Iron Catalysis in Organic Synthesis

Iron-containing enzymes are one of Nature’s main means of effecting key biological transformations. The mononuclear non-heme iron oxygenases and oxidases have received the most attention recently, primarily because of the recent availability of crystal structures of many different enzymes and the stunningly diverse oxidative transformations that these enzymes catalyze. The wealth of available structural data has furthermore established the so-called 2-His-1-carboxylate facial triad as a new common structural motif for the activation of dioxygen. This superfamily of mononuclear iron(II) enzymes catalyzes a wide range of oxidative transformations, ranging from the cis-dihydroxylation of arenes to the biosynthesis of antibiotics such as isopenicillin and fosfomycin. The remarkable scope of oxidative transformations seems to be even broader than that associated with oxidative heme enzymes. Not only are many of these oxidative transformations of key biological importance, many of these selective oxidations are also unprecedented in synthetic organic chemistry. In this critical review, we wish to provide a concise background on the chemistry of the mononuclear non-heme iron enzymes characterized by the 2-His-1-carboxylate facial triad and to discuss the many recent developments in the field. New examples of enzymes with unique reactivities belonging to the superfamily have been reported. Furthermore, key insights into the intricate mechanistic details and reactive intermediates have been obtained from both enzyme and modeling studies. Sections of this review are devoted to each of these subjects, i.e. the enzymes, biomimetic models, and reactive intermediates (225 references).

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Mononuclear non-heme iron enzymes with the 2-His-1-carboxylate facial triad: recent developments in enzymology and modeling studies.

High-valent nonheme iron-oxo complexes: Synthesis, structure, and spectroscopy

Pd(II)-catalyzed ortho-hydroxylation of variously substituted benzoic acids under 1 atm of O2 or air is achieved under nonacidic conditions. Extensive labeling studies support a direct oxygenation of aryl C−H bonds with molecular oxygen.

Pd(II)-Catalyzed Hydroxylation of Arenes with 1 atm of O2 or Air

Recent efforts to design synthetic iron catalysts for the selective and efficient oxidation of C-H and C═C bonds have been inspired by a versatile family of nonheme iron oxygenases. These bioinspired nonheme (N4)Fe(II) catalysts use H2O2 to oxidize substrates with high regio- and stereoselectivity, unlike in Fenton chemistry where highly reactive but unselective hydroxyl radicals are produced. In this Account, we highlight our efforts to shed light on the nature of metastable peroxo intermediates, which we have trapped at -40 °C, in the reactions of the iron catalyst with H2O2 under various conditions and the high-valent species derived therefrom. Under the reaction conditions that originally led to the discovery of this family of catalysts, we have characterized spectroscopically an Fe(III)-OOH intermediate (EPR g(max) = 2.19) that leads to the hydroxylation of substrate C-H bonds or the epoxidation and cis-dihydroxylation of C═C bonds. Surprisingly, these organic products show incorporation of (18)O from H2(18)O, thereby excluding the possibility of a direct attack of the Fe(III)-OOH intermediate on the substrate. Instead, a water-assisted mechanism is implicated in which water binding to the iron(III) center at a site adjacent to the hydroperoxo ligand promotes heterolytic cleavage of the O-O bond to generate an Fe(V)(O)(OH) oxidant. This mechanism is supported by recent kinetic studies showing that the Fe(III)-OOH intermediate undergoes exponential decay at a rate enhanced by the addition of water and retarded by replacement of H2O with D2O, as well as mass spectral evidence for the Fe(V)(O)(OH) species obtained by the Costas group. The nature of the peroxo intermediate changes significantly when the reactions are carried out in the presence of carboxylic acids. Under these conditions, spectroscopic studies support the formation of a (κ(2)-acylperoxo)iron(III) species (EPR g(max) = 2.58) that decays at -40 °C in the absence of substrate to form an oxoiron(IV) byproduct, along with a carboxyl radical that readily loses CO2. The alkyl radical thus formed either reacts with O2 to form benzaldehyde (as in the case of PhCH2COOH) or rebounds with the incipient Fe(IV)(O) moiety to form phenol (as in the case of C6F5COOH). Substrate addition leads to its 2-e(-) oxidation and inhibits these side reactions. The emerging mechanistic picture, supported by DFT calculations of Wang and Shaik, describes a rather flat reaction landscape in which the (κ(2)-acylperoxo)iron(III) intermediate undergoes O-O bond homolysis reversibly to form an Fe(IV)(O)((•)OC(O)R) species that decays to Fe(IV)(O) and RCO2(•) or isomerizes to its Fe(V)(O)(O2CR) electromer, which effects substrate oxidation. Another short-lived S = 1/2 species just discovered by Talsi that has much less g-anisotropy (EPR g(max) = 2.07) may represent either of these postulated high-valent intermediates.

Bioinspired Nonheme Iron Catalysts for C-H and C═C Bond Oxidation: Insights into the Nature of the Metal-Based Oxidants.

Regioselective hydroxylation of aromatic acids with hydrogen peroxide proceeds readily in the presence of iron(II) complexes with tetradentate aminopyridine ligands [Fe"(BPMEN)-(CH 3 CN) 2 ](ClO 4 ) 2 (1) and [Fe II (TPA)-(CH 3 CN) 2 ](OTf) 2 (2), where BPMEN = N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)-1,2-ethylenediamine, TPA = tris-(2-pyridylmethyl)amine. Two cis-sites, which are occupied by labile acetonitrile molecules in 1 and 2, are available for coordination of H 2 O 2 and substituted benzoic acids. The hydroxylation of the aromatic ring occurs exclusively in the vicinity of the anchoring carboxylate functional group: ortho-hydroxylation affords salicylates, whereas ipso-hydroxylation with concomitant decarboxylation yields phenolates. The outcome of the substituent-directed hydroxylation depends on the electronic properties and the position of substituents in the molecules of substrates: 3-substituted benzoic acids are preferentially ortho-hydroxylated, whereas 2- and, to a lesser extent, 4-substituted substrates tend to undergo ipso-hydroxylation/decarboxylation. These two pathways are not mutually exclusive and likely proceed via a common intermediate. Electron-withdrawing substituents on the aromatic ring of the carboxylic acids disfavor hydroxylation, indicating an electrophilic nature for the active oxidant. Complexes 1 and 2 exhibit similar reactivity patterns, but 1 generates a more powerful oxidant than 2. Spectroscopic and labeling studies exclude acylperoxoiron(III) and Fe IV =O species as potential reaction intermediates, but strongly indicate the involvement of an Fe III -OOH intermediate that undergoes intramolecular acid-promoted heterolytic O-O bond cleavage, producing a transient iron(V) oxidant.

Iron-Promoted ortho- and/or ipso-Hydroxylation of Benzoic Acids with H2O2

https://www.rsc.org/suppdata/CC/b5/b508004e/b508004e.pdf

ortho-Hydroxylation of benzoic acids with hydrogen peroxide at a non-heme iron center

The crystal structure of the title compound, C36H40N2O2, has been determined at 173 (2) K. The mol­ecule has C2 symmetry and the asymmetric unit contains one half-mol­ecule. An intra­molecular O—H⋯N hydrogen bond is formed between the phenol OH group and the Schiff base N atom.

Margaret Flook

Papers

Iron-Promoted ortho- and/or ipso-Hydroxylation of Benzoic Acids with H2O2

ortho-Hydroxylation of benzoic acids with hydrogen peroxide at a non-heme iron center

(1R,2R)-(+)-4,4′-Di-tert-butyl-2,2′-[1,2-diphenylethane-1,2-diylbis(nitrilomethylidyne)]diphenol

Margaret Flook

Papers

Iron-Promoted ortho- and/or ipso-Hydroxylation of Benzoic Acids with H2O2

ortho-Hydroxylation of benzoic acids with hydrogen peroxide at a non-heme iron center

(1R,2R)-(+)-4,4′-Di-tert-butyl-2,2′-[1,2-diphenyl­ethane-1,2-diylbis(nitrilo­methyl­idyne)]diphenol

(1R,2R)-(+)-4,4′-Di-tert-butyl-2,2′-[1,2-diphenylethane-1,2-diylbis(nitrilomethylidyne)]diphenol