Current challenges of modeling diiron enzyme active sites for dioxygen activation by biomimetic synthetic complexes

Abstract

This tutorial review describes recent progress in modeling the active sites of carboxylate-rich non-heme diiron enzymes that activate dioxygen to carry out several key reactions in Nature. The chemistry of soluble methane monooxygenase, which catalyzes the selective oxidation of methane to methanol, is of particular interest for (bio)technological applications. Novel synthetic diiron complexes that mimic structural, and, to a lesser extent, functional features of these diiron enzymes are discussed. The chemistry of the enzymes is also briefly summarized. A particular focus of this review is on models that mimic characteristics of the diiron systems that were previously not emphasized, including systems that contain (i) aqua ligands, (ii) different substrates tethered to the ligand framework, (iii) dendrimers attached to carboxylates to mimic the protein environment, (iv) two N-donors in a syn-orientation with respect to the iron-iron vector, and (v) a N-rich ligand environment capable of accessing oxygenated high-valent diiron intermediates.

Figure 1

The multicomponent enzyme system of sMMO from Methylococcus capsulatus (Bath) consists of a hydroxylase (MMOH, pdb reference 1MTY), an oxidoreductase (MMOR; consisting of FAD domain, 1TVC, and [2Fe2S]-Fd domain, 1JQ4), and a regulatory (binding) protein (MMOB, 1CKV). The ribbon diagram representation of MMOH is based on X-ray coordinates and those of MMOB and the two truncated MMOR fragments, on NMR structures.

Figure 2

The inactive (resting state) diiron(III) site of MMOH_ox (left) is activated by two-electron reduction and a carboxylate shift of E243 to the diiron(II) state (MMOH_red), which can then react with O₂ in the presence of MMOB to form high-valent diiron-oxo species. Ball and stick structures of MMOH_ox and MMOH_red adopted from D. A. Kopp, S. J. Lippard Curr. Opin. Chem. Biol. 2002, 6, 568-576.

Figure 3

The nuclearity of carboxylate-rich iron complexes is sterically controlled. Sterically highly demanding ligands like ⁻O₂CAr^4-tBuPh form monoiron complexes, [Fe₁], whereas sterically open ligands like ⁻O₂Cph form polymeric species, [Fe_∞]. Reversible cluster interconversions occur between windmill, [Fe₂]_wm, and paddlewheel, [Fe₂]_pw, complexes (presumably via a triply bridged species, [Fe₂]_tb) with ⁻O₂CAr^Tol and between triiron, [Fe₃], and tetrairon complexes, [Fe₄], with ⁻O₂Cbiph. Interconversions must occur via carboxylate shifts (see text).

Figure 4

General synthetic pathway via Pd-catalyzed cross-coupling reactions to (A) syn N-donor, and (B) C-clamp ligands. (C) Energy-minimized structure of [Fe₂{DEB(PICMe)₂}{DEB(terphCO₂)₂}] displaying the substrate-access cavity (adapted from ref. 69).

Scheme 1

Catalytic cycle of O₂ activation and CH₄ hydroxylation in sMMO. The oxidized diiron(III) state (MMOH_ox) is activated via two-electron reduction by MMOR (R, red circle) to a diiron(II) state (MMOH_red), which reacts in the presence of MMOB (B, blue circle) with dioxygen to form intermediate P*, presumably via a superoxo species. Intermediate P* then transforms via proton transfer (PT) into MMOH_peroxo, which can either decay to MMOH_ox via oxidation of electrophilic substrates RH (e.g. ethers), or form the diiron(IV) intermediate Q, which is responsible for CH₄ hydroxylation. In the absence of CH₄, intermediate Q decays slowly to intermediate Q*, which is not on the methane activation pathway, and then to MMOH_ox. The bridging glutamates (E144 and E243) are also shown. Characteristic physical parameters of the intermediates can be found in the text.

Scheme 2

Catalytic cycle of O₂ activation and tyrosyl radical formation in RNR-R2. The diiron(II) species reacts with O₂ to form the peroxo intermediate R2_peroxo, which oxidizes a tryptophan residue (Trp48) to form intermediate X. This Fe^IIIFe^IV species then generates a tyrosine (Tyr122) radical and restores the resting diiron(III) state, which can be activated again by a two-electron reduction to form R2_red.

Scheme 3

Formation of a high-valent Fe^IIIFe^IV-oxo intermediate upon oxygenation of carboxylate-rich diiron(II) of [Fe₂(O₂CR)₄(L)₂] type complexes at −78 °C in CH₂Cl₂ or toluene.

Scheme 4

Addition of water to [Fe₂(O₂CR)₄(4-RPy)₂] (R = CN, acetyl) results in a windmill [Fe₂(μ-O₂CR)₂(O₂CR)₂(H₂O)₂(L)₂] complex, which reacts more rapidly with dioxygen than the non-aquated paddlewheel and windmill mixture.

Scheme 5

Oxidation of various substrates tethered to coordinated amine or pyridine ligands in carboxylate-rich [Fe₂(O₂CR)₄(L)_1-2] complexes. (A and B) C–H bond activation, (C) catalytic oxidation of 2-PyPPh₂ and (D) Fe⃛S distance dependent sulfoxidation; R = phenyl (Fe–S distance 2.66 Å), mesityl (Fe⃛S = 3.20 Å) and 2,4,6-triisopropylphenyl (Fe⃛S = 4.03 Å).

Scheme 6

Synthesis of an encapsulated [Fe₂(μ-O₂CR)₂(O₂CR)₂(L)₂] complex with aid of dendritic carboxylates and formation of a superoxo intermediate after reaction with dioxygen.

Scheme 7

Proposed mechanism of superoxo formation of diiron complexes with 6-Me₃-TPA (Chart 2) and reactivity with 2,4-di-tert-butylphenol (DTBP). Resonance Raman data (given in cm⁻¹) for the ν(O–O) and ν(Fe–O) frequencies and the ¹⁸O-downshifts (given in parentheses) is listed below each intermediate.

Scheme 8

Different protonation pathways of peroxodiiron(III) complexes. Protonation of μ-oxo (A), and μ-peroxo (B) in two different model systems. For structures of 6-Me₂-BPP and 3,5-Me₆-4-OMe₃-TPA see Chart 2.

Scheme 9

Comparison of C–H activation by mono- and diiron(IV) complexes with 3,5-Me₆-OMe₃-TPA ligand (adapted from ref. 76).

Scheme 10

Electrochemical generation of a diiron(IV) complex and its ability for C–H and O–H bond activation. The dinucleating ligand L is shown in the inset.

Chart 1

Structures of complexes (from left to right): [Fe₂(μ-O)(μ-CO₃)BPG₂DEV], [NaFe(PIC₂DET)(μ-O₂CTrp)₃], [Fe₂(μ-O₂CAr^Tol)₃-(Et₂BCQEBEt)]⁺, [Fe₂(μ-OTf)₂(PIC₂DET)₂]²⁺, and comparison of the M–M distances in these compounds.

Chart 2

Commonly used classical N-rich capping ligands for the assembly of diiron complexes (top) and ligands used to study peroxo complexes in Scheme 7 and 8.