Reaction monitoring on micro-second timescales by nuclear magnetic resonance: aiming for a paradigm shift in the study of reaction mechanisms

We are all familiar with the concept of what is necessary to win a cycle race, simply to cross the finish line first. When we reflect on this process, however, there are lots of potential questions we might ask about the event. These include, how many participants were there, did they all start at the same point in time, did they all follow the same route, what was their average speed, did they all end up at the same finish-point, what was the effect of the bike, and then in the event of a close finish who indeed was first.
A similar range of questions would result if we were to examine transition metal catalysed reactions that are used to produce many of the chemicals we take for granted in today's high-tech world. Now, however, the participants are much smaller and very special methods are needed to view them. Furthermore, we still need a starting gun if we are to learn precisely about the efficiency of the reaction and indeed, just like in the cycle race, if we train hard and design the best catalyst (bike) we can influence the outcome in a desirable way. Here, this might simply be to reduce the energy need or indeed to increase the proportion of desired product (yield) which is vital to minimise waste if the reaction is completed on a 1,000,000 tonne scale.
In Chemistry, there is a very special method called nuclear magnetic resonance spectroscopy (NMR) that allows us to take a picture of the participants in such a process but it normally measures its information over a period of seconds and it requires a larger amount of material than some other methods. We overcome this limitation by viewing as many as a million million million copies of the same molecule simultaneously in order to produce its response. Even then, some measurements can take days to complete. In this project we aim to develop a new method using NMR to examine the route taken by molecules during their conversion to high value products in catalytic reactions. We plan to use this information to improve on the reactions' outcomes in a positive way. We will use light from a laser to start the race and employ a special form of hydrogen, known as parahydrogen to enable us to increase the sensitivity of the NMR measurement to a level that will allow us to complete the monitoring of reactions within time periods from a thousandth to a millionth of a second. Parahydrogen was actually the fuel of the space shuttle. Here, one might view it as acting like a molecular video camera whilst at the same time removing (filtering) any unwanted signals from the spectators (other molecules present in the solution). We will build-up our understanding of the reaction's route by taking our NMR picture which contains precise information about the identity of the participants (molecules) at different times after the start of the race. We will monitor the same process several times under different conditions in order to produce the necessary molecular level picture that will ultimately allow us to optimise our chosen catalytic process. The enhanced level of understanding that will result from this process will enable scientists to develop and optimise catalytic processes in a way that was previously impossible and hence contribute more positively to society.
In order to achieve this goal, we will first have to develop this new method and then build up a rigorous understanding of how it works. When that has been achieved, we can start to select specific reactions. We will aim to design and then optimise new catalysts to improve on those currently available through the improved understanding achieved by our methods. We hope that ultimately the new method will be used elsewhere and hence have a substantial impact in both academia and industry.

Synthetic chemists build new materials or molecules which can be harnessed industrially in a range of situations that span fine chemicals, bulk chemicals and pharmaceuticals to name but three. Furthermore, experimentalists take these molecules and examine them to elucidate specific types of information that add to both to fundamental knowledge and ultimately to the commercial viability of the chemical industry in places such as the UK. Over the last hundred years many powerful methods have been developed to study reactions and indeed to characterise molecules in solution. This in itself reflects a multi billion dollar industry. Examples are provided by UV-visible spectroscopy, Infrared spectroscopy and Raman spectroscopy. Hardware advances have seen these three observation methods linked with time-resolved spectroscopy in order to enable the study of dynamic processes in chemical compounds. With the help of pulsed lasers, it has proven possible to study processes that occur on time scales as short as 1e-16 seconds using what is commonly called a 'pulse-probe' experiment. One aspect of such a study is called femtochemistry (eg Zewail, Nobel Prize 1999) and which deals with examining the motion of atoms during bond breaking and bond making processes. On the slightly slower timescale of pico to micro seconds, vibrational relaxation, metal-ligand bond splitting, bond activation, intramolecular electron and energy transfer and intraligand rearrangement processes can also be studied. The importance of developing methods to study chemical events has often been recognised by the wider community (Fenn 2002, Ernst, NP 1991, Wüthrich, 2002). Building on this understanding of reactivity has led in turn to significant developments in applied chemistry (Noyori, NP 2001, Grubbs, 2005, Suzuki, 2010). The impact of such studies is therefore immense. The project is of relevance to areas of strategic importance as identified by the research councils (critical (c) to supportive (s)): analytical science (c), catalysis (c), chemical reaction dynamics and mechanisms (c), chemical structure (c), computational and theoretical chemistry (s), sensors and instrumentation (c) and synthetic coordination chemistry (c). In order to ensure the commercial potential of promising catalysts, we will seek both intellectual property (IP) protection with help from the University of York.
Moving to a more specific level, the study of rates of reaction by NMR spectroscopy is typically associated with slow reactions that occur on a timescale of minutes or with faster reactions in which there is dynamic exchange between different species in solution on a millisecond timescale. Here we plan to make NMR spectroscopy into a pump-probe technique that can probe reactions that require photochemical initiation and occur on timescales as short as microseconds. If this method proves generally applicable as we intend, it will have a major impact on photochemists and those studying many reaction mechanisms. Moreover, it provides access to unusual magnetic phenomena as shown in our proof-of-concept experiments. It will therefore have impact on scientists developing magnetic resonance techniques. This project will train two PDRAs in the area of hyperpolarisation which is clearly one of the leading research areas of NMR. They will also acquire photochemical and synthetic skills. The research will maintain the UK in a leading position for applications of hyperpolarisation in NMR technology. Our dissemination strategy is designed to inform several different groups of scientists of our advances: magnetic resonance, photochemistry, catalysis and reaction mechanism communities. We will also bring our techniques to the attention of the public through popular articles and Cafe Scientifique presentations.