Lawrence Que

Biologically inspired oxidation catalysis.

The development of processes for selective hydrocarbon oxidation is a goal that has long been pursued. An additional challenge is to make such processes environmentally friendly, for example by using non-toxic reagents and energy-efficient catalytic methods. Excellent examples are naturally occurring iron- or copper-containing metalloenzymes, and extensive studies have revealed the key chemical principles that underlie their efficacy as catalysts for aerobic oxidations. Important inroads have been made in applying this knowledge to the development of synthetic catalysts that model enzyme function. Such biologically inspired hydrocarbon oxidation catalysts hold great promise for wide-ranging synthetic applications.

Biomimetic nonheme iron catalysts for alkane hydroxylation

Abstract The catalytic functionalization of alkanes under mild conditions is a subject of great current interest. Nature has evolved a number of metalloenzymes such as the heme-containing cytochrome P450 and the nonheme methane monooxygenase, which are capable of effecting such transformations. There has thus been significant interest in modeling such enzyme active sites and developing biomimetic alkane hydroxylation catalysts. In this review, the efforts of the last 10 years in the development of nonheme iron catalysts are summarized and discussed. These catalysts typically act in concert with ROOH or H 2 O 2 . With ROOH as oxidant, it is clear from mechanistic studies that alkoxyl radicals are the principal agents that cleave the alkane CH bond to generate long-lived alkyl radicals. This conclusion, for the most part, applies also for oxidations involving H 2 O 2 . In a few cases, however, stereospecific alkane hydroxylation is observed. For these instances, there is evidence from H 2 18 O exchange experiments that a high-valent iron-oxo species is involved.

The 2-His-1-carboxylate facial triad: a versatile platform for dioxygen activation by mononuclear non-heme iron(II) enzymes

General knowledge of dioxygen-activating mononuclear non-heme iron(II) enzymes containing a 2-His-1-carboxylate facial triad has significantly expanded in the last few years, due in large part to the extensive library of crystal structures that is now available. The common structural motif utilized by this enzyme superfamily acts as a platform upon which a wide assortment of substrate transformations are catalyzed. The facial triad binds a divalent metal ion at the active site, which leaves the opposite face of the octahedron available to coordinate a variety of exogenous ligands. The binding of substrate activates the metal center for attack by dioxygen, which is subsequently converted to a high-valent iron intermediate, a formidable oxidizing species. Herein, we summarize crystallographic and mechanistic features of this metalloenzyme superfamily, which has enabled the proposal of a common but flexible pathway for dioxygen activation.

Reversible cleavage and formation of the dioxygen O-O bond within a dicopper complex

A key step in dioxygen evolution during photosynthesis is the oxidative generation of the O-O bond from water by a manganese cluster consisting of M2(μ-O)2 units (where M is manganese). The reverse reaction, reductive cleavage of the dioxygen O-O bond, is performed at a variety of dicopper and di-iron active sites in enzymes that catalyze important organic oxidations. Both processes can be envisioned to involve the interconversion of dimetal-dioxygen adducts, M2(O2), and isomers having M2(μ-O)2 cores. The viability of this notion has been demonstrated by the identification of an equilibrium between synthetic complexes having [Cu2(μ-η2:η2-O2)]2+ and [Cu2(μ-O)2]2+ cores through kinetic, spectroscopic, and crystallographic studies.

Bis(μ‐oxo)dimetal “Diamond” Cores in Copper and Iron Complexes Relevant to Biocatalysis

Although quite a familiar feature in high-valent manganese chemistry, the M(2)(mu-O)(2) diamond core motif has only recently been found in synthetic complexes for M=Cu or Fe. Structural and spectroscopic characterization of these more reactive Cu(2)(mu-O)(2) and Fe(2)(mu-O)(2) compounds has been possible through use of appropriately designed supporting ligands, low-temperature handling methods, and techniques such as electrospray ionization mass spectrometry and X-ray crystallography with area detector instrumentation for rapid data collection. Despite differences in electronic structures that have been revealed through experimental and theoretical studies, Cu(2)(mu-O)(2) and Fe(2)(mu-O)(2) cores exhibit analogously covalent metal-oxo bonding, remarkably congruent Raman and extended X-ray absorption fine structure (EXAFS) signatures, and similar tendencies to abstract hydrogen atoms from substrates. Core isomerization is another common reaction attribute, although different pathways are traversed; for Fe, bridge-to-terminal oxo migration has been discovered, while for Cu, reversible formation of an O-O bond to yield a peroxo isomer has been identified. Our understanding of biocatalysis has been enhanced significantly through the isolation and comprehensive characterization of the Cu(2)(mu-O)(2) and Fe(2)(mu-O)(2) complexes. In particular, it has led to the development of new mechanistic notions about how non-heme multimetal enzymes, such as methane monooxygenases, fatty acid desaturase, and tyrosinase, may function in the activation of dioxygen to catalyze a diverse array of organic transformations.

An FeIV=O complex of a tetradentate tripodal nonheme ligand.

The reaction of [FeII(tris(2-pyridylmethyl)amine, TPA)(NCCH3)2]2+ with 1 equiv. peracetic acid in CH3CN at −40°C results in the nearly quantitative formation of a pale green intermediate with λmax at 724 nm (ɛ ≈ 300 M−1⋅cm−1) formulated as [FeIV(O)(TPA)]2+ by a combination of spectroscopic techniques. Its electrospray mass spectrum shows a prominent feature at m/z 461, corresponding to the [FeIV(O)(TPA)(ClO4)]+ ion. The Mössbauer spectra recorded in zero field reveal a doublet with ΔEQ = 0.92(2) mm/s and δ = 0.01(2) mm/s; analysis of spectra obtained in strong magnetic fields yields parameters characteristic of S = 1 FeIVO complexes. The presence of an FeIVO unit is also indicated in its Fe K-edge x-ray absorption spectrum by an intense 1-s → 3-d transition and the requirement for an O/N scatterer at 1.67 Å to fit the extended x-ray absorption fine structure region. The [FeIV(O)(TPA)]2+ intermediate is stable at −40°C for several days but decays quantitatively on warming to [Fe2(μ-O)(μ-OAc)(TPA)2]3+. Addition of thioanisole or cyclooctene at −40°C results in the formation of thioanisole oxide (100% yield) or cyclooctene oxide (30% yield), respectively; thus [FeIV(O)(TPA)]2+ is an effective oxygen-atom transfer agent. It is proposed that the FeIVO species derives from O—O bond heterolysis of an unobserved FeII(TPA)-acyl peroxide complex. The characterization of [FeIV(O)(TPA)]2+ as having a reactive terminal FeIVO unit in a nonheme ligand environment lends credence to the proposed participation of analogous species in the oxygen activation mechanisms of many mononuclear nonheme iron enzymes.

A Synthetic High‐Spin Oxoiron(IV) Complex: Generation, Spectroscopic Characterization, and Reactivity

High versus low: The high-yield generation of a synthetic high-spin oxoiron(IV) complex, [Fe(IV)(O)(TMG(3)tren)](2+) (see picture, TMG(3)tren = 1,1,1-tris{2-[N2-(1,1,3,3-tetramethylguanidino)]ethyl}amine), has been achieved by using the very bulky tetradentate TMG(3)tren ligand, in order to both sterically protect the oxoiron(IV) moiety and enforce a trigonal bipyramidal geometry at the iron center, for which an S = 2 ground state is favored.

A thiolate-ligated nonheme oxoiron(IV) complex relevant to cytochrome P450.

Thiolate-ligated oxoiron(IV) centers are postulated to be the key oxidants in the catalytic cycles of oxygen-activating cytochrome P450 and related enzymes. Despite considerable synthetic efforts, chemists have not succeeded in preparing an appropriate model complex. Here we report the synthesis and spectroscopic characterization of [FeIV(O)(TMCS)]+ where TMCS is a pentadentate ligand that provides a square pyramidal N4(SR)apical, where SR is thiolate, ligand environment about the iron center, which is similar to that of cytochrome P450. The rigidity of the ligand framework stabilizes the thiolate in an oxidizing environment. Reactivity studies suggest that thiolate coordination favors hydrogen-atom abstraction chemistry over oxygen-atom transfer pathways in the presence of reducing substrates.

One motif — many different reactions

The structure of the trifunctional clavaminic acid synthase exhibits an emerging structural motif found among nonheme iron oxygen activating enzymes that provides the metal active site the flexibility to catalyze a remarkable range of reactions.

AN FEIVO COMPLEX COMPLEX OF A TETRADENTATE TRIPODAL NONHEME LIGAND

The reaction of [FeII(tris(2-pyridylmethyl)amine, TPA)(NCCH3)2]2+ with 1 equiv. peracetic acid in CH3CN at −40°C results in the nearly quantitative formation of a pale green intermediate with λmax at 724 nm (ɛ ≈ 300 M−1⋅cm−1) formulated as [FeIV(O)(TPA)]2+ by a combination of spectroscopic techniques. Its electrospray mass spectrum shows a prominent feature at m/z 461, corresponding to the [FeIV(O)(TPA)(ClO4)]+ ion. The Mössbauer spectra recorded in zero field reveal a doublet with ΔEQ = 0.92(2) mm/s and δ = 0.01(2) mm/s; analysis of spectra obtained in strong magnetic fields yields parameters characteristic of S = 1 FeIVO complexes. The presence of an FeIVO unit is also indicated in its Fe K-edge x-ray absorption spectrum by an intense 1-s → 3-d transition and the requirement for an O/N scatterer at 1.67 Å to fit the extended x-ray absorption fine structure region. The [FeIV(O)(TPA)]2+ intermediate is stable at −40°C for several days but decays quantitatively on warming to [Fe2(μ-O)(μ-OAc)(TPA)2]3+. Addition of thioanisole or cyclooctene at −40°C results in the formation of thioanisole oxide (100% yield) or cyclooctene oxide (30% yield), respectively; thus [FeIV(O)(TPA)]2+ is an effective oxygen-atom transfer agent. It is proposed that the FeIVO species derives from O—O bond heterolysis of an unobserved FeII(TPA)-acyl peroxide complex. The characterization of [FeIV(O)(TPA)]2+ as having a reactive terminal FeIVO unit in a nonheme ligand environment lends credence to the proposed participation of analogous species in the oxygen activation mechanisms of many mononuclear nonheme iron enzymes.