Matrix-Assisted DOSY

Nuclear magnetic resonance (NMR) spectroscopy is the single tool most widely used by chemists for determining the molecular structures of unknown compounds. It is a wonderfully versatile and sensitive tool, but it has one major drawback: it is poor at analysing mixtures, so it is mostly used on carefully purified single compounds. Because many of Nature's most challenging problems - and many of those posed by synthetic chemists and by industry - are presented to us as mixtures, a great deal of effort goes into separating mixtures into their individual components so that they can be identified. Diffusion-ordered spectroscopy (DOSY) tries to get around this limitation by separating the NMR signals of different molecules, so that the signals from different species can be distinguished. Over the last decade our research group and others have developed the technique and applied it with great success - but almost always to simple solutions. In this project, a postdoctoral research fellow will investigate separating the spectra of mixture components more effectively by adding substances such as surfactants (the active ingredients of soaps and detergents), gels and soluble polymers to solvents to make a solution (a matrix ) that changes the way that molecules diffuse. These substances diffuse very slowly, but they also attract other molecules. The result is that the rates at which solute molecules diffuse in such a matrix are changed, by an amount that depends on how strong the attraction is. By tuning the properties of the matrix we should be able to optimise the separation of the NMR signals of different species, even resolving the spectra of isomers that cannot be separated by normal DOSY experiments. Initially DOSY was used largely by chemists, but it is now being applied in fields as varied as food science, forensic medicine, and environmental science. Using different matrices for DOSY will give such users much greater control over how signals of different species in a mixture are separated, opening up new applications.

Who will benefit? Researchers in chemistry, biochemistry, pharmacology, medicine and other areas. Many of the UK's wealth-creating industries, including the pharmaceutical and chemical sectors, use analytical methodologies such as DOSY for, inter alia, research and development, quality control, toxicology, and product deformulation. Improved DOSY methods will impact, amongst other fields, metabolomics, drug discovery, toxicology, process development, the nanosciences, and many branches of chemistry (including synthetic, medicinal, natural product, prebiotic, supramolecular, cluster). At present a paper using DOSY is published every three days on average, and almost all of the applications described could potentially benefit from the improved resolution and specificity that matrix-assisted DOSY offers. Recent examples of the diversity of DOSY applications include pharmaceutical chemistry (the detection and identification of synthetic drugs in supposedly herbal remedies), forensic medicine (the identification of oversulfated chondroitin sulfate in heparin), and environmental science (the classification of organic matter components of soils). How will they benefit? DOSY relies on differences in diffusion between analyte species. In simple solution the diffusion coefficient is an intrinsic property of the solute and solvent; with matrix-assisted methods, diffusion coefficients can be manipulated to discriminate between analytes by suitable choice of matrix. This increases both the scope of DOSY methods (e.g. to include resolution of isomer spectra), and the quality of the results obtainable (maximising diffusional discrimination between species). The benefit to end users is more effective, more versatile, quicker, and cheaper, analysis. This translates to more efficient routes to the discovery of new products, better ways to characterise both those products (including new pharmaceuticals) and the results of their biological and environmental degradation, better methods for optimising chemical processes for their production, and thence to wealth creation and improved competitiveness. DOSY requires no special hardware, using standard instrumentation, and the matrix-assisted methods described here use almost exclusively materials that are readily available commercially. The impact of new developments can therefore be felt very quickly; new DOSY techniques typically reach users in industry within months of publication. Effective exploitation of NMR techniques, both in industry and academia, relies on skilled practitioners. A secondary impact of this project is the training of a postdoctoral researcher in new DOSY techniques and in the core skills of NMR spectroscopy, as well as in the more widely transferable skills of organisation, communication, critical and creative thinking, and exploitation of information technologies that are fundamental to research in the physical sciences. What will be done to ensure that they benefit? The results of this work will be published in widely-read journals, specialist, general and review as appropriate. Results will be presented at national and international conferences, and at meetings with industrial and academic collaborators in cognate areas. Collaborations with academic and industrial partners ensure that our methodological developments remain focused on real analytical needs; indeed this project grew out of one such collaboration. Pulse sequence developments will be made available electronically through web-based release of source code and model parameter sets, and data processing developments through the DOSY Toolbox (http://personalpages.manchester.ac.uk/staff/mathias.nilsson/software.htm). Previous EPSRC-supported research has been efficiently propagated through these and other electronic means; almost all NMR spectrometers worldwide use our pulse sequences and algorithms, and we have just signed a 10 year licensing agreement for DOSY software with a major manufacturer.