PROJECT SUMMARY Transition metal-catalyzed cross coupling reactions are among the most widely used strategies for C—C and C—N bond formation during the synthesis of small molecules for biomedical research. Despite their widespread use, limitations to these methods can often be attributed to poor control over the metal's reactivity or selectivity during key elementary steps of the catalytic cycle. In particular, problems with oxidative addition can limit the chemical space that can be accessed through cross coupling methods. During this elementary step, a transition metal oxidatively inserts into a bond of an electrophile (typically a carbon–heteroatom bond). Challenges related to this step include (1) subverting conventional site selectivity when two or more identical halides are present on aromatic substrates, (2) exploiting relatively non-labile phenol derivatives as electrophilic coupling partners, and (3) developing selective, mild cross-coupling reactions catalyzed by low-toxicity base metals such as iron and cobalt. This proposal seeks to develop solutions to these challenges through a combined experimental and computational approach. Completion of this work will help to streamline access to pharmacologically relevant compounds through more efficient catalytic methods. Furthermore, an in-depth understanding of the mechanistic origin of selectivity and reactivity in these systems will lay the groundwork for future rational design of new catalytic systems.