36 Pyridines
Substitution of leaving groups
Nucleophilic displacement of good leaving groups such as a halide (as opposed to hydrogen) from either the - or -posi-
tions requires very much milder conditions and proceeds via a two-step mechanism – addition–elimination. The initial
addition is facilitated by the polarisation of the carbon–halogen bond; the second step is also facilitated – elimination of Hal–
producing the fi nal product is much easier than expelling ‘hydride’. 4-Halopyridines are more reactive than 2-halopyridines
in these nucleophilic displacement reactions.
A very important distinction from nucleophilic displacements of saturated alkyl halides must be made. In pyri-
dines (and related systems such as diazines, Chapter 6), fl uoride is a better leaving group than other halides,
whereas in the alkyl fl uorides, this halogen is a very poor leaving group. In the addition–elimination mecha-
nism, the fi rst step is rate limiting and is accelerated by the strong electron-withdrawing effect of the fl uorine,
whereas in the concerted one-step (SN2) mechanism for alkyl halides, the high strength of the carbon–fl uorine
bond dominates.
Halogen at a -position is much less easily displaced, as little mesomeric stabilisation of an intermediate is available.
However -halides are still somewhat more reactive than in corresponding carbocyclic (benzene) systems, due to the
inductive effect of the nitrogen.
Nucleophilic addition to pyridinium salts
Owing to the full positive charge on nitrogen, 1-alkyl- and 1-acylpyridinium salts are much more reactive to nucle-
ophiles than simple pyridines, and again show the same propensity for attack at C-2/C-4. Dihydropyridines are usually
the products from these reactions but while the N-alkyl dihydropyridines are often unstable (easily oxidised back to
pyridinium systems), the N-acyl derivatives are generally stable and easily isolated. Nucleophilic additions of organo-
metallic nucleophiles to pyridinium salts, especially to 1-alkoxy(or 1-aryloxy)carbonylpyridinium salts (N-CO 2 R),
have become very important, giving synthetic intermediates that can be utilised in various ways for further transforma-
tions. The dihydro-adducts can be aromatised to give substituted pyridines or the enamide character can be employed
for the introduction of substituents at C-3.
The/-selectivity in these additions varies with the nucleophile and can also be controlled by the use of removable
bulkyN-blocking groups or by using cuprate nucleophiles to encourage 1,4-addition – these aspects are illustrated in
the examples below.