Synthesis, Characterization, and Spectroscopic Studies of 2,6-Dimethylpyridyl-Linked Cu(I)-CNC Complexes: The Electronic Influence of Aryl Wingtips on Copper Centers.

Six new Cu(I) complexes containing pincer ligands of the type 2,6-bis(3-alkyl/arylimidazol-2-ylidene) methylpyridine I(R/R'Ar) CN̂C, where R = trifluoroethyl (TFE) and R' = 4-CF3, 4-NO2, 4-CN, 4-H, and 4-CH3, have been synthesized. These complexes, namely, [Cu(I(TFE)CN̂C)]PF6, 1-TFE; [Cu(ICF3Ar CN̂C]PF6, 2-CF3; [Cu(INO2Ar CN̂C)]PF6, 3-NO2; [Cu(ICNAr CN̂C]PF6, 4-CN; [Cu(IHAr CN̂C)]2(PF6)2, 5-H; and [Cu(ICH3Ar CN̂C)]2(PF6)2, 6-CH3, were fully characterized by 1H, 13C, and HMBC NMR spectroscopy, elemental analysis, electrochemical studies, and single-crystal X-ray crystallography. The crystallographic data revealed different structures and copper nuclearities for the complexes bearing aryl wingtips with electron-withdrawing (2-CF3, 3-NO2, and 4-CN) and electron-donating (5-H and 6-CH3) substituents. The solution-phase conductivity measurements in acetonitrile revealed a mix-electrolyte behavior for these complexes, supporting the presence of both mono- and binuclear forms of each complex. The fast monomer-dimer equilibrium of the Cu-CNC complexes at room temperature is reflected in their simple 1H NMR spectra in acetonitrile. However, both mono- and binuclear forms were identifiable in 1H diffusion-ordered spectroscopy (DOSY) at low temperatures. The dynamic behavior of these complexes in solution was further examined by variable-temperature 1H NMR (VT 1H NMR) experiments, and the relevant thermodynamic parameters were determined. The process was also probed by one-dimensional rotating-frame Overhauser enhancement spectroscopy (1D ROESY) experiments to elucidate the coexisting species in solution. The 2,6-dimethylpyridyl-linked Cu-CNC complexes also presented a quasi-reversible Cu(II)/Cu(I) couple in cyclic voltammetry studies, wherein a clear influence of the aryl wingtips on the E1/2 values was observed. Furthermore, the percent buried volumes (% Vbur) of the complexes were calculated, showing a similar steric hindrance around copper in all complexes. These findings support the importance of electronic effects, induced by the aryl wingtips, on the preferred coordination geometry, copper nuclearity, and redox properties of the Cu-CNC complexes.

pH Changes That Induce an Axial Ligand Effect on Nonheme Iron(IV) Oxo Complexes with an Appended Aminopropyl Functionality.

Nonheme iron enzymes often utilize a high-valent iron(IV) oxo species for the biosynthesis of natural products, but their high reactivity often precludes structural and functional studies of these complexes. In this work, a combined experimental and computational study is presented on a biomimetic nonheme iron(IV) oxo complex bearing an aminopyridine macrocyclic ligand and its reactivity toward olefin epoxidation upon changes in the identity and coordination ability of the axial ligand. Herein, we show a dramatic effect of the pH on the oxygen-atom-transfer (OAT) reaction with substrates. In particular, these changes have occurred because of protonation of the axial-bound pendant amine group, where its coordination to iron is replaced by a solvent molecule or anionic ligand. This axial ligand effect influences the catalysis, and we observe enhanced cyclooctene epoxidation yields and turnover numbers in the presence of the unbound protonated pendant amine group. Density functional theory studies were performed to support the experiments and highlight that replacement of the pendant amine with a neutral or anionic ligand dramatically lowers the rate-determining barriers of cyclooctene epoxidation. The computational work further establishes that the change in OAT is due to electrostatic interactions of the pendant amine cation that favorably affect the barrier heights.

Computational studies of DNA base repair mechanisms by nonheme iron dioxygenases: selective epoxidation and hydroxylation pathways.

DNA base repair mechanisms of alkylated DNA bases is an important reaction in chemical biology and particularly in the human body. It is typically catalyzed by an α-ketoglutarate-dependent nonheme iron dioxygenase named the AlkB repair enzyme. In this work we report a detailed computational study into the structure and reactivity of AlkB repair enzymes with alkylated DNA bases. In particular, we investigate the aliphatic hydroxylation and C[double bond, length as m-dash]C epoxidation mechanisms of alkylated DNA bases by a high-valent iron(iv)-oxo intermediate. Our computational studies use quantum mechanics/molecular mechanics methods on full enzymatic structures as well as cluster models on active site systems. The work shows that the iron(iv)-oxo species is rapidly formed after dioxygen binding to an iron(ii) center and passes a bicyclic ring structure as intermediate. Subsequent cluster models explore the mechanism of substrate hydroxylation and epoxidation of alkylated DNA bases. The work shows low energy barriers for substrate activation and consequently energetically feasible pathways are predicted. Overall, the work shows that a high-valent iron(iv)-oxo species can efficiently dealkylate alkylated DNA bases and return them into their original form.

C-X (X = N, O) Cross-Coupling Reactions Catalyzed by Copper-Pincer Bis(N-Heterocyclic Carbene) Complexes.

Over the last two decades, N-heterocyclic carbene (NHC)-copper catalysts have received considerable attention in organic synthesis. Despite the popularity of copper complexes containing monodentate NHC ligands and recent development of poly(NHC) platforms, their application in C-C and C-heteroatom cross-coupling reactions has been limited. Recently, we reported an air-assisted Sonogashira-type cross-coupling catalyzed by well-defined cationic copper-pincer bis(NHC) complexes. Herein, we report the application of these complexes in Ullmann-type C-X (X = N, O) coupling of azoles and phenols with aryl halides in a relatively short reaction time. In contrast to other well-defined copper(I) catalysts that require an inert atmosphere for an efficient C-X coupling, the employed Cu(I)-pincer bis(NHC) complexes provide good to excellent yields in air. The air-assisted reactivity, unlike that in the Sonogashira reaction, is also affected by the base employed and the reaction time. With Cs2CO3 and K2CO3, the oxygen-generated catalyst is more reactive than the catalyst formed under argon in a short reaction time (12 h). However, the difference in reactivity is compromised after a 24 h reaction with K2CO3. The efficient pincer Cu-NHC/O2/Cs2CO3 system provides great to excellent cross-coupling yields for electronically diverse aryl iodides and imidazole derivatives. The catalyst scope is controlled by a balance between nucleophilicity, coordinating ability, and the steric hindrance of aryl halides and N-/O-nucleophiles.

Synthesis, characterization, and photoluminescent studies of three-coordinate Cu(i)-NHC complexes bearing unsymmetrically-substituted dipyridylamine ligands.

A series of heteroleptic three-coordinate Cu(i) complexes bearing monodentate N-heterocyclic carbene (NHC) ligands of the type 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene (SIPr), and bidentate N-donor ligands of the type unsymmetrically-substituted dimethyl dipyridylamine (Me2Hdpa) and bis(mesityl)biazanaphthenequinone (mesBIAN) have been synthesized. The complexes [Cu(IPr)(3,4'-Me2Hdpa)]PF6, 1; [Cu(IPr)(3,5'-Me2Hdpa)]PF6, 2; [Cu(IPr)(3,6'-Me2Hdpa)]PF6, 3; [Cu(IPr)(mesBIAN)]PF6, 6; [Cu(SIPr)(3,4'-Me2Hdpa)]PF6, 7; [Cu(SIPr)(3,5'-Me2Hdpa)]PF6, 8; and [Cu(SIPr)(3,3'-Me2Hdpa)]PF6, 11 have been characterized by 1H and 13C NMR spectroscopies, elemental analysis, cyclic voltammetry, and photophysical studies in solid and solution phase. Single crystal X-ray structures were obtained for all complexes except 11. The crystallographic data reveal a mononuclear structure for all complexes with the copper atom ligated by one C and two N atoms. The UV-Vis absorption spectra of all dipyridylamine complexes in CH2Cl2 show a strong ligand-centered absorption band around 250 nm and a strong metal-to-ligand charge transfer (MLCT) band around 300 nm. When irradiated with UV light, the complexes exhibit strong emission maxima at 453-482 nm with photoluminescence quantum yields (PLQY) ranging from 0.21 to 0.87 in solid state. While the PLQY values are comparable to those of the symmetrical [Cu(IPr)(Me2Hdpa)]PF6 complexes, a stabilizing CH-π interaction has been reduced in the current systems. In particular, complex 3 lacks any strong CH-π interaction, but emits more efficiently than 1 and 2 wherein the interactions exist. Structural data analysis was performed to clarify the role of ligands' plane angle and the NH/CH⋯F interactions to the observed light interaction of unsymmetrical [Cu(NHC)(Me2Hdpa)]PF6 complexes. DFT calculations were performed to assist in the assignment of the electronic structure and excited state behavior of the complexes.

Square-planar Co(iii) in {O4} coordination: large ZFS and reactivity with ROS.

Oxidation of distorted square-planar perfluoropinacolate Co compound [CoII(pinF)2]2-, 1, to [CoIII(pinF)2]1-, 2, is reported. Rigidly square-planar 2 has an intermediate-spin, S = 1, ground state and very large zero-field splitting (ZFS) with D = 67.2 cm-1; |E| = 18.0 cm-1, (E/D = 0.27), g⊥ = 2.10, g‖ = 2.25 and χTIP = 1950 × 10-6 cm3 mol-1. This Co(iii) species, 2, reacts with ROS to oxidise two (pinF)2- ligands to form tetrahedral [CoII(Hpfa)4]2-, 3.

Cu(I) Complexes of Pincer Pyridine-Based N-Heterocyclic Carbenes with Small Wingtip Substituents: Synthesis and Structural and Spectroscopic Studies.

Six new Cu(I) complexes with pincer N-heterocyclic carbene (NHC) ligands of the type 2,6-bis(3-alkylimidazol-2-ylidene)pyridine, I(R)CNC, and 2,6-bis(3-alkylimidazol-2-ylidene)methylpyridine, I(R)C^N^C, where R = Me, Et, and iPr have been synthesized using Cu precursors and bis(imidazolium) salts. All of these compounds, namely, [Cu2(IMeCNC)2](PF6)2, 1; [Cu2(IEtCNC)2](PF6)2, 2; [Cu2(IiPrCNC)2](PF6)2, 3; [Cu(IMeC^N^C)](PF6), 4; [Cu(IEtC^N^C)](PF6), 5; and [Cu(IiPrC^N^C)](PF6), 6, have been characterized by 1H and 13C NMR spectroscopies, elemental analysis, solution conductivity, and electrochemical studies. Single crystal X-ray structures were obtained for all complexes except 1. The crystallographic data reveal a binuclear structure containing two Cu atoms at a close distance, 2.622-2.811 Å for all the complexes except 5, which shows a unique mononuclear structure. Spatial syn arrangement of ethyl groups and extensive π-π stacking in the solid state accounts for the mononuclear structure of complex 5. A pseudolinear coordination geometry about metal centers consisting of two Cu-carbene bonds, as well as weak Cu-pyridine interactions, exist among all the complexes independent of their ligand. Solution-state conductivity data reveal a dominant 1:2 electrolyte behavior for 1-3 but 1:1 electrolyte for 4-6, consistent with the sustainable binuclear structure in solutions of Cu(I)-I(R)CNC complexes. Cyclic voltammetry and differential pulse voltammetry studies reveal an irreversible and two quasi-reversible peaks for the one-electron oxidation of solvent-bound and solvent-free binuclear and mononuclear Cu-NHC species in complexes 1-3. In contrast, the reversible Cu(II)/Cu(I) couples of 4-6 at potentials close to that of complexes with tripodal polydentate NHC scaffolds indicate the electronic and structural flexibility of I(R)C^N^C ligands to accommodate both Cu(I) and Cu(II) ions.

Structural and electronic properties of old and new A2[M(pin(F))2] complexes.

Seven new homoleptic complexes of the form A2[M(pin(F))2] have been synthesized with the dodecafluoropinacolate (pin(F))(2-) ligand, namely (Me4N)2[Fe(pin(F))2], 1; (Me4N)2[Co(pin(F))2], 2; ((n)Bu4N)2[Co(pin(F))2], 3; {K(DME)2}2[Ni(pin(F))2], 4; (Me4N)2[Ni(pin(F))2], 5; {K(DME)2}2[Cu(pin(F))2], 7; and (Me4N)2[Cu(pin(F))2], 8. In addition, the previously reported complexes K2[Cu(pin(F))2], 6, and K2[Zn(pin(F))2], 9, are characterized in much greater detail in this work. These nine compounds have been characterized by UV-vis spectroscopy, cyclic voltammetry, elemental analysis, and for paramagnetic compounds, Evans method magnetic susceptibility. Single-crystal X-ray crystallographic data were obtained for all complexes except 5. The crystallographic data show a square-planar geometry about the metal center in all Fe (1), Ni (4), and Cu (6, 7, 8) complexes independent of countercation. The Co species exhibit square-planar (3) or distorted square-planar geometries (2), and the Zn species (9) is tetrahedral. No evidence for solvent binding to any Cu or Zn complex was observed. Solvent binding in Ni can be tuned by the countercation, whereas in Co only strongly donating Lewis solvents bind independent of the countercation. Indirect evidence (diffuse reflectance spectra and conductivity data) suggest that 5 is not a square-planar compound, unlike 4 or the literature K2[Ni(pin(F))2]. Cyclic voltammetry studies reveal reversible redox couples for Ni(III)/Ni(II) in 5 and for Cu(III)/Cu(II) in 8 but quasi-reversible couples for the Fe(III)/Fe(II) couple in 1 and the Co(III)/Co(II) couple in 2. Perfluorination of the pinacolate ligand results in an increase in the central C-C bond length due to steric clashes between CF3 groups, relative to perhydropinacolate complexes. Both types of pinacolate complexes exhibit O-C-C-O torsion angles around 40°. Together, these data demonstrate that perfluorination of the pinacolate ligand makes possible highly unusual and coordinatively unsaturated high-spin metal centers with ready thermodynamic access to rare oxidation states such as Ni(III) and Cu(III).

K⋠⋠⋠F/O interactions bridge copper(I) fluorinated alkoxide complexes and facilitate dioxygen activation.

Seven E[Cu(OR)2] copper(I) complexes (E = K(+), {K(18C6)}(+) (18C6 = [18]crown-6), or Ph4P(+); R = C4F9, CPhMe(F)2, and CMeMe(F)2) have been prepared and their reactivity with O2 studied. The K[Cu(OR)2] species react with O2 in a copper-concentration-dependent manner such that 2:1 and 3:1 Cu/O2 adducts are observed manometrically at -78 °C. Analogous reactivity with O2 is not observed with the {K(18C6)}(+) or Ph4P(+) derivatives. Solution conductivity data demonstrate that these K[Cu(OR)2] complexes do not behave as 1:1 electrolytes in solution. The K(+) ions induce aggregation of multiple [Cu(OR)2](-) units through K⋅⋅⋅F/O interactions and thereby effect irreversible O2 reduction by multiple Cu centers. Bond valence analyses for the potassium cations confirm the dominance of the fluorine interactions in the coordination spheres of K(+) ions. Intramolecular hydroxylation of ligand aryl and alkyl C-H bonds is observed. Nucleophilic reactivity with CO2 is observed for the oxygenated Cu complexes and a Cu(II) carbonate has been isolated and characterized.

Factors that control catalytic two- versus four-electron reduction of dioxygen by copper complexes.

The selective two-electron reduction of O(2) by one-electron reductants such as decamethylferrocene (Fc*) and octamethylferrocene (Me(8)Fc) is efficiently catalyzed by a binuclear Cu(II) complex [Cu(II)(2)(LO)(OH)](2+) (D1) {LO is a binucleating ligand with copper-bridging phenolate moiety} in the presence of trifluoroacetic acid (HOTF) in acetone. The protonation of the hydroxide group of [Cu(II)(2)(LO)(OH)](2+) with HOTF to produce [Cu(II)(2)(LO)(OTF)](2+) (D1-OTF) makes it possible for this to be reduced by 2 equiv of Fc* via a two-step electron-transfer sequence. Reactions of the fully reduced complex [Cu(I)(2)(LO)](+) (D3) with O(2) in the presence of HOTF led to the low-temperature detection of the absorption spectra due to the peroxo complex [Cu(II)(2)(LO)(OO)] (D) and the protonated hydroperoxo complex [Cu(II)(2)(LO)(OOH)](2+) (D4). No further Fc* reduction of D4 occurs, and it is instead further protonated by HOTF to yield H(2)O(2) accompanied by regeneration of [Cu(II)(2)(LO)(OTF)](2+) (D1-OTF), thus completing the catalytic cycle for the two-electron reduction of O(2) by Fc*. Kinetic studies on the formation of Fc*(+) under catalytic conditions as well as for separate examination of the electron transfer from Fc* to D1-OTF reveal there are two important reaction pathways operating. One is a rate-determining second reduction of D1-OTF, thus electron transfer from Fc* to a mixed-valent intermediate [Cu(II)Cu(I)(LO)](2+) (D2), which leads to [Cu(I)(2)(LO)](+) that is coupled with O(2) binding to produce [Cu(II)(2)(LO)(OO)](+) (D). The other involves direct reaction of O(2) with the mixed-valent compound D2 followed by rapid Fc* reduction of a putative superoxo-dicopper(II) species thus formed, producing D.

Regioselectivity of aliphatic versus aromatic hydroxylation by a nonheme iron(II)-superoxo complex.

Many enzymes in nature utilize molecular oxygen on an iron center for the catalysis of substrate hydroxylation. In recent years, great progress has been made in understanding the function and properties of iron(IV)-oxo complexes; however, little is known about the reactivity of iron(II)-superoxo intermediates in substrate activation. It has been proposed recently that iron(II)-superoxo intermediates take part as hydrogen abstraction species in the catalytic cycles of nonheme iron enzymes. To gain insight into oxygen atom transfer reactions by the nonheme iron(II)-superoxo species, we performed a density functional theory study on the aliphatic and aromatic hydroxylation reactions using a biomimetic model complex. The calculations show that nonheme iron(II)-superoxo complexes can be considered as effective oxidants in hydrogen atom abstraction reactions, for which we find a low barrier of 14.7 kcal mol(-1) on the sextet spin state surface. On the other hand, electrophilic reactions, such as aromatic hydroxylation, encounter much higher (>20 kcal mol(-1)) barrier heights and therefore are unlikely to proceed. A thermodynamic analysis puts our barrier heights into a larger context of previous studies using nonheme iron(IV)-oxo oxidants and predicts the activity of enzymatic iron(II)-superoxo intermediates.

Electron-transfer reduction of dinuclear copper peroxo and bis-µ-oxo complexes leading to the catalytic four-electron reduction of dioxygen to water.

The four-electron reduction of dioxygen by decamethylferrocene (Fc*) to water is efficiently catalyzed by a binuclear copper(II) complex (1) and a mononuclear copper(II) complex (2) in the presence of trifluoroacetic acid in acetone at 298 K. Fast electron transfer from Fc* to 1 and 2 affords the corresponding Cu(I) complexes, which react at low temperature (193 K) with dioxygen to afford the η(2):η(2)-peroxo dicopper(II) (3) and bis-µ-oxo dicopper(III) (4) intermediates, respectively. The rate constants for electron transfer from Fc* and octamethylferrocene (Me(8)Fc) to 1 as well as electron transfer from Fc* and Me(8)Fc to 3 were determined at various temperatures, leading to activation enthalpies and entropies. The activation entropies of electron transfer from Fc* and Me(8)Fc to 1 were determined to be close to zero, as expected for outer-sphere electron-transfer reactions without formation of any intermediates. For electron transfer from Fc* and Me(8)Fc to 3, the activation entropies were also found to be close to zero. Such agreement indicates that the η(2):η(2)-peroxo complex (3) is directly reduced by Fc* rather than via the conversion to the corresponding bis-µ-oxo complex, followed by the electron-transfer reduction by Fc* leading to the four-electron reduction of dioxygen to water. The bis-µ-oxo species (4) is reduced by Fc* with a much faster rate than the η(2):η(2)-peroxo complex (3), but this also leads to the four-electron reduction of dioxygen to water.

Oxidative properties of a nonheme Ni(II)(O2) complex: Reactivity patterns for C-H activation, aromatic hydroxylation and heteroatom oxidation.

Density functional theory calculations on the reactivity of a Ni(II)-superoxo complex in C-H bond activation, aromatic hydroxylation and heteroatom oxidation reactions have been explored; the Ni(II)-superoxo complex is able to react with substrates with weak C-H bonds and PPh(3).

The axial ligand effect on aliphatic and aromatic hydroxylation by non-heme iron(IV)-oxo biomimetic complexes.

Iron(IV)-oxo heme cation radicals are active species in enzymes and biomimetic model complexes. They are potent oxidants in oxygen atom transfer reactions, but the reactivity is strongly dependent on the ligand system of the iron(IV)-oxo group and in particular the nature of the ligand trans to the oxo group (the axial ligand). To find out what effect the axial ligand has on the reactivity of non-heme iron(IV)-oxo species, we have performed a series of density functional theory (DFT) calculations on aliphatic and aromatic hydroxylation reactions by using [Fe(IV)=O(TMC)(L)](n+) (TMC=1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane, and L=acetonitrile or chloride). The studies show that the regioselectivity of aliphatic over aromatic hydroxylation is preferred. The studies are in good agreement with experimental product distributions. Moreover, the system with the acetonitrile axial ligand is orders of magnitude more reactive than that with a chloride axial ligand. We have analyzed our results and we have shown that the metal-ligand interactions influence the orbital energies and as a consequence also the electron affinities and hydrogen atom abstraction abilities. Thermodynamic cycles explain the regioselectivity preferences.

Manganese substituted Compound I of cytochrome P450 biomimetics: a comparative reactivity study of Mn(V)-oxo versus Mn(IV)-oxo species.

Manganese-oxo porphyrins have been well studied as biomimetic models of cytochromes P450 and are known to be able to catalyze substrate hydroxylation reactions. Recent experimental studies [J.Y. Lee, Y.-M. Lee, H. Kotani, W. Nam, S. Fukuzumi, Chem. Commun. (2009) 704] showed that Mn(V)-oxo porphyrins react rapidly with 10-methyl-9,10-dihydroacridine (AcrH(2)) via a proton-coupled-electron-transfer followed by an electron transfer. In this work, we present a computational study on the reactivity patterns of Mn(V)-oxo and Mn(IV)-oxo with respect to AcrH(2). This study shows that although both oxidants are capable of hydroxylating AcrH(2), the Mn(V)-oxo species is the more active oxidant. We have generalized these observations with thermodynamic cycles that explain the reaction mechanisms and electron transfer processes. For the Mn(V)-oxo mechanism the reactions proceed with a fast spin state crossing from the ground state singlet to the triplet spin state prior to a hydrogen atom transfer followed by another electron transfer. The present results are fully consistent with previous studies on iron-oxo porphyrins and manganese-oxo porphyrins and shows that the interplay of low lying singlet and triplet spin state surfaces influences the reaction mechanisms and kinetics.

Effect of porphyrin ligands on the regioselective dehydrogenation versus epoxidation of olefins by oxoiron(IV) mimics of cytochrome P450.

The cytochromes P450 are versatile enzymes involved in various catalytic oxidation reactions, such as hydroxylation, epoxidation and dehydrogenation. In this work, we present combined experimental and theoretical studies on the change of regioselectivity in cyclohexadiene oxidation (i.e., epoxidation vs dehydrogenation) by oxoiron(IV) porphyrin complexes bearing different porphyrin ligands. Our experimental results show that meso-substitution of the porphyrin ring with electron-withdrawing substituents leads to a regioselectivity switch from dehydrogenation to epoxidation, affording the formation of epoxide as a major product. In contrast, electron-rich iron porphyrins are shown to produce benzene resulting from the dehydrogenation of cyclohexadiene. Density functional theory (DFT) calculations on the regioselectivity switch of epoxidation vs dehydrogenation have been performed using three oxoiron(IV) porphyrin oxidants with hydrogen atoms, phenyl groups, and pentachlorophenyl (ArCl(5)) groups on the meso-position. The DFT studies show that the epoxidation reaction by the latter catalyst is stabilized because of favorable interactions of the substrate with halogen atoms of the meso-ligand as well as with pyrrole nitrogen atoms of the porphyrin macrocycle. Hydrogen abstraction transition states, in contrast, have a substrate-binding orientation further away from the porphyrin pyrrole nitrogens, and they are much less stabilized. Finally, the regioselectivity of dehydrogenation versus hydroxylation is rationalized using thermodynamic cycles.

Fundamental differences of substrate hydroxylation by high-valent iron(IV)-oxo models of cytochrome P450.

An Iron(IV)-oxo heme(+*) complex (Compound I, Cpd I) is the proposed active species of heme enzymes such as the cytochromes P450 and is elusive; therefore, biomimetic studies on active site mimics give valuable insight into the fundamental properties of heme active species. In this work we present density functional theory (DFT) calculations on substrate hydroxylation by a Compound I mimic [Fe(IV)=O(Por(+*))Cl] and its one-electron reduced form [Fe(IV)=O(Por)Cl](-). Thus, recent experimental studies showed that [Fe(IV)=O(Por)Cl](-) is able to react with substrates via hydride transfer reactions [Jeong, Y. J.; Kang, Y.; Han, A.-R.; Lee, Y.-M.; Kotani, H.; Fukuzumi, S.; Nam, W. Angew. Chem., Int. Ed. 2008, 47, 7321-7324]. By contrast, theoretical studies on camphor hydroxylation by these two oxidants concluded that the one-electron reduced form of Compound I is a sluggish oxidant of hydroxylation reactions [Altun, A.; Shaik, S.; Thiel, W. J. Am. Chem. Soc. 2007, 129, 8978-8987]. To resolve the question why the one-electron reduced Compound I is an oxidant in one case and a sluggish oxidant in other cases, we have performed a DFT study on 10-methyl-9,10-dihydro acridine (AcrH(2)) hydroxylation by [Fe(IV)=O(Por(+*))Cl] and [Fe(IV)=O(Por)Cl](-). The calculations presented in this work show that both [Fe(IV)=O(Por(+*))Cl] and [Fe(IV)=O(Por)Cl](-) are plausible oxidants, but [Fe(IV)=O(Por(+*))Cl] reacts via much lower reaction barriers. Moreover, [Fe(IV)=O(Por(+*))Cl] reacts via hydride transfer, while [Fe(IV)=O(Por)Cl](-) by hydrogen abstraction. The differences between hydride and hydrogen atom transfer reactions have been rationalized with thermodynamic cycles and shown to be the result of differences in electron abstraction abilities of the two oxidants. Thus, the calculations predict that [Fe(IV)=O(Por)Cl](-) is only able to hydroxylate weak C-H bonds, whereas [Fe(IV)=O(Por(+*))Cl] is more versatile.

How does the axial ligand of cytochrome P450 biomimetics influence the regioselectivity of aliphatic versus aromatic hydroxylation?

The catalytic activity of high-valent iron-oxo active species of heme enzymes is known to be dependent on the nature of the axial ligand trans to the iron-oxo group. In a similar fashion, experimental studies on iron-oxo porphyrin biomimetic systems have shown a significant axial ligand effect on ethylbenzene hydroxylation, with an axial acetonitrile ligand leading to phenyl hydroxylation products and an axial chloride anion giving predominantly benzyl hydroxylation products. To elucidate the fundamental factors that distinguish this regioselectivity reversal in iron-oxo porphyrin catalysis, we have performed a series of density functional theory calculations on the hydroxylation of ethylbenzene by [Fe(IV)=O(Por(+.))L] (Por = porphyrin; L = NCCH(3) or Cl(-)), which affords 1-phenylethanol and p-ethylphenol products. The calculations confirm the experimentally determined product distributions. Furthermore, a detailed analysis of the electronic differences between the two oxidants shows that their reversed regioselectivity is a result of differences in orbital interactions between the axial ligand and iron-oxo porphyrin system. In particular, three high-lying orbitals (pi*(xz), pi*(yz) and a(2u)), which are singly occupied in the reactant complex, are stabilised with an anionic ligand such as Cl(-), which leads to enhanced HOMO-LUMO energy gaps. As a consequence, reactions leading to cationic intermediates through the two-electron reduction of the metal centre are disfavoured. The aliphatic hydroxylation mechanism, in contrast, is a radical process in which only one electron is transferred in the rate-determining transition state, which means that the effect of the axial ligand on this mechanism is much smaller.