In the Classroom
r-Oxocarboxylic Acids Robert C. Kerber* and Marian S. Fernando Department of Chemistry, Stony Brook University, Long Island, New York 11794-3400 *
[email protected] One of the authors (R.C.K.) recently took exception to the common textbook misrepresentation of oxidized ascorbic acid as a tricarbonyl compound, and summarized spectroscopic and crystallographic data, which pointed to 1 as the predominant structure in aqueous solution (1).
Inspired by a thoughtful response from a reader of the previous article, we wondered whether the properties of other Rdicarbonyl compounds might have been obfuscated by disregard of hydration reactions in water solution. Hydration of aldehydes and, to a lesser extent, ketones is mentioned in most organic textbooks. The reaction is catalyzed by acids and bases, and both hydration and dehydration are fairly rapid in aqueous solution. Compounds with adjacent carbonyl groups are less stable than simple carbonyls, as shown for example by the gas-phase enthalpies of the following hypothetical conversions (2): CH3 CH3 þ CO f CH3 COCH3 ΔH° ¼ - 217:5 - ð - 84:0Þ - ð - 110:5Þ ¼ - 23:0
kJ mol
ð1Þ
CH3 COCH3 þ CO f CH3 COCOCH3 ΔH° ¼ - 326:8 - ð - 217:5Þ - ð - 110:5Þ kJ ¼ þ 1:2 mol
Oxoethanoic (Glyoxylic) Acid ð2Þ
A consequence of this reduced stability is a tendency for such compounds to be more extensively hydrated than simple carbonyl compounds. For example, 2,3-butanedione (biacetyl) is 77% hydrated in water at 25 °C, whereas propanone is only 0.1% hydrated (3). R-Oxocarboxylic acids (4), although seldom encountered in organic chemistry courses, are an important class of compounds in biological chemistry, accounting for three of the nine components of the tricarboxylic acid cycle (Krebs cycle, citric acid cycle). Pyruvic acid (2-oxopropanoic acid) in particular sits at the nexus of several essential metabolic processes. A fourth oxoacid, glyoxylic acid, participates in an atom-economical alternative cycle by which plants and bacteria convert fatty acids into
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carbohydrates. The structures and names of these four biological oxoacids are shown in Table 1. The electron-withdrawing R-carbonyl groups of these compounds are expected to increase their acidity compared to ordinary aliphatic carboxylic acids. Qualitatively, this is consistent with the empirical pKa0 values in Table 1. But comparison of these tabulated acid ionization constants with those of oxalic acid (1.23, 4.19) (5), ethyl oxalate (1.72) (6), or oxamic acid (1.84) (7) reveals some quantitative anomalies. The keto groups of 3-5 appear to be less effective electron-withdrawers than the acid, ester, and amide groups of the oxalate analogues, and the formyl group of 2 seems to be weakest of all, contrary to the usual sequence of electron-withdrawing power of carbonyl groups. These results are consistent with predominance of hydrated aldehyde and ketone species in solution, so that the empirical pKa0 values correspond more to those of R,R-dihydroxycarboxylic acids (or of equilibrium mixtures of hydrated and unhydrated acids), rather than the oxocarboxylic acids implied by the conventional names. As early as 1961, Ono (8) reported that hydration of un-ionized R-ketoacids led to decreased polarographic limiting currents below pH 4, and he pointed out that empirical pKa0 values1 would therefore be higher than the pKa values of the unhydrated oxoacids. Nevertheless, researchers and tabulators have continued to attribute results of pKa measurements to the nominal oxoacids, perhaps assuming that “everybody knows” the limitations of this arbitrary structural assignment. This article describes the experimental facts on the biological oxoacids and model compounds that “everybody”, especially students, may not know. In the supporting information, we provide some exercises suitable for use in general and organic chemistry, which should help to teach equilibrium concepts and clarify the properties of these important compounds.
Crystallization of this acid from water yields a hydrate, with the water being present as a covalent hydrate, that is, dihydroxyethanoic acid, rather than as a water of crystallization (9). The same is true in a cocrystal of the acid with quinoxaline (10). There appear to be no crystal structures of unhydrated glyoxylic acid, although there are many of unhydrated arylglyoxylic acids (ArCOCO2H). Moreover, the crystal structures of sodium (11), potassium, rubidium (12), and manganese(II) (9) glyoxylate salts all show the hydrated anion as a dihydroxyacetate ion. The crystal structures thus favor a persistent dihydroxyethanoyl structure for both the acid and its conjugate base. 13C NMR spectra in the solid state and in 0.5 M D2O solution likewise showed only hydrated anion (resonances at δ 88 and 179) (13). Although a 1971 IR study of oxoethanoic acid in the gas phase (14) described only the anhydrous form, a more recent
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r 2010 American Chemical Society and Division of Chemical Education, Inc. pubs.acs.org/jchemeduc Vol. 87 No. 10 October 2010 10.1021/ed1003096 Published on Web 08/06/2010
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Journal of Chemical Education
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In the Classroom Table 1. Essential Biological R-Oxocarboxylic Acids
a
pKa0 is defined in Note 1.
gas-phase study revealed both the hydrated and unhydrated forms (15). The tenacity with which the solid hydrate holds on to water has been noted, so one would expect dihydroxyethanoic acid to predominate in aqueous solutions and to be the species to which the empirical pKa0 of Table 1 refers. Proton NMR studies at fairly high concentration (0.5 M) in D2O showed 9% unhydrated oxoethanoic acid at 21 °C and 15% at 85 °C (16). Distinct peaks were observed for the hydrate (H2 at δ 4.9) and the unhydrated oxoacid (H2 at δ 9.3). Several values of the empirical pKa0 of dihydroxyethanoic acid have been reported, sometimes disguised as the pKa of “glyoxylic acid”. Titrimetric values of 3.3 (17), 3.46 (18), 3.38 (19), 2.98 (20), and 3.42 (21) have been reported at 25 °C and various ionic strengths. These values are roughly consistent with pKa values reported for ether analogues of dihydroxyethanoic acid: dimethoxyethanoic acid, 2.92; 1,3-dioxane-2carboxylic acid, 2.97 (22). The pKa of unhydrated oxoethanoic acid cannot be measured directly, but can be estimated from knowledge of the hydration equilibria of the acid and anion (its conjugate base). Measurements combining kinetic and polarographic data yield values for the hydration equilibrium constants KHoxo = [HC(OH)2CO2H]/[HCOCO2H] of 1100 ( 200 for the acids and KHion = [HC(OH)2CO2-]/[HCOCO2-] of 67 ( 5 for the anions (23). From the relationship KH oxo 0 KH oxo ¼ Ka þ KH ion 0
pKa oxo ¼ pKa þ pKH oxo - pKH ion
ð3Þ
(the terms are defined in Scheme 1; also see the supporting information) and using pKa0 of 2.9 measured at 25 °C and ionic strength 0.3 M, these yield a value of 1.7 for the pKaoxo (2 10-2 for the Kaoxo) of the unhydrated oxoethanoic acid. This value is much more consistent with the pKa values of the oxalic acid derivatives (1.2-1.9) cited above than the composite pKa0 of “glyoxylic acid”. An earlier study (19) gave smaller values for the 1080
Journal of Chemical Education
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Vol. 87 No. 10 October 2010
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Scheme 1. Equilibria in Aqueous R-Oxocarboxylic Acid Solutions
hydration constants and a slightly larger but comparable value (2.0) for the pKaoxo of 2. Given that all of the spectroscopic and acidity data make sense if and only if “glyoxylic acid” in aqueous solution is understood as being dihydroxyethanoic (dihydroxyacetic) acid, we can see little purpose in retaining the historic name, which obfuscates the facts. Its use has led, for example, to such peculiarities as the assignment of a 13C resonance at δ 89.4 “to the aldehyde group of glyoxylic acid” (21). 2-Oxopropanoic (Pyruvic) Acid Several values have been reported for the empirical pKa0 of pyruvic acid (2.4 ( 0.2). Although the values are internally consistent, they are higher than expected for the actual oxoacid (ca. 1.8) and lower than expected for 2,2-dihydroxypropanoic acid (ca. 3.0). The values appear to represent a composite value reflecting the intrinsic acidities of both the hydrated and unhydrated forms and their relative concentrations. As in the previous case, knowledge of the hydration equilibria can be used to deconvolute the pKa data, and calculations involving them can be used to teach and assess students' understanding of equilibria (see the supporting information). Crystal structures of pyruvic acid (24), its sodium and potassium salts (25), and a benzamidinium salt (26) all show
pubs.acs.org/jchemeduc
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r 2010 American Chemical Society and Division of Chemical Education, Inc.
In the Classroom Table 2. Equilibrium Constants for Hydration and Ionization of Pyruvic Acid Ratioa
Reference
0.35, 4.29
1.24
28
0.35, 4.29
1.23
29
0.74
29
b
Kaoxo
Kahyd
KHoxo
KHion
T/°C
10-2.18 = 0.00661
10-3.6 = 2.51 10-4
1.55
0.073
25
10-3.6 = 2.51 10-4
4.42
0.207
0
10-2.95 = 1.12 10-3
1.80
0.053
23
0.6, 6.0
10
-2.18
= 0.00661
10-1.55 = 0.0282
-3
1.18
0.17
27
2.0, 4.0
2.45
30
10-1.97 = 0.0107
10-3.53 = 2.95 10-4
2.31
0.063
25
