Crystallization and Recrystallization particularly On Scale

Kilomentor has already written about this subject. See the blog, Making a Good Recrystallization Better.

Kilomentor consistently prefers processe that utilize iintermediates that can be protonated or deprotonated at pHs accessible in water and which therefore can undergo phase switches as part of purifications. Such routes are more rugged to the extent that they are less depend upon purification by crystallization of intermediates whose physical properties at the time the route is designed, are unknown. Nevertheless, even with ones best efforts to use routes where the intermediates are acidic or basic, once the molecular weight of intermediates exceeds what can be practically distilled, crystallization is the predominant isolation and purification method for neutral-unionizable intermediates.

Crystallization is of such importance that it is taught early on in (what there is of) laboratory training in universities. The disadvantage of this is that treatment is elementary and laboratory scientists never seem to get around to more sophisticated discussions about it, but learn what more they can by experience, both good and bad.

The crystallization / recrystallization procedures are probably the most important in the laboratory, yet the basic principles that underlie the operations are not widely understood by the average practitioner and rule-of-thumb insights are not passed on.

The most common mistake relating to crystallization is try to crystallize without first applying other methods of purification. The deleterious effect by impurities upon the rate and completeness of crystal formation for the main product is so pronounced that crystallization of crude products should never be attempted until other methods of purification have been applied This is particularly true because these pre-treatments are often very simple. Although crystallization has a high probability for successfully removing impurities, many synthetic chemists do not recognize that they pay an unnecessarily heavy penalty by recrystallizing crude products because the loss from incomplete sluggish crystallization is avoidable. Consideration should be given to first:

� distilling in vacuum

� co-distilling with another solvent

� steam distillation with or without the presence of salt

� superheated vacuum steam distillation;

� exhaustive digestion with a poor solvent

� extraction in a continuous extraction apparatus;

� passage through a plug of a solid adsorbant;

� or acid base extraction (to remove acidic or basic impurities even when the major compound is neutral)

� treatment with derivatizing reagent to trap identified (or guessed impurities)

� charcoaling

� treatment with ionic exchange resins

� treatment with scavenger resins

Water and other solvent residues count as impurities that reduce the rate and completeness of crystallizations. Of course these solvents also play a part by affecting the actual crystalline substance that is obtained since they form solvates and hydrates. Thus adding water during the work up means that a thorough drying and pumping down needs to be done before crystallization. This in turn leads to the question whether the traditional pouring into water is always a good idea.

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