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. 

The Quinoline Tag to enable Phase Switching Isolations in Chemical Synthesis Process Development

 

The KiloMentor blog is dedicated to transmitting useful ‘tricks of the trade’ to the synthetic organic chemists who do the actual laboratory experimentation that creates chemical processes that are intended to be performed at-scale.

The KiloMentor blog therefore particularly highlights the importance of the workup of chemical reactions with their separations, isolations, and purification operations since it is these that consume the most time in the plant setting. It is also these methods which are most difficult to uncover by electronic data base searching.

In 1999, Hélène Perrier and Marc Labelle published a paper titled Liquid-Phase Synthesis with Solid-Phase Workup: Application to Multistep and Combinatorial Syntheses, J. Org. Chem. 1999, 64, 2110-2113 which was designed to make the workup of every step of a reaction sequence a simple filtration until the tagged target molecule was completely assembled whereupon the facilitating functional ‘tag’ can be cleaved off to leave the target molecule itself in practically pure form.

Another way of looking at what they are enabling is an alcohol-protecting group that so long as it remains in process intermediates makes them simple to isolate and purify from their reactions. In the terminology of Dennis P. Curran, it makes phase switching of these intermediates possible. In the terminology of Jun-ichi Yoshida, it introduces tags on these intermediates.

These chemists discovered that if an alcohol functionality in a starting material was made into the ester of 3-quinolinecarboxylic acid and other functionalities in the alcohol used to elaborate some larger assemblage all the intermediates in that sequence could be easily isolated and purified by first precipitating them from the reaction solvents as insoluble sulphuric acid salts and then reconstituting the free quinoline by neutralizing the salts and extracting the intermediate back into the solvent for the next reaction in the desired synthetic route.

The salts with sulphuric acid were found to be the choice that most dependably crystallized from a wide range of solvents. The original paper should be consulted for the experimental details.

Finally, the 3-quinolinecarboxylic acid could be recovered at the end of their test sequences and was sufficiently pure to be reused!

Although these authors don’t go that far, KiloMentor concludes that protection groups generally, besides protecting functional groups, should be selected to promote the isolation and purification of the intermediates into which they are introduced.

Methyl Ethyl Ketone (2-Butanone) as a Uniquely Useful Solvent

Anhydrous Hydrochloride and Hydrobromide Salts

The reason that I write the blog KiloMentor is to pass along whatever ‘tricks of the trade’ I have picked up in my career doing organic synthesis. While I was Research Director and President at QuébéPharma Recherche Inc. in Montreal Canada, a consultant, Lars Svendsen, said in an aside to our discussions that methylethylketone (MEK, 2-butanone) was a particularly good solvent for making a hydrochloride or hydrobromide salt because the water could be removed by heating to distill the water azeotrope. 

The azeotrope between MEK and water boils at 73.4℃ and has 12% water in the distillate. Since MEK itself boils at 79.6℃ the temperature gap between it and the azeotrope will be sufficient that a distillation column will not be required to take off fairly uncontaminated azeotrope.

It is not clear whether this process of making the solution anhydrous is performed before or after adding the basic group that is to be formed into a salt. It would logically be more likely that the heating to distill the azeotropic composition would be done after the neutralization. Distilling first would likely drive off some of the volatile hydrogen chloride gas and could cause some degradation of the ketone solvent.

MEK/Water Liquid-Liquid Extractions

KiloMentor is always on the lookout for mixtures of two liquids that are not completely miscible but could partition similar solutes usefully between the two layers. This would make liquid-liquid partitioning a practicable separation method.  A mixture of methyl ethyl ketone and water might do that. I calculate that at 25℃, water will dissolve 18.2% of its weight of MEK while a MEK phase will dissolve 12.5% of its weight of water.

Other Useful Methyl Ethyl Ketone Azeotropes

Besides its behavior with water, MEK  forms lower boiling azeotropes with ethyl acetate (77℃/18% in distillate) and cyclohexane (71.8℃/40.0% in distillate).