Hydrogen Bond Acceptor Ability Research Articles

On the Role of the Solvent and Substituent on the Protonation Equilibria of Di-Substituted Anilines in Dioxane–Water Mixed Solvents

Protonation constants of a number of di-substituted anilines were determined potentiometrically in 0, 20, 30, 40, 50, and 60% (v/v) dioxane–water mixtures at (25.00 ± 0.02) ∘C with an ionic strength of 0.10 mol-dm−3 sodium perchlorate. The data are discussed in terms of the electronic character of the substituents. Two different methods were used to study the effects of the solvents on the protonation constants; one involved a single polarity parameter, the Dimroth–Reichardt parameter ET(30); the other involved the Kamlet–Taft multi-parametric method. The protonation constants of di-substituted anilines correlate with the molecular parameters for the dipolarity/polarizability of the solvent, π∗, and its hydrogen-bond acceptor ability, β.

In Silico Prediction of Peptide Binding Affinity to Class I Mouse Major Histocompatibility Complexes: A Comparative Molecular Similarity Index Analysis (CoMSIA) Study

Current methods for the in silico identification of T cell epitopes (which form the basis of many vaccines, diagnostics, and reagents) rely on the accurate prediction of peptide-major histocompatibility complex (MHC) affinity. A three-dimensional quantitative structure-activity relationship (3D-QSAR) for the prediction of peptide binding to class I MHC molecules was established using the comparative molecular similarity index analysis (CoMSIA) method. Three MHC alleles were studied: H2-D(b), H2-K(b), and H2-K(k). Models were produced for each allele. Each model consisted of five physicochemical descriptors-steric bulk, electrostatic potentials, hydrophobic interactions, and hydrogen-bond donor and hydrogen-bond acceptor abilities. The models have an acceptable level of predictivity: cross-validation leave-one-out statistical terms q2 and SEP (standard error of prediction) ranged between 0.490 and 0.679 and between 0.525 and 0.889, respectively. The non-cross-validated statistical terms r2 and SEE (standard error of estimate) ranged between 0.913 and 0.979 and between 0.167 and 0.248, respectively. The use of coefficient contour maps, which indicate favored and disfavored areas for each position of the MHC-bound peptides, allowed the binding specificity of each allele to be identified, visualized, and understood. The present study demonstrates the effectiveness of CoMSIA as a method for studying peptide-MHC interactions. The peptides used in this study are available on the Internet (http://www.jenner.ac.uk/AntiJen). The partial least-squares method is available commercially in the SYBYL molecular modeling software package.

Characterization of immobilized artificial membrane (IAM) and XTerra columns by means of chromatographic models

Immobilized artificial membranes (IAMs) prepared from phosphatidylcholine analogs are used as stationary phases in liquid chromatography systems to model drug partitioning between an aqueous phase (mobile phase) and a cell membrane (IAM column). Two different chromatographic models, which describe retention as a function of solute and column-mobile phase properties, have been applied to characterization of an IAM and two reversed phase C18 columns (Waters XTerra MSC18 and XTerra RP18) with acetonitrile–water mobile phases. The comparison of the results shows that the phosphatidylcholine group makes IAM column more polar than both XTerra columns, specially in terms of hydrogen-bond acceptor ability. XTerra RP18 is slightly more polar than XTerra MSC18 because of the presence of the embedded carbamate polar group.

Physicochemical Descriptors in Property-Based Drug Design

The contribution of physicochemical descriptors to lipophilicity, water solubility, and intestinal absorption and oral bioavailability in humans is considered. Partitioning in the octanol/water system is presented as a competition between two opposing effects: volume and hydrogen bond acceptor ability. Water solubilities of liquid compounds are roughly equal to their reciprocal logP values. However, there is also a detectable contribution of H-bond donor ability to water solubility. The main problem in predicting the solubilities of solid chemicals and drugs is the estimation of their crystal lattice energies. QSAR approaches that add terms such as melting point, and the product of H-bond donor and acceptor parameters are not sufficient to make these predictions practical. Human intestinal absorption for passively transported drugs is almost completely correlated with hydration processes that are determined by H-bond acceptor and donor abilities. It is emphasized that structural features of drug molecules have significant influences on their properties. Classic QSAR approaches are not enough to create stable, predictive models for diverse drugs. A combination of Similarity and QSAR approaches is one possibility to take all physicochemical properties in addition to structural features into account.

Improved prediction of fish bioconcentration factor of Hydrophobic Chemicals

Using a large heterogeneous data-set of 640 organic chemicals, we have developed predictive Quantitative Structure-Activity Relationship models for fish bioconcentration factor (BCF). For 539 chemicals with a log K ow (octanol-water partition coefficient) range of −2.3 to 6.0, we developed a model with [Formula: See Text] and a standard error of 0.661; the primary descriptor was log K ow, and others were polarisability, number of amino groups, hydrogen bond acceptor ability and a molecular shape factor. For 101 chemicals with a log K ow range of 6.0-12.7, we developed a model with [Formula: See Text] and a standard error of 0.777; the descriptors were aqueous solubility (reflecting the importance of this property in governing uptake from aqueous solution), polarity, polarisability, hydrogen bond donor ability and molecular size. Bearing in mind the very great range of BCF values of highly hydrophobic chemicals, our model offers good predictivity of this important environmental property.

Kinetics of the reactions between 1‐fluoro‐2,6‐dinitrobenzene and pyrrolidine and piperidine in binary solvent systems: Influence of the nucleophile structure

AbstractWe studied the kinetics of the reaction between 1‐fluoro‐2,6‐dinitrobenzene and pyrrolidine or piperidine in ethyl acetate–chloroform or acetonitrile and acetonitrile–chloroform binary solvent mixtures. The kinetic response of these reactions was compared with that of the reactions with homopiperidine. The aim of this work was to evaluate the influence of the nucleophile structure and of solvent effects on those reactive systems. The amine structure has a great influence on second‐order rate constants, especially on the rate constants related to the catalyzed step. In mixtures with chloroform the amine structure is also responsible for the change in the reaction mechanism. Theoretical quantum mechanics calculations confirm that the origin of these results lies in stereoelectronic effects due to the conformational difference between the amino moieties in the intermediate σ adducts as they release the nucleofuge. Solvation effects are dominated by non‐specific interactions. The order of incidence of the molecular–microscopic solvent properties on the second‐order rate coefficient kA is dipolarity/polarizability>hydrogen‐bond donor ability (HBD)>hydrogen‐bond acceptor ability (HBA). The (HBA+HBD) and (HBA+HBA/HBD) solvent systems have similar solvation mechanisms: the critical state is preferentially solvated by the structure formed by intersolvent hydrogen‐bonded species. Mixtures of the type (HBA/HBD+HBD) manifest a particular solvation behavior. Among the reactive systems selected there is only one example in which preferential solvation is not operative. Copyright © 2004 John Wiley & Sons, Ltd.Additional material for this paper is available in Wiley Interscience

Structural analysis of nine-coordinate lanthanide complexes: steric control of the metal-water distance across the series.

The structures of 10 isomorphous lanthanide (Ln) complexes of a chiral DOTA tetra-amide ligand (L(1)), [LnL(1)(H(2)O)](CF(3)SO(3))(3).3H(2)O, crystallizing in space group P2(1), have been studied by single-crystal X-ray diffraction. The Ln coordination is a O(4)N(4) square antiprism, the O(4) base of which is capped by an aqua ligand. The sterically demanding position of the latter results in the lengthening of the Ln-OH(2) distance along the Pr to Lu series by 0.06 A (after allowing for the lanthanide contraction). In parallel, the distance between the bound water oxygen and the second-sphere water oxygen is reduced from 3.17 A (Pr) to 3.04 A (Lu), consistent with the enhanced hydrogen bond acceptor ability of the coordinated water oxygen across the series. A Cambridge Structural Database survey of [Ln(H(2)O)(9)](CF(3)SO(3))(3) salts (space group P6(3)/m) and of six reported isostructural complexes of DOTA [L(2)] revealed a similar trend. The implications of the resultant destabilization of the ground state structure for the water interchange process are discussed.

Solvent-induced polymorphism of three-dimensional hydrogen-bonded networks of hexakis(4-carbamoylphenyl)benzene.

The crystal structures for three types of three-dimensional (3-D) hydrogen-bonded networks of hexakis(4-carbamoylphenyl)benzene (1), the network morphologies of which depend greatly on crystallization conditions, have been determined. When this compound is crystallized from hot DMSO, the resulting crystals, 1.12DMSO (orthorhombic, Pca2(1)), showed a 3-D hydrogen-bonded porous network (type A) via 1-D catemer chains as a hydrogen-bonding motif of six primary amide groups. The type A network creates chambers surrounded by six molecules of 1 and channels along the c axis to give the highest porosity among the network polymorphs of 1 investigated here. Crystallization from a boiling mixture of n-PrOH and water gave 1.6n-PrOH (monoclinic, P2(1)/c), which exhibits another type of 3-D hydrogen-bonded porous network (type B) via cyclic dimers as another hydrogen-bonding motif of six primary amide groups. The type B network leads to triangle-like channels along the a axis having a cross section of ca. 9.2 x 9.7 x 9.7 A (including van der Waals radii). The crystal structure of 1.H(2)O (monoclinic, P2(1)/c), which was produced under hydrothermal conditions, showed a nonporous 3-D hydrogen-bonded network chain of amide groups (type C) composed of a mixed hydrogen bonding motif of helical catemer chains/cyclic dimer/catemer. Solvent-induced topological isomerism of these 3-D hydrogen-bonded networks of 1 arises from (i) the guest inclusion ability based on a radially functionalized hexagonal structure of 1, (ii) the correlation between the hydrogen bond donor ability of the syn and anti protons of the primary amide group in host 1 and the hydrogen bond acceptor ability of the oxygen atoms of 1 and guest solvents, and (iii) the polarity of the bulk crystallization solvents.

Quantitative approaches to computational vaccinology.

This article reviews the newly released JenPep database and two new powerful techniques for T-cell epitope prediction: (i) the additive method; and (ii) a 3D-Quantitative Structure Activity Relationships (3D-QSAR) method, based on Comparative Molecular Similarity Indices Analysis (CoMSIA). The JenPep database is a family of relational databases supporting the growing need of immunoinformaticians for quantitative data on peptide binding to major histocompatibility complexes and to the Transporters associated with Antigen Processing (TAP). It also contains an annotated list of T-cell epitopes. The database is available free via the Internet (http://www.jenner.ac.uk/JenPep). The additive prediction method is based on the assumption that the binding affinity of a peptide depends on the contributions from each amino acid as well as on the interactions between the adjacent and every second side-chain. In the 3D-QSAR approach, the influence of five physicochemical properties (steric bulk, electrostatic potential, local hydrophobicity, hydrogen-bond donor and hydrogen-bond acceptor abilities) on the affinity of peptides binding to MHC molecules were considered. Both methods were exemplified through their application to the well-studied problem of peptides binding to the human class I MHC molecule HLA-A*0201.

Spectroscopic and theoretical studies of derivatives of 1,6- and 1,7-naphthyridines

The solvatochromism in 8-hydroxy-1,6-naphthyridin-5(6H)-one-7-carboxylic acid methyl ester ( 1), 5-hydroxy-1,7-naphthyridin-8(7H)-one-6-carboxylic acid methyl ester ( 2), and 4-hydroxy-2-methyl-1(2H)-isoquinolone-3-carboxylic acid methyl ester ( 3), has been studied in solvents of different polarity and hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) ability. The relative stabilities of isomers for these naphthyridine derivatives and their interaction with the solvent are reported. Two intramolecular hydrogen-bonded structures contribute to the ground state of compound 1. Temperature effects on the absorption bands were recorded to analyse the possible equilibrium between covalent and zwitterionic forms. The formation of zwitterionic species was observed only in HBD solvents, from which is inferred the solvent assistance in the proton transference. AM1 and PM3 semi-empirical calculations were used in support of the proposed interpretations.

Temperature-dependent microscopic solvent properties of ‘dry’ and ‘wet’ 1-butyl-3-methylimidazolium hexafluorophosphate: correlation with ET(30) and Kamlet–Taft polarity scales

As a result of heightened awareness of a wealth of potential in clean manufacturing processes, room temperature ionic liquids (RTILs) have been the target of increased investigation. As an integral part of the green chemistry movement, RTILs have found application in synthesis, catalysis, polymerization, industrial cleaning, liquid/liquid extraction, and separations. While some groundwork has been laid, the optimal utilization and tailoring of these solvents has been hobbled by an incomplete understanding of their solvent properties, particularly at the molecular level. In this work, we use solvatochromic measurements to determine ‘energy of transition’ ET(30) values and Kamlet–Taft solvent parameters (α, β, π*) for the relatively hydrophobic RTIL 1-butyl-3-methylimidazolium hexafluorophosphate, [bmim]+[PF6]−, as a function of temperature (10–70 °C) and water content (50 ppm or less water, ‘dry’ or 2% water (v/v), ‘wet’). The results of these experiments demonstrate that dry [bmim]+[PF6]− exhibits a hydrogen bond donor strength on the order of short chain alcohols with a linear temperature dependence. Dry and wet [bmim]+[PF6]− exhibit hydrogen bond acceptor abilities, which are weak functions of temperature, intermediate between that of water and acetonitrile. The π* parameter for wet and dry [bmim]+[PF6]− is higher than short chain alcohols, but lower than water or dimethylsulfoxide at ambient conditions, and it exhibits a strong linear temperature dependence. Finally, the addition of water to [bmim]+[PF6]− does not affect the β and π* values significantly.

Amino nitrogen and carbonyl oxygen in competitive situations: which is the best hydrogen-bond acceptor site?

The relative hydrogen-bond acceptor abilities of amino nitrogen and carbonyl oxygen in various chemical environments have been investigated using data retrieved from the Cambridge Structural Database (CSD) and viaab initio molecular orbital calculations. Surveys of the CSD for hydrogen bonds between HX (X = N, O) donors and push–pull or saturated aminoketone and aminoester molecular fragments show that the hydrogen bonds are much more frequent on the oxygen than on the amino nitrogen. In the push–pull families, the hydrogen-bonding (HB) ability of the carbonyl oxygen is increased by conjugation between the lone pair of the amino substituent and the CO group, a behaviour similar to resonance-assisted hydrogen bonding. The unexpected behaviour of twisted amides, in which only the amino nitrogen is involved in hydrogen bonding, is pointed out. This unusual feature is explained by the disruption of conjugation between the amino lone pair and the carbonyl owing to the cyclisation involving the amino moiety. In aliphatic systems, the amino nitrogen retains its HB ability but is still involved in a rather low number of contacts. This behaviour reflects the sensitivity of the amino nitrogen to steric hindrance. The relative strengths of the hydrogen bonds on the carbonyl oxygen in ketones and esters follow the experimental order of hydrogen-bond basicity as observed in solution through the pKHB scale. Ab initio molecular orbital calculations (B3LYP/6-31+G** level) of electrostatic and charge transfer descriptors also confirm the experimental observations.

Amino and cyano N atoms in competitive situations: which is the best hydrogen-bond acceptor? A crystallographic database investigation.

The relative hydrogen-bond acceptor abilities of amino and cyano N atoms have been investigated using data retrieved from the Cambridge Structural Database and via ab initio molecular orbital calculations. Surveys of the CSD for hydrogen bonds between HX (X = N, O) donors, N-T-C identical with N (push-pull nitriles) and N-(Csp(3))(n)-C identical with N molecular fragments show that the hydrogen bonds are more abundant on the nitrile than on the amino nitrogen. In the push-pull family, in which T is a transmitter of resonance effects, the hydrogen-bonding ability of the cyano nitrogen is increased by conjugative interactions between the lone pair of the amino substituent and the C identical with N group: a clear example of resonance-assisted hydrogen bonding. The strength of the hydrogen-bonds on the cyano nitrogen in this family follows the experimental order of hydrogen-bond basicity, as observed in solution through the pK(HB) scale. The number of hydrogen bonds established on the amino nitrogen is greater for aliphatic aminonitriles N-(Csp(3))(n)-C identical with N, but remains low. This behaviour reflects the greater sensitivity of the amino nitrogen to steric hindrance and the electron-withdrawing inductive effect compared with the cyano nitrogen. Ab initio molecular orbital calculations (B3LYP/6-31+G** level) of electrostatic potentials on the molecular surface around each nitrogen confirm the experimental observations.

Hydrogen bonding and dipolar interactions between quinolines and organic solvents. Nuclear magnetic resonance and ultraviolet–visible spectroscopic studies

Solvatochromic studies on quinoline (Q), 3-cyanoquinoline (CNQ), 3-bromoquinoline (BrQ) and 8-hydroxyquinoline (OHQ) in pure solvents and alcohol–cyclohexane mixtures have been performed. The results are compared with Proton Nuclear Magnetic Resonance, 1H NMR, studies and AM1 calculations. Taft and Kamlet's solvatochromic comparison method was used to disclose solvent effects in pure solvents. These studies shows that the hydrogen bond acceptor ability of the Q ring is diminished and its polarity is increased by the presence of the cyano group in CNQ and the bromo group in BrQ. In OHQ, intramolecular hydrogen bonding has been observed. This interaction is weakened by the interaction with protic solvents. The studies in binary mixtures, alcohol–cyclohexane, show solute–solvent interactions, which compete with solvent self-association in the preferential solvation phenomena. Alcohols with strong ability to self-associate have less preference toward solvation of these compounds. The association constants for solute–ethanol systems were determined by 1H NMR. The results show that the solvent hydrogen bond donor ability is the main factor involved in the interaction with these solutes at the aza aromatic site.

Quantitative Study of the Structural Requirements of Phthalazine/Quinazoline Derivatives for Interaction with Human Liver Aldehyde Oxidase.

Aldehyde oxidase is a molybdenum-containing enzyme distributed throughout the animal kingdom. Although this enzyme is capable of metabolizing a wide range of aldehydes and N-heterocyclic compounds, there is no reported detailed study of physicochemical requirements of the enzyme-substrate interactions. The aim of this study, therefore, was to investigate quantitatively the relationships between the kinetic constants of aldehyde oxidase-catalyzed oxidation of some phthalazine and quinazoline derivatives (as substrates) and their structural parameters. Multiple regression and stepwise regression analyses showed that polarity of phthalazines (expressed as dipole moment mu, cohesive energy density deltaT and an indicator variable for hydrogen-bond acceptor ability of R1 substituent, HBA) had a negative effect on the enzyme activity (leading to the reduction of Vmax and increase of Km). Electron withdrawing substituents in the quinazoline series are favorable for interaction with the enzyme. This finding and also the relationships of 1/Km of phthalazines with the energy of the lowest unoccupied molecular orbital and log Vmax/log Km of phthalazines with degree of bonding of the two nitrogen atoms in the molecules are consistent with the mechanism of action. The reaction involves a nucleophilic attack on an electron-deficient sp2-hybridized carbon atom and formation of an epoxide intermediate following the disruption of the aromatic structure.

Relevant physicochemical factors in chromatographic separation of Alternaria alternata mycotoxins

The solute–solvent interactions of Alternaria alternata mycotoxins, alternariol (AOH) and alternariol monomethyl ether (AME) were studied using spectroscopic and chromatographic techniques with the aim to rationalize the separation methods. The Kamlet and Taft's solvatochromic comparison method was applied to analyze the UV-Visible spectra and to compare with normal and reversed-phase high-performance liquid chromatography (HPLC) data. It is found that the normal phase chromatographic behavior of these mycotoxins can be predicted from the spectroscopic studies. The main factor involved in the chromatographic process is the hydrogen bond acceptor ability of the solvent. Due to the multicollinearity detected for the solvent parameters for hydroorganic mixtures used in reversed-phase HPLC, the factors involved were determined by the ridge regression. The tests performed show that in these cases the ridge regression could be the option to obtain statistical meaningful results. The results of the regression indicated a dependence of the retention parameter on the polarity–polarizability and hydrogen bond donor capacity of the solvent mixtures. Thus, the solutes seem to be much less sensitive to the hydrogen bond acceptor ability of the eluent than for normal phase HPLC.

Kamlet−Taft Solvatochromic Parameters of the Sub- and Supercritical Fluorinated Ethane Solvents

The Kamlet−Taft parameters describing the dipolarity-polarizability, π*, and hydrogen bond acceptor ability, β, for ethane and six fluorinated ethane solvents in the sub- and supercritical region of the phase diagram were measured using solvatochromic probe molecules. The measured ultraviolet electronic transitions of the solvatochromic probes in a given solvent were fitted to third-order polynomials in solvent density for all isotherms investigated. The values of π* and β were calculated for each of the solvents as a function of the solvent density. Trends in π* values were related to the degree of fluorination about the ethane molecule, while the average β values for all solvents were negative and were interpreted as an inability on the solvents part to act as hydrogen bond acceptors.

Kinetic Studies and Solvent Effect on the Pyrrolidinolysis of Some Nitro Activated O-aryl Oximes

The effect of two solvent parameters, hydrogen bond acceptor ability and the dielectric constant, on the mechanistic pathway of the pyrrolidinolysis of nitro-activated O-aryl oximes has been kinetically investigated.

Kamlet-Taft Solvatochromic Parameters for 25 Glycol Ether Solvents and Glycol Ether Aqueous Solutions

The Kamlet–Taft parameters for 25 glycol ethers and their aqueous solutions were measured. Values for the three Kamlet–Taft parameters: the hydrogen-bond donor ability, hydrogen-bond acceptor ability, and the dipolarity/polarizability, as well as the index of refraction, were determined for each pure glycol ether and each aqueous glycol solution. A correlation matrix between other known solvent parameters and the measured Kamlet–Taft values revealed only one correlation, suggesting that the three measured Kamlet–Taft parameters for the glycol ethers are independent solvent descriptors. Last, trends in the measured Kamlet–Taft values were related to functional group modifications to the basic glycol ether structure.

Hydrogen-Bond Acceptor and Donor Properties of Divalent Sulfur (Y-S-Z and R-S-H)

The hydrogen-bond acceptor ability of divalent sulfur in Y—S—Z systems, Y, Z= C, N, O or S, and the donor ability of thiol S—H have been studied using crystallographic data retrieved from the Cambridge Structural Database. Of 1811 Y—S—Z substructures that co-occur with N—H or O—H donors, only 86 (4.75%) form S...H—N,O bonds within S...H < 2.9 Å. In dialkylthioethers, the frequency of S...H bond formation is 6.24%, but drops below 3% when the alkyl groups are successively replaced by Csp 2 centres. This parallels an increasing \delta-positivity of S as calculated using ab initio methods. A similar frequency trend is observed for O...H—N,O bond formation by analogous oxyethers. Mean intermolecular >S...H distances for O—H [2.67 (3) Å] and N—H [2.75 (2) Å] donors (with H positions normalized to neutron values) are ca 0.25 Å longer than in C=S...H—N,O systems, indicative of very weak hydrogen bonding to >S. Intramolecular >S...H are slightly more frequent (8.56%), with S...H slightly shorter than for the intermolecular case. In contrast, 26 (70.3%) out of 37 S—H donors that co-occur with suitable acceptors form X...H—S bonds. The C=O...H—S system is predominant with a mean O...H distance of 2.34 (4) Å, considerably longer (weaker) than in C=O...H—O systems.