Hans-Jörg Schneider

The hydrophobic effect revisited--studies with supramolecular complexes imply high-energy water as a noncovalent driving force.

Traditional descriptions of the hydrophobic effect on the basis of entropic arguments or the calculation of solvent-occupied surfaces must be questioned in view of new results obtained with supramolecular complexes. In these studies, it was possible to separate hydrophobic from dispersive interactions, which are strongest in aqueous systems. Even very hydrophobic alkanes associate significantly only in cavities containing water molecules with an insufficient number of possible hydrogen bonds. The replacement of high-energy water in cavities by guest molecules is the essential enthalpic driving force for complexation, as borne out by data for complexes of cyclodextrins, cyclophanes, and cucurbiturils, for which complexation enthalpies of up to -100 kJ mol(-1) were reached for encapsulated alkyl residues. Water-box simulations were used to characterize the different contributions from high-energy water and enabled the calculation of the association free enthalpies for selected cucurbituril complexes to within a 10% deviation from experimental values. Cavities in artificial receptors are more apt to show the enthalpic effect of high-energy water than those in proteins or nucleic acids, because they bear fewer or no functional groups in the inner cavity to stabilize interior water molecules.

Supramolecular Chemistry, Part 85[+] Flexibility, Association Constants, and Salt Effects in Organic Ion Pairs: How Single Bonds Affect Molecular Recognition

The free energies of association ΔGof ten organic ion pairs (such as the ones shown here) in water have a linear dependence on the number of rotatable bonds within the ions, but with a surprisingly small sensitivity of only 0.5 kJ mol−1 per single bond. The dependence of ΔG on the ionic strength I can be well described with the Debye–Huckel equation and yields an increment of 8 kJ mol−1 per salt bridge for I = 0.0.

Affinity and nuclease activity of macrocyclic polyamines and their CuII complexes.

The stability constants of Cu(II) complexes that consist of either an oxaaza macrocycle with two triamine moieties linked by dioxa chains, or two macrocyclic ligands with a polyamine chain which are connecting the 2 and 9 positions of phenanthroline, have been determined by means of potentiometric measurements. The results are compared to those reported for other ligands with a similar molecular architecture. Of the complexes that contain phenanthroline in their macrocycle, the Cu(II) ion of the complex with the smallest and most rigid macrocycle (L3) has an unsaturated coordination sphere, while in the complex with the largest macrocycle (L5) the Cu(II) ion is coordinatively almost saturated. These results are corroborated by the crystal structure of the [CuL5](ClO4)2 complex. The affinity of the ligands and the complexes towards nucleic acids was studied by measuring the changes in the melting temperature, which showed that the affinity of the macrocyclic ligands towards double-stranded DNA or RNA is generally smaller than that of their linear analogues that bear a similar charge, with a strong preference for polyA-polyU, a model for RNA. However, the complexes of two of the changed macrocyclic ligands which contain a phenanthroline unit (L4, L5) showed a distinctly larger increase in their melting temperature deltaTm with DNA (polydA-polydT), which is reversed again in favor of RNA upon metallation to the dinuclear copper complex with L5. Experiments with supercoiled plasmid DNA showed a particularly effective cleavage with a mononuclear Cu(II) complex that contains a phenanthroline unit (L6). Related ligands showed less activity towards DNA, but not so towards the biocidic bis(p-nitrophenyl)phosphate (BNPP). In both cases (with DNA and BNPP) the activity seemed to increase with decrease of coordinative saturation of the Cu(II) ion, with the exception of one particular ligand (L6). Experiments with radical scavengers in the DNA experiments showed some decrease in cleavage, which indicates the participation of redox processes.

Deprotonation induced 13 C NMR shifts in phenols and flavonoids

13C-NMR shift changes associated with deprotonation are measured for 15 phenols and 4 flavonoids, leading to several corrections of literature reports. The additive shifts are useful for OH-group acidity determinations and 13C signal assignments.

Copper complexes of polyaza[n]cyclophanes and their interaction with DNA and RNA ☆

Abstract The complexation properties of Cu 2+ ions with the cyclophane receptors 2,6,9,13-tetraaza[14]metacyclophane ( L1 ), 2,6,10,13,17,21-hexaaza[22]metacyclophane ( L2 ) and 2,6,10,13,17,21-hexaaza[22]paracyclophane ( L3 ) are presented. Formation of mononuclear complexes in the case of L1 and of mono- and binuclear complexes in the case of the hexaaazcyclophane ligands L2 and L3 is observed. The coordination numbers around each Cu 2+ in the binuclear complexes involve at most three nitrogen donors for each metal ion. Cyclophanes L1 – L3 and several acyclic polyamine ligands are tested for their affinity towards double-stranded nucleic acid models of RNA and DNA. The binding affinity of the acyclic and macrocyclic polyamines towards DNA and RNA models, measured by changes in their melting temperature Δ T M , increases progressively with the average number of charges present on the amine, with higher stabilisation for RNA. Unusually large differences of up to Δ(Δ T M )=30°C were observed with tripropylenetetraamine ( L15 ) and with the macrocyclic amines ( L2 and L3 ). Introduction of copper in the ligands leads to considerable affinity variations. One macrocyclic copper complex (with L3 ) shows a strong discrimination between the RNA and DNA polymers with a record value of ΔΔ T M =41°C, and a small destabilisation of the DNA. The copper complexes exhibit nuclease activity; with plasmid DNA nicking was increased by one complex by a factor of k / k un =10 7 . Experiments with hydroxyl radical quenchers indicate a predominant redox cleavage mechanism.

Crown Ether–Ammonium Complexes: Binding Mechanisms and Solvent Effects

Thermodynamics of 18-crown-6 complexes with ammonium cations (NH4, MeNH3, Me2NH2, Me3NH, Me4N, Et4N, PhNH3, and PhCH2NH3 ) in methanol were determined by titration calorimetry. The results show strong contributions from entropy terms counteracting the enthalpy of complexation, and a linear decrease of the complexation free energy ΔG with the number of available N–H hydrogen bonds. In several cases formation of relatively strong complexes containing two ammonium ions per crown unit was observed. Tetramethylammonium ions show no detectable association with the crown ether, demonstrating the absence of significant Coulomb-type interaction between the partial charges at the crown ether oxygen and the N+–C–H atoms. Ammonium ions bind to aza crown ethers with almost equal affinity as to the all-oxygen anologs only, if methyl groups at the nitrogen atoms force the lone pairs into equatorial position. Molecular mechanics calculations (CHARMm) of corresponding gas-phase complexes yield geometries and energies in agreement with this, with energetically equally good conformations of an essentially undistorted D3d crown accepting either 3 linear hydrogen bonds, or 6 bifurcated bonds from the primary ammonium cations. Complexation equilibria were measured with PhNH3, and PhCH2NH3 in water, 2-propanol, tert-butyl alcohol, n-octanol, DMF, DMSO, pyridine, HMPT and acetone mostly by calorimetry, in some cases by potentiometry. The observed association constants varied by factors of up to 1000; the solvent effects can be described generally as a linear function of the hydrogen bond accepting power of the solvent molecules, in line with the mechanisms derived above. The lgK and ΔH values of the complexation of the PhNH3 or PHCH2NH3 cation with 18-crown-6 ligand are compared with a large range of available solvent properties. The best correlations (R ≈ 0.9) for lgK (or ΔG) are obtained with values characterizing the electron donor capacity of the solvent (Ca, β*, DN) for lgK, as found earlier for complexes between K+ and 18C6.

Stabilities of Hydrogen‐Bonded Supramolecular Complexes with Various Numbers of Single Bonds: Attempts To Quantify a Dogma in Host–Guest Chemistry

The disadvantage of flexible bonds in supramolecular host-guest complexes is much smaller than usually assumed. In the association of dicarboxlic acids with diamides (shown on the right), freely rotatable single bonds have only a minor disadvantageous influence on the free energy of complexation ΔGcplx . From the linear correlation between ΔGcplx and the number of single bonds n, a decrease in the free energy of complexation of only 1.3 kJ mol-1 per single bond was determined.

Design and analysis of molecular motifs for specific recognition of RNA.

Selective targeting of RNA has become a recent priority in drug design strategies due to the emergence of retroviruses, the need for new antibiotics to counter drug resistance, and our increased awareness of the essential role RNA and RNA structures play in the progression of disease. Most organic compounds known to specifically target RNA are complex, naturally occurring antibiotics that are difficult to synthesize or derivatize and modification of these compounds to optimize interactions with structurally unique RNAs is difficult. The de novo design of synthetically accessible analogues is one possible alternative; however, little is known about the RNA recognition principles on which to design new compounds and limited information on RNA structure in general is available. To contribute to the growing body of knowledge on RNA recognition principles, we have prepared two series of polycationic RNA-binding agents, one with a linear scaffold, the other with a macrocyclic scaffold. We evaluated these compounds for their ability to bind to DNA and RNA, as well as to a specific RNA, the regulatory sequence, RRE, derived from HIV-1, by using thermal melting, circular dichroism, and electrophoresis gel shift methods. Out results suggest that cationic charge centers of high pKa that are displayed along a scaffold of limited flexibility bind preferentially to RNA, most likely within the major groove. Related derivatives that bind more strongly to DNA more closely mimic classical DNA minor-groove binding agents. Several of the macrocyclic polycations expand on a new binding motif where purine bases in duplex RNA are complexed within the macrocyclic cavity, enhancing base-pair opening processes and ultimately destabilizing the RNA duplex. The results in this report should prove a helpful addition to the growing information on molecular motifs that specifically bind to RNA.

13C-NMR-Spektroskopische und stereochemische untersuchungen—XIV: Sessel- und bootkonformationen bei bicyclo[3.3.1]nonanverbindungen

Zusammenfassung Die Synthesen und 13C-NMR-spektroskopischen Eigenschaften von Bicyclo[3.3.1]nonanen mit Substituenten in 1-(X = F, Cl, Br, J, OR), 3-exo-(X = Cl, Br, OR) und 3-endo-(X = COOR, CH3, OR)-Stellung werden beschrieben. Die Verschiebungen der funktionellen Cα-Atome unter Einschluss der 1-Jodverbindung zeigen die bekannte Abhangigkeit vom Elektronenzug des Heterosubstituenten, jedoch werden bei den tertiaren Derivaten nicht Abschwachungen des Substituenteneffektes, sondern in Vergleich zu sekundaren Vergleichsverbindungen Zunahmen um bis zu 25ppm beobachtet. Die Verschiebungen aller β-C-Mome lassen sich quantitativ mit dem quadratischen Feldeffekt nach Buckingham erklaren; doch macht sich hier und mehr noch bei den γ-C-Atomen fur die 1- und 3-exo-Verbindungen die Anderung des linearen Feldeffektes durch Abdachung der Sesselhalften bemerkbar. Die bei antiperiplanaren X-Cα-Cβ-Cγ, -Anordnungen eintretende Entschirmung des γ-C-Atoms beschrankt sich nicht auf bruckenkopfsubstituierte Verbindungen und kann mit linearen Feldeffekten approximiert werden. Der bei den 3-exo-Verbindungen beobachtbare transanulare Effekt von Cα-X-Substituenten auf die C-7-Verschiebung zeigt die geringe Grosse reiner “through space”-Weitbereichseffekte auf 13C-Verschiebungen. Fur alle ausser den 3-endo-substituierten Verbindungen indizieren die 13C-Verschiebungen ebenso wie 13C-19F-Kopplungen eine abgeflachte Doppelsesselform CC. Die fur 3-endo-Verbindungen gefundenen Parameter zeigen das Uberwiegen von Boot-Sessel-Formen, jedoch kann erst auf Grund lanthanideninduzierter Verschiebungen auf die Dominanz der Konformation mit dem Substituenten im Boot-Teil geschlossen werden. Obwohl die BC-Form als unsubstituiertes Gerust nicht messbar ist, konnen dessen Verschiebungen durch Subtraktion geeigneter Substituenteneffekte erhalten werden. Tieftemperaturexperimente zeigen die Abwesenheit von hoheren CC-Anteilen; jedoch indiziert der Vergleich von Temperaturgradienten der 13C-Verschiebungen bei der Methoxyverbindung die Beimengung einer hier etwas stabileren Sesselform mit axialen Substituenten.

The kinetic effects of water and of cyclodextrins on Diels–Alder reactions. Host–guest chemistry. Part 18

The rates of 19 different dienophiles with mostly cyclopentadiene have been measured in a range of solvents. Water, by comparison with methanol, is found to accelerate the cycloadditions by factors ranging from 15–7 680. While there is no simple correlation of the rate enhancement with the hydrophobicity of the substrates, a correlation can be made in the case of acrylates, which show a decreasing rate effect due to water, and with β-cyclodextrin, which is found to lead to inhibition in these and several other cases. Computer analysis of enzyme-like saturation kinetics—observed with some fumarates in the presence of β-cyclodextrin—indicates apparent binding constants for the ternary complex of ca. 102 dm3 mol–1 and catalytic kcat/ko ratios of up to 100. Heptakis-6-piperidino-β-cyclodextrin in the form of its ammonium salt leads to rate retardation in most of the cases investigated; sodium dodecylsulphate also decreases the constants. α-Cyclodextrin generates small effects, rate retardation, or in one case complete inhibition.