Proximity Effects in Organic Chemistry—The Photoelectron Spectroscopic Investigation of Non-Bonding and Transannular Interactions

Classical structural formulas often convey the impression only those relationships between the atoms are of importance which hold a molecule together as symbolized by the chemical bonds. However, many interactions between atoms or groups of atoms are not adequately denoted in this manner. Nevertheless, their existence can have important consequences for ground state energies (cis-difluoroethylene is more stable than trans-difluoroethylene), conformations (the syn form of methyl vinyl ether is more stable than the anti form), reactivities (an endo cyclopropane ring in 7-anti-norbornyl derivatives accelerates solvolysis by a factor of 10¹⁴), UV spectra (“superposition” of the π-systems of acridine and purine-bonded through a four-membered chain-results in hypochromism), CD spectra (the inherently symmetrical but dissymmetrically perturbed chromophore of 2-deuterionorbornadiene allows the observation of three transitions in the near UV), and ESR spectra (the long-range coupling with H-4 in the bridgehead bicyclo[2.1.1]hex-1-yl radical equals 22.5 G). Since orbital interactions are involved in most intramolecular effects of this kind, photoelectron spectroscopy has proven an informative and valuable extension to other methods.     

Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and Inhibitors

Found throughout biology , polyvalent interactions are characterized by the simultaneous binding of multiple ligands on one biological entity to multiple receptors on another (top part of the illustration) and have a number of characteristics that monovalent interactions do not (bottom). In particular, polyvalent interactions can be collectively much stronger than corresponding monovalent interactions, and they can provide the basis for mechanisms of both agonizing and antagonizing biological interactions that are fundamentally different from those available in monovalent systems.     

对位环芳烃及其衍生物分子轨道的通过空间和通过键相互作用研究

应用改进的重叠模型多重散射Ｘα自洽场方法对对位环芳烃及其衍生物分子的分子轨道通过空间和通过键的相互作用进行了研究，讨论分子轨道相互作用对分子轨道能级顺序的影响以及不同的连接桥对分子轨道相互作用的影响，进一步应用过渡态理论方法计算对位环芳烃及其衍生物分子的分子轨道电离能，计算结果与实验结果符合较好。     

Dissecting Hofmeister Effects: Direct Anion–Amide Interactions Are Weaker than Cation–Amide Binding

Whereas there is increasing evidence for ion‐induced protein destabilization through direct ion–protein interactions, the strength of the binding of anions to proteins relative to cation–protein binding has remained elusive. In this work, the rotational mobility of a model amide in aqueous solution was used as a reporter for the interactions of different anions with the amide group. Protein‐stabilizing salts such as KCl and KNO₃ do not affect the rotational mobility of the amide. Conversely, protein denaturants such as KSCN and KI markedly reduce the orientational freedom of the amide group. Thus these results provide evidence for a direct denaturation mechanism through ion–protein interactions. Comparing the present findings with results for cations shows that in contrast to common belief, anion–amide binding is weaker than cation–amide binding.     

Direct X‐Ray Scattering Evidence for Metal–Metal Interactions in Solution at the Molecular Level

The study of the aggregation of small molecules in solution induced by metallophilic interactions has been traditionally performed by spectroscopic methods through identification of chemical changes in the system. Herein we demonstrate the use of SAXS (small‐angle X‐ray scattering) to identify structures in solution, taking advantage of the excellent scattering intensity of heavy metals which have undergone association by metallophilic interactions. An analysis of the close relationship between solid‐state and solution arrangements of a dynamic [Ag₂(bisNHC)₂]²⁺ (NHC=N‐heterocyclic carbene) system, and how they are complementary to each other, is reported.     

Origin of the Director Tilt in the Lyotropic Smectic C* Analog Phase: Hydration Interactions and Solvent Variations

The origin and long‐range correlation of the director tilt in the recently discovered phase, which is the lyotropic analog of the thermotropic smectic C* (SmC*) liquid crystalline phase, are investigated. Polarized micro‐Raman spectroscopy reveals that the director tilt in the phase originates from a tilting of the aromatic 2‐phenylpyrimidine cores of the surfactant molecules. Optical measurements of the tilt angle show that its magnitude decreases with increasing solvent concentration, suggesting that the long‐range inter‐lamellar correlation of the tilt directions is reduced at increasing thickness of the solvent layers. The phase diagrams with four different solvents (water, formamide, N‐methylformamide, N,N‐dimethylformamide) are investigated, showing that the phase is only formed with those solvents that exhibit a dense network of hydrogen bonds. This observation suggests that these hydrogen bond networks play an essential role in the long‐range correlation of the director tilt between adjacent surfactant layers. To verify this assumption, mixtures with deuterated solvents are investigated, showing that the tilt angle in the phase is indeed reduced by this modification of the solvent′s hydrogen bond network.     

Optimization of Experimental Parameters to Explore Small‐Ligand/Aptamer Interactions through Use of 1H NMR Spectroscopy and Molecular Modeling

Aptamers constitute an emerging class of molecules designed and selected to recognize any given target that ranges from small compounds to large biomolecules, and even cells. However, the underlying physicochemical principles that govern the ligand‐binding process still have to be clarified. A major issue when dealing with short oligonucleotides is their intrinsic flexibility that renders their active conformation highly sensitive to experimental conditions. To overcome this problem and determine the best experimental parameters, an approach based on the design‐of‐experiments methodology has been developed. Here, the focus is on DNA aptamers that possess high specificity and affinity for small molecules, L ‐tyrosinamide, and adenosine monophosphate. Factors such as buffer, pH value, ionic strength, Mg²⁺‐ion concentration, and ligand/aptamer ratio have been considered to find the optimal experimental conditions. It was then possible to gain new insight into the conformational features of the two ligands by using ligand‐observed NMR spectroscopic techniques and molecular mechanics.     

Hydrogen‐Bond Cooperativity in Formamide2–Water: A Model for Water‐Mediated Interactions

The rotational spectrum of formamide₂–H₂O formed in a supersonic jet has been characterized by Fourier‐transform microwave spectroscopy. This adduct provides a simple model of water‐mediated interaction involving the amide linkages, as occur in protein folding or amide‐association processes, showing the interplay between self‐association and solvation. Mono‐substituted ¹³C, ¹⁵N, ¹⁸O, and ²H isotopologues have been observed and their data used to investigate the structure. The adduct forms an almost planar three‐body sequential cycle. The two formamide molecules link on one side through an N?H???O hydrogen bond and on the other side through a water‐mediated interaction with the formation of C=O???H?O and O???H?N hydrogen bonds. The analysis of the quadrupole coupling effects of two ¹⁴N‐nuclei reveals the subtle inductive forces associated to cooperative hydrogen bonding. These forces are involved in the changes in the C=O and C?N bond lengths with respect to pure formamide.     

The Peculiar Nature of Molecular Interactions between an Imidazolium Ionic Liquid and Acetone

We present novel insights into the molecular interactions between polar solvents and imidazolium ionic liquids using the example of 1‐ethyl‐3‐methylimidazolium ethyl sulfate and acetone. Recently published volumetric property data of this particular system have revealed peculiarities which could not be fully explained by steric effects. In order to shed light on the behavior at a molecular level, we apply IR spectroscopy and analyze solvent‐induced line shifts as well as the excess IR spectra. From the spectroscopic results a conclusive picture of the site‐specific molecular interactions is developed and our explanation is in concert with the volumetric effects. The data suggest the initial formation of trimers in which acetone interacts with existing ion pairs through interactions of the acetone oxygen atom with the imidazolium ring rather than forming directed hydrogen bonds at the CH moieties. With further addition of acetone, tetramers are formed which significantly weaken the interionic interactions and eventually initiate ion pair dissociation. Once the ions are released, the anion is rapidly saturated with acetone while the cation solvation proceeds more slowly with acetone addition.     

Symmetrization of Cationic Hydrogen Bridges of Protonated Sponges Induced by Solvent and Counteranion Interactions as Revealed by NMR Spectroscopy

The properties of the intramolecular hydrogen bonds of doubly ¹⁵N‐labeled protonated sponges of the 1,8‐bis(dimethylamino)naphthalene (DMANH⁺) type have been studied as a function of the solvent, counteranion, and temperature using low‐temperature NMR spectroscopy. Information about the hydrogen‐bond symmetries was obtained by the analysis of the chemical shifts δ_H and δ_N and the scalar coupling constants J(N,N), J(N,H), J(H,N) of the ¹⁵NH¹⁵N hydrogen bonds. Whereas the individual couplings J(N,H) and J(H,N) were averaged by a fast intramolecular proton tautomerism between two forms, it is shown that the sum |J(N,H)+J(H,N)| generally represents a measure of the hydrogen‐bond strength in a similar way to δ_H and J(N,N). The NMR spectroscopic parameters of DMANH⁺ and of 4‐nitro‐DMANH⁺ are independent of the anion in the case of CD₃CN, which indicates ion‐pair dissociation in this solvent. By contrast, studies using CD₂Cl₂, [D₈]toluene as well as the freon mixture CDF₃/CDF₂Cl, which is liquid down to 100 K, revealed an influence of temperature and of the counteranions. Whereas a small counteranion such as trifluoroacetate perturbed the hydrogen bond, the large noncoordinating anion tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate B[{C₆H₃(CF₃)₂}₄]^? (BARF^?), which exhibits a delocalized charge, made the hydrogen bond more symmetric. Lowering the temperature led to a similar symmetrization, an effect that is discussed in terms of solvent ordering at low temperature and differential solvent order/disorder at high temperatures. By contrast, toluene molecules that are ordered around the cation led to typical high‐field shifts of the hydrogen‐bonded proton as well as of those bound to carbon, an effect that is absent in the case of neutral NHN chelates.     

FT IR ATR Study of Molecular Interactions in the Urea/Dimethyl Sulfoxide and Urea/Diethyl Sulfoxide Binary Systems

FT IR ATR spectra of urea/dimethyl sulfoxide and urea/diethyl sulfoxide mixtures in the S=O and N—H stretching vibration regions at different molar ratios have been measured. On the basis of the band deconvolution data, various types of intermolecular associated forms, including dimers and hydrogen-bonded urea–sulfoxide complexes, have been revealed. The latter has been confirmed also by ab initio calculations.     

Direct Identification of Protein–Protein Interactions by Single‐Molecule Force Spectroscopy

Single‐molecule force spectroscopy based on atomic force microscopy (AFM‐SMFS) has allowed the measurement of the intermolecular forces involved in protein‐protein interactions at the molecular level. While intramolecular interactions are routinely identified directly by the use of polyprotein fingerprinting, there is a lack of a general method to directly identify single‐molecule intermolecular unbinding events. Here, we have developed an internally controlled strategy to measure protein–protein interactions by AFM‐SMFS that allows the direct identification of dissociation force peaks while ensuring single‐molecule conditions. Single‐molecule identification is assured by polyprotein fingerprinting while the intermolecular interaction is reported by a characteristic increase in contour length released after bond rupture. The latter is due to the exposure to force of a third protein that covalently connects the interacting pair. We demonstrate this strategy with a cohesin–dockerin interaction.     

The Role of Binary and Many-center Molecular Interactions in Spin Crossover in the Solid State. Part III. Expressing Many-body Interactions

Summary. The approach of molecular potentials describing the shape of transition curves of spin crossover in the solid state developed earlier has been extended to many-body interactions characterized by the Axilrod-Teller potential. An improved procedure for the minimization of energy developed for this case is presented. Calculations for systems involving Lennard-Jones, electric dipole–dipole, and dispersive Axilrod-Teller triple interactions yield non-zero asymmetries of splittings in expanded/compressed systems alone. The excess energy is unaffected by the Axilrod-Teller potential. Triple interactions of the Axilrod-Teller type thus increase the sensitivity of a transition curve towards compression. Another approach presented employs the deviations of molecules from positions of mechanical equilibrium set up by the known binary potential. In the approximation of small perturbations these deviations are proportional to the gradients of many-center potentials. This allows one to parametrically define non-ideality parameters as functions of gradients of triple potentials of unknown types. Employing regularization bounds an adequate parameterization of experimental transition curve of spin crossover has been achieved in terms of parameters of Lennard-Jones potential and relative deviations of molecules from the position of mechanical equilibrium.     

The Effects of Substituents on the Geometry of π–π Interactions

We have designed and utilized a simple molecular recognition system to study the substituent effects in aromatic interactions. Recently, we showed that 3‐ and 3,5‐disubstituted benzoyl leucine diethyl amides with aromatic rings of varying electronic character organized into homochiral dimers in the solid state through a parallel displaced π–π interaction and two hydrogen bonds, but no such homochiral dimerization was observed for the unsubstituted case. This phenomenon supports the hypothesis that substituents stabilize π–π interactions regardless of their electronic character. To further investigate the origin of substituent effects for π–π interactions, we synthesized and crystallized a series of 4‐substituted benzoyl leucine diethyl amides. Surprisingly, only two of the 4‐substituted compounds formed homochiral dimers. A comparison among the 4‐substituted compounds that crystallized as homochiral dimers and their 3‐substituted counterparts revealed that there are differences in regard to the geometry of the aromatic rings with respect to each other, which depend on the electronic nature and location of the substituent. The crystal structures of the homochiral dimers that showed evidence of direct, local interactions between the substituents on the aromatic rings also displayed nonequivalent dihedral angles in the individual monomers. The crystallographic data suggests that such “flexing” may be the result of the individual molecules orienting themselves to maximize the local dipole interactions on the respective aromatic rings. The results presented here can potentially have broad applicability towards the development of molecular recognition systems that involve aromatic interactions.     

Cooperative and Diminutive Effects of Pnicogen Bonds and Cation–π Interactions

The interplay between pnicogen bonds and cation–π interactions has been investigated at the MP2/aug‐cc‐pVDZ level. Interesting cooperative and diminutive effects are observed when pnicogen bonds and cation–π interactions coexist in the same complex. These effects have been analyzed in terms of the structural, energetic, and charge‐transfer properties of the complexes. The variations in electron density at critical points of the intermolecular bond have been used to analyze bond strengthening or weakening. The nature of the interactions and the mechanisms of cooperative and diminutive effects have been studied by means of symmetry‐adapted perturbation theory and molecular electrostatic potentials.     

Determination of Allosteric Effects and Interstrand Bidentate Interactions in DNA‐Peptide Molecular Recognition

To study DNA allostery, quantitative DNase I footprinting studies were carried out on a newly designed peptide His‐Hyp‐Lys‐Lys‐(Py)₄‐Lys‐Lys‐NH₂ (HypKK‐10) containing the XHypKK (Hyp = hydroxyproline) and polyamide motifs. The interconnection of DNA footprints of peptides HypKK‐10 and the parent peptide PyPro‐12 supports the proposal that interaction network cooperativity is preferred in DNA‐peptide interactions between multiple recognition sites. A simple method of determining interstrand bidentate interactions between the peptide moieties and DNA bases is introduced. It is envisaged that interstrand bidentate interactions also participate in the relay of conformational changes to recognition sites on the complementary strands. Circular dichroism studies of the titration of peptide HypKK‐10 with an oligonucleotide duplex indicate that this peptide binds in a dimeric fashion to DNA in the minor groove. This work may prompt the design of new DNA binding ligands for the study of DNA‐peptide allosteric interactions and DNA interaction network.