64 Quinolines and Isoquinolines
stabilisation is lost in proceeding to the intermediate (strictly, the transition state which leads to it). Some examples
serve to illustrate this point: both quinoline and isoquinoline can be hydroxylated (at C-2 and C-1, respectively) by
heating with potassium hydroxide – no such transformation is possible with pyridines. The products exist in the car-
bonyl tautomeric forms in an exact parallel to the hydroxypyridine–pyridone situation (page 41).
A second example of the ease of nucleophilic addition is the reaction of amide anion with isoquinoline, which takes
place even at –65 °C, re-aromatisation occurring in situ by reaction at room temperature (amination of pyridine needs
strong heating).
It is a corollary of the easier addition of a nucleophile to the heterocyclic ring of the bicyclic systems, and the relative
stability of the adduct, that such adducts can be sometimes isolated, but then require more effort for re-aromatisation.
Substitution of leaving groups
Nucleophilic displacement of leaving groups from the quinoline-2- and -4-positions and the isoquinoline-1-position
occurs under quite mild conditions via the two-step, addition–elimination mechanism. Halogens at other positions
are best regarded as being exactly like those in benzene compounds, though an isoquinoline 3-halide can be displaced
under more vigorous conditions.
Nucleophilic addition to quinolinium/isoquinolinium salts
Addition of nucleophiles to quinolinium and isoquinolinium salts is a very easy process; the point made earlier, that in
such products there still remains a complete aromatic ring, is again relevant. Such processes are suffi ciently important that
we give three examples as illustrations. In the fi rst, an N-tosylquinolinium salt is prepared and used in situ for the addition
of cyanide at C-2; additionally, base-catalysed elimination of p-toluenesulfi nate then produces 2-cyanoquinoline – an
overall nucleophilic substitution of hydrogen.