Deprotonative carbonylation cross-couplings

通过这一奖项，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的帕特里克·J·沃尔什教授的研究。沃尔什教授正在开发合成化学方法，使用一氧化碳(CO)和其他更复杂的分子作为关键试剂来制备分子化合物。采用的反应顺序制备的产品含有一个“酮”官能团，该官能团含有一个碳，该碳与一个氧形成双键，与另外两个碳形成单键。酮存在于许多天然产物和生物活性化合物中，使它们成为非常有价值的中间体和产品。酮可能很难制备，因此，它们是本研究的目标。除了合成酮的简化方法外，研究人员还在进行实验，帮助他们了解反应是如何发生的。其他研究人员可以在这一基本认识的基础上使用这些方法来设计新的反应。通过这一奖项，大学生将参与沃尔什教授实验室的本科生研究经验，并将成为参考出版物的共同作者。毕业后，这些熟练的研究人员将为化学工业做出贡献，支持美国经济。此外，沃尔什教授每年都会给高中的有机化学学生讲授他的NSF资助的研究。在这项提议中，沃尔什教授正在开发新的催化剂，开发新的实际反应，并描述它们的反应机理。大部分研究涉及弱酸性亲核试剂在碱性条件下碳氢(C-H)功能化/羰化反应中的应用。这种方法避免了官能化前和指导基团策略，从而能够有效地构建C-C键。研究的目标包括开发去质子化的羰基化交叉偶联反应(DCCC)和绘制用于DCCC反应的弱酸性底物的范围。芳基卤代化合物的羰基化反应是一种有效的酯类、酰胺类、醛类和酮类化合物的合成方法。尽管在通过这种羰基化合成酮方面取得了进展，但在知识方面仍然存在重大差距，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制有机金属试剂存在下的羰基化反应。这种方法的缺点包括需要制备或购买这些有机金属试剂，这些试剂可能有毒(有机锡)或对空气/水敏感(有机硼)。这些试剂的合成增加了成本，并产生了额外的废物。沃尔什小组正在推进的实用方法涉及亲核C-H键在芳基卤化物的羰化反应(1 Atm CO)中的官能化。该反应是在机理研究和参数筛选的基础上进行的。目前正在探索该方法的范围和局限性。除了上述社会效益外，这里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在学术或工业中用于中间体、药物、农产品或材料的制备时，可能会对生活质量产生积极影响。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.