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Rapid reaction optimization by robust and economical quantitative benchtop 19F NMR spectroscopy

Nature Protocols volume 19, pages 1529–1556 (2024)Cite this article

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A Publisher Correction to this article was published on 05 March 2024

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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

  • Discovery and optimization of chemical transformations involve screening numerous reaction parameters. Quantification of all reaction constituents is often the bottleneck in this process.

  • 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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Fig. 1: Reaction optimization by benchtop 19F quantitative NMR spectroscopy.
Fig. 2: Influence of the excitation profile on integral ratios.
Fig. 3: Correlation between measurement time, relaxation delay and integrals.
Fig. 4: Minimizing the analysis time by non-shifting relaxation agents.
Fig. 5: Influence of post-processing parameters on precision.
Fig. 6: Limit of detection (LOD) and limit of quantification (LOQ).
Fig. 7: Application of the protocol to a Buchwald-Hartwig amination reaction.
Fig. 8: Ligand screening for the Buchwald-Hartwig amination reaction.
Fig. 9: Base screening for the Buchwald-Hartwig amination reaction.
Fig. 10: Ligand screening for the Suzuki reaction.
Fig. 11: Effect of B(OH)3 on the T1 relaxation times of the model mixture of the Suzuki reaction.
Fig. 12: Base screening for the Suzuki reaction.
Fig. 13: Precursor screening for the C–H arylation reaction.

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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.

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References

  1. Carlson, R. & Carlson, J. Design and Optimization in Organic Synthesis Vol. 24 (Elsevier, 1992).

  2. 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).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Robbins, D. W. & Hartwig, J. F. A simple, multidimensional approach to high-throughput discovery of catalytic reactions. Science 333, 1423–1427 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Troshin, K. & Hartwig, J. F. Snap deconvolution: an informatics approach to high-throughput discovery of catalytic reactions. Science 357, 175–181 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nat. Chem. 5, 597–601 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Prieto Kullmer, C. N. et al. Accelerating reaction generality and mechanistic insight through additive mapping. Science 376, 532–539 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. 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).

  11. 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).

    Article  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. Buitrago Santanilla, A. et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 49–53 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Welch, C. J. High throughput analysis enables high throughput experimentation in pharmaceutical process research. React. Chem. Eng. 4, 1895–1911 (2019).

    Article  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. Holzgrabe, U. Quantitative NMR spectroscopy in pharmaceutical applications. Prog. Nucl. Magn. Reson. Spectrosc. 57, 229–240 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

  20. Diehl, B., Holzgrabe, U., Monakhova, Y. & Schönberger, T. Quo vadis qNMR? J. Pharm. Biomed. Anal. 177, 112847 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. Danieli, E., Perlo, J., Blümich, B. & Casanova, F. Small magnets for portable NMR spectrometers. Angew. Chem. Int. Ed. 49, 4133–4135 (2010).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Matheis, C., Jouvin, K. & Goossen, L. J. Sandmeyer difluoromethylation of (hetero-)arenediazonium Salts. Org. Lett. 16, 5984–5987 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Danoun, G. et al. Sandmeyer trifluoromethylation. Synthesis 46, 2283–2286 (2014).

    Article  CAS  Google Scholar 

  27. 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).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. 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).

    Article  CAS  Google Scholar 

  30. Sivendran, N. et al. Photochemical Sandmeyer-type halogenation of arenediazonium salts. Chem. Eur. J. 28, e202103669 (2022).

    Article  CAS  PubMed  Google Scholar 

  31. Bertoli, G. et al. C−H fluoromethoxylation of arenes by photoredox catalysis. Angew. Chem. Int. Ed. 62, e202215920 (2023).

    Article  CAS  Google Scholar 

  32. Holzgrabe, U. Quantitative NMR spectroscopy in pharmaceutical R&D. In eMagRes 45–56 (John Wiley & Sons, Ltd., 2015).

  33. Schoenberger, T. ENFSI Guideline for qNMR Analysis. Available at https://enfsi.eu/wp-content/uploads/2017/06/qNMR-Guideline_version001.pdf (2019).

  34. International Organization for Standardization. ISO 24583:2022 Available at https://www.iso.org/standard/78997.html (2022).

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. Dolbier, W. R. Jr. Guide to Fluorine NMR for Organic Chemists (John Wiley & Sons, Ltd., 2016).

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  PubMed  Google Scholar 

  39. O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 37, 308–319 (2008).

    Article  PubMed  Google Scholar 

  40. Mattes, A. O. et al. Application of 19F quantitative NMR to pharmaceutical analysis. Concepts Magn. Reson. Part A 45A, e21422 (2016).

    Article  Google Scholar 

  41. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Inoue, M., Sumii, Y. & Shibata, N. Contribution of organofluorine compounds to pharmaceuticals. ACS Omega 5, 10633–10640 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Campbell, M. G. & Ritter, T. Modern carbon–fluorine bond forming reactions for aryl fluoride synthesis. Chem. Rev. 115, 612–633 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Landelle, G., Bergeron, M., Turcotte-Savard, M.-O. & Paquin, J.-F. Synthetic approaches to monofluoroalkenes. Chem. Soc. Rev. 40, 2867–2908 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Umemoto, T. et al. Power- and structure-variable fluorinating agents. The N-fluoropyridinium salt system. J. Am. Chem. Soc. 112, 8563–8575 (1990).

    Article  CAS  Google Scholar 

  47. Watson, D. A. et al. Formation of ArF from LPdAr(F): catalytic conversion of aryl triflates to aryl fluorides. Science 325, 1661–1664 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. Molnár, I. G. & Gilmour, R. Catalytic difluorination of olefins. J. Am. Chem. Soc. 138, 5004–5007 (2016).

    Article  PubMed  Google Scholar 

  50. Prakash, G. K. S. & Yudin, A. K. Perfluoroalkylation with organosilicon reagents. Chem. Rev. 97, 757–786 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Tomashenko, O. A. & Grushin, V. V. Aromatic trifluoromethylation with metal complexes. Chem. Rev. 111, 4475–4521 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Cho, E. J. et al. The palladium-catalyzed trifluoromethylation of aryl chlorides. Science 328, 1679–1681 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Charpentier, J., Früh, N. & Togni, A. Electrophilic trifluoromethylation by use of hypervalent iodine reagents. Chem. Rev. 115, 650–682 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. 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).

    Article  CAS  Google Scholar 

  55. Hafner, A. & Bräse, S. Ortho-trifluoromethylation of functionalized aromatic triazenes. Angew. Chem. Int. Ed. 51, 3713–3715 (2012).

    Article  CAS  Google Scholar 

  56. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Britton, R. et al. Contemporary synthetic strategies in organofluorine chemistry. Nat. Rev. Methods Prim. 1, 1–22 (2021).

    Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  CAS  PubMed  Google Scholar 

  60. Dolbier, W. R. Fluorine chemistry at the millennium. J. Fluor. Chem. 126, 157–163 (2005).

    Article  CAS  Google Scholar 

  61. Wiesenfeldt, M. P. et al. General access to cubanes as benzene bioisosteres. Nature 618, 513–518 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Power, J. E. et al. Increasing the quantitative bandwidth of NMR measurements. Chem. Commun. 52, 2916–2919 (2016).

    Article  CAS  Google Scholar 

  63. 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).

    Article  Google Scholar 

  64. Jacobsen, N. E. NMR Spectroscopy Explained: Simplified Theory, Applications and Examples for Organic Chemistry and Structural Biology (Wiley, 2007).

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. Schoenberger, T., Monakhova, Y. B., Lachenmeier, D. W. & Kuballa, T. Guide to NMR Method Development and Validation – Part I: Identification and Quantification Available at https://eurolab-d.de/files/guide_to_nmr_method_development_and_validation_-_part_i_identification_and_quantification_may_2014.pdf (2014).

  67. Bloembergen, N., Purcell, E. M. & Pound, R. V. Relaxation effects in nuclear magnetic resonance absorption. Phys. Rev. 73, 679–712 (1948).

    Article  CAS  Google Scholar 

  68. Callaghan, P. T. Principles of Nuclear Magnetic Resonance Microscopy (Clarendon Press, 1993).

  69. Bloch, F. Nuclear induction. Phys. Rev. 70, 460–474 (1946).

    Article  CAS  Google Scholar 

  70. Bloembergen, N., Purcell, E. M. & Pound, R. V. Nuclear magnetic relaxation. Nature 160, 475–476 (1947).

    Article  CAS  PubMed  Google Scholar 

  71. 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).

    Article  CAS  Google Scholar 

  72. Bara-Estaún, A. et al. Paramagnetic relaxation agents for enhancing temporal resolution and sensitivity in multinuclear FlowNMR spectroscopy. Chem. Eur. J. 29, e202300215 (2023).

    Article  PubMed  Google Scholar 

  73. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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).

    Article  CAS  Google Scholar 

  75. Mestrelab Research. MestreNova Manual. Available at https://mnova.pl/files/download/MestReNova-12-0-0_Manual.pdf (2017).

  76. 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)

  77. Ernst, R. R. Sensitivity enhancement in magnetic resonance. In Advances in Magnetic and Optical Resonance Vol. 2 1–135 (Elsevier, 1966).

  78. 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).

    Article  CAS  Google Scholar 

  79. Guide to NMR method development and validation – part 1: identification and quantification. In Handbook of Transnational Economic Governance Regimes 1041–1053 (Brill | Nijhoff, 2010).

  80. 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).

    Article  CAS  PubMed  Google Scholar 

  81. Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherification of aryl halides. Acc. Chem. Res. 41, 1534–1544 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C–N cross-coupling reactions. Chem. Rev. 116, 12564–12649 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    Article  CAS  Google Scholar 

  84. 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).

    Article  CAS  PubMed  Google Scholar 

  85. Altman, R. A. & Buchwald, S. L. Pd-catalyzed Suzuki–Miyaura reactions of aryl halides using bulky biarylmonophosphine ligands. Nat. Protoc. 2, 3115–3121 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Armarego, W. L. F. & Chai, C. L. L. C. Purification of Laboratory Chemicals Edn. 5 (Butterworth-Heinemann, 2003).

  87. Leuven NMR Core. Excitation profileAvailable at https://nmrcore.chem.kuleuven.be/knowledgebase/excitation_profile.php (2022).

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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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  1. Faculty for Chemistry and Biochemistry, Ruhr-Universität Bochum, Bochum, Germany

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

  2. Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany

    M. P. Wiesenfeldt

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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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