Exploring Intra- and Intermolecular Interactions in Selected N-Oxides-The Role of Hydrogen Bonds.

Intra- and intermolecular interactions have been explored in selected N-oxide derivatives: 2-(N,N-dimethylamino-N-oxymethyl)-4,6-dimethylphenyl (1) and 5,5'-dibromo-3-diethylaminomethyl-2,2'-biphenol N-oxide (2). Both compounds possess intramolecular hydrogen bonding, which is classified as moderate in 1 and strong in 2, and resonance-assisted in both cases. Density Functional Theory (DFT) in its classical formulation as well as Time-Dependent extension (TD-DFT) were employed to study proton transfer phenomena. The simulations were performed in the gas phase and with implicit and explicit solvation models. The obtained structures of the studied N-oxides were compared with experimental data available. The proton reaction path was investigated using scan with an optimization method, and water molecule reorientation in the monohydrate of 1 was found upon the proton scan progress. It was found that spontaneous proton transfer phenomenon cannot occur in the electronic ground state of the compound 1. An opposite situation was noticed for the compound 2. The changes of nucleophilicity and electrophilicity upon the bridged proton migration were analyzed on the basis of Fukui functions in the case of 1. The interaction energy decomposition of dimers and microsolvation models was investigated using Symmetry-Adapted Perturbation Theory (SAPT). The simulations were performed in both phases to introduce polar environment influence on the interaction energies. The SAPT study showed rather minor role of induction in the formation of homodimers. However, it is worth noticing that the same induction term is responsible for the preference of water molecules' interaction with N-oxide hydrogen bond acceptor atoms in the microsolvation study. The Natural Bond Orbital (NBO) analysis was performed for the complexes with water to investigate the charge flow upon the polar environment introduction. Finally, the TD-DFT was applied for isolated molecules as well as for microsolvation models showing that the presence of solvent affects excited states, especially when the N-oxide acceptor atom is microsolvated.

Aggregation of N,N'-diallylurea and N,N'-diallylthiourea in solutions.

Joint studies by IR spectroscopy, dipole moments, average molecular weight measurements and DFT calculations on the self-aggregation of N,N'-diallylureas and N,N'-diallylthioureas in solvents of different polarities were performed. Simultaneous uses of all these methods are required for better understanding the mechanism of aggregation and the effects of different polarity of solvents. In this study also the measurements of IR spectra in polarized light were additionally performed, which gives information on arrangement of aggregates in liquid crystal matrix-built of 4-CN biphenyl derivative. It was demonstrated that in such conditions two forms of dimers the linear and cyclic ones are in equilibrium with different arrangements according the axis of CN group.

Self-aggregation mechanisms of N-alkyl derivatives of urea and thiourea.

The mechanisms of self-aggregation of N-alkyl and N,N'-dialkyl derivatives of urea and thiourea in weakly polar solvents (chloroform and 1,2-dichloroethane) were examined. The C-H···O or C-H···S hydrogen bonds formed with these two acidic solvents compete with the N-H···O or N-H···S hydrogen bonds formed between solute molecules, influencing the self-aggregation of urea derivatives in a particular solvent. The peculiarities of the solvent interactions were discussed and the stronger interaction of chloroform was noted. Aggregation of the N-alkyl derivatives was followed using IR spectroscopy, with two gradual aggregation constants (K1 and K2) determined. The average molecular weight and dipole moments were shown to depend on the concentration, and the form of aggregation was analyzed through the study of the dipole moments. All of the urea derivatives demonstrated an increase in dipole moment with increased concentration, resulting in stronger NH2···O hydrogen bond interactions and leading to linear-type aggregation. Contrastingly, the dipole moments of the mono-N-alkyl-substituted thioureas decreased with concentration. Density-functional theory calculation of these processes showed that reliable results could only be obtained if solvent interactions were considered, with a specific combination of local and bulk effects. It was also shown that going from N,N'-disubstituted to N-monoalkyl derivatives the ability to aggregate increases, which is related to a diminished steric hindrance to hydrogen bonding. Finally, it was demonstrated that the mechanisms of self-aggregation depend on the acid-base properties of the solute, hydrogen bonding to the solvent molecules, and steric interactions of the aliphatic chains.

Interaction of piperidin derivative of Mannich base with DPPC liposomes.

The long chain Mannich bases, especially with the piperidine and morpholine groups, display very promising antimicrobial activity. In order to extend our knowledge on their impact on biological systems, we examined the interactions of the 5-pentadecyl-2-((piperidin-1-yl)methyl)phenol (PPDP) with model lipid membrane by means of differential scanning calorimetry (DSC) and fluorescence measurements. The small unilamellar vesicles of dipalmitoylophosphatidylcholine (DPPC) with different piperidine Mannich base concentration were investigated as a function of the increase of temperature. The phase separation accompanied by the rise of the transition enthalpy of both subcomponents, the increase of the function of the GP values of Laurdan versus the wavelength of excitation in the gel phase of PPDP/DPPC systems, and no remarkable differences in the fluorescence anisotropy of PPDP molecules in lipid environment for different mixtures of PPDP/DPPC was observed. Additionally, it was shown that PPDP itself interdigitated in solid state.

p-Nitrobenzoic acid adsorption on nanostructured gold surfaces investigated by combined experimental and computational approaches.

Adsorption of guest molecules on host surfaces can lead to dramatic changes in the spectral properties of the guest. One such effect is surface-enhanced infrared absorption (SEIRA), observed when the guest is adsorbed on, for example, thin films, metal surfaces, or nanotubes. p-Nitrobenzoic acid (p-NBA) exhibits a SEIRA effect when adsorbed on Ag and Au. Herein, the IR spectra of p-NBA adsorbed on a homemade rough Au surface, recorded in reflection mode with an angle of incidence of 16.5°, are reported. This SEIRA experiment reveals more bands than found by previous SEIRA studies. The intensities of both symmetric and asymmetric COO(-) and NO(2) stretching, in-plane CH, and C=C ring stretching modes are enhanced. Theoretical models constructed on the basis of density functional theory reveal the binding mode of p-NBA to gold "particles". The p-NBA anion binds to gold much more strongly than the neutral form, and interaction via the carboxylic oxygen atoms is preferred over the nitro group-gold contact. A significant charge transfer during chemisorption is found, which is considered to be crucial in leading to a high SEIRA enhancement factor.

Direct observation of the substitution effects on the hydrogen bridge dynamics in selected Schiff bases--a comparative molecular dynamics study.

We have studied substituent effects on the properties of the intramolecular hydrogen bond of some ortho-hydroxy Schiff bases using density functional theory (DFT) based first-principle molecular dynamics (FPMD) and path integral molecular dynamics. The studied compounds possess a strong intramolecular hydrogen bond (r((O⋅⋅⋅N)) ≤ 2.6 Å), which can be tuned by substitution to either (i) enhance the basicity of the acceptor moiety by induction effects or (ii) decrease the hydrogen bond length through steric repulsion. DFT calculations and FPMD were employed to investigate structural and dynamical properties of the selected molecules, while quantum effects on the structural properties were assessed using path integral FPMD. The simulations were performed in vacuo and in the solid state to study the influence of the environment on the hydrogen bond and spectroscopic properties. We give computational support to the suggestion that induction effects are less effective to tune the intramolecular hydrogen bond properties of the discussed ortho-hydroxy Schiff bases than the steric or the environmental effects.

Structure of aggregates of dialkyl urea derivatives in solutions.

Combined IR spectroscopy, dipole moment, and average molecular weight measurements and DFT calculations on the self-aggregation of N,N'- and N,N-dialkylureas in solvents of different polarities were performed. It was found that, to acquire a better understanding of the mechanisms of associations, the simultaneous use of all of these methods is required. It was found that symmetric dialkyl derivatives of urea associate much more strongly, giving in CCl(4) even a 12-fold mass of monomers, in contrast to asymmetric ones, where the average molecular weight reaches only a 2-fold mass of monomers. The very strong influence of solvents was discovered. The aggregation is much weaker in more polar chloroform and 1,2-dichloroethane leading to only a 2-fold increase in the average molecular weight. A strong influence of the symmetry of dialkylurea molecules was also found. Dipole moments of symmetric N,N'-dialkylurea increase with concentration, suggesting a rather linear arrangement of vectors in an aggregate. For asymmetric N,N-derivatives dipole moments decrease with concentration. DFT calculations were used to predict the form of aggregation.

Generalized solvent scales as a tool for investigating solvent dependence of spectroscopic and kinetic parameters. Application to fluorescent BODIPY dyes.

Two difluoroboron dipyrromethene (BODIPY) based fluorescent dyes - 4,4-difluoro-3-{2-[4-(dimethylamino)phenyl]ethenyl}-8-[4-(methoxycarbonyl)phenyl]-1,5,7-trimethyl-3a,4a-diaza-4-bora-s-indacene (1) and 4,4-difluoro-3-[2-(4-fluoro-3-hydroxyphenyl)ethenyl]-8-[4-(methoxycarbonyl)phenyl]-1,5,7-trimethyl-3a,4a-diaza-4-bora-s-indacene (3) - have been synthesized via condensation of p-N,N-dimethylaminobenzaldehyde and 4-fluoro-3-hydroxybenzaldehyde, respectively, with 4,4-difluoro-8-[4-(methoxycarbonyl)phenyl]-1,3,5,7-tetramethyl-3a,4a-diaza-4-bora-s-indacene (2). UV-vis spectrophotometry and steady-state and time-resolved fluorometry have been used to study the spectroscopic and photophysical characteristics of in various solvents. The multi-parameter Kamlet-Taft {pi*, alpha, beta} solvent scales and a new, generalized treatment of the solvent effect, proposed by Catalán (J. Phys. Chem. B, 2009, 113, 5951-5960), have been used in the analysis of the solvatochromic shifts of the UV-vis absorption and fluorescence emission maxima of 1-3, and the rate constants of excited-state deactivation via fluorescence (k(f)) and radiationless decay (k(nr)). The four Catalán solvent scales (dipolarity, polarizability, acidity and basicity of the medium) are the most appropriate for describing the solvatochromic effects. Solvent dipolarity and polarizability are the important causes for the solvatochromism of 1. Conversely, the absorption and emission maxima of 2 and 3 are hardly dependent on the solvent: the small changes reflect primarily the polarizability of the solvent surrounding the dye. Fluorescence decay profiles of 1 can be described by a single-exponential function in aprotic solvents, whereas two decay times are found in alcohols. The fluorescence decays of 2 (lifetimes tau in 1.9-2.9 ns range) and 3 (tau between 3.5 and 4.0 ns) are mono-exponential in all solvents studied. The fluorescence properties of dye are very sensitive to the solvent: upon increasing solvent dipolarity, the fluorescence quantum yields and k(f) values decrease and the emission maxima become more red-shifted. The k(f) values of 2 [(1.6 +/- 0.3) x 10(8) s(-1)] and 3 [(1.5 +/- 0.2) x 10(8) s(-1)] are practically independent of the solvent properties. The crystal structure of reveals that the BODIPY core is nearly planar with the boron atom moved out of the plane. The angle between the phenyl group at the meso-position and the BODIPY plane equals 80 degrees.

Influence of the substituents on the structure and properties of benzoxaboroles.

Benzoxaboroles possessing aryl substituents in the oxaborole ring were synthesized, and their structures were determined by single-crystal X-ray diffraction. Structures in the solid state are centrosymmetric dimers with two intermolecular hydrogen bonds. These compounds were investigated using a combination of the spectroscopic and the computational approach, comparing their properties with the unsubstituted compound. Investigated compounds were characterized by (1)H, (13)C, and (11)B NMR spectroscopy in solution. Assignment of (1)H and (13)C signals was made on the basis of HSQC and HMBC spectra. The molecular structure of 1,3-dihydro-1-hydroxy-3-phenyl-2,1-benzoxaborole was calculated by the density functional (B3LYP) method with the extended 6-311++G(d,p) basis set. The calculated geometrical parameters were compared with experimental X-ray data, and the differences between experimental and calculated values were found to be of the order of experiment standard deviation, confirming a good description by this level of theory. The harmonic frequencies, potential energy distribution (PED), and IR intensities of this compound and its deuterated analogue were calculated with the B3LYP method. The assignment of the experimental spectra was made on the basis of the calculated PED. The consequence of dimer formation is the splitting of the vibrational modes into symmetric and antisymmetric vibrations. The structure modification resulting from the hydrogen bonded dimers formation is presented.

Interactions of dihydrochloride fluphenazine with DPPC liposomes: ATR-IR and 31P NMR studies.

The influence of dihydrochloride fluphenazine (FPh) on the dipalmitoylphosphatidylcholine (DPPC) bilayer structure was investigated using ATR-IR and (31)P NMR methods. The ATR-IR results indicate an increase in conformational disorder in the hydrophobic part compared with pure DPPC liposomes and a decrease in temperature of the chain-melting phase transition in FPh/DPPC liposomes. These effects depended on the concentration of the drug in the DPPC bilayer. The dihydrochloride fluphenazine molecules form H-bonds with the proton-acceptor carbonyl groups of DPPC molecules. At a higher concentration of the drug, the lipid bilayer structure is destroyed, and an isotropic phase is observed using (31)P NMR spectroscopy. The interactions between FPh and the lipid bilayer have a crucial role in MDR (multidrug-resistant) activity of this drug. These results improve one possible strategy of cancer chemoprevention with FPh accompanied by fluidization and destabilization of the model lipid bilayer structure.

The effect of 3-pentadecylphenol on DPPC bilayers ATR-IR and 31P NMR studies.

The influence of 3-pentadecylphenol (PDP) on the structure and physicochemical properties of the lipid bilayers of DPPC liposomes was studied using ATR-IR and (31)P NMR methods. On the basis of analysis of the bands assigned to the CH(2) stretching, CH(2) scissoring, C=O stretching, and PO(2)(-) stretching vibrations it was revealed that PDP influences both the hydrophobic and hydrophilic parts of the DPPC liposome bilayer. Analysis of the (31)P NMR line-shape indicated a lamellar to non-lamellar phase transition in PDP-doped DPPC dispersions. It was shown that PDP/DPPC isotropic aggregates have similar nuC=O and nu(as)PO(2)(-) band positions and lower gauche populations in the hydrophobic chain region compared with the DPPC bilayer in the liquid-crystal phase.

Spectroscopic properties of a strongly anharmonic Mannich base N-oxide.

Car-Parrinello molecular dynamics simulations in vacuum and in the solid state are performed on a strongly anharmonic system, namely, 2-(N-diethylamino-N-oxymethyl)-4,6-dichlorophenol, to investigate its molecular and spectroscopic properties. The investigated compound contains two slightly different molecules in the crystal cell with very short intramolecular hydrogen bonds (of 2.400 and 2.423 A), as determined previously by neutron diffraction. The vibrational properties of the compound are studied on the basis of standard approaches, that is, Fourier transformation of the autocorrelation functions of the atomic velocities and dipole moments. Then, the trajectory obtained from ab initio molecular dynamics is sampled and the obtained snapshots are used to solve the vibrational Schrödinger equations and to calculate the O--H stretching envelope as a superposition of the 0-->1 transition. Using an envelope method, the a posteriori quantum effects are included in the O--H stretching. In addition, NMR spectra are calculated also using the obtained snapshots. One- and two-dimensional potentials of mean force (1D and 2D pmf) are derived to explain the details of the proton dynamics. The computational results are supported by NMR experimental data. In addition, the calculated results are compared with previously published X-ray, neutron diffraction, and spectroscopic descriptions. A detailed analysis of the bridged proton's dynamics is thus obtained. The application of 1D and 2D pmf in a system with a strong bridged-proton delocalization is also demonstrated.

Density functional theory study of intramolecular hydrogen bonding and proton transfer in o-hydroxyaryl ketimines.

The potential energy surface and the reaction pathway for the intramolecular hydrogen transfer in o-hydroxyaryl ketimines are characterized using DFT methods. Structural changes in the proton-transfer process in quasi-aromatic hydrogen bonding are described. A transition state and a state with a low proton-transfer barrier were studied in sterically compressed o-hydroxyaryl ketimines (2(N-methyl-alpha-iminoethyl)phenols) possessing two potential minimums. The potentials for proton vibration in the OH and HN tautomers of o-hydroxyaryl ketimines were investigated and anharmonic frequencies were determined. Solvent and substituent effects were analyzed. The energies of the various conformers of the OH and HN tautomers were compared with the related forms of o-hydroxyaryl aldimine.

Car-Parrinello simulation of an O-H stretching envelope and potential of mean force of an intramolecular hydrogen bonded system: application to a Mannich base in solid state and in vacuum.

Car-Parrinello molecular dynamics (CPMD) study was performed for an anharmonic system-an intramolecularly hydrogen bonded Mannich-base-type compound, 4,5-dimethyl-2(N,N-dimethylaminemethyl)phenol, to investigate the vibrational spectrum associated with the O-H stretching. Calculations were carried out for the solid state and for an isolated molecule. The classical CPMD simulation was performed and then the proton potential snapshots were extracted from the trajectory. The vibrational Schrodinger equation for the snapshots was solved numerically, and the (O-H) envelope was calculated as a superposition of the 0-->1 transitions. The potential of mean force for the proton stretching mode was calculated from the proton vibrational eigenfunctions and eigenvalues incorporating statistical sampling, nuclear quantum effects, and effects of the environment. Perspectives for application of the presented methodology in the computational support of biocatalysis are given in the study.

Car-Parrinello molecular dynamics study of the blue-shifted F3CH...FCD3 system in liquid N2.

Fluoroform, as confirmed by both experimental and theoretical studies, can participate in improper H-bond formation, which is characterized by a noticeable increase in the fundamental stretching frequency nu(C-H) (so-called blue frequency shift), an irregular change of its integral intensity, and a C-H bond contraction. A Car-Parrinello molecular dynamics simulation was performed for a complex formed by fluoroform (F3CH) and deuterated methyl fluoride (FCD3) in liquid nitrogen. Vibrational analysis based on the Fourier transform of the dipole moment autocorrelation function reproduces the blue shift of the fundamental stretching frequency nu(C-H) and the decrease in the integral intensity. The dynamic contraction of the C-H bond is also predicted. The stoichiometry of the solvated, blue-shifted complexes and their residence times are examined.

Ab initio studies of electron acceptor-donor interactions with blue- and red-shifted hydrogen bonds.

The features of blue- and red-shifted electron acceptor-donor (ACH/B) hydrogen bonds have been compared by using quantum chemical calculations. The geometry, the interaction energy and the vibrational frequencies of both blue- (ACH=F3CH, Cl3CH with B=FCD3) and red-shifted (ACH=F3CH, Cl3CH with B=NH3 and ACH=CH3CCH with B=FCD3, NH3) complexes were obtained by using ab initio MP2(Full)/6-31+G(d,p) calculations with the a priori basis-set superposition error (BSSE) correction method. One-dimensional potential energy and dipole moment functions of the dimensionless normal coordinate Q1, corresponding to the CH stretching mode of ACH, have been compared for both types of complexes. Contributions of separate components of the interaction energy to the frequency shift and the effect of electron charge transfer were examined for a set of intermolecular distances by using the symmetry-adapted perturbation theory (SAPT) approach and natural bond orbitals (NBO) population analysis.

Molecular modeling study of leflunomide and its active metabolite analogues.

Leflunomide is known as a compound with various sorts of biological activity, which found a practical application in medicine. Search of current literature revealed an active metabolite of Leflunomide together with its eight analogues synthesized as protein tyrosine kinase inhibitors with potential anticancer activity. Accurate description of the molecular structure of these compounds is valuable. The detailed geometrical parameters description was performed using DFT theory. The conformational analysis and intramolecular proton transfer were considered. Using the most stable conformation the detailed electronic structure description was obtained by analysis of electron density and electrostatic potential distribution in the first step. Next, the topological analysis of the electron density by AIM method and electron localization function (ELF) theories supplemented this study. The AIM and ELF theories were applied to study the topology of the molecules, atomic charges distribution, and details of bonding. The theoretical investigations were performed in the gas phase and by using SCRF/PCM solvent reaction field. In this study the molecular modeling results for Leflunomide and the analogues of its active metabolite are presented.

Influence of substituents on the anharmonicity of nus(OH) vibration in phenol derivatives explored by experimental and theoretical approach.

Very good reproducibility of the first five vibrational transitions of phenol in the gas phase by the MP2/ 6-31G potential for O-H bond stretching was found. The vibrational levels were calculated by a program for variational solving of the time-independent Schrödinger equation in one dimension. Relative intensities of particular transitions were determined on the basis of the function of the dipole moment. The substituent effects on the nu(s)(OH) transitions and on the intensity of these transitions, as well as on the structure of eleven phenols, was analyzed as a function of the pK(a) values.

Density functional calculation of the 2D potential surface and deuterium isotope effect on 13C chemical shifts in picolinic acid N-oxide. Comparison with experiment.

2D free energy surfaces V = V(rOH, rO...O) for the intramolecular H-bond in the title compound were calculated by the DFT method and used in the calculation of primary and secondary chemical shifts of the compound dissolved in chloroform and acetonitrile. Solvent effects were accounted for by the SCRF/PCM method. The corresponding two-dimensional chemical shift surfaces with included solvent reaction field were obtained using the Continuous Set of Gauge Transformations approach at the B3LYP/6-311+G(2d,2p) level of theory. The chemical shifts were estimated as quantum averages along the two internal coordinates in the hydrogen bond and along several vibrational levels according to the Boltzmann distribution at room temperature. Fairly good agreement between the experimental and calculated isotope effects was obtained. 1D and 2D NMR spectra of solutions of picolinic acid N-oxide and its deuterated analogue were recorded and assigned.

Structure/activity investigations of 5-substituted 3-methylisoxazole[5, 4-d]1, 2, 3-triazin-4-one derivatives.

The series of 5-substituted 3-methylisoxazole[5, 4-d]1, 2, 3-triazin-4-one derivatives was obtained by diazotization of 5-amino-3-methylisoxazol-4-carboxylic acid hydrazide. The immunological activity of these compounds was investigated experimentally in several in vitro and in vivo assays in mice and human models. In the next step, quantum-chemical investigations were performed using density functional theory with the B3LYP hybrid exchange-correlation energy functional and 6-31G(d, p) basis set. The Polarizable Continuum (SCRF/PCM) solvent model was also taken into account in order to show solvent influence on electron density and electrostatic potential around the exemplary molecules. Correlations between molecular structure and biological properties were found using a stepwise selection of scales for the multiple linear regression (MLR).