How Is a Metabolic Intermediate Formed in the Mechanism‐Based Inactivation of Cytochrome P450 by Using 1,1‐Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation?

A precise understanding of the mechanism‐based inactivation of cytochrome P450 enzymes (P450s) at the quantum mechanical level should allow more reliable predictions of drug–drug interactions than those currently available. Hydrazines are among the molecules that act as mechanism‐based inactivators to terminate the function of P450s, which are essential heme enzymes responsible for drug metabolism in the human body. Despite its importance, the mechanism explaining how a metabolic intermediate (MI) is formed from hydrazine is not fully understood. We used density functional theory (DFT) calculations to compare four possible mechanisms underlying the reaction between 1,1‐dimethylhydrazine (or unsymmetrical dimethylhydrazine, UDMH) and the reactive compound I (Cpd I) intermediate of P450. Our DFT calculations provided a clear view on how an aminonitrene‐type MI is formed from UDMH. In the most favorable pathway, hydrogen is spontaneously abstracted from the N2 atom of UDMH by Cpd I, followed by a second hydrogen abstraction from the N2 atom by Cpd II. Nitrogen oxidation of nitrogen atoms and hydrogen abstraction from the C? H bond of the methyl group were found to be less favorable than the hydrogen abstraction from the N? H bond. We also found that the reaction of protonated UDMH with Cpd I is rather sluggish. The aminonitrene‐type MI binds to the ferric heme more strongly than a water molecule. This is consistent with the notion that the catalytic cycle of P450 is impeded when such an MI is produced through the P450‐catalyzed reaction.     

Theoretical density functional theory studies on interactions of small biologically active molecules with isolated heme group

We present ab-initio density functional theory studies on the interactions of small biologically active molecules, namely NO, CO, O(2), H(2)O, and NO(2) (-) with the full-size heme group. Our results show that the small molecule-iron bond is the strongest in carbonyl and the weakest in nitrite system. Trans influence induced by NO binding to the five-coordinate heme complex is shown. Nitric oxide in the resulting complex might be described as NO(-). The differences among the small ligands of XO type (CO, NO, O(2)), and their distant chemical behavior from H(2)O and NO(2) (-) ligands in binding to the Fe(II) ion, are shown. Moreover, the role of the heme ring as a reservoir of electrons in the studied complexes is invoked. The analysis of the parameters defining the iron-histidine bond indicates that this bond is longer and weaker in nitrosyl and carbonyl complexes than in the other systems. Our findings support the proposed mechanism of soluble guanylate cyclase (sGC) activation and suggest that the first step of sGC activation by CO may be the same as during the activation by NO. Obtained results are then compared with the data concerning smaller model of the heme, the porphyrin complexes, available in the literature.     

Structure of the deoxymyoglobin model [Fe(TPP)(2-MeHIm)] reveals unusual porphyrin core distortions

The preparation and characterization of the deoxymyoglobin model (2-methylimidazole)(tetraphenylporphinato)iron(II) is described. The preparation and crystallization from chlorobenzene leads to a new crystalline phase that has been structurally characterized. The complex is the most ordered example of a deoxymyoglobin model yet characterized. The X-ray structure determination reveals a number of distortions both in the iron coordination group and in the porphyrin core that result from the steric bulk of the axial ligand. Some of these distortions have been noted previously in related species; however, the demonstration of porphyrin core distortions and an asymmetry in the Fe-N(p) bond distances are new observations. These may have functional significance for this important type of heme protein coordination group. The new structure emphasizes that high-spin iron(II) porphyrinate derivatives display substantial structural pliability with significant variations in iron atom displacements, porphyrin core hole size, and axial and equatorial Fe-N bond lengths. The new complex has also been characterized by zero-field and applied field magnetic M?ssbauer spectroscopy. M?ssbauer parameters are characteristic for high-spin iron, although they also reveal an extremely rhombic site for iron(II). Crystal data at 130 K for [Fe(TPP)(2-MeHIm)].1.5C(6)H(5)Cl: a = 12.334(3) A, b = 13.515(6) A, c = 14.241(7) A, alpha = 70.62(3) degrees, beta = 88.29(2) degrees, gamma = 88.24(3) degrees, triclinic, space group, P, V = 2238(2) A(3), Z = 2.     

Study on the Gas Phase Stability of Heme-binding Pocket in Cytochrome Tb_5 and Its Mutants by Electrospray Mass Spectrometry

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The role of metal-oxygen intermediates in biological and chemical monooxygenation of alkanes

The role of metal-peroxo, -hydroperoxo, and -oxo intermediates in activation of O₂ and transfer of an oxygen atom to the C—H bond in biocatalysis by heme and non-heme monooxygenases and biomimetic oxidation of alkanes is reviewed.     

Solution 1h NMR characterization of equilibrium heme orientational disorder with functional consequences in mouse neuroglobin

The solution 1H NMR spectrum of oxidized (met) mouse neuroglobin, metNgb, demonstrates that it is low-spin and hexacoordinate with strong spectral similarities to ferricytochrome b5. The axial ligands are identified as His(F8) and His(E7), with the latter exhibiting an unstrained Fe-His bond. The presence of two sets of resonances is shown to arise from equilibrium heme orientational isomers ( approximately 2:1). The ligation of cyanide is shown to be extraordinarily slow with a factor approximately 2 difference in rate for the two heme orientations. Not only is Ngb the first mamalian globin with equilibrium heme disorder, but the disorder also has additional functional consequences.     

Theoretical study of the mechanism of oxoiron(IV) formation from H2O2 and a nonheme iron(II) complex: O-O cleavage involving proton-coupled electron transfer

It has recently been shown that the nonheme oxoiron(IV) species supported by the 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane ligand (TMC) can be generated in near-quantitative yield by reacting [Fe(II)(TMC)(OTf)(2)] with a stoichiometric amount of H(2)O(2) in CH(3)CN in the presence of 2,6-lutidine (Li, F.; England, J.; Que, L., Jr. J. Am. Chem. Soc. 2010, 132, 2134-2135). This finding has major implications for O-O bond cleavage events in both Fenton chemistry and nonheme iron enzymes. To understand the mechanism of this process, especially the intimate details of the O-O bond cleavage step, a series of density functional theory (DFT) calculations and analyses have been carried out. Two distinct reaction paths (A and B) were identified. Path A consists of two principal steps: (1) coordination of H(2)O(2) to Fe(II) and (2) a combination of partial homolytic O-O bond cleavage and proton-coupled electron transfer (PCET). The latter combination renders the rate-limiting O-O cleavage effectively a heterolytic process. Path B proceeds via a simultaneous homolytic O-O bond cleavage of H(2)O(2) and Fe-O bond formation. This is followed by H abstraction from the resultant Fe(III)-OH species by an ?OH radical. Calculations suggest that path B is plausible in the absence of base. However, once 2,6-lutidine is added to the reacting system, the reaction barrier is lowered and more importantly the mechanistic path switches to path A, where 2,6-lutidine plays an essential role as an acid-base catalyst in a manner similar to how the distal histidine or glutamate residue assists in compound I formation in heme peroxidases. The reaction was found to proceed predominantly on the quintet spin state surface, and a transition to the triplet state, the experimentally known ground state for the TMC-oxoiron(IV) species, occurs in the last stage of the oxoiron(IV) formation process.     

Heme protein oxygen affinity regulation exerted by proximal effects

Heme proteins are found in all living organisms and are capable of performing a wide variety of tasks, requiring in many cases the binding of diatomic ligands, namely, O(2), CO, and/or NO. Therefore, subtle regulation of these diatomic ligands' affinity is one of the key issues for determining a heme protein's function. This regulation is achieved through direct H-bond interactions between the bound ligand and the protein, and by subtle tuning of the intrinsic heme group reactivity. In this work, we present an investigation of the proximal regulation of oxygen affinity in Fe(II) histidine coordinated heme proteins by means of computer simulation. Density functional theory calculations on heme model systems are used to analyze three proximal effects: charge donation, rotational position, and distance to the heme porphyrin plane of the proximal histidine. In addition, hybrid quantum-classical (QM-MM) calculations were performed in two representative proteins: myoglobin and leghemoglobin. Our results show that all three effects are capable of tuning the Fe-O(2) bond strength in a cooperative way, consistently with the experimental data on oxygen affinity. The proximal effects described herein could operate in a large variety of O(2)-binding heme proteins-in combination with distal effects-and are essential to understand the factors determining a heme protein's O(2) affinity.     

Quantum chemical studies of dioxygen activation by mononuclear non-heme iron enzymes with the 2-His-1-carboxylate facial triad

Density functional theory with the B3LYP hybrid functional has been used to study the mechanisms for dioxygen activation by four families of mononuclear non-heme iron enzymes: alpha-ketoacid-dependent dioxygenases, tetrahydrobiopterin-dependent hydroxylases, extradiol dioxygenases, and Rieske dioxygenases. These enzymes have a common active site with a ferrous ion coordinated to two histidines and one carboxylate group (aspartate or glutamate). In contrast to the heme case, this type of weak field environment always leads to a high-spin ground state. With the exception of the Rieske dioxygenases, which have an electron source outside the active site, the dioxygen activation process passes through the formation of a bridging-peroxide species, which then undergoes O-O bond cleavage finally leading to the four electron reduction of O(2). In the case of tetrahydrobiopterin- and alpha-ketoacid-dependent enzymes, the O-O heterolysis yields a high-valent iron-oxo species, which is capable of performing a two-electron oxidation chemistry on various organic substrates. For the other two families of enzymes (extradiol dioxygenases and Rieske dioxygenases) the substrate oxidation and the O-O bond cleavage are found to be coupled. In the extradiol dioxygenases the product of the O-O bond cleavage is a ferric iron with an oxy-substrate with a mixture of radical and anionic character, which is essential for the selectivity of the catechol cleavage.     

Theory favors a stepwise mechanism of porphyrin degradation by a ferric hydroperoxide model of the active species of heme oxygenase

The report uses density functional theory to address the mechanism of heme degradation by the enzyme heme oxygenase (HO) using a model ferric hydroperoxide complex. HO is known to trap heme molecules and degrade them to maintain iron homeostasis in the biosystem. The degradation is initiated by complexation of the heme, then formation of the iron-hydroperoxo species, which subsequently oxidizes the meso position of the porphyrin by hydroxylation, thereby enabling eventually the cleavage of the porphyrin ring. Kinetic isotope effect studies indicate that the mechanism is assisted by general acid catalysis, via a chain of water molecules, and that all the events occur in concert. However, previous theoretical treatments indicated that the concerted mechanism has a high barrier, much higher than an alternative mechanism that is initiated by O-O bond homolysis of iron-hydroperoxide. The present contribution studies the stepwise and concerted acid-catalyzed mechanisms using H(3)O(+)(H(2)O)(n)(), n = 0-2. The effect of the acid strength is tested using the H(4)N(+)(H(2)O)(2) cluster and a fully protonated ferric hydroperoxide. All the calculations show that a stepwise mechanism that involves proton relay and O-O homolysis, in the rate-determining step, has a much lower barrier (>10 kcal/mol) than the corresponding fully concerted mechanism. The best fit of the calculated solvent kinetic isotope effect, to the experimental data, is obtained for the H(3)O(+)(H(2)O)(2) cluster. The calculated alpha-deuterium secondary kinetic isotope effect is inverse (0.95-0.98), but much less so than the experimental value (0.7). Possible reasons for this quantitative difference are discussed. Some probes are suggested that may enable experiment to distinguish the stepwise from the concerted mechanism.     

Exploring the Strength of the H‐Bond in Synthetic Models for Heme Proteins: The Importance of the N−H Acidity of the Distal Base

The distal hydrogen bond (H‐bond) in dioxygen‐binding proteins is crucial for the discrimination of O₂ with respect to CO or NO. We report the preparation and characterization of a series of Zn^II porphyrins, with one of three meso‐phenyl rings bearing both an alkyl‐tethered proximal imidazole ligand and a heterocyclic distal H‐bond donor connected by a rigid acetylene spacer. Previously, we had validated the corresponding Co^II complexes as synthetic model systems for dioxygen‐binding heme proteins and demonstrated the structural requirements for proper distal H‐bonding to Co^II‐bound dioxygen. Here, we systematically vary the H‐bond donor ability of the distal heterocycles, as predicted based on pK_a values. The H‐bond in the dioxygen adducts of the Co^II porphyrins was directly measured by Q‐band Davies‐ENDOR spectroscopy. It was shown that the strength of the hyperfine coupling between the dioxygen radical and the distal H‐atom increases with enhanced acidity of the H‐bond donor.     

A "push-pull" mechanism for heterolytic o-o bond cleavage in hydroperoxo manganese porphyrins

A water-soluble manganese porphyrin, 5,10,15,20-tetrakis-(1,3-dimethylimidazolium-2-yl)porphyrinatomanganese(III) (Mn(III)TDMImP) is shown to react with H(2)O(2) to generate a relatively stable dioxomanganese(V) porphyrin complex (a compound I analog). Stopped-flow kinetic studies revealed Michaelis Menton-type saturation kinetics for H(2)O(2). The visible spectrum of a compound 0 type intermediate, assigned as Mn(III)(OH)(OOH)TDMImP, can be directly observed under saturating H(2)O(2) conditions (Soret band at 428 nm and Q bands at 545 and 578 nm). The rate-determining O-O heterolysis step was found to have a very small activation enthalpy (ΔH(≠) = 4.2 ± 0.2 kcal mol(-1)) and a large, negative activation entropy (ΔS(≠) = -36 ± 1 cal mol(-1) K(-1)). The O-O bond cleavage reaction was pH independent at 8.8 < pH < 10.4 with a first-order rate constant of 66 ± 12 s(-1). These observations indicate that the O-O bond in Mn(III)(OH)(OOH)TDMImP is cleaved via a concerted "push-pull" mechanism. In the transition state, the axial (proximal) (-)OH is partially deprotonated ("push"), while the terminal oxygen in (-)OOH is partially protonated ("pull") as a water molecule is released to the medium. This mechanism is reminiscent of O-O bond cleavage in heme enzymes, such as peroxidases and cytochrome P450, and similar to the fast, reversible O-Br bond breaking and forming reaction mediated by similar manganese porphyrins. The small enthalpy of activation suggests that this O-O bond cleavage could also be made reversible.     

Rational Heme Protein Design: All Roads Lead to Rome

Heme proteins are among the most abundant and important metalloproteins, exerting diverse biological functions including oxygen transport, small molecule sensing, selective C? H bond activation, nitrite reduction, and electron transfer. Rational heme protein designs focus on the modification of the heme‐binding active site and the heme group, protein hybridization and domain swapping, and de novo design. These strategies not only provide us with unique advantages for illustrating the structure–property–reactivity–function (SPRF) relationship of heme proteins in nature but also endow us with the ability to create novel biocatalysts and biosensors.     

The structures and electronic configuration of compound I intermediates of Helicobacter pylori and Penicillium vitale catalases determined by X-ray crystallography and QM/MM density functional theory calculations

The structures of Helicobacter pylori (HPC) and Penicillium vitale (PVC) catalases, each with two subunits in the crystal asymmetric unit, oxidized with peroxoacetic acid are reported at 1.8 and 1.7 A resolution, respectively. Despite the similar oxidation conditions employed, the iron-oxygen coordination length is 1.72 A for PVC, close to what is expected for a Fe=O double bond, and 1.80 and 1.85 A for HPC, suggestive of a Fe-O single bond. The structure and electronic configuration of the oxoferryl heme and immediate protein environment is investigated further by QM/MM density functional theory calculations. Four different active site electronic configurations are considered, Por*+-FeIV=O, Por*+-FeIV=O...HisH+, Por*+-FeIV-OH+ and Por-FeIV-OH (a protein radical is assumed in the latter configuration). The electronic structure of the primary oxidized species, Por*+-FeIV=O, differs qualitatively between HPC and PVC with an A2u-like porphyrin radical delocalized on the porphyrin in HPC and a mixed A1u-like "fluctuating" radical partially delocalized over the essential distal histidine, the porphyrin, and, to a lesser extent, the proximal tyrosine residue. This difference is rationalized in terms of HPC containing heme b and PVC containing heme d. It is concluded that compound I of PVC contains an oxoferryl Por*+-FeIV=O species with partial protonation of the distal histidine and compound I of HPC contains a hydroxoferryl Por-FeIV-OH with the second oxidation equivalent delocalized as a protein radical. The findings support the idea that there is a relation between radical migration to the protein and protonation of the oxoferryl bond in catalase.     

Spin-forbidden ligand binding to the ferrous-heme group: ab initio and DFT studies

The potential energy surfaces (PESs) and associated energy barriers that characterize the spin-forbidden recombination reactions of the gas-phase ferrous deoxy-heme group with CO, NO, and H2O ligands have been calculated using density functional theory (DFT). The bond energy for binding of O2 has also been calculated. Extensive large basis set CCSD(T) calculations on two small models of the heme group have been used to calibrate the accuracy of different DFT functionals for treating these systems. Pure functionals are shown to overestimate the stability of the low-spin forms of the deoxy-heme model, and to overestimate the binding energy of H2O and CO, whereas hybrid functionals such as B3PW91 and B3LYP yield accurate results. Accordingly, the latter functionals have been used to explore the PESs for binding. CO binding is found to involve a significant barrier of ca. 3 kcal mol-1 due to the need to change from the deoxy-heme quintet ground state to the bound singlet state. Binding of water does not involve a barrier, but the resulting bond is weak and may be further weakened in the protein environment, which should explain why water binding is not usually observed in heme proteins such as myoglobin. NO binding involves a low barrier, which is consistent with observed rapid geminate recombination. The calculated bond energies are in good agreement with previous reported values and in fair agreement with experiment for CO and O2. The value for NO is significantly lower than the experimentally derived bond energy, suggesting that B3LYP is less accurate in this case.     

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.     

Control of quinone redox potentials in photosystem II: Electron transfer and photoprotection

In O(2)-evolving complex Photosystem II (PSII), an unimpeded transfer of electrons from the primary quinone (Q(A)) to the secondary quinone (Q(B)) is essential for the efficiency of photosynthesis. Recent PSII crystal structures revealed the protein environment of the Q(A/B) binding sites. We calculated the plastoquinone (Q(A/B)) redox potentials (E(m)) for one-electron reduction with a full account of the PSII protein environment. We found two different H-bond patterns involving Q(A) and D2-Thr217, resulting in an upshift of E(m)(Q(A)) by 100 mV if the H bond between Q(A) and Thr is present. The formation of this H bond to Q(A) may be the origin of a photoprotection mechanism, which is under debate. At the Q(B) side, the formation of a H bond between D2-Ser264 and Q(B) depends on the protonation state of D1-His252. Q(B) adopts the high-potential form if the H bond to Ser is present. Conservation of this residue and H-bond pattern for Q(B) sites among bacterial photosynthetic reaction centers (bRC) and PSII strongly indicates their essential requirement for electron transfer function.     

Quantum mechanical/molecular mechanical study of mechanisms of heme degradation by the enzyme heme oxygenase: the strategic function of the water cluster

Heme degradation by heme oxygenase (HO) enzymes is important in maintaining iron homeostasis and prevention of oxidative stress, etc. In response to mechanistic uncertainties, we performed quantum mechanical/molecular mechanical investigations of the heme hydroxylation by HO, in the native route and with the oxygen surrogate donor H2O2. It is demonstrated that H2O2 cannot be deprotonated to yield Fe(III)OOH, and hence the surrogate reaction starts from the FeHOOH complex. The calculations show that, when starting from either Fe(III)OOH or Fe(III)HOOH, the fully concerted mechanism involving O-O bond breakage and O-C(meso) bond formation is highly disfavored. The low-energy mechanism involves a nonsynchronous, effectively concerted pathway, in which the active species undergoes first O-O bond homolysis followed by a barrier-free (small with Fe(III)HOOH) hydroxyl radical attack on the meso position of the porphyrin. During the reaction of Fe(III)HOOH, formation of the Por+*FeIV=O species, compound I, competes with heme hydroxylation, thereby reducing the efficiency of the surrogate route. All these conclusions are in accord with experimental findings (Chu, G. C.; Katakura, K.; Zhang, X.; Yoshida, T.; Ikeda-Saito, M. J. Biol. Chem. 1999, 274, 21319). The study highlights the role of the water cluster in the distal pocket in creating "function" for the enzyme; this cluster affects the O-O cleavage and the O-Cmeso formation, but more so it is responsible for the orientation of the hydroxyl radical and for the observed alpha-meso regioselectivity of hydroxylation (Ortiz de Montellano, P. R. Acc. Chem. Res. 1998, 31, 543). Differences/similarities with P450 and HRP are discussed.     

Proton-coupled electron transfer reactions at a heme-propionate in an iron-protoporphyrin-IX model compound

A heme model system has been developed in which the heme-propionate is the only proton donating/accepting site, using protoporphyrin IX-monomethyl esters (PPIX(MME)) and N-methylimidazole (MeIm). Proton-coupled electron transfer (PCET) reactions of these model compounds have been examined in acetonitrile solvent. (PPIX(MME))Fe(III)(MeIm)(2)-propionate (Fe(III)~CO(2)) is readily reduced by the ascorbate derivative 5,6-isopropylidine ascorbate to give (PPIX(MME))Fe(II)(MeIm)(2)-propionic acid (Fe(II)~CO(2)H). An excess of the hydroxylamine TEMPOH or of hydroquinone similarly reduces Fe(III)~CO(2), and TEMPO and benzoquinone oxidize Fe(II)~CO(2)H to return to Fe(III)~CO(2). The measured equilibrium constants, and the determined pK(a) and E(1/2) values, indicate that Fe(II)~CO(2)H has an effective bond dissociation free energy (BDFE) of 67.8 ± 0.6 kcal mol(-1). In these PPIX models, electron transfer occurs at the iron center and proton transfer occurs at the remote heme propionate. According to thermochemical and other arguments, the TEMPOH reaction occurs by concerted proton-electron transfer (CPET), and a similar pathway is indicated for the ascorbate derivative. Based on these results, heme propionates should be considered as potential key components of PCET/CPET active sites in heme proteins.     

Amine-Free,Directing-Group-Free and Redox-Neutral α-Alkylation of Saturated Cyclic Ketones

The activation of the α-C−H bond of ketones typically requires an amine and a directing group to guide the reaction selectivity in amine-catalysis carbonyl chemistry. For an α-C−H bond activation of ketone, directing groups are also required to control the reaction selectivity. Reported herein is the first α-alkylation of cyclic ketones in the absence of an amine catalyst and directing group. ¹H NMR, XPS, EPR studies and DFT calculations indicate that an α-carbon radical intermediate is formed through direct and selective activation of the inert α-C−H bond of ketones chelating on the surface of colloidal quantum dots (QDs). Such an interaction is essential for weakening the C−H bond, as exemplified, using CdSe QDs as the sole photocatalyst to execute α-C−H alkylation of cyclic ketones under visible-light irradiation. Without an amine catalyst and directing group, the high step- and atom-economy transformation under redox-neutral condition opens a new way for α-C−H functionalization of ketones in carbonyl chemistry.