22 Heterocyclic Chemistry CI Me I N-Methylpyridinium iodide Scheme 2.7 2.3 Pyridine N-Oxides Pyridine N-oxides are frequently used in place of pyridines to facilitate 2.2 D)and it is important to note. electrophilic substitution.In such reactions there is a balance between however.that because of the o withdrawal,caused by the inductiveec of thxygen atom. and elease throuh resonance from the same atom in the oppo site direction.Here,the resonance effect is more important,and elec- trophiles react at C-2(6)and C-4 (the antithesis of the effect of resonance in pyridine itself). The N-oxide is prepared from pyridine by the action of a peracid(e.g hydrogen peroxide in acetic acid,forming peracetic acid in situ,or m-chloroperbenzoic acid,MCPBA);pyridine is regenerated by de- 0 oxygenation by heating with triphenylphosphine (Ph,PPh,PO) (Scheme 2.8). There is thus a subtlety in the tions of pyridine N-ox es that is not e explained Scheme 2.8 As long as the conditions are selected so that the N-oxygen atom is not irreversibly protonated,reactions with electrophiles give 2-and 4-substituted products.Thionyl chloride,for example,gives a mixture of 2-and 4-chloropyridine N-oxides in which the 4-is spredominant. However,pyridine N-oxide reacts with acetic anhydride first to give 1-acetoxypyridinium acetate and then,on heating,to yield 2- acetoxypyridine through an addition-elimination process(Scheme 2.9a) Whena similar eaction is carried out upo the23-dimethyl the acetoxy group rearranges from N-I to the C-2 methyl group,at 180C,to form 2-acetoxymethyl-3-methylpyridine(possibly as shown in Scheme 2.9b). Nitration at C-4 occurs with conc.sulfuric acid and fuming nitric acid (Scheme 2.10a);very little 2-nitropyridine N-oxide is formed,but in cases where the electrophile binds strongly to the oxygen atom of the N-oxide, 22 Heterocyclic Chemistry Scheme 2.7 Pyridine N-oxide exhibits a dipole moment of 4.25 D (cf. pyridine, 2.2 D) and it is important to note, however, that because of the formal positive charge upon the nitrogen atom, pyridine N-oxides are also susceptible to nucleophilic reactions at C-2(6) and C-4. $- 0- 0 OLIrJ - PhCH2C1 N N+ 1 N+ Me I- Ph I c1- N-Benzylpyridinium chloride N-Methylpyridinium iodide 2.3 Pyridine NlOxides Pyridine N-oxides are frequently used in place of pyridines to facilitate electrophilic substitution. In such reactions there is a balance between electron withdrawal, caused by the inductive effect of the oxygen atom, and electron release through resonance from the same atom in the oppo￾site direction. Here, the resonance effect is more important, and elec￾trophiles react at C-2(6) and C-4 (the antithesis of the effect of resonance in pyridine itself). The N-oxide is prepared from pyridine by the action of a peracid (e.g. hydrogen peroxide in acetic acid, forming peracetic acid in situ, or rn-chloroperbenzoic acid, MCPBA); pyridine is regenerated by de￾oxygenation by heating with triphenylphosphine (Ph,P + Ph,PO) (Scheme 2.8). There is thus a subtlety in the reactions of pyridine N-oxides with both electrophiles and nucleophiles that is not easily explained. Scheme 2.8 As long as the conditions are selected so that the N-oxygen atom is not irreversibly protonated, reactions with electrophiles give 2- and 4-substituted products. Thionyl chloride, for example, gives a mixture of 2- and 4-chloropyridine N-oxides in which the 4-isomer is predominant. However, pyridine N-oxide reacts with acetic anhydride first to give 1-acetoxypyridinium acetate and then, on heating, to yield 2- acetoxypyridine through an addition-elimination process (Scheme 2.9a). When a similar reaction is carried out upon the 2,3-dimethyl analogue, the acetoxy group rearranges from N-1 to the C-2 methyl group, at 180 "C, to form 2-acetoxymethyl-3-methylpyridine (possibly as shown in Scheme 2.9b). Nitration at C-4 occurs with conc. sulfuric acid and fuming nitric acid (Scheme 2.1Oa); very little 2-nitropyridine N-oxide is formed, but in cases where the electrophile binds strongly to the oxygen atom of the N-oxide