Synthesis and Reactivity at the Edges of Electrocyclic Chemistry

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Alison J. Frontier of the University of Rochester is studying the preparation of cyclic molecules using chemical reactions that can be formally characterized as "electrocyclizations." The processes being explored lie on the borderline between well-defined reaction classes that are typically considered to be separate from one another and which operate according to different principles.

A central goal of the project is to learn more about these ambiguous and little explored transformations by investigating the reactivity of molecules specially designed to exhibit behavior at the "edges" of an accepted paradigm. Beyond the theoretical advances anticipated from the research, which combine insights gained from both experimental and computational chemistry, the work is expected to provide new practical approaches for the synthesis of complex molecules containing multiple rings and that possess well-defined three-dimensional structures.

Such compounds are of potential utility as precursors to new pharmaceutical agents, agrochemicals, and other advanced chemical materials of value to society. The broader impacts of this award will extend to the benefits to chemical education accrued as Professor Frontier continues to develop and maintain the innovative "Not Voodoo" website that she created in 2004.

The site, which is now complemented by useful social media-based outreach, is designed to help practitioners of synthetic organic chemistry to demystify laboratory techniques and procedures. It serves hundreds of experimentalists each day, from students just beginning their independent research, to more advanced scientists looking for tips or tricks. "Not Voodoo" also plays a valuable role in promoting chemical safety.

This research in the Frontier group at the University of Rochester will focus on the development of three new synthetic methods, each involving an underdeveloped reaction type that occurs by an ill-defined mechanistic pathway at the edges of known electrocyclic chemistry. In Project 1, the scope of an ambiguous type of pentannulation, the "iso-Nazarov" cyclization, is being expanded upon and the electrocyclic vs. ionic nature of these borderline reactions interrogated by a combination of experimental and computational techniques.

In Project 2, the boundaries of electrocyclic reactivity are being extended to previously unknown higher-order cationic electrocyclizations (e.g., 6 pi-election processes leading to 7-membered rings) by studies of carefully designed unsaturated substrates. Finally, Project 3 has as its aim the discovery of a route, or a bridge, allowing efficient passage from radical to electrocyclic chemistry.

Herein, a 1,5-hydrogen atom transfer-based radical-polar crossover strategy is being explored as a means to generate both cationic and anionic intermediates, thereby potentially accessing electrocyclic chemistry in a novel way. All three projects are anticipated to lead to significant new methods for the synthesis of unusual polycycles, including examples containing cycloheptane rings, spirocyclic motifs, and nitrogen and oxygen heterocycles.

Improvements to the Not Voodoo website are also underway, including: (1) addition of chemical information resources; (2) introduction of new chemical safety content using information collected from the Chemical Safety Library; (3) site maintenance, which evolves continuously with user input; and (4) expanding the scope of the practical technical content.

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.