Nucleophilic Cobalt Photocatalysis and Organic Single-Electron Photoreductants; Two Enabling
Approaches for Chemical Synthesis – Project Summary
The objectives of this proposal are two-fold and include the development and fundamental advancement of
nucleophilic cobalt photocatalysis and organic single-electron photoreductants. The unifying theme of these two
distinct proposed research programs is the expansion of the breadth of carbon radical precursors available to
practitioners of synthetic organic chemistry. The successful completion of both objectives will positively and
fundamentally impact the field of chemical synthesis by giving medicinal chemists new synthetic methods that
provide access to new chemical space, thereby benefiting human health.
While carbon-centered radicals have become an increasingly important tool in organic synthesis, the breadth of
radical precursors available to synthetic chemists remains underdeveloped. One underutilized strategy for radical
generation is the use of nucleophilic catalysts to engage electrophiles as radical precursors. We hypothesize
that simple cobaloxime complexes can serve as nucleophilic photocatalysts for the visible-light-generation of
carbon-centered radicals from non-traditional electrophilic precursors including haloforms, electron-deficient
alkenes, iminium ions, vinyl halides and triflates, and primary alcohols. Cobaloximes are among the strongest
nucleophiles known when in the Co(I) oxidation state and can undergo classical substitution reactions with
electrophiles. The resulting alkyl–cobaloximes can undergo facile homolytic cleavage when irradiated with visible
light to generate carbon-centered radicals. This work will advance our understanding of the reactivity of these
cobaloxime complexes, allowing for the development of more efficient catalytic processes that can access new
classes of radical precursors, enabling new bond disconnection strategies for organic synthesis.
To further advance the field of radical chemistry, general approaches that serve to generate radicals directly
from readily available alkyl halides and carbonyl compounds which circumvent the use of tin hydrides and ground
state metal reductants would be of great value. We hypothesize that organic single-electron photoreductants can
serve as a general platform for visible-light-mediated radical generation directly from unactivated precursors.
Our approach will be enabled by two distinct strategies: namely, halogen-bonding photocatalysis and 1,4-
dihydropyridine (DHP) anion photoreductants. For our halogen-bonding photocatalysis approach, our substituted
hydroquinone catalysts directly engage with carbon–halide bonds via a halogen-bonding interaction, leading to
a catalytically generated electron donor-acceptor complex that can be activated by visible-light irradiation. This
work is expected to lead to a general strategy for radical generation from a broad range of alkyl halide precursors,
yielding methods that have unprecedented functional group tolerance. For our second approach, we hypothesize
that simple 1,4-DHPs in the presence of a suitable base can serve as potent excited state reductants. Our work
on 1,4-DHP anions will lead to a mild and operationally simple method for ketyl radical formation, which has
been shown to be valuable synthetic intermediates in the synthesis of complex, highly functionalized compounds.
