A systematic theoretical study is carried out on the mechanism for Pd(II)-catalyzed oxidative cross-coupling between electron-deficient arenes and alkenes. Two types of reaction pathways involving either a sequence of initial arene C-H activation followed by alkene activation, or the reverse sequence of initial alkene C-H activation followed by arene activation are evaluated. Several types of C-H activation mechanisms are discussed including oxidative addition, σ-bond metathesis, concerted metalation/deprotonation, and Heck-type alkene insertion. It is proposed that the most favored reaction pathway should involve an initial concerted metalation/deprotonation step for arene C-H activation by (L)Pd(OAc)(2) (L denotes pyridine type ancillary ligand) to generate a (L)(HOAc)Pd(II)-aryl intermediate, followed by substitution of the ancillary pyridine ligand by alkene substrate and direct insertion of alkene double bond into Pd(II)-aryl bond. The rate- and regio-determining step of the catalytic cycle is concerted metalation/deprotonation of arene C-H bond featuring a six-membered ring transition state. Other mechanism alternatives possess much higher activation barriers, and thus are kinetically less competitive. Possible competing homocoupling pathways have also been shown to be kinetically unfavorable. On the basis of the proposed reaction pathway, the regioselectivity predicted for a number of monosubstituted benzenes is in excellent agreement with experimental observations, thus, lending further support for our proposed mechanism. Additionally, the origins of the regioselectivity of C-H bond activation is elucidated to be caused by a major steric repulsion effect of the ancillary pyridine type ligand with ligands on palladium center and a minor electronic effect of the preinstalled substituent on the benzene ring on the cleaving C-H bond. This would finally lead to the formation of a mixture of meta and para C-H activation products with meta products dominating while no ortho products were detected. Finally, the multiple roles of the ancillary pyridine type ligand have been discussed. These insights are valuable for our understanding and further development of more efficient and selective transition metal-catalyzed oxidative C-H/C-H coupling reactions.

The density functional theory method augmented with the CPCM solvation model was used to study the mechanism of Cu(I)-catalyzed aryl amidation. On the basis of the comparison of multiple reaction pathways, it was determined that diamine-ligated copper(I) amidate was the most reactive intermediate in the reaction mixture for the oxidative addition to aryl halide. Cationic diamine-ligated Cu(I) was calculated to have a lower free energy barrier for oxidative addition, but its concentration in the reaction mixture was too low to represent a useful catalyst. On the other hand, multiple ligation of the amide to Cu(I) at low diamine concentration led to the least reactive intermediate and, thereby, retarded the oxidative addition. Further calculations showed that oxidative addition was the rate-limiting step in Cu-catalyzed aryl amidation. Unlike the transformation from Pd(0) to Pd(II), the Cu(I) → Cu(III) oxidative addition product was pentacoordinated and, thereby, more sensitive to the steric hindrance. A major portion of the overall energy barrier in the oxidative addition to Cu(I) was contributed by the highly unfavorable formation of a 2η complex between copper(I) amidate and aryl halide. Reductive elimination occurred through a square pyramidal structure from the pentacoordinated Cu(III) intermediate. Reductive elimination was a very facile step as compared to oxidative addition. Furthermore, our calculation indicated that trans-N,N‘-dimethylcyclohexane-1,2-diamine was an excellent ligand for Cu-catalyzed aryl amidation, whereas TMEDA was almost completely inactive. These theoretical results were in good agreement with experimental observations, suggesting the possibility of using a combined theoretical and experimental approach to rationally improve Cu(I)-catalyzed cross-coupling reactions.

Pd-catalyzed decarboxylative cross-coupling of aryl iodides, bromides, and chlorides with potassium oxalate monoesters has been discovered. This reaction is potentially useful for laboratory-scale synthesis of aryl and alkenyl esters. Bulky, electron-rich bidentate phosphine ligands are preferred in the reaction, whereas Cu is not needed for decarboxylation. Theoretical calculations suggest a five-coordinate Pd(II) transition state for decarboxylation with an energy barrier of approximately 30 kcal/mol.