Purifying Compounds by Recrystallization

Perform all steps in a fume hood to prevent exposure to solvent fumes.

1. Selecting a Solvent

1. Place 50 mg of the sample (N-bromosuccinimide) in an Erlenmeyer flask.
2. Add 0.5 mL of boiling solvent (water). If the sample dissolves completely, the solubility in the cold solvent is too high to be a good recrystallization solvent.
3. If the sample does not dissolve in the cold solvent, heat the test tube until the solvent boils.
   1. If the sample has not completely dissolved at this point, add more boiling solvent drop-wise, until all of the solid dissolves. If it takes more than 3 mL to dissolve the sample in the hot solvent, the solubility in this solvent is probably too low to make it a good recrystallization solvent.
4. If the first choice of solvent is not a good recrystallization solvent, try others. If a single solvent that works cannot be found, try a two solvent system.
   1. If you cannot find a suitable single solvent system, then a solvent pair may be necessary. When identifying a solvent pair, there are several key considerations 1) The first solvent should readily dissolve the solid. 2) The second solvent must be miscible with the 1^st solvent, but have a much lower solubility for the solute.
   2. As a general rule "likes dissolve likes" meaning that polar compounds tend to be soluble in polar solvents and non-polar compounds are often more soluble non-polar compounds.
   3. Common solvent pairs (Table 1)
5. Make sure the solvent has a boiling point of at least 40 °C, so there is a reasonable temperature difference between boiling solvent and room-temperature solvent.
6. Ensure that the solvent has a boiling point below about 120 °C, so it's easier to remove the last traces of solvent from the crystals.
7. Also make sure the boiling point of the solvent is lower than the melting point of the compound, so the compound forms as solid crystals rather than as an insoluble oil.
8. Confirm that the impurities are either insoluble in the hot solvent (so they can be hot-filtered out, once the compound is dissolved) or soluble in the cold solvent (so they stay dissolved during the entire process).

2. Dissolving the Sample in Hot Solvent

1. Place the compound to be recrystallized in an Erlenmeyer flask. This is a better choice than a beaker, since the sloping sides help trap solvent vapors and slow the rate of evaporation.
2. Place the solvent (water) in a separate Erlenmeyer flask, and add boiling chips or a stir bar to keep it boiling smoothly. Heat it to boiling on a hotplate.
3. Add hot solvent to a flask at room temperature containing the compound in small portions, swirling after each addition, until the compound is completely dissolved.
   1. During the dissolution process, keep the solution hot at all times by resting it on the hotplate, too. Do not add more hot solvent than necessary - just enough to dissolve the sample.
4. If a portion of the solid does not seem to dissolve, even after more hot solvent has been added, it is likely due to the presence of very insoluble impurities. If this happens, stop adding solvent and do a hot filtration before proceeding.
   1. To perform a hot filtration, fold a piece of filter paper into a fluted cone shape and place it into a glass stemless funnel.
   2. Add a 10-20% excess of hot solvent to the hot solution to allow for evaporation in the procedure.
   3. Pour the solution through the paper. If crystals begin to form at any time during the process, add a small portion of warm solvent to dissolve them.

3. Cooling the Solution

1. Set the flask containing the dissolved compound on a surface that does not conduct the heat away too quickly, such as a paper towel set on a benchtop.
2. Lightly cover the flask as it cools to prevent evaporation and to prevent dust from falling into the solution.
3. Leave the flask undisturbed until it cools to room temperature.
4. Once the crystals have formed, place the solution in an ice bath to ensure that the maximum amount of crystals is obtained. The solutions should be left undisturbed in the ice bath for 30 min to 1 h, or till the compound appears to have completely crystalized out of solution.
5. If no crystal formation is evident, it can be induced by scratching the inside walls of the flask with a glass rod or by adding a small seed crystal of the same compound.
   1. If this still fails to work, then too much solvent was probably used. Reheat the solution, allow some of the solvent to boil off, then cool it.

4. Isolating and Drying the Crystals

1. Set the cold flask containing the newly formed crystals on a benchtop.
2. Lightly cover the flask to prevent evaporation and to prevent dust from falling into the solution.
3. Isolate the crystals by vacuum filtration, using either a Büchner or Hirsch funnel (clamp the flask to a ring stand first).
4. Rinse the crystals on the Büchner funnel with a small amount of fresh, cold solvent (the same solvent used for recrystallization) to remove any impurities that may be sticking to the crystals.
5. To dry the crystals, leave them in the filter funnel and draw air through them for several minutes. Crystals can also be air-dried by allowing them to stand uncovered for several hours or days. More efficient methods include vacuum drying or placing in a desiccator.

Polar Solvent	Less Polar Solvent
Ethyl acetate	Hexane
Methanol	Methylene chloride
Water	Ethanol
Toluene	Hexane

Table 1. Common solvent pairs.