2,154 research outputs found

    Proton transfer, electron binding and electronegativity in ammonium-containing systems

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    Using modern electronic structure methods, the ammonia-hydrogen halide complexes and their anions are characterised to determine the number, type, and properties of their minima, and their electron binding energies. Methodological issues of determining the potential energy surfaces of reactive monomers are addressed in the course of this investigation. The energetic origins of the hydrogen-bonded minima are determined by evaluation of the one-body and two-body terms composing the total energy of the complexes, and a rationale for the drive to proton transfer is presented. It is concluded that the systems have qualitatively similar potential surfaces, and that the balance of the one-body and two-body forces determines the number and depth of minima, while the electron acts as a perturbing agent on the one- or two-body energy, depending upon the nature of the minimum encountered. The halogen-bonded structures of ammonia-hydrogen bromide, iodide, and astatide complexes are shown to be stable, and one may perhaps bind an electron. The concept of the ammonium radical as a pseudo-atom is presented and tested. It is found to show competing pseudo-atomic and molecular properties.Engineering and Physical Sciences Research Council (EPSRC

    Quantum Mechanical Studies of Charge Assisted Hydrogen and Halogen Bonds

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    This dissertation is mainly focused on charge assisted noncovalent interactions specially hydrogen and halogen bonds. Generally, noncovalent interactions are only weak forces of interaction but an introduction of suitable charge on binding units increases the strength of the noncovalent bonds by a several orders of magnitude. These charge assisted noncovalent interactions have wide ranges of applications from crystal engineering to drug design. Not only that, nature accomplishes a number of important tasks using these interactions. Although, a good number of theoretical and experimental studies have already been done in this field, some fundamental properties of charge assisted hydrogen and halogen bonds still lack molecular level understanding and their electronic properties are yet to be explored. Better understanding of the electronic properties of these bonds will have applications on the rational design of drugs, noble functional materials, catalysts and so on. In most of this dissertation, comparative studies have been made between charge and neutral noncovalent interactions by quantum mechanical calculations. The comparisons are primarily focused on energetics and the electronic properties. In most of the cases, comparative studies are also made between hydrogen and halogen bonds which contradict the long time notion that the H-bond is the strongest noncovalent interactions.Besides that, this dissertation also explores the long range behavior and directional properties of various neutral and charge assisted noncovalent bonds

    The Halogen Bond

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    The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. In this fairly extensive review, after a brief history of the interaction, we will provide the reader with a snapshot of where the research on the halogen bond is now, and, perhaps, where it is going. The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design

    X-Panding Halogen Bonding Interactions: Hybrid Cocrystals Composed of Ionic Halides, Iodine and Organoiodines

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    Halogen bonding referred to as an attractive, noncovalent interaction between an electrophilic region of a halogen atom X (acts as Lewis acid) and a nucleophilic region of a molecule Y (acts as Lewis base). Such interactions and the resulting polymeric networks play an important role in many fields related to crystal engineering, including for example, the fabrication of liquid crystals and novel drug design. The application of halogen bonding has particular promise in biological systems by increasing the lipophilicity of drugs to improve penetration through lipid membranes and tissues, enabling better intracellular delivery. Based on this concept, my research at Clemson University included the synthesis and characterization of many cocrystals derived from different alkyl/aryl ammonium/phosphonium iodides, an additional iodine source and neutral organohalogen compounds to establish versatile halogen bonding networks. Iodide salts such as PPh3MeI, NMe3PhI, (Me)4NI, (Et)4NI, 2-chloro-1-methylpyridinium iodide, 3-methylbenzothiazolium iodide, trimethylbenzylammonium iodide, tributylbenzylammonium iodide etc., an additional iodine source such as I2, iodoform etc., and several neutral organoiodines such as 1,2- or 1,4-diiodotetraflurobenzene, tetraiodoethylene, etc. have been used to synthesize salt-solvate cocrystals, where iodide or triiodide anions couple with the organic cation to form the salt component, and the neutral organiodine molecule can act as a “solvating” species. The anions and organoiodine molecules then form robust and varied halogen bonding networks, while the cations can also influence the structure based on their size, and their participation in complementary intermolecular interactions such as phenyl embraces, pi-pi interactions, and CH-pi interactions. For example, triphenylmethyl phosphonium iodide reacts with iodine and tetraiodoethylene to form triphenylmethylphosphonium triiodide cocrystal with tetraiodoethylene both by a simple mechanochemical synthesis (grinding the components together) and by solution chemistry (slow evaporation) in a variety of solvents. By varying the reaction stoichiometry, temperature, and solvent type, a robust crystal chemistry has been revealed. The resulting halogen bonding networks exhibit different chains, layers, or three-dimensional networks and broadened the scope and potential applications of halide crystal engineering. Additionally, several polyiodide salts have been synthesized by varying the reaction stoichiometry of iodide salts and the source of iodine used. The resulting polyiodide networks also exhibit different chains, layers, or three-dimensional networks based on the halogen bonding interactions formed. This study helps to understand the structural nature of higher polyiodides on a fundamental level and provides new insights into the classification of such polyiodides within the continuum of covalent and halogen bonding interactions. Moreover, some iodide cocrystals with organoiodine compounds have also been synthesized and their halogen bonding networks have been investigated and further compared with that in triiodide cocrystals having the same cation. This study helps to better understand the directional (or, non-directional) nature of the anions in establishing the halogen bonding motifs and provides an additional tool to apply to problems in crystal engineering. Finally, presence of other intermolecular noncovalent interactions such as phenyl embracing, pi-pi stacking, CH-pi interactions, F-pi interactions and hydrogen bonding have been studied for all the cocrystals

    Theoretical and Experimental Investigation of Non-Covalent Interactions in S-Nitrosothiols and Thio-Carboxylic Acids

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    S-Nitrosothiols (RSNOs) are ubiquitous biomolecules whose chemistry is tightly controlled in unknown. In this work, we demonstrate, using high-level ab initio and DFT calculations, the ability of RSNOs to participate in intermolecular interactions with electron pair donors/Lewis bases (LBs) via a σ-hole, a region of positive electrostatic potential on the molecular surface at the extension of the N–S bond. Analysis of the nature of the intermolecular interactions in σ-hole bound RSNO-LB complexes shows the dominant role of electrostatic and dispersion interactions. Importantly, σ-hole binding is able to modulate the properties of RSNOs by changing the balance between two chemically opposite (antagonistic) resonance components, R–S+=N–O– (D) and R–S–/NO+ (I), which are, in addition to the main resonance structure R–S–N=O, necessary to describe the unusual electronic structure of RSNOs. σ-Hole binding at the sulfur atom of RSNO promotes the resonance structure D and reduces the resonance structure I, thereby stabilizing the weak N–S bond and making the sulfur atom more electrophilic. On the other hand, increasing the D-character of RSNO by other means (e.g. via N- or O-coordination of a Lewis acid) enhances the σ-hole bonding. Our calculations suggest that in the protein environment a combination of σ-hole bonding of a negatively charged amino acid sidechain at the sulfur atom and N- or O-coordination of a positively charged amino acid sidechain is expected to have a profound effect on the RSNO electronic structure and reactivity.Additionally, protein functionalities are highly dependent on the pKa value of their amino acids. The sequence of deprotonation in thiol containing amino acid side chains determine their nucleophilicity and reactivity. Cysteine as a sulfur containing amino acid is actively involved in the oxidases, reductases and disulfide isomerases through thiol-disulfide exchange reactions. In this study, we investigated the sequence of deprotonation between thiol and carboxylic acid as two active and determining groups in protein structures. This study have been performed in two different types of molecules. First, thiosalicylic acid was considered as an aromatic geminal bifunctional model molecule. The sequence of ionization was analyzed both computationally through DFT calculations and experimentally through UV-vis, NMR and X-ray diffraction measurements. Our experimental analysis were in agreement with our computational analysis confirming the fact that the sequence of deprotonation in bifunctional aromatic thiol-carboxylic acid is not following the classic rules of ionization. Second, we extended our experiment in to aliphatic molecules with vicinal and geminal thiol-carboxylic acid groups. In this part computational studies illustrate untraditional fashion of deprotonation which was incompatible with experimental X-ray diffraction measurements

    Quantum Mechanical Study of Weak Molecular Interactions

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    Noncovalent interactions have a long history and have received huge attention since their discovery almost a century ago. The prevalence of noncovalent interactions can be seen in the formation of simple dimers to structural and functional modification of large biomolecules. Even though plenty of experimental and theoretical studies are performed to understand various noncovalent interactions, the nature and variety of those interactions are still subject of study. And still they are receiving tremendous attention due to their significant role in the stability and conformation of biomolecules, catalysis of organic and inorganic reactions, crystal packing and material design. This dissertation explores various new sorts of noncovalent interactions, compares them with existing ones, and extensively studies the relevance of noncovalent interactions to various biological systems of interest by applying quantum mechanical tools. A new sort of noncovalent interaction has been identified where two electronegative atoms interact directly with each other with no intervening hydrogen or halogen atoms. These interactions are found to be surprisingly strong, even stronger than regular OH···O and NH···O hydrogen bonds in some cases, and are stabilized by the charge transfer from electron donor to electron acceptor. The major portion of this dissertation deals with the rigorous investigation of new sorts of interactions like P···N, S···N, Cl···N and several other charge transfer types of interactions with side by side comparison with hydrogen and halogen bonds. Similarly, a new carbonyl-carbonyl stacking geometry in peptide-peptide interactions is explored. These stacking geometries are energetically close to stronger NH···O hydrogen bonds, and get some assistance from CH···O hydrogen bonds. Carbon is considered one of the potent H-bond donors, albeit weaker, due to its ubiquitous presence in biomolecules. So, another portion of this dissertation is focused on the study of neutral and charged CH hydrogen bonds simulating various interpeptide interactions and enzyme catalysis. And the last part of this dissertation deals with the putative H-bonds that might be present in tip functionalized carbon nanotubes

    Molecular simulations on proteins of biomedical interest : A. Ligand-protein hydration B. Cytochrome P450 2D6 and 2C9 C. Myelin associated glycoprotein (MAG)

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    TOPIC 1: Water molecules mediating polar interactions in ligand–protein complexes contribute to both binding affinity and specificity. To account for such water molecules in computer-aided drug discovery, we performed an extensive search in the Cambridge Structural Database (CSD) to identify the geometrical criteria defining interactions of water molecules with ligand and protein. In addition, ab initio calculations were used to derive the propensity of ligand hydration. Based on these information we developed an algorithm (AcquaAlta) to reproduce water molecules bridging polar interactions between ligand and protein moieties. This approach was validated using 20 crystal structures and yielded a match of 76% between experimental and calculated water positions. The solvation algorithm was then applied to the docking of oligopeptides to the periplasmic oligopeptide binding protein A (OppA), supported by a pharmacophore-based alignment tool. TOPIC 2: Drug metabolism, toxicity, and interaction profile are major issues in the drug discovery and lead optimization processes. The Cytochromes P450 (CYPs) 2D6 and 2C9 are enzymes involved in the oxidative metabolism of a majority of the marketed drugs. By identifying the binding mode using pharmacophore pre-alignement and automated flexible docking, and quantifying the binding affinity by multi-dimensional QSAR, we validated a model family of 56 compounds (46 training, 10 test) and 85 (68 training, 17 test) for CYP2D6 and CYP2C9, respectively. The correlation with the experimental data (cross- validated r2 = 0.811 for CYP2D6 and 0.687 for CYP2C9) suggests that our approach is suited for predicting the binding affinity of compounds towards the CYP2D6 and CYP2C9. The models were challenged by Y-scrambling, and by testing an external dataset of binding compounds (15 compounds for CYP2D6 and 40 for CYP2C9) and not binding compounds (64 compounds for CYP2D6 and 56 for CYP2C9). TOPIC 3: After injury, neurites from mammalian adult central nervous systems are inhibited to regenerate by inhibitory proteins such as the myelin-associated glycoprotein (MAG). The block of MAG with potent glycomimetic antagonists could be a fruitful approach to enhance axon regeneration. Libraries of MAG antagonists were derived and synthesized starting from the (general) sialic acid moiety. The binding data were rationalized by docking studies, molecular dynamics simulations and free energy perturbations on a homology model of MAG. The pharmacokinetic profile (i.e. stability in cerebrospinal fluid, logD, and blood-brain barrier permeation) of these compounds has been thoroughly investigated to evaluate the drug-likeness of the identified antagonists

    Computational Study About Noncovalent Bonding Systems Involving Halogen, Chalcogen and Pnicogen Bonds

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    First terms used in this thesis are introduced and defined as follows. In the periodic table, the elements in the 17th column are named halogen including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The elements in the 16th column are named chalcogen including oxygen (O), sulfur (S), selenium (Se) and tellurium (Te). The elements in the 15th column are named pnicogen including nitrogen (N), phosphorus (P), arsenic (As) and antimony (Sb). After hydrogen bonds (B-H⋅⋅⋅B) are well studied and understood by scientists and researchers, halogen bonds (R-X⋅⋅⋅B) have drawn attention due to the similarities in bonding format and geometries. However, it is not straightforward to understand how the overall negative halogen atoms interact with the electronegative chemical group, which is usually a Lewis base until scientists proved the existence of the positive region surrounding the halogen atom X directly opposite the R group by Molecular Electrostatic Potential analysis. This thesis studied the detailed structural, geometric and spectroscopic features quantitatively by computational chemistry. The research studied the halogen transfer in symmetric (between two same molecules) and asymmetric systems (between two different molecules). In either case, the potential contains a single symmetric well for short halogen bond length and transferred to a double well when the distance was increased. Furthermore, the partial transfer calculations of halogen as bridging atom between two molecules suggests the degree of halogen transfer to form an ion pair is small even when a strong acid is combined with a strong base. Moreover, the thesis extended the application of Badger-Bauer rules from hydrogen bonds to halogen, chalcogen and pnicogen bonds. Badger-Bauer rules states the spectroscopic change were linearly related to the bond strength of hydrogen bonds. The theory extension will improve the understanding of bond strength of a specific bond in the complicated systems by detecting the spectroscopic change
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