Zhang Tianyi, Whitehurst William G, Pecoraro Matthew V, Kim Junho, Koenig Stefan G, Chirik Paul J
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States.
Synthetic Molecule Process Chemistry, Genentech Inc, South San Francisco, California 94080, United States.
J Am Chem Soc. 2024 Nov 6;146(44):30637-30652. doi: 10.1021/jacs.4c12329. Epub 2024 Oct 25.
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)Fe(CH) (depe = 1,2-bis(diethylphosphino)ethane) promoted the directed, regioselective C(sp)-H methylation of pivalophenone. The rate of the iron(II)-mediated C(sp)-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 PFeX complexes. The C(sp)-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 transition metals was also established by studying the stoichiometric reactivity of the differentially substituted (depe)Fe(Me)R complexes (R = alkyl, aryl), where the Fe-R bond with greater -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.
已经开展了实验和计算研究，并确立了铁（II）配合物实现氧化还原中性C-H活化的一般原则。理想化的八面体铁（II）二甲基配合物（depe）Fe（CH）（depe = 1,2-双（二乙基膦基）乙烷）促进了新戊苯乙酮的定向、区域选择性C（sp）-H甲基化。铁（II）介导的C（sp）-H官能化速率取决于L型膦配体的活性、铁中心的自旋态以及PFeX配合物中X型配体（卤化物、烃基）的大小。C（sp）-H烷基化反应在多种带有导向基团的底物中普遍存在，这些导向基团包括羰基、亚胺和吡啶。其中，酮和醛被确定为最佳底物，并且与各种空间环境以及酸性α-氢的存在兼容。对于更强的氮供体，观察到形成产物的还原消除的能垒更高。通过研究不同取代的（depe）Fe（Me）R配合物（R = 烷基、芳基）的化学计量反应性，还确立了轨道杂化对过渡金属通过σ-CAM途径进行C-H活化化学选择性的影响，其中具有更大 - 特征的Fe-R键优先促进选择性C-H活化。氘标记和动力学研究，结合计算分析，支持了一条涉及膦解离和速率决定步骤的C-H键活化的途径，从而得到观察到的产物。
