Variational particle number approach for rational compound design

Within density functional theory, a variational particle number approach for rational compound design (RCD) is presented. An expression for RCD is obtained in terms of minimization of a suitably defined energy penalty functional whose gradients are the nuclear and the electronic chemical potential. Using combined quantum and molecular mechanics, a nonpeptidic anticancer drug candidate is designed.     

Optimization of effective atom centered potentials for london dispersion forces in density functional theory

We add an effective atom-centered nonlocal term to the exchange-correlation potential in order to cure the lack of London dispersion forces in standard density functional theory. Calibration of this long-range correction is performed using density functional perturbation theory and an arbitrary reference. Without any prior assignment of types and structures of molecular fragments, our corrected generalized gradient approximation density functional theory calculations yield correct equilibrium geometries and dissociation energies of argon-argon, benzene-benzene, graphite-graphite, and argon-benzene complexes.     

Über das Glykol und Aldol aus Isobutyr- und Isovaleraldehyd

Ohne ZusammenfassungAn dieser Stelle erfüllen wir mit grosser Freude die angenehme Pflicht, unserem hochverehrten Lehrer, Herrn Hof-rath Professor Dr. Adolf Lieben, für vielfache Anregung und lebhaftes Interesse, welches er unserer Arbeit entgegenbrachte, unseren tiefgefühlten Dank auszusprechen.     

Über das Aldol und Glykol aus Isobutyr- und Acetaldehyd

Ohne Zusammenfassung     

Microwave-assisted parallel synthesis of fused heterocycles in a novel parallel multimode reactor

New rotor types using disposable glass vials for small-scale parallel synthesis in multimode microwave reactors are introduced. One rotor comprises 16 groups of four vials, whereas the second uses four silicon carbide plates with a 6 x 4 matrix to process the vials. Both rotors achieve utmost temperature homogeneity upon microwave irradiation and can be used for microwave-mediated reactions at temperatures of up to 200 degrees C and pressures of 20 bar. The generation of three different heterocycle libraries furnishing thiophenes, oxindoles, and benzimidazoles using the new rotor types is described.     

Spectroscopic properties of trichlorofluoromethane CCl(3)F calculated by density functional theory

Density functional theory is used to generate local potential energy surfaces in normal coordinates for several chlorine isotopomers of trichlorofluoromethane (CCl(3)F, CFC11). An examination of predicted structures suggested that the PBE0 functional would be suitable. Anharmonic surfaces around the equilibrium geometries are reported, as determined by energies, gradients, and second derivatives. Vibrational levels for fundamentals, overtones and combination bands are reported, as well as harmonic frequencies, anharmonic constants, rotational constants, isotope shifts, and infrared intensities. These are compared with experimental information.     

Tuning electronic eigenvalues of benzene via doping

Using variable atomic numbers within molecular grand-canonical ensemble theory, the highest occupied Kohn-Sham eigenvalue of isoelectronic benzene derivatives is tuned. The performed transmutational changes correspond to the iterative doping with boron and nitrogen. The molecular Fukui function proves to be a reliable index in order to predict the changes in the highest occupied molecular orbital eigenvalue due to doping.     

NMR-based characterization of phenothiazines as a RNA binding scaffold

Phenothiazines were identified by virtual screening as promising ligands for HIV-1 TAR RNA and A-site ribosomal RNA, and binding in each case was verified experimentally. Consequently, since phenothiazines generally possess high bioavailability and low toxicity, we used several NMR techniques to explore the binding characteristics of acetopromazine with a total of five different RNA constructs: four as potential drug targets plus one control RNA construct. Acetopromazine was able to bind to various internal bulges and terminal loops containing both purines and pyrimidines, but no binding could be detected with double-stranded RNA or tetraloops. Dissociation constants determined via NMR varied from 0.27 to >3 mM. Analysis of differential saturation transfer difference (STD) NMR effects of acetopromazine suggests that the phenothiazine moiety has the closest contact to the binding sites of TAR and A-site RNA while the flexible N,N-dimethylpropylamino side chain contributes less to binding. NMR studies on A-site ribosomal RNA binding by six commercially available phenothiazines, while too few to establish a true structure-activity relationship, revealed a distinct dependence on aromatic ring and side chain substituents. Substituted phenothiazines have low molecular weight, are not highly charged, and have an inherent affinity for irregular tertiary RNA folds, suggesting that they can serve as a novel scaffold for constructing RNA-binding ligands.     

Data enhanced Hammett-equation: reaction barriers in chemical space

It is intriguing how the Hammett equation enables control of chemical reactivity throughout chemical space by separating the effect of substituents from chemical process variables, such as reaction mechanism, solvent, or temperature. We generalize Hammett''s original approach to predict potential energies of activation in non aromatic molecular scaffolds with multiple substituents. We use global regression to optimize Hammett parameters ρ and σ in two experimental datasets (rate constants for benzylbromides reacting with thiols and ammonium salt decomposition), as well as in a synthetic dataset consisting of computational activation energies of ∼2400 S_N2 reactions, with various nucleophiles and leaving groups (–H, –F, –Cl, –Br) and functional groups (–H, –NO₂, –CN, –NH₃, –CH₃). Individual substituents contribute additively to molecular σ with a unique regression term, which quantifies the inductive effect. The position dependence of substituents can be modeled by a distance decaying factor for S_N2. Use of the Hammett equation as a base-line model for Δ-machine learning models of the activation energy in chemical space results in substantially improved learning curves reaching low prediction errors for small training sets.

We generalize Hammett''s original approach to predict potential energies of activation in non aromatic molecular scaffolds with multiple substituents.