Mechanistic Aspects of the Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction

Abstract

The story of C-C bond formation includes several reactions, and surely Suzuki-Miyaura is among the most outstanding ones. Herein, a brief historical overview of insights regarding the reaction mechanism is provided. In particular, the formation of the catalytically active species is probably the main concern, thus the preactivation is in competition with, or even assumes the role of the rate determining step (rds) of the overall reaction. Computational chemistry is key in identifying the rds and thus leading to milder conditions on an experimental level by means of predictive catalysis.

Keywords: Cross coupling; C−C bond formation; DFT; Suzuki-Miyaura; palladium; preactivation.

Scheme 1

General scheme for C−C cross‐coupling reactions.

Scheme 2

Ullmann and Kharasch C−C bond formation achievements.

Scheme 3

Highlighted C−C cross‐coupling reactions, catalysed by Pd, presented in chronological order of discovery.

Scheme 4

Highlighted C‐Het cross‐coupling reactions catalysed with Pd presented in chronological order of discoveries.

Figure 1

Timeline of the discovery and development of metal‐catalysed cross‐coupling reactions. Figure extracted from reference [4].

Figure 2

Increase of the cross‐coupling reports over the decades leading up to 2020 (source: Web of Science).

Scheme 5

General scheme for the palladium catalysed Suzuki‐Miyaura cross‐coupling reaction.

Scheme 6

Types of pre‐catalysts bearing novel, electron‐donating and bulky phosphine and NHC ligands.

Scheme 7

The main, well‐defined Pd precatalysts with a 1 : 1 Pd to ligand ratio.

Scheme 8

Two different mechanisms of activation for Nolan's π‐allyl precatalysts.

Figure 3

Computed stationary points of the activation mechanism for the studied precatalyst [Pd]‐Cl‐1−4 series ([Pd]‐Cl‐4, R₁=R₂=H; [Pd]‐Cl‐2, R₁=H, R₂=Me; [Pd]‐Cl‐3, R₁=R₂=Me; [Pd]‐Cl‐4, R₁=H, R₂=Ph). Relative Gibbs energies are given in kcal/mol. Figure extracted from Ref. [94].

Scheme 9

General catalytic cycle for Pd‐catalysed Suzuki‐Miyaura C−C cross‐coupling reaction.

Scheme 10

General equation for the oxidative addition step.

Scheme 11

Plausible pathways of the oxidative addition step.

Scheme 12

General equation for the transmetalation step.

Scheme 13

Plausible pathways of the transmetalation step: pathway A and pathway B.

Scheme 14

Mechanism for the reductive elimination step.

Scheme 15

Resonance stabilization of amides.

Scheme 16

Proposed C−N activation of amides.

Figure 4

Free energy profile (in kcal/mol) of the overall catalytic cycle of the SMC of amides in THF as referred to Pd⁰(NHC), NHC=IPr (in black) and IPr* (in red). Figure extracted from Ref. [151].