290 2. MALEATE 



this being perhaps an instance of proton adsorption. Crawford (1953) 

 argued that, although maleic acid in the crystal is quite planar, in solution 

 one carboxyl group may not lie in the plane of the molecule, and resonance 

 symmetry will be lost. Electrons will tend to be withdrawn from the non- 

 planar carboxyl group and its acidity will be increased, accounting for the 

 low ])K„ , the ionization of the second carboxyl group being simultaneously 

 depressed. This theory would assume a decreased stability of the undisso- 

 ciated acid rather than an increased stability of the anion. Recent studies 

 have minimized the importance of the hydrogen bonding. Although in- 

 frared data indicate that H-maleate- is internally hydrogen bonded, while 

 maleic acid is not, it was felt that the \)K^ values can be accounted for 

 adequately on the basis of electrostatic and dipole interactions (Dodd et 

 al., 1961). Ionization enthalpies of dicarboxylic acids suggest that hydrogen 

 bonding is not important when Ay)K„ is less than 4, but becomes progres- 

 sively important at values greater than this; thus the contribution for 

 maleic acid must be very small (Eberson and Wadso, 1963). It is difficult 

 to decide between these mechanisms and possibly several contribute signi- 

 ficantly. 



At pH's around neutrality there would be relatively more of the singly 

 charged H-maleate" anion than of the comparable anion of other dicarbox- 

 ylic acids, and this might facilitate the penetration of maleate into cells if 

 the monanion can enter. The ratio of the dianion to the monanion at pH 7.4 

 is 45, so that around 2% would exist as the monanion, whereas in the case 

 of malonate only 0.7% would be in this form. On the other hand, if only 

 the undissociated acid can penetrate, very little will enter the cell since 

 the concentration of this form at pH 7.4 would be near 4 X 10"' mM when 

 the total concentration of maleate is 10 mM. We may note that the pH 

 of a 100 mM solution of maleic acid is 1.90 and of sodium hydrogen maleate 

 is 4.18, so that adjustment of the pH is required before use (Kolthoff 

 and Tekelenburg, 1927). 



Cis-Trans Isomerization 



The JF for the reaction maleic acid -^ fumaric acid was determined by 

 Parks and Huffman (1930) to be —6.6 kcal/mole at 25°, but more recent 

 studies have pointed to a somewhat lower value. Thus Davies and Evans 

 (1956) determined the equilibrium constant, ^^q = (fumaric acid)/(maleic 

 acid), at temperatures between 80^ and 130°, and from these data the 

 following thermodynamic parameters may be obtained: AH = — 8.0 kcal/ 

 mole, J;S = - 17.1 cal/mole/degree, and AF (37°) = - 2.4 kcal/mole. 

 Extrapolation of their data to 37° gives a ^^q around 47, so that at equi- 

 librium there would be approximately 2% maleic acid and 98% fumaric 

 acid. The K^^^ for the dianions, i. e., (fumarate)/(maleate), would be larger 

 and perhaps around 175, taking into account the differences in ionization. 



