Redox-Neutral, Iron-Mediated\nDirected C–H Activation:\nGeneral Principles and Mechanistic Insights

Experimental and computational studies have been conducted\nand\nestablished the general principles for enabling redox-neutral C–H\nactivation by iron(II) complexes. The idealized octahedral iron(II)\ndimethyl complex, (depe)<sub>2</sub>Fe(CH<sub>3</sub>)<sub>2</sub> (depe = 1,2-bis(diethylphosphino)ethane) promoted the directed,\nregioselective <i>ortho</i> C(sp<sup>2</sup>)–H methylation\nof pivalophenone. The rate of the iron(II)-mediated C(sp<sup>2</sup>)–H functionalization depended on the lability of L-type phosphine\nligands, the spin state of the iron center, and the size of the X-type\nligands (halide, hydrocarbyl) in P<sub>4</sub>Fe<sup>II</sup>X<sub>2</sub> complexes. The C(sp<sup>2</sup>)–H alkylation reaction\nproved general among multiple substrates with directing groups including\ncarbonyl, imines and pyridines. Among these, ketones and aldehydes\nwere identified as optimal and were compatible with various steric\nenvironments and presence of acidic α-hydrogens. With stronger\nnitrogen donors, higher barriers for product-forming reductive elimination\nwere observed. The effect of orbital hybridization on the chemoselectivity\nof C–H activation through a σ-CAM pathway by <i>d</i><sup><i>n</i>>0</sup> transition metals was\nalso\nestablished by studying the stoichiometric reactivity of the differentially\nsubstituted (depe)<sub>2</sub>Fe(Me)R complexes (R = alkyl, aryl),\nwhere the Fe–R bond with greater <i>s</i>-character\npreferentially promoted selective C–H activation. Deuterium\nlabeling and kinetic studies, coupled with computational analysis,\nsupported a pathway involving phosphine dissociation and rate-determining\nC–H bond activation, leading to the observed products.