Project Summary This project aims to solve numerous challenges in aryne difunctionalization en route to highly decorated arene rings, critical components of most pharmaceuticals. Currently, methods to functionalize arenes in multiple positions require iterative coupling reactions. Difunctionalization of arynes provides an attractive strategy to incorporate multiple functional groups into an arene ring. Unfortunately, these reactions are plagued with problems with accessing starting materials due to multistep syntheses, limited reaction scope, and poor site selectivity for the two possible positions of the triple bond in an aryne. Our group aims to overcome all of these challenges by using transition metal catalysis to expand the scope and utility of aryne difunctionalization. We plan to use C1 symmetric ligands in order to control regioselectivity of the functional group addition to the aryne. Additionally, by the introduction of transition metal catalysis with new aryne precursors that have previously never been used in catalysis, we will allow access to aryne rings that were previously inaccessible due to ring strain. The transition metal catalyst will be able to bind to the aryne and relieve ring strain. Finally, a wide variety of new difunctionalization reactions are proposed. These new reactions encompass additions of F, N, and CF3 groups due to their importance in medicinal chemistry. If the goals of this proposal are achieved, we anticipate that this chemistry will provide easy access to a wide variety of highly functionalized arene rings. These will provide important building blocks and opportunities for late stage functionalization of medically relevant molecules.