Mehmed Z. Ertem

Divergence between organometallic and single-electron-transfer mechanisms in copper(II)-mediated aerobic C-H oxidation.

Copper(II)-mediated C-H oxidation is the subject of extensive interest in synthetic chemistry, but the mechanisms of many of these reactions are poorly understood. Here, we observe different products from Cu(II)-mediated oxidation of N-(8-quinolinyl)benzamide, depending on the reaction conditions. Under basic conditions, the benzamide group undergoes directed C-H methoxylation or chlorination. Under acidic conditions, the quinoline group undergoes nondirected chlorination. Experimental and computational mechanistic studies implicate an organometallic C-H activation/functionalization mechanism under the former conditions and a single-electron-transfer mechanism under the latter conditions. This rare observation of divergent, condition-dependent mechanisms for oxidation of a single substrate provides a valuable foundation for understanding Cu(II)-mediated C-H oxidation reactions.

The cis‐[RuII(bpy)2(H2O)2]2+ Water‐Oxidation Catalyst Revisited

The only operating mechanism in the oxidation of water to dioxygen catalyzed by the mononuclear cis-[RuII(bpy)2(H2O)2]2+ complex when treated with excess CeIV was unambiguously established. Theoretical calculations together with 18O-labeling experiments (see plot) revealed that it is the nucleophilic attack of water on a Ru=O group.

Quantum chemical characterization of the mechanism of an iron-based water oxidation catalyst

Theoretical models are used to demonstrate a catalytic cycle for the generation of O2 from an iron(III)-centered tetraamido macrocycle in water that is consistent with experimentally observed energetics in the presence of a sacrificial oxidant. Application of density functional theory and multireference second-order perturbation theory indicates that two proton-coupled electron transfer steps followed by an electron-transfer step first generate a reactive species that is well described as an iron(V)-oxo supported by a macrocycle that has also suffered a one-electron oxidation. Subsequent O–O bond formation occurs through water nucleophilic attack on the iron-oxo with the local solvent shell serving to relay a proton away from the reacting partners. Subsequent steps of proton-coupled electron transfer and low-energy water displacement of O2 complete the catalytic cycle. Modification of the TAML ligand to reduce the likely instability of the non-innocent aromatic radical may prove useful in future catalyst design.

S0-State Model of the Oxygen-Evolving Complex of Photosystem II

The S0 → S1 transition of the oxygen-evolving complex (OEC) of photosystem II is one of the least understood steps in the Kok cycle of water splitting. We introduce a quantum mechanics/molecular mechanics (QM/MM) model of the S0 state that is consistent with extended X-ray absorption fine structure spectroscopy and X-ray diffraction data. In conjunction with the QM/MM model of the S1 state, we address the proton-coupled electron-transfer (PCET) process that occurs during the S0 → S1 transition, where oxidation of a Mn center and deprotonation of a μ-oxo bridge lead to a significant rearrangement in the OEC. A hydrogen bonding network, linking the D1-D61 residue to a Mn-bound water molecule, is proposed to facilitate the PCET mechanism.

A Self‐Improved Water‐Oxidation Catalyst: Is One Site Really Enough?

The homogeneous catalysis of water oxidation by transition-metal complexes has experienced spectacular development over the last five years. Practical energy-conversion schemes, however, require robust catalysts with large turnover frequencies. Herein we introduce a new oxidatively rugged and powerful dinuclear water-oxidation catalyst that is generated by self-assembly from a mononuclear catalyst during the catalytic process. Our kinetic and DFT computational analysis shows that two interconnected catalytic cycles coexist while the mononuclear system is slowly and irreversibly converted into the more stable dinuclear system: an extremely robust water-oxidation catalyst that does not decompose over extended periods of time.

Experimental and quantum chemical characterization of the water oxidation cycle catalysed by [RuII(damp)(bpy)(H2O)]2+

The water-oxidation catalytic activity of [RuII(damp)(bpy)(H2O)]2+ has been determined from manometric and mass spectroscopy studies. Mechanistic details of the catalytic cycle have been studied both experimentally and using DFT and CASSCF/CASPT2 calculations. Characterisation of this Ru(II) complex and more highly oxidized catalytic intermediates has been accomplished through UV-vis and XAS spectroscopy, as well as through electrochemical techniques. Comparison of XAS spectra with CASSCF/CASPT2 calculations provides insight into the electronic structures of the more highly oxidized species, especially the degree to which oxidation occurs over both atoms of the Ru–O fragment. 18O-labelling experiments indicate that the O–O bond formation step proceeds via a water nucleophilic attack mechanism, and a detailed DFT analysis of the catalytic cycle predicts that step to be rate-determining and to take place for a formal Ru(V)O species. A number of alternative higher energy pathways have also been characterised in order to provide a more complete vision of the whole system.

Reduction of Nitrous Oxide to Dinitrogen by a Mixed Valent Tricopper-Disulfido Cluster

The greenhouse gas N(2)O is converted to N(2) by a mu-sulfido-tetracopper active site in the enzyme nitrous oxide reductase (N(2)OR) via a process postulated to involve mu-1,3 coordination of N(2)O to two Cu(I) ions. In efforts to develop synthetic models of the site with which to test mechanistic hypotheses, we have prepared a localized mixed valent Cu(II)Cu(I)(2) cluster bridged in a mu-eta(2):eta(1):eta(1) fashion by disulfide, [L(3)Cu(3)(mu(3)-S(2))]X(2) (L = 1,4,7-trimethyl-triazacyclononane, X = O(3)SCF(3)(-) or SbF(6)(-)). This cluster exhibits spectroscopic features superficially similar to those of the active site in N(2)OR and reacts with N(2)O to yield N(2) in a reaction that models the function of the enzyme. Computations implicate a transition state structure that features mu-1,1-bridging of N(2)O via its O-atom to a [L(2)Cu(2)(mu-S(2))](+) fragment and provide chemical precedence for an alternative pathway for N(2)O reduction by N(2)OR.

Active Site Models for the CuA Site of Peptidylglycine α-Hydroxylating Monooxygenase and Dopamine β-Monooxygenase

A mononuclear copper(II) superoxo species has been invoked as the key reactive intermediate in aliphatic substrate hydroxylation by copper monooxygenases such as peptidylglycine α-hydroxylating monooxygenase (PHM), dopamine β-monooxygenase (DβM), and tyramine β-monooxygenase (TβM). We have recently developed a mononuclear copper(II) end-on superoxo complex using a N-[2-(2-pyridyl)ethyl]-1,5-diazacyclooctane tridentate ligand, the structure of which is similar to the four-coordinate distorted tetrahedral geometry of the copper-dioxygen adduct found in the oxy-form of PHM (Prigge, S. T.; Eipper, B. A.; Mains, R. E.; Amzel, L. M. Science2004, 304, 864-867). In this study, structures and physicochemical properties as well as reactivity of the copper(I) and copper(II) complexes supported by a series of tridentate ligands having the same N-[2-(2-pyridyl)ethyl]-1,5-diazacyclooctane framework have been examined in detail to shed light on the chemistry dictated in the active sites of mononuclear copper monooxygenases. The ligand exhibits unique feature to stabilize the copper(I) complexes in a T-shape geometry and the copper(II) complexes in a distorted tetrahedral geometry. Low temperature oxygenation of the copper(I) complexes generated the mononuclear copper(II) end-on superoxo complexes, the structure and spin state of which have been further characterized by density functional theory (DFT) calculations. Detailed kinetic analysis on the O(2)-adduct formation reaction gave the kinetic and thermodynamic parameters providing mechanistic insights into the association and dissociation processes of O(2) to the copper complexes. The copper(II) end-on superoxo complex thus generated gradually decomposed to induce aliphatic ligand hydroxylation. Kinetic and DFT studies on the decomposition reaction have suggested that C-H bond abstraction occurs unimolecularly from the superoxo complex with subsequent rebound of the copper hydroperoxo species to generate the oxygenated product. The present results have indicated that a superoxo species having a four-coordinate distorted tetrahedral geometry could be reactive enough to induce the direct C-H bond activation of aliphatic substrates in the enzymatic systems.

Generating Cu(II)-oxyl/Cu(III)-oxo species from Cu(I)-alpha-ketocarboxylate complexes and O2: in silico studies on ligand effects and C-H-activation reactivity.

A mechanism for the oxygenation of Cu(I) complexes with alpha-ketocarboxylate ligands that is based on a combination of density functional theory and multireference second-order perturbation theory (CASSCF/CASPT2) calculations is elaborated. The reaction proceeds in a manner largely analogous to those of similar Fe(II)-alpha-ketocarboxylate systems, that is, by initial attack of a coordinated oxygen molecule on a ketocarboxylate ligand with concomitant decarboxylation. Subsequently, two reactive intermediates may be generated, a Cu-peracid structure and a [CuO](+) species, both of which are capable of oxidizing a phenyl ring component of the supporting ligand. Hydroxylation by the [CuO](+) species is predicted to proceed with a smaller activation free energy. The effects of electronic and steric variations on the oxygenation mechanisms were studied by introducing substituents at several positions of the ligand backbone and by investigating various N-donor ligands. In general, more electron donation by the N-donor ligand leads to increased stabilization of the more Cu(II)/Cu(III)-like intermediates (oxygen adducts and [CuO](+) species) relative to the more Cu(I)-like peracid intermediate. For all ligands investigated, the [CuO](+) intermediates are best described as Cu(II)-O(*-) species with triplet ground states. The reactivity of these compounds in C-H abstraction reactions decreases with more electron-donating N-donor ligands, which also increase the Cu-O bond strength, although the Cu-O bond is generally predicted to be rather weak (with a bond order of about 0.5). A comparison of several methods to obtain singlet energies for the reaction intermediates indicates that multireference second-order perturbation theory is likely more accurate for the initial oxygen adducts, but not necessarily for subsequent reaction intermediates.

Implausibility of the vibrational theory of olfaction

Block et al. (1) have written a critique of the vibrational theory of olfaction that rests on twomain points: (i) they report negative results (i.e., identical responses to normal and deuterated musk isotopomers) in a cultured human embryonic kidney cell derivative line expressing heterologous olfactory receptors; and (ii) they claim that our previous report (2) that humans can smell the difference between undeuterated and deuterated musk isotopomers is in error because of a contaminating impurity they suggest is responsible for the smell difference. We wish to answer these points. Block et al. (1) graciously made the primary data of the musk receptor screen (depicted in figure S3.1 of ref. 1) available to us. We ran an unpaired t test on the entire receptor repertoire and found two (296 and 173 in their numbering) that showed differences between H and D isotopomers. Receptor 296 is their OR51E1, which “was determined to be a nonresponsive OR [odorant receptor] in the follow-up confirmation experiments due to a high receptor background” (1). Its larger response to deuterated isotopomers was not mentioned. Receptor 173 was not described in Block et al.’s paper at all. Its response (Fig. 1) to D24 and D28 musks was smaller (P < 0.02) than to H and the response to D4 was intermediate. We urge Block et al. to publish the identity of receptor 173 and to reexamine these two receptors that potentially invalidate the main conclusion of their paper. Block et al. (1) assert that an impurity may have affected the odor of our deuterated musks. The peak in our NMR spectra, which they point to, is likely to be caused by a small fraction of cyclopentadecane. Block et al. describe the same impurity in their synthesis, and it is visible in their NMR spectra (figure S2.6 of ref. 1) at 0.87. This impurity does not coelute with the musk and is shown and correctly labeled in figure 2 of ref. 2. Furthermore, our sham deuteration protocol controlled for this. We therefore remain entirely confident that the difference in smell between isotopomers revealed by our doubleblind trials is because of the pure peak of deuterated musk. We are struck by the omission of any description of odor character of the deuterated musks Block et al. (1) synthesized and tested. One assumes that a paper entitled “Implausibility of the vibrational theory of olfaction” would have made use of this information if the isotopes smelled identical. Block et al. (1) assert that deuteration affects many physicochemical properties of odorants. This assertion should be contrasted with their report that in all 14 dose–response curves shown, the affinity of the receptors for deuterated odorants was indistinguishable from that of the hydrogen counterparts. Their results show convincingly that those properties of odorants that are involved in molecular recognition (and therefore in shape theories of olfaction) are left unaltered by deuteration. How then do flies (3), humans (2), and possibly their receptors 173 and 296 detect isotopes? On balance, we feel that Block et al.’s (1) conclusion that vibrational theories are implausible is premature.