Reactions on the pyridine substituents

What are reactions on the pyridine substituents?

The reactions on pyridine substituents are those that instead of taking place on the same ring of the heterocycle, take place on the substituents of the ring producing an functional group interconversion (FGI).

Reactions on alkyl groups

These alkyl groups undergo the same reactions as those attached to benzene:

Oxidation with potassium permanganate (KMnO4) transforms them into acids, as in the case of the conversion of β-picolin to nicotinic acid.

fig-29

In addition, controlled vapor-phase oxidation leads to aldehydes (CHO).

The alkyl groups, located at α and γ of the pyridine, can lose the proton (H) of the alkyl group, which is adjacent to the ring, with strong bases. In addition, these resulting carbanions can react with weak electrophiles.

fig-30

Reactions on carboxylic acids

Pyridine carboxylic acids are amino acids and are partially in the form of zwitteriones or betaines.

fig-31

These compounds decarboxylate very easily in the order β << γ < α.

Pyridines with a -CH2-COOH group at α or γ also undergo facile decarboxylation similar to that of β-ketoacids.

Reactions on hydroxypyridines

These compounds are also weak acids of the phenol type. In addition, they have a basic character of the amine, which is in the form of betaine.

fig-32

The 2- and 4-hydroxypyridines are known as 2- and 4-pyridones, due to their canonical form of this type, which are the predominant species in aqueous solution.

fig-33

For the α and βhydroxypyridine only 1 % is found as hydroxypyridine. In addition, nucleophilic reagents that attack amides also do so on pyridones.

Reactions on aminopyridines

The 2- and 4-aminopyridines can exist in tautomer form (amino-imine tautomerism) as hydroxy compounds. However, the pyridon-imine form is one per thousand versus the amine form. The different tautomers that can occur are listed below.

fig-34

Resonance stabilization (I ↔ II) is higher than in pyridones. As for the reactivity of amino pyridines they have to be divided into two groups.

  • Those substituted at positions C2 and C4.

In the first group (C2 and C4), the canonical forms of type II increase the reactivity of the ring nitrogen atom, and that of the α and γ carbon atoms (with respect to NH2) towards electrophiles. Consequently, protons (H)), alkylating agents, etc. react with the ring nitrogen. Whereas nitro groups (NO2), SO3, etc. react on the C2 and C4 positions.

  • Those substituted in position C3.

The β-aminopyridines exhibit aniline-like behavior, and form more or less stable diazonium salts.

Aminopyridines are capable of undergoing reactions on both nitrogen atoms. In general, when the aminopyridine is initially converted to its anion, as a strong base, alkylation of the side chain is observed.

Acylation usually gives a similar product. However, alkylation of the free base usually gives mixtures of products.

fig-35

Substituents on the ring nitrogen

The most relevant substituents are carbon and oxygen, for example:

Transposition reactions

  • Ladenburg transposition: alkylpyridinium halides give mixtures of alkylpyridines when heated.

fig-36

  • The N-pyridine oxides by heating with acetic anhydride (Ac2O) give rise to pyridones.

fig-37