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

在化学系化学合成（SYN）项目的支持下，加州大学洛杉矶分校的Abigail Doyle教授正在开发新的化学反应，使有机氟化合物的合成成为可能；也就是那些含有碳-氟键的。这种键结构的需求量很大，因为下一代药物、农用化学品和生物医学显像剂中都发现了C-F键。这里正在开发的化学反应使用一种催化剂，这种催化剂可以利用可见光中的能量来产生高能量的反应中间体，即碳正离子，这种物质通常只能在恶劣的条件下（热或强酸性或刘易斯酸）才能获得。由于Doyle教授和她的学生所追求的策略是在与可见光照射相关的温和条件下获得这种中间体，因此正在开发反应，以产生以前难以获得的化学结构，从丰富和廉价的试剂开始。研究人员将使用各种工具来帮助他们了解反应是如何在分子水平上起作用的，这样这些知识就可以用来发现新的过程和设计改进的反应。从事这些研究活动的学生将有机会发展一套广泛的技能，既包括科学性质，也包括沟通、指导、领导能力，以及拥抱和建立多样性、公平、包容和归属感，这将帮助他们成为独立职业生涯中的领导者。这项工作的更广泛影响还包括开展旨在从代表性不足的群体招募和留住学生到科学、技术、工程和数学（STEM）领域的活动。例如，该计划包括开发本科教材，以突出来自不同背景、经验和观点的研究人员的科学贡献，并为进入研究生设计研讨会，主题包括引用偏见、冲突管理和微侵略。碳正离子是广泛合成转化的活性中间体，因为它们与丰富而稳定的亲核试剂如水、醇、卤化物、胺和烯烃发生反应。然而，碳正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前体，如烷基卤化物。这些限制妨碍了在更复杂的情况下的应用，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。该项目旨在通过使用光催化剂和光将丰富而稳定的C(sp3) -OH， -NH2和-H前体转化为自由基，然后转化为碳正离子（所谓的自由基-极性交叉）来解决这些挑战。这些努力的一个重点将是利用氟化物捕获碳正离子中间体，以便生产在制药和农用化学工业中有用的有机氟产品。在进行这些合成工作的同时，还将进行机理研究，最有效的策略也将用于合成18-氟放射性标记的小分子，用于正电子发射断层扫描（PET），这是一种检测疾病的重要诊断工具。这项研究将为研究生、本科生和博士后提供一个严格的多学科培训环境。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.