In the opinion of Kilomentor, the most under appreciated and under utilized method of separation that can be used in chemical process development is dissociation extraction. Dissociation extraction crystallization and dissociation leaching are two powerful variations on this same method. Fractional crystallization, which is hardly every used, in practice is frequently mentioned while this method, which is more frequently applicable, is effectively unknown.

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Dissociation Extraction

Dissociation extraction is a separation method that can be applied to a mixture of two (or more) chemical substances that are each ionizable in solution and have at least a small difference in pKas. Following the method, the mixture is partitioned between two liquid phases and then partially neutralized with a reagent so that the partition coefficients of the components of the mixture are further favorably enhanced. Most optimally the moles of neutralizing agent are equal to equal to the moles of the more reactive component of the binary mixture. This is best made clear with an example.

A mixture of 3- and 4- picoline (3-methyl pyridine and 4-methylpyridine) cannot be separated by distillation because the boiling points differ by only a fraction of a degree and have similar solubilities in common solvents. Their dissociation constants are 4.54 and 10.62 X 10^-9 respectively. Contacting it with a stoichiometric deficiency of an aqueous acid solution separates a mixture. The Picolines compete for the available acid, which preferentially reacts with the base with the higher dissociation constant to form a salt in the aqueous phase. The weaker base remains unassociated and is preferentially extracted by an organic solvent. What is not obvious at all is that the separation efficiency is a sensitive function of the organic solvent used with the aqueous acid. It is quite remarkable how a small difference in pKas and an optimized selection of an organic solvent can produce dramatic separations.

This technique is equally applicable to the concentration of a trace impurity in a substantially pure single substance. The differences between two molecules may be quite remote from the acidic or basic functional group upon which the dissociation depends so long as the difference can be transmitted electronically or sterically to the ionizing function. Since pharmaceutical substances are most often salt forming species, this technique provides a powerful method to identify an impurity with only minor differences from the drug substance and a close retention time by HPLC.

Selection of the Solvent for Dissociation Extraction

Organic solvents can be classified according to their ability to interact with carboxylic, phenolic and basic substances. Aliphatic hydrocarbons, such as heptane, cyclohexane, etc. represent the inert solvents with negligible tendency to interact with CO2H, OH and NH2 groups. These are followed by aromatic hydrocarbons, halogenated hydrocarbons, ethers and ketones, esters and finally alcohols, in the order of increasing tendency to interact with the solutes. The knowledge of these particular interactions can help in the selection of the proper organic solvent partner.

Gaikar and Sharma formulated guidelines on the basis of the thermodynamic considerations of solute-solvent interactions, solute-solute interactions and steric hindrance to functional group solvation as follows:

(i) Use an inert solvent if the stronger component has a relatively free aquophilic ionizing group and

(ii) Use a polar solvent if the weaker component has a relatively free aquophilic group.

Examples of polar solvent s that associate well with free ionizable groups are di-butyl ether and n-octanol.

Gaikar and Sharma [V.G. Gaikar and M.M. Sharma, Separations through Reactions and Other Novel Strategies, Separation and Purification Methods, 18(2) 111 (1989).] as chemical engineers devote a considerable part of their treatment to means for reducing the cost of Dissociative Extraction. If this turns out to be important in your application refere to the original article. For high value items like pharmaceuticals and pharmaceutical intermediates the cost of the chemicals required for dissociative extraction are very reasonable for the simplicity, power and ruggedness that the method promises.

Dissociative Leaching

Sometimes the two phases do not have to be both liquids. If the more reactive species forms a soluble a more water soluble form upon reacting with the insufficiency of reagent while the less reactive constituent remains insoluble in the water then excellent separations can be achieved simply by leaching the crude slid mixture with water and the less than stoichiometric reagent, filtering the residual solid from the aqueous liquid and isolating the more reactive component from the aqueous phase and the less reactive material in the filtrand. Thus for example the separation of o-chlorobenzoic acid/ p-chlorobenzoic acids was carried out by suspending the solid mixture in an aqueous solution containing an appropriate amount of sodium hydroxide. The separation factor was as high as 26. At 65 C the o-isomer was leached out completely from a mixture initially containing 40% o-isomer. Higher solubility of o-isomer coupled with a lower pKa than p-isomer is responsible for such excellent separation.

Dissociative Extractive Crystallization?

There is a technique with the above designation in the literature but from what I can see it is a misnomer. In the technique a binary mixture is treated in a single liquid phase with an insufficiency of a salt forming reagent and one of the components crystallizes or precipitates out as a salt. To me this is simply fractional crystallization and depends not upon the pKas of the components or of the relative solubilities between two liquid phases but on the insolubility of a particular salt in a particular liquid. Because this cannot be predicted, the method is essentially empirical and has no power. The method succeeds in the unlikely condition that the required insolubility results and fails utterly in all other cases. Dissociative extraction itself should always succeed to some extent if there is a difference in pKas (which is qualitatively predictable) and should succeed well if one chooses the solvent pairs wisely (also somewhat predictable).

The Effect and Utility of the Hydrolysis of Weak Salts

In an old chemistry laboratory text written by Avery Adrian Morton, [Laboratory Technique in Organic Chemistry, McGraw-Hill Book Company, inc. New York and London 1938 ] on pg. 196-197 the effect of changes in the organic solvent upon the extraction of a portion of thymol in water, which has been exactly neutralized with sodium hydroxide with one portion of the organic solvent. The amounts of thymol extracted into the organic phase were reported to be ether 88%; benzene 38%; crbon tetrachloride 25%; and petroleum ether 22%. Morton explains that these results arise from the partial hydrolysis of the phenolate sodium back into phenol and sodium hydroxide with the simultaneous removal of the free phenol to the organic layer.

In another interesting table he shows that as the structure of the sodium phenolate becomes more hydrophobic and particularly as the steric hindrance to selective hydrogen bond solvation of the phenol becomes greater, the percentage extracted into ether increases. Thus for phenol it is just 7.5% extracted; for o-cresol 20.8% for p-cresol 13.3%for o-propylphenol 68.5%; for p-propylphenol 28.7%; for di o-allylphenol 91.7% etc.

As the excess of base over the stoichiometric requirement increases, the tendency for solvolysis extraction is suppressed.

Taken with the previous teaching concerning dissociative extraction, this understanding of the partial solvolysis can help us decide how much of the non stoichiometric amount of neutralization we need to do for an optimal result. For example if we are using a strong solvent like amyl alcohol in a dissociative extraction there may be a need to use more than an amount for the neutralization of the more reactive component if we want to hold it in the aqueous layer against the power of the hydrolysis effect.

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