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

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

Major depressive disorder and oxidative stress: In silico investigation of fluoxetine activity against ROS

Major depressive disorder is a psychiatric disease having approximately a 20% lifetime prevalence in adults in the United States (U.S.), as reported by Hasin et al. in JAMA Psichiatry 2018 75, 336\u2013346. Symptoms include low mood, anhedonia, decreased energy, alteration in appetite and weight, irritability, sleep disturbances, and cognitive deficits. Comorbidity is frequent, and patients show decreased social functioning and a high mortality rate. Environmental and genetic factors favor the development of depression, but the mechanisms by which stress negatively impacts on the brain are still not fully understood. Several recent works, mainly published during the last five years, aim at investigating the correlation between treatment with fluoxetine, a non-tricyclic antidepressant drug, and the amelioration of oxidative stress. In this work, the antioxidant activity of fluoxetine was investigated using a computational protocol based on the density functional theory approach. Particularly, the scavenging of five radicals (HO\u2022, HOO\u2022, CH3OO\u2022, CH2=CHOO\u2022, and CH3O\u2022) was considered, focusing on hydrogen atom transfer (HAT) and radical adduct formation (RAF) mechanisms. Thermodynamic as well as kinetic aspects are discussed, and, for completeness, two metabolites of fluoxetine and serotonin, whose extracellular concentration is enhanced by fluoxetine, are included in our analysis. Indeed, fluoxetine may act as a radical scavenger, and exhibits selectivity for HO\u2022 and CH3O\u2022, but is inefficient toward peroxyl radicals. In contrast, the radical scavenging efficiency of serotonin, which has been demonstrated in vitro, is significant, and this supports the idea of an indirect antioxidant efficiency of fluoxetine

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

C(spn)−X (n=1–3) bond activation by palladium

We have studied the palladium-mediated activation of C(sp(n))-X bonds (n = 1-3 and X = H, CH3, Cl) in archetypal model substrates H3C-CH2-X, H2C=CH-X and HC equivalent to C-X by catalysts PdLn with L-n = 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(sp(3))-X, to C(sp(2))-X, to C(sp)-X. Activation strain and matching energy decomposition analyses reveal that the decreased oxidative addition barrier going from sp(3), to sp(2), 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(sp(n))-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(sp(3))-X to C(sp)-X.Bio-organic Synthesi

Toward a Rational Design of Half-Sandwich Group 9 Catalysts for [2+2+2] Alkynes Cycloadditions

Filling the gap between molecular structure and reactivity is a well-known challenging task in chemistry. The rational design of catalysts may greatly benefit of computational aid, provided state-of-the-art methodologies are employed. The case of metal catalyzed [2+2+2] cycloaddition of alkynes/alkynes-nitriles to benzene/pyridine is investigated in detail, due to the paramount importance of these reactions for the synthesis of cyclic and polycyclic organic compounds. Catalysts of general formula Cp\u2019M are considered, where Cp\u2019 is the cyclopentadienyl anion or the cyclopentadienyl moiety of larger polycyclic aromatic/heteroaromatic ligands, and M=Co, Rh, Ir. Energy profiles of the whole cycles with a number of intermediates ranging from 5 to 9 connected by the corresponding transition states are computed and the catalyst performance is evaluated based on its turnover frequency (TOF), by implementing the equations of the energy span model. TOF values are related to peculiar structural features of the Cp\u2019M fragment, i.e. to the M-Cp\u2019 bonding mode which results in slippage phenomena during the catalytic cycle. In fact, the metal is never coordinated to the five carbon atoms ring in highly symmetric fashion (eta5), but is slipped and the amount of this distortion changes during the various steps of the catalysis. This fluxionality is found to affect importantly the efficiency of the catalyst

Organodiselenides: Organic catalysis and drug design learning from glutathione peroxidase

Organodiselenides are an important class of compounds characterized by the presence of two adjacent covalently bonded selenium nuclei. Among them, diaryldiselenides and their parent compound diphenyl diselenide attract continuing interest in chemistry as well as in close disciplines like medicinal chemistry, pharmacology and biochemistry. A search in SCOPUS database has revealed that in the last three years 105 papers have been published on the archetypal diphenyl diselenide and its use in organic catalysis and drug tests. The reactivity of the Se-Se bond and the redox properties of selenium make diselenides efficient catalysts for numerous organic reactions, such as Bayer- Villiger oxidations of aldehydes/ketones, epoxidations of alkenes, oxidations of alcohols and nitrogen containing compounds. In addition, organodiselenides might find application as mimics of glutathione peroxidase (GPx), a family of enzymes, which, besides performing other functions, regulate the peroxide tone in the cells and control the oxidative stress level. In this review, the essential synthetic and reactivity aspects of organoselenides are collected and rationalized using the results of accurate computational studies, which have been carried out mainly in the last two decades. The results obtained in silico provide a clear explanation of the anti-oxidant activity of organodiselenides and more in general of their ability to reduce hydroperoxides. At the same time, they are useful to gain insight into some aspects of the enzymatic activity of the GPx, inspiring novel elements for rational catalyst and drug design

Radical Scavenging Potential of the Phenothiazine Scaffold: A Computational Analysis

The reactivity of phenothiazine (PS), phenoselenazine (PSE), and phenotellurazine (PTE) with different reactive oxygen species (ROS) has been studied using density functional theory (DFT) in combination with the QM-ORSA (Quantum Mechanics-based Test for Overall Free Radical Scavenging Activity) protocol for an accurate kinetic rate calculation. Four radical scavenging mechanisms have been screened, namely hydrogen atom transfer (HAT), radical adduct formation (RAF), single electron transfer (SET), and the direct oxidation of the chalcogen atom. The chosen ROS are HO., HOO., and CH3OO.. PS, PSE, and PTE exhibit an excellent antioxidant activity in water regardless of the ROS due to their characteristic diffusion-controlled regime processes. For the HO. radical, the primary active reaction mechanism is, for all antioxidants, RAF. But, for HOO. and CH3OO., the dominant mechanism strongly depends on the antioxidant: HAT for PS and PSE, and SET for PTE. The scavenging efficiency decreases dramatically in lipid environment and remains only significant (via RAF) for the most reactive radical (HO.). Therefore, PS, PSE, and PTE are excellent antioxidant molecules, especially in aqueous, physiological environments where they are active against a broad spectrum of harmful radicals. There is no advantage or significant difference in the scavenging efficiency when changing the chalcogen since the reactivity mainly derives from the amino hydrogen and the aromatic sites

RATIONAL DESIGN OF HALF-SANDWICH GROUP 9 CATALYSTS FOR [2+2+2] ALKYNES CYCLOADDITIONS

Nowadays, modern computational facilities allow us to predict reactivity in silico and tackle molecular systems that are otherwise difficult to rationalize. In this work, state-of-the-art relativistic density functional (DFT) methodologies are employed to design catalytic fragments for the [2+2+2] alkynes/alkynes-nitriles cycloaddition to benzene/pyridine. The very good selectivity and the possibility to maintain a solvent-free environment make this type of reactions very attractive and justify the continuing investigations.1 The catalyst\u2019s structure is Cp\u2019M, where Cp\u2019 is the cyclopentadienyl ligand (Cp) or a more extended aromatic/heteroaromatic moiety, and M is a group 9 metal (Co, Rh, Ir). The singlet potential energy surface of the process is explored by locating all intermediates/transition states and the catalysts\u2019 performance is calculated in terms of turnover frequency (TOF), by implementing the equations of the energy span model.2,3 The different bonding mode of the substrate to the catalyst, and, vicariously, the nature of Cp\u2019-M coordination, is investigated using the activation strain model (ASA) and energy decomposition analysis (EDA) in order to follow the metal displacement (slippage) and connect structural information with the energy.4 Commonly, the highly symmetric coordination of the metal to the aromatic ligand is never achieved, but the distortions during the cycle can be larger or smaller under different conditions (different metal center, changes in the aromatic ligand, presence of an additional ancillary ligand, etc.) and this fluxionality is found to significantly influence the overall efficiency