The Pd-catalyzed amination of aryl halides (Buchwald-Hartwig amination) has
become a versatile and widely used technology to synthesize and produce aromatic
amines relevant in pharmaceutical and agrochemical industries. The aim of the work
presented in this thesis is to achieve a better mechanistic understanding of this
reaction. The methodologies used were not traditional and focused on kinetic
studies, carried out using in-situ tools, mainly reaction calorimetry.
Reactions using different amines have been considered: the kinetic behaviour of a
straight-chain primary amine (n-hexylamine) was found to be very different from the
kinetics of benzophenone hydrazone. This difference was rationalised by considering
the mechanism and by proposing a change in the rate-limiting step. Spectroscopic
studies, aimed at determining the catalyst resting state, supported our proposals.
We subsequently started studies on the competitive system of two amines and one
aryl halide. We found that, surprisingly, the less reactive amine, when in competition,
reacted first. This intriguing behaviour was rationalised by considering the Curtin-
Hammett principle and by recognizing that in this case selectivity was controlled by
relative stability of intermediates, not relative reactivity. This was termed
“monopolizing” regime, in contrast to the “major-minor” regime in which the minor
but more reactive intermediate produces the major product.
Subsequent studies revealed that the benzophenone hydrazone product also binds to the Pd/BINAP catalyst, and, during the hexylamine reaction, inhibits the rate and
induces a change in the rate limiting step and catalyst resting state.
Reactions using benzophenone imine were then studied. The competitive system of
benzophenone imine and benzophenone hydrazone provided an example of a
system showing a change from the “monopolizing regime” to the “major-minor”
regime.
These concepts can be generalized and applied to explain selectivity in other
competitive catalytic systems.