Greener Approaches to Cross-Coupling - New Trends in Cross-Coupling: Theory and Applications - page 646

safe and renewable solvents should be used when required. Starting
materials derived from renewable sources should be used if possible.
Catalysts should be used to promote highly selective reactions under
conditions that are not energy intensive.
As increasing attention is paid to the environmental impact of chemical
processes, it is necessary to have metrics to evaluate these impacts. 2 Lifecycle
assessment (LCA) is the most rigorous approach to evaluating fully the
overall impact of a process. 3 LCA is a cradle-to-grave assessment that con-
siders all facets of a process from the gathering of raw materials through the
products' end of life when all materials are returned to the Earth. An LCA is
an expensive and time-consuming task, which has led to the development of
simpler approaches to assess the environmental impact of a process. The
E-factor is often used to evaluate chemical processes as it can be easily
calculated. 4 The E-factor is the ratio of the mass of waste to the mass of
desired product produced in a process. The amount of waste is defined as
the mass of all materials used in the process with the exception of water,
which is usually not considered. Typical E-factors increase for smaller scale
producers carrying out more complex processes, such as the pharmaceutical
industry. Whereas bulk chemical producers have typical E-factors of o 5kg
waste kg 1 product, the E-factor for the pharmaceutical industry is typically
25-100 kg waste kg 1 product. More recently the process mass intensity
(PMI) has been proposed as an alternative to the E-factor. 5 The PMI is the
total mass of materials used to produce a given mass of product. Unfortu-
nately, these metrics are rarely applied in reports of more sustainable
synthetic methods, so it is often dicult to evaluate the increased eciency
of these processes. 6
As described throughout this topic, palladium-catalyzed cross-coupling
reactions are powerful methods for the formation of carbon-carbon and
carbon-heteroatom bonds. As generally highly selective catalytic processes
that can be run under relatively mild conditions, cross-coupling reactions
adhere to many of the principles of green chemistry. Many opportunities to
reduce the environmental impact of cross-coupling reactions remain. As a
substitution reaction, cross-couplings have an inherent lack of atom
economy (Scheme 14.1). Although the substitution by-product cannot be
completely avoided, its environmental impact can be minimized. Chloride
produces less waste on a per mass basis (lower E-factor) than iodide or
bromide. Direct C-H activation avoids the use of halides altogether. In cross-
coupling of organometallic nucleophiles, the metal by-product should be
chosen to be of low toxicity. For example, Stille couplings use toxic orga-
nostannanes. This reaction has largely been supplanted by Suzuki coupling,
which uses organoboron compounds that are much less toxic. Again,

Pd/L (cat)
additives
solvent

RX + MR' RR' + MX

Scheme 14.1