II. CHEMISTRY 11 



methylamine either on ethylene chlorohydrin or on ethylene oxide \vith the 

 formation of the chloride or the free base, respectively. 



Several of the early synthetic methods for choline were based on (2-bro- 

 moethyl)trimethylammonium bromide as the starting compound. This 

 substance is easily prepared by reacting trimethylamine with ethylene 

 bromide according to the following equation: 



(CH3)3N + BrCH2CH2Br->Br(CH3)3NCH2CH2Br 



Bode^^ converted the brominated product into choline by heating it in a 

 solution of silver nitrate. Kriiger and BergelP^ effected the same conversion 

 by heating its aqueous solution for 4 hours at 160° in a sealed tube. Lucius^^ 

 heated the compound for 1 hour in an alcoholic solution of potassium 

 hydroxide at 120° and obtained a mixture of choline and neurine (vinyl- 

 trimethylammonium hydroxide) . 



Choline has been synthesized also by the exhaustive methylation of 

 aminoethanol with methyl iodide in a methanolic solution of potassium 

 hydroxide," by modifications of the original methods of Wurtz^^ using 

 trimethylamine,^*"^^'' by preparation of dimethylaminoethanol and its con- 

 version to choline through the methiodide,^" and by hydrolysis of 2-(ethoxy- 

 methoxy)ethyl-trimethylammonium formate formed from the correspond- 

 ing dimethylamine derivative and methyl formate. ^^ 



The general problem involving the synthesis of hydroxy bases and of 

 homologs of choline was studied by von Braun.^" This worker has shoAvn 

 that, by means of the compounds Br(CH2)jOBz and NHMe2, bases of the 

 type Me2H(CH2)iOBz can be prepared. These are quantitatively converted 

 to the hydroxy bases, Me2N(CH2)xOH, by alkaline hydrolysis. The methi- 

 odide of the product can then be treated with silver chloride to give 

 Me3NCl(CH2)xOH. 



The synthesis of choline mth the hydrogens of the methyl groups re- 

 placed by deuterium was first undertaken by du Vigneaud^^ and his co- 

 workers. Deuteriomethyl alcohol was converted with phosphorus and 

 iodine to deuteriomethyliodide. The iodide with aminoethanol yielded 

 choline with an overall yield of 64% based on deuteriomethyl alcohol. 



■'* J. Bode, Ann. 267, 268 (1891). 



75 M. Kriiger and P. Bergell, Ber. 36, 290 (1903). 



•'B R. Lucius, Arch. Pharm. 245, 248 (1907). 



" G. Trier, Hoppe-Seyler's Z. physiol. Chem. 80, 409 (1912). 



78 R. R. Renshaw, /. Am. Chem. Soc. 32, 128 (1910). 



79 F. Korner, French Pat. 736,107 (April 29, 1932). 



79^ II. Hopff and K. Vierling, German Pat. 801,210 (December 28, 1950). 

 8» J. von Braun, Ber. 49, 966 (1916). 



81 W. F. Gresham, U. S. Pat. 2,457,226 (December 28, 1948). 



82 V. du Vigneaud, J. P. Chandler, M. Cohn, and G. B. Brown, /. Biol. Chem. 134, 

 787 (1940). 



