Hydrogen Bond Acceptor Sites Research Articles

Crystal Structure Investigations on Imines derived from 3‐Ferrocenyl‐prop‐2‐enal Crystallizing in Non‐centrosymmetric Space Groups

AbstractThe condensation of 3‐ferrocenyl‐prop‐2‐enal with primary amines leads to the formation of the corresponding imines in good yields. The crystal structures of imines derived from p‐dimethylamino‐aniline and furfurylamine are determined by the ability of the functional groups to act as hydrogen bond donor or acceptor sites. Although N, N‐dimethyl‐N′‐(3‐ferrocenyl‐allylidene)‐benzene‐1, 4‐diamine and furan‐2‐ylmethyl‐(3‐ferrocenyl‐allylidene)‐amine are achiral molecules they crystallize in the non‐centrosymmetric space groups P21 and Pca21, respectively. The molecular architecture of N, N‐dimethyl‐N′‐(3‐ferrocenyl‐allylidene)‐benzene‐1, 4‐diamine is realized by the incorporation of dichloromethane acting as hydrogen bond donor and acceptor with both hydrogen and both chlorine atoms. On the other hand, the molecules of furan‐2‐ylmethyl‐(3‐ferrocenyl‐allylidene)‐amine are linked by hydrogen bonds towards the centroid of one of the cyclopentadienyl ligands and towards the oxygen atom of the furan ring to produce infinite chains.

Structural Variations and Polymorphism of Some Derivatives of 6-Amino-2-phenylsulfonylimino- 1,2-dihydropyridine

Following up from a study of polymorphism in the title compound, 6-amino-2-phenylsulfonylimino-1,2-dihydropyridine, 12 phenyl-substituted derivatives were examined for polymorphism by recrystallization from a large number of solvents. The title compound contains hydrogen bond donor (D) and acceptor sites (A) located in a AADD juxtapositioning. Two structural families that differ in their use of the AADD hydrogen bond functionality may be identified. Methyl and chloro substitution in the ortho position or fluoro substitution in the para position leads to a catemer motif, which is related to the kinetic form of the title molecule. Meta Substitution by methyl and larger substituents in the para position block this structural option. While meta-methyl and para-chloro substitution lead to unique structures, two polymorphs of the para-methyl-substituted derivative could be crystallized and these adopt the dimer arrangement. With the larger bromo, iodo, methoxy, and trifluoromethyl substituents in the para position, dimers arranged into interconnected layers are obtained. These dimer structures are reminiscent of the thermodynamic form of the title compound. It is noteworthy that the majority of derivatives of the title compound fail to show polymorphic behavior, and this shows that our understanding of polymorphism is still far from complete.

Successful prediction of the hydrogen bond network of the 3-oxo-12α-hydroxy-5β-cholan-24-oic acid crystal from resolution of the crystal structure of deoxycholic acid and its three 3,12-dihydroxy epimers

Crystal structures of p-xylene-crystallized deoxycholic acid (3α,12α-dihydroxy-5β-cholan-24-oic acid) and its three epimers (3β,12α-; 3α,12β-; and 3β,12β-) have been solved. Deoxycholic acid forms a crystalline (P21) complex with the solvent with a 2:1 stoichiometry whereas crystals of the three epimers do not form inclusion compounds. Crystals of the 3β,12β-epimer are hexagonal, whereas the 3α,12β-and 3β,12α-epimers crystallize in the P212121 orthorhombic space group. The three hydrogen bond sites (two hydroxy groups, i. e. O3H, and O12H, and the carboxylic acid group of the side chain, O24bO24aH) simultaneously act as hydrogen bond donors and acceptors.The hydrogen bond network in the crystals was analyzed and the following sequences have been observed: two chains (abcabc… or acbacb…) and two rings (▪), which constitute a complete set of all the possible sequences which can be drawn for an intermolecular hydrogen bond network formed by three hydrogen bond donor/acceptor sites forming crossing hydrogen bonds. The orientation of O3H (α or β) determines the sequence of the acceptor and the donor groups involved in the pattern: O24a→O12→O3→O24b when it is α and O24a→O3→O12→O24b when it is β.These observations were used to predict the hydrogen bond network of p-xylene-crystallized 3-oxo,12α-hydroxy-5β-cholan-24-oic acid. This compound has two hydrogen bond donor and three potential hydrogen bond acceptor sites. According to the previous sequence set, this compound should crystallize in the monoclinic P21 system, should form a complex with the solvent, O24b should not participate in the hydrogen bond network, and the chain sequence O24a→O12→O3 would be followed. All predictions were confirmed experimentally.

Crystal structure of bis(2-benzimidazolylmethyl)amino-2-methylbenzimidazolium 3-nitrobenzoate 3-nitrobenzoic acid, (C24H22N7(C7H4NO4(C7H5NO4)

Article Crystal structure of bis(2-benzimidazolylmethyl)amino-2-methylbenzimidazolium 3-nitrobenzoate 3-nitrobenzoic acid, (C24H22N7(C7H4NO4(C7H5NO4) was published on April 1, 2004 in the journal Zeitschrift für Kristallographie - New Crystal Structures (volume 219, issue 1-4).

The self-assembly switching of the group 13 tetrahedral Schiff base complexes by changing the character of coordination centre

The reaction of Et3B with one equivalent of N-substituted salicylideneimine (HsaldR′) yields the monomeric O,N-chelate complexes Et2B(saldR′), where R′ = Me (1) or Ph (2). The crystal structure of the resulting complexes has been determined by X-ray crystallography. The molecular structure of these complexes consists of monomeric four-coordinate chelates and their primary arrangement in the crystal structure is determined by the C–H⋯Oaryloxide hydrogen bonds. An extended crystal structure analysis reveals that the adjacent monomeric moieties of 1 are interconnected by C–Himino⋯O hydrogen bridges resulting in a 1-D motif infinite H-bonded chain, whereas the crystalline complex 2 comprises dimeric molecules linked through a pair of intermolecular C–Harom⋯O interactions. The supramolecular arrangement of both compounds is discussed with relation to the structure of analogous aluminium and gallium complexes, and the role played by the coordination centre on the molecular assembly is analyzed. It is shown that the steric congestion at the hydrogen bond donor and acceptor sites, as a result of changes in the N-alkyl substituents or the coordination centre environment, affect the strength of the intermolecular C–H⋯O hydrogen bonds and may lead to the self-assembly switching of the bidentate Schiff base complexes.

2-Amino-6-(1-imidazolylmethyl)-4-(3,5,5-trimethyl-2-pyrazolin-1-yl)-1,3,5-triazine and 2-amino-6-(1-benzimidazolylmethyl)-4-(3,5,5-trimethyl-2-pyrazolin-1-yl)-1,3,5-triazine hemihydrate.

The two title compounds, C(13)H(18)N(8) and C(17)H(20)N(8).0.5H(2)O, possess similar molecular shapes, with the pyrazoline moiety and s-triazine ring located approximately in one plane, and the imidazole or benzimidazole ring nearly perpendicular to the s-triazine nucleus. In both crystal structures, despite there being a large number of accessible hydrogen-bond acceptor sites, only one H atom from the NH(2) group is involved in hydrogen bonding; the molecules are assembled into discrete centrosymmetric dimers via a pair of nearly linear N-H.N hydrogen bonds.

The nicotinic pharmacophore: thermodynamics of the hydrogen-bonding complexation of nicotine, nornicotine, and models.

The thermodynamics of the hydrogen-bonding complexation of the acetylcholine agonists nicotine and nornicotine and of model pyridines, pyrrolidines, and N-methylpyrrolidines has been measured in CCl(4) by FTIR spectrometry toward a reference hydrogen-bond donor, 4-fluorophenol. Various methods are devised for measuring separately the hydrogen-bond acceptor strength of each nitrogen of nicotine and nornicotine: variation of the stoichiometry of complexation; correlations with electrostatic potentials on nitrogens and with substituent constants in the series of 3-substituted pyridines, 2-substituted pyrrolidines, and 2-substituted N-methylpyrrolidines; and linear free energy relationships between 4-fluorophenol and hydrogen fluoride hydrogen-bonded complexes. It is consistently found that nicotine and nornicotine have two active hydrogen-bond acceptor sites, the pyridine and pyrrolidine nitrogens, and that ca. 90% (for nicotine) and 80% (for nornicotine) of the 1:1 hydrogen-bonded complexes are formed to the pyridine nitrogen, although the pyrrolidine nitrogen is the first protonation site of nicotine and nornicotine in water. The low hydrogen-bond basicity of the pyrrolidine nitrogen in nicotine is mainly explained by the inductive electron-withdrawing and steric effects of the 2-(3-pyridyl) substituent. The partition of the Gibbs energy of the isomerism of complexation (AH...Nsp(2) <==> AH...Nsp(3)) into enthalpic and entropic contributions shows that the selectivity in favor of the pyridine nitrogen is driven by entropy. It is important to recognize the bifunctionality of nicotine in hydrogen bonding for understanding its lipophilicity and molecular recognition in non protonic media. When monoprotonated on their sp(3) nitrogen, nicotine and nornicotine keep, through their sp(2) nitrogen, a significant hydrogen-bond basicity which is greater than that of the ester group of acetylcholine.

Quantitative structure-based design: formalism and application of receptor-dependent RD-4D-QSAR analysis to a set of glucose analogue inhibitors of glycogen phosphorylase.

A method for performing quantitative structure-based design has been developed by extending the current receptor-independent RI-4D-QSAR methodology to include receptor geometry. The resultant receptor-dependent RD-4D-QSAR approach employs a novel receptor-pruning technique to permit effective processing of ligands with the lining of the binding site wrapped about them. Data reduction, QSAR model construction, and identification of possible pharmacophore sites are achieved by a three-step statistical analysis consisting of genetic algorithm optimization followed by backward elimination multidimensional regression and ending with another genetic algorithm optimization. The RD-4D-QSAR method is applied to a series of glucose inhibitors of glycogen phosphorylase b, GPb. The statistical quality of the best RI- and RD-4D-QSAR models are about the same. However, the predictivity of the RD- model is quite superior to that of the RI-4D-QSAR model for a test set. The superior predictive performance of the RD- model is due to its dependence on receptor geometry. There is a unique induced-fit between each inhibitor and the GPb binding site. This induced-fit results in the side chain of Asn-284 serving as both a hydrogen bond acceptor and donor site depending upon inhibitor structure. The RD-4D-QSAR model strongly suggests that quantitative structure-based design cannot be successful unless the receptor is allowed to be completely flexible.

Processible conducting nanoscale cylinders due to self-organized polyaniline supramolecules

Polyaniline sulphonates contain hydrogen bonding acceptor sites, which allow construction of supramolecules and self-organized structures. Here we have characterized the phase behavior of complexes of polyaniline, camphorsulphomc acid (CSA) and 4-hexylresorcinol (tires), PANI(CSA)(x)(Hres)(y), using small-angle X-ray scattering (SAXS) and electrical conductivity. A hexagonal cylindrical structure with period around 35 Angstrom allows plastication due to the flexible side chains. The conductivity of complexes increased when CSA or tires were added to the nominal complex PANI(CSA)(0.5) indicating that CSA and Hres can be co-solvents for PANI(CSA)(0.5).

The organochlorine pesticides γ-hexachlorocyclohexane (lindane), α-endosulfan and dieldrin differentially interact with GABA A and glycine-gated chloride channels in primary cultures of cerebellar granule cells

The neurotoxic organochlorine pesticides γ-hexachlorocyclohexane, α-endosulfan and dieldrin induce in mammals a hyperexcitability syndrome accompanied by convulsions. They reduce the GABA-induced Cl − flux. The strychnine-sensitive glycine receptor also regulates Cl −-flux inhibitory responses. We studied the effects of these compounds on Cl − channels associated with glycine receptors in cultured cerebellar granule cells in comparison to the GABA A receptor. Both GABA (EC 50: 5 μM) and glycine (EC 50: 68 μM) increased 36Cl − influx. This increase was antagonized by bicuculline and strychnine, respectively. Lindane inhibited with similar potency both GABA A (IC 50: 6.1 μM) and glycine (5.0 μM) receptors. α-Endosulfan and dieldrin inhibited the GABA A receptor (IC 50 values: 0.4 μM and 0.2 μM, respectively) more potently than the glycine receptor (IC 50 values: 3.5 μM and 3 μM, respectively). Picrotoxinin also inhibited the glycine receptor, although with low potency (IC 50>100 μM). A 3D pharmacophore model, consisting of five hydrophobic regions and one hydrogen bond acceptor site in a specific three-dimensional arrangement, was developed for these compounds by computational modelling. We propose that the hydrogen bond acceptor moiety and the hydrophobic region were responsible for the affinity of these compounds at the GABA A receptor whereas only the hydrophobic region of the molecules was responsible for their interaction with the glycine receptors. In summary, these compounds could produce neuronal hyperexcitability by blocking glycine receptors besides the GABA A receptor. We propose that two zones of the polychlorocycloalkane pesticide molecules (a lipophilic zone and a polar zone) differentially contribute to their binding to GABA A and glycine receptors.

A 3D QSAR Pharmacophore Model and Quantum Chemical Structure—Activity Analysis of Chloroquine(CQ)‐Resistance Reversal.

Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent reversal activity. Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.

Four Hydrogen Bonds − DDAA, DADA, DAAD and ADDA Hydrogen Bond Motifs

Receptor molecules containing four hydrogen-bond acceptor or donor sites based on aminopyridines, aminonaphthyridines and urea subunits have been synthesized and their association has been investigated. DDAA (13a−c) and DADA (18a−b) arrays may form homodimers, while DAAD (24a−d) with ADDA (25a−b) may form heterodimers. While most parent heterocycles were only slightly soluble in standard organic solvents, substitution was able to enhance the solubility in most cases. The naphthyridine 24d, bearing a substituent derived from lysine, possesses potential anchor groups for a covalent connection. Binding studies were carried out in chloroform and monitored by 1H NMR, and the binding constants Kass for the heterodimers DAAD·ADDA (24·25) were compared to the binding of smaller (ADD, 26) or mismatching (DADD, 27) counterparts, showing that the matching heterodimer is formed with a selectivity of > 50. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2002)

Vapor-liquid interfacial properties of mutually saturated water/1-butanol solutions.

Adsorption and ordering at the vapor-liquid interfaces of mutually saturated water/1-butanol solutions at a temperature of 298.15 K were investigated using configurational-bias Monte Carlo simulations in the Gibbs ensemble and compared to the surface properties of neat water and 1-butanol liquids. A dense 1-butanol monolayer is observed at the surface of the water-rich phase, which results in a substantial decrease of its surface tension. In contrast, there is no enrichment of water molecules at the surface of the butanol-rich phase, and its surface tension is not significantly changed. Analysis of the interfacial structures reveals that these systems exhibit orientational ordering and composition heterogeneity. Analysis of the hydrogen-bonding distributions suggests that the formation of the 1-butanol monolayer is driven by an excellent match between water and the primary alcohol; that is, additional hydrogen bonds are formed between the excess free hydrogens of surface water and the excess hydrogen-bond acceptor sites of 1-butanol.

A 3D QSAR pharmacophore model and quantum chemical structure--activity analysis of chloroquine(CQ)-resistance reversal.

Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.

Efficacy of proton pump inhibitor drugs against Plasmodium falciparum in vitro and their probable pharmacophores.

The substituted benzimidazoles omeprazole, lansoprazole, rabeprazole, and pantoprazole were found to have in vitro activity against three different isolates of Plasmodium falciparum: D6 (which is chloroquine and pyrimethamine sensitive), W2 (chloroquine and pyrimethamine resistant), and TM91C235 (multidrug resistant). Lansoprazole and rabeprazole were the most effective against all three isolates, with a 50% inhibitory concentration (IC(50)) range of 7 to 11 microM. Omeprazole showed intermediate activity against D6 and W2 isolates, with IC(50)s of 27 to 28 microM, but had poor activity against TM91C235, with an IC(50) of 76 microM. Pantoprazole was the least effective, with IC(50)s of 73 microM against D6, 53 microM against W2, and 39 microM against TM91C235. A pharmacophore model describing the important features responsible for potent activity of the drugs was developed using computational techniques of semiempirical quantum chemical methods and the three-dimensional QSAR procedure of the CATALYST software. The important features of the pharmacophore, according to the findings based on the CATALYST procedures, are the hydrogen bond acceptor and donor sites at the benzimidine nitrogen atoms and the two aromatic hydrophobic sites in the molecules. AM1 quantum chemical calculations identified the electrostatic potential surface surrounding the sulfoxide atom as crucial for potent activity.

Hydrogen bonding and perhalometallate ions: a supramolecular synthetic strategy for new inorganic materials.

A synthetic strategy for constructing ionic hydrogen-bonded materials by combining perhalometallate anions with cations able to serve as hydrogen bond donors is presented. The approach is based on identification of well defined hydrogen bond acceptor sites on the anions by a combination of experimental and theoretical approaches. Selective population of these sites by hydrogen bond donors has the potential to afford organized crystalline arrays in one, two, or three dimensions. The approach is applicable to a wide range of metal centers.

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.

Superstructural Variety from an Alkylated Triazine: Formation of One-Dimensional Hydrogen-Bonded Arrays or Cyclic Rosettes

The propensity of an alkylated 2,6-diamino-1,3,5-triazine to establish dimeric hydrogen bonding motifs has been examined. Either alone, or when partnered with a linear aromatic diimide, the triazine crystallizes in extended one-dimensional hydrogen-bonded arrays. In contrast, the cocrystal with thiophene-2,5-dicarboxylic acid presents closed cyclic hexameric arrays comprised of alternating triazine and diacid units. In all cases, the triazine employs the same hydrogen bond donor and acceptor sites in establishing these extended structures, using only the sites that flank the smallest of the triazine substituents.

Acentric Extended Solids by Self Assembly of 4,4'-Bipyrazolyls The authors gratefully acknowledge support from the Deutsche Forschungsgemeinschaft and the Sächsisches Staatsministerium für Wissenschaft und Kunst.

The inter-ring angle φ of 4,4′-bipyrazolyls, which can be controlled by varying the 3,3′- and 5,5′-substituents, determines their association into different three-dimensional arrays through interaction of their self-complementary hydrogen-bond donor and acceptor sites. Thus, for φ≈90°, a (10,3)-b net is formed (see picture, top), while for φ≈60°, the inherently chiral (10,3)-c net is obtained (see picture, bottom).

Hydrogen bonds assist the organization of up to 11 guests within self-assembling cavities of nanometer dimensions

The self-assembly of C-methylresorcin[4]arene with 4,4′-bipyridine affords the formation of closed solid state cavities with internal volumes of ca. 1.0 nm 3 which encapsulate up to an unprecedented 11 guests involving three different molecules. These cages exhibit functionality directed into the cavities, in the form of hydrogen bond donor and acceptor sites, which assists the organization of their guests. In one case, the guests interact, with each other and the walls of the host, via 15 hydrogen bonds, to produce chiral molecular assemblies within the solid.