Mechanistic Study of the Role of Substrate Steric Effects and Aniline Inhibition on the Bis(trineopentylphosphine)palladium(0)-Catalyzed Arylation of Aniline Derivatives

The mechanism of
the bis­(trineopentylphosphine)­palladium(0) (Pd­(PNp3)2)-catalyzed coupling of aryl halides and aniline
derivatives was studied in an effort to understand the role of substrate
steric effects on the reaction. Prior studies had shown that the rate
of Pd/PNp3-catalyzed coupling of aryl bromides and aniline
derivatives was largely unaffected by substrate steric demand. The
oxidative addition of aryl bromides to Pd­(PNp3)2 is found to follow first-order kinetics with a rate that is independent
of both ligand and aryl halide concentration. Thus, the rate limiting
step for oxidative addition of aryl bromides is irreversible ligand
dissociation. In the case of aryl chlorides, the oxidative addition
rate has a first-order dependence on [ArCl] and an inverse dependence
on [PNp3], indicating a mechanism involving reversible
dissociation of the ligand followed by rate limiting oxidative addition.
This difference in aryl halide effect was also found for the catalytic
coupling reaction. Aryl bromide steric demand does not affect the
coupling rate with hindered anilines, whereas the coupling rate of
aryl chlorides is negatively affected by substrate steric demand.
These results suggest that oxidative addition is rate limiting in
the catalytic reaction for aryl chlorides but that oxidative addition
is not rate limiting for aryl bromides. Aniline was found to give
coupling rates significantly slower than those of 2,6-diisopropylaniline
for both aryl bromides and chlorides. Aniline promotes the decomposition
of the [(PNp3)­Pd­(Ar)­(μ-X)]2 catalytic
intermediate to a catalytically inactive palladacycle ([(κ2-P,C-Np2PCH2C­(Me2)­CH2)­Pd­(μ-X)]2) through C–H activation of a neopentyl group and elimination
of arene. These studies show that the ability of the Pd/PNp3 catalyst system to tolerate steric demand in aryl bromides stems
from the fact that the rate limiting step of the catalytic cycle is
independent of the concentration and steric demand of aryl bromides.
A catalyst deactivation pathway involving ligand metalation was identified
that is promoted by unhindered aniline derivatives.