9.3 Palladium Clusters Catalyse Cross-Coupling Reactions
145
9.3 Palladium Clusters Catalyse Cross-Coupling Reactions
As mentioned above, the development of Pd-catalyzed cross-coupling reactions
represents one of the most significant advancements in contemporary organic
synthesis, and these reactions are of strategic importance in the assembly of highly
functionalized organic molecules [63, 64]. These developments in chemistry have
increased the accessibility to molecules of great chemical complexity, particularly in
the area of pharmaceutical drug discovery and development. The Pd-catalyzed crosscoupling reactions are typically performed under homogenous conditions, utilizing
ligands to enhance activity and selectivity, and are extensively used in the assembly
of API. However, the process leads to residual metal that contaminates the reaction
product [65, 66]. This is particularly a major issue in pharmaceutical applications
where this chemistry is extensively used, since palladium compounds can be highly
toxic. Therefore, posttreatment coupled with the inability to recycle the platinum
group metal, as well as the ligand, results in a significant cost component in API
applications [4]. The development of supported catalysts that could reduce/eliminate
leaching and sintering, could enhance the performance, and that could be recycled,
would be a giant step in lowering the cost of the synthesis of chemicals and drugs.
Such a development could open a pathway to “Drugs when Needed”. Understanding
the factors controlling the different reaction steps in the supported catalysis including
the role of support in lowering the reaction barriers is the first step towards optimizing the catalysts. Such an understanding could also provide pathways to replace
Palladium by less expensive and more effective metals. Following we describe some
recent advances where joint experimental/theory efforts are providing new directions
towards these objectives.
Several problems including residual metal contamination are germane to the
homogeneous catalysts as the metal in solution is used to catalyze the reaction. One
way to overcome the limitation is then to perform the catalysis by particles bound to
supports so that they would prevent leaching of the catalyst into the solutions. These
have led to the evaluation of palladium metal clusters with a wide range of traditional
catalyst support systems employing a variety of synthetic techniques [65, 67–70].
However, several efforts in this area suggest that deposited Pd nanoparticles on solid
supports merely serve as a reservoir for active and small soluble Pd n species that
catalyse cross-coupling reactions via a leaching/redeposition mechanism [71–76].
For the few examples of supported Pd catalysts that attest to function via a heterogeneous pathway, the dispersity of metal nanoparticles appears to play a major role
in the mode of action.
It was recently discovered that palladium clusters/particles supported on reduced
graphene oxide could represent a high-performance heterogeneous catalyst. These
studies focused on a model Suzuki reaction using 4-bromobenzoic acid and phenylboronic acid as reagents. The reaction follows a three-step pathway of oxidative addition, trans-metalation and reductive elimination that could be recycled for multiple
times, indicative of overcoming the leaching and recyclability issues [77]. In these
145
9.3 Palladium Clusters Catalyse Cross-Coupling Reactions
As mentioned above, the development of Pd-catalyzed cross-coupling reactions
represents one of the most significant advancements in contemporary organic
synthesis, and these reactions are of strategic importance in the assembly of highly
functionalized organic molecules [63, 64]. These developments in chemistry have
increased the accessibility to molecules of great chemical complexity, particularly in
the area of pharmaceutical drug discovery and development. The Pd-catalyzed crosscoupling reactions are typically performed under homogenous conditions, utilizing
ligands to enhance activity and selectivity, and are extensively used in the assembly
of API. However, the process leads to residual metal that contaminates the reaction
product [65, 66]. This is particularly a major issue in pharmaceutical applications
where this chemistry is extensively used, since palladium compounds can be highly
toxic. Therefore, posttreatment coupled with the inability to recycle the platinum
group metal, as well as the ligand, results in a significant cost component in API
applications [4]. The development of supported catalysts that could reduce/eliminate
leaching and sintering, could enhance the performance, and that could be recycled,
would be a giant step in lowering the cost of the synthesis of chemicals and drugs.
Such a development could open a pathway to “Drugs when Needed”. Understanding
the factors controlling the different reaction steps in the supported catalysis including
the role of support in lowering the reaction barriers is the first step towards optimizing the catalysts. Such an understanding could also provide pathways to replace
Palladium by less expensive and more effective metals. Following we describe some
recent advances where joint experimental/theory efforts are providing new directions
towards these objectives.
Several problems including residual metal contamination are germane to the
homogeneous catalysts as the metal in solution is used to catalyze the reaction. One
way to overcome the limitation is then to perform the catalysis by particles bound to
supports so that they would prevent leaching of the catalyst into the solutions. These
have led to the evaluation of palladium metal clusters with a wide range of traditional
catalyst support systems employing a variety of synthetic techniques [65, 67–70].
However, several efforts in this area suggest that deposited Pd nanoparticles on solid
supports merely serve as a reservoir for active and small soluble Pd n species that
catalyse cross-coupling reactions via a leaching/redeposition mechanism [71–76].
For the few examples of supported Pd catalysts that attest to function via a heterogeneous pathway, the dispersity of metal nanoparticles appears to play a major role
in the mode of action.
It was recently discovered that palladium clusters/particles supported on reduced
graphene oxide could represent a high-performance heterogeneous catalyst. These
studies focused on a model Suzuki reaction using 4-bromobenzoic acid and phenylboronic acid as reagents. The reaction follows a three-step pathway of oxidative addition, trans-metalation and reductive elimination that could be recycled for multiple
times, indicative of overcoming the leaching and recyclability issues [77]. In these