Charles D. H U Northwestern University Evanston, Minois 60201
~
I
I
The Acidities of Ascorbic and sialic Acids
Ascorbic and sialic acids are important compounds biologically. The former is vitamin C. The latter, among other functions, inhibits the agglutination of vertebrate red blood cells by influenza virus' even a t a dilution of 1.5 X lo'. Important sources of sialic acids are animal tissues (as salivary glands, cell surfaces) and secretions (as blood serum, saliva, gastric juice). This note concerning the pK2s of ascorbic and sialic acids is presented since the compounds are of general interest to organic chemists and carbohydrate chemists as well as to biochemists. Ascorbic acid (I) is the gamma lactone of the en01 form of 2-hexulosonic acid (11). Sialic acid is a generic name for acyl derivatives of neuraminic acid. A sialic
hut if the carbonyl group of 111is converted to the dimethyl mercaptal (>C=O -+ >C(SMe)J then a gamma lactone is readily formed. Since ascorbic and sialic acids may both be regarded as derivatives of alpha keto acids of carbohydrate character one might expect a close relationship to exist between them but it is evident from the above that differences are large. The pK. of acetic acid is 4.75. N-Acetylneuraminic acid, also a carboxylic acid, is considerably stronger (pK. 2.60) which reflects augmentation by the a-keto group (111) or the a-hemiacetal group (IV). The pK. of pymvic acid, CH,COCOOH, is of the same order of magnitude (2.5-2.7). Ascorbic acid lacks a carboxyl group hut it too is a stronger acid (pK, 4.17) than acetic acid. The enediol structure of I, per se, cannot account for its acidity since catechol (V), also an enediol, is a very weak acid (pK, 9.5-9.8).
A I
I1 acid that has been studied extensively is N-acetylneuraminic acid (111). This alpha keto acid has been synthesized by condensation of 2-acetamido-2-D-deoxymannose (N-acetyl-D-mannosamine) with pyruvic acid.
*
AcNH
HCOH
I
-
II I
I
grouping -CC=C-OH. 0
I
6
Although the structure of I is established beyond question, one might ask if a glycopyranose form VI of 11, related to IV, could represent ascorbic acid. Such a carhoxylic structure would explain the low pK., although it still would not be low enough. Of course, VI cannot represent I if for no other reason than that it contains HpOtoo much in its empirical formula. Inspection of structure I shows that it contains the n
~
8
~
IV Evidence is strong that it exists in the glycopyranose form IV (p configuration): it undergoes mutarotation, for example, in dimethyl sulfoxide ([a] from -115" to -24") and i t gives rise to a methyl glycoside with methanol (HC1). In contrast to the facile lactonization of I1 into I compound I11 does not lactonize or enolize,
This is a vinylog of a car-
II
hoxylic acid, -&OH. A simple cyclic compound to contain this grouping is tetronic acid, VII.
GOTTSCHALK, A., AND MCKENZIE, H . A., Bwchim. Bwphys. Ada, 54, 226 (1961); GOTTSCHALK, A,, Ref.Pure Appl. Chem., 12, 46 (1962). a
KWMLER, W . D., J . Am. Chem. Soc., 60,859 (1938). HAYNES, L. J., AND PLIMMEB, J. R., Quart. Rev. (London), 14,
292 (1960).
, ~ anion VIIa is Its pK. is 3.76 in aqueous s o l ~ t i o n . ~Its stabilized by resonance, thus accounting for the strength of VII as an acid. Volume 47, Number 6, June 1970
/
481
I n other words, whereas the low pK, of sialic acid is caused by the carboxyl group with an alpha keto function, the somewhat weaker ascorbic acid traces its low pK, to the fact that it is a tetronic acid. Of the two enolic hydroxyls in I, that on carbon-3 is the one of stronger acidity. This would be inferred from the relationship to VIIa but it is supported also by direct evidence. Titration of I with diazomethane yields the 3-0-methyl derivative of I. The fact that the sialic acids are 3-deoxy compounds
482 / Journal of Chemical Educafion
is the determining structural feature that separates them so widely from the 2-hexulosonic acids and the ascorbic acids. Structure 111 cannot lactonize and still give rise to an anion that is resonance-stabilized in the manner of VIIa. Lactonization of IV is evidently inhibited by a trans relationship between carboxyl and the gamma hydroxyl. It is interesting to note that the alkyltetronic acids and ascorbic acid show a comparable carbonyl ahsorption in the infrared, being much higher than simple gamma lactones. Gamma lactones absorb near 5.65 p but ascorbic acid4absorbs at 5.94 p. Alkyltetronic acids absorb in the solid state? a t 5.9-6.0 p, but at 5.75 p in chloroform solution.
' WEIQL,J., Anal. Chem., 24, 1483 (1952).
