CHEMICAL PROPERTIES 11 



Metabolic studies of the substituted malonates and malonic esters wiU be 

 taken up after the actions of malonate have been discussed (see page 235). 

 It is interesting to note (Table 1-2) that the pK^ 's of the substituted 

 malonic acids are generally higher than for malonic acid itself. This is 

 mainly the result of the reduction of the dielectric constant of the region 

 between the interacting carboxyl groups, and is particularly evident for 

 the disubstituted ethyl and w-propyl derivatives. This increase in pK^ 

 should facilitate penetration of these compounds into cells; in addition they 

 are more lipid-soluble, which will also favor penetration. The esters are not 

 active inhibitors of succinate dehydrogenase, at least by the same mechanism 

 as malonate, but have been used because of their ability to enter cells and 

 tissues readily, some hydrolysis to active malonate within the cells being 

 assumed. The presence of two keto groups on either side of the methylene 

 group makes this latter group more reactive and, indeed, imparts some 

 acidic character to it, malonic diethyl ester having a p^^ of approximately 

 5 X 10~^^ (Pearson and Mills, 1950). The rate of ionization is, however, 

 quite slow (A; = 1.8 X 10-^ min-^). 



Chelation with Metal Cations 



Malonate is able to form fairly stable complexes with various cations 

 normally present in media used in metabolic studies. The importance of 

 this in malonate inhibition will be discussed later (see page 66), and in the 

 present section we shall investigate the magnitudes of the effects expected. 

 These complexes are chelates with a six-membered ring structure, accounting 



o or o. /O 



for the relatively high stability compared to complexes with the monocar- 

 boxylates. The chelate dissociation constant is given by: 



(M++) (A=) 



K=- — - (1-1) 



(MA) 



where A= represents the anion of any dicarboxylic acid. The values for the 

 piii's of some of the more important chelates are given in Table 1-4. These 

 constants are dependent on temperature and ionic strength. The pK for 

 Mg-malonate is related to the temperature at zero ionic strength in the 

 following way: pZ = 2.92 - 0.008 (35 - «oC) (Evans and Monk, 1952). 

 Thus the pii's at 37° are approximately 0.1 unit higher than at 25°, the 

 temperature at which the constants are most commonly determined. It 

 was calculated from the data on the complexes of malonate with Mg++, 

 Ca++, Ba++, and Zn++ that the pK at an ionic strength of 0.15 is about 



