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.