Kinetics and mechanism of phase-transfer catalysed fluorination

Abstract

Phase-transfer catalysis (PTC) enormously enhances the reaction rate between reagents located in immiscible phases. The main advantages of PTC are mild reaction conditions, inexpensive reagents, and simple work-up, which lead to the possibility of large-scale production, and make PTC appealing to industrial applications. However, due to the inherent challenges associated with monitoring a heterogeneous system in situ, there is a lack of mechanistic investigation on PTC and most of the efficient phase-transfer catalysts have been developed by trial and error, which restricts their applications. To address this, a plunger-based in-situ mixing device has been designed and developed, which is portable and can be easily adapted to any NMR spectrometer to enable in-situ reaction monitoring of heterogeneous reaction that requires agitation. The effect of key parameters, such as plunger type, mixing speed and settling time on the mixing efficiency and spectral resolution was explored to guide the selection of optimum settings. The robustness of this system was demonstrated by measuring the kinetics for a range of reactions and comparison of these with that obtained by conventional ex-situ monitoring method.

The reaction mechanism of a novel phase-transfer catalysed asymmetric nucleophilic fluorination developed by the Gouverneur group in 2018 has then been investigated using extensive reaction monitoring by both in-situ and ex-situ 19F NMR spectroscopy followed by kinetic modelling. Formation of substrate-alkylated catalyst was identified and supported by degradation experiment and ESI-MS. Its catalytic activity varied between catalysts. Two pathways of fluorine delivery were identified, and incorporation of both was essential to correctly simulate the reaction evolution from low to high catalyst loadings. The rate of ionisation of substrate, β-bromosulfide, was measured by magnetisation transfer, and both catalysts were found to accelerate this process by more than two orders of magnitude. The fluorination of β-chloramine was enabled by the same type of catalyst. Its mechanism has been explored using similar approaches and compared with that of β-bromosulfide. In this case, the formation of substrate-alkylated catalyst was much less pronounced, the catalysts had negligible effects on the rate of ionisation of substrate, and a simpler catalytic cycle has been proposed. Understanding these fluorinations provides useful insights for further optimisation of catalysts and mechanistic studies of similar reactions. Furthermore, the development of the mixing device will promote mechanistic investigations of PTC reactions in general.