Conformation and internal mobility of 5H-dibenzo[a,d]cycloheptene derivatives in solution. Conformational analysis of highly flexible structures,part II

Summary The conformational possibilities of 5-(3-N,N-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene (1), 5-(3-N,N-dimethylaminopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2), and 5-(3-N,N-dimethylaminopropyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (3) are analysed using empirical force field methods. Minimum energy conformations, interconversion pathways, interconversion graphs and interconversion energies are examined in view of the analysis of conformer equilibria of1,2, or3 in solution. In addition, some basic requirements of the analysis of fast interconverting conformers using the lanthanide induced shift method are discussed.

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Konformation und interne Beweglichkeit von 5H-Dibenzo[a,d]cyclohepten Derivaten in Lösung. Konformationsanalyse hochflexibler Strukturen, Teil 2

Zusammenfassung Die konformativen Möglichkeiten von 5-(3-N,N-dimethylaminopropyl)-5H-dibenzo[a,d]cyclohepten (1), 5-(3-N,N-dimethylaminopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten (2) und 5-(3-N,N-dimethylaminopropyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten (3) wurden mit Hilfe empirischer Kraftfeldmethoden analysiert. Jene Konformationen, die einem energetischen Minimum entsprechen, sowie Interkonversionswege, Interkonversionsgraphen und Interkonversionsenergien wurden in Hinblick auf die Analyse der Konformerengleichgewichte von1,2 oder3 in Lösung untersucht. Weiters werden noch einige grundlegende Voraussetzungen für die Analyse von sich schnell ineinander umwandelnden Konformeren mittels der Lanthaniden-induzierten Verschiebungsmethode besprochen.

     

Lanthanide induced 1H and 13C NMR shifts and their use for geometry analysis with alicyclic compounds

Based on computations with conformationally rigid substrates the ambiguities involved in the geometrical analysis of pseudocontact shifts are demonstrated. The minimal agreement factors R and the corresponding lanthanide positions (usually more than one) are extremely dependent upon the chosen structural data for the model substrate and on the errors of the experimental shift values. It is observed, that a difference or improvement of R factors of less than 3% is not significant in most cases. This is so, even on the basis of Ytterbium induced ¹³C shifts, which are found to be more accurate than ¹H shifts and free from contact contributions within the experimental error. Using lanthanide induced shifts some ¹³C signal assignment problems are discussed. The computed minima for five substituted norbornanols indicate a lanthanide position with an L . . . O distance of d = 2·5 Å for the secondary alcohols and an orientation avoiding gauche interactions with the two neighbouring CC bonds. Similar computed results are obtained with five bicyclic ketones, except for an L . . . O distance from 3 to 4 Å increasing with steric hindrance. The particular problems with the analysis of symmetrical compounds like cyclohexyl derivatives are pointed out.     

Lanthanide induced shifts of sterically hindered aromatic carbonyl compounds oxomethylene-bridged,acetyl-, and formyl-2,2′-spirobiindanes

The lanthanide induced shift (LIS) data of 10 polysubstituted 2,2-spirobiindanes with a carbonyl group in conjugation to an aromatic ring were simulated using theMcConnell-Robertson equation. In the case of oxomethylene-bridged derivates (with CO incorporated in a more or less rigid ring) the classical one site or two site models gave reasonable results. For sterically hindered acetyl or formyl derivates (bothortho positions alkyl-substituted) a new model was developed: the carbonyl group was found to be 30° out of the aromatic plane and the possible 4 positions (±30° and ±150°) turned out to be populated differently depending on theortho substituents. The LIS programme had to be modified to account for this situation.Dedicated to Prof. Dr.A. Neckel on the occasion of his 60th birthday.     

Molecular complex-based dispersive liquid-liquid microextraction: analysis of polar compounds in aqueous solution

A novel molecular complex-based dispersive liquid-liquid microextraction (DLLME) method was established via hydrogen bond interaction between the extractant and the analytes. In this approach, tri-n-butylphosphate (TBP), a Lewis base, was directly used, instead of the traditional water-immiscible organic solvents, as the extractant for DLLME. The phenols (p-benzenediol, m-benzenediol, o-benzenediol and phenol), which are typical Lewis acids, were successfully extracted from environmental aqueous samples. In addition, phase separation was achieved in a disposable polyethylene pipet with the open and narrow tip upside, for a collection of the above extractant layer, i.e. TBP. To achieve satisfactory extraction performance, several extraction parameters, such as type of extractant solvents, extractant volume, pH of sample solution, ionic strength of sample solution and extraction time, were optimized. Additionally, the proposed method was applied to environmental water samples. Under the optimized conditions, the limits of detection and limits of quantification for the phenols were 7-29 and 25-98 μg/L, respectively. The calibration curves showed good linearity (r(2)≥0.9961) over the investigated concentration range. The repeatability of the method was investigated by evaluating the intra- and inter-day precisions. The relative standard deviations (RSDs) obtained were lower than 11.2% and 13.9% at different concentration levels. The recoveries ranged from 83.2% to 117.8%, with RSDs less than 13.1%. The developed approach provides a new way to facilitate DLLME of organic polar compounds from aqueous solutions. Moreover, it enables a convenient collection of solvent less dense making use of a cheap and disposable polyethylene pipet.     

Conformational analysis of kainate in aqueous solution in relation to its binding to AMPA and kainic acid receptors

Conformational analyses for kainate in aqueous solution have been performed by using the MM3*, AMBER* and MMFF94 force fields in conjunction with the Generalized Born Solvent Accessible Surface (GB/SA) hydration model. A comparison of calculated results with experimentally determined conformational data indicates that MM3*-GB/SA strongly overestimates the stability of a hydrogen bonded ion-pair in aqueous solution in comparison with the separated and solvated ions. This results in an incorrect prediction by MM3* of the most stable conformer of kainate in aqueous solution, whereas AMBER* and MMFF94 correctly predict the lowest energy conformer. Calculated conformational energy penalties for binding of kainate to the AMPA iGluR2 receptor indicate that the lower affinity of kainate for AMPA receptors compared to its affinity for kainic acid (KA) receptors is not due to a higher energy bioactive conformation of kainate at AMPA receptors. This conclusion is strongly supported by an analysis of a recently reported nonselective AMPA/KA ligand and a comparison of the conformational and structural properties of this ligand with iGluR2-bound kainate. This comparison strongly suggests that kainate binds to AMPA and KA receptors in closely the same conformation.     

Theoretical study of morphine and heroin: Conformational study in gas phase and aqueous solution and electron distribution analysis

The conformational preferences of morphine and heroin were studied in gas phase and with inclusion of solvent effects. At 298.15 K, three conformers are significant for isolated morphine, all of them displaying antiperiplanar arrangement for the C2? C3? O? H unit, and there is only one significantly populated conformer for heroin. Quantum theory of atoms in molecules analysis of the electron density in their most populated conformers in gas phase indicates that the positive charge is shared among the amino hydrogen, those hydrogens of the methylamino group, and all of the hydrogens attached to the bridgehead carbons. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem 110:2472–2482, 2010     

Solvent property induced morphological changes of ABA amphiphilic triblock copolymer micelles in dilute solution: A self-consistent field simulation study

The morphological changes of ABA amphiphilic triblock copolymer micelles in dilute solution were systematically studied by tuning the solvent property using self-consistent field simulation. The solvent property was tuned by changing the Flory-Huggins interaction parameters between each type of blocks and solvent, respectively. The simulation results show that by changing the solvent properties, a series of micelle morphologies such as vesicle, cage-like, ring-shaped, rod-like and spherical micelle morphologies can be obtained. Variations of the free energy of the solution system and the surface area of micelles with the Flory-Huggins interaction parameters were calculated to better understand the effect of solvent property on micelle morphologies. In addition, a phase diagram showing the morphological changes of micelles with the Flory-Huggins interaction parameters is provided.     

A Symmetry adapted tessellation of the GEPOL surface: applications to molecular properties in solution

A procedure to partition the GEPOL molecular surface into tesserae that respects the molecular symmetry constraints is presented. Using this method it is possible to build a solvent reaction field for the Polarizable Continuum Model with the same symmetry of the nuclear potential. Several applications are reported and discussed to evaluate the performance of this new procedure. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1262–1272, 2001     

Understanding sterol-membrane interactions part I: Hartree-Fock versus DFT calculations of 13C and 1H NMR isotropic chemical shifts of sterols in solution and analysis of hydrogen-bonding effects

1H and 13C NMR chemical shifts are exquisitely sensitive probes of the local environment of the corresponding nuclei. Ultimately, direct determination of the chemical shifts of sterols in their membrane environment has the potential to reveal their molecular interactions and dynamics, in particular concerning the hydrogen-bonding partners of their OH groups. However, this strategy requires an accurate and efficient means to quantify the influence of the various interactions on chemical shielding. Herein the validity of Hartree-Fock and DFT calculations of the 13C and 1H NMR chemical shifts of cholesterol and ergosterol are compared with one another and with experimental chemical shifts measured in solution at 500 MHz. A computational strategy (definition of basis set, simpler molecular models for the sterols themselves and their molecular complexes) is proposed and compared with experimental data in solution. It is shown in particular that the effects of hydrogen bonding with various functional groups (water as a hydrogen-bond donor and acceptor, acetone) on NMR chemical shifts in CDCl3 solution can be accurately reproduced with this computational approach.