b S Supporting Information T here is a surge of interest in synthetic models of mononuclear nonheme iron enzymes, 1À6 which perform CÀH activation and lead to the formation of alcohols and alkenes. Both the enzymes 1 and the synthetic models utilize high-valent iron-(IV)-oxo complexes as the active species. 2À5 One of the potent synthetic complexes is [N4PyFe IV O] 2+ (N4Py: N,N-bis (2-pyridylmethyl)-bis(2-pyridyl) methylamine), which is depicted in Scheme 1 and which is capable of activating even cyclohexane. 6,7 However, unlike the enzymatic complexes that have high-spin quintet (S = 2) ground states, the synthetic variants are generally characterized by triplet ground states (S = 1) 4 and low-lying quintet excited states (S = 2) and as such have a more complex reactivity behavior. Density functional theory (DFT) has contributed to the understanding of this reactivity, which was characterized as two-state reactivity (TSR), 8 wherein the S = 2 state cuts through the larger S = 1 barrier and mediates the reaction. 9À13 However, because most of the synthetic complexes carry a high positive charge, usually 2+, the gas-phase calculations have resulted in some nonphysical anomalies, such as barrier-free S = 2 surfaces, 10,11 electron transfer processes, artificial charge delocalization, 14 formation of charged organic intermediates due to hydride abstractions instead of the experimentally observed hydrogen atom abstraction (HAT), 6 and discontinuities in the potential energy profiles. 10,15 These anomalies were invincibly shown 14,16,17 to originate in the self-interaction error inherent in DFT. As such, an important class of these bioinorganic reactions cannot be confidently studied with DFT unless these anomalies can be evaded. Siegbahn et al. 14,16 have suggested that the anomalies can be muted by masking the charge of the iron oxo reagent, for example, by using counterions. 14 In this Letter, we report the boon of incorporating counterions in the UB3LYP calculations of the reactions, depicted in Scheme 1, of the synthetic complex 6 [N4PyFe IV O] 2+ with cyclohexadiene, with which all of the above anomalies manifest with the bare oxidant (model 1), and cyclohexane, for which the anomalies appear after the first HAT, in the follow-up steps in Scheme 1a. As shall be shown, adding the two ClO 4À counterions (model 2) as in the [N4PyFe II (CH 3 CN)](ClO 4 ) 2 crystal structure 18 removes the anomalies and creates smooth energy profiles that enable one to study the entire stepwise processes in Scheme 1a, explore various reaction trajectories (σ/π) 9b,19À21 of the rate-limiting HAT step, offer unequivocal characterization of the reaction intermediates, assess and derive coherent reactivity Scheme 1. (a) Reactions Studied Using (b) Oxidant Models 1, 1-solv, and 2 (1-solv Signifies That All Species Are Optimized in the Solvent) and (c) Two Substrates a a Reb and 2H are abbreviated processes.

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The host response to the low pathogenic avian influenza (LPAI) H5N2, H5N3 and H9N2 viruses were examined in A549, MDCK, and CEF cells using a systems-based approach. The H5N2 and H5N3 viruses replicated efficiently in A549 and MDCK cells, while the H9N2 virus replicated least efficiently in these cell types. However, all LPAI viruses exhibited similar and higher replication efficiencies in CEF cells. A comparison of the host responses of these viruses and the H1N1/WSN virus and low passage pH1N1 clinical isolates was performed in A549 cells. The H9N2 and H5N2 virus subtypes exhibited a robust induction of Type I and Type III interferon (IFN) expression, sustained STAT1 activation from between 3 and 6 hpi, which correlated with large increases in IFN-stimulated gene (ISG) expression by 10 hpi. In contrast, cells infected with the pH1N1 or H1N1/WSN virus showed only small increases in Type III IFN signalling, low levels of ISG expression, and down-regulated expression of the IFN type I receptor. JNK activation and increased expression of the pro-apoptotic XAF1 protein was observed in A549 cells infected with all viruses except the H1N1/WSN virus, while MAPK p38 activation was only observed in cells infected with the pH1N1 and the H5 virus subtypes. No IFN expression and low ISG expression levels were generally observed in CEF cells infected with either AIV, while increased IFN and ISG expression was observed in response to the H1N1/WSN infection. These data suggest differences in the replication characteristics and antivirus signalling responses both among the different LPAI viruses, and between these viruses and the H1N1 viruses examined. These virus-specific differences in host cell signalling highlight the importance of examining the host response to avian influenza viruses that have not been extensively adapted to mammalian tissue culture.

Mononuclear Ru-based water oxidation catalysts (WOCs) are an important class of WOCs for water splitting. In this work, through high-level coupled cluster calculations (CCSD(T)/CBS), we have examined a variety of density functionals for their performances in the whole catalytic cycle of water oxidation catalyzed by mononuclear Ru-based WOCs. The tested functionals cover a wide range from pure GGA and meta-GGA to hybrids and double hybrids (TPSS, OLYP, BP86, M06-L, B3LYP, PBE0, M06, M06-2X, TPSSh, CAM-B3LYP, wB97X, B2-PLYP, B2GP-PLYP). Depending on different reaction types and species in the catalytic cycle, the performances of different DFTs vary severely, whose trends are summarized in the paper. Our results indicate that using a single approximate functional to accurately model all reactions involved in the whole Ru-based WOC catalytic cycle is still a very challenging task. In the current status, PBE0 and M06 may be recommended for the whole catalytic cycle. Generally, this study provides a guide for selecting an appropriate DFT method in modeling each of the various steps in water oxidation catalyzed by Ru-based WOCs. The sensitivity of DFT and ab initio results upon the degree of basis set completeness found in this work is also worthy of attention in the future theoretical study of mononuclear Ru-based WOCs.

AurF and CmlI are currently the only two known diiron arylamine oxygenases. On the basis of extensive quantum mechanical/molecular mechanical (QM/MM) spectroscopic and mechanistic modelings, here we predict that the key oxygenated intermediates in AurF and CmlI, so-called P, are uniformly hydroperoxo species having similar structures. As a basis for mechanistic unification in AurF and CmlI, the proposed diferric-hydroperoxo P is calculated to be able to promote the arylamine N-oxygenation with highly accessible kinetics. This convergent μ-η:η structural assignment of P's in AurF and CmlI can rationalize many conundrums for P, including the different Mössbauer spectroscopic parameters, low O-O vibrational frequency, ambiphilic reactivity, and inertness toward C-H activation. In view of the very limited knowledge about hydroperoxo species in diiron enzymes, the novel diferric-hydroperoxo-mediated N-oxygenation mechanism revealed in this work opens up a new avenue for understanding the O activation mode in nature. For elucidating the structures of transient oxidants for diiron enzymes, the promising approach of QM/MM Mössbauer spectroscopic modeling is highlighted as a key problem solver in mechanistic enzymatic research.

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We report nickel-catalyzed cyanation and hydrocyanation methods to prepare aryl nitriles and vinyl nitriles from aryl halides and alkynes, respectively. Using inexpensive and nontoxic 4-cyanopyridine N-oxide as the cyano shuttle, the methods provide an efficient approach to prepare aryl cyanides and vinyl nitriles under mild and operationally simple reaction conditions with a broad range of functional group tolerances. In hydrocyanation of alkynes, the method demonstrated good regioselectivity, producing predominantly E- or Z-alkenyl nitriles in a controlled manner and exclusively Markovnikov vinyl nitriles when internal diaryl alkynes and terminal alkynes were applied as the substrates, respectively. The preliminary mechanistic investigation indicated that the C–CN bond cleavage process is promoted by oxidative addition to the nickel­(I) complex in the cyanation of aryl halides, and further studies via a series of deuterium exchange experiments indicated that water serves as the hydrogen source for the hydrocyanation of alkynes.