Cross-Coupling Chemistry in Continuous Flow - New Trends in Cross-Coupling: Theory and Applications - page 613

13.3 Catalytic Systems for Cross-Coupling
in Continuous Flow
13.3.1 Heterogeneous Supported Catalysts
A large number of the cross-coupling reactions that have been performed
under continuous flow conditions have utilized immobilized palladium
sources. 3,10 It has been generally stated that the use of immobilized pal-
ladium allows for facile recuperation and reuse of the catalyst source. Such
immobilized catalysts are often loaded in a micro packed-bed reactor over
which the reagents are directed. Owing to the large quantities of catalyst
available in the packed bed, short reaction times are observed for a wide
array of cross-coupling reactions. These apparent advantages have led to the
development of solid supports (Table 13.2) on which catalysts can be im-
mobilized via covalent bonding of the ligand or physical absorption of the
metal. 11-14 One of the main drawbacks of a micro packed-bed reactor is the
rather high pressure drop over the bed. This has been overcome by engin-
eering novel polymer supports with high porosity, i.e. monolithic supports,
which allow for excellent mass-transfer characteristics while minimizing the
associated pressure drop. 15 Another possibility for avoiding large pressure
drops consists in immobilizing the palladium catalyst on the reactor walls. 16
Despite the low leaching behavior of Pd for many supports (Table 13.2,
Entries 2-4), it is generally accepted that during cross-coupling reactions the
catalytically active species is leached into solution. 17 After reaction, the
leached metal can redeposit on the carrier material (so-called boomerang
mechanism). Consequently, the actual amount of residual Pd in solution can
be fairly low ( o 1 ppm) for batch reactions, which can mask the leaching
behavior of the immobilized catalyst. Leaching can be promoted by
using more polar solvents [e.g. N,N-dimethylformamide (DMF), N-methyl-2-
pyrrolidinone (NMP)], by the oxidation state of the immobilized palladium
[Pd(II) leaches more rapidly] and by the presence of soluble ligands. The true
nature of the active catalyst can be revealed via a three-phase test in which an
immobilized substrate is utilized to verify the homogeneous or hetero-
geneous character of the reaction. 18 In continuous flow, the packed bed
functions as a huge palladium reservoir that gradually leaches the catalyti-
cally active species into a continuous liquid phase. As such, the palladium is
dragged with the solution further downstream and, after reaction, the metal
is deposited on the reactor walls. Such a leaching-deposition cycle can be
compared with a chromatography effect (Figure 13.2). Eventually, all of
the catalyst will leach from the microreactor, which results in complete
deactivation of the catalyst bed.
Notwithstanding the homogeneous nature of cross-coupling reactions, the
use of immobilized catalysts in micro packed-bed reactors can still be ad-
vantageous owing to their operational flexibility. Such microreactors have
been made commercially available or, alternatively, can be rapidly made by
packing open tubes (e.g. HPLC columns) with the immobilized catalyst.