Specific Proton-Donor Properties of Glycine Betaine. Metric Parameters and Enthalpy of Noncovalent Interactions in its Dimer, Water Complexes and Crystalline Hydrate.

Trimethylglycine (glycine betaine, GB) is an important organic osmolyte that accumulates in various plant species in response to environmental stresses and has significant potential as a bioactive agent with low environmental impact. It is assumed that the hydration of GB is playing an important role in the protective mechanism. The hydration and aggregation properties of GB have not yet been studied in detail at the atomistic level. In this work, noncovalent interactions in the GB dimer and its complexes with water and crystalline monohydrate are studied. Depending on the object, periodic and non-periodic DFT calculations are used. Particular attention is paid to the metric parameters and enthalpies of intermolecular hydrogen bonds. The identification of noncovalent interactions is carried out by means of the Bader analysis of periodic or non-periodic electron density. The enthalpy of hydrogen bonds is estimated using the Rosenberg formula (PCCP 2 (2000) 2699). The specific proton donor properties of glycine betaine are due to its ability to form intermolecular C-H∙∙∙O bonds with the oxygen atom of a water molecule or the carboxylate group of a neighboring GB. The enthalpy of these bonds can be significantly greater than 10 kJ/mol. The water molecule that forms a hydrogen bond with the carboxylate group of GB also interacts with its CH groups through lone pairs of electrons. The C-H∙∙∙O bonds contribute up to 40% of the total entropy of the GB-water interaction, which is about 45 kJ/mol. The possibility of identifying C-H∙∙∙O bonds by the proton nuclear magnetic resonance method is discussed.

Diclofenac Ion Hydration: Experimental and Theoretical Search for Anion Pairs.

Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work, aqueous solutions of sodium diclofenac are investigated, which, like most medicinal compounds, is poorly soluble in water. Classical MD modeling of an aqueous solution of diclofenac sodium showed equilibrium between the hydrated anion and the hydrated dimer of the diclofenac anion. The assignment and interpretation of the bands in the UV, NIR, and IR spectra are based on DFT calculations in the discrete-continuum approximation. It has been shown that the combined use of spectroscopic methods in various frequency ranges with classical MD simulations and DFT calculations provides valuable information on the association processes of medical compounds in aqueous solutions. Additionally, such a combined application of experimental and calculation methods allowed us to put forward a hypothesis about the mechanism of the effect of diclofenac sodium in high dilutions on a solution of diclofenac sodium.

Interplay of π-stacking and inter-stacking interactions in two-component crystals of neutral closed-shell aromatic compounds: periodic DFT study.

This paper bridges the gap between high-level ab initio computations of gas-phase models of 1 : 1 arene-arene complexes and calculations of the two-component (binary) organic crystals using atom-atom potentials. The studied crystals consist of electron-rich and electron-deficient compounds, which form infinite stacks (columns) of heterodimers. The sublimation enthalpy of crystals has been evaluated by DFT periodic calculations, while intermolecular interactions have been characterized by Bader analysis of the periodic electronic density. The consideration of aromatic compounds without a dipole moment makes it possible to reveal the contribution of quadrupole-quadrupole interactions to the π-stacking energy. These interactions are significant for heterodimers formed by arenes with more than 2 rings, with absolute values of the traceless quadrupole moment (Q zz) larger than 10 D Å. The further aggregation of neighboring stacks is due to the C-H⋯F interactions in arene/perfluoroarene crystals. In crystals consisting of arene and an electron-deficient compound such as pyromellitic dianhydride, aggregation occurs due to the C-H⋯O interactions. The C-H⋯F and C-H⋯O inter-stacking interactions make the main contribution to the sublimation enthalpy, which exceeds 150 kJ mol-1 for the two-component crystals formed by arenes with more than 2 rings.

Influence of Secondary Interactions on the Structure, Sublimation Thermodynamics, and Solubility of Salicylate:4-Hydroxybenzamide Cocrystals. Combined Experimental and Theoretical Study.

Cocrystal screening of 4-hydroxybenzamide with a number of salicylates (salicylic acid, SA; 4-aminosalicylic acid, PASA; acetylsalicylic acid, ASA; and salicylsalicylic acid, SSA) was conducted to confirm the formation of two cocrystals, [SA+4-OHBZA] (1:1) and [PASA+4-OHBZA] (1:1). Their structures were determined using single-crystal X-ray diffraction, and the hydrogen-bond network topology was studied. Thermodynamic characteristics of salicylic acid cocrystal sublimation were obtained experimentally. It was proved that PASA cocrystallization with 4-OHBZA makes the drug more stable and prevents the irreversible process of decarboxylation of PASA resulting in formation of toxic 3-aminophenol. The pattern of non-covalent interactions in the cocrystals is described quantitatively using solid-state density functional theory followed by Bader analysis of the periodic electron density. It has been found that the total energy of secondary interactions between synthon atoms and the side hydroxyl group of the acid molecule in [SA+4-OHBZA] (1:1) and [PASA+4-OHBZA] (1:1) cocrystals is comparable to the energy of the primary acid-amide heterosynthon. The theoretical value of the sublimation enthalpy of [SA+4-OHBZA], 231 kJ/mol, agrees fairly well with the experimental one, 272 kJ/mol. The dissolution experiments with [SA+4-OHBZA] have proved that the relatively large cocrystal stability in relation to the stability of its components has a negative effect on the dissolution rate and equilibrium solubility. The [PASA+4-OHBZA] (1:1) cocrystal showed an enhancement of apparent solubility compared to that of the corresponding pure active pharmaceutical ingredient, while their intrinsic dissolution rates are comparable.

Salicylamide cocrystals: screening, crystal structure, sublimation thermodynamics, dissolution, and solid-state DFT calculations.

A new cocrystal of 2-hydroxybenzamide (A) with 4-acetamidobenzoic acid (B) has been obtained by the DSC screening method. Thermophysical analysis of the aggregate [A:B] has been conducted and a fusion diagram has been plotted. Cocrystal formation from melts was studied by using thermomicroscopy. A cocrystal single-crystal was grown and its crystal structure was determined. The pattern of noncovalent interactions has been quantified using the solid-state DFT computations coupled with the Bader analysis of the periodic electron density. The sublimation processes of A-B cocrystal have been studied and its thermodynamic functions have been calculated. The classical method of substance transfer by inert gas-carrier was chosen to investigate sublimation processes experimentally. The lattice energy is found to be 143 ± 4 kJ/mol. It is lower than the sum of the corresponding values of the cocrystal pure components. The theoretical value of the lattice energy, 156 kJ/mol, is in reasonable agreement with the experimental one. A ternary phase diagram of solubility (A-B-ethanol) has been plotted and the areas with solutions for growing thermodynamically stable cocrystals have been determined.

Cl···Cl interactions in molecular crystals: insights from the theoretical charge density analysis.

The structure, IR harmonic frequencies and intensities of normal vibrations of 20 molecular crystals with the X-Cl···Cl-X contacts of different types, where X = C, Cl, and F and the Cl···Cl distance varying from ~3.0 to ~4.0 Å, are computed using the solid-state DFT method. The obtained crystalline wave functions have been further used to define and describe quantitatively the Cl···Cl interactions via the electron-density features at the Cl···Cl bond critical points. We found that the electron-density at the bond critical point is almost independent of the particular type of the contact or hybridization of the ipso carbon atom. The energy of Cl···Cl interactions, E(int), is evaluated from the linking E(int) and local electronic kinetic energy density at the Cl···Cl bond critical points. E(int) varies from 2 to 12 kJ/mol. The applicability of the geometrical criterion for the detection of the Cl···Cl interactions in crystals with two or more intermolecular Cl···Cl contacts for the unique chlorine atom is not straightforward. The detection of these interactions in such crystals may be done by the quantum-topological analysis of the periodic electron density.

The experimental and theoretical QTAIMC study of the atomic and molecular interactions in dinitrogen tetroxide.

The atomic and molecular interactions in a crystal of dinitrogen tetraoxide, alpha-N2O4, have been studied in terms of the quantum topological theory of molecular structure using high-resolution, low-temperature X-ray diffraction data. The experimental electron density and electrostatic potential have been reconstructed with the Hansen-Coppens multipole model. In addition, the three-dimensional periodic electron density of crystalline alpha-N2O4 has been calculated at the B3LYP/cc-pVDZ level of theory with and without the geometry optimization. The application of the quantum theory of atoms in molecules and crystals (QTAIMC) recovered the two types of intermolecular bond paths between O atoms in crystalline alpha-N2O4, one measuring 3.094, the other 3.116 A. The three-dimensional distribution of the Laplacian of the electron density around the O atoms showed that the lumps in the negative Laplacian fit the holes on the O atoms in the adjacent molecules, both atoms being linked by the intermolecular bond paths. This shows that the Lewis-type molecular complementarity contributes significantly to intermolecular bonding in crystalline N2O4. Partial overlap of atomic-like basins created by zero-flux surfaces in both the electron density and the electrostatic potential show that attractive electrostatic interaction exists between O atoms even though they carry the same net formal charge. The exchange and correlation contributions to the potential energy density were also computed by means of the model functionals, which use the experimental electron density and its derivatives. It was found that the intermolecular interactions in alpha-N2O4 are accompanied by the correlation energy-density ;bridges' lowering the local potential energy along the intermolecular O...O bond paths in the electron density, while the exchange energy density governs the shape of bounded molecules.