Pyridine hydrochloride, bromination

The direct bromination of 2-hydroxypyridine is regioselective at C-3 whereas chlorination is not. Qu6guiner has developed a halide exchange reaction. Heating 3-bromo-2-hydroxypyridine in pyridine hydrochloride at reflux gives 3-chloro-2-hydroxypyridine in good yield <96TL(37)6695>. The directed aminomethylation of 3-hydroxy-2(lH)-pyridones and 3-hydroxy-4(lfl)-pyridones has been studied <96T(52)1835>. 

Bromination of pyridine is much easier than chlorination. Vapour phase bromination over pumice or charcoal has been studied extensively (B-67MI20500) and, as with chlorination, orientation varies with change in temperature. At 300 °C, pyridine yields chiefly 3-bromo-and 3,5-dibromo-pyridine (electrophilic attack), whilst at 500 °C 2-bromo- and 2,6-dibromo-pyridine predominate (free radical attack). At intermediate temperatures, mixtures of these products are found. Similarly, bromination of quinoline over pumice at 300 °C affords the 3-bromo product, but at higher temperatures (450 °C) the 2-bromo isomer is obtained (77HC(32-1)319). Mixtures of 3-bromo- and 3,5-dibromo-pyridine may be produced by heating a pyridine-bromine complex at 200 °C, by addition of bromine to pyridine hydrochloride under reflux, and by heating pyridine hydrochloride perbromide at 160-170 °C (B-67MI20500). 

Chlorination of steroid ketones has been studied in only a few cases. The reaction with elementary chlorine [iS ] is generally similar to bromination, but other sources of electrophilic chlorine have also been used. These include sulphuryl chloride, pyridine hydrochloride perchloride, and tert-butyl hypochlorite [J57]. 

A 3-1. three-neck flask is equipped with a stirrer, a dropping funnel, and a wide-bore distillation head with attached air condenser and distillation receiver. Bromine (800 g., 5.0 moles) is added to 1155 g. (10.0 moles) of pyridine hydrochloride in the flask over a period of 5 minutes with stirring. Hood.) The flask is heated to 160-170° for 1 hour and then to 195-200° for another hour as evolution of hydrogen chloride ceases. The system is evacuated with a water pump, and a manometer is connected to the flask in place of the dropping funnel. The distillation receiver is cooled with running water. 3,5-Dibromopyridine distils over, followed by 3-bromopyridine hydrobromide as the bath temperature is raised to 220° and the pressure drops to about 25 mm. The combined solid distillate is treated with a solution of 200 g. of sodium hydroxide in 1 1. of water, the mixture is extracted with benzene, and the benzene solution is distilled. There is obtained 300 g. (37%) of 3-bromopyridine boiling at 61-63°/15 mm. The residue from the above operation is distilled with steam to give in the distillate 144 g. (26%) of 3,5-dibromopyridine, m.p. 110-111°. 

Energetic reduction with lithium aluminum hydride led to the reduction of the carbonyl group with the formation of the correct alcohol epimer, as expected from the steric hindrance presented by the benzene ring, and to removal of the aromatic bromine. This last reaction is a noteworthy example of the removal of aromatically bound halogen without reduction of either an allyhc hydroxyl or a double bond. The codeine so produced (CCCLXXXIII) was then demethylated to morphine (CCCLXXXIV) by short heating to 220° with pyridine hydrochloride. 

Pyridine dibromide-HBr (pyridinium perbromide) can be used to mono-brominate polyhydric phenols such as pyrocatechol, pyrogallol, and also aryl ethers at or below room temperature.66-69,453 The solid reagent may be used (for preparation see page 112) alternatively glacial acetic acid containing a known amount of bromine is dropped into a mixture of the phenol or ether with pyridine hydrochloride (prepared by passing dry HC1 into an ethereal solution of pyridine) or with quinoline sulfate. 

The pyridine-bromine complex or its hydrochloride, heated at 200°, gives 3-bromo- and 3,5-dibromo-pyridinei 7, Later workers Tt obtained more complex results, the 3-bromopyridine probably being contaminated with 3,4-dibromopyridine or other reactive halogen derivatives which subsequently decomposed to polymeric salt-like material. More practicable is the preparation of 3-bromo- and 3,5-dibromo-pyridine by adding bromine to pyridine hydrochloride under reflux (a reaction in which iron and mercuric chloride have been used as catalysts) 3-Bromopyridine in good... 

The reaction of a dibromochalcone with hydroxylamine hydrochloride in pyridine gave three products with the expected 2-isoxazoline product as the predominate compound. A ring bromination product and an isoxazole were also isolated (70UC796). The reaction of hydroxylamine with /S-thiosulfates of propiophenone at reflux produced 3-phenyl-2-isoxazo-line (455). At room temperature a bis-Michael product (456) was produced. The reaction with N -phenylhydroxylamine yielded a mono-Michael type product (457) (74CPB1990). 

A very large number of complexes of pyridines and quinolines with all the halogens and interhalogen compounds are known, and as they have been enumerated elsewhere (74HQ14-S2)407,77HC(32-1)319) just a few examples are illustrated (Scheme 14). Treatment of pyridine with chlorine or bromine in the presence of aluminum chloride yields 4-pyridylpyridinium salts (equation 29), but rather curiously the action of iodine chloride on pyridinium hydrochloride at 250 °C produces the 2-isomer (51 equation 30). 

Procedure. The reaction is conducted on a spot plate. A drop of the test solution is treated with a drop of 25 % potassium cyanide solution and a drop of a mixture of 25 % pyridine and 2 % benzidine hydrochloride solution. If elementary chlorine or bromine is present, a red precipitate or color results. Limit of Identification 2.6 y chlorine or bromine... 

Also surprising is the conversion of nicotinic acid chloride hydrochloride into 5-bromonicotinic acid in 87 per cent yield, by heating with bromine at 150-170°. Direct chlorination was much less successfuP . This may be a direct electrophilic substitution, but the nicotinic acid chloride hydrochloride was prepared from nicotinic acid and thionyl chloride (see p. 322), and it is just possible that the reaction is related to the substitutions into pyridine-thionyl chloride complexes discussed below (p. 228). It might even be that nicotinic acid chloride hydrochloride is not a simple salt but possesses a structure like the pyridine-thionyl chloride complex. 

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