Additional Intramolecular Hydrogen Bond Research Articles

C-Terminal-Modified Oligourea Foldamers as a Result of Terminal Methyl Ester Reactions under Alkaline Conditions.

Hybrids of short oligourea foldamers with residues of α, β and γ-amino acids esters at the C-terminus were obtained and subjected to a reaction with LiOH. There are two possible transformations under such conditions, one of which is ester hydrolysis and the formation of a carboxylic group and the other is the cyclization reaction after abstraction of a proton from urea by a base. We have investigated this reaction with difference C-terminal residue structures, as well as under different work-up conditions, especially for oligourea hybrids with α-amino acid esters. For these compounds, an oligourea-hydantoin combination is the product of cyclization. The stability of the hydantoin ring under alkaline conditions has been alsotested. Furthermore, this work reports data related to the structure of C-terminal-modified oligourea foldamers in solution and, for one compound, in the solid state. Helical folding is preserved both for cyclized and linear modifications, with oligourea-acid hybrids appearing to be more conformationally stable, as they are stabilized by an additional intramolecular hydrogen bond in comparison to cyclic derivatives.

Influence of Hydrogen Bonds and π–π Interactions on the Fluorescence of Crystalline (N-Alkylpyridyl)enamino-pyrrolo[2,3-b]quinoxalin-2-one Derivatives

This paper presents the relationship between the fluorescent properties of (E/Z)-(N-alkylpyridyl)enamino-pyrrolo[2,3-b]quinoxalin-2-one derivatives in the crystalline state and the molecular packing governed by the conformation of the molecules, hydrogen bonding, and π–π interactions. In particular, the type of 2-pyridyl alkyl chain (2-Py(CH2)n with n = 0,1,2) is responsible for the molecular packing and influences the fluorescence properties of crystalline pyrrolo[2,3-b]quinoxalines. The molecules studied exhibit permanent dipole moments that, in the crystalline phases, promote either the formation of dimers with an antiparallel orientation or stacks with a parallel dipole moment orientation. In dimers and stacks, the main observed interaction is the π–π type. The conformations of both (E)- and (Z)-enamines are stabilized by intramolecular hydrogen bonds from the NH group of the enamine to either the nitrogen atom N4 of the quinoxaline (E)-diastereoisomer or the oxygen atom of the amide carbonyl group in the (Z)-diastereoisomer. When an additional intramolecular hydrogen bond from the enamine NH group to the pyridyl nitrogen atom forms, it affects the conformation of the molecules, causing the reorientation of the molecular permanent dipole moment. Density functional theory (DFT) calculations performed for two neighboring molecules in dimers or stacks indicate two charge transfer mechanisms: intra- and intermolecular mechanisms. For centrosymmetric dimers, charge transfer occurs within each component molecule (intramolecular charge transfer). For stacks with molecules arranged by translation and noncentrosymmetric dimers, charge transfer is of an intermolecular nature. Higher absolute fluorescence quantum yields (Φf = 12.06–13.77%) are exhibited by the (E-diastereoisomers, which contain methylene or ethylene chains and form either translational stacks of the molecules or noncentrosymmetric dimers. The lowest absolute fluorescence quantum yields (Φf = 3.80–4.00%) are typical for the centrosymmetric dimers present in crystalline (Z)-(N-pyridyl)enaminopyrrolo[2,3-b]quinoxaline and (E)-(N-ethylpyridyl)enamino-pyrrolo[2,3-b]quinoxaline. The fluorescence liftimes τ were determined for single crystals of the studied phases (from 13.3 to 15.6 ns) and revealed one single process of radiative energy transfer.

Determining the solution conformational entropy of oligosaccharides by SEC with on-line viscometry detection

Introduced here is a method for determining the solution conformational entropy of oligosaccharides (−ΔS) that relies on the on-line coupling of size-exclusion chromatography (SEC), an entropically-controlled separation technique, and differential viscometry (VISC). Results from this SEC/VISC method were compared, for the same injections of the same sample dissolutions and under identical solvent/temperature conditions, to results from a benchmark SEC/differential refractometry (SEC/DRI) method which has been applied successfully over the last decade to determining −ΔS of a variety of mono-, di-, and oligosaccharides. The accuracy (as compared to SEC/DRI) and precision of SEC/VISC were found to be excellent, as was the sensitivity of the viscometer in the oligomeric region. The experiments presented here contrast three sets of (1→4)-β-d-oligosaccharides, namely manno-, cello-, and N-acetylchitooligosaccharides of degree of polymerization (DP) 2 through 6. For each series, the dependence of −ΔS on DP was found to be monotonic while, between series, differences at each DP could be ascribed to either the additional degrees of freedom imparted by large, multi-atomic substituent groups, or to the presence or absence of additional intramolecular hydrogen bonds, depending on the axial versus equatorial arrangement of particular hydroxyl groups. An hypothesis is advanced to explain the unexpectedly high sensitivity of viscometric detection for low-molar-mass analytes. The method presented can be extended to the analysis of oligosaccharides other than those studied here.

The role of additional O–H…O intramolecular hydrogen bonds for acylphloroglucinols' conformational preferences in vacuo and in solution

Acylphloroglucinols (ACPLs) are phloroglucinol derivatives characterised by the presence of a COR group and exhibiting a variety of biological activities, making them potentially interesting for drug development. The structural variety of these compounds prompts specific studies of relevant features characterising significant subsets of compounds. One of the more interesting features is the presence, in various structures, of additional intramolecular hydrogen bonds (IHBs), besides the one between the sp2 O of COR and an ortho phenol OH, which characterises all ACPLs. This work studies the geometric characteristics and the stabilising effects of additional O–H…O IHBs, considering a selection of structures representative of the more common possibilities for their formation and comparing the results in vacuo, chloroform, acetonitrile and water. The results highlight patterns depending on the types and positions of the atoms forming the additional IHBs and, for the results in solution, also on the nature of the solvent. The stabilising effects, important in vacuo, decrease with increasing solvent polarity. In water solution, the additional IHB breaks if its breaking makes a donor or acceptor group fully (no steric hindrances) available for solute–solvent intermolecular hydrogen bonds.

Insights from Molecular Simulations into the Temperature-Induced Collapse of Unfolded Proteins

Single molecule Forster resonance energy transfer (FRET) and dynamic light scattering experiments on the unfolded state of a small cold shock protein have shown a compaction with increasing temperature, in contrast to expectations for a simple polymer (1). A comparable collapse of the intrinsically disordered protein prothymosin a suggests that the temperature-dependence of the hydrophobic effect is not the sole reason for the collapse. We have used all-atom replica exchange molecular dynamics simulations with explicit solvent to investigate the origin of the collapse. We find that the results of the simulation are dependent on the protein force field, and particularly on the solvent model employed. Use of the TIP4P-Ew water model together with the Amber ff03∗ protein force field (2) produces qualitatively similar results to experiment, however with TIP3P water, the protein is found to expand with temperature; this probably reflects the more accurate temperature dependent properties of TIP4P-Ew. The simulations suggest that collapse is correlated with the formation of additional intramolecular hydrogen bonds and loss of hydrogen bonds to water, as well as the formation of more turn and beta-structure, consistent with CD measurements. Finally, we have also used simulations of simple model compounds to investigate the molecular origin of the temperature dependence of the intrachain interactions.1. D. Nettels, S. Muller-Spath, F. Kustera, H. Hofmann, D. Haenni, S. Ruegger, L. Reymond, A. Hoffmann, J. Kubelka, B. Heinz, K. Gast, R. B. Best, B. Schuler. “Single molecule spectroscopy of the temperature-induced collapse of unfolded proteins”, Proc. Natl. Acad. Sci., in press.2. R. B. Best, G. Hummer. “Optimized Molecular Dynamics Force Fields Applied to the Helix-Coil Transition of Polypeptides”, J. Phys. Chem. B, 113, 9004-9015 (2009).”

13C CP MAS NMR and crystal structure of methyl glycopyranosides

The X-ray diffraction analysis, 13C CP MAS NMR spectra and powder X-ray diffraction patterns were obtained for selected methyl glycosides: α- and β- d-lyxopyranosides ( 1, 2), α- and β- l-arabinopyranosides ( 3, 4), α- and β- d-xylopyranosides ( 5, 6) and β- d-ribopyranoside ( 7) and the results were confirmed by GIAO DFT calculations of shielding constants. In X-ray diffraction analysis of 1 and 2, a characteristic shortening and lengthening of selected bonds was observed in molecules of 1 due to anomeric effect and, in crystal lattice of 1 and 2, hydrogen bonds of different patterns were present. Also, an additional intramolecular hydrogen bond with the participation of ring oxygen atom was observed in 1. The observed differences in chemical shifts between solid state and solution come from conformational effects and formation of various intermolecular hydrogen bonds. The changes in chemical shifts originating from intermolecular hydrogen bonds were smaller in magnitude than conformational effects. Furthermore, the powder X-ray diffraction (PXRD) performed for 4, 5 and 7 revealed that 7 existed as a mixture of two polymorphs, and one of them probably consisted of two non-equivalent molecules.

Directing-protecting groups for carbohydrates. Design, conformational study, synthesis and application to regioselective functionalization

A novel concept of regioselective transformation of secondary hydroxyl groups in carbohydrates is presented. First, the relative reactivity of the free hydroxyl groups of onoprotected d-glucose derivatives was assessed using acetylation as a model reaction. As a result, acylation of these polyols gave a mixture of monosubstituted products in which the 3- O functionalized derivatives predominated. Novel hydrogen bond acceptor protecting groups were next designed to modulate the 4-OH and 3-OH reactivity in the hope to mediate higher regioselective transformations. A molecular modeling study later validated by spectroscopic analysis predicted additional intramolecular hydrogen bonds between the hydroxyl groups and pyridyl-containing protecting groups. Taking advantage of this induced hydrogen bond network, we achieved regioselective acetylation of the hydroxyl group at position 3 without protecting any secondary hydroxyl groups of the carbohydrate moiety. This designed protecting/directing group increased the nucleophilicity and the steric hindrance of position 3. As a result, optimization of the reaction conditions enabled the monoacetylation (not affected by steric hindrance) of 6- O-protected glucopyranosides at position 3 and selective silylation (affected by steric hindrance) of position 2 in high isolated yields and regioselectivities. This result certainly opens doors to the regioselective open glycosylation of carbohydrates.

Conformational rigidity: a necessary prerequisite of chiral modifiers used in heterogeneous enantioselective catalysis?

In the hydrogenation of ketopantolactone, the ( R, R) and ( R, S) diastereomers of a new chiral modifier, pantoyl-naphthylethylamine, afforded 74 and 40% ee, respectively, to ( R)-pantolactone. On the basis of NOE studies and theoretical calculations, the different properties of the diastereomers and in particular the effect of acid on the modifier structure are deduced from differences in conformational rigidity and steric constraint. In case of the ( R, R)-diastereomer, a loose, extended structure in apolar solvent changes to a compact conformation via an additional intramolecular hydrogen bond, resulting in a more defined “chiral pocket” available for the reactant on the Pt surface.

Shape of 4(S)- and 4(R)-Hydroxyproline in Gas Phase

The alpha-amino acids 4(S)-hydroxyproline and 4(R)-hydroxyproline have been studied under isolation conditions in gas phase using laser-ablation molecular-beam Fourier transform microwave spectroscopy. Two conformers of each molecule have been detected in the jet-cooled rotational spectrum. The most stable conformer in both molecules exhibits an intramolecular N...H-O hydrogen bond (configuration 1) between the hydrogen atom of the carboxylic group and the nitrogen atom. The second conformer is characterized by an intramolecular N-H...O=C hydrogen bond (configuration 2). The conformers of 4(R)-hydroxyproline adopt a C(gamma)-exo puckering, while those of 4(S)-hydroxyproline present a C(gamma)-endo ring conformation. These ring conformations, which show the same propensity observed in collagen-like peptides, are stabilized by additional intramolecular hydrogen bonds involving the 4-hydroxyl group, with the exception of the most stable form of 4(S)-hydroxyproline for which a n-pi interaction between the oxygen atom of the 4-hydroxyl group and the carboxyl group carbon seems to be established. A gauche effect could be also contributing to stabilize the observed conformers.

Self-Complementarity Achieved through Quadruple Hydrogen Bonding

Highly stable dimers are formed in solution and in the solid state by a class of readily synthesized, self-complementary building blocks for supramolecular chemistry, which associate through a donor-acceptor-donor-acceptor array of four hydrogen-bonding sites. An additional intramolecular hydrogen bond in the compound whose crystal structure is shown on the right preorganizes the molecule for dimerization.

Conformation, Inversion Barrier, and Solvent-Induced Conformational Shift in Exo- and Endo/Exo-Calix[4]arenes.

Calixarenes 4a and 4b having hydroxyl groups in endo and exo positions and the ethanediyl-bridged exo-calixarene 5a were synthesized by a stepwise strategy. Single-crystal X-ray structures were obtained for 4a and for the exo-calixarene 3d, showing the molecules to exist in the 1,2-alternate conformation which is also found for 4a,b in solution. The inversion barriers of 4a and 4b (10.3 and 10.8 kcal mol(-1)) are similar to that determined for the endo-dihydroxycalixarene 12, indicating that the additional intramolecular hydrogen bond between the exo OH groups does not decrease the flexibility of the molecule. In CDCl(3) solution exo-calixarene 5a adopts a 1,2-alternate conformation with the methyl group at the bridge located in an axial position, while in DMSO-d(6) the conformation adopted is the partial cone. Similar solvent-induced conformational shifts were found for the exo-calixarenes 3b and 3d. MM3 calculations predict that the cone form is the lowest energy conformation of 4 and the exo-calixarenes 3 and 5. The calculations suggest that the conformational preferences of the methyl group at the bridge for either the axial or equatorial positions are in large part determined by the repulsive steric interactions with the hydroxyl groups. The inversion barrier of 4b is satisfactorily reproduced by calculations, which indicate that the rotation of the exo rings is less energetically demanding than the rotation of the endo rings.

NMR conformational studies of fenamate non‐steroidal anti‐inflammatory drugs

Abstract1H and 13C NMR spectra of the non‐steroidal anti‐inflammatory drugs mefenamic acid, meclofenamic acid and flufenamic acid were assigned and the solution dynamics and conformations of the compounds were probed by the analysis of NMR chemical shifts, temperature coefficients, 3J(C,H) coupled constants, nuclear Overhauser enhancement (NOE) effects and saturation transfer experiments. At low concentrations the anthranilic acid derivatives (the fenamates) exist as monomer units with intramolecular hydrogen bonding between the amine proton and the carboxylic acid group. At concentrations of 10 mM and above, solution aggregates exist. The intermolecular association does not disrupt the intramolecular NH…OC hydrogen bonding, resulting in a similar conformation for mefenamic and flufenamic acids at both low and high concentrations. Meclofenamic acid has an additional intramolecular hydrogen bond, resulting in a slightly different conformation to the other two fenamates. The results from this conformational study are of potential value in molecular and pharmacophore modelling studies on the bioactive conformations of these drugs.

Crystal structure of the α‐helical undecapeptide Boc‐L‐Ala‐Aib‐Ala‐Aib‐Ala‐Glu(OBzl)‐Ala‐Aib‐Ala‐Aib‐Ala‐OMe

AbstractThe x‐ray structure of Boc‐L‐Ala‐Aib‐Ala‐Aib‐Ala‐Glu(OBzl)‐Ala‐Aib‐Ala‐Aib‐Ala‐OMe(I) represents the first α‐helix determined by direct methods. This undecapeptide is a model of the N‐terminus of alamethicin, and it exhibits voltage‐dependent pores in bilayer membranes at a higher voltage and concentration than alamethicin. The molecule crystallizes in the monoclinic space group P21 with a = 10.602(1), b = 23.884(3), c = 13.622(1) Å, β = 95.61(6)°, and Z = 2. It adopts a right‐handed α‐helical conformation in the solid state with intramolecular 5 → 1 hydrogen bonds. An additional intramolecular hydrogen bond is bifurcated, forming a stronger 4 → 1 interaction (i.e., a β‐turn III) and a weaker 5 → 1 interaction, thus prolonging the α‐helical part up to 9 residues. The α‐helix radius of 2.1 Å, the height per residue (distance Ni … Ni + 4) of 1.53 Å, the resulting length of the α‐helical part of 13.8 Å (9 residues) resp. 15.3 Å (10 residues), the van der Waals radius (4.7 Å), and the minimal diameter of pores formed by aggregation of 3–10 α‐helices were calculated omitting the Glu(OBzl) side chain. In the crystal, the α‐helices are linked head to tail via two hydrogen bridges forming continuous chains. Adjacent helices are oriented in antiparallel with their helix axes and have only van der Waals contacts.

Structure of N-tert-butyloxycarbonyl-D-leucyl-L-phenylalanylethanolamide. An N alpha-protected analogue of the COOH-terminal dipeptide of linear gramicidins.

Solid state conformational analysis of N-tert-butyloxycarbonyl-D-leucyl-L-phenylalanylethanolamide (t-Boc-D-Leu-L-Phe-EA), an N alpha-protected analogue of the COOH-terminal dipeptide of linear gramicidins, carried out by x-ray diffraction, has indicated that the molecules are characterized by an N-H...O = C intramolecularly hydrogen-bonded chain reversal of the beta-turn II' type. One of the two independent molecules in the asymmetric unit shows an additional intramolecular hydrogen bond of the O-H...O = C type, linking the hydroxyl function of the COOH-terminal ethanolamide moiety to the carbonyl oxygen of the urethane N-protecting group. This is the first experimental evidence for a beta-turn conformation fused with the oxy analogue of an alpha-turn. The results of an investigation in a solvent of low polarity (deuteriochloroform), using infrared absorption and 1' nuclear magnetic resonance, strongly support the view that an intramolecularly hydrogen-bonded beta-turn conformation is the most populated conformation of t-Boc-D-Leu-L-Phe-EA molecules at high dilution. In the self-association process, taking place at high concentration, the urethane and peptide NH groups are involved as hydrogen-bonding donors.