Connection between nuclear and electronic Fukui functions beyond frontier molecular orbitals.

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.

Unconventional OFF-ON Response of a Mono(calix[4]arene)-Substituted BODIPY Sensor for Hg2+ through Dimerization Reversion.

A new selective fluorogenic chemosensor for Hg2+, which combines a calixarene derivative with a BODIPY core as a fluorescent reporter, is described. The remarkable change in its fluorogenic properties in DMSO and CHCl3 has been analyzed. A study of its spectral properties on dilution, along with molecular modeling studies, allowed us to explain that this behavior involves the formation of a J-dimer, as well as how the sensing mechanism of Hg2+ proceeds.

A deeper analysis of the role of synchronicity on the Bell-Evans-Polanyi plot in multibond chemical reactions: a path-dependent reaction force constant.

The role of the degree of synchronicity in the formation of the new single-bonds in a large set of 1,3-dipolar cycloadditions and its relation in the fulfilment of the classical Bell-Evans-Polanyi principle and Hammond-Leffler postulate are deeply investigated. Our results confirm that asynchronicity is an important path-dependent factor to be taken into account: (i) the Bell-Evans-Polanyi is fulfilled as the degree of (a)synchronicity is quite the same, and a linear relationship between reorganisation energy and asynchronicity is found; (ii) the asynchronicity is the origin of deviations of this classical principle of chemical reactivity since any decrease of the energy barrier is due to an increase of asynchronicity at the same exothermicity; and (iii) the less exothermic the reaction is, the more asynchronous the mechanism is, at the same energy barrier. Thus, this implies that TS imbalance decreases the reorganisation energy, consequently affecting the reaction exothermicity as well.

5-HT2 Receptor Subfamily and the Halogen Bond Promise.

The binding of C-4-halogenated 1-(4-X-2,5-dimethoxyphenyl)-2-aminopropane (DOX) serotonin agonist psychedelics at all three 5-HT2 receptor subtypes is up to two orders of magnitude stronger for X = Cl, Br, or I (but not F) than when C-4 bears a hydrogen atom and more than expected from their hydrophobicities. Our docking and molecular dynamics simulations agree with the fact that increasing the polarizability of halogens results in halogen-oxygen distances to specific backbone C═O groups, and C-X···O angles, in ranges expected for halogen bonds (XBs), which could contribute to the high affinities observed. Good linear correlations are found for each receptor type, indicating that the binding pocket-ligand affinity is enhanced as the XB interaction becomes stronger (i.e., I ≈ Br > Cl > F). It is also striking to note how the linear equations unveil that the receptor's response on the strength of the XB interaction is quite similar among 5-HT2A and 5-HT2C, whereas the 5-HT2B's sensitivity is less. The calculated dipole polarizabilities in the binding pocket of the receptors reflect the experimental affinity values, indicating that less-polarizable and harder binding sites are more prone to XB formation.

1,3-Dipolar Cycloadditions by a Unified Perspective Based on Conceptual and Thermodynamics Models of Chemical Reactivity.

The main aim in the present report is to gain a deeper understanding of typical 1,3-dipolar cycloadditions by means of three chemical reactivity models in a unified perspective: conceptual density functional theory, distortion/interaction, and reaction force analysis. The focus is to explore the information provided by each reactivity model and how they complement or reinforce each other. Our results showed that the Bell-Evans-Polanyi (BEP) relationship is fulfilled, which is consistent with the Hammond-Leffler postulate. The electronic chemical potential based analysis classifies the reactions as HOMO-, HOMO/LUMO-, and LUMO-controlled reactions as the activation energy increases. It seems likely that HOMO-controlled reaction shifts into LUMO-controlled one as the transition state (TS) position does from early into late. Therefore, the transition from HOMO- (and early TS) into LUMO-controlled (and late TS) is paid by shifting the overall energy change into an endothermic direction, thus supporting the fulfillment of the BEP principle. While thermodynamic models unveil that the distortion or structural rearrangements mainly drive the activation barriers rather than interaction or electronic rearrangements in accord with the distortion/interaction and reaction force analysis, respectively. It is also found that both models are consistent when energy associated with structural and electronic reordering from reaction force analysis is respectively confronted with destabilizing (distortion and Pauli repulsion) and stabilizing (electrostatic and orbital interactions) contributions from the distortion/interaction model, which, on the other hand, increases as low activation barrier and high exothermicity are converted into the high barrier and low exothermicity along with the BEP relation. Finally, the reaction force constant reveals that all 1,3-dipolar cycloaddition reactions proceed by a synchronous single-step mechanism, unveiling that the degree of synchronicity is quite the same in all reactions, confirming the statement that BEP is fulfilled for similar reactions proceeding by a quite alike degree of synchronicity.

Synthesis, in vitro evaluation and molecular docking of a new class of indolylpropyl benzamidopiperazines as dual AChE and SERT ligands for Alzheimer's disease.

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 ß-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 (IC50 = 3.4 and 3.6 µM respectively) exhibited AChE inhibition profile in the same order of magnitude as donepezil (DPZ, IC50 = 2.17 µM), also displaying nanomolar affinity in SERT. Moreover, compounds 17 and 24 displayed high SERT affinities (IC50 = 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 ß-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.

Real-Space Approach to the Reaction Force: Understanding the Origin of Synchronicity/Nonsynchronicity in Multibond Chemical Reactions.

In this article, we present a complementary analysis based on the reaction force F(ξ)/reaction force constant κ(ξ) and noncovalent interactions (NCI) index to characterize the energetics (kinetic and thermodynamics) and mechanistic pathways of two sets of multibond chemical reactions, namely, two double-proton transfer and two Diels-Alder cycloaddition reactions. This approach offers a very straightforward and useful way to delve into a deeper understanding of this type of process. While F(ξ) allows the partition of the whole pathway into three regions or phases, κ(ξ) describes how orchestrated are the bond-breaking and bond-formation events. In turn, NCI indicates how the inter- and intramolecular bonds evolve. The most innovative aspect is the inclusion of the formation of the reactant complex along the pathway, which, by means of NCI, unveils the early molecular recognition and the comprehension of its role in determining the degree of the synchronicity/nonsynchronicity of one-step processes. This approach should be a useful and alternative tool to characterize the energetics and the mechanism of general chemical reactions.

Further understanding of the Ru-centered [2+2] cycloreversion/cycloaddition involved into the interconversion of ruthenacyclobutane using the Grubbs catalysts from a reaction force analysis.

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.

Scrutinizing the substituent effect on Mo-based electrocatalysts for molecular hydrogen release through axial-equatorial decomposition: a DFT study.

Based on the experimental precedent discovered by Kuranadasa and coworkers [H. I. Karunadasa et al., Nature, 2010, 464, 1329] to produce dihydrogen from water electrocatalyzed by 2,6-bis[1,1-bis(2-pyridyl)ethyl]-pyridine oxo-molybdenum complexes, we performed an extensive analysis to study the substituent group effect of derivatised compounds coming from the before mentioned Mo-based metal-organic cations in terms of two kinds of substitutions: axial and equatorial at the para-position of pyridine rings; several conceptual tools were used to back up our conclusions. We found that each type of substituent group (electron-withdrawing and electron-donating ones) exerts an independent influence on energetic parameters (energy barrier and overall energy). This opens the chance to search for a synergistic effect by combining these opposite behaviours of these substituents located in the equatorial and axial para-positions of pyridine rings to computationally modulate the aforementioned energetic parameters. This procedure will make easier the proposal of new catalysts to favour either kinetically or thermodynamically or in both ways the production of dihydrogen from water. Additionally, we encompassed a key point: the number of solvent molecules, so that including their presence in further investigations is mandatory.

Effect of the exchange-correlation functional on the synchronicity/nonsynchronicity in bond formation in Diels-Alder reactions: a reaction force constant analysis.

In this paper, we assess the performance of 24 density functional theory (DFT) based methods classified into 5 categories (GGA, MGGA, HGGA, HMGGA and DHGGA) in predicting reaction energetics, transition state geometries, and the degree of synchronicity/nonsynchronicity in the formation of two new C-C single-bonds in three Diels-Alder reactions between symmetrically and unsymmetrically substituted cyanoethylenes and cyclopentadiene, which gradually proceed from fully synchronous to highly asynchronous concerted mechanisms. This important concept in reaction mechanisms is revealed by the fine structure of the reaction force constant κ(ξ) along the transition region. Some wave function theory (WFT) based methods are also assessed against the CCSD(T) and CCSD benchmarks for the energy and geometry, respectively. The results and the statistical analysis of the errors confirm the robustness of SCS-MP2 (a WFT-based method) as one of the most reliable computational approaches. Regarding DFT-based methods, hybrid exchange-correlation functionals combined with medium-range electron correlation effects or long-range corrected exchange appear as the best performing methods, highlighting both M11 and M06-2X, since a certain percentage of exact Hartree-Fock exchange could counterbalance the delocalization errors that affect pure functionals. Thus, they reliably describe energetics, geometries and the degree of synchronicity in the formation of new C-C single bonds in Diels-Alder reactions. Noticeably, moderate performance for double hybrid functionals and poor performance for the most popular B3LYP method were found as well.

Hydrogenation of Multiple Bonds by Geminal Aminoborane-Based Frustrated Lewis Pairs.

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.

Solvent effect on the degree of (a)synchronicity in polar Diels-Alder reactions from the perspective of the reaction force constant analysis.

In this work, we computationally evaluated the influence of six different molecular solvents, described as a polarizable continuum model at the M06-2X/6-31+G(d,p) level, on the activation barrier/reaction rate, overall energy change, TS geometry, and degree of (a)synchronicity of two concerted Diels-Alder cycloadditions of acrolein (R1) and its complex with Lewis acid acrolein···BH3 (R2) to cyclopentadiene. In gas-phase, we found that both exothermicity and activation barrier are only reduced by about 2.0 kcal mol-1, and the asynchronicity character of the mechanism is accentuated when BH3 is included. An increment in the solvent's polarity lowers the activation energy of R1 by 1.3 kcal mol-1, while for R2 the reaction rate is enhanced by more than 2000 times at room temperature (i.e., the activation energy decreases by 4.5 kcal mol-1) if the highest polar media is employed. Therefore, a synergistic effect is achieved when both external agents, i.e., Lewis acid catalyst and polar solvent, are included together. This effect was ascribed to the ability of the solvent to favor the encounter between cyclopentadiene and acrolein···BH3. This was validated by the asymmetry of the TS which becomes highly pronounced when either both or just BH3 is considered or the solvent's polarity is increased. Finally, the reaction force constant κ(ξ) reveals that an increment in the solvent's polarity is able to turn a moderate asynchronous mechanism of the formation of the new C-C σ-bonds into a highly asynchronous one. Graphical abstract A synergistic effect is achieved when both external agents, i.e., Lewis acid catalyst and polar solvent, are included together: lowered energy barriers and increased asynchronicities.

A 3D visualization of the substituent effect : A brief analysis of two components of the operational formula of dual descriptor for open-shell systems.

Six organometallic compounds coming from a basic Mo-based complex were analyzed from the perspective of the dual descriptor in order to detect subtle influences that a substituent group could exert on the reactive core at a long range. Since the aforementioned complexes are open-shell systems, the used operational formula for the dual descriptor is that one defined for those aforementioned systems, which was then compared with spin density. In addition, dual descriptor was decomposed into two terms, each of which was also applied on every molecular system. The obtained results indicated that components of dual descriptor could become more useful than the operational formula of dual descriptor because differences exerted by the substituents at the para position were better detected by components of dual descriptor rather than the dual descriptor by itself.

Deeper Insight into the Factors Controlling H2 Activation by Geminal Aminoborane-Based Frustrated Lewis Pairs.

H2 activation mediated by geminal aminoborane-based frustrated Lewis pairs (FLPs; R2 N-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.

A computational and conceptual DFT study on the mechanism of hydrogen activation by novel frustrated Lewis pairs.

A computational and conceptual density functional theory (DFT) study on the mechanism of molecular hydrogen activation by a set of three frustrated Lewis pairs (FLPs) was performed at the ωB97X-D/6-311G(d,p) level of theory. A reduced model and other two prototypes derived from experimental data, based on the donor nitrogen and acceptor boron atoms, were used. Analysis based on the energy results, geometries and the global electron density transfer at the TSs made it possible to obtain some interesting conclusions: (i) despite the well-known very low reactivity of molecular hydrogen, the catalytic effectiveness of the three FLPs produces reactions with almost unappreciable activation energies; (ii) the reactions, being exothermic, follow a one-step mechanism via polarised TSs; (iii) there are neither substituent effects on the kinetics nor on the thermodynamics of these reactions; (iv) the activation of molecular hydrogen seems to be attained when the N-B distance in the FLP derivatives is around 2.74 Å; and (v) the proposed FLP model is consistent with the behaviour of the experimental prototypes. Finally, the ability of the three FLPs as efficient catalysts was evaluated studying the hydrogenation of acetylene to yield ethylene.

Traditional and ion-pair halogen-bonded complexes between chlorine and bromine derivatives and a nitrogen-heterocyclic carbene.

A theoretical study of the halogen-bonded complexes (A-X···C) formed between halogenated derivatives (A-X; A = F, Cl, Br, CN, CCH, CF3, CH3, H; and X = Cl, Br) and a nitrogen 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 long C-X distances and small binding energies (8-54 kJ·mol(-1)). In general, these complexes show the traditional behavior of systems containing halogen-bonding interactions. The second type is characterized by short C-X distances and large binding energies (148-200 kJ·mol(-1)), and on the basis of the topological analysis of the electron density, they correspond to ion-pair halogen-bonded complexes. These complexes can be seen as the interaction between two charged fragments: A(-) and (+)[X-CIMe] with a high electrostatic contribution in the binding energy. The charge transfer between lone pair A(LP) to the σ* orbital of C-X bond is also identified as a significant stabilizing interaction in type-II complexes.

Photoemission spectra and density functional theory calculations of 3d transition metal-aqua complexes (Ti-Cu) in aqueous solution.

Photoelectron spectroscopy measurements and density functional calculations are combined to determine the lowest electron binding energies of first-row transition-metal aqua ions, titanium through copper, with 3d(1) through 3d(9) electronic configurations, in their most common oxidation states. Vertical ionization energies are found to oscillate considerably between 6.76 and 9.65 eV for the dications and between 7.05 and 10.28 eV for the respective trivalent cations. The metal cations are modeled as [M(H2O)n](q+) clusters (q = 2, 3, and 4; n = 6 and 18) surrounded by continuum solvent. The performance of 10 exchange-correlation functionals, two GGAs, three MGGAs, two HGGAs and three HMGGAs, combined with the MDF10(ECP)/6-31+G(d,p) basis set is assessed for 11 M-O bond distances, 10 vertical ionization energies, 6 adiabatic ionization energies, and the associated reorganization free energies. We find that for divalent cations the HGGA and HMGGA functionals in combination with the 18 water model show the best agreement with experimental vertical ionization energies and geometries; for trivalent ions, the MGGA functionals perform best. The corresponding reorganization free energies (λo) of the oxidized ions are significantly underestimated with all DFT functionals and cluster models. This indicates that the structural reorganization of the solvation shell upon ionization is not adequately accounted for by the simple solvation models used, emphasizing the importance of extended sampling of thermally accessible solvation structures for an accurate computation of this quantity. The photoelectron spectroscopy measurements reported herein provide a comprehensive set of transition-metal redox energetic quantities for future electronic structure benchmarks.

Complementarity of reaction force and electron localization function analyses of asynchronicity in bond formation in Diels-Alder reactions.

We have computationally compared three Diels-Alder cycloadditions involving cyclopentadiene and substituted ethylenes; one of the reactions is synchronous, while the others are slightly or highly asynchronous. Synchronicity and weak asynchronicity are characterized by the reaction force constant κ(ξ) having just a single minimum in the transition region along the intrinsic reaction coordinate ξ, while for high asynchronicity κ(ξ) has a negative maximum with minima on both sides. The electron localization function (ELF) shows that the features of κ(ξ) can be directly related to the formation of the new C-C bonds between the diene and the dienophile. There is thus a striking complementarity between κ(ξ) and ELF; κ(ξ) identifies the key points along ξ and ELF describes what is happening at those points.

The reaction force constant as an indicator of synchronicity/nonsynchronicity in [4+2] cycloaddition processes.

A variety of experimental and computational analyses support the concept that a chemical reaction has a transition region, in which the system changes from distorted states of the reactants to distorted states of the products. The boundaries of this region along the intrinsic reaction coordinate ξ, which includes the traditional transition state, are defined unambiguously by the minimum and maximum of the reaction force F(ξ), which is the negative gradient of the potential energy V(ξ). The transition region is characterized by the reaction force constant κ(ξ), the second derivative of V(ξ), being negative throughout. It has recently been demonstrated that the profile of κ(ξ) in the transition region is a sensitive indicator of the degree of synchronicity of a concerted reaction: a single κ(ξ) minimum is associated with full or nearly full synchronicity, while a κ(ξ) maximum (negative) between two minima is a sign of considerable nonsynchronicity, i.e. a two-stage concerted process. We have now applied reaction force analysis to the Diels-Alder cycloadditions of the various cyanoethylenes to cyclopentadiene. We examine the relative energy requirements of the structurally- and electronically-intensive phases of the activation processes. We demonstrate that the variation of κ(ξ) in the transition region is again indicative of the level of synchronicity. The fully synchronous cycloadditions are those in which the cyanoethylenes are symmetrically substituted. Unsymmetrical substitution leads to minor nonsynchronicity for monocyanoethylene but much more - i.e. two stages - for 1,1-dicyano- and 1,1,2-tricyanoethylene. We also show that the κ(ξ) tend to become less negative as the activation energies decrease.

Fine structure in the transition region: reaction force analyses of water-assisted proton transfers.

We have analyzed the variation of the reaction force F(ξ) and the reaction force constant κ(ξ) along the intrinsic reaction coordinates ξ of the water-assisted proton transfer reactions of HX-N = Y (X,Y = O,S). The profile of the force constant of the vibration associated with the reactive mode, k ξ (ξ), was also determined. We compare our results to the corresponding intramolecular proton transfers in the absence of a water molecule. The presence of water promotes the proton transfers, decreasing the energy barriers by about 12 - 15 kcal mol(-1). This is due in part to much smaller bond angle changes being needed than when water is absent. The κ(ξ) profiles along the intrinsic reaction coordinates for the water-assisted processes show striking and intriguing differences in the transition regions. For the HS-N = S and HO-N = S systems, two κ(ξ) minima are obtained, whereas for HO-N = O only one minimum is found. The k ξ (ξ) show similar behavior in the transition regions. We propose that this fine structure reflects the degree of synchronicity of the two proton migrations in each case.