Crystal Growth

Recommended resources for crystal growth:

The primary challenge in a single-crystal diffraction experiment is obtaining a good crystal. The fundamental equation, Garbage in = Garbage out, very much applies to crystallograpy (Müller, 2009) and the quality of crystal is the most important factor in obtaining good data. While some compounds are easier to crystallize than others, it is always a good idea to expend effort in obtaining the best crystal possible. Starting with a pure (or as pure as possible) sample often helps. Crystallization of a sample for single-crystal measurements should be distinguished from preparatory crystallization in purifications. While quickly-grown crystals might be suitable for diffraction, a quality single crystal often requires slow growth and can take anywhere between a few hours to a few months (hopefully not years). The ideal crystal size is somewhere between 100 - 300 μm in each dimension, although small crystals that are ~30 μm in at least two dimensions can be measured depending on composition.

General tips

  • Start by figuring out the solubility profile of your material - what it dissolves in and what it doesn't
  • Choose a solvent for your compound in which solubility is moderate
  • Fewer sites of nucleation are desirable, so try to keep dust and other contaminants out of your vessel
  • Avoid disturbing your crystal - leave crystallizations in a quiet, vibration-free area
  • Exercise patience - good crystals grow slowly

Crystallization Methods

Slow evaporation

This is the simplest method to grow crystals, but is often not the best method. A homogenous sub-saturated or saturated solution of compound is left to evaporate in a clean vessel with an open top, which induces nucleation and crystallization as solvent evaporates. Slowing down the rate of evaporation by limiting the open area of the vessel can help greatly. For example, if performing slow evaporation in a glass vial, covering the top with Parafilm or aluminum foil and poking a small hole will slow down the process and improve crystallization. Leaving NMR tubes with the cap loosely attached is also a common way to crystallize material by slow evaporation. When performing slow evaporation try not to let it evaporate fully to dryness to avoid desolvation.

Advantages - Easy to set up

Disadvantages - Requires a relatively large amount of sample, does not perform well for compounds that co-crystallize with solvent, often not viable for sensitive compounds

Slow cooling

Slow cooling can work quite well especially if the rate of cooling is not sudden. A solution of material close to its saturation point is reduced in temperature which induces crystallization. This can be performed 'hot', where the compound is suspended in solution and heated above room temperature to form a saturated solution. This is filtered to obtain a homogenous, saturated solution which is allowed to cool slowly to room temperature. Slow cooling can also be performed by cooling a homogenous, saturated solution (at room temperature) of a compound to low temperatures. This is a popular way of crystallizing air-sensitive materials as many gloveboxes are equipped with freezers in the 233 - 243 K range.

Advantages - Easy to set up, avoids exposure to the surrounding atmosphere

Disadvantages - Requires a relatively large amount of sample, often difficult for very non-polar compounds (soluble in alkanes, etc.)

Vapour diffusion

Vapour diffusion is one of the best methods for growing high-quality crystals. A solvent is used to dissolve the compound and an anti-solvent, which must have a lower vapour pressure, evaporates slowly such that the solvent and anti-solvent mix slowly to lower the solubility of the compound in the combined solvent system. The solvent and anti-solvent must also be miscible so that mixing occurs. Some common solvents are toluene, tetrahydrofuran, ethyl acetate, acetonitrile, dichloromethane, chloroform, ethanol, methanol, dimethylformamide, etc. Suitable anti-solvents include diethyl ether, pentane, hexane, and cyclohexane (check miscibility, boiling point, and vapour pressure!).

Advantages - Works for small amounts of compound, good for trying many solvent combinations, easy to setup up serial crystallizations

Disadvantages - Requires slightly more effort

Layering

Layering is similar to vapour diffusion and can work very well, but requires careful setup. Like diffusion, the solvent should dissolve the compound and the anti-solvent should not. Again, the solvent and anti-solvent must be miscible. The compound is dissolved in solvent and the anti-solvent is added slowly, usually dropwise with a pipette or syringe along the side of the vessel, to create an interface between the solvent and anti-solvent. Anecdotally, solvents with a high density (e.g. dichloromethane or chloroform) layered with an anti-solvent can produce good results. A third solvent can also be used to interface the solvent and anti-solvent; for example, the compound can be dissolved in dichloromethane, layered with benzene/toluene, then layered with diethyl ether/pentane. NMR tubes are very convenient for layering, especially if an NMR sample was prepared with chloroform. One can add ~ 1 mL of anti-solvent slowly to the NMR tube and leave it undisturbed for a while.

Advantages - Easy to set up with your NMR samples

Disadvantages - Poor results if not performed carefully enough or if accidentally disturbed

What if none of these methods work?

Some compounds are harder to crystallize than others. Alternative crystallization methods can be explored, such as sublimation, crystallization from the melt, reactant diffusion, and seeding. If that fails, chemical modification can modify crystallization characteristics or increase the scattering power of the crystal. Functionalizing your molecule with 'rigid' groups (e.g. phenyl or other arenes) can make crystallization easier. Protonation or deprotonation of your compound to form a salt may also help. Counter-ion exchange can also improve crystallinity in charged compounds. Incorporating a heavy atom can be very useful especially for light-atom organic compounds that contain atoms with Z < 8. If a compound contains an alcohol or amine, consider a protecting group that contains an heavy element (Z > 15) such as sulfur, bromine, iodine, etc.