Hajime Hirao

Axial ligand tuning of a nonheme iron(IV)–oxo unit for hydrogen atom abstraction

The reactivities of mononuclear nonheme iron(IV)–oxo complexes bearing different axial ligands, [FeIV(O)(TMC)(X)]n+ [where TMC is 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane and X is NCCH3 (1-NCCH3), CF3COO− (1-OOCCF3), or N3− (1-N3)], and [FeIV(O)(TMCS)]+ (1′-SR) (where TMCS is 1-mercaptoethyl-4,8,11-trimethyl-1,4,8,11-tetraazacyclotetradecane), have been investigated with respect to oxo-transfer to PPh3 and hydrogen atom abstraction from phenol OH and alkylaromatic CH bonds. These reactivities were significantly affected by the identity of the axial ligands, but the reactivity trends differed markedly. In the oxidation of PPh3, the reactivity order of 1-NCCH3 > 1-OOCCF3 > 1-N3 > 1′-SR was observed, reflecting a decrease in the electrophilicity of iron(IV)–oxo unit upon replacement of CH3CN with an anionic axial ligand. Surprisingly, the reactivity order was inverted in the oxidation of alkylaromatic CH and phenol OH bonds, i.e., 1′-SR > 1-N3 > 1-OOCCF3 > 1-NCCH3. Furthermore, a good correlation was observed between the reactivities of iron(IV)–oxo species in H atom abstraction reactions and their reduction potentials, Ep,c, with the most reactive 1′-SR complex exhibiting the lowest potential. In other words, the more electron-donating the axial ligand is, the more reactive the iron(IV)–oxo species becomes in H atom abstraction. Quantum mechanical calculations show that a two-state reactivity model applies to this series of complexes, in which a triplet ground state and a nearby quintet excited-state both contribute to the reactivity of the complexes. The inverted reactivity order in H atom abstraction can be rationalized by a decreased triplet-quintet gap with the more electron-donating axial ligand, which increases the contribution of the much more reactive quintet state and enhances the overall reactivity.

A Two-State Reactivity Rationale for Counterintuitive Axial Ligand Effects on the CH Activation Reactivity of Nonheme FeIVO Oxidants

This paper addresses the observation of counterintuitive reactivity patterns of iron-oxo reagents, TMC(L)FeO(2+,1+); L=CH(3)CN, CF(3)CO(2) (-), N(3) (-), and SR(-), in O-transfer to phosphines versus H-abstraction from, for example, 1,4-cyclohexadiene. Experiments show that O-transfer reactivity correlates with the electrophilicity of the oxidant, but H-abstraction reactivity follows an opposite trend. DFT/B3 LYP calculations reveal that two-state reactivity (TSR) serves as a compelling rationale for these trends, whereby all reactions involve two adjacent spin-states of the iron(IV)-oxo species, triplet and quintet. The ground state triplet surface has high barriers, whereas the excited state quintet surface features lower ones. The barriers, on any single surface, are found to increase as the electrophilicity of TMC(L)FeO(2+,1+) decreases. Thus, the counterintuitive behavior of the H-abstraction reactions cannot be explained by considering the reactivity of only a single spin state but can be rationalized by a TSR model in which the reactions proceed on the two surfaces. Two TSR models are outlined: one is traditional involving a variable transmission coefficient for crossover from triplet to quintet, followed by quintet-state reactions; the other considers the net barrier as a blend of the triplet and quintet barriers. The blending coefficient (x), which estimates the triplet participation, increases as the quintet-triplet energy gap of the TMC(L)FeO(2+,1+) reagent increases, in the following order of L: CH(3)CN > CF(3)CO(2) (-) > N(3) (-) > SR(-). The calculated barriers predict the dichotomic experimental trends and the counterintuitive behavior of the H-abstraction series. The TSR approaches make a variety of testable predictions.

A two-state reactivity model explains unusual kinetic isotope effect patterns in C-H bond cleavage by nonheme oxoiron(IV) complexes.

Its in the bond: The cleavage of C-H bonds by two related oxoiron(IV) complexes shows a range of kinetic isotope effect (KIE) values that exhibit an unusual dependence on the C-H bond strength. Large nonclassical KIEs are observed for bond strengths below 93 kcal mol(-1), while semiclassical values are found above this value (see graph, DHA = 9,10-dihydroanthracene). This nonintuitive behavior can be rationalized by invoking a two-state reactivity model.

Reactivity patterns of cytochrome P450 enzymes: multifunctionality of the active species, and the two states–two oxidants conundrum

Covering: up to 2006 but not exhaustively n This focused review discusses mechanisms of oxygenation of organic compounds by cytochrome P450, based on density functional theory (DFT) and hybrid DFT and molecular mechanics (DFT/MM). The reactivity of the active species, Compound I, generally involves two-state reactivity (TSR) and sometimes multi-state reactivity (MSR). The reactivity of the ferric-hydroperoxide species (Compound 0) is reviewed too. According to DFT calculations, Compound 0 must be silent in the presence of Compound I. Much of the experimental mechanistic data is shown to be accounted for by the TSR/MSR concept.

Experiment and Theory Reveal the Fundamental Difference between Two‐State and Single‐State Reactivity Patterns in Nonheme FeIVO versus RuIVO Oxidants

Recent developments in the emerging field of nonheme iron chemistry have provided chemists with a number of synthetic mononuclear nonheme iron(IV) oxo complexes, which have been implicated as the key reactive intermediates in enzymatic and biomimetic oxidation processes. A notable example is the recently synthesized iron(IV) oxo complex bearing a nonheme macrocyclic ligand [Fe(O)(tmc)(NCCH3)] 2+ (1-NCCH3; tmc = 1,4,8,11-tetramethyl-1,4,8,11tetraazacyclotetradecane; Figure 1a). Characterization of the iron oxo species by spectroscopic techniques and X-ray crystallography and studies of their reactivity patterns in various oxidation reactions have created a great opportunity for understanding the chemical and physical properties of these complexes. 3] Substitution of the acetonitrile ligand of 1-NCCH3 with a variety of anionic axial ligands (e.g., X = CF3CO2 , N3 , or SR ) made it possible to demonstrate that the reactivity of [Fe(O)(tmc)(X)] (1-X) is significantly affected by the nature of the axial ligands in a manner that depends on the type of reaction. 5] Thus, while electron-donating axial ligands diminished the oxidative reactivity of 1-X in oxotransfer reactions (towards PPh3, for which the reactivity order is 1-NCCH3> 1-CF3CO2> 1-N3> 1-SR), they enhanced the reactivity of 1-X in H-abstraction reactions (from phenol O H and alkyl aromatic C H bonds), that is, a reactivity order of 1’-SR> 1-N3> 1-CF3CO2> 1-NCCH3. [5] Theoretical studies proposed that the puzzling reactivity trends arose from the fact that these nonheme iron(IV) oxo reagents have two closely lying spin states, a ground state with a triplet spin state (T) and a low-lying quintet spin state (Q), as shown schematically in Figure 1b. 7] Thus, the triplet state has a high energy barrier, while the quintet state has a much lower barrier that crosses through the larger triplet barrier. Therefore, the H-abstraction reactions proceed on the two energy surfaces, and the resulting blended reactivity is behind the unusual reactivity patterns. Without the two-state blend, the reactivity on any one of the spin-state surfaces was shown to follow the electrophilicity of 1-X. How can one test this two-state reactivity (TSR) concept for the dichotomic reactivity pattern in oxo-transfer and H-abstraction processes by [Fe(O)(tmc)(X)]? The most straightforward way to interrogate the TSR hypothesis is to design a family of metal oxo complexes as closely analogous to [Fe(O)(tmc)(X)] as possible, while replacing only the iron ion with a different metal ion so that the quintet state becomes energetically inaccessible. Theory predicts that such probe complexes will not exhibit dichotomic reactivity trends in oxo-transfer and H-abstraction reactions. To test this prediction, we focused on Ru oxo complexes due to their propensity to prefer low-spin states to high-spin states. Accordingly, we synthesized ruthenium(IV) oxo analogues bearing different axial ligands [Ru(O)(tmc)(X)] (2-X; Figure 1a) and examined their reactivity in oxo-transfer and H-abstraction reactions. Herein we report experimental and theoretical studies on the effects of axial ligands of the Ru oxo complexes in oxo-transfer and H-abstraction reactions. Figure 1. a) The structures of [Fe(O)(tmc)(X)] (1-X) and [Ru(O)(tmc)(X)] (2-X); b) the TSR scenario in H-abstraction reactions by [Fe(O)(tmc)(X)].

Compound I in heme thiolate enzymes: a comparative QM/MM study.

This study directly compares the active species of heme enzymes, so-called Compound I (Cpd I), across the heme-thiolate enzyme family. Thus, sixty-four different Cpd I structures are calculated by hybrid quantum mechanical/molecular mechanical (QM/MM) methods using four different cysteine-ligated heme enzymes (P450(cam), the mutant P450(cam)-L358P, CPO and NOS) with varying QM region sizes in two multiplicities each. The overall result is that these Cpd I species are similar to each other with regard to many characteristic features. Hence, using the more stable CPO Cpd I as a model for P450 Cpd I in experiments should be a reasonable approach. However, systematic differences were also observed, and it is shown that NOS stands out in most comparisons. By analyzing the electrical field generated by the enzyme on the QM region, one can see that (a) the protein exerts a large influence and modifies all the Cpd I species compared with the gas-phase situation and (b) in NOS this field is approximately planar to the heme plane, whereas it is approximately perpendicular in the other enzymes, explaining the deviating results on NOS. The calculations on the P450(cam) mutant L358P show that the effects of removing the hydrogen bond between the heme sulfur and L358 are small at the Cpd I stage. Finally, Mossbauer parameters are calculated for the different Cpd I species, enabling future comparisons with experiments. These results are discussed in the broader context of recent findings of Cpd I species that exhibit large variations in the electronic structure due to the presence of the substrate.

A reactive bond orbital investigation of the Diels‐Alder reaction between 1,3‐butadiene and ethylene: Energy decomposition, state correlation diagram, and electron density analyses

The reactive bond orbital (RBO) method (Hirao, Chem Phys Lett 2007, 443, 141) is extended and applied to the Diels‐Alder reaction between 1,3‐butadiene and ethylene, with the aim of understanding the nature of their interaction. The roles of distortion, electrostatic, exchange, polarization, and charge transfer (CT) interaction energies at the transition state of the reaction are evaluated by means of RBO energy decomposition analysis. The effects of the hypothetical interactions on electron density redistribution are also identified by analysis based on the RBO method. CT is shown to play essential roles in the new bond formation between the reacting molecules and their internal bond order alterations. However, each of the CT interactions from butadiene to ethylene and from ethylene to butadiene does not necessarily contribute to the bond‐order alteration process effectively. A state correlation diagram approach based on the RBO method is also proposed, and its usefulness in understanding the origin of the barrier in the Diels‐Alder reaction is demonstrated.

QM/MM theoretical study of the pentacoordinate Mn(III) and resting states of manganese-reconstituted cytochrome P450 cam

Quantum mechanical/molecular mechanical (QM/MM) theoretical calculations were performed for the pentacoordinate Mn(III) and water-bound resting states of the Mn-reconstituted mutant of cytochrome P450cam (Mn-P450cam) in order to obtain insights into their characters, especially, their spin state ordering. The QM/MM study was carried out by use of the B3LYP and BLYP density functional theory (DFT) methods coupled to the CHARMM force field. Although the relative energies of possible spin states for the Mn-P450cam species varied depending on the functional, this dependence was less significant compared with previous calculations on the corresponding intermediates of wild-type P450cam. The results suggested that both Mn-P450cam intermediates have quintet ground states. Additional time-dependent DFT (TDDFT) calculations were carried out for the quintet states of these species using the B3LYP and BP86 functionals with the electrostatic environmental effect included. The TDDFT results enabled us to assign the origins of the peaks observed in optical absorption spectra (Makris et al. in J. Inorg. Biochem. 100:507–518, 2006).