Abstract
FlowNMR has previously been shown as a useful reaction monitoring technique to collect kinetic and mechanistic data beyond initial rates and stoichiometric experiments under forcing conditions. However, there is still room to develop this technique by designing methods to monitor reactions that are not homogeneous and by multiple NMR active nuclei. This thesis shows how FlowNMR can be utilised to monitor multiple NMR active nuclei in one experiment on both homogeneous and biphasic solvent mixtures. This is demonstrated for two different mechanistic studies. The first is a Suzuki-Miyaura Cross Coupling of 3-chloropyridine and phenylboronic acid in a biphasic n-butanol/H2O solvent mixture with a Pd(OAc)2/XPhos catalyst system. The second mechanistic study involved the investigation of the photochemical oxidation of N-allylbenzylamine, catalysed by Eosin Y with the requirement of sustained light and air.The development of methodology to flow biphasic organic/aqueous systems is discussed including its challenges and the practical changes that are required to ensure that biphasic reactions can be sampled so that reaction conditions in the flask do not change and the sample is adequate to achieve high quality NMR spectra. This required the modification of an InsightMR Flow tube (Bruker) that could withstand the pressures required to flow viscous biphasic solvents.
Optimisation of NMR parameters for 1H, 11B, 13C and 31P NMR is discussed in Chapter 3 so that acquisition of NMR spectra is maximised for signal-per-time. This was achieved using a Design of Experiments approach to statistically calculate and visualise the interplay between factors that were tested for their impact on signal intensity. For 31P NMR, investigation into the different experiment types that may improve signal-per-time was also investigated. Lastly, quantification of 31P NMR, and therefore other long T1 nuclei, in flow was studied to improve the time efficiency of collecting calibration spectra which can require multiple hours to collect.
The biphasic and multinuclear FlowNMR methods were then utilised on a mechanistic study of a Suzuki-Miyaura Cross Coupling of 3-chloropyridine and phenylboronic acid. The mode of catalyst activation (Pd(OAc)2 and XPhos) under both stoichiometric and catalytic conditions was investigated to determine how pre-catalyst activation occurred and its effectiveness. The impact of each reagent was investigated, and knowledge used to determine an optimised order of reagent addition that could increase the efficiency of pre-catalyst activation and allow loading of both catalyst and hydroxide base to be reduced.
The mechanistic study unveiled that pre-catalyst activation occurred via sacrificial reduction of the XPhos ligand and was inefficient under catalytic conditions due to the competing reaction between Pd(OAc)2 and 3-chloropyridine. Multiple intermediates were detected under catalytic conditions, including Pd0(XPhos)2, XPhosPdII(pyr)Cl, XPhosPdII(pyr)(OH), and their identity and relevance to turnover confirmed using a combination of stoichiometric and on-line NMR experiments. Reaction success was also impacted by boronic acid speciation in-situ, requiring careful experimental design to ensure that unreactive variants, such as trihydroxy boronates or boronic esters, do not form. The order of reagent addition was found to be divisive to reaction success and so is recommended to be controlled when investigating new palladium catalysed reactions.
Finally, the photochemical oxidation of N-allylbenzylamine was investigated using FlowNMR in the presence of sustained light. This uncovered the pathway to formation of the primary product imines, but also the undesired aldehyde side products that were formed after extended periods of time. Utilising FlowNMR enabled the reaction to be monitored under conditions identical to the bench and probe the action of different reagents in the reaction including O2, H2O and light.
| Date of Award | 29 Mar 2023 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Sponsors | AstraZeneca UK Ltd |
| Supervisor | Uli Hintermair (Supervisor) & John Lowe (Supervisor) |
Cite this
- Standard