Browsing by Author "Hill, DE"

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    Computational studies on hypervalent iodonium(III) compounds as activated precursors for 18F radiofluorination of electron-rich arenes
    (Elsevier B.V., 2015-08-15) Hill, DE; Holland, JP
    Fluorination of deactivated and non-activated electron-rich arenes via nucleophilic aromatic substitution (SNAr) reactions represents a major challenge in medicinal and radiochemistry. In efforts to activate electron-rich arenes for facile synthesis of fluoroarenes, a wide range of reagents have been developed. In particular, aryliodonium(III) species (salts and ylides) show promise as reagents for synthesising 18F-radiolabelled molecules for use in positron emission tomography (PET). However, in fluorination reactions involving a reductive elimination mechanism, aryliodonium(III) reagents present two competing pathways that lead to product (via transition state 1 (TS1)) or by-product (TS2) formation. Here, we present detailed computational studies using Density Functional Theory (DFT) methods on the relatively stability of these competing transition states and present an analysis based on transition state theory that allows prediction of chemoselectivity in aryliodonium(III) fluorination reactions. The methods developed indicate that the calculated difference in free energy (ΔΔG‡) and the calculated equilibrium constant (ln K‡) between the two transition states are chemically accurate molecular descriptors of chemoselectivity in aryliodonium(III) fluorination. It is anticipated that the tools developed here will aid design of the next generation of reagents with increased chemoselectivity for fluorination and radiofluorination of electron-rich arenes. © 2015 Elsevier B.V.
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    Evaluating the accuracy of density functional theory for calculating 1H and 13C NMR chemical shifts in drug molecules
    (Elsevier B.V., 2015-01-01) Hill, DE; Vasdev, N; Holland, JP
    The accuracy of different DFT methodologies for calculating 1H and 13C NMR chemical shifts in (R)-ispinesib, a complex drug molecule with multiple chemical groups and one stereocentre, has been evaluated. The accuracy of 6 basis sets and 16 different XC functionals was tested. In addition, we present a detailed study on the role of geometry optimisation (in gas and solution phase using a chloroform polarisable continuum model) on the accuracy of the calculated NMR spectra. NMR calculations using the double-ζ basis sets DGDZVP and 6-31++G(d,p) were found to be more accurate (and computationally more efficient) than those using larger triple-ζ basis sets. The O3LYP/DGDZVP methodology in solution phase using a geometry optimised at the same level of theory was found to be the most accurate method with mean absolute errors (MAEs) for 1H and 13C chemical shifts of 0.174 ppm and 3.972 ppm, respectively. Irrespective of the choice of XC or basis set used, complete geometry optimisation in either gas or solvent phase was found to be essential for attaining the highest accuracy in both 1H and 13C calculated chemical shifts. Finally, the role of molecular conformation was examined by calculating the Boltzmann-weighted 1H and 13C chemical shifts. Overall, we demonstrate that DFT shows exceptional promise for use in calculating the NMR chemical shifts in complex drug molecules. In the future, DFT calculations of NMR parameters are set to play an increasingly important role in drug discovery and chemical optimisation. © 2014 Elsevier B.V.
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    The hydrochemical response of cave drip waters to sub-annual and inter-annual climate variability, Wombeyan Caves, SE Australia
    (Elsevier, 2007-10-15) McDonald, J; Drysdale, RN; Hill, DE; Chisari, R; Wong, HKY
    A thorough understanding of cave seepage waters is necessary to interpret geochemical variations in speleothem calcite in terms of changing surface climatic conditions at a particular site. Here we present the hydrochemistry of ten cave drip waters from a karst system in SE Australia based on up to 5.5 years of monitoring. Discharge was continuously measured at six sites and manually at the other sites. Dripwater samples were analysed for pH, electrical conductivity, cations and anions at all sites at monthly or more frequent intervals. Each drip possesses a unique chemistry, and not all drip waters responded to antecedent short-term hydrological variations. For example, the hydrochemical behaviour of three adjacent drips at a bedrock depth of 45 m was completely different to that of shallower sites, and was apparently un-related to surface hydrology throughout the investigation. Based on modelled calcite precipitation vectors, prior calcite precipitation was demonstrated at several sites but can only be linked directly to changes in surface recharge at the shallowest sites. At extremely low flow, shallow drip waters accessed a high Mg, Sr and Ba source, thought to be the overlying soil. High-frequency sample collection allows for the calculation of predicted Mg/Ca-calcite and Sr/ Ca-calcite values, highlighting that the sites with the greatest potential to record high-resolution palaeohydrological records are those situated at shallow depth. Longer temporal-resolution palaeohydrological records may be recorded at deeper sites but longer-term monitoring is required to identify probable time scales. Inherent system non-linearities, dissolution of secondary calcite in pore spaces of the aquifer, changes in the source of trace elements, and the presence of multiple reservoirs confirm the need for the use of multiple speleothems and a multi-proxy approach to gain accurate palaeohydrological records from this site. © 2007, Elsevier Ltd.