Half-Sandwich Metal-Catalyzed Alkyne [2+2+2] Cycloadditions and the Slippage Span Model

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 \u3b75, if the five metal\u2013carbon distances are identical, through \u3b73+\u3b72, in the presence of allylic distortion, and \u3b73, in the case of allylic coordination, to \u3b71, if a \u3c3 metal\u2013carbon 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

Multiscale modeling of reaction rates: application to archetypal SN2 nucleophilic substitutions

We propose an approach to the evaluation of kinetic rates of elementary chemical reactions within Kramers\u2019 theory based on the definition of the reaction coordinate as a linear combination of natural, pseudo Z-matrix, internal coordinates of the system. The element of novelty is the possibility to evaluate the friction along the reaction coordinate, within a hydrodynamic framework developed recently [J. Campeggio et al., J. Comput. Chem. 2019, 40, 679\u2013705]. This, in turn, allows to keep into account barrier recrossing, i.e. the transmission coefficient that is employed in correcting transition state theory evaluations. To test the capabilities and the flaws of the approach we use as case studies two archetypal SN2 reactions. First, we consider to the standard substitution of chloride ion to bromomethane. The rate constant at 295.15 K is evaluated to k/c 96 = 2.7 7 10 126 s 121 (with c 96 = 1 M), which compares well to the experimental value of 3.3 7 10 126 s 121 [R. H. Bathgate and E. A. Melwyn-Hughes, J. Chem. Soc 1959, 2642\u20132648]. Then, the method is applied to the SN2 reaction of methylthiolate to dimethyl disulfide in water. In biology, such an interconversion of thiols and disulfides is an important metabolic topic still not entirely rationalized. The predicted rate constant is k/c 96 = 7.7 7 103 s 121. No experimental data is available for such a reaction, but it is in accord with the fact that the alkyl thiolates to dialkyl disulfides substitutions in water have been found to be fast reactions [S. M. Bachrach, J. M. Hayes, T. Dao and J. L. Mynar, Theor. Chem. Acc. 2002, 107, 266\u2013271]

The 125Te Chemical Shift of Diphenyl Ditelluride: Chasing Conformers over a Flat Energy Surface

The interest in diphenyl ditelluride (Ph2Te2) is related to its strict analogy to diphenyl diselenide (Ph2Se2), whose capacity to reduce organic peroxides is largely exploited in catalysis and green chemistry. Since the latter is also a promising candidate as an antioxidant drug and mimic of the ubiquitous enzyme glutathione peroxidase (GPx), the use of organotellurides in medicinal chemistry is gaining importance, despite the fact that tellurium has no recognized biological role and its toxicity must be cautiously pondered. Both Ph2Se2 and Ph2Te2 exhibit significant conformational freedom due to the softness of the inter-chalcogen and carbon\u2013chalcogen bonds, preventing the existence of a unique structure in solution. Therefore, the accurate calculation of the NMR chemical shifts of these flexible molecules is not trivial. In this study, a detailed structural analysis of Ph2Te2 is carried out using a computational approach combining classical molecular dynamics and relativistic density functional theory methods. The goal is to establish how structural changes affect the electronic structure of diphenyl ditelluride, particularly the 125Te chemical shift

Charge Transfer Properties of Benzo[b]thiophene Ferrocenyl Complexes

The synthesis of 2-ferrocenylbenzo[b]-thiophene, 3-ferrocenylbenzo[b]thiophene, 1,1-bis(2-indene)-ferrocene, and the two isomers of 1,1'-bis(2-benzo[b]-thiophene)ferrocene was efficiently achieved by using the palladium-catalyzed Negishi C,C cross-coupling reaction of the appropriate bromobenzo[b]thiophene derivative with ferrocenylzinc chloride. The accessibility of differently substituted benzo[b]thiophenes and a comparison with indene analogues allowed an in-depth investigation on how the geometric modifications and the presence of sulfur affect their physical properties. The molecular structure of 3-ferrocenylbenzo[b]-(t)hiophene has been determined by X-ray diffraction. Electrochemistry and UV-vis-NIR spectroscopy, in particular the appearance upon oxidation of a charge transfer absorption in the NIR region, are rationalized through quantum chemistry calculations and in the framework of the Hush theory

Integrating Diphenyl Diselenide and Its MeHg+ Detoxificant Mechanism on a Conceptual DFT Framework

Methylmercury is an important environmental contaminant and its toxicity in vertebrates is associated with its interaction with selenium (e.g., selenol groups of selenoproteins or HSe- the pivotal metabolite for selenium incorporation into selenoproteins). In a previous study, we demonstrated that diphenyl diselenide (PhSe)2 decreased the deposition of Hg in mice treated with MeHg+. We hypothesized that (PhSe)2 could be reduced metabolically to its selenol intermediate phenylselenol (PhSeH), which reacted with MeHg+ to form PhSeHgMe. To further support our hypothesis, in this work, we investigate the electronic chemical reactivity descriptors at ZORA-OPBE-D3(BJ)/ level of theory using the Fukui functions and the Dual descriptors. The results indicate that (PhSe)2 and diphenyl disulfide (PhS)2 (f+ > f- ) act as poor nucleophiles towards MeHg+ and thus cannot be the detoxificant agent. As further proof, the reaction between diphenyl diselenide and MeHgCl was followed via UV-vis spectrophotometry and the spectra of the relevant species were computed using time-dependent density functional theory (TD-DFT) (CPCM-ZORA-CAM-B3LYP/ZORA-def2-TZVP). The large aromatic system in (PhSe)2 ensures the delocalization of electrons and directly influences the HOMO-LUMO gap (HLG) (3.34 eV) < HLG of PhSeH (3.99 eV). A similar trend was observed with HLG (2.65 eV) for (PhS)2 and 4.13 eV for PhSH. This selenol intermediate is the active reactant, experimentally generated from the reduction of (PhSe)2 by NaBH4, which in presence of MeHgCl forms methylmercury phenylselenide complex (PhSeHgMe), i.e. a non-toxic metabolite of methylmercury formed after administration of (PhSe)2 to mice

Psychiatric Disorders and Oxidative Injury: Antioxidant Effects of Zolpidem Therapy disclosed In Silico

Zolpidem (N,N-Dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide) is a well-known drug for the treatment of sleeping disorders. Recent literature reports on positive effects of zolpidem therapy on improving renal damage after cisplatin and on reducing akinesia without sleep induction. This has been ascribed to the antioxidant and neuroprotective capacity of this molecule, and tentatively explained according to a generic structural similarity between zolpidem and melatonin. In this work, we investigate in silico the antioxidant potential of zolpidem as scavenger of five ROSs, acting via hydrogen atom transfer (HAT) mechanism; computational methodologies based on density functional theory are employed. For completeness, the analysis is extended to six metabolites. Thermodynamic and kinetic results disclose that indeed zolpidem is an efficient radical scavenger, similarly to melatonin and Trolox, supporting the biomedical evidence that the antioxidant potential of zolpidem therapy may have a beneficial effect against oxidative injury, which is emerging as an important etiopathogenesis in numerous severe diseases, including psychiatric disorders

Insight into the mechanism of ferroptosis inhibition by ferrostatin-1

Ferroptosis is a form of cell death primed by iron and lipid hydroperoxides and prevented by GPx4. Ferrostatin-1 (fer-1) inhibits ferroptosis much more efficiently than phenolic antioxidants. Previous studies on the antioxidant efficiency of fer-1 adopted kinetic tests where a diazo compound generates the hydroperoxyl radical scavenged by the antioxidant. However, this reaction, accounting for a chain breaking effect, is only minimally useful for the description of the inhibition of ferrous iron and lipid hydroperoxide dependent peroxidation. Scavenging lipid hydroperoxyl radicals, indeed, generates lipid hydroperoxides from which ferrous iron initiates a new peroxidative chain reaction. We show that when fer-1 inhibits peroxidation, initiated by iron and traces of lipid hydroperoxides in liposomes, the pattern of oxidized species produced from traces of pre-existing hydroperoxides is practically identical to that observed following exhaustive peroxidation in the absence of the antioxidant. This supported the notion that the anti-ferroptotic activity of fer-1 is actually due to the scavenging of initiating alkoxyl radicals produced, together with other rearrangement products, by ferrous iron from lipid hydroperoxides. Notably, fer-1 is not consumed while inhibiting iron dependent lipid peroxidation. The emerging concept is that it is ferrous iron itself that reduces fer-1 radical. This was supported by electroanalytical evidence that fer-1 forms a complex with iron and further confirmed in cells by fluorescence of calcein, indicating a decrease of labile iron in the presence of fer-1. The notion of such as pseudo-catalytic cycle of the ferrostatin-iron complex was also investigated by means of quantum mechanics calculations, which confirmed the reduction of an alkoxyl radical model by fer-1 and the reduction of fer-1 radical by ferrous iron. In summary, GPx4 and fer-1 in the presence of ferrous iron, produces, by distinct mechanism, the most relevant anti-ferroptotic effect, i.e the disappearance of initiating lipid hydroperoxides

A DFT investigation of the structural and electronic properties ofCo(I) and Rh(I) half-sandwich complexes with heteroaromatic Pi ligands

Co(I) and Rh(I) half-sandwich complexes of the heteroaromatic 1,2-azaborolyl and 3a,7a-azaborindenyl anions with the ancillary ligand COD (1,5-cycloctadiene) are designed by using accurate state-of-the-art Density Functional Theory (DFT) calculations. Their structural and electronic properties are compared to those of the analogous compounds containing the classic hydrocarbon isoelectronic ligands, i.e. cyclopentadienyl and indenyl anions. A comparison is made between the catalytic ability of (\u3b75-C5H5)-Co and (1,2-azaborolyl)-Co fragments toward alkyne [2+2+2] cyclizations, a class of reactions of paramount importance in industrial and pharmaceutical research for the synthesis of substituted benzenes, polycyclic and heterocyclic compounds, by theoretically addressing the fundamental mechanistic steps