Transition-State Stabilization by Secondary Orbital Interactions between Fluoroalkyl Ligands and Palladium During Reductive Elimination from Palladium(aryl)(fluoroalkyl) Complexes

Palladium-catalyzed fluoroalkylations
of aryl halides
are valuable
reactions for the synthesis of fluorinated, biologically active molecules.
Reductive elimination from an intermediate Pd(aryl)(fluoroalkyl) complex
is the step that forms the C(aryl)–C(fluoroalkyl) bond, and
this step typically requires higher temperatures and proceeds with
slower rates than the reductive elimination of nonfluorinated alkylarenes
from the analogous Pd(aryl)(alkyl) complexes. The experimental rates
of this step correlate poorly with common parameters, such as the
steric property or the electron-withdrawing ability of the fluoroalkyl
ligand, making the prediction of rates and the rational design of
Pd-catalyzed fluoroalkylations difficult. Therefore, a systematic
study of the features of fluoroalkyl ligands that affect the barrier
to this key step, including steric properties, electron-withdrawing
properties, and secondary interactions, is necessary for the future
development of fluoroalkylation reactions that occur under milder
conditions and that tolerate additional types of fluoroalkyl reagents.
We report computational studies of the effect of the fluoroalkyl (RF) ligand on the barriers to reductive elimination from Pd(aryl)(RF) complexes (RF = CF2CN, CF2C(O)Me, etc.) containing the bidentate ligand di-tert-butyl(2-methoxyphenyl)phosphine (L). The computed Gibbs
free-energy barriers to reductive elimination from these complexes
suggest that fluoroalkylarenes should form quickly at room temperature
for the fluoroalkyl ligands we studied, excluding RF =
CF3, CF2Me, C2F5, CF2CFMe2, CF2Et, CF2iPr, or CF2tBu. Analyses of
the transition-state structures by natural bond orbital (NBO) and
independent gradient model (IGMH) approaches reveal that orbital interactions
between the Pd center and a hydrogen atom or π-acid bonded to
the α-carbon atom of the RF ligand stabilize the
lowest-energy transition states of Pd(aryl)(RF) complexes.
Comparisons between conformers of transition-state structures suggest
that the magnitude of such stabilizations is 4.7–9.9 kcal/mol.
In the absence of these secondary orbital interactions, a more electron-withdrawing
fluoroalkyl ligand leads to a higher barrier to reductive elimination
than a less electron-withdrawing fluoroalkyl ligand. Computations
on the reductive elimination from complexes containing para-substituted aryl groups on palladium reveal that the barriers to
reductive elimination from complexes containing more electron-rich
aryl ligands tend to be lower than those to reductive elimination
from complexes containing less electron-rich aryl ligands when the
fluoroalkyl ligands of these complexes can engage in secondary orbital
interactions with the metal center. However, the computed barriers
to reductive elimination do not depend on the electronic properties
of the aryl ligand when the fluoroalkyl ligands do not engage in secondary
orbital interactions with the metal center.