓的自由基-极性交叉）。这些努力的重点是使用氟化物捕获碳正离子中间体，以产生碳正离子中间体。可用于制药和农用化学工业的有机氟产品的机理研究将伴随这些合成工作，并且大多数策略也将适用于合成用于高效正电子发射断层扫描（PET）的 18-氟放射性标记小分子。这项研究将为不同群体的研究生、本科生和博士后研究员提供严格的多学科培训环境。该奖项是 NSF 的法定使命，并被认为值得支持。通过使用基金会的智力优点和更广泛的影响审查标准进行评估。