Palladium Catalyzed Reactions

Introduction:

Palladium-catalyzed cross-coupling reactions are synthetically important C-C and C-N bond forming processes that have found large number of applications in academia and industry. Since the dawn of Wackers process for the synthesis of acetaldehyde from ethylene, palladium catalysis has rapidly undergone a change with the advent of cross-coupling reactions which were introduced as early as 1970s.

The cross-coupling reactions can be commonly defined as the coupling between two different substrates with one acting as an electrophilic centre and other acting as nucleophilic centre. Electrophilic coupling partners could be anything ranging from aryl, alkenyl, alkyl, alkynyl, vinyl halides (tosylates, mesylates etc.). Nucleophlic reagents commonly are classified as organometallic reagents with aryl, alkenyl, alkynyl metal reagents. Depending on the type of organometallic reagents employed variety of cross-coupling reactions are known in literature. (For further details see: cross-coupling)

Given below are the different cross-coupling reactions that are known and have found wide-spread applications.

a) Kumada coupling (1972): Organomagnesium reagents as nucleophilic partners.

b) Heck alkenylation reaction (1972): Alkenes as carbon-based nucleophiles

c) Sonogashira coupling (1975): Alkynes as carbon-based nucleophiles

d) Negishi coupling (1977): Organozinc reagents as nucleophilic partners

e) Stille coupling (1978): Organotin reagents as nucleophilic partners

f) Suzuki coupling (1979): Organoboron reagents as nucleophilic partners

g) Hiyama coupling (1988): Organosilicon reagents as nucleophilic reagents

h) Buchwald-Hartwig amination (1994): Amines as nucleophilic reagents

The importance of the palladium-catalyzed cross-coupling was further recognized by a Nobel prize being awarded to Prof. Eichi Negishi, Prof. Akira Suzuki and Prof. Richard Heck reaction in 2010 (for further details see: 2010 Nobel prize winners). A general schematic about the coupling processes showing their importance in synthesis has been given below. 

This rapid growth in palladium-catalyzed cross-coupling processes could be directly associated with the development of efficient catalytic systems made possible through the incorporation of highly electron-rich and sterically hindered phosphines and N-Heterocyclic carbenes as ligands. Electron-rich nature of these ligands enhances the nucleophilicity at the palladium centre, thus allowing insertion into the less reactive C-Cl or sometimes C-F bonds. Buchwald ligands with large steric hindrance has been a cornerstone in researchers quest to develop such systems. 

Mechanisms for palladium-catalyzed cross-coupling processes:

Palladium-catalyzed coupling processes are commonly performed using air-stable Pd(II) sources such as Pd(OAc)2 or PdCl2 in combination with electron-rich ligand systems. Most of the cross-coupling processes would be initiated in this form with the consequent reduction to Pd(0) by the organometallic reagents. Although, such a proposal remained unsupported for years, recent work by researchers providing evidence in the form of x-ray single crystal characterization of the intermediates has given an insight into this process (see the following link for more information).

The formation of Pd(0) species (could also be achieved by using a Pd(0) source such as Pd(PPh3)4 which undergoes ligand dissociation or Pd2dba3 with ligands) in solution also known as the catalytically active species sets the stage for the catalytic coupling process to be performed. Pd(0) with d10 electronic configuration would be nucleophilic enough to attack the electrophilic partner (R-X) resulting into an oxidative insertion between the C-X (X = halogens, OTf, OMs etc. as leaving groups) with the process called as Oxidative addition. In most cases, the geometry around the palladium centre in the oxidative addition product is trans (both R and X groups are present on the opposite sides), however certain cases it remains on the same side (cis). In this process the oxidation of Pd(0) has taken place to Pd(II).

Organometallic reagent (R'-M) acting as the nucleophlic coupling partner then undergoes what is known as the Transmetallation process (Pd and the other metal present in the organometallic reagent) leading to the replacement of leaving group X with R'. If the orientation of the R and R' groups are anti (trans) with respect to each other then is some cases a cis/trans isomerization step takes place aligning the two groups close together allowing the formation of the C-C bond. This finally undergoes a reductive elimination step (where Pd(II) is reduced back to Pd(0)) eliminating the  product and regenerating Pd(0) in the process.