CAREER: Elucidating Isodiazene Reactivity with Anomeric Amide Reagents

University Of Chicago, Chicago IL

Investigators

Abstract

With support of the Chemical Synthesis Program in the Division of Chemistry, Mark Levin of the University of Chicago is studying a process that allows for the excision of single nitrogen-atoms from complex molecules while leaving the rest of the structure intact. This so-called 'molecular editing' technique provides scientists with the capacity to effect profound changes to existing compounds and it may facilitate the design and evaluation of new candidate pharmaceutical agents, advanced materials, and agrochemicals of potential benefit to society. In addition to developing more efficient and effective variants of the nitrogen-deleting transformation of interest, an understanding of its microscopic mechanism will be sought to inform on future variants of the process and to expand upon its range of applicability. The broader impacts of the funded project extend to the training and career development of the diverse team of graduate and undergraduate students conducting the research, many of whom will go on to become a part of the science, technology, engineering, and mathematics (STEM) workforce. Also under the auspices of the award, Professor Levin and a colleague at the University of Chicago continue their commitment to organizing the recently inaugurated Future Faculty Conference (FFC), a meeting designed to empower postdoctoral fellows belonging to groups traditionally underrepresented in the chemical sciences with the tools and knowledge necessary to successfully navigate the academic job market. It is envisioned that the annual FFC will help to improve the future diversity of the academy with the expected ancillary benefit of promoting inclusivity in higher education. The funded project focuses on the in situ generation of isodiazenes from amine substrates and anomeric amide reagents and detailed study of the subsequent transformations of these reactive intermediates, which typically involve extrusion of molecular nitrogen. The investigational plan of the project is divided into two themes. In the first, the development of improved anomeric amide reagents that subvert known decomposition modes of current best-in-class reagents, will be pursued to enable more challenging, weakly nucleophilic amine substrates to be successfully engaged. The challenges of this aim will be addressed through a systematic, computation-aided experimental structure-activity relationship survey of the reagent. The second research theme concerns an examination of the subtle mechanistic differences between how separate substrate classes react and leveraging the findings to develop additional synthetically useful transformations. A better understanding of the rules governing the partitioning of the isodiazene as a function of substrate structure will enable more effective nitrogen deletion reactions to be developed as well as nitrogen insertion, pericyclic rearrangements, and deaminative functionalizations. Each type of process has valuable applications and it is anticipated that the new knowledge emanating from this research will lead to important advances to the theory and practice of molecular editing and to the wider field of synthetic organic chemistry in general. 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.