Catalytic cross-coupling methods that form carbon-carbon bonds have become an essential tool of medicinal chemistry and revolutionized organic synthesis, but the need for pre-formed organometallic reagents remains a challenge. Limited commercial availability and limited stability translate to extra steps in synthesis. Because carbon electrophiles, such as organic halides, are more abundant than carbon nucleophiles, an attractive solution to this problem is the cross-coupling of two different electrophiles. Although the dimerization of electrophiles has been known for 100 years, achieving cross-selectivity and understanding its origins remain the central challenges of cross-electrophile coupling. This program's long-term goals are the development of general, selective cross-electrophile reactions and the explanation of the factors that control selectivity and reactivity. In the proposed grant, a team composed of graduate students, a postdoc, and a lab technician will build upon the advances of the previous grant period to develop cross-electrophile coupling reactions based around two mechanistic models, and develop new ligands to support these efforts. Our guiding mechanistic hypothesis is that selective cross-coupling arises from systems where one persistent intermediate reacts with a transient, reactive intermediate. In the first case the persistent intermediate is an organonickel species and the transient intermediate is an organic radical. In the second case, the persistent intermediate is an organopalladium species and the transient intermediate is an organonickel species.
The specific aims of this proposal are to: (1) dramatically expand the number of electrophiles that can participate in radical-mediated cross-electrophile coupling and to further study the reactive intermediates in the proposed mechanism; (2) study a new mechanistic model for cross-electrophile coupling, multimetallic cross-electrophile coupling, and develop new cross-electrophile couplings of electrophiles that do not as easily form carbon radicals; and, (3) discover and study new ligands for cross-electrophile coupling through both mechanism-guided design and the screening of novel ligand libraries. The approach is innovative because it focuses on cross-electrophile coupling, a rapidly growing area that is complementary to the better-studied areas of cross-coupling and C-H functionalization. By focusing on an area that has not been extensively studied, there is the potential to discover new types of bond disconnections and new, general mechanisms. The proposed research is significant because it will enable the coupling of easily accessible building blocks in new combinations, simplifying organic synthesis. In addition, our mechanistic studies will shed light on fundamental questions of selectivity and cooperative catalysis, laying a foundation for further development in several fields.
The cross-electrophile coupling reactions proposed in this application will greatly expand the number of molecules that can be synthesized from readily available starting materials. This is relevant to public health and the mission of the NIH because it is from this pool of molecules that future drugs will be discovered. A larger pool of molecules increases the odds of finding the very best treatments for diseases.
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