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

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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.