about the formation of a carbon–carbon bond. Such a transformation relies on the
prefunctionalisation of the starting reagents, leading to the generation of waste
(usually metal salt by-products). Such reactions need to avoid formation of
homocoupled products, deriving from each starting reagent. It should be noted that
coupling of two different organohalide partners has also been reported and has been
practically examined by Lipshutz et al. [11–12]. During the mid-2000s [13–16],
building on initial work reported in 1993 [17], more direct approaches were developed, as potential replacements for classical cross-coupling reactions. An example is
the reaction of a suitable substrate containing a suitable C–H bond with an
organohalide, generating a carbon–carbon bond, by the so-called direct approach.
A variant of this process involves oxidative reaction of an organometallic reagent,
again with a reagent possessing a suitable reactive C–H bond. Generally speaking,
an oxidant is required for such a process. The “holy grail” in such chemistry is to
bring together the oxidative cross-coupling reaction of two different C–H bonds,
with metal salts such as AgX or CuX 2 being obvious oxidants, or more ideally
oxygen (O 2 ). The disadvantage of using metal salts is the generation of stoichiometric by-products (e.g. either Ag metal or CuX) [18].
Site (regio)selectivity is of paramount importance in the context of C–H bond
functionalisation reactions, which is often implicit, but usually guided by principles
of underlying reactivity, be that of an intrinsic nature or through metal (catalyst)
proximity (i.e. through a directed orientation of a metal centre to the C–H bond of
interest, for functionalisation) [19–21]. While the obvious metal catalyst for such
reactions processes is Pd-containing, many other metals can mediate formation of
new carbon-carbon bonds [4], either by classical coupling, direct coupling or
oxidative coupling strategies.
Many methodologies have been developed for C(sp)–H, C(sp
2 )–H and C(sp
3 )–H
bond functionalisation reactions; indeed, the most promising examples have been
discussed in recent comprehensive reviews, which are beyond the scope and focus of
the current discussion described herein, but add great value in terms of an understanding and appreciation of the field as a whole. Without doubt the most challenging reactions are selective C(sp
3 )–H cross-coupling reactions, noting several
remarkable methodologies that have been developed in recent years, for which
further progress in terms of application, over the next 10 years or so, is likely.
By far and away the best studied catalysts for the functionalisation of C–H bonds
are based on homogeneous systems, i.e. starting with a fully soluble metal catalyst
system, either preformed or generated in situ. It is straightforward to come up with
appropriate catalysts that fit the homogeneous regime; however the true nature of the
active metal catalysts remains hotly debated [22–24]. In this context, quasihomogeneous–heterogeneous catalyst systems are likely involved in many reactions,
especially those involving Pd, but by no means limited to. When heterogeneous
catalyst species are involved, inevitably there is the question can the catalyst be
immobilised and recycled, minimising loss of catalytic activity and loss of metal
(e.g. through leaching processes, leading also to non-desirable product contamination). With elemental sustainability in mind, and the pragmatic consideration that
precious metals are likely to be used in chemical processes for at least the next
25 years, then it is incumbent on the scientific community to develop heterogeneous
Pd Nanoparticles in C–H Activation and Cross-coupling Catalysis
173
prefunctionalisation of the starting reagents, leading to the generation of waste
(usually metal salt by-products). Such reactions need to avoid formation of
homocoupled products, deriving from each starting reagent. It should be noted that
coupling of two different organohalide partners has also been reported and has been
practically examined by Lipshutz et al. [11–12]. During the mid-2000s [13–16],
building on initial work reported in 1993 [17], more direct approaches were developed, as potential replacements for classical cross-coupling reactions. An example is
the reaction of a suitable substrate containing a suitable C–H bond with an
organohalide, generating a carbon–carbon bond, by the so-called direct approach.
A variant of this process involves oxidative reaction of an organometallic reagent,
again with a reagent possessing a suitable reactive C–H bond. Generally speaking,
an oxidant is required for such a process. The “holy grail” in such chemistry is to
bring together the oxidative cross-coupling reaction of two different C–H bonds,
with metal salts such as AgX or CuX 2 being obvious oxidants, or more ideally
oxygen (O 2 ). The disadvantage of using metal salts is the generation of stoichiometric by-products (e.g. either Ag metal or CuX) [18].
Site (regio)selectivity is of paramount importance in the context of C–H bond
functionalisation reactions, which is often implicit, but usually guided by principles
of underlying reactivity, be that of an intrinsic nature or through metal (catalyst)
proximity (i.e. through a directed orientation of a metal centre to the C–H bond of
interest, for functionalisation) [19–21]. While the obvious metal catalyst for such
reactions processes is Pd-containing, many other metals can mediate formation of
new carbon-carbon bonds [4], either by classical coupling, direct coupling or
oxidative coupling strategies.
Many methodologies have been developed for C(sp)–H, C(sp
2 )–H and C(sp
3 )–H
bond functionalisation reactions; indeed, the most promising examples have been
discussed in recent comprehensive reviews, which are beyond the scope and focus of
the current discussion described herein, but add great value in terms of an understanding and appreciation of the field as a whole. Without doubt the most challenging reactions are selective C(sp
3 )–H cross-coupling reactions, noting several
remarkable methodologies that have been developed in recent years, for which
further progress in terms of application, over the next 10 years or so, is likely.
By far and away the best studied catalysts for the functionalisation of C–H bonds
are based on homogeneous systems, i.e. starting with a fully soluble metal catalyst
system, either preformed or generated in situ. It is straightforward to come up with
appropriate catalysts that fit the homogeneous regime; however the true nature of the
active metal catalysts remains hotly debated [22–24]. In this context, quasihomogeneous–heterogeneous catalyst systems are likely involved in many reactions,
especially those involving Pd, but by no means limited to. When heterogeneous
catalyst species are involved, inevitably there is the question can the catalyst be
immobilised and recycled, minimising loss of catalytic activity and loss of metal
(e.g. through leaching processes, leading also to non-desirable product contamination). With elemental sustainability in mind, and the pragmatic consideration that
precious metals are likely to be used in chemical processes for at least the next
25 years, then it is incumbent on the scientific community to develop heterogeneous
Pd Nanoparticles in C–H Activation and Cross-coupling Catalysis
173