Pure Shift Proton NMR: A Resolution of the Resolution Problem?

Proton (hydrogen) 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 a major drawback: it struggles to separate the signals from the different hydrogen atoms in a molecule, because each atom typically gives rise to multiple signals. This multiplicity of signals arises because of the magnetic interactions between hydrogen nuclei, and it typically leads to spectra being about ten times more crowded than would be the case if these interactions could be switched off. Unfortunately, while such a broadband decoupling is routine where interactions between different types of atom (e.g. hydrogen and carbon) are involved, there is no general way of achieving it for interactions between atoms of the same type. What we have recently shown, however, is that by suitable choice of experimental methods we can in many cases reverse the effects of interactions, allowing us to measure pure shift spectra in which a single signal is seen for each hydrogen atom in a molecule. The simplicity such techniques offer means that we should be able to resolve the signals of individual atoms in much larger species, or in much more complex mixtures, than is currently the case. At the moment the only way to resolve signals better is to spread them out by using a higher magnetic field, but progress in building better magnets is agonisingly slow - over the last 30 years the highest field available has increased on average by just a few per cent each year. With pure shift methods we should be able to get almost a tenfold improvement in the space of a few years. In this project, a postdoctoral research fellow and a postgraduate student will investigate turning our initial proof of principle into practical tools. If they are successful, these tools will end up being used by chemists, biochemists and other scientists all over the world.

Who will benefit from this research? Researchers in chemistry, biochemistry, pharmacology, medicine and other areas. A significant proportion of the UK's wealth-creating industries, including the pharmaceutical and chemical sectors, use proton NMR for, inter alia, research and development, quality control, and process development. Pure shift methods will impact not only many branches of chemistry (including synthetic, medicinal, polymer, natural product, prebiotic, supramolecular, cluster), but fields as diverse as drug discovery, materials science, toxicology, metabolomics, and chemical process development. How will they benefit from this research? Proton (hydrogen) nuclear magnetic resonance (NMR) spectroscopy is the single tool most widely used by chemists for determining the molecular structures of unknown compounds, but struggles to separate the signals from the different hydrogen atoms in a molecule, because couplings between protons give rise to multiple signals. Pure shift NMR produces spectra in which this multiplicity is suppressed, giving almost an order of magnitude improvement in resolution in both 1D and multidimensional methods. The benefit to end users is more effective, more versatile, quicker, and cheaper, analysis. Pure shift NMR requires no special hardware, using standard instrumentation; all that is required is pulse sequence code for acquiring experimental data, and processing software for turning it into immediately interpretable spectra. The impact of new developments can therefore be felt very quickly; new techniques typically reach users in industry within months of publication. A secondary impact of this project is the training of a postdoctoral researcher and a graduate student in new pure shift 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 from this research? The results of this work will be published in widely-read journals, specialist, general and review as appropriate, and presented by the team at national and international conferences, and at meetings with industrial and academic collaborators. Appropriate training will be given to the PDRA and PhD student in the writing of papers, the preparation of posters, and in oral presentation. Collaborations with academic and industrial partners ensure that our technique developments remain focused on real analytical needs; indeed the developments underpinning this project have partly been funded by industry. We will continue to share early results with our portfolio of collaborators, who provide valuable feedback and context. We routinely meet with colleagues in academia and industry, consult for industrial partners, and conduct workshops at international meetings. Pulse sequences will be made available through web-based release of code and parameter sets, and data processing developments by extending (and possibly renaming) the DOSY Toolbox (http://personalpages.manchester.ac.uk/staff/mathias.nilsson/software.htm; M Nilsson, J Magn Reson 2009, 200, 296-302). Previous EPSRC-supported research has been efficiently propagated by similar means; almost all NMR spectrometers worldwide make use of methods developed in this group. A recent example both of this process of propagation and of IP exploitation is the signing of a10 year licensing agreement for all Varian spectrometers to offer our code for processing the results of diffusion experiments. We routinely engage with the three major NMR instrument manufacturers to ensure that they can implement our pulse sequences and data processing algorithms on the appropriate proprietary systems for their end users, including training their applications staff, as well as with many individual users who seek our help.