The main pro of recrystallization is that it is convenient to try. If you have a lot of different separations on your TODO list, you can start with the one that needs the chromatography and sacrifice before that 20 min of recrystallization optimization. If it doesn’t work the compound is still there. This is especially true if you use the “quick-‘nd-dirty” setup with a condenser plugged with septa.
Table 6. Common solvents for recrystallization.
| Solvent (mixture) | Comment |
|---|---|
| EtOH | Easily one of the most general solvents that is if you have minor impurities |
| nHex/acetone | Works nice especially if you can leave open in the back of the fume hood for cooling thereby decreasing solvent amount |
| nHex/THF | Also a nice general mixture |
| nHex/EA | Less well suited than acetone but works occsionally. Mostly, if there are a lot of impurities. |
| nHex | If your compound solubilizes in hot nHex might be worth a try but prone to problems with oiling out |
| Water | I know, I know. But do consider that water doesn’t like to solubilize organics but can be heated very high. For compounds polar enough this can be a good choice. Can be... |
| nHex/Et2O | If your compound doesn’t want to solubilizes but dissolves well in pure Et2O then dissolve and add another 50% volumn of solvent. Then, slowly add hexane until the solution is cloudy. Heat carefully and leave the flask open for cooling in the back of the fume hood for 1-2 h. Works sometimes. |
There are no precise rules for choice of solvent or which solvent solubilizes what. One rule of thumb might be helpful: solvents containing the same functional group as the compound often are very good solubilizers for this molecule. So, ethyl acetate for esters, acetone for ketones etc. Certain molecular fragments or functional groups can indicate a good crystallization behaviour and others are more likely to lead to oils. This is a table from experience and not related to any real property.
Table 8. General estimation of influence of particular moieties on recrystallization.
| Name | Crystallization | Comment |
|---|---|---|
| Aliphats | ↓ ↓ | Even for long chains, the solids do not crystallize well. |
| Adamantyl | ↑ ↑ | Works nice with mixtures Hex/EA |
| Alkene | ↓ | Simple internal or external alkenes don’t like crystallization |
| Alcohol | ↓ | |
| Ketone | → | |
| Aldehyde | → | |
| Ether | ↓ | |
| Ester | ↓ ↓ | |
| Thioester | ↓ ↓ | Thioesters need another good crystallizing moiety and generally work good with mixtures of nHexane |
| Carboxylic Acid | ↑ ↑ | Good in EtOH/MeOH/Water |
| Carboxylic Acid Salt | ↑ ↑ ↑ | Crystallization depends on counter ion |
| Amide | ↑ | While amides like to solidify recrystallization can be a pain |
| Amine | ↓ ↓ | Amines are bad. Try strategies with protonation e.g. HCl in Et2O or in water |
| Oxime | ↑ ↑ | |
| Thioether | ↓ ↓ | |
| Thiols | ↓ | Aryl thiolates can crystallize but are tricky. Thiolates are easy to make but solubilize bad. |
| Sulfones | ↑ ↑ | |
| Sulfonic Acids | ↑ ↑ ↑ | Acidic Media |
| Pyridine | ↓ ↓ | Pyridine and annulated pyridines crystallize worse than their non-heteroaromatic counterparts. |
| Naphthalene | ↑ ↑ | Works well in light petroleum or hexanes |
| Anthracene | ↑ ↑ | Crystallize really well in solvents like toluene, however, are also prone to sublimation. |
| Aryl- | → | Generally, the more substituted with crystallizing moieties the better. |
| Toluyl- | ↑ | |
| Methoxyphenyl | ↑ ↑ | |
| Nitroaryl | ↑ ↑ | Alcoholic solvents |
| Haloaryl | ↑ ↑ | Work nice in boiling hexanes/PE |
| Benzyl | ↑ | |
| Tosylates | ↑ ↑ | EA is sometimes a good solvent |
For acidic or basic moieties the possibility of crystallizing the salt is also something to make use of. Amines with otherwise non-polar groups (chlorophenol, aryl, ester) can be protonated by acidic extraction with HCl. For each acid/base, modification on crystallization there is also an option of change in cations or anions, e.g. make hydrochloride salt from an amine, filter, then precipitate as sulfate salt. For these moieties, the option of co-crystallisation exists in which hydrogen bonds are leveraged to manipulate the solubility of a single compound. This is obviously a problematic as the separation needs another compound and should only be applied to rare examples or APIs.
First of all, it’s important to know if you ever find a procedure to crystallize in water, the product will be as pure as hell. Whoever implements something like this knows what he is doing! Water is not a nice solvent because if the crystallization didn’t work the getting rid of is tedious. On high heat, water can act much more like an organic solvent as you might think, this is why as a last resort, this is worth a try.
Always use a plastic stopper with no red plastic plate. as an under pressure might occur during cooling of the crystallization mixture. With the hole in the cap LN2 can be filled in and the stopper ejected from the flask.
In old literature data, you might find the last part of the purification as recrystallization in CCl4. This has been employed as to increase the weight of the compound due to the low visibility of this particular solvent in NMR. Be careful when you see this.