Acid–base extraction is a subclass of liquid–liquid extractions and involves the separation of chemical species from other acidic or basic compounds. It is typically performed during the work-up step following a chemical synthesis to purify crude compounds and results in the product being largely free of acidic or basic impurities. A separatory funnel is commonly used to perform an acid-base extraction. Acid-base extraction utilizes the difference in solubility of a compound in its acid or base form to induce separation. Typically, the desired compound is changed into its charged acid or base form, causing it to become soluble in aqueous solution and thus be extracted from the non-aqueous (organic) layer. Acid-base extraction is a simple alternative to more complex methods like chromatography. It is not possible to separate chemically similar acids or bases using this simple method.

Background theory

Acid-base extraction works on the fundamental principle that salts are ionic compounds with a high solubility in water, while neutral molecules typically lack solubility in water. Consider a mixture of acidic and basic compounds dissolved in an organic solvent. Adding aqueous acid will cause the acidic component to stay uncharged, while the basic component will be protonated to form a salt. The uncharged acid component will remain dissolved in the organic solvent, while the highly charged basic salt will migrate to the aqueous solvent. Since the acidic and basic components are now in two different layers, they can easily be separated. Alternatively, adding aqueous base will cause the acidic component to be deprotonated and form a salt, while the basic component will remain uncharged. In this case, the uncharged base will stay in the organic layer, while the highly charged acidic salt will migrate to the aqueous layer. If the organic acid component is relatively weak and has a pKa value of ~5 (such as a carboxylic acid), adding additional acid can further improve separation by lowering the pH of the solution. This minimizes the self ionization of the organic acid component and limits its tendency to enter the aqueous layer. This principle is also applicable to an organic base when it is a relatively weak base. Although acid-base extractions are most commonly used to separate acids from bases, they can be used to separate two acids or two bases from each other. However, the acids and bases must differ greatly in strength, e.g. one strong acid and one very weak acid. Therefore, the two acids must have a pKa (or pKb) difference that is as large as possible. For example, the following can be separated: When separating two acids or two bases, the pH is usually adjusted to a value roughly between the pKa (or pKb) constants. Separation occurs at this intermediate pH because one component is fully ionized, while the other is fully in its neutral form. Often, the solutions used to extract the acids or bases can also be used to control the pH. When separating two acids, the mixture is first washed with a weak base (e.g. sodium bicarbonate) to extract the strong acid, then washed with a strong base (e.g. sodium hydroxide) to extract the weak acid. For separating basic components, weak acid (e.g. dilute acetic acid) is first used to extract the stronger base, then more concentrated acid (e.g. hydrochloric acid or nitric acid) is used to create strongly acidic pH values and separate the weaker base.

Technique

The following procedure is typically followed when performing an acid-base extraction for a mixture containing an acidic and/or basic compound:

Common uses in chemical synthesis

Acid-base extraction is frequently used as the first step in a work-up procedure following a chemical synthesis to remove acidic and basic starting materials or impurities. Acid-base extraction is typically a precursor to more complicated purification techniques, such as recrystallization, if the product synthesized is still not completely pure. Organic synthesis often uses acid-base extractions during work-up procedures. For example, consider a Fischer esterification –– the condensation of a carboxylic acid with an alcohol to form an ester. The post-reaction mixture often consists of small amounts of leftover acid and alcohol, in addition to the desired ester. Acid-base extraction can be used to easily separate out the acidic starting materials from the ester. By rinsing the crude product mixture with a weak base (e.g. sodium bicarbonate), the carboxylic acid and alcohol will be washed away with the aqueous layer, leaving purified ester in the organic layer. The choice of base used for extraction is critical, as a strong base (e.g. sodium hydroxide) will hydrolyze the ester. Another common example of acid-base extraction occurs following peptide coupling, where the amide product must be separated from leftover carboxylic acid and amine. The carboxylic acid can be removed by rinsing the organic layer with weak base (sodium bicarbonate), while the amine can be removed by rinsing with a weak acid (10% hydrochloric acid). Following these two extractions, the amide will remain in the organic layer and has been significantly purified.

Troubleshooting

The following issues are commonly observed during acid-base extraction and typically have simple solutions

Limitations

Acid-base extraction is efficient at separating compounds with a large difference in solubility between their charged and their uncharged form. Therefore, this procedure will not work for:

Alternatives

Alternatives to acid–base extraction include: