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Based on the relationship between average local ionization energy I ̄ (r) and average local electron affinity A ̄ (r) with the electronic Fukui functions, i.e., f−(r) and f+(r), respectively, in this paper, we establish a connection between nuclear and electronic Fukui functions beyond frontier molecular orbitals. As a consequence of this connection, we obtain expressions of average nuclear Fukui functions interpreted as a variation of average nucleophilicity or electrophilicity (weighted by the electronic orbital Fukui functions) with respect to nuclear displacements, which goes beyond the highest occupied molecular orbital/or lowest unoccupied molecular orbital consideration. Furthermore, from this connection and considering the frontier molecular orbital approximation, we derive expressions of nuclear Fukui functions in terms of the atom-condensed electronic Fukui functions, which imply a locality in the chemical reactivity and could be used to study the variation of local nucleophilicity or electrophilicity with respect to nuclear displacements. Finally, this new way to interpret the nuclear Fukui function could be useful in the future to study the chemical reactivity related to molecular vibrations, internal rotations, bond dissociation, chemical reaction along the model of reaction coordinate, and so on. [ABSTRACT FROM AUTHOR]

Peroxides play a central role in many chemical and biological processes such as the Fenton reaction. The relevance of these compounds lies in the low stability of the O–O bond which upon dissociation results in radical species able to initiate various chemical or biological processes. In this work, a set of 64 DFT functional-basis set combinations has been validated in terms of their capability to describe bond dissociation energies (BDE) for the O–O bond in a database of 14 ROOH peroxides for which experimental values of BDE are available. Moreover, the electronic contributions to the BDE were obtained for four of the peroxides and the anion H 2 O 2 - at the CBS limit at CCSD(T) level with Dunning's basis sets up to triple- ζ quality providing a reference value for the hydrogen peroxide anion as a model. Almost all the functionals considered here yielded mean absolute deviations around 5.0 kcal mol - 1 . The smallest values were observed for the ω B97 family and the Minnesota M11 functional with a marked basis set dependence. Despite the mean deviation, order relations among BDE experimental values of peroxides were also considered. The ω B97 family was able to reproduce the relations correctly whereas other functionals presented a marked dependence on the chemical nature of the R group. Interestingly, M11 functional did not show a very good agreement with the established order despite its good performance in the mean error. The obtained results support the use of similar validation strategies for proper prediction of BDE or other molecular properties by DFT methods in subsequent related studies. [ABSTRACT FROM AUTHOR]

Abstract: The hydrogenation reaction of multiple bonds that is mediated by geminal aminoborane‐based frustrated Lewis pairs (FLPs) has been explored by means of density functional theory calculations. It was found that the release of the activated dihydrogen occurred in a concerted, yet highly asynchronous, manner. The physical factors that control the transformation were quantitatively described in detail by using the activation strain model of reactivity in combination with the energy decomposition analysis method. This approach suggested a cooperative double hydrogen‐transfer mechanism, which involves the initial migration of the protic (N)H followed by the nucleophilic attack of the (B)H hydride to the carbon atom of the multiple bond. The influence of both the substituents directly attached to the boron atom of the initial FLP and the nature of the multiple bond on the transformation was also investigated. [ABSTRACT FROM AUTHOR]

H2 activation mediated by geminal aminoborane-based frustrated Lewis pairs (FLPs; R2N-CH2-BR′2) has been computationally explored within the density functional theory framework. It is found that the activation barrier of this process as well as the geometry of the corresponding transition states strongly depend on the nature of the substituents directly attached either to the acidic or the basic centers of the FLPs. The physical factors controlling the whole activation path are quantitatively described in detail by means of the activation strain model of reactivity combined with the energy decomposition analysis method. This methodology suggests a highly orbital-controlled mechanism where the degree of charge transfer cooperativity between the most important donor-acceptor orbital interactions, namely LP(N)→σ*(H2) and σ(H2)→pπ(B), along the reaction coordinate constitutes a suitable indicator of the reaction barrier. [ABSTRACT FROM AUTHOR]

The adsorption of dibenzyl disulfide (DBDS) on a pentagonal bipyramid Cu7 cluster was investigated by using density functional calculations, from energetic and electronic viewpoints. The resulting complexes are mainly driven by Cu···S interaction, and an extra stabilization can be conferred by a secondary π···Cu weak interaction. They were classified as physi- or chemisorption according to their binding energy, and by applying a distortion/interaction decomposition model. Disulfide bond dissociation was observed in the most stable complexes, which includes higher distortion energy. From an electronic viewpoint, an electronic flow from copper to DBDS was observed. [ABSTRACT FROM AUTHOR]

The Ru PR 3 bonds of 1 – 2 ( a - b )- PC , Ru CHPh bonds of 1a - b , 2 - Inact / Act and 1a - b , 2 - RCB were analyzed by charge decomposition (CDA) and natural bond orbital (NBO). We have found that the dissociation step of the Ru PR 3 bond is driven by charge transfer, while the RCB by polarization effects. Furthermore, the π(C ipso )–π*(Ru C) interaction was associated with delocalization effects in the benzylidene ring. Likewise, the nature of the rotameric changes in the carbene was studied through the resonance stabilization energy ( E NLW ). 2 presented a lower Δ E NLW (Inactive → Active) than 1a - b , which confirms that the delocalization effects are related to a low carbene rotameric energy. [ABSTRACT FROM AUTHOR]

A theoretical study of the halogen-bondedcomplexes (A–X···C)formed between halogenated derivatives (A–X; A = F, Cl, Br,CN, CCH, CF3, CH3, H; and X = Cl, Br) and anitrogen heterocyclic carbene, 1,3-dimethylimidazole-2-ylidene (MeIC)has been performed using MP2/aug′-cc-pVDZ level of theory.Two types of A–X:MeIC complexes, called here type-I and -II,were found and characterized. The first group is described by longC–X distances and small binding energies (8–54 kJ·mol–1). In general, these complexes show the traditionalbehavior of systems containing halogen-bonding interactions. The secondtype is characterized by short C–X distances and large bindingenergies (148–200 kJ·mol–1), and onthe basis of the topological analysis of the electron density, theycorrespond to ion-pair halogen-bonded complexes. These complexes canbe seen as the interaction between two charged fragments: A–and +[X–CIMe] with a high electrostatic contributionin the binding energy. The charge transfer between lone pair A(LP)to the σ* orbital of C–X bond is also identified as asignificant stabilizing interaction in type-II complexes. [ABSTRACT FROM AUTHOR]

Five new heteroleptic copper(I) complexes (C1‐5) of the type [Cu(dpa)(P,P)]BF4 based on dipyridylamine (dpa) as N,N ligand and commercial diphosphines as P,P ancillary ligands have been synthesised through a simple methodology with high yields. All complexes were thoroughly characterised by spectroscopic and spectrometric techniques, as well by theoretical calculations. These showed Metal to Ligand Charge Transfer (MLCT) absorptions in the 300–370 nm region, and emission in the 450–520 nm region with quantum yields and lifetimes that depend on the nature of the P,P ligand. The photocatalytic performance of copper(I) complexes C1‐5 was evaluated for their use as photoredox catalysts in ATRA reactions, decarboxylative coupling and an Appel‐type reaction. The use of readily available dpa as N,N ligand constitutes an attractive alternative to the well‐established phenanthroline ligands typically used in photocatalysis. [ABSTRACT FROM AUTHOR]

The chemical reactivity of the first- and second-generation Grubbs catalysts has always been a significant issue in olefin metathesis. In the present work, we study the [2+2] cycloreversion/cycloaddition and the alkylidene rotation involved into the interconversion of the ruthenacyclobutane intermediate, through the reaction force and reaction force constant analysis. It has been found that the structural contribution controls the barrier energy in the interconversion of ruthenacyclobutane via [2+2] cycloreversion/cycloaddition, which is slightly lower in the second generation of Grubbs catalysts while its electronic contribution is slightly higher, which unveils a major rigidity and donor/acceptor properties of the NHC. This finding explains a greater structural contribution in the rate constant. Moreover, on the basis of the reaction force constant, the process can be classified as "two-stage"-concerted reactions, noting a more asynchronous process when the first generation is used as a catalyst. Finally, a similar analysis into the alkylidene rotation was performed. It was determined that [2+2] cycloreversion and alkylidene rotations take place in a sequential manner, the energy barrier is again controlled by structural reorganization, and the pathway is less asynchronous. [ABSTRACT FROM AUTHOR]

To analyze the evolution of a chemical property along the reaction path, it is necessary to extract all the information from a set of electronic structure computations. However, this process is time‐consuming and prone to human error. Here we introduce intrinsic reaction coordinate (IRC)‐Analysis, a new extension in Eyringpy, to monitor the evolution of chemical properties along the intrinsic reaction coordinate, including the complete reaction force analysis. IRC‐Analysis collects the entire data set for each snapshot of the reaction coordinate, avoiding human error in data capture, and allowing the study of several chemical reactions in seconds. Eyringpy is written in Python, has a simple input format, and no programming skills are required. Python's Matplotlib library is used for plotting the evolution of the properties along the reaction coordinate. This version can analyze the evolution of bond distances, angles, Wiberg bond indices, natural charges, dipole moments, and orbital energies (and related properties). [ABSTRACT FROM AUTHOR]

New 4-amino-3-iminoquinoline derivative ligands (L1–4) were synthesized through an intramolecular exo-dig cyclization of anionic β-diketiminates, containing an N-benzonitrile moiety. The effect of the alkali-metal in this reaction was investigated and an inverse effect between the size of the cation and the cyclization rate was revealed. The effect of the reaction temperature was also studied, in which a direct dependence was observed. Kinetic and theoretical studies were performed in an attempt to clarify the reaction mechanism, obtaining a first-order reaction rate dependence with an activation energy of 20.6 kcal mol−1, with DFT-based calculations supporting the proposed mechanism. In addition, four new aluminium complexes were isolated in high yields (C1–4), which were evaluated as catalysts for the preparation of cyclic carbonates from epoxides and CO2, thus becoming the first examples of the use of β-diketiminate ligands in this catalytic process. The reactions were performed at 80 °C and 1 bar CO2 pressure under solvent-free conditions. We were able to prepare a large variety of cyclic carbonates in excellent selectivities and yields, employing the aluminium complex C3. The L1–4 ligands and C1–4 complexes were characterized using NMR, FT-IR, HRMS, and X-ray diffraction methods. [ABSTRACT FROM AUTHOR]

Four new neutral N,N imidoyl-indazole ligands ( L1 , L3, L6, L7 ) and six new Pt(II)-based complexes ( C1 – 5 and C7 ) were synthesized and characterized by spectroscopic and spectrometric techniques. Additionally, compounds L6 , L7 , C3 , C5 and C7 were analyzed using X-ray diffraction. An evaluation of cytotoxicity and cell death in vitro for both ligands and complexes was performed by colorimetric assay and flow cytometry, in four cancer cell lines and VERO cells as the control, respectively. Cytotoxicity and selectivity demonstrated by each compound were dependent on the cancer cell line assayed. IC 50 values of complexes C1 – 5 and C7 were lower than those exhibited for the reference drug cisplatin, and selectivity of these complexes was in general terms greater than cisplatin on three cancer cell lines studied. In HL60 cells, complexes C1 and C5 exhibited the lowest values of IC 50 and were almost five times more selective than cisplatin. Flow cytometry results suggest that each complex predominantly induced necrosis, and its variant necroptosis, instead of apoptosis in all cancer cell lines studied. DNA binding assays, using agarose gel electrophoresis and UV–visible spectrophotometry studies, displayed a strong interaction only between C4 and DNA. In fact, theoretical calculations showed that C4 -DNA binding complex was the most thermodynamic favorable interaction among the complexes in study. Overall, induction of cell death by dependent and independent-DNA-metal compound interactions were possible using imidoyl-indazole Pt(II) complexes as anticancer agents. [ABSTRACT FROM AUTHOR]

DFT(M06-L) calculations have been used to determine the relativestabilities of the metallacyclobutane intermediates arising from thecross-metathesis reactions of terminal olefins as well as to get insightsinto the origin of the nondetection of the α,β-substitutedspecies. For that, we discuss the structures, NMR signatures, stabilitieswith respect to separated reactants, and experimentally proposed interconversionpathways of all potential metallacyclobutane intermediates arisingfrom propene and styrene homocoupling. For the case of propene, theunsubstituted and mono- and disubstituted metallacycles are lowerin Gibbs energy than the separated reactants under the NMR experimentalconditions. Moreover, for the same number of substituents, regardlessof their nature, the metallacycles presenting substituents at theCαcarbons are always lower in energy than thosepresenting substituents at Cβ, the energy differencebeing between 1.7 and 8.8 kcal mol–1. The computedenergy barriers associated with the olefin and carbene rotation processes,two of the experimentally proposed pathways for the metallacycle interconversion,are low and are in excellent agreement with the values previouslydetermined through NMR studies. Cycloaddition and cycloreversion energybarriers are also low, and in fact, there is not a significant differencebetween the barrier heights of the processes leading to observed ornonobserved intermediates. Therefore, the nondetection of metallacyclobutaneintermediates with substituents in Cβseems to arisefrom their lower stability in comparison with the isomers with substituentsin Cα, which makes their detection not feasible underthermodynamic equilibrium conditions. That is, for cross-metathesisprocesses involving small terminal alkenes and activated carbenes,the nature of the observed metallacycles is based on thermodynamiccontrol. The preference of having the substituents in Cαis attributed to the formation of stronger M–C and C–Cbonds during the cycloaddition when the substituents are in an αposition due to higher charge transfer from the original alkene fragmentto the metal carbene. [ABSTRACT FROM AUTHOR]

The reaction force F( ξ) is the negative gradient of the potential energy of a chemical process along the intrinsic reaction coordinate ξ. We extend the rigorous concept of F( ξ) to the 'activation strain model' of Bickelhaupt et al., to formulate the 'strain' force F( ξ) that retards a reaction and the 'interaction' force F( ξ) that drives it. These are investigated for a group of Diels-Alder cycloadditions. The results fully support the interpretation of the minimum of F( ξ) as defining the beginning of the transition from deformed reactants to eventual products. [ABSTRACT FROM AUTHOR]

During the last decade, the one drug-one target strategy has resulted to be inefficient in facing diseases with complex ethiology like Alzheimer's disease and many others. In this context, the multitarget paradigm has emerged as a promising strategy. Based on this consideration, we aim to develop novel molecules as promiscuous ligands acting in two or more targets at the same time. For such purpose, a new series of indolylpropyl-piperazinyl oxoethyl-benzamido piperazines were synthesized and evaluated as multitarget-directed drugs for the serotonin transporter (SERT) and acetylcholinesterase (AChE). The ability to decrease β-amyloid levels as well as cell toxicity of all compounds were also measured. In vitro results showed that at least four compounds displayed promising activity against SERT and AChE. Compounds 18 and 19 (IC 50 = 3.4 and 3.6 μM respectively) exhibited AChE inhibition profile in the same order of magnitude as donepezil (DPZ, IC 50 = 2.17 μM), also displaying nanomolar affinity in SERT. Moreover, compounds 17 and 24 displayed high SERT affinities (IC 50 = 9.2 and 1.9 nM respectively) similar to the antidepressant citalopram, and significant micromolar AChE activity at the same time. All the bioactive compounds showed a low toxicity profile in the range of concentrations studied. Molecular docking allowed us to rationalize the binding mode of the synthesized compounds in both targets. In addition, we also show that compounds 11 and 25 exhibit significant β-amyloid lowering activity in a cell-based assay, 11 (50% inhibition, 10 μM) and 25 (35% inhibition, 10 μM). These results suggest that indolylpropyl benzamidopiperazines based compounds constitute promising leads for a multitargeted approach for Alzheimer's disease. Image 1 • A series of indolylpropyl benzamidopiperazines have been synthesized as dual target compounds for Alzheimer's Disease. • A variety of substitution patterns of indole and benzamide ring has been studied. • Potent AChE inhibitors and SERT ligands were achieved. • Two compounds exhibited promising Aβ inhibition profiles. • The most active compounds displayed low toxicity in biological assays. [ABSTRACT FROM AUTHOR]

Hydroxyl radical reduction and peroxide bond breaking in hydrogen peroxide are reactions involved in various processes such as the Fenton reaction, which has applications as e.g. groundwater remediation. Here, we study these two reactions from a thermodynamical point of view through the bond dissociation energy (BDE) of the O-O bond in hydrogen peroxide and the electron affinity (EA) of the hydroxyl radical. High-level ab-initio calculations at the complete basis set (CBS) limit were carried out, and the performance of different DFT-based methods was addressed by following a specific classification on the basis of the Jacob’s ladder in combination with various Pople’s basis sets. The ab-initio calculations at the CBS limit are in agreement with experimental reference data and identify a significant contribution of the electron correlation energy to the BDE and EA. The studied DFT-based methods were able to reproduce the ab-initio reference values, although no functional was particularly detected as the best for both reactions. The inclusion of certain percentage of Hartree-Fock (HF) exchange in DFT functionals leads in most cases to smaller BDE and EA values, which might be related to the poor description of the two reactions by the HF method. Considering the computational cost, DFT methods provide better BDE and EA values than HF methods with an accuracy comparable to the MP2 or CCSD level of theory. Additionally, the quality of the hydrogen peroxide, hydroxyl radical and hydroxyl anion structures obtained from these functionals was compared to experimental reference data. In general, bond lengths were well reproduced and the errors in the angles were between one and two degrees with some systematic trend with respect to the basis set’s size. From our results we conclude that DFT methods present a computationally less expensive alternative to describe these two reactions that play a role in the Fenton reaction. The benchmark that is carried out in this study provides a systematic validation of various approximated Exc[ρ] functionals combined with different basis sets, which could serve as a stepping-stone for future research on the Fenton reaction. [ABSTRACT FROM AUTHOR]