New Paradigms for Pure Shift NMR

Knowing the structures and behaviour of molecules is of critical importance in understanding the world around us, and in using chemistry to develop new materials. The most useful method for determining molecular structure in solution is NMR spectroscopy. Each hydrogen atom in a molecule - and most molecules contain many - produces a family of signals known as a multiplet. The position of the multiplet within the spectrum (the chemical shift) depends on the local environment of the atom; the multiplet structure depends on interactions (scalar couplings) with nearby atoms.

As our understanding of chemistry and biochemistry advances, the species we need to study increase in size and complexity. The number of NMR signals grows accordingly, leading to very crowded, and difficult to interpret, NMR spectra. Chemists and life scientist fight a continual battle to extract structural information from the complex sets of overlapping multiplets that are found in most NMR spectra.

Our research will produce two new families of NMR methods that produce spectra in which the multiplet structure has been suppressed, with a single signal for each hydrogen atom (a "pure shift" spectrum). We will show how reducing the complexity of NMR spectra can be achieved simply and efficiently, with applications across a wide range of disciplines. Existing pure shift NMR experiments are almost all relatively insensitive: they need concentrated samples and take quite a long time to perform. The new experimental methods should give cleaner spectra, more quickly; the structural information that scalar couplings provide can still be accessed, by incorporating the new pure shift methods into multidimensional NMR experiments

Improved pure shift NMR methods will find use across a wide range of academic research areas and industrial sectors including chemistry, biochemistry, biology, pharmaceuticals, healthcare, agrochemistry, and flavours and fragrances.

Who will benefit from this research?

Nuclear magnetic resonance (NMR) spectroscopy is a vital tool for many of the UK's wealth-generating industrial sectors, including the pharmaceutical, petrochemical and biotechnological industries. It is essential to the development of healthcare technologies, in particular for drug development and pharmaceutical process development, and throughout the chemical industry. NMR is widely used in chemical, biological and medical research, in academic, industrial and government laboratories, and is a crucial method for the determination of molecular structure and dynamics. For the great majority of users of NMR, proton NMR is a primary tool, and almost all applications of proton NMR stand to benefit from the development of improved pure shift methods.

How will they benefit from this research?

We propose to design better tools for NMR spectroscopy, attacking a classic limitation of the method and equipping both academic researchers and core UK industries with greatly enhanced resolution with minimum or no loss in sensitivity. The spectral resolution improvements we propose to deliver would at the current rate of progress take centuries to achieve from increased magnetic field. The new methods will produce simpler spectra that are easier to interpret and much better suited to automated analysis than those currently used. The two new families of methods can be implemented on industry-standard commercial spectrometers, without the need for hardware modification. Equipping researchers with higher resolution NMR tools will enhance wealth generation in all of the sectors noted above, and impact on health through improved methods for the characterisation of potential drugs and APIs, for the development and regulatory approval of new processes for the production of APIs, and for the analysis of biofluids in toxicology and metabolomics.

Because academic and industrial end-users of NMR spectroscopy are strongly integrated and new developments are often more readily accepted by industry when they have been adopted by academic researchers, we will use electronic delivery to encourage early adoption and to minimise barriers to the implementation. A secondary impact of the research will be the training of a highly-skilled postdoctoral fellow, with transferable skills in organisation, communication, critical and creative thinking, and exploitation of information technologies that are fundamental to research in the physical sciences, and the training of a range of researchers in collaborators' laboratories in pure shift NMR methods. From previous experience we anticipate take-up of new methods within 12-18 months of development; it is never easy to second-guess progress, particularly where NMR is concerned, but previous methodological developments in this area (e.g. multidimensional NMR methods) have had useful lifetimes measured in decades.