Aromatic C–F Hydroxylation by Nonheme Iron(IV)–Oxo Complexes: Structural, Spectroscopic, and Mechanistic Investigations

The synthesis and reactivity of a series of mononuclear nonheme iron complexes that carry out intramolecular aromatic C–F hydroxylation reactions is reported. The key intermediate prior to C–F hydroxylation, [Fe^IV(O)­(N4Py^2Ar₁)]­(BF₄)₂ (<b>1-O</b>, Ar₁ = −2,6-difluorophenyl), was characterized by single-crystal X-ray diffraction. The crystal structure revealed a nonbonding C–H···OFe interaction with a CH₃CN molecule. Variable-field Mössbauer spectroscopy of <b>1-O</b> indicates an intermediate-spin (<i>S</i> = 1) ground state. The Mössbauer parameters for <b>1-O</b> include an unusually small quadrupole splitting for a triplet Fe^IV(O) and are reproduced well by density functional theory calculations. With the aim of investigating the initial step for C–F hydroxylation, two new ligands were synthesized, N4Py^2Ar₂ (<b>L2</b>, Ar₂ = −2,6-difluoro-4-methoxyphenyl) and N4Py^2Ar₃ (<b>L3</b>, Ar₃ = −2,6-difluoro-3-methoxyphenyl), with −OMe substituents in the <i>meta</i> or <i>ortho</i>/<i>para</i> positions with respect to the C–F bonds. Fe^II complexes [Fe­(N4Py^2Ar₂)­(CH₃CN)]­(ClO₄)₂ (<b>2</b>) and [Fe­(N4Py^2Ar₃)­(CH₃CN)]­(ClO₄)₂ (<b>3</b>) reacted with isopropyl 2-iodoxybenzoate to give the C–F hydroxylated Fe^III–OAr products. The Fe^IV(O) intermediates <b>2-O</b> and <b>3-O</b> were trapped at low temperature and characterized. Complex <b>2-O</b> displayed a C–F hydroxylation rate similar to that of <b>1-O</b>. In contrast, the kinetics (via stopped-flow UV–vis) for complex <b>3-O</b> displayed a significant rate enhancement for C–F hydroxylation. Eyring analysis revealed the activation barriers for the C–F hydroxylation reaction for the three complexes, consistent with the observed difference in reactivity. A terminal Fe^II(OH) complex (<b>4</b>) was prepared independently to investigate the possibility of a nucleophilic aromatic substitution pathway, but the stability of <b>4</b> rules out this mechanism. Taken together the data fully support an electrophilic C–F hydroxylation mechanism