Rapid reaction optimization by robust and economical quantitative benchtop19F NMR spectroscopy

G. Heinrich, M. Kondratiuk, L. J. Gooßen, M. P. Wiesenfeldt

Published: 2024-02-26 DOI: 10.1038/s41596-023-00951-3

benchtop NMR spectroscopy

19F NMR

reaction optimization

fluorine-labeled substrates

processing parameters

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Figures

References

Introduction
Materials
Procedure 1: general procedure
Procedure 2: Buchwald-Hartwig amination reaction—screening of ligands and bases
- Preparation of the stock solution (indicated reagents, 0.5-mmol scale, 1.5-ml volume per reaction, all multiplied by 10)
- Performing the screening
Procedure 3: Suzuki reaction screening
- Preparation of the stock solution (indicated reagents, 0.5-mmol scale, 1-ml volume per reaction, all multiplied by 6)
- Performing the screening
Procedure 4: C–H arylation screening
- Preparation of the stock solutions (indicated reagents, 0.5-mmol scale, 3-ml volume per reaction, all multiplied by 16.67)
- Performing the screening
Troubleshooting
Timing
Anticipated results
Acknowledgements

Ernst, R. R. Sensitivity enhancement in magnetic resonance. In Advances in Magnetic and Optical Resonance Vol. 2 1–135 (Elsevier, 1966).
Carlson, R. & Carlson, J. Design and Optimization in Organic Synthesis Vol. 24 (Elsevier, 1992).
Markert, C., Rösel, P. & Pfaltz, A. Combinatorial ligand development based on mass spectrometric screening and a double mass-labeling strategy. J. Am. Chem. Soc. 130, 3234–3235 (2008).
McNally, A., Prier, C. K. & MacMillan, D. W. C. Discovery of an α-amino C–H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011).
Robbins, D. W. & Hartwig, J. F. A simple, multidimensional approach to high-throughput discovery of catalytic reactions. Science 333, 1423–1427 (2011).
Hopkinson, M. N., Gómez-Suárez, A., Teders, M., Sahoo, B. & Glorius, F. Accelerated discovery in photocatalysis using a mechanism-based screening method. Angew. Chem. Int. Ed. 55, 4361–4366 (2016).
Troshin, K. & Hartwig, J. F. Snap deconvolution: an informatics approach to high-throughput discovery of catalytic reactions. Science 357, 175–181 (2017).
Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nat. Chem. 5, 597–601 (2013).
Prieto Kullmer, C. N. et al. Accelerating reaction generality and mechanistic insight through additive mapping. Science 376, 532–539 (2022).
Sivendran, N. et al. Photochemical Sandmeyer-type halogenation of arenediazonium salts. Chem. Eur. J. 28, e202103669 (2022).
Pitzer, L., Schäfers, F. & Glorius, F. Rapid assessment of the reaction-condition-based sensitivity of chemical transformations. Angew. Chem. Int. Ed. 58, 8572–8576 (2019).
Schafer, W., Bu, X., Gong, X., Joyce, L. A. & Welch, C. J. High-throughput analysis for high-throughput experimentation in organic chemistry. In Comprehensive Organic Synthesis Edn. 2 (ed. Knochel, P.) 28–53 (Elsevier, 2014).
de Vries, A. H. & de Vries, J. G. The power of high-throughput experimentation in homogeneous catalysis research for fine chemicals. Eur. J. Org. Chem. 2003, 799–811 (2003).
Krska, S. W., DiRocco, D. A., Dreher, S. D. & Shevlin, M. The evolution of chemical high-throughput experimentation to address challenging problems in pharmaceutical synthesis. Acc. Chem. Res. 50, 2976–2985 (2017).
Mennen, S. M. et al. The evolution of high-throughput experimentation in pharmaceutical development and perspectives on the future. Org. Process Res. Dev. 23, 1213–1242 (2019).
Isbrandt, E. S., Sullivan, R. J. & Newman, S. G. High throughput strategies for the discovery and optimization of catalytic reactions. Angew. Chem. Int. Ed. 58, 7180–7191 (2019).
Buitrago Santanilla, A. et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 49–53 (2015).
Welch, C. J. High throughput analysis enables high throughput experimentation in pharmaceutical process research. React. Chem. Eng. 4, 1895–1911 (2019).
Welch, C. J. et al. MISER chromatography (multiple injections in a single experimental run): the chromatogram is the graph. Tetrahedron Asymmetry 21, 1674–1681 (2010).
Holzgrabe, U. Quantitative NMR spectroscopy in pharmaceutical applications. Prog. Nucl. Magn. Reson. Spectrosc. 57, 229–240 (2010).
Marquez, B. L. & Williamson, R. T. Quantitative applications of NMR spectroscopy. In Chemical Engineering in the Pharmaceutical Industry 133–149 (John Wiley & Sons, Ltd, 2019).
Diehl, B., Holzgrabe, U., Monakhova, Y. & Schönberger, T. Quo vadis qNMR? J. Pharm. Biomed. Anal. 177, 112847 (2020).
Mitchell, J., Gladden, L. F., Chandrasekera, T. C. & Fordham, E. J. Low-field permanent magnets for industrial process and quality control. Prog. Nucl. Magn. Reson. Spectrosc. 76, 1–60 (2014).
Danieli, E., Perlo, J., Blümich, B. & Casanova, F. Small magnets for portable NMR spectrometers. Angew. Chem. Int. Ed. 49, 4133–4135 (2010).
Dalitz, F., Cudaj, M., Maiwald, M. & Guthausen, G. Process and reaction monitoring by low-field NMR spectroscopy. Prog. Nucl. Magn. Reson. Spectrosc. 60, 52–70 (2012).
Dyga, M., Oppel, C. & Gooßen, L. J. RotoMate: An open-source, 3D printed autosampler for use with benchtop nuclear magnetic resonance spectrometers. HardwareX 10, e00211 (2021).
Matheis, C., Jouvin, K. & Goossen, L. J. Sandmeyer difluoromethylation of (hetero-)arenediazonium Salts. Org. Lett. 16, 5984–5987 (2014).
Danoun, G. et al. Sandmeyer trifluoromethylation. Synthesis 46, 2283–2286 (2014).
Bertoli, G., Exner, B., Evers, M. V., Tschulik, K. & Gooßen, L. J. Metal-free trifluoromethylthiolation of arenediazonium salts with Me4NSCF3. J. Fluor. Chem. 210, 132–136 (2018).
Ou, Y. & Gooßen, L. J. Copper-mediated synthesis of (diethylphosphono)difluoromethyl thioethers from diazonium salts, NaSCN, and TMS-CF2PO(OEt)2. Asian J. Org. Chem. 8, 650–653 (2019).
Weber, P. et al. A highly active ylide-functionalized phosphine for palladium-catalyzed aminations of aryl chlorides. Angew. Chem. Int. Ed. 58, 3203–3207 (2019).
Bertoli, G. et al. C−H fluoromethoxylation of arenes by photoredox catalysis. Angew. Chem. Int. Ed. 62, e202215920 (2023).
Holzgrabe, U. Quantitative NMR spectroscopy in pharmaceutical R&D. In eMagRes 45–56 (John Wiley & Sons, Ltd., 2015).
Schoenberger, T. ENFSI Guideline for qNMR Analysis. Available at http://enfsi.eu/wp-content/uploads/2017/06/qNMR-Guideline_version001.pdf (2019).
International Organization for Standardization. ISO 24583:2022 Available at http://www.iso.org/standard/78997.html (2022).
Silva Elipe, M. V. & Milburn, R. R. Monitoring chemical reactions by low-field benchtop NMR at 45 MHz: pros and cons. Magn. Reson. Chem. 54, 437–443 (2016).
Dolbier, W. R. Jr. Guide to Fluorine NMR for Organic Chemists (John Wiley & Sons, Ltd., 2016).
Wang, X., Patil, S. M., Keire, D. A., Xu, X. & Chen, K. Application of ultra-centrifugation and bench-top 19F NMR for measuring drug phase partitioning for the ophthalmic oil-in-water emulsion products. AAPS PharmSciTech 19, 1647–1651 (2018).
Howe, P. W. A. Recent developments in the use of fluorine NMR in synthesis and characterisation. Prog. Nucl. Magn. Reson. Spectrosc. 118–119, 1–9 (2020).
O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 37, 308–319 (2008).
Mattes, A. O. et al. Application of 19F quantitative NMR to pharmaceutical analysis. Concepts Magn. Reson. Part A 45A, e21422 (2016).
Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).
Inoue, M., Sumii, Y. & Shibata, N. Contribution of organofluorine compounds to pharmaceuticals. ACS Omega 5, 10633–10640 (2020).
Campbell, M. G. & Ritter, T. Modern carbon–fluorine bond forming reactions for aryl fluoride synthesis. Chem. Rev. 115, 612–633 (2015).
Champagne, P. A., Desroches, J., Hamel, J.-D., Vandamme, M. & Paquin, J.-F. Monofluorination of organic compounds: 10 years of innovation. Chem. Rev. 115, 9073–9174 (2015).
Landelle, G., Bergeron, M., Turcotte-Savard, M.-O. & Paquin, J.-F. Synthetic approaches to monofluoroalkenes. Chem. Soc. Rev. 40, 2867–2908 (2011).
Umemoto, T. et al. Power- and structure-variable fluorinating agents. The N-fluoropyridinium salt system. J. Am. Chem. Soc. 112, 8563–8575 (1990).
Watson, D. A. et al. Formation of ArF from LPdAr(F): catalytic conversion of aryl triflates to aryl fluorides. Science 325, 1661–1664 (2009).
Fier, P. S. & Hartwig, J. F. Selective C-H fluorination of pyridines and diazines inspired by a classic amination reaction. Science 342, 956–960 (2013).
Molnár, I. G. & Gilmour, R. Catalytic difluorination of olefins. J. Am. Chem. Soc. 138, 5004–5007 (2016).
Prakash, G. K. S. & Yudin, A. K. Perfluoroalkylation with organosilicon reagents. Chem. Rev. 97, 757–786 (1997).
Tomashenko, O. A. & Grushin, V. V. Aromatic trifluoromethylation with metal complexes. Chem. Rev. 111, 4475–4521 (2011).
Cho, E. J. et al. The palladium-catalyzed trifluoromethylation of aryl chlorides. Science 328, 1679–1681 (2010).
Charpentier, J., Früh, N. & Togni, A. Electrophilic trifluoromethylation by use of hypervalent iodine reagents. Chem. Rev. 115, 650–682 (2015).
Claridge, T. D. W. Chapter 2 – Introducing high-resolution NMR. In High-Resolution NMR Techniques in Organic Chemistry Edn. 3 (ed. Claridge, T. D. W.) 11–59 (Elsevier, 2016)
Umemoto, T. & Ishihara, S. Power-variable electrophilic trifluoromethylating agents. S-, Se-, and Te-(trifluoromethyl)dibenzothio-, -seleno-, and -tellurophenium salt system. J. Am. Chem. Soc. 115, 2156–2164 (1993).
Hafner, A. & Bräse, S. Ortho-trifluoromethylation of functionalized aromatic triazenes. Angew. Chem. Int. Ed. 51, 3713–3715 (2012).
Le, C., Chen, T. Q., Liang, T., Zhang, P. & MacMillan, D. W. C. A radical approach to the copper oxidative addition problem: trifluoromethylation of bromoarenes. Science 360, 1010–1014 (2018).
Britton, R. et al. Contemporary synthetic strategies in organofluorine chemistry. Nat. Rev. Methods Prim. 1, 1–22 (2021).
Wiesenfeldt, M. P., Nairoukh, Z., Li, W. & Glorius, F. Hydrogenation of fluoroarenes: direct access to all-cis-(multi)fluorinated cycloalkanes. Science 357, 908–912 (2017).
Chen, K., Berg, N., Gschwind, R. & König, B. Selective single C(sp3)–F bond cleavage in trifluoromethylarenes: merging visible-light catalysis with Lewis acid activation. J. Am. Chem. Soc. 139, 18444–18447 (2017).
Dolbier, W. R. Fluorine chemistry at the millennium. J. Fluor. Chem. 126, 157–163 (2005).
Wiesenfeldt, M. P. et al. General access to cubanes as benzene bioisosteres. Nature 618, 513–518 (2023).
Power, J. E. et al. Increasing the quantitative bandwidth of NMR measurements. Chem. Commun. 52, 2916–2919 (2016).
Yamazaki, T., Saito, T. & Ihara, T. A new approach for accurate quantitative determination using fluorine nuclear magnetic resonance spectroscopy. J. Chem. Metrol. 11, 16–22 (2017).
Jacobsen, N. E. NMR Spectroscopy Explained: Simplified Theory, Applications and Examples for Organic Chemistry and Structural Biology (Wiley, 2007).
Ellis, D. A., Martin, J. W., Muir, D. C. G. & Mabury, S. A. Development of an 19F NMR method for the analysis of fluorinated acids in environmental water samples. Anal. Chem. 72, 726–731 (2000).
Schoenberger, T., Monakhova, Y. B., Lachenmeier, D. W. & Kuballa, T. Guide to NMR Method Development and Validation – Part I: Identification and Quantification Available at http://eurolab-d.de/files/guide_to_nmr_method_development_and_validation_-_part_i_identification_and_quantification_may_2014.pdf (2014).
Bloembergen, N., Purcell, E. M. & Pound, R. V. Relaxation effects in nuclear magnetic resonance absorption. Phys. Rev. 73, 679–712 (1948).
Callaghan, P. T. Principles of Nuclear Magnetic Resonance Microscopy (Clarendon Press, 1993).
Bloch, F. Nuclear induction. Phys. Rev. 70, 460–474 (1946).
Bloembergen, N., Purcell, E. M. & Pound, R. V. Nuclear magnetic relaxation. Nature 160, 475–476 (1947).
Levy, G. C. & Komoroski, R. A. Paramagnetic relaxation reagents. Alternatives or complements to lanthanide shift reagents in nuclear magnetic resonance spectral analysis. J. Am. Chem. Soc. 96, 678–681 (1974).
Bara-Estaún, A. et al. Paramagnetic relaxation agents for enhancing temporal resolution and sensitivity in multinuclear FlowNMR spectroscopy. Chem. Eur. J. 29, e202300215 (2023).
Kocman, V., Di Mauro, G. M., Veglia, G. & Ramamoorthy, A. Use of paramagnetic systems to speed-up NMR data acquisition and for structural and dynamic studies. Solid State Nucl. Magn. Reson. 102, 36–46 (2019).
Mortimer, R. D. & Dawson, B. A. Using fluorine-19 NMR for trace analysis of fluorinated pesticides in food products. J. Agric. Food Chem. 39, 1781–1785 (1991).
Mestrelab Research. MestreNova Manual. Available at http://mnova.pl/files/download/MestReNova-12-0-0_Manual.pdf (2017).
Rosenau, C. P., Jelier, B. J., Gossert, A. D. & Togni, A. Exposing the origins of irreproducibility in fluorine NMR spectroscopy. Angew. Chem. Int. Ed. 57, 9528–9533 (2018).
Guide to NMR method development and validation – part 1: identification and quantification. In Handbook of Transnational Economic Governance Regimes 1041–1053 (Brill | Nijhoff, 2010).
Clarke, C. J., Tu, W.-C., Levers, O., Bröhl, A. & Hallett, J. P. Green and sustainable solvents in chemical processes. Chem. Rev. 118, 747–800 (2018).
Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherification of aryl halides. Acc. Chem. Res. 41, 1534–1544 (2008).
Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C–N cross-coupling reactions. Chem. Rev. 116, 12564–12649 (2016).
Biafora, A., Krause, T., Hackenberger, D., Belitz, F. & Gooßen, L. J. ortho-C−H arylation of benzoic acids with aryl bromides and chlorides catalyzed by ruthenium. Angew. Chem. Int. Ed. 55, 14752–14755 (2016).
Altman, R. A., Fors, B. P. & Buchwald, S. L. Pd-catalyzed amination reactions of aryl halides using bulky biarylmonophosphine ligands. Nat. Protoc. 2, 2881–2887 (2007).
Altman, R. A. & Buchwald, S. L. Pd-catalyzed Suzuki–Miyaura reactions of aryl halides using bulky biarylmonophosphine ligands. Nat. Protoc. 2, 3115–3121 (2007).
Armarego, W. L. F. & Chai, C. L. L. C. Purification of Laboratory Chemicals Edn. 5 (Butterworth-Heinemann, 2003).
Leuven NMR Core. Excitation profileAvailable at http://nmrcore.chem.kuleuven.be/knowledgebase/excitation_profile.php (2022).

Rapid reaction optimization by robust and economical quantitative benchtop19F NMR spectroscopy

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