Aqueous Extracts of Organic Mulch Materials Have Nematicide and Repellent Effect on Meloidogyne incognita Infective Juveniles: A Laboratory Study.

While the nematicidal effectiveness of mulching against root-knot nematodes (Meloidogyne spp.) is calculated within organic crop protection, underlying mechanisms are not yet fully explored. Laboratory experiments were set up to determine whether mulch-derived substances cause mortality directly, or repel Meloidogyne juveniles from crop rhizosphere. Mortality and area choice tests were conducted with mulch-derived extracts, supported by the measurements on tannic acid content and the pH values of extracts as supplementary examinations. In our study, leaf litter and straw extracts were generally found lethal to the juveniles, which is in line with the results from area preference tests. However, compost extract had no effect on Meloidogyne incognita juveniles. Tannic acid content showed positive correlation with mortality only in the case of straw and sycamore leaf litter extracts. Tannic acid and pH weakly correlated with repellent effect of the applied extracts generally. Our results have inspired further experiments to explore nematicidal components of leaf litters, contributing to the development of a new approach in crop protection based on the repellent effect of these materials.

Replacement of Oxygen by Sulfur in Small Organic Molecules. 3. Theoretical Studies on the Tautomeric Equilibria of the 2OH and 4OH-Substituted Oxazole and Thiazole and the 3OH and 4OH-Substituted Isoxazole and Isothiazole in the Isolated State and in Solution.

This follow-up paper completes the author's investigations to explore the in-solution structural preferences and relative free energies of all OH-substituted oxazole, thiazole, isoxazole, and isothiazole systems. The polarizable continuum dielectric solvent method calculations in the integral-equation formalism (IEF-PCM) were performed at the DFT/B97D/aug-cc-pv(q+(d))z level for the stable neutral tautomers with geometries optimized in dichloromethane and aqueous solution. With the exception of the predictions for the predominant tautomers of the 3OH isoxazole and isothiazole, the results of the IEF-PCM calculations for identifying the most stable tautomer of the given species in the two selected solvents agreed with those from experimental investigations. The calculations predict that the hydroxy proton, with the exception for the 4OH isoxazole and 4OH isothiazole, moves preferentially to the ring nitrogen or to a ring carbon atom in parallel with the development of a C=O group. The remaining, low-fraction OH tautomers will not be observable in the equilibrium compositions. Relative solvation free energies obtained by the free energy perturbation method implemented in Monte Carlo simulations are in moderate accord with the IEF-PCM results, but consideration of the ΔGsolv/MC values in calculating ΔG(s)tot maintains the tautomeric preferences. It was revealed from the Monte Carlo solution structure analyses that the S atom is not a hydrogen-bond acceptor in any OH-substituted thiazole or isothiazole, and the OH-substituted isoxazole and oxazole ring oxygens may act as a weak hydrogen-bond acceptor at most. The molecules form 1.0-3.4 solute-water hydrogen bonds in generally unexplored numbers at some specific solute sites. Nonetheless, hydrogen-bond formation is favorable with the NH, C=O and OH groups.

Theoretical in-Solution Conformational/Tautomeric Analyses for Chain Systems with Conjugated Double Bonds Involving Nitrogen(s).

Conformational/tautomeric transformations for X=CH-CH=Y structures (X = CH2, O, NH and Y = NH) have been studied in the gas phase, in dichloromethane and in aqueous solutions. The paper is a continuation of a former study where s-cis/s-trans conformational equilibria were predicted for analogues. The s-trans conformation is preferred for the present molecules in the gas phase on the basis of its lowest internal free energy as calculated at the B97D/aug-cc-pvqz and CCSD(T)CBS (coupled-cluster singles and doubles with non-iterative triples extrapolated to the complete basis set) levels. Transition state barriers are of 29-36 kJ/mol for rotations about the central C-C bonds. In solution, an s-trans form is still favored on the basis of its considerably lower internal free energy compared with the s-cis forms as calculated by IEF-PCM (integral-equation formalism of the polarizable continuum dielectric solvent model) at the theoretical levels indicated. A tetrahydrate model in the supermolecule/continuum approach helped explore the 2solute-solvent hydrogen bond pattern. The calculated transition state barrier for rotation about the C-C bond decreased to 27 kJ/mol for the tetrahydrate. Considering explicit solvent models, relative solvation free energies were calculated by means of the free energy perturbation method through Monte Carlo simulations. These calculated values differ remarkably from those by the PCM approach in aqueous solution, nonetheless the same prevalent conformation was predicted by the two methods. Aqueous solution structure-characteristics were determined by Monte Carlo. Equilibration of conformers/tautomers through water-assisted double proton-relay is discussed. This mechanism is not viable, however, in non-protic solvents where the calculated potential of mean force curve does not predict remarkable solute dimerization and subsequent favorable orientation.

Competing intramolecular vs. intermolecular hydrogen bonds in solution.

A hydrogen bond for a local-minimum-energy structure can be identified according to the definition of the International Union of Pure and Applied Chemistry (IUPAC recommendation 2011) or by finding a special bond critical point on the density map of the structure in the framework of the atoms-in-molecules theory. Nonetheless, a given structural conformation may be simply favored by electrostatic interactions. The present review surveys the in-solution competition of the conformations with intramolecular vs. intermolecular hydrogen bonds for different types of small organic molecules. In their most stable gas-phase structure, an intramolecular hydrogen bond is possible. In a protic solution, the intramolecular hydrogen bond may disrupt in favor of two solute-solvent intermolecular hydrogen bonds. The balance of the increased internal energy and the stabilizing effect of the solute-solvent interactions regulates the new conformer composition in the liquid phase. The review additionally considers the solvent effects on the stability of simple dimeric systems as revealed from molecular dynamics simulations or on the basis of the calculated potential of mean force curves. Finally, studies of the solvent effects on the type of the intermolecular hydrogen bond (neutral or ionic) in acid-base complexes have been surveyed.

Differential Induction of Cytoplasmic Vacuolization and Methuosis by Novel 2-Indolyl-Substituted Pyridinylpropenones.

Because many cancers harbor mutations that confer resistance to apoptosis, there is a need for therapeutic agents that can trigger alternative forms of cell death. Methuosis is a novel form of non-apoptotic cell death characterized by accumulation of vacuoles derived from macropinosomes and endosomes. Previous studies identified an indole-based chalcone, 3-(5-methoxy-2-methylindol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (MOMIPP), that induces methuosis in human cancer cells. Herein, we describe the synthesis of related 2-indolyl substituted pyridinylpropenones and their effects on U251 glioblastoma cells. Increasing the size of the 2-indolyl substituent substantially reduces growth inhibitory activity and cytotoxicity, but does not prevent cell vacuolization. Computational models suggest that the results are not due to steric-driven conformational effects. The unexpected uncoupling of vacuolization and cell death implies that the relationship between endosomal perturbations and methuotic cell death is more complex than previously realized. The new series of compounds will be useful in further defining the molecular and cellular mechanisms underlying methuosis.

In-solution conformational analysis of the XCYCH3 moiety for small esters and ethers with all combinations of X, Y = O, S.

Favorable steric and electrostatic fit of a ligand to a receptor is of central interest in theoretical drug design. This paper considers the effects of non-protic solvents, in comparison with the gas phase, on the preferred conformation of the XCYCH3 moiety of simple aliphatic esters and heterocyclic methyl ethers with all combinations of the X and Y atoms as oxygen and sulfur. An IEF-PCM/B97D/aug-cc-pv(t+d)z continuum dielectric solvent study in chloroform and acetonitrile explores the through-space polarization effect of the environment on the conformational preference, not affected by possible solute-solvent hydrogen bond formation. The inherently favored structure for the present molecules is important, since the hypothetical oxygen and sulfur lone-pairs point approximately in opposite directions in the cis conformation of esters, whereas the trans and gauche conformations for the methyl group in ethers define nearly parallel or perpendicular directionality for the lone pairs of the ring heteroatoms and the O or S atoms connecting to the ring. These different preferences for the studied two families of compounds allow for designing formation of hydrogen bonds with a protein in fairly different regions of the latter still within the ligand-binding cavity. For a fine-tuning of these hydrogen bonds, a replacement of an oxygen atom of the ligand by a sulfur atom could be a straightforward possibility.

Are the intramolecular O-H···F and O-H···Cl hydrogen bonds maintained in solution? A theoretical study.

The present case study aims at calculating the equilibrium conformer compositions for 2X-ethanol and 2X-phenol (X = F, Cl) in solution, and exploring the effect of the applied theoretical method and basis set on the obtained results, as well as considering the usefulness of the continuum solvent approach in comparison with the explicit solvent Monte Carlo model utilizing the free energy perturbation method. Gas-phase optimizations at the DFT/B97D/aug-cc-pvtz and ab initio MP2/aug-cc-pvtz levels predicted structures in good agreement with the available experimental data for three test molecules. Because in-solution geometries change only slightly according to the IEF-PCM continuum solvent calculations in carbon tetrachloride and water, the two theoretical levels were applied further on, and complete basis set (CBS) relative internal free energies were estimated for the conformers under study. The predicted OCCF gauche/trans ratio for 2F-ethanol was well reproduced in comparison with available experimental compositions. The predominant gauche structure maintains an intramolecular hydrogen bond in carbon tetrachloride (HB structure), whereas HB and NoHB gauche conformers appear in nearly the same fraction in aqueous solution. The internally hydrogen-bonded conformer is predominant also for 2X-phenol species, as calculated on the basis of relative CBS internal free energies and IEF-PCM and FEP/MC solvation free energies. Use of a trihydrate supermolecule model for 2F-ethanol conformers leads to the prediction of the aqueous-solution composition in contrast to the experiment. Solution structure modeling predicts weak hydrogen-bond formation capacity for both the covalently bound F and Cl atoms, even in conformations where they are fully exposed to hydration.

Theoretical study of the gauche-trans equilibrium with and without an intramolecular hydrogen bond for +H3NCH2CH2X systems (X = OH, NH2, COO-) in solution.

The gauche-trans conformational equilibrium has been studied for (+)H(3)NCH(2)CH(2)X systems (X = OH, NH(2), COO(-)) and for the neutral model of the simplest ß-amino acid in aqueous solution and chloroform. Each structure exhibits an intramolecular hydrogen bond in the NCCX gauche conformation, which is necessarily disrupted in the local energy minimum trans form. Geometries were optimized at the IEF-PCM/B97D/aug-cc-pvtz level of theory and indicated that the solvent effect of chloroform vs. water is moderate when the geometries for the corresponding gauche and trans conformers are compared. The only remarkable difference was found for ß-alanine, which can exist in gauche, zwitterionic form in aqueous solution but not in chloroform. Total relative free energies were obtained as the sum of the relative IEF-PCM/B97D/aug-cc-pvtz internal free energy and ΔG(solv). The latter was calculated both by means of IEF-PCM and the explicit solvent FEP/Monte Carlo methods. The resulting ΔG(tot) values could differ by 1-2 kcal mol(-1) depending on the accepted ΔG(solv) value, but any calculation indicated that the internally bound gauche conformers are far more populated than the corresponding trans species. A difference of 2.6 kcal mol(-1) for ΔG(solv) by the two methods resulted in the preference of the zwitterionic gauche ß-alanine structure by FEP/MC in contrast to IEF-PCM favoring the neutral form in aqueous solution. Monte Carlo characterization of the solution structure in the first solvation shell of polar groups indicates that solvation of a N-H(+) bond is sensitive to its involvement in an intramolecular hydrogen bond. For the zwitterionic, gauche ß-alanine, almost no water oxygen can reach that N-H(+) bond, which is in strong interaction with the -COO(-) group by forming a six-membered ring and favorable local geometry for the hydrogen bond.

Theoretical studies of the solvent effect on the conformation of the HO-C-C-X (X = F, NH2, NO2) moiety with competing intra- and intermolecular hydrogen bonds.

Theoretical calculations up to the ab initio IEF-PCM/CCSD(T)/CBS//IEF-PCM/B3LYP/6-311++G** and IEF-PCM/B97D/aug-cc-pvtz levels have been performed for 2X-ethanol and 2X-phenol systems with X = F, NH(2), NO(2) in chloroform and aqueous solution. The calculated relative free energies by means of the IEF-PCM continuum dielectric method do not differ very much at the DFT and ab initio levels. Application of explicit solvent models and the FEP/MC method for determining relative solvation free energies causes, however, large deviations in the predicted equilibrium compositions, although the predominant conformation for the solute is generally in agreement with that from the corresponding IEF-PCM calculations. Existence of an intramolecular hydrogen bond (HB structure) for species with the HO-C-C-X moiety is preferred compared with a conformation when the hydrogen bond is disrupted (NoHB) for the considered F- and NO(2)-substituted molecules both in chloroform and aqueous solution. For 2NH(2)-ethanol, the HB structure is predominant in chloroform, whereas the 93:7 ratio for the OCCN trans/gauche species was obtained in aqueous solution. 2NH(2)-phenol exhibits a subtle equilibrium of the HB and NoHB conformations in both solvents. Potential of mean force calculations predict about a 10% solute association for the trans 2NH(2)-ethanol solute even in the fairly dilute 0.22 molar solution, whereas direct MC simulations do not support the maintenance of a doubly hydrogen-bonded dimer. Aqueous solution characteristics, as coordination numbers and numbers of strongly bound water molecules to the solute at T = 298 K and p = 1 atm, correspond reasonably to the derived molecular structures.

On the interaction of aliphatic amines and ammonium ions with carboxylic acids in solution and in receptor pockets.

Association energies of the acetate ion with cationic amines bearing one to three methyl groups were calculated in the range of -14 to -17 kcal/mol in aqueous solution by means of the IEF-PCM method at the CCSD(T)/CBS//MP2/aug-cc-pvdz and DFT/B97D/CBS//B97D/aug-cc-pvtz levels. The main stabilization factor for the association is the possibility for the formation of an ionic intermolecular hydrogen bond between the elements of the complex. For a quaternary ammonium ion, the favorable electrostatic interaction energy is the only driving force, and the stabilization energy for the complex is reduced to -4 kcal/mol. The internal free energies of the ion-pair tautomers of the studied species are higher by 10-15 kcal/mol in water than those for the neutral, hydrogen-bonded forms. Monte Carlo free energy perturbation calculations at T = 298 K and p = 1 atm predict -11 to -16 kcal/mol relative solvation free energy in favor of the corresponding ionic form. As a result, the ion-pair tautomer is the prevailing form in aqueous solution and on the extracellular surface of a receptor. Modeling the complex of a protonated ligand interacting with an Asp/Glu carboxylate side-chain in the binding cavity of a receptor, two strongly bound water molecules were considered so as to form hydrogen-bonded water bridges between the elements of the ion-pair. Nonetheless, the low polarity environment mimicked by a chloroform solvent cannot stabilize the ionic tautomer. A proton jump was predicted, which suggests that acetylcholine, an inherent cation by structure, might have evolved as the natural agonist for muscarinic receptors because a quaternary ammonium system assures the maintenance of the ion-pair form with a carboxylate side-chain in a protein cavity, the latter perhaps then being needed for receptor activation.

Structure simulations for the 0.22 and 1 molar aqueous dimethylammonium chloride solutions.

Monte Carlo simulations have been performed for characterizing the 0.22 and 1 molar aqueous dimethylammonium chloride solutions at p = 1 atm and T = 310 K. On the basis of potential of mean force curves for the two systems with increasing concentrations, the N···N separations of about 8.7 and 7.5 Å correspond to a vague and a more pronounced minimum, respectively. Nitrogen separations at the minima are considerably smaller than those what the cations would take if the solutes comprised uniform local solute density on a microscale. The derived N by N coordination numbers predict non-negligible cation association and concomitant inhomogeneity for the studied systems. The calculated N···N distance distribution in the molar solution indicates that about 12% of the N···N separations are shorter than 8.5 Å compared with R(N···N) = 11.84 Å corresponding to the closest distance in a uniform cation local density. Despite a global minimum of -1.79 ± 0.63 kcal mol(-1) at N···Cl separation of 3.24 Å, obtained from the pmf for the 0.22 molar model, the N by Cl coordination number is only 0.14 in the first coordination shell, suggesting frequent disruption of an N-H(+)···Cl(+) hydrogen bond in a relatively dilute solution. The expression for the chemical potential of a solute includes a concentration-dependent activity coefficient, whose varying values are expected to reflect the different degrees of solute association in the 0.2-1 molar range. Theoretical follow-up of the changes in the activity coefficient values is difficult, thus calculation of the K(c) equilibrium constant has been proposed by considering 1 molar solutions as the standard state.

Combined ab initio/DFT and Monte Carlo calculation of relative standard chemical potentials in solution.

A method has been proposed for pure theoretical estimation of relative standard chemical potentials (1 mol/dm(3) standard state) and related K(c) equilibrium constants for tautomers/conformers dissolved in some solvents. The relative internal free energy could be obtained by means of in-solution ab initio/DFT methods. Using the free energy perturbation method for the transformation of the involved species, the solvation contribution to the relative standard chemical potential can be determined by considering 1 M solution models. Comparison of the ΔG(solv)/MC value calculated for the 1 M solution with those obtained for the system at other concentrations helps explore the ratio of the activity coefficients in nonstandard states. The method has been applied for the study of the tautomeric pair of formaldoxime and nitrosomethane with large structural differences. It was pointed out that the ΔG(solv)/MC values for the 1 and 0.11 M solutions differ by up to 0.2 kcal/mol, when atomic charges are derived on the basis of the in-solution IEF-PCM/B3LYP/aug-cc-pvtz molecular electrostatic potential. On the basis of calculated free energy differences, the ratio of the CH(3)NO and CH(2)NOH activity coefficients in 0.11 molar aqueous and dichloromethane solutions were predicted as of 1.4 and 0.8, respectively. The 0.11 M model is hypothetical by assuming that only one of the tautomers exists in the solution box. As an extension of the method, a procedure has been outlined where contributions to the change of the solvation free energy by terms related to relative activity coefficients might be assessed at physically relevant concentrations for the equilibrated tautomers.

Theoretical studies of the in-solution isomeric protonation of non-aromatic six-member rings with two nitrogens.

For exploring the preferred site for hydrogen bond formation, theoretical calculations have been performed for a number of six-member, nonaromatic rings allowing for alternative protonation on the ring nitrogens. Gas-phase protonation studies for test molecules indicate that the B3LYP/aug-cc-pvtz and QCISD(T)(CBS) calculations approach the experimental values within about 1 kcal/mol with considerable improvement for relative enthalpies and free energies. Relative free energies calculated at the IEF-PCM/B3LYP/aug-cc-pvtz level predict favorable protonation on the tertiary rather than on the secondary nitrogen both in aqueous solution and in a dichloromethane solvent for saturated rings. Protonation on a nitrogen atom next to a C═C bond is disfavored due to a large increase in internal energy. Monte Carlo simulations considering a counterion and Ewald summation for the long-range electrostatic effects for a 0.1 molar model system predict ΔG(solv)/MC values generally less negative than from the IEF-PCM calculations. These results make the protonation on the tertiary nitrogen even more favored. The solute-solvent pair-energy distribution depends sensitively on the applied model. In conclusion, the freely moving anion has been considered as the most relevant model with overall neutrality for the system and applying the least restrictions.

Molecular dynamics and Monte Carlo simulations for the structure of the aqueous trimethylammonium chloride solution in the 0.2-1 molar range.

Molecular dynamics and Monte Carlo simulations have been performed for characterizing the structure of the 0.2 and 1 molar aqueous trimethylammonium chloride solutions. Atomic charges were derived through the CHELPG and RESP fits to the molecular electrostatic potentials calculated for the cation in water at the IEF-PCM/B3LYP level using the 6-31G* and 6-311++G** basis sets. Maxima and minima of the calculated radial distribution functions were not sensitive to the four atomic charge sets. Simulated solution structures suggest non-negligible solute-solute interactions and remarkable inhomogeneity at both concentrations. This means that equilibrium ratios, derived for conformers/tautomers by means of ab initio calculations with the IEF-PCM continuum dielectric solvent model, should be corrected for free energy changes following solute association when compared to experimental data obtained for the 0.1-1 molar aqueous solutions.

Theoretical studies of salt-bridge formation by amino acid side chains in low and medium polarity environments.

Salt-bridge formation between Asp/Glu···Lys and Asp/Glu···Arg side chains has been studied by model systems including formic and acetic acids as proton donors and methylamine, guanidine, and methylguanidine as proton acceptors. Calculations have been performed up to the CCSD(T)(CBS)//MP2/aug-cc-pvtz level with formic acid proton donors. Complexes formed with acetic acid were studied at the CCSD(T)/aug-cc-pvdz//MP2/aug-cc-pvdz level. Protein environments of low and moderate polarity were mimicked by a continuum solvent with dielectric constants (ε) set to 5 and 15, respectively. Free energy differences, ΔG(tot), were calculated for the neutral, hydrogen-bonded form and for the tautomeric ion pair. These values predict that a salt bridge is not favored for the Asp/Glu···Lys pair, even in an environment with ε as large as 15. In contrast, the Asp/Glu···Arg salt bridge is feasible even in an environment with ε = 5. Charge transfers for the complexes were calculated on the basis of CHELPG and AIM charges.

The catalytic effect of water on the keto-enol tautomerism. Pyruvate and acetylacetone: a computational challenge.

The catalytic effect of explicit water molecules on the keto-enol tautomerism in a system of biological interest (enolpyruvate) has been investigated at the B3LYP/6-31++G** level by exploring the potential energy surface in the presence of 1 or 2 water molecules and comparing the energy profiles to the direct tautomerisation one. The water-assisted mechanisms turned out to be more favourable than the direct ones, in agreement with what occurred for the acetylacetone tautomerism in the presence of a single water molecule. To compare the behaviour of water in pyruvate and in acetylacetone, the two-water-assisted mechanism has been also examined for the latter at the B3LYP/6-31G* level. A number of stationary points for both compounds in vacuo and in the presence of explicit water molecules have been computed with DFT coupled to larger basis sets and at the MP2 level. Two diketo forms more stable than any of the keto-enol tautomers have been located, while for pyruvate the keto form is always more favourable than the enol one. The equilibrium constant for acetylacetone tautomerisation has been computed with high accuracy, performing a complete basis set extrapolation for the relative internal energy, to determine whether the quality of the method/basis set is responsible for the earlier modest agreement with the experimental value. Monte Carlo and molecular dynamics simulations helped characterize the solution structure and association features in the 0.03-0.22 molar concentration range.

Theoretical and experimental studies of the isomeric protonation in solution for a prototype aliphatic ring containing two nitrogens.

Theoretical calculations were carried out for studying the tautomeric protonation of N-methylpiperazine as a prototype six-member aliphatic ring containing a secondary and a tertiary nitrogen atom. The protonation was investigated in three solvents, water, acetonitrile, and dichloromethane. Calculations were performed up to the B3LYP/aug-cc-pvtz and QCISD(T)/CBS levels by applying the IEF-PCM polarizable continuum dielectric solvent model. Relative solvation free energies also were calculated upon explicit solvent models by utilizing the free-energy perturbation theory as implemented in Monte Carlo simulations. The relative free energy for the N-methylpiperazine tautomer protonated at the secondary (NMps) rather than at the tertiary (NMpt) nitrogen was calculated at a ratio of 47/53 in infinitely dilute aqueous solution. The ratio further decreased in lower-polarity solvents. In contrast, NMR experiments suggested that the protonation takes place primarily at the secondary nitrogen in 0.37 molar aqueous solution with NMps/NMpt = 80/20. The NMps tautomer was exclusive in dichloromethane at the same concentration. The discrepancy between theory and experiment was resolved by considering association equilibria in parallel with the protonation for the solute. As a result, the theoretically predicted tautomer ratios were obtained in close agreement with the experimental values. The NMps tautomer could form a preferable dimeric structure, where one or two chloride anion(s) was/were in hydrogen bonds with protons of the associating monomers. The calculations suggest that the proton relocation may take place by solvent assistance in water or along an intramolecular proton jump in the twist-boat conformation. The predicted activation free energy was about 10 kcal/mol on the basis of variable-temperature NMR experiments in DCM.

Ab initio study of hydrogen-bond formation between aliphatic and phenolic hydroxy groups and selected amino acid side chains.

Hydrogen bonding was studied in 24 pairs of isopropyl alcohol and phenol as one partner, and water and amino-acid mimics (methanol, acetamide, neutral and protonated imidazole, protonated methylalamine, methyl-guanidium cation, and acetate anion) as the other partner. MP2/6-31+G* and MP2/aug-cc-pvtz calculations were conducted in the gas phase and in a model continuum dielectric environment with dielectric constant of 15.0. Structures were optimized in the gas phase with both basis sets, and zero-point energies were calculated at the MP2/6-31+G* level. At the MP2/aug-cc-pvtz level, the BSSE values from the Boys-Bernardi counterpoise calculations amount to 10-20 and 5-10% of the uncorrected binding energies of the neutral and ionic complexes, respectively. The geometry distortion energy upon hydrogen-bond formation is up to 2 kcal/mol, with the exception of the most strongly bound complexes. The BSSE-corrected MP2/aug-cc-pvtz binding energy of -27.56 kcal/mol for the gas-phase acetate...phenol system has been classified as a short and strong hydrogen bond (SSHB). The CH3NH3+...isopropyl alcohol complex with binding energy of -22.54 kcal/mol approaches this classification. The complete basis set limit (CBS) for the binding energy was calculated for twelve and six complexes on the basis of standard and counterpoise-corrected geometry optimizations, respectively. The X...Y distances of the X-H...Y bridges differ by up to 0.03 A as calculated by the two methods, whereas the corresponding CBS energy values differ by up to 0.03 kcal/mol. Uncorrected MP2/aug-cc-pvtz hydrogen-bonding energies are more negative by up to 0.35 kcal/mol than the MP2/CBS values, and overestimate the CCSD(T)/CBS binding energies generally by up to 5% for the eight studied complexes in the gas phase. The uncorrected MP2/aug-cc-pvtz binding energies decreased (in absolute value) by 11-18 kcal/mol for the ionic species and by up to 5 kcal/mol for the neutral complexes when the electrostatic effect of a polarizable model environment was considered. The DeltaECCSD(T) - DeltaEMP2 corrections still remained close to their gas-phase values for four complexes with 0, +/-1 net charges. Good correlations (R2 = 0.918-0.958) for the in-environment MP2/aug-cc-pvtz and MP2/6-31+G* hydrogen-bonding energies facilitate the high-level prediction of these energies on the basis of relatively simple MP2/6-31+G* calculations.

Monte Carlo structure simulations for aqueous 1,4-dioxane solutions.

Monte Carlo simulations in the NpT ensembles have been performed for the structure exploration of aqueous 1,4-dioxane solutions. Three different systems with all-atom dioxane:TIP4P water molar compositions of 2:500 (code:D2), 8:465 (D8), and 17:425 (D17) modeled solutions of 0.22, 0.88, and 1.86 mol/dm3 concentrations, respectively, at T = 298 K and p = 1 atm. The calculated solution densities increase from 0.992 to 1.002 g/cm3 with increasing dioxane concentration and approach the experimentally determined densities within 1%. This close agreement was achieved by utilizing RESP charges fitted to the in-solution IEF-PCM/B3LYP/6-31G* electrostatic potential of dioxane taken in its chair conformation and recently developed C, H steric parameters for ethers for calculations with a 12-6-1 all-atom potential. Solution structure analyses pointed out that the dioxane molecules arrange in the solutions with favorable distances of 4-8 angstroms for the ring symmetry centers. Within this range not only pairs of rings but triangular triads and tetrads have also been observed with center-center distances <8 angstroms. For the D8 system, about 25% of the sampled configurations included such a triad. In the case of the D17 model, two simulations starting from different solution configuration predicted different degrees for the dioxane aggregation in aqueous solution. In the more aggregated structure 3-21 triads are consistently maintained and 1-2 tetrads are formed in 58% of the configurations. Each dioxane oxygen forms about one hydrogen bond, on average, to a water molecule in the 0.22-1.86 molar range. The most likely O(dioxane)...H(water) hydrogen bond distance is 1.75-1.80 angstroms compared to the optimal distance of 1.72 angstroms in the isolated dimer. The optimal dioxane-water interaction energy of -5.65 kcal/mol indicates a remarkable hydrogen-bond acceptor character for dioxane.

Theoretical Investigation of Tautomeric Equilibria for Isonicotinic Acid, 4-Pyridone, and Acetylacetone in Vacuo and in Solution.

Tautomeric equilibria have been theoretically calculated for isonicotinic acid (neutral and zwitterionic forms), the 4-pyridone/4-hydroxypyridine system, and the keto-enol transformation for acetylacetone in vacuo and in tetrahydrofuran, methanol, and water solvents. Solvent, basis set, and cavity model effects have been studied in the integral equation formalism for the polarizable continuum model (IEF-PCM)/B3LYP framework, as well as the effect of the procedure, CHELPG or RESP, applied in fitting atomic charges to the in-solution molecular electrostatic potential (ELPO). The in-solution optimized geometries obtained at the IEF-PCM/B3LYP/6-31G* and 6-311++G** levels differ moderately but deviate from their gas-phase counterparts. Atomic charges fitted to the in-solution ELPO show small variations in the considered solvents, as well as when the united-atom cavity model, or a model with explicit consideration of polar hydrogens and scaled Bondi radii, has been applied. In contrast, the fitting procedure considerably affects the derived charges producing more separated atomic charges when the CHELPG rather than the RESP procedure is utilized. The fitted charges increase up to 20% in absolute value when the basis set is enlarged from 6-31G* to 6-311++G** in the IEF-PCM/B3LYP calculations. The relative free energy, calculated as ΔGtot = ΔEint + ΔG(solv) + ΔGthermal + (symmetry correction), in an ab initio/density funtional theory (DFT) + free energy perturbation (FEP)/Monte Carlo (MC) approximation strongly depends on the accepted value for the relative internal energy, ΔEint, of the tautomers. ΔEint is to be calculated at the IEF-PCM/QCISD(T)/cc-pVTZ//IEF-PCM/B3LYP/6-31G* level for the isonicotinic acid tautomers for producing relative free energies in aqueous solution close to experimental values. In other solvents, for this system and for the other two tautomeric equilibria, calculation of ΔEint at the IEF-PCM/B3LYP/6-31G* level produces ΔGtot in agreement up to 1 kcal/mol with the experimental values. FEP/MC ΔG(solv) calculations provide robust results with RESP charges derived by a fit to the in-solution ELPO generated at the IEF-PCM/B3LYP/6-31G* level. Molecular dynamics simulations pointed out that isonicotinic acid forms a dimeric zwitterion in tetrahydrofuran, in contrast to what happens in aqueous solution, and this structural peculiarity was interpreted as the reason for the failure of the ab initio/DFT + FEP/MC method in this particular solution.