High-resolution Nuclear Magnetic Resonance and Mass spectrometry methodology for the analysis of complex mixtures

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Background behind the proposed research. Complex mixtures are all around us and have a greatimpact on our daily lives. Natural organic matter of soils, rivers, oceans or aerosols, food andbeverages, bio-fluids or biologic medical products are all examples of very complex mixtures. Thestatus quo in compound identification is to expend lots of energy combating the second law ofthermodynamics to try to isolate individual compounds from a mixture. However, wouldn't it bewonderful if we did not have to go through such an arduous process and were able to simply bypassthe customary purification step? This is particularly relevant, as the separation of individualcompounds from a mixture of thousands of molecules is beyond the capability of today'schromatographic methods.2The methodology I aim to develop will be relevant to environmental issues, food and medicineproduction and regulation.Methodology. NMR spectroscopy and mass spectrometry are the two state-of-the-art highresolutiontechniques that have the potential to tackle the analysis of complex mixtures at amolecular level.3,4 The hardware and software capabilities of NMR and MS spectrometers areconstantly improving, opening doors for the development of new methodology. The School ofChemistry of the University of Edinburgh is one of only two UK universities that houses both cuttingedge NMR and MS spectrometers (800 MHz NMR cryoprobe instrument and 12 T FT-ICR massspectrometer). Researchers here also have access to the world-leading NMR and MS equipment ofthe Pacific Northwest National Laboratory (PNNL), USA.An overarching aim of my research thus is to advance NMR and MS methodology for theanalysis of complex mixtures by developing new methods for data acquisition, processingand analysis.My objectives. To apply the developed methodology to answer important questions concerning reallife complex mixtures:(i) Disinfection by-products (DBPs) in drinking water(ii) Scotch whisky(iii) Biological medicinesResearch questions and hypotheses. Each of the above objectives poses a unique researchquestion that is briefly elaborated on in the following paragraphs.(i) Characterisation of DBPs generated during the production of potable water. Extensive physicaland chemical treatment is required to reduce the levels of dissolved organic matter (DOM) below 2mg/l when microbial disinfectant can be applied. In Scotland, this involves chlorination/chloramination. In addition to dealing with microbes, radical reactions involving DOM moleculesproduce hundreds of chlorinated molecules that become part of potable water.5 At present only ahandful of these is regulated, as the structures of a vast majority of DBPs are unknown. Knowingstructures of DBPs is essential if we are to determine their potential effects on human health.Hypothesis. A single fluorine atom used as a tag on DOM constituent molecules (representingdifferent classes of DOM molecules) will allow structure determination of DBPs through newlydeveloped NMR and MS methodology. This approach is necessary since Cl is not "a NMR friendlynucleus", which is in complete contrast to 19F that has 100% natural abundance, high sensitivity,large chemical shift range and far reaching couplings with 1H and 13C, facilitating structuredetermination. Chlorine isotopes on the other hand a