Professor Julie Kovacs
Professor Julie A. Kovacs
Department of Chemistry
University of Washington
Host: Professor Lawrence Que Jr.
A Thiolate-Ligated FeIII-Superoxo Complex That Cleaves Strong C-H Bonds
Thiolate (RS–) ligands have been shown to lower the activation barrier to O2 binding, and facilitate peroxo O-O bond cleavage, and the cleavage of strong C-H bonds. We will describe an alkyl thiolate-ligated Fe(II) complex that reacts with dioxygen (O2) to form an unprecedented example of a reactive iron superoxo (RS-Fe(III)-O2) intermediate that is capable of cleaving strong C-H bonds. A thiolate-ligated iron superoxo is proposed to play a key role in the biosynthesis of β-lactam antibiotics, as well as the prevention of cancerous tumor metastases. Isopenicillin N-synthase (IPNS) catalyzes the former, and cysteine dioxygenase (CDO) the latter. Very few iron superoxo compounds have been reported, and none are capable of cleaving strong C-H bonds. Spectroscopic characterization, and calibrated DFT and TD-DFT calculations, show that the frontier orbitals of our RS-Fe(III)-O2 consist of two strongly coupled unpaired electrons of opposite spin, one in a superoxo 𝝅*(O-O) orbital, and the other in an Fe(dxy) orbital.1 Both the calculated and experimental electronic absorption spectrum of our RS-Fe-O2 are similar to that of the putative IPNS superoxo intermediate, as well as an intermediate involved in the catalytic cycle of CDO. The rate at which our superoxo converts to a putative iron hydroperoxo (Fe(III)-OOH), is shown to depend on the C-H bond strength of the solvent or sacrificial H-atom donor, and a deuterium isotope effect (kH/kD= 4.8), comparable to that of IPNS (kH/kD= 5.6), is observed.1 As demonstrated by the presence of a low energy thiolate Fe-O2 charge transfer transition, the electron-rich alkyl thiolate likely plays a role in increasing reactivity by creating a more basic superoxo. The bond dissociation energy (BDE) of the C-H bonds cleaved by our RS-Fe-O2 superoxo compound (92 kcal/mol) are comparable to those cleaved by the enzyme IPNS (93 kcal/mol).
Professor Julie Kovacs' research program is aimed at determining how cysteinates influence function in non-heme iron enzymes. Non-heme iron enzymes promote important biological reactions, including tumor suppression, the biosynthesis of antibiotics, scavenge reactive oxygen species, and detoxification of heavy metals. However, the mechanisms by which these reactions are carried out are not well understood.
Julie Kovacs has been a bioinorganic and inorganic professor a the University of Washington since 1988. She earned her bachelor's degree from Michigan State University, and her doctorate from Harvard University. She also was a post-doctoral fellow at the University of California, Berkeley.