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In 1973, two major discoveries changed the face of selenium chemistry: the identification of the first mammal selenoenzyme, glutathione peroxidase 1, and the discovery of the synthetic utility of the so‐called selenoxide elimination. While the chemical mechanism behind the catalytic activity of glutathione peroxidases appears to be mostly unveiled, little is known about the mechanisms of other selenoproteins and, for some of them, even the function lies in the dark. In chemistry, the capacity of organoselenides of catalyzing hydrogen peroxide activation for the practical manipulation of organic functional groups has been largely explored, and some mechanistic details have been clearly elucidated. As a paradox, despite the long‐standing experience in the field, the nature of the active oxidant in various reactions still remains matter of debate. While many successes characterize these fields, the pharmacological use of organoselenides still lacks any true application, and while some organoselenides were found to be non‐toxic and safe to use, to date no therapeutically approved use was granted. In this review, some fundamental and chronologically aligned topics spanning organoselenium biochemistry, chemistry and pharmacology are discussed, focusing on the current mechanistic picture describing their activity as either bioactive compounds or catalysts. [ABSTRACT FROM AUTHOR]

The C−X bond activation (X = H, C) of a series of substituted C(n°)−H and C(n°)−C(m°) bonds with C(n°) and C(m°) = H3C− (methyl, 0°), CH3H2C− (primary, 1°), (CH3)2HC− (secondary, 2°), (CH3)3C− (tertiary, 3°) by palladium were investigated using relativistic dispersion‐corrected density functional theory at ZORA‐BLYP‐D3(BJ)/TZ2P. The effect of the stepwise introduction of substituents was pinpointed at the C−X bond on the bond activation process. The C(n°)−X bonds become substantially weaker going from C(0°)−X, to C(1°)−X, to C(2°)−X, to C(3°)−X because of the increasing steric repulsion between the C(n°)‐ and X‐group. Interestingly, this often does not lead to a lower barrier for the C(n°)−X bond activation. The C−H activation barrier, for example, decreases from C(0°)−X, to C(1°)−X, to C(2°)−X and then increases again for the very crowded C(3°)−X bond. For the more congested C−C bond, in contrast, the activation barrier always increases as the degree of substitution is increased. Our activation strain and matching energy decomposition analyses reveal that these differences in C−H and C−C bond activation can be traced back to the opposing interplay between steric repulsion across the C−X bond versus that between the catalyst and substrate. [ABSTRACT FROM AUTHOR]

We have quantum chemically studied the palladium‐mediated activation of C(spn)−X bonds (n=1–3; X=F, Cl, Br, I) in the archetypal model substrates H3C−CH2−X, H2C=CH−X, and HC≡C−X by a model bare palladium catalyst, using relativistic density functional theory at ZORA‐BLYP/TZ2P. The bond activation reaction barrier decreases, for all sp‐hybridized carbon centers, when the substituent X of the substrate is changed from X=F to I. Activation strain and energy decomposition analyses reveal that the enhanced reactivity along this series originates from (i) a less destabilizing activation strain due to an intrinsically weaker C(spn)−X bond; and (ii) an increasingly more stabilizing electrostatic interaction between the catalyst and the substrate. The latter is a direct consequence of the more diffuse electron density and higher nuclear charge of the X atom in the C(spn)−X bond when going from X=F to I, which, in turn, engages in a more favorable electrostatic attraction with the nucleus and electrons, respectively, of the palladium catalyst. [ABSTRACT FROM AUTHOR]

We have studied the palladium‐mediated activation of C(spn)−X bonds (n = 1–3 and X = H, CH3, Cl) in archetypal model substrates H3C−CH2−X, H2C=CH−X and HC≡C−X by catalysts PdLn with Ln = no ligand, Cl−, and (PH3)2, using relativistic density functional theory at ZORA‐BLYP/TZ2P. The oxidative addition barrier decreases along this series, even though the strength of the bonds increases going from C(sp3)−X, to C(sp2)−X, to C(sp)−X. Activation strain and matching energy decomposition analyses reveal that the decreased oxidative addition barrier going from sp3, to sp2, to sp, originates from a reduction in the destabilizing steric (Pauli) repulsion between catalyst and substrate. This is the direct consequence of the decreasing coordination number of the carbon atom in C(spn)−X, which goes from four, to three, to two along this series. The associated net stabilization of the catalyst–substrate interaction dominates the trend in strain energy which indeed becomes more destabilizing along this same series as the bond becomes stronger from C(sp3)−X to C(sp)−X. [ABSTRACT FROM AUTHOR]

The so‐called peroxidatic cysteines and selenocysteines in proteins reduce hydroperoxides through a dual attack to the peroxide bond in a two‐step mechanism. First, a proton dislocation from the thiol/selenol to a close residue of the enzymatic pocket occurs. Then, a nucleophilic attack of the anionic cysteine/selenocysteine to one O atom takes place, while the proton is shuttled back to the second O atom, promoting the formation of a water molecule. In this computational study, we use a molecular model of GPx to demonstrate that the enzymatic environment significantly lowers the barrier of the latter SN2 step. Particularly, in our Se‐based model the energy barriers for the two steps are 29.82 and 2.83 kcal mol−1, both higher than the corresponding barriers computed in the enzymatic cluster, i. e., 21.60 and null, respectively. Our results, obtained at SMD‐B3LYP‐D3(BJ)/6‐311+G(d,p), cc‐pVTZ//B3LYP‐D3(BJ)/6‐311G(d,p), cc‐pVTZ level of theory, show that the mechanistic details can be well reproduced using an oversimplified model, but the energetics is definitively more favorable in the GPx active site. In addition, we pinpoint the role of the chalcogen in the peroxide reduction process, rooting the advantages of the presence of selenium in its acidic and nucleophilic properties. [ABSTRACT FROM AUTHOR]

Methylmercury is a highly toxic compound and human exposure is mainly related to consumption of polluted fish and seafood. The inactivation of thiol‐based enzymes, promoted by the strong affinity binding of electrophilic mercuric ions to thiol and selenol groups of proteins, is likely an important factor explaining its toxicity. A key role is played by the chemistry and reactivity of the mercury–chalcogens bond, particularly HgS and HgSe, which is the focus of this computational work (level of theory: (COSMO)‐ZORA‐BLYP‐D3(BJ)/TZ2P). We analyze nine ligand‐exchange model reactions (the so‐called Rabenstein's reactions) involving an entering ligand (methylchalcogenolate) and a substrate (methylchalcogenolatemethylmercury). Trends in reaction and activation energies are discussed and a change in mechanism is reported for all cases when going from gas phase to water, that is, from a single‐well potential energy surface (PES) to a canonical SN2‐like mechanism. The reasons accounting for the biochemically challenging and desired displacement of methylmercury from a seleno/thiol protein can be found already in these model reactions, as can be seen from the similarities of the ligand exchange reactions in solution in thermodynamics and kinetics. [ABSTRACT FROM AUTHOR]

Half‐sandwich RhI compounds display good catalytic activity toward alkyne [2+2+2] cycloadditions. A peculiar structural feature of these catalysts is the coordination of the metal to an aromatic moiety, typically a cyclopentadienyl anion, and, in particular, the possibility to change the bonding mode easily by the metal slipping over this aromatic moiety. Upon modifying the ancillary ligands, or proceeding along the catalytic cycle, hapticity changes can be observed; it varies from η5, if the five metal–carbon distances are identical, through η3+η2, in the presence of allylic distortion, and η3, in the case of allylic coordination, to η1, if a σ metal–carbon bond forms. In this study, we present the slippage span model, derived with the aim of establishing a relationship between slippage variation during the catalytic cycle, quantified in a novel and rigorous way, and the performance of catalysts in terms of turnover frequency, computed with the energy span model. By collecting and comparing new data and data from the literature, we find that the highest performance is associated with the smallest slippage variation along the cycle. Slip up: A peculiar structural feature of half‐sandwich compounds is the possibility to change the bonding mode easily by slippage of the metal over the aromatic moiety. The slippage span model is used to predict the performance of the half‐sandwich group 9 metal catalysts for [2+2+2] alkyne cycloadditions based on the metal slippage. [ABSTRACT FROM AUTHOR]

The Cover Feature shows the glacier of Marmolada, the highest Dolomite (3343 m), with superimposed the aromatic ligand of the group 9 half‐matallocene catalysts for [2+2+2] cycloadditions of unsaturated molecules. When large changes of metal slippage from the centroid of the coordinated cyclopentadienyl moiety occur during catalysis, the turnover frequency (TOF) of the catalytic cycle decreases, similar to what happens to the inexperienced climber who drifts on ice and gets away from the longed‐for TOP. (Photo credit to Foto Riva) More information can be found in the Full Paper by M. Dalla Tiezza et al. on page 143 in Issue 2, 2019 (DOI: 10.1002/open.201800191). [ABSTRACT FROM AUTHOR]