Comparison of Proton Acceptor and Proton Donor Properties of H2O and H2O2 in Organic Crystals of Drug-like Compounds: Peroxosolvates vs. Crystallohydrates

Two new peroxosolvates of drug-like compounds were synthesized and studied by a combination of X-ray crystallographic, Raman spectroscopic methods, and periodic DFT computations. The enthalpies of H-bonds formed by hydrogen peroxide (H2O2) as a donor and an acceptor of protons were compared with the enthalpies of analogous H-bonds formed by water (H2O) in isomorphic (isostructural) hydrates. The enthalpies of H-bonds formed by H2O2 as a proton donor turned out to be higher than the values of the corresponding H-bonds formed by H2O. In the case of H2O2 as a proton acceptor in H-bonds, the ratio appeared reversed. The neutral O∙∙∙H-O/O∙∙∙H-N bonds formed by the lone electron pair of the oxygen atom of water were the strongest H-bonds in the considered crystals. In the paper, it was found out that the low-frequency Raman spectra of isomorphous crystalline hydrate and peroxosolvate of N-(5-Nitro-2-furfurylidene)-1-aminohydantoin are similar. As for the isostructural hydrate and peroxosolvate of the salt of protonated 2-amino-nicotinic acid and maleic acid monoanion, the Raman spectra are different

Environmental effects on vibrational proton dynamics in H5O2+: DFT study on crystalline H5O2+ClO4–

The structure as well as IR and inelastic neutron scattering (INS) spectra of H5O2+ in crystalline H5O2+ClO4– were simulated using Car–Parrinello molecular dynamics with the BLYP functional. The potential of the OH+O fragment is very shallow. The Pnma structure, assumed in the X-ray study to be the most suitable choice, is a saddle point on the potential energy surface, while the P212121 minimum structure is only 20 cm–1 lower in energy. The computed INS and IR spectra enable us to achieve a complete assignment of the observed spectra. The broad band between 1000 and 1400 cm–1 is due to the asymmetric stretch and one of the bending vibrations of the OH+O fragment, while the band between 1600 and 1800 cm–1 is due to the bending vibration of the water molecules and the second bending of the OH+O fragment. Comparison with the vibrational spectra of isolated H5O2+, obtained using Born–Oppenheimer molecular dynamics simulation, reveals environmental effects on vibrational proton dynamics in strong H-bonded species. The most pronounced changes are found for the OH+O bending modes because the two bending coordinates become distinctly different for the structure that the H5O2+ ion assumes in the crystal.Peer Reviewe

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

High-Mobility Naphthalene Diimide Derivatives Revealed by Raman-Based In Silico Screening

Charge transport in crystalline organic semiconductors (OSCs) is considerably hindered by low-frequency vibrations introducing dynamic disorder in the charge transfer integrals. Recently, we have shown that the contributions of various vibrational modes to the dynamic disorder correlate with their Raman intensities and suggested a Raman-based approach for estimation of the dynamic disorder and search for potentially high-mobility OSCs. In the present paper, we showcase this approach by revealing the highest-mobility OSC(s) in two series of crystalline naphthalene diimide derivatives bearing alkyl or cycloalkyl substituents. In contrast to our previous studies, Raman spectra are not measured, but are instead calculated using periodic DFT. As a result, an OSC with a potentially high charge mobility is revealed in each of the two series, and further mobility calculations corroborate this choice. Namely, for the naphthalene diimide derivatives with butyl and cyclopentyl substituents, the estimated room-temperature isotropic electron mobilities are as high as 6 and 15 cm2 V–1 s–1, respectively, in the latter case even exceeding 20 cm2 V–1 s–1 in a two-dimensional plane. Thus, our results highlight the potential of using the calculated Raman spectra to search for high-mobility crystalline OSCs and reveal two promising OSCs, which were previously overlooked

Local-structure effects on 31P NMR chemical shift tensors in solid state

The effect of the local structure on the P-31 NMR chemical shift tensor (CST) has been studied experimentally and simulated theoretically using the density functional theory gauge-independent-atomic-orbital approach. It has been shown that the dominating impact comes from a small number of noncovalent interactions between the phosphorus-containing group under question and the atoms of adjacent molecules. These interactions can be unambiguously identified using the Bader analysis of the electronic density. A robust and computationally effective approach designed to attribute a given experimental P-31 CST to a certain local morphology has been elaborated. This approach can be useful in studies of surfaces, complex molecular systems, and amorphous materials. Published under license by AIP Publishing

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

Crystalline Peroxosolvates: Nature of the Coformer, Hydrogen-Bonded Networks and Clusters, Intermolecular Interactions

Despite the technological importance of urea perhydrate (percarbamide) and sodium percarbonate, and the growing technological attention to solid forms of peroxide, fewer than 45 peroxosolvates were known by 2000. However, recent advances in X-ray diffractometers more than tripled the number of structurally characterized peroxosolvates over the last 20 years, and even more so, allowed energetic interpretation and gleaning deeper insight into peroxosolvate stability. To date, 134 crystalline peroxosolvates have been structurally resolved providing sufficient insight to justify a first review article on the subject. In the first chapter of the review, a comprehensive analysis of the structural databases is carried out revealing the nature of the co-former in crystalline peroxosolvates. In the majority of cases, the coformers can be classified into three groups: (1) salts of inorganic and carboxylic acids; (2) amino acids, peptides, and related zwitterions; and (3) molecular compounds with a lone electron pair on nitrogen and/or oxygen atoms. The second chapter of the review is devoted to H-bonding in peroxosolvates. The database search and energy statistics revealed the importance of intermolecular hydrogen bonds (H-bonds) which play a structure-directing role in the considered crystals. H2O2 always forms two H-bonds as a proton donor, the energy of which is higher than the energy of analogous H-bonds existing in isostructural crystalline hydrates. This phenomenon is due to the higher acidity of H2O2 compared to water and the conformational mobility of H2O2. The dihedral angle H-O-O-H varies from 20 to 180° in crystalline peroxosolvates. As a result, infinite H-bonded 1D chain clusters are formed, consisting of H2O2 molecules, H2O2 and water molecules, and H2O2 and halogen anions. H2O2 can form up to four H-bonds as a proton acceptor. The third chapter of the review is devoted to energetic computations and in particular density functional theory with periodic boundary conditions. The approaches are considered in detail, allowing one to obtain the H-bond energies in crystals. DFT computations provide deeper insight into the stability of peroxosolvates and explain why percarbamide and sodium percarbonate are stable to H2O2/H2O isomorphic transformations. The review ends with a description of the main modern trends in the synthesis of crystalline peroxosolvates, in particular, the production of peroxosolvates of high-energy compounds and mixed pharmaceutical forms with antiseptic and analgesic effects

Molecular Dynamics Simulation of Association Processes in Aqueous Solutions of Maleate Salts of Drug-like Compounds: The Role of Counterion

The study of the formation of microstructures during the interaction of a protonated drug-like compound (API) with a maleic acid monoanion sheds light on the assembly processes in an aqueous solution at the molecular level. Molecular dynamics (MD) simulations coupled with density functional theory (DFT) calculations made it possible to find initial hydrogen bonding motifs during the assembly process, leading to the formation of heterodimers and trimers. The process of trimer formation [protonated API—maleic acid monoanion—protonated API] proceeds through the formation of three intermolecular H-bonds by the CO2− group of the maleic acid monoanion in both systems. The total enthalpy/energy of these H-bonds is more than 70 kJ/mol. Thus, the maleic acid monoanion plays a key role in the processes of association in aqueous solution, and the interaction of the maleic acid monoanion with API is more preferable than the interaction of API molecules with each other. DFT computations in the discrete continuum approximation reveal the spectral features of heterodimers and trimers, and the ATR-IR spectra confirmed these findings. MD simulations followed by DFT calculations made it possible to describe the initial stages of the formation of pharmaceutical cocrystals in an aqueous solution