SOFTNMR – Sensitive online flow NMR techniques
The SOFTNMR project aims to provide insight into reaction mixtures, through the development of original NMR pulse sequences and hyperpolarisation methods.
Project summary
Chemical reactions are of fundamental interest, and are the principal means to access new chemical structures and properties. Real-time reaction monitoring is a powerful approach to describe, understand and optimise chemical reactions. An array of analytical methods is available for reaction monitoring, and they typically provide kinetic information for previously identified compounds. Obtaining detailed and compound-specific structural information directly from reactions carried out in experimentally relevant conditions would be transformative for chemical synthesis through, e.g., the possibility to identify reaction intermediates and side or by products. The SOFTNMR project aims at providing extensive information on organic chemical reactions through the development of sensitive methods for the analysis of reaction mixtures by flow nuclear magnetic resonance (NMR) spectroscopy. NMR monitoring classically consists of carrying out a reaction directly in an NMR tube, which limits the reliability of the data, and the scope of reactions that can be studied. Online monitoring by flow NMR makes it possible to overcome these challenges and to monitor reactions in relevant experimental conditions. However, flow NMR currently relies on methods that are limited by i/ spectral complexity and ii/ the modest sensitivity of NMR.
The SOFTNMR project will address these two limitations. We will develop novel fast ultraselective NMR methods, in order to extract compound-specific spectra by online monitoring. We will notably design experiments that are applicable in continuous flow, and provide controlled selectivity. We will also develop an innovative setup that relies on sample flow to continuously hyperpolarise compounds with parahydrogen, without contamination. We will rely on signal amplification by reversible exchange (SABRE), using grafted polarisation transfer catalysts integrated in a custom flow circuit. These general methods, relying on original spin dynamics concepts and instrumentation, will make it possible to observe and identify a large number of compounds. The SOFTNMR methods will then be used to guide the design of novel reactions, and in particular tackle the moderate to low reactivity of classes of N-heterocycles in Diels-Alder reactions, thanks to key information obtained by online flow NMR monitoring.
The consortium involves three complementary partners.
- CEISAM, where the MIMM team works on the development and applications of NMR methods for the analysis of mixtures, and in chemical synthesis with a focus on flow chemistry.
- NIMBE, where the LSDRM develops and apply new NMR tools, notably for hyperpolarised systems, and work on the chemical functionalisation of surfaces and nanomaterials.
- LIMA, where the BSM team works on synthetic organic chemistry and their applications to life and material sciences.
The SOFTNMR project will have significant scientific impact in the many areas that benefit from real-time online monitoring, thanks to the general and robust methods that will be developed. These methods will be beneficial for batch organic chemical synthesis and also, beyond the project, for flow synthesis and its applications. The spin dynamics concept and hyperpolarisation instrumentation introduced during the SOFTNMR project will also be relevant for other applications, such as the high-throughput and sensitive analysis of mixtures. The pulse sequence developments will be openly distributed, to allow for broad uptake. The economic impact of the project will be ensured by frequent interactions of each of the partners with companies, as well as communication of the results to a general audience.