Separation of a Mixture of Ketones of Similar Structure Using Dissociative Extractio

 

KiloMentor blog articles normally are restricted to assessing and highlighting what the author has found useful and important during his career— applying organic chemistry, most significantly in the scale-up of reaction schemes for fine chemicals and pharmaceuticals.

This article is more speculative and requires laboratory experimentation for validation. It proposes a strategy for work-up, isolation, and purification which as far as the author is aware is not backed-up by experimental science. He suggests ways that the technology can build towards taking more into account making these ‘work-ups’ more dependably rugged by incorporating functionality into intermediates that enable reversible derivatizations that make useful partitioning of reaction mixture components between an aqueous and an immiscible organic phase possible.

Although this proposal is speculative in that it is not experimentally verified, it is realistic to expect success based on what chemistry already teaches us. The basic idea is to modify a ‘neutral’ non-ionizable intermediate’s structure so that in a modified form it can be usefully partitioned between an aqueous and an organic phase.

A reader will more easily understand the general principle after examining the specific application to the ketone functionalized as exemplified below.

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Suppose you need to separate a synthetic reaction mixture of 7-phenyl-3-heptanone (A) and an iodinated product 7-(4’-iodophenyl)-3-heptanone (B). What methods might be applicable to retrieve the two compounds both separated and pure?  Distillation is the most immediate thought, but the boiling points will both be quite high and iodo compounds can be unstable at higher temperatures. Well— vacuum distillation or steam distillation… At an industrial scale vacuum distillation is limited in the actual reduction in pressure that can be dependably obtained. Steam distillation, even vacuum steam distillation, produces large volumes of waste water. It probably requires special equipment and the large maximum volume limits the throughput for the step.  Perhaps the uniodinated aromatic compound could be selectively sulfonated, then selectively extracted into dilute aqueous alkali, acidified, taken back into a water-immiscible organic solvent, concentrated, and desulfonated to give the original 7-phenyl-3-heptanone.

Thinking about this problem caused me to ask myself, “Why is this such a difficult problem?”  The reason I think is that both substances are neutral. What if the problem were to separate the two similarly related carboxylic acids? Although the two would have very close to the same pKas, the lipophilicity difference should make dissociative extraction between hydrocarbon and water phases using just enough base to neutralize the 7-phenyl-3-heptanone work well.

But to apply such a strategy an ionizable functionality is required in the molecules. The carboxylic acid provides this; the ketone does not!

Suppose then I try to provide one. Suppose the mixture is treated with enough R, S-tartaric acid to completely form ketals of both compounds. Each substance gives rise to a pair of optical isomers (two R/S pairs) but each racemic pair has a simple NMR because the ketal carbon is not a chiral center.

From the spectrum of the mixture of tartrate ketals, the proportions of each can be closely estimated. Now, just as in the simple carboxylic acid model, the pKas will not substantially differ but the lipophilicity difference between them will be substantial. Dissociative extraction between hydrocarbon and water phases using just enough base to neutralize the ketal tartrate derived from 7-phenyl-3-heptanone should work well. The uniodinated compound should end up substantially in the aqueous phase as the monosodium salt. The brominated compound should be retained in the hydrocarbon layer.

Note that neither the R- tartaric acid nor the S-tartaric acid will work in this method because then each of the compounds will give two ketals creating two sets of diastereomers in the mixture.