Umpolung Methods with Electron Rich Aromatic Systems: Amine-Derived Reactive Intermediates in Synthesis

About This Grant

With the support of the Chemical Synthesis Program of the Division of Chemistry, Professor William Chain of the Department of Chemistry and Biochemistry at the University of Delaware is developing new classes of reactions with aromatic compounds. The goal of this research is to exploit weak bonds and temporarily elevate the reactivity of normally inert chemical compounds. This temporary inversion of reactivity of aromatic compounds facilitates formation of a wide array of new carbon–carbon, carbon–oxygen, carbon–nitrogen, and carbon–sulfur bonds, forging new cyclic frameworks that lie at the heart of many chemical structures and serve myriad purposes in industrial, chemical, and medical applications, including novel therapeutic agents. The project provides a high level of education and training for students starting as early as high school. The PI is also active in outreach to local elementary, middle, and high schools to promote science education and engagement of students in science disciplines. This project applies umpolung methodology, in which normal reactivity patterns are inverted, to functionalization of electron-rich aromatic systems, starting with oxidation to introduce relatively weak nitrogen–oxygen bonds and to activate the system for functionalization, including by electrochemical means. The manipulation of latent aromatic compounds and/or the temporary engagement of heteroatom-bound electron pairs, and the harnessing of these energetic structures, offer opportunity for new bond formations and the construction of polycyclic arrays. This project leverages three unconventional reactivity manifolds facilitated by amines utilizing both traditional and electrochemical reaction processes. In the first reactivity manifold, N,N-diarylamines and carbazoles undergo a wide array of bond formations via group transfers that take advantage of the excision of the weak N–O bond within amine N-oxides and N-hydroxylamines. In the second reactivity manifold, a variety of amine N-oxides undergo elimination reactions to afford N-aryl iminium ions, facilitating Povarov cyclizations. In the third reactivity manifold, N-acylanilines, N-arylamino acids, and N,N-diaryl-N-alkyl-amines are converted to iminium ions via electrochemical oxidation sequences, thus constituting more efficient, less waste-producing pathways toward Povarov cyclizations. Broader impacts include workforce development starting with high school students and outreach to local elementary, middle, and high schools. 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.