Formation Of Intramolecular Hydrogen Bond Research Articles

Intramolecular Hydrogen Bonding in Medicinal Chemistry

The formation of intramolecular hydrogen bonds has a very pronounced effect on molecular structure and properties. We study both aspects in detail with the aim of enabling a more rational use of this class of interactions in medicinal chemistry. On the basis of exhaustive searches in crystal structure databases, we derive propensities for intramolecular hydrogen bond formation of five- to eight-membered ring systems of relevance in drug discovery. A number of motifs, several of which are clearly underutilized in drug discovery, are analyzed in more detail by comparing small molecule and protein-ligand X-ray structures. To investigate effects on physicochemical properties, sets of closely related structures with and without the ability to form intramolecular hydrogen bonds were designed, synthesized, and characterized with respect to membrane permeability, water solubility, and lipophilicity. We find that changes in these properties depend on a subtle balance between the strength of the hydrogen bond interaction, geometry of the newly formed ring system, and the relative energies of the open and closed conformations in polar and unpolar environments. A number of general guidelines for medicinal chemists emerge from this study.

Effects of side-chain packing on the formation of secondary structures in protein folding

We have recently shown that protein folding is driven by the water-entropy gain. When the alpha-helix or beta-sheet is formed, the excluded volumes generated by the backbone and side chains overlap, leading to an increase in the total volume available to the translational displacement of water molecules. Primarily by this effect, the water entropy becomes higher. At the same time, the dehydration penalty (i.e., the break of hydrogen bonds with water molecules) is compensated by the formation of intramolecular hydrogen bonds. Hence, these secondary structures are very advantageous units, which are to be formed as much as possible in protein folding. The packing of side chains, which leads to a large increase in the water entropy, is also crucially important. Here we investigate the roles of the side-chain packing in the second structural preference in protein folding. For some proteins we calculate the hydration entropies of a number of structures including the native structure with or without side chains. A hybrid of the angle-dependent integral equation theory combined with the multipolar water model and the morphometric approach is employed in the calculation. Our major findings are as follows. For the structures without side chains, there is an apparent tendency that the water entropy becomes higher as the alpha-helix or beta-sheet content increases. For the structures with side chains, however, a higher content of alpha-helices or beta-sheets does not necessarily lead to larger entropy of water due to the effect of the side-chain packing. The thorough, overall packing of side chains, which gives little space in the interior, is unique to the native structure. To accomplish such specific packing, the alpha-helix and beta-sheet contents are prudently adjusted in protein folding.

Exploration of SAR features by modifications of thiazoleacetic acids as CRTH2 antagonists

The SAR features have been further explored for (2-benzhydryl-4-phenyl-thiazol-5-yl)acetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. The introduction of a nitrogen or a methyl substituent in the benzhydrylic position offer two alternative drugable scaffolds attractive for unsymmetrically substituted derivatives. An imidazole analogue lacks activity due to formation of a favored coplanar intramolecular hydrogen bond. The pyrimidine derivative 18 represents a potent and selective compound that will be subject to continued investigations.

Theoretical study on the structure, spectra and thermodynamic property of 5-(2-aryloxy-methylbenzimidazole-1-carbadehyde)-1,3,4-oxadiazole-2-thione

The geometry structure optimization and frequency calculation of the title compound molecule have been studied using density functional theory B3LYP method, and infrared spectrum, Raman spectrum and thermodynamic properties at different temperatures have been obtained. The electronic absorption spectrum in gas and different solvent have been calculated and simulated. The results showed that the formation of intra-molecular hydrogen bond was helpful to stability of the title compound molecule, which was in good agreement with experimental crystal structure. The peak of maximal absorption located at 236 nm in gas, belonging to near UV, and solvent effect made the maximal absorption wavelength blue-shifted about 20 nm, and independent of solvent polarity.

Effect of Molecular Organization in Micelles and Bilayers on Binding and Conformation of Biologically Active Peptides

Amphiphiles form different types of aggregates, such as micelles and bilayers, depending on their shape and hydrophilic-hydrophobic balance. While bilayers form vesicles containing an inner aqueous compartment, micelles are smaller, approximately spherically-shaped, and have no internal aqueous compartment. Thus, molecular packing and mobility vary in these aggregates, and EPR spectra of spin probes can be used to examine these properties. EPR spectra evince tighter molecular packing and slower rate of motion in bilayers than in micelles. Such differences affect binding of peptides, both qualitatively and quantitatively. Fluorescence, CD, and EPR were employed to investigate interactions of micelles and vesicles with antimicrobial peptides, as well as fragments of GPCR and cytolytic toxins. EPR was also used for peptide analogues containing the paramagnetic amino acid TOAC. Two-component spectra indicated slow exchange between bound peptide and peptide tumbling fast in aqueous solution, allowing the calculation of binding constants. Peptide-membrane interaction was also monitored by changes in peptide fluorescence intensity and emission wavelengths, as well as accessibility to a water soluble quencher. CD spectra showed that upon binding the peptides acquired secondary structure due to formation of intramolecular hydrogen bonds, favored by the decreased polarity at the lipid interface. While in most cases, bilayer binding was only observed when electrostatic interactions occurred between positively charged peptides and negatively charged phospholipids, electrostatic effects played a less important role in peptide-micelle interaction. These differences were ascribed to differences in molecular packing and curvature in both types of aggregates. The positive curvature of micelles is proposed to mimic the lipid organization of toroidal pores. Thus, the conformational behavior in the presence of micelles would correspond to that of peptides forming toroidal pores in bilayer membranes.Supported by FAPESP, CNPq, CAPES.

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).”

Thermodynamic Investigation of Enol↔Keto Tautomerism for Alcohol Sensors Based on Carbon Nanotubes as Chemical Sensors

Single‐walled carbon nanotubes (SWNT) are molecular‐scale wires with high mechanical stiffness and strength. The faster response and substantially higher sensitivity of chemical nanotubes sensors over existing solid‐state sensors, which was due to exposure of gaseous molecules such as C2H5OH, served as the basis to consider gas sensors based on SWNT. These factors also focused on the ethanol sensing effects of the sensors on the acetaldehyde and ethyl methyl ketone tautomerism at room temperature, which have been formed within alcohol dehydrogenation and condensation reactions involved in chain growth pathways on SWNT. Since temperature has a strong effect on structure and stability, we were interested in calculating some specific thermo chemical properties to justify the structural stability of existing isomers in keto↔enol tautomerism. So, the thermodynamic and electric properties of produced ethyl‐methyl ketone involved in keto↔enol tautomerism have been investigated using semi‐empirical methods. The obtained results showed that the keto structure is more stable because of intramolecular hydrogen bond formation due to strong C = O bond existence in the keto tautomers. Our finding implies that the semi‐empirical quantum chemical calculations can be suggested as proper methods to study the interaction of different chemical compounds with SWNT in a reliable way.

Bifunctional influence of 3-chloro substitution on structural and energetic characteristics of N-methyl-salicylidene imines

Energetic and structural effects of formation of intramolecular hydrogen bonds in the group of eight differently chloro-substituted ortho-hydroxy aromatic Schiff bases ( N-methyl-salicylidene imines) containing the 3-chloro substituent in all compounds were studied. The aim was to explain the specific function of this substituent, giving rise to an especially large increase of the strength of intramolecular hydrogen bonds. DFT B3LYP/6–31 + G(d,p) calculations of the structures of particular conformers as well as the potential energy surfaces were carried out. The method of thermodynamic cycle-like scheme was adapted, where the three open conformers are used to estimate the steric corrections connected with formation of chelate rings in the fourth conformer. Problems arising for the estimation of the energy of intramolecular hydrogen bonds connected with the selection of reference states and various structural aspects are discussed in detail. 3-Chloro-substituted Schiff bases can be accounted as sterically enhanced intramolecular hydrogen bonds. Participation of steric and electronic functions in increasing of the energy of intramolecular hydrogen bonds was analyzed. Low energetic proton transfer reaction was found in these molecules, which can be potentially interesting from the point of view of possible thermochromic applications.

Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer

Through conformational restriction of a benzamide by formation of a seven-membered hydrogen-bond with an oxindole carbonyl group, a series of PARP inhibitors was designed for appropriate orientation for binding to the PARP surface. This series of compounds with a 3-oxoisoindoline-4-carboxamide core structure, displayed modest to good activity against PARP-1 in both intrinsic and cellular assays. SAR studies at the lactam nitrogen of the pharmacophore have suggested that a secondary or tertiary amine is important for cellular potency. An X-ray structure of compound 1e bound to the protein confirmed the formation of a seven-membered intramolecular hydrogen bond. Though revealed previously in peptides, this type of seven-membered intramolecular hydrogen bond is rarely observed in small molecules. Largely due to the formation of the intramolecular hydrogen bond, the 3-oxoisoindoline-4-carboxamide core structure appears to be planar in the X-ray structure. An additional hydrogen bond interaction of the piperidine nitrogen to Gly-888 also contributes to the binding affinity of 1e to PARP-1.

Catechol‐Based Macrocyclic Rods: En Route to Redox‐Active Molecular Switches

AbstractThe design and synthesis of the macrocyclic turnstile 1 comprising a terminally sulfur‐functionalized molecular rod and a redox‐active catechol subunit is described. The shape‐persistent macrocyclic scaffold consists of alternating arylene and ethynylene units. A freely rotating 2,6‐diethynyl‐catechol subunit is clamped between both terminal arylene subunits as molecular turnstile. While the electrochemical switching between the catechol and the quinone form of this catechol subunit is displayed by cyclic voltammetry, conformational rearrangements by favoring and disfavoring the formation of intramolecular hydrogen bonds are the subject of current investigations. Terminal acetyl‐protected sulfur anchor groups enabled the immobilization of the macrocycle between an Au tip and an Au substrate of a STM set‐up. Preliminary single‐molecule transport investigations of the turnstile 1 display comparable values as for the parent molecular rod. An electrochemically‐controlled single‐molecule transport experiment to investigate redox‐state‐dependent transport properties is currently under way.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

New Type of Dual Solid-State Thermochromism: Modulation of Intramolecular Charge Transfer by Intermolecular π−π Interactions, Kinetic Trapping of the Aci-Nitro Group, and Reversible Molecular Locking

When heated above room temperature, some crystalline polymorphs of the 1,3-bis(hydroxyalkylamino)-4,6-dinitrobenzenes (BDBn, n = 2-5), bis(hydroxyalkyl) analogues of the intramolecular charge-transfer molecule 1,3-diamino-4,6-dinitrobenzene, exhibit "dual" thermochromism: gradual color change from yellow to orange at lower temperatures, and sharp color change from orange to red at higher temperatures. These two thermochromic changes are related to different solid-state processes. When allowed to cool to room temperature, the yellow color of the thermochromic molecules with different alkyl length (n) is recovered with unexpectedly different kinetics, the order of the respective rate constants ranging from 10(-7)-10(-6) s(-1) for BDB2 to about 0.1 s(-1) in the case of BDB3. The thermochromic mechanism and the reasons behind the different kinetics were clarified on the basis of detailed crystallographic characterization, kinetic thermoanalysis, and spectroscopic study of eight crystalline forms (seven polymorphs and one solvate). It was found that the polymorphism is due to the possibility of "locking" and "unlocking" of the alkyl arms by formation of a strong intramolecular hydrogen bond between the hydroxyl groups at their hydroxyl termini. The locking of BDB2, with shortest alkyl arms, is reversible and it can be controlled thermally; either of the two conformations can be obtained in the solid state by proper thermal treatment. By use of high temperature in situ single crystal X-ray diffraction analysis of BDB3, direct evidence was obtained that the gradual thermochromic change is related to increased distance and weakened pi-pi interactions between the stacked benzene rings: the lattice expands preferably in the stacking direction, causing enhanced oscillator strength and red shift of the absorption edge of the intramolecular charge transfer transition. The second, sharp thermochromic change had been assigned previously to solid-solid phase transition triggered by intramolecular proton transfer of one amino proton to the nitro group, whereupon an aci-nitro form is thermally populated. Contrary to the numerous examples of solid thermochromic molecules based on either pericyclic reactions or keto-enol tautomerism, this system appears to be the first organic thermochromic family where the thermochromic change appears as an effect of intermolecular pi-pi interactions and thermal intramolecular proton transfer to aromatic nitro group.

Nanofibers from Oxazolidi‐2‐one Containing Hybrid Foldamers: What is the Right Molecular Size?

A series of oligomers of the type Boc-(L-Phe-D-Oxd)(n)-OBn (Boc = tert-butoxycarbonyl; Oxd = 4-methyl-5-carboxy oxazolidin-2-one; Bn = benzyl) were prepared for n = 2-5. The shortest oligomer, Boc-(L-Phe-D-Oxd)(2)-OBn, aggregates and forms a fiber-like material with an anti-parallel beta-sheet structure in which the oligopeptide units are connected to each other by only one intermolecular hydrogen bond. The longer oligomers exhibit structural heterogeneity. They start to organize into secondary structures by the formation of intramolecular hydrogen bonds at the pentamer level. Microscopy and diffraction of the oligomers indicated a crystalline character for only the shorter ones.

THEORETICAL STUDIES ON HEATS OF FORMATION OF PYRIDINE N-OXIDES USING DENSITY FUNCTIONAL THEORY AND COMPLETE BASIS METHOD

The heats of formation (HOFs) for 11 pyridine N-oxide compounds are calculated by employing the hybrid density functional theory (B3LYP, B3PW91, B3P86, PBE1PBE) methods with 6-31G** basis set and ab initio CBS-4M method. It is demonstrated that the B3PW91 method is accurate to compute the reliable HOFs for pyridine N-oxide compounds. It is also noted that the HOF is the smallest for the pyridine N-oxide which has the substituent group on the para-position, such as 4-NC–c- C 5 H 4 NO , 4- H 2 NOC – C 5 H 4 N – O , and 4- HO 2 C –c- C 5 H 4 NO . In addition, we think that the HOF of 2- HO 2 C –c- C 5 H 4 NO is much larger than that of 3- HO 2 C –c- C 5 H 4 NO and 4- HO 2 C –c- C 5 H 4 NO , which may be the result of intramolecular hydrogen bond formation and further measurements are needed to reexamine the HOFs for 2- HO 2 C –c- C 5 H 4 NO , 3- HO 2 C –c- C 5 H 4 NO , and 4- HO 2 C –c- C 5 H 4 NO .

Gabapentin: A Stereochemically Constrained γ Amino Acid Residue in Hybrid Peptide Design

Nature has used the all-alpha-polypeptide backbone of proteins to create a remarkable diversity of folded structures. Sequential patterns of 20 distinct amino acids, which differ only in their side chains, determine the shape and form of proteins. Our understanding of these specific secondary structures is over half a century old and is based primarily on the fundamental elements: the Pauling alpha-helix and beta-sheet. Researchers can also generate structural diversity through the synthesis of polypeptide chains containing homologated (omega) amino acid residues, which contain a variable number of backbone atoms. However, incorporating amino acids with more atoms within the backbone introduces additional torsional freedom into the structure, which can complicate the structural analysis. Fortunately, gabapentin (Gpn), a readily available bulk drug, is an achiral beta,beta-disubstituted gamma amino acid residue that contains a cyclohexyl ring at the C(beta) carbon atom, which dramatically limits the range of torsion angles that can be obtained about the flanking C-C bonds. Limiting conformational flexibility also has the desirable effect of increasing peptide crystallinity, which permits unambiguous structural characterization by X-ray diffraction methods. This Account describes studies carried out in our laboratory that establish Gpn as a valuable residue in the design of specifically folded hybrid peptide structures. The insertion of additional atoms into polypeptide backbones facilitates the formation of intramolecular hydrogen bonds whose directionality is opposite to that observed in canonical alpha-peptide helices. If hybrid structures mimic proteins and biologically active peptides, the proteolytic stability conferred by unusual backbones can be a major advantage in the area of medicinal chemistry. We have demonstrated a variety of internally hydrogen-bonded structures in the solid state for Gpn-containing peptides, including the characterization of the C(7) and C(9) hydrogen bonds, which can lead to ribbons in homo-oligomeric sequences. In hybrid alphagamma sequences, distinct C(12) hydrogen-bonded turn structures support formation of peptide helices and hairpins in longer sequences. Some peptides that include the Gpn residue have hydrogen-bond directionality that matches alpha-peptide helices, while others have the opposite directionality. We expect that expansion of the polypeptide backbone will lead to new classes of foldamer structures, which are thus far unknown to the world of alpha-polypeptides. The diversity of internally hydrogen-bonded structures observed in hybrid sequences containing Gpn shows promise for the rational design of novel peptide structures incorporating hybrid backbones.

Role of Intramolecular and Intermolecular Hydrogen Bonding in Both Singlet and Triplet Excited States of Aminofluorenones on Internal Conversion, Intersystem Crossing, and Twisted Intramolecular Charge Transfer

Time-dependent density functional theory method was performed to investigate the intramolecular and intermolecular hydrogen bonding in both the singlet and triplet electronic excited states of aminofluorenones AF, MAF, and DMAF in alcoholic solutions as well as their important roles on the excited-state photophysical processes of these aminofluorenones, such as internal conversion, intersystem crossing (ISC), twisted intramolecular charge transfer (TICT), and so forth. The intramolecular hydrogen bond C=O...H-N can be formed between the carbonyl group and amino group for the isolated AF and MAF. However, no intramolecular hydrogen bond for DMAF can be formed. At the same time, the most stable conformation of DMAF is out-of-plane structure, where the two dihedral angles formed between dimethyl groups and fluorenone plane are 163.1 degrees and 41.74 degrees, respectively. The formation of intramolecular hydrogen bond for AF and MAF is tightly associated with the intersystem crossing of these aminofluorenones. Furthermore, the ISC process can be dominantly determined by the change of intramolecular hydrogen bond between S(1) and T(1) states of aminofluorenones. Since the change of hydrogen bond between S(1) and T(1) states of AF is stronger than that of MAF, the rate of ISC process for AF is faster than that for MAF. Moreover, the rate constant of the ISC process of DMAF is nearly close to zero because of the absence of intramolecular hydrogen bond. On the other hand, the intermolecular hydrogen bond C=O...H-O can be also formed between all aminofluorenones and alcoholic solvents. The internal conversion process from S(1) to S(0) state of these aminofluorenones is facilitated by the intermolecular hydrogen bond strengthening in the electronic excited state of aminofluorenones because of the decrease of energy gap between S(1) and S(0) states. At the same time, the change of intermolecular hydrogen bond between S(1) and T(1) states for AF is much stronger than that for MAF, which may also contribute to the faster ISC process for AF than that for MAF in the same solvents. The TICT process plays an important role in the deactivation of the photoexcited DMAF, since the TICT process along the twisted dihedral angle is nearly barrierless in the S(1) state of DMAF. However, the TICT cannot take place for AF and MAF because of the presence of the intramolecular hydrogen bond.

Intramolecular and Intermolecular Hydrogen Bond Formation by Some Ortho-Substituted Phenols: Some Surprising Results from an Experimental and Theoretical Investigation

The effects produced by addition of various concentrations of the strong hydrogen bond (HB) acceptor, dimethyl sulfoxide (DMSO), on the OH fundamental stretching region of the IR spectra of several o-methoxy, o-nitro, and o-carbonyl phenols in CCl(4) are reported. In most of these phenols the intramolecular HB is not broken by the DMSO. Instead, the DMSO acts as a HB acceptor to the intramolecular HB forming a bifurcated intra/intermolecular HB. For o-methoxyphenols the bifurcated HBs are observed as new IR bands at much lower wavenumbers (Deltanu(OH) approximately -300 cm(-1)) than the band due to their intramolecular HB. The formation of bifurcated HBs and the large frequency shift of their OH bands in o-methoxyphenols are well reproduced by theoretical modeling. In contrast to the o-methoxyphenols DMSO has little effect (other than causing some broadening) on the intramolecular HB OH bands of o-nitro and o-carbonyl phenols, with the single exception of 2,4-dinitrophenol. In this case, but not for 2,4-diformylphenol, the intramolecular HB OH band decreases as the DMSO concentration increases and a new absorption grows in at lower wavenumbers, indicating that DMSO can break this intra-HB and form an inter-HB, a result well reproduced by theory. Although DMSO has little effect on the O-H stretching band of 2-nitrophenol, theory indicates extensive formation (90%) of bifurcated HBs with OH stretching bands at slightly higher wavenumbers (Deltanu(OH) approximately +20 cm(-1)) than that for the intramolecular HB OH group and 10% of a "simple" intermolecular HB in which the intramolecular HB has been broken. Theory also indicates that, with DMSO, 2-formylphenol also forms a bifurcated HB (Deltanu(OH) approximately +150 cm(-1)), whereas 2,4-diformylphenol forms both intermolecular HBs (Deltanu(OH) approximately -130 cm(-1)) and bifurcated HBs (Deltanu(OH) approximately +165 cm(-1)). The IR spectrum of 2-methoxymethylphenol shows that although an intramolecular HB conformer is dominant there is a small percentage of a "free" OH, non-HB conformer (2.1% in CCl(4), 1.5% in cyclohexane). These results are quantitatively reproduced by theory. We conclude that theory can provide important insights into the formation and structure of inter, intra, and bifurcated HBs, and into their OH stretching frequencies, that are not always revealed by IR studies alone.

Intramolecular interactions in antiviral derivatives of 4,6-di-tert-butyl-2-aminophenol

We have used Fourier transform IR (FTIR) spectroscopy to study intramolecular interactions in solutions of 4,6-di-tert-butyl-2-aminophenol in n-hexane. When the hydroxyl group in the molecule is ortho to the amino group, an O―H⋅⋅⋅N intramolecular hydrogen bond is formed in the 4-6-di-tert-butyl-2-aminophenol derivatives, where the strength of the hydrogen bond depends on the type of substituent at the para position of the phenyl ring. If there are electron-donor groups on the phenyl ring, then a stronger O―H⋅⋅⋅N bond is formed in the 4,6-di-tert-butyl-2-aminophenol derivatives than in molecules containing electron-acceptor Cl and Br atoms. Formation of the above-indicated intramolecular hydrogen bond affects the course of radiation-induced reactions occurring in n-hexane with participation of these compounds and also affects their antiviral activity.

O−H···N Heterosynthon: A Robust Supramolecular Unit For Crystal Engineering

To explore the robust nature of template resorcinols in organic solid-state reactions, a series of mono- and dipyridines were cocrystallized with different substituted resorcinols. The organizational consequences of hydrogen-bonds in the hydroxyl···pyridine heterosynthon in the presence of competitive hydrogen-bonding functional groups are elucidated. C−O bond flexibility, steric hindrance, and formation of undesired intramolecular hydrogen bonds have strongly affected the ability of the template for a parallel alignment of olefins. Finally, structural changes that occurred at a molecular level during [2 + 2] photodimerization of the complex of 1,4-bis[(E)-2-(4-pyridyl)ethenyl]-2-fluorobenzene (bpef) with 2,4-dihydroxy-benzaldehyde were studied in detail by performing a rather rare single-crystal-to-single-crystal photoirradiation.

Towards Allosteric Receptors: Adjustment of the Rotation Barrier of 2,2′‐Bipyridine Derivatives

What a difference! The energy differences between anti and syn conformers as well as the energy barrier for the rotation around the aryl-aryl bond of a number of 2,2'-bipyridine molecules were examined by quantum-chemical methods. The energy differences were found to be governed by the substituents directly attached to the bipyridine and their ability to form intramolecular hydrogen bonds.Quantum-chemical calculations at the BP86/TZVP level of theory were performed to determine the energy differences between the syn and the anti conformers, as well as the energy barrier for the rotation of the aryl-aryl bond of 2,2'-bipyridine molecules and a number of disubstituted derivatives. Substitutents with hydrogen-bond donor (or electron acceptor) functions or hydrogen-bond acceptors (or electron donors) are generally found to have large effects on the difference and the barrier. Substitution with a hydrogen-bond donor (or an electron acceptor) at position 6 and 6' leads to a decrease owing to a charge transfer from the pyridine nitrogen lone pair to the donor, which is caused by the formation of weak intramolecular hydrogen bonds and/or dipolar interactions, respectively. Conversely, substitution at position 4 and 4' causes an increase in the energy barrier. Substitution with a hydrogen-bond acceptor (or an electron donor) shows the opposite behavior, which can be explained by the weak intramolecular interactions. Interestingly, even very weak CH hydrogen-bond donors (electron acceptors) such as methyl groups have a significant influence. This indicates the importance of such weak interactions for the structure and energetics of supramolecular systems. The energy differences are mainly governed by the substituents directly attached to the bipyridine core as the introduction of sterically demanding groups in the periphery hardly influences the barriers or energy differences of the conformers. These findings are important for the design of heterotropic positive cooperative allosteric receptors with 2,2'-bipyridines as the allosteric centre.

Competition between OH⋯O and multiple halogen–dipole interactions on the formation of intramolecular three-centred hydrogen bond in 3-acyl coumarins

This paper describes the synthesis and structural study in solution, by NMR, and in the solid state, by X-ray analysis, of 6-substituted (H, NO2, OCH3, Cl, Br) 2-oxo-2H-chromene-3-carboxylic acid (2-hydroxy-ethyl) amides. The results were supported by ab initio calculations at RHF-631G** level of theory. The crystal structures of compounds 6-Cl and 6-Br show deviations from the predicted theoretical conformation and also from that observed in solution, pointing to the influence exerted by intermolecular interactions on the molecular structure and on intramolecular three-centred hydrogen bond formation (O2⋯H12⋯O1). The significance of the plethora of non-covalent interactions [C‒H⋯A (A = O, X, π), CO⋯CO, CO⋯π, C‒X⋯OC (X = halogen), Br⋯Br and π‒π stacking] is discussed.