Computational Perspective on Pd-Catalyzed C–C Cross-Coupling Reaction Mechanisms

Abstract

Palladium-catalyzed C-C cross-coupling reactions (Suzuki-Miyaura, Negishi, Stille, Sonogashira, etc.) are among the most useful reactions in modern organic synthesis because of their wide scope and selectivity under mild conditions. The many steps involved and the availability of competing pathways with similar energy barriers cause the mechanism to be quite complicated. In addition, the short-lived intermediates are difficult to detect, making it challenging to fully characterize the mechanism of these reactions using purely experimental techniques. Therefore, computational chemistry has proven crucial for elucidating the mechanism and shaping our current understanding of these processes. This mechanistic elucidation provides an opportunity to further expand these reactions to new substrates and to refine the selectivity of these reactions. During the past decade, we have applied computational chemistry, mostly using density functional theory (DFT), to the study of the mechanism of C-C cross-coupling reactions. This Account summarizes the results of our work, as well as significant contributions from others. Apart from a few studies on the general features of the catalytic cycles that have highlighted the existence of manifold competing pathways, most studies have focused on a specific reaction step, leading to the analysis of the oxidative addition, transmetalation, and reductive elimination steps of these processes. In oxidative addition, computational studies have clarified the connection between coordination number and selectivity. For transmetalation, computation has increased the understanding of different issues for the various named reactions: the role of the base in the Suzuki-Miyaura cross-coupling, the factors distinguishing the cyclic and open mechanisms in the Stille reaction, the identity of the active intermediates in the Negishi cross-coupling, and the different mechanistic alternatives in the Sonogashira reaction. We have also studied the closely related direct arylation process and highlighted the role of an external base as proton abstractor. Finally, we have also rationalized the effect of ligand substitution on the reductive elimination process. Computational chemistry has improved our understanding of palladium-catalyzed cross-coupling processes, allowing us to identify the mechanistic complexity of these reactions and, in a few selected cases, to fully clarify their mechanisms. Modern computational tools can deal with systems of the size and complexity involved in cross-coupling and have a continuing role in solving specific problems in this field.

The activation strain model and molecular orbital theory: understanding and designing chemical reactions

“…This process involves cleaving the C-X bond and forming two new coordination bonds at the transition metal (TM), thus increasing its oxidation state by two units. 25 Two main mechanisms have been proposed for this fundamental reaction: (a) the concerted pathway, which involves the simultaneous formation of the TM-C and TM-X bonds in the transition state, and (b) an S N 2-type mechanism, where the central carbon atom is attacked by the transition metal expelling X À and forming a cationic species; subsequently, both charged species combine to yield the product (Scheme 2). 25 The difference between both reaction pathways is important since, similarly to the back-and frontside nucleophilic attack (see above), it corresponds to a change in stereochemistry at the carbon atom involved, namely, from retention of configuration for the concerted oxidative insertion (OxIn) to inversion of configuration for the S N 2 pathway.…”

Oxidative Addition to Palladium(0) Made Easy through Photoexcited‐State Metal Catalysis: Experiment and Computation

“…Next, radical clock and TEMPO trapping experiments were conducted to support the proposed light-mediated SET oxidative addition mechanism. Differently from the oxidative addition of aryl-halides within Mizoroki-Heck coupling, [14] the catalytically active Pd 0 -(PPh 3 ) 2 species J is reluctant to undergo oxidative addition of the alkyl-bromide 2c,b ecause of the very high energy barrier required to reach transition state J-K (DG°= 41.6 kcal mol À1 ,F igure S1 in the Supporting Information). [10] Further,t oexclude the possibility of aradical chain process,light on-off experiments were carried out.…”

Fabrication of PEI grafted Fe3O4/SiO2/P(GMA-co-EGDMA) nanoparticle anchored palladium nanocatalyst and its application in Sonogashira cross-coupling reactions

“…Generally, the cross-coupling reaction between aryl halides and alkene halides or terminal alkyne catalyzed by palladium complexes is named Sonogashira cross-coupling reaction, and it is the effective reaction to synthesis aryne, eneyne and acetyenic ketone [1][2][3][4][5]. The general equation of the reaction has been shown as below: The cross-coupling reaction between aryl halides and alkenes or terminal alkynes catalyzed by palladium complexes had undergone such a period that Cassar firstly discovered it, then Heck and Sonogashira et al modified it subsequently.…”