Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group


First Advisor

Patrick J. Walsh


Metal-catalyzed cross-coupling reactions to form C-C bonds are a mainstay in the preparation of small molecules, which have applications ranging from biological studies to treatment of human disease. Traditional cross-coupling methods (such as Negishi, Suzuki, etc.) require prefunctionalized coupling partners, consisting of an organometallic reagent and an aryl halide or pseudohalide. Because prefunctionalization requires substantial time and effort, chemists are turning to direct functionalization of C-H bonds as a more efficient and atom-economical synthetic approach. Catalytic C-H bond functionalization has therefore emerged as a promising synthetic tool in organic chemistry, with the vast majority concentrated on the functionalization of sp2 hybridized C-H bonds of arenes and heteroarenes. Recently the functionalization of more challenging sp3 hybridized C-H bonds has received attention and has become the focus of increasing effort.

This dissertation describes two strategies for directing group free C(sp3)-H bond functionalizations. These involve the direct metallation and subsequent cross-coupling of benzylic C-H bonds with high pKa values (> 30).

The first strategy is directed toward functionalization of challenging toluene derivatives (pKa = 44±1). It relies on eta6-coordination of arenes to tricarbonylchromium, which increases the acidity of the benzylic C-H bonds to the point that they can be reversibly deprotonated under relatively mild conditions. The resulting benzylic nucleophiles undergo palladium-catalyzed allylic substitution processes, including enantioselective variants. Furthermore, a tandem C(sp3)-H bond functionalization/demetallation procedure is developed that affords the corresponding metal-free products, rendering arene-metal pi-complexation as a traceless activation strategy for C(sp3)-H bond functionalization.

The second strategy does not employ eta6-arene activation, but is based on the direct, reversible deprotonation of weakly acidic C(sp3)-H bonds (pKa > 30). This approach to C-C bond formation, which will be abbreviated as DCCP (Deprotonative-Cross-Coupling Process), enables rapid access to polyarylmethane and heteroaryl-containing derivatives frameworks. Current catalysts are not available for such DCCPs. We have discovered a unique catalyst system (Pd-NiXantphos) capable of conducting room temperature DCCPs under mild conditions with the C(sp3)-H bonds of diarylmethanes (pKa up to > 32) and 2-substituted furans (pKa up to > 30).

Mechanistic studies reveal the origin of the unique reactivity of this Pd-NiXantphos catalyst system. Under the basic DCCP conditions, the heterobimetallic Pd(M-NiXantphos)-based catalyst system (M = main group metal) readily activates aryl chlorides at room temperature and successfully promotes the arylation of diarylmethane derivatives with a broad scope of aryl chlorides.

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