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In this contribution, we propose a deeper understanding of the electronic effects affecting the nucleation of water around the Au+ and Hg2+ metal cations using quantum chemistry. To do so, and in order to go beyond usual energetical studies, we make extensive use of state of the art quantum interpretative techniques combining ELF/NCI/QTAIM/EDA computations to capture all ranges of interactions stabilizing the well characterized microhydrated structures. The Electron Localization Function (ELF) topological analysis reveals the peculiar role of the Au+ outer-shell core electrons (subvalence) that appear already spatially preorganized once the addition of the first water molecule occurs. Thus, despite the addition of other water molecules, the electronic structure of Au(H2O)+ appears frozen due to relativistic effects leading to a maximal acceptation of only two waters in gold's first hydration shell. As the values of the QTAIM (Quantum Theory of Atoms in Molecules) cations's charge is discussed, the Non Covalent Interactions (NCI) analysis showed that Au+ appears still able to interact through longer range van der Waals interaction with the third or fourth hydration shell water molecules. As these types of interaction are not characteristic of either a hard or soft metal cation, we introduced the concept of a "pseudo-soft" cation to define Au+ behavior. Then, extending the study, we performed the same computations replacing Au+ with Hg2+, an isoelectronic cation. If Hg2+ behaves like Au+ for small water clusters, a topological, geometrical, and energetical transition appears when the number of water molecules increases. Regarding the HSAB theory, this transition is characteristic of a shift of Hg2+ from a pseudosoft form to a soft ion and appears to be due to a competition between the relativistic and correlation effects. Indeed, if relativistic effects are predominant, then mercury will behave like gold and have a similar subvalence/geometry; otherwise when correlation effects are predominant, Hg2+ behaves like a soft cation.

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In Nature, the family of copper monooxygenases comprised of peptidylglycine α-hydroxylating monooxygenase (PHM), dopamine ß-monooxygenase (DßM), and tyramine ß-monooxygenase (TßM) is known to perform dioxygen-dependent hydroxylation of aliphatic C-H bonds by using two uncoupled metal sites. In spite of many investigations, including biochemical, chemical, and computational, details of the C-H bond oxygenation mechanism remain elusive. Herein we report an investigation of the mechanism of hydroxylation by PHM by using hybrid quantum/classical potentials (i.e., QM/MM). Although previous investigations using hybrid QM/MM techniques were restricted to geometry optimizations, we have carried out ab initio molecular dynamics simulations in order to include the intrinsic flexibility of the active sites in the modeling protocol. The major finding of this study is an extremely fast rebound step after the initial hydrogen-abstraction step promoted by the cupric-superoxide adduct. The hydrogen-abstraction/rebound sequence leads to the formation of an alkyl hydroperoxide intermediate. Long-range electron transfer from the remote copper site subsequently triggers its reduction to the hydroxylated substrate. We finally show two reactivity consequences inherent in the new mechanistic proposal, the investigation of which would provide a means to check its validity by experimental means.

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Pb(2+) complexes can attain several different topologies, depending of the shape of the Pb 6s6p lone pair. In this paper, we study structures with a bisdirected Pb lone pair with quantum mechanics (DFT) and QM/MM calculations. We study small symmetric Pb(2+) models to see what factors are needed to get a bisdirected lone pair. Two important mechanisms have been found: First, the repulsion of the lone pair of Pb(2+) with other lone pairs in the equatorial plane leads to a bisdirected structure. Second, a bisdirected lone pair can also arise due to interactions with double bonds, lone pairs, or hydrogen atoms. Moreover, we have analyzed Pb(2+) sites in proteins and to see if a bisdirected lone pair can exist in an asymmetrical environment. Several instances of bisdirected lone pairs were discovered.

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In this article, we resort to first-principles molecular dynamic simulations to examine the thermal effects on the structure of [Pb(CO)(n)](2+) complexes. Values of n are chosen to sample structures where hemidirected (n = 2, 4 and 6) or holodirected (n = 7 and 8) structures are found when using static approaches. In all cases, highly flexible structures are observed. In particular, hemidirectional distortions are characterized using geometrical and topological analysis. The octacarbonyl complex exhibits the decoordination of one of its carbonyl ligands at 300 K.

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We have quantified the extent of the nonadditivity of the short-range exchange-repulsion energy, E(exch-rep), in several polycoordinated complexes of alkali, alkaline-earth, transition, and metal cations. This was done by performing ab initio energy decomposition analyses of interaction energies in these complexes. The magnitude of E(exch-rep(n-body, n > 2)) was found to be strongly cation-dependent, ranging from close to zero for some alkali metal complexes to about 6 kcal/mol for the hexahydrated Zn(2+) complex. In all cases, the cation-water molecules, E(exch-rep(three-body)), has been found to be the dominant contribution to many-body exchange-repulsion effects, higher order terms being negligible. As the physical basis of this effect is discussed, a three-center exponential term was introduced in the SIBFA (Sum of Interactions Between Fragments Ab initio computed) polarizable molecular mechanics procedure to model such effects. The three-body correction is added to the two-center (two-body) overlap-like formulation of the short-range repulsion contribution, E(rep), which is grounded on simplified integrals obtained from localized molecular orbital theory. The present term is computed on using mostly precomputed two-body terms and, therefore, does not increase significantly the computational cost of the method. It was shown to match closely E(three-body) in a series of test cases bearing on the complexes of Ca(2+), Zn(2+), and Hg(2+). For example, its introduction enabled to restore the correct tetrahedral versus square planar preference found from quantum chemistry calculations on the tetrahydrate of Hg(2+) and [Hg(H(2)O)(4)](2+).

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Although potentially powerful, molecular oxygen is an inert oxidant due to the triplet nature of its ground state. Therefore, many enzymesse various metal cations (M) to produce singlet active species M(n) O(2) . In this communication we investigate the topology of the Electron Localization Function (ELF) within five biomimetic complexes which are representative of the strategies followed by metalloenzymes to activate O(2) . Thanks to its coupling to the constrained DFT methods the ELF analysis reveals the tight connection between the spin state of the adduct and the spatial organization of the oxygen lone pairs. We suggest that enzymes could resort to spin state control to tune the regioselectivity of substrate oxidations.

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Reduced Variational Space (RVS) calculations are reported that afford insight into the energetic origins of the hemi- and holo-directing behavior of [Pb(H2O)n](2+) complexes. It is shown that the distribution of ligands around the Pb(2+) center arises from a delicate balance between the first-order Coulomb plus exchange-repulsion energy that favors holo-directionality, and the second-order charge transfer plus polarization term that favors hemi-directionality. It is additionally demonstrated that the pseudopotential/basis set combination used to study such complexes should be carefully selected, as artifacts can arise when using large-core pseudopotentials. Finally, based on these findings, we introduce a new SIBFA force field parametrization for Pb(2+). Results yield close agreement with ab initio complexation energies in a series of [Pb(H2O)n](2+) complexes and successfully encapsulate the hemi- and holo-directing properties. SIBFA thus appears to be the first classical force field to be able to model the holo-/hemi-directed transition within Pb complexes, avoiding the need for explicit wave function treatment and consequently providing the opportunity to deal with large leaded systems of biological interest.

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The coordination of neutral ligands (L = OC, HCN, NH3, PH3, SH2, HNCO and H2O) to Pb2+ is investigated and analyzed by means of the topological analysis of the Electronic Localization Function (ELF). It is shown that the mean charge density of the V(Pb) basin ((V(Pb))) can reach a ligand-independent limiting value from n = 6, a coordination number from which the [PbL(n)]2+ complexes adopt holodirected structures. The investigations performed on anionic series (L = HS-, OH-, CN-, F-, Cl-, and Br-) lead to optimized stable structures in which the coordination number does not exceed n = 4, even in the presence of a model aqueous solvent. This different behavior with respect to the neutral ligand series is interpreted by means of natural populations and electrostatic repulsions. The main result of this contribution is that stable Pb(II) complexes could be those exhibiting reasonable values of (V(Pb)), namely those not exceeding the saturation plateau evidenced in the present piece of work.

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A Zn(II)-funnel complex based on a calix[6]arene ligand decorated with three tris(imidazolyl) arms at one end of the cone and three NH(2) substituents at the other end, acts as a multipoint recognition host for polyfunctionalized guests. The selectivity is ensured by coordination to Zn(II), CH-pi interaction within the calix cone, and H-bonding at both rims of the cavity. As a result of these multiple interactions, the host can wrap and orient an unsymmetrical triamine guest with a high selectivity. Furthermore, a proton-monitored switch between the regio-isomeric adducts allows reversible inversion of the directionality of the system. Thanks to this directional control, the regioselective mono-carbamoylation of the unsymmetrical triamine guest was successfully achieved on a preparative scale. This case study shows that a funnel-like receptor can be used as a supramolecular protecting tool allowing a transformation which would be impracticable with conventional covalent chemistry.

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A mononuclear cuprous complex is proposed as a novel in silico model for the Cu(M) active site of noncoupled copper monooxygenases. To the best of our knowledge, it is one of the first biomimicking models that allows one to recover the intimate structural features of the enzymatic oxygenated adducts and to gain clear-cut insights relevant to dioxygen activation by these enzymes.

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The aim of the paper is to characterize Cu complexes in the P(Ar)N(3) environment provided by ligands derived from triphenylphosphine P(C(6)H(4)CH(2)NHR)(3) and compare their coordination behavior and reactivity with those obtained with all-nitrogen ligands such as tren. It is shown that coordination of the PN(3) ligand (R = iPr) to Cu(I) and Cu(II) leads to complexes whose coordination sphere is hardly controlled as they readily undergo decoordination of either one N or the P donor together with oxidation of the latter. In strong contrast, when grafted on the small rim of a calix[6]arene, the P(Ar)N(3) is geometrically constrained into a tripod that enforces the metal center to remain in the same environment with a P-Cu bond for both oxidation states. These calix[6]PN(3)-based Cu(I) and Cu(II) complexes react readily with exogenous ligands, making a comparison with calix[6]tren-based copper complexes possible. Indeed, reactivity studies in solution highlight very different behaviors. The complex [Cu(calix[6]PN(3))](2+) shows an unusual affinity for weak sigma-donors (e.g., MeCN > EtOH), while the analogous cuprous complex, [Cu(calix[6]PN(3))](+), displays a surprising affinity for hard O-donor ligands (EtOH, DMF), which has never been observed for the tren analogues. Even more surprising is the lack of reactivity of [Cu(calix[6]PN(3))](+) toward dioxygen, which contrasts strongly with the high reactivity of the [Cu(calix[6]tren)](+) complex. In an attempt to explain the observed differences in binding properties and reactivity, Density Functional Theory calculations and electronic spectra simulations were undertaken. They suggest that coordination of the soft P(Ar)(3) center allows to tune the metal ion properties, either by absorbing excess electron density from Cu(I), or by increasing the electronic density of Cu(II). This is due to the simultaneous presence of the phosphorus atom (sigma-donor) in apical position and the aromatic groups (pi-acceptors) bound to the P-atom.

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The exchange of Me(6)Li aggregated to a lithium amide by (7)LiCl leads to a specific isotope distribution whose microscopic origin is assigned to an edge-to-edge interaction between the R(2)NLi-MeLi aggregate and (LiCl)(2) by NMR and Car-Parrinello molecular dynamics.

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A multipoint recognition system based on a calix[6]arene is described. The calixarene core is decorated on alternating aromatic subunits by 3 imidazole arms at the small rim and 3 aniline groups at the large rim. This substitution pattern projects the aniline nitrogens toward each other when Zn(II) binds at the Tris-imidazole site or when a proton binds at an aniline. The XRD structure of the monoprotonated complex having an acetonitrile molecule bound to Zn(II) in the cavity revealed a constrained geometry at the metal center reminiscent of an entatic state. Computer modeling suggests that the aniline groups behave as a tritopic monobasic site in which only 1 aniline unit is protonated and interacts with the other 2 through strong hydrogen bonding. The metal complex selectively binds a monoprotonated diamine vs. a monoamine through multipoint recognition: coordination to the metal ion at the small rim, hydrogen bonding to the calix-oxygen core, CH/pi interaction within the cavity's aromatic walls, and H-bonding to the anilines at the large rim.

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Singlet and triplet H-transfer reaction paths from C-H and N-H bonds were examined by means of DFT and spin-flip TD-DFT computations on the [(tren Me1)CuO2]+ adduct. The singlet energy surfaces allow its evolution towards H2O2 and an imine species. Whereas N-H cleavage appears to be a radical process, C-H rupture results in a carbocation intermediate stabilized by an adjacent N atom and an electrostatic interaction with the [CuIOOH] metal core. Upon injection of an additional electron, the latter species straightforwardly forms a hydroxylated product. Based on these computational results, a new mechanistic description of the reactivity of copper monooxygenases is proposed.

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In this contribution, we focus to the currently unknown [Pb(CO)(n)](2+) model series (n=1 to 10), a set of compounds which allows us to investigate in-depth the holo- and hemidirectional character that lead complexes can exhibit. By means of DFT computations performed using either relativistic four-component formalisms coupled to all-electron basis sets for [Pb(CO)](2+), [Pb(OC)](2+) and [Pb(CO)(2)](2+), or scalar relativistic pseudopotentials for higher n values, the structure and the energetics of these species are investigated. The results are complemented by Constrained Space Orbital Variations (CSOV) and Electron Localization Function (ELF) comprehensive analyses in order to get better insights into the poorly documented chemical fundamentals of the Pb(2+) cation. Whereas the discrimination between holo- and hemidirected structures is usually done according to the geometry, we here provide a quantitative indicator grounded on (V(Pb)), the mean charge density of the valence monosynaptic V(Pb) ELFic basin associated to the metal cation. Free-enthalpy relying discussions show, moreover, that those gas-phase complexes having n=7, 8 or 9 may be experimentally instable and should dissociate into [Pb(CO)(6)](2+) and a number of CO ligands. According to second-order differences in energy, it is anticipated that the n=3 or 6 structures should be the most probable structures in the gas phase. Gathering all data from the present theoretical study allows us to propose some concepts that the versatile structural chemistry of Pb(2+) complexes could rely on.

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The active sites of copper enzymes have been the subject of many theoretical and experimental investigations from a number of years. Such studies have embraced topics devoted to the modeling of the first coordination sphere at the metallic cations up to the development of biomimetic, or bioinspired, catalytic systems. At least from the theoretical viewpoint, fewer efforts have been dedicated to elucidate how the two copper cations act concertedly in noncoupled dicopper enzymes such as peptidylglycine alpha-hydroxylating monooxygenase (PHM) and dopamine beta-monooxygenase (DbetaM). In these metalloenzymes, an electronic transfer is assumed between the two distant copper cations (11 A). Recent experimental results suggest that this transfer occurs through water molecules, a phenomenon which has been theoretically evidenced to be of high efficiency in the case of cytochrome b5 (Science, 2005, 310, 1311). In the present contribution dedicated to PHM, we overpass the common theoretical approaches dedicated to the electronic and geometrical structures of sites CuM or CuH restricted to their first coordination spheres and aim at directly comparing theoretical results to the experimentally measured activity of the PHM enzyme. To achieve this goal, molecular dynamics simulations were performed on wild-type and various mutants of PHM. More precisely, we provide an estimate of the electron-transfer efficiency between the CuM and CuH sites by means of such molecular dynamics simulations coupled to Marcus theory joined to the Beratan model to approximate the required coupling matrix elements. The theoretical results are compared to the kinetics measurements performed on wild and mutated PHM. The present work, the dynamic aspects of which are essential, accounts for the experimental results issued from mutagenesis. It supports the conclusion that an electronic transfer can occur between two copper(I) sites along a bridge involving a set of hydrogen and chemical bonds. Residue Gln170 is evidenced to be the keystone of this water-mediated pathway.

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The proper description of low-spin states of open-shell systems, which are commonly encountered in the field of bioinorganic chemistry, rigorously requires using multireference ab initio methodologies. Such approaches are unfortunately very CPU-time consuming as dynamic correlation effects also have to be taken into account. The broken-symmetry unrestricted (spin-polarized) density functional theory (DFT) technique has been widely employed up to now to bypass that drawback, but despite a number of relative successes in the determination of singlet-triplet gaps, this framework cannot be considered as entirely satisfactory. In this contribution, we investigate some alternative ways relying on the spin-flip time-dependent DFT approach [Y. Shao et al. J. Chem. Phys. 118, 4807 (2003)]. Taking a few well-documented copper-dioxygen adducts as examples, we show that spin-flip (SF)-DFT computed singlet-triplet gaps compare very favorably to either experimental results or large-scale CASMP2 computations. Moreover, it is shown that this approach can be used to optimize geometries at a DFT level including some multireference effects. Finally, a clear-cut added value of the SF-DFT computations is drawn: if pure ab initio data are required, then the electronic excitations revealed by SF-DFT can be considered in designing dramatically reduced zeroth-order variational spaces to be used in subsequent multireference configuration interaction or multireference perturbation treatments.

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Car-Parrinello (CP) molecular dynamics were applied to sample conformations of various models of organolithium aggregates which are chosen to estimate (1)J(Li,C) NMR coupling constants. The results show that the deviations from the values computed using static (optimized) geometries are small provided no large-amplitude motions occur within the timescale of the simulations. In the case of the vinyllithium dimer, for which rotation of the vinyl chain is observed, this approach allows analysis of the various contributions to the experimentally measured constants. For the trisolvated methyllithium monomer, partial decoordination of solvating dimethyl ether is observed and results in a significant shift of (1)J(Li,C). All these results highlight that a varied physicochemical machinery is hidden behind general empirical formulas, such as the Bauer-Winchester-Schleyer rule used experimentally.

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