Greener Approaches to Cross-Coupling - New Trends in Cross-Coupling: Theory and Applications - page 660

the iron/18 system, the reaction yield decreased from 92% to 74% over six
reaction cycles, whereas in the absence of ligand a complete loss of activity
occurred within five cycles.
Although the copper- and iron-catalyzed systems appear to offer the ad-
vantage of using a cheaper and more abundant metal than palladium, it
should be noted that optimized palladium catalysts are typically much more
active. Catalyst loadings for copper- and iron-catalyzed reactions are usually
5-10 mol%, whereas palladium loadings are often r 1 mol%. Even with
several orders of magnitude higher loadings, the cost of iron or copper
catalysts can be less than that of palladium catalysts, however. From an
environmental standpoint, the additional heavy metal may cause problems.
In particular, the high loadings may make meeting residual metal specifi-
cations for pharmaceuticals challenging.
14.2.2 Hydrophobic Catalyst Systems
Much of the early effort in developing aqueous-phase cross-coupling re-
actions was focused on the design of hydrophilic catalysts to allow reactions
to be carried out under biphasic conditions. Less attention has been devoted
to the role that water as a unique reaction medium can play in reactions. In
1980, Rideout and Breslow noted that water accelerated Diels-Alder reactions
of hydrophobic substrates. 80 They called this a hydrophobic effect and
hypothesized that reactions with negative volumes of activation would be
favored when carried out in water because the hydrophobic phase would
want to minimize its interaction with water. This observation initially re-
ceived limited attention, but over the past decade the ability of water to
accelerate reactions, even when all reagents are insoluble in water, has at-
tracted increasing attention. 81 The so-called on-water reactions often provide
higher rates than homogeneous-phase reactions. The use of water can de-
crease the environmental impact of reactions compared with traditional
organic-phase reactions. A disadvantage of on-water reactions is that the
precious metal catalyst typically cannot be recycled.
14.2.2.1 Cross-Coupling Reactions on Water
Truly on-water cross-coupling reactions in which no surfactant or phase-
transfer catalyst is used have been reported for a number of systems. Pre-
catalysts Pd(PPh 3 ) 4 and Pd(PPh 3 ) 2 Cl 2 effectively catalyze the Sonogashira
coupling of aryl iodides and bromides on water using amine bases. 82 High-
yielding, on-water Suzuki couplings of aryl and heteroaryl bromides can be
achieved with low catalyst loadings (0.01-0.1 mol%) of Pd(DPPF)Cl 2 . 83
Interestingly, with PEG as an additive, the catalyst could be retained in the
aqueous phase and recycled, although the yield decreased from 91% to 80%
over three cycles. A P 2 N 2 ligand (28) in combination with Pd(OAc) 2 catalyzed
the Suzuki coupling of aryl bromides on water with catalyst loadings as low
as 0.001 mol% (Scheme 14.26). 84 Good yields were also obtained with