SHARPER NMR: fast and accurate analysis of molecules, reactions and processes

Nuclear Magnetic Resonance (NMR) spectroscopy is a very useful analytical technique, which has applications across the range of sciences, including medicine, biology, geosciences, physics and chemistry. It can be performed on living organisms, solid state materials, or molecules dissolved in liquids. This proposal focusses on the solution state NMR spectroscopy.

Solution state NMR is a bread and butter technique for chemists. It has been around for 70 years, but does not show any sign of slowing down in its development, improvement, and increased efficiency. What distinguishes NMR from other spectroscopies is the longevity of the excited states of nuclei (or spins, as we often called them) that are subjects of NMR experiments. Their lifetime on the order of milliseconds to seconds allows scientists to design elaborate ways of spin manipulation before, or these days also during, signal acquisition. The purpose of these manipulations is to obtain specific information about the structure or the chemical state of the molecule, including interactions with other molecules.

Such manipulations are important for several reasons: (i) sometimes there is too much to see and we need to simplify NMR spectra in order to access the information we require. (ii) NMR is a relatively insensitive technique and compared to other analytical techniques, such as for example mass spectrometry (MS), requires large amounts of material (typically milligram quantities, compared to micro, nano grams or even pico grams that are sufficient for MS). (iii) In its standard implementation, NMR can be too slow to monitor fast processes that are occurring on millisecond to second times scales. (iv) Ideally, solution state NMR is performed on homogeneous samples and standard techniques struggle to provide high quality information about heterogeneous system, e.g. characterisation of processes taking place at the interface of two immiscible liquids, or when a gas is bubbled through a solution.

This proposal addresses the difficulties outlined above and aims to design novel NMR techniques that allow information to be obtained under circumstances where this is not as yet possible (e.g. heterogeneous systems), or bring evident improvements to existing techniques in terms of efficiencies (time saving) and quality of information obtained. Accuracy of NMR parameters, that are ultimately interpreted to provide chemical structures, characterise chemical reactions, or determine molecular sizes, will be improved.

The focus is on (i) monitoring of fast chemical reactions and (ii) characterising molecular sizes and (iii) going beyond the primary structure of molecules (the order in which the individual atoms are connected to each other) to how the atoms are arranged in the three-dimensional space (conformation, tertiary structure). Such information is crucial to our ability to rationalise intermolecular interactions (e.g. interactions of drugs with biomacromolecules).

Another important aspect of the proposed techniques is that they can be applied to complex systems. NMR has traditionally been very good in studying pure compounds, but to this day struggles to study them as part of mixtures. In real life situations it is not always possible to separate out individual molecules from mixtures, and many industries must learn how to deal with mixtures efficiently.

We will work with a manufacture of benchtop NMR spectrometers to bring the developed techniques directly into fume hoods and production lines, out of the specialised NMR laboratories.

We anticipate that the new methods we will develop will be applied across a wide spectrum of academic and industrial research.

Who will benefit from this research?

NMR is essential for UK wealth-generating industries, including chemical, petrochemical, pharmaceutical, biotechnological and food industries, which use NMR to monitor the synthesis of their products (e.g. fine chemical, pharmaceuticals), characterise molecular properties and intermolecular interactions. NMR is fundamental to the drug discovery process. As new and more powerful NMR techniques emerge, industries dealing with complex materials and mixtures, e.g. food and beverage industry, are ever more reliant on this technique. This work will not just be of great benefit to discovery chemistry, it will also impact on process research and development where efficient in situ analysis will allow fuller characterisation of desired processes. The latter is not just of benefit in terms of process reliability, safety, efficiency and minimising environmental impact, but also has profound economic implications for time to market in e.g. pharmaceutical, agrochemical and materials chemistry development.

The ultimate beneficiary of methodology driven NMR research is society - health and quality of life. NMR based knowledge and the scientific advances it generates stimulate wealth creation through supporting new companies that attract investment, generate high quality products ultimately benefiting people. An important part of this process, of course, are the manufactures of NMR equipment who benefit from methodology driven research that drives their product development. They play a crucial role in the dissemination of this technology.

The NMR methodology research produces highly skilled specialists that are able to move between different branches of NMR, perpetuating the progress of the field, participating in the knowledge exchange, finding new applications for their inventions. NMR specialists are the beneficiaries of their own research, but importantly play a crucial role in the dissemination of technology that ultimately advances wider academic and industrial research.

How will they benefit from this research?

The proposed methods will work on current commercial spectrometers with very few limitations mostly on some current benchtop systems. They will nevertheless drive the development of NMR hardware of both the established NMR manufactures (Bruker, JEOL) and upcoming manufactures of bench top NMR systems (Magritek, Oxford Instruments and Nanalysis). The line narrowing properties of SHARPER are significant. On benchtop systems equipped with persistent magnets, which have several fold worse magnetic field homogeneity than the high field superconductive magnets, implementation of this methodology will be ground breaking: it will significantly decrease the threshold of detection. It is easily envisaged that future small, portable NMR systems will be able to monitor progress of chemical production and other processes on an industrial scale using methodology developed here.

Equipping researchers with new efficient NMR tools for molecular studies will ultimately enhance wealth creation in many sectors of the UK economy. The new methods, which produce simple spectra and maximise the S/N ratio, allow faster and more reliable interpretation of chemical and structural information than is possible with the current methodology. By developing tools assisting with processing of SHARPER spectra we will make characterisation of chemical reactions and molecular structures more efficient and importantly, accessible to non-specialist.

The proposed methods inject selectivity into NMR spectra that is not reliant on a complete separation of signals. Because of this, they are applicable to the analysis of mixtures. These new NMR tools will push the boundaries of mixture analysis, providing information about molecular sizes and/or intermolecular interactions.