CHEMISTRY OF PURINES AND PYRIMIDINES lOl 



orotidiiie hydrolyzes in dilute mineral acid as readily as do the ribosides 

 of the purines. 



Biscaro and Belloni degraded orotic acid to urea with permanganate and 

 proposed a 7-memliered cyclic ureido structure for their compound.^'" 

 Wheeler el a/.-"'*' pointed out that the empirical formula of orotic acid cor- 

 responded to that of a carboxyuracil, and they synthesized the 5-carboxylic 

 acid only to find it different from orotic acid. Wheeler also synthesized^^^ 

 uracil-4-carboxylic acid, but its melting point (347°, dec.) was not the same 

 as that (260°, dec.) reported^^^ for orotic acid. In a reconsideration of this 

 problem twenty-two years later, Johnson and Caldwell described a syn- 

 thesis of 2,5-dihydroxypyrimidine-4-carboxylic acid; its melting point, 

 259°, led them to believe that it was identical wath orotic acid.^-^ It re- 

 mained for Bachstez"^^ to prove the identity of orotic acid when he com- 

 pared a specimen (prepared by Biscaro) which now melted at 345-6° (dec.) 

 with uracil-4-carboxylic acid previously synthesized by Wheeler-^ and by 

 Behrend and Struve.^^" Although Wheeler did in fact synthesize XXXI,--^ 

 he did not realize that XXXI had resulted from the alkaline hydrolysis 

 and rearrangement of 5-(carbethoxymethylidene)hydantoin (XXXII, pre- 

 pared from oxalacetic ethyl ester and urea by MiillerV^^ method) rather than 

 (as he thought) from the saponification of the ethyl ester of XXXI. For the 

 clarification and a discussion of these points the reader is referred to the 

 interesting work of Mitchell and Nyc.^'"-"^ In the other early synthesis,^^"^ 

 4-methyluracil (XVIII) was converted to orotic acid upon alkaline ferri- 

 cyanide oxidation. Thymine is not oxidized (see Johnson and Schroeder-^^) 

 to the isomeric 5-carboxylic acid. 



An improved synthesis^^^ of orotic acid (which has been adapted-^^ for 

 the introduction of C'* in position 6) is shown below together with the re- 

 actions already discussed . 



c. Purine and Pyrimidine Derivatives and Analogues oj Biological Importance 



The early investigators of purines and pyrimidines could hardly have 

 suspected that what appeared as academic exercises in pure chemistry 

 would furnish a broad foundation for future biological thought and en- 



"6 H. L. Wheeler, T. B. Johnson, and C. O. Johns, Am. Chem. J. 2,1, 392 (1907). 



2" H. L. Wheeler, Am. Chem. J. 38, 358 (1907). 



"8 T. B. Johnson and W. T. Caldwell, J. Am. Chem. Soc. 51, 873 (1929). 



"9 M. Bachstez, Ber. 63, 1000 (1930). 



"0 R. Behrend and K. Struve, Ann. 378, 153 (1911). 



"1 R. Muller, J. prakt. Chem. [2] 55, 505; 56, 475 (1897). 



"2 H. K. Mitchell and J. F. Nye, /. Am. Chem. Soc. 69, 674 (1947). 



2" J. F. Nye and H. K. Mitchell, /. Am. Chem. Soc. 69, 1382 (1947). 



23" T. B. Johnson and E. F. Schroeder, /. Am. Chem. Soc. 53, 1989 (1931). 



236 C. Heidelberger and R. B. Hurlbert, /. Am. Chem. Soc. 72, 4704 (1950). 



