Interplay Between Steric and Electronic Effects: A Joint Spectroscopy and Computational Study of Nonheme Iron(IV)-Oxo Complexes

Iron is an essential element in nonheme enzymes that plays a crucial role in many vital oxidative transformations and metabolic reactions in the human body. Many of those reactions are regio- and stereospecific and it is believed that the selectivity is guided by second-coordination sphere effects in the protein. Here, results are shown of a few engineered biomimetic ligand frameworks based on the N4Py (N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine) scaffold and the second-coordination sphere effects are studied. For the first time, selective substitutions in the ligand framework have been shown to tune the catalytic properties of the iron(IV)-oxo complexes by regulating the steric and electronic factors. In particular, a better positioning of the oxidant and substrate in the rate-determining transition state lowers the reaction barriers. Therefore, an optimum balance between steric and electronic factors mediates the ideal positioning of oxidant and substrate in the rate-determining transition state that affects the reactivity of high-valent reaction intermediates.     

Differences and Comparisons of the Properties and Reactivities of Iron(III)–hydroperoxo Complexes with Saturated Coordination Sphere

Heme and nonheme monoxygenases and dioxygenases catalyze important oxygen atom transfer reactions to substrates in the body. It is now well established that the cytochrome P450 enzymes react through the formation of a high‐valent iron(IV)–oxo heme cation radical. Its precursor in the catalytic cycle, the iron(III)–hydroperoxo complex, was tested for catalytic activity and found to be a sluggish oxidant of hydroxylation, epoxidation and sulfoxidation reactions. In a recent twist of events, evidence has emerged of several nonheme iron(III)–hydroperoxo complexes that appear to react with substrates via oxygen atom transfer processes. Although it was not clear from these studies whether the iron(III)–hydroperoxo reacted directly with substrates or that an initial O?O bond cleavage preceded the reaction. Clearly, the catalytic activity of heme and nonheme iron(III)–hydroperoxo complexes is substantially different, but the origins of this are still poorly understood and warrant a detailed analysis. In this work, an extensive computational analysis of aromatic hydroxylation by biomimetic nonheme and heme iron systems is presented, starting from an iron(III)–hydroperoxo complex with pentadentate ligand system (L₅²). Direct C?O bond formation by an iron(III)–hydroperoxo complex is investigated, as well as the initial heterolytic and homolytic bond cleavage of the hydroperoxo group. The calculations show that [(L₅²)Fe^III(OOH)]²⁺ should be able to initiate an aromatic hydroxylation process, although a low‐energy homolytic cleavage pathway is only slightly higher in energy. A detailed valence bond and thermochemical analysis rationalizes the differences in chemical reactivity of heme and nonheme iron(III)–hydroperoxo and show that the main reason for this particular nonheme complex to be reactive comes from the fact that they homolytically split the O?O bond, whereas a heterolytic O?O bond breaking in heme iron(III)–hydroperoxo is found.     

Enhanced Reactivities of Iron(IV)‐Oxo Porphyrin π‐Cation Radicals in Oxygenation Reactions by Electron‐Donating Axial Ligands

The proximal axial ligand in heme iron enzymes plays an important role in tuning the reactivities of iron(IV)‐oxo porphyrin π‐cation radicals in oxidation reactions. The present study reports the effects of axial ligands in olefin epoxidation, aromatic hydroxylation, alcohol oxidation, and alkane hydroxylation, by [(tmp)^+. Fe^IV(O)(p‐Y‐PyO)]⁺ ( 1 ‐Y) (tmp=meso‐tetramesitylporphyrin, p‐Y‐PyO=para‐substituted pyridine N‐oxides, and Y=OCH₃, CH₃, H, Cl). In all of the oxidation reactions, the reactivities of 1 ‐Y are found to follow the order 1 ‐OCH₃ > 1 ‐CH₃ > 1 ‐H > 1 ‐Cl; negative Hammett ρ values of ?1.4 to ?2.7 were obtained by plotting the reaction rates against the σ_p values of the substituents of p‐Y‐PyO. These results, as well as previous ones on the effect of anionic nucleophiles, show that iron(IV)‐oxo porphyrin π‐cation radicals bearing electron‐donating axial ligands are more reactive in oxo‐transfer and hydrogen‐atom abstraction reactions. These results are counterintuitive since iron(IV)‐oxo porphyrin π‐cation radicals are electrophilic species. Theoretical calculations of anionic and neutral ligands reproduced the counterintuitive experimental findings and elucidated the root cause of the axial ligand effects. Thus, in the case of anionic ligands, as the ligand becomes a better electron donor, it strengthens the FeO? H bond and thereby enhances its H‐abstraction activity. In addition, it weakens the Fe?O bond and encourages oxo‐transfer reactivity. Both are Bell–Evans–Polanyi effects, however, in a series of neutral ligands like p‐Y‐PyO, there is a relatively weak trend that appears to originate in two‐state reactivity (TSR). This combination of experiment and theory enabled us to elucidate the factors that control the reactivity patterns of iron(IV)‐oxo porphyrin π‐cation radicals in oxidation reactions and to resolve an enigmatic and fundamental problem.     

Toward Functional Type III [Fe]‐Hydrogenase Biomimics for H2 Activation: Insights from Computation

The chemistry of [Fe]‐hydrogenase has attracted significant interest due to its ability to activate molecular hydrogen. The intriguing properties of this enzyme have prompted the synthesis of numerous small molecule mimics aimed at activating H₂. Despite considerable effort, a majority of these compounds remain nonfunctional for hydrogenation reactions. By using a recently synthesized model as an entry point, seven biomimetic complexes have been examined through DFT computations to probe the influence of ligand environment on the ability of a mimic to bind and split H₂. One mimic, featuring a bidentate diphosphine group incorporating an internal nitrogen base, was found to have particularly attractive energetics, prompting a study of the role played by the proton/hydride acceptor necessary to complete the catalytic cycle. Computations revealed an experimentally accessible energetic pathway involving a benzaldehyde proton/hydride acceptor and the most promising catalyst.     

Direct Comparison of the Reactivity of Model Complexes for Compounds 0, I,and II in Oxygenation,Hydrogen‐Abstraction,and Hydride‐Transfer Processes

The iron(III) meso‐tetramesitylporphyrin complex is a good biomimetic to study the catalytic reactions of cytochrome P450. All of the three most discussed reactive intermediates concerning P450 catalysis (namely, Cpd 0, Cpd I, and Cpd II) can be selectively produced, identified, and stabilized for many minutes in solution at low temperature by choosing appropriate reaction conditions. In this way, their reactivity against various substrates was determined by utilizing low‐temperature rapid‐scan UV/Vis spectroscopy. Since all reactive intermediates are derived from a single model complex, the results of these kinetic measurements provide for the first time a full comparability of the determined rate constants for the three intermediates. The rate constants reveal a significant dependence of the reactivity on the type of reaction (e.g., oxygenation, hydrogen abstraction, or hydride transfer), which closely correlates with the chemical nature of Cpds 0, I, and II. The detailed knowledge of the reactivity of these intermediates provides a valuable tool to evaluate their particular role in biological systems.     

Multinuclear Non‐Heme Iron Complexes for Double‐Strand DNA Cleavage

Bleomycin mimics : Efficient oxidative double‐strand DNA cleavage has been achieved with multinuclear non‐heme iron complexes (see scheme). These complexes therefore represent model compounds that mimic the mode of action of the anti‐tumor drug bleomycin.

     

Mechanistic Insight into the Nitric Oxide Dioxygenation Reaction of Nonheme Iron(III)–Superoxo and Manganese(IV)–Peroxo Complexes

Reactions of nonheme Fe^III–superoxo and Mn^IV–peroxo complexes bearing a common tetraamido macrocyclic ligand (TAML), namely [(TAML)Fe^III(O₂)]^2? and [(TAML)Mn^IV(O₂)]^2?, with nitric oxide (NO) afford the Fe^III–NO₃ complex [(TAML)Fe^III(NO₃)]^2? and the Mn^V–oxo complex [(TAML)Mn^V(O)]^? plus NO₂^?, respectively. Mechanistic studies, including density functional theory (DFT) calculations, reveal that M^III–peroxynitrite (M=Fe and Mn) species, generated in the reactions of [(TAML)Fe^III(O₂)]^2? and [(TAML)Mn^IV(O₂)]^2? with NO, are converted into M^IV(O) and ^.NO₂ species through O?O bond homolysis of the peroxynitrite ligand. Then, a rebound of Fe^IV(O) with ^.NO₂ affords [(TAML)Fe^III(NO₃)]^2?, whereas electron transfer from Mn^IV(O) to ^.NO₂ yields [(TAML)Mn^V(O)]^? plus NO₂^?.     

Mononuclear Nonheme Iron(III)‐Iodosylarene and High‐Valent Iron‐Oxo Complexes in Olefin Epoxidation Reactions

High‐spin iron(III)‐iodosylarene complexes are highly reactive in the epoxidation of olefins, in which epoxides are formed as the major products with high stereospecificity and enantioselectivity. The reactivity of the iron(III)‐iodosylarene intermediates is much greater than that of the corresponding iron(IV)‐oxo complex in these reactions. The iron(III)‐iodosylarene species—not high‐valent iron(IV)‐oxo and iron(V)‐oxo species—are also shown to be the active oxidants in catalytic olefin epoxidation reactions. The present results are discussed in light of the long‐standing controversy on the one oxidant versus multiple oxidants hypothesis in oxidation reactions.     

Ligand‐Controlled Regiodivergent Pathways of Rhodium(III)‐Catalyzed Dihydroisoquinolone Synthesis: Experimental and Computational Studies of Different Cyclopentadienyl Ligands

Rh^III‐catalyzed directed C?H functionalizations of arylhydroxamates have become a valuable synthetic tool. To date, the regioselectivity of the insertion of the unsaturated acceptor into the common cyclometalated intermediate was dependent solely on intrinsic substrate control. Herein, we report two different catalytic systems that allow the selective formation of regioisomeric 3‐aryl dihydroisoquinolones and previously inaccessible 4‐aryl dihydroisoquinolones under full catalyst control. The differences in the catalysts are computationally examined using density functional theory and transition state theory of different possible pathways to elucidate key contributing factors leading to the regioisomeric products. The stabilities of the initially formed rhodium complex styrene adducts, as well as activation barrier differences for the migratory insertion, were identified as key contributing factors for the regiodivergent pathways.     

Spontaneous Reduction of Mononuclear High‐Spin Iron(III) Complexes to Mononuclear Low‐Spin Iron(II) Complexes in Aqueous Media and Nuclease Activity via Self‐Activation

Mononuclear high‐spin [Fe^III(Pyimpy)Cl₃]?2 CH₂Cl₂ ( 1 ?2 CH₂Cl₂) and [Fe^III(Me‐Pyimpy)Cl₃] ( 2 ), as well as low‐spin Fe^II(Pyimpy)₂](ClO₄)₂ ( 3 ) and [Fe^II(Me‐Pyimpy)₂](ClO₄)₂ ( 4 ) complexes of tridentate ligands Pyimpy and Me‐Pyimpy have been synthesized and characterized by analytical techniques, spectral, and X‐ray structural analyses. We observed an important type of conversion and associated spontaneous reduction of mono‐chelated high‐spin Fe^III ( 1 ?2 CH₂Cl₂ and 2 ) complexes to low‐spin bis‐chelated Fe^II complexes 3 and 4 , respectively. This process has been explored in detail by UV/Vis, fluorescence, and ¹H NMR spectroscopic measurements. The high positive potentials observed in electrochemical studies suggested a better stabilization of Fe^II centers in 3 and 4 . Theoretical studies by density functional theory (DFT) calculations supported an increased stabilization for 3 in polar solvents. Self‐activated nuclease activity of complexes 1 ?2CH₂Cl₂ and 2 during their spontaneous reduction was examined for the first time and the mechanism of nuclease activity was investigated.     

σ‐Insertive Mechanism versus Concerted Non‐insertive Mechanism in the Intramolecular Hydroamination of Aminoalkenes Catalyzed by Phenoxyamine Magnesium Complexes: A Synthetic and Computational Study

The phenoxyamine magnesium complexes [{ONN}MgCH₂Ph] ( 4 a : {ONN}=2,4‐tBu₂‐6‐(CH₂NMeCH₂CH₂NMe₂)C₆H₂O^?; 4 b : {ONN}=4‐tBu‐2‐(CH₂NMeCH₂CH₂NMe₂)‐6‐(SiPh₃)C₆H₂O^?) have been prepared and investigated with respect to their catalytic activity in the intramolecular hydroamination of aminoalkenes. The sterically more shielded triphenylsilyl‐substituted complex 4 b exhibits better thermal stability and higher catalytic activity. Kinetic investigations using complex 4 b in the cyclisation of 1‐allylcyclohexyl)methylamine ( 5 b ), respectively, 2,2‐dimethylpent‐4‐en‐1‐amine ( 5 c ), reveal a first‐order rate dependence on substrate and catalyst concentration. A significant primary kinetic isotope effect of 3.9±0.2 in the cyclisation of 5 b suggests significant N?H bond disruption in the rate‐determining transition state. The stoichiometric reaction of 4 b with 5 c revealed that at least two substrate molecules are required per magnesium centre to facilitate cyclisation. The reaction mechanism was further scrutinized computationally by examination of two rivalling mechanistic pathways. One scenario involves a coordinated amine molecule assisting in a concerted non‐insertive N?C ring closure with concurrent amino proton transfer from the amine onto the olefin, effectively combining the insertion and protonolysis step to a single step. The alternative mechanistic scenario involves a reversible olefin insertion step followed by rate‐determining protonolysis. DFT reveals that a proton‐assisted concerted N?C/C?H bond‐forming pathway is energetically prohibitive in comparison to the kinetically less demanding σ‐insertive pathway (ΔΔG^≠=5.6 kcal mol^?1). Thus, the σ‐insertive pathway is likely traversed exclusively. The DFT predicted total barrier of 23.1 kcal mol^?1 (relative to the {ONN}Mg pyrrolide catalyst resting state) for magnesium?alkyl bond aminolysis matches the experimentally determined Eyring parameter (ΔG^≠=24.1(±0.6) kcal mol^?1 (298 K)) gratifyingly well.     

Axial Ligand and Spin‐State Influence on the Formation and Reactivity of Hydroperoxo–Iron(III) Porphyrin Complexes

The present study focuses on the formation and reactivity of hydroperoxo–iron(III) porphyrin complexes formed in the [Fe^III(tpfpp)X]/H₂O₂/HOO^? system (TPFPP=5,10,15,20‐tetrakis(pentafluorophenyl)‐21H,23H‐porphyrin; X=Cl^? or CF₃SO₃^?) in acetonitrile under basic conditions at ?15 °C. Depending on the selected reaction conditions and the active form of the catalyst, the formation of high‐spin [Fe^III(tpfpp)(OOH)] and low‐spin [Fe^III(tpfpp)(OH)(OOH)] could be observed with the application of a low‐temperature rapid‐scan UV/Vis spectroscopic technique. Axial ligation and the spin state of the iron(III) center control the mode of O? O bond cleavage in the corresponding hydroperoxo porphyrin species. A mechanistic changeover from homo‐ to heterolytic O? O bond cleavage is observed for high‐ [Fe^III(tpfpp)(OOH)] and low‐spin [Fe^III(tpfpp)(OH)(OOH)] complexes, respectively. In contrast to other iron(III) hydroperoxo complexes with electron‐rich porphyrin ligands, electron‐deficient [Fe^III(tpfpp)(OH)(OOH)] was stable under relatively mild conditions and could therefore be investigated directly in the oxygenation reactions of selected organic substrates. The very low reactivity of [Fe^III(tpfpp)(OH)(OOH)] towards organic substrates implied that the ferric hydroperoxo intermediate must be a very sluggish oxidant compared with the iron(IV)–oxo porphyrin π‐cation radical intermediate in the catalytic oxygenation reactions of cytochrome P450.     

Structure Controlling Factors of Oxido-Bridged Dinuclear Iron(III) Complexes

Oxido bridges commonly form between iron(III) ions, but their bond angles and symmetry vary with the circumstances. A large number of oxido-bridged dinuclear iron(III) complexes have been structurally characterized. Some of them belong to the C₂ point group, possessing bent Fe–O–Fe bonds, while some others belong to the C_i symmetry, possessing the linear Fe–O–Fe bonds. The question in this study is what determines the structures and symmetry of oxido-bridged dinuclear iron(III) complexes. In order to gain further insights, three oxido-bridged dinuclear iron(III) complexes were newly prepared with 2,2′-bipyridine (bpy) and 1,10-phenanthroline (phen) ligands: [Fe₂OCl₂(bpy)₄][PF₆]₂ (1), [Fe₂O(NO₃)₂(bpy)₄][PF₆]₂·0.6MeCN·0.2(2-PrOH) (2), and [Fe₂OCl₂(phen)₄][PF₆]₂·MeCN·0.5H₂O (3). The crystal structures of 1, 2, and 3 were determined by the single-crystal X-ray diffraction method, and all of them were found to have the bent Fe–O–Fe bonds. Judging from the crystal structure, some intramolecular interligand hydrogen bonds were found to play an important role in fixing the structures. Additional density functional theory (DFT) calculations were conducted, also for a related oxido-bridged dinuclear iron(III) complex with a linear Fe–O–Fe bond. We conclude that the Fe–O–Fe bridge tends to bend like a water molecule, but is often stretched by interligand steric repulsion, and that the structures are mainly controlled by the intramolecular interligand interactions.     

A Computational Study of the Olefin Epoxidation Mechanism Catalyzed by Cyclopentadienyloxidomolybdenum(VI) Complexes

A DFT analysis of the epoxidation of C₂H₄ by H₂O₂ and MeOOH (as models of tert‐butylhydroperoxide, TBHP) catalyzed by [Cp*MoO₂Cl] ( 1 ) in CHCl₃ and by [Cp*MoO₂(H₂O)]⁺ in water is presented (Cp*=pentamethylcyclopentadienyl). The calculations were performed both in the gas phase and in solution with the use of the conductor‐like polarizable continuum model (CPCM). A low‐energy pathway has been identified, which starts with the activation of ROOH (R=H or Me) to form a hydro/alkylperoxido derivative, [Cp*MoO(OH)(OOR)Cl] or [Cp*MoO(OH)(OOR)]⁺ with barriers of 24.9 (26.5) and 28.7 (29.2) kcal mol^?1 for H₂O₂ (MeOOH), respectively, in solution. The latter barrier, however, is reduced to only 1.0 (1.6) kcal mol^?1 when one additional water molecule is explicitly included in the calculations. The hydro/alkylperoxido ligand in these intermediates is η²‐coordinated, with a significant interaction between the Mo center and the O^β atom. The subsequent step is a nucleophilic attack of the ethylene molecule on the activated O^α atom, requiring 13.9 (17.8) and 16.1 (17.7) kcal mol^?1 in solution, respectively. The corresponding transformation, catalyzed by the peroxido complex [Cp*MoO(O₂)Cl] in CHCl₃, requires higher barriers for both steps (ROOH activation: 34.3 (35.2) kcal mol^?1; O atom transfer: 28.5 (30.3) kcal mol^?1), which is attributed to both greater steric crowding and to the greater electron density on the metal atom.     

Monitoring of the Pre-Equilibrium Step in the Alkyne Hydration Reaction Catalyzed by Au(III) Complexes: A Computational Study Based on Experimental Evidences

The coordination ability of the [(ppy)Au(IPr)]²⁺ fragment [ppy = 2-phenylpyridine, IPr = 1,3-bis(2,6-di-isopropylphenyl)-imidazol-2-ylidene] towards different anionic and neutral X ligands (X = Cl⁻, BF₄⁻, OTf⁻, H₂O, 2-butyne, 3-hexyne) commonly involved in the crucial pre-equilibrium step of the alkyne hydration reaction is computationally investigated to shed light on unexpected experimental observations on its catalytic activity. Experiment reveals that BF₄⁻ and OTf⁻ have very similar coordination ability towards [(ppy)Au(IPr)]²⁺ and slightly less than water, whereas the alkyne complex could not be observed in solution at least at the NMR sensitivity. Due to the steric hindrance/dispersion interaction balance between X and IPr, the [(ppy)Au(IPr)]²⁺ fragment is computationally found to be much less selective than a model [(ppy)Au(NHC)]²⁺ (NHC = 1,3-dimethylimidazol-2-ylidene) fragment towards the different ligands, in particular OTf⁻ and BF₄⁻, in agreement with experiment. Effect of the ancillary ligand substitution demonstrates that the coordination ability of Au(III) is quantitatively strongly affected by the nature of the ligands (even more than the net charge of the complex) and that all the investigated gold fragments coordinate to alkynes more strongly than H₂O. Remarkably, a stabilization of the water-coordinating species with respect to the alkyne-coordinating one can only be achieved within a microsolvation model, which reconciles theory with experiment. All the results reported here suggest that both the Au(III) fragment coordination ability and its proper computational modelling in the experimental conditions are fundamental issues for the design of efficient catalysts.     

Understanding Electrogenerated Chemiluminescence Efficiency in Blue‐Shifted Iridium(III)‐Complexes: An Experimental and Theoretical Study

Compared to tris(2‐phenylpyridine)iridium(III) ([Ir(ppy)₃]), iridium(III) complexes containing difluorophenylpyridine (df‐ppy) and/or an ancillary triazolylpyridine ligand [3‐phenyl‐1,2,4‐triazol‐5‐ylpyridinato (ptp) or 1‐benzyl‐1,2,3‐triazol‐4‐ylpyridine (ptb)] exhibit considerable hypsochromic shifts (ca. 25–60 nm), due to the significant stabilising effect of these ligands on the HOMO energy, whilst having relatively little effect on the LUMO. Despite their lower photoluminescence quantum yields compared with [Ir(ppy)₃] and [Ir(df‐ppy)₃], the iridium(III) complexes containing triazolylpyridine ligands gave greater electrogenerated chemiluminescence (ECL) intensities (using tri‐n‐propylamine (TPA) as a co‐reactant), which can in part be ascribed to the more energetically favourable reactions of the oxidised complex (M⁺) with both TPA and its neutral radical oxidation product. The calculated iridium(III) complex LUMO energies were shown to be a good predictor of the corresponding M⁺ LUMO energies, and both HOMO and LUMO levels are related to ECL efficiency. The theoretical and experimental data together show that the best strategy for the design of efficient new blue‐shifted electrochemiluminophores is to aim to stabilise the HOMO, while only moderately stabilising the LUMO, thereby increasing the energy gap but ensuring favourable thermodynamics and kinetics for the ECL reaction. Of the iridium(III) complexes examined, [Ir(df‐ppy)₂(ptb)]⁺ was most attractive as a blue‐emitter for ECL detection, featuring a large hypsochromic shift (λ_max=454 and 484 nm), superior co‐reactant ECL intensity than the archetypal homoleptic green and blue emitters: [Ir(ppy)₃] and [Ir(df‐ppy)₃] (by over 16‐fold and threefold, respectively), and greater solubility in polar solvents.