Ionization of carbonic acid in sodium chloride solutions at 25°C

The stoichiometric pK ₁ ^* and pK ₂ ^* for the ionization of carbonic acid has been determined from emf measurements in NaCl soluions to 6.0m at 25°C. Our results at low concentrations are in good agreement with the results of Harned and Bonner, of Dyrssen and Hansson and of Roy et al. The calculated values of pK ₁ ^* using Pitzer's equations agree with the measured values to ±0.01 pK units provided higher order terms are used. It was necessary to use a triplet interaction parameter () and higher order electrostatic terms (^E) to calculate reliable values of pK ₂ ^* (±0.03 pK units) over the entire concentration range. These results demonstrate the reliability of the Pitzer equations to estimate activity coefficients in concentrated salt solutions.     

Stereoselective synthesis of individual isomers of Leu-enkephalin analogues containing substituted beta-turn bicyclic dipeptide mimetics

Novel constrained beta-turn dipeptide mimetics, 8-phenyl thiaindolizidinone amino acids 3, have been synthesized stereoselectively and incorporated into Leu-enkephalin peptides as a replacement of dipeptide Gly3-Phe4 to afford four individual isomers of Leu-enkephalin analogues 6.     

Different approaches toward an automatic structural alignment of drug molecules: Applications to sterol mimics,thrombin and thermolysin inhibitors

Summary A relative comparison of the binding properties of different drug molecules requires their mutual superposition with respect to various alignment criteria. In order to validate the results of different alignment methods, the crystallographically observed binding geometries of ligands in the pocket of a common protein receptor have been used. The alignment function in the program SEAL that calculates the mutual superposition of molecules has been optimized with respect to these references. Across the reference data set, alignments could be produced that show mean rms deviations of approximately 1 Å compared to the experimental situation. For structures with obvious skeletal similarities a multiple-flexible fit, linking common pharmacophoric groups by virtual springs, has been incorporated into the molecular mechanics program MOMO. In order to combine conformational searching with comparative alignments, the optimized SEAL approach has been applied to sets of conformers generated by MIMUMBA, a program for conformational analysis. Multiple-flexible fits have been calculated for inhibitors of ergosterol biosynthesis. Sets of different thrombin and thermolysin inhibitors have been conformationally analyzed and subsequently aligned by a combined MIMUMBA/SEAL approach. Since for these examples crystallographic data on their mutual alignment are available, an objective assessment of the computed results could be performed. Among the generated conformers, one geometry could be selected for the thrombin and thermolysin inhibitors that approached reasonably well the experimentally observed alignment.     

REDUCED PHOTOINACTIVATION OF 10-DODECYL ACRIDINE ORANGE-SENSITIZED YEAST CELLS AT HIGH FLUENCE RATES MEASUREMENTS AND COMPUTER SIMULATIONS

Abstract-During the development of a photodamage cell sorter several photosensitizers were tested for their ability to photoinactivate more than 90% of the sensitized cells after a brief irradiation with a fluence of 10 kJ/m². In pilot experiments, yeast cells sensitized with 10-dodecyl acridine orange (DAO) were effectively photoinactivated after receiving a fluence of 10 kJ/m² delivered in 8 s. However, when the same fluence was delivered in 3 μ s during passage through a focused laser beam in the cell sorter, all cells survived.
Computer simulations of the relevant photophysical and chemical reactions inside the irradiated cell were used to investigate the cause of this phenomenon. The results indicated that the absence of photoinactivation by DAO, after flash irradiations, was caused by the combined effects of (1) limited oxygen diffusion into the cell and (2) a reduced number of collisions between photosensitizer triplet and oxygen molecules during the irradiation due to saturation of the intracellular photosensitizer triplet concentration. The contributions of triplet-triplet annihilation and triplet quenching by ground state photosensitizer molecules were found to be minimal and not significant. These findings indicate that Type II photosensitizers are incapable of rapid selective photoinactivation in cell sorters.     

Ab initio study of the binding of Trichostatin A (TSA) in the active site of histone deacetylase like protein (HDLP)

Histone deacetylase (HDAC) inhibitors have recently attracted considerable interest because of their therapeutic potential for the treatment of cell proliferative diseases. An X-ray structure of a very potent inhibitor, Trichostatin A (TSA), bound to HDLP (an HDAC analogue isolated from Aquifex aeolicus), is available. From this structure, an active site model (322 atoms), relevant for the binding of TSA and structural analogues, has been derived, and TSA has been minimized in this active site at HF 3-21G* level. The resulting conformation is in excellent accordance with the X-ray structure, and indicates a deprotonation of the hydroxamic acid in TSA by His 131. Also, a water molecule was minimized in the active site. In addition to a similar deprotonation, in accordance with a possible catalytic mechanism of HDAC as proposed by Finnin et al. (M. S. Finnin, J. R. Donigian, A. Cohen, V. M. Richon, R. A. Rifkind and P. A. Marks, Nature, 1999, 401, 188-193), a displacement of the resulting OH- ion in the active site was observed. Based on these results, the difference in energy of binding between TSA and water was calculated. The resulting value is realistic in respect to experimental binding affinities. Furthermore, the mechanism of action of the His 131-Asp 166 charge relay system was investigated. Although the Asp residue in this motif is known to substantially increase the basicity of the His residue, no proton transfer from His 131 to Asp 166 was observed on binding of TSA or water. However, in the empty protonated active site, this proton transfer does occur.     

COSMO-RS: A novel view to physiological solvation and partition questions

Both, dielectric continuum solvation models as well as surface or group based methods using polarity and lipophilicity parameters have been proven to be useful tools for the analysis of solvation and partition questions. For the first time, COSMO-RS provides an integrated theory, which combines the aspects of continuum solvation and surface interactions, and which ends up with chemical potentials of molecules in almost arbitrary solvents and mixtures. Due to its sound theoretical basis, COSMO-RS does not only provide a new quantitative access to solvation and partition properties in well defined solvents, but it also opens a novel view and gives a better understanding of the general problem of solvation. Finally, this allows for a generalisation of COSMO-RS to sophisticatedphysiological partition problems involving as complex phases as blood, brain, or cell membranes. The use of COSMO-RS for drug discovery and design is demonstrated by applications to blood-brain partition coefficients, and water solubility.     

Integral approximations for molecular orbital theory

The electron repulsion integrals arising in LCAO-MO theory are approximated by replacement of the product of two orbitals on different centers by linear combinations of one-center products. The approximation differs from those previously proposed in that the coefficients of the various terms are determined by requiring agreement for certain integrals, and in the emphasis of the role of symmetry in selecting the one-center products. For two-center integrals, the new approximation is significantly better than older approximate methods. Reasons are given for expecting this improvement to extend also to multi-center integrals.

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Zusammenfassung Es wird ein Verfahren zur näherungsweisen Berechnung von Elektronenwechselwirkungsintegralen der LCAO-MO-Theorie beschrieben, bei welchem das Produkt zweier Zustandsfunktionen an verschiedenen Zentren durch eine Linearkombination von Produkten am gleichen Zentrum ersetzt wird. Der Unterschied zu ähnlichen Ansätzen liegt in der Justierung der Koeffizienten. Für Zweizentrenintegrale liefert die hier vorgeschlagene Methode bedeutend bessere Ergebnisse als das Mulliken-Verfahren.

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Résumé Les intégrales de répulsion électroniques intervenant dans la théorie LCAO MO sont calculées d'une manière approchée en remplaçant le produit de deux orbitales sur des centres différents par des combinaisons linéaires de produits à un centre. Cette approximation diffère de celles proposées auparavant par la détermination des coefficients des différents termes au moyen de l'ajustement de certaines intégrales et par l'importance du rôle de la symétrie dans le choix des produits monocentriques. Cette nouvelle approximation est bien meilleure que les anciennes en ce qui concerne les intégrales bi-centriques. Nous donnons des raisons d'espérer que cette amélioration s'étendra aux intégrales polycentriques.

     

π-Olefin—iridium -komplexe : III. Über (η4-cyclodien)(η5-cyclodienyl)iridium-verbindungen,einen neuartigen hydridoiridium-komplex und das (η4-cyclooctadien)(η6-cyclooctatrien)iridium-kation

The complexes [Ir(COD)(η⁵-C₇H₉)] and [Ir(COD)(η⁵-C₈H₁₁)] are obtained by the isoprophyl Grignard synthesis of [Ir(COD)Cl]₂ (COD = η⁴-1,5-cyclooctadiene) in the presence of cycloheptatriene, and cyclooctatriene, respectively. The later reaction yields [IrH(COD)(δ⁴-1,3,6-C₈H₁₀)] as a by-product which, in contrast to other [IrH(η⁴-cyclodiene)₂] complexes, does not show H-addition-elimination equilibria. Reduction of [Ir(1,3-C₇H₁₀)₂Cl] with C₂H₅OH/Na₂CO₃ yields [Ir(η⁴-1,3-C₇H₁₀)](η⁵-C₇H₉)] which was characterized by X-ray analysis. [Ir(COD)Cl]₂ reacts with Na₂C₈H₈, and after hydrolysis unstable [Ir(COD)(η⁵-C₈H₉)] is formed which by protonation with HPF₆ is converted into the [Ir(COD)(η⁶-1,3,5-C₈H₁₀)]⁺ cation. All these compounds are fluxional in solution.     

Thermodynamic and kinetic data for adduct formation, cis-trans isomerization and redox reactions of ML4 complexes: a case study with rhodium- and iridium-tropp complexes in d8, d9 and d10 valence electron configurations (tropp=dibenzotropylidene phosphanes)

The formation of adducts of the square-planar 16-electron complexes trans-[M(tropp(ph))(2)](+) and cis-[M(tropp(ph))(2)](+) (M=Rh, Ir; tropp(Ph)=5-diphenylphosphanyldibenzo[a,d]cycloheptene) with acetonitrile (acn) and Cl(-), and the redox chemistry of these complexes was investigated by various physical methods (NMR and UV-visible spectroscopy, square-wave voltammetry), in order to obtain some fundamental thermodynamic and kinetic data for these systems. A trans/cis isomerization cannot be detected for [M(tropp(ph))(2)](+) in non-coordinating solvents. However, both isomers are connected through equilibria of the type trans-[M(tropp(ph))(2)](+)+L<==>[ML(tropp(ph))(2)](n)<==>cis-[M(tropp(ph))(2)](+)+L, involving five-coordinate intermediates [ML(tropp(ph))(2)](n) (L=acn, n=+1; L=Cl(-), n=0). Values for K(d) (K(f)), that is, the dissociation (formation) equilibrium constant, and k(d) (k(f)), that is, the dissociation (formation) rate constant, were obtained. The formation reactions are fast, especially with the trans isomers (k(f)>1x10(5) m(-1) s(-1)). The reaction with the sterically more hindered cis isomers is at least one order of magnitude slower. The stability of the five-coordinate complexes [ML(tropp(ph))(2)](n) increases with Ir>Rh and Cl(-)>acn. The dissociation reaction has a pronounced influence on the square-wave (SW) voltammograms of trans/cis-[Ir(tropp(ph))(2)](+). With the help of the thermodynamic and kinetic data independently determined by other physical means, these reactions could be simulated and allowed the setting up of a reaction sequence. Examination of the data obtained showed that the trans/cis isomerization is a process with a low activation barrier for the four-coordinate 17-electron complexes [M(tropp(ph))(2)](0) and especially that a disproportionation reaction 2 trans/cis-[M(tropp(ph))(2)](0)-->[M(tropp(ph))(2)](+)+[M(tropp(ph))(2)](-) may be sufficiently fast to mask the true reactivity of the paramagnetic species, which are probably less reactive than their diamagnetic equilibrium partners.     

Hard-soft acid-base interactions of silylenes and germylenes

A detailed investigation of the electrophilic and nucleophilic character of singlet silylenes and germylenes, divalent compounds of silicon and germanium, respectively, substituted by first- and second-row elements is presented. In a first part, the Lewis acid properties of these compounds were studied through their complexation reaction with the Lewis bases NH3, PH3, and AsH3. The results indicate that this complexation is most favorable with the hardest base NH3, classifying these compounds as hard Lewis acids. This is confirmed by the linear correlation between the interaction energies and the value of the electrostatic potential, used as an approximation to the local hardness, near the empty p orbital of these compounds, indicating a charge-controlled interaction in the complex. Also the electrophilicity index, proposed by Parr et al., computed both at the global and the local level, correlates linearly with the complexation energies of the compounds with NH3. The Lewis base character of these silylenes has been investigated, through their interaction with the acids BH3 and AlH3. Also in this case, the electrostatic potential can be used to probe the reactivity of the compounds. It will finally be demonstrated that an increasing stability of the silylenes and germylenes is accompanied by an increase in their nucleophilicity and a decrease of the electrophilicity.