Discovering trends in the Lewis acidity of beryllium and magnesium hydrides and fluorides with increasing clusters size.

We have reported in the last years the strong effect that Be- and Mg-containing Lewis acids have on the intrinsic properties of typical bases, which become acids upon complexation. In an effort to investigate these changes when the Be and Mg derivatives form clusters of increasing size, we have examined the behavior of the (MX2)n (M = Be, Mg; X = H, F; n = 1, 2, 3) clusters when they interact with ammonia, methanimine, hydrogen cyanide and pyridine, and with their corresponding deprotonated forms. The complexes obtained at the M06-2X/aug-cc-pVTZ level were analyzed using the MBIE energy decomposition formalism, in parallel with QTAIM, ELF, NCIPLOT and AdNDP analyses of their electron density. For n = 1 the interaction enthalpy for the different families of monomers, Be (Mg) hydrides and Be (Mg) fluorides, follows the same trend as the intrinsic basicity of the base that interacts with them. This interaction is greatly reinforced after the deprotonation of the base, resulting in a significant enhancement of the intrinsic acidity of the corresponding MX2-Base complex. For (MX2)2 clusters a further reinforcement of the interaction with the base is observed, this reinforcement being again larger for the deprotonated complexes. However, the concomitant increase of their intrinsic acidity is one order of magnitude larger for hydrides than for fluorides. Unexpectedly, the cyclic conformers (MX2)3, which are more unstable than the linear ones, become the global minima after association with the base and the same is true for the deprotonated complex. Accordingly, a further increase of the intrinsic acidity of the (MX2)3-Base complexes with respect to the (MX2)2-Base ones is observed. This effect is maximum for (MgF2)3 clusters, to the point that the (MgF2)3-Base complexes become more acidic than nitric acid, the extreme case being the cluster (MgF2)3-NCH, whose acidity is higher than that of perchloric acid.

Hydrogen Bonds Are Never of an "Anti-electrostatic" Nature: A Brief Tour of a Misleading Nomenclature.

A large amount of scientific works have contributed through the years to rigorously reflect the different forces leading to the formation of hydrogen bonds, the electrostatic and polarization ones being the most important among them. However, we have witnessed lately with the emergence of a new terminology, anti-electrostatic hydrogen bonds (AEHBs), that seems to contradict this reality. This nomenclature is used in the literature to describe hydrogen bonds between equally charged systems to justify the existence of these species, despite numerous proofs showing that AEHBs are, as any other hydrogen bond between neutral species, mostly due to electrostatic forces. In this Viewpoint, we summarize the state of the art regarding this issue, try to explain why this terminology is very misleading, and strongly recommend avoiding its use based on the hydrogen bond physical grounds.

A Holistic View of the Interactions between Electron-Deficient Systems: Clustering of Beryllium and Magnesium Hydrides and Halides.

In the search for common bonding patterns in pure and mixed clusters of beryllium and magnesium derivatives, the most stable dimers and trimers involving BeX2 and MgX2 (X = H, F, Cl) have been studied in the gas phase using B3LYP and M06-2X DFT methods and the G4 ab initio composite procedure. To obtain some insight into their structure, stability, and bonding characteristics, we have used two different energy decomposition formalisms, namely MBIE and LMO-EDA, in parallel with the analysis of the electron density with the help of QTAIM, ELF, NCIPLOT, and AdNDP approaches. Some interesting differences are already observed in the dimers, where the stability sequence observed for the hydrides differs entirely from that of the fluorides and chlorides. Trimers also show some peculiarities associated with the presence of compact trigonal cyclic structures that compete in stability with the more conventional hexagonal and linear forms. As observed for dimers, the stability of the trimers changes significantly from hydrides to fluorides or chlorides. Although some of these clusters were previously explored in the literature, the novelty of this work is to provide a holistic approach to the entire series of compounds by using chemical bonding tools, allowing us to understand the stability trends in detail and providing insights for a significant number of new, unexplored structures.

Metastable Charged Dimers in Organometallic Species: A Look into Hydrogen Bonding between Metallocene Derivatives.

Multiply charged complexes bound by noncovalent interactions have been previously described in the literature, although they were mostly focused on organic and main group inorganic systems. In this work, we show that similar complexes can also be found for organometallic systems containing transition metals and deepen in the reasons behind the existence of these species. We have studied the structures, binding energies, and dissociation profiles in the gas phase of a series of charged hydrogen-bonded dimers of metallocene (Ru, Co, Rh, and Mn) derivatives isoelectronic with the ferrocene dimer. Our results indicate that the carboxylic acid-containing dimers are more strongly bonded and present larger barriers to dissociation than the amide ones and that the cationic complexes tend to be more stable than the anionic ones. Additionally, we describe for the first time the symmetric proton transfer that can occur while in the metastable phase. Finally, we use a density-based energy decomposition analysis to shine light on the nature of the interaction between the dimers.

Dispersion, Rehybridization, and Pentacoordination: Keys to Understand Clustering of Boron and Aluminum Hydrides and Halides.

The structure, stability, and bonding characteristics of dimers and trimers involving BX3 and AlX3 (X = H, F, Cl) in the gas phase, many of them explored for the first time, were investigated using different DFT (B3LYP, B3LYP/D3BJ, and M06-2X) and ab initio (MP2 and G4) methods together with different energy decomposition formalisms, namely, many-body interaction-energy and localized molecular orbital energy decomposition analysis. The electron density of the clusters investigated was analyzed with QTAIM, electron localization function, NCIPLOT, and adaptive natural density partitioning approaches. Our results for triel hydride dimers and Al2X6 (X = F, Cl) clusters are in good agreement with previous studies in the literature, but in contrast with the general accepted idea that B2F6 and B2Cl6 do not exist, we have found that they are predicted to be weakly bound systems if dispersion interactions are conveniently accounted for in the theoretical schemes used. Dispersion interactions are also dominant in both homo- and heterotrimers involving boron halide monomers. Surprisingly, B3F9 and B3Cl9 C3v cyclic trimers, in spite of exhibiting rather strong B-X (X = F, Cl) interactions, were found to be unstable with respect to the isolated monomers due to the high energetic cost of the rehybridization of the B atom, which is larger than the two- and three-body stabilization contributions when the cyclic is formed. Another important feature is the enhanced stability of both homo- and heterotrimers in which Al is the central atom because Al is systematically pentacoordinated, whereas this is not the case when the central atom is B, which is only tri- or tetra-coordinated.

Thiol-yne chemistry of diferrocenylacetylene: from synthesis and electrochemistry to theoretical studies.

The thiol-yne coupling chemistry of diferrocenylacetylene (FcCCFc) 1, bearing two electron rich and redox-active ferrocenyl units (Fc = Fe(η5-C5H4)(η5-C5H5)) and an internal triple bond, has been investigated for the first time. In order to determine whether steric limitations might affect hydrothiolation, a model reaction using a functionalized monothiol was tested, namely 2-mercaptoethanol I. The thiol-diferrocenylacetylene reactions were initiated either thermally (in toluene with AIBN) or by UV light irradiation (in THF and in the presence of DMPA as the photoinitiator). The outcomes of these thiol-yne reactions showed a strong dependence on the initiation method used, with the thermally initiated one being the most efficient. These thiol-diferrocenylacetylene reactions mainly afforded the (Z)-stereoisomer of the newly obtained vinyl thioether sulfide FcCHC(Fc)S-(CH2)2OH (2), unlike the more common (E)-vinyl sulfides found in other additions to alkynes. The hydrothiolation of the internal -CC- bond in 1 was successfully extended to dithiol 2,2'-(ethylenedioxy)diethanethiol II, leading to the formation of the (ZZ)-isomer, with four ferrocenyl units, as the major product. According to the electrochemical studies, the new asymmetrical ferrocenyl-vinyl sulfides show iron-iron electronic and electrostatic interactions. Theoretical results for the (Z)-stereoisomer (2) suggest that adiabatic oxidation would lead to the loss of almost one electron on the ferrocenyl subunit closer to the thioether chain. Furthermore, the thiol-yne chemistry of the internal -CC- bond in diferrocenylacetylene has been compared to the external triple bond in ethynylferrocene, the theoretical results of which helped us to rationalize the very different reactivities observed in both metallocenes.

Open questions on toxic heavy metals Cd, Hg and Pb binding small components of DNA and nucleobases. Are there any predictable trends?

In this perspective article, we provide a bibliographic compilation of experimental and theoretical work on Cd, Hg, and Pb, and analyze in detail the bonding of M2+ and CH3M+ (M = Zn, Cd, Hg, Pb) with urea and thiourea as suitable models for larger biochemical bases. Through the use of DFT calculations, we have found that although in principle binding energies decrease according to ionic size (Zn2+ > Cd2+ > Pb2+), Hg2+ largely breaks the trend. Through the use of EDA (Energy Decomposition Analysis) it is possible to explain this behavior, which is essentially due to the strong contribution of polarization to the binding. This conclusion is ratified by the NEDA (Natural Energy Decomposition Analysis) formalism, showing that the charge transfer term is very large in all cases, but particularly in the case of the mercury-thiourea system. The general trends observed for the interactions with CH3M+ monocations show however CH3Hg+ binding energies systematically smaller than the CH3Zn+ ones, likely because the relativistic contraction of the Hg orbitals is very much attenuated by the attachment to the methyl group. Finally, we have investigated the gas-phase reactivity between EtHg+ and uracil to compare it with that exhibited by CH3Hg+ and n-ButHg+ previously described in the literature. This comparison gathers new information that highlights the importance of the length of the alkyl chain attached to the metal on the mechanisms of these reactions. For methyl mercury, only the alkyl transfer process is allowed; for butyl mercury, protonation is clearly favored, and for ethyl mercury, both paths are competitive experimentally.

Disrupting bonding in azoles through beryllium bonds: Unexpected coordination patterns and acidity enhancement.

Although triazoles and tetrazole are amphoteric and may behave as weak acids, the latter property can be hugely enhanced by beryllium bonds. To explain this phenomenon, the structure and bonding characteristics of the complexes between triazoles and tetrazoles with one and two molecules of BeF2 have been investigated through the use of high-level G4 ab initio calculations. The formation of the complexes between the N basic sites of the azoles and the Be center of the BeF2 molecule and the (BeF2)2 dimer leads to a significant bonding perturbation of both interacting subunits. The main consequence of these electron density rearrangements is the above-mentioned increase in the intrinsic acidity of the azole subunit, evolving from a typical nitrogen base to a very strong nitrogenous acid. This effect is particularly dramatic when the interaction involves the (BeF2)2 dimer, that is, a Lewis acid much stronger than the monomer. Although the azoles investigated have neighboring N-basic sites, their interaction with the (BeF2)2 dimer yields a monodentate complex. However, the deprotonated species becomes extra-stabilized because a second N-Be bond is formed, leading to a new five-membered ring, with the result that the azole-(BeF2)2 complexes investigated become stronger nitrogenous acids than oxyacids such as perchloric acid.

Stand up for Electrostatics: The Disiloxane Case.

The basicity of the simplest silicone, disiloxane (H3 Si-O-SiH3 ), is strongly affected by the Si-O-Si angle (α). We use high-level ab initio MP2/aug'-cc-pVTZ calculations and the molecular electrostatic potential (MEP) to analyze the relationship between the increase in basicity and the reduction of α. Our results clearly point out that this increase can be explained through the MEP, as the interactions between oxygen from disiloxane and the acceptors are mostly electrostatic. Furthermore, the effect of α on the tetrel bond between disiloxane and several Lewis bases can again be rationalized using the MEP. Finally, we explore the cooperativity throughout α for ternary complexes where disiloxane simultaneously interacts with a Lewis acid and a Lewis base. Both non-covalent interactions remain cooperative for all α values, although the largest cooperativity effects are not always those maximizing the binding energy in the binary complexes. Overall, the MEP remains a powerful predictor for noncovalent interactions.

Large Stabilization Effects by Intramolecular Beryllium Bonds in Ortho-Benzene Derivatives.

Intramolecular interactions are shown to be key for favoring a given structure in systems with a variety of conformers. In ortho-substituted benzene derivatives including a beryllium moiety, beryllium bonds provide very large stabilizations with respect to non-bound conformers and enthalpy differences above one hundred kJ·mol-1 are found in the most favorable cases, especially if the newly formed rings are five or six-membered heterocycles. These values are in general significantly larger than hydrogen bonds in 1,2-dihidroxybenzene. Conformers stabilized by a beryllium bond exhibit the typical features of this non-covalent interaction, such as the presence of a bond critical point according to the topology of the electron density, positive Laplacian values, significant geometrical distortions and strong interaction energies between the donor and acceptor quantified by using the Natural Bond Orbital approach. An isodesmic reaction scheme is used as a tool to measure the strength of the beryllium bond in these systems in terms of isodesmic energies (analogous to binding energies), interaction energies and deformation energies. This approach shows that a huge amount of energy is spent on deforming the donor-acceptor pairs to form the new rings.

Spontaneous bond dissociation cascades induced by Ben clusters (n = 2,4).

High-level single and multireference ab initio calculations show that the Be4 cluster behaves as a very efficient Lewis acid when interacting with conventional Lewis bases such as ammonia, water or hydrogen fluoride, to the point that the corresponding acid-base interaction triggers a sequential dissociation of all the bonds of the Lewis base. Notably, this behavior is already found for the simplest beryllium cluster, the Be2 dimer. However, whereas for Be2 the first dissociation process involves a low activation barrier which is above the reactants, for Be4 all the bond dissociation processes involve barriers below the entrance channel leading to a cascade of successive exothermic processes, which end up spontaneously in a global minimum in which the bonding patterns of both the base and the Lewis acid are completely destroyed. Indeed, the global minimum, in all cases, is stabilized by three-center Be-H-Be bonds and covalent interactions between the Be atoms and the basic center of the base, which replace the initial metallic bond stabilizing the Be4 cluster. As a consequence, in the global minimum the basic atoms (N, O and F) behave as hyper-coordinated centers. Also importantly, the Be4 cluster and its complexes present RHF-UHF instabilities (not reported before for Be4), which require the use of multireference methods to correctly describe them.

Significant bonding rearrangements triggered by Mg4 clusters.

The structure, stability, and bonding of the complexes formed by the interaction of Mg4 clusters and first row Lewis bases, namely, ammonia, water, and hydrogen fluoride, have been investigated through the use of high-level G4 single-reference and CASPT2 multireference formalisms. The adducts formed reflect the high electrophilicity of the Mg4 cluster through electron density holes in the neighborhood of each metallic center. After the adduct formation, the metallic bonding of the Mg4 moiety is not significantly altered so that the hydrogen shifts from the Lewis base toward the Mg atoms lead to new local minima with enhanced stability. For the particular case of ammonia and water, the global minima obtained when all the hydrogens of the Lewis base are shifted to the Mg4 moiety have in common a very stable scaffold with a N or an O center covalently tetracoordinated to the four Mg atoms, so the initial bonding arrangements of both reactants have completely disappeared. The reactivity features exhibited by these Mg4 clusters suggest that nanostructures of this metal might have an interesting catalytic behavior.

The Importance of Strain (Preorganization) in Beryllium Bonds.

In order to explore the angular strain role on the ability of Be to form strong beryllium bonds, a theoretical study of the complexes of four beryllium derivatives of orthocloso-carboranes with eight molecules (CO, N2, NCH, CNH, OH2, SH2, NH3, and PH3) acting as Lewis bases has been carried out at the G4 computational level. The results for these complexes, which contain besides Be other electron-deficient elements, such as B, have been compared with the analogous ones formed by three beryllium salts (BeCl2, CO3Be and SO4Be) with the same set of Lewis bases. The results show the presence of large and positive values of the electrostatic potential associated to the beryllium atoms in the isolated four beryllium derivatives of ortho-carboranes, evidencing an intrinsically strong acidic nature. In addition, the LUMO orbital in these systems is also associated to the beryllium atom. These features led to short intermolecular distances and large dissociation energies in the complexes of the beryllium derivatives of ortho-carboranes with the Lewis bases. Notably, as a consequence of the special framework provided by the ortho-carboranes, some of these dissociation energies are larger than the corresponding beryllium bonds in the already strongly bound SO4Be complexes, in particular for N2 and CO bases. The localized molecular orbital energy decomposition analysis (LMOEDA) shows that among the attractive terms associated with the dissociation energy, the electrostatic term is the most important one, except for the complexes with the two previously mentioned weakest bases (N2 and CO), where the polarization term dominates. Hence, these results contribute to further confirm the importance of bending on the beryllium environment leading to strong interactions through the formation of beryllium bonds.

Steric clash in real space: biphenyl revisited.

A textbook case of twisted structure due to hydrogen-hydrogen steric clash, the biphenyl molecule, has been studied in real space from a new perspective. Long-term discrepancies regarding the origin of the steric repulsion are now reconciled under the NCI (Non Covalent Interaction) method, which reflects in 3D the balance between attractive and repulsive interactions taking place in the region between the phenyl rings. The NCI method confirms that the steric repulsion does not merely come from the H-H interaction itself, but from the many-atom interactions arising from the Cortho-H region, therefore providing rigorous physical grounds for the steric clash. This method allows a continuous scan of all the subtle changes on the electron density on going from the planar to the perpendicular biphenyl structure. The NCI results agree with other topological approaches (IQA, ELF) and are in line with previous findings in the literature regarding controversial H-H interactions in steric clash situations: H-H interactions are attractive, but repulsion appears between (Cortho-H)(Cortho-H), raising the intraatomic energy of the ortho H. ELF is also used to support these conclusions. Indeed, deformations are observed in compressed basins that allow to visualize the intraatomic effect of steric repulsion. These results can be easily extrapolated to systems with similar topological features in which steric clash is claimed to be the reason for instability.

Looking for the Azeotrope: A Computational Study of (Ethanol)6-Water, (Methanol)6-Water, (Ethanol)7, and (Methanol)7 Heptamers.

Considering that a molecular-level understanding of the azeotropic ethanol-water system can contribute to the search of new methodologies and/or modifications of industrial separation methods, this study tries to provide some clues to understand why azeotropes should be expected for ethanol, but not for methanol. Our exploration of the potential energy surface of (ethanol)6-water heteroheptamers, carried out at the B3LYP-D3/6-311++G(d,p) level, shows these heteroclusters to exhibit a cyclic structure where the cooperativity effects between the OH···O HBs is a fundamental ingredient. An analysis of this cooperativity clearly indicates that ethanol-water systems will exhibit a similarly high stability as the heterocluster size approaches the azeotrope. However, a similar behavior should not be expected for the methanol-containing analogues. A comparison between (ethanol)7, (ethanol)6-water, (methanol)7, and (methanol)6-water shows the ethanol-containing systems to be significantly more stable than the methanol-containing analogues. This result is probably due to the fact that the OH···O HBs are weaker than those found between ethanol molecules. However, our atoms in molecule (AIM) and noncovalent interaction (NCI) analyses unambiguously show that important contributors to the enhanced stability of the ethanol-containing clusters are the secondary van der Waals interactions between ethyl groups, which are not observed between methyl groups. Hence, while the formation of stable azeotropes is expected for the case of ethanol, for the methanol-containing analogues, the relative stability of the clusters is significantly smaller, and its formation is accompanied by an increase of the free energy.

Mutual Influence of Pnicogen Bonds and Beryllium Bonds: Energies and Structures in the Spotlight.

Pnicogen bonds, which are weak noncovalent interactions (NCIs), can be significantly modified by the presence of beryllium bonds, one of the strongest NCIs known. We demonstrate the importance of this influence by studying ternary complexes in which both NCIs are present, that is, the ternary complexes formed by a nitrogen base (NH3, NHCH2, and NCH), a phosphine (fluorophosphane, PH2F) and a beryllium derivative (BeH2, BeF2, BeCl2, BeCO3, and BeSO4). Energies, structures, and nature of the chemical bonding in these complexes are studied by means of ab initio computational methods. The pnicogen bond between the nitrogen base and the phosphine and the beryllium bond between the fluorine atom of fluorophosphane and the beryllium derivative show large cooperativity effects both on energies and geometries, with dissociation energies up to 296 kJ mol-1 and cooperativity up to 104 kJ mol-1 in the most strongly bound complex, CH2HN:PH2F:BeSO4. In the complexes between the strongest nitrogen bases and the strongest beryllium donors, phosphorus-shared and phosphorus-transfer bonds are found.

From Very Strong to Inexistent Be-Be Bonds in the Interactions of Be2 with π-Systems.

Isolated Be2 is a typical example of a weakly bound system, but interaction with other systems may give rise to surprising bonding features. The interactions between Be2 and a set of selected neutral Cn Hn (n=2-8) π-systems have been analyzed through the use of G4 and G4MP2 ab initio methods, along with multireference CASPT2//CASPT2 calculations. Our results systematically show that the Cn Hn -Be2 -Cn Hn clusters formed are always very stable. However, the nature of this interaction is completely different when the π-system involved is a closed shell species (n=2, 4, 6, 8), or a radical (n=3, 5, 7). In the first case, the interaction does not occur with the π-system as a whole, but with specific C centers yielding rather polar but strong C-Be bonds. Nonetheless, although the Be-Be distances in these complexes are similar to the ones in compounds with ultra-strong Be-Be bonds, a close examination of their electron density distribution reveals that no Be-Be bonds exist. The situation is totally different when the interaction involves two π-radicals, Cn Hn -Be2 -Cn Hn (n=3, 5, 7). In these cases, a strong Be-Be bond is formed. Indeed, even though Be is electron deficient, the Be2 moiety behaves as an efficient electron donor towards the two π-radicals, so that the different Cn Hn -Be2 -Cn Hn (n=3, 5, 7) clusters are the result of the interaction between Be2 2+ and two L- anions. The characteristics of these two scenarios do not change when dealing with bicyclic π-compounds, such as naphthalene and pentalene, because the interaction with the Be2 moiety is localized on one of the unsaturated cycles, the other being almost a spectator.

Microscopical Techniques to Analyze the Hepatic and Peritoneal Changes Caused by Fasciola hepatica Infection.

The helminth parasite Fasciola hepatica modulates the host immune response at early stages of infection (Rodríguez et al., PLoS Negl Trop Dis 9:e0004234, 2015; Vukman et al., J Immunol 190:2873-2879, 2013). Nevertheless, little is known about the cell composition of the peritoneal fluid at these early stages of infection.In this chapter, we describe a method to perform peritoneal lavages and to recover peritoneal fluid from sheep experimentally infected and noninfected with F. hepatica at early stages of infection. In addition, with the aim to characterize the peritoneal fluid immune cell phenotype, we describe a procedure to obtain the total leukocyte count, the differential leukocyte count and the preparation and storage of peritoneal fluid smears, together with the application of an immunocytochemical technique and an automatic method to count the immunoreactive cells. Finally, the present protocol describes the evaluation of the gross and the histopathological lesions together with the immunohistochemical analysis of the hepatic tissue.

Are Anions of Cyclobutane Beryllium Derivatives Stabilized through Four-Center One-Electron Bonds?

High-level G4 ab initio calculations allowed us to show that C4H4(BeX)4 (X = H, Cl) derivatives behave as rather efficient electron capturers due to their ability to trap the extra electron through the formation of a four-membered beryllium ring. This finding is in agreement with previous work showing the ability of highly electron-deficient atoms, such as beryllium, to lead to multicenter one-electron bonds. In our particular case, the formation of the four-center bond is characterized, in very good harmony, by different topological methods such as quantum theory of atoms in molecules (QTAIM), the electron localization function (ELF), and the noncovalent interactions (NCI) approach and is accompanied by large electron affinity values, around 300 kJ·mol-1, in the gas phase. Preliminary results may anticipate that the ability of groups of beryllium atoms to trap electrons decays on going to bigger systems.

Relativistic Effects on NMR Parameters of Halogen-Bonded Complexes.

Relativistic effects are found to be important for the estimation of NMR parameters in halogen-bonded complexes, mainly when they involve the heavier elements, iodine and astatine. A detailed study of 60 binary complexes formed between dihalogen molecules (XY with X, Y = F, Cl, Br, I and At) and four Lewis bases (NH3, H2O, PH3 and SH2) was carried out at the MP2/aug-cc-pVTZ/aug-cc-pVTZ-PP computational level to show the extent of these effects. The NMR parameters (shielding and nuclear quadrupolar coupling constants) were computed using the relativistic Hamiltonian ZORA and compared to the values obtained with a non-relativistic Hamiltonian. The results show a mixture of the importance of the relativistic corrections as both the size of the halogen atom and the proximity of this atom to the basic site of the Lewis base increase.