Catalytic hydrodeoxygenation of methyl-substituted phenols: correlations of kinetic parameters with molecular properties.

The hydrodeoxygenation of methyl-substituted phenols was carried out in a flow microreactor at 300 degrees C and 2.85 MPa hydrogen pressure over a sulfided CoMo/Al(2)O(3) catalyst. The primary reaction products were methyl-substituted benzene, cyclohexene, cyclohexane, and H(2)O. Analysis of the results suggests that two independent reaction paths are operative, one leading to aromatics and the other to partially or completely hydrogenated cyclohexanes. The reaction data were analyzed using Langmuir-Hinshelwood kinetics to extract the values of the reactant-to-catalyst adsorption constant and of the rate constants characterizing the two reaction paths. The adsorption constant was found to be the same for both reactions, suggesting that a single catalytic site center is operative in both reactions. Ab initio electronic structure calculations were used to evaluate the electrostatic potentials and valence orbital ionization potentials for all of the substituted phenol reactants. Correlations were observed between (a) the adsorption constant and the two reaction rate constants measured for various methyl-substitutions and (b) certain moments of the electrostatic potentials and certain orbitals' ionization potentials of the isolated phenol molecules. On the basis of these correlations to intrinsic reactant-molecule properties, a reaction mechanism is proposed for each pathway, and it is suggested that the dependencies of adsorption and reaction rates upon methyl-group substitution are a result of the substituents' effects on the electrostatic potential and orbitals rather than geometric (steric) effects.

Molecular electrostatic potentials: a new approach to the study of the metabolic and carcinogenic activities of hydrocarbons.

The electrostatic potentials of a group of aromatic hydrocarbons have been determined and have revealed that each molecule possesses several regions of negative potential, which would attract an approaching electrophile. These regions include all those portions of the molecules at which major amounts of metabolic products are found. While the K-regions of the hydrocarbons studied are invariably quite negative, the magnitudes of their potentials do not correlate with the molecules' carcinogenic potencies. The presence of other strong negative regions in addition to the K-region, especially in the more active molecules, suggests that some of these others may participate in the carcinogenic process. tof particular interest is the possibility that the significant negative potentials that have been found to be associated with many CH3 and CH2 groups may play such a role, Perhaps two or more negative regions are involved in hydrocarbon carcinogenesis.

Molecular electrostatic potentials: an effective tool for the elucidation of biochemical phenomena.

The electrostatic potential V(r) that is created in the space around a molecule by its nuclei and electrons (treated as static distributions of charge) is a very useful property for analyzing and predicting molecular reactive behavior. It is rigorously defined and can be determined experimentally as well as computationally. The potential has been particularly useful as an indicator of the sites or regions of a molecule to which an approaching electrophile is initially attracted, and it has also been applied successfully to the study of interactions that involve a certain optimum relative orientation of the reactants, such as between a drug and its cellular receptor. A variety of methods for calculating V(r) is available, at different levels of rigor. For large biologically active molecules, multipole expansions and superposition of potentials computed for subunits have been found to be effective. A large number of chemical and biochemical systems and processes have now been studied in terms of electrostatic potentials. Three examples of such applications are surveyed in this paper. These deal with: (a) reactive properties of nucleic acids, including their component bases; (b) biological recognition processes, including drug-receptors and enzyme-substrate interactions; and (c) chemical carcinogenesis, referring specifically to the polycyclic aromatic hydrocarbons and halogenated olefins and their epoxides. For each of these areas, examples of the use of electrostatic potentials in elucidating structure-activity patterns are given.

Molecular properties of the chlorinated ethylenes and their epoxide metabolites.

This paper has presented the initial results of a computational study of the chlorinated ethylenes and their epoxides. Particular attention was devoted to those properties which may be related to the reactivities, and specifically carcinogenicities, of these molecules. Detailed calculations of their optimum structures have been carried out, and stabilities, dipole moments, charge distributions, and epoxide C-O bond strengths were determined and have been discussed. For the epoxides, most of this information, including the structural data, has not previously been available. It is hoped that this will help to bring about a better understanding of the biological activities of the chlorinated ethylenes, and of the manner in which these activities are related to the numbers and locations of the chlorine substituents. Particularly promising in this respect are the qualitative assessments of the epoxide C-O bond strengths presented above. More quantitative measures of this key property are currently being computed.

Computational approaches to the identification of suspect toxic molecules.

We have presented computational approaches that can be used for the relatively rapid identification of suspect toxigens, including carcinogens, in two different classes of compounds: (a) halogenated olefins and epoxides, and (b) substituted dibenzo-p-dioxins. A common element in these approaches is the key role played by the molecular electrostatic potential. It is applied in two different ways, however; it is used to assess the reactivity of a specific site in the case of the epoxides, and for the dibenzo-p-dioxins the focus is on the overall pattern of negative regions above the molecular plane. While we are continuing to develop and refine both types of analysis, especially that related to the dibenzo-p-dioxins, the results obtained so far are encouraging, and indicate that these can be regarded as useful screening techniques for identifying compounds that require further and more exhaustive investigation.

Magnetic-flux pumping in high-performance, stationary plasmas with tearing modes.

Analysis of the change in the magnetic field pitch angles during edge localized mode events in high performance, stationary plasmas on the DIII-D tokamak shows rapid (<1 ms) broadening of the current density profile, but only when a m/n=3/2 tearing mode is present. This observation of poloidal magnetic-flux pumping explains an important feature of this scenario, which is the anomalous broadening of the current density profile that beneficially maintains the safety factor above unity and forestalls the sawtooth instability.

Seventeenth Annual Interdisciplinary Cancer Research Workshop.

The Seventeenth Annual Interdisciplinary Cancer Research Workshop was held at the University of New Orleans on March 4, 1994. It was again sponsored by the Cancer Association of Greater New Orleans, a United Way Agency. As all the previous workshops in this highly successful series, it was organized by Peter Politzer (University of New Orleans), with the assistance of Anita H. Buckel (University of New Orleans) and James R. Jeter (Tulane University School of Medicine, New Orleans). The three invited speakers were Robert J. Coffey (Vanderbilt University, Nashville, TN), Suzanne A. W. Fuqua (University of Texas Health Science Center, San Antonio, TX), and Frank M. Torti (Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC). A one-hour-discussion period in the afternoon presented ample opportunity for an exchange of ideas and research findings among the speakers and the workshop participants. James R. Jeter served as the moderator of this lively discussion session.

Eighteenth Annual Interdisciplinary Cancer Research Workshop.

The Eighteen Annual Interdisciplinary Cancer Research Workshop was another one in a highly successful series of these New Orleans workshops. It was held on March 3, 1995, in a new location-at the J. Bennett Johnston Building of the Tulane University Medical Center. With a single exception, all the previous workshops took place at the University of New Orleans. Similarly, as all the past workshops, it was sponsored by the Cancer Association of Greater New Orleans, a United Way Agency. It was again organized by Peter Politzer (University of New Orleans), with the assistance of Anita H. Buckel (University of New Orleans) and James R. Jeter (Tulane University School of Medicine, New Orleans). The three invited speakers were William N. Hait (The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ), Joachim G. Liehr (Department of Pharmacology & Toxicology, The University of Texas Medical Branch at Galveston, Galveston, TX), and Patrice C. Ferriola (Department of Cell and Molecular Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, NC). A one-hour discussion period after the conclusion of the last presentation represented an excellent forum for an exchange of ideas and research results among the speakers and the workshop participants. Lee Roy Morgan (Dekk-Tec, New Orleans) served as the moderator of the discussion session.

Halogenated hydrocarbon epoxides: some predictive methods for carcinogenic activity based on electronic mechanisms.

We summarize some of our computational studies (involving an ab initio self-consistent-field molecular orbital procedure) of the reactive properties of halogenated hydrocarbon epoxides. Two of the factors that are believed to determine the carcinogenicities of halogenated olefins and their metabolically produced epoxides are discussed in detail. These are the epoxide's tendency toward oxygen protonation, and its subsequent reactivity. The first of these provides a means for identifying suspect carcinogens, on the basis of our earlier observation that epoxide carcinogenicities are associated with relatively strong negative electrostatic potentials near the oxygens (the protonation sites). With regard to the epoxide's reactivity, optimum carcinogenicity appears to require that this be at an intermediate level. We have investigated the feasibility of using calculated C-O bond orders as measures of reactivity, with encouraging initial results, which suggest that this reactivity requirement may provide a means for ranking the activities of carcinogens.

Relationships between the electrostatic potential, epoxide hydrase inhibition and carcinogenicity for some hydrocarbon and halogenated hydrocarbon epoxides.

For a group of nine hydrocarbon and halogenated hydrocarbon epoxides, there is shown to be a good correlation between their abilities to inhibit epoxide hydrase and the quantity Vmin /Es, where Vmin is the most negative value of the molecule's electrostatic potential in the neighborhood of the epoxide oxygen and Es is a factor that takes account of steric effects. It is also demonstrated that carcinogenicity, for thirteen epoxides, appears to be associated with Vmin having a relatively large negative value. On this basis, several other epoxides are predicted to be carcinogenic. The electrostatic potentials used in developing these relationships have been computed by an ab initio self-consistent-field molecular orbital procedure, using optimized molecular geometries.

Calculated surface electrostatic potentials of molecular sieve models containing SiO4, AlO4, and PO4 units.

Surface electrostatic potentials have been computed at the ab initio HF/STO-5G* level for two model systems: a fragment of a zeolite channel wall; and a fragment composed of SiO4, AlO4 and PO4 units. The potential above the SiO4 network is negative everywhere, despite these units commonly being regarded as electrically neutral. In marked contrast, the AlO4 and PO4 units introduce strongly negative and positive regions, respectively, giving rise to a much more heterogeneous surface potential.

The structure and properties of 7-(2-oxoethyl)guanine: a model for a key DNA alkylation product of vinyl chloride.

Recent laboratory studies have shown that the major in-vivo DNA alkylation product of vinyl chloride is the 7-(2-oxoethyl) derivative of guanine, and the suggestion has been made that this derivative is responsible for the carcinogenicity of vinyl chloride. Some nuclear magnetic resonance evidence indicates that this alkylation product may be in equilibrium with a cyclic hemiacetal; this would affect the hydrogen bonding between guanine and cytosine. In order to help elucidate the properties of this key DNA alkylation product, we have computed the structure and properties of the same derivative of the isolated guanine molecule, i.e., 7-(2-oxoethyl)guanine. An ab initio self-consistent-field molecular orbital procedure was used. In this paper, we present the optimized (STO-3G) structure of 7-(2-oxoethyl)guanine, and the STO-5G energy, atomic charges and dipole moment. We found very little tendency for the formation of a cyclic hemiacetal; the equilibrium constant was estimated to be about 10(-9).

Validation of neoclassical bootstrap current models in the edge of an H-mode plasma.

Analysis of the parallel electric field E(parallel) evolution following an L-H transition in the DIII-D tokamak indicates the generation of a large negative pulse near the edge which propagates inward, indicative of the generation of a noninductive edge current. Modeling indicates that the observed E(parallel) evolution is consistent with a narrow current density peak generated in the plasma edge. Very good quantitative agreement is found between the measured E(parallel) evolution and that expected from neoclassical theory predictions of the bootstrap current.

[The treatment of respiratory failure in severe chest injury (author's transl)]. / Die Therapie der Atemstörung beim schweren Thoraxtrauma

The use of artificial ventilation versus conservative treatment in 101 patients with severe chest injuries is reconsidered, because major ventilation therapy carries a high incidence of complications. This technique within the past few years has increasingly been replaced by differentiated conservative respiratory treatment. On the basis of a retrospective study it is concluded that under special conditions even the unstable chest accompanied by respiratory insufficiency may be treated successfully by this technique.

The use of the electrostatic potential at the molecular surface in recognition interactions: dibenzo-p-dioxins and related systems.

An ab initio self-consistent-field molecular orbital approach was used to compute the electrostatic potentials of dibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), two analogues of the latter, and two isomeric benzoflavones on a three-dimensional molecular surface corresponding to the contour of constant electronic density equal to 0.002 electrons/bohr3. The results are discussed in relation to the biological activities of the respective molecules. It is shown that the electrostatic potential graphically depicted on the molecular surface is well suited for the study of recognition interactions, such as are believed to be involved in the initial receptor-mediated step leading to toxicity in the dibenzo-p-dioxins. The surface potential has the advantage of clearly showing steric features that may play a role in understanding the recognition process being investigated.

Comparison of quantum chemical parameters and Hammett constants in correlating pK(a) values of substituted anilines.

Historically, Hammett constants have been extremely effective in describing the influence of substituents on chemical reactivity and other physical and chemical properties, whereas variables derived from quantum chemical calculations have generally been less effective. Taking the experimental pK(a)s of substituted anilines as a representative physicochemical property, five ab initio quantum chemical indices are compared for effectiveness as one-parameter regression descriptors for pK(a). All of the tested descriptors performed well for a set of 19 mono-, 13 di-, and 4 trisubstituted anilines, and two performed somewhat better than the traditional Hammett sigma constants. Among the calculated quantities, the best representation of the aniline pK(a)s is produced by the minimum average local ionization energy on the molecular surface.