Choice of recrystallisation solvent

The ideal solvent for a recrystallisation is one in which the compound is highly soluble when hot, but poorly soluble when cold; additionally, the impurities should either be insoluble in the solvent (so that they can be filtered out before the recrystallisation), or very soluble in the solvent (so that they remain in the solvent when the desired product crystallises, and can be washed away). Typical requirements of a recrystallisation solvent with the compound to be recrystallised are:

• Low solubility when cold

• High solubility when hot

• Chemically compatible

• Impurities readily soluble

• Easy removal from crystals (eg volatile enabling drying)

Additionally, the following factors should be considered:

• Safety: both toxicity and physical hazards (eg flammability)

• Cost

Determining a solvent system

There are a number of pointers to help determine a suitable solvent system for recrystallisation. A good starting point is to look up the compound of interest or compounds of similar structure and see what solvent systems have previously been reported. Databases such as Reaxys or SciFinder usually include notes for the recrystallisation system alongside melting point values. If a suitable solvent is not known, then the solubility of the crude compound should be tested in a variety of different solvents. In general, compounds with polar functionality will dissolve better in polar solvents and vice-versa. Screening solvents is usually carried out by dissolving small quantities (typically ~100 mg) of material with a solvent (~ 1 mL) at room temperature. Any solvents that do not dissolve the compound should then be warmed up to see if the compound dissolves at higher temperatures and hopefully a suitable solvent can be found.

In some cases, a single-solvent recrystallisation is not possible, as there is no single solvent which dissolves the product with an adequate difference in solubility at low and high temperature. This can be overcome by conducting a mixed-solvent recrystallisation, by combining a pair of miscible solvents, chosen so that one solvent dissolves the compound well, and the other dissolves it poorly. This is generally effected by using a “solvent/antisolvent” approach, but if a particularly suitable ratio of solvent mixture is already known, then it is possible to simply use this mixture in place of a single solvent.

Determining a solvent/antisolvent system follows on from the initial solubility tests. Here, you are looking for pairs of miscible solvents where one has a high solubility and the other a very low solubility which may have been identified from the single solvent screening and adding a potential antisolvent to one of the solubility tests where the comound readily dissolved and see if the compound precipitates out.

Boiling points of common solvents

Common solvent pairs

• ethanol/water

• 2-propanol/water

• acetone/water

• ethyl acetate/petrol

• Methanol/diethyl ether