Halogenopyridines 1-oxides

The halogen atom in 3-chloropyridine 1-oxide is very much less activated than those in 2- and 4-halogenopyridine 1-oxides but more so than that in 3-chloropyridine (see below). 3-Fluoropyridine 1-oxide reacts with piperidine or hydrazine more readily than do the chloro- or bromo-compounds . Surprisingly, reaction of amines or hydrazine with 3-halogeno-4-nitropyri-dine 1-oxides causes replacement of halogen and not of the nitro-group " 2. 

Amination by replacement of the nitro group in 4-nitropyridine 1-oxide has proved surprisingly unsuccessful a, 714. With ammonia, the main product seems to be 4,4 -azopyridine l,T-dioxide. Thus, although 4-nitro-pyridine 1-oxides are important sources of a range of 4-aminopyridine 1-oxides and 4-aminopyridines, this is so only because the 4-nitropyridine 1-oxides can be efficiently converted into 4-halogenopyridine 1-oxides (p. 233) and thence into the amines. 

Qualitatively 2- and 4-halogenopyridine 1-oxides are more reactive towards amines than are 2- and 4-halogenopyridines, and the 3-isomers are in the same order (p. 213). Quantitative studies give the order 2 > 4 > 3, but involvement of the oxide function in the transition state of the replacement occurring at the 2-position may affect the relative order of the 2- and 4-positions (p. 217). As with the pyridines themselves, the best evidence for the relative positional reactivities in the oxides comes from the reaction of halo-genopyridine 1-oxides and alkoxides (p. 245). 

Table 6.13. Some Halogenopyridines and Halogenopyridine -Oxides (see also Tables 6.2, 6.8 and 6.18) ...

Fig. 3.23 Oxidation of halogenated quinolines to halogenopyridine-2,3-dicarboxylic acids [260]...

Both reactions are directed to C-2(6) and C-4 (attack at C-2 is shown below). Electrophilic reactions require the loss of a proton, whereas those for nucleophiles require the loss of hydride ion. 2(4)-Halogenopyridine A-oxides are good substrates for nucleophilic substitution, and the thus site of attack is strongly iniluenced by the position of the halogen atom. 

N-Oxidation of tveakly basic N-heteroaromatic compounds. N-Oxidation of poly-halogenopyridines is difficult owing to the low basicity of the nitrogen atom. For example, treatment of pentachloropyridine with trifluoroacetic acid and 90% hydrogen peroxide under optimum conditions gives only a 20% yield of the 1-oxide. Chivers and Suschitzky1 now find that the oxidation can be effected in 95% yield by use of 90% hydrogen peroxide, acetic acid, and concentrated sulfuric acid. The more expensive trifluoroacetic acid can also be used but with no improvement in yield. No oxidation occurs with use of 75% aqueous sulfuric acid. The function of the sulfuric acid is probably to protonate the peracid and hence facilitate transfer of OH +. ... 

Bas M, Gueret C, Perrio C, Lasne M, Barr6 L (2001) Oxidation of 2- and 3-halogenated quinolines an easy access to 5- and 6-halogenopyridine-2,3-dicarboxylic acids. Synthesis... 

Pyridynes also arise in the amination of halogenopyridine l-oxides ... 

A few 3-cyanopyridines have been prepared, in 40-50 per cent yield, by reaction of a 3-pyridyl diazonium salt with potassium cuprocyanide or cuprous cyanide2i8, 755-7 Though 2- and 4-aminopyridines have been converted into 2- and 4-halogenopyridines via the diazonium reaction, the ready reaction of the 2- and 4-pyridyldiazonium ions with nucleophiles present in the solutions in which they are formed makes their use in cyana-tion difficult if not impossible. The difference in ease of diazotization between a 2- and a 3-aminopyridine permits the conversion of 2,5-diaminopyridine into 2-amino-5-cyanopyridine by diazotization in dilute acid is. The easier diazotization (p. 359) of 4-aminopyridine 1-oxides and the greater stability... 

Concentrated halogen hydracids convert 4-nitropyridine 1-oxide into 4-halogenopyridine l-oxides, 849 hut with dilute acids products arise from an initial hydrolysis to 4-hydroxypyridine l-oxide, 849-50 With sulphuryl chloride, 4-nitropyridine 1-oxide gives mainly 2,4-dichloropyridine (35-40 per cent) 248, 796. 

Acetyl halides are probably the best reagents for converting 4-nitropyri-dine 1-oxides into 4-halogenopyridine l-oxides247, 252, 852-5 and the reaction is of great preparative value. 2-Nitropyridine 1-oxides behave similarly856. 3-Nitropyridine 1-oxide does not react with acetyl chloride, but with phosphoryl chloride gives 2- and 6-chlor-3-nitropyridine i . 

Most of these reactions producing sulphur derivatives from halogeno-pyridines are also readily effected with 2- and 4-halogenopyridine l-oxides290 89, 771, 852, 987, 991-2 4-Bromopyridine 1-oxide does not react with potassium thiocyanate, but the activation produced by a 3-bromo- or 3-nitro-group makes the reaction possible . ... 

The behaviour of acylpyridinium, acyloxypyridinium and oxide quaternary salts, and the occurrence of acid catalysis in nucleophilic replacements (pp. 215, 233, 242) lead to the expectation of high reactivity towards nucleophiles in quaternary pyridinium salts. Quantitatively, the reactivity sequence in the reaction of halogen compounds with alkoxides is quaternary salt > oxide > pyridine. The positional sequence is 4 > 2 > 3 in halogenopyridines and their 1-oxides, and 2 > 4 > 3 in the 1-methyl-halogenopyridinium salts. However, in all three series activation energies would give the order 4 > 2 > 3 for the quaternary salts this order is modified by the entropy factor. 

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