394 VITAMIN K GROUP 



groups. Chick assays of the 2-methyl, the 2-hydroxy, and the 2-methyl-3- 

 hydroxy naphthoquinone showed that the 2-methyl compound (see Fig. 1) 

 was more active and the 2-hydroxy compound less active than phthiocol. 

 This indicated that the methyl group was functionally important whereas 

 the hydroxyl group seemed to reduce activity.^^ Phthiocol was readily 

 brought into water solution which was effective by intramuscular or in- 

 travenous injection. It is probably the first synthetic form of the vitamin 

 to be employed in human cases. 



Confirming reports of vitamin K activity of these and certain other syn- 

 thetic and natural substituted naphthoquinones immediately appeared.^^"^^ 

 It had also been noted that the absorption spectrum of 2,3-dimethyl-l ,4- 

 naphthoquinone most closely resembled that of vitamins Ki and Ko, and 

 it was suggested that the vitamins were derivatives of 1 , 4-naphthoquinone 

 with side chains at the 2 and 3 positions. 



Since it had become plainly evident that the active nucleus of the natu- 

 rally occurring vitamin was represented by 2-methyl-l , 4-naphthoquinone 

 with substituents at position 3, the remaining problem in the cases of vita- 

 mins Ki and K2 was to determine the nature of the substituents. Mac- 

 Corquodale et aZ.*° have published the details of their studies on the struc- 

 ture of vitamin Ki. Oxidation with chromic acid resulted in the formation 

 of a mixture from which two acids were isolated. One of these was phthalic 

 acid, and the other was ultimately identified with 2-methyl-l ,4-napthoqui- 

 none-3-acetic acid by comparison of melting point and other properties 

 with those of products synthesized for this purpose. A comparable acid 

 was obtained from the oxidation of diacetyl dihydro vitamin Ki (Fig. 2). 



Also among the oxidation fragments was a ketone which could be sep- 

 arated by steam distillation. This was found to be identical with 2,6,10- 

 trimethylpentadecanone-14, which was previously known to be formed in 

 the oxidation of phytol (Fig. 2). Phytol, if present as a side chain on the 

 vitamin, was evidently located so that its double bond was between the 

 second and third carbon atoms from the quinone ring, since this was the 

 point of scission upon oxidation. The formula of vitamin Ki was given as 

 2-methyl -3-phytyl-l, 4-naphthoquinone (Fig. 2). 



38 H. J. Almquist and A. A. Klose, J. Am. Chem. Soc. 61, 1923 (1939). 

 36 S. Ansbacher and E. Fernholz, J. Am. Chem. Soc. 61, 1924 (1939). 

 " L. F. Fieser, D. M. Bowen, W. P. Campbell, M. Fieser, E. M. Fiy, R. N. Jones, 

 B. Riegel, C. W. Schweitzer, and P. G. Smith, /. Am. Chem. Soc. 61, 1925 (1939). 



38 L. F. Fieser, D. M. Bowen, W. P. Campbell, E. M. Fry, and M. D. Gates, Jr., 

 /. Am. Chem. Soc. 61, 1926 (1939). 



39 S. A. Thayer, L. C. Cheney, S. B. Binkley, D. W. MacCorquodale, and E. A. Doisy, 

 J. Am. Chem. Soc. 61, 1932 (1939). 



" D. W. MacCorquodale, L. C. Cheney, S. B. Binkley, W. F. Holcomb, R. W. McKee, 

 S. A. Thayer, and E. A. Doisy, J. Biol. Chem. 131, 357 (1939). 



