Secondary Electrostatic Interactions Research Articles

Supramolecular Structure of Tris(1,10-phenanthroline)zinc(II)-Cation and N,N′,N″-tris(carboxymethyl)-1,3,5-benzenetricarboxamide-Anion: Synthesis, Crystal Structure, Vibrational Spectra, and Theoretical Investigations

The present work reports on the synthesis, structural, spectroscopic, and theoretical studies of a new solid state ionic compound mainly composed of tris(1,10-phenanthroline)zinc(II) cations and N,N′,N″-tris(carboxymethyl)-1,3,5-benzenetricarboxamide anions. Colorless and well-shaped crystals were obtained from an alkaline aqueous methanolic solution, and single-crystal X-ray diffraction revealed a distinct supramolecular network. Powder diffraction techniques and Rietveld analysis confirmed the phase purity of the crystalline probes. The compound crystallizes in the orthorhombic space group Pbca with a cell volume of 9517.0 Å3. The complex cations [Zn(phen)3]2+ are interconnected via π–π-interactions and form a cationic layer network with holes. The organic counterion, as a dianion, forms dimeric units through π–π-interactions and hydrogen bonds, which also form an anionic layer network with honeycomb-like holes through cooperative classical hydrogen bonds of the O∙∙∙H–O and O∙∙∙H–N type with attractive secondary electrostatic interactions. Using the holes, the resulting supramolecular framework can be described as an interpenetrated network of separate anionic and cationic layers linked by further weaker non-covalent interactions such as C–H∙∙∙π and lone-pair∙∙∙π interactions. DFT calculations confirmed the experimentally observed spectroscopic (IR and Raman) findings. For a deeper insight into the structural arrangement in the crystal, the different Hirshfeld surfaces of the cation and anion, the pairwise interaction energies as well as the energy framework were calculated, supporting the dominance of attractive and repulsive electrostatic forces between the ions.

How Bases Catalyze Diels-Alder Reactions.

We have quantum chemically studied the base-catalyzed Diels-Alder (DA) reaction between 3-hydroxy-2-pyrone and N-methylmaleimide using dispersion-corrected density functional theory. The uncatalyzed reaction is slow and is preceded by the extrusion of CO2 via a retro-DA reaction. Base catalysis, for example, by triethylamine, lowers the reaction barrier up to 10 kcal mol-1 , causing the reaction to proceed smoothly at low temperature, which quenches the expulsion of CO2 , yielding efficient access to polyoxygenated natural compounds. Our activation strain analyses reveal that the base accelerates the DA reaction via two distinct electronic mechanisms: i) by the HOMO-raising effect, which enhances the normal electron demand orbital interaction; and ii) by donating charge into 3-hydroxy-2-pyrone which accumulates in its reactive region and promotes strongly stabilizing secondary electrostatic interactions with N-methylmaleimide.

Hydrogen-Bond Donors in Drug Design.

Hydrogen-bond donors are seen to cause more problems for drug designers than hydrogen-bond acceptors. Most of the polarity in drug-like compounds comes from hydrogen-bond acceptors since they typically exceed the hydrogen-bond donors in number and are more heavily solvated on an individual basis. The implications of this polarity imbalance for optimization of permeability and aqueous solubility are discussed. A factor that should be considered in optimization of ligand recognition by targets is that the presence of a hydrogen-bond donor generally implies that a hydrogen-bond acceptor is also present (but not vice versa). Frustrated solvation and secondary electrostatic interactions result from aligned hydrogen-bond donors and acceptors, and the design opportunities presented by these phenomena are discussed. Hydrogen-bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements, and halogen- and chalcogen-bond donors are discussed as hydrogen-bond donor equivalents.

Quantification of secondary electrostatic interactions in H-bonded complexes.

The H-bonding properties of compounds that contain multiple functional groups are difficult to predict, because there are through-bond polarisation effects and long-range secondary electrostatic interactions that have significant effects on the interactions with solvents and other molecules. Here we use experimental measurements of association constants for formation of 1 : 1 H-bonded complexes that contain a single well-defined H-bond and a single well-defined secondary electrostatic interaction to quantify the magnitude of this effect. The results were used to develop a computational method for calculating functional group H-bond parameters that accurately reproduce the magnitudes of both primary H-bonding interaction and secondary electrostatic interactions. The effects of secondary electrostatic interactions are observed in calculations of ab initio Molecular Electrostatic Potential (MEP) values, but at the van der Waals surface, the magnitude of the effect is highly overestimated. MEP values calculated on electron density isosurfaces that lie closer to the nuclei provide a more accurate description of the experimental observations. H-bond parameters calculated using this approach successfully account for the properties of arrays of multiple H-bond donor and acceptor groups in different configurations. The results provide insight into the factors that govern the interaction properties of molecules that contain multiple functional groups and provide an accurate method for prediction of solution phase complexation free energies based on gas phase calculations of individual molecules.

Do Secondary Electrostatic Interactions Influence Multiple Dihydrogen Bonds? AA-DD Array on an Amine-Borane Aza-Coronand: Theoretical Studies and Synthesis.

Hydrogen bond plays a key role in a wide range of inorganic, organic, as well as biological systems. The understanding on how the chemical environment can affect this kind of interaction is crucial to predict its binding strength and consequently the robustness and the dynamic properties of many supramolecular systems. In this paper a new donor-acceptor complex was synthesized and characterized by SCXRD, showing for the first time in an organic system an AA-DD pattern of a particular hydrogen interaction, called dihydrogen bond. Over 250 functionals were computationally evaluated to select the best method to reproduce the binding interaction geometry of this new pattern. Moreover, a new vector force model was used to split the contribution of primary and secondary electrostatic interactions (SEIs), in order to evaluate how the latter one can modify the binding strength of this unusual hydrogen-hydrogen interaction.

Hydrogen bond design principles.

Hydrogen bonding principles are at the core of supramolecular design. This overview features a discussion relating molecular structure to hydrogen bond strengths, highlighting the following electronic effects on hydrogen bonding: electronegativity, steric effects, electrostatic effects, π-conjugation, and network cooperativity. Historical developments, along with experimental and computational efforts, leading up to the birth of the hydrogen bond concept, the discovery of nonclassical hydrogen bonds (C-H…O, O-H…π, dihydrogen bonding), and the proposal of hydrogen bond design principles (e.g., secondary electrostatic interactions, resonance-assisted hydrogen bonding, and aromaticity effects) are outlined. Applications of hydrogen bond design principles are presented.

Supramolecular Architecture in a Ni(II) Complex with a Weakly Bonded N,N′-(1,4-phenylenedi- carbonyl)Diglycinate Counter-Anion: Crystal Structure Investigation and Hirshfeld Surface Analysis

In this work, we describe the structural investigation of a Ni(II) complex, [Ni(C12H8N2)2(H2O)2]2·(C12H10N2O6)·(NO3)2·10H2O, with phenanthroline ligands, a deprotonated aromatic dicarboxylic acid, N,N′-(1,4-phenylenedicarbonyl)diglycine, and a nitrate as counter-anions, as well as water molecules. Noncovalent interactions, such as π–π stacking, lone-pair···π, and C–H···π between the phenanthrolines of the cationic complex, [Ni(C12H8N2)2(H2O)2]2+, and counter-anions are observed. Moreover, the solvated and noncoordinating counter-anion, N,N′-(1,4-phenylenedicarbonyl)diglycinate, is embedded in classical and nonclassical hydrogen-bonding interactions with water molecules and phenanthrolines. The two water molecules coordinated by the NiII atom and hydrogen bonded to the carboxylate of the N,N′-(1,4-phenylenedicarbonyl)diglycinate show attractive secondary electrostatic interactions, and a DD/AA hydrogen bonding pattern is formed. The noncovalent interactions of the cationic complex and the solvated N,N′-(1,4-phenylenedicarbonyl)diglycinate counter anion were explored with a Hirshfeld surface analysis, and related contributions to crystal cohesion were determined. The results of the N,N′-(1,4-phenylenedicarbonyl)diglycinate counter anion were compared to those of a solvated N,N′-(1,4-phenylenedicarbonyl)diglycine molecule of a previously described copper(II) complex.

Theoretical studies on the bond strength and electron density characteristics in multiple hydrogen bonded arrays

Multipoint hydrogen bonded motifs with intermolecular N–H⋯N hydrogen bonds have been theoretically studied at the PBE0-D3/ma-def2-TZVP level. The properties of electron density at the bond critical points of hydrogen bonds have been analyzed through “atoms in molecule” (AIM) theory and “electron localization function” (ELF) method. The results imply that the secondary electrostatic interactions have a significant effect to the strength of multipoint hydrogen bonds. Good relationships are found between ρ, ELF parameters and CVB indices. Moreover, they also show good relationships with hydrogen bond distances. These parameters may be treated as universal indicators of the hydrogen bond strength. The investigations would be useful in understanding comprehensively the multipoint hydrogen bonded motifs and helpful in designing the supramolecular systems through multipoint hydrogen bonds.

The Nature of Hydrogen Bonds: A Delineation of the Role of Different Energy Components on Hydrogen Bond Strengths and Lengths.

Hydrogen bonds are a complex interplay between different energy components, and their nature is still subject of an ongoing debate. In this minireview, we therefore provide an overview of the different perspectives on hydrogen bonding. This will be done by discussing the following individual energy components: 1) electrostatic interactions, 2) charge‐transfer interactions, 3) π‐resonance assistance, 4) steric repulsion, 5) cooperative effects, 6) dispersion interactions and 7) secondary electrostatic interactions. We demonstrate how these energetic factors are essential in a correct description of the hydrogen bond, and discuss several examples of systems whose energetic and geometrical features are not captured by easy‐to‐use predictive models.

Exploiting directional long range secondary forces for regulating electrostatics-dominated noncovalent interactions.

It has been well established that long range secondary electrostatic interactions (SEIs) have a significant effect on the stability of supramolecular complexes. However, general rules for exploiting SEIs in the rational design of diverse supramolecular complexes have been difficult to obtain. In this work, we outline a quantum chemical approach for understanding the strength of electrostatic interactions. This approach is seen to provide excellent correlation between the electrostatic force and the binding energy between two partners in hydrogen-bonded complexes, as well as that between two ions in ion-pair complexes. Furthermore, we illustrate how the understanding of the binding allows for the rational design of new complexes where the association constant between the two partners can be increased or decreased, as desired, by several orders of magnitude. Hence, the current work showcases a general, simple and powerful method of understanding and exploiting long range secondary electrostatic interactions.

Comprehensive study on the effects of sodium and potassium additives in size exclusion chromatographic separations of protein biopharmaceuticals

To separate proteins solely based on their difference in hydrodynamic volume in size exclusion chromatography (SEC), the ionic strength of the mobile phase has to be increased in order to avoid secondary ionic interactions between proteins and the stationary phase. However, adding salts to the mobile phase can have a serious effect on protein aggregation and can lead to artifacts. In the present study, several monoclonal antibodies (mAbs) and the antibody-drug conjugate (ADC), trastuzumab emtansine were selected to study the effect of mobile phase salt additive on aggregation measurements. In a first instance, the same aggregation ratios between the dimeric and monomeric forms of ten mAbs approved by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) were obtained with three UHP-SEC columns. However, SEC analysis using various amounts of NaCl provided surprising results for rituximab, e.g. presence of 0.8% aggregates with a mobile phase containing 0.2M NaCl, while no aggregates were observed without NaCl in the mobile phase. Despite the absence of monomeric protein adsorption at the surface of the SEC resin, the comparison of sodium- and potassium-based salts demonstrated the superiority of potassium-based salts to reduce possible secondary electrostatic interactions, mainly between protein dimers and the SEC support as well as to lower protein-salts interaction. To investigate the effect of mobile phase salt additives on SEC measurements, fluorescence spectroscopy provided insights related to the possible contribution of protein tertiary structure. Indeed, biopharmaceuticals could be classified depending on the exposure of their tryptophan residues to the solvent in order to understand their propensity to interact with the stationary phase or/and to undergo self-association.

Theoretical study on the nature of S···H and O ··· H hydrogen bonds

Hydrogen bond acceptor ability of sulfur and oxygen has been analyzed in the adducts of dimethyl sulfide ((CH3)2S) and dimethyl ether ((CH3)2O) with H2O, CH3OH, HCOOH, NH2OH, CH3NH2, NH2NH2, HCONH2, HF and HCl. The stabilization energies have been evaluated using MP2/aug-cc-pVDZ, B3LYP/aug-cc-pVDZ, gaussian2 (G2) and complete basis set (CBS) theoretical levels. The contributors to stabilization energies are explored by employing symmetry adapted perturbation theory analysis, natural bond orbital analysis in addition to molecular orbital methods. Electrostatic component is the major contributor toward stabilization energy in both the type of adducts involving (CH3)2S and (CH3)2O which has been assigned to secondary electrostatic interactions. The second important contributor to comparable stabilization energies in the two series is the repulsive Eexch component which is relatively higher in adducts of (CH3)2O because of the relatively longer proximity of the monomeric units arising from smaller size of oxygen.

Absolute and relative binding affinity of cucurbit[7]uril towards a series of cationic guests

We determined the relative binding constants (Krel) for guests 1–19 towards cucurbit[7]uril by 1H NMR competition experiments in 100 mM Na3PO4-buffered D2O. In these experiments, we use guest 11 as the reference guest because of its strong binding towards CB[7] and its advantageous spectroscopic properties (e.g. slow exchange on NMR timescale and distinct resonances for key protons). To convert the determined Krel values to absolute binding constants, we performed a direct UV–vis titration of 1 with CB[7] to determine Ka for CB[7]√1. The trends in the determined values of Krel and Ka are discussed with respect to the importance of the concentration of metal ions in the buffer, the influence of hydroxyl groups located at the portals or inside the CB[7] cavity, geometry of the guest (e.g. regioisomers), the number of guest C atoms and secondary electrostatic interactions.

Amino acid side chain induced selectivity in the hydrolysis of peptides catalyzed by a Zr(iv)-substituted Wells–Dawson type polyoxometalate

In this paper the reactivity of K15H[Zr(α2-P2W17O61)2]·25H2O (1), a Zr(IV)-substituted Wells-Dawson polyoxometalate, is examined towards a series of Gly-Aa, Aa-Gly or Aa-Ser dipeptides, in which the nature and the size of the Aa amino acid side chain were varied. The rate of peptide bond hydrolysis, determined by (1)H NMR experiments, in Gly-Aa dipeptides is strongly dependent on the molecular volume and the chemical structure of the Aa side chain. When the volume of the aliphatic side chain of the Aa residue in Gly-Aa increased, a clear decrease in the hydrolysis rate was observed. Replacing one α-H in the C-terminal Gly residue of Gly-Gly by a methyl group (Gly-Ala) resulted in a 6-fold reactivity decrease, pointing towards the importance of steric factors for efficient peptide bond hydrolysis. The rate constants for peptide bond hydrolysis in Gly-Aa dipeptides at pD 5.0 and 60 °C ranged from 208.0 ± 15.6 × 10(-6) min(-1) for Gly-Ser to 5.0 ± 1.0 × 10(-6) min(-1) for Gly-Glu, reflecting the influence of the different nature of the amino acid side chains on the hydrolysis rate. Faster hydrolysis was observed for peptides containing Ser and Thr since the hydroxyl group in their side chain is able to facilitate amide bond hydrolysis by promoting an N→O acyl rearrangement. Peptides containing positively charged side chains at pD 5.0 show enhanced hydrolysis rates as a result of the secondary electrostatic interactions with the negatively charged surface of the polyoxometalate, which stabilize the peptide-polyoxometalate complex. A slow hydrolysis rate was observed for Gly-Glu, because of the preferential coordination of the carboxylate group in the side chain of Glu to Zr(IV), which prevents coordination of the peptide carbonyl group and its activation towards hydrolysis.

Synthesis, characterization and biological activity of trans-platinum(II) complexes with chloroquine

Three platinum-chloroquine complexes, trans-Pt(CQDP) 2(I) 2 [ 1], trans-Pt(CQDP) 2(Cl) 2 [ 2] and trans-Pt(CQ) 2(Cl) 2 [ 3], were prepared and their most probable structure was established through a combination of spectroscopic analysis and density functional theory (DFT) calculations. Their interaction with DNA was studied and their activity against 6 tumor cell lines was evaluated. Compounds 1 and 2 interact with DNA primarily through electrostatic contacts and hydrogen bonding, with a minor contribution of a covalent interaction, while compound 3 binds to DNA predominantly in a covalent fashion, with weaker secondary electrostatic interactions and possibly hydrogen bonding, this complex also exerted greater cytotoxic activity against the tumor cell lines.

Relationship Between Conformational Flexibility and Chelate Cooperativity

A family of four biscarbamates (AA) and four bisphenols (DD) were synthesized, and H-bonding interactions between all AA•DD combinations were characterized using (1)H NMR titrations in carbon tetrachloride. A chemical double mutant cycle analysis shows that there are no secondary electrostatic interactions or allosteric cooperativity in these systems, and the system therefore provides an ideal platform for investigating the relationship between chemical structure and chelate cooperativity. Effective molarities (EMs) were measured for 12 different systems, where the number of rotors in the chains connecting the two H-bond sites was varied from 5 to 20. The association constants vary by less than an order of magnitude for all 12 complexes, and the variation in EM is remarkably small (0.1-0.9 M). The results provide a relationship between EM and the number of rotors in the connecting chains (r): EM ≈ 10r(-3/2). The value of 10 M is the upper limit for the value of EM for a noncovalent intramolecular interaction. Introduction of rotors reduces the value of EM from this maximum in accord with a random walk analysis of the encounter probability of the chain ends (r(-3/2)). Noncovalent EMs never reach the very high values observed for covalent processes, which places limitations on the magnitudes of the effects that one is likely to achieve through the use of chelate cooperativity in supramolecular assembly and catalysis. On the other hand, the decrease in EM due to the introduction of conformational flexibility is less dramatic than one might expect based on the behavior of covalent systems, which limits the losses in binding affinity caused by poor preorganization of the interaction sites.

An AAAA–DDDD quadruple hydrogen-bond array

Secondary electrostatic interactions between adjacent hydrogen bonds can have a significant effect on the stability of a supramolecular complex. In theory, the binding strength should be maximized if all the hydrogen-bond donors (D) are on one component and all the hydrogen-bond acceptors (A) are on the other. Here, we describe a readily accessible AAAA–DDDD quadruple hydrogen-bonding array that exhibits exceptionally strong binding for a small-molecule hydrogen-bonded complex in a range of different solvents (K(a) > 3 × 10(12) M(-1) in CH2Cl2, 1.5 × 10(6) M(-1) in CH3CN and 3.4 × 10(5) M(-1) in 10% v/v DMSO/CHCl3). The association constant in CH2Cl2 corresponds to a binding free energy (ΔG) in excess of –71 kJ mol(-1) (more than 20% of the thermodynamic stability of a carbon–carbon covalent bond), which is remarkable for a supramolecular complex held together by just four intercomponent hydrogen bonds.

Retention behavior of estrogen metabolites on hydrophilic interaction chromatography stationary phases

Estrogens and estrogen metabolites are important biological mediators of the endocrine system. They have also been implicated in detrimental carcinogenesis and beneficial neuroprotective processes. The retention behavior of estrogen metabolites was investigated on five polar stationary phases, used for hydrophilic interaction chromatography, and coupled with ESI-MS. Data were fit to partitioning and surface adsorption models. Retention of the compounds, especially estrogen glucuronides, on the amide- and diol-bonded stationary phases, could be best described by the surface adsorption model; however, mixed modes of retention were observed on most stationary phases. Retention time increased while the peak efficiency decreased proportional to the number of hydroxyl groups in the analytes. The effects of salt concentration and salt type were also investigated. The presence of solvated salt ions, which interact with the stationary phase and the analyte, enhanced retention of the analytes. This was believed to be due to two effects. The increased ionic strength reduced the contribution of secondary electrostatic interactions (mixed-mode effects). It also enhanced hydrogen-bonding and partitioning (hydrophilic interaction) between the analyte and the stationary phase, likely facilitated by the associated solvated salt ions.

Noncovalent Synthesis of Shape-Persistent Cyclic Hexamers from Ditopic Hydrazide-Based Supramolecular Synthons and Asymmetric Induction of Supramolecular Chirality

With properly encoded recognition sites and a well-defined algorithm for intermolecular and intramolecular interactions, the 120 degrees spacer linked ditopic hydrazide-based supramolecular synthons were found to self-assemble into shape-persistent cyclic hexamers in apolar solvents. The two hydrazide motifs displayed separate sets of signals in the NMR spectra because of the interlocked conformation. While in hydrogen bonding competitive solvent such as DMSO-d(6) the spectra were in agreement with the structures with C(2) axes. Moreover, the terminative groups were found to affect the stability of the assemblies substantially. Consequently, the monomer with ureido-hydrazide terminative groups could form the most stable cyclic hexamer in solution for the attractive spectator secondary electrostatic interactions. Owing to the dynamically and kinetically stable nature of these kinds of assemblies, the assembly from the monomer with chiral auxiliary terminative groups also displayed supramolecular chirality in solution, which was confirmed by concentration-dependent CD spectra.

The Effective Concentration of Unbound Ink Anchors at the Molecular Printboard

Self-assembled monolayers terminating in beta-cyclodextrin cavities can be used to bind ink molecules and so provide a molecular printboard for nanopatterning applications. Multivalent or multisite binding strengthens the attachment of large inks and provides more robust patterns. In the present work we use computer simulations to probe the behavior of functionalized dendrimer inks at the printboard. We performed a series of long 10 ns fully atomistic molecular dynamics (MD) simulations to measure the effective local concentration of unbound ink anchor groups at the printboard for a variety of binding modes and also for the partial unbinding prerequisite for ink diffusion on the printboard. These simulations allow us to describe the conformational space occupied by partially bound inks and estimate the likelihood of an additional binding interaction. Furthermore, by simulating the shift from a divalent to monovalent binding mode we show that the released anchor quickly moves to the periphery of the dendrimer binding hemisphere but then reapproaches the printboard and remains in the vicinity of alternative binding sites. Secondary electrostatic interactions between the protonated dendrimer core and hydroxyl groups at the entrance to the beta-cyclodextrin cavities give "flattened" dendrimer binding orientations and may aid dendrimer diffusion on the printboard, allowing the dendrimer to "walk" along the printboard by switching between different partially bound states and minimizing complete unbinding to bulk solution, crucial for the application of the printboard in, for example, medical diagnostics.