Nucleophilic substitution of pyridines

What is nucleophilic substitution of pyridines?

The nucleophilic substitution reaction is not a common process in benzene chemistry, but it is much easier in pyridines, and particularly at the C2 and C4 positions which are activated by nitrogen.

Nucleophilic displacement of a good leaving group, via addition-elimination, occurs most easily for groups at C2 and C4 positions. The intermediates of these processes would be the following:

fig-29

The structures of amines with a negative charge on nitrogen are stabilized with respect to the others. This nucleophilic displacement of a good group through addition-elimination mechanisms is even easier in the N-alkyl pyridinium salts which are very easily attacked by nucleophiles at the C2 and C4 positions.

Examples

Some examples of reactions of pyridine with different nucleophiles are described below.

Reactions with HO ions

Pyridine resists alkali (base) treatment up to 100 ºC but at 300 ºC it is transformed into 2-pyridone, which is the most stable tautomer of 2-hydroxypyridine.

fig-30

This reaction is facilitated by electron-withdrawing substituents and condensed rings.

Reactions with alkyl pyridinium ions

These alkyl pyridinium ions are formed by treatment of pyridine with alkylating agents. Thus, they react reversibly, giving a small proportion of pseudobase (so called because it does not react instantaneously with acids).

fig-31

Pseudobases can undergo various subsequent reactions:

  • Oxidation (with Fe(CN)6K3) to give N-substituted 2-pyridones.
  • Fission of the ring, followed by closure to give a new heterocycle.

Reactions with amines

The amines do not have sufficient basic strength to react with pyridine. However, amides can react.

fig-32

In this reaction, called the Chichibabin reaction, the deactivating effect of the amino groups already introduced into the pyridine is evident.

The mechanism of the Chichibabin reaction is as follows:

It is initiated by attack of the nucleophile at the C2 or C4 position. This attack occurs at these positions because the negative charge is delocalized to the nitrogen of the ring.

fig-33

In the next step of this reaction, the elimination of a hydride ion takes place, which reacts with the amino pyridine giving hydrogen (H2). The driving force for the elimination of the hydride ion is the formation of the aromatic cycle.

Reacciones con carbaniones

Pyridine reacts with R—C or R—Cδ compounds, such as organometallic compounds, under fairly vigorous conditions (e.g. xylene at 100 °C) giving the corresponding C2-position (C-R) derivative. The reaction proceeds through the dihydro pyridine which at lower temperature can be isolated.

Grignard reagents give worse yields for being weaker.

Cationic rings react readily with compounds of this type.

One reaction of this class is that between the pyridine-sulfur trioxide complex and cyclopentadienide to give azulene.

Halogen displacement

All chloropyridines are much more reactive than chlorobenzene and the order of reactivity is 4 > 2 > 3. The same as for chloronitrobenzenes with which there is a strong parallelism.

The 2– and 4-halopyridine halide can be displaced by good nucleophiles such as hydrazine and stabilized carbanions.

These reactions are facilitated if there are activating substituents in the appropriate positions.

For example, a nitro group that stabilizes the transition state.

fig-34

The 2-halo-N-methylpyridinium salts are much more reactive than the neutral halopyridines and react with a wide variety of nucleophiles. Therefore, these reactions are of great application in synthesis.

fig-35

The displacement of a nucleophile of halopyridines halide, can be catalyzed with protonated acids or Lewis acids, so that, in these cases, the reaction occurs on the pyridinium salt.

Dehydropyridine reactions

In the reactions of 3-halopyridines with potassium amide (KNH2) in liquid ammonia (NH3), or with potassium terbutoxide (tBuOK), a different mechanism occurs.

The halide at the C3 position is relatively unreactive, as opposed to direct displacement, so that a competitive reaction takes place in which the proton at C4 is removed.

These anions produce 3,4-dehydropyridine by loss of halide.

The 3,4-dehydropyridine can then be reacted with different reagents to give the products shown in the scheme.

fig-36

The ratio of 3- and 4-aminopyridines obtained (35:65) is independent of the nature of the X leaving group.

In addition, 2-aminopyridine is not formed, nor is the intermediate isomer 2,3-dehydropyridine generated.

However, this intermediate can be generated by another method. For example, using butyllithium with 3-bromo-2-chloro-pyridine in the presence of furan.

fig-37

Homolytic substitution (radicals)

Pyridines undergo homolytic substitution (replacement of by ) by different types of radicals.

This reaction preferably takes place at the C2 position and if the reaction is carried out in an acidic medium the selectivity obtained is high.

They give better results when the radicals have a certain nucleophilic character and the pyridines have electron-attracting substituents.

fig-38

Photochemical halogenation gives 2-Cl-pyridine with good yield.

It is likely to be a substitution by radicals.

Chemical Reduction

The reduction of pyridines and pyridinium salts with reducing agents of the hydride type is essentially a nucleophilic addition, and therefore it is easier to reduce pyridines than benzenes.

Sodium in ethanol (EtOH) or ammonia (NH3) reduces pyridines first to dihydrocompound, then to tetrahydrocompound and finally to the corresponding piperidine.

fig-39

Pyridinium ions are readily reduced under mild conditions with sodium borohydride (NaBH4).

fig-40

The final product of the reduction of pyridines with sodium (Na) to ammonia (NH3) (Birch reduction) depends on the reaction conditions and substituents.

In the first step of the reaction a radical anion (I) will be formed, which can be dimerized and if there are no substituents at C4 the dimer can be oxidized to a 4,4-bipyridyl.

fig-41

Further reduction of the radical anion (I), in the presence of a proton source such as ethanol (EtOH), leads to the formation of the 1,4-dihydropyridine monomers.

fig-42