Reaction of Ethylene Oxide with Nicotinamide and Nicotinic Acid

It has been shown that treatment of animal diets with ethylene oxide results in severe destruction of thiamine, niacin, pyridoxine, riboflavin, and folic acid (2, 3) and of the essential amino acids, histidine, methionine (4)) and lysine (5). Consequently, studies were undertaken to elucidate the nature of the reactions of ethylene oxide with the above nutrients. The realization that a tertiary nitrogen group was common to six of the labile nutrients prompted the investigation of the reaction of ethylene oxide with pyridine and the closely related nicotinamide and nicotinic acid. Lohmann (6), in 1939, reported that the addition of ethylene oxide to pyridine or quinolme results in the formation of highly colored methanol-water soluble products of undetermined structure. Eastham et al. (7-9) demonstrated that ethylene oxide reacts as readily with tertiary as with primary and secondary amines, and that the reaction with pyridine, in the presence of an acid, yields the Nl-(2-hydroxyethyl)pyridinium salt. The rate of reaction in excess pyridine was shown to be second order, being proportional to the concentration of acid and epoxide. The present paper offers evidence that ethylene oxide reacts with nicotinamide under very mild conditions to yield, after acidification with HCl, the chloride of Nl-(2-hydroxyethyl)nicotinamide, and with nicotinic acid to produce the betaine of N1-(2-hydroxyethyl)nicotinic acid.