Nucleophilic substitution is easy with pyridines
المؤلف:
Jonathan Clayden , Nick Greeves , Stuart Warren
المصدر:
ORGANIC CHEMISTRY
الجزء والصفحة:
ص727-728
2025-07-13
612
Nucleophilic substitution is easy with pyridines
By contrast, the nitrogen atom makes pyridines more reactive towards nucleophilic substitu tion, particularly at the 2- and 4-positions, by lowering the LUMO energy of the π system of pyridine. You can see this effect in action in the ease of replacement of halogens in these positions by nucleophiles.
The intermediate anion is stabilized by electronegative nitrogen and by delocalization round the ring. These reactions have some similarity to nucleophilic aromatic substitution but are more similar to carbonyl reactions. The intermediate anion is a tetrahedral inter mediate that loses the best leaving group to regenerate the stable aromatic system. Nucleophiles such as amines or thiolate anions work well in these reactions.
The leaving group does not have to be as good as chloride in these reactions. Continuing the analogy with carbonyl reactions, 2- and 4-chloropyridines are rather like acid chlorides but we need only use less reactive pyridyl ethers, which react like esters, to make amides. Substitution of a 2-methoxypyridine allows the synthesis of flupirtine.
The fi rst step is a nucleophilic aromatic substitution. In the second step the nitro group is reduced to an amino group without any effect on the pyridine ring—another piece of evidence for its aromaticity. Finally, the one amino group whose lone pair is not delocalized onto the pyridine N is acylated in the presence of two others.
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