Dicarboxylic Acids
A dicarboxylic acid has two -COOH groups. Each can ionize separately, giving two distinct pKa values: pKa1 (first ionization) and pKa2 (second ionization). Critically, pKa1 < pKa2 because once the first carboxylate forms, its negative charge destabilizes removal of the second proton.
The pKa Splitting Pattern
| Diacid | pKa1 | pKa2 | Gap |
|---|---|---|---|
| Oxalic (HOOC-COOH) | 1.25 | 3.81 | 2.56 |
| Malonic (HOOC-CH₂-COOH) | 2.85 | 5.70 | 2.85 |
| Succinic (HOOC-(CH₂)₂-COOH) | 4.21 | 5.64 | 1.43 |
| Glutaric (HOOC-(CH₂)₃-COOH) | 4.34 | 5.27 | 0.93 |
| Adipic (HOOC-(CH₂)₄-COOH) | 4.43 | 5.41 | 0.98 |
| Fumaric (trans-HOOC-CH=CH-COOH) | 3.03 | 4.44 | 1.41 |
| Maleic (cis-HOOC-CH=CH-COOH) | 1.83 | 6.07 | 4.24 |
Note two patterns:
- pKa1 < pKa2 always. The first deprotonation is easier than the second because the second one is disfavored by the electrostatic cost of creating a second anion near the first.
- Shorter diacids have more separation between pKa1 and pKa2. Oxalic (2 C between COOHs: 1 bond, so ~3 Å) has pKa2 - pKa1 ≈ 2.5. Adipic (4 C between) has the two pKas much closer together (~1 unit separation).
The shorter the chain between the two COOH groups, the stronger the electrostatic interaction between them, and the greater the pKa splitting.
Maleic Acid: The Extreme Case
Maleic acid has cis-C=C between two COOH groups. The two carboxylic acid groups are held close in space (~3 Å), and after pKa1 (1.83, very acidic), the resulting monoanion forms an intramolecular hydrogen bond with the remaining COOH. This stabilizes the monoanion, making pKa1 very low. But the hydrogen bond also stabilizes the monoanion enough that removing the second H is very hard - pKa2 is 6.07, much higher than typical.
Result: maleic acid has pKa1 = 1.83 and pKa2 = 6.07 - a huge 4-unit gap. Fumaric (trans) does not have the intramolecular H-bond (the two COOHs are on opposite sides), so its gap is much smaller.
Oxalic Acid: The Most Acidic Simple Diacid
Oxalic acid (pKa1 = 1.25) is one of the strongest common carboxylic acids because the adjacent COOH strongly withdraws electrons from the ionizing COOH. Each COOH’s carboxylate would destabilize the adjacent carboxylate, but the first ionization is significantly accelerated by the inductive effect of the unionized second COOH.
Oxalic acid is toxic in high doses because its calcium salt (calcium oxalate) forms kidney stones. Rhubarb leaves and spinach contain enough oxalic acid to be moderately toxic in large quantities.
Biological Dicarboxylic Acids
The Krebs cycle (TCA cycle) is full of dicarboxylic acids:
- Oxaloacetate (OAA): HOOC-CO-CH₂-COOH. A 4-carbon diacid with a ketone. Starting material of the cycle.
- Malate: HOOC-CHOH-CH₂-COOH. 4-carbon diacid with a hydroxyl.
- Fumarate: trans-HOOC-CH=CH-COOH. 4-carbon diacid with a double bond.
- Succinate: HOOC-(CH₂)₂-COOH. 4-carbon diacid (no extras).
- Citrate: HOOC-CH₂-C(OH)(COOH)-CH₂-COOH. 6-carbon triacid!
All of these are fully ionized at pH 7 (both COOHs deprotonated). Their pKa values (around 3-5 for the first, 4-6 for the second) are well below physiological pH.
Amino Acids: Another pKa Splitting Story
Amino acids have both a -COOH (pKa ~2) and a -NH₃⁺ (pKa ~9). At pH 7, the COOH is deprotonated (5 units above its pKa → 99.999% deprotonated) and the NH₃⁺ is still protonated (2 units below its pKa → 99% protonated). The result is the zwitterion: +H₃N-CHR-COO⁻.
The isoelectric point (pI) of a simple amino acid is (pKa1 + pKa2)/2. For glycine: (2.35 + 9.78)/2 = 6.06. This calculation is covered in more detail in the Biochemistry book on amino acids.