Nucleophilic Substitution of Pyridine

Nucleophilic substitution of pyridines is discussed in previous sections in relation to the following cyclic transition states (Section II, B, 5), hydrogen bonding and cationization (Section II, C), the leaving group (Section II, D,) and the effect of other substituents (Section II, E) and of the nucleophile (Section II, F). 

In fact nucleophilic substitution of pyridine N-oxides occurs more easily than on simple pyridines, as the nitrogen atom is positively charged. 

Five-Membered Unsaturated Heterocycles 1151 Structures of Pyrrole, Furan, and Thiophene 1152 Electrophilic Substitution Reactions of Pyrrole, Furan, and Thiophene 1153 Pyridine, a Six-Membered Heterocycle Electrophilic Substitution of Pyridine Nucleophilic Substitution of Pyridine Fused-Ring Heterocycles 1158 Nucleic Acids and Nucleotides 1160 Structure of Nucleic Acids 1163 Base Pairing in DNA The Watson-Crick Model Nucleic Acids and Heredity 1166 Replication of DNA 1167... 

Because the pyridine ring is relatively electron deficient, it undergoes nucleophilic substitution much more readily than does benzene (Section 22-4). Attack at C2 and C4 is preferred because it leads to intermediates in which the negative charge is on the nitrogen. An example of nucleophilic substitution of pyridine is the Chichibabin reaction, in which the heterocycle is converted into 2-aminopyridine by treatment with sodium amide in liquid anunonia. 

In most nucleophilic substitutions of pyridines, halides are leaving groups, the 2- and 4-halopyridines being particularly reactive. 

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