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.     

A model proton-transfer system in the condensed phase: NH4(+)OOH(-), a crystal with short intermolecular H-bonds

The crystal structure of NH(4)(+)OOH(-) is determined from single-crystal x-ray data obtained at 150 K. The crystal belongs to the space group P2(1)/c and has four molecules in a unit cell. The structure consists of discrete NH(4)(+) and OOH(-) ions. The OOH(-) ions are linked by short hydrogen bonds (2.533 A?) to form parallel infinite chains. The ammonium ions form links between these chains (the N?O distances vary from 2.714 to 2.855 A?) giving a three-dimensional network. The harmonic IR spectrum and H-bond energies are computed at the Perdew-Burke-Ernzerhof (PBE)/6-31G(??) level with periodic boundary conditions. A detailed analysis of the shared (bridging) protons' dynamics is obtained from the CPMD simulations at different temperatures. PBE functional with plane-wave basis set (110 Ry) is used. At 10 K the shared proton sits near the oxygen atom, only a few proton jumps along the chain are detected at 70 K while at 270 K numerous proton jumps exist in the trajectory. The local-minimum structure of the space group Cc is localized. It appears as a result of proton transfer along a chain. This process is endothermic (～2?kJ/mol) and is described as P2(1)/c?2Cc. The computed IR spectrum at 10 K is close to the harmonic one, the numerous bands appear at 70 K while at 270 K it shows a very broad absorption band that covers frequencies from about 1000 to 3000?cm(-1). The advantages of the NH(4)(+)OOH(-) crystal as a promising model for the experimental and DFT based molecular dynamics simulation studies of proton transfer along the chain are discussed.     

A quantum-topological analysis of short (strong) H bonds in three-dimensional periodic crystals

The characteristics of the critical electron density points of the O-H···A fragment (A = O or N) in molecular crystals with short H bonds were analyzed in terms of the Bader quantum-topological theory of molecular structure. The wave functions (B3LYP/6-31G** approximation) of the ground state of 26 three-dimensional periodic crystals with experimentally determined structures were used. Intermediate-type interactions separating the limiting cases of covalent and closed shell-type interactions were found to be characterized by the following geometric parameters: 2.45 Å ≤ D(O···O) ≤ 2.6 Å, 1.35 Å ≤ d(H···O) ≤ 1.65 Å, and 1.0 Å ≤ d(O-H) ≤ 1.10 Å. Such interactions are observed in molecular crystals with the O-H···A fragment and high bridge proton mobility. Differences between H···O and H···N interactions were quantitatively characterized by the dependence of ρ _b on d(H···A), where A = O or N. The dependence parameter values were shown to be determined by the nature of the A atom that forms the H bond. The influence of the crystalline environment on systems with strong H bonds manifested itself by changes in the position of the bridge proton. The d(O-H)/d(H···O) ratio was, however, the same for gas-phase complexes and molecular crystals with weakly bent O-H···O fragments (∠O-H···O > 160°).     

The structure and vibrational features of proton disolvates in water–ethanol solutions of HCl: the combined spectroscopic and theoretical study

The infrared (IR) spectra of water–ethanol (EtOH) solutions of HCl are measured over a wide range of acid concentration at fixed H₂O―EtOH ratios (1 : 1, 1 : 2, and 1 : 40). In these systems, different proton disolvates with (quasi)symmetrical H‐bonds are formed. Their structure and vibrational features are revealed by the density functional theory method coupled with the polarizable continuum model of solvation. In dilute acidic solutions, the Zundel‐type H₅O₂⁺ ion is mainly formed. In concentrated HCl solutions, the ions (H₂O···H···O(H)Et)⁺ and (Et(H)O···H···O(H)Et)⁺ with the quasi‐symmetrical O···H⁺···O unit having O···O separation <2.45 Å appear. The first ion characterized by the IR‐intensive band around 1800 cm^?1 is mainly formed in the 1 : 1 water–ethanol systems. The second ion exists in the 1 : 2 and 1 : 40 water–ethanol systems. Its spectroscopic signatures are the groups of the IR‐intensive bands around 800 and 1050 cm^?1. In highly concentrated HCl solutions with the 1 : 40 water–ethanol ratio, a neutral Et(H)O···H⁺···Cl^? complex exists. Copyright © 2013 John Wiley & Sons, Ltd.     

Molecular simulations of outersphere reorganization energies in polar and quadrupolar solvents. The case of intramolecular electron and hole transfer

Outersphere reorganization energies (lambda) for intramolecular electron and hole transfer are studied in anion- and cation-radical forms of complex organic substrates (p-phenylphenyl-spacer-naphthyl) in polar (water, 1,2-dichloroethane, tetrahydrofuran) and quadrupolar (supercritical CO2) solvents. Structure and charge distributions of solute molecules are obtained at the HF/6-31G(d,p) level. Standard Lennard-Jones parameters for solutes and the nonpolarizable simple site-based models of solvents are used in molecular dynamics (MD) simulations. Calculation of lambda is done by means of the original procedure, which treats electrostatic polarization of a solvent in terms of a usual nonpolarizable MD scheme supplemented by scaling of reorganization energies at the final stage. This approach provides a physically relevant background for separating inertial and inertialless polarization responses by means of a single parameter epsilon(infinity), optical dielectric permittivity of the solvent. Absolute lambda values for hole transfer in 1,2-dichloroethane agree with results of previous computations in terms of the different technique (MD/FRCM, Leontyev, I. V.; et al. Chem. Phys. 2005, 319, 4). Computed lambda values for electron transfer in tetrahydrofuran are larger than the experimental values by ca. 2.5 kcal/mol; for the case of hole transfer in 1,2-dichloroethane the discrepancy is of similar magnitude provided the experimental data are properly corrected. The MD approach gives nonzero lambda values for charge-transfer reaction in supercritical CO2, being able to provide a uniform treatment of nonequilibrium solvation phenomena in both quadrupolar and polar solvents.     

QTAIM study of the closed-shell interactions in peptide secondary structures: A cluster treatment of oligo- and polyalanines

The closed-shell interactions in oligo- and polyalanines are studied by the quantum theory of atoms in molecules (QTAIM) using electron densities derived from the B3LYP/6-31+G^** ground-state electronic wave-functions. The QTAIM enabled us to identify a large number of the intraturn closed-shell stabilizing interactions in the β-turns, which were presented by several conformers of the tetrapeptide model compound. We found that only β-turn type IVa exhibits a 10-member pseudocycle. The intrachain H-bonds between the adjacent N–H and CO groups in the antiparallel β-sheet conformation of polyalanine have not been found. At the same time, these interactions do exist in the parallel conformation and are even stronger than the interchain N–H…O bonds. A weak interaction between the CO group at the position i and the side-chain C–H group at the position i + 3 was detected in the -helical conformation of polyalanine.     

QTAIM study of strong H-bonds with the O-H...a fragment (A=O, N) in three-dimensional periodical crystals

The relationship between the d(H...A) distance (A=O, N) and the topological properties at the H...A bond critical point of 37 strong (short) hydrogen bonds occurring in 26 molecular crystals are analyzed using the quantum theory of atoms in molecules (QTAIM). Ground-state wave functions of the three-dimensional periodical structures representing the accurate experimental geometries calculated at the B3LYP/6-31G** level of approximation were used to obtain the QTAIM electron density characteristics. The use of an electron-correlated method allowed us to reach the quantitatively correct values of electron density rhob at the H...A bond critical point. However, quite significant differences can appear for small absolute values of the Laplacian (<0.5 au). The difference between the H...O and H...N interactions is described using the rhob versus d(H...A) dependence. It is demonstrated that the values of parameters in this dependence are defined by the nature of the heavy atom forming the H...A bond. An intermediate (or transit) region separating the shared and closed-shell interactions is observed for the H-bonded crystals in which the bridging proton can move from one heavy atom to another. The crystalline environment changes the location of the bridging proton in strong H-bonded systems; however, the d(O-H)/d(H...O) ratio is approximately the same for both the gas-phase complexes and molecular crystals with a linear or near-linear O-H...O bond.     

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 G_b and potential V_b densities at the H···O bond critical point and the H‐bond energy E_HB. Comparison of the computed E_HB 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 V_b?E_HB approach overestimates the energy of moderate H‐bonds (E_HB < 60 kJ/mol) by ～20% and gives unreliably high energies for crystals with strong H‐bonds. On the other hand, the G_b?E_HB approach affords reliable results for the crystals under consideration. The linear relationship between G_b and E_HB 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 G_b value can be recommended to be obtained from both density functional theory (DFT) computations with periodic boundary conditions and precise X‐ray diffraction experiments. © 2012 Wiley Periodicals, Inc.     

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.