Palladium in Heterocyclic Chemistry 31Selectivity
Achieving a selective coupling reaction involving just one particular halogen in a polyhalo-compound can be very
useful synthetically. Selectivity in polyhalo-compounds is governed by the fi rst step – the oxidative addition, which is
irreversible. Also useful, but less common, is selection between two different metals.
There are two main forms of halide selectivity: (i) between different leaving groups and (ii) between different carbons
bearing the same leaving group (regioselectivity). Selectivity between different leaving groups almost always dominates
over regioselectivity.
Leaving groups
The reactivity of different ‘leaving groups’ to oxidative addition is related inversely to the strength of the carbon–halogen
bond, that is I > Br ~ OTf > Cl. However, although iodide is the most reactive in oxidative addition, it may not give the
fastest reaction overall, as this step may not be rate-limiting. Iodides also have a tendency to give more side reactions
than the other halides. Bromides are the most widely used substrates although the cheaper and more readily available
chlorides are also important, due to the development of more active catalysts.
Regioselectivity (between the same halogen at different positions)
Oxidative addition involves a concerted nucleophilic-like attack by Pd(0), but differs from the standard two-step aro-
matic nucleophilic displacement in that direct attack at the carbon–halogen bond occurs and mesomeric stabilisation
of an intermediate is not involved. That being said, those same mesomeric relationships do contribute, together with
inductive effects, to the total electron density at the carbons involved. The tendency is for oxidative addition to select
the carbon with the lowest electron density. In simple systems, there seems to be a good correlation with total electron
density at carbon – pyridine, furan and thiophene show highest reactivity at C-2. In more complex (and reactive)
systems such as pyrimidines, the correlation is not as clear-cut and other factors may be involved. In pyridines, for
oxidative addition the order is C-2 > C-4 > C-3, whereas for nucleophilic displacement (see page 35) it is C-4 > C-2 >
C-3, showing the greater effect of induction at C-2 in the former, whereas in the latter, stabilisation of an intermediate
adduct is more important.
Organometallic selectivity
Different classes of organometallic reagent may require very different conditions to achieve coupling. Whereas stan-
nane couplings are usually carried out in non-polar solvents, boronic acids are usually reacted under polar conditions