Abstract
The instrumental analysis of reaction mixtures is usually the rate-determining step in the optimization of chemical processes. Traditionally, reactions are analyzed by gas chromatography, HPLC or quantitative NMR spectroscopy on high-field spectrometers. However, chromatographic methods require elaborate work-up and calibration protocols, and high-field NMR spectrometers are expensive to purchase and operate. This protocol describes an inexpensive and highly effective analysis method based on low-field benchtop NMR spectroscopy. Its key feature is the use of fluorine-labeled model substrates that, because of the wide chemical shift range and high sensitivity of 19F, enable separate, quantitative detection of product and by-product signals even on low-field, permanent magnet spectrometers. An external lock/shim device obviates the need for deuterated solvents, permitting the direct, noninvasive measurement of crude reaction mixtures with minimal workup. The low field-strength facilitates a homogeneous excitation over a wide chemical shift range, minimizing systematic integration errors. The addition of the optimal amount of the nonshifting relaxation agent tris(acetylacetonato) iron(III) minimizes relaxation delays at full resolution, reducing the analysis time to 32 s per sample. The correct choice of processing parameters is also crucial. A step-by-step guideline is provided, the influence of all parameters, including adjustments needed when using high-field spectrometers, is discussed and potential pitfalls are highlighted. The wide applicability of the analytical protocol for reaction optimization is illustrated by three examples: a Buchwald-Hartwig amination, a Suzuki coupling and a C–H arylation reaction.
Key points
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Discovery and optimization of chemical transformations involve screening numerous reaction parameters. Quantification of all reaction constituents is often the bottleneck in this process.
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For most reactions, there are suitable fluorinated model substrates enabling analysis by 19F NMR spectroscopy. Inexpensive and maintenance-free benchtop NMR spectrometers are optimal for 19F NMR analysis because of the wide excitation profile. In the presence of Fe(acac)3, quantitative results can be obtained in <1 min per sample.
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Data availability
The data supporting the findings of this study are available within the article, its Supplementary Information and its Source Data files, as well as the primary supporting research papers25,26,27,28,29,30,31. Electronic NMR spectral data are available in a repository (https://sciflection.com/96fadf14-bd22-4322-8650-8e034f76b978). Source data are provided with this paper.
Change history
05 March 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41596-024-00982-4
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Acknowledgements
The research reported in this article was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2033 – 390677874 – RESOLV and SFBTRR88 ‘3MET’, BMBF, the state of NRW (Center of Solvation Science ‘ZEMOS’) and the Fonds der Chemischen Industrie (FCI, Liebig Fellowship for M.P.W.). We thank Martin Gartmann for assistance with NMR expertise and proofreading. We thank Umicore AG & Co. KG for the donation of catalysts and K. Gooßen for proofreading.
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G.H., M.K. and M.P.W. conducted and analyzed experiments. All authors designed experiments. The manuscript was assembled and edited by all authors. L.J.G. and M.P.W. supervised the project.
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Key references using this protocol
Bertoli, G. et al. Angew. Chem. Int. Ed. 62, e202215920 (2023): https://doi.org/10.1002/anie.202215920
Sivendran, N. et al. Chemistry 28, e202103669 (2022): https://doi.org/10.1002/chem.202103669
Weber, P. et al. Angew. Chem. Int. Ed. 58, 3203–3207 (2019): https://doi.org/10.1002/anie.201810696
Bertoli, G. et al. J. Fluor. Chem. 210, 132–136 (2018): https://doi.org/10.1016/j.jfluchem.2018.03.011
Ou, Y. et al. Asian J. Org. Chem. 8, 650–653 (2019): https://doi.org/10.1002/ajoc.201800461
Matheis, C. et al. Org. Lett. 16, 5984–5987 (2014): https://doi.org/10.1021/ol5030037
Danoun, G. et al. Synthesis 46, 2283–2286 (2014): https://doi.org/10.1055/s-0034-1378549
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Heinrich, G., Kondratiuk, M., Gooßen, L.J. et al. Rapid reaction optimization by robust and economical quantitative benchtop 19F NMR spectroscopy. Nat Protoc 19, 1529–1556 (2024). https://doi.org/10.1038/s41596-023-00951-3
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DOI: https://doi.org/10.1038/s41596-023-00951-3
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