28 Palladium in Heterocyclic Chemistry
Mechanisms of palladium(0)-catalysed processes
None of the palladium(0)-catalysed transformations, exemplifi ed above, are single-step processes but all involve three-
step catalytic cycles, with changes in the oxidation state of the metal. Each starts with the reaction of Pd(0) with a halide
(trifl ate) and fi nishes with the expulsion of Pd(0), allowing the cycle to continue. Note: the metal in species ArPdX and
ArPdR is at the oxidation level of Pd(II).
In the scheme below, all palladium compounds are in a variable state of coordination with phosphines or other ligands,
which are not shown for the sake of clarity.
Note: The intermediate arylpalladium halides (Ar-Pd-Hal), despite an apparent resemblance to Grignard reagents, are
generally fairly stable to air and water and do not react with electrophiles.
Individual steps in the cross-coupling mechanism
Although some seem similar to classical nucleophile/electrophile interactions, the steps shown below are generally
concerted cyclic processes. Some reactions with simple nucleophiles in the transmetallation step can be regarded as
classical in nature, although those of the standard organometallics (boron, tin, etc.) are concerted.
Theoxidative addition of Pd(0) to the halide is the basis and starting point for all these reactions and as such, is the
most important single palladium reaction in organic chemistry. Pd(0) has some nucleophilic character but inserts into
the carbon–halogen bond directly, rather than via an addition–elimination attack at carbon. However, the reaction can
be promoted by similar factors to those that favour nucleophilic substitution, for example, the reactivity of Pd(0) can
be increased by electron-rich ligands, which increase the electron density on the metal.
Thetransmetallation step involves transfer of the organic residue from the organometallic reactant, RM, to palladium.
It can be regarded conveniently as equivalent to a nucleophilic displacement of the halide from Pd. Organometallic
reagents, such as Grignards and zinc compounds can be used but the conventionally ‘less reactive’ boron and tin com-
pounds are best. Acetylenes (Sonogashira reaction) react via an organocopper compound formed in situ. For boronic
acids, a nucleophile such as hydroxide is required to generate a tetrahedral boronate, which is the species involved in
transmetallation. The equivalent step with covalent derivatives of heteronucleophiles, for example R 3 SnNR 2 , probably
involves a similar mechanism to tin reagents in the Stille reaction. However, the base-catalysed reaction with free amines
occurs via a simple coordination to the palladium (much as for coordination of a simple ligand such as a phosphine),
followed by reaction with base to eliminate HX.