Perhalopyridines: Synthesis and Synthetic Utility

The introduction of halogen atoms on the pyridine ring causes significant changes in its properties. Halogens reduced basicity of pyridine ring as well as dipole moment. The presence of dense halogen atoms renders a higher density of perhalopyridines than pyridine. Fluorine atoms cause a low-field shift of pyridine carbons than chlorine and bromine atoms. Perhalopyridines are mainly involved in nucleophilic substitution reactions due to the electron-withdrawing nature of halogens while perfluoropyridines are more active than others.

Fluorine atom has unique properties and has a great interest in organic chemistry and pharmaceuticals. Insertion of fluorine atoms on pyridines induces significant properties to the pyridine ring. The introduction of fluorine atoms on pyridine is carried out by the fluorination of pyridine or pentachloropyridine. The withdrawing nature of these atoms is mainly responsible for the high reactivity of perfluoropyridines toward nucleophilic attack. Therefore, perfluoropyridines are a significant starting material for the synthesis of other substituted pyridines, ring-fused systems as well as macrocyclic compounds via reaction with various monodentate and bidentate nucleophiles, whereas the nature of nucleophile, reaction condition, and solvent have a basic role in the regiochemistry of the reactions. Furthermore, these compounds could participate in organometallic reactions by the reaction of halogen atom with metals and organometallic reagents. Additionally, they underwent hydrodefluorination in photochemical reactions in the presence of catalysts.

Preparation of pentachloropyridine is carried out by chlorination of pyridine ring or it is obtained from perchlorocyclopentene-3-one via several steps. Perchloropyridines are mainly involved in nucleophilic reactions and produce various substituted perchloropyridines, whereas the nature of solvent and nucleophile hindrance affect the regiochemistry of the reactions. Furthermore, these compounds participated in cross-coupling reactions and produced arylated and alkenylpyridines pyridines. Additionally, they are involved in photochemical reactions and produce ring-fused systems. Oxidation of pentachloropyridine gave pentachloropyridine-Noxide, which is active toward nucleophiles at ortho positions. The reaction of perchloropyridines with methyl fluorosulphonate produced corresponding Nmethylated compounds, which are active toward nucleophilic attack. Organometallic compounds obtained from pentachloropyridined in reaction with various electrophiles produced corresponding substituted products.

Pentabromopyridine is prepared from 4-hydroxypyridine via two pathways. Pentabromopyridine is less active than pentachloro- and pentafluoropyridine toward nucleophilic attack. Its nucleophilic reaction is affected by the hindrance of the bromine atom. Oxidation and methylation of pentabromopyridine give pentabromopyridine-N-oxide and N-methylbromopyridinium salt. Metal-halogen exchange between pentabromopyridine and n-butyl-lithium or magnesium give tetrabromo-4-pyridyl-lithium and tetrabromo-4-pyridylmagnesium bromide. 2,4,6- tribromo-3,5-difluoropyridine is obtained from the bromination of pentafluoropyridine in the reaction with nucleophiles at the C-F bond. Cross-coupling reactions of 2,4,6- tribromo-3,5-difluoropyridine and 3,5-dibromo-2,6-dichloropyridine produced arylated and alkenylpyridines pyridines.