Regioselective [2+2+2] Cyclotrimerizations

在化学系化学合成项目的支持下，西弗吉尼亚大学的Gregory Dudley和Brian Popp正在研究制备苯和其他芳香（类苯）化合物的复杂衍生物的选择性新方法。芳香族化合物在医疗保健、农业、电子和能源领域的应用为社会带来了许多好处，但更复杂的例子的阐述是一个挑战，因为它需要在这些环分子的周围正确放置多个取代基。该资助项目的中心假设是，乙炔的衍生物（一种容易获得的二碳结构块和相关化合物）可以与催化剂以三倍的方式连接在一起，以制造苯的衍生物，其组合的方向由三种结构块的性质和所使用的催化剂类型精确控制。这项研究将与大学教育和其他协同活动相结合，有可能推进化学合成领域的基础知识，并在分子科学领域内外产生积极影响。资助项目的更广泛影响包括支持研究团队成员开展的广泛的外展活动，这些活动将促进更广泛地参与STEM（科学、技术、工程和数学），包括来自服务不足的阿巴拉契亚社区的个人参与。区域选择性[2+2+2]环三聚化是一个长期存在的挑战，没有通用的解决方案。与预先存在的芳烃的功能化相比，直接苯并化策略是有吸引力的，但众所周知，它们很难减少到实践中，特别是作为一种获得高取代芳环体系的手段。该资助项目的重点是通过结合一系列底物控制原理来克服这些困难，这些原理旨在通过精确的区域控制来实现炔和/或炔代物的聚合组装。目前正在研究两种方法来实现Rh或ni催化的苯并环化化学的高区域选择性：第一种方法涉及底物之间的氢键和其他模板效应（包括共价系缚），第二种方法利用乙烯基砜作为具有独特立体电子结构的炔替代品。在达德利实验室，面向目标的合成（到三聚烷型倍半萜类）和方法开发工作将集中在区域选择性双组分偶联上，用于会聚合成四、五和六取代苯环，其中三种构建块（炔和/或乙烯基砜）中的两种（炔和/或乙烯基砜）。Popp实验室同时进行的实验和计算机制以及有机金属研究将集中在涉及乙烯基砜作为极化炔替代品的三组分耦合的发展上。这些互补的努力涉及研究生和本科生在沉浸式研究培训环境中一起工作，预计所获得的经验将帮助他们成为未来全球创新经济的潜在领导者。该研究有望在高取代苯衍生物的化学合成方面取得重大进展，并在理论、机理和实验上为区域选择性[2+2+2]环三聚化反应提供新的设计范式。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 Program in the Division of Chemistry, Gregory Dudley and Brian Popp of West Virginia University are studying selective new methods for preparing complex derivatives of benzene and other aromatic (benzenoid) compounds. Aromatic compounds offer many benefits to society with applications in the healthcare, agriculture, electronic, and energy sectors, but the elaboration of more complex examples is a challenge because it requires the correct placement of multiple substituents around the periphery of these cyclic molecules. The central hypothesis of the funded project is that derivatives of acetylene, a readily available two-carbon building block, and related compounds, can be stitched together with catalysts in a three-fold fashion to make derivatives of benzene with the orientation of their combination being precisely controlled by the nature of the three building blocks and the type of catalyst employed. The research, which will be integrated with university education and other synergistic activities, has the potential to advance fundamental knowledge in the field of chemical synthesis and create positive impact across and beyond the molecular sciences. The broader impacts of the funded project extend to supporting a wide range of outreach activities conducted by the research team members that will foster broadening participation in STEM (science, technology, engineering and mathematics) and including engagement of individuals from underserved Appalachian communities.Regioselective [2+2+2] cyclotrimerization as a route to aromatic compounds is a long-standing challenge with no general solution. Compared with functionalization of pre-existing arenes, direct benzannulation strategies are attractive but they have been notoriously difficult to reduce to practice, especially as a means to access highly substituted aromatic ring systems. The funded project is focused on overcoming these difficulties by combining a range of substrate control principles designed to enable the convergent assembly of alkynes and/or alkyne surrogates with precise regiocontrol. Two approaches to achieve high regioselectivity in Rh- or Ni-catalyzed benzannulation chemistries are being pursued: the first involves hydrogen bonding and other templating effects (including covalent tethering) between substrates, and the second utilizes vinyl sulfones as alkyne surrogates with a distinct stereoelectronic profile. Target-oriented synthesis (to illudalane-type sesquiterpenoids) and methodological development efforts in the Dudley laboratory will be focused on regioselective two-component couplings for the convergent synthesis of tetra-, penta-, and hexa-substituted benzene rings in which two of the three building blocks (alkynes and/or vinyl sulfones) are tethered together. Concurrent experimental and computational mechanistic and organometallic studies in the Popp laboratory will be focused on the development of three-component couplings involving vinyl sulfones as polarized alkyne surrogates. These complementary efforts involve graduate and undergraduate students working together in an immersive research training environment and it is anticipated that the experiences gained will help them to emerge as potential future leaders of the global innovation-based economy. The research is expected to lead to significant advances in the chemical synthesis of highly substituted benzene derivatives and to provide new design paradigms for regioselective [2+2+2] cyclotrimerization reactions based on theory, mechanism, and experiment.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.