Manganese Catalyzed C–H Halogenation

Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States

Acc. Chem. Res., Article ASAP

DOI: 10.1021/acs.accounts.5b00062

Publication Date (Web): June 4, 2015

Special Issue

Published as part of the Accounts of Chemical Research special issue “Earth Abundant Metals in Homogeneous Catalysis”.

Biography

Wei Liu received his Ph.D. in 2014 at Princeton University with Prof. John T. Groves, where he was working on new synthetic strategies for C-halogen bond formation reactions using manganese complexes as catalysts. He then spent a year in the Groves group as a postdoctoral fellow developing novel 18F labeling methods. He is planning to move to the bay area working as a joint-postdoctoral fellow between Prof. Christopher Chang at UC Berkeley and Prof. David Wilson at UCSF.

Biography

John T. Groves is currently the Hugh Stott Taylor Chair of Chemistry at Princeton University. He was an early pioneer in the use of diagnostic substrates as probes of redox enzyme mechanism and the preparation of high-valent metalloporphyrins as heme protein active site models while at the University of Michigan. That work from the 1970s led to the elucidation of the oxygen rebound mechanism of cytochrome P450 as well as the first syntheses and characterizations of ferryl, manganyl, and chromyl porphyrins. He is a fellow of the American Academy of Arts and Sciences, a fellow of the Royal Society of Chemistry, and a member of the National Academy of Sciences and has received the ACS Award in Inorganic Chemistry for 2015.

Abstract

Conspectus

The remarkable aliphatic C–H hydroxylations catalyzed by the heme-containing enzyme, cytochrome P450, have attracted sustained attention for more than four decades. The effectiveness of P450 enzymes as highly selective biocatalysts for a wide range of oxygenation reactions of complex substrates has driven chemists to develop synthetic metalloporphyrin model compounds that mimic P450 reactivity. Among various known metalloporphyrins, manganese derivatives have received considerable attention since they have been shown to be versatile and powerful mediators for alkane hydroxylation and olefin epoxidation. Mechanistic studies have shown that the key intermediates of the manganese porphyrin-catalyzed oxygenation reactions include oxo- and dioxomanganese(V) species that transfer an oxygen atom to the substrate through a hydrogen abstraction/oxygen recombination pathway known as the oxygen rebound mechanism. Application of manganese porphyrins has been largely restricted to catalysis of oxygenation reactions until recently, however, due to ultrafast oxygen transfer rates.

In this Account, we discuss recently developed carbon–halogen bond formation, including fluorination reactions catalyzed by manganese porphyrins and related salen species. We found that biphasic sodium hypochlorite/manganese porphyrin systems can efficiently and selectively convert even unactivated aliphatic C–H bonds to C–Cl bonds. An understanding of this novel reactivity derived from results obtained for the oxidation of the mechanistically diagnostic substrate and radical clock, norcarane. Significantly, the oxygen rebound rate in Mn-mediated hydroxylation is highly correlated with the nature of the trans-axial ligands bound to the manganese center (L–MnV═O). Based on the ability of fluoride ion to decelerate the oxygen rebound step, we envisaged that a relatively long-lived substrate radical could be trapped by a Mn–F fluorine source, effecting carbon–fluorine bond formation. Indeed, this idea led to the discovery of the first Mn-catalyzed direct aliphatic C–H fluorination reactions utilizing simple, nucleophilic fluoride salts. Mechanistic studies and DFT calculations have revealed a trans-difluoromanganese(IV) species as the key fluorine transfer intermediate. In addition to catalyzing normal 19F-fluorination reactions, manganese salen complexes were found to enable the incorporation of radioactive 18F fluorine via C–H activation. This advance represented the first direct Csp3–H bond 18F labeling with no-carrier-added [18F]fluoride and facilitated the late-stage labeling of drug molecules for PET imaging. Given the high reactivity and enzymatic-like selectively of metalloporphyrins, we envision that this new Heteroatom-Rebound Catalysis (HRC) strategy will find widespread application in the C–H functionalization arena and serve as an effective tool for forming new carbon–heteroatom bonds at otherwise inaccessible sites in target molecules.

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