Diazines 51Substitution of leaving groups
The nucleophilic displacement of halogen and other leaving groups by ‘soft’ nucleophiles (amines, thiols, alkoxides, eno-
lates) is a very important method for manipulation of diazines. Only 5-halopyrimidines, in analogy to 3-halopyridines, are
resistant. The relative reactivities are summarised below – all halodiazines (except 5-halopyrimidines) are more reactive
than the corresponding pyridine halide.
Chlorine is the most commonly used leaving group but sulfones are also very useful and even methoxy groups can
be displaced in these highly reactive systems. The use of the sodium salts of carbamates as nucleophiles gives good
4-selectivity in 2,4,6-trichloropyrimidines.
Stannanes can be prepared via nucleophilic displacements at low temperature.
An important point to remember is that the presence on the ring of an electron-donating group, particularly an amino
group, greatly reduces the reactivity of a halide. This means that clean mono-substitution in dihalo-compounds is easy if
the fi rst displacement introduces an electron-releasing group, but also that special methods may be necessary to achieve
displacement of the second halide, such as the use of ‘supernucleophiles’. Hydroxylamines are very reactive nucleophiles
and, as the N-O bond in the products can be hydrogenolysed, nucleophilic substitution with a hydroxylamine provides
a means for the introduction of (a second) amine.
A device used to enhance reactivity, which is also used in pyridine and purine chemistry, is the initial replacement of
halogen with a tertiary amine, the resulting salt, now having a better leaving group for carbon nucleophiles, undergoes
substitution more easily.