Biomimetic Aryl Hydroxylation Derived from Alkyl Hydroperoxide at a Nonheme Iron Center. Evidence for an Fe^IVO Oxidant

Many nonheme iron-dependent enzymes activate dioxygen to catalyze hydroxylations of arene substrates. Key features of this chemistry have been developed from complexes of a family of tetradentate tripodal ligands obtained by modification of tris(2-pyridylmethyl)amine (TPA) with single α-arene substituents. These included the following: −C6H5 (i.e., 6-PhTPA), L1; −o-C6H4D, o-d1-L1; −C6D5, d5-L1; −m-C6H4NO2, L2; −m-C6H4CF3, L3; −m-C6H4Cl, L4; −m-C6H4CH3, L5; −m-C6H4OCH3, L6; −p-C6H4OCH3, L7. Additionally, the corresponding ligand with one α-phenyl and two α-methyl substituents (6,6-Me2-6-PhTPA, L8) was also synthesized. Complexes of the formulas [(L1)FeII(NCCH3)2](ClO4)2, [(Ln)FeII(OTf)2] (n = 1−7, OTf = -O3SCF3), and [(L8)FeII(OTf)2]2 were obtained and characterized by 1H NMR and UV−visible spectroscopies and by X-ray diffraction in the cases of [(L1)FeII(NCCH3)2](ClO4)2, [(L6)FeII(OTf)2], and [(L8)FeII(OTf)2]2. The complexes react with tert-butyl hydroperoxide (tBuOOH) in CH3CN solutions to give iron(III) complexes of ortho-hydroxylated ligands. The product complex derived from L1 was identified as the solvated monomeric complex [(L1O-)FeIII]2+ in equilibrium with its oxo-bridged dimer [(L1O-)2FeIII2(μ2-O)]2+, which was characterized by X-ray crystallography as the BPh4- salt. The L8 product was also an oxo-bridged dimer, [(L8O-)2FeIII2(μ2-O)]2+. Transient intermediates were observed at low temperature by UV−visible spectroscopy, and these were characterized as iron(III) alkylperoxo complexes by resonance Raman and EPR spectroscopies for L1 and L8. [(L1)FeII(OTf)2] gave rise to a mixture of high-spin (S = 5/2) and low-spin (S = 1/2) FeIII-OOR isomers in acetonitrile, whereas both [(L1)Fe(OTf)2] in CH2Cl2 and [(L8)Fe(OTf)2]2 in acetonitrile afforded only high-spin intermediates. The L1 and L8 intermediates both decomposed to form respective phenolate complexes, but their reaction times differed by 3 orders of magnitude. In the case of L1, 18O isotope labeling indicated that the phenolate oxygen is derived from the terminal peroxide oxygen via a species that can undergo partial exchange with exogenous water. The iron(III) alkylperoxo intermediate is proposed to undergo homolytic O−O bond cleavage to yield an oxoiron(IV) species as an unobserved reactive intermediate in the hydroxylation of the pendant α-aryl substituents. The putative homolytic chemistry was confirmed by using 2-methyl-1-phenyl-2-propyl hydroperoxide (MPPH) as a probe, and the products obtained in the presence and in the absence of air were consistent with formation of alkoxy radical (RO•). Moreover, when one ortho position was labeled with deuterium, no selectivity was observed between hydroxylation of the deuterated and normal isotopomeric ortho sites, but a significant 1,2-deuterium shift (“NIH shift”) occurred. These results provide strong mechanistic evidence for a metal-centered electrophilic oxidant, presumably an oxoiron(IV) complex, in these arene hydroxylations and support participation of such a species in the mechanisms of the nonheme iron- and pterin-dependent aryl amino acid hydroxylases.诸多非血红素铁依赖性酶可活化氧气以催化芳烃底物的羟基化反应。该类反应的关键特征，可通过对三(2-吡啶甲基)胺（tris(2-pyridylmethyl)amine, TPA）进行单α-芳烃取代修饰得到的一系列四齿三脚架配体家族配合物得以阐明。这些配体包括：−C6H5（即6-PhTPA，记为L1）、−o-C6H4D（o-d1-L1）、−C6D5（d5-L1）、−m-C6H4NO2（L2）、−m-C6H4CF3（L3）、−m-C6H4Cl（L4）、−m-C6H4CH3（L5）、−m-C6H4OCH3（L6）、−p-C6H4OCH3（L7）。此外，还合成了同时带有一个α-苯基与两个α-甲基取代基的对应配体（6,6-Me2-6-PhTPA，记为L8）。制备了通式为[(L1)FeII(NCCH3)2](ClO4)2、[(Ln)FeII(OTf)2]（n=1−7，其中OTf为−O3SCF3）以及[(L8)FeII(OTf)2]2的配合物，并通过氢核磁共振（1H NMR）、紫外-可见光谱（UV−visible spectroscopy）对其进行表征；针对[(L1)FeII(NCCH3)2](ClO4)2、[(L6)FeII(OTf)2]与[(L8)FeII(OTf)2]2，还通过X射线衍射（X-ray diffraction）完成了结构解析。上述配合物在乙腈（CH3CN）溶液中可与叔丁基过氧化氢（tert-butyl hydroperoxide, tBuOOH）反应，生成邻位羟基化配体的铁(III)配合物。由L1衍生得到的产物配合物，被鉴定为溶剂化单核配合物[(L1O-)FeIII]2+，该配合物与其氧桥联二聚体[(L1O-)2FeIII2(μ2-O)]2+处于平衡状态；后者以四苯硼酸根（BPh4-）盐的形式通过X射线晶体学完成表征。L8的产物同样为氧桥联二聚体[(L8O-)2FeIII2(μ2-O)]2+。在低温条件下通过紫外-可见光谱可观测到瞬态中间体，针对L1与L8，通过共振拉曼光谱（resonance Raman）与电子顺磁共振光谱（EPR）将其鉴定为铁(III)烷基过氧配合物。[(L1)FeII(OTf)2]在乙腈中会生成高自旋（S=5/2）与低自旋（S=1/2）两种FeIII-OOR异构体的混合物；而二氯甲烷（CH2Cl2）中的[(L1)Fe(OTf)2]以及乙腈中的[(L8)Fe(OTf)2]2仅能生成高自旋中间体。L1与L8的中间体均会分解生成对应的酚盐配合物，但二者的反应时长相差三个数量级。针对L1的18O同位素标记实验表明，酚盐氧原子源自过氧化物的末端氧原子，且该过程可与外源性水发生部分交换。研究提出，铁(III)烷基过氧中间体将经历O-O键均裂，生成氧铁(IV)物种作为未被直接观测到的活性中间体，进而催化悬挂α-芳基取代基的羟基化反应。以2-甲基-1-苯基-2-丙基过氧化氢（2-methyl-1-phenyl-2-propyl hydroperoxide, MPPH）作为探针，验证了该推测的均裂反应过程；在有氧与无氧条件下得到的产物，均与烷氧自由基（RO•）的形成过程相符。此外，当一个邻位位点被氘标记时，氘代与正常同位素异构体的邻位位点羟基化反应未表现出选择性，但却发生了显著的1,2-氘迁移（即“NIH迁移”）。上述实验结果为这类芳烃羟基化反应中以金属为中心的亲电氧化剂（推测为氧铁(IV)配合物）提供了强有力的机理证据，并支持这类物种参与了非血红素铁依赖性与蝶呤依赖性芳基氨基酸羟化酶的催化机制。