Controlling and exploiting the caesium effect in palladium catalysed coupling reactions

Caesium bases are routinely used in several industrially relevant palladium-catalysed coupling reactions such as Suzuki-Miyaura and Buchwald-Hartwig amination, and regularly excel as the optimal base in published work. The mechanism by which caesium bases can improve yields and rates is not well understood, and this so called ‘caesium effect’ has anecdotally been attributed to factors such as increased solubility or the polarizability of the cation.
In this project, non-commercial caesium species have been synthesised and utilised in reaction monitoring studies to probe in which palladium-catalysed coupling reactions the ’caesium effect’ was present. Increased knowledge of the mechanism and magnitude of the effect will allow for better optimisation of these industrially relevant reaction classes.
Evidence is provided against the theory that solubility is the prevailing reason for increased reaction rate using caesium bases, and that a direct interaction of the caesium cation with the palladium catalyst is more likely, reducing the activation energy barrier of the rate limiting step resulting in higher rates in Buchwald-Hartwig amination and Suzuki cross couplings.
133Cs and 31P NMR monitoring experiments along with X-Ray diffraction techniques on palladium species provide evidence towards a potential Pd-Cs bimetallic intermediate in these reactions, corroborating previous DFT results in the literature which propose Pd-Cs intermediate and Cs stabilised transition states.
The utility of caesium phosphate monohydrate in Suzuki-Miyaura cross coupling reactions involving boronic acids liable to protodeboronation under reaction conditions is discussed, with the base proposed to be a viable alternative to existing methodologies of boronic acid protection and precatalyst activation. The use of caesium phosphate in base screens for these reactions provides a facile pathway for increased yields and negates the need for expensive catalyst or addition synthetic steps, which can be prohibitively expensive at process scale.