II. CHEMISTRY 119 



;ici(l with tlinl of IcucoNoiiii. A study of the ult r;i\iol('f ;il)Sor|)lioii of XXIX 

 iiiidci- jicid and \K\s\r coiiditioiis (shows {hat il behaves (juite similarly to 



O 



II 



CH H 



^ ^N N^ 





CH2 — CH2 

 XXIX 



[N-(2-Anilinoethyl)formanilide] 



CH 





CHo— CH2 

 XXX 



leucovoriii; thus, in acid the maximum shifts in a maimer which suggests a 

 more highly conjugated system (XXX). Furthermore, a rapid change from 

 strongly acidic to strongly basic solutions results in an equally rapid re- 

 generation of XXIX. At intermediate pH values, however, the intercon- 

 version of the two forms occurs much more slowly, which shows that the 

 shift of the maximum is not an immediate effect of pH but represents a 

 more drastic change in the molecular structure. 



It is readily apparent that opening the imidazolinium ring of XXX to 

 form XXIX can give a product with the formyl group on either nitrogen; 

 but, because the molecule is symmetrical, only one product is formed. How- 

 ever, treatment of isoleucovorin chloride with alkali may give either the 

 10- or o-formyl derivative. The major product appears to be 10-formyl- 

 5.6,7,8-tetrahydro PGA (XIV), although some regeneration to leucovorin 

 also occurs. Thus, when isoleucovorin chloride is treated with alkali 

 aerobically, one-half of a molecular equivalent of oxygen is rapidlj'' con- 

 sumed to give a product which slowly o.xidizes in acidic solution to 10-formyl 

 PGA (XV). Since 10-formyl PGA can be hydrolyzed readily to PGA with 

 alkali, it is therefore possible to reconvert leucovorin to PGA. 



As can be seen from Fig. 7, several other products have been isolated 

 during investigations on the chemistry of leucovorin. One of these is an- 

 hydroleucovorin-A (XVIII), ^"' ^* which is formed by dissolving isoleu- 

 covorin chloride in boiling water, then cooling slowly. This crystalline sui)- 

 stance is thought to be an imidazolinium "betaine-type" derivative of 

 leucovorin. By treatment of anhydroleucovorin-A or isoleucovorin chloride 



