Modeling Enzymatic Reactivity with Copper Coordination Complexes

Synthetic models of enzyme intermediates play an important role in evaluating mechanistic
hypotheses for critical biochemical reactions. In the first part of my talk, I will present the
synthesis of tricopper clusters as small-molecule models of multicopper oxidases, a class
of copper proteins that catalyze four-electron reduction of O2 to H2O. We found that an
enzyme-like macrocyclic ligand can provide the rigid coordination environment to support
multi-electron multi-proton transfers at tricopper clusters. Three-electron two-proton
PCET from CuIICuIICuII(μ3-O) to CuICuICuI(μ2-OH2) was achieved within a narrow
potential range of 170 mV, exemplifying the redox potential leveling effect of secondary
proton relays during the accumulation of multiple redox equivalents at metal clusters. In
the second part of my talk, I will discuss how synthetic models of monocopper oxygenases
can be applied in the synthesis of pharmaceutically relevant organic molecules. Inspired
by lytic polysaccharide monooxygenases, we develop a general CuII/CuIII platform to
activate simple nucleophiles (Nu) toward C-H functionalization. Oxidation of CuII-Nu to
CuIII-Nu endows the Nu moiety with hydrogen atom transfer and radical capture reactivity.
Building on this platform, we have established a catalytic C-H fluorination method that
selectively produces monofluorinated products in an undivided electrochemical cell at
room temperature.