Buchwald-Hartwig Amination - Base Effect

30 August 2005

The reaction of arylhalides with amines under palladium catalysis (Buchwald-Hartwig amination) has established itself as the most important C-N bond forming reaction. The improvement in the catalysts and ligands allows the use of weaker bases than the traditional butoxide, which gives more functional group compatibility. If weak bases such as carbonates are used in the reaction, deprotonation of the Pd(II)-amine intermediate in the catalytic cycle often becomes rate limiting. Surprisingly, in the reactions of amines with iodides in toluene use of 5 equivalents of caesium carbonate gives faster reactions than 2 equivalents, even though the carbonate is virtually insoluble in the toluene. The reaction rate is also sensitive to the supplier of caesium carbonate. Acros material (99.5% pure) contains uniformly “bulbed” particles when examined by electron microscopy whereas Aldrich material (99%) showed rough, irregularly shaped particles with a broad size distribution containing many small
particles. The Aldrich material gave a very much faster reaction (approx 4 times faster).

These differences were shown to be due to the particle size/shape difference and not to the fact that the Aldrich material picks up more water during its handling (caesium carbonate is quite hygroscopic). Thus grinding the caesium carbonate to give smaller particles leads to an increased rate of reaction. (Meyers C et al, J Org Chem, 2004, 69, 6011). On scale up, it is likely that good mixing will be crucial and that the reaction may be mass-transfer limited.