Table of Contents

Dr. Paul Boyle's Crystal Growing Recipes--an excellent resource.

Introduction

Producing good quality crystals of a suitable size is the first and most important step in determining any crystal structure. Crystallization is the process of arranging atoms or molecules that are in a fluid or solution state into an ordered solid state. This process occurs in two steps--nucleation and growth. Nucleation may occur at a seed crystal, but in the absence of seed crystals usually occurs at some particle of dust or at some imperfection in the surrounding vessel. Crystals grow by the ordered deposition of material from the fluid or solution state to a surface of the crystal.

The shapes of crystals depend on both the internal symmetry of the material and on the relative growth rate of the faces. In general, the faces of the crystal that grow most rapidly are those to which the crystallizing particles are bound most securely. These rapidly growing faces are usually the smaller, less well developed faces. Thus, the larger faces are usually associated with directions in the crystal where there are only weak intermolecular interactions.

There are numerous ways to grow crystals. The choice of method depends greatly upon the physical and chemical properties of the sample. For solution methods of crystallization, the solubility of the sample in various solvent systems must be explored. If heating methods are selected for growing crystals, the thermal stability and melting point of the sample should be determined.

There are a few general points that apply to all crystallization methods.

• It is important that the sample be as pure as possible. When crystallization attempts consistently yield oils, the sample is probably not pure. The solvents or cocrystallizing materials should be as pure as possible. Contaminants may often break down the desired sample.
• It is important for most solution methods that the glassware be thoroughly clean and "old" or "used." New glassware is so smooth that there are no nucleation sites available on the exposed surfaces. Also, new glassware from the manufacturer usually has a variety of dusty contaminants.
• If a sample only yields small crystals, the method should be altered so as to slow down the growth step. Slowing the crystal growth sometimes requires changing the method used to grow the crystals.
• Avoid vibrations near your growing crystals.
• Finally be patient! Some methods work in a few hours, and other methods require weeks or even months for success.

Evaporation

Evaporation is by far one of the easiest methods for crystallizing organic and organometallic small molecule compounds. The choice of solvent is very important because it can greatly influence the mechanism of crystal growth and because the solvent may be incorporated into the crystalline lattice. It is customary to screen a large number of solvents or solvent mixtures to find the best conditions for crystal growth. The rate of crystal growth can be slowed either by reducing the rate of evaporation of the solvent or by cooling the solution. Formation of only a few rosette-shaped masses is an indication of an insufficient number of nucleation sites. The number of nucleation sites may be increased either by seeding the solution or by scratching the exposed surfaces of the glass vessel.

Vapor and Liquid Diffusion

Liquid and vapor diffusion methods are often tried when evaporation methods do not immediately succeed. Both methods require finding two solvents or solvent mixtures in which the compound is soluble in one system but insoluble in the other. The two solvent systems should be immiscible or nearly immiscible for liquid diffusion and should be miscible for vapor diffusion. Crystal growth may be slowed somewhat by cooling the apparatus.

Liquid diffusion usually requires that the less dense solvent system be carefully layered on top of the more dense system. The sample can be dissolved in either solvent system. Crystals grow at the interface between the solutions. When compounds precipitate immediately upon being formed, it is possible to slow down the reaction and thus grow larger crystals by putting the reactants in different liquid layers which are separated by a third solvent layer that is not miscible with either of the layers or with the sample. Note that the top layer should be added very slowly to assure a minimum of mixing of the layers.

Vapor diffusion is carried out by dissolving a small amount of the sample in a small vial, then placing this inner vial inside a larger vial that contains a small volume of a solvent system in which the sample is insoluable. The outer vial is then sealed. Vapor from the solvent of the outer vial then diffuses into the solution in the inner vial, causing the compound to grow crystals. The vertical surfaces of the inner vial should not touch the outer vial to keep the outer solution from rising by capillary action and filling the inner vial.

Thermal Gradient

Thermal gradient methods usually produce very high quality crystals. Such methods include slow cooling of sealed, saturated solutions, refluxing of saturated solutions, sublimation, and zonal heating. Zonal heating is used primarily for crystallizing solid solutions or mixtures. Small crystals may sometimes be grown larger by zonally refluxing a supersaturated solution. Sublimation may be carried out in a variety of tubes or vessels. Sealed vessels offer an advantage for sublimation in that the chamber may be evacuated or a partial pressure of some inert gas may be introduced before sealing the sample in the apparatus. Sublimation methods consistently produce very high quality crystals. Larger crystals may be grown either by decreasing the thermal gradient or by cyclic heating and cooling of the sample.

Gel Diffusion

Some compounds, that precipitate as very small crystals immediately upon synthesis, are extremely insoluble. Suitable crystals of these compounds can often be prepared by greatly decreasing the rate at which the reactants combine by making the reactants diffuse through a gel barrier. This is often carried out by forming a gel in a U-tube, then introducing the reactants in the two separate ends of the tube. Such methods usually take weeks to months to produce crystals, depending on the rate of diffusion of reactants through the gel.

Cocrystals and Clathrates

The crystal structure of some compounds can only be determined by coordinating the compound with another material or by incorporating the compounds into a lattice of another material. Crystals that contain two or more different compounds are called cocrystals. Some crystal mixtures are simply formed by the incorporation of one or more solvent molecules into the lattice of the compounds of interest. Other cocrystal mixtures are formed when the compound of interest is bonded to a large molecule such as triphenylphosphine oxide usually through a hydrogen bond. A final group of cocrystals can be thought of as being formed by incorporating the compound of interest or guest molecule into the small vacant regions in the lattice around large, rigid host molecules. This lattice of host/guest molecules is called a clathrate. Structures of porphyrin-based clathrates are very common.

Choice of Solvents and Counter Ions

There are a number of solvents and counter ions that are commonly found to be disordered in crystal structures and thus should be avoided if possible. The solvents giving the most trouble are petrolueum ether, mixed hydrocarbons like hexanes or kerosene, and halogenated hydrocarbons such as methylene chloride and chloroform. Often these solvents occupy sites in a crystal structure that are larger than the solvent molecule. The halogenated solvents are particularly troublesome because the disorder includes heavier atoms. Better choices of solvents are benzene, xylene, primary and secondary alcohols, and tetrahydrofuran. If good quality crystals can only be grown using these problematic solvent(s), then by all means use these solvent(s). Getting good quality crystals is the most important step in the whole crystal structure process.

The counter ions most likely to cause difficulties are are Bu₄N⁺, BF₄^-, and PF₆^-. Some alternative counter ions that are usually ordered are triflate, BPh₄^-, (Ph₄P)₂N⁺, and Ph₄As⁺.

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To evaluate the quality and appropriate size of crystalline samples, the samples should be examined under low power (10X to 40X) magnification. Good crystals usually have smooth flat faces, sharp edges, no inclusions, no striations, and no obvious dislocations. Careful notes should be made if the bulk sample is not visibly homogeneous. The selected crystal should show no obvious external twinning (e.g. reentrant faces or different parts of the crystal extinguishing at different rotation angles under a polarizing microscope). The typical crystal habit and point group symmetry should be noted.

The crystal chosen for analysis needs to be large enough to produce an adequate diffraction pattern and, at the same time, as small as possible to minimize absorption problems. The calculation of structure factor amplitudes assumes that the crystal is being completely bathed in a uniform beam of X-rays. Since the uniform region of the X-ray beam is about 0.5 mm in diameter, this is taken as the maximum dimension of any crystal. For most samples, a minimum dimension of 0.1 mm is needed to produce adequate X-ray scattering. Compounds with few atoms or very heavy atoms can have all three dimensions toward the small end of this 0.1 to 0.5 mm range. The best crystals for compounds with many light atoms should have all three dimensions toward the large end (0.4-0.5 mm) of this range. Crystals that are too large can be cut with a razor blade, scalpel, or solvent saw.

If the crystals are strongly absorbing (contain heavy atoms), it is worthwhile to reshape the crystal to make it as nearly spherical as possible. This reshaping may be done by cutting, grinding or dipping the crystal in solvent.

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An excellent treatment of crystal mounting is given by Dr. Bev Vincent from MSC/Rigaku.

Crystal mountings must be rigid to hold the sample in the same orientation and must minimize the amount of extraneous material that is in the incident and diffracted beam paths. The sample support is usually made from an amorphous material such as glass that is held in a metal pin and clamped on a goniometer head. Solid glass fibers may be used; however, fibers pulled from glass tubing are actually small capillary tubes and are more rigid than solid glass fibers. These narrow tubes also place less non-crystalline material in the X-ray beam path than solid fibers.

Air stable crystals are usually glued (using epoxy, Elmers/water, Duco/amyl acetate, etc.) to the end of a glass fiber. The sample should be mounted with its smallest surface on the end of the glass fiber to minimize absorption effects and to minimize background scattering from the sample mount.

Mildly air unstable compounds can be coated with epoxy or an inert viscous material such as Paratone N™ or Krytox™ oil. These mountings are usually carried out in an inert atmosphere such as a dish filled with argon gas. The crystal is further kept from reacting during data collection by cooling the sample in a chilled, inert (nitrogen) gas stream.

Very reactive compounds must be mounted in a glove bag or glove box and sealed in capillary tubes. Crystals of these compounds are usually wedged in capillary tubes or are held in place by a small amount of grease. Capillary tubes containing unstable compounds must be sealed by melting the ends of the glass tube.

Capillaries do introduce two kinds of problems. The curvature of the capillary distorts the image of the crystal when centering the sample on the diffractometer. Also, the glass itself significantly increases both the background scattering and the absorption of the incident beam of X rays. It is crucial that the capillaries be made out of thin glass similar to that found in commercially available capillaries. Thick glass capillaries absorb X rays so much that very little scattered radiation will leave the capillary.

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