Electrophilic Substitutions
Many electrophilic substitutions on pyridine either do not proceed or proceed only partially; however, the heteroaromatic character can be activated by electron-donating functionalization. Common alkylations and acylations, such as Friedel–Crafts alkylation or acylation, usually fail for pyridine because they only lead to the addition at the nitrogen atom. Substitutions usually occur at the 3-position which is the most electron-rich carbon atom in the ring and is therefore more susceptible to an electrophilic addition.
Substitutions to pyridine at the 2- or 4-position result in an energetically unfavorable σ complex. They can be promoted, however, using clever experimental techniques, such as conducting electrophilic substitution on the pyridine-N-oxide followed by deoxygenation of the nitrogen atom. Addition of oxygen reduces electron density on the nitrogen atom and promotes substitution at the 2- and 4-carbons. The oxygen atom can then be removed via several routes, most commonly with compounds of trivalent phosphorus or divalent sulfur which are easily oxidized. Triphenylphosphine is a frequently used reagent, which is oxidized in this reaction to triphenylphosphine oxide. The following paragraphs describe representative electrophilic substitution reactions of pyridine.
Direct nitration of pyridine requires harsh conditions and has very low yields. The 3-nitropyridine can be obtained instead by reacting pyridine with dinitrogen pentoxide in presence of sodium. Pyridine derivatives where the nitrogen atom is screened sterically and/or electronically can be obtained by nitridation with nitronium tetrafluoroborate (NO2BF4). In this way, 3-nitropyridine can be obtained via the synthesis of 2,6-dibromopyridine followed by removal of the bromine atoms. Direct sulfonation of pyridine is even more difficult than direct nitridation. However, pyridine-3-sulfonic acid can be obtained at acceptable yield by boiling pyridine in an excess of sulfuric acid at 320 °C. Reaction with the SO3 group also facilitates addition of sulfur to the nitrogen atom, especially in the presence of a mercury(II) sulfate catalyst.
In contrast to the nitration and sulfonation, the direct bromination and chlorination of pyridine proceed well. The reaction of pyridine with molecular bromine in sulfuric acid at 130 °C readily produced 3-bromopyridine. The yield is lower for 3-chloropyridine upon chlorination with molecular chlorine in the presence of aluminium chloride at 100 °C. Both 2-bromopyridine and 2-chloropyridine can be produced by direct reaction with halogen with a palladium(II) chloride catalyst.