Acid-Base Extraction

Updated Apr 17, 2026

Acid-base extraction is a clever variant of liquid-liquid extraction where the pH of the aqueous layer is adjusted to selectively ionize specific compounds, forcing them into the aqueous layer. By doing two or three sequential extractions at different pH, you can separate a mixture into acidic, basic, and neutral components.

The Principle: Ionize to Dissolve

Neutral organic compounds dissolve preferentially in the organic layer. Charged organic compounds dissolve preferentially in the aqueous layer.

An organic acid (RCOOH, pKa 4-5) is neutral below its pKa (goes to organic layer). Above its pKa, it is deprotonated (RCOO⁻, goes to aqueous layer).
An organic base (RNH₂, conjugate acid pKa 9-10) is neutral above its pKa (goes to organic layer). Below its pKa, it is protonated (RNH₃⁺, goes to aqueous layer).
A phenol (ArOH, pKa 10) is neutral below its pKa (organic). Above its pKa, it is deprotonated (ArO⁻, aqueous).
A neutral compound (hydrocarbon, alcohol, ether, ester, ketone, aldehyde) has no acid-base sensitivity at reasonable pH - stays in organic layer regardless.

Standard Separation Sequence

For a mixture of a carboxylic acid, an amine, and a neutral compound dissolved in an organic solvent:

Step 1: Wash with aqueous 5% NaOH. This deprotonates the carboxylic acid (pKa 4-5 << 14) to carboxylate anion, which goes into the aqueous layer. The amine stays neutral (not basic enough to be deprotonated). The neutral compound stays in organic.

After Step 1: organic layer has amine + neutral. Aqueous layer has sodium carboxylate.

Step 2: Wash the organic layer with aqueous 5% HCl. This protonates the amine (pKa ~10 >> 1) to ammonium cation, which goes into the aqueous layer. The neutral compound stays in organic.

After Step 2: organic layer has neutral compound only. Second aqueous layer has ammonium chloride.

Step 3: Wash the organic layer with water to remove any remaining acids or bases.

Step 4: Dry, filter, and evaporate to recover the neutral compound.

Step 5: Recovering each component:

Aqueous layer 1: acidify with HCl → carboxylic acid precipitates or can be extracted back into ether.
Aqueous layer 2: basify with NaOH → amine precipitates or can be extracted back into ether.

Phenols: The Intermediate Case

Phenols (pKa ~10) are too weak to be deprotonated by NaHCO₃ (carbonic acid pKa ~6) but are deprotonated by NaOH (water pKa ~16). So you can distinguish:

NaHCO₃ wash: extracts only carboxylic acid (pKa ~5). Phenol and everything else stay in organic.
NaOH wash: extracts both carboxylic acid AND phenol.

Using NaHCO₃ first, then NaOH, separates carboxylic acid from phenol:

Step 1: NaHCO₃ wash → aqueous layer gets only carboxylic acid.
Step 2: NaOH wash → aqueous layer gets only phenol.

Practical Tips

Use DILUTE acid/base (5-10%). Concentrated acid/base can cause emulsions and degradation.
Emulsions can be broken by adding brine (saturated NaCl), changing temperature, or filtering through Celite.
Keep track of which layer has which component. A simple table helps.

Biological Parallel: Drug Pharmacokinetics

Acid-base extraction principles govern drug distribution in the body:

Weakly acidic drugs (aspirin, pKa ~3.5) are uncharged in the stomach (pH 1-2) and absorbed there.
Weakly basic drugs (amphetamine, pKa ~10) are charged in the stomach (pH 1-2) and stay in the GI lumen; they absorb in the small intestine (pH 6-7) where they are less ionized.
Lipid-soluble (neutral, nonpolar) drugs cross membranes easily; ionized forms do not.

This pH-dependent partitioning is why drug pKa and environmental pH together determine absorption, distribution, and excretion.

Describe how to separate a mixture of benzoic acid, aniline, and naphthalene using acid-base extraction.

Click to reveal answer

Step 1: Dissolve the mixture in an organic solvent (like ether). Step 2: Wash with aqueous 5% HCl. Aniline (basic amine) is protonated to anilinium chloride and goes into the aqueous layer. Organic layer retains benzoic acid + naphthalene. Step 3: Wash the organic layer with aqueous 5% NaOH. Benzoic acid is deprotonated to sodium benzoate and goes into the aqueous layer. Organic layer retains only naphthalene. Step 4: Recover each: (a) basify the aniline aqueous layer with NaOH and extract back into ether to get free aniline; (b) acidify the benzoate aqueous layer with HCl to precipitate benzoic acid; (c) evaporate the organic layer to obtain naphthalene.