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Maschmeyer-Tombs, Tristan

University of British Columbia

The ability to quantitatively monitor chemical species through a reaction allows for insight to enhance process efficiency and/or safety. Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical technique, known for the ability to provide structural and quantitative data in a non-destructive manner. There has been significant growth in the development and availability of benchtop NMR spectrometers in the last decade. The use of permanent magnets result in smaller applied magnetic fields, a decrease in sensitivity and signal dispersion, but a more compact size and affordable cost. Particularly, benchtop NMR can allow for the powerful analytical capabilities associated with NMR spectroscopy to enter non-traditional settings, such as a synthetic laboratory. Therefore, this thesis focuses on leveraging these systems for reaction monitoring. First, an on-line continuous-flow benchtop NMR system is explored. Particular attention is given to the impact of flow on the mixing behaviour of analyte within the flow cell, mixing/emptying behaviour, the spin-lattice relaxation time, and sensitivity of data measurement with two sets of acquisition parameters. The complex nature of continuous-flow analyses prompted the development and application of an on-line stopped-flow benchtop NMR system, with all hardware centrally controlled with a Python script. The utility of this system was showcased using difficult to monitor model reaction systems. These reactions include activation of a carboxylic acid with sulfuryl fluoride (SO₂F₂) and carbamate formation as a result of an alcohol reacting with an isocyanate resultant from a modified Curtius rearrangement. An external calibration quantitative NMR (qNMR) method is further highlighted, allowing for robust qNMR analyses without an internal standard or special hardware. The utility of the qNMR method is demonstrated by monitoring all synthetic steps of a highly relevant chemical transformation to the pharmaceutical industry: 1,1’-carbonyldiimidazole (CDI) mediated amide coupling. Lastly, on-line stopped- and continuous-flow benchtop NMR systems were compared for reaction monitoring, using two model reactions: a homogenous imination reaction and the activation of a carboxylic acid using perfluorobutanesulfonyl fluoride (PBSF). The on-line stopped-flow benchtop NMR system resulted in more robust quantitative analyses and, therefore, more easily achievable mechanistic information.

Text

2023-12-18

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86975

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/