Mikhail V. Vener

Intermolecular hydrogen bond energies in crystals evaluated using electron density properties: DFT computations with periodic boundary conditions

The hydrogen bond (H‐bond) energies are evaluated for 18 molecular crystals with 28 moderate and strong OH···O bonds using the approaches based on the electron density properties, which are derived from the B3LYP/6‐311G** calculations with periodic boundary conditions. The approaches considered explore linear relationships between the local electronic kinetic Gb and potential Vb densities at the H···O bond critical point and the H‐bond energy EHB. Comparison of the computed EHB values with the experimental data and enthalpies evaluated using the empirical correlation of spectral and thermodynamic parameters (Iogansen, Spectrochim. Acta Part A 1999, 55, 1585) enables to estimate the accuracy and applicability limits of the approaches used. The Vb−EHB approach overestimates the energy of moderate H‐bonds (EHB < 60 kJ/mol) by ∼20% and gives unreliably high energies for crystals with strong H‐bonds. On the other hand, the Gb−EHB approach affords reliable results for the crystals under consideration. The linear relationship between Gb and EHB is basis set superposition error (BSSE) free and allows to estimate the H‐bond energy without computing it by means of the supramolecular approach. Therefore, for the evaluation of H‐bond energies in molecular crystals, the Gb value can be recommended to be obtained from both density functional theory (DFT) computations with periodic boundary conditions and precise X‐ray diffraction experiments.

H-bond network in amino acid cocrystals with H2O or H2O2. The DFT study of serine-H2O and serine-H2O2.

The structure, IR spectrum, and H-bond network in the serine-H(2)O and serine-H(2)O(2) crystals were studied using DFT computations with periodic boundary conditions. Two different basis sets were used: the all-electron Gaussian-type orbital basis set and the plane wave basis set. Computed frequencies of the IR-active vibrations of the titled crystals are quite different in the range of 10-100 cm(-1). Harmonic approximation fails to reproduce IR active bands in the 2500-2800 frequency region of serine-H(2)O and serine-H(2)O(2). The bands around 2500 and 2700 cm(-1) do exist in the anharmonic IR spectra and are caused by the first overtone of the OH bending vibrations of H(2)O and a combination vibration of the symmetric and asymmetric bendings of H(2)O(2). The quantum-topological analysis of the crystalline electron density enables us to describe quantitatively the H-bond network. It is much more complex in the title crystals than in a serine crystal. Appearance of water leads to an increase of the energy of the amino acid-amino acid interactions, up to ~50 kJ/mol. The energy of the amino acid-water H-bonds is ~30 kJ/mol. The H(2)O/H(2)O(2) substitution does not change the H-bond network; however, the energy of the amino acid-H(2)O(2) contacts increases up to 60 kJ/mol. This is caused by the fact that H(2)O(2) is a much better proton donor than H(2)O in the title crystals.

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.

Density Functional Study of the Proton Transfer Effect on Vibrations of Strong (Short) Intermolecular O−H···N/O−···H−N+ Hydrogen Bonds in Aprotic Solvents

The structure and spectroscopic properties of the 1:1 complexes of substituted pyridines with benzoic acid and phenol derivatives in aprotic solvents are studied using B3LYP functional combined with the polarizable continuum model approximation. Two extreme structures are investigated: the state without (HB) and with proton transfer (PT). In the presence of an external electric field the O...N distance is contracted and the PT state does appear. The PT state of both the pyridine-benzoic and the pyridine-phenol complexes displays the only IR-active band in the 2800-1800 frequency region, which is located around 2000 cm(-1). However, the nature of the band is different for these two complexes. In the pyridine-benzoic acid complex it is practically a pure stretching vibration of the HN(+) group, while in the pyridine-phenol complex it is the mixed vibration of the bridging proton. A specific feature of the PT state in the pyridine-phenol complex is an IR-intensive band near 600 cm(-1), associated with the asymmetric stretching vibrations of the O(-)...HN(+) fragment. Its intensity is reciprocally proportional to the O...N distance. The appearance of this band provides an efficient criterion to differentiate between the HB and PT states of the 1:1 complexes of phenols with pyridines in aprotic solvents.

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.

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.

DFT Study of Proton Dynamics in the Potassium Hydrogen Maleate Crystal: the Infrared Versus the Inelastic Neutron Scattering Spectra

Abstract The structure, harmonic frequencies and infrared (IR) intensities of the fundamental transitions in potassium hydrogen maleate (KHM) crystal have been computed using the BLYP/6-31G** method with periodic boundary conditions. The inelastic neutron scattering (INS) intensities of the fundamental transitions were evaluated and compared with the experimental INS spectra of hydrogenated sample and isotopic analogues of the KHM crystal; the agreement is reasonable good. Spectroscopic manifestations of the proton dynamics in the strong intramolecular H-bond were clarified by comparison of the computed frequencies of the IR and INS-active fundamental transitions. Due to several reasons, the number of the bands and their relative intensity were found to differ between the INS and IR spectra of the KHM crystal. Reduced masses for the asymmetric O…H…O stretching vibrations of the hydrogen maleate ion appear to be larger 1 a.m.u. because of the strong coupling between the bridging proton motion and the various intramolecular vibrations.

Hydration of the Carboxylate Group in Anti-Inflammatory Drugs: ATR-IR and Computational Studies of Aqueous Solution of Sodium Diclofenac

Diclofenac (active ingredient of Voltaren) has a significant, multifaceted role in medicine, pharmacy, and biochemistry. Its physical properties and impact on biomolecular structures still attract essential scientific interest. However, its interaction with water has not been described yet at the molecular level. In the present study, we shed light on the interaction between the steric hindrance (the intramolecular N–H···O bond, etc.) carboxylate group (−CO2–) with water. Aqueous solution of sodium declofenac is investigated using attenuated total reflection-infrared (ATR-IR) and computational approaches, i.e., classical molecular dynamics (MD) simulations and density functional theory (DFT). Our coupled classical MD simulations, DFT calculations, and ATR-IR spectroscopy results indicated that the −CO2– group of the diclofenac anion undergoes strong specific interactions with the water molecules. The combined experimental and theoretical techniques provide significant insights into the spectroscopic manifestation of these interactions and the structure of the hydration shell of the −CO2– group. Moreover, the developed methodology for the theoretical analysis of the ATR-IR spectrum could serve as a template for the future IR/Raman studies of the strong interaction between the steric hindrance −CO2– group of bioactive molecules with the water molecules in dilute aqueous solutions.

Specific features of supramolecular organisation and hydrogen bonding in proline cocrystals: a case study of fenamates and diclofenac

New zwitterionic cocrystals of fenamate drugs and diclofenac with the naturally occurring amino acid L-proline have been obtained and thoroughly characterised by a variety of experimental and theoretical techniques. A crystal structure analysis and a CSD survey allowed us to establish a distinct supramolecular motif formed by the double chain arrangement of proline entities, which was found to play the structure-directing role in the proline zwitterionic cocrystals. Special graph set notation has been introduced to describe the particular type of the bifurcated H-bond observed in the crystal structures of proline with different APIs. Solid state DFT calculations enabled us to quantify different intermolecular interactions in the new cocrystals obtained, to interpret specific features of supramolecular organisation, and to explain the reasons for selective cocrystallisation of L-proline with fenamates. Cocrystallisation of the diclofenac and fenamate APIs with L-proline improved the solubility of these drugs in comparison with the parent drugs. The cocrystal solubility advantage values determined from eutectic concentrations at pH 6.8 and 25.0 °C were found to be in the range from 9 to 25.

Hypercoordinated Oligosilanes Based on Aminotrisphenols

The hypercoordinated silicon chlorides ClSi[(o-OC6H4)3N] (3) and ClSi[(OC6H2Me2CH2)3N] (5) were used for the synthesis of catenated derivatives (Me3Si)3SiSi[(o-OC6H4)3N] (9), (Me3Si)3SiSiMe2SiMe2Si(SiMe3)2Si[(o-OC6H4)3N] (11), and (Me3Si)3SiSi[(OC6H2Me2CH2)3N] (13) in reactions with (Me3Si)3SiK·THF (7) or (Me3Si)3SiK·[18-crown-6] (8). It was found that the nature of the (Me3Si)3SiK solvate determines the product of interaction, resulting in the formation of (Me3Si)3Si(CH2)4OSi[(OC6H2Me2CH2)3N] (12) or 13. Compounds obtained were characterized using multinuclear NMR and UV–vis spectroscopy and mass spectrometry. The molecular structures of 3, 9, and 11–13 were investigated by single-crystal X-ray analysis, featuring hypercoordinated Si atoms in a trigonal-bipyramidal coordination environment with O atoms in the equatorial plane. The structure of the side product [N(CH2C6H2Me2O)3Si]2O (6) was also studied, indicating highly tetrahedrally distorted trigonal-bipyramidal environment at the Si atoms, which was confirmed by crystal density functional theory calculations indicating the very weak Si ← N interaction. The Si···N interatomic distances span a broad range (2.23–2.78 Å). The dependence of structural and NMR parameters for hypercoordinated catenated compounds from the type of the ligand was established.