Mechanism of Palladium-Catalyzed Alkylation of Aryl Halides with Alkyl Halides through C–H Activation: A Computational Study

Pd-catalyzed
C­(sp3)–H activation/alkylation of
2-tert-butylaryl halides with alkyl halides and CH2Br2 represents an advantageous strategy for the
C–H functionalization with halogens as traceless directing
groups. Several possible mechanisms were proposed for the reactions,
but no further evidence was available to judge their relative feasibilities.
Herein, a mechanistic study was performed with the aid of density
functional theory (DFT) methods. Calculations indicate that the coupling
of aryl bromides with alkyl chlorides is likely to generate alkylated
benzocyclobutenes via aryl–Br oxidative addition on Pd(0) catalysts,
C­(sp3)–H activation, alkyl–Cl oxidative addition,
aryl–alkyl reductive elimination, aryl–H activation,
and aryl–C­(sp3) reductive elimination. The coupling
of aryl iodides with CH2Br2 is likely to
generate indane derivatives via aryl–I oxidative addition,
C­(sp3)–H activation, alkyl–Br oxidative addition,
aryl–CH2Br reductive elimination, alkyl–Br
oxidative addition, C­(sp3)–alkyl reductive elimination,
and reduction of palladium dibromide complexes by amines. By comparison,
the metathesis of alkyl chlorides on Pd­(II) intermediates and the
pathway involving palladium carbene intermediates are found to be
less favored. Meanwhile, the coordination of in situ generated salts KI, KBr, and KHCO3 to palladium complexes,
which has been less considered in previous mechanistic studies, is
found to lead to more energetically favored pathways in most of the
steps. Finally, the oxidative addition of alkyl halides generating
Pd­(IV) intermediates or the reduction of palladium dibromide complexes
by amines, rather than the previously proposed C­(sp3)–H
activation, is found to be the rate-determining step in the two types
of coupling reactions. This result does not go against the reported
primary kinetic isotope effect (KIE) based on intramolecular competition
reactions because the C­(sp3)–H activation is irreversible
according to our calculations.