Redox-Neutral, Iron-Mediated Directed C–H Activation: General Principles and Mechanistic Insights

Experimental and computational studies have been conducted and established the general principles for enabling redox-neutral C–H activation by iron(II) complexes. The idealized octahedral iron(II) dimethyl complex, (depe)₂Fe(CH₃)₂ (depe = 1,2-bis(diethylphosphino)ethane) promoted the directed, regioselective ortho C(sp²)–H methylation of pivalophenone. The rate of the iron(II)-mediated C(sp²)–H functionalization depended on the lability of L-type phosphine ligands, the spin state of the iron center, and the size of the X-type ligands (halide, hydrocarbyl) in P₄Fe^IIX₂ complexes. The C(sp²)–H alkylation reaction proved general among multiple substrates with directing groups including carbonyl, imines and pyridines. Among these, ketones and aldehydes were identified as optimal and were compatible with various steric environments and presence of acidic α-hydrogens. With stronger nitrogen donors, higher barriers for product-forming reductive elimination were observed. The effect of orbital hybridization on the chemoselectivity of C–H activation through a σ-CAM pathway by d^n>0 transition metals was also established by studying the stoichiometric reactivity of the differentially substituted (depe)₂Fe(Me)R complexes (R = alkyl, aryl), where the Fe–R bond with greater s-character preferentially promoted selective C–H activation. Deuterium labeling and kinetic studies, coupled with computational analysis, supported a pathway involving phosphine dissociation and rate-determining C–H bond activation, leading to the observed products.