C-H Bond Cleavage by Bioinspired Nonheme Metal Complexes

Abstract

The functionalization of C-H bonds is one of the most challenging transformations in synthetic chemistry. In biology, these processes are well-known and are achieved with a variety of metalloenzymes, many of which contain a single metal center within their active sites. The most well studied are those with Fe centers, and the emerging experimental data show that high-valent iron oxido species are the intermediates responsible for cleaving the C-H bond. This Forum Article describes the state of this field with an emphasis on nonheme Fe enzymes and current experimental results that provide insights into the properties that make these species capable of C-H bond cleavage. These parameters are also briefly considered in regard to manganese oxido complexes and Cu-containing metalloenzymes. Synthetic iron oxido complexes are discussed to highlight their utility as spectroscopic and mechanistic probes and reagents for C-H bond functionalization. Avenues for future research are also examined.

Figure 1.

Terminal Fe^III–oxido complexes: [Fe^IIIH₃buea(O)]²⁻ (A), [N(afa^Cy)₃Fe^III(O)]⁺ (B), and [LFe₃O(PzNHtBu)₃Fe(O)]⁺ (C).

Figure 2.

The first reported S = 1 Fe^IV-oxido complexes: [Fe^IV(O)(TMC)(MeCN²⁺ (A) and [Fe^IV(O)(N4Py)]²⁺ (B).

Figure 3.

Qualitative d-orbital splitting diagrams for Fe^IV–oxido complexes with tetragonal (strong- and weak-field), trigonal, and tetrahedral symmetries.

Figure 4.

Trigonal Fe^IV–oxido complexes with S = 2 spin ground states: [Fe^IV(O)TMG₃tren]²⁺ (A), [Fe^IVH₃buea(O)]⁻ (B), [Fe^IV(O)tpa^Ph]⁻ (C), and [Fe^IVpoat(O)]⁻ (D).

Figure 5.

Systematic weakening of ligand field by incorporation of steric bulk in [Fe^IV(O)(TPA)(MeCN)]²⁺ (A), [Fe^IV(O)(QBPA)(MeCN)]²⁺ (B), and [Fe^IV(O)(TQA)(MeCN)]²⁺(C).

Figure 6.

Effects of electrostatic interactions on metal-oxido and -hydroxido complexes. Addition of LAⁿ⁺ accelerates the rate of electron transfer for [Fe^IV(O)(N4Py)]²⁺ by up to 10⁸-fold (A). [(15c5)⊃LA^II-(μ-OH)-Fe^IIIMST]⁺ (LA = Ca, Sr) (B). The previously characterized [(TMC)Fe^IV–O–Sc^III(OTf)₄(OH)] was reformulated as [(TMC)Fe^III–O–Sc^III(OTf)₄(OH₂)] (C).

Figure 7.

Binding and electrostatic effect of redox-inactive Group 2 metal ions on [Fe^IVpoat(O)]⁻.

Figure 8.

Preparative route to [(TMTACN)Mg^II–(μ-OH)–Fe^IIIpoat]OTf from K[Fe^IIIpoat(OH)] (A). Thermal ellipsoid diagram depicting the molecular structure of [(TMTACN)Mg^II–(μ-OH)–Fe^IIIpoat]⁺ determined by X-ray diffraction (B). Ellipsoidsc are shown at 50% probability level, and only the hydroxido H atom is shown for clarity. Selected bond distances (Å) and angles (deg): Fe1–O1, 1.892(2); Fe1–N1, 2.236(3); Fe1–N_eq,avg, 2.012(3); O1⋯O2, 2.661(3); Mg1–O1, 1.983(3); Mg1–O3, 2.015(3); Mg1–O4, 2.037(3); Mg1–N_TMTACN,avg, 2.257(3); O1–Fe1–N1, 175.74(11); Fe1–O1–Mg1, 120.09(12).

Figure 9.

Synthetic attempts for Fe^IV-hydroxido complexes: [Fe(OH)(ttppc)] (A), [(TAML)Fe^IV-OH_n]^n-2 (B, n = 1 or 2), and [Fe^IVH₄buea(O)] (C).

Figure 10.

Representative work in Fe molecular catalysis in chemical synthesis. Electronic and steric modifications in the N₄-based ligands modulate chemoselectivity (A & B). Incorporation of supramolecular directing groups improve regioselectivity of C─H bond activation (C). Late-stage transformations of various natural products and their derivatives (D). Use of Fe-TAML catalysts in environmentally beneficial catalysis, such as waste treatment (E).

Figure 11.

Thermodynamic scheme for a metal-oxido complex.

Figure 12.

Relationship between reduction potential and pK_a for generic metal-oxido species in the homolytic cleavage of a C─H bond in methane with BDFE_C─H = 102 kcal/mol from eq 2. The vertical lines indicate regions of relatively high (blue) and low (red) potentials.

Figure 13.

The intramolecular H-bond donor strength in a series of [Mn^IIIH₃bpuea-R(O)]²⁻ complexes is modulated remotely by the R-group, which affects the basicity of the complex and the reaction rate towards 9,10-dihydroanthracene. The experimentally determined second order rate constant k₂ was corrected to k to account for 4 equivalents of C─H bonds that can possibly be cleaved in DHA.

Figure 14.

Square scheme for asynchronous CPET (red arrows, (A)), Anderson’s Co^III-oxido (B), Tolman’s Cu^III-O₂CAr (C). Scheme in A is adapted from Anderson.

Figure 15.

Crystallographic data for LPMOs. Surface representation of AA9 showing the protein in purple and the active site in pink (A), and the molecular structures of a fungal LPMO (AA9, PDB: 5ACG) (B), a bacterial LPMO (AA10, PDB: 6RW7) (C), and an AA9 in the presence of substrate analog (G3, pink, PDB: 5ACJ) (D). Secondary coordination sphere interactions are represented by dashed lines. Cu(II) is shown as a cyan sphere and Cu(I) is shown as a brass sphere.

Figure 16.

Synthetic Cu^III–OH complex by Tolman (A), and synthetic Cu^II complex by Itoh with a histidine brace-type ligand (B).

Figure 17.

Proposed CuII-OOH showing H-bonds to the distal O-atom involving H161 and Q167.

Scheme 1.

Cleavage of C─H bond by metal complexes using an organometallic approach (A) such as an IrCp-based precursor, or a metal-oxido (or hydroxido) approach (B).

Scheme 2.

Catalytic mechanism of aliphatic hydroxylation by cytochrome P450 enzymes.

Scheme 3.

Catalytic mechanism of aliphatic hydroxylation by TauD.

Scheme 4.

Catalytic mechanism of aliphatic halogenation by SyrB2.

Scheme 5.

Addition of Sc^III or Al^III ions to [Mn^III(OH)(dpaq)]⁺ resulted in the protonation of the complex.

Scheme 6.

Synthetic non-heme Fe(III) complexes demonstrate rebound reactivity of hydroxido and halide ligands with trityl radical substrates.

Scheme 7.

Reactivity of [Mn^IIIH₃buea(O)]²⁻ towards 9,10-dihydroanthracene.

Scheme 8.

The proposed (A) and experimentally verified (B) mechanisms of benzoate 1,2-dioxygenase, a Rieske enzyme. An Fe^V intermediate was not observed.

Scheme 9.

Substrate transformation performed by LPMOs on cellulose.