Nicotinic acid chloride

To a solution of 93.8 g of the monoglycol ester in 500 ml of benzene, there are added 55 g of nicotinic acid chloride and 25 g of trimethylemine dissolved in 200 ml of benzene. The solution is stirred gently at a temperature of 60°C for two hours. After this time, the solution is cooled and washed successively with water, dilute hydrochloric acid, dilute ammonia and water until neutrality, it is dried over anhydrous sodium sulfate, and the sol vent Is evaporated under vacuum In this wey llOg of glycol 2-(p-chlorophenoxy)-2-methylpropionate nico-tlnate Is prepared, which represents a yield of 84%. The product is a sllghly yellow oil having a refraction index of no = 1.5422 and which is distilled with decomposition et 214°C at a pressure of 0.3 mm. 

Hydroxylamine hydrochloride Lithium aluminum hydride Nicotinic acid chloride... 

To a mixture of 60 cc of benzene, 40 cc of pyridine and 17 g of hydrochloric acid salt of nicotinic acid chloride, was added 4.5 g of 2,2,6,6-tetramethylolcyclohexanol, and the whole mixture was refuxed at 75°C to 80°C for 2.5 hours. After the mixture was cooled water was added. Precipitate formed was separated by filtration, washed thoroughly with water and dried. Recrystallization from dilute acetic acid gave 14gof the final compound, melting point 177°Cto 180°C. 

Nicotinamide is prepared by partial hydrolysis of the nitrile, or by animation of nicotinic acid chloride or its esters, Some of the compounds mentioned in the foregoing aie shown below. 

Hydroxylamine hydrochloride Nicotinic acid chloride Lithium aluminum hydride... 

When nicotinic acid is heated for 8 hours at 180° with thionyl chloride, a low yield of 5-chloronicotiriic acid is obtained.182 The orientation observed in this case suggests an electrophilic attack, perhaps on a complexed nicotinic acid chloride molecule (which would thus behave somewhat like a pyridine A-oxide). If the reaction is carried out at 150° and the reaction time lengthened to 50 hours, a 30% yield of 5,6-dichloronicotinic acid is obtained.182 Both mechanistic pathways may be involved here. Isonicotinic acid reacts with thionyl chloride at 180-220°, presumably by, way of an electrophilic attack since 3-chloro-and 3,5-dichloroisonicotinic acid are formed.182 Nicotinoyl chloride (from nicotinic acid and thionyl chloride—probably in the complexed form) gives an 87% yield of 5-bromonicotinic acid on reaction with bromine for 10 hours at 150-1700.185... 

Two molar proportions of the cation (122 X = NMe, 0, S) react with one of hydrazine in the presence of triethylamine, to give the corresponding bis compound (123).148 Bisnicotinoylhydrazine was prepared149 from nicotinic acid chloride (2 moles) and hydrazine hydrate (1 mole) 2-pyridoyl, 4-pyridoyl, 2-quinoloyl, and 4-quinoloyl analogs were made similarly.149... 

Rinderknecht and Ma, requiring a quantity of nicotinic acid anhydride, noted that the known methods suffer from the extreme sensitivity of nicotinic acid chloride, and employed with success a method analogous to the mixed anhydride method of peptide synthesis. Equimolar amounts of nicotinic acid and triethylamine were dissolved in chloroform to produce a solution of the salt (1), and the solution was... 

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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