Adducts of acylphloroglucinols with explicit water molecules: Similarities and differences across a sufficiently representative number of structures

Acylphloroglucinols constitute a broad class of compounds, derivatives of 1,3,5‐trihydroxybenzene, characterized by at least one COR group and exhibiting a variety of biological activities. The presence of several hydrogen bond donor or acceptor sites (the three phenol OH of the phloroglucinol moiety and the sp² O of the COR group), and their comparatively close spacing, makes the study of adducts with explicit water molecules particularly interesting, because it is possible to consider adducts in which water molecules surround the entire acylphloroglucinol molecule, or a large part of it, providing expectedly realistic images of possible arrangements of water molecules in the close vicinity of the acylphloroglucinol molecule in the aqueous medium. This work considers a number of different monomeric structures sufficiently representative of the broad structural variety of acylphloroglucinols and considers adducts of all the relevant conformers for each structure. Calculations use the HF/6‐31G(d,p) level because of affordability reasons in view of the adducts' size. The results: show that the intramolecular hydrogen bond (IHB) between the sp² O of COR and an ortho OH does not break on competition with solute–solvent intermolecular H‐bonding; highlight general trends and trends related to specific geometry features of the conformers; enable an interpretation of the additional solvent stabilization of the conformers without IHBs, observed from polarizable continuum model results in water solution; and highlight the significance, for this class of compounds, of considering adducts in whichthe water molecules directly H‐bonded to the central molecule are bridged by other water molecules, to approximate a continuous layer. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem 110:2378–2390, 2010     

Computational Study of Hydrogen Bonding in Substituted Phenol‐Acetonitrile‐Water Clusters

The calculations for a water‐acetonitrile‐substituted phenols system and the comparison with the experimental parameters will be given. Here we study change in the nature of the interactions into the system with donor and acceptor electron substituents on the phenolic ring, the structures, relative energies and harmonic frequencies. The conformers showed a significant difference in the OH and CN band shift depending on the type of the hydrogen bond formed and the position of the substituent on the phenolic ring. The cyclical hydrogen bonds between water‐acetonitrile and substituted phenol OH are important evidence of the relative stability in the system under study.     

Solvent‐Modulated Influence of Intramolecular Hydrogen‐Bonding on the Conformational Properties of the Hydroxymethyl Group in Glucose and Galactose: A Molecular Dynamics Simulation Study

Intramolecular hydrogen‐bonding (H‐bonding) is commonly regarded as a major determinant of the conformation of (bio)molecules. However, in an aqueous environment, solvent‐exposed H‐bonds are likely to represent only a marginal (possibly adverse) conformational driving as well as steering force. For example, the hydroxymethyl rotamers of glucose and galactose permitting the formation of an intramolecular H‐bond with the adjacent hydroxyl group are not favored in water but, in the opposite, least populated. This is because the solvent‐exposed H‐bond is dielectrically screened as well as subject to intense H‐bonding competition by the water molecules. In the present study, the effect of a decrease in the solvent polarity on this rotameric equilibrium is probed using molecular dynamics simulation. This is done by considering six physical solvents (H₂O, DMSO , MeOH , CHC l₃, CC l₄, and vacuum), along with 19 artificial water‐like solvent models for which the dielectric permittivity and H‐bonding capacity can be modulated independently via a scaling of the O–H distance and of the atomic partial charges. In the high polarity solvents, the intramolecular H‐bond is observed, but arises as an opportunistic consequence of the proximity of the H‐bonding partners in a given rotameric state. Only when the polarity of the solvent is decreased does the intramolecular H‐bond start to induce a conformational pressure on the rotameric equilibrium. The artificial solvent series also reveals that the effects of the solvent permittivity and of its H‐bonding capacity mutually enhance each other, with a slightly larger influence of the permittivity. The hydroxymethyl conformation in hexopyranoses appears to be particularly sensitive to solvent‐polarity effects because the H‐bond involving the hydroxymethyl group is only one out of up to five H‐bonds capable of forming a network around the ring.     

Modelling zwitterions in solution: 3-fluoro-γ-aminobutyric acid (3F-GABA)

The conformations and relative stabilities of folded and extended 3-fluoro-γ-aminobutyric acid (3F-GABA) conformers were studied using explicit solvation models. Geometry optimisations in the gas phase with one or two explicit water molecules favour folded and neutral structures containing intramolecular NH···O-C hydrogen bonds. With three or five explicit water molecules zwitterionic minima are obtained, with folded structures being preferred over extended conformers. The stability of folded versus extended zwitterionic conformers increases on going from a PCM continuum solvation model to the microsolvated complexes, though extended structures become less disfavoured with the inclusion of more water molecules. Full explicit solvation was studied with a hybrid quantum-mechanical/molecular-mechanical (QM/MM) scheme and molecular dynamics simulations, including more than 6000 TIP3P water molecules. According to free energies obtained from thermodynamic integration at the PM3/MM level and corrected for B3LYP/MM total energies, the fully extended conformer is more stable than folded ones by about -4.5 kJ mol(-1). B3LYP-computed (3)J(F,H) NMR spin-spin coupling constants, averaged over PM3/MM-MD trajectories, agree best with experiment for this fully extended form, in accordance with the original NMR analysis. The seeming discrepancy between static PCM calculations and experiment noted previously is now resolved. That the inexpensive semiempirical PM3 method performs so well for this archetypical zwitterion is encouraging for further QM/MM studies of biomolecular systems.     

Probing the influence of solvent effects on the conformational behavior of 1,3-diazacyclohexane systems

The conformational behavior of a 1,3-diazacyclohexane system has been investigated using the DFT B3LYP/6-311+G** level of theory. The structural parameters and relative energies predicted that anomeric effects are operative in the conformations of 1,3-diazacyclohexane. The stability of conformers predicted in the solvent continuum model (water and acetonitrile) is similar to the gas-phase results. The explicit water molecules stabilized the least-stable conformer, and the predictive trend is opposite to that of the gas-phase results. The stability of the conformers in the gas phase is a compromise between avoiding repulsions and maximizing hyperconjugative stabilization. The NBO analysis suggests that the interactions of explicit solvent molecules with 1,3-diazacyclohexane conformers attenuate the anomeric stabilization. The hydrogen-bonding interactions of explicit solvent molecules with 1,3-diazacyclohexane swamped the anomeric effects to alter the conformational stability compared to the gas-phase and solvent continuum model studies.     

Ultrafast anisotropy dynamics of water molecules dissolved in acetonitrile

Infrared pump-probe experiments are performed on isolated H(2)O molecules diluted in acetonitrile in the spectral region of the OH stretching vibration. The large separation between water molecules excludes intermolecular interactions, while acetonitrile as a solvent provides substantial hydrogen bonding. Intramolecular coupling between symmetric and asymmetric modes results in the anisotropy decay to the frequency-dependent values of approximately 0-0.2 with a 0.2 ps time constant. The experimental data are consistent with a theoretical model that includes intramolecular coupling, anharmonicity, and environmental fluctuations. Our results demonstrate that intramolecular processes are essential for the H(2)O stretching mode relaxation and therefore can compete with the intermolecular energy transfer in bulk water.     

Density functional study of hydrogen‐bonded acetonitrile–water complex

We report the interaction of acetonitrile with one, two, and three water molecules using the Density Functional Theory method and the 6‐31+G* basis set. Different conformers were studied and the most stable conformer of acetonitrile–(water)_n complex has total energies –209.1922504, –285.6224478, and –362.068728 hartrees with one, two, and three water molecules, respectively. The corresponding binding energy for these three structures is 4.52, 8.34, and 22.48 kcal/mol. The hydrogen‐bonding results in blue, blue, and redshift in C?N stretching mode in acetonitrile with one, two, and three water molecules, respectively, whereas there was a redshift in O? H symmetric stretching mode of water. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

A comparative study of the dimers of selected hydroxybenzenes

Hydroxybenzenes are the parent compounds of large classes of derivatives, many of which exhibit biological activities. This work presents the results of a comparative study of the dimers of selected hydroxybenzenes, considering all the possible mutual geometrical arrangements of the two monomers and comparing their relative stabilities and interaction energies. The OH···OH hydrogen bond between the two monomers is the dominant stabilizing factor, with frequent preference for mutual perpendicularity of the two aromatic rings. C? H···O unconventional H‐bonds, OH···π unconventional H‐bonds, H···π interactions and π··π interactions also may play significant roles. The factors stabilizing individual hydroxybenzenes (presence of intramolecular hydrogen bonds; number, positioning and orientation of the OH groups; symmetry features) have greater influence on the dimers' relative energy than on the interaction energy between monomers. While results from different calculations methods (HF, MP2, and DFT/B3LYP) show consistency for all the features just‐mentioned, they show some relevant differences in the way they take into account different types of interactions between monomers, resulting in some differences in the geometry arrangements of the monomers in the lowest energy dimers and in differences in the relative preferences among higher‐energy dimer geometries. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

Structural analysis of sterically hindered 1,4‐diols from the naturally occurring lignan hydroxymatairesinol a quantum chemical study

The structures of TADDOL‐like α‐conidendrin‐based chiral 1,4‐diols (LIGNOLs) have been studied at molecular mechanics, Hartree‐Fock (HF)/6‐31G* and DFT/B3LYP/TZVP level of theory. The molecules included were 1,1‐diphenyl, two diastereomers of 1,1,4‐triphenyl, 1,1,4,4‐tetraphenyl, and 1,1,4,4‐tetramethyl 1,4‐diol. Several conformers of each molecule were studied thorougly also including the entropy contributions. For the triphenyl 1,4‐diols, which can form π ? π interactions between phenyl rings, the DFT optimized structures differed significantly from the HF optimized ones. A property for the most stable structures, in addition to the ability to form π ? π interactions, seemed to be the possibility to have the aliphatic six‐membered ring in a boat conformation. For all of the studied LIGNOLs some conformers were found, where the two OH groups pointed almost to the same direction. By this an intramolecular hydrogen bond can be formed between them. The bridging hydrogen atom falls at the same place as a chelate‐bonded metal ion would be situated, as in the case of the analogous molecules, TADDOLs, but only a few of these molecules would be able to work well as ligands for asymmetric catalysis. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Study on Preferential Solvation of Water by Electrochemical Method

The preferential solvation of water plays an important role in ferrocene research which is a subject of current interest. Voltammetric investigations were carried out for Au electrode in acetonitrile/water, showing preferential solvation of water. In our work, the preferential solvation of water in acetonitrile/water was studied by electrochemical methods including cyclic volitammetry, electrochemical impedance spectra and double‐step chronoamperometry. Ferrocenemethanol (FcCH₂OH) molecules as a solute spontaneously adsorb on the electrode surface in anhydrous acetonitrile, resulting from acetonitrile molecules tend to form an acetonitrile solvent layer on the surface of the electrode and acetonitrile solvent layer has a lower energy barrier than the aqueous solvent layer, which has been obtained by modeling solvation. The solvent strongly influences electrochemical behavior of solute. Once there is an amount of water in acetonitrile solvent, FcCH₂OH that adsorbed on the electrode surface desorb. This is because water preferentially solvate with FcCH₂OH in term of intermolecular forces between solvent and solute. Moreover, hydrogen bond between water molecules and FcCH₂OH molecules is stronger than dipole‐dipole interaction between acetonitrile molecules and FcCH₂OH molecules in solvation effect. Through electrochemical behavior of FcCH₂OH changing, preferential solvation of water is analyzed by electrochemical methods.     

Ab Initio MP2 and Density Functional Theory Computational Study of AcAlaNH2 Peptide Hydration: A Bottom‐Up Approach

AcAlaNH₂?n H₂O (n=1–13) complexes have been proposed as models to account for water solvent effects on the molecular properties of N‐acetyl‐L ‐alanine amide. Ab initio computations are planned to evaluate peptide–water interactions and to provide a means for approximating relative effects of the short‐range many‐body interactions arising in real solution without introducing any external parameters intended to quantify empirical or semiempirical potential‐energy functions. The present bottom‐up approach reveals the formation of compact ring clusters of water molecules strongly bonded to peptidic polar groups throughout hydrogen bonds. The explicit coordination of water molecules around the peptide renders the fully extended (FE) and polyproline II (PPII) conformers more stable with respect to the 3₁₀ helix or γ turn. The alternance of donor and acceptor groups on both sides of the FE and PPII conformers allows for synergy and extensive H‐bonding.     

Cyclic tetraureas with variable flexibility--synthesis, crystal structures and properties

Macrocyclic molecules containing several amide or urea functions may serve as anion receptors. We describe the synthesis of 32-membered macrocycles, in which four rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All six possible combinations of these units (XXXX, XXXD, XXDD, XDXD, XDDD and DDDD) were synthesized and two examples were characterised by single-crystal X-ray analyses (DDDD and two structures for XXXD). Both macrocycles showed distinct differences in their overall conformation and consequently in their hydrogen-bonding pattern. Hydrogen-bonded solvent molecules are found for both compounds and intramolecular hydrogen bonds for the two structures of XXXD, but surprisingly no direct intermolecular hydrogen bonds between the macrocyclic tetraurea molecules. The interaction with various anions was studied by (1)H NMR spectroscopy. Stability constants for all tetramers were determined by UV spectroscopy for complexes with chloride, bromide, acetate and dihydrogenphosphate in acetonitrile-THF (3:1). The strongest binding was found for XXXD and acetate (log beta = 7.4 +/- 0.2), the weakest for XXXX and acetate (log beta = 5.1 +/- 0.5). MD simulations in chloroform and acetonitrile boxes show that all molecules except DDDD adopt very similar conformations characterized by an up-down-up-down arrangement of the spacer groups. Clustered solvation shells of acetonitrile molecules around XXXX and DDDD suggest their preorganization for spherical/planar and tetrahedral/bidentate anions, respectively, which in turn was corroborated by simulation of the corresponding complexes with chloride and dihydrogenphosphate.     

Conformation of 1,2-Dimethoxyethane in Water

To understand the conformation of 1,2-dimethoxyethane (DME) in water, a system of two kinds of molecules, DME and H_2O, was focused. The interaction of various conformers of DME with water was studied by means of ab initio molecular orbital calculation with 6-31G (d) basis set. It is shown that there are two forms of interactions between the two molecules in the system, the close touched (H_2O attaches to the two oxygen atoms of DME) and the open touched (H_2O attaches to one oxygen atom of DME) structures. The conformation of DME is remarkably influenced by the interactions. Instead the ttt conformer is preferred in the gas state, with a close touched H_2O the tgt conformer becomes the most stable one. The obtained hydration energies show that the stabilized order of DME conformers by water is tgt>tgg′>ttt.     

Solvent effect on the tautomers' stabilities of protonated N,N‐dimethylnitrosamine: The role of hydrogen bonds network

DFT calculations have been applied in order to study the free energies of the structures corresponding to the three different protonation sites of N,N‐dimethylnitrosamine (DMNA). The solvent effect has been taken into account through the study of clusters consisting of protonated DMNA and up to four explicit water molecules, either in the absence or in the presence of a continuum (CPCM) solvation model. Addition of water molecules has been done by a careful screening procedure through which all important hydrogen bonds are likely to be considered. Protonation of DMNA makes all their lone pairs no longer available for hydrogen bond formation with water molecules, such that hydrogen bonds have been observed, for almost all structures, only between water molecules and between one water molecule and the protonated DMNA, in this latter case intermediated by the proton. The stabilities of the solvated structures are governed not only by the number of hydrogen bonds but also by the positions of the water molecules involved in these bonds, as well as by which of them donate or accept H atoms. Our results indicate that oxygen protonation is the most favorable one, regardless of the presence of water molecules. In vacuum protonation at the N‐amino ( 2a ) is approximately as favorable as protonation at the N nitroso ( 2c ). However, in water the former protonation is by far the less favorable one. Our best estimates for the ΔG values in bulk solvent are: ΔG( 2a ) ≈ 17.9, ΔG( 1c ) ≈ 4.3, and ΔG( 2c ) ≈ 4.9 kcal/mol.     

2‐{[(3‐Fluorophenyl)amino]methylidene}‐3‐oxobutanenitrile and 5‐{[(3‐fluorophenyl)amino]methylidene}‐2,2‐dimethyl‐1,3‐dioxane‐4,6‐dione: X‐ray and DFT studies

In the crystal structures of the title compounds, C₁₁H₉FN₂O, (I), and C₁₃H₁₂FNO₄, (II), the molecules are joined pairwise via different hydrogen bonds and the constituent pairs are crosslinked by weak C—H...O hydrogen bonds. The basic structural motif in (I), which is partially disordered, comprises pairs of molecules arranged in an antiparallel fashion which enables C—H...N[triple‐bond]C interactions. The pairs of molecules are crosslinked by two weak C—H...O hydrogen bonds. The constituent pair in (II) is formed by intramolecular bifurcated C—H...O/O′ and combined inter‐ and intramolecular N—H...O hydrogen bonds. In both structures, F atoms form weak C—F...H—C interactions with the H atoms of the two neighbouring methyl groups, the H...F separations being 2.59/2.80 and 2.63/2.71 Å in (I) and (II), respectively. The bond orders in the molecules, estimated using the natural bond orbitals (NBO) formalism, correlate with the changes in bond lengths. Deviations from the ideal molecular geometry are explained by the concept of non‐equivalent hybrid orbitals. The existence of possible conformers of (I) and (II) is analysed by molecular calculations at the B3LYP/6–31+G** level of theory.     

Computational study of the patterns of weaker intramolecular hydrogen bonds stabilizing acylphloroglucinols

Acylphloroglucinols (ACPLs) are polyphenolic compounds derivative from phloroglucinol, characterized by the presence of at least one COR group and exhibiting a variety of biological activities, which makes them interesting for drug development possibilities. This study investigates patterns in the ways in which weaker intramolecular hydrogen bonds contribute to their conformational stabilization, considering the C? H···O H‐bonds, present in all ACPLs, and the O? H···π H‐bonds, present in ACPLs in which one or more substituents contain a π bond or system sufficiently close to a phenol OH for the H‐bond to be possible. The results in vacuo and in three different solvents (chloroform, acetonitrile, and water) show that, whereas C? H···O plays a significant roles in all these media, the role of O? H···π decreases with increasing solvent polarity. Calculations in vacuo are performed at various levels to enable performance comparisons; calculations in solution use the polarizable continuum model. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Conformational study of (8alpha,8'beta)-bis(substituted phenyl)-lignano-9,9'-lactones by means of combined computational, database mining, NMR, and chemometric approaches

Beta-(3,4-Methylenedioxybenzyl)-gamma-butyrolactone (MDBL) and (-)-hinokinin (HK) were obtained by partial synthesis and characterized by 1H NMR and computational methods (conformational analysis, molecular modeling, structural data mining and chemometrics). Three conformers were detected for MDBL and nine were found for HK. The energy differences are around 1 and 2 kcal mol(-1) and rotation barriers are less than 3 and 5 kcal mol(-1) for MDBL and HK conformers, respectively. The geometries of these conformers, obtained from semiempirical PM3 and density functional theory (DFT) B3LYP 6-31G** calculations agree satisfactorily with 1H NMR data (vicinal proton-proton coupling constants) and structures retrieved from the Cambridge Structural Database (torsion angles). DFT combined with some variants of the Haasnoot-de Leeuuw-Altona equations gives the best predictions for the coupling constants. The molecular conformation of MDBL, of HK, and of related systems depends not only on intramolecular interactions but also on crystal packing forces and solvent-solute interactions, in particular hydrogen bonds and polar interactions. Hydration favors more stable HK conformers, which can be important for their behavior in chemical and biological systems.     

Unusual H‐Bond Topology and Bifurcated H‐bonds in the 2‐Fluoroethanol Trimer

By using a combination of rotational spectroscopy and ab initio calculations, an unusual H‐bond topology was revealed for the 2‐fluoroethanol trimer. The trimer exhibits a strong heterochiral preference and adopts an open OH???OH H‐bond topology while utilizing two types of bifurcated H‐bonds involving organic fluorine. This is in stark contrast to the cyclic OH???OH H‐bond topology adopted by trimers of water and other simple alcohols. The strengths of different H‐bonds in the trimer were analyzed by using the quantum theory of atoms in molecules. The study showcases a remarkable example of a chirality‐induced switch in H‐bond topology in a simple transient chiral fluoroalcohol. It provides important insight into the H‐bond topologies of small fluoroalcohol aggregates, which are proposed to play a key role in protein folding and in enantioselective reactions and separations where fluoroalcohols serve as a (co)solvent.     

Hydrogen bonding and cooperativity in isolated and hydrated sugars: mannose, galactose, glucose, and lactose

The conformation of phenyl-substituted monosaccharides (mannose, galactose, and glucose) and their singly hydrated complexes has been investigated in the gas phase by means of a combination of mass selected, conformer specific ultraviolet and infrared double resonance hole burning spectroscopy experiments, and ab initio quantum chemistry calculations. In each case, the water molecule inserts into the carbohydrate at a position where it can replace a weak intramolecular interaction by two stronger intermolecular hydrogen bonds. The insertion can produce significant changes in the conformational preferences of the carbohydrates, and there is a clear preference for structures where cooperative effects enhance the stability of the monosaccharide conformers to which the water molecule chooses to bind. The conclusions drawn from the study of monosaccharide-water complexes are extended to the disaccharide lactose and discussed in the light of the underlying mechanisms that may be involved in the binding of carbohydrate assemblies to proteins and the involvement, or not, of key structural water molecules.     

Molecular‐Dynamics and NMR Investigation of the Property Space of the Zwitterionic Antihistamine Cetirizine

The zwitterionic antihistamine cetirizine and its parent drug hydroxyzine as reference compound were examined for their 3D structures and dynamics. After attributing, by NMR spectroscopy, the two basic pK_a values, the most common conformations for each electrical species were determined by molecular‐dynamics simulations and confirmed by NMR measurements. For cetirizine, the results demonstrate that the zwitterion, which is the predominant species at physiological pH, exists as folded conformers able to partly mask polar groups. Extended and folded conformers of similar energy were also found for neutral hydroxyzine, whereas its monocationic species displayed folded conformers stabilized by intramolecular H‐bonds. These findings are in full agreement with previous results on the lipophilicity behavior of cetirizine in isotropic solvent systems and, taken together, could explain the favorable pharmacokinetic properties of the drug.