Noncovalent Interactions in Palladium(II)-Catalyzed Meta-Selective C-H Functionalization: Mechanistic Insights and Origins of Regioselectivity.

The use of noncovalent interactions to control the regioselectivity of transition metal-catalyzed C-H functionalization of arenes has received significant attention in recent years. Herein, we present a mechanistic study based on Density Functional Theory (DFT) of palladium(II)-catalyzed meta-selective C-H olefination employing a noncovalent directing template. We analyze the key steps of the mechanism and discuss the origins of reaction selectivity. The role of the directing template was elucidated, demonstrating its essential function in lowering reaction barriers and controlling selectivity. Our results reveal a competition in activation between ortho- and meta-C-H bonds. Contrary to the previous proposal in the literature, hydrogen bonds between the N-H bonds of the urea moiety and the carbonyl oxygen of the substrate predominantly favor ortho-selectivity over meta-selectivity. DFT results, alongside Quantum Theory of Atoms in Molecules (QTAIM) and Non-Covalent Interaction Index analysis, suggest that secondary interactions between the R group linked to the urea moiety and the catalyst exert a more pronounced influence compared to the aforementioned hydrogen bonds, directing the selectivity towards the meta C-H bond.

Experimental Elucidation of a Cubane Water Cluster in the Hydrophobic Cavity of UiO-66.

Nanoscale water plays a pivotal role in determining the properties and functionalities of materials, and the precise control of its quantity and atomic-scale ordered structure is a focal point in nanotechnology and chemistry. Several studies have theoretically discussed the nano-ordered ice within one- or two-dimensional space and without confinement through hydrogen bonds. In particular, the water cluster has been predicted to play a significant role in biomolecules or functional nanomaterials; however, there has been little experimental evidence for their presence in hydrophobic cavities. In this study, the cubane water octamer - the most stable isomer among small water clusters - was detected within the hydrophobic cavities of UiO-66 metal-organic frameworks, revealing the presence of the smallest ice in their hydrophobic cavity, in the absence of hydrogen bonding. This observation contrasts earlier examples of water clusters confined within nanocavities through hydrogen bonds and provides experimental evidence for water-cluster capturing within hydrophobic cavities. Consequently, our renewed understanding of hydrophilicity and hydrophobicity warrants a design re-evaluation of materials for chemical applications, including fuel cells, water harvesting, catalysts, and batteries.

Analysis of the Behavior of Deep Eutectic Solvents upon Addition of Water: Its Effects over a Catalytic Reaction.

This study presents the potential role of deep eutectic solvents (DESs) in a lipase-catalyzed hydrolysis reaction as a co-solvent in an aqueous solution given by a phosphate buffer. Ammonium salts, such as choline chloride, were paired with hydrogen bond donors, such as urea, 1,2,3-propanetriol, and 1,2 propanediol. The hydrolysis of p-nitrophenyl laureate was carried out with the lipase Candida antarctica Lipase B (CALB) as a reaction model to evaluate the solvent effect and tested in different DES/buffer phosphate mixtures at different % w/w. The results showed that two mixtures of different DES at 25 % w/w were the most promising solvents, as this percentage enhanced the activities of CALB, as evidenced by its higher catalytic efficiency (kcatKM). The solvent analysis shows that the enzymatic reaction requires a reaction media rich in water molecules to enable hydrogen-bond formation from the reaction media toward the enzymatic reaction, suggesting a better interaction between the substrate and the enzyme-active site. This interaction could be attributed to high degrees of freedom influencing the enzyme conformation given by the reaction media, suggesting that CALB acquires a more restrictive structure in the presence of DES or the stabilized network given by the hydrogen bond from water molecules in the mixture improves the enzymatic activity, conferring conformational stability by solvent effects. This study offers a promising approach for applications and further perspectives on genuinely green industrial solvents.

Probing Self-Assembly of Ammeline in Chloroform and Aqueous Media: Interplay Between Hydrogen Bonding Diversity and Dimerization.

Ammeline (AM) is a molecule with a very low reputation in the field of supramolecular community, but with a recently proven potential both experimentally and theoretically. In this work, dispersion-corrected density functional theory (DFT-D) computations and molecular dynamics (MD) simulations were employed to understand the aggregation mechanism of AM in chloroform and water media. Our DFT-D and MD analyzes show that the most important interactions are those formed by the amine groups (-NH2) with both the pyridine-type nitrogen atoms and the carbonyl groups (C=O). In the more polar solvent, the interactions between water molecules and the C=O group prevent the AM from forming more interactions with itself. Nevertheless, four types of dimers involving N-H∙∙∙O interactions were found to exist in water solutions. The overlooked tetrel bond between endocyclic N and C atoms can also stabilize dimers in solution. Moreover, while most AM dimers are enthalpy-driven, our results indicate that the unique DD-AA dimer (D=donor, A=acceptor) that originates cyclic rosettes is entropy-driven.

trans-Di-chlorido-bis-(secnidazole-κN 3)copper(II).

The use of acetic acid (HOAc) in a reaction between CuCl2·2H2O and secnid-azole, an active pharmaceutical ingredient useful in the treatment against a variety of anaerobic Gram-positive and Gram-negative bacteria, affords the title complex, [CuCl2(C7H11N3O3)2]. This compound was previously synthesized using ethanol as solvent, although its crystal structure was not reported [Betanzos-Lara et al. (2013 ▸). Inorg. Chim. Acta, 397, 94-100]. In the mol-ecular complex, the Cu2+ cation is situated at an inversion centre and displays a square-planar coordination environment. There is a hydrogen-bonded framework based on inter-molecular O-H⋯Cl inter-actions, characterized by H⋯Cl separations of 2.28 (4) Šand O-H⋯Cl angles of 175 (3)°. The resulting supra-molecular network is based on R2 2 (18) ring motifs, forming chains in the [010] direction.

Chlorido-(2-{(2-hy-droxy-eth-yl)[tris-(hy-droxy-meth-yl)meth-yl]amino}-ethano-lato-κ5 N,O,O',O'',O''')copper(II).

The title complex, [Cu(C8H18NO5)Cl] or [Cu(H4bis-tris-)Cl], was obtained starting from the previously reported [Cu(H5bis-tris-)Cl]Cl compound. The deprotonation of the amino-polyol ligand H5bis-tris {[bis-(2-hy-droxy-eth-yl)amino]-tris-(hy-droxy-meth-yl)methane, C8H19NO5} promotes the formation of a very strong O-H⋯O inter-molecular hydrogen bond, characterized by an H⋯O separation of 1.553 (19) Šand an O-H⋯O angle of 178 (4)°. The remaining hy-droxy groups are also engaged in hydrogen bonds, forming R 2 2(8), R 4 4(16), R 4 4(20) and R 4 4(22) ring motifs, which stabilize the triperiodic supra-molecular network.

Intramolecular hydrogen bonds interactions in the isomers of the bilirubin molecule: DFT and QTAIM analysis.

CONTEXT: Bilirubin is an important molecule, used as a marker of some liver diseases, and it can also be toxic and cause jaundice, especially in newborns. The main treatment for neonatal jaundice is phototherapy with blue light, which is still widely studied because the photophysical processes involved are not fully understood. METHODS: Calculations based on the density functional theory (DFT) at M062X/6-31G(d,p) level were performed in order to evaluate the structural, electronic, and topological properties of bilirubin isomers. It was found that the ZZ conformation can form a greater number of hydrogen bonds, which gives the isomer greater energy stabilization compared to the other ZE, EZ, and EE isomers, and that the EE isomer is the conformer with the lowest energy of stabilization. The hydrogen bonds were characterized by the quantum theory of atoms in molecules (QTAIM) and for the ZZ isomer four hydrogen bonds (HBs) were found classified as intermediate, ∇2ρ(r) > 0, H(r) > 0. The ZE, EZ, and EE isomers show weak HBs, ∇2ρ(r) > 0, H(r) > 0.

2-[3-(1H-Benzimidazol-2-yl)prop-yl]-1H-benzimidazol-3-ium 3,4,5-tri-hydroxy-benzoate-1,3-bis-(1H-benzimidazol-2-yl)propane-ethyl acetate (2/1/2.94): co-crystallization between a salt, a neutral mol-ecule and a solvent.

The chemical formula of the title compound, 2C17H17N4 +·2C7H5O5 -·C17H16N4·2.94C4H8O2, was established by X-ray diffraction of a single-crystal obtained by reacting 1,3-bis-(benzimidazol-2-yl)propane (L) and gallic acid (HGal) in ethyl acetate. The mol-ecular structure can be described as a salt (HL)+(Gal)- co-crystallized with a mol-ecule L, with a stoichiometric relation of 2:1. Moreover, large voids in the crystal are filled with ethyl acetate, the amount of which was estimated by using a solvent mask during structure refinement, affording the chemical formula (HL +·Gal-)2·L·(C4H8O2)2.94. The arrangement of components in the crystal is driven by O-H⋯O, N-H⋯O and O-H⋯N hydrogen bonds rather than by π-π or C-H⋯π inter-actions. In the crystal, mol-ecules and ions shape the boundary of cylindrical tunnels parallel to [100] via R (rings) and D (discrete) supra-molecular motifs. These voids, which account for about 28% of the unit-cell volume, contain disordered solvent mol-ecules.

Boron-π interactions in two 3-(dihydroxyboryl)anilinium salts analyzed by crystallographic studies and supported by the noncovalent interactions (NCI) index theoretical approach.

In the title compounds, 3-(dihydroxyboryl)anilinium bisulfate monohydrate, C6H9BNO2+·HSO4-·H2O (I), and 3-(dihydroxyboryl)anilinium methyl sulfate, C6H9BNO2+·CH3SO4- (II), the almost planar boronic acid molecules are linked by pairs of O-H...O hydrogen bonds, forming centrosymmetric motifs that can be described by the graph-set R22(8) motif. In both crystals, the B(OH)2 group acquires a syn-anti conformation (with respect to the H atoms). The presence of the hydrogen-bonding functional groups B(OH)2, NH3+, HSO4-, CH3SO4- and H2O generates three-dimensional hydrogen-bonded networks, in which the bisulfate (HSO4-) and methyl sulfate (CH3SO4-) counter-ions act as the central building blocks within the crystal structures. Furthermore, in both structures, the packing is stabilized by weak boron-π interactions, as shown by noncovalent interactions (NCI) index calculations.

Exploring the Non-Covalent Bonding in Water Clusters.

QTAIM and source function analysis were used to explore the non-covalent bonding in twelve different water clusters (H2O)n obtained by considering n = 2-7 and various geometrical arrangements. A total of seventy-seven O-H⋯O hydrogen bonds (HBs) were identified in the systems under consideration, and the examination of the electron density at the bond critical point (BCP) of these HBs revealed the existence of a great diversity of O-H⋯O interactions. Furthermore, the analysis of quantities, such as |V(r)|/G(r) and H(r), allowed a further description of the nature of analogous O-H⋯O interactions within each cluster. In the case of 2-D cyclic clusters, the HBs are nearly equivalent between them. However, significant differences among the O-H⋯O interactions were observed in 3-D clusters. The assessment of the source function (SF) confirmed these findings. Finally, the ability of SF to decompose the electron density (ρ) into atomic contributions allowed the evaluation of the localized or delocalized character of these contributions to ρ at the BCP associated to the different HBs, revealing that weak O-H⋯O interactions have a significant spread of the atomic contributions, whereas strong interactions have more localized atomic contributions. These observations suggest that the nature of the O-H⋯O hydrogen bond in water clusters is determined by the inductive effects originated by the different spatial arrangements of the water molecules in the studied clusters.

Impact of Covalent Modifications on the Hydrogen Bond Strengths in Diaminotriazine Supramolecules.

Melamine (M) is a popular triamine triazine compound in the field of supramolecular materials. In this work, we have computationally investigated how substituents can be exploited to improve the binding strength of M supramolecules. Two types of covalent modifications were studied: the substitution of an H atom within an amine group -NHR, and the replacement of the whole -NH2 group (R=H, F, CH3 and COCH3 ). Through our dispersion-corrected density functional theory computations, we explain which covalent modification will show the best self-assembling capabilities, and why the binding energy is enhanced. Our charge density and molecular orbital analyses indicate that the best substituents are those that generate a charge accumulation on the endocyclic N atom, providing an improvement of the electrostatic attraction. At the same time the substituent assists the main N-H⋅⋅⋅N hydrogen bonds by interacting with the amino group of the other monomer. We also show how the selected group notably boosts the strength of hexameric rosettes. This research, therefore, provides molecular tools for the rational design of emerging materials based on uneven hydrogen-bonded arrangements.

Structural, dynamic, and hydration properties of quercetin and its aggregates in solution.

Quercetin is a flavonoid present in the human diet with multiple health benefits. Quercetin solutions are inhomogeneous even at very low concentrations due to quercetin's tendency to aggregate. We simulate, using molecular dynamics, three systems of quercetin solutions: infinite dilution, 0.22 M, and 0.46 M. The systems at the two highest concentrations represent regions of the quercetin aggregates, in which the concentration of this molecule is unusually high. We study the behavior of this molecule, its aggregates, and the modifications in the surrounding water. In the first three successive layers of quercetin hydration, the density of water and the hydrogen bonds formations between water molecules are smaller than that of bulk. Quercetin has a hydrophilic surface region that preferentially establishes donor hydrogen bonds with water molecules with relative frequencies from 0.12 to 0.46 at infinite dilution. Also, it has two hydrophobic regions above and below the planes of its rings, whose first hydration layers are further out from quercetin (≈0.3 Å) and their water molecules do not establish hydrogen bonds with it. Water density around the hydrophobic regions is smaller than that of the hydrophilic. Quercetin molecules aggregate inπ-stacking configurations, with a distance of ≈0.37 nm between the planes of their rings, and form bonds between their hydroxyl groups. The formation of quercetin aggregates decreases the hydrogen bonds between quercetin and the surrounding water and produces a subdiffusive behavior in water molecules. Quercetin has a subdiffusive behavior even at infinite dilution, which increases with the number of molecules within the aggregates and the time they remain within them.

Non-conventional interactions of N3 inhibitor with the main protease of SARS-CoV and SARS-CoV-2.

The extensive spread of COVID-19 in every continent shows that SARS-CoV-2 virus has a higher transmission rate than SARS-CoV virus which emerged in 2002. This results in a global pandemic that is difficult to control. In this investigation, we analyze the interaction of N3 inhibitor and the main protease of SARS-CoV and SARS-CoV-2 by quantum chemistry calculations. Non-covalent interactions involved in these systems were studied using a model of 469 atoms. Density Functional Theory and Quantum Theory of Atoms in Molecules calculations lead us to the conclusion that non-conventional hydrogen bonds are important to describe attractive interactions in these complexes. The energy of these non-conventional hydrogen bonds represents more than a half of the estimated interaction energy for non-covalent contacts. This means that hydrogen bonds are crucial to correctly describe the bonds between inhibitors and the main proteases. These results could be useful for the design of new drugs, since non-covalent interactions are related to possible mechanisms of action of molecules used against these viruses.

How a crosslinker agent interacts with the ß-glucosidase enzyme surface in an aqueous solution: Insight from quantum mechanics calculations and molecular dynamics simulations.

In this study, surficial interactions of glutaraldehyde (GA) as an important crosslinker agent with the ß-glucosidase (BGL) enzyme surface were investigated by theoretical methods. Since the inherent constraints of experimental methods limit their application to find the molecular perspective of these significant interactions in enzyme immobilization, theoretical methods were used as a complementary tool to understand this concept. The Minnesota density functional calculations showed that the chair conformations of the oxane-2,6-diol form of the GA were more stable than its free aldehyde form. MD simulations of propylamine-GA molecules, as a representative of attached-GA, in aqueous solutions of different concentrations were done to determine the molecular basis of surficial interactions with the BGL surface. The root mean square fluctuation (RMSF) demonstrated that the maximum flexibility of the BGL enzyme belonged to 460-480 residues in all solutions. Based on the spatial distribution function (SDF) analysis, the active site entrance was the most favored region to accumulate solute molecules. Radial distribution function (RDF) results showed that all forms of propylamine-GA molecules interacted from their head side with the lysine residues of BGL, which Lys247, Lys376, and Lys384 were found to be the most interactive lysine residues. Also, hydrogen bond (HB) analysis from two viewpoints confirmed HB formation possibility between propylamine-GA molecules and these lysine residues. These results explained which regions of the BGL have the maximum possibility to interact and link to GA and help us in understanding the process of enzyme immobilization.

Synthesis of Poly(methacrylic acid-co-butyl acrylate) Grafted onto Functionalized Carbon Nanotube Nanocomposites for Drug Delivery.

Design of a smart drug delivery system is a topic of current interest. Under this perspective, polymer nanocomposites (PNs) of butyl acrylate (BA), methacrylic acid (MAA), and functionalized carbon nanotubes (CNTsf) were synthesized by in situ emulsion polymerization (IEP). Carbon nanotubes were synthesized by chemical vapor deposition (CVD) and purified with steam. Purified CNTs were analyzed by FE-SEM and HR-TEM. CNTsf contain acyl chloride groups attached to their surface. Purified and functionalized CNTs were studied by FT-IR and Raman spectroscopies. The synthesized nanocomposites were studied by XPS, 13C-NMR, and DSC. Anhydride groups link CNTsf to MAA-BA polymeric chains. The potentiality of the prepared nanocomposites, and of their pure polymer matrices to deliver hydrocortisone, was evaluated in vitro by UV-VIS spectroscopy. The relationship between the chemical structure of the synthesized nanocomposites, or their pure polymeric matrices, and their ability to release hydrocortisone was studied by FT-IR spectroscopy. The hydrocortisone release profile of some of the studied nanocomposites is driven by a change in the inter-associated to self-associated hydrogen bonds balance. The CNTsf used to prepare the studied nanocomposites act as hydrocortisone reservoirs.

Understanding the Chloride Affinity of Barbiturates for Anion Receptor Design.

Due to their potential binding sites, barbituric acid (BA) and its derivatives have been used in metal coordination chemistry. Yet their abilities to recognize anions remain unexplored. In this work, we were able to identify four structural features of barbiturates that are responsible for a certain anion affinity. The set of coordination interactions can be finely tuned with covalent decorations at the methylene group. DFT-D computations at the BLYP-D3(BJ)/aug-cc-pVDZ level of theory show that the C-H bond is as effective as the N-H bond to coordinate chloride. An analysis of the electron charge density at the C-H⋅⋅⋅Cl- and N-H⋅⋅⋅Cl- bond critical points elucidates their similarities in covalent character. Our results reveal that the special acidity of the C-H bond shows up when the methylene group moves out of the ring plane and it is mainly governed by the orbital interaction energy. The amide and carboxyl groups are the best choices to coordinate the ion when they act together with the C-H bond. We finally show how can we use this information to rationally improve the recognition capability of a small cage-like complex that is able to coordinate NaCl.

Photochemistry in Real Space: Batho- and Hypsochromism in the Water Dimer.

The development of chemical intuition in photochemistry faces several difficulties that result from the inadequacy of the one-particle picture, the Born-Oppenheimer approximation, and other basic ideas used to build models. It is shown herein how real-space approaches can be efficiently used to gain valuable insights in photochemistry through a simple example of red and blue shift effects: the double hypso- and bathochromic shifts in the low-lying valence excited states of (H2 O)2 . It is demonstrated that 1) the use of these techniques allows the perturbative language used in the theory of intermolecular interactions, even in the strongly interacting short-range regime, to be maintained; 2) one and only one molecule is photoexcited in each of the addressed excited states and 3) the electrostatic interaction between the in-the-cluster molecular dipoles provides a fairly intuitive rationalisation of the observed batho- and hypsochromism. The methods exploited and illustrated herein are able to maintain the individuality and properties of the interacting entities in a molecular aggregate, and thereby they allow chemical intuition in general states, at any geometry and using a broad variety of electronic structure methods to be kept and built.

Competitive Reactivity of Tautomers in the Degradation of Organophosphates by Imidazole Derivatives.

The harmful impact caused by pesticides on human health and the environment necessitates the development of efficient degradation processes and control of prohibited stocks of such substances. Organophosphates (OPs) are among the most used agrochemicals in the world and their degradation can proceed through several possible pathways. Investigating the reactivity of OPs with nucleophilic species allows one to propose new and efficient catalyst scaffolds for use in detoxification. In light of the remarkable catalytic activity of imidazole (IMZ) at promoting dephosphorylation processes of OPs, the reactivity of 4(5)-hydroxymethylimidazole (HMZ) with diethyl-2,4-dinitrophenylphosphate (DEDNPP) and Paraoxon are evaluated by combining experimental and theoretical approaches. It is observed that HMZ is an efficient and regiospecific catalyst with reactivity modulated by competing tautomers. To propose an optimal IMZ-based catalyst, quantum chemical calculations were performed for monosubstituted 4(5)IMZ derivatives that might cleave DEDNPP. Both inductive effects and hydrogen bonding by the substituents are shown to influence barriers and mechanisms.

Tris(1H-benzimidazol-2-ylmeth-yl)amine methanol tris-olvate.

The structure of the tertiary amine tris-(1H-benzimidazol-2-ylmeth-yl)amine (C24H21N7, abbreviated ntb) has been previously reported twice as solvates, namely the monohydrate and the aceto-nitrile-methanol-water (1/0.5/1.5) solvate, both with the tripodal conformation formed via multiple hydrogen bonds. Now, we report the tri-methanol adduct, ntb·3CH3OH, where the amine has the stair conformation featuring one benzimidazole group oriented in the opposite direction from the other two. The asymmetric unit contains one-half amine, completed through the mirror plane m in space group Pmn21 to form the ntb mol-ecule, with the H atom for each imidazole moiety equally disordered between both N sites available in the imidazole ring. The asymmetric unit also contains one and a half methanol mol-ecules, one being placed in general position with the hy-droxy H atom disordered over two sites with occupancy ratio 1:1, while the other lies on the m mirror plane, and has thus its hy-droxy H atom disordered by symmetry. As in the previously reported solvates, all imine and amine groups of the ntb mol-ecules and the methanol mol-ecules are involved in N-H⋯O and O-H⋯N hydrogen bonds. In the title compound, however, the involved H atom is systematically a disordered H atom provided by an imidazole group or a methanol mol-ecule.

A multilamellar nanoliposome stabilized by interlayer hydrogen bonds increases antimalarial drug efficacy.

Lipid particles for drug delivery can be modified to create multilayer vesicles with higher stability and improved cargo interaction. Here, we used lipids capable of forming hydrogen bonds instead of covalent bonds and designed stable vesicles-inside-vesicles with a high capacity of entrapping antimalarial drugs such as chloroquine (hydrophilic) and Artemisinin (lipophilic). In vitro treatment of the drug-sensitive P. falciparum strain NF54 showed that encapsulated drugs resulted in 72% and 60% lower IC50 values for each drug, respectively. Fluorochrome-labeling of a cargo-peptide or of membrane-resident lipids indicated that vesicles interacted more specifically with parasite-infected erythrocytes than with normal red blood cells. Accordingly, vesicle-confined chloroquine was able to elicit a stronger antiparasitic effect than free chloroquine in a lethal murine model of infection. Being permissive not only to small molecules but also to larger peptides, hydrogen-bond linked multilamellar liposomes are a very promising approach for enhanced drug delivery.