Deprotonative carbonylation cross-couplings

有了这个奖项，美国国家科学基金会化学部的化学催化计划正在支持宾夕法尼亚大学教授帕特里克J.沃尔什的研究。沃尔什教授正在开发合成化学方法，以一氧化碳（CO）和其他更复杂的分子作为关键试剂来制备分子化合物。所采用的反应顺序制备含有“酮”官能团的产物，所述“酮”官能团含有带有与氧的双键和与两个其它碳的单键的碳。酮存在于许多天然产物和生物活性化合物中，使其成为非常有价值的中间体和产品。 酮可能难以制备，因此，它们是本研究的目标。除了合成酮的简化方法外，研究人员正在进行实验，帮助他们了解反应是如何发生的。其他研究人员可以使用这些方法来设计基于这种基本理解的新反应。通过这个奖项，大学生参与本科生的研究经验，在教授沃尔什的实验室，并将共同作者的参考出版物。毕业后，这些熟练的研究人员有助于化学工业，支持美国经济。此外，沃尔什教授每年给高中有机化学的学生关于他的NSF支持的研究讲座。 在这项提案中，沃尔什教授正在开发新的催化剂，开发新的实用反应，并描绘其反应机理。许多研究涉及弱酸亲核试剂在碱性条件下的碳氢（C-H）官能化/羰基化反应中的应用。这种方法避免了预官能化和定向基团策略，从而能够有效地构建C-C键。研究的目标包括开发去质子羰基化交叉偶联反应（DCCC）和绘制DCCC反应的弱酸底物范围。卤代芳烃的羰基化反应是合成酯、酰胺、醛、酮的有效方法。尽管在通过这种羰基化合成酮方面取得了进展，但知识上的巨大差距仍然阻碍了其全部潜力的实现。目前的方法依赖于芳基卤化物在预先形成的有机金属试剂存在下的羰基化。这种方法的缺点包括需要制备或购买这些有机金属试剂，它们可能是有毒的（有机锡）或对空气/水敏感的（有机硼）。这些试剂的合成增加了成本并产生额外的废物。沃尔什小组正在推进涉及芳基卤化物羰基化（1 atm CO）中亲核C-H键官能化的实用方法。该反应是基于机理研究和参数筛选进行的。目前正在探讨这一方法的范围和局限性。除了上述社会效益外，本文开发的方法还使其他研究人员能够解决重要的合成问题。此外，新的概念和合成方法可能会对生活质量产生积极的影响，当用于制备中间体，药物，农产品，或材料在学术或工业。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

With this award, the Chemical Catalysis Program of the NSF Division of Chemistry is supporting the research of Professor Patrick J. Walsh at the University of Pennsylvania. Professor Walsh is developing synthetic chemical methods to prepare molecular compounds using carbon monoxide (CO) and other more complex molecules as key reagents. The sequence of reactions employed prepares products that contain a "ketone" functional group, which contains a carbon bearing a double bond to an oxygen and single bonds to two other carbons. Ketones are found in numerous natural products and biologically active compounds, making them highly valuable intermediates and products. Ketones can be difficult to prepare and thus, they are the targets of this study. In addition to a streamlined method to synthesize ketones, the researchers are performing experiments that help them understand how the reactions occur. Other researchers can use these methods to design new reactions based on this fundamental understanding. Through this award, university students are involved in undergraduate research experiences in Professor Walsh's labs and will be co-authors on refereed publications. Upon graduation, these skilled researchers contribute to chemical industry, supporting the US economy. In addition, Professor Walsh gives annual lectures to high school organic chemistry students about his NSF supported research. In this proposal, Professor Walsh is developing new catalysts, developing novel practical reactions, and delineating their reaction mechanisms. Much of the research involves the application of weakly acidic pro-nucleophiles in carbon-hydrogen (C-H) functionalization/carbonylation reactions under basic conditions. This approach avoids prefunctionalization and directing group strategies, enabling the efficient construction of C-C bonds. The objectives of the investigations include developing deprotonative carbonylation cross-coupling reactions (DCCC) and mapping the scope of weakly acidic substrates for DCCC reactions. The carbonylation of aryl halides is a powerful method to access esters, amides, aldehydes and ketones. Despite progress in the synthesis of ketones via such carbonylations, a significant gap in knowledge remains that prevents realization of its full potential. Current methods rely on carbonylation of aryl halides in the presence of preformed organometallic reagents. Drawbacks to this approach include the need to prepare or purchase these organometallic reagents, which can be toxic (organotins) or air/water sensitive (organoborons). The synthesis of these reagents adds costs and generates additional waste. The Walsh group is advancing practical approaches involving functionalization of pro-nucleophile C-H bonds in the carbonylation (1 atm CO) of aryl halides. This reaction is being performed based on mechanistic investigations and parameter screening. The scope and limitations of the method are being explored. In addition to the above-mentioned societal benefits, the methods developed herein are enabling other researchers to solve important synthetic problems. Furthermore, the new conceptual and synthetic methods may have a positive impact on the quality of life when used in the preparation of intermediates, medications, agricultural products, or materials in academics or industry.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.