Stereoelectronic interactions are too weak to explain the molecular conformation in solid state of cis-2-tert-butyl-5-(tert-butylsulfonyl)-1,3-dioxane.

cis-2-tert-Butyl-5-(tert-butylsulfonyl)-1,3-dioxane (cis-1) exhibits a high degree of eclipsing in the H-C5-S-C segment in the solid state, the origin of which remains unexplained. The eclipsed conformation that corresponds to an energetic minimum in the solid state practically corresponds to a rotational transition state in solution, which allows an approach to understand transitions states. The difference in the enthalpy of sublimation ΔsubH between cis-1 and the more stable trans-1 is 8.40 kcal mol-1, lets to consider that the intermolecular interactions in the crystalline structure must be responsible for the conformational effect observed in the solid state. The study of the experimental electron density of cis-1 in solid state allowed to establish that CH⋯OS intermolecular interaction is the main contribution to the observed eclipsing. The charge density analysis was also performed using the quantum theory of atoms in molecules to evaluate the nature and relevance of the intermolecular interactions in the crystal structure.

Spin Energy Contributions of the Kinetic Energy Density in the Stabilization of the Metal-Ligand Interactions.

The kinetic energy (KE) density plays an essential role in the stabilization mechanism of covalent, polar covalent, and ionic bondings; however, its role in metal-ligand bindings remains unclear. In a recent work, the energetic contributions of the spin densities α and ß were studied to explain the geometrical characteristics of a series of metal-ligand complexes. Notably, the KE density was found to modulate/stabilize the spin components of the intra-atomic nucleus-electron interactions within the metal in the complex. Here, we investigate the topographic properties of the spin components of the KE density for a family of high-spin hexa-aquo complexes ([M(H2O)6]2+) to shed light on the stabilization of the metal-ligand interaction. We compute the Lagrangian, G(r), and Hamiltonian, K(r), KE densities and analyze the evolution of its spin components in the formation of two metal-ligand coordination complexes. We study Kα/ß(r) along the metal-oxygen (M-O) internuclear axis as a function of the metal. Our results indicate that K(r) is a more distance-sensitive quantity compared to G(r) as it displays topographic features at larger M-O distances. Furthermore, K(r) allows one to identify the predominant interaction mechanism in the complexes.

Hydrolysis of ester phosphates mediated by a copper complex.

Phosphate ester hydrolysis is an important reaction that plays a major role in both enzymatic and non-enzymatic processes, including DNA and pesticide breaking. Although it is a widely studied reaction, the precise mechanistic details, especially for copper complexes, remain under discussion. To contribute to the debate, we present the catalyzed hydrolysis of phosphomono-, di- and tri-esters mediated by the [Cu(II)(1,10-phenanthroline)] complex. The reaction coordinates for several substrates were explored through the metadynamics formalism. Thus, we found that for mono- and di-substituted ester phosphates a concerted mechanism is observed, where a coordinated hydroxyl group attacks the phosphorus atom at the same side as the leaving group, along with a proton transfer. In contrast, tri-substituted phosphate remains coordinated with the metal, and the nucleophile acts independently following an addition-elimination process. That is, the metallic complex achieves a specific nucleophile-phosphate interaction that produces a concerted transition state in the phosphoester hydrolysis process.

How do density functionals affect the Hirshfeld atom refinement?

In this work, the effect of mixing different amounts of Hartree-Fock (HF) exchange with hybrid density functionals applied to the Hirshfeld atom refinement (HAR) of urea and oxalic acid dihydrate is explored. Together, the influence of using different basis sets, methods (including MP2 and HF) and cluster sizes (to model bulk effects) is studied. The results show that changing the amount of HF exchange, no matter the level of theory, has an impact almost exclusively on the H atom refinement parameters. Contrary to pure quantum mechanical calculations where good geometries are obtained with intermediate HF exchange mixtures, in the HAR the best match with neutron diffraction reference values is not necessarily found for these admixtures. While the non-hydrogen covalent bond lengths are insensitive to the combination of method or basis set employed, the X-H bond lengths always increase proportionally to the HF exchange for the analysed systems. This outcome is opposite to what is normally observed from geometry optimisations, i.e., shorter bonds are obtained with greater HF exchange. Additionally, the thermal ellipsoids tend to shrink with larger HF exchange, especially for the H atoms involved in strong hydrogen bonding. Thus, it may be the case that the development of density functionals or basis sets suitable for quantum crystallography should take a different path than those fitted for quantum chemistry calculations.

Benzene and Borazine, so Different, yet so Similar: Insight from Experimental Charge Density Analysis.

Although benzene and borazine are isoelectronic and isostructural, they have very different electronic structures, mainly due to the polar nature of the B-N bond. Herein, we present an experimental study of the charge density distribution obtained from the multipole model formalism and Hirshfeld atom refinement (HAR) based on high-resolution X-ray diffraction data of borazine B3N3H6 (1) and B,B',B″-trichloroborazine (2) crystals. These data are compared to those obtained from HAR for benzene (4) and 1,3,5-trichlorobenzene (5) and further compared with values obtained from density functional theory calculations in the gas phase, where N,N',N″-trichloroborazine (3) was also included. The results confirm that, unlike benzene, borazines are only weakly aromatic with an island-like electronic delocalization within the B3N3 ring involving only the nitrogen atoms. Furthermore, delocalization indices and interacting quantum atom energy for bonded and non-bonded atoms were found to be highly suitable indicators capable of describing the origin of the discrepancies observed when the degree of aromaticity in 2 and 3 is evaluated using common aromaticity indices. Additionally, analysis of intermolecular interactions in the crystals brings further evidence of a weakly aromatic character of the borazines as it reveals surprising similarities between the crystal packing of borazine and benzene and also between B,B',B″-trichloroborazine and 1,3,5-trichlorobenzene.

Intermediate Detection in the Casiopeina-Cysteine Interaction Ending in the Disulfide Bond Formation and Copper Reduction.

A strategy to improve the cancer therapies involves agents that cause the depletion of the endogenous antioxidant glutathione (GSH), increasing its efflux out of cells and inducing apoptosis in tumoral cells due to the presence of reactive oxygen species. It has been shown that Casiopeina copper complexes caused a dramatic intracellular GSH drop, forming disulfide bonds and reducing CuII to CuI. Herein, through the determination of the [CuII]-SH bond before reduction, we present evidence of the adduct between cysteine and one Casiopeina as an intermediate in the cystine formation and as a model to understand the anticancer activity of copper complexes. Evidence of such an intermediate has never been presented before.

Laplacian of the Hamiltonian Kinetic Energy Density as an Indicator of Binding and Weak Interactions.

The kinetic energy is the center of a controversy between two opposite points of view about its role in the formation of a chemical bond. One school states that a lowering of the kinetic energy associated with electron delocalization is the key stabilization mechanism of covalent bonding. In contrast, the opposite school holds that a chemical bond is formed by a decrease in the potential energy due to a concentration of electron density within the binding region. In this work, a topographic analysis of the Hamiltonian Kinetic Energy Density (KED) and its laplacian is presented to gain more insight into the role of the kinetic energy within chemical interactions. This study is focused on atoms, diatomic and organic molecules, along with their dimers. In addition, it is shown that the laplacian of the Hamiltonian KED exhibits a shell structure in atoms and that their outermost shell merge when a molecule is formed. A covalent bond is characterized by a concentration of kinetic energy, potential energy and electron densities along the internuclear axis, whereas a charge-shift bond is characterized by a fusion of external concentration shells and a depletion in the bonding region. In the case of weak intermolecular interactions, the external shell of the molecules merge into each other resulting in an intermolecular surface comparable to that obtained by the Non-covalent interaction (NCI) analysis.

From the Linnett-Gillespie model to the polarization of the spin valence shells of metals in complexes.

In this paper, we present a novel approach to track the origin of the metal complex structure from the topology of the α and ß spin densities as an extension of the Linnett-Gillespie model. Usually, the theories that explain the metal-ligand interactions consider the disposition and the relative energies of the empty or occupied set of d orbitals, ignoring the spin contribution explicitly. Our quantum topological approach considers the spatial distribution of the α and ß spin valence shells, and the energy interaction between them. We used the properties of the atomic graph, a topological object that summarises the charge concentrations and depletions on the valence shell of an atom in a molecule, and the interacting quantum atoms (IQA) energy partition scheme. Unlike the Linnett-Gillespie model, which is based on electron-electron repulsion, our approach states that the ligands provoke a redistribution of the electron density to maximize the nuclear-electron interactions in each spin valence shell to bypass the concentration of electron-electron interactions, resulting in a polarization pattern which determines the position of the ligands.

Predicting reactive sites with quantum chemical topology: carbonyl additions in multicomponent reactions.

Quantum Chemical Topology (QCT) is a well established structural theoretical approach, but the development of its reactivity component is still a challenge. The hypothesis of this work is that the reactivity of an atom within a molecule is a function of its electronic population, its delocalization in the rest of the molecule, and the way it polarizes within an atomic domain. In this paper, we present a topological reactivity predictor for cabonyl additions, κ. It is a measure of the polarization of the electron density with the carbonyl functional group. κ is a model obtained from a QSAR procedure, using quantum-topological atomic descriptors and reported hydration equilibrium constants of carbonyl compounds. To validate the predictive capability of κ, we applied it to organic reactions, including a multicomponent reaction. κ was the only property that predicts the reactivity in each reaction step. The shape of κ can be interpreted as the change between two electrophilic states of a functional group, reactive and non-reactive.

Origin of the Photoinduced Geometrical Change of Copper(I) Complexes from the Quantum Chemical Topology View.

Copper(I) complexes (CICs) are of great interest due to their applications as redox mediators and molecular switches. CICs present drastic geometrical change in their excited states, which interferes with their luminescence properties. The photophysical process has been extensively studied by several time-resolved methods to gain an understanding of the dynamics and mechanism of the torsion, which has been explained in terms of a Jahn-Teller effect. Here, we propose an alternative explanation for the photoinduced structural change of CICs, based on electron density redistribution. After photoexcitation of a CIC (S0 →S1 ), a metal-to-ligand charge transfer stabilizes the ligand and destabilizes the metal. A subsequent electron transfer, through an intersystem crossing process, followed by an internal conversion (S1 →T2 →T1 ), intensifies the energetic differences between the metal and ligand within the complex. The energy profile of each state is the result of the balance between metal and ligand energy changes. The loss of electrons originates an increase in the attractive potential energy within the copper basin, which is not compensated by the associated reduction of the repulsive atomic potential. To counterbalance the atomic destabilization, the valence shell of the copper center is polarized (defined by ∇2 ρ(r) and ∇2 Vne (r)) during the deactivation path. This polarization increases the magnitude of the intra-atomic nuclear-electron interactions within the copper atom and provokes the flattening of the structure to obtain the geometry with the maximum interaction between the charge depletions of the metal and the charge concentrations of the ligand.

Enhancing Acute Oral Toxicity Predictions by using Consensus Modeling and Algebraic Form-Based 0D-to-2D Molecular Encodes.

Quantitative structure-activity relationships (QSAR) are introduced to predict acute oral toxicity (AOT), by using the QuBiLS-MAS (acronym for quadratic, bilinear and N-Linear maps based on graph-theoretic electronic-density matrices and atomic weightings) framework for the molecular encoding. Three training sets were employed to build the models: EPA training set (5931 compounds), EPA-full training set (7413 compounds), and Zhu training set (10 152 compounds). Additionally, the EPA test set (1482 compounds) was used for the validation of the QSAR models built on the EPA training set, while the ProTox (425 compounds) and T3DB (284 compounds) external sets were employed for the assessment of all the models. The k-nearest neighbor, multilayer perceptron, random forest, and support vector machine procedures were employed to build several base (individual) models. The base models with REPA-training ≥ 0.75 ( R = correlation coefficient) and MAEEPA-training ≤ 0.5 (MAE = mean absolute error) were retained to build consensus models. As a result, two consensus models based on the minimum operator and denoted as M19 and M22, as well as a consensus model based on the weighted average operator and denoted as M24, were selected as the best ones for each training set considered. According to the applicability domain (AD) analysis performed, model M19 (built on the EPA training set) has MAEtest-AD = 0.4044, MAEProTox-AD = 0.4067 and MAET3DB-AD = 0.2586 on the EPA test set, ProTox external set, and T3DB external set, respectively; whereas model M22 (built on the EPA-full set) and model M24 (built on the Zhu set) present MAEProTox-AD = 0.3992 and MAET3DB-AD = 0.2286, and MAEProTox-AD = 0.3773 and MAET3DB-AD = 0.2471 on the two external sets accounted for, respectively. These outcomes were compared and statistically validated with respect to 14 QSAR methods (e.g., admetSAR, ProTox-II) from the literature. As a result, model M22 presents the best overall performance. In addition, a retrospective study on 261 withdrawn drugs due to their toxic/side effects was performed, to assess the usefulness of prospectively using the QSAR models proposed in the labeling of chemicals. A comparison with regard to the methods from the literature was also made. As a result, model M22 has the best ability of labeling a compound as toxic according to the globally harmonized system of classification and labeling of chemicals. Therefore, it can be concluded that the models proposed, especially model M22, constitute prominent tools for studying AOT, at providing the best results among all the methods examined. A freely available software was also developed to be used in virtual screening tasks ( http://tomocomd.com/apps/ptoxra ).

Self-Assembly of Aluminum- and Gallium-Based meso-Metallaporphyrins.

The molecular meso-metallaporphyrin has been obtained from the reaction of AlMe3 with the bulky 4,5-(Ph2(HO)C)2-1,2,3-triazole (1). The presence of Al-Me groups coordinated to the triazole rings creates three different stereoisomers that were identified by single-crystal X-ray diffraction. Further studies revealed that, for steric reasons, only one of the two main stereoisomers is active in the polymerization of ε-caprolactone. When GaMe3 is used instead of AlMe3, a trimetallic species is formed instead of the meso-metallaporphyrin pointing to a metal-directed self-assembly. On the other hand, the reaction of the monolithium salt [{Li(THF)2}{κ2- N, N'-4,5-(Ph2(HO)C)-1,2,3-triazole}]2 (2; THF = tetrahydrofuran) with MCl3 (M = Al, Ga) yields meso-metallaporphyrin species with a lithium atom in the center of the metallacycle. While the gallium derivative is rather stable in solution, the aluminum analogue decomposes rapidly. In the solid state, continuous cationic columns running throughout the whole crystal are formed from alternating Li⊂[M]4 (M = Al, Ga) meso-metallaporphyrin and [Li(THF)4]+ cations. Density functional theory calculations determined that the weak Cl···H, H···H, N···H, and Cl···O interactions with a total interaction energy of -38.6 kcal·mol-1 are responsible for this unusual packing.

Is Hexachloro-cyclo-triphosphazene Aromatic? Evidence from Experimental Charge Density Analysis.

Experimental charge density studies of hexachloro-cyclo-triphosphazene (1) and the boat conformation of octachloro-cyclo-tetraphosphazene (2 a) were performed to unambiguously describe the origin of the electron delocalization in the P3 N3 ring in 1. The obtained results were compared to DFT studies in the solid state and the gas phase. Electron density analysis revealed a highly polarized nature of the P-N bonds and a modular structure of the P3 N3 and P4 N4 rings, which can be separated into independent Cl2 PN units with a perfect transferability between the compounds. Further analysis of the source function experimentally proves the presence of negative hyperconjugation involving both out-of-plane and in-plane nitrogen electrons as well as electrons of the chlorine atoms. Finally, these results discard the presence of pseudoaromatic delocalization in the nearly planar P3 N3 ring.

The Role of the DNA Backbone in Minor-Groove Ligand Binding.

Molecular recognition between ligands and nucleic acids plays a key role in therapeutic activity. Some molecules interact with DNA in a nonbonded manner through intercalation or through the DNA grooves. The recognition of minor-groove binders is attributed to a set of hydrogen-bonding interactions between the binders and the hydrogen-bond-acceptor groups on the groove floor and walls. It is commonly considered that interactions with the sugar groups of the DNA backbone are insignificant and do not contribute to the binding affinity or the specificity. However, our group has found that the deoxyribose rings have a central function in the recognition and the intercalation of metal complexes into DNA. Herein, we determined the specific interactions between the binder CGP 40215A and the minor-groove atoms, based on the local properties of electron density. We found that specific interactions between the deoxyribose moiety within the backbone of DNA and the binder are essential for molecular recognition, and they are responsible for one third of the interaction energy.

Synthesis of Cyclic and Cage Borosilicates Based on Boronic Acids and Acetoxysilylalkoxides. Experimental and Computational Studies of the Stability Difference of Six- and Eight-Membered Rings.

A series of borosilicates was synthesized, where the structure of the borosilicate core was easily modulated using two strategies: blocking of condensation sites and controlling the stoichiometry of the reaction. Thus, on the one hand, the condensation of phenylboronic or 3-hydroxyphenylboronic acid with diacetoxysilylalkoxide [(tBuO)(Ph3CO)Si(OAc)2] led to the formation of borosilicates (tBuO)(Ph3CO)Si{(µ-O)BPh}2(µ-O) (1), [{(tBuO)(Ph3CO)Si(µ-O)BPh(µ-O)}2] (2), and [{(tBuO)(Ph3CO)Si(µ-O)B(3-HOPh)(µ-O)}2] (3) with a cyclic inorganic B2SiO3 or B2Si2O4 core, respectively. On the other hand, the reaction of phenylboronic acid with triacetoxysilylalkoxide (Ph3CO)Si(OAc)3 in 3:2 ratio resulted in the formation of a cagelike structure [{(Ph3CO)Si(µ-O)2BPh(µ-O)}2] (4) with B4Si4O10 core, while the reaction of the boronic acid with silicon tetraacetate generated an unusual 1,3-bis(acetate)-1,3-diphenyldiboraxane PhB(µ-O)(µ-O,O'-OAc)2BPh (5). Additionally, compound 1 was used to evaluate the possibility to form N→B donor-acceptor bond between the boron atom in the borosilicates and a nitrogen donor. Thus, coordination of 1 with piperazine yielded a tricyclic [{(tBuO)(Ph3CO)Si(OBPh)2(µ-O)}2·C4H10N2] compound 6 with two borosilicate rings bridged by a piperazine molecule. Finally, the processes involved in the formation of the six- and eight-membered rings (B2SiO3 and B2Si2O4) in compounds 1 and 2 were explored using solution 1H NMR studies and density functional theory calculations. These molecules represent to the best of our knowledge first examples of cyclic molecular borosilicates containing SiO4 units.

Intercalation processes of copper complexes in DNA.

The family of anticancer complexes that include the transition metal copper known as Casiopeínas® shows promising results. Two of these complexes are currently in clinical trials. The interaction of these compounds with DNA has been observed experimentally and several hypotheses regarding the mechanism of action have been developed, and these include the generation of reactive oxygen species, phosphate hydrolysis and/or base-pair intercalation. To advance in the understanding on how these ligands interact with DNA, we present a molecular dynamics study of 21 Casiopeínas with a DNA dodecamer using 10 µs of simulation time for each compound. All the complexes were manually inserted into the minor groove as the starting point of the simulations. The binding energy of each complex and the observed representative type of interaction between the ligand and the DNA is reported. With this extended sampling time, we found that four of the compounds spontaneously flipped open a base pair and moved inside the resulting cavity and four compounds formed stacking interactions with the terminal base pairs. The complexes that formed the intercalation pocket led to more stable interactions.

The role of induced current density in Steroelectronic effects: Perlin effect.

The normal and reverse Perlin effect is usually explained by the redistribution of electron density produced by hyperconjugative mechanisms, which increases the electron population within axial or equatorial proton in normal or reverse effect, respectively. Here an alternative explanation for the Perlin effect is presented on the basis of the topology of the induced current density, which directly determines the nuclear magnetic shielding. Current densities around the C-H bond critical point and intra-atomic and interatomic contributions to the magnetic shielding explain the observed Perlin effect. The balance between intra-atomic and interatomic contributions determines the difference in the total atomic shielding. Normal Perlin effect is dominated by intra-atomic part, whereas reverse effect is dominated by interatomic contribution.

The rotational barrier of ethane and some of its hexasubstituted derivatives in terms of the forces acting on the electron distribution.

A novel and alternative explanation of the rotational barrier of ethane and several hexasubstituted derivatives, CX3CX3 (X = H, F, CH3, Cl, Br), is suggested based on the evaluation of the properties of the electron distribution. The forces exerted on the electron density of the topological atoms making up a molecule, the Ehrenfest forces, are analyzed and, with the help of the virial theorem, they are used to explain the experimental rotational barriers. According to this approach, the barrier is mainly a consequence of the decrease of the always attractive Ehrenfest forces (EFs) linking the two C atoms. In addition, the behavior of the EFs is related to a decrease of stability of the central C atoms, which is not compensated by the stabilization of the substituents. Also, during rotation from the staggered to the equilibrium conformation, the electron density at the C-C bond critical point and the electron delocalization between C atoms decrease and are accompanied by an increase of electron delocalization between the substituents. According to the analysis of the EF field lines and to the behavior of the integrated forces, the rotational barrier cannot be explained as a result of any repulsive forces acting on the electron density, although a possible interpretation of the quantum force that balances the EF in stationary states as a measure of traditional Pauli repulsions is also examined.

Ultrafast excited state hydrogen atom transfer in salicylideneaniline driven by changes in aromaticity.

We investigated two important unresolved issues on excited state intramolecular proton transfer (ESIPT) reactions, i.e., their driving force and the charge state of the transferred species by means of quantum chemical topology. We related changes in the aromaticity of a molecule after electron excitation to reaction dynamics in an excited state. Additionally, we found that the conveyed particle has a charge intermediate between that of a bare proton and a neutral hydrogen atom. We anticipate that the analysis presented in this communication will yield valuable insights into ESIPT and other similar photochemical reactions.

Properties of atoms in electronically excited molecules within the formalism of TDDFT.

The topological analysis of the electron density for electronic excited states under the formalism of the quantum theory of atoms in molecules using time-dependent density functional theory (TDDFT) is presented. Relaxed electron densities for electronic excited states are computed by solving a Z-vector equation which is obtained by means of the Sternheimer interchange method. This is in contrast to previous work in which the electron density for excited states is obtained using DFT instead of TDDFT, that is, through the imposition of molecular occupancies in accordance with the electron configuration of the excited state under consideration. Once the electron density of the excited state is computed, its topological characterization and the properties of the atoms in molecules are obtained in the same manner that for the ground state. The analysis of the low-lying π→π* singlet and triplet vertical excitations of CO and C6H6 are used as representative examples of the application of this methodology. Altogether, it is shown how this procedure provides insights on the changes of the electron density following photoexcitation and it is our hope that it will be useful in the study of different photophysical and photochemical processes.