Intramolecular Hydrogen-bonding Interactions Research Articles

Two pseudo-enantiomeric forms of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ(6),1-benzothiazine-3-carboxamide and their analgesic properties.

The fact that molecular crystals exist as different polymorphic modifications and the identification of as many polymorphs as possible are important considerations for the pharmaceutic industry. The molecule of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ(6),1-benzothiazine-3-carboxamide, C17H16N2O4S, does not contain a stereogenic atom, but intramolecular hydrogen-bonding interactions engender enantiomeric chiral conformations as a labile racemic mixture. The title compound crystallized in a solvent-dependent single chiral conformation within one of two conformationally polymorphic P212121 orthorhombic chiral crystals (denoted forms A and B). Each of these pseudo-enantiomorphic crystals contains one of two pseudo-enantiomeric diastereomers. Form A was obtained from methylene chloride and form B can be crystallized from N,N-dimethylformamide, ethanol, ethyl acetate or xylene. Pharmacological studies with solid-particulate suspensions have shown that crystalline form A exhibits an almost fourfold higher antinociceptive activity compared to form B.

Far-Infrared Signatures of Hydrogen Bonding in Phenol Derivatives.

One of the most direct ways to study the intrinsic properties of the hydrogen-bond interaction is by gas-phase far-infrared (far-IR) spectroscopy because the modes involving hydrogen-bond deformation are excited in this spectral region; however, the far-IR regime is often ignored in molecular structure identification due to the absence of strong far-IR light sources and difficulty in assigning the observed modes by quantum chemical calculations. Far-IR/UV ion-dip spectroscopy using the free electron laser FELIX was applied to directly probe the intramolecular hydrogen-bond interaction in a family of phenol derivatives. Three vibrational modes have been identified, which are expected to be diagnostic for the hydrogen-bond strength: hydrogen-bond stretching and hydrogen-bond-donating and -accepting OH torsion vibrations. Their position is evaluated with respect to the hydrogen bond strength, that is, the length of the hydrogen-bonded OH length. This shows that the hydrogen bond stretching frequency is diagnostic for the size of the ring that is closed by the hydrogen bond, while the strength of the hydrogen bond can be determined from the hydrogen-bond-donating OH torsion frequency. The combination of these two normal modes allows the direct probing of intramolecular hydrogen-bond characteristics using conformation-selective far-IR vibrational spectroscopy.

Hydrogen Peroxide Complex of Zinc.

Metal(H2O2) complexes have been implicated in kinetic and computational studies but have never been observed. Accordingly, H2O2 has been described as a very weak ligand. We report the first metal(H2O2) adduct, which is made possible by incorporating intramolecular hydrogen-bonding interactions with bound H2O2. This Zn(II)(H2O2) complex decays in solution by a second-order process that is slow enough to enable characterization of this species by X-ray crystallography. This report speaks to the intermediacy of metal(H2O2) adducts in chemistry and biology and opens the door to exploration of these species in oxidation catalysis.

Understanding the Amide-II Vibrations in β-Peptides.

In this work, the vibrational characteristics of the amide-II modes in β-peptides in five helical conformations, namely, 8-, 10-, 12-, 14-, and 10/12-helices, have been examined. Remarkable conformational dependence of the amide-II spectral profile is obtained by ab initio computations as well as modeling analysis. Intramolecular hydrogen-bonding interaction and its influence on backbone structure and on the amide-II local-mode transition frequencies and intensities are examined. Through-space and through-bond contributions of the amide-II vibrational couplings are analyzed, and it was found that hydrogen-bonding interaction is not a determining factor for the coupling strength. The results reported here provide useful benchmarks for understanding experimental amide-II infrared spectra of β-peptides and suggest the potential application of this mode on monitoring the structures and dynamics of β-peptides.

Central-to-Axial Chirality Transfer-Induced CD Sensor for Chiral Recognition andeeValue Detection of 1,2-DACH Enantiomers

The paper is mainly focused on the induced circular dichroism (ICD) based on central-to-axial chirality transfer for direct chiral recognition and ee value detection of 1,2-diaminocyclohexane (1,2-DACH) enantiomers. A novel achiral polymer sensor with potential axial chirality feature is designed and synthesized. This conjugated polymer incorporating biphenol moiety can bind chiral 1,2-DACH substrates via intramolecular hydrogen-bonding interactions, which could result in the detectable exciton-coupled circular dichroism (CD) spectrum due to the chirality transfer from an enantiopure building block to a dynamically racemic 1,1′-biphenyl-2,2′-diol moiety in the polymer chain backbone. The linear regression analysis of ICD sensing shows an excellent agreement between CD intensity and concentration of chiral 1,2-DACH, which indicates this biphenol-based achiral polymer can be used as a chiral sensor for direct recognition and ee value detection of 1,2-DACH enantiomers by using ICD spectra of achiral polymer sensor.

Chiral Cyclobutane β-Amino Acid-Based Amphiphiles: Influence of Cis/Trans Stereochemistry on Solution Self-Aggregation and Recognition.

Novel diastereomeric anionic amphiphiles based on the rigid cyclobutane β-amino acid scaffold have been synthesized and deeply investigated with the aim of generating new functional supramolecular architectures on the basis of the rational design of original amphiphilic molecules and the control of their self-assembly. The main interest has been focused on the effect that cis/trans stereochemistry exerts on their molecular organization and recognition. In diluted solutions, the relative stereochemistry mainly influences the headgroup solvation and anionic-charge stabilization, i.e., better stabilized in the cis diastereoisomer due to intramolecular hydrogen-bonding and/or charge-dipole interactions. This provokes differences in their physicochemical behavior (pKa, cmc, conductivity) as well as in the structural parameters of the spherical micelles formed. Although both diastereoisomers form fibers that evolve with time from the spherical micelles, they display markedly different morphology and kinetics of formation. In the lyotropic liquid crystal domain, the greatest differences are observed at the highest concentrations and can be ascribed to different hydrogen-bonding and molecular packing imposed by the stereochemical constraints. Remarkably, the spherical micelles of the two anionic surfactants show dramatically diverse enantioselection ability for bilirubin enantiomers. In addition, both the surfactants form heteroaggregates with bilirubin at submicellar concentrations but with a different expression of supramolecular chirality. This points out that the unlike relative configuration of the two surfactants influences their chiral recognition ability as well as the fashion in which chirality is expressed at the supramolecular level by controlling the molecular organization in both micellar aggregates and surfactant/bilirubin heteroaggregates. All these differential features can be appropriate and useful for the design and development of new soft materials with predictable and tunable properties and reveal the cyclobutane motif as a valuable scaffold for the preparation of new amphiphiles.

An experimental and theoretical study of a hydrogen-bonded complex: O-phenylenediamine with 2,6-pyridinedicarboxylic acid

The hydrogen-bonded complex, [(OPDH)+(dipicH)−.H2O], between o-phenylenediamine (OPD) and 2,6-pyridinedicarboxylic acid (dipicH2) has been characterized in water by the 1H, 13C NMR and IR spectroscopies. The crystal structure showed that the edge to face C–H⋯π and C–O⋯π stacking interactions between the dipicH2 and OPD rings play an extra significant role in the formation of the hydrogen-bonded complex and supported the H-bonding interactions. The proton transfer also investigated theoretically in gas phase and thermodynamic parameters such as ΔH‡, ΔG‡, ΔS‡ were calculated for this process. Moreover, intramolecular hydrogen-bonding interaction has been recognized by calculating the electron density ρ(r) and Laplacian ∇2ρ(r) at the bond critical point (BCP) using Atoms-In-Molecule (AIM) method and also the interaction between electron acceptor (σ*) of OH with the lone pair of the nitrogen atom as an electron donor using Natural Bond Orbital (NBO) analysis. In addition, the protonation constants of dipicH2 and OPD and the equilibrium constants for the dipic-OPD (1:1) proton transfer system were obtained by the potentiometric pH titration method using the Hyperquad 2008 program. The stoichiometry of the proton transfer species in the solution confirmed the solid state result.

Hydrogen Bonding, (1)H NMR, and Molecular Electron Density Topographical Characteristics of Ionic Liquids Based on Amino Acid Cations and Their Ester Derivatives.

Amino acid ionic liquids (AAILs) have attracted significant attention in the recent literature owing to their ubiquitous applications in diversifying areas of modern chemistry, materials science, and biosciences. The present work focuses on unraveling the molecular interactions underlying AAILs. Electronic structures of ion pairs consisting of amino acid cations ([AA(+)], AA = Gly, Ala, Val, Leu, Ile, Pro, Ser, Thr) and their ester substituted derivatives [AAE(+)] interacting with nitrate anion [NO3(-)] have been obtained from the dispersion corrected M06-2x density functional theory. The formation of ion pair is accompanied by the transfer of proton from quaternary nitrogen to anion facilitated via hydrogen bonding. The [Ile], [Pro], [Ser], and [Thr] and their esters reveal relatively strong inter- as well as intramolecular hydrogen-bonding interactions. Consequently, the hierarchy in binding energies of [AA][NO3] ion pairs and their ester analogues turns out to be [Gly] > [Ala] > [Ser] ∼ [Val] ∼ [Ile] > [Leu] ∼ [Thr] > [Pro]. The work underlines how the interplay of intra- as well as intermolecular hydrogen-bonding interactions in [AA]- and [AAE]-based ILs manifest in their infrared and (1)H NMR spectra. Substitution of -OCH3 functional group in [AA][NO3] ILs lowers the melting point attributed to weaker hydrogen-bonding interactions, making them suitable for room temperature applications. As opposed to gas phase structures, the presence of solvent (DMSO) does not bring about any proton transfer in the ion pairs or their ester analogues. Calculated (1)H NMR chemical shifts of the solvated structures agree well with those from experiment. Correlations of decomposition temperatures in [AA]- and [AAE]-based ILs with binding energies and electron densities at the bond critical point(s) in molecular electron density topography, have been established.

A critical approach toward resonance-assistance in the intramolecular hydrogen bond interaction of 3,5-diiodosalicylic acid: a spectroscopic and computational investigation.

The photophysics of a prospective drug molecule, 3,5-diiodosalicylic acid (3,5-DISA), having a wide spectrum of biological and medicinal applications, have been investigated using spectroscopic techniques and computational analyses. The remarkably large Stokes' shifts in various solvents from 3,5-DISA has been intertwined with the occurrence of an excited-state intramolecular proton transfer (ESIPT) reaction. Concurrently, the emergence of an intriguing dual emission feature in less interacting solvents is also reported and the spectral response of 3,5-DISA toward the variation of medium acidity/basicity has been exploited to decipher the nature of various species present in different solvents. Our experimental results, unveiling the occurrence of an ESIPT reaction in 3,5-DISA, have been aptly substantiated from computational studies in which the operation of ESIPT has been explored from structural as well as energetics (analysis of potential energy surface (PES)) perspectives. A major focus of the present study is on the evaluation of the intramolecular hydrogen bond (IMHB) interaction in 3,5-DISA, including the application of various methodologies to estimate the IMHB energy and subsequently, an in-depth analysis of the IMHB interaction reveals its partially covalent nature through the application of advanced quantum chemical tools, e.g., the natural bond orbital (NBO) method. In this context, the interplay between the aromaticity of the benzene nucleus and the IMHB energy has been rigorously explored, showing indications for the occurrence of resonance-assisted hydrogen bonding (RAHB) in 3,5-DISA. To this end, the geometric as well as magnetic criteria of aromaticity have been analyzed.

Hydrogen-bonded supramolecular architecture in nonlinear optical ammonium 2,4-dinitrophenolate hydrate

Single crystals of ammonium 2,4-dinitrophenolate hydrate (ADH) were grown by the slow evaporation solution growth technique. The structure is elucidated by single-crystal X-ray diffraction analysis and the crystal belongs to an orthorhombic system with noncentrosymmetric space groupPna21. The second harmonic generation efficiency of ADH is superior to that of the reference material KH2PO4. The X-ray study reveals that molecules are associated by weak C—H...O, O—H...N, N—H...π and π–π stacking interactions, which are responsible for the formation and strengthening of the supramolecular assembly. Inter- and intramolecular hydrogen-bonding interactions support the supramolecular architecture in the crystal packing. Three different types of architecture,i.e.column-like packing, a sandwich model of packing and a cluster network type of infrastructure, are observed. Optical studies reveal that the absorption is minimum in the visible region and the cutoff wavelength is at ∼240 nm. The band-gap energy was estimated by the application of the Kubelka–Munk algorithm. The powder X-ray diffraction pattern reveals the good crystallinity of the as-grown specimen. Investigation of the intermolecular interactions and crystal packing using Hirshfeld surface analysis, based on single-crystal X-ray diffraction, reveals that the close contacts are associated with molecular interactions. Fingerprint plots of Hirshfeld surfaces were used to locate and analyze the percentage of hydrogen-bonding interactions.

Discovery and structural analyses of S-adenosyl-l-homocysteine hydrolase inhibitors based on non-adenosine analogs

Optimization of a new series of S-adenosyl-l-homocysteine hydrolase (AdoHcyase) inhibitors based on non-adenosine analogs led to very potent compounds 14n, 18a, and 18b with IC50 values of 13±3, 5.0±2.0, and 8.5±3.1nM, respectively. An X-ray crystal structure of AdoHcyase with NAD+ and 18a showed a novel open form co-crystal structure. 18a in the co-crystals formed intramolecular eight membered ring hydrogen bond formations. A single crystal X-ray structure of 14n also showed an intramolecular eight-membered ring hydrogen bond interaction.

A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design.

Electron deficient, bivalent sulfur atoms have two areas of positive electrostatic potential, a consequence of the low-lying σ* orbitals of the C-S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramolecular interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a molecule. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramolecular hydrogen-bonding interaction, appears to be underappreciated by the medicinal chemistry community. In this Perspective, we discuss the theoretical basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and organic synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermolecular interactions between ligand C-S σ* orbitals and proteins are illustrated.

Co–C Bond Dissociation Energies in Cobalamin Derivatives and Dispersion Effects: Anomaly or Just Challenging?

Accurate Co-C bond dissociation energies (BDEs) of large cobalamin derivatives in the gas phase and solution are crucial for understanding bond activation mechanisms in various enzymatic reactions. However, they are challenging for both experiment and theory as indicated by an obvious discrepancy between experimental and theoretical gas phase data for adenosylcobinamide. State-of-the-art dispersion-corrected DFT and LPNO-CCSD calculations are conducted for the Co-C BDEs of some neutral and positively charged cobalamin derivatives with adenosyl and methyl ligands and compared with available experimental gas phase and solution data to resolve the controversy. Our results from various levels of electronic structure theory are fully consistent with chemical and physical reasoning. We show undoubtedly that the Co-C bonds in complexes with the bulky adenosyl ligand are indirectly enhanced by many ligand-host noncovalent interactions and that the overall BDE are larger than those with the small methyl ligand in the gas phase. The additional intramolecular dispersion and hydrogen-bond interactions are significantly but not fully quenched in aqueous solution. The theoretical results including standard continuum solvation and dispersion corrections to DFT are in full accordance with experimental solution data. This is in agreement with several successful joined experimental/theoretical studies in recent years employing similar quantum chemical methodology. We see therefore no empirical basis for questioning the reliability of current dispersion corrections like D3 or VV10 to standard density functional approximations neither for these compounds nor for organometallic chemistry in general.

Quantum chemical study on influence of the substitution effect on the structural and electronic properties and intramolecular hydrogen bonding of 2-nitrophenyl hydrosulfide in ground and electronic excited state

A density functional theory (DFT)-based quantum chemical computational study has been carried out to characterize the intramolecular hydrogen bonding (IMHB) interaction in 2-nitrophenyl hydrosulfide. This compound and its 24 derivatives are optimized by B3LYP method using 6-311++G** basis set in the gas phase and the water solution. The following substituents have been taken into consideration: F, Cl, Br, C2H5, CH3, CF3, NHCOCH3, NO2, OH, OCH3, SH, CH2F, CH2Cl, CH2Br, CH2OH, SH, SCH3, SCF3, SCOCH3, CH2CF3, CH2OCH3, CHO, COCH3, and OCHF2. The IMHB interaction has been explored by calculation of electron density ρ(r) and Laplacian ∇2ρ(r) at the bond critical point using atoms-in-molecule (AIM) theory. The electron density (ρ) and Laplacian (∇2ρ) properties, estimated by AIM calculations, indicate that H6···O1 bond possesses low ρ and positive ∇2ρ values which are in agreement with electrostatic character of the HBs, whereas S5–H6 bond has covalent character (∇2ρ < 0). The natural bond orbital analysis is applied to get a more precise insight into the nature of such H6···O1 interactions. Vibrational frequencies, several well-established indices of aromaticity, and physical properties such as dipole moment, chemical potential, and chemical hardness of these compounds have been systematically explored. Also, the excited-state properties of intramolecular hydrogen bonding in these systems have been investigated theoretically using the time-dependent DFT method.

Theoretical studies on the structures, intra- and inter-molecular hydrogen bonding interactions in HNF and HNF–H2O clusters in the gaseous, aqueous and solid phases

Hydrazimium nitroformate ([N2H5]+[C(NO2)3]− , HNF) is an ionic oxidiser used in solid propellants. Its properties are easily affected by H2O because of its hygroscopicity. In this article, density functional theory (DFT) and molecular dynamics (MD) were employed to study the isolated HNF molecule and the HNF–H2O cluster in gas phase and in the aqueous solution. Three stable conformations were obtained for HNF in the gas phase and in the aqueous solution, respectively, and each conformation can form several different HNF–H2O clusters. Irrespective of whether it is in gas phase or in solution, intramolecular hydrogen bond interactions and other interactions (e.g. the binding energy, the dispersion energy, the second-order perturbation energy and the energy gap between frontier orbitals) of HNF are weaker in the clusters than in the isolated state. The initial decomposition energy of the cluster is lower than that of the isolated HNF molecule in both gaseous and aqueous phases, while the dissociation processes are the same. Molecular dynamic simulations showed that the clustered H2O elongates and weakens the C–NO2 bond in the solid HNF–H2O cluster compared with that in the solid HNF. H2O reduces and weakens intramolecular N–HΛO bonds too, and O–HΛN is the dominant intermolecular hydrogen bond between HNF and H2O.

Kinetic Method Analysis of the Effect of cis- and trans-Hydroxylation on the Proton Affinity of Proline

Proton affinities of proline and hydroxyproline were measured using the Cooks’ kinetic method. The measurements show that hydroxylation increases the proton affinity, which is consistent with X3LYP computation results. This work supports findings from a previous study (S. Mezzache et al., Rapid Commun. Mass Spectrom. 2005, 19, 2279) that modification of proline increases its proton affinity, but it does not provide compelling evidence for the prediction in the same study that proton affinity of the molecule is substantially influenced by intramolecular interactions involving the proton. PBE1PBE calculations suggest that isotropic polarizability rather than intramolecular hydrogen-bonding interactions provides a more suitable diagnosis for trends in proton affinity changes associated with modifications.

DFT studies on antioxidant mechanisms, electronic properties, spectroscopic (FT-IR and UV) and NBO analysis of C-glycosyl flavone, an isoorientin

The relationship between structure and electronic properties of isoorientin, a C-glycoside flavone is investigated to relate its radical scavenging activity using molecular descriptors. To elucidate the antioxidant activity of polyphenolics, three mechanisms namely hydrogen atom transfer (HAT), single electron transfer–proton transfer (SET–PT) and sequential proton-loss electron-transfer (SPLET) are employed. In gas-phase, OH bond dissociation enthalpies (BDE), ionization potential (IP), proton dissociation enthalpies (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) are computed and correlated relevant to antioxidant potency of the title compound employing DFT/6-311G(d,p) protocol. The theoretically simulated FT-IR and the UV–visible absorption spectra have been compared with the experimental data. Based on the absorbed UV spectra and TD-DFT calculations, assignment of the absorption bands are carried out. In addition, formation of intramolecular hydrogen bond and most possible interaction sites are explained by using natural bond orbital (NBO) analysis.

Designing foldamer-foldamer interactions in solution: the roles of helix length and terminus functionality in promoting the self-association of aminoisobutyric acid oligomers.

The biological activity of antibiotic peptaibols has been linked to their ability to aggregate, but the structure-activity relationship for aggregation is not well understood. Herein, we report a systematic study of a class of synthetic helical oligomer (foldamer) composed of aminoisobutyric acid (Aib) residues, which mimic the folding behavior of peptaibols. NMR spectroscopic analysis was used to quantify the dimerization constants in solution, which showed hydrogen-bond donors at the N terminus promoted aggregation more effectively than similar modifications at the C terminus. Elongation of the peptide chain also favored aggregation. The geometry of aggregation in solution was investigated by means of titrations with [D6]DMSO and 2D NOE NMR spectroscopy, which allowed the NH protons most involved in intermolecular hydrogen bonds in solution to be identified. X-ray crystallography studies of two oligomers allowed a comparison of the inter- and intramolecular hydrogen-bonding interactions in the solid state and in solution and gave further insight into the geometry of foldamer-foldamer interactions. These solution-based and solid-state studies indicated that the preferred geometry for aggregation is through head-to-tail interactions between the N and C termini of adjacent Aib oligomers.

Density functional theory (DFT) and natural bond orbital (NBO) study of vibrational spectra and intramolecular hydrogen bond interaction of l-ornithine–l-aspartate

In this study, exhaustive conformations of (S)-4-amino-4-carboxybutan-1-aminium (S)-3-amino-3-carboxypropanoate (LOLA) have been scanned. Experimental and theoretical studies on the structure and vibrations of the title compound are presented. The optimized molecular structure, vibrational wavenumbers, Mulliken atomic charges, natural bond orbital (NBO) and molecular electrostatic potential studies have been performed by density functional theory (DFT) using B3LYP method with the 6-311++G(d,p) basis set. Computed X-ray powder diffraction (XRPD) data has been carried out by DFT calculations and ab initio from measured XRPD finding. The LOLA molecular geometry has been determined which exists in the form of salt by intramolecular H-bonds and ionic bonding. Moreover, calculated vibrational frequencies were applied to simulate IR and Raman spectra of the title compound which showed excellent agreement with observed spectra. Reliable vibrational assignments have been made on the basis of potential energy distribution (PED) and 0.992 has been obtained by least squares method which is the uniform scaled factor for theoretical frequencies at 6-311++G(d,p) basis set. In addition, the hydrogen bonding in LOLA molecule has been explored by calculation of the hyperconjugative charge transfer interaction on [LP X-σ*(Y-H)], under NBO analysis, Mulliken atomic charge analysis, molecular electrostatic potential map (MEP) and vibrational spectra. Finally, HOMO–LUMO of the title compound has been plotted for predicting reactive sites.

Electronic structures, intramolecular hydrogen bond interaction, and aromaticity of substituted 4-amino-3-penten-2-one in ground and electronic excited state

The hydrogen bond strength, molecular structure, and several well-established indices of aromaticity have been evaluated for 4-amino-3-penten-2-one and its 20 derivatives by means of density functional theory (DFT) with 6-311++G** basis set in the gas phase and the water solution. Moreover, the excited-state properties of intramolecular hydrogen bonding (IHB) in these systems have been investigated theoretically using the time-dependent density functional theory (TD-DFT). The nature of IHB interaction has been explored by calculation of electron density ρ(r) and Laplacian ∇2ρ(r) at the bond critical point (BCP) using atoms-in-molecule (AIM) theory. Results of AIM calculations indicate that H···O bond possesses low ρ and positive ∇2ρ(r), which are in agreement with electrostatic character of the IHB, whereas N–H11 bond has covalent character (∇2ρ < 0). Furthermore, the analysis of hydrogen bond in this molecule and its derivatives by natural bond orbital (NBO) methods supports the DFT results. The various correlations are found between geometrical, energetic, and topological parameters. The substituent effect is also analyzed and it is found that the strongest/weakest hydrogen bonds exist for CF3/F substitutions.