GOALI: Designing Adaptive Hydrogen-bonded Frameworks for Molecular Structure Determination

非技术性总结。分子的结构是化学的核心，自19世纪世纪科学家的先驱努力以来，如雅各布斯·范特霍夫（Henricus van 't Hoff）和路易斯·巴斯德（Louis Pasteur），他们阐明了四面体碳原子的结构，揭示了分子手性与其相应晶体形式之间的关系。手性是一种通常与碳原子周围四个不同基团的空间排列相关的性质，对于蛋白质和DNA等生命分子以及有益于人类健康的药物化合物至关重要。在材料研究部和多学科活动办公室的固态和材料化学计划的支持下，该项目使用计算和实验的结合来设计自适应的主体框架，由分子构建，这些分子围绕形状笨拙的大客体分子结晶，一些手性分子，否则无法自己结晶。这种方法揭示了分子组装成多组分晶体的规则，同时还允许使用X射线衍射确定分子结构，为学术和商业实验室的有机合成化学家提供了一个有价值的工具，包括需要药物开发结构信息的制药公司。利用美国国家科学基金会（NSF）计划的结构，为学术界与工业界的联络（GOALI），纽约大学的本科生和研究生受益于实习支持默克未来人才计划，以获得在附近的GOALI合作伙伴，默克公司的工业环境中的研究经验，Inc.该项目还与纽约大学大学科学和技术入学方案合作，向来自代表性不足群体的学生介绍分子结构，包括制作一本配有与人类健康有关的分子插图的教育着色书;为学生和博士后提供专业发展活动;为波多黎各大学里奥皮德拉斯分校的本科生和研究生研究建立一个基础广泛的渠道;并为学术、政府和工业部门举办化学晶体学研讨会和大师班。因此，该项目使多个层次的学习者受益，并拓宽了STEM（科学、技术、工程和数学）领域的机会和职业渠道。分子框架，跨越金属有机，共价有机和氢键，在固态化学中占据核心作用，主要是由于能够通过分子设计来调节其性能。氢键骨架（HBF）是独特的，因为它们能够通过将客体分子封装在明确定义的空腔中来形成结晶的化学计量包合物。氢键键合的胍-有机磺酸盐（GS）主体框架在这方面是非常通用的，具有在具有适应客体的大小和形状的结构的框架的可调谐腔中捕获宽范围的客体分子的能力。这些特征提供了一个独特的机会来解开，然后部署，管理主机-客户组织和固态结构的规则。在GOALI结构下运行，在材料研究部和多学科活动办公室的固态和材料化学计划的支持下，纽约大学和默克&公司的研究人员部署了大量的GS框架，目的是设计优化方案-从简单的几何拟合到机器学习工具-通过单-高质量单晶分步结晶。该方案能够确定包封客体的分子结构，包括立体中心的绝对构型，解决了学术和工业领域合成化学家面临的关键挑战。因此，该研究计划为HBFs的全新应用提供了一个跳板，同时揭示了通常负责包合物组装和结构的因素。GOALI利用默克的知识基础来确定该方法的范围和一般性，重点关注现实世界感兴趣的目标分子，无论是反应中间体，化学杂质，活性药物成分或其类似物。该方法通过出版物、直接电子邮件和一个独立网站向公众传播，该网站将宣布新的结构分配、将结果存档并整合计算工具用于框架选择。该奖项反映了NSF的法定使命，并被认为值得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来支持。

Non-Technical Summary. The structure of molecules is central to chemistry, recognized since the pioneering efforts of 19th century scientists such as Jacobus Henricus van't Hoff, who formulated the structure of the tetrahedral carbon atom, and Louis Pasteur, who unraveled the relationship between molecular chirality and their corresponding crystal forms. Chirality, a property typically associated with the spatial arrangement of four different groups about a carbon atom, is essential to molecules of life such as proteins and DNA, as well as pharmaceutical compounds beneficial to human health. With support from the Solid State and Materials Chemistry Program in the Division of Materials Research and the Office of Multidisciplinary Activities, this project uses a combination of computation and experiment to design adaptive host frameworks, built from molecules, that crystallize around awkwardly shaped large guest molecules, some chiral, that otherwise cannot crystallize on their own. This approach unravels the rules for assembly of molecules into multicomponent crystals while also allowing determination of molecular structure using X-ray diffraction, providing a valuable tool to organic synthetic chemists in academic and commercial laboratories, including pharmaceutical companies that need structural information for drug development. Capitalizing on the structure of the NSF program Grant Opportunities for Academic Liaison with Industry (GOALI), New York University undergraduate and graduate students benefit from internships supported by the Merck Future Talent Program to gain research experience in an industrial setting at the nearby GOALI partner, Merck & Co., Inc. The project also partners with the NYU Collegiate Science and Technology Entry Program to introduce students from underrepresented groups to the structure of molecules, including creation of an educational coloring book with illustrations of molecules that are relevant to human health; provides professional development activities for students and postdocs; builds a broad-based conduit to the University of Puerto Rico-Rio Piedras for undergraduate and graduate research; and hosts chemical crystallography workshops and master classes for the academic, government and industrial sectors. Consequently, the project benefits learners at multiple levels and widens the pipeline for opportunities and careers in STEM (Science, Technology, Engineering and Mathematics).Technical Summary. Molecular frameworks, spanning metal-organic, covalent-organic and hydrogen-bonded, occupy a central role in solid-state chemistry, largely owing to the ability to tune their properties through molecular design. Hydrogen-bonded frameworks (HBFs) are unique owing to their ability to form crystalline stoichiometric inclusion compounds by encapsulating guest molecules in well-defined cavities. Hydrogen-bonded guanidinium-organosulfonate (GS) host frameworks are remarkably versatile in this respect, with an ability to capture a wide range of guest molecules in tunable cavities of frameworks with architectures that adapt to the size and shape of the guests. These characteristics provide a unique opportunity to unravel, and then deploy, the rules governing host-guest organization and solid-state structure in general. Operating under a GOALI construct, with support from the Solid State and Materials Chemistry Program in the Division of Materials Research and the Office of Multidisciplinary Activities, New York University and Merck & Co. investigators deploy a substantial collection of GS frameworks with an aim of devising optimization protocols – from simple geometric fitting to machine learning tools – for targeted inclusion of guest molecules through single-step crystallization of high quality single crystals. This protocol enables determination of the molecular structure of encapsulated guests, including absolute configuration of stereogenic centers, addressing a critical challenge faced by synthetic chemists in the academic and industrial sectors. Consequently, the research plan provides a springboard for an entirely new application for HBFs while revealing factors responsible for assembly and structure of inclusion compounds in general. The GOALI capitalizes on the knowledge base of Merck to determine the scope and generality of this approach with a focus on target molecules of real-world interest, whether reaction intermediates, chemical impurities, active pharmaceutical ingredients or their analogs. The methodology is disseminated to the public through publications, direct E-mail, and a stand-alone website that will announce new structure assignments, archive the results and integrate computational tools for framework selection.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.