Reza Latifi

Valence Tautomerism in a High-Valent Manganese–Oxo Porphyrinoid Complex Induced by a Lewis Acid

Addition of the Lewis acid Zn(2+) to (TBP(8)Cz)Mn(V)(O) induces valence tautomerization, resulting in the formation of [(TBP(8)Cz(+•))Mn(IV)(O)-Zn(2+)]. This new species was characterized by UV-vis, EPR, the Evans method, and (1)H NMR and supported by DFT calculations. Removal of Zn(2+) quantitatively restores the starting material. Electron-transfer and hydrogen-atom-transfer reactions are strongly influenced by the presence of Zn(2+).

Structural Characterization and Remarkable Axial Ligand Effect on the Nucleophilic Reactivity of a Nonheme Manganese(III)–Peroxo Complex

The dark side of the Mn: A manganese(III) complex bearing a 13-membered macrocyclic ligand (1, see picture) binds a peroxo ligand in a side-on eta(2) fashion. The reactivity of 1 is influenced by the introduction of anionic ligands trans to the peroxo group. Electronic and structural changes upon trans-ligand binding explain the increased nucleophilicity of the resulting complexes 1-X.

Origin of the Correlation of the Rate Constant of Substrate Hydroxylation by Nonheme Iron(IV)-oxo Complexes with the Bond-Dissociation Energy of the C-H Bond of the Substrate

Mononuclear nonheme iron containing systems are versatile and vital oxidants of substrate hydroxylation reactions in many biosystems, whereby the rate constant of hydroxylation correlates with the strength of the C-H bond that is broken in the process. The thermodynamic reason behind these correlations, however, has never been established. In this work results of a series of density functional theory calculations of substrate hydroxylation by a mononuclear nonheme iron(IV)-oxo oxidant with a 2 His/1 Asp structural motif analogous to alpha-ketoglutarate dependent dioxygenases are presented. The calculations show that these oxidants are very efficient and able to hydroxylate strong C-H bonds, whereby the hydrogen abstraction barriers correlate linearly with the strength of the C-H bond of the substrate that is broken. These trends have been rationalized using a valence bond (VB) curve-crossing diagram, which explains the correlation using electron transfer mechanisms in the hydrogen abstraction processes. We also rationalized the subsequent reaction step for radical rebound and show that the barrier is proportional to the electron affinity of the iron(III)-hydroxo intermediate complex. It is shown that nonheme iron(IV)-hydroxo complexes have a larger electron affinity than heme iron(IV)-hydroxo complexes and therefore also experience larger radical rebound barriers, which may have implications for product distributions and rearrangement reactions. Thus, detailed comparisons between heme and nonheme iron(IV)-oxo oxidants reveal the fundamental differences in monoxygenation capabilities of these important classes of oxidants in biosystems and synthetic analogues for the first time and enable us to make predictions of experimental processes.

Rationalization of the Barrier Height for p-Z-styrene Epoxidation by Iron(IV)-Oxo Porphyrin Cation Radicals with Variable Axial Ligands

A versatile class of heme monoxygenases involved in many vital functions for human health are the cytochromes P450, which react via a high-valent iron(IV) oxo heme cation radical species called Compound I. One of the key reactions catalyzed by these enzymes is C═C epoxidation of substrates. We report here a systematic study into the intrinsic chemical properties of substrate and oxidant that affect reactivity patterns. To this end, we investigated the effect of styrene and para-substituted styrene epoxidation by Compound I models with either an anionic (chloride) or neutral (acetonitrile) axial ligand. We show, for the first time, that the activation enthalpy of the reaction is determined by the ionization potential of the substrate, the electron affinity of the oxidant, and the strength of the newly formed C-O bond (approximated by the bond dissociation energy, BDE(OH)). We have set up a new valence bond model that enables us to generalize substrate epoxidation reactions by iron(IV)-oxo porphyrin cation-radical oxidants and make predictions of rate constants and reactivities. We show here that electron-withdrawing substituents lead to early transition states, whereas electron-donating groups on the olefin substrate give late transition states. This affects the barrier heights in such a way that electron-withdrawing substituents correlate the barrier height with BDE(OH), while the electron affinity of the oxidant is proportional to the barrier height for substrates with electron-donating substituents.

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.

Pycup—A Bifunctional, Cage-like Ligand for 64Cu Radiolabeling

In developing targeted probes for positron emission tomography (PET) based on (64)Cu, stable complexation of the radiometal is key, and a flexible handle for bioconjugation is highly advantageous. Here, we present the synthesis and characterization of the chelator pycup and four derivatives. Pycup is a cross-bridged cyclam derivative with a pyridyl donor atom integrated into the cross-bridge resulting in a pentadentate ligand. The pycup platform provides kinetic inertness toward (64)Cu dechelation and offers versatile bioconjugation chemistry. We varied the number and type of additional donor atoms by alkylation of the remaining two secondary amines, providing three model ligands, pycup2A, pycup1A1Bn, and pycup2Bn, in 3-4 synthetic steps from cyclam. All model copper complexes displayed very slow decomplexation in 5 M HCl and 90 °C (t1/2: 1.5 h for pycup1A1Bn, 2.7 h for pycup2A, 20.3 h for pycup2Bn). The single crystal crystal X-ray structure of the [Cu(pycup2Bn)](2+) complex showed that the copper was coordinated in a trigonal, bipyramidal manner. The corresponding radiochemical complexes were at least 94% stable in rat plasma after 24 h. Biodistribution studies conducted in Balb/c mice at 2 h postinjection of (64)Cu labeled pycup2A revealed low residual activity in kidney, liver, and blood pool with predominantly renal clearance observed. Pycup2A was readily conjugated to a fibrin-targeted peptide and labeled with (64)Cu for successful PET imaging of arterial thrombosis in a rat model, demonstrating the utility of our new chelator in vivo.

Manganese substituted Compound I of cytochrome P450 biomimetics: A comparative reactivity study of MnV-oxo versus MnIV-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.

Carbon dioxide: A waste product in the catalytic cycle of α-ketoglutarate dependent halogenases prevents the formation of hydroxylated by-products

We present the first density functional theory study on alpha-ketoglutarate dependent halogenases and focus on the mechanism starting from the iron(IV)-oxo species. The studies show that the high-valent iron(IV)-oxo species reacts with substrates via an initial and rate determining hydrogen abstraction that is characterized by a large kinetic isotope effect (KIE) of 26.7 leading to a radical intermediate. This KIE value is in good agreement with experimental data. The reaction proceeds via two-state reactivity patterns on competing quintet and septet spin state surfaces with close lying hydrogen abstraction barriers. However, the septet spin radical intermediate gives very high barriers for hydroxylation and chlorination whereas the barriers on the quintet spin state surface are much lower. The calculations give extra information regarding the nature of the intermediates and a prediction of a new low-energy mechanism starting from the radical intermediate, whereby a waste product from an earlier step in the catalytic cycle (CO(2)) is recycled and takes the hydroxyl radical away to form bicarbonate via an OH trapping mechanism. As a consequence, this mechanism prevents the occurrence of hydroxylated byproduct and gives a rationale for the sole observance of halogenated products. By contrast, a direct halogenation reaction cannot compete with hydroxylation due to higher reaction barriers. Our findings support experimental work in the field and give a rationale for the lack of hydroxylation products in alpha-ketoglutarate dependent halogenases.

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).

Activation of hydrocarbon C–H bonds by iodosylbenzene: how does it compare with iron(IV)–oxo oxidants?

Combined experimental and theoretical studies on the reactivity of iodosylbenzene (PhIO) show that PhIO is capable of activating weak C-H bonds of hydrocarbons via a hydrogen abstraction mechanism.