Immobilized Transition Metals as Catalysts for Cross-Couplings in Continuous Flow-A Critical Assessment of the Reaction Mechanism and Metal Leaching

In the not too distant future many industrially important chemicals (including pharmaceuticals) will probably be manufactured using continuous flow technology. For a significant number of synthetic steps involved in these protocols transition metal (mostly palladium)-catalyzed carbon-carbon or carbon-heteroatom bond forming reactions ( cross-coupling chemistry) will play an important role. Designing a process for continuous cross-coupling chemistry involves either the use of a homogeneous or of a heterogeneous (immobilized) catalyst/ligand system. In the latter case, the catalyst/ligand system is typically in the form of a packed-bed reactor, through which the reaction mixture is pumped, employing an appropriate temperature regime and residence time. Although this approach has been widely popular during the past 15 years, there is growing evidence that suggests that the use of immobilized transition metal catalysts for performing cross-coupling chemistry in continuous flow is, in fact, not very practical. As demonstrated in this review, significant leaching of the transition metal out of the packed-bed catalyst will almost inevitably occur, leading to decreased catalyst activity and contamination of the product with transition metal. This is a consequence of the well-known fact that the reaction mechanism for these kinds of transformations is (quasi) homogeneous and involves the transformation of a Pd-0 species into a (soluble) Pd-II species. Using an immobilized catalyst in a batch protocol the transient leaching of palladium will not be immediately obvious, as, after completion of the catalytic cycle, Pd0 will typically redeposit onto the support. In contrast, in continuous flow mode, the palladium metal will progressively be chromatographed through the packed-bed catalyst until, ultimately, all palladium will be removed from the support. This effect typically will become only evident when long run experiments are performed. The preferred alternative, in particular for larger scale experiments, is to use a homogeneous (pre) catalyst in combination with an appropriate catalyst recycling technology.