416 D. M. BROWN AND A. R. TODD 



The prerequisite for alkali-lability in dialkyl phosphates is thus the pres- 

 ence of hydroxyl function in proximity to the phosphoryl group. 



It is well known that triesters of phosphoric acid are sensitive both to 

 alkali and to acid.*'^®^ Brown and Todd®^ envisaged a mechanism for the 

 hydrolysis of the hydroxylated dialkyl phosphates in which a cyclic inter- 

 mediate is involved. Thus, in the alkaline hydrolysis of glycerol-a methyl 

 phosphate (IV; R = Me) an intermediate e.g. IX (R = Me) is produced 

 and immediately cleaved to methanol and the cyclic phosphate X which 

 then gives rise to glycerol-a- and -/3-phosphate. No other major products 

 are to be expected, since it is evident that although the three ester linkages 

 are of comparable reactivity, yet only by fission of the bond retaining 

 the singly-linked substituent can degradation of the molecule occur. Other 

 structures for the intermediate IX have been proposed.^® ^^ Brown and 

 Todd®* point out that the classical neutral triester intermediate of type IX 

 was originally advanced to simplify discussion, and suggest that the true 

 mechanism of processes of type IV —^ X depends probably on an acid- or 

 base-catalyzed attack by the vicinal hydroxyl group on the — P=0 

 bond with simultaneous elimination of the R group as an alkoxy anion, 

 possibly with the intervention of a pentacovalent transition complex.*** 



Fon6,®^ as early as 1947, noted the importance of the neighboring hy- 

 droxyl groups in causing lability of diesters of phosphoric acid containing a 

 glycerol or ethylene glycol residue, and postulated the existence of a cyclic 

 triester in their hydrolysis. He put forward the view that the alkali-labihty 

 of ribonucleic acid, in contrast to the alkali -stability of deoxyribonucleic 

 acid, may depend on the extra hydroxyl group present at C 2 in the sugar 

 residues of the former, i.e., that ribonucleic acids are analogous to glycerol 

 alkyl phosphates in their hydrolytic behavior. Although evidence was not 

 available at the time to permit detailed conclusions to be drawn, subsequent 

 work has clearly established the validity of Fono's basic idea. 



Brown and Todd,^*'®^ during their synthesis of adenylic acids a and 6, 

 isolated two substances shown to be adenosine-2' benzyl phosphate and 

 adenosine-3' benzyl phosphate (XI and XII; R' = CH2C6H6 ; R = adenine 

 residue). These substances were found to be readily hydrolyzed in both 



•0 R. H. A. Plimmer and W. J. N. Burch, J. Chem. Soc. 1929, 279. 



*i G. M. Kosolapoff, "Organophosphorus Compounds," p. 232. John Wiley & Sons, 

 New York, 1950. 



^•^ D. M. Brown and A. R. Todd, J. Chem. Soc. 1952, 52. 



" D. M. Brown and A. R. Todd, J. Chem. Soc. 1953, 2040. 



**" This view of the mechanism finds confirmation in the experiments of D. Lipkin, 

 P. T. Talbert and M. Cohn (/. Am. Chem. Soc. 76, 2871, 1954) who showed that 

 alkaline hydrolysis of yeast ribonucleic acid in H2O'* yields mononucleotides con- 

 taining only one atom of O'* per atom of phosphorus 



" A. Fono, Arkiv. Kemi Mineral. Geol. 24A, No. 33, 14, 15 (1947). 



