New and improved methods for mixture analysis by NMR

NMR spectroscopy is a wonderful tool for identifying chemical compounds, known or unknown; without it, synthetic chemists would be lost. Any serious chemical laboratory therefore has at least one NMR spectrometer. It is, though, much better at analysing pure compounds than mixtures, for a number of reasons. First, NMR is information-rich, so spectra even of fairly simple compounds tend to be crowded; when multiple species are present, signals overlap and obscure each other. Second, one NMR signal looks much like another: it is tricky to tell which signals come from which species in a mixture. Third, while NMR is inherently quantitative signal intensity is directly proportional to the number of spin-active nuclei present the practicalities of measurement mean that NMR parameters such as relaxation times, J couplings and chemical shifts can affect quantitation.

Fortunately, NMR is a remarkably flexible phenomenon; unlike other branches of spectroscopy, it allows spectra to be measured in many different ways. Relatively simple changes in the way NMR signals are excited and measured allow chemists to tailor experiments to provide different sorts of information. For example, adding pulses of magnetic field gradient to an experiment makes signal intensities depend on molecular diffusion. These diffusion-ordered spectroscopy (DOSY) experiments help tackle the second problem above, sorting the NMR signals in a spectrum in order of the size of molecule responsible for them. Similarly, in the last few years a wide range of new experimental techniques (pure shift methods) has been developed that allows spectra to be greatly simplified, replacing each wide multiplet in an NMR spectrum with a single sharp singlet signal at the chemical shift. This attacks the first problem, that of spectral crowding and signal overlap, by reducing sharply the number of individual signals in the spectrum of a mixture.

Mixture analysis is a key tool in the pharmaceutical industry, so this project is partly supported by AstraZeneca. It will involve extensive experimental work both in the School of Chemistry, where we have 11 superconducting NMR spectrometers, and at AstraZenecas Macclesfield laboratories.

This project will investigate a range of ideas for extending the scope of NMR spectroscopy for both qualitative and quantitative analysis of mixtures. These will include the latest pure shift methods, such as PSYCHE [see Angew. Chem., Int. Ed. 53, 6990 (2014); J. Am Chem Soc. 136, 11867 (2014)]; DOSY experiments, including the use of chemically-selective co-solvents (matrix-assisted DOSY) to allow the signals of species of similar size to be separated; and new experiments for the accurate compensation of the effects of couplings and chemical shifts on quantitation. The project supervisors are Professor Gareth Morris FRS (http://www.chemistry.manchester.ac.uk/people/staff/profile/?ea=Gareth.Morris) and Dr Mathias Nilsson http://www.chemistry.manchester.ac.uk/people/staff/profile/?ea=mathias.nilsson of Manchester University, and Drs Andy Phillips and Steve Coombes of AstraZeneca. Further information on this and other work in NMR at Manchester can be found at http://nmr.chemistry.manchester.ac.uk.