Hydroxylation of Aromatics by H2O2 Catalyzed by Mononuclear Non-heme Iron Complexes: Role of Triazole Hemilability in Substrate-Induced Bifurcation of the H2O2 Activation Mechanism

Rieske dioxygenases are metalloenzymes capable of achieving cis-dihydroxylation of aromatics under mild conditions using O₂ and a source of electrons. The intermediate responsible for this reactivity is proposed to be a cis-Fe^V(O)(OH) moiety. Molecular models allow the generation of a Fe^III(OOH) species with H₂O₂, to yield a Fe^V(O)(OH) species with tetradentate ligands, or {Fe^IV(O); OH^.} pairs with pentadentate ones. We have designed a new pentadentate ligand, mtL₄², bearing a labile triazole, to generate an “in-between” situation. Two iron complexes, [(mtL₄²)FeCl](PF₆) and [(mtL₄²)Fe(OTf)₂]), were obtained and their reactivity towards aromatic substrates was studied in the presence of H₂O₂. Spectroscopic and kinetic studies reflect that triazole is bound at the Fe^II state, but decoordinates in the Fe^III(OOH). The resulting [(mtL₄²)Fe^III(OOH)(MeCN)]²⁺ then lies on a bifurcated decay pathway (end-on homolytic vs. side-on heterolytic) depending on the addition of aromatic substrate: in the absence of substrate, it is proposed to follow a side-on pathway leading to a putative (N₄)Fe^V(O)(OH), while in the presence of aromatics it switches to an end-on homolytic pathway yielding a {(N₅)Fe^IV(O); OH^.} reactive species, through recoordination of triazole. This switch significantly impacts the reaction regioselectivity.     

PtII-Catalyzed Hydroxylation of Terminal Aliphatic C(sp3)−H Bonds with Molecular Oxygen

The practical application of Shilov-type Pt catalysis to the selective hydroxylation of terminal aliphatic C−H bonds remains a formidable challenge, due to difficulties in replacing Pt^IV with a more economically viable oxidant, particularly O₂. We report the potential of employing FeCl₂ as a suitable redox mediator to overcome the kinetic hurdles related to the direct use of O₂ in the Pt reoxidation. For the selective conversion of butyric acid to γ-hydroxybutyric acid (GHB), a significantly enhanced catalyst activity and stability (turnover numbers (TON)>30) were achieved under 20 bar O₂ in comparison to current state-of-the-art systems (TON<10). In this regard, essential reaction parameters affecting the overall activity were identified, along with specific additives to attain catalyst stability at longer reaction times. Notably, deactivation by reduction to Pt⁰ was prevented by the addition of monodentate pyridine derivatives, such as 2-fluoropyridine, but also by introducing varying partial pressures of N₂ in the gaseous atmosphere. Finally, stability tests revealed the involvement of Pt^II and FeCl₂ in catalyzing the non-selective overoxidation of GHB. Accordingly, in situ esterification with boric acid proved to be a suitable strategy to maintain enhanced selectivities at much higher conversions (TON>60). Altogether, a useful catalytic system for the selective hydroxylation of primary aliphatic C−H bonds with O₂ is presented.     

Lignin Biodegradation by a Cytochrome P450 Enzyme: A Computational Study into Syringol Activation by GcoA

A recently characterized cytochrome P450 isozyme GcoA activates lignin components through a selective O-demethylation or alternatively an acetal formation reaction. These are important reactions in biotechnology and, because lignin is readily available; it being the main component in plant cell walls. In this work we present a density functional theory study on a large active site model of GcoA to investigate syringol activation by an iron(IV)-oxo heme cation radical oxidant (Compound I) leading to hemiacetal and acetal products. Several substrate-binding positions were tested and full energy landscapes calculated. The study shows that substrate positioning determines the product distributions. Thus, with the phenol group pointing away from the heme, an O-demethylation is predicted, whereas an initial hydrogen-atom abstraction of the weak phenolic O-H group would trigger a pathway leading to ring-closure to form acetal products. Predictions on how to engineer P450 GcoA to get more selective product distributions are given.     

Second-Coordination Sphere Effects on Selectivity and Specificity of Heme and Nonheme Iron Enzymes

Mononuclear iron-containing enzymes are highly versatile oxidants that often react stereospecifically and/or regioselectively with substrates. Combined experimental and computational studies on heme monooxygenases, nonheme iron dioxygenases and halogenases have revealed the intricate details of the second-coordination sphere, which determine this specificity and selectivity. These second-coordination sphere effects originate from the positioning of the substrate and oxidant, which involve the binding of the co-factors and substrate into the active site of the protein. In addition, some enzymes affect the selectivity and reactivity through charge-stabilization from nearby bound cations/anions, an induced electric field or through the positioning of salt bridges and hydrogen-bonding interactions to first-coordination sphere iron ligands and/or the substrate. Examples of all of these second-coordination sphere effects in iron-containing enzymes and how these influence structure and reactivity are given.     

Amphiphilic poly(ionic liquid)/Wells–Dawson-type phosphovanadomolybdate ionic composites as efficient and recyclable catalysts for the direct hydroxylation of benzene with H2O2

Three novel amphiphilic poly(ionic liquid) (PIL)/Wells–Dawson-type phosphovanadomolybdate (V-POM) ionic composites with tunable oxidative catalytic activity and unique nanostructure were synthesized using carboxylic acid-functionalized PIL and H₇[P₂Mo₁₇VO₆₂], H₈[P₂Mo₁₆V₂O₆₂] and H₉[P₂Mo₁₅V₃O₆₂] as synthetic units via self-assembly in water. The results of characterization indicated that V-POM anions were finely dispersed in the PIL cation framework, and their structures were well preserved. The three composites are amorphous V-POM salts of PIL cation with a considerable thermal stability, and an open three-dimensional network structure with hierarchical porosity. The as-synthesized composites were found to be efficient heterogeneous catalysts for the direct hydroxylation of benzene to phenol with H₂O₂ in the liquid phase. Under optimum conditions, a phenol yield of 37.3% was achieved with selectivity of 100%. The high catalytic performance could be attributed to the synergistic catalytic effect between V-POM anion and carboxylic acid-functionalized PIL cation framework, and good benzene adsorption and phenol desorption ability of amphiphilic micropores in the structure of the composites. Additionally, these composites exhibited high stability under the reaction conditions and could be easily recovered and reused at least six times without noticeably loss of activity.     

Cover Feature: Mechanism of Oxidative Activation of Fluorinated Aromatic Compounds by N-Bridged Diiron-Phthalocyanine: What Determines the Reactivity? (Chem. Eur. J. 63/2019)

The biodegradation of compounds with C−F bonds is challenging due to the fact that these bonds are stronger than the C−H bond in methane. In this work, results on the unprecedented reactivity of a biomimetic model complex that contains an N-bridged diiron-phthalocyanine are presented; this model complex is shown to react with perfluorinated arenes under addition of H₂O₂ effectively. To get mechanistic insight into this unusual reactivity, detailed density functional theory calculations on the mechanism of C₆F₆ activation by an iron(IV)-oxo active species of the N-bridged diiron phthalocyanine system were performed. Our studies show that the reaction proceeds through a rate-determining electrophilic C−O addition reaction followed by a 1,2-fluoride shift to give the ketone product, which can further rearrange to the phenol. A thermochemical analysis shows that the weakest C−F bond is the aliphatic C−F bond in the ketone intermediate. The oxidative defluorination of perfluoroaromatics is demonstrated to proceed through a completely different mechanism compared to that of aromatic C−H hydroxylation by iron(IV)-oxo intermediates such as cytochrome P450 Compound I.     

Copper‐Catalyzed Reaction Cascade of Thiophenol Hydroxylation and S‐Arylation through Disulfide‐Directed C−H Activation

Copper‐catalyzed thiophenol C?H activation is described. Through an initial attempt to conduct C‐arylation with arylboronic acid, a rather surprising sequential C?H activation and S‐arylation was discovered. Mechanistic investigation revealed the disulfide intermediate as the key component in directing C?H oxidation. The overall reaction proceeded under mild conditions with molecular oxygen as the oxidant. Discovery of disulfide as the directing group provides a potential new direction for catalytic C?H functionalization under mild conditions.