Key factors influencing nucleophilic substitution on heteroaromatics

Nucleophilic substitution of aromatic compounds proceeds via addition of nucleophile and then elimination of the leaving group, in a two steps sequence. The former step is often the rate determining one and the stabilisation of the charged intermediate (Meisenheimer complex) the key factor for such processes to succeed. As many times in organic chemistry the product distribution is controlled by the kinetics of the slowest step (kinetic control).

In heteroaromatic compounds, the same general rules apply. In this case, the difference between 5 or 6-membered rings is noticeable, as in electrophilic aromatics substitution (the yesterday's post) there's a big difference between 5 and 6-membered rings. In the former case, the displacement of a good leaving group is more difficult, so the displacement of good leaving groups by a nucleophile is specially important in six-membered pi-electron-poor systems while in their five-membered pi-electron-rich systems such processes only come into play in special situations (i.e., in azoles when the leaving group is attached to an azomethine link).

In general, and as a rule of thumbs, positions alfa and gamma of an azomethine N are activated for the initial addition of a nucleophile by 2 factors:
1.- Inductive (electronegativity based) and mesomeric (resonance based) withdrawal of electrons by the nitrogen,
2.- Inductive withdrawal of electrons by the leaving group,
The sigma-adduct intermediate is stabilised when the attack is at alfa and gamma positions. In these situations the negative charge resides largely on the nitrogen, meaning that beta position is usually much less reactive in nucleophilic displacements. For instance, in Cl-pyridines the displacement of chloride by methoxide in methanol undergo with these approximate rates 10^8, 10^4 and 10^9 (alfa, beta and gamma, resp.).

Other effects:

The presence of a formal positive charge on the nitrogen, as in N-oxides and N-alkylpyridinium salts, enhances the rate of nucleophilic substitutions (more in quaternisation than in oxidation). All positions are enhanced, especially the alfa position, meaning that as in neutral pyridines the gamma position is a little bit more enhanced than the alfa position, in positively charged pyridines the order is the other way around.

In bicyclic systems, a certain increase on rate is observed in quinolines derivatives than in their monocyclic counterparts. Quaternisation again greatly increase the rate of substitution having a larger effect at the alfa position than in the gamma position.

Diazines with halogen at alfa and gamma positions are much more reactive than similar pyridines.