Quantitative benchtop 19F NMR spectroscopy: a robust and economical tool for rapid reaction optimization

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 (GC), high-performance liquid chromatography (HPLC), or quantitative nuclear magnetic resonance (qNMR) spectroscopy on high-field spectrometers. However, chromatographic methods require elaborate work-up and calibration protocols, while high-field NMR spectrometers are expensive to purchase and operate. We herein disclose 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 which, due to the wide chemical shift range and high sensitivity of 19F, enables 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, non-invasive measurement of crude reaction mixtures with minimal work-up. The low field-strength allows a homogeneous excitation over a wide chemical shift range, minimizing systematic integration errors. The addition of the correct amount of the non-shifting relaxation agent Fe(acac)3 minimizes relaxation delays at full resolution, reducing the analysis time to 32 seconds per sample. The correct choice of processing parameters is also crucial. A step-by-step guideline is provided, the influence of all parameters 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 functionalization reaction.