Greener Approaches to Cross-Coupling - New Trends in Cross-Coupling: Theory and Applications - page 647

avoiding the metallic reagent altogether through the use of a C-H activation
process would be most desirable.
Lifecycle analyses of pharmaceutical processes have shown that volatile
organic solvents make up the bulk of waste that is produced. 7 Much of the
effort to decrease the environmental impact of cross-coupling reactions has
focused on using more benign solvents, such as water. Systems that avoid the
use of stoichiometric additives, such as the base required in many cross-
coupling reactions, can also lower the E-factor of these processes. The catalyst
also provides an opportunity to enhance the sustainability of these processes.
Palladium is one of the least abundant elements in the Earth's crust. Strat-
egies to minimize the use of palladium by lowering the required catalyst
loading or eciently recycling the catalyst would improve the sustainability of
its use as a catalyst. Alternatively, replacing palladium with more Earth-
abundant metals, such as copper, nickel or iron, would be desirable.
In this chapter, various approaches to improving the ''green-ness'' of
cross-coupling reactions are highlighted. The majority of this work has been
focused on the use of alternative solvents, particularly water. Efforts to use
new types of substrates in order to decrease the amount or toxicity of the
reaction by-products are also highlighted.
14.2 Metal-Catalyzed Cross-Couplings in Aqueous
Media
Water as an alternative solvent for organic chemistry has attracted signifi-
cant attention. 8 Water is a non-toxic, non-flammable, relatively cheap and
renewable solvent, in contrast to typical organic solvents that are potentially
toxic, flammable and non-renewable. Caution should be taken when con-
sidering water as a green solvent, however. Once water has come into contact
with organic compounds, it is classified as hazardous waste and cannot be
returned to the environment without treatment. Aqueous waste can be more
problematic than organic waste, because it often cannot be incinerated.
Rather, it must be treated to remove contaminants or stored. Although water
may not be a perfect green solvent, it does offer significant advantages over
organic solvents in terms of safety and sustainability.
The use of water as a solvent can also simplify product purification, which
can have a significant impact on waste production for a process. An aqueous-
biphasic solvent system can allow the simple separation of organic products
from inorganic by-products. If a water-soluble catalyst is used, that can also
be retained in the aqueous layer. This simplified catalyst separation can
overcome the significant challenge of separating homogeneous metal cata-
lysts from organic products. 9 Furthermore, this approach provides the op-
portunity to recycle the aqueous catalyst solution, thus minimizing the
amount of water and catalyst that must be used in the process. This concept
was commercialized in the Rhˆne-Poulenc aqueous-phase hydroformylation
of propene in the 1970s. 10 Significant effort has been devoted to the devel-
opment of aqueous-phase metal-catalyzed cross-coupling reactions.